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Doctoral Thesis

Asymmetric C - F bond formation catalyzed by ruthenium PNNPcomplexes

Author(s): Althaus, Martin

Publication Date: 2008

Permanent Link: https://doi.org/10.3929/ethz-a-005645106

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Diss. ETH No. 17673

Asymmetric C—F Bond Formation

Catalyzed by Ruthenium PNNP Complexes

A dissertation submitted to

ETH ZURICH

for the degree of

DOCTOR OF SCIENCES

presented by

MARTIN ALTHAUS

Dipl. Chem. ETH

born on October 10th, 1979

citizen of Lauperswil BE

accepted on the recommendation of

Prof. Dr. Antonio Togni, examiner

Prof. Dr. Antonio Mezzetti, co-examiner

Prof. Dr. E. Peter Kündig, co-examiner

Prof. Dr. Paul S. Pregosin, co-examiner

Zurich 2008

dedicated to

Jolanda and my parents

Problems worthy of attack prove their worth by fighting back.

Paul Erdõs (1913 – 1996)

The important thing is not to stop questioning.

Albert Einstein (1879 – 1955)

i

Acknowledgments

I am grateful to all the people who have helped and supported me during the past years

and during the completion of this thesis:

I thank Prof. Dr. Antonio Togni for giving me the opportunity to carry out my Ph.D. in

his group, and for allowing me much freedom within my research. It was a delight to work in

the productive, friendly, and relaxed atmosphere he is encouraging.

Many thanks to Prof. Dr. Antonio Mezzetti for his excellent mentoring, his enthusiasm,

and encouragement throughout my entire Ph.D. I profited a lot from our countless scientific

discussions that helped to improve my chemical knowledge and led to many essential

advances of our projects: It was a pleasure to work with you!

Thanks are given to Prof. Dr. E. Peter Kündig and Prof. Dr. Paul S. Pregosin for kindly

acting as co-examiners and for their valuable inputs.

I thank my semester project students Christian Eberle and Alex Huber for their

dedicated and skillful experimental work.

I am thankful to Dr. Heinz Rüegger and Serena Filipuzzi for all the practical and

theoretical support about NMR techniques.

I thank all members of the Togni group (current and former) for the great time we

shared and for the assistance everyone gave me during my Ph.D. The nice working

atmosphere and all the fun we had (inside and outside the lab) make this time unforgettable.

In particular, I would like to thank:

Claus Becker for introducing me to the secrets of fluorine chemistry, and for letting me

continue the project about β-keto ester fluorination. I guess neither of us had expected which

surprising twists and turns this project would take…

ii

Dominik Huber for his assistance with many instruments and techniques. Furthermore, I

very much enjoyed our numerous funny coffee breaks, Pizza dinners, cinema trips, etc.

Kyrill Stanek for our friendship and for the continuous, productive discussions about the

ups and downs of our projects. Apart from daily business, the conference in Prague (“lecker

Bierschen?”) and the “Jass”-evenings were definitely among the highlights of our shared time

in the Togni group.

I am thankful to Mihai Viciu for all the helpful discussions about the differences and

similarities between the Ru/PNNP- and the Ti/TADDOLate-catalyzed β-keto ester

fluorinations.

I am indebted to Sebastian Gischig, Francesco Camponovo, and Pietro Butti who

thoroughly measured and solved the X-ray crystal structures.

I thank Cristina Bonaccorsi and Francesco Santoro for the fruitful collaboration about

Ru/PNNP complexes of β-keto esters and α-acyl lactames.

Thanks are given to my labmates, namely Isabelle Haller, Cristina Bonaccorsi, Pietro

Butti, Marco Ranocchiari, and Aline Sondenecker: I enjoyed working with you in H228!

I thank the secretary of our group, Andrea Sachs, for taking care of administrative tasks.

The services of the chemistry department at ETH (the “D floor”) played an important

part in the daily life in the lab. I thank the employees of the “Schalter”, glass washing,

mechanical workshop, gas/solvent supply, and waste disposal for the friendly collaboration.

Meiner Familie danke ich von Herzen für die wertvolle Unterstützung über all die

Jahre, für unser tolles Verhältnis und das Interesse an meiner Arbeit.

Jolanda, Du bist der Mensch, der mich trägt und beflügelt: Tausend Dank für alles!

iii

Publications

Part of the work described in this thesis has been published:

Bonaccorsi, C.; Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. ”Chiral Ru/PNNP

Complexes in Catalytic and Stoichiometric Electrophilic O- and F-Atom Transfer to 1,3-

Dicarbonyl Compounds”, Pure Appl. Chem. 2006, 78, 249 – 254.

Althaus, M.; Bonaccorsi, C.; Mezzetti, A.; Santoro, F. ”Chiral Ruthenium PNNP Complexes

of Non-Enolized 1,3-Dicarbonyl Compounds: Acidity and Involvement in Asymmetric

Michael Addition”, Organometallics 2006, 25, 3108 – 3110.

Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. “Ruthenium-Catalyzed Asymmetric

Electrophilic Fluorination of 1,3-Dicarbonyl Compounds”, Organometallics 2007, 26, 5902 –

5911.

Santoro, F.; Althaus, M.; Bonaccorsi, C.; Gischig, S.; Mezzetti, A. “Acidic Ruthenium PNNP

Complexes of Non-Enolized 1,3-Dicarbonyl Compounds as Catalysts for Asymmetric

Michael Addition”, submitted to Organometallics.

Poster presentations at international conferences:

“Ruthenium PNNP Complexes as Catalysts for Asymmetric Nucleophilic Fluorination

Reactions”, 13th IUPAC Symposium on Organometallic Chemistry Directed Towards Organic

Synthesis (OMCOS 13), Geneva, Switzerland, July 17th – 21st, 2005.

“Asymmetric α-Fluorination of α-Aryl-α-Alkyl Acetaldehydes Catalyzed by Ruthenium

PNNP Complexes”, 18th International Symposium on Fluorine Chemistry (ISFC 18), Bremen,

Germany, July 30th – August 4th, 2006.

“Catalytic Enantioselective Fluorinations with Ru/PNNP Complexes”, 15th European

Symposium on Fluorine Chemistry (ESFC 15), Prague, Czech Republic, July 15th – 20th,

2007.

v

Table of Contents

Abstract ................................................................................................................................ xi

Zusammenfassung.............................................................................................................xiii

1 General Introduction ................................................................................... 1

1.1 Fluorine: An Exceptional Halogen ............................................................................ 1

1.2 Electronic and Stereoelectronic Effects .................................................................... 3

1.3 Organofluorine Compounds in Nature ..................................................................... 5

1.3.1 Biosynthesis of Organofluorine Compounds ..................................................... 7

1.4 Applications of Organofluorine Compounds ........................................................... 9

1.4.1 Perfluorinated Compounds................................................................................. 9

1.4.2 Fluorinated Bioactive Compounds................................................................... 11

1.4.3 Bioactive Compounds Containing a C—F Stereocenter.................................. 13

1.5 Objectives and Structure of this Thesis .................................................................. 15

1.6 References Chapter 1................................................................................................ 16

2 Ruthenium/PNNP Complexes Containing β-Keto Ester Ligands ......... 19

2.1 Introduction............................................................................................................... 19

2.1.1 Ruthenium PNNP Complexes.......................................................................... 19 2.1.1.1 Salen Ligands ...................................................................................................................... 19 2.1.1.2 PNNP Ligands and Complexes............................................................................................ 21 2.1.1.3 Applications of Ru/PNNP Catalysts in our Group............................................................... 23

2.1.2 Stereochemistry of Octahedral PNNP Complexes........................................... 27

2.1.3 1,3-Dicarbonyl Compounds as Ligands ........................................................... 29 2.1.3.1 General Aspects ................................................................................................................... 29 2.1.3.2 Complexes of Monoanionic 1,3-Dicarbonyl Compounds ................................................... 31 2.1.3.3 Complexes of Neutral 1,3-Dicarbonyl Compounds............................................................. 32

2.2 Results and Discussion.............................................................................................. 36

2.2.1 Adduct Complexes: Initial Attempts................................................................ 36

2.2.2 Synthesis and Characterisation of Dicarbonyl Complex 2a............................. 37

2.2.3 Synthesis and Characterisation of Enolato Complex 3a .................................. 40 2.2.3.1 X-Ray Crystal Structure of 3a ............................................................................................. 42

vi

2.2.4 Structural Comparison of 2a and 3a by 1H,1H-NOESY NMR Spectroscopy.. 43

2.2.5 A Ru/PNNP Complex with a Non-Ionized β-Keto Acid Ligand..................... 45 2.2.5.1 Literature Examples of Carboxylate and Carboxylic Acid Ligands .................................... 47

2.2.6 Determination of the pKa of 2a ........................................................................ 48 2.2.6.1 pKa Measurements with Triphenylphosphine as Reference................................................. 48 2.2.6.2 pKa Measurements with Diphenylamine as Reference ........................................................ 50 2.2.6.3 pKa Estimations with Other References............................................................................... 51

2.2.7 Dicarbonyl and Enolato Complexes of an Acyl Lactame ................................ 52

2.3 Conclusions and Perspectives .................................................................................. 54

2.4 References Chapter 2................................................................................................ 55

3 Ruthenium/PNNP-Catalyzed Fluorination of β-Keto Esters................. 61

3.1 Introduction............................................................................................................... 61

3.1.1 Reagents for Electrophilic Fluorination ........................................................... 61

3.1.2 Stoichiometric Asymmetric Fluorinations ....................................................... 63 3.1.2.1 Diastereoselective Fluorinations Using Chiral Auxiliaries.................................................. 63 3.1.2.2 Chiral N—F Reagents.......................................................................................................... 64

3.1.3 Metal-Catalyzed Enantioselective Electrophilic Fluorinations........................ 65 3.1.3.1 Titanium(IV) TADDOLate Catalyst.................................................................................... 65 3.1.3.2 Palladium(II) Catalysts ........................................................................................................ 67 3.1.3.3 Copper(II), Nickel(II), and Zinc(II) Catalysts ..................................................................... 69 3.1.3.4 Aluminium(III), Scandium(III), and Nickel(II) Catalysts.................................................... 71 3.1.3.5 Ruthenium(II) PNNP Catalyst ............................................................................................. 71

3.2 Results and Discussion.............................................................................................. 73

3.2.1 Absolute Configuration of a Fluorinated Catalysis Product ............................ 73 3.2.1.1 X-Ray Crystal Structure of the Camphanic Acid Derivative 18 .......................................... 75

3.2.2 Enantiomeric Excess vs. Conversion ............................................................... 76

3.2.3 Attempted Ru(II)-Ru(III) Oxidation of β-Keto Ester Complexes ................... 77 3.2.3.1 Attempted Oxidation of the Ruthenium(II) Bis-Ether Complex 6....................................... 78 3.2.3.2 Attempted Oxidation of the Ruthenium(II) Enolato Complex 3a........................................ 79 3.2.3.3 Dehydrogenation of 3a by Ph3C+......................................................................................... 80 3.2.3.4 X-Ray Crystal Structure of Complex 19.............................................................................. 82

3.2.4 Catalytic Fluorination with Additives .............................................................. 84

3.2.5 Catalytic Fluorination in Solvent Mixtures...................................................... 85 3.2.5.1 Other Substrates in CH2Cl2/Et2O (1:1) Solvent Mixture ..................................................... 86

3.2.6 Catalysis Under Ether-Free Conditions............................................................ 87

vii

3.2.7 Stoichiometric Reactions of Dicarbonyl Complex 2a with NFSI.................... 89

3.2.8 Stoichiometric and Catalytic Fluorinations with Complex 3a ......................... 91

3.2.9 The Role of NHSI and NSI–............................................................................. 92 3.2.9.1 Ruthenium PNNP Complexes with Coordinated NSI-......................................................... 93 3.2.9.2 Acid-Base Reaction of 2a and 3a with NHSI and NSI- ....................................................... 94 3.2.9.3 Literature Examples of Bis(organosulfonyl)amide Complexes ........................................... 95

3.2.10 Coordination of Fluorinated β-Ketoester 5a to Ruthenium ............................. 96

3.2.11 Enantiomeric Excess vs. Conversion with Limiting NFSI .............................. 98

3.2.12 Stoichiometric Fluorination of 2a with β-Keto Ester Additives ...................... 99

3.2.13 Dynamic Exchange Between Complexes 2a and 3a...................................... 101

3.2.14 Rate Constants for the Exchange Between 2a and 3a.................................... 104 3.2.14.1 Notes on the Basicity of 1,3-Dicarbonyl Compounds................................................... 105

3.2.15 A Ru/PNNP Complex with a Coordinated β-Keto Ester Enol?..................... 108 3.2.15.1 Previous Observations .................................................................................................. 108 3.2.15.2 Hints from Low-Temperature 1H NMR and 1H NOESY Exchange Spectra ................ 109 3.2.15.3 Low-Temperature Protonation of 3a with HBF4·OEt2 .................................................. 110 3.2.15.4 Low-Temperature Protonation of 3a with (DL)-10-Camphorsulfonic Acid ................. 111

3.2.16 Mechanistic Suggestion for the Fluorination of 4a ........................................ 115

3.3 Conclusions and Perspectives ................................................................................ 117

3.4 References Chapter 3.............................................................................................. 118

4 Ruthenium/PNNP-Catalyzed Asymmetric α-Fluorination of 2-Alkylphenylacetaldehydes................................................................ 123

4.1 Introduction............................................................................................................. 123

4.1.1 Reagents for Nucleophilic Fluorination ......................................................... 123

4.1.2 Ru/PNNP-Catalyzed Nucleophilic Fluorination of Alkyl Halides ................ 125

4.1.3 Ring-Opening Hydrofluorination of Epoxides............................................... 127 4.1.3.1 General Considerations...................................................................................................... 127 4.1.3.2 Cr(III)-Mediated Asymmetric Hydrofluorination of meso- and rac-Epoxides.................. 128

4.1.4 Organocatalytic Asymmetric α-Fluorination of Aldehydes .......................... 129

4.1.5 Electrochemical α-Fluorination of Carbonyl Compounds............................. 133

4.1.5.1 α-(Arylthio)carbonyl Compounds ..................................................................................... 133 4.1.5.2 α-Aryl-Carbonyl Compounds............................................................................................ 134 4.1.5.3 Diastereoselective Electrochemical α-Fluorination of Carbonyl Compounds................... 135

4.2 Results and Discussion............................................................................................ 137

viii

4.2.1 Reactivity of Ru/PNNP Complexes Towards meso-Epoxides....................... 137

4.2.2 Ru/PNNP-Catalyzed Hydrofluorination of meso-Epoxides........................... 139 4.2.2.1 Reactions with [RuCl(PNNP)]+ (9) as Catalyst ................................................................. 139 4.2.2.2 Reactions with [Ru(OEt2)2(PNNP)]2+ (6) as Catalyst ........................................................ 140

4.2.3 Ruthenium/PNNP-Catalyzed Asymmetric α-Fluorination of 2-Phenylpropionaldehyde .......................................................................... 143

4.2.3.1 Initial Attempts with [Ru(OEt2)2(PNNP)]2+ (6) as Catalyst............................................... 143 4.2.3.2 Asymmetric α-Fluorination in 1,2-Dichloroethane as Solvent.......................................... 145 4.2.3.3 Variation of Solvents and PNNP Ligands ......................................................................... 148

4.2.4 Asymmetric α-Fluorination of Related Aldehydes........................................ 149 4.2.4.1 Syntheses of Substrates Containing Other Alkyl Groups .................................................. 149 4.2.4.2 Catalysis with Substrates Containing Other Alkyl Groups................................................ 150 4.2.4.3 Unactivated Substrates....................................................................................................... 151

4.2.5 Mechanistic Considerations and Literature Comparison ............................... 153

4.3 Conclusions and Perspectives ................................................................................ 156

4.4 References Chapter 4.............................................................................................. 157

5 Experimental Part .................................................................................... 161

5.1 General Procedures................................................................................................. 161

5.2 Chapter 2 ................................................................................................................. 164

5.2.1 Ru/PNNP Complexes..................................................................................... 164

5.2.2 Determination of the pKaaq of Complex 2a .................................................... 167

5.3 Chapter 3 ................................................................................................................. 169

5.3.1 Substrate Synthesis......................................................................................... 169

5.3.2 Catalytic Fluorination of β-Keto Esters ......................................................... 170

5.3.3 Stoichiometric Reactions with Complexes 2a and 3a.................................... 173

5.3.4 Derivatisation of Catalysis Product (R)-5a .................................................... 173

5.3.5 Attempted Synthesis of a Ruthenium(III) β-Keto Ester Complex................. 175

5.3.6 Ru/PNNP Complexes of the Reaction Products 5a and NSI−........................ 176

5.3.7 Determination of Exchange Rates in the Equilibrium 2a↔3a ...................... 178

5.3.8 Low-Temperature Protonation of 3a with CSA............................................. 179

5.4 Chapter 4 ................................................................................................................. 180

5.4.1 Reactivity of Ru/PNNP Complexes Towards meso-Epoxides....................... 180

5.4.2 Ring-Opening Hydrofluorination of meso-Epoxides ..................................... 180

ix

5.4.3 Synthesis of 2-Alkylphenylacetaldehydes ..................................................... 182

5.4.4 Ruthenium Catalyzed α-Fluorination of Aldehydes ...................................... 187

5.5 References Experimental Part ............................................................................... 189

6 Appendix ................................................................................................... 191

6.1 List of Abbreviations .............................................................................................. 191

6.2 List of Numbered Compounds............................................................................... 194

6.3 Crystallographic Data............................................................................................. 195

6.3.1 Enolato Complex 3a....................................................................................... 195

6.3.2 β-Keto Acid Complex 14 ............................................................................... 199

6.3.3 Camphanic Acid Ester 18............................................................................... 202

6.3.4 α-Alkylidene-β-keto Ester Complex 19......................................................... 204

6.4 Copper(II)-Mediated Oxidative α-Amination of 2-Phenylpropionaldehyde .... 207

6.4.1 Literature Examples for One-Electron Oxidation of Enolates ....................... 207

6.4.2 Attempted Radical Trapping of 2-Phenylpropionaldehyde (10a).................. 208

6.4.3 Screening of Reaction Conditions.................................................................. 210 6.4.3.1 Screening of Other Oxidants.............................................................................................. 211 6.4.3.2 Separation of Base and Amine........................................................................................... 212

6.4.4 Literature Comparison and Outlook............................................................... 213

6.4.5 Experimental Procedure ................................................................................. 214

6.4.6 References Appendix 6.4 ............................................................................... 215

6.5 Curriculum Vitae .................................................................................................... 217

xi

Abstract

Starting from the chiral ruthenium(II) complex [RuCl2(PNNP)] (1), the synthesis and

characterization of complexes 2a and 3a is described in Chapter 2 of this thesis. The

dicationic complex 2a contains the β-keto ester 2-tert-butoxycarbonylcyclopentanone (4a) in

its non-deprotonated form, which is a rare case among transition metal complexes. The

structure and configuration of 2a was established by multi-dimensional NMR spectroscopy in

solution, whereas its enolato analogue 3a was structurally characterized by X-ray

crystallography. The pseudo-aqueous pKa of 2a was determined to be ~2, approximately 8

orders of magnitude lower than free β-keto ester 4a.

O

OO

RuP

N

N

P

H

(PF6)2

2aO

OO

RuP

N

N

P

PF6

3a

pKa ~2

N N

PPPh2 Ph2

Ru

Cl

Cl1

S S

The topic of Chapter 3 are mechanistic investigations about the Ru/PNNP-catalyzed

asymmetric electrophilic fluorination of β-keto esters. Previous studies have shown that β-

keto esters 4 react with NFSI to the α-fluoro derivatives 5 in high yield and enantioselectivity

by using catalyst [Ru(OEt2)2(PNNP)](PF6)2 (6), prepared from 1 and (Et3O)PF6 (2 equiv).

R1

O

OR3

O

R2R1

∗

O

OR3

O

R2 F

6(10 mol%)

+ +(PhSO2)2NF (PhSO2)2NH

4 5NFSI NHSIup to 94% yield

93% ee The best-performing substrate 4a is fluorinated in 94% yield and with up to 93% ee.

Interestingly, the enantiomeric excess of 5a increases with ongoing conversion. Furthermore,

solvent mixtures of CH2Cl2 and ethers influence reaction rates and selectivities significantly

compared to pure CH2Cl2. To identify the catalytically active species, the involvement of

complexes 2a and 3a in the catalytic cycle was studied in detail. The stoichiometric

fluorination of 3a gives 5a with almost complete selectivity (97% ee), whereas the reaction of

2a with NFSI gives only 82% ee. In the presence of the weak bases 4a, 5a, or Et2O, an acid-

base equilibrium between complexes 2a and 3a was observed by NMR spectroscopy.

Measuring the exchange rates and equilibrium position revealed that the combined presence

xii

of the fluorinated β-keto ester 5a and Et2O promotes the deprotonation of 2a

thermodynamically and accelerates the exchange.

2a + B + BH+3ak1

k-1

B = 4a, 5a, Et2O

Based on these observations, a catalytic cycle for the Ru/PNNP-catalyzed fluorination is

proposed, in which the weakly basic 4a, 5a, and Et2O play a crucial role as proton-shuttles.

Chapter 4 outlines the development of a Ru/PNNP-catalyzed asymmetric α-fluorination

of aldehydes. The project started with the use of complex 6 as catalyst for the ring-opening

hydrofluorination of meso-epoxides (7). Cyclopentene oxide (7a) reacts with AgHF2 as HF-

source to the corresponding fluorohydrin 8a, but with low yield (11%) and enantioselectivity

(25% ee). Surprisingly, under identical conditions, cis-stilbene oxide (7d) rearranges to

diphenylacetaldehyde, which is fluorinated in the α-position by AgHF2.

OOH

F

6(20 mol%)

AgHF28a7a 11% yield

25% ee

O

Ph PhPh

H

O

Ph F

PhH

O

Ph7d

Prompted by this observation, the possibility of an asymmetric α-fluorination of

aldehydes was investigated. The screening of substrates, catalysts, fluorine sources, and

solvents is described. Thus, the five-coordinate cationic ruthenium complex 9SbF6 was found

to catalyze the fluorination of aldehyde 10a by AgHF2 in 24% yield and with 27% ee. This is

the first example of a transition metal-catalyzed enantioselective α-fluorination of aldehydes,

as all reported reactions involve organocatalysis.

CH3

H

O∗

H

O

H3C F

9SbF6(5 mol%)

AgHF2

24% yield27% ee

10a 11a

RuP

N

N

P

(SbF6)

Cl

+

9SbF6

1AgSbF6

-AgCl

Currently, the scope of substrates is limited to 2-alkylphenylacetaldehydes. Possible

reaction mechanisms are discussed and compared with reported ones. The present results

suggest the oxidation of the aldehyde to an α-carbonyl cation (umpolung) and subsequent

trapping by fluoride.

xiii

Zusammenfassung

Ausgehend vom chiralen Ruthenium(II)komplex [RuCl2(PNNP)] (1), sind die Synthese

und Charakterisierung der Komplexe 2a und 3a in Kapitel 2 dieser Arbeit beschrieben. Der

dikationische Komplex 2a enthält den β-Ketoester 2-tert-Butoxycarbonyl Cyclopentanon (4a)

in dessen nicht-deprotonierten Form, was bei Übergangsmetallkomplexen selten vorkommt.

Die Struktur und Konfiguration von 2a wurde mittels mehrdimensionaler NMR

Spektroskopie in Lösung bestimmt, währenddem der analoge Enolatokomplex 3a durch

Röntgenstrukturanalyse charakterisiert werden konnte. Für 2a wurde ein pKa-Wert von ~2 auf

der pseudo-wässrigen Skala ermittelt, was einer Verminderung von ungefähr 8

Grössenordnungen gegenüber freiem β-Ketoester 4a entspricht.

O

OO

RuP

N

N

P

H

(PF6)2

2aO

OO

RuP

N

N

P

PF6

3a

pKa ~2

N N

PPPh2 Ph2

Ru

Cl

Cl1

S S

Das Thema von Kapitel 3 sind mechanistische Untersuchungen über die Ru/PNNP-

katalysierte asymmetrische elektrophile Fluorierung von β-Ketoestern. Frühere Arbeiten

haben gezeigt, dass β-Ketoester (4) mit NFSI in hoher Ausbeute und Enantioselektivität zu

den entsprechenden α-fluorierten Derivaten 5 reagieren. Als Katalysator dient dabei

[Ru(OEt2)2(PNNP)](PF6)2 (6), welcher aus 1 und (Et3O)PF6 (2 Äquiv.) hergestellt wird.

R1

O

OR3

O

R2R1

∗

O

OR3

O

R2 F

6(10 mol%)

+ +(PhSO2)2NF (PhSO2)2NH

4 5NFSI NHSIbis zu 94% Ausbeutebis zu 93% ee

Das erfolgreichste Substrat 4a wird in 94% Ausbeute und mit bis zu 93% ee fluoriert.

Interessanterweise steigt der Enantiomerenüberschuss von 5a im Laufe der Reaktion an. Des

Weiteren beeinflusst der Zusatz von Ethern zum Lösungsmittel CH2Cl2 die Reaktions-

geschwindigkeit und Selektivität stark. Um die katalytisch aktiven Spezies zu identifizieren,

wurde die Beteiligung der Komplexe 2a und 3a im Katalysezyklus untersucht. Die

stöchiometrische Fluorierung von 3a erzeugt 5a mit fast vollständiger Selektivität (97% ee),

aber mit nur 82% ee ausgehend von 2a. Ein Säure-Base-Gleichgewicht zwischen 2a und 3a

wurde in Anwesenheit der schwachen Basen 4a, 5a und Et2O NMR-spektroskopisch

xiv

beobachtet. Durch Messung der Geschwindigkeits- und Gleichgewichtskonstanten wurde

ersichtlich, dass die gleichzeitige Anwesenheit des fluorierten β-Ketoesters 5a und Et2O die

Deprotonierung von 2a thermodynamisch begünstigt, und den Austausch beschleunigt.

2a + B + BH+3ak1

k-1

B = 4a, 5a, Et2O

Davon ausgehend wird ein Katalysezyklus vorgeschlagen, in welchem die schwach-

basischen 4a, 5a und Et2O eine wichtige Rolle als Protonentransfer-Reagenzien spielen.

Kapitel 4 beschreibt die Entwicklung einer Ru/PNNP-katalysierten asymmetrischen α-

Fluorierung von Aldehyden. Ausgangspunkt dieses Projekts war die Anwendung von

Komplex 6 als Katalysator für eine ringöffnende Hydrofluorierung von meso-Epoxiden (7).

Cyclopentenoxid (7a) reagiert dabei mit AgHF2 zum entsprechenden Fluorhydrin 8a,

wenngleich in tiefer Ausbeute (11%) und Enantioselektivität (25% ee). Hingegen wird cis-

Stilbenoxid (7d) unter analogen Bedingungen zu Diphenylacetaldehyd umgelagert, welcher

anschliessend durch AgHF2 in α-Stellung fluoriert wird.

OOH

F

6(20 mol%)

AgHF28a7a 11% Ausbeute

25% ee

O

Ph PhPh

H

O

Ph F

PhH

O

Ph7d

Von dieser Beobachtung ausgehend wurde die Möglichkeit einer asymmetrischen α-

Fluorierung von Aldehyden untersucht. Verschiedene Substrate, Katalysatoren, Fluorquellen

und Lösungsmittel wurden geprüft. Der fünffach koordinierte, kationische Komplex 9SbF6

katalysiert die α-Fluorierung des Aldehyds 10a in 24% Ausbeute und mit 27% ee. Diese

Reaktion ist somit das erste Beispiel einer Übergangsmetall-katalysierten enantioselektiven α-

Fluorierung von Aldehyden, da alle in der Literatur beschriebenen Reaktionen

organokatalytisch durchgeführt wurden.

CH3

H

O*

H

O

H3C F

9SbF6(5 mol%)

AgHF2

24% Ausbeute27% ee

10a 11a

RuP

N

N

P

(SbF6)

Cl

+

9SbF6

1AgSbF6

-AgCl

Der Anwendungsbereich ist momentan auf 2-Alkyl-Phenylacetaldehyde beschränkt.

Mögliche Reaktionsmechanismen werden diskutiert und mit Literaturberichten verglichen.

Unsere aktuellen Resultate deuten auf eine Oxidation des Aldehyds zu einem α-

Carbonylkation hin (Umpolung), welches danach von einem Fluoridion abgefangen wird.

1 General Introduction

1


The aim of this general introduction is to highlight the exceptional and sometimes even

exotic role of fluorine in organic chemistry. Its unique properties allocate a special status to

fluorine in the periodic table as a whole, and in the row of the halogens in particular. In this

context, Manfred Schlosser wrote adoringly about fluorine: “As a substituent, it is rarely

boring, always good for a surprise, but often completely unpredictable.”1

In the first sections of this chapter, some important physical properties of the fluorine

atom, the fluoride anion, and the carbon-fluorine bond will be addressed. These properties are

the basis for an understanding of the diverse effects exerted by fluorine on an organic

molecule and its transformations.2,3,4 Furthermore, this chapter sheds light on the fascinating

niche of naturally occuring organofluorine compounds and their biosynthesis.

Finally, several applications of fluoroorganic molecules will be discussed, showing their

enormous impact on our lives today and their bright perspectives for the future. The emerging

field of bioactive compounds with a C—F stereocenter underlines the relevance of the topic

of this thesis: The development and understanding of catalytic methods for enantioselective

carbon-fluorine bond formation.

1.1 Fluorine: An Exceptional Halogen

For the understanding of the exceptional properties of organofluorine compounds, it is

helpful to compare some physical data of fluorine with the other halogens, as summarized in

Table 1.1.

The carbon-fluorine bond-length (1.38 Å on average) is considerably shorter than the

C—X bonds of the other halogens, and it is the second shortest single bond to carbon after

C—H (1.09 Å). The C—F bond is much stronger in energy than the C—H bond (bond

dissociation energies BDE of 116 and 98 kcal/mol, respectively) and the other carbon-halogen

bonds. This extreme stability of the C—F bond is a consequence of an excellent geometrical

match between the 2s and 2p orbitals of fluorine and the corresponding orbitals of carbon.2

The size of a fluorine atom (van-der-Waals radius rvdW = 1.47 Å) is very small

compared to the other halogens. Interestingly, the difference in size between fluorine and


2

chlorine is even bigger than the difference between chlorine and iodine. The van-der-Waals

radius of a fluorine substituent is very similar to the one of a hydroxy group (1.52 Å).

Replacing a hydroxy with a fluorine substituent is therefore a common method in medicinal

chemistry (see 1.4.2).

Table 1.1. Physical data for halogens X and their C—X bonds.a

X dC—X (Å)

BDE(C−X) (kcal/mol)

rvdW (Å)

EN (Pauling)

EA (kcal/mol)

αV (Å−3)

ΔhydH0 (X−) (kcal/mol)

F 1.38 116 1.47 3.98 79.5 0.56 −130.6

Cl 1.77 77 1.75 3.16 84.5 2.18 −95.0

Br 1.94 64 1.85 2.96 78.7 3.05 −87.5

I 2.13 51 1.98 2.66 71.5 4.7 −77.8 a dC—X: Bond length, from Ref. [2]; BDE(C−X): Bond dissociation energy, from Ref. [2]; rvdW: Van-der-Waals radius, from Ref. [2]; EN: Electronegativity; EA: Electron affinity of X·, from Ref [5]; αV: Atom polarizability parameter in volume units, from Ref [8]; ΔhydH0: Hydration enthalpy of the anions X−, from Ref. [9].

Fluorine is the most electronegative of all elements, with an EN value of 3.98 on the

Pauling scale. The electronegativities decrease continuously by going down the row of the

halogens. However, the electron affinities (EA) of the halogen atoms draw a different picture.

The electron affinity for the fluorine atom (79.5 kcal/mol) is very similar to the one for

bromine (78.7 kcal/mol), and the maximum of 84.5 kcal/mol is obtained for chlorine.5 On first

sight, it seems odd that the trends in electronegativities and electron affinities are nonparallel

for the halogens. It must be considered, though, that the uptake of an electron produces an ion

with an exceptionally high charge density in the case of fluorine (small van-der-Waals radius)

compared to the other halogens. This increases the energy barrier for the uptake of an electron

and thus decreases the electron affinity. In a phenomenological way, this property of fluorine

directly translates into the outstanding hardness of the fluoride ion with respect to the other

halides. The absolute hardness parameters according to Parr and Pearson are (in eV): η 7.0

(F−), 4.7 (Cl−), 4.2 (Br−), 3.7 (I−).6 However, it must be considered that hardness values for

anions are approximations, because electron affinities of anions cannot be measured.7

The hardness is also expressed by the atom polarizability parameter αV.8 Fluorine has a

very small αV value of 0.56, which means that it is barely polarizable and thus very hard. The

values for the other halogens range from 2.18 for chlorine up to 4.7 for iodine, confirming

their softer nature as compared to fluorine.


3

A further interesting value is the enthalpy of hydration (ΔhydH0) for the halide anions.

There is an enormous difference between fluoride and chloride, with values of −130.6 and

−95.0 kcal/mol, respectively.9 The differences going from chloride to bromide and iodide are

rather small. Obviously, the fluoride ion experiences a far better stabilization by solvation

with water molecules than the other halides, which is again explained by its high charge-

density. This constitutes a significant problem for reactions with fluoride in aqueous media,

since it carries a huge shell of coordinated water molecules. Consequently, fluoride is a bad

nucleophile in water, because the energy barrier for desolvation prior to nucleophilic attack is

very high. To overcome this problem, nucleophilic fluorinations are often carried out with

fluoride salts of large, non-coordinating cations in aprotic solvents. They are much more

reactive than solvated fluoride, and are sometimes referred to as “naked fluoride” sources.10

Examples are tetraalkylammonium fluorides, cobaltocenium fluoride,11 or phosphazenium

fluorides.12

1.2 Electronic and Stereoelectronic Effects

Fluorine, as the most electronegative element, acts as an inductively electron-

withdrawing substituent in organic molecules (−Iσ). Carbon-fluorine bonds are therefore

polarized with a positive partial charge on carbon and a negative partial charge on fluorine

(Figure 1.1). However, the lone-pairs on the fluorine atom can donate electron-density into an

attached π-system (+Iπ), leading to a partially negatively charged β-carbon and a partially

positively charged α-carbon. Taken together, fluorine is a σ-acceptor, π-donor substituent.3,4

C Fδ+ δ- C C

F

δ+δ- C CF

-Iσσ-acceptor

+Iππ-donor

Fluorine:

Perfluoroalkyl: C CF3δ+ δ-

-Iσσ-acceptor

C CCF3

δ+δ-

C CCF2

-Iππ-acceptor

F

Figure 1.1. Electronic effects of fluorine and perfluoroalkyl substituents.


4

The situation is different with perfluoroalkyl substituents, e.g. the CF3 group. They are

always electron-withdrawing, irrespective whether they are attached to sp3- or sp2-carbons

(−Iσ and −Iπ).

The effect of a fluorine substituent on nearby cationic or anionic centers can be derived

from its properties as σ-acceptor and π-donor. Despite the inductive electron-withdrawing

effect, a carbocation in α-position to fluorine is stabilized by π-conjugation of the fluorine

lone-pairs into the empty carbon p-orbital (Figure 1.2, top left). On the other hand, a β-

carbocation is destabilized due to the −Iσ effect, which generates a partial positive charge

adjacent to a cationic center (Figure 1.2, top right).

Cations: C F C Cδ+

δ-F

Anions: CF

C F C C

F

α-carbocationstabilization

β-carbocationdestabilization

α-carbaniondestabilization

β-carbanionstabilization

σ∗C-F

Figure 1.2. Effects of fluorine on α- and β-carbocations and carbanions.

The effects are reversed with an anionic center in α- or β-position. A carbanion in α-

position to fluorine experiences a strong lone-pair – lone-pair repulsion and is thus

destabilized (Figure 1.2, bottom left). A β-carbanion is stabilized by negative

hyperconjugation, that is, by interaction of the lone-pair electrons on carbon with the anti-

bonding orbital of the C—F bond (n→σ*C−F). This interaction can also be formulated as a

double-bond/no-bond resonance, in which a fluoride anion is eliminated (Figure 1.2, bottom

right).13

The preferred conformation of a fluorinated molecule can be determined by

stereoelectronic effects of fluorine substituents. It was found that the gauche conformation in

some 1,2-diheterosubstituted ethanes is preferred over the anti conformation.14 1,2-

Difluoroethane is such a case, and the effect was called “fluorine gauche effect”. This finding

is counter-intuitive, because steric repulsion and the minimization of the overall dipole would

seem to favor the anti arrangement. However, experiments15 and ab initio calculations have

shown that the gauche conformation is lower in energy than the anti conformation by 2.4 –


5

3.4 kJ/mol.16 The reason is found in stereoelectronic effects of the fluorine substituents. In the

gauche conformation, a filled C—H σ-orbital of each CH2F unit is antiperiplanar to the empty

C—F σ*-orbital of the other CH2F unit. The resulting σC−H→σ*C−F donation is responsible

for the stabilization of the gauche conformation. One pair of the involved orbitals is shown in

Figure 1.3.

F

H HH

H F

F

H H

F

H H

F

H HσC-H

σ∗C-F

H

F

HF

H H

F

H

H

anti gauche

Figure 1.3. Explanation for the fluorine gauche effect.

1.3 Organofluorine Compounds in Nature

Organohalogen compounds occur quite frequently in nature. Many different terrestrial

and marine organisms incorporate halogens into their metabolites, creating a wide range of

structurally diverse organohalogen natural products.17 To date, more than 4500 have been

identified, and this number is likely to rise substantially over the next years.18

Table 1.2 gives an overview about the abundance of halogens in the biosphere, divided

into continental crust and seawater. It is notable that fluorine is by far the most abundant

halogen in the earth’s crust. In contrast, the amount of chloride is four orders of magnitude

higher than fluoride in seawater. This is a reflection of the insoluble nature of many fluorine-

containing minerals, such as CaF2 or (Ca5(PO4)3)F).

Table 1.2. Abundance of the halogens and halogenated natural products in the biosphere.

halogen continental crust (mg/kg)

seawater (mg/kg)

number of natural products

F 585 1.3 13

Cl 145 19’400 ~2300

Br 2.4 67 ~2100

I 0.45 0.06 ~120


6

Regarding the naturally occurring organohalogen compounds, only 13 organofluorine

compounds have been identified.19 It is surprising that Nature has not been able to develop a

significant biochemistry with fluorine after millennia of evolution. Even iodine, which is

much less frequent in both earth crust and seawater than fluorine, appears ten times more

often in natural products. One reason for the lack of organofluorines is the aforementioned

insolubility of fluorine-containing minerals, which renders the element biologically

unavailable. An additional worsening of the low bioavailability is the poor nucleophilic

reactivity of fluoride in water, due to the high energy necessary for desolvation, as mentioned

in paragraph 1.1. A further reason for the mere absence of fluorine in biochemical processes is

discussed in 1.3.1.

Of the 13 natural fluorine-containing compounds, the most prominent ones are

fluoroacetic acid (fluoroacetate), (2R,3R)-fluorocitrate, and a family of structurally related ω-

fluoro fatty acids (Figure 1.4).

OHF

OF

CO2HHO2C CO2H

F

OHHO2C

fluoroacetic acidfluoroacetate (2R,3R)-fluorocitrate ω-f luoro fatty acids

e.g. ω-fluoro-oleic acid

Figure 1.4. The most important fluorinated natural products.

Fluoroacetate was discovered in 1943 as the first naturally occurring organofluorine

compound. It was found in the leaves of the South African plant Dichapetalum cymosum in

concentrations of up to 2.5 mg/g.20 Fluoroacetate is highly toxic, with an oral lethal dose LD50

of 2 – 5 mg/kg in humans (similar to cyanide). It affects the brain, cardiovascular system and

nerves. The uptake of a lethal dose leads to cycles of depression, excitement and convulsions,

and death usually occurs after 3 hours to 5 days by heart block or respiratory failure.21

The mechanism of action of fluoroacetate in the body is well-understood. Fluoroacetate

is transformed to fluoroacetyl-CoA that then enters the tricarboxylic acid cycle (TCA cycle;

other names: citrate cycle, Krebs cycle) instead of the non-fluorinated acetyl-CoA. The TCA

cycle is the main energy-producing enzymatic process in mitochondria. C2 units, originating

for instance from the metabolism of carbohydrates, are transformed to 2 CO2 by eight

subsequent enzyme-catalyzed reactions. The by-products NADH (3 equiv), FADH2, and ATP

are used as energy carriers in the body.22 The first reaction in the TCA cycle, catalyzed by an

enzyme called citrate synthase, is the aldol addition of acetyl-CoA to oxaloacetate, giving

citrate. The next step is a dehydration – rehydration sequence leading to isocitrate, which is


7

catalyzed by the enzyme aconitase. In case of the fluorinated starting material fluoroacetyl-

CoA, the first step produces (2R,3R)-fluorocitrate (Scheme 1.1). After dehydration by

aconitase, fluoro-cis-aconitate does not undergo a rehydration, but an SN2’ reaction with F− as

leaving group. The product (R)-4-hydroxy-trans-aconitate remains bound to aconitase, and

inhibits the enzyme. In concentrations as low as 50 pmol/L in mitochondria, (2R,3R)-

fluorocitrate irreversibly inhibits citrate metabolism and thus disrupts the TCA cycle.

OHF

O

SCoAF

O

HO2CCO2H

O

enzyme:citrate synthase

H2O, -CoA-SH

HO2C CO2H

F

OHHO2C

enzyme:aconitase

-H2OHO2C CO2H

F

CO2Henzyme:aconitase

-F-

(2R,3R)-fluorocitrate

f luoro-cis-aconitate (R)-4-hydroxy-trans-aconitate

HO2CCO2H

CO2HOH

fluoroacetyl-CoA

HO

Scheme 1.1. Fluoroacetate in the TCA cycle.

ω-Fluoro fatty acids were found in the seeds of several fluoroacetate-producing plants

in concentrations of up to 1.8 mg/g, e.g. in the West African Dichapetalum toxicarium. Its

toxic effects are similar to the ones of fluoroacetate, which is easily explained by the

mechanism of fatty acid metabolism. The fluorinated fatty acids are broken down in the body

by subsequent β-oxidations, leading to fluoroacetate as the final cleavage product in the case

of even-numbered carbon chains.

1.3.1 Biosynthesis of Organofluorine Compounds

In the years after the discovery of fluoroacetate in plants, efforts have been made to

explore its biosynthesis, unfortunately without substantial progress. It was clear that

whichever enzyme was able to catalyze C—F bond formation must follow a completely

different mechanism than the ones for biological chlorination, bromination, and iodination.

Several known enzymes carry out these latter halogenations via oxidative strategies. They

convert the abundant anions Cl−, Br−, and I− to formally electrophilic (“X+”) or radical species

(“X·”), which then react with carbon nucleophiles. A type of enzymes called haloperoxidases


8

employ H2O2 as oxidant, whereas O2 is used by flavin-dependent halogenases and non-heme

iron halogenases.18,23 However, the strategy of oxidizing a fluoride ion would be forbiddingly

high in energy for biological systems. Consequently, the lack of an oxidative route for C—F

bond formation suggests that the corresponding enzyme has to apply a nucleophilic

fluorination of a carbon electrophile.

The turning point in the question of fluoroacetate biosynthesis came in 1986. It was

recognized that the bacterium Streptomyces cattleya is able to biosynthesize fluoroacetate and

4-fluorothreonine when fluoride salts are added to its growth medium.24 These bacteria

offered a much more amenable system to study the fluoroacetate biosynthesis in detail.

In 2003, the C—F bond forming enzyme in S. cattleya was identified and characterized

by O’Hagan and co-workers.25 The enzyme 5’-fluoro-5’-deoxyadenosine synthase (trivially

named: “fluorinase”) uses S-adenosyl-L-methionine (SAM) as substrate for an SN2 reaction

with a fluoride ion to give 5’-fluoro-5’-deoxyadenosine (5’-FDA), as depicted in Scheme 1.2.

Some mechanistic details of this transformation were revealed in 2004 by a crystal structure

of the enzyme with bound reaction products.26 In the binding pocket of fluorinase, the fluoride

ion is stripped of its complete hydrate shell, and fixed by three hydrogen bonds in an ideal

position for nucleophilic attack on SAM. Calculations gave an activation energy of 53 kJ/mol

for the enzymatic fluorination, which corresponds to a 106-fold rate acceleration compared to

the activation barrier of 92 kJ/mol in solution.27

O

HO

N

NN

N

NH2

S

OH

CH3O2C

NH3 O

HO

N

NN

N

NH2

F

OH

SCH3O2C

NH3

S-adenosyl-L-methionine (SAM) 5'-f luoro-5'-deoxy-adenosine (5'-FDA)

L-methionine

enzyme:f luorinase

F-+

FO

OPO32-OH

OH5-f luororibulose-1-phosphate

OHF

OHF

O

F CO2

OH

NH35'-FDA

fluoro-acetaldehyde

4-f luorothreonine

Scheme 1.2. Biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya.

In subsequent enzyme-catalyzed transformations, the adenine moiety in 5’-FDA is

replaced by phosphate, and the ribose is isomerized to 5-fluororibulose-1-phosphate. A retro-


9

Aldol reaction leads to fluoroacetaldehyde, the common precursor for both fluoroacetate and

4-fluorothreonine (Scheme 1.2).28

5’-Fluoro-5’-deoxyadenosine synthase (fluorinase) is the only enzyme identified to this

day that is able to catalyze the formation of carbon-fluorine bonds. The nucleophilic strategy

is unique compared to other halogenating enzymes, and is reserved to a handful of highly

specialized plants and microorganisms. Thus, it is a logical consequence that organofluorine

compounds live a niche existence among the vastness of natural products. At the same time,

this rarity certainly accounts for the fascination of organofluorine chemistry, as the field is

almost entirely subject to the creation and innovation of man.

1.4 Applications of Organofluorine Compounds

Over the last decades, a tremendous number of organic compounds containing one or

more fluorine atoms found their way into our everyday life. Their broad occurrence and

diverse applications make fluoroorganic compounds indispensable in our modern world.

Polymers, surfactants, liquid crystals, agrochemicals, pharmaceuticals – these are just a few

fields of their applications.2

In the context of this thesis, perfluorinated organic compounds will only be mentioned

briefly, even though they had probably the largest impact on the general public. A few

important examples of those versatile compounds will be presented (1.4.1). Paragraph 1.4.2

highlights the most important fluorinated bioactive compounds for pharmaceutical and

agrochemical applications. The main focus of this section is on bioactive fluorinated

compounds that possess a C—F stereogenic center and their application as pharmaceuticals

(1.4.3).

1.4.1 Perfluorinated Compounds

Hydrocarbons, in which every hydrogen atom is replaced by fluorine are termed

perfluorinated compounds. In general, these are heavy, non-polar liquids with low affinities

for other substances, irrespective whether they are polar or non-polar. Thus, perfluorinated

hydrocarbons are bad solvents, except for gases or other perfluorinated compounds.


10

The industrial application of perfluorinated compounds started already in the early

stages of fluorine chemistry. In the early 1930s, the first chlorofluorocarbons (CFC’s) were

developed as safe and non-flammable refrigerants, e.g. dichlorodifluoromethane (Freon-12)

(Figure 1.5). They were used in everyone’s kitchen until their influence on the ozone layer

depletion was uncovered, leading to global restrictions about production and use of CFC’s.

Nowadays, a range of environmentally more friendly hydrofluorocarbons (HFC’s) replace the

harmful CFC’s. 29

Towards the end of the 1930’s, polytetrafluoroethylene (PTFE), the perfluoro analog of

polyethylene, was discovered in the laboratories of the company DuPont. It is the most

prominent member of a whole family of highly fluorinated polymers with exceptional thermal

and chemical stability. The development of those inert polymers paved the way for the

successful fabrication of the first atomic bomb, since the enrichment of 235U via UF6 required

equipment that could withstand highly corrosive conditions.30 Later, PTFE found more

civilian applications, such as in Teflon®-coatings for kitchenware, or in clothing that is

waterproof but still permeable for vapor from transpiration (e.g. Gore-Tex®).

Freon-12i

Ref r igerant

CF2Cl2F F

F F

n

PTFE / Tef lon®

Iner t mater ial

C2F5

OF3C

F3C F

Novec 1230®

Fire extinguisher

OF3C

CF3

F

Sevof luranei

Inhalat ion anaesthet ic

F3C (CF2)6 CF2Br

Perflubron / Oxygent®

Oxygen car r ier

Figure 1.5. Applications of perfluorinated compounds.

Further applications of perfluorinated compounds include fire extinguishing agents (e.g.

dodecafluoro-2-methylpentan-3-one; Novec 1230®)31 and inhalation anaesthetics (e.g. 2,2,2-

trifluoro-1-(trifluoromethyl)ethyl fluoromethyl ether; sevoflurane).2 The ability of

perfluorinated hydrocarbons to dissolve and transport large quantities of oxygen was used for

the first development of an artificial blood substitute in 1966 by Clark and Gollan.32 They

demonstrated that cats and mice survive upon respiring fluorocarbons saturated with O2. Of

course, this artificial blood can assume none of the other important roles of natural blood

except oxygen transport. As an example, 1-bromoperfluorooctane (perflubron, Oxygent®) can

be used as blood substitute for humans during surgery.33,34


11

1.4.2 Fluorinated Bioactive Compounds

Compounds containing one or more fluorine substituent experienced a tremendous

upsurge in the areas of pharmaceuticals and agrochemicals in the last few years. Today,

around 20% of all pharmaceuticals on the market contain fluorine,35 and the figure is even

higher for agrochemicals, reaching up to 30%.36 Among them are the world-wide best-seller

drugs fluoxetine (Prozac®), paroxetine (Paxil®), and ciprofloxacin (Cipro®). Fipronil,

epoxiconazole, and clodinafop belong to the top-selling crop protection agents (Figure 1.6).37

Fluoxetine / Prozac®

Eli LillyAnt idepressant

F3C

O NHCH3

HN

F

O

O

O HNN N

F CO2HO

Paroxetine / Paxil®

Smith Kline BeechamAntidepressant

Ciprof loxacin / Cipro®

BayerAntibacter ial

NCl Cl

CF3

N NH2

SNCO

CF3

OClF

NN

N

Fipronili

Aventis/BayerInsecticide

Epoxiconazolei

BASFFungicide

N

F

Cl

O

OO

O

Clodinafopi

SyngentaHerbicide

Figure 1.6. Fluorinated best-seller drugs and agrochemicals.

A single fluorine substituent sometimes alters the bioactivity, bioavailability, or

pharmacokinetics of a compound dramatically. These effects are understood in detail for

many fluorinated pharmaceuticals due to extensive structure-activity relationship studies. It

should not be forgotten, though, that the introduction of a fluorine atom in a certain position

of a lead structure is still purely empirical in most of the cases. The effects of a fluorine

substituent have to be investigated for each compound individually.

The following list highlights some well-established fluorine substituent effects in

biologically active compounds:38,39


12

− Bioisosteric mimicking: The van der Waals radius of fluorine (1.47 Å) is only slightly

larger than that of hydrogen (1.20 Å), and very similar to a hydroxy group (1.52 Å). As a

consequence, fluorine can mimic one of those groups in bioactive compounds with respect to

steric requirements in the active pocket of a receptor enzyme. It can thus alter (or imitate) the

polarity and electrostatic charge distribution of the original compound.

The question whether fluorine in an organic compound can act as hydrogen bond

acceptor is still controversial. C—F·····H—O hydrogen bonds were found in some structures,

but their strength (ca. 2.4 kcal/mol) is only half the average of the O·····H strength. It seems

that fluorine only accepts hydrogen bonds reluctantly and in the absence of a better

acceptor.40,41 It should be noted that, unlike in C—F compounds, the fluoride anion is an

excellent hydrogen bond acceptor, and forms the strongest known H-bond of about 40

kcal/mol in the bifluoride anion FHF− (see 4.1.1).

− Metabolic stability: Fast metabolic degradation is a frequent problem for

pharmaceuticals in the body. In particular, C—H oxidation by cytochrome P-450 enzymes in

the liver often is the initial metabolic process. A frequently employed strategy to circumvent

this problem is to replace the oxidizable C—H group by a more inert C—F. This approach

proved successful for many bioactive compounds.

− Electronic effects on neighbouring groups: Fluorine exerts an inductive electron-

withdrawing effect on nearby functional groups, which changes their acidity or basicity. The

pKa of a functional group can have a profound effect on the binding affinity of the compound

to a receptor. Moreover, compounds containing a strongly basic group have a limited ability

to pass through membranes. A strategically positioned fluorine substituent decreases the

basicity of the basic functional group, and thus enhances the bioavailability of the compound

in question.

− Lipophilicity: Fluorine substituents usually increase the lipophilicity of a compound,

which leads to a higher (non-specific) binding affinity for the target protein and better

diffusion through membranes. However, too high lipophilicity results in reduced solubility in

water and makes the administration of the respective drug difficult. The right balance between

increased lipohilicity and a minimal overall polarity of the compound has to be found.

− Molecular conformation: Through its well-known stereoelectronic effects (see

paragraph 1.2), a fluorine substituent can lead to a change in the preferred conformation of a

compound. A solution conformation similar to the required conformation at a binding site is

beneficial, because it gives a higher gain in binding free energy. An optimal preorganization

in solution will thus lead to increased binding efficacy.


13

1.4.3 Bioactive Compounds Containing a C—F Stereocenter

Although they are not among the top-selling fluorinated drugs, several bioactive

compounds with a fluorinated stereogenic center are marketed or in clinical trials. The aim of

this section is to portray some representative examples from different substance classes and

for various therapeutic applications.42,43,44

The first C—F stereogenic pharmaceutical agent was prepared in 1954 by Fried and

Sabo.45 The mono-fluorinated steroid 9-fluorocortisol exhibited an about 10-fold higher

biological activity than its non-fluorinated parent compound cortisol (Figure 1.7). This

increase is related to a higher metabolic stability of 9-fluorocortisol. The degradation of

cortisol derivatives includes an oxidation of the 11β hydroxy group to a ketone. The

developing partial positive charge on C(11) during the oxidation is destabilized by the

neighbouring fluorine substituent, hence, the life-time of 9-fluorocortisol in the body

increases.

O

HOH3C

H

F H

H3C

O

OH

OH

9

11

O

HOH3C

H

F H

H3C

O

OH

OH

9

11

CH3

O

HOH3C

H

F H

H3C

O

9

11

F

SO

F

OCH3

9-Fluorocortisol DexamethasoneTobraDex®

Fluticasone propionateFlovent®

Figure 1.7. Fluorinated steroid derivatives.

Today, other fluorinated corticosteroids are used for the treatment of inflammations and

asthma.46 Dexamethasone is sold in combination with an antibiotic agent under the brand

name TobraDex®.47 The triply fluorinated steroid fluticasone propionate is marketed as

Flovent® for asthma inhalation devices by GlaxoSmithKline (Figure 1.7).48

Fluorine-containing vitamin D3 analogs were synthesized about 20 years ago and

showed activity against human leukaemia cells.49 More recently, the analog BXL-628

(formerly Ro 26-9228) was prepared and tested for the treatment of benign prostate

hyperplasia, an enlargement of the prostate common among aging men (Figure 1.8).50,51 The

company Bioxell announced successful results from their phase II clinical trials with BXL-

628 (Elocalcitol) in 2007.52


14

F

HO CH3CH3

OH

Elocalcitol (BXL-628)(formerly Ro 26-9228)

Figure 1.8. BXL-628, a fluorinated analog of vitamin D3.

A famous class of antibiotics are the erythromycins. The fluorinated member

flurithromycin is licenced since 1997 and exhibits an improved stability towards the acids of

the stomach compared to the non-fluorinated analogs (Figure 1.9, left). Furthermore, a higher

tissue-penetration is obtained. Erythromycins with an α-fluoro-β-keto ester motif (HMR-3562

and HMR-3787) were found to be active against bacteria resistant to the parent compound

erythromycin A, and are currently under clinical development (Figure 1.9, right).53

O

O

O

OHHO OH

F

O

O

O

OH

OMe

O

NMe2OH

Flurithromycin

O

O

O

OMe

O

O

O

NMe2OH

F

ON

O

R

NHN

N

N

HNN

R = R =

HMR-3562 HMR-3787

Figure 1.9. Fluorinated analogs of the antibiotic erythromycin.

The two compounds shown in Figure 1.10 are active against completely different

diseases. The fluorinated nucleoside clofarabine (left) is a potent chemotherapeutic agent

against leukaemia and is available on the market under the brand name Clolar®.54,55 On the

right side, a fluorinated analog of prostacyclin is displayed, which is active against several

serious vascular diseases.56,57 What the two compounds have in common is that the fluorine

substituent in both cases enhances the hydrolytic stability, thus increasing the life-time of the

active form. In clofarabine, the enzymatic hydrolysis at the anomeric center is slowed down

by the fluorine at the 2’ position due to destabilization of the partially positive charge

accompanying hydrolysis. The enol ether moiety in the prostacylins is sensitive to hydrolysis

in slightly acidic media, leading to a ring-opened, biologically inactive keto from. Placing a


15

fluorine atom in β-position to the enolic double bond retards the hydrolysis by a factor of

about 150.2

ClofarabineClolar®O

OH

N

NN

N

NH2

ClFHO

O

H

HF

C5H11HO

CO2H

Fluoro-dehydroprostacyclin

Figure 1.10. Fluorine substituents prevent enzymatic hydrolysis in clofarabine (left) and in a prostacyclin derivative (right).

This overview of pharmaceuticals containing a C—F stereocenter clearly shows the

potential of selective fluorine substitution at sp3-hybridized carbon atoms to obtain derivatives

with enhanced properties. And that potential is by far not exhausted yet. Whenever the mode

of action of a particular bioactive compound is uncovered, fluorine substitution of the lead

structure will be a promising option.

1.5 Objectives and Structure of this Thesis

The previous sections have emphasized the significance of C—F stereogenic

organofluorine compounds. As this area is continuously growing, the development and

understanding of methods for regio- and stereoselective C—F bond formation are of utmost

importance. Therefore, we formulated the following goals for this thesis:

1) Investigation of the Ru/PNNP-catalyzed asymmetric fluorination of β-keto esters,

with the aim of gaining mechanistic insight and a deeper understanding of the

Ru/PNNP system and its reactions with β-keto esters in general.

2) Development of new catalytic asymmetric methods for C—F bond formation.

Chapter 2 describes the synthesis and characterization of new Ru/PNNP complexes,

containing a β-keto ester in its non-enolized or enolized form, respectively. Chapter 3 covers

the catalytic fluorination of β-keto esters with a focus on mechanistic investigations. A novel

Ru/PNNP-catalyzed asymmetric α-fluorination of aldehydes is described in Chapter 4. Each

of theses Chapters is divided into a specific introduction and a section with results and


16

discussion. Chapter 5 contains all the experimental procedures and analytical data of the

synthesized compounds. Finally, lists of abbreviations and numbered compounds,

crystallographic data, the details of a side-project about the α-amination of aldehydes, and a

curriculum vitae are appended in Chapter 6.

1.6 References Chapter 1

[1] Schlosser, M. Angew. Chem. Int. Ed. 1998, 110, 1496 – 1513.

[2] Kirsch, P. Modern Fluoroorganic Chemistry; Wiley: Weinheim, 2004.

[3] Uneyama, K. Organofluorine Chemistry; Blackwell Publishing: Oxford, 2006.

[4] Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: Berlin, 2000.

[5] Huheey, J. E. Anorganische Chemie; Walter de Gruyter: Berlin 1988.

[6] Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512 – 7516.

[7] Pearson, R. G. Inorg. Chem. 1988, 27, 734 – 740.

[8] Nagle, J. K. J. Am. Chem. Soc. 1990, 112, 4741 – 4747.

[9] Schmid, R.; Miah, A. M.; Sapunov, V. N. Phys. Chem. Chem. Phys. 2000, 2, 97 – 102.

[10] Seppelt, K. Angew. Chem. Int. Ed. Engl. 1992, 31, 292 – 293.

[11] Bennett, B. K.; Harrison, R. G.; Richmond, T. G. J. Am. Chem. Soc. 1994, 116, 11165 – 11166.

[12] Schwesinger, R.; Link, R.; Thiele, G.; Rotter, H.; Honert, D.; Limbach, H.-H.; Männle, F. Angew. Chem.

Int. Ed. Engl. 1991, 30, 1372 – 1375.

[13] IUPAC Compendium of Chemical Terminology; Electronic version; URL:

http://goldbook.iupac.org/H02924.html [Accessed 01 Feb 2008].

[14] Wolfe, S. Acc. Chem. Res. 1972, 5, 102 – 111.

[15] Huber-Wälchli, P.; Günthard, H. H. Spectrochim. Acta, Part A 1981, 37, 285 – 304.

[16] Craig, N. C.; Chen, A.; Suh, K. H.; Klee, S.; Mellau, G. C.; Winnewisser, B. P.; Winnewisser, M. J. Am.

Chem. Soc. 1997, 119, 4789 – 4790.

[17] Gribble, G. W. Acc. Chem. Res. 1998, 31, 141 – 152.

[18] Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106,

3364 – 3378.

[19] O’Hagan, D.; Harper, D. B. J. Fluorine Chem. 1999, 100, 127 – 133.

[20] Harper, D. B.; O‘Hagan, D. Nat. Prod. Rep. 1994, 123 – 133.

[21] Goncharov, N. V.; Jenkins, R. O.; Radilov, A. S. J. Appl. Toxicol. 2006, 26, 148 – 161.

[22] Voet, D.; Voet, J. G.; Pratt, C. W. Lehrbuch der Biochemie; Wiley: Weinheim, 2002; pp 491 – 514.

[23] Yarnell, A. Chem. Eng. News, May 22, 2006, p. 12 – 18.

[24] Sanada, M.; Miyano, T.; Iwadare, S.; Williamson, J. M.; Arison, B. H.; Smith, J. L.; Douglas, A. W.;

Liesch, J. M.; Inamine, E. J. Antibiot. 1986, 39, 259 – 265.

[25] Schaffrath, C.; Deng, H.; O’Hagan, D. FEBS Lett. 2003, 547, 111 – 114.


17

[26] Dong, S.; Huang, F.; Deng, H.; Schaffrath, C.; Spencer, J. B.; O’Hagan, D.; Naismith, J. H. Nature 2004,

427, 561 – 565.

[27] O’Hagan, D. J. Fluorine Chem. 2006, 127, 1479 – 1483.

[28] Onega, M.; McGlinchey, R. P.; Deng. H.; Hamilton, J. T. G.; O’Hagan, D. Bioorg. Chem. 2007, 35, 375 –

385.

[29] Sandford, G. Phil. Trans. R. Soc. Lond. A 2000, 358, 455 – 471.

[30] Goldwhite, H. J. Fluorine Chem. 1986, 33, 109 – 132.

[31] 3MTM, Product Information Sheet; [web document] Sept 2003; URL:

http://multimedia.mmm.com/mws/mediawebserver.dyn?ssssssa&kDGsMWtsFWtsssEDz15SSSSR-

[Accessed 03 Jan 2008].

[32] Clark Jr., L. C., Gollan, F. Science 1966, 152, 1755 – 1756.

[33] Riess, J. G. Chem. Rev. 2001, 101, 2797 – 2919.

[34] Kim, H. W.; Greenburg, A. G. Artificial Organs 2004, 28, 813 – 828.

[35] Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881 – 1886.

[36] Jeschke, P. ChemBioChem 2004, 5, 570 – 589.

[37] Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93 – 99.

[38] Smart, B. E. J. Fluorine Chem. 2001, 109, 3 – 11.

[39] Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.

ChemBioChem 2004, 5, 637 – 643.

[40] Howard, J. A. K. Hoy, V. J.; O’Hagen, D.; Smith, G. T. Tetrahedron 1996, 52, 12613 – 12622.

[41] Dunitz, J. D.; Taylor, R. Chem. Eur. J. 1997, 3, 89 – 98.

[42] Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303 – 319.

[43] Bégué, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992 – 1012.

[44] Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013 – 1029.

[45] Fried, J.; Sabo, E. F. J. Am. Chem. Soc. 1954, 76, 1455 – 1456.

[46] Vlahos, R.; Stewart, A. G. Br. J. Pharmacol. 1999, 126, 1315 – 1324.

[47] FDA, US Food and Drug Administration; [web document] 11 Apr 2005; URL:

http://www.fda.gov/cder/foi/label/2003/50592slr032_tobradex_lbl.pdf [Accessed 28 Dec 2007].

[48] GlaxoSmithKline, Prescribing Information; [web document] Jan 2007; URL:

http://us.gsk.com/products/assets/us_flovent_hfa.pdf [Accessed 28 Dec 2007].

[49] Shiuey, S.-J.; Kulesha, I.; Baggiolini, E. G.; Uskoković, M. R. J. Org. Chem. 1990, 55, 243 – 247.

[50] Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.; Liu, W.; Okabe, M.; Radinov, R.;

Zhou, Y. J. Org. Chem. 2001, 66, 6141 – 6150.

[51] Crescioli, C.; Ferruzzi, P.; Caporali, A.; Scaltriti, M.; Bettuzzi, S.; Mancina, R.; Gelmini, S.; Serio, M.;

Villari, D.; Vannelli, G. B.; Colli, E.; Adorini, L.; Maggi, M. Eur. J. Endocrinol. 2004, 150, 591 – 603.

[52] Bioxell, Press Release; [web document] 12 Oct 2007; URL:

http://www.bioxell.com/filedownload.lbl?uid=106C7483-E8B3-4ED4-A37C-8B0E63CA5348 [Accessed

28 Dec 2007].


18

[53] Liang, C.-H.; Yao, S.; Chiu, Y.-H.; Leung, P. Y.; Robert, N.; Seddon, J.; Sears, P.; Hwang, C.-K.;

Ichikawa, Y.; Romero, A. Bioorg. Med. Chem. Lett. 2005, 15, 1307 – 1310.

[54] Bauta, W. E.; Schulmeier, B. E.; Burke, B.; Puente, J. F.; Cantrell Jr., W. R.; Lovett, D.; Goebel, J.;

Anderson, B.; Ionescu, D.; Guo, R. Org. Process Res. Dev. 2004, 8, 889 – 896.

[55] FDA, Patient Information Sheet; [web document] June 2005; URL:

http://www.fda.gov/cder/drug/InfoSheets/patient/clofarabinePIS.pdf [Accessed 03 Jan 2008].

[56] Bannai, K.; Toru, T.; Oba, T.; Tanaka, T.; Okamura, N.; Watanabe, K.; Hazato, A.; Kurozumi, S.

Tetrahedron 1983, 39, 3807 – 3819.

[57] Matsumura, Y.; Shimada, T.; Nakayama, T.; Urushihara, M.; Asai, T.; Morizawa, Y.; Yasuda, A.

Tetrahedron 1995, 51, 8771 – 8782.

2 Ruthenium/PNNP Complexes Containing β-Keto Ester Ligands

19

2 Ruthenium/PNNP Complexes Containing β-

Keto Ester Ligands

Chapter 2 and Chapter 3 of this thesis are strongly connected. Together, they describe

the mechanistic investigations of the ruthenium/PNNP-catalyzed asymmetric electrophilic

fluorination of β-keto esters. This Chapter focuses on coordination chemical aspects of

catalyst-substrate adduct complexes, which laid the foundation to a mechanistic

understanding of the Ru/PNNP-catalyzed fluorination. Even though they have to be

understood as a whole, the separation into two Chapters facilitates the discussion of the topic.

2.1 Introduction

The first section of this introduction deals with the development of tetradentate

diiminodiphosphine (PNNP) ligands and their application in transition metal complexes. In

our group, chiral ruthenium PNNP complexes have been used as catalysts for several

enantioselective reactions, which will be presented in 2.1.1.3. In 2.1.2, the stereochemical

nomenclature of octahedral complexes is discussed. The third part (2.1.3) introduces 1,3-

dicarbonyl compounds as neutral, monoanionic, or dianionic ligands in metal complexes.

2.1.1 Ruthenium PNNP Complexes

2.1.1.1 Salen Ligands

An introduction about PNNP ligands and their complexes inevitably starts with another

class of ligands, the salens. The simplest, achiral member of those tetradentate ONNO

bis(imine) ligands is prepared by condensation of two equivalents of salicylaldehyde with

ethylenediamine (Figure 2.1). The combined abbreviations of the components give the name

to a whole ligand class. Salen and some of its metal complexes were synthesized and

investigated as early as 1933.1


20

N N

HOOH

O

OH

H

2 + H2N NH2

salen

Figure 2.1. Salen: The prototype of a class of tetradentate ONNO ligands.

The easiest way to access chiral versions of salen is to replace the ethylenediamine

bridge with a chiral diamine. Chiral salens are among the most widely used ligand

frameworks in asymmetric catalysis, mainly due to their easy preparation and their versatile

applications. Complexes of a variety of first-row transition metals and main-group metals are

known.2 The ONNO donor set consists of four hard coordinating atoms, and thus complexes

with hard metal ions are formed preferably. Nevertheless, complexes of the softer, second-

row transition metal ions ruthenium(II)3,4 and palladium(II)5 have been reported and

successfully employed in catalysis as well.

The modular synthesis of salen ligands allows for the straightforward preparation of

many analogs with different steric and electronic properties.6,7 Owing to their diversity and

broad applicability in asymmetric synthesis, the salens were given the term “privileged

ligands”.8

The most prominent applications of salen complexes in asymmetric catalysis were

developed by Jacobsen and co-workers (Scheme 2.1). The asymmetric epoxidation of

unfunctionalized olefins uses a Mn(III) salen complex and proceeds with high

enantioselectivities.9,10 The Co(III) complex of the same salen ligand proved exceedingly

successful for the hydrolytic kinetic resolution (HKR) of terminal racemic epoxides.11,12

N N

OO

salen =tBu

tBu tBu

tBu

[MnCl(salen)](4 mol%)

aq. NaOClCH2Cl2 84% yield

92% ee

PhO

Ph

O

R

[Co(OAc)(salen)](0.2 - 2 mol%)

H2O (0.55 equiv)

O

R R

OHOH+

40-45% yield>99% ee

Scheme 2.1. Salen complexes in the asymmetric epoxidation of olefins and in the hydrolytic kinetic resolution of terminal epoxides.


21

2.1.1.2 PNNP Ligands and Complexes

The first achiral salen-type diiminodiphosphine ligand (PNNP ligand) was synthesized

by Rauchfuss in 1980. Similar to salen, a condensation of diphenylphosphino benzaldehyde

and ethylenediamine lead to the desired structure (Figure 2.2).13

O

PPh2

H

2 + H2N NH2

PNNP analog of salen

N N

PPPh2 Ph2

Figure 2.2. A tetradentate PNNP ligand analogous to salen.

Since phosphorus is a softer donor than oxygen, the ligands with a PNNP donor set

were mainly employed for complexes of soft metal cations. Thus, Rauchfuss prepared the first

PNNP complexes of nickel(II), copper(I), and silver(I).13

In 1984, the first chiral PNNP ligand was reported in literature by Pignolet and co-

workers. They used an enantiomerically pure 2,2’-diaminobiphenyl backbone for the

condensation with diphenylphosphino benzaldehyde. With this chiral PNNP ligand,

complexes of Rh(I) and Ir(I) were prepared and characterized by single-crystal X-ray

diffraction.14

Wong et. al. reported chiral PNNP ligands derived from a 1,2-diaminocyclohexane

scaffold in 1996.15 They used the diimino ligand 12 and its reduced diamino analog 12’ in a

Cu(I) and a Ag(I) complex, respectively (Figure 2.3, top).

N N

PPPh2 Ph2

NH HN

PPPh2 Ph2

12 12'

N N

PPPh2 Ph2

Ru

Cl

Cl

N N

PPPh2 Ph2

Ru

Cl

Cl

HH

1 1'

Figure 2.3. Chiral PNNP ligands and their dichloro-ruthenium complexes.


22

Gao, Ikariya, and Noyori used ligands 12 and 12’ to prepare the corresponding

ruthenium(II) complexes trans-[RuCl2(12)] (1) and trans-[RuCl2(12’)] (1’, Figure 2.3,

bottom). They found application as efficient catalysts for the asymmetric transfer

hydrogenation of ketones with iPrOH.16,17 The best result was achieved with complex 1’ and

acetophenone, giving (R)-1-phenylethanol in 93% yield and with 97% ee (Scheme 2.2). Later,

Gao reported that ligand 12’ can be employed for the same reaction also in combination with

Rh(I),18 Ir(I),19 and Ir(III).20

O OH1' (0.5 mol%)

iPrOK (0.5 equiv)

iPrOH, 45 °C, 7 h

93% yield97% ee

Scheme 2.2. Transfer hydrogenation of acetophenone catalyzed by complex 1’.

Throughout the years, several chiral diiminodiphosphine ligands have been reported, in

which the chiral information was built into another part of the molecule instead of the

diamine. For example, the benzylidene group has been replaced by a chiral ferrocenyl unit by

Kagan and co-workers.21 Wild introduced PNNP ligands with an achiral diamine backbone

and stereogenic phosphorus centers.22 A tetradentate PNNP ligand with a bis(oxazoline) unit

instead of a diimine was developed by Lee et. al.23 However, these types of ligands will not be

discussed here in more detail.

Another famous class of ligands is worth mentioning, though, because of their structural

similarity to the diiminodiphosphine ligands. The PNNP ligands reported by Trost contain an

amide linker between the chiral diamine and the phosphine groups (Figure 2.4).24 The amides,

with their high energy barrier for rotation around the C(O)—N bond, make the structure rigid,

similar to the C=N double bonds in the diimine ligands mentioned above.

NH HN

PPPh2 Ph2

O O NH HN

PPPh2 Ph2

O O

PdL L

Trost ligand

Figure 2.4. Trost ligand and its palladium(II) complex.


23

The main application of the Trost ligands are palladium-catalyzed asymmetric allylic

alkylations, often with very high levels of enantioselectivity.25 However, it was suggested that

in the catalytically active complex, the ligand coordinates in a bidentate fashion with the two

phosphorus donors only (Figure 2.4).26

For the purpose of this thesis, only diimine PNNP ligands of type 12 were used. From

now on, the abbreviation PNNP denotes ligand 12 exclusively, unless otherwise stated.

2.1.1.3 Applications of Ru/PNNP Catalysts in our Group

The ruthenium complex 1 was studied and applied as catalyst in our group for several

years. The most important applications from our laboratory will be presented in this

paragraph.27 Robert Stoop systematically investigated the reactivity of [RuCl2(PNNP)]

complexes towards halide scavengers.28 He found that thallium(I) or silver(I) salts (1 equiv)

abstract one chloro ligand from complex 1, giving the five-coordinate, 16-electron complex

[RuCl(PNNP)]+ (9, Scheme 2.3). Its distorted trigonal bipyramidal geometry (Y-shape) was

proposed based on NMR spectroscopic studies in solution.29 The cationic complex 9 is highly

reactive towards oxygen donors (oxophilic), thus readily forms adducts with THF, MeOH,

H2O, Et2O, and acetone.

N N

PPPh2 Ph2

Ru

Cl

Cl

MPF6

CH2Cl2Ru

P

N

N

P

(PF6)

Cl

+

+ MCl

1 9PF6 M = Tl, Ag

Scheme 2.3. Single chloride abstraction from 1 with Tl(I) or Ag(I).

Complex 9PF6, prepared in situ from 1 and TlPF6 (1 equiv), was used as catalyst for the

asymmetric epoxidation of olefins with H2O2 as oxidant.30,31 Under these conditions, the

reaction of styrene reached 35% conversion, giving (S)-styrene oxide in 28% yield and with

42% ee (Scheme 2.4).

9PF6 (1 mol%)aq. H2O2 (7 equiv)

CH2Cl2, 2 h, r.t.

O 35% conv.28% yield42% ee

Scheme 2.4. Ru/PNNP-catalyzed asymmetric epoxidation of styrene.


24

It was postulated that the mechanism of epoxidation involves the formation of a Ru(IV)-

oxo complex that subsequently transfers the oxygen atom to the olefin.

The concept of oxo-transfer was extended to carbene-transfer, and thus led to the

development of a Ru/PNNP-catalyzed cyclopropanation by Stephan Bachmann and Cristina

Bonaccorsi.32,29 The reaction of styrene with ethyl diazoacetate is catalyzed by complex 9PF6,

giving the corresponding cis-cyclopropane as major diastereoisomer with an

enantioselectivity of 87% ee (Scheme 2.5).33,34

9PF6 (5 mol%)

CH2Cl2, 20 h , r.t.41% yield

+ N2 OEt

OCO2Et CO2Et+

cis87% ee

trans24% ee

91 : 9

Scheme 2.5. Asymmetric cyclopropanation of styrene catalyzed by complex 9PF6.

The cyclopropanation reaction was developed further by tuning the electronic properties

of the PNNP ligand, and by variation of the counterion of the catalyst.29,35 PNNP ligands with

electron-withdrawing groups at the phenyl groups of the PPh2 moieties were synthesized,

namely the Ph-4-CF3 and the Ph-3,5-(CF3)2 derivatives. Chloride abstraction from the

respective dichloro-ruthenium complexes required the use of Ag(I) salts, being the stronger

halide scavengers than Tl(I). The best combination turned out to be the Ph-4-CF3 ligand and

AgSbF6 as chloride abstractor. The results for the cyclopropanation of styrene could thus be

improved to 69% yield, a cis/trans selectivity of 99:1, and an enantioselectivity of 96% ee for

the cis-isomer.

+

cis99% ee

trans98% ee

85 : 15

H13C6 CO2Et H13C6 CO2Et

catalyst (10 mol%)N2CHCO2Et

CH2Cl2, 20 h, r.t.

N N

PPAr2 Ar2

Ru

Cl

Cl

RuP

N

N

P

(SbF6)

Cl

+AgSbF6(1 equiv)

-AgClCH2Cl2

Catalyst:

Ar = Ph-4-CF3

Scheme 2.6. Highly selective Ru/PNNP-catalyzed cyclopropanation of 1-octene.


25

More interestingly, the catalytic system was now amenable also to terminal aliphatic

olefins, which are considered to be difficult substrates for cis-selective cyclopropanation.

Under the same conditions, 1-octene underwent cyclopropanation with excellent

diasteroselectivity (cis/trans = 85:15) and enantioselectivities (99% ee cis, 98% ee trans), as

shown in Scheme 2.6.36

Other applications of the atom-transfer chemistry by Ru/PNNP complexes are currently

studied in our group by Marco Ranocchiari, who is investigating the carbene-transfer to C=N

double bonds, and the nitrene-transfer to olefins.37

Ruthenium PNNP complexes served not only for atom-transfer from the metal to a non-

coordinated substrate, but also for reactions in which the substrate is bound to the metal and

the incoming atom (or group) is transferred from a non-coordinated reagent. The high

oxophilicity of coordinatively unsaturated Ru/PNNP complexes was recognized earlier. This

property is utilized for the following reactions that involve the binding and activation of

oxygen-containing substrates to the Lewis acidic ruthenium complex.

The first of those reactions to be explored was the α-hydroxylation of 1,3-dicarbonyl

compounds. Ti(TADDOLate) complexes were successfully applied in the first asymmetric

metal-catalyzed α-hydroxylation of β-keto esters with dimethyldioxirane or an oxaziridine as

oxygen source in our group.38 The five-coordinate ruthenium complex 9 was then tested for

the same reaction, however, poor enantioselectivity was obtained. Interestingly, when

chloride abstraction from 1 was carried out with 2 equivalents of (Et3O)PF6 (the reaction

products are EtCl and Et2O), the performance of the catalytic hydroxylation improved

considerably. The question about the nature of the active catalyst arose immediately. From

NMR spectroscopic investigations, there is previous evidence that both chloro ligands of 1 are

removed and replaced by Et2O.27,39 Thus, we tentatively formulate the generated complex as

[Ru(OEt2)2(PNNP)](PF6)2 (6), with the configuration shown in Scheme 2.7.

N N

PPPh2 Ph2

Ru

Cl

Cl

1 6

Et2O

Et2ORu

P

N

N

P

(PF6)2(Et3O)PF6(2 equiv)

- 2 EtClCH2Cl2

Scheme 2.7. Double chloride abstraction with (Et3O)PF6, giving the elusive complex 6.


26

Complex 6 resisted all attempts of isolation so far. Indirect evidence for its structure

was gained by analogy with a crystallographically characterized diaqua complex

[Ru(OH2)2(PNNP)]2+, which was formed from 1 in the presence of silver(I) salts (2 equiv) and

water.40 Further proof that (Et3O)PF6 is able to abstract both chloro ligands came from studies

of the coordination of a β-keto ester to the Ru/PNNP fragment. These investigations are part

of the present thesis and will be presented in 2.2. It cannot be excluded, though, that even an

excess of (Et3O)PF6 causes the abstraction of only one chloro ligand, and a better, bidentate

ligand (e. g. a reaction substrate) is needed to replace the second one subsequently.41

Coming back to the Ru/PNNP-catalyzed hydroxylation of 1,3-dicarbonyl compounds,

complex 6 catalyzes the reaction of α-acyl lactame 13 with cumene hydroperoxide, furnishing

the corresponding hydroxylated compound in 60% yield and with 47% ee (Scheme 2.8).

N

OO

Ph N

OO

PhHO

OOH OH

+

6 (5 mol%)CH2Cl2

0 °C, 30 minr.t., 20 h

+

60% yield47% ee

13

Scheme 2.8. Ru/PNNP-catalyzed asymmetric α-hydroxylation of 13.

Despite detailed investigations, it is not unambiguously clear whether the hydroxylation

reaction really occurs via Lewis acid activation of the 1,3-dicarbonyl compound, or via atom-

transfer from a Ru(IV)-oxo species.29

Claus Becker applied the dicationic complex 6 as catalyst for the asymmetric

electrophilic α-fluorination of 1,3-dicarbonyl compounds.39 Furthermore, he carried out

preliminary experiments concerning the coordination of β-keto esters to Ru/PNNP complexes.

The continuation of his work is part of the thesis at hand. Thus, a detailed introduction and

discussion about the Ru/PNNP-catalyzed asymmetric electrophilic fluorination will be given

in Chapter 3. The detailed investigations about ruthenium complexes containing β-keto ester

ligands are the subject of this chapter.

The enantioselective Michael addition of β-keto esters to enones, a synthetically useful

C—C bond forming reaction, was investigated by Francesco Santoro.41 He found that the

dicationic Ru/PNNP complex 6 is an efficient catalyst for this transformation, creating an all-

carbon quaternary stereogenic center with high levels of asymmetric induction. Thus, the best

result was obtained in the reaction of 2-tert-butoxycarbonylcyclopentanone (4a) with methyl


27

vinyl ketone, giving the Michael adduct in 95% yield and with 79% ee (Scheme 2.9).

Moreover, he discovered a significant improvement of the enantioselectivities when the

reactions were run with ethers as co-solvents to dichloromethane. For the above reaction, a

quantitative yield and an enantioselectivity of 93% ee were observed in CH2Cl2/Et2O (1:1) as

solvent.

A mechanistic aspect of Santoro’s work, which overlaps with some parts of the present

thesis, will be discussed in paragraph 3.2.15.

O O

O

O O

O+

6 (5 mol%)

solvent, r.t., 18 h

4a

O

O

CH2Cl2:CH2Cl2/Et2O (1:1):

95% yield, 79% ee>99% yield, 93% ee

Scheme 2.9. Michael addition of β-keto ester 4a to methyl vinyl ketone catalyzed by 6.

2.1.2 Stereochemistry of Octahedral PNNP Complexes

A precise nomenclature is essential when relative and absolute configurations of

coordination compounds are discussed. The well-known Cahn-Ingold-Prelog (CIP) rules were

originally developed for tetrahedral carbon atoms with four substituents. They do not suffice

to define the configuration of coordination compounds, where high coordination numbers and

a variety of stereoisomers are possible. Thus, a systematic and unequivocal stereochemical

notation for coordination compounds was proposed by the IUPAC.42 The stereochemical

descriptor of a coordination compound consists of four parts: 1) a polyhedral symbol, 2) a

configuration index, describing the diastereomeric arrangement of the ligands, 3) a central

atom chirality symbol, and 4) stereochemical labels for the individual ligands. How to find a

correct descriptor is exemplified with an octahedral complex and illustrated in Figure 2.5.

Step A: The polyhedral symbol for an octahedral complex is OC-6. Each donor site of the

octahedron is assigned a priority number, according to the CIP sequence rules, with the

highest priority being 1. Identical monodentate ligands, or identical donors in a symmetric

multidentate ligand (such as in PNNP) are assigned equal priority numbers.

Step B: The axis containing the priority number 1 is assigned as principal axis of the

octahedron. If more than one donor has priority 1, the axis with the largest trans-difference is


28

chosen. The priority number of the ligand trans to number 1 on the principal axis represents

the first digit of the configuration index. In the example, this digit is 3.

M

1

2

3

4 5

6M

1

2

3

4 5

6M

1

2

3

4 5

6M

1

2

3

4 5

6

C

A

Step A Step B Step C Step D

OC-6-35-COC-6-35OC -6-3OC -6

Figure 2.5. Definition of the stereochemical descriptor in an octahedral complex.

Step C: The equatorial plane perpendicular to the principle axis is considered. The

priority number trans to the highest priority donor in the plane constitutes the second digit of

the configuration index, which is 5 in the example.

Step D: To assign the central atom chirality symbol, the complex is viewed along the

principle axis from site 1. The clockwise and anticlockwise sequence of priority numbers in

the equatorial plane are then compared. The symbol C or A is assigned, according to whether

the clockwise (C) or anticlockwise (A) sequence is of higher priority. In the example, the

sequence 2-4-5 (C) has higher priority than 2-6-5 (A). The stereochemical descriptor of the

complex in Figure 2.5 is thus (OC-6-35-C).

A drawback of the complete IUPAC notation is that it is not very illustrative regarding

the configuration of multidentate ligands (e.g. the PNNP ligand), as it treats each donor atom

individually, irrespective whether it is connected to further donors or not.

For that reason, it is often convenient to use the “skew line reference system” that was

developed for octahedral bis-bidentate and tris-bidentate complexes. It should be noted that

the skew line descriptor is fully contained in the more complete IUPAC notation, but cannot

define the stereochemistry unambiguously in the general case. However, it can be applied to

complexes of tetradentate ligands, and sometimes offers practical advantages.

A linear tetradentate ligand (a-b-c-d) can adopt three diastereomeric geometries in an

octahedral complex, namely trans, cis-α, and cis-β (Figure 2.6). The trans isomer is C2v-

symmetric, and thus the metal is not stereogenic. The C2-symmetric cis-α and the C1-

symmetric cis-β structures are chiral and exist in two enantiomeric forms, denoted Δ and Λ.


29

c

d

b

a d

c

d

a

c

b

a c

d

b

d

a

c

b

ac

d

b

tr ans cis-α cis-β

b ac

dba

c

da b

c

dab

Δ Λ Δ Λ

Figure 2.6. Skew line reference system applied to a tetradentate ligand.

To assign the absolute configuration, the lines a—b and c—d are defined as skew lines.

A pair of skew lines are two non-intersecting lines in space that are neither parallel nor

orthogonal. If the line in the back (c—d) has to be turned clockwise through an acute angle to

be congruent with the line in the front (a—b), the absolute configuration is Δ. If a counter-

clockwise rotation is required, the configuration is Λ.

For the discussion of the complexes in the present thesis, the skew line notation will be

used preferentially, as it describes the configuration of the PNNP ligands more intuitively.

2.1.3 1,3-Dicarbonyl Compounds as Ligands

2.1.3.1 General Aspects

The importance of 1,3-dicarbonyl compounds was recognized already in the early days

of organic chemistry, and is manifested by their wide application in fundamental organic

transformations.43 The nucleophilic reactivity of 1,3-dicarbonyl compounds is defined by

tautomerism and deprotonation. Neutral 1,3-dicarbonyl compounds exist as an equilibrium

mixture of dicarbonyl (diketo) and enol tautomers (Scheme 2.10). The equilibrium position,

exchange rate, and preference of one enol form over the other depend amongst others on

solvent, temperature, and electronic properties of the substituents X and Y.

Deprotonation of a 1,3-dicarbonyl compound leads to its monoanionic enolate. Due to

the electron-withdrawing effect of the two carbonyls, and the resonance stabilization within

the enolate, the α-methylene group of the dicarbonyl form is acidic enough to be deprotonated

under relatively mild conditions. A comparison of some pKa values of carbonyl and

dicarbonyl compounds is given below (Figure 2.7).


30

X Y

OOX, Y = alkyl, aryl, OR, SR, NR2X Y

OHO

X Y

OOH

X Y

OO

X Y

OO

X Y

OO

X Y

OOB:

-BH+

Y

OOB:

-BH+X = alkyl:

Diketo tautomer Enol tautomers

Dienolate

Enolate: resonance structures

Scheme 2.10. Tautomerism and deprotonation of 1,3-dicarbonyl compounds.

Whether one of the mesomeric forms predominates in a non-symmetric enolate is

mainly determined by the electronic properties of the substituents X and Y. An enolate, in

which X or Y is an alkyl group bearing an α-hydrogen, can undergo a further deprotonation to

a dienolate by the action of a strong base.

All three forms of 1,3-dicarbonyl compounds (neutral, monoanionic, dianionic) can

react with electrophiles. As they are ambiphilic nucleophiles, the nature of the electrophile

and the reaction conditions determine whether a reaction takes place at carbon or oxygen.

Assuming a carbon attack, an enol can react with an electrophile followed by proton loss,

whereas an enolate can be trapped directly by electrophiles in α-position (Scheme 2.11). A

dienolate undergoes two subsequent reactions with different electrophiles under regiocontrol.

X Y

OO

Y

OO

X Y

OO

EY

OOE1

E2

X Y

OHO

E+-H+ E+ 1) (E1)+

2) (E2)+

Enol Enolate Dienolate

X Y

OO

E

Scheme 2.11. Reactions of enol, enolate, and dienolate with electrophiles.

The attractive feature of 1,3-dicarbonyl compounds compared to simple ketones or

esters is the enhanced acidity of the α-methylene group (or α-methine, in case of α-

substituted compounds). This property gave rise to the term “active methylene compounds”

for β-diketones and β-keto esters. A comparison of pKa values shows the dramatic influence


31

of an additional carbonyl group on the acidity. Figure 2.7 displays four carbonyl compounds

with their respective pKa values measured in DMSO solution.44 Thus, acetylacetone is about

13 orders of magnitude more acidic than acetone. Within 1,3-dicarbonyl compounds, it is

evident that the acidity decreases with the introduction of ester instead of keto groups.

O O O

OEt

O

EtO

O

OEt

O O

acetylacetonepKa ~ 13

ethyl acetoacetatepKa ~ 14

diethylmalonatepKa ~ 16

acetonepKa ~ 26

Figure 2.7. Comparison of pKa values (in DMSO) of carbonyl compounds.44

1,3-Dicarbonyl compounds are known to act as ligands in metal complexes in their

neutral, monoanionic, or dianionic form.45 In fact, those seemingly simple compounds exhibit

an extremely rich and diverse coordination chemistry, which will be highlighted in the

following sections. Complexes of dianionic 1,3-dicarbonyl compounds will not be discussed

in this context.

2.1.3.2 Complexes of Monoanionic 1,3-Dicarbonyl Compounds

Despite the fact that complexes of monoanionic 1,3-dicarbonyl enolates are by far the

most widespread in literature, they will be discussed only briefly in this introduction. Enolato

complexes of a broad range of transition metals, lanthanides, and main-group elements have

been reported.46 The most widely used ligand in those complexes is acetylacetonate (acac−),

the enolate of the β-diketone acetylacetone (Hacac). Figure 2.8 gives some examples of the

observed coordination modes of 1,3-dicarbonyl enolates in metal complexes.45 For simplicity,

all complexes are drawn with acac-ligands in this representation. Apart from the classical

O,O’-bidentate chelate (A), there are examples where one (B) or both oxygen donors (C)

coordinate to a second metal center. Furthermore, a β-dicarbonyl enolate can act as O-

monodentate (D) or as bridging ligand (E). Examples F – H show the coordination to two,

three, and four metal centers by combined chelating/bridging modes. Also monodentate

carbon-coordination is known (I – K), as well as η3-allylic (L).


32

OO

[M]

OO

[M][M]

O O[M][M]

O O[M]

OO

[M][M][M]

OO[M][M]

OO[M][M]

[M]OO

[M][M]

[M][M]

O O

[M]

OO

[M]

[M]

O O[M]

O OH

[M]

A B C D E

F G H

I J K L

Figure 2.8. Selected coordination modes of monoanionic 1,3-dicarbonyl enolates.

The applications of β-dicarbonyl enolato complexes (especially acac complexes) are

manifold. They are often used as easily accessible precursors for the synthesis of other

complexes. Metal complexes with 1,3-dicarbonyl enolato ligands are employed as catalysts

for a variety of reactions, for instance the epoxidation of allylic alcohols with [VO(acac)2],47

the C—H oxidation of alkanes with Co(III) complexes,48 or the Cu(I)-catalyzed C—N

coupling of aryl halides and amines.49,50 Further catalytic applications include hetero-Diels-

Alder reactions with Eu(III),51 hydrosilylation of ketones52 and hydrogermylation of alkynes

with Rh(I),53 and cyclopropanation with Cu(I).54

Catalysis is not the only field of application, though. Lanthanide complexes of chiral,

mostly camphor-derived 1,3-diketonates are used as NMR shift reagents.55,56 Sn(IV)

complexes containing β-diketonato ligands were identified as anti-tumor agents.57 Many

different transition-metal β-diketonates were used as precursors for chemical vapour

deposition (CVD), a technique to produce thin metal films for applications in coating industry

and microelectronics.58,59

2.1.3.3 Complexes of Neutral 1,3-Dicarbonyl Compounds

Non-deprotonated 1,3-dicarbonyl ligands occur much less frequently in metal

complexes than their enolato counterparts. In general, these complexes are not very stable,

because the neutral ligands are more labile than the enolates. Furthermore, the coordination of

a 1,3-dicarbonyl compound to a Lewis acidic metal center enhances its Brønsted acidity, thus


33

making these complexes very prone to deprotonation. Despite these restrictions, several

complexes containing non-enolized 1,3-dicarbonyl ligands have been prepared.45 Only three

different coordination modes have been identified, as illustrated by acetylacetone (Hacac) as

model ligand in Figure 2.9. The most common case is O,O’-bidentate coordination (A). The

two rarer cases are a O-monodentate enol form (B), and a η2-C2-bonded enol (C).

OO

[M]OO

H [M] OOH

[M]A B C

Figure 2.9. Coordination modes of non-deprotonated 1,3-dicarbonyl compounds.

Type A complexes of Ti(IV) and Sn(IV) were prepared by adding acetylacetone to

TiCl4 or SnCl4, giving the octahedral complexes [TiCl4(Hacac)] and [SnCl4(Hacac)].60 An

analogous adduct of diethylmalonate to TiCl4 was synthesized and characterized by X-ray

crystallography (Figure 2.10, left).61,62

Octahedral complexes of type A containing two non-enolized Hacac ligands were

reported for Ni(II). X-ray crystal structures of the neutral complex [NiBr2(Hacac)2] (Figure

2.10, middle) and of the dication [Ni(H2O)2(Hacac)2]2+ showed that, in both cases, the

monodentate ligands occupy positions trans to each other and that the two diketones

coordinate in the equatorial plane.63,64 Analogous dicationic diaqua complexes of Zn(II)65 and

Mg(II)66 were synthesized and isolated as their perchlorate salts. The same type of complexes

was prepared and crystallographically characterized with malonamide as 1,3-dicarbonyl

ligand and divalent transition metal cations, namely Co(II),67 Cu(II),67,68 and Ni(II).67,69

Cl

ClTi

O

OCl

Cl

OEt

OEtO

ONi

O

OBr

Br

CoO

OCl

Cl

OEt

Figure 2.10. Selected type A complexes of non-deprotonated 1,3-dicarbonyl compounds.

Tetrahedral complexes containing one neutral dicarbonyl ligand and two halide ligands

were reported for Co(II), Zn(II), and Mn(II). These complexes were accessible with either

acetylacetone, ethyl acetoacetate, or diethylmalonate as 1,3-dicarbonyl compound. A

representative example of this family of complexes is shown in Figure 2.10, right.70,71


34

An interesting dicarbonyl complex was published by Schwarz and co-workers, who

studied solutions of Fe(ClO4)3 and methyl acetoacetate by ESI-MS.72 As predominant charged

species, they identified a cationic, octahedral Fe(III) complex containing two β-keto ester

enolates and one non-enolized β-keto ester ligand (Figure 2.11, left).

Several lanthanides are known to form complexes with non-enolized N,N,N’,N’-

tetraalkylmalonamides with bidentate type A coordination. Thus, derivatives of La(III),73,74,75

Sm(III),76 Er(III),76 Nd(III),77 and Pr(III)77 have been prepared and characterized by X-ray

crystallography. Figure 2.11 (right) shows an Er(III) complex of tetramethylmalonamide.

O

OFe

O

OO

O

OMe

OMe

MeO

+

OO Er

O

OO

O

O

O

NMe2Me2N

NMe2

NMe2

NMe2Me2N

Me2N

Me2N

(PF6)3

Figure 2.11. Iron(III) and erbium(III) complexes with neutral 1,3-dicarbonyl ligands.

Coordination of 1,3-dicarbonyl compounds according to type B, that is, by an O-

monodentate enol, has been reported in a few cases only. The two complexes that have been

characterized by X-ray crystallography contain Mn(II) and Re(I). The Mn(II) system consists

of infinite μ2-Br linked (MnBr2) chains, with two O-monodentate Hacac enol ligands in the

axial positions (Figure 2.12, left).78 The enol coordinates with the carbonyl oxygen and

exhibits an intramolecular hydrogen bond. The Re(I) complex is a μ2-chloro bridged dimer,

having three CO ligands per rhenium. Surprisingly, the two β-ketoenol ligands occupy the

same side of the ReCl2Re plane (Figure 2.12, middle).79,80

Br

BrMn

Br

BrO

OH

O

OH

n

OC

OCRe

Cl

ClO

O

Ph

H

CO

ReCO

COO

O

Ph

H

CO

PtO Cl

O

O

OH

Figure 2.12. Mn(II) and Re(I) complexes of type B, and a Pt(II) complex of type C.


35

Furthermore, a U(VI) complex of type B with the formula [UO2(acac)2(Hacac)] has

been published.81

Only a single Pt(II) complex of coordination mode C was reported up to date. It

contains an anionic O,O’-bidentate acac, a chloro ligand, and a η2-C2-bonded Hacac enol

(Figure 2.12, right).82,83 [PtCl(acac)(Hacac)] is not very stable, though. Upon standing in

solution, the neutral enol ligand dissociates and the μ2-chloro bridged dimer [PtCl(acac)]2 is

formed.

To the best of our knowledge, only three ruthenium complexes of non-enolized 1,3-

dicarbonyl compounds have been identified so far, all of them being of type A. In 1973, Blum

et. al. isolated the Ru(II) complex [RuCl2(PPh3)(O—O)], where O—O is a neutral N,N’-

diphenylmalonamide ligand (Figure 2.13, left).84 An octahedral Ru(III) complex of Hacac was

reported by Paul and Poddar in 1993. The reaction of RuCl3·3H2O with acetylacetone gave

[RuCl2(acac)(Hacac)], a complex with both a deprotonated and a non-deprotonated β-

diketone (Figure 2.13, right).85

RuO

OCl

Cl

PhHN

PhHNO

ORu

O

OCl

Cl

PPh3II I II

Figure 2.13. Ruthenium complexes with non-enolized 1,3-dicarbonyl ligands.

Peterson and co-workers investigated the electrochemistry of some ruthenium

complexes by cyclic and pulsed voltammetry. Starting from the Ru(III) complex

[Ru(NH3)4(acac)]2+, they observed a proton-coupled electron transfer, giving the Ru(II)

complex [Ru(NH3)4(Hacac)]2+. Thus, the electron is transferred to the metal center and the

proton to the acetylacetonato ligand (Scheme 2.12).86 From the pH dependency of the

reaction, it was concluded that the pKa of the non-enolized acetylacetone ligand in the

corresponding Ru(III) complex [Ru(NH3)4(Hacac)]3+ is about 2.6.

H3N

H3NRu

O

ONH3

NH3

III

2+

H3N

H3NRu

O

ONH3

NH3

II

2+

+ e-, + H+

Scheme 2.12. Proton-coupled electron transfer to [Ru(NH3)4(acac)]2+.


36

2.2 Results and Discussion

In a preliminary investigation, Claus Becker studied the coordination behavior of β-keto

esters to Ru/PNNP complexes in our group.39 He treated a solution of complex 6, prepared in

situ from [RuCl2(PNNP)] (1) and (Et3O)PF6 (2 equiv), with an excess of β-keto ester 4a (10

equiv, see Figure 2.14) in dichloromethane at 60 °C in a closed vessel. After column

chromatography, he obtained a red solid, whose 31P NMR spectrum (doublets at δ 63.3 and

52.4) and mass spectra were assigned to the enolato complex 3a (Figure 2.14). Unfortunately,

several elemental analyses exhibited large deviations to the calculated values, and the

compound failed to crystallize for X-ray crystallographic analysis. As a consequence, the

identity of 3a was not unambiguously proven.

O

OO

RuP

N

N

P

PF6

3a

O O

O

4a

O

HOO

RuP

N

N

P

H

2+

14

Figure 2.14. Structures of compounds 4a, 3a, and 14.

In view of the not very well-defined reaction conditions (heating above boiling-point in

a closed vessel), and the open questions concerning the characterization of 3a, we decided to

investigate the coordination of 1,3-dicarbonyl compounds to ruthenium in more detail. This

class of substrates is used in the group for hydroxylation, fluorination, and Michael addition

catalyzed by Ru/PNNP complexes. The adduct complexes of 1,3-dicarbonyl compounds are

of common interest for all the aforementioned projects, and were thus studied in a joined

effort within the group. The contributions of Cristina Bonaccorsi and Francesco Santoro are

mentioned below.

2.2.1 Adduct Complexes: Initial Attempts

As a starting point, the reactions were carried out under the conditions described by

Becker.39 A dichloromethane solution of complex 6 and β-keto ester 4a (10 equiv) was stirred

for 24 h at 60 °C in closed vessel. Then, the solvents were evaporated and the resulting


37

brown-orange solid was analyzed by NMR spectroscopy. The 31P NMR spectrum showed the

formation of two major compounds with AB spin patterns at δ 62.3 and 49.6, and 60.9 and

47.8, respectively, but none of these signals matched the ones described for enolato complex

3a. Interestingly, only after filtration through a short silica column, the doublets of 3a at δ

63.3 and 52.4 appeared as the main product in the 31P NMR spectrum, together with several

unidentified signals.

This implies that the initially formed compounds are transformed on SiO2, and that the

enolato complex must be the product of a two-step process. The observation that not only

SiO2 but also the base NEt3 effects this transformation suggested that the second step is a

deprotonation. Hence, the species that is formed initially could contain a non-deprotonated β-

keto ester coordinated to ruthenium. We decided to explore this possibility under milder

reaction conditions, that is, at room temperature and without excess β-keto ester.

2.2.2 Synthesis and Characterisation of Dicarbonyl Complex 2a

When β-keto ester 4a (1 equiv) is added to a freshly prepared solution of

[Ru(OEt2)2(PNNP)](PF6)2 (6) in CD2Cl2 at room temperature, a color change from brown-red

to bright yellow is observed within 3 – 8 h. The analysis of the reaction solution by NMR

spectroscopy revealed that the product is indeed the dicationic complex 2a, in which the β-

keto ester is bound to ruthenium in its non-deprotonated form (Scheme 2.13). Due to the

coordination of 4a in its dicarbonyl form, we refer to complex 2a as the “dicarbonyl complex”

(not to be mistaken for a complex containing two CO ligands).

N N

PPPh2 Ph2

Ru

Cl

ClO

OO

RuP

N

N

P

H

(PF6)21) (Et3O)PF6 (2.05 equiv)CH2Cl2, r.t., 15 h

2) (4a)O

O

O

1 2a

Scheme 2.13. Synthesis of the dicarbonyl complex 2a.

The assumption, that the β-keto ester is immediately deprotonated upon coordination to

ruthenium, does obviously not hold. The reasons for the observed fluctuations in reaction time

are not clear yet. Probably, trace amounts of water or H+ (from the reaction Et3O+ + H2O →


38

Et2O + EtOH + H+) catalyze the ligand exchange at ruthenium, giving different reaction rates.

However, we later found a method for the synthesis of 2a that avoids the use of (Et3O)PF6 and

the formation of the intermediate 6 (see 3.2.6).

All attempts of isolating pure 2a by precipitation or concentration failed, and gave

several decomposition products in various amounts. Among them was a dicationic ruthenium

complex 14 (Figure 2.14), containing non-ionized 2-oxo-1-cyclopentanecarboxylic acid,

which was characterized by X-ray crystallography (see 2.2.5). 2a is stable for several hours in

solution under argon, before increasing amounts of decomposition products are detected.

Therefore, it was characterized by NMR spectroscopic methods in freshly prepared CD2Cl2

solutions. As no single crystals for X-ray crystallographic analysis could be obtained,

information about the configuration of 2a was gathered by comparison of its NMR spectra

with those of the enolato analog 3a, which was prepared and structurally characterized (see

2.2.3).

The 31P NMR spectrum of 2a exhibits a sharp AB spin pattern at δ 61.2 and 51.3 (JP,P’ =

29.1 Hz). 2a is formed in a purity of 92 % by integration of the 31P NMR signals, along with

small amounts of the diaqua complex [Ru(H2O)2(PNNP)]2+ (5 – 10 %) and an unidentified

impuritiy with signals at δ 59.7 and 43.4 (< 5 %).

In the 1H NMR spectrum, the imine protons Hb and Hb’ of the PNNP ligand give a

doublet at δ 9.03 (JP,H = 9.0 Hz) and a singlet at δ 8.83, respectively. A strong coupling over

four bonds through the metal shows that the imine moiety bearing Hb and phosphorus Peq are

trans to each other. On the other hand, Hb’ shows no coupling with the two phosphorus nuclei

Peq and Pap, which indicates a cis configuration (the designations eq = equatorial and ap =

apical are chosen with respect to the meridial PNN plane of the PNNP ligand). Thus, the

configuration of 2a can be derived from the NMR data by analogy with spectra of the

crystallographically characterized complexes 3a and 14 (see 2.2.3 and 2.2.5), and is shown in

Figure 2.15. The absolute configuration of the stereogenic ruthenium center is (OC-6-42-A-

(S,S)), which implies the coordination of the (S,S)-PNNP ligand in Λ-cis-β configuration.


39

Ha'

Ca'

RuOOCiCk

CdCj

O

CH3e

H3C

H3CHd N

NPap

Peq

CaHa

Hb Hc

Hb'

Hc'

2a

Figure 2.15. Drawing of 2a with labelled diagnostic hydrogen and carbon atoms.

The identification of the α-methine proton Hd gives proof for the coordination of β-keto

ester 4a in its non-deprotonated form. The 1H NMR spectrum of 2a features its signal as a

doublet of doublet at δ 3.78 (JH,H = 11.0, 9.1 Hz), as shown in Figure 2.16. As a result of the

coordination to ruthenium, the signal is shifted considerably towards high frequency with

respect to the resonance of the α-proton in free β-ketoester 4a at δ 3.04.

Figure 2.16. 1H NMR signals of the α-protons of coordinated and free β-keto ester 4a.

The one-bond 13C,1H-HMQC spectrum confirms that this is indeed the signal of the

hydrogen atom Hd bound to the α-carbon atom (Cd—Hd), whose 13C NMR signal appears at δ

55.5 (Figure 2.17). In the long-range 13C,1H-HMQC spectrum, correlations of Hd to both the

ketone (Ci) and the ester carbonyl carbons (Cj), and to the adjacent methylene group (Ck) in

the cyclopentanone ring are visible.


40

Figure 2.17. Section of the one-bond 13C,1H-HMQC NMR spectrum of 2a.

2.2.3 Synthesis and Characterisation of Enolato Complex 3a

The addition of NEt3 (1 equiv) to a freshly prepared CH2Cl2 solution of 2a effects the

clean deprotonation to the corresponding monocationic enolato complex 3a as a single

diastereoisomer (Scheme 2.14). The reaction is reversed by addition of the strong acid

HBF4·OEt2 to 3a. The deprotonation is indicated by an immediate color change of the solution

from yellow to deep orange. 3a was isolated as an air-stable solid in good yields by filtration

over SiO2 and subsequent trituration with hexane/CH2Cl2 20:1.

O

OO

RuP

N

N

P

H

(PF6)2

2a

NEt3 (1 equiv)

- (Et3NH)PF6O

OO

RuP

N

N

P

PF6

82 % yield

3a

Scheme 2.14. Deprotonation of 2a to the enolato complex 3a.


41

The 31P NMR spectrum of 3a is very similar to the one of 2a. An AX spin pattern is

observed at δ 63.4 and 52.5 with a coupling constant of JP,P = 31.2 Hz (2a: δ 61.2 and 51.3

(JP,P’ = 29.1 Hz), Figure 2.18). Even though the neutral β-keto ester ligand in 2a is replaced

by the anionic enolato ligand in 3a, the 31P NMR signals are shifted by only 2.2 and 1.2 ppm

towards higher frequency.

The signal of the imine proton Hb’ appears as a singlet at δ 8.89, whereas Hb shows a

doublet at δ 8.69 (JP,H = 9.5 Hz), as depicted in Figure 2.18. The resonance of the methine

proton Hd has disappeared, as expected for a deprotonation in α-position.

Figure 2.18. Sections of 1H and 31P NMR spectra of 2a (top) and 3a (bottom). The impurity in the top spectra is [Ru(OH2)2(PNNP)]2+.

The signal at δ 93.1 in the 13C NMR spectrum is assigned to the α-carbon Cd by 13C,1H

correlation spectra (Figure 2.19). Its chemical shift is in the typical region for an enolate or

enol 2-carbon atom.87 The low-frequency shift of the ketonic carbon Ci from δ 227.3 in 2a to

δ 192.0 in 3a reflects the change in its environment, going from the ketone to the enolate.

2a 3aδ 227.3

δ 55.5

δ 175.2

δ 192.0

δ 93.1

δ 168.3

CiCd

O

CjtBuO

ORu

P

N

N

P

2+

CiCd

O

CjtBuO

ORu

P

N

N

P

+

Figure 2.19. 13C NMR chemical shifts (in ppm) of the β-keto ester in 2a (left) and 3a (right).


42

2.2.3.1 X-Ray Crystal Structure of 3a

The attempts to obtain X-ray quality crystals of enantiomerically pure 3a were not

successful. However, the racemic analog (rac)-3a, synthesized from racemic trans-

[RuCl2(PNNP)], readily crystallized by diffusion of pentane into a CH2Cl2 solution. The

crystals of space group P−1 contain two pairs of crystallographically independent complex

molecules and PF6− anions, as well as disordered CH2Cl2 molecules in four different sites. As

the two cations possess very similar metrical parameters, only one will be discussed. An

ORTEP projection of the enantiomer containing (S,S)-PNNP is shown in Figure 2.20. The

coordination polygon around ruthenium is a distorted octahedron, with the smallest angle

N(1)—Ru(1)—O(2) of 79.70(9)° and the largest angle P(1)—Ru(1)—P(2) of 104.58(3)°.

Figure 2.20. ORTEP plot of the enantiomer of 3a containing (S,S)-PNNP.

The absolute configuration at the metal is (OC-6-42-A-(S,S)), with the PNNP ligand in

Λ-cis-β configuration. The β-keto ester enolate coordinates in a bidentate fashion, and is

almost perfectly planar. The torsion angles in the enolate plane are close to zero, namely

1.7(6)° for the angle O(1)—C(45)—C(49)—C(50), and –2.7(6)° for the angle C(45)—

C(49)—C(50)—O(2), respectively. The bond lengths within the enolate moiety pinpoint its

slightly asymmetric electron distribution. The C(45)—O(1) bond is longer than the C(50)—


43

O(2) bond, and has thus more single-bond character (Figure 2.21). Accordingly, the C(45)—

C(49) bond has more double-bond character compared to the C(49)—C(50) bond. However,

the system is still delocalized to a certain extent, as all bond lengths are between the average

values for the corresponding single and double bonds.

O(1)

OO(2)

+Ru(PNNP)

1.281(4)

1.259(4)1.411(4)

1.383(4)

C O : 1.43C O : 1.20C C : 1.54C C : 1.34

Average bond lengths:

45

49 50

Figure 2.21. Bond lengths (Å) in the enolate part of 3a and average values (Å).88

The above considerations of the bond lengths show that oxygen O(1) carries more

negative charge than O(2), thus acting as the stronger donor. This is confirmed by the shorter

coordination bond length of 2.082(2) Å for Ru(1)—O(1) as compared to 2.144(2) Å for

Ru(1)—O(2). For that reason, O(1) occupies the position trans to nitrogen N(1), which exerts

a lower trans-influence than phosphorus P(2). This is an electronic factor that favours the

observed configuration of 3a. Additionally, steric factors certainly play an important role. The

bulky tert-butyl group is pointing away from the two diphenylphosphine groups towards the

more open space near the cyclohexane part of the PNNP ligand.

One phenyl ring of the P(1)Ph2 group is located below the coordinated enolate and

effectively shields its si enantioface. The re face is unblocked, and accessible to electrophilic

attack (Figure 2.20).

2.2.4 Structural Comparison of 2a and 3a by 1H,1H-NOESY NMR

Spectroscopy

The structural characterisation of 3a by X-ray crystallography allowed for the

assignment of several of its NOE contacts in the 1H,1H-NOESY NMR spectrum. The

observation of similar NOE cross-peaks was used to deduce the configuration of the

dicarbonyl complex 2a. Figure 2.22 shows a comparison of the relevant NOE contacts for

complexes 3a (left) and 2a (right). NOE cross-peaks from the tert-butyl protons He to the

imine proton Hb’ and to the benzylidene ortho-proton Hc’ are observed for both complexes.

These contacts point out the relative configuration of the β-keto ester to the PNNP ligand,


44

such that the tert-butyl group is placed in close proximity to Hb’ and Hc’, as confirmed by the

crystal structure of 3a.

RuOO

O

CH3e

H3C

H3CHd

N

NP

P

Ha

Hb Hc

RuO

O

N

NP

P

O

H3C

H3C CH3e

Hb' Hb'

Hc'Hc'

2a3a

Re faceRe face

Figure 2.22. Relevant NOE contacts (dashed lines) in complexes 3a (left) and 2a (right).

In 2a, the additionally observed weak NOE contacts from the methine proton of the β-

keto ester (Hd) to the hydrogens Ha, Hb, and Hc of the PNNP ligand indicate that Hd points

“up” (absolute configuration S), towards the cyclohexane backbone of the PNNP ligand

(Figure 2.23). Thus, the α-H is located on the unshielded re enantioface of the β-keto ester, as

in the case of 3a. In the right part of Figure 2.23, a strong NOE cross-peak between the α-

proton Hd and a multiplett at δ 2.5 – 2.4 is visible. This multiplett is the resonance of a

methylene group of the cyclopentanone ring that is much closer to Hd than the PNNP

hydrogens, which leads to a stronger NOE.

Figure 2.23. Sections of 1H,1H-NOESY NMR spectra of 2a, showing contacts between the β-keto ester α-proton Hd and the hydrogens Hb, Hc (left), and Ha (right) of the PNNP ligand.


45

It is worth of notice that, apart from the obvious changes in the 1,3-dicarbonyl ligand,

the structures of 2a and 3a are very similar, especially for the conformation of the PNNP

ligand. The si face of the β-keto ester is shielded by a phenyl group in both complexes,

leaving the re face accessible for electrophilic attack. This is relevant for Ru/PNNP-catalyzed

reactions with β-keto esters, and explains the observed absolute configurations of the catalysis

products. These issues will be discussed in detail for the electrophilic fluorination of 4a

(Chapter 3), where both 2a and 3a could be intermediates in the catalytic cycle.

2.2.5 A Ru/PNNP Complex with a Non-Ionized β-Keto Acid Ligand

Many attempts were undertaken to isolate the dicarbonyl complex 2a in the solid state

and to grow X-ray quality crystals thereof. As described above, all efforts were unsuccessful,

but not unavailing, though. In one experiment, racemic 2a was prepared by protonation of

(rac)-3a with HBF4·OEt2 in CD2Cl2. The crystallisation was attempted by overlaying the

solution with toluene under a nitrogen atmosphere in a glove box. After several weeks, a

yellow single-crystal had formed, and its X-ray analysis revealed that it contains (rac)-14, a

dicationic complex featuring non-ionized 2-oxo-1-cyclopentanecarboxylic acid as ligand. The

tert-butyl ester is probably cleaved by acid-catalyzed elimination of iso-butene from the

coordinated β-keto ester 4a (Scheme 2.15). The acid might be formed from hydrolysis of PF6–

by water, which could be present in small traces even in the glove box. Even though 14 is not

the desired product, it serves as a useful model of the β-keto ester complex 2a, and confirms

the structure elucidation of 2a by NMR spectroscopy.

O

OO

RuP

N

N

P

H

2+

2a

cat. H+

O

HOO

RuP

N

N

P

H

2+

14

+

PF6- + 2 H2O PO2F2- + 4 HF

Scheme 2.15. Formation of complex 14 from 2a by iso-butene elimination.

The asymmetric unit of the crystal (space group P21/n) contains one molecule of the

dicationic complex, one BF4− anion, and three highly disordered sites that are partially


46

occupied either by BF4− or by PO2F2

−. The coordination of ruthenium is distorted octahedral

with the absolute configuration (OC-6-42-A), which implies a Λ-cis-β configuration for the

(S,S)-PNNP ligand, as depicted in Figure 2.24.

The metrical parameters and the conformation of the PNNP ligand are very similar to

those in 3a. The β-keto carboxylic acid coordinates to ruthenium in a O,O-bidentate fashion,

with the keto carbonyl oxygen O(1) trans to nitrogen N(1), and the acid carbonyl O(2) trans

to phosphorus P(2).

Figure 2.24. ORTEP plot of (S,S)-14, showing the O(3)—H···O(6) hydrogen bond between the carboxylic acid group and the counterion PO2F2

−.

The coordination bond lengths are 2.101(8) Å for Ru(1)—O(1) and 2.181(7) Å for

Ru(1)—O(2), respectively. As expected, these distances are longer than in the case of the

enolato complex 3a (2.082(2) and 2.144(2) Å), because the anionic enolate is a better donor

than the neutral β-keto carboxylic acid. The absolute configuration of the coordinated β-keto

acid is S, which places the α-hydrogen atom towards the cyclohexane part of the PNNP

ligand, analogous to the situation in 2a.

The carbon-oxygen distances within the carboxylic acid group (C(50)—O(2): 1.224(6)

Å, C(50)—O(3): 1.348(7) Å) indicate its coordination with the carbonyl oxygen O(2) (Figure

2.25). The acidic hydrogen O(3)—H is involved in a strong hydrogen bond to an oxygen atom


47

of a disordered PO2F2− anion, as indicated by the short distance of 2.641(17) Å between O(3)

and O(6). Furthermore, the hydrogen O(3)—H was located on a Fourier difference map.

O(1)

O(3)O(2)

2+Ru(PNNP)

1.230(6)

1.224(6)1.469(11)

1.512(8)

(O=)C O : 1.31(O-)C O : 1.22

C O : 1.20C C : 1.54


4549 50

H1.348(7)

Figure 2.25. Bond lengths (Å) in the β-keto acid part of 14 and average values (Å).88,89

2.2.5.1 Literature Examples of Carboxylate and Carboxylic Acid Ligands

Carboxylic acids are found as ligands in transition-metal complexes mainly in their

deprotonated form, as carboxylates. Three distinct coordination modes of carboxylates are

common, namely, monodentate (A), chelating bidentate (B), and bridging (C) (Figure 2.26).90

RO

OR

O

O[M] R

O

O

[M]

[M][M]

A B C

Figure 2.26. Common coordination modes of carboxylates in transition-metal complexes.

Monodentate coordination of a non-deprotonated carboxylic acid through its carbonyl

oxygen is much less frequent. For the case of ruthenium, the crystal structures of μ-

carboxylato-bridged dinuclear complexes were reported. They possess a monodentate benzoic

acid ligand on each ruthenium center with an intramolecular hydrogen bond to one of the

bridging carboxylates (Figure 2.27).91 Another example from literature is a dichloro(EDTA)

complex of ruthenium(III), in which one glycinate arm of EDTA coordinates through the

carbonyl oxygen and forms a hydrogen bond to one molecule of water.92

RuO

O

CC

RuPh

O H O

Ph

O O

O

O

O

Ph

HO

Ph

CCOO

RuN

Cl Cl

N

O

O

O

OO

OH

OHO

H OH

H

Figure 2.27. Ruthenium complexes with monodentate carboxylic acid ligands.


48

2.2.6 Determination of the pKa of 2a

Our observation of the non-deprotonated β-keto ester complex 2a prompted us to

reconsider several aspects of the Ru/PNNP-catalyzed reactions of 1,3-dicarbonyl compounds

with electrophiles. Above all, the inevitable removal of the α-proton during catalysis sets a

particular spotlight on the acid-base equilibria between dicarbonyl and enolato complexes.

Thus, we decided to measure the acidity of 2a.

A common method for pseudo-aqueous pKa determination in non-aqueous media is the

NMR spectroscopic observation of an acid-base equilibrium, using a base with a known

aqueous pKa value appropriate to partially deprotonate the acid of interest.93,94 The

approximation that the acidity transforms linearly from the aqueous scale to a non-aqueous

scale has to be made with this method, and could lead to an intrinsic error of the method.

Paragraph 2.2.6.1 describes our initial pKa determination of 2a with PPh3 as a reference base.

During our later investigations of the ruthenium-catalyzed fluorination of 4a, and of the low-

temperature protonation of 3a (see 3.2.15), the issue had to be reconsidered. Thus, the pKa

was determined by a second method with diphenylamine as base (paragraph 2.2.6.2).

2.2.6.1 pKa Measurements with Triphenylphosphine as Reference

We carried out a first set of measurements using the acid-base equilibrium between 2a

and PPh3 (Scheme 2.16). A well-established pseudo-aqueous pKa value of 2.7 for HPPh3+ was

reported in literature over several years.95 However, very recently Pestovsky and Bakac

published a significantly lower value of ~0, based on 31P NMR spectroscopy and kinetic

measurements in CH3CN/H2O mixtures.96 The extrapolation to the pseudo-aqueous scale is

afflicted by some inaccuracies, though. This might be an explanation for the different value

obtained by using other measuring techniques.

O

OO

RuP

N

N

P

H

2+

2a

O

OO

RuP

N

N

P

+

3a

+ PPh3 + HPPh3+Keq

Scheme 2.16. Acid-base equilibrium between 2a and PPh3.


49

The constant Keq of the equilibrium in Scheme 2.16 is defined in eq 2.1:

(2.1)

The pKa of 2a is then calculated according to eq 2.2:

(2.2)

The integrated intensities of the 31P NMR signals of 2a, 3a, PPh3, and HPPh3+ can be

used directly in eq 2.1 to calculate Keq. However, the integration values of phosphorus nuclei

in different chemical environments are not comparable in standard 31P NMR spectroscopic

experiments, due to different T1 relaxation times, and different sensitivity enhancements by

NOE’s from hydrogen atoms. By setting the delay time between pulses to 60 s, a complete T1

relaxation can be assumed. Furthermore, with the so-called “inverse-gated 1H-decoupling”

technique, the Overhauser effect can be suppressed, and 31P{inverse-gated 1H} NMR spectra

with a meaningful integration of the signals are obtained.97

In the case of a fast exchange between PPh3 and HPPh3+, a coalescence signal at the

chemical shift δeq is observed in the NMR spectrum, and the [HPPh3+]/[PPh3] ratio can be

calculated by the weighted average of chemical shifts by using eq 2.3:93

(2.3)

Furthermore, under the assumption that [3a] = [HPPh3+] and [2a] = [PPh3], the

following approximations for Keq can be made (eq 2.4):

(2.4)

The integration values and the average chemical shift δeq were obtained from two

independent measurements: deprotonation of 2a with PPh3 (Figure 2.28), and protonation of

3a with (HPPh3)BF4, using both the Fourier transformed spectra and Lorentz line fits for the

calculations (see Experimental Part for detailed data).

The deprotonation and the protonation experiment gave the same average value of

4.6±0.5 for the pseudo-aqueous pKa of complex 2a, using the reference pKaaq of 2.7 for PPh3.

Assuming the revised pKa of ~0 for PPh3, a pseudo-aqueous pKa of 1.9±0.5 is obtained for 2a.

]][PPh[]][HPPh[

3

3eq 2a

3a +

=K

)(PPhpp)(p 3aqaeqa KKK +=2a

eqHPPh

PPheq

3

3

3

3

]PPh[][HPPh

δδδδ−

−=

+

+

2

3

32

eq ][PPh][HPPh

][][

⎟⎟⎠

⎞⎜⎜⎝

⎛≅⎟⎟

⎠

⎞⎜⎜⎝

⎛≅

+

2a3aK


50

Figure 2.28. 31P{inverse-gated 1H} NMR spectrum from the reaction of 2a with PPh3.

The precision of the determined pKa is obviously limited by the large discrepancy of the

reported reference pKa values for PPh3, rather than by the standard deviation. Therefore, it is

reasonable to assume a range of 2 – 5 for the pseudo-aqueous pKa of 2a.

Nevertheless, the coordination to the Ru/PNNP fragment enhances the acidity of β-keto

ester 4a considerably. The pKaaq value of free 4a can be estimated to be ~10.5, as reported for

the analogous ethyl ester 2-ethoxycarbonylcyclopentanone (4b).98 This means that the β-keto

ester is 6 – 8 orders of magnitude more acidic in complex 2a than in the free form.

2.2.6.2 pKa Measurements with Diphenylamine as Reference

Besides phosphines, amines are widely used reference bases for pKa determinations.

The availability of variously substituted amines is a further advantage, as a broad pKa range

can be covered. For our purpose, diphenylamine seemed to have approximately the right

basicity, with a reported pKaaq value of 0.78 for Ph2NH2

+.99

Analogous to the determinations with PPh3, two measurements were carried out by

either the reaction of 2a with Ph2NH, or of 3a with (Ph2NH2)BF4. Numerical values for the

3a:2a ratio were obtained from 31P NMR spectra, and were used in an approximation for Keq

analogous to eq 2.4.

In case of the reaction of 2a with Ph2NH, small signals of 3a were observed and could

be integrated independently. When (Ph2NH2)BF4 was added to 3a, an immediate reaction was


51

indicated by a color change from orange to yellow. The 31P NMR spectrum exhibited an

equilibrium signal slightly shifted from the one of pure 2a, which was used to determine the

3a:2a ratio by the equilibrium chemical shift method, analogous to eq 2.3. Taking together the

single values from Fourier transformed spectra and from Lorentz line fits for both the

deprotonation of 2a and the protonation of 3a, an average pseudo-aqueous pKa of 3.3±0.3 was

obtained (see Experimental Part for detailed data).

This value fits very well into the pKa range of 2 – 5 that was obtained with the two

different reference values for PPh3. Since phosphines and amines are frequently used for

acidity measurements, these values seem trustworthy. During our further investigations on

complexes 2a and 3a, we collected several hints that 2a might be yet a bit more acidic.

However, the values obtained from those estimations must certainly be treated as qualitative.

2.2.6.3 pKa Estimations with Other References

In the context of low-temperature protonations, we studied the reaction of enolato

complex 3a with (DL)-10-camphorsulfonic acid (CSA) at −90 °C. The experiment will be

described in more detail in section 3.2.15.4. To foreclose one of the results, separated 31P

NMR signals of complexes 2a and 3a were detected at −90 °C, and an averaged signal of the

high-frequency doublet was observed at an equilibrium chemical shift δeq 63.026 at 0 °C,

indicating that 2a and 3a undergo fast exchange at this temperature. The exchange was also

observed by 1H NMR spectroscopy, where the imine doublets of 2a and 3a formed a

coalescence signal at δeq 8.807. The equilibrium chemical shift values δeq of the 31P and 1H

NMR spectra at 0 °C were used to estimate the pKa of 2a with CSA as reference.

We could not find literature pKa values for camphorsulfonic acid, therefore we took

methanesulfonic acid as a model. The reported values are wide-spread, however. Bordwell

and Algrim measured a value of 1.62,100 whereas Furukawa and Fujihara reported −1.92 for

methanesulfonic acid.101

Assuming the reference value of 1.62 for CSA, an average pseudo-aqueous pKa of

1.0±0.4 is obtained for 2a. On the other hand, a value of −2.6±0.4 is calculated when −1.92 is

taken as reference for CSA (see Experimental Part for detailed data). Thus, also with CSA as

reference, a range of more than three logarithmic units is obtained for the pKa of 2a. The

upper border of this range, a value around 1, is about one pKa unit lower than observed with

PPh3 as reference. The lower border in the negative region seems very low, though,

considering that such a value would be highly unusual for a C—H acid.


52

A further hint that 2a might be a bit more acidic than assumed, came from the reaction

of 3a with dibenzenesulfonimide (NHSI), which was a part of our studies concerning the

Ru/PNNP-catalyzed fluorination of β-keto esters (see 3.2.9.2). 3a did not react with NHSI (1

equiv) in CD2Cl2, whereas the reaction of 2a with the dibenzenesulfonamide anion (NSI−)

lead to complete deprotonation. This means that 2a is the stronger acid than NHSI, for which

an aqueous pKa of 1.45 has been reported.102

It should be noted that the values obtained with CSA and NHSI as references are rather

rough estimations only. Furthermore, sulfonic acids and sulfonimides are not usual reference

substances for acidity measurements. It is thus not self-evident that those acidities transform

linearly from the aqueous scale (where the pKa values of the references were determined) to a

non-aqueous scale.

Table 2.1. Pseudo-aqueous pKa values for 2a obtained with different reference acids.

reference acid reference pKa pKa of 2a (range)

Ph3PH+ 2.7 / ~0a 4.6±0.5 to 1.9±0.5a

Ph2NH2+ 0.78 3.3±0.3

CSA 1.62 / −1.92a 1.0±0.4 to −2.6±0.4a

NHSI 1.45 < 1.45 a Different pKa values of the reference acid are reported in literature.

The values from all measurements and estimations are collected in Table 2.1. In sum,

we believe that the originally determined pKa of 2a must be adjusted slightly downwards.

Taking together the measurements with PPh3 and Ph2NH, and the estimations from the

reactions with CSA and NHSI, a value around 2 seems reasonable. As even the pKa values of

the reference substances are subject to substantial vagueness, it will not be possible to obtain a

more precise pKa value for 2a. We will thus work with a value of ~2, keeping in mind that it

is afflicted with some uncertainty.

2.2.7 Dicarbonyl and Enolato Complexes of an Acyl Lactame

Parallel to the investigations about β-keto ester complexes, Cristina Bonaccorsi studied

the coordination behavior of an α-acyl lactame to ruthenium.29 α-Acetyl-N-benzyl-δ-


53

valerolactame (13) was the best performing substrate in terms of yield and enantioselectivity

in the Ru/PNNP-catalyzed hydroxylation with H2O2 or cumene hydroperoxide (see paragraph

2.1.1.3).

Adding 13 (1 equiv) to a dichloromethane solution of freshly prepared bis-ether

complex 6 leads to the formation of the dicationic adduct complex 15, containing the acyl

lactame ligand in its non-deprotonated form. 15 was isolated as a solid in 91% yield, and

reacts with Hünig’s base (1 equiv) to the corresponding enolato complex 16 in 55% yield

after chromatographic purification (Scheme 2.17). An X-ray crystal structure of (rac)-16

revealed the displayed configuration of the enantiomer containing (S,S)-PNNP, namely (OC-

6-42-A).103

1

O

ORu

P

N

N

P

N

Ph

H O

ORu

P

N

N

P

N

Ph

(PF6)2 PF6

N

O O

Ph

1) (Et3O)PF6(2 equiv)CH2Cl2

2)

91 %

EtNiPr2

55 %

15 16(13)

Scheme 2.17. Synthesis of dicarbonyl and enolato complexes of acyl lactame 13.

Analogous to the β-keto ester complex 2a, the α-hydrogen of 13 is located on the

accessible re side of the acyl lactame, pointing towards the cyclohexane ring of the PNNP

ligand, as indicated by 1H,1H-NOESY NMR studies.

Francesco Santoro determined the pseudo-aqueous pKa of 15 by the acid-base

equilibrium with pyridine, and calculated a value of 4.67±0.02.41 This pKa is similar to the

one we measured for the β-keto ester complex 2a with the reference value of 2.7 for Ph3PH+.

Unfortunately, no pKa value for free 13 is reported in literature. However, the comparison of

ethyl acetoacetate (pKa ~14 in DMSO)44 with the structurally related N,N-

dimethylacetoacetamide (pKa ~18 in DMSO)104 shows that a β-keto ester is about four orders

of magnitude more acidic than the corresponding β-keto amide. We would expect that also in

the Ru/PNNP complexes, the β-keto ester is more acidic than the β-keto amide. This is a

further indication that the pKa value of 2a is most likely a bit lower than assumed.


54

2.3 Conclusions and Perspectives

The identification and characterisation of ruthenium PNNP complex 2a, which contains

the non-deprotonated β-keto ester 4a as a ligand, was essential for our investigations about

Ru/PNNP-catalyzed transformations of β-keto esters. The fact that 2a is the predominant

catalyst-substrate adduct under neutral conditions prompted us to study some mechanistic

details about the Ru/PNNP-catalyzed fluorination (see Chapter 3) and Michael addition

(Francesco Santoro)41 of β-keto esters. Furthermore, the finding of 2a is of interest from a

fundamental point of view, as it represents one of the rare examples of late transition-metal

complexes of non-enolized 1,3-dicarbonyl compounds. Its enolato analog 3a was prepared

and characterized by X-ray crystallography.

O

OO

RuP

N

N

P

H

(PF6)2

2aO

OO

RuP

N

N

P

PF6

3a

pKa ~2

The pKaaq of 2a was estimated by NMR spectroscopic methods using different reference

substances. Unfortunately, the pKa values of the references stated in literature vary

considerably. Together with the uncertainty inflicted by the extrapolation from the aqueous to

a non-aqueous scale, it is not possible to determine an exact pKa value. However, taking

together all measurements with different references, we estimate a pKa of ~2. This means that

2a is around 8 orders of magnitude more acidic than free β-keto ester 4a.

During attempts to grow single-crystals of 2a, we unexpectedly obtained a complex (14)

with a non-ionized β-keto acid as ligand. 14 serves as model compound for 2a, and its X-ray

crystal structure supports the structure and configuration that we proposed for 2a based on

NMR spectroscopy. The coordination of a β-keto acid to the Ru/PNNP fragment opens the

possibility for catalysis with this type of substrates. For future studies, β-keto acids could be

tested in α-functionalization reactions with subsequent (enantioselective?) decarboxylation. In

this fashion, decarboxylative Michael additions, fluorinations, or aldol reactions could be

considered. As an extension, one could envision ways to generate sensitive β-keto acids in

situ from stable precursors.


55

In a broader picture about ruthenium PNNP complexes of β-keto esters, the

coordination properties of other 1,3-dicarbonyl compounds could be tested. For example, it

would be challenging to study the coordination chemistry of 1,3-diketones with the Ru/PNNP

fragment. It would be interesting to see whether simple electronic differentiation of the ketone

substituents (e.g. aryl and alkyl) could define the configuration at ruthenium. Furthermore, the

influence of the PNNP ligand on the acidity of a coordinated 1,3-dicarbonyl compound could

be investigated. Electron-withdrawing or electron-donating substituents at the PAr2 groups of

PNNP should, in principle, lead to a change of the pKa value. The quantification of these

effects could help for the design and optimization of Ru/PNNP-catalyzed reactions with 1,3-

dicarbonyl compounds by electronic tuning of the PNNP ligand.


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60

3 Ruthenium/PNNP-Catalyzed Fluorination of β-Keto Esters

61

3 Ruthenium/PNNP-Catalyzed Fluorination of

β-Keto Esters

The Ru/PNNP-catalyzed asymmetric fluorination of β-keto esters has been previously

developed in our group. Apart from having devised the methodology, it was our goal to get

insight into the reaction mechanism. To that end, the identification of the β-keto ester

complexes 2a and 3a has already been described in Chapter 2.

The introduction to Chapter 3 gives an overview about electrophilic fluorinating

reagents and methods for stoichiometric asymmetric fluorinations. In section 3.1.3, the

currently known metal-catalyzed enantioselective electrophilic fluorinations are reviewed.

The results of the mechanistic investigations are presented and discussed in 3.2, leading

stepwise to a deeper understanding of the Ru/PNNP-catalyzed fluorination.

3.1 Introduction

3.1.1 Reagents for Electrophilic Fluorination

The reaction of a nucleophile with a source of electrophilic fluorine, formally “F+”, is

called “electrophilic fluorination”. For carbon-fluorine bond formation, many suitable carbon

nucleophiles are available, first and foremost 1,3-dicarbonyl compounds, but also enolates of

monocarbonyl compounds. The importance and advantages of 1,3-dicarbonyl compounds as

easily accessible C-nucleophiles have already been discussed in paragraph 2.1.3.1. However,

finding sources of “F+” is more problematic. Such reagents must either contain groups that

withdraw electron-density from fluorine, an excellent leaving group directly attached to

fluorine, or a combination of both.1

In this manner, elemental fluorine (F2) has been used for reactions with carbon

nucleophiles. Even though F2 can act as a source of fluorine radicals, it behaves as an

electrophile under appropriate conditions.2,3 Other reagents that have been employed for C—F

bond formation include perchloryl fluoride (FClO3),4 acetyl hypofluorite (CH3COOF),5


62

trifluoromethyl hypofluorite (CF3OF),6 and xenon difluoride (XeF2).7 It is a drawback,

though, that these reagents are toxic, highly oxidizing, and some even explosive.

More recently, N—F fluorinating reagents have been developed as generally safer,

easier to handle, and more selective sources of electrophilic fluorine.8 They have enjoyed an

increasing popularity over the last 25 years, mainly because several of them are commercially

available and can be handled in standard laboratory glassware. N—F reagents can be divided

in two main groups: neutral reagents (R2N—F) and cationic ammonium/iminium reagents

(R3NF+X−), as shown in Figure 3.1 (chiral N—F reagents will be discussed in 3.1.2.2).

Neutral: SNS

FPh

O O

Ph

OO

SN

S

F

O OO O S

NF

OO

SNS

FCF3

O O

F3C

OONF

O

N

N

F

CH2Cl

(BF4)-2N

N

F

OH

(BF4)-2NF

TfO-

NF

TfO-

NF

NF

(BF4)-2Cationic:

NFSI NFOBS

F-TEDASelect f luorTM

NFThAccuf luorTM SynFluorTM

Figure 3.1. Neutral and cationic N—F fluorinating reagents.

Today, the most widely used of those reagents are N-fluorobenzenesulfonimide (NFSI)

and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoro-borate) (F-

TEDA). In general, the cationic ammonium/iminium reagents are the more powerful

fluorinating agents than the neutral ones, with the exception of (CF3SO2)2NF. The relative

order of reactivity of the different families of N—F reagents is given in Figure 3.2.9

SNS

FAr

O O

Ar

OO RSNF

ROO

SNS

FCF3

O O

F3C

OO N

N

F

R

(X)-2NF

X-R

> > > >

Figure 3.2. Order of fluorinating power within N—F reagents.

Since the time of their invention, the mechanism by which N—F reagents react with

nucleophiles has been debated controversially. Two possible pathways can be considered. In a


63

classical SN2 mechanism, a concerted Nu—F bond formation and N—F bond cleavage take

place by a direct attack of the nucleophile on the fluorine atom. The other possible pathway

includes a single-electron transfer (SET) followed by fast recombination of the resulting tight

radical pair (Scheme 3.1).

SN2:

SET:

Nu + F NR2 F NR2Nuδ- δ-

Nu F + R2N

Nu + F NR2 Nu F + R2NF NR2Nu

Scheme 3.1. SN2 vs. SET mechanism for the fluorination with N—F reagents.

Numerous experimental and theoretical investigations have been carried out on model

systems in order to find evidence for one of the mechanisms.9,10 However, the results vary for

each system. Depending on substrate, N—F reagent, solvent, and technique of measurement,

convincing proof has been found for either mechanism. Furthermore, the two pathways must

be regarded as idealized boundaries of a continuum of mechanisms. The actual difference

between SN2 and SET in a real system is thus very difficult to establish, which may leave the

question of mechanism unresolved.

3.1.2 Stoichiometric Asymmetric Fluorinations

Stereoselective fluorination has been achieved by different methods. Diastereoselective

reactions, in which an existing stereogenic center of the substrate directs the attack of a

fluorinating agent, are widely used.11 However, this section concentrates on two special

approaches only. First, diastereoselective fluorinations using chiral auxiliaries, and secondly,

enantioselective fluorinations using stoichiometric amounts of chiral N—F reagents. Catalytic

enantioselective fluorinations with N—F reagents will be discussed in detail in 3.1.3.

3.1.2.1 Diastereoselective Fluorinations Using Chiral Auxiliaries

The auxiliary approach is based on the temporary, covalent attachment of an

enantiopure chiral fragment to an achiral substrate. After a diastereoselective reaction, the

auxiliary is removed, thus liberating the desired chiral product.

Highly diastereoselective electrophilic fluorinations have been developed by Davis et.

al., using chiral oxazolidinones as auxiliaries, and NFSI or NFOBS as fluorinating agent.12,13


64

For example, the chiral lithium imide enolate of hexanoic acid is fluorinated in 88% yield and

with a diastereoselectivity of 97% de (Scheme 3.2). Subsequent cleavage of the auxiliary gave

the corresponding α-fluorocarboxylic acids, α-fluoro ketones, or β-fluoro alcohols with high

enantiomeric purity.

NO

O OnBu

Ph Me

1) LDA, THF, -78 °C

2) NFOBS, -78 -> 0 °CNO

O OnBu

Ph MeF

88% yield97% de

Scheme 3.2. Diastereoselective fluorination with an oxazolidinone auxiliary.

Another chiral auxiliary was applied for the asymmetric fluorination of β-keto acids.

Their 1,3-dioxine-4-ones derived from l-menthone underwent diastereoselective fluorination

with elemental fluorine (5% F2/N2). After in situ hydrolysis and esterification, the α-fluoro-β-

keto esters were obtained with excellent enantiomeric excesses.14 Malonates containing a

chiral 8-phenylmenthyl substituent on one ester group were used for a diastereoselective

fluorination with N-fluoropyridinium salts. The α-fluorinated products were obtained in good

yields, but with a maximal diastereomeric ratio of 79:21 only.15

3.1.2.2 Chiral N—F Reagents

The first enantioselective electrophilic fluorinations of enolates were accomplished with

stoichiometric amounts of chiral N—F reagents. Differding and Lang reported the synthesis

of an optically pure N-fluorocamphor sultam in 1988.16 It was applied for the α-fluorination

of ester and β-keto ester enolates, giving enantioselectivities of up to 70% ee (Figure 3.3).

NS F

ClCl

O O

NS F

O O

NS

F

O O

Me

Langup to 70% ee

Davisup to 76% ee

Takeuchiup to 88% ee

Cahardup to 61% ee

N

N

HF

O

(BF4)-MeO

O

ClTakeuchi

up to 91% ee

N

N

HF

OH

(BF4)-

Figure 3.3. Chiral N—F fluorinating agents.


65

Later, Davis and co-workers reached 76% ee for the fluorination of a tetralone

derivative by using a slightly modified camphor sultam reagent.17,18 A saccharin-based N-

fluorosulfonamide was disclosed by Takeuchi. The reaction with ketone enolates produced α-

fluoro ketones in good yields and with high enantioselectivity (up to 88% ee).19

The most recent innovation in the field of chiral N—F reagents is the development of N-

fluoro cinchona alkaloids. In 2000, Cahard reported a cinchonidine derivative that was

utilized for the fluorination of enolates and silyl enol ethers, giving up to 61% ee (Figure

3.3).20 At the same time, Takeuchi published a dihydroquinine-derived fluorinating agent,

which was conveniently prepared in situ by premixing the alkaloid and F-TEDA.21 Silyl enol

ethers of ketones were fluorinated with up to 91% ee, β-keto esters with up to 80% ee.

3.1.3 Metal-Catalyzed Enantioselective Electrophilic Fluorinations

As presented in the previous section, several methods for diastereoselective

electrophilic fluorinations, or enantioselective fluorinations with stoichiometric amounts of

chiral N—F reagents had been developed towards the end of the last century. However,

efficient catalytic methods for enantioselective C—F bond formation using commercially

available electrophilic fluorinating agents were still eagerly sought after. The new millennium

brought about the discovery of the first chiral Lewis acid-catalyzed electrophilic fluorination,

which initiated a new era in fluorine chemistry. This section gives an overview about the

developments in the field of (transition) metal-catalyzed electrophilic fluorination of 1,3-

dicarbonyl and related compounds.22 It is structured according to the metals that have been

employed as catalysts.

3.1.3.1 Titanium(IV) TADDOLate Catalyst

In the year 2000, the first catalytic enantioselective fluorination was developed in our

laboratory. Chiral Ti/TADDOLate complexes were shown to efficiently catalyze the

fluorination of β-keto esters with F-TEDA as fluorinating agent, giving enantioselectivities up

to 90% ee (Scheme 3.3).23,24 In general, bulky ester groups lead to an increase of

stereoselectivity, whereas steric bulk in the 2-position decreases the selectivity. In later

studies, the substrate scope of the reaction was successfully extended to β-keto thioesters,24c

and β-keto amides (with NFSI as fluorinating agent).25


66

Np = 1-naphthyl

Ti

Cl

ClMeCN NCMe

O O

Np

NpNp

Np

O O

R1

O

OR3

O

R2R1

O

OR3

O

R2 F

catalyst (5 mol%)F-TEDA

MeCN, r.t.

catalyst:

O

O

O

F

(S)

89% yield, 90% ee

O O

O

O O

OEt

O

OEt

O

F

71% yield, 62% ee

O

OEt

O

F

(S)

76% yield, 6% ee

O

OEt

O

F

F F

44% yield, 45% ee

66% ee86% ee

(S)

O

SPh

O

F

91% ee

N

O O

F

(S)

87% ee

Ph

4 5

5a 5b

5c5d

Scheme 3.3. Ti(IV)-catalyzed enantioselective fluorination of 1,3-dicarbonyl compounds.

As a mechanistic hypothesis, it was postulated that a β-keto ester enolate coordinates to

titanium by replacing an acetonitrile and a chloro ligand. QM/MM calculations revealed that

the most stable complex diastereoisomer has the remaining chloro ligand in axial position,

and the acetonitrile in the equatorial plane defined by the Ti center and the two TADDOL

oxygens.26 The enolate binds with the ester oxygen in equatorial position, which leads to a

complete shielding of its re face by a naphthyl group of TADDOL (Scheme 3.4). This

diastereoisomer can be attacked by F-TEDA only from the unshielded si face of the enolate,

in accordance with the experimentally observed (S) configuration of the fluorinated product.

Ti

Cl

ClMeCN NCMe

O O

Np

NpNp

Np

O O R1

O

OR3

O

R2

Ti

Cl

OMeCN O

O O

Np

Np

Np

O O

R1OR3

R2

Ti

Cl

OMeCN O

O O

Np

NpNp

Np

O O

R1OR3F

R2

-H+F-TEDA

Si face

(S)

Scheme 3.4. Proposed formation of a titanium(IV) β-keto ester enolato complex.


67

Mechanistic investigations with the Ti/TADDOLate system have been recently resumed

in our group. Kinetic measurements are conducted with a model system consisting of a

[TiCl2(THF)2(TADDOLate)] catalyst, a fluorine-tagged β-keto ester substrate, and NFSI as

fluorinating agent.27 A rate law for this particular system could be derived, which defines the

transition-state stoichiometry of the reaction (Figure 3.4). The current results suggest that the

rate is 0th order in substrate, 1st order in Ti-enolate, −1 order in THF, and 1st order in NFSI. In

addition, a non-catalyzed background reaction between β-keto ester enolate and NFSI appears

in the rate law.

Ti

Cl

OO O

O O

Np

NpNp

Np

O O

OF

F

R2N

rate α [substrate]0[Ti-enolate]1[THF]-1[NFSI]1

+ [enolate]1[NFSI]1

Figure 3.4. Proposed transition-state stoichiometry and rate law.

Particularly interesting is the 0th order in substrate, meaning that the substrate by itself is

not involved in the rate-determining process, but rather the titanium-bound enolate. The actual

fluorine transfer is rate-limiting, though. Furthermore, the negative order in THF indicates

that coordinated THF must dissociate from the complex during the reaction.

3.1.3.2 Palladium(II) Catalysts

In 2002, Sodeoka and co-workers reported the asymmetric fluorination of β-keto esters

using “soft”, late transition metal catalysts. Dicationic diaqua palladium(II) complexes and

related dinuclear bis-μ2-hydroxy palladium(II) complexes of BINAP or SEGPHOS ligands

are efficient catalysts in combination with NFSI as fluorinating agent (Scheme 3.5). Several

cyclic and acyclic substrates containing a tert-butyl ester group were fluorinated in high

yields (up to 96%) and with enantioselectivites exceeding 90% ee.28 One of the most

successful substrates turned out to be 2-tert-butoxycarbonylcyclopentanone (4a), giving the

α-fluorinated derivative 5a in 90% yield and with 92% ee.


68

R1

O

O tBu

O

R2R1

O

OtBu

O

R2 F

catalyst (2.5 mol%)NFSI

EtOH, r.t.

PdP

HO

P OH

PdP

P

2+

PdP OH2

P OH2

2+ P

P=

catalyst:

PAr2PAr2

Ar = Ph, Ph-3,5-(CH3)2

PAr2PAr2

O

O

O

OBINAP SEGPHOS

oror

O O

OF

90% yield92% ee

5a4 5

Scheme 3.5. Catalytic asymmetric fluorination with palladium(II) complexes.

As a mechanistic hypothesis, Sodeoka postulated a hydroxo-palladium(II) complex that

contains both the Lewis acidic Pd(II) center and a basic ligand (OH−) for the deprotonation of

the β-keto ester upon coordination (Scheme 3.6).29,30 The resulting palladium enolato

complexes were observed by NMR spectroscopy.

PdP

HO

P OH

PdP

P

2+

PdP OH2

P OH2

2+Pd

P OH

P L

+ R1

O

OR3

O

R2

-L, -H2OPd

P O

P O

+

R1

OR3

R2

1/2

+L

-H2O-HX

+L

Scheme 3.6. Proposed formation of palladium(II) enolato complexes.

In an extension of the above methodology, the palladium complexes were immobilized

in ionic liquids, allowing for the efficient reuse of the catalyst.31 Thus, the high

enantioselectivites of the fluorination were reproduced even after ten reaction cycles at the

cost of only a small decrease of reaction rate.

The same catalysts were used in later studies for the electrophilic fluorination of other

substrate classes by the research groups of Sodeoka and Kim. Examples are shown in Figure

3.5. Among them are β-keto phosphonates,32,33 α-alkoxycarbonyl lactones and lactames,34 α-

cyano arylacetates,35 and α-aryl-α-cyanophosphonates.36,37 Interestingly, also oxindoles,

being substrates with only one carbonyl group, underwent Pd-catalyzed fluorination with high

levels of asymmetric induction (Figure 3.5, rightmost structure).38


69

OP(OEt)2

O

F

97% yield94% ee

HN

O O

OtBuF

50% yield99% ee

NCO tBu

O

F

83% yield99% ee

P(OEt)2NCO

F

Cl98% yield91% ee

NBoc

O

F

86% yield95% ee

Figure 3.5: Examples of fluorinated products obtained with Pd(II) catalysts.

3.1.3.3 Copper(II), Nickel(II), and Zinc(II) Catalysts

Sodeoka’s findings demonstrated that late transition metals are also suitable catalysts for

the fluorination of 1,3-dicarbonyl compounds. Other chiral late transition metal complexes

were tested for this transformation thereafter.

Copper(II) bis(oxazoline) complexes were used by Cahard and co-workers,39 and soon

after by Shibata.40 The catalyst was prepared in situ from Cu(OTf)2 and phenyl bis(oxazoline)

(Ph-BOX). With NFSI as fluorinating agent, enantioselectivities of 85% ee were obtained

with substrate 4a, and up to 84% ee for bulky indanone derivatives (Figure 3.6).

O O

O

96% yield85% ee

5a

OO

ON

O

N

O

Ph PhCuL L

(OTf)2

catalyst:

79% yield84% eeCu(II)/Ph-BOX

FF

Figure 3.6. Copper(II) bis(oxazoline) catalyst.

Shibata applied another, highly unusual catalytic system with Cu(II) for the asymmetric

fluorination of β-keto esters. The chiral catalyst was prepared by mixing Cu(NO3)·3H2O, a

non-chiral bipyridine ligand, and double-strand DNA fragments (MW = 1.3 x 106) in water.

The chiral environment was proposed to be created by intercalation of the bipyridine ligand

between the DNA strands. With the fluorinating agent F-TEDA, enantioselectivities as high

as 74% ee were obtained for an indanone-derived substrate.41

Shibata introduced Ni(II) bis(oxazoline) complexes for enantioselective fluorinations in

2004. Interestingly, the Ni/BOX catalyst produced the fluorinated β-keto esters with opposite


70

absolute configuration as compared to the Cu/BOX catalyst.40 The enantioselectivities were

even higher with the nickel system, reaching up to 93% ee for an indanone substrate.

Superior results were achieved by changing the ligand to a tridentate bis(oxazoline)

derivative, namely 4,6-dibenzofurandiyl-2,2’-phenylbis(oxazoline) (Ph-DBFOX). Its

nickel(II) perchlorate complex (10 mol%) catalyzes the enantioselective fluorination of β-keto

esters and oxindoles with NFSI, giving up to 99% ee (Figure 3.7).42

O O

O

84% yield93% ee

5a

OO

O

(ClO4)2

catalyst:

76% yield99% eeNi(II)/Ph-DBFOX

F F

OO

N NO

Ph Ph

Ni

L

NBoc

O

Ph F

72% yield96% ee

Figure 3.7. Highly enantioselective fluorinations with a Ni(II)/Ph-DBFOX catalyst.

Very recently, Shibata and co-workers published an elegant application of the Ph-

DBFOX ligand in combination with zinc(II). They achieved an efficient enantioselective

fluorination of non-symmetrically substituted malonates with NFSI.43 Various tert-butyl

methyl malonates were fluorinated in high yields and with enantioselectivities between 90%

and 99% ee. Furthermore, the two ester groups of the product can be functionalized

selectively, which can be used to synthesize a range of useful chiral fluorinated compounds,

e.g. α-fluoro-β-amino acids, or α-fluoro-β-lactams (Scheme 3.7).

90% yield98% ee

Zn(OAc)2 (10 mol%)Ph-DBFOX (11 mol%)

NFSI (1.2 equiv)MS 4Å, CH2Cl2, reflux

MeO

O

OtBu

O

Ph

MeO

O

O tBu

O

FPhBocHN OtBu

O

FPh

Scheme 3.7. Zn(II)-catalyzed enantioselective fluorination of a malonate.


71

3.1.3.4 Aluminium(III), Scandium(III), and Nickel(II) Catalysts

Apart from the abovementioned examples, some other catalytic systems for the

fluorination of β-keto esters have been reported during the last few years. Cahard et. al.

reported a heterobimetallic Al(III)/Li/BINOL complex that catalyzes the fluorination of β-

keto esters with moderate enantioselectivities (Figure 3.8).44 A Sc(III) complex bearing

octafluoro binaphthyl phosphate ligands was published by Inanaga.45 This catalyst efficiently

promotes β-keto ester fluorination with good levels of asymmetric induction. A tridentate

ligand that combines a binaphthyl and an oxazoline moiety as stereogenic elements was used

in combination with Ni(II), Cu(II), Fe(II), and Mg(II) by Iwasa. The best results were

obtained with the Ni(II) complex, which gave enantioselectivity of up to 94% ee.46

OO O

OAl

Li

OO

PO

OSc

3

NN

N

O

M

L

2+

M = Ni, Cu, Fe, MgCahard Inanaga Iwasa

F4

F4

III IIII I

Figure 3.8. Further catalysts for enantioselective fluorination of β-keto esters.

3.1.3.5 Ruthenium(II) PNNP Catalyst

Soon after Sodeoka’s discovery of the Pd(II) catalysts, Claus Becker initiated a project

in our group aimed at the development of a ruthenium(II) catalyst for the asymmetric

electrophilic fluorination of 1,3-dicarbonyl compounds.47 With the β-keto ester ethyl 2-

methyl-3-oxobutanoate (4c) and NFSI, he screened the chiral ruthenium(II) complexes

[Ru(OAc)2(BINAP)], [Ru(acac)2(BINAP)], and [RuCl(η6-p-cymene)(BINAP)]PF6 for

catalytic activity. However, the yields were not higher than 52%, and the products were

invariably racemic.

Eventually, nonracemic fluorinated β-keto ester 5c was obtained with the five-

coordinate complex [RuCl(PNNP)]PF6 (9PF6) in 81% yield and with 27% ee within 24 hours

reaction time in dichloromethane. Catalyst [Ru(OEt2)2(PNNP)](PF6)2 (6), prepared by double

chloride abstraction from [RuCl2(PNNP)] (1) with (Et3O)PF6 (2 equiv), proved to be more


72

successful. Product 5c was produced by reaction with NFSI in 91% yield and with an

enantioselectivity of 59% ee. With catalyst 6 (10 mol%) and NFSI in CH2Cl2, several β-keto

esters were successfully fluorinated. Selected examples are given in Scheme 3.8.

(R)

R1

O

OR3

O

R2R1

O

OR3

O

R2 F

6 (10 mol%)NFSI (1.1 equiv)

CH2Cl2, r.t., 24 h

O O

O

O

OEt

O

F

O O

OEt

O

OEt

O

FF F

(R)

Et2O

Et2ORu

P

N

N

P

(PF6)2

6

(R)

91% yield92% ee

82% yield58% ee

91% yield59% ee

48% yield69% ee

4 5

5a 5b 5c 5d

Scheme 3.8. Ru/PNNP-catalyzed asymmetric fluorination of β-keto esters.

Some trends were elaborated by comparing the Ru/PNNP with the Ti/TADDOLate

catalyst. In general, the Ru/PNNP system gives superior results for substrates with bulky

substituents in the 2-position. On the other hand, the titanium catalyst tolerates extremely

large ester groups better than ruthenium. However, moderately bulky groups at the ester

functionality are beneficial also for Ru/PNNP, as indicated for instance by the comparison

between substrates 4a and 4b.

By successfully developing the methodology, as well as screening substrates and

reaction conditions, Claus Becker laid the foundation of the project about Ru/PNNP-catalyzed

asymmetric fluorination. Continuing his efforts, one goal of the present thesis was to gain a

deeper understanding of the reaction, and hopefully to elucidate its mechanism. Becker

carried out some preliminary mechanistic investigations, which will be referred to and

discussed at the appropriate places in the following sections.


73


In continuation of Claus Becker’s work, the ruthenium-catalyzed fluorination of β-keto

ester 4a with NFSI was repeated with slightly modified reaction conditions. The in situ

preparation of the catalyst [Ru(OEt2)2(PNNP)](PF6)2 (6) was carried out in more concentrated

solution than described by Becker, and after the end of the reaction, the catalyst was quenched

by addition of an excess of Bu4NCl, instead of just evaporating the solvents (see Experimental

Part).

O O

O

O O

OFPhO2S

NSO2Ph

F

PhO2SNSO2Ph

H+ +

6 (10 mol%)

CH2Cl224 h, r.t.

4a NFSI 5a NHSI91% yield88% ee

Scheme 3.9. Ruthenium/PNNP-catalyzed asymmetric electrophilic fluorination of 4a.

5a was obtained with an enantiomeric excess not higher than 88% ee (Scheme 3.9),

using different batches of catalyst precursor 1 and NFSI, whereas Becker reported a value of

92% ee for the same reaction.47 It is not clear why the original result could not be reproduced

under the given conditions. Finally, however, the enantioselectivity was increased to 93% ee

under optimized conditions, as discussed in detail in 3.2.5.

3.2.1 Absolute Configuration of a Fluorinated Catalysis Product

Determining the absolute configuration of a catalysis product was an early goal in our

investigations. Since we have elucidated the structures of the adduct complexes 2a and 3a,

our catalysis product of choice was the tert-butyl ester 5a. A match between the structures of

the complexes and the configuration of 5a would be a strong hint at the intermediacy of 2a or

of 3a in catalysis.

A convenient method for the determination of the absolute configuration of an organic

compound is X-ray crystallography. To do this directly, though, the molecule must contain a

heavy atom, preferably sulfur or heavier.48 If this is not fulfilled, as in 5a, a frequently used

approach is the derivatisation of the compound of interest with a chiral fragment of known

absolute configuration. Highly crystalline and easily available auxiliaries are the most


74

advantageous for this purpose, such as menthol or camphor derivatives, as well as chiral

amines from natural sources.

The initial plan was to convert the tert-butyl ester into a menthyl ester. However, the

cleavage of the tert-butyl ester with trifluoroacetic acid or with p-toluenesulfonic acid was

unsuccessful. Instead of the desired α-fluoro-β-keto acid, only decomposition was observed,

probably initiated by decarboxylation and subsequent reactions of the resulting α-fluoro

ketone enolate. To avoid the formation of the free acid, a trans-esterification of 5a with (−)-

menthol was attempted. No conversion was obtained neither under Brønsted nor Lewis acid

catalysis, even in molten (−)-menthol as solvent. The reason could be an alternative

mechanism for trans-esterifications of β-keto esters that replaces the “traditional” addition –

elimination mechanism. Witzeman found that acetoacetates first undergo an unimolecular

elimination to form an acetylketene, which is then trapped by the appropriate alcohol (Scheme

3.10).49 He was able to isolate and identify the intermediate acetylketene by IR spectroscopy

in an argon matrix at 6 K. The elimination step was found to be particularly fast with bulky

ester groups.

O

OtBu

OO

CO

- tBuOH

tBuOH

ROH

- ROH

O

OR

O

H H

O

OtBu

O

R' R''

Scheme 3.10. Trans-esterification mechanism for β-keto esters.

The essential requirement for such a mechanism is the existence of an α-proton. In its

absence, which is the case in 5a, the substrate is not able to form the corresponding ketene,

and is thus unreactive towards trans-esterification.

We then focussed on the functionalization of the ketone part in 5a. In our group, Yanyun

Liu had successfully derivatized an α-fluoro-β-keto amide by transfer hydrogenation of the

ketone with Noyori’s catalyst, followed by formation of the corresponding (1S)-(+)-

camphorsulfonic acid ester. She was able to crystallize this derivative and measured its X-ray

crystal structure.50

Following an analogous strategy, the keto group in 5a (a sample with 88% ee) was

reduced by asymmetric transfer hydrogenation in iso-propanol with (R,R)-[Ru(TsDPEN)(p-


75

cymene)] as catalyst.51 Alcohol 17 was obtained as a 92:8 mixture of diastereoisomers, and as

a single diastereoisomer in 81% yield after separation by column chromatography (Scheme

3.11). Both enantiomers of camphorsulphonyl chloride were reacted with 17, DMAP and

Et3N in CH2Cl2 to give both the (1S)-(+)- and (1R)-(−)-camphorsulfonic acid esters in good

yields. Unfortunately, both compounds are viscous oils and failed to crystallize.

O O

OtBuF

OH O

OtBuF

catalyst(1.5 mol%)

iPrOH, r.t.81 %

O O

OF

SOO

O

OSO

O

O

F

OO

83 %

84 %

SO2ClO

OSO2Cl

S

R

DMAP (1.2 equiv)NEt3 (30 equiv)CH2Cl2, r.t.

O O

OF

O

O

O

DMAP (1.2 equiv)NEt3 (30 equiv)CH2Cl2, r.t.

(3 equiv)

(3 equiv)

Cl

O

O

O(2.3 equiv)

pyridine, r.t.

97 %

NRu

NPh

Ph

Ts

H

S

(R,R)-[Ru(TsDPEN)(p-cymene)]

Catalyst:RR

5a 17

18

Scheme 3.11. Synthesis of enantiomerically pure camphor derivatives from 5a.

As an alternative, alcohol 17 was treated with (1S)-(−)-camphanic acid chloride in

pyridine, giving ester 18 as a single diastereoisomer in nearly quantitative yield.

3.2.1.1 X-Ray Crystal Structure of the Camphanic Acid Derivative 18

The camphanic ester 18 is a crystalline solid, and formed needle-shaped single-crystals

in the orthorhombic space group P212121 by slow evaporation of a diethylether solution. The

X-ray crystal structure analysis revealed that the absolute configuration of the stereogenic

C(5)—F(1) center is R (Figure 3.9).


76

The R absolute configuration of the catalysis product 5a is in agreement with the

structures observed for the complexes 2a and 3a. In both complexes, the si face of the

coordinated β-keto ester is blocked by a phenyl ring, and electrophilic attack from the

exposed re side leads to the observed R configuration.

Figure 3.9. ORTEP drawing of the camphanic acid ester 18, proving the absolute configuration of the catalysis product (R)-5a.

3.2.2 Enantiomeric Excess vs. Conversion

One of the observations of Claus Becker was that the enantiomeric excess is not

constant during the fluorination of ethyl 2-methyl-3-oxobutanoate (4c), but is increasing with

ongoing conversion.47 We could confirm a similar behavior for the tert-butyl ester 4a by

sampling a standard catalytic reaction after 30 min, 1 h, 2.5 h, and 6 h (Figure 3.10). The

conversion was determined by quantitative GC-analysis (see Experimental Part), and the

enantiomeric excess by chiral GC.

A selectivity of only 65% ee is observed after 15% conversion. The enantioselectivity

then increases, reaching 82% ee at 76% conversion, and finally 87% ee at the end of the

reaction.


77

Figure 3.10. Enantiomeric excess vs. conversion for the fluorination of 4a.

A possible explanation for this phenomenon is the involvement of different catalytic

species. Assuming that the active catalyst, giving a certain enantioselectivity, is transformed

to a more selective catalyst during the course of the reaction, an increase of enantiomeric

excess can be expected. But what could be the second catalytic species in the present case?

Becker postulated the oxidation of the ruthenium(II) catalyst to a more selective

ruthenium(III) species by NFSI.47 In that case, such a Ru(III) complex should lead to better

results if it could be synthesized and be itself used as catalyst for the fluorination. The next

section describes the attempts to prepare and detect β-keto ester complexes of Ru(III),

analogous to the Ru(II) complexes 2a or 3a.

3.2.3 Attempted Ru(II)-Ru(III) Oxidation of β-Keto Ester Complexes

We envisaged two different approaches for the synthesis of Ru(III) β-keto ester

complexes to test the hypothesis of their involvement in catalysis. The first option was to

oxidize the Ru(II) bis-ether complex 6 (prepared by double chloride abstraction from 1), and

then add β-keto ester 4a and optionally a base. The second possibility was to attempt the

direct oxidation of the Ru(II) enolato complex 3a.

Ruthenium(III) is paramagnetic and is thus expected to give very broad signals for the

phosphorus atoms of the PNNP ligand in 31P NMR spectra. Also the 1H NMR resonances

should be broad, at least for the hydrogens in close proximity to the paramagnetic center.

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

% Conversion

% e

e O O

OF


78

3.2.3.1 Attempted Oxidation of the Ruthenium(II) Bis-Ether Complex 6

Solutions of the Ru(II) bis-ether complex 6 were treated with various amounts of AgPF6

as oxidant, followed by β-keto ester 4a (1 equiv or in excess), with or without the addition of

NEt3 as base. In all cases, however, the Ru(II) dicarbonyl complex 2a was identified or

isolated as the major product together with several side-products. The fact that the 1H and 31P

NMR spectra invariably featured sharp lines indicates that the oxidation to Ru(III) did not

take place.

Nevertheless, one of the attempts showed an intriguing result. A CD2Cl2 solution of 6

was added to AgPF6 (3.1 equiv) and stirred in the dark for 4.5 hours. After filtration, the 31P

NMR spectrum exhibited several broad signals between δ 75 and δ 35, which hints at a

paramagnetic Ru(III) species. Upon addition of β-keto ester 4a (1 equiv), a mixture of

compounds with sharp 31P NMR signals was obtained, among them 2a (37%) and

[Ru(OH2)2(PNNP)]2+ (38%) as the major components. Then, further 8 equivalents of 4a were

added and the mixture was stirred at room temperature for 15 hours. After that time, almost

the complete excess of 4a had decomposed. 2-Oxocyclopentanecarboxylic acid,

cyclopentanone, and tert-butylfluoride could be identified from the 1H and 19F NMR spectra

in a ratio of 11:10:1. A possible decomposition pathway is shown in Scheme 3.12.

PF6- + 2 H2O PO2F2- + 4 HF

O O

O

O O

O-

F

CH3H3CCH3

O

F--CO2+ H+

4a

Scheme 3.12. Decomposition of 4a (9 equiv) in the possible presence of a Ru(III) complex.

After cleavage of the tert-butyl group, the β-keto carboxylate can undergo

decarboxylation to give cyclopentanone. The tert-butyl cation is trapped by fluoride that

stems from hydrolysis of PF6− by traces of water.

By 31P NMR spectroscopy, the Ru(II) complex 2a was identified as major component

(67%), accompanied by [Ru(OH2)2(PNNP)]2+ (6%) and at least four additional compounds


79

with AX spin systems. All detected signals were sharp, indicating that no more ruthenium(III)

complexes were present.

A substrate decomposition as described above was never observed in standard catalytic

reactions with ruthenium(II) complexes. If a ruthenium(III) complex was indeed formed in

the reaction with AgPF6, it does not seem to tolerate the presence of a β-keto ester. 4a

decomposes and the supposed Ru(III) species is reduced back to Ru(II), as only sharp signals

are obtained in the 31P NMR spectra after the addition of 4a. Therefore, the outcome of these

experiments does not support the involvement of Ru(III) complexes in catalysis.

3.2.3.2 Attempted Oxidation of the Ruthenium(II) Enolato Complex 3a

The direct oxidation of 3a to a ruthenium(III) complex containing the β-keto ester

enolate of 4a as ligand was attempted with some one-electron oxidants. The results are

summarized in Table 3.1. Cerium(IV) ammonium nitrate (CAN) and potassium persulfate

proved completely unreactive (runs 1 and 2). With AgPF6 as oxidant, 3a was converted to a

mixture of products (run 3). Among them, the ruthenium(II) dicarbonyl complex 2a was

formed in 37% yield by integration of the 31P NMR signals. Interestingly, a ruthenium(II)

complex 19, which we later found to contain 2-tert-butoxycarbonyl-2-cyclopenten-1-one as

ligand (see below), was formed as major product (46%).

Table 3.1. Oxidants for the attempted Ru(II) → Ru(III) oxidation of 3a.

O

OO

RuP

N

N

P

+

3a

oxidant

CD2Cl2O

OO

RuP

N

N

P

2+

19

O

OO

RuP

N

N

P

H

2+

2a

+

run oxidant equiv product

1 (NH4)2Ce(NO3)6 1.2 −

2 K2S2O8 + 18-crown-6 0.5 + 1 −

3 AgPF6 1.5 2a (37%) + 19 (46%) + unidentified (17%)

4 (Ph3C)PF6 1.0 19


80

The reaction of 3a with triphenylcarbenium hexafluorophosphate (1 equiv) as oxidant

gave clean complex 19 in quantitative yield (run 4), which is described in more detail in the

following paragraph.

3.2.3.3 Dehydrogenation of 3a by Ph3C+

The triphenylcarbenium ion (tritylium cation) is known to react along two possible

pathways (Scheme 3.13).52 It can either react with a hydride to give triphenylmethane, or it

can be reduced by one electron to the trityl radical, which dimerizes to the so-called

Gomberg’s dimer, named after Moses Gomberg, who studied the chemistry of tritylium

cations more than 100 years ago.53

He-H-

Ph Ph

PhPhPh

1/2

Gomberg's dimer

Scheme 3.13. Reactions of the tritylium cation with hydride and with an electron.

Thus, when a tritylium salt is used as reagent for an oxidation, the side-product gives

useful information about the type of reaction. In the case of a hydride abstraction,

triphenylmethane is formed as by-product, and on the other hand, a single-electron transfer is

indicated by the formation of Gomberg’s dimer. The hydride abstracting properties of

tritylium salts have been used in organic reactions, for instance for the conversion of

secondary alcohols to ketones,54 or for the synthesis of enones from silyl enol ethers.55

The addition of (Ph3C)PF6 (1 equiv) to a CD2Cl2 solution of enolato complex 3a leads

to a color change from orange to yellow within seconds. The 31P NMR spectrum of the

reaction solution displays the signals of an AX spin system at δ 63.2 and δ 50.4 (JP,P’ = 29.3

Hz). The 1H NMR spectrum features the characteristic signal for the tertiary C—H hydrogen

in Ph3CH (δ 5.59), showing that a hydride abstraction must have occurred. A doublet of

doublets at δ 8.38 is indicative for the vinylic proton of the coordinated α-alkylidene β-keto

ester (Scheme 3.14). Both the 1H and 31P NMR spectrum prove that the hydride abstraction is

quantitative and clean, as no side-products apart from Ph3CH are detected.


81

O

OO

RuP

N

N

P

(PF6)2

O

OO

RuP

N

N

P

PF6

+ (Ph3C)PF6CD2Cl2

r.t.+ Ph3CH

3a 19

HHH

Scheme 3.14. Synthesis of complex 19 by dehydrogenation of 3a.

Evidently, the oxidant (Ph3C)PF6 did not effect the expected oxidation of the metal

center, but oxidized the ligand by dehydrogenation instead.

An attempt to isolate complex 19 resulted in partial decomposition, therefore it was

characterized in solution by 2D NMR spectroscopy. The carbon atoms of the double bond

resonate at δ 131.9 and 188.3 in the 13C NMR spectrum (Figure 3.11). The vinylic proton at δ

8.38 shows correlation cross-peaks to both the keto carbonyl carbon at δ 215.5 and to the ester

carbonyl C atom at δ 165.7 in the long-range 13C,1H-HMQC NMR spectrum.

δ 215.5

δ 188.3

δ 165.7

O

tBuOO

RuP

N

N

P

2+

H

δ 8.38

δ 131.919

δ 202.9

δ 171.9

δ 161.7

O

EtOO

H

δ 8.33

δ 137.2

Figure 3.11. Selected 13C and 1H NMR shifts (ppm) of complex 19 and of a related free enone ester for comparison.

In complex 19, the 13C NMR signal of the olefinic carbon atom at δ 188.3 is shifted

considerably towards higher frequency compared with a related free enone ester (δ 171.9,

Figure 3.11, right). It should be noted that, for nuclei higher than hydrogen, the shielding

constant σ for the chemical shift is determined mainly by a paramagnetic term σpara (eq 3.1).

This contribution to the shielding arises from the interaction between the magnetic field and

the non-spherically distributed p-electrons and involves the ground as well as excited

electronic states.56 Thus, σpara is influenced by the p-electron excitation energy ΔE and by the

expectation value r2p for the distance between a 2p-electron and the nucleus.

(3.1)

32 pr⋅Δ

−∝E

1paraσ


82

In the present case, ΔE can be understood as the energy difference for the π→π*

transition, or in other words, the HOMO-LUMO gap of the enone ester ligand. r2p is

determined mostly by the charge density at the corresponding carbon atom. Considering eq

3.1, the highly deshielded carbon resonance at δ 188.3 originates either from a small ΔE, a

small r2p, or from both. A small ΔE in complex 19 might arise from a lowering of the π*-

orbital with respect to the free enone ester. A small r2p, that is, the contraction of the p-orbital

coefficient, may result from the considerable cationic character of the carbon center due to

polarisation, which is enforced upon coordination.

The hydride abstraction from silyl enol ethers with Ph3C+ to give enones has literature

precedent, as stated above.55 Thus, the observed reaction with the ruthenium-bound β-keto

ester enolate is not surprising in retrospect. It is rather unexpected, though, that also AgPF6

effects the same transformation to a considerable extent (Table 3.1, run 3).

3.2.3.4 X-Ray Crystal Structure of Complex 19

Structural proof was gained by an X-ray crystal structure of (rac)-19, prepared from the

racemic enolato complex (rac)-3a and (Ph3C)PF6 (1 equiv) in CD2Cl2. Single crystals of the

triclinic space group P−1 were grown by layering the solution directly after the reaction in an

NMR tube with hexane. An ORTEP drawing of the enantiomer containing (S,S)-PNNP is

reproduced in Figure 3.12. The coordination polygon around ruthenium is a distorted

octahedron with the absolute configuration (OC-6-42-A). Thus, the PNNP ligand is arranged

in Λ-cis-β configuration and in a conformation very similar to those in the crystals of the

related complexes 3a and β-keto acid complex 14.

The dicarbonyl ligand binds with the keto oxygen O(1) trans to N(1), and with the ester

carbonyl oxygen O(2) trans to P(2). As expected, this is the same configuration as in the

enolato complex 3a, resulting from the hydride abstraction without structural rearrangement.


83

Figure 3.12. ORTEP plot of the (S,S)-enantiomer of 19, viewed along the C(48)=C(49) double bond of the α-alkylidene β-keto ester ligand.

The ruthenium-oxygen bond length Ru(1)—O(1) is 2.107(2) Å, whereas a distance of

2.172(2) Å is measured for Ru(1)—O(2). These values are very similar to those of the β-keto

acid complex 14 (2.101(8) and 2.181(7) Å).

O(1)

OO(2)

Ru(PNNP)

1.235(4)

1.235(4)1.463(5)

1.465(5)

C O : 1.43C O : 1.20C C : 1.54C C : 1.34


454950 2+1.339(5)

48

19

Figure 3.13. Selected bond lengths (Å) in the α-alkylidene-β-keto ester ligand of 19 and average values (Å) for comparison.57

The C—C and C—O bond distances in the coordinated enone ester differ only

marginally from average values (Figure 3.13). The slight lengthening of both carbonyl C=O

bonds might originate from the polarisation of the conjugated system, as discussed above, or

from a d→π* back-donation of the metal into the antibonding π* orbital of the ligand.

Summarizing the attempts to oxidize the ruthenium(II) complexes [Ru(OEt2)2(PNNP)]2+

(6) or the enolato complex 3a, we did not find evidence for an oxidation to ruthenium(III)


84

compounds with the oxidants tested. In the only case where an oxidation seemed probable,

excess amounts of substrate 4a were decomposed, an outcome that is not observed in catalytic

reactions. At that point, we decided to discard the hypothesis of an involvement of

ruthenium(III) in catalysis, and started to search elsewhere for an explanation of the observed

enantioselectivity increase.

3.2.4 Catalytic Fluorination with Additives

In an early study, we reasoned that the addition of a base should increase the rate or the

enantioselectivity of the catalytic fluorination, because the reaction of a β-keto ester with

NFSI requires the removal of the α-proton at some point. Interestingly, this is not the case.

When 10 mol% of NEt3 or PPh3 are added to the catalytic fluorination of 4a, basically the

same results are observed as without additive (Table 3.2, runs 1 and 3). A full equivalent of

NEt3 slows down the reaction, and 5a is obtained only in 32% yield after 96 h, with an

enantioselectivity of 73% ee (run 2). A decrease in yield and ee is also observed for K2CO3

(run 5), and a complete inhibition took place upon adding 1 equiv of PPh3 (run 4), in this case

probably due to deactivation of the catalyst by coordination.

Table 3.2. Influence of additives on the catalytic fluorination of 4a.

O O

O

O O

OF


AdditiveCH2Cl2, r.t.4a 5a

run additive mol % time (h) yield (%) ee (%)

1 NEt3 10 23 86 88

2 NEt3 100 96 32 73

3 PPh3 10 24 91 88

4 PPh3 100 96 0 0

5a K2CO3 100 72 72 25

6 NHSI 50 23 83 87

7b NSI– 10 24 92 64 a The yield was determined by 1H NMR spectroscopy from the 5a:4a ratio. b NSI– is the bis(benzenesulfonyl)-amide anion (PhSO2)N–, introduced as its tetraphenylphosphonium salt.


85

The addition of 50 mol% of NHSI (dibenzenesulfonimide), the reaction product of

NFSI after F/H-exchange, has no significant influence on rate and selectivity (run 6). Its

conjugated base bis(benzenesulfonyl)amide (we use the abbreviation NSI– in analogy to

NHSI) leads to a decrease in enantioselectivity when added in a 10 mol% ratio as the salt

(Ph4P)NSI. The role of NHSI and NSI– will be discussed in more detail in 3.2.9.

Initially, we were puzzled by the overall negative effect of bases as additives in

catalysis. As we found later, only very weak bases have a positive influence, probably acting

as highly reversible proton-shuttles rather than for irreversible deprotonation (see below).

3.2.5 Catalytic Fluorination in Solvent Mixtures

During his investigations on the Ru/PNNP catalyzed Michael addition of β-keto esters

to methyl vinyl ketone, Francesco Santoro studied the effect of weakly basic etheral co-

solvents to dichloromethane solutions. He found significant enhancements of the reaction

rates and the enantioselectivity for all tested substrates. For example, the reaction of 4a with

methyl vinyl ketone gave the Michael adduct in 94% yield and 79% ee after 24 hours in pure

CH2Cl2. In a CH2Cl2/Et2O (1:1) mixture, the product was obtained in quantitative yield and

with 93% ee after 18 hours.

Prompted by those results, we applied solvent mixtures in the catalytic fluorination of

the standard substrate 4a with NFSI (Table 3.3).

Table 3.3. Catalytic Fluorination of 4a in solvent mixtures.

O O

O

O O

OF


solventr.t.4a 5a

run solvent time (h) yield (%) ee (%)

1 CH2Cl2 24 91 88

2 CH2Cl2/Et2O 1:1 4 94 93

3 CH2Cl2/THF 1:1 4 93 85

4 CH2Cl2/dioxane 1:1 3.5 84 83


86

The catalyst [Ru(OEt2)2(PNNP)](PF6)2 (6) was prepared in CH2Cl2, then the substrate

and the appropriate co-solvent (1:1 to CH2Cl2) were added. By this mode of addition it is

assured that the catalyst formation by chloride abstraction from 1 is not influenced by the co-

solvent.

A dramatic rate acceleration is observed in the reactions with Et2O, THF, or dioxane as

co-solvents (runs 2 – 4). Quantitative conversion is observed within 3.5 – 4 h, whereas a

reaction time of 24 h is required in pure CH2Cl2. In terms of enantioselectivity, the

CH2Cl2/Et2O (1:1) mixture is the solvent of choice, giving the fluorinated β-keto ester 5a with

93% ee. In CH2Cl2/THF (1:1) and in CH2Cl2/dioxane (1:1), 4a is fluorinated with 85% and

with 83% ee, respectively.

The observation of the rate enhancement in CH2Cl2/Et2O (1:1) opened the possibility to

reduce the catalyst loading in the fluorination of 4a, as shown in Table 3.4.

Table 3.4. Various catalyst loadings in the fluorination of 4a in CH2Cl2/Et2O (1:1).

run mol % 6 time (h) yield (%) ee (%)

1 10 4 94 93

2 5 6.5 91 91

3 2 24 96 89

With 5 mol% of catalyst, 4a is quantitatively converted within 6.5 h (run 2), with only a

slight loss of enantioselectivity (91% ee as compared to 93% ee with 10 mol% catalyst). A

reaction time of 24 h is required with 2 mol% catalyst, giving 5a with 89% ee (run 3).

3.2.5.1 Other Substrates in CH2Cl2/Et2O (1:1) Solvent Mixture

A selection of other substrates was fluorinated in the CH2Cl2/Et2O (1:1) solvent mixture

and in pure CH2Cl2, using 10 mol% of catalyst 6 (Table 3.5). A rate enhancement in the

solvent mixture is observed for all substrates 4a – 4d. The effect of the solvent on

enantioselectivity, however, is substrate specific. Besides 4a, an improvement was achieved

for its ethyl ester analog 4b, whose enantiomeric excess increases from 58% ee in CH2Cl2

(run 3) to 65% ee in CH2Cl2/Et2O (1:1) (run 4). An increase is also observed for the open-

chain β-keto ester 4c, going from 59% ee in CH2Cl2 to 77% ee in the solvent mixture. On the


87

other hand, the phenyl ketone derivative 4d gives only 24% ee in CH2Cl2/Et2O (1:1) (run 8),

whereas 69% ee are obtained in CH2Cl2 (run 7).

Table 3.5. Fluorination of substrates 4a – 4d in CH2Cl2 and CH2Cl2/Et2O (1:1).

run substrate solvent time (h) yield (%) ee (%)

1 CH2Cl2 24 91 88

2

4a

CH2Cl2/Et2O (1:1) 4 94 93

3 CH2Cl2 24 82 58

4

4b

CH2Cl2/Et2O (1:1) 3.5 84 65

5 CH2Cl2 24 91a 59

6

4c

CH2Cl2/Et2O (1:1) 6 96a 77

7 CH2Cl2 24 48 69

8

4d

CH2Cl2/Et2O (1:1) 24 65 24 a The yield was determined from the 5c:4c ratio in 1H NMR spectra.

In sum, the addition of ethers as co-solvents enhances the activity of the catalyst for the

fluorination of β-keto esters. For the enantioselectivity, there is no general rule. First, the

change of enantiomeric excess for 5a depends on the choice of the ether, that is, an

improvement is only achieved with Et2O from the ethers that were tested. Secondly, whether

an increase or a decrease of the ee is obtained in CH2Cl2/Et2O (1:1) depends on the substrate.

These facts indicate that rather subtle effects must be at play upon addition of Et2O. As we

found out later (see below), these effects are associated with the ability of Et2O to act as a

weakly basic proton-shuttle.

3.2.6 Catalysis Under Ether-Free Conditions

The strong influence of Et2O on the reaction rate and selectivity prompted us to

examine the catalytic fluorination of 4a under ether-free conditions. In fact, 20 mol% of Et2O

are always present in the standard catalytic reaction. The chloride abstraction from

[RuCl2(PNNP)] (1) with (Et3O)PF6 (2 equiv) to prepare the active catalyst (method a)

produces two equivalents of Et2O and chloroethane as by-products. Hence, catalysis under

ether-free conditions would require an alternative method for chloride abstraction. An

important criterion thereby is that the dicarbonyl complex 2a, an assumed catalysis

O O

O

O O

OEt

O

OEt

O

O

OEt

O


88

intermediate, can be formed under those conditions. Consequently, the goal was to find a

method for the preparation of 2a that avoids the use of (Et3O)PF6.

Silver(I) salts were used as scavengers for the abstraction of both chloro ligands from 1

in the group.58 When AgBF4 or AgSbF6 (2 equiv) were reacted with 1, followed by addition

of β-keto ester 4a, considerable quantities of the diaqua complex [Ru(H2O)2(PNNP)]2+ were

formed apart form 2a. Most probably, water was carried into the reaction mixture by the

highly hygroscopic silver salts.

A very clean method for the abstraction of one chloro ligand from 1 involves the

reaction with thallium(I) salts. Even with an excess of TlPF6, the penta-coordinate

monocationic complex [RuCl(PNNP)]+ (9) is the only product, and no double abstraction is

observed (Scheme 3.15). However, we found that when the chloride abstraction with TlPF6

(2.4 equiv) is carried out in the presence of β-keto ester 4a (1.4 equiv), the desired complex

2a is formed along with 5 – 10% of the diaqua complex [Ru(H2O)2(PNNP)]2+, which is in the

same range as observed in the reaction with (Et3O)PF6. The by-product TlCl is removed by

filtration together with excess amounts of TlPF6 after the reaction.

O

OO

RuP

N

N

P

H

(PF6)2

O

O

O

1

2a

1) (4a)

(1.4 equiv)

2) TlPF6 (2.4 equiv)CH2Cl2, r.t.

TlPF6(excess)

CH2Cl2r.t.

PF6

RuP

N

N

P

Cl

9PF6

Scheme 3.15. Synthesis of 2a with TlPF6 as chloride scavenger (method b).

We now had a method for the synthesis of 2a in hand that circumvents the formation of

Et2O as a side-product. Catalytic fluorinations were carried out with this protocol to study the

difference between ether-free conditions (TlPF6 abstraction) and the standard conditions with

20 mol% of Et2O ((Et3O)PF6 abstraction). The results are compiled in Table 3.6. For the

catalytic reactions, NFSI was added to a solution of 2a, prepared from 1 and TlPF6 (2.4

equiv) in the presence of β-keto ester 4a (10 equiv).


89

Table 3.6. Comparison of chloride scavengers and solvents in the catalytic fluorination of 4a.

O O

O

O O

OF4a 5a

catalyst (10 mol%)NFSI (1.08 equiv)

solvent, r.t.

run Cl-scavenger solvent time (h) yield (%) ee (%)

1a (Et3O)PF6 CH2Cl2 24 91 88

2a (Et3O)PF6 CH2Cl2/Et2O (1:1) 4 94 93

3b TlPF6 CH2Cl2 24 88 86

4b TlPF6 CH2Cl2/Et2O (1:1) 4 92 93 a The catalyst was prepared by method a from 1 and (Et3O)PF6 (2.05 equiv), then 4a and NFSI were added. b The catalyst was prepared by method b from 1 and TlPF6 (2.4 equiv) in the presence of 4a (10 equiv), NFSI was added after filtration.

Two main points are worth of notice in Table 3.6. First, under ether-free conditions with

TlPF6 as chloride scavenger in CH2Cl2 as solvent (run 3), the fluorinated product 5a is

obtained in 88% yield and with 86% ee. This enantiomeric excess is slightly lower than the

88% ee that are observed under standard conditions (run 1). If regarded as significant, it

indicates that even small amounts of Et2O (20 mol% from the chloride abstraction with

(Et3O)PF6) have a positive effect on the enantioselectivity. Secondly, in the presence of a

large excess of Et2O in the CH2Cl2/Et2O (1:1) solvent mixture, 93% ee are obtained

irrespective whether (Et3O)PF6 or TlPF6 are used as chloride scavenger (runs 2 and 4).

3.2.7 Stoichiometric Reactions of Dicarbonyl Complex 2a with NFSI

Stoichiometric reactions of catalyst-substrate adduct complexes can give useful

mechanistic information, as only the actual stereodifferentiating step at the metal is

considered, and all effects of turnover are ruled out. With the dicarbonyl complex 2a and the

enolato complex 3a, we had the adduct complexes of the best-performing substrate 4a

available to test in stoichiometric reactions. Furthermore, the parameters solvent (CH2Cl2 vs.

CH2Cl2/Et2O (1:1)) and chloride scavenger for the synthesis of 2a ((Et3O)PF6 vs. TlPF6) were

varied. Especially from the comparison of the stoichiometric reactions in CH2Cl2 and the

CH2Cl2/Et2O mixture, we hoped to find an explanation for the rate and selectivity

enhancement in the latter solvent.


90

Complex 2a was prepared in situ from [RuCl2(PNNP)] (1) either by method a (chloride

abstraction with (Et3O)PF6) or by method b (chloride abstraction with TlPF6), in pure CH2Cl2

or in CH2Cl2/Et2O (1:1). After the addition of NFSI (1.05 equiv), the mixture was stirred over

night, then the reaction was quenched by the addition of Bu4NCl and 5a was isolated by

column chromatography. The results are summarized in Table 3.7. All reactions of 2a with

NFSI gave the (R)-enantiomer of 5a, which is the same sense of asymmetric induction as

observed in the catalytic reaction.

Table 3.7. Stoichiometric fluorination of 2a.

O

OO

RuP

N

N

P

H

(PF6)2

2a

1) NFSI (1.05 equiv)

2) Bu4NCl,chromatography

O O

OF

5a

run Cl-scavenger solvent yield (%) ee (%)

1 (Et3O)PF6 CH2Cl2 92 82

2 (Et3O)PF6 CH2Cl2/Et2O (1:1) 96 82

3 TlPF6 CH2Cl2 95 81

4 TlPF6 CH2Cl2/Et2O (1:1) 74 81

Surprisingly, neither the preparation method for 2a, nor the presence of a large excess

of Et2O makes a significant difference in the outcome of the stoichiometric reactions (runs 1 –

4). Moreover, 5a is obtained with 81 – 82% ee only, whereas 86% ee is observed for the

catalytic reaction under ether-free conditions, or 93% ee for the catalytic fluorination in the

CH2Cl2/Et2O (1:1) solvent mixture (see Table 3.6). The fact that the stoichiometric

fluorinations of 2a are less enantioselective than the catalysis is in accord with the observation

that the enantiomeric excess increases with ongoing conversion in the catalytic reaction.

Apparently, the dicarbonyl complex 2a is not the species that gives the highest

enantioselectivity in the catalysis solution.

The finding that diethylether as co-solvent has a strong influence on catalysis, but is

completely ineffective in the stoichiometric reaction of 2a is more puzzling, though. It implies

that further factors besides the presence of Et2O are necessary to achieve high enantiomeric

excess in the catalytic reaction.


91

3.2.8 Stoichiometric and Catalytic Fluorinations with Complex 3a

A different situation is observed with the enolato complex 3a in stoichiometric

fluorinations. The reaction of isolated 3a with NFSI (1 equiv) in CH2Cl2 yields the fluorinated

β-keto ester 5a with almost complete enantioselectivity of 97% ee (Table 3.8, run 1). Taken

together with the attempts with 2a, this is the only stoichiometric fluorination that gives a

higher selectivity than the catalytic reactions.

Table 3.8. Enolato complex 3a in stoichiometric and catalytic fluorination.

run mode solvent yield (%) ee (%)

1 stoichiometrica CH2Cl2 81 97

2 stoichiometrica CH2Cl2/Et2O (1:1) 99 93

3 catalyticb CH2Cl2 61c 47

4 catalyticb CH2Cl2/Et2O (1:1) 83 35 a Isolated 3a was reacted with NFSI (1 equiv). b 3a (0.1 equiv) and 4a (0.9 equiv) were treated with NFSI (1.05 equiv) in the specified solvent. c After 24 h, the reaction reached only 65% conversion, as indicated by 1H NMR spectroscopy.

In contrast to the reaction of 2a, the presence of diethylether as a co-solvent does have

an influence on the stoichiometric fluorination of 3a. The enantioselectivity decreases to 93%

ee in CH2Cl2/Et2O (run 2), a fact for which we have no viable explanation at the moment.

It should be noted that the stoichiometric reaction of 3a is quite sensitive to impurities.

When a batch of 3a is used, that contains small amounts of impurities such as free β-keto

ester 4a, significantly lower enantioselectivities are observed. Values as low as 83% ee were

obtained initially, which was deceiving and supported the hypothesis of an active Ru(III)

species in the catalytic cycle. The stepwise improvement of the experimental procedures and

the gain of experience with the handling finally led to reproducible and high enantiomeric

excesses for the stoichiometric fluorination of 3a.

The results in Table 3.8 show that despite its outstanding performance in the

stoichiometric reaction, 3a is unsuitable as a catalyst for the fluorination of 4a. The reaction

with 10 mol% of 3a is slow in dichloromethane (run 3), giving 5a with only 47% ee and 61%

yield at 65% substrate conversion after 24 hours. The fluorination is faster and reaches

complete conversion after 24 hours in CH2Cl2/Et2O (1:1), but is even less selective, giving

35% ee only (run 4). Why is there such a difference between the stoichiometric and catalytic


92

fluorination for 3a, while being much more similar in the case of 2a (stoichiometric: 81 –

82% ee, catalytic: 86 – 93% ee, see Table 3.6 and 3.7)?

The difference between 2a and 3a is that the first turnover of the reaction with NFSI

produces (PhSO2)2NH (NHSI) in the case of 2a and (PhSO2)2N– (NSI–) with 3a. Or to put it

more prosaic: One equivalent of protons is missing for the continuation of the catalytic cycle

with 3a. Therefore, we assessed the effects of NHSI and NSI– to reveal their roles in

stoichiometric and catalytic fluorination, as described in the following paragraph.

In conclusion, the stoichiometric fluorinations of 2a and 3a were helpful in many

respects for a better understanding of the reaction. The observation that 3a is fluorinated with

much higher enantioselectivity than 2a led us to the assumption that in fact 3a could be our

sought-after most enantioselective species in catalysis. Furthermore, the finding that Et2O

does not affect the stoichiometric fluorination of 2a suggests that it can unfold its beneficial

action only in connection with a turnover event. We speculated that the changing composition

of the catalysis mixture with time – a direct consequence of turnover – could be responsible

for the observed phenomena. Our investigations to that end are described in detail below.

3.2.9 The Role of NHSI and NSI–

Dibenzenesulfonimide (NHSI) is the final reaction product of NFSI after F/H-exchange

with a β-keto ester. So far, we considered NHSI to be an innocent by-product, especially

because we did not find any effect upon addition of 50 mol% of NHSI to the catalytic reaction

(see 3.2.4). Its conjugated base bis(phenylsulfonyl)amide (NSI–), however, does not seem to

be innocent. The fluorination of 4a with the enolato complex 3a as catalyst (paragraph 3.2.8),

as well as the catalysis with 10 mol% of NSI– as additive (3.2.4) exhibit significantly lower

enantioselectivities as compared to the standard catalytic reaction.

To study its effects in more detail, a convenient and soluble source of NSI– was

required. The sodium salt was easily prepared by deprotonation of NHSI with sodium hydride

in THF. As suspected, NaNSI is completely insoluble in dichloromethane unless 18-crown-6

is added. Since it is not clear whether the crown ether would interfere with the fluorination

reaction, we were looking for soluble NSI– salts. The tetraphenylphosphonium salt was

prepared by deprotonation of NHSI in aqueous NaOH, followed by salt metathesis with

Ph4PBr (Scheme 3.16). The product is highly crystalline and soluble in CH2Cl2.


93

81 %SNS

H

O O OO SNS

O O OO

Ph4P

1) NaOH, H2O

2) Ph4PBr,H2O/EtOH 1:1

Scheme 3.16. Preparation of tetraphenylphosphonium bis(phenylsulfonyl)amide (Ph4P)NSI.

4a does not react with NFSI in the presence of (Ph4P)NSI (1 equiv), giving only about

1% conversion after 28 hours. This excludes the possibility of a NSI–-mediated background

reaction as explanation for the negative effect of NSI– on the enantioselectivity.

3.2.9.1 Ruthenium PNNP Complexes with Coordinated NSI-

To uncover the effect of NSI– in catalysis, we studied its coordinating properties

towards ruthenium. [Ru(OEt2)2(PNNP)](PF6)2 (6), prepared in situ from 1 and (Et3O)PF6

(2.05 equiv), was treated with (Ph4P)NSI (1 equiv) in CD2Cl2 (Scheme 3.17). The color of the

solution changed from brown to red, and a white solid precipitated, probably (Ph4P)PF6. The

solution was analyzed by NMR spectroscopy after removing the solids by filtration.

SN

O

S ORu

P

N

N

P

PF6O

O

Ph

Ph

20a-c

N N

PPPh2 Ph2

Ru

Cl

Cl

1) (Et3O)PF6 (2.05 equiv)CD2Cl2, r.t., 15 h

2) (Ph4P)NSI (1 equiv)

1

unidentifiedby-products+

Scheme 3.17. Coordination of NSI– to the Ru/PNNP fragment.

In the 31P NMR spectrum, three new AB spin patterns appeared, indicating the

formation of three new complexes 20a, 20b, and 20c in the ratio 1.2:1:1.7. Besides, several

broad signals were observed. Correspondingly, the 1H NMR spectrum showed three sets of

signals that are diagnostic for the PNNP ligand in cis-β-configuration. These are three

doublets and singlets for the imine protons (HC=N) and three multiplets for a HC—N

cyclohexane proton. We assumed that complexes 20 contain coordinated NSI–, but as they

were not formed cleanly, we envisioned another approach for their preparation.

As an alternative synthesis of complexes 20, the isolated enolato complex 3a was

reacted with NFSI (1 equiv) in CD2Cl2. The prerequisite for this strategy is that the

fluorinated β-keto ester 5a is replaced as a ligand by NSI– after the stoichiometric


94

fluorination. In fact, this turned out to be the case: a clean and quantitative reaction was

observed (Scheme 3.18). The 19F NMR spectrum of the reaction mixture shows a doublet of

doublets at δ −162.8, proving that 5a is not coordinated to ruthenium. Interestingly, only two

of the three complexes from the previous experiment are formed (20a and 20b) in a 1.4:1

ratio, as indicated by 31P and 1H NMR spectra.

O

OO

RuP

N

N

P

PF6

3a

SN

O

S ORu

P

N

N

P

PF6O

O

Ph

Ph

O O

OF

5a

NFSI (1 equiv)

CD2Cl21 h, r.t.

+

20a,b

Scheme 3.18. Synthesis of complexes 20a and 20b (tentatively drawn structure) from 3a.

In the ESI mass spectrum of the reaction solution, a molecular ion with m/z = 1056 is

observed, which has a daughter ion at m/z = 759. The mass of the molecular ion suggests that

both 20a and 20b are ruthenium complexes containing a PNNP and a NSI– ligand. A mass of

759 is obtained after loss of NSI– and one-electron reduction to give a [Ru(PNNP)]+ fragment.

The attempts of growing single crystals from the reaction mixture containing 20a and

20b for X-ray analysis failed so far, thus we do not have any information about the structure

and configuration of complexes 20. The drawing in Scheme 3.17 and 3.18 with the O,O’-

bidentate coordination of NSI– is a purely tentative formulation. O- or N-monodentate as well

as O,O’- or O,N-bidentate coordination is observed for this type of ligands in transition metal

complexes (see 3.2.9.3). It is not clear at present whether 20a, 20b, and 20c differ in the

coordination mode of NSI– or in the configuration of the PNNP ligand. It is important to

notice that NSI− is able to bind to ruthenium after stoichiometric fluorination of 3a. In

contrast, none of complexes 20 were observed after stoichiometric fluorine transfer to 2a,

where NHSI is produced instead of NSI−.

3.2.9.2 Acid-Base Reaction of 2a and 3a with NHSI and NSI-

We then investigated the acid-base reactions between NSI– and 2a, and between NHSI

and 3a, respectively. An aqueous pKa value of 1.45 has been reported for NHSI,59 showing

that it is a relatively strong acid in water. In CD2Cl2, however, NSI– is strong enough a base to

cleanly deprotonate the dicarbonyl complex 2a. The reverse experiment was carried out by


95

adding NHSI (1 equiv) to a CD2Cl2 solution of 3a. No protonation seems to take place, as the 31P NMR spectrum shows the signals of 3a exclusively, and the acidic N—H proton gives a

broad signal at δ 4.4 in the 1H NMR spectrum. By adding further 8 equivalents of NHSI, the 31P NMR doublets broaden and shift from the position observed for 3a (δ 63.4 and 52.5) to δ

62.8 and 52.2, that is, towards those of 2a (δ 61.2 and 51.3). We take this as an indication that

3a is protonated to a small extent in the presence of an excess of NHSI. Upon addition of

Et2O in a CD2Cl2/Et2O ratio of 7:1, however, the signals return to their original shape,

suggesting that only 3a is present. Taken together, it can be anticipated that NHSI mainly

exists in its non-ionized form in the presence of the dicarbonyl complex 2a, and not as the

NSI– anion.

As mentioned in paragraph 2.2.6, the acid-base experiments with NHSI suggest a

correction of the pKa value of 2a. From the reaction with NSI–, it must be concluded that 2a is

the stronger acid than NHSI, that is to say, a pKa lower than 1.45 on the pseudo-aqueous

scale. As explained before, these results have rather qualitative character and support a slight

correction downwards from the original pKa determination with PPh3 as reference.

In conclusion, the NSI– anion is present only under basic conditions, for instance with

3a as catalyst. Under such conditions, NSI– is able to bind to ruthenium and form the adduct

complexes 20. This is irrelevant in the case of the stoichiometric reaction, because the

coordination occurs after fluorine transfer. On the other hand, when 3a is used as catalyst, the

first turnover produces complexes 20, which then continue in the catalytic cycle. Our results

suggest that these catalytic species are able to fluorinate 4a, but with lower enantioselectivity

than 2a or 3a. This explains the decrease of the enantiomeric excess when 3a is used as

catalyst, or upon addition of (Ph4P)NSI (10 mol%) to a standard catalytic run.

3.2.9.3 Literature Examples of Bis(organosulfonyl)amide Complexes

A range of bis(organosulfonyl)amide complexes with a variety of different metals and

different organosulfonyl groups have been reported in literature. The most prominent ligand

certainly is the bis(trifluoromethylsulfonyl)imide anion (F3CSO2)2N– (also called triflimide,

abbreviated as Tf2N–). Figure 3.14 displays a selection of crystallographically characterized

complexes, illustrating the diverse coordination modes of the triflimide ligand.

Simple metal triflimide salts are potent catalysts for some organic reactions. For

example, Co(NTf2)2, Ni(NTf2)2, and Mn(NTf2)2 were successfully employed in Friedel-Crafts


96

acylations.60 Cu(NTf2)2 proved to be an effective catalyst for the Diels-Alder reaction of

cyclopentadiene with methyl vinyl ketone.61

Cu

N

OC CO

SSF3C CF3

O O O O

Cp2Ti

O

O

SN

OCF3

SCF3

OO

SN

OCF3

SCF3

OO

η1-N η1-O

F3CSN

OSCF3

OO O

Ti OS N

O CF3

S CF3O O

SitBuN

η2-O,O'η1-O

SO N

OF3CSCF3

O O

Ru OSNSCF3

O O

O

F3C

η2-N,Oη1-O

Figure 3.14. Complexes containing the Tf2N– ligand in different coordination modes.62,63

The aromatic counterparts, bis(arylsulfonyl)amide complexes, were reported mainly in

gold(I)64 and silver(I)65 complexes.

3.2.10 Coordination of Fluorinated β-Ketoester 5a to Ruthenium

We briefly investigated the coordination properties of the fluorinated catalysis product

5a towards the ruthenium/PNNP fragment. We were interested to see whether a distinct

adduct complex could be prepared by a method similar to the synthesis of dicarbonyl complex

2a. To that end, a CD2Cl2 solution of [RuCl2(PNNP)] (1) was treated with TlPF6 (2.4 equiv)

and (rac)-5a (1.1 equiv) at room temperature.

As displayed by the 31P NMR spectrum after filtration, about 50% of 1 underwent single

chloride abstraction to complex 9PF6 only, which is consistent with the observation of free 5a

(47%) in the 19F NMR spectrum (Scheme 3.19). Apparently, 5a is the weaker ligand than 4a,

whose reaction with complex 1 and TlPF6 leads to complete double chloride abstraction.

Apart from the signals of [RuCl(PNNP)]+ (9), the 31P NMR spectrum features several sharp

doublets and several broad singlets that could not be interpreted.


97

1

O

OO

RuP

N

N

P

F

(PF6)2

O

OO

RuP

N

N

P

F

(PF6)2

1) (rac)-5a (1.1 equiv)2) TlPF6 (2.4 equiv)

1) (R)-5a (1.1 equiv)2) TlPF6 (2.4 equiv)

21a-e

21a,c,e

PF6

RuP

N

N

P

Cl

PF6

RuP

N

N

P

Cl

+

+

~ 50%

~ 50%

9PF6

9PF6

Scheme 3.19. Synthesis of adduct complexes 21 from (rac)- and (R)-5a.

The 19F NMR spectrum gave further useful hints, though. Five broad triplet-shaped

signals are visible besides the resonance for free 5a. We assign these signals to different

diastereoisomers of [Ru(5a)(PNNP)]2+ (21a-e), containing the fluorinated β-keto ester as

ligand (Table 3.9). However, we do not have structural proof for those complexes, and the

configuration drawn in Scheme 3.19 is arbitrarily chosen. When (R)-5a (91% ee) is used for

the reaction, only three signals corresponding to 21a, 21c, and 21e are observed in the 19F

NMR spectrum (Table 3.9).

Table 3.9. Product distribution in the formation of complexes 21, determined by integration of 19F NMR spectra.

5a 21a 21b 21c 21d 21e

δ (ppm) −162.7 −162.3 −163.3 −164.3 −164.9 −165.3

(rac)-5a 47% 28% 5% 9% 6% 4%

(R)-5a 44% 38% − 14% − 4%

A ligand competition experiment with complex 2a and fluorinated β-keto ester (rac)-5a

showed that 4a is not displaced even in the presence of 10 equivalents of 5a. On the other

hand, (rac)-5a is gradually liberated from preformed complexes 21a-e upon stepwise addition

of 4a. The ligand exchange is accompanied by some decomposition to unidentified products,

though.

In conclusion, the coordination experiments and ligand exchange reactions described

above indicate that the non-fluorinated β-keto ester 4a binds more strongly to ruthenium than


98

5a. This is also reasonable regarding the catalytic turnover in the fluorination of 4a with

NFSI. If the catalysis product was the better ligand than the substrate, the catalytic cycle

would be inhibited after the first turnover.

3.2.11 Enantiomeric Excess vs. Conversion with Limiting NFSI

As mentioned above, Et2O as co-solvent increases the rate and the enantioselectivity of

the ruthenium-catalyzed fluorination of 4a, but does not affect the stoichiometric fluorination

of the dicarbonyl complex 2a. But still, we could not answer the question what the function of

Et2O is, or which other factors come into play to achieve high enantiomeric excess.

The fact that the stoichiometric reaction of complex 2a with NFSI in CH2Cl2/Et2O (1:1)

gives lower enantiomeric excess than the corresponding catalytic one, implies that the

enantioselectivity of fluorine transfer must increase during the course of the reaction. Such a

behavior was observed in pure CH2Cl2 by taking samples at several reaction times (see

paragraph 3.2.2). Unfortunately, analogous experiments in CH2Cl2/Et2O (1:1) failed.

Especially at low substrate conversion, the results were unreliable and not reproducible. We

speculate that in CH2Cl2/Et2O (1:1), the reaction continues after quenching the catalyst with

Bu4NCl, probably catalyzed in a non-enantioselective manner by Bu4N+.

Consequently, we devised a set of experiments that delivers essentially the same

information. Catalytic reactions with limiting amounts of NFSI were run to determine the

enantiomeric excess of 5a as a function of the conversion. These reaction series were carried

out in both CH2Cl2 and CH2Cl2/Et2O (1:1) as solvents for comparison.

Figure 3.15. Enantiomeric excess vs. conversion for the catalytic fluorination of 4a with limiting amounts of NFSI in the solvents CH2Cl2 (♦) and CH2Cl2/Et2O (○).

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

% Conversion

% e

e

O O

OF

CH2Cl2

CH2Cl2/Et2O (1:1)


99

As depicted in Figure 3.15, the enantiomeric excess of 5a increases in both solvents

with increasing amounts of NFSI added. However, whereas being rather steady in CH2Cl2, the

increase is dramatic in CH2Cl2/Et2O (1:1). The enantioselectivity goes from 73% ee with 0.1

equivalents of NFSI to above 90% ee with 0.25 equivalents of NFSI and stays approximately

constant thereafter. This head start seems to be responsible for the overall higher enantiomeric

excess in the solvent mixture.

These experiments hold the important clue that the first turnover is considerably less

selective than all the following ones. We have seen before that the production of NHSI or

NSI– is not responsible for the selectivity enhancement of the later turnovers. One remaining

possibility is that the accumulation of the fluorinated β-keto ester 5a causes the increase of the

enantioselectivity. In the first turnover, the substrate 4a is present in excess, whereas the last

turnover takes place in the presence of an excess of 5a.

3.2.12 Stoichiometric Fluorination of 2a with β-Keto Ester Additives

To test the hypothesis whether the 4a:5a ratio is responsible for the increase of

enantioselectivity, we devised experiments to simulate the first and the last turnover of

catalysis independently. Thus, the stoichiometric fluorine transfer to complex 2a was carried

out in the presence of either excess β-keto ester 4a (9 equiv), or of the structurally closely

related fluorinated ethyl ester 5b (9 equiv) in CH2Cl2 or in CH2Cl2/Et2O (1:1) as solvents

(Table 3.10). 5b was chosen as a model product that allows for the independent determination

of the enantiomeric excess of 5a formed in the stoichiometric fluorination of 2a. Using an

excess of 5a with known enantiomeric excess would require the calculation of incremental

ee’s from the observed total ee, a procedure that amplifies the experimental error.

The results in both solvent systems show that excess substrate 4a, simulating the first

turnover of catalysis, decreases the enantioselectivity. 66% and 57% ee are obtained in

CH2Cl2 and CH2Cl2/Et2O (1:1), respectively (Table 3.10, runs 3 and 4), whereas 81% ee is

obtained in the stoichiometric reactions without additives (runs 1 and 2). Conversely, the

presence of an excess of the “pseudo-product” (rac)-5b, simulating the final turnover of

catalysis, leads to significantly better selectivities than with excess 4a. 79% ee is obtained in

CH2Cl2 (run 5), and an even more pronounced effect is observed in CH2Cl2/Et2O (1:1), where

5a is produced with 86% ee (run 6), a value that is close to the best catalytic results.


100

Table 3.10. Stoichiometric fluorination of 2a in the presence of additives 4a and 5b.a

O

OO

RuP

N

N

P

H

2+

2a

O O

OF

5a

Additive(9 equiv)

solventr.t.

+NFSI

(1 equiv)

run additive solvent ee (%)

1b CH2Cl2 81

2b none

CH2Cl2/Et2O (1:1) 81

3 CH2Cl2 66

4 4a

CH2Cl2/Et2O (1:1) 57

5 CH2Cl2 79

6 (rac)-5b

CH2Cl2/Et2O (1:1) 86

7 (R)-5b CH2Cl2 78

8 (S)-5b CH2Cl2 77

a Complex 2a was prepared in situ from 1 and TlPF6 (method b). b See Table 3.7.

In addition, the influence of the pure (R)- and (S)-enantiomers of 5b as additives was

tested in CH2Cl2 as solvent. To this end, the enantiomers were separated by preparative HPLC

and were obtained in nearly optically pure from, that is, (R)-5b with 99.8% ee and (S)-5b with

97.8% ee. In the stoichiometric reaction of 2a, the fluorinated β-keto ester 5a was formed

with 78% ee in the presence of (R)-5b (run 7), and with 77% ee in the presence of (S)-5b,

respectively (run 8). The small differences to the value obtained with (rac)-5b in CH2Cl2

(79% ee) cannot be regarded as significant. Thus, the improved results with 5b as additive are

not connected with its absolute configuration.

In conclusion, the combined presence of the fluorinated β-keto ester 5b and Et2O as

additives leads to an optimal outcome of the stoichiometric fluorination of complex 2a. The

fact that the enantioselectivity is higher with an excess of fluorinated product than with

substrate as additive is consistent with the increase of selectivity observed in the catalytic

fluorination of 4a. The 4a:5a ratio is shifted towards 5a with ongoing conversion, which

creates more and more selective conditions with each turnover.

O O

OEtF

O O

O

O O

OEtF

O O

OEtF


101

3.2.13 Dynamic Exchange Between Complexes 2a and 3a

As described in the previous section, the increasing concentration of 5a, together with

Et2O, might be responsible for the increase of the enantioselectivity in the catalytic

fluorination of 4a. By which mechanism, however, we did not know so far. In view of the

high selectivities achieved in the stoichiometric reaction of enolato complex 3a, we

speculated that the formation of 3a in catalysis could be the reason, but we had no proof.

Then, an unexpected clue came from an experiment that was meant for another purpose.

We planned to examine a solution of complex 2a by NMR spectroscopy at various

temperatures to confirm that no other diastereoisomers are formed. 2a was prepared by

method b (TlPF6 abstraction) in a concentration of 0.045 M in CD2Cl2, which is higher than

the reactions conducted previously. The 31P NMR spectrum of the solution exhibited, apart

from 2a (85% by integration) and small amounts of the diaqua complex (8%), slightly

broadened signals of the enolato complex 3a (7%). This was surprising, because 3a was never

observed in the synthesis of 2a without the addition of a base. It should be noted that the

enolato complex 3a was not detected when similar experiments were carried out by chloride

abstraction with (Et3O)PF6. In that case, the conditions are slightly acidic, because Et3O+

forms one equivalent of Et2OH+ in the reaction with adventitious water (Et3O+ + H2O →

EtOH + Et2OH+). With TlPF6 abstraction at lower concentrations, the intensity of the signals

of 3a was probably too low to be distinguishable from the baseline noise.

Upon cooling the CD2Cl2 solution of complex 2a to −30 °C, the 31P NMR signals of 3a

sharpened. Experiments with selective irradiation on the phosphorus resonances showed that

complexes 2a and 3a are slowly exchanging at room temperature. Furthermore, a two-

dimensional phase-sensitive 31P,31P{1H}-EXSY NMR spectrum was recorded. This technique

allows for the detection of slow exchange processes under equilibrium conditions, giving

clear cross-peaks also for species with signals of low intensity.66 The region of interest is

reproduced in Figure 3.16. The cross-peaks between the 31P NMR signals of 2a and 3a

(highlighted by dashed lines) prove their chemical exchange. The dispersive-shape cross-

peaks between the two doublets of 2a are remains of zero quantum coherences (COSY-type

signals) that cannot be filtered completely for intense signals.67


102

Figure 3.16. Contour plot of the 2D 31P{1H}-EXSY NMR spectrum of complex 2a (prepared by method b, recorded at 298 K), proving its slow chemical exchange with 3a.

The absence of cross-peaks to the diaqua complex and to the signals of minor impurities

indicates that no other species is involved in the exchange process.

The exchange between complexes 2a and 3a was also observed by 1H,1H-NOESY

NMR spectroscopy. In a phase-sensitive NOESY spectrum, the cross-peaks originating from

magnetization exchange through dipole-dipole relaxation (NOE effect) and those originating

from chemical exchange can be distinguished by their phase. A chemical exchange peak has

the same phase as the diagonal signals, whereas NOE cross-peaks have the opposite phase.68

The chemical exchange is nicely displayed by the imine doublets of 2a (δ 9.03) and 3a (δ

8.69) in Figure 3.17. The superimposed dashed spectrum shows the imine region of pure

enolato complex 3a as reference. The intensity of its doublet is very low in the one-

dimensional 1H NMR spectrum of 2a, but the cross-peak clearly indicates its presence in the

equilibrium. Further distinctive exchange cross-peaks are observed for a characteristic

aromatic proton, a HC—N cyclohexane proton and for the tert-butyl group.


103

Figure 3.17. Section of the 1H,1H-NOESY NMR spectrum of 2a prepared by method b, showing chemical exchange between 2a (solid 1D spectrum) and 3a (dashed 1D spectrum).

The data from the 2D 31P{1H}-EXSY and from the 1H-NOESY NMR experiments

provide evidence that the partner for dynamic exchange of 2a is indeed the enolato complex

3a. Also a 31P,1H-COSY experiment conducted at −30 °C gives concurrent results. The broad

low-intensity 31P doublets, observed in the solution of complex 2a prepared with TlPF6,

exhibit correlation cross-peaks to several hydrogen atoms characteristic of 3a.

A base is obviously required for the exchange between 2a and 3a to take place. In the

CD2Cl2 solution of complex 2a, the only viable candidate as a base is free β-keto ester 4a,

which is present in small amounts because it is liberated during the formation of

[Ru(OH2)2(PNNP)]2+. A β-keto ester acting as a base has also been proposed by Schwarz and

co-workers, who studied Fe(III) complexes of methyl acetoacetate by ESI-MS.69 They found

that mixing Fe(ClO4)3 with methyl acetoacetate gives a cationic complex with two enolato

ligands and a non-enolized β-keto ester ligand (see 2.1.3.3). Upon adding an excess of β-keto

ester, however, the concentration of the measurable cationic species decreased. They

attributed this behavior to the ability of the excess β-keto ester to deprotonate the complex to

neutral [Fe(enolate)3], which cannot be detected by ESI-MS.


104

3.2.14 Rate Constants for the Exchange Between 2a and 3a

The possible involvement of the (undoubtedly very weak) base 4a in the acid-base

equilibrium between 2a and 3a opens a new perspective on the mechanistic details of the

ruthenium-catalyzed fluorination. It implies that in catalysis, all the present oxygenated

molecules could participate in this equilibrium as a base, namely substrate, fluorinated

product, and diethylether. Consequently, they would influence the equilibrium concentration

and the availability of the highly selective enolato complex 3a.

We decided to determine the exchange rate constants and the equilibrium ratios with an

excess of β-keto ester 4a or of its fluorinated analog 5a as weak base, either in CD2Cl2 or in

CD2Cl2/Et2O mixtures as solvent. These are again conditions that are modelled on the

situation in the first and last turnover of catalysis.

Exchange rates can be determined by NMR line-shape analysis of the two exchanging

species, in our case the 31P NMR signals of complexes 2a and 3a.70 The results are

summarized in Table 3.11, and average values are given where multiple determinations were

carried out. The calculations and all detailed values are given in the Experimental Part.

Table 3.11. Rate constants and equilibrium ratios for the exchange between 2a and 3a.a

O

OO

RuP

N

N

P

H

2+

2a

+ B + BH+

O

OO

RuP

N

N

P

+

3a

k1

k-1

entry solvent additive B k1 (s−1)b k−1 (s−1)b 2a:3a

1 CD2Cl2 − 2.6±0.4 28±4.9 92:8

2 CD2Cl2 4a (8 equiv) 3.0 27 90:10

3 CD2Cl2 5a (8 equiv) 3.1 32 91:9

4c CD2Cl2/Et2O − 2.3±0.8 18±2.9 89:11

5c CD2Cl2/Et2O 4a (8 equiv) 5.5±1.1 38±8.0 87:13

6c CD2Cl2/Et2O 5a (8 equiv) 14±3.6 75±6.6 85:15 a Determined by line width analysis of the 31P NMR spectra (Lorentz lines). b Values with ± one standard deviation. c With a CD2Cl2/Et2O ratio of 8:1.


105

The rate constant for the formation of complex 3a, k1, is of particular interest. Without

additives and in pure CD2Cl2 (entry 1), a k1 of 2.6±0.4 s−1 is observed. As described above,

small amounts of free β-keto ester 4a might act as base B in that case. A similar k1, but a

somewhat decreased k−1 of 18±2.9 s−1 is obtained in CD2Cl2/Et2O (entry 4). In CD2Cl2, the

addition of an excess of 4a or 5a does not change the rate and equilibrium constants to a

significant extent (entries 2 and 3). Strong effects are only observed when both Et2O and a β-

keto ester are present. k1 increases by about a factor of two in the presence of an excess of 4a

with respect to the situations without additives (entry 5). However, with an excess of the

fluorinated β-keto ester 5a, a more than 5-fold increase of k1, and a 2.5-fold increase of k−1 are

obtained (entry 6). Furthermore, 3a is formed in a mol fraction of 15%, the highest value

measured in this series.

The above results indicate that Et2O is crucial for the acceleration of proton transfer in

the presence of β-keto esters 4a or 5a. In the solvent mixture, all exchange rate constants and

the equilibrium constants are higher as compared to pure CH2Cl2 solutions. The comparison

of entries 5 and 6 gives a possible explanation for the increasing (and overall higher)

enantioselectivity in the catalytic fluorination of 4a in CH2Cl2/Et2O (1:1). k1 and the

concentration of 3a are larger in the presence of the catalysis product, than in the presence of

the substrate. These observations are in accord with the results from the stoichiometric

fluorination of 2a in the presence of 4a or 5b (see 3.2.12). As the concentration of the reaction

product 5a steadily increases during catalytic fluorination, the increasing rate of formation

and equilibrium concentration of the highly selective enolato complex 3a may account for the

higher selectivities obtained towards the end of the catalysis.

3.2.14.1 Notes on the Basicity of 1,3-Dicarbonyl Compounds

As presented in the previous section, the addition of an excess of fluorinated β-keto

ester 5a to the acid-base equilibrium between complexes 2a and 3a creates a higher

concentration of the deprotonated complex 3a than the addition of 4a. This suggests that 5a is

a slightly stronger base than 4a for some reason. Despite the common β-keto ester motif, 4a

and 5a differ in two respects. 4a possesses an α-hydrogen atom, and is thus able to

tautomerize after protonation to an enol oxoniumion (Scheme 3.20). 5a lacks the possibility

for tautomerisation, but has a fluorine substituent instead that can alter the electronic

properties of the molecule considerably.


106

O O

O

O O

OF

HO O

O

H H H

O O

O

O O

OF

H+-H+ H+-H+

4a 5a

Enol oxoniumion

Scheme 3.20. Comparison of the species formed by protonation of 4a and 5a.

Basicities of carbonyl compounds have been studied by several research groups, mainly

due to the importance of protonation equilibria in acid-catalyzed organic reactions. However,

difficulties of the analytical techniques and the subsequent data treatment have led to a large

spread of literature values. Protonation constants (pKBH+ values) of protonated acetone, for

instance, have been reported between –0.24 and –7.5.71

The basicity of 1,3-diketones has been investigated by Kröger and co-workers by UV

and 1H NMR spectroscopic measurements in H2O/H2SO4 mixtures.72 For acetylacetone, they

were able to determine the pKBH+ values for the tautomers separately. They reported a value

of about –2.9 for the keto form, and about –1.9 for the enol form, showing that the enol is

more basic (Scheme 3.21). The numeric values were obtained by extrapolation to ideal

aqueous solutions, though. In the real solutions over almost the whole acidity range, the keto

form was more basic than the enol form, and the half-protonation of the keto form was

reached at lower acidity of the medium. For both protonation pathways, they proposed a

common enol oxoniumion as the most stable protonated species.

O O

O OH

H+

-H+O OH

O OHHH+

-H+

Extrapolated pKBH+: -2.9

Extrapolated pKBH+: -1.9

Enol oxoniumion

Scheme 3.21. Basicity of the keto and enol tautomer of acetylacetone.


107

In an article by Lee and Sadar, several basicity constants of aliphatic esters were

reported, among them those of the β-keto ester ethyl acetoacetate and of its α-chloro

derivative.73 For ethyl acetoacetate, they found a pKBH+ between –3.2 and –4.3, whereas they

determined a value between –1.7 and –2.3 for ethyl 2-chloroacetoacetate (Figure 3.18). Thus,

the α-chloro substituent significantly increases the basicity of the β-keto ester, which is in

accord with our own finding that the halogenated β-keto ester 5a is more basic than 4a.

O

OEt

OO

OEt

O

Cl

-3.2 > pKBH+ > -4.3 -1.7 > pKBH+ > -2.3

Figure 3.18. pKBH+ values of ethyl acetoacetate and ethyl 2-chloroacetoacetate.

On the other hand, a similar study with α-halogenated acetone by Levy et. al. showed

the opposite behavior. Substitution of acetone with fluorine, chlorine or bromine causes a

substantial decrease of the pKBH+ value by about 3 units, a fact that was explained by the

inductive, electron-withdrawing effect of the halogens. Quite surprisingly, the three halogens

are almost equivalent in their quantitative effect on acetone basicity.74

Relating to our observed basicity difference between 4a and 5a, the collected data from

literature is not very conclusive and leaves room for interpretation. The increased basicity of

fluorinated β-keto ester 5a with respect to 4a seems to be a combined effect of the halogen

substitution, and the incapability of 5a to form an enol tautomer. The two effects probably

work in opposite directions, resulting in a slight net increase of basicity.

An interesting suggestion was made by Scorrano and co-workers, who investigated the

protonation of aliphatic and aromatic ketones and esters in H2O/H2SO4. For several of the

sterically less hindered carbonyl bases they found a deviation from theoretical behavior. They

attributed these differences to a distinct hydrogen-bonding equilibrium with H3O+, which

competes with the classical protonation (Scheme 3.22).75

R R'

OH+

-H+R R'

OH H3O+

-H3O+

R R'

OHOH

H

Scheme 3.22. Hydrogen-bonding equilibrium and protonation of ketones and esters.


108

The equilibrium constants for the formation of the hydrogen-bonded associate are in

most cases more than 1.5 logarithmic units higher than the pKBH+ of the protonated carbonyl.

As a consequence, a large fraction of the carbonyl compound is present as a hydrogen-bonded

complex in acidic aqueous solution, for example 43% in the case of acetone at 25 °C.

Assuming the formation of analogous adducts for β-keto esters could give a potential

rationalization for the importance of Et2O for the deprotonation of complex 2a in the presence

of α-fluoro-β-keto ester 5a. In dichloromethane solutions, a hydrogen-bonded adduct between

Et2OH+ and 5a might well exist, and might be more stabilized than the product of simple

protonation. Thus, such an additional stabilization might account for the shift of the 2a↔3a

equilibrium constant in the combined presence of 5a and Et2O.

3.2.15 A Ru/PNNP Complex with a Coordinated β-Keto Ester Enol?

3.2.15.1 Previous Observations

The ruthenium/PNNP-catalyzed asymmetric Michael addition of β-keto esters to enones

was studied in our group by Francesco Santoro, as introduced in 2.1.1.3. After the

identification of the complexes 2a and 3a, he investigated some mechanistic aspects. An

analogous reaction was reported by Sodeoka and co-workers, using chiral Pd(II)/BINAP

complexes as catalysts.76 They found that a Pd(II) complex containing a coordinated enolate

(similar to 3a) reacts with methyl vinyl ketone only in the presence of a strong acid, allegedly

for the protonation of the enone and not for the enolato ligand. In the Ru/PNNP system, this

seems rather unlikely though, considering the large pKa difference between 2a (pKa ~2) and

protonated methyl vinyl ketone (pKa around −4).77,78 Furthermore, Santoro demonstrated that

2a is able to react with stoichiometric amounts of methyl vinyl ketone, whereas 3a is

unreactive even in the presence of the weak acid Et3NH+.79 From these observations, he

postulated the involvement of a tautomer 2a’ of complex 2a, containing a coordinated

bidentate β-keto ester enol in the catalytic cycle. Such an enol tautomer would be able to react

directly with methyl vinyl ketone, without deprotonation to the enolato complex 3a. Santoro

tried to detect 2a’ by 1H and 2H NMR spectroscopy after the reaction of 3a with HBF4·OEt2

or D2SO4 at −80 °C (Scheme 3.23), reasoning that the protonation under kinetic conditions

would preferably take place on oxygen rather than on carbon. He observed broad peaks at

around δ 10.5 in 1H NMR spectra, and around δ 9 in 2H NMR spectra, which he attributed to


109

the enol resonance of 2a’. At higher temperatures, the broad signals disappeared and the

characteristic α-proton of 2a became visible.

O

OO

RuP

N

N

P

X

2+

2a

O

OO

RuP

N

N

P

+

3a

O

OO

RuP

N

N

P

2+

2a'X

Acid = HBF4 OEt2:Acid = D2SO4:

X = HX = D

acid

-80 °C

Δ

?

Scheme 3.23. Low-temperature protonation/deuteration of complex 3a performed by Franceso Santoro.

Unfortunately, the alleged enol complex 2a’ could not be identified by 31P NMR

spectroscopy. Moreover, no hints for a keto-enol tautomer equilibrium were found at room

temperature. We decided to address these two problems by 1H-exchange NMR experiments

and by low-temperature 31P NMR spectroscopy after protonation of 3a at low temperature.

3.2.15.2 Hints from Low-Temperature 1H NMR and 1H NOESY Exchange Spectra

As outlined in 3.2.13, when complex 2a is prepared with TlPF6 in CD2Cl2 solution, it is

in slow exchange with 3a. Might an enol tautomer of type 2a’ be involved in the exchange

process? Closer examination of the 1H NMR spectra revealed a broadened peak of low

intensity at δ 10.5 with an integration of only 0.5% compared to the calibrated integrals of 2a.

Upon cooling the solution, the signal shifts towards higher frequency, broadens between 0

and −30 °C, and ends up as a sharp signal at −90 °C and a chemical shift of δ 10.75 (Figure

3.19, left). A peak at δ 10.45 moves towards lower frequency and broadens upon cooling. A

room temperature 1H,1H-NOESY NMR spectrum shows an exchange cross-peak between the

broad signal at δ 10.5 and the acidic α-methine proton of the β-keto ester in complex 2a at δ

3.78 (Figure 3.19, right).


110

Figure 3.19. Left: Sections of 1H NMR spectra of 2a at various temperatures. Right: Section of a room temperature 1H,1H-NOESY NMR spectrum of 2a.

The question is, whether the signal at δ 10.5 does indeed belong to an enol complex 2a’.

It does not feature any other cross-peaks in the NOESY spectrum, neither from NOE, nor

from chemical exchange. In the 2D 31P{1H}-EXSY spectrum, the only observed equilibrium

was between complexes 2a and 3a, and no further exchanging species was identified (see

Figure 3.16). The line width of the broad 1H NMR signal at δ 10.5 is around 14 Hz, which is

approximately the same as the 31P NMR resonance of the enolato complex 3a (14.5 Hz) in

exchange with 2a. This is an indication that they follow similar exchange rate constants and

are thus involved in the same dynamic process.80 Since we have no hint for the existence of

another species in equilibrium apart from 2a and 3a by 1H and 31P NMR spectroscopy, we

assume that the signal at δ 10.5 originates from an external protonated species, probably from

protonated β-keto ester 4a.

3.2.15.3 Low-Temperature Protonation of 3a with HBF4·OEt2

Protonations of 3a at low temperature were first attempted with HBF4·OEt2 (1 equiv) as

acid. For that purpose, CD2Cl2 solutions of 3a in NMR tubes were cooled to the desired

temperature, then HBF4·OEt2 was added slowly along the cold glass wall of the tubes. The

samples were kept in the cooling bath, shaken quickly, and inserted into the NMR magnet

pre-cooled at −90 °C. 1H and 31P NMR spectra were then measured during stepwise warming

to room temperature.


111

When the addition of the acid was performed at −80 °C (cooling bath: CO2(s)/acetone)

or −100 °C (cooling bath: MeOH/N2(l)), an instantaneous color change from orange to yellow

occurred. The immediately measured 1H and 31P NMR spectra at −90 °C showed complete

protonation to complex 2a. The same result was obtained when the acid addition was carried

out at −105 °C (EtOH/N2(l)), and the solution was frozen directly thereafter at −130 °C

(pentane/N2(l)) before inserting it into the NMR magnet at −90 °C. When HBF4·OEt2 was

added on top of a frozen CD2Cl2 solution of 3a, no mixing was achieved regardless of

extensive spinning of the NMR tube in the magnet. The mixture remained biphasic

throughout the whole experiment with 3a below and a layer of protonation product 2a above.

In some of those experiments, broad signals at around δ 12 were observed in the 1H

NMR spectra. Since the imine hydrogens, the α-methine proton and the 31P NMR resonances

clearly indicate quantitative protonation, we assign the broad signals to slight excess of acid.

We cannot explain why the reactions with HBF4·OEt2 gave different results than those

obtained by Francesco Santoro, because the experimental procedure we followed was

identical. The reaction is expected to be highly sensitive, though, and even slight differences

in temperature, mixing time, or NMR measurement conditions could account for such a

different outcome.

3.2.15.4 Low-Temperature Protonation of 3a with (DL)-10-Camphorsulfonic Acid

As an alternative to tetrafluoroboric acid, we attempted the low-temperature protonation

of complex 3a with (DL)-10-camphorsulfonic acid (CSA), which is widely used as strong

acid in organic reactions.81 CSA has some particular advantages over other sulfonic acids

because it is solid, non-hygroscopic, and of quite high molecular weight.

We tried the reaction of 3a with CSA in CD2Cl2 at room temperature first, giving a

conversion of 60% after one hour. However, the protonated complex 2a was not among the

observed products. Free β-keto ester 4a and two new complexes 22a and 22b with AX spin

systems in 31P NMR spectra were obtained instead (22a: δ 61.9, 47.5; 22b: δ 62.0, 47.7).

Most likely, complex 3a is protonated first, then the β-keto ester 4a is replaced by the

sulfonate anion as a ligand (Scheme 3.24). Since the racemic camphorsulfonic acid was used,

both diastereoisomeric complexes 22 are formed, not as a statistical mixture, though, but in a

1.6:1 ratio. Only one of the diastereoisomers is drawn in Scheme 3.24.


112

O

OO

RuP

N

N

P

+

3a

O O

O

4a

CSA (1 equiv)

CD2Cl2r.t.

+

22a,b

O

ORu

P

N

N

P

+

SO

O

Scheme 3.24. Reaction of 3a with (DL)-10-camphorsulfonic acid (CSA) at room temperature.

We then carried out the addition of CSA at −90 °C, and measured 1H and 31P NMR

spectra while increasing the temperature of the solution stepwise. No ligand substitution was

observed as long as the mixture was kept below 0°C. The NMR data indicate a temperature-

dependent equilibrium between 3a and 2a, that is, protonation at carbon (Scheme 3.25).

O

OO

RuP

N

N

P

+

3a

O

OO

RuP

N

N

P

H

2+

2a

O O+ +CD2Cl2

< 0 °CSO3H SO3-

Scheme 3.25. Acid-base equilibrium by reaction of 3a with (DL)-10-camphorsulfonic acid.

The high-frequency 31P NMR doublets (Pap) of complexes 2a and 3a show textbook

behavior for dynamic chemical exchange. Two separate, sharp signals are present in the slow-

exchange regime at −90 °C, each at the same chemical shift as observed with reference

samples at identical temperature. The peaks get broader upon warming, lose their couplings at

around −60 °C, and collapse into a broad coalescence signal at −40 °C (Figure 3.20). At

higher temperatures, the signal sharpens and reaches an equilibrium chemical shift δeq 63.0 at

0 °C, indicating fast exchange compared to the NMR timescale. No other species is observed

by 31P NMR spectroscopy.

In the analogous 1H NMR spectra, the chemical exchange is illustrated by several

resonances, and was confirmed by selective irradiation of the involved signals at different

temperatures. The imine doublets of 2a and 3a appear as separate signals at −90 °C, coalesce

at around −40 °C, and sharpen again at 0 °C in an equilibrium position overlapped with the

imine singlet, being itself at an equilibrium chemical shift (Figure 3.21). Furthermore, a HC—

N cyclohexane proton behaves in a similar manner.


113

Figure 3.20. High-frequency section of 31P NMR spectra from the reaction of 3a with CSA at various temperatures.

Figure 3.21. Various temperature 1H NMR spectra of the protonation of 3a with CSA.


114

The most interesting dynamic phenomenon is displayed by a hydrogen atom, which

forms two broad signals at around δ 10 and δ 4.3 at −90 °C. We assign those to the acidic

proton exchanging between the sulfonic acid and the α-position of the β-keto ester in complex

2a. The fact that the α-H for 2a is shifted from its usual chemical shift of δ 3.5 at −90 °C is

not surprising, since it is the atom that is actually involved in the bond cleavage and bond

formation during the exchange. Thus, its NMR signal is expected to act in the most sensitive

way even when the exchange rates are very slow. Upon warming, the signals move (dashed

arrows in Figure 3.21) and finally reach an equilibrium chemical shift δeq 5.8 at 0 °C.

All the observed effects are fully reversible. After re-cooling the solution to −70 °C,

identical 31P and 1H NMR spectra are obtained as before the warming. The observed

reversibility disfavors the hypothesis that a kinetic product is formed at low temperature,

which is transformed to a thermodynamic product upon warming. In that case, the original

situation should not be restored after thermal equilibration.

It is difficult to draw conclusions concerning the existence of a complex with a

coordinated β-keto ester enol (2a’). The low-temperature protonations of 3a with CSA prove

an equilibrium between complexes 3a and 2a, with no other species involved. With

HBF4·OEt2 as acid, only complete carbon-protonation of 3a was observed at −90 °C. From

the data we currently have at hand, we conclude that the observed NMR spectra and effects do

not originate from an enol complex such as 2a’.

Undoubtedly, some experimental results can be interpreted in different ways. For

example, the broad signal observed in the 1H NMR spectrum at δ 10 at −90 °C (Figure 3.21)

could be interpreted as an enol OH resonance. Besides that, however, the 1H and 31P NMR

spectra hold no indication for a species other than complexes 2a or 3a. Also the reversible

nature of the temperature-dependency renders the interpretation of the signal at δ 10 as a

coordinated enol rather improbable.

To come back to the title question of this section: Does a ruthenium PNNP complex

with a coordinated β-keto ester enol exist? We have no spectral evidence for its existence, and

more experimentation is certainly required to answer this question conclusively. An enol

complex 2a’ might well exist in equilibrium with 2a, or after low-temperature protonation of

3a, but not in a concentration or with a lifetime that is detectable by NMR spectroscopy.


115

3.2.16 Mechanistic Suggestion for the Fluorination of 4a

Taking together the results from stoichiometric reactions, the assesment of the role of

NSI–, and the investigations on the dynamic exchange between complexes 2a and 3a, we can

now propose a catalytic cycle for the ruthenium-catalyzed fluorination.

It must be noted that, as a general rule, a reaction mechanism can never be proved by

experiments. The only proof one can give experimentally is that a suggested mechanism is

incorrect and must be excluded. At best, one can say that a reaction mechanism is consistent

with experimental evidence, and therefore reflects reality best within the explored boundaries.

In this sense, we propose our catalytic cycle (Scheme 3.26) as a working hypothesis,

explaining the observations from the experiments, but still leaving room for future studies.

O

tBuOO

RuP

N

N

P

F

2+

21

O

tBuOO

RuP

N

N

P

+

3a

O

tBuOO

RuP

N

N

P

H

2+

2a

4a

O O

OF (R)-5a

O O

O

B

BH+NFSI

NHSI NSI-

BH+B Et2O

NFSINHSI

(a)

(b)

(c)

(d)

(e)

Scheme 3.26. Proposed catalytic cycle for the fluorination of 4a with NFSI.

In step a, the β-keto ester 4a binds to the Ru/PNNP fragment and liberates the

fluorinated product (R)-5a. The thus formed dicarbonyl complex 2a is in equilibrium with its

enolato analog 3a (step b). Both complexes 2a and 3a can react with NFSI. The direct

fluorination of 2a (step c) proceeds with lower enantioselectivity than the fluorination of 3a

(step d). β-keto esters 4a or 5a, supported by diethylether, act as a base B for the

deprotonation of 2a in equilibrium (b). The fluorinated derivative 5a causes faster exchange

rates and a higher equilibrium concentration of 3a, which undergoes fluorine transfer with


116

higher enantioselectivity than 2a. Therefore, the accumulation of 5a during catalysis is

responsible for the increase of enantiomeric excess with conversion.

The reaction of complex 3a with NFSI produces complex 21 and NSI–, which is

protonated by BH+ (step e) to prevent its coordination to ruthenium. Under conditions where a

proton source BH+ is missing (e.g. by using 3a as catalyst), NSI– replaces the weakly bound

fluorinated β-keto ester 5a in 21, and forms a complex 20 that interrupts the cycle.

An essential feature of the suggested catalytic cycle is that the weak base B participates

in two steps (b and e), which emphasizes its importance as a proton-shuttle. The base B could

be interpreted as the kinetic base that ultimately delivers the proton to the thermodynamic

base NSI−. It might also explain why the influence of diethylether on the enantioselectivity is

substrate-specific. For the best possible outcome, the basicities of the respective substrate 4

and product 5, and the acidity of complex 2 have to be optimally attuned to each other.

Two important questions remain open, though. First, what is the interplay between the

weak oxygen-containing bases 4a, 5a, and Et2O? All we presently know from stoichiometric

reactions and from the 2a↔3a exchange rate constants is, that strong effects are only

observed with the combination 5a + Et2O. Nonetheless, we do not understand the nature of

this synergy. Probably, a hydrogen-bonded adduct between 5a and Et2OH+ is formed upon

deprotonation of complex 2a (see paragraph 3.2.14.1). Secondly, how does the direct

fluorination of 2a occur? A tautomer 2a’ of 2a, featuring the coordinated β-keto ester in its

enol form could be involved, but we do not have a conclusive proof for the existence of such

a species until now (see 3.2.15).


117


As formulated in the opening paragraph of this section, it was our goal to gain a better

understanding of the Ru/PNNP-catalyzed fluorination of β-keto esters. Taking the project

further from the previously developed reaction meant to look into details and to critically

question our own results again and again. More often than not, one answer brought up two

new questions, which proved to be a scientifically highly stimulating process.

We found that Et2O as cosolvent significantly enhances the reaction rates of the

fluorination of β-keto esters with NFSI, analogous to the Michael addition studied by

Francesco Santoro. The effect on enantioselectivity is substrate-specific, giving an

improvement to 93% ee for the fluorination of substrate 4a. Many of our efforts were

focussed on the catalyst-substrate adduct complexes 2a, containing the non-enolized β-keto

ester 4a, and 3a, featuring the β-keto ester enolate as ligand. The stoichiometric reaction of

the dicarbonyl complex 2a with NFSI gives 5a in 82% ee, whereas its enolato analog 3a is

fluorinated with 97% ee. In catalysis, the enantiomeric excess of the fluorinated product 5a is

increasing with ongoing conversion. As an explanation for this behavior, we found an

equilibrium between 2a and 3a, which is faster and favors the formation of the more selective

3a in the combined presence of Et2O and fluorinated product 5a (situation towards the end of

the catalytic reaction) rather than substrate 4a (beginning of catalysis). Thus, weakly basic

oxygenated molecules are essential to achieve high reaction rates and selectivities by fine-

tuning the proton transfer steps. This concept of proton-shuttles might be relevant to other

catalytic reactions with β-keto esters, and might help to understand and optimize those

reactions.

O

OO

RuP

N

N

P

H

2+

2a

+ B + BH+

O

OO

RuP

N

N

P

+

3a

k1

k-1B = 4a, 5a, Et2O

As a goal for future studies, the mechanism of the ruthenium-catalyzed fluorination of

β-keto esters could be studied by kinetic methods. The quantification of reaction rates and the

determination of reaction orders would give useful information to refine and complete our

current mechanistic picture. Furthermore, the detection of complexes with coordinated enols


118

remains a challenging task for future investigations. A conclusive answer to this question

would be beneficial for a more complete understanding of the reactivity of β-keto ester

complexes, and the catalytic reactions they are involved in.

During our investigations, we found that not only β-keto esters and β-keto acids (paragraph

2.2.5), but also α-alkylidene-β-keto esters (3.2.3.3) can form distinct complexes with the

Ru/PNNP fragment. Catalytic reactions with this substance class as substrates might thus be

considered. The unsaturated β-keto esters may be used as acceptors for 1,4-additions, or as

electron-poor alkenes for cycloaddition reactions. A first test of the Diels-Alder reaction

between 2-ethoxycarbonyl-2-cyclohexen-1-one and cyclopentadiene, catalyzed by

[Ru(OEt2)2(PNNP)]2+ (6), showed promising results. The cycloadduct is produced with an

endo/exo ratio (with respect to the ester group) of 5:1, and in an unoptimized yield of 19%.

The enantioselectivity of the endo-diastereoisomer is 70% ee, a value that is exceptionally

high for reactions with α-alkylidene-β-keto esters, not being of quinone-type.

O

OEt

O

+

O CO2Et

H

O CO2Et

Hendo exo

+6 (10 mol%)

CH2Cl2/Et2O (1:1), r.t.19% yield

(10 equiv) 5 : 1

70% ee

The results from our group show that ruthenium PNNP complexes are successful chiral

Lewis-acid catalysts for several reactions with substrates capable of bidentate binding, namely

for the hydroxylation, Michael addition, and fluorination of 1,3-dicarbonyl compounds. For

future research, the applications of the Ru/PNNP catalytic system may be extended to other

types of reactions with promising perspectives, for example the Diels-Alder cycloaddition

mentioned above.


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[33] Kim, S. M.; Kim, H. R.; Kim, D. Y. Org. Lett. 2005, 7, 2309 – 2311.

[34] Suzuki, T.; Goto, T.; Hamashima, Y.; Sodeoka, M. J. Org. Chem. 2007, 72, 246 – 250.

[35] Kim, H. R.; Kim, D. Y. Tetrahedron Lett. 2005, 46, 3115 – 3117.

[36] Moriya, K.; Hamashima, Y.; Sodeoka, M. Synlett 2007, 1139 – 1142.

[37] Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135 – 1138.

[38] Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164 –

10165.

[39] Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007 – 1011.

[40] Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703 – 1706.

[41] Shibata, N.; Yasui, H.; Nakamura, S.; Toru, T. Synlett 2007, 1153 – 1157.

[42] Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem. Int.

Ed. 2005, 44, 4204 – 4207.

[43] Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem. Int. Ed. 2008,

47, 164 – 168.

[44] Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2004, 125, 1357 – 1361.

[45] Suzuki, S.; Furuno, H.; Yokoyama, Y.; Inanaga, J. Tetrahedron: Asymmetry 2006, 17, 504 – 507.

[46] Shibatomi, K.; Tsuzuki, Y.; Nakata, S.; Sumikawa, Y.; Iwasa, S. Synlett 2007, 551 – 554.


[48] Massa, M. Kristallstrukturbestimmung; 3. Aufl.; Teubner: Stuttgart, 2002; pp 165 – 173.

[49] Witzman, J. S. Tetrahedron Lett. 1990, 31, 1401 – 1404.

[50] Perseghini, M.; Massaccesi, M.; Liu, Y.; Togni, A. Tetrahedron 2006, 62, 7180 – 7190.

[51] (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562 –

7563. (b) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl.

1997, 36, 285 – 288.

[52] Cheng, T.-Y.; Szalda, D. J.; Zhang, J.; Bullock, R. M. Inorg. Chem. 2006, 45, 4712 – 4720.

[53] Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757 – 771.

[54] Jung, M. E.; Brown, R. W. Tetrahedron Lett. 1978, 31, 2771 – 2774.

[55] Jung, M. E.; Pan, Y.-G. J. Org. Chem. 1977, 42, 3961 – 3963.

[56] Wehrli, F. W.; Marchand, A. P.; Wehrli, S. Interpretation of Carbon-13 NMR Spectra; Wiley: Chichester

1988; 2nd Ed.; pp 34 – 38.

[57] Huheey, J. E. Anorganische Chemie; Walter de Gruyter: Berlin 1988.



121

[59] (a) Dauphin, G.; Kergomard, A. Bull. Soc. Chim. Fr. 1961, 486 – 492. (b) Foropoulos, J. Jr.; DesMarteau,

D. D. Inorg. Chem. 1984, 23, 3720 – 3723.

[60] Earle, M. J.; Hakala, U.; McAuley, B. J.; Nieuwenhuyzen, M.; Ramani, A.; Seddon, K. R. Chem.

Commun. 2004, 1368 – 1369.

[61] Nie, J.; Kobayashi, H.; Sonoda, T. Catalysis Today 1997, 36, 81 – 84.

[62] Polyakov, O. G.; Ivanova, S. M.; Gaudinski, C. M.; Miller, S. M.; Anderson, O. P.; Strauss, S. H.

Organometallics 1999, 18, 3769 – 3771.

[63] Williams, D. B.; Stoll, M. E.; Scott, B. L.; Costa, D. A.; Oldham, W. J. Jr. Chem. Commun. 2005, 1438 –

1440.

[64] See, for instance: Jones, P. G.; Blaschette, A.; Lautner, J.; Thöne, C. Z. Anorg. Allg. Chem. 1997, 623,

775 – 779.

[65] See, for instance: Jones, P. G.; Henschel, D.; Weitze, A.; Blaschette, A. Z. Anorg. Allg. Chem. 1994, 620,

1514 – 1520.

[66] (a) For a review on 2D EXSY for different nuclei, see: Perrin, C. L.; Dwyer, T. J. Chem. Rev. 1990, 90,

935 – 967. (b) For an example of an application of 2D 31P{1H}-EXSY, see: Heise, J. D.; Raferty, D.;

Breedlove, B. K.; Washington, J.; Kubiak, C. P. Organometallics 1998, 17, 4461 – 4468.

[67] Bircher, H.; Bender, B. R.; von Philipsborn, W. Magn. Reson. Chem. 1993, 31, 293 – 298; and references

therein.

[68] The described behavior of the phases applies only to the conditions of „extreme narrowing limit“

(ω0τc<<1), that is, for small molecules in nonviscous solvents tumbling at fast rates compared to the

Larmor observation frequency. See also: Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect

in Structural and Conformational Analysis; 2nd Ed.; Wiley: New York, 2000.

[69] Trage, C.; Schröder, D.; Schwarz, H. Chem. Eur. J. 2005, 11, 619 – 627.

[70] Sandström, J. Dynamic NMR Spectroscopy; Academic Press: London, 1982; pp 14 ff.

[71] Freiberg, W. J. Prakt. Chem. 1994, 336, 565 – 574.

[72] Kröger, C.-F.; Freiberg, W.; Hauer, U. J. Prakt. Chem. 1987, 329, 895 – 900.

[73] Lee, D. G.; Sadar, M. H. J. Am. Chem. Soc. 1974, 96, 2862 – 2867.

[74] Levy, G. C.; Cargioli, J. D.; Racela, W. J. Am. Chem. Soc. 1970, 92, 6238 – 6246.

[75] Bagno, A.; Lucchini, V.; Scorrano, G. J. Phys. Chem. 1991, 95, 345 – 352.

[76] Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240 – 11241.

[77] Levi, A.; Modena, G.; Scorrano, G. J. Am. Chem. Soc. 1974, 96, 6585 – 6588.

[78] Jensen, J. L.; Thibeault, A. T. J. Org. Chem. 1977, 42, 2168 – 2170.

[79] Santoro, F. ETH, Ph.D. Thesis No. 17024, Zurich, Switzerland, 2007.

[80] The assumption is made that the contribution of T2 relaxation to the line width is small compared to the

exchange contribution. This approximation is reasonable because 31P NMR line widths of only 2 – 3 Hz

are observed for pure enolato complex 3a without exchange processes.

[81] Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol. 2,

pp 969 – 973.


122

4 Ru/PNNP-Catalyzed α-Fluorination of 2-Alkylphenylacetaldehydes

123

4 Ruthenium/PNNP-Catalyzed Asymmetric α-

Fluorination of 2-Alkylphenylacetaldehydes

Chapter 4 of this thesis describes our investigations about Ru/PNNP-catalyzed

fluorination reactions with nucleophilic fluoride sources. Departing from a ring-opening

hydrofluorination of meso-epoxides, we discovered a ruthenium-catalyzed asymmetric

oxidative α-fluorination of 2-alkylphenylacetaldehydes.

4.1 Introduction

This introduction covers three main topics, starting with an overview about reagents and

methods for nucleophilic fluorination. A special focus is on a chromium-mediated asymmetric

ring-opening hydrofluorination of epoxides (4.1.1 to 4.1.3). Unlike enantioselective

electrophilic fluorinations, only a few examples of their nucleophilic counterparts are known

to date. The second subject is the asymmetric electrophilic α-fluorination of aldehydes

(4.1.4), a reaction for which no enantioselective version was known until recently. At present,

organocatalysis offers the most viable solutions. As the third main topic, the electrochemical

oxidative α-fluorination of carbonyl compounds is presented in section 4.1.5. The underlying

concept of this approach offers an interesting alternative to the fluorination methods described

so far and is connected to our own findings about the α-fluorination of aldehydes.

4.1.1 Reagents for Nucleophilic Fluorination

The prototypical reagent containing nucleophilic fluoride is hydrogen fluoride (HF),

either in its anhydrous form (aHF), or as an aqueous solution (hydrofluoric acid). HF is an

extremely hazardous, highly toxic and corrosive substance with a low boiling point of 19.5

°C.1 It is employed for the industrial manufacture of various organofluorine compounds by

nucleophilic substitution reactions of acyl halides, alkyl halides, or alkyl sulfonates.

Furthermore, HF can be used for additions to olefins or for the ring-opening of epoxides and


124

aziridines (hydrofluorination). To avoid the use of special equipment, and to enable a safer

and more convenient handling, several HF-derived reagents have been invented for laboratory

use.2,3 For example, the formation of adducts between aHF and organic Lewis bases decreases

the vapour pressure and acidity of the reagent and increases the fluoride nucleophilicity.

The first example of those “tamed HF” reagents, pyridinium poly(hydrogen fluoride),

was reported by George Olah and is composed of pyridine and HF in a molar ratio of 1:9. By

weight, py·9HF contains 70% of HF.4,5 Py·9HF is strongly acidic, does not release HF up to a

temperature of 55 °C and etches glass in a similar manner as aHF. By changing the amine and

the amine/HF ratio, the acidity and nucleophilicity of these reagents can be modified over a

wide range. HF adducts of trialkylamines, such as Et3N·3HF (TREAT-HF) and iPr2EtN·HF

are neutral or even slightly basic, and have no HF vapor pressure at all.6,7 They are sources of

highly nucleophilic fluoride and can be handled in normal glassware.

A related class of HF reagents are the adducts of HF to fluoride salts, which are species

of the general formula (M+)F−(HF)n. Alternatively, they can be formulated as

(M+)(FHF−)·nHF, which highlights the role of the hydrogen difluoride anion (FHF−) in these

reagents. Examples of this type are KHF2, K+(H2F3)−, Bu4N+(HF2)−, and Bu4N+(H2F3)−.

Hydrogen difluoride (also called bifluoride) is a well-defined entity and can be understood as

the symmetric, linear adduct of F− to HF by a very strong hydrogen bond with a bond energy

of about 40 kcal/mol.8 The bifluoride anion features extremely short F—H distances of 1.13

Å, only 0.20 Å longer than the covalent bond of HF (Figure 4.1).9 The dihydrogen trifluoride

anion (H2F3−) is the adduct of two HF to F−, and features a bent geometry with a bond angle

of ~130°.10

NEt

EtEt H F

H

H

F

F

H FF[ ] FH H

F F130°1.13 Å

TREAT-HF HF2- H2F3-

Figure 4.1. Structures of the HF-reagents Et3N·3HF, HF2−, and H2F3

−.

Historically, the most prominent bifluoride salt is KHF2, being of paramount importance

for the early developments in fluorine chemistry. In 1856, Edmond Frémy succeeded in the

first preparation of anhydrous HF through thermal decomposition of KHF2 to KF and HF.11

The bifluoride anion and Frémy’s method to prepare anhydrous HF thus set the stage for the


125

biggest milestone in fluorine chemistry, that is, the first electrolytic synthesis of F2 by Henri

Moissan in 1886.12,13

Apart from HF and the aforementioned HF surrogates, many other fluoride reagents are

used for different applications.10,14 Simple metal fluorides, such as KF, CsF, or AgF can be

used as sources of nucleophilic fluoride. Salts of large organic cations exhibit increased

nucleophilicity, according to the concept of “naked” fluoride ions (see paragraph 1.1).

Examples are Bu4N+F− (TBAF), Ph4P+F−, or phosphazenium fluorides.

Hypervalent fluorosilicates15 and fluorostannates16 provide fluoride ions by an

equilibrium in organic solvents. Their non-hygroscopic nature is an advantage over simple

fluoride salts. The most common representatives of the silicates are Bu4N+(Ph3SiF2)− and

(Et2N)3S+(Me3SiF2)−, abbreviated as TBAT and TASF, respectively. A widely used stannate

is Bu4N+(Ph3SnF2)− (TBAFPS).

The transformation of alcohols to the corresponding fluorides, or of carbonyl to

difluoromethylene groups can be carried out with SF4. The reagent activates the oxygenated

functional group under liberation of fluoride, which then acts as nucleophile. Nowadays, the

aminosulfuranes Et2NSF3 (DAST), or (H3COCH2CH2)2NSF3 (DeoxofluorTM) are convenient

alternative reagents for the same reactions.17

4.1.2 Ru/PNNP-Catalyzed Nucleophilic Fluorination of Alkyl Halides

Coordinatively unsaturated 16-electron ruthenium(II) fluoro complexes have been

prepared and studied in our group. It has been shown that these complexes are able to transfer

the fluoro ligand in a nucleophilic fashion to activated alkyl halides.18 For example, the

reaction of [RuF(dppp)2]+ (dppp = 1,3-bis(diphenylphosphino)propane) with 1,3-diphenylallyl

bromide gave the corresponding fluoride in high yield (Scheme 4.1). The overall reaction is a

halide metathesis, thus the resulting ruthenium complex is [RuBr(dppp)2]+.19,20,21

RuPh2P

Ph2PPPh2

PPh2

FII

+

RuPh2P

Ph2PPPh2

PPh2

BrII

+

Ph Ph

Br

Ph Ph

F+ +

CDCl3

r.t., 1 min

> 80%

Scheme 4.1. Nucleophilic fluorination of alkyl halides by [RuF(dppp)2]+.


126

A catalytic fluorination was obtained when the above reaction was combined with the

halide metathesis between the resulting complex [RuBr(dppp)2]+ and thallium(I) fluoride.

Thereby, the fluoro complex is regenerated and the catalytic cycle is closed. In these catalytic

reactions, TlF has the role both of stoichiometric source of fluoride and of terminal halide

scavenger. It is a particularly interesting feature of this system that the catalyst is involved in

the actual fluorine-transfer, and not in an activation of the organic substrate.

The feasibility of a catalytic and enantioselective version of the nucleophilic

fluorination of alkyl halides was tested with the chiral, five-coordinate complex

[RuCl(PNNP)]PF6 (9PF6) as catalyst. Racemic 1-bromo-1-phenylethane was converted to the

corresponding 1-fluoro-1-phenylethane by TlF. An enantiomeric excess of 16% ee was

measured after 1% conversion, but the selectivity dropped to 3% ee at full conversion

(Scheme 4.2).22 This behavior suggests that a kinetic resolution of the racemic substrate

occurs, albeit at a low level.

Br

∗

F

+ TlBrTlF+

9PF6(10 mol%)

CH2Cl2, r.t.Ru

P

N

N

P

PF6

Cl

9PF616% ee @ 1% conv.3% ee @ 100% conv.

Scheme 4.2. Catalytic nucleophilic fluorination with 9PF6 as catalyst.

The reaction was further investigated by Claus Becker in our group. He achieved higher

enantioselectivities by preparing the catalyst (5 mol%) from [RuCl2(PNNP)] (1) and

(Et3O)PF6 (1 equiv), leading to the formation of [RuCl(OEt2)(PNNP)]PF6 as active catalyst.23

In the best case, 1-fluoro-1-phenylethane was obtained with 15% ee and in 21% yield, starting

from the racemic bromide.24 Unfortunately, the reaction suffered from poor reproducibility.

Both yields and enantioselectivities varied over a wide range, even under seemingly identical

conditions. The results were not reliable, and could only be used to derive average values and

trends.

Nevertheless, the Ru/PNNP-catalyzed nucleophilic fluorination of alkyl halides is one

of the first reported examples in which non-racemic organofluorine compounds are obtained

by metal-catalyzed nucleophilic fluorination.


127

4.1.3 Ring-Opening Hydrofluorination of Epoxides

As introduced in paragraph 4.1.1, epoxides can undergo ring-opening hydrofluorination

with HF sources. The resulting 2-fluoroalcohols (fluorohydrins) are useful building blocks for

the synthesis of monofluorinated natural product analogs, or for technical applications such as

liquid crystal materials.1 Ring-opening of epoxides is the most extensively used method to

access fluorohydrins and offers several advantages over other methods. For example,

epoxides with a variety of carbon skeletons are readily available substrates for the fluorination

step. Furthermore, high levels of regio- and diastereoselectivity can be achieved under

appropriate reaction conditions (see below).

4.1.3.1 General Considerations

Many different HF sources have been employed for epoxide hydrofluorinations.25

Among them are the aforementioned amine adducts py·9HF,26 Et3N·3HF,27,28 and iPr2EtN·HF.29 Also bifluoride and dihydrogen trifluoride salts have been successfully used,

e.g. KHF2,26,30 KH2F3,31 or Bu4N+(H2F3)−.32

The choice of an appropriate reagent is crucial for the regiocontrol in reactions with

unsymmetrically substituted epoxides. Ring-opening can occur by either an SN1 or SN2

mechanism, depending on the acidity of the HF reagent. This dependency is most pronounced

with terminal epoxides. Using highly acidic HF sources, the epoxide is protonated and opens

towards the more stable carbocation, according to an SN1 mechanism. The cation is then

trapped by fluoride in the 2-position. With less acidic, thus more nucleophilic HF sources,

fluoride attacks the less substituted carbon atom in a SN2 process, leading to the 1-fluoro

compound.

EtO2CO

8

EtO2CO

8

HEtO2C

8OH EtO2C

8OH

F

EtO2CO

8

H+

δ+δ+

F-

-F

EtO2C8

FOH

SN1

SN2

SN1 SN2

92 : 845 : 5518 : 82

py 9HFEt3N 3HF

KHF2

Scheme 4.3. SN1 vs. SN2 mechanism in the ring-opening of a terminal epoxide.


128

With the terminal epoxide of a fatty acid ester, a regioselective SN1-type

hydrofluorination was obtained with the acidic reagent py·9HF (92:8), whereas the opposite

selectivity of 18:82 was observed with KHF2 (Scheme 4.3). Et3N·3HF is a reagent of medium

acidity that enables both pathways to occur, hence, a poor selectivity of 45:55 is obtained.25

Under SN2 conditions, stereospecific hydrofluorination with inversion of configuration can be

achieved when an enantiomerically pure epoxide is used as starting material. Many examples

of this strategy have been published, providing access to optically active fluorohydrins.

Enantiomerically pure epoxides derived from allylic alcohols by Sharpless epoxidation have

proven particularly successful, yielding the corresponding fluorohydrins with almost complete

regio- and diastereoselectivity.33

4.1.3.2 Cr(III)-Mediated Asymmetric Hydrofluorination of meso- and rac-Epoxides

The first enantioselective ring-opening hydrofluorination of epoxides was reported in

the year 2000 by Haufe and co-workers. They used stoichiometric amounts of a chiral

chromium(III) salen complex as Lewis acid for the activation of the epoxides, and KHF2 as

HF source.34 The meso-epoxide cyclohexene oxide (7b) was transformed with 92%

conversion to a 89:11 mixture of fluorohydrin 8b and 2-chlorocyclohexanol. An enantiomeric

excess of 55% ee was measured for 8b (Scheme 4.4). When the amount of [CrCl(salen)] was

reduced to 10 mol%, a conversion of 65% was observed, but 8b was formed with 11% ee

only. Similar reaction conditions were applied to the kinetic resolution of racemic epoxides.

Using 0.5 equivalents of [CrCl(salen)], the reaction of rac-styrene oxide gave the

corresponding fluorohydrin in 29% yield and with an enantioselectivity of 90% ee.

N N

OOtBu

tBu tBu

tBuCr

Cl

O

OH

F

OH

Cl

[CrCl(salen)] (1 equiv)KHF2 / 18-crown-6

DMF, 60 °C, 80 h92% conv.

+ [CrCl(salen)] =

PhO

PhF

OH[CrCl(salen)] (0.5 equiv)KHF2 / 18-crown-6

DMF, 60 °C, 60 h

42% conv.29% yield90% ee

89 : 1155% ee 20% ee

7b 8b

Scheme 4.4. Enantioselective epoxide hydrofluorination with KHF2.


129

In a further development of the enantioselective epoxide opening, Haufe used AgF as

source of fluoride and obtained slightly better results than with KHF2.35,36 Thus, cyclopentene

oxide (7a) was converted to 2-fluorocyclopentanol (8a) in 80% yield and with 62% ee by

using a stoichiometric amount of the Cr(III)/salen mediator (Table 4.1, entry 1). The use of 50

mol% of [CrCl(salen)] gave a similar yield (75%) but a significantly lower enantiomeric

excess of 44% ee (entry 2). The same trend is observed for cyclohexene oxide (7b). The

reaction with 100 mol% of [CrCl(salen)] produces the corresponding fluorohydrin 8b with

72% ee, whereas only 66% ee are obtained with 50 mol% of the chromium complex (entries 3

and 4).

Table 4.1. Effect of the catalyst loading on the Cr(III)-mediated epoxide opening.

[CrCl(salen)]AgF (1.5 equiv)

CH3CN, 50 °CO

OH

Fn n

n=1: 8an=2: 8b

n=1: 7an=2: 7b

entry epoxide [CrCl(salen)] (mol%) yield (%) ee (%)

1 7a 100 80 62

2 7a 50 75 44

3 7b 100 90 72

4 7b 50 85 66

By his efforts, Haufe has supplied the evidence that a chiral transition-metal complex is

able to mediate the asymmetric ring-opening hydrofluorination of epoxides. However, a clear

drawback of his method is the requirement for stoichiometric, or at best sub-stoichiometric,

amounts of the chromium complex.

4.1.4 Organocatalytic Asymmetric α-Fluorination of Aldehydes

The second part of this introduction deals again with electrophilic fluorination, and

focuses on the catalytic enantioselective α-fluorination of aldehydes.37,38 Apart from a few


130

exceptions (oxindoles, see sections 3.1.3.2 and 3.1.3.3), no methods for the catalytic

enantioselective fluorination of monocarbonyl compounds had been developed until recently.

In 2005, the four research groups of Enders,39 Jørgensen,40 Barbas,41 and MacMillan42

almost simultaneously disclosed their results on organocatalytic asymmetric α-fluorination of

aldehydes and ketones. The common ground of all four approaches is the use of a chiral

cyclic secondary amine as catalyst, and an N—F reagent as source of electrophilic fluorine.

As shown in Scheme 4.5, the catalytic cycle for this kind of reaction is initiated by the

condensation of the carbonyl compound and the secondary amine, forming an enamine. In the

enantiodiscriminating step, the chiral enamine is fluorinated by the N—F reagent. The

resulting iminium intermediate is then hydrolyzed, liberates the α-fluoro carbonyl compound,

and regenerates the amine catalyst.

N∗

H

N∗

RR'

N∗

∗RR'

F

R

OR'

R ∗

OR'

F

R2N F

-H2O

+H2O

Scheme 4.5. Mechanism of the organocatalytic α-fluorination of aldehydes.

The first of the four reports on organocatalytic α-fluorination was published by Enders.

His work focused on the fluorination of cyclohexanone with F-TEDA as fluorine source and

with several derivatives of (S)-proline as organocatalysts. However, the yields and

enantiomeric excesses were rather low. The best catalyst (R)-4-hydroxy-(S)-proline produced

α-fluorocyclohexanone in a conversion of 56% and with 34% ee (Scheme 4.6).39

O∗

OF

R2NH (30 mol%)F-TEDA

CH3CN, r.t., 21 h NH

COOH

HO

R2NH =56% conv.34% ee

Scheme 4.6. α-Fluorination of cyclohexanone by Enders.


131

The successive publications by Jørgensen, Barbas, and MacMillan all concentrated on

aldehydes as substrates and NFSI as electrophilic fluorinating agent. The organocatalyst

chosen by Jørgensen is also a proline-derivative, namely TMS-protected (S)-prolinol

substituted with two electron-poor aromatic groups (Figure 4.2, left).40

NH

OTMS

F3CCF3CF3

CF3

N

NH

O

Ph

N

N

O

PhH H

O

OCl

Cl

Jørgensen Barbas MacMillan

Figure 4.2. Organocatalysts for the α-fluorination of aldehydes.

Barbas and MacMillan both relied on a similar imidazolidinone as catalyst. Barbas

employed it as the free base,41 whereas MacMillan used its dichloroacetate salt42 (Figure 4.2,

middle and right). In the asymmetric α-fluorination of primary aldehydes, all three systems

give good yields and excellent enantioselectivities (Table 4.2).

Table 4.2. Asymmetric organocatalytic α-fluorination of primary aldehydes.

H

OR

catalyst

NFSI∗

H

OR

F

substrate catalyst mol% yield (%) ee (%)

Jørgensen 1 74 93

Barbas 100 97 88 H

O

Ph MacMillan 20 71 96

Jørgensen (n=5) 1 55 96

Barbas (n=7)a 30 65 76 H

O

n MacMillan (n=8) 20 70 94

Jørgensen 1 69 96

H

O

MacMillan 20 96 99 a An imidazolidinone with a tert-butyl instead of the two methyl substituents was used as catalyst.


132

The protocol of Jørgensen is the most successful in terms of catalyst loading: 1 mol% is

sufficient for an effective enantioselective transformation. Owing to their instability, the α-

fluoroaldehydes were in several cases reduced in situ to the corresponding fluorohydrins.

The groups of both Jørgensen and Barbas encountered difficulties in the fluorination of

α,α-disubstituted aldehydes. With their standard organocatalysts (see Figure 4.2), they

observed a substantial decrease of the reaction rates, probably due to steric hindrance of the

enamine intermediate. Consequently, they developed slightly modified catalysts for the

fluorination of the α-branched aldehyde 2-phenylpropionaldehyde (10a) with NFSI. Using

(S)-proline derivatives in all cases, the α-fluoroaldehyde 10a was obtained in high yields of

78 to 99% (Table 4.3, entries 1 – 3). The enantioselectivity, however, reached only 48% ee in

the best case (entry 1). A significant improvement was recently achieved by Jørgensen and

co-workers. They synthesized enantiomerically pure atropisomeric 8-amino-2-naphthols that

exhibit superior results in the α-fluorination of 10a (entry 4). At a temperature of 4 °C, the α-

fluoroaldehyde 11a is produced in 95% conversion and with a selectivity of 90% ee.43

Interestingly, and complementary to the proline and imidazolidinone derivatives, the 8-amino-

2-naphthol catalysts are completely ineffective for the fluorination of primary aldehydes.

Table 4.3. Organocatalytic α-fluorination of 2-phenylpropionaldehyde (10a).

CH3

H

O∗

H

O

H3C F10a 11a

catalyst

NFSI

entry catalyst mol% yield (%) ee (%)

1 NH

Ar

ArAr = Ph-3,5-(CF3)2

Jørgensen 5 78 48

2 NH OTIPS

Barbas 30 90 44

3 NH HN N

NN

Barbas 30 99 45

4 H2N N

OH

Boc NHBoc

Jørgensen 20 95a 90

a Conversion, as determined from the 11a/10a ratio by GC analysis.


133

The above examples of aldehyde α-fluorinations nicely reflect the way in which

transition-metal catalysis and organocatalysis coexist. Transition-metal catalysts are superior

for the electrophilic fluorination of 1,3-dicarbonyl compounds, but they mostly fail when

monocarbonyl compounds, and aldehydes in particular, are concerned. This gap has now

successfully been occupied by organocatalysts. However, it is a disadvantage that the current

organocatalytic systems lack generality, as they are applicable only for either linear or α,α-

disubstituted aldehydes. Finding a general method that might be extended also to other

monocarbonyl compounds still remains a desirable and challenging goal.

4.1.5 Electrochemical α-Fluorination of Carbonyl Compounds

In this section, yet another method for the α-fluorination of monocarbonyl compounds

is presented. Electrochemical oxidative fluorinations have been developed mainly by the

research groups of Laurent and Fuchigami. Their strategy is to oxidize the substrate at a

platinum or graphite anode, and then trap the generated cation with a source of nucleophilic

fluoride. Suitable substrates for this transformation are either carbonyl compounds with a

thioether or an aryl substituent in α-position. The reactions of these substrate classes follow

different mechanisms and will be discussed separately in the two following sections.

4.1.5.1 α-(Arylthio)carbonyl Compounds

Fuchigami et. al. reported the anodic α-fluorination of ethyl 2-(phenylthio)acetate by

reaction with Et3N·3HF in an electrolytic cell with Pt electrodes. The application of a constant

potential of 1.6 V gave the corresponding α-fluorinated ester in 76% yield (Scheme 4.7).44

SOEt

OS

OEt

O

F

Pt anodeEt3N 3HF

CH3CN- 2e-, - H+ 76% yield

Scheme 4.7. Electrochemical oxidative α-fluorination of ethyl 2-(phenylthio)acetate.

A variety of other sulfides with electron-withdrawing substituents in α-position were

successfully fluorinated under oxidative electrolytic condititions. The phenyl group at sulfur

was replaced by heteroaromatics, such as pyridyl,45 pyrimidinyl,46 thiadiazolyl,47 or tetrazolyl


134

groups.48 Instead of ester groups, methyl ketones, nitriles, or phosphonates49 were used as

electron-withdrawing groups.

The proposed mechanism for the electrochemical fluorination (Scheme 4.8) includes the

attack of fluoride on the one-electron oxidized sulfur atom.50 The resulting sulfur-centered

radical undergoes a second one-electron oxidation to give the corresponding fluoro-sulfonium

ion. The electron-withdrawing group in α-position facilitates the subsequent loss of HF to

give a delocalized cation that is trapped by fluoride at the α-carbon. The overall reaction can

be understood as a variant of the classical Pummerer rearrangement, which transforms a

sulfoxide into an α-acetoxy sulfide.51,52

EWGSAr

F

H

EWGSAr

EWGSAr

FEWGS

Ar

EWGSAr EWGS

Ar EWGSAr

F- e- + F- - e-

- HF + F-

Scheme 4.8. Mechanism for the anodic fluorination of α-(arylthio)carbonyl compounds.

In one example, Brigaud and Laurent achieved an oxidative α-fluorination by chemical

instead of electrolytic oxidation.53 The oxidant 1,3-dibromo-5,5’-dimethylhydantoin (DBH)

acts as a source of electrophilic bromine, producing an intermediate bromo-sulfonium ion.

Elimination of HBr and trapping by fluoride leads to the corresponding α-fluorinated product

(Scheme 4.9). Sadly, they do not specify a yield for this reaction. The only given statement is

that the yield is lower than by the electrochemical route, which is 84%.

OEt

O Et3N 3HF

CH3CNSPh

OEt

O

FPhS

NN

O

O

Br Br NHN

O

O

Br+ + + Br-

DBH (< 84% yield)

Scheme 4.9. Oxidative α-fluorination of an α-(arylthio)ester by chemical oxidation.

4.1.5.2 α-Aryl-Carbonyl Compounds

Besides carbonyl compounds containing a thioether moiety, also sulfur-free substrates

with aromatic groups in α-position to the carbonyl group were subjected to electrolytic

fluorinations. Brigaud and co-workers treated 1-arylacetone derivatives and arylacetic acid


135

esters with Et3N·3HF at a platinum anode.54,55 Furthermore, also α-branched esters were used

as substrates.56 Electrochemical fluorinations at the α-position proceeded smoothly and in

good yields (Scheme 4.10).

X

O

X

O

FRR

MeO MeOPt anodeEt3N 3HF

CH3CN- 2e-, - H+

R = H, X = MeR = H, X = OEtR = Me, X = OEt

: 72% yield: 69% yield: 60% yield

Scheme 4.10. Anodic α-fluorination of sulfur-free α-aryl-carbonyl compounds.

In this case, a slightly different mechanism as compared to the sulfur-containing

substrates has been proposed. It is exemplified by a simple phenylacetic acid ester in Scheme

4.11. The reaction is initiated by the anodic one-electron oxidation of the aryl group.

Deprotonation in the α-position generates a benzylic radical that is further oxidized to the

benzylic cation. The reaction with F− from Et3N·3HF then leads to the desired α-fluoroester.55

- e- + F-

OEt

O - e-OEt

O

OEt

O

H

OEt

OOEt

O

F

- H+

Scheme 4.11. Mechanism for the electrolytic fluorination of α-aryl-carbonyl compounds.

Also for this type of substrates, the scope of electron-withdrawing groups was extended

to nitriles57 and phosphonates.58 However, the oxidation was invariably carried out by

electrolysis and not by chemical oxidation.

4.1.5.3 Diastereoselective Electrochemical α-Fluorination of Carbonyl Compounds

Both Laurent and Fuchigami devised a diastereoselective version of their

electrochemical fluorination. The approach of Laurent is based on (−)-8-phenylmenthol as

chiral auxiliary in an arylacetic acid ester. The anodic fluorination with Et3N·3HF in

acetonitrile gave the α-fluorinated ester in 65% yield and with a diasteromeric excess of 60%

de (Scheme 4.12).59 Fuchigami used a camphorsulfonamide derivative of thioglycolic acid as

chiral substrate, and the HF-reagent Et4NF·4HF as fluoride source.


136

O

OMeO

Ph

O

OMeO

PhF

O

S

OSO2iPr2N

O

S

OSO2iPr2N

F

Pt anodeEt3N 3HF

CH3CN- 2e-, - H+

Pt anodeEt4NF 4HF

DME- 2e-, - H+

65% yield60% de

88% yield>99% de

Scheme 4.12. Diastereoselective anodic fluorinations by Laurent and Fuchigami.

In 1,2-dimethoxyethane (DME) as solvent, the electrochemical fluorination proceeded

in high yield (88%) and with an excellent diastereoselectivity of >99% de (Scheme 4.12).60


137


As introduced in 4.1.2, it has been demonstrated by previous studies in our group that

the complex [RuF(PNNP)]+ is able to transfer fluoride to non-coordinated alkyl halides in an

enantioselective fashion. Following a complementary approach, we became interested in the

application of Ru/PNNP complexes as catalysts for the enantioselective transfer of F− from a

non-coordinated fluoride source to a coordinated substrate, preferably a meso-epoxide.

4.2.1 Reactivity of Ru/PNNP Complexes Towards meso-Epoxides

We initiated our investigations by studying the coordination properties of four selected

meso-epoxides to ruthenium PNNP complexes. We chose the bicyclic epoxides cyclopentene

oxide (7a) and cyclohexene oxide (7b) as well as cis-2,3-epoxybutane (7c) and cis-stilbene

oxide (7d) as substrates (Figure 4.3).

O OO

H3C CH3

O

Ph Ph7a 7b 7c 7d

Figure 4.3. Selected meso-epoxides for reactivity tests with Ru/PNNP complexes.

The Ru/PNNP complexes chosen for the survey of reactivity were prepared from

[RuCl2(PNNP)] (1) and either TlPF6 (1 equiv) or AgSbF6 (2 equiv) in CD2Cl2. After removal

of TlCl or AgCl by filtration, the appropriate epoxide 7a-d (10 equiv) was added, and the

mixture was analyzed by NMR spectroscopy. The results are summarized in Table 4.4.

The five-coordinate, monocationic complex [RuCl(PNNP)]PF6 (9PF6), obtained by

chloride abstraction from 1 with TlPF6 (1 equiv), does not react with epoxides 7c and 7d.

With 7b, polymerization of the epoxide was observed, as indicated by broad signals at δ 3.5

(CH—OR) and between δ 1 and 2 (CH2) in the 1H NMR spectrum. In the case of 7a, the 31P

NMR spectrum features new signals of an AB spin system (15% by integration) at δ 64 and

45 after addition of the epoxide (10 equiv), which we tentatively assign to a complex with

coordinated 7a. Epoxide 7a polymerizes rather slowly in the presence of 9PF6, as only 25% of

polymer are observable after 24 h.


138

Table 4.4. Reactions of Ru/PNNP complexes with epoxides 7a-d (10 equiv).

complex 7a 7b 7c 7d

9PF6 coordination? polymerisation - -

1 + 2 AgSbF6 polymerisation polymerisation polymerisation Meinwald rearrangement

The tentatively formulated dicationic complex [Ru(PNNP)](SbF6)2, obtained by double

chloride abstraction from 1 with AgSbF6 (2 equiv),61 is expected to be a better Lewis acid

than [RuCl(PNNP)]PF6 (9PF6). Accordingly, the epoxides 7a-c polymerize rapidly in its

presence (see Table 4.4). Cis-stilbene oxide (7d) exhibits a different reactivity, though. When

7d (10 equiv) is added to a freshly prepared CD2Cl2 solution of [Ru(PNNP)](SbF6)2, it is

transformed with 96% conversion to diphenylacetaldehyde within 30 min. This reaction is

known in the literature as Meinwald rearrangement, named after its discoverer who reported

the reaction with Brønsted acid catalysis in 1963.62 It was found later that many Lewis acids

are also effective catalysts for these rearrangements, among others Al(III),63 Bi(III),64 Ir(III),65

and Cr(III) complexes.66 Scheme 4.13 sketches the mechanism of a Lewis acid-catalyzed

Meinwald rearrangement of cis-stilbene oxide. Coordination of the epoxide causes a strong

polarisation or even cleavage of the C—O bond, producing a stabilized benzylic cation, which

then undergoes a [1,2]-migration of the phenyl group.

O

Ph PhO

Ph Ph

[LA]

δ+δ-

Ph

O [LA]H

PhPh

PhO

H

[LA][LA]

Scheme 4.13. Lewis acid-catalyzed Meinwald rearrangement of cis-stilbene oxide.

As a result of the above reactivity tests, cyclopentene oxide (7a) seems to have the most

promising properties for catalysis. There are hints that it coordinates to complex 9, whereas its

polymerisation is slow. Thus, we chose 7a as standard substrate for the subsequent studies

about ring-opening hydrofluorination catalyzed by Ru/PNNP complexes.


139

4.2.2 Ru/PNNP-Catalyzed Hydrofluorination of meso-Epoxides

4.2.2.1 Reactions with [RuCl(PNNP)]+ (9) as Catalyst

With cyclopentene oxide (7a) as substrate and complex 9PF6 as catalyst (20 mol%), a

first screening of mild and easy-to-handle HF sources for epoxide ring-openings was carried

out. As shown in Table 4.5, the HF sources used in runs 1 – 4 gave either no conversion or led

to polymerisation of the epoxide.

Table 4.5. Screening of HF sources for the hydrofluorination of meso-epoxide 7a.

O

7a

F

OH

1) 9PF6 (20 mol%)

2) HF sourceCH2Cl2 8a

run HF source (equiv) products

1 Et3N·3HF (1.5) polymers

2 (Bu4N)H2F3 (1.0) -

3a KHF2 (1.5) polymers

4b PhCOF (1.1) -

5 AgHF2 (1.0) (rac)-8a + F-polymers (1.5:1)

6 AgHF2 (2.0) (rac)-8a + F-polymers (2.7:1)

7 AgHF2 (4.0) (rac)-8a + F-polymers (2.3:1) a 20 mol% of [Ru(OEt2)2(PNNP)]2+ (6) was used as catalyst. b Product 8a with a benzoyl protected hydroxy group was expected.

However, hydrofluorination of 7a did take place with silver(I) bifluoride (AgHF2) as HF

source (run 5), producing the corresponding fluorohydrin trans-2-fluorocyclopentan-1-ol (8a)

as a racemic mixture. Polymers with incorporated fluorine (abbreviated as F-polymers) were

observed as by-products in various quantities, depending on the amount of AgHF2 used (runs

6 and 7). The ratios of 8a to F-polymers were determined by integration of the 19F NMR

signals in the crude reaction mixtures. Attempts of purifying the products by filtration over

SiO2 led to a considerable increase of the polymeric products. Figure 4.4 shows sections of

typical 19F and 1H NMR spectra of a reaction solution with AgHF2 after filtration, where the 19F NMR spectroscopic ratio of 8a and F-polymers is 1.5:1. The 19F NMR signal of 8a is at δ


140

−180.1 (multiplicity dddd), whereas the resonance of the fluorinated polymers appears as a

multiplet between δ −178.7 and −179.7. The diagnostic 1H NMR signal of the methine group

bearing the fluorine substituent appears at δ 4.88 for 8a (2JF,H = 52.0 Hz), and with a slight

up-frequency shift for the F-polymers. The spectral features of the F-polymers are analogous

to those of the dimer and trimer of the related epoxide 7b after ring-opening with HF sources

described by Haufe.34

Figure 4.4. 19F and 1H NMR spectra of the Ru/PNNP-catalyzed reaction of 7a with AgHF2.

The reaction mixtures of the epoxide openings are heterogeneous, as AgHF2 does not

dissolve in CH2Cl2. Consequently, HF might be delivered into the solution more slowly than

with a soluble HF source, which could be advantageous if the catalyst is deactivated or

decomposed by HF.

It is intriguing that hydrofluorination was only achieved with the rather uncommon HF

source silver(I) bifluoride. AgHF2 is a white, hygroscopic, half-molten solid that turns dark

upon exposure to light. It was therefore stored and handled in a glove box under an

atmosphere of dry nitrogen, and protected from direct light whenever possible.

4.2.2.2 Reactions with [Ru(OEt2)2(PNNP)]2+ (6) as Catalyst

As no enantioselectivity was obtained with catalyst 9, we turned our attention to the

dicationic complex [Ru(OEt2)2(PNNP)]2+ (6), prepared by double chloride abstraction from 1

with (Et3O)PF6 (2 equiv). The Lewis acid strength of 6 is assumed to be between that of

[RuCl(PNNP)]PF6 and [Ru(PNNP)](SbF6)2, nevertheless it is strong enough to effect rapid

epoxide polymerisation when added to an excess of 7a (10 equiv). To lessen this problem, all

reactions were carried out by slow addition of a CH2Cl2 solution of the epoxide via syringe

pump to the heterogeneous mixture of catalyst 6 (20 mol%) and AgHF2 in CH2Cl2. As

reaction vessels, Teflon® tubes, protected from light with aluminium foil, were used.


141

Table 4.6. Asymmetric hydrofluorination of cyclopentene oxide and cyclohexene oxide.

OOH

F

catalyst 6 (20 mol%)AgHF2

CH2Cl2, r.t.n n

n=1: 8an=2: 8b

+O

Fn

O

n

n=1: 7an=2: 7b F-polymer

run substrate addition time (h)

AgHF2 (equiv)

reaction time (h)

conv. (%)a

yield (%)a

ee (%)

1 7a 2 2.0 24 95 11 25

2 7a 2.5 1.0 21 93 9 25

3b 7a 2.5 1.2 96 54 4 15

4 7b 17 1.2 24 100 8 10 a Determined by quantitative GC analysis of the reaction mixtures after precipitation of the catalyst with hexane. b A catalyst loading of 5 mol% was used.

Cyclopentene oxide (7a) undergoes 95% conversion within 24 h after slow addition

(during 2 h) to 6 (20 mol%) and AgHF2 (2.0 equiv). Indeed, complex 6 does catalyze the ring-

opening with asymmetric induction. The fluorohydrin 8a is obtained in 11% yield and with an

enantioselectivity of 25% ee (Table 4.6, run 1). The low yield suggests that polymerisation is

the main reaction pathway under the applied conditions. The outcome is almost identical

when a stoichiometric amount of AgHF2 is used (run 2). When the catalyst loading is

decreased to 5 mol%, the reaction is much slower, reaching only 54% conversion after 96 h

(run 3). Fluorohydrin 8a is formed in only 4% yield and 15% ee. In a background reaction

between 7a and AgHF2 (1 equiv) without ruthenium catalyst, only F-polymer was formed,

and no monomeric fluorohydrin was observed.

Cyclohexene oxide (7b) reacts under analogous conditions with AgHF2 (1.2 equiv) in

the presence of 6 (20 mol%). Due to its faster polymerisation, the addition time of the epoxide

was extended to 17 h. Full conversion was reached within 24 h after complete addition, but

the fluorohydrin 8b was obtained in 8% yield and with 10% ee only (Table 4.6, run 4). Also

in that case, polymerisation clearly prevails over hydrofluorination.

When cis-stilbene oxide (7d) was used as substrate, an unexpected reaction was

observed. Surprisingly, fluoro-diphenylacetaldehyde was identified as the major product in

the reaction mixture after 24 h, together with two diastereomeric fluorohydrins (threo-8d and


142

erythro-8d) and diphenylacetaldehyde (Scheme 4.14). The ratio of fluoro-diphenyl-

acetaldehyde to the fluorohydrins is 5:1:1 by integration of the 19F NMR signals.

Ph

F OH

Ph Ph

F OH

Ph

Ph

PhH

O

F

O

Ph Ph

6 (20 mol%)AgHF2 (1.3 equiv)

CH2Cl2, r.t.+Ph

PhH

O

+

major product

7d threo-8d ery thro-8d

Scheme 4.14. Unexpected reaction of 7d with AgHF2 catalyzed by a Ru/PNNP complex.

The occurrence of both diastereoisomers of 8d suggests an SN1-like mechanism for the

hydrofluorination. Lewis acid-catalyzed ring-opening of 7d produces a benzylic carbocation,

whose lifetime is long enough to undergo isomerisation before being trapped by fluoride.

Diphenylacetaldehyde is the product of the ruthenium-catalyzed Meinwald rearrangement, as

described above. The formation of the fluorinated aldehyde, however, is more intriguing.

An independent reaction starting from diphenylacetaldehyde under otherwise identical

conditions gave about 75% conversion to fluoro-diphenylacetaldehyde within 6 h, and neither

stilbene oxide nor fluorohydrins were observed in the reaction mixture. That excludes the

possibility of a retro Meinwald rearrangement (aldehyde → epoxide), and proves that

diphenylacetaldehyde is directly fluorinated in α-position by AgHF2 with complex 6 as

catalyst. Thus, a two-step process takes place in the catalysis with cis-stilbene oxide (7d),

namely Meinwald rearrangement to diphenylacetaldehyde and subsequent α-fluorination. The

formation of the C—F bond is counter-intuitive, though. An enolizable aldehyde is

nucleophilic in α-position, and AgHF2 is a source of nucleophilic F− ions. Apparently, one of

the components undergoes an umpolung (oxidation) during the course of the reaction. The

overall process is therefore similar to the known electrochemical α-fluorination of thiols or

carbonyl compounds (see 4.1.5), leading to C—F bond formation under oxidation.

We were immediately fascinated by this finding, because an oxidative fluorination with

the nucleophilic fluoride source AgHF2 could be a complementary approach for the α-

fluorination of carbonyl compounds, reactions that are usually accomplished by electrophilic

N—F fluorinating agents. At that point, we decided to abandon the ruthenium-catalyzed

epoxide hydrofluorinations, because the strong preference for the undesired polymerisation


143

seemed difficult to overcome. Instead, we decided to investigate the α-fluorination of

aldehydes with AgHF2 in more detail, in particular for aldehydes with two different α-

substituents, from which chiral α-fluoroaldehydes could be obtained.

4.2.3 Ruthenium/PNNP-Catalyzed Asymmetric α-Fluorination of 2-

Phenylpropionaldehyde

As a model substrate for the α-fluorination of aldehydes with AgHF2, we chose the

commercially available 2-phenylpropionaldehyde (10a). The phenyl and methyl substituents

in α-position to the aldehyde carbonyl group allow for the formation of a fluorinated

quaternary stereogenic center. The absence of a further α-proton prevents racemization after

the fluorination step. We initiated our investigations by exposing 10a to reaction conditions

similar to those, which effected the Meinwald rearrangement and α-fluorination of cis-

stilbene oxide, or the direct α-fluorination of diphenylacetaldehyde.

4.2.3.1 Initial Attempts with [Ru(OEt2)2(PNNP)]2+ (6) as Catalyst

As we soon realized, and as others have reported before,40,41,67,68 α-fluorinated

aldehydes are generally not stable, and decompose upon purification. Therefore, we analyzed

the crude reaction mixtures after either quick filtration through a short plug of Al2O3

(deactivated with 10 w-% of water) or after precipitation of the catalyst with hexane. GC-MS

measurements and NMR spectroscopy were used for estimating the conversions and product

distributions.

The first experiments were carried out by mixing 2-phenylpropionaldehyde (10a) with a

CH2Cl2 solution of [Ru(OEt2)2(PNNP)]2+ (6), freshly prepared from [RuCl2(PNNP)] (1) and

(Et3O)PF6 (2 equiv). The combined catalyst-substrate solution was then added to AgHF2 in a

Teflon® tube that was protected from light with aluminium foil. Running the reaction with 1.3

equivalents of AgHF2 at room temperature did not lead to any conversion within 24 h (Table

4.7, run 1). When the reaction was carried out in a Teflon® tube closed with a screw cap at an

oil bath temperature of 60 °C, around 70% conversion was observed after 23 h, but the

desired α-fluoroaldehyde 11a was formed only in about 20% yield (run 2). The main product

was identified as acetophenone (23a). Its formation from 10a by decarbonylation under


144

oxidative C—C bond cleavage with O2 is known. Several Brønsted and Lewis acids were

reported to catalyze this transformation.69 Oxygen was probably able to diffuse into the

Teflon® tube, because it was closed with a screw cap, and not connected to argon pressure.

Also in the reactions described later, acetophenone was always present as by-product in small

quantities, indicating that oxygen could not be excluded completely.

Table 4.7. α-Fluorination of 10a with AgHF2 catalyzed by complex 6.

10aCH3

H

O

H

Ocatalyst 6AgHF2

CH2Cl2, 24 h H3C F

11a

run 6 (mol%)

AgHF2 (equiv) T (°C) yield (%)a ee (%)

1 20 1.3 23 0 n.d.

2b 20 1.3 60 20 n.d.

3b 20 2.5 60 35 0

4b 5 2.5 60 70 0 a Estimated from 1H NMR spectra of the crude reaction mixtures. b The reactions were carried out in sealed Teflon® tubes at oil bath temperatures of 60 °C.

A considerable improvement was achieved by using 2.5 equivalents of AgHF2. α-

fluoroaldehyde 11a was produced in about 35% yield with 20 mol% of catalyst 6 (run 3).

Interestingly, the reaction worked better with less catalyst (5 mol%), forming the product in

about 70% yield (run 4). In both runs 3 and 4, however, fluoroaldehyde 11a was obtained as a

racemic mixture. The 19F NMR signal of 11a appears at δ −160.9 as a doublet of quartet, with

a coupling constant of 3JF,H = 22.7 Hz to the methyl group, and 3JF,H = 4.9 Hz to the aldehyde

hydrogen.

Under similar reaction conditions as above, the non-silver fluoride sources KHF2 and

Et3N·3HF did not react with 2-phenylpropionaldehyde. With AgF, some conversion was

observed after 20 h at 60 °C, but the product was formed sluggishly and in small quantities

only. When the silver(II) salt AgF2 was used as reagent, many fluorinated products were

detected after 2 h by 19F NMR spectroscopy and by GC-MS, but the desired fluoroaldehyde

11a was present in trace amounts only. The main products were identified as 1-fluoro-1-


145

phenylethane and 2-phenylpropionic acid fluoride (Scheme 4.15). The former originates from

fluorination and decarbonylation, the latter from oxidation of the aldehyde carbonyl group.

10aCH3

H

OPh

H

O6 (10 mol%)AgF2 (2.5 equiv)

CH2Cl2, 2 h H3C F

11a

Ph CH3

FPh

F

O

+ +

CH3

unidentifiedproducts+

Scheme 4.15. Reaction of 2-phenylpropionaldehyde (10a) with silver(II) fluoride.

Similar products have been observed by Stavber et. al. in the reaction of aldehydes with

cesium fluoroxysulfate (CsSO4F),70 a fluorinating agent with exceptional oxidizing power

(SO4F− + 2 H+ + 2 e− → HSO4− + HF: E0 = +2.52 V).71 It was postulated that these reactions,

leading to decarbonylation or to acyl fluorides, both proceed via radical pathways. In view of

the high oxidation potential of AgF2 (Ag2+ + e− → Ag+: E0 = +1.98 V)72 it is not surprising

that similar reaction pathways as with CsSO4F are predominant.

This initial screening shows that 10a requires higher temperatures for the α-fluorination

than was necessary for diphenylacetaldehyde. Apparently, the missing aromatic group

decreases the reactivity of the substrate considerably. Moreover, 2.5 equivalents of AgHF2 are

needed to obtain good substrate conversions, and non-silver fluoride sources do not react at

all. Those facts could hold helpful clues about the reaction mechanism, which will be

speculated about in paragraph 4.2.5.

4.2.3.2 Asymmetric α-Fluorination in 1,2-Dichloroethane as Solvent

So far, the α-fluorinations were conducted in CH2Cl2 as solvent. The solutions had to be

heated above boiling point in a closed vessel, making the reproducibility of the reaction

conditions questionable. Dichloromethane was thus replaced by 1,2-dichloroethane (DCE) as

reaction medium, having a boiling point of 83 °C. The reactions were now carried out at 60

°C in Teflon® tubes, connected to argon pressure via a rubber septum. To our delight, the

reactions of aldehyde 10a with AgHF2 (2.4 equiv) in DCE gave the product 11a in

enantiomerically enriched form (Table 4.8). With [Ru(OEt2)2(PNNP)]2+ (6, 5 mol%) as

catalyst, a conversion of 50% was estimated after 20 h by GC-MS and an enantiomeric excess

of 18% ee was measured for 11a (run 1). A slightly better conversion, but a similar

enantioselectivity of 19% ee were obtained with 20 mol% of catalyst 6 (run 2).


146

Table 4.8. Screening of Ru/PNNP catalysts for the α-fluorination of 10a in DCE.

10aCH3

H

O

H

O

H3C F

11a

[RuCl2(PNNP)] (1)Cl-scavenger

AgHF2 (2.4 equiv)DCE, 60 °C

run 1 (mol%) Cl-scavenger (mol%) time (h) conv. (%)a ee (%)

1 5 (Et3O)PF6 (10) 20 50 18

2 20 (Et3O)PF6 (40) 20 70 19

3 5 TlPF6 (5) 2 20 43

8 50 40

23 60 39

4b 5 AgSbF6 (5) 2 20 44

8 50 37

23 60 36

5 5 AgSbF6 (10) 2 20 42

8 50 39

23 60 38 a Estimated from GC-MS measurements of the crude reaction mixtures. b In later experiments, however, the enantioselectivities were not reproducible, and only 27% ee were obtained (see below).

We then went back to test different ruthenium PNNP catalysts by varying the method of

chloride abstraction from [RuCl2(PNNP)] (1). Almost identical results are obtained with the

catalysts prepared with TlPF6 (1 equiv) or AgSbF6 (1 or 2 equiv). In all three cases (runs 3-5),

an enantiomeric excess of 42 – 44% ee is measured after a conversion of about 20%, which

then drops to 36 – 39% ee at conversions of around 60% after 23 h. The decrease of

enantioselectivity could be interpreted by a transformation or decomposition of the catalyst to

a less selective species during the reaction. This option is by all means reasonable under the

oxidative and acidic conditions that are employed. We chose the system with the highest

initial enantioselectivity to continue our investigations, that is, with catalyst 9SbF6, prepared

from 1 and AgSbF6 (1 equiv).

As a proof of principle, we tried the α-fluorination of 10a in a tandem reaction starting

from α-methylstyrene oxide (24a). In a first step, catalyst 9SbF6 effects a quantitative

Meinwald rearrangement of 24a in 1,2-dichloroethane at room temperature. The subsequent


147

addition of the reaction mixture to AgHF2 (2.4 equiv) in a Teflon® tube at 60 °C leads to the

α-fluorination of 10a with an estimated conversion of 50% by GC-MS (Scheme 4.16). The α-

fluoroaldehyde 11a was obtained with an enantioselecitivitiy of 34% ee.

CH3

O

H

O

CH3H

O

FH3C

50 % conv.34 % ee

9SbF6 (5 mol%)

DCE, r.t., 1.5 h

AgHF2(2.4 equiv)

60°C, 24 h

24a 11a10a

Scheme 4.16. Tandem Meinwald rearrangement – α-fluorination.

Unfortunately, we were not able to reproduce the aforementioned enantioselectivities

for the α-fluorination of 10a in later experiments. An enantiomeric excess not higher than

27% ee was achieved for 11a, despite the 36 – 44% ee obtained in the initial trials (Table 4.8,

run 4). Also the use of fresh batches of 1, AgSbF6 and AgHF2 did not improve the results. The

reaction seems to be very sensitive to minor changes in the conditions, a fact that leads to

problems with reproducibility.

In the later reactions, we used octafluoronaphthalene as an internal standard to

determine the yields of the sensitive α-fluoroaldehydes by 19F NMR spectroscopy. The

catalyst and silver salts were removed from the reaction mixture by filtration through a short

plug of Al2O3.

CH3

H

O

H

O

H3C F

9SbF6(5 mol%)

AgHF2 (2.4 equiv)DCE, 60 °C, 24 h

24% yield27% ee

10a 11a

Figure 4.5. 19F NMR spectrum of 11a and internal standard octafluoronaphthalene.


148

After evaporation of the solvents, the crude product and a defined amount of

octafluoronaphthalene were dissolved in CDCl3 and a 19F NMR spectrum was recorded

immediately. The delay time between pulses was set to 30 – 60 s in order to allow the

complete relaxation of the different fluorine nuclei, which ensures a meaningful integration of

the signals. A typical 19F NMR spectrum of 11a and octafluoronaphthalene is reproduced in

Figure 4.5.

4.2.3.3 Variation of Solvents and PNNP Ligands

Three other solvents with boiling points above 60 °C were tested for the α-fluorination

of 10a, namely toluene, THF, and 1,4-dioxane (Table 4.9, runs 1-3). The conversions are

lower than in 1,2-dichloroethane, reaching only about 20% in toluene, and 40% in THF. The

α-fluoroaldehyde 11a is formed as a racemate in toluene. Surprisingly, the opposite

enantiomer as observed in DCE is produced in THF and 1,4-dioxane with −30% and −22%

ee, respectively.

Table 4.9. Screening of solvents and electronically tuned PNNP ligands.

10a

CH3

H

O

H

O

H3C F

11a

pre-catalyst (5 mol%)AgSbF6 (5 mol%)

AgHF2 (2.4 equiv)solvent, 60 °C, 24 h

N N

PPAr2 Ar2

Ru

Cl

Cl

pre-catalyst:

run Ar solvent conv. (%)a yield (%)a ee (%)b

1 Ph toluene 20 10 0

2 Ph THF 40 10 −30

3 Ph 1,4-dioxane 25 5 −22

4 Ph-4-CF3 DCE 30 10 −11

5 Ph-3,5-(CF3)2 DCE 50 10 0

6 Ph-4-OMe DCE 40 20 0 a Estimated from GC-MS measurements of the crude reaction mixtures. b Negative signs indicate the formation of the opposite enantiomer as major product.


149

For a variation of electronic properties of the catalyst, we chose ligands with a para-

CF3, two meta-CF3, and a para-OMe substituent at the phenyl groups of the PAr2 moieties

(Table 4.9, runs 4-6). The Ph-3,5-(CF3)2 (run 5) and the Ph-4-OMe catalyst (run 6) both gave

racemic 11a. The complex containing para-CF3 groups produced 11a in about 30%

conversion and with −11% ee. Also in this case, the opposite enantiomer is formed

preferentially as compared to standard conditions.

We were not able to deduce any conclusive tendencies from the data in Table 4.9. In

particular, the reversal of enantioselectivity in some cases is inexplicable to us at the moment.

Also the electronic tuning of the PNNP ligand, which should have a direct influence on the

Lewis acidity and reactivity of the ruthenium complexes,73,74 gives no obvious trend.

4.2.4 Asymmetric α-Fluorination of Related Aldehydes

Some homologs of the standard substrate 2-phenylpropionaldehyde (10a) with different

alkyl groups in the aldehyde α-position were synthesized and tested in catalytic fluorination

(10b-d). We were interested in the effect of increased steric bulk of the alkyl groups on

activity and enantioselectivity.

4.2.4.1 Syntheses of Substrates Containing Other Alkyl Groups

2-Phenylbutyraldehyde (10b), the homolog of 10a containing an ethyl group instead of

methyl, was synthesized by a reduction – oxidation sequence from (rac)-2-phenylbutyric acid.

The reduction to (rac)-2-phenylbutan-1-ol with LiAlH4 in diethylether proceeded smoothly in

95% yield (Scheme 4.17). The oxidation to aldehyde 10b was first attempted with pyridinium

chlorochromate (PCC) as oxidant, but the results were unsatisfactory. A 5:1 mixture of 10b

and propiophenone was obtained in 52% yield, whose separation by distillation failed.

However, a fast and clean reaction was achieved with Dess-Martin periodinane (1,1,1-

triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, abbreviated as DMP), which was

prepared in two steps from 2-iodobenzoic acid (Scheme 4.17). Treatment of (rac)-2-

phenylbutan-1-ol with DMP (1.1 equiv) and distillation of the crude product furnished pure

aldehyde 10b in 87% yield.


150

OH

O

OH H

OLiAlH4(0.9 equiv)

Et2O, r.t., 14 h95%

DMP (1.1 equiv)

CH2Cl2, r.t., 1 h87%

10b

OH

O

IIO

O

OOH

: IO

O

AcOOAc

OAc

KBrO3(1.3 equiv)

H2SO4 (0.7 M)55°C -> 70°C

85%

p-TsOH(0.7 mol%)

Ac2O, 80°C, 2 h83%

Dess-Martin periodinane(DMP)

Scheme 4.17. Synthesis of 2-phenylbutyraldehyde (10b) and Dess-Martin periodinane.

The aldehydes 10c and 10d, containing a iPr and a tBu group, respectively, were

synthesized by C1-homologation of the corresponding aryl ketones 23c and 23d, following a

two-step procedure (Scheme 4.18). A solvent-free epoxidation of ketones 23 with

dimethylsulfonium methylide gave the oxiranes 24 in good yields. The subsequent Meinwald

rearrangement to aldehydes 10c and 10d was accomplished with BF3·OEt2 as Lewis acid.

RH

O

R

O O

R

(Me3S+)I- (1.2 equiv)KOtBu (1.2 equiv)

neat, 70°C, 2-4 h

BF3 OEt2(1.5 equiv)

toluener.t., 1 h

24c: 77%i24d: 73%

10c: 84%i

10d: 79%23c: R=iPr23d: R=tBu

Scheme 4.18. Syntheses of aldehydes 10c and 10d from ketones 23.

4.2.4.2 Catalysis with Substrates Containing Other Alkyl Groups

The aldehydes 10b-d, containing different alkyl groups, were tested in the asymmetric

α-fluorination with AgHF2 catalyzed by 9SbF6 (5 mol%). The results are summarized in

Table 4.10. In entry 1, the previously obtained result for 2-phenylpropionaldehyde (10a) is

given for comparison. The higher homologs 10b and 10c give better yields, with 35% and

31%, respectively (entries 2 and 3). Only trace amounts of the corresponding phenyl alkyl

ketones (products of oxidative decarbonylation) were observed in these cases. The

enantiomeric excesses of the α-fluoroaldehydes are lower though, reaching 23% ee for 11b,

and 18% ee for 11c. The tert-butyl-substituted aldehyde 10d is poorly reactive, and was

fluorinated in 13% yield only (entry 4). The enantioselectivity could not be determined, as the

enantiomers were not separable by chiral GC.


151

Table 4.10. α-Fluorination of differently substituted 2-alkylphenylacetaldehydes.

RH

O

H

O

R F

9SbF6(5 mol%)


11a: R=Me11b: R=Et11c: R=iPr11d: R=tBu

10a-d

entry substrate yield (%)a ee (%)

1 10a 24 27

2 10b 35 23

3 10c 31 18

4 10d 13 n.d.b

a Determined by integration of the 19F NMR signals with internal standard octafluoronaphthalene. b No separation of the enantiomers was achieved by chiral GC analysis.

The trend for the enantioselectivities clearly points in the unwanted direction, it

decreases with increasing steric bulk of the alkyl group. Thus, the highest selectivity is still

obtained with the simplest substrate, 2-phenylpropionaldehyde.

4.2.4.3 Unactivated Substrates

To assess whether aldehydes other than 2-alkylphenylacetaldehydes would undergo

Ru/PNNP-catalyzed α-fluorination, we tested several primary aldehydes and a 2,2-

dialkylacetaldehyde. However, all the substrates shown in Figure 4.6 were unreactive under

standard catalysis conditions.

H

OH

O

H

OH

O

Figure 4.6. Primary aldehydes and a 2,2-dialkylacetaldehyde tested in catalysis.

H

O

H

O

H

O

H

O


152

Considering the difference in reactivity between diphenylacetaldehyde (reacts in

CH2Cl2 at room temperature) and 2-phenylpropionaldehyde (10a, requires 60 °C in DCE), a

further loss of reactivity for primary aldehydes is plausible. Thus, the presence of at least one

aromatic substituent in α-position seems to be mandatory to achieve a useful reactivity.

So far, we only used aldehydes as substrates. Concerning the stability of the catalysis

products, it might be beneficial to use substrates with another carbonyl functional group, such

as ketones or esters. To test their performance in the catalytic α-fluorination, the methyl

ketone and ethyl ester analogs of aldehyde 10a were synthesized. For the ketone, a two-step

procedure was followed. A Grignard reaction of 10a with CH3MgI, followed by Dess-Martin

oxidation of the resulting secondary alcohol gave the desired 3-phenylbutan-2-one (25) in

good yield (Scheme 4.19).

CH3

H

O

10a CH3

CH3

OH

CH3

CH3

OCH3MgI(1.1 equiv)

Et2O, r.t., 14 h97%

DMP (1.1 equiv)

CH2Cl2, r.t., 75 min83%

25

CH3

OH

O

CH3

OEt

OH2SO4 (0.5 equiv)

EtOH, reflux, 5 h83%

26

Scheme 4.19. Synthesis of 3-phenylbutan-2-one (25) and ethyl 2-phenylpropionate (26).

The related ethyl ester, ethyl 2-phenylpropionate (26), was easily prepared by acid-

catalyzed esterification of 2-phenylpropionic acid in ethanol (Scheme 4.19). Pure ester 26 was

isolated in 83% yield after distillation.

Unfortunately, both substrates 25 and 26 did not react under standard catalytic

conditions, that is, with AgHF2 (2.4 equiv) in the presence of catalyst 9SbF6 (5 mol%) in DCE

at 60 °C.

The above experiments with carbonyl compounds of different structure show that the

substrate scope for the α-fluorination with AgHF2 is rather limited at the moment. The

substrates that give enantiomerically enriched fluorinated products are restricted to secondary

aldehydes bearing both an aryl and an alkyl group in α-position.


153

4.2.5 Mechanistic Considerations and Literature Comparison

As explained in paragraph 4.2.2.2, the starting point of this project was the

serendipitous observation of the Ru/PNNP-catalyzed α-fluorination of diphenylacetaldehyde

with AgHF2. Building up the project from this empirical angle, we were long time in the dark

about the mechanism of this reaction. Through the screenings described in the previous

paragraphs, several mechanistic clues could be collected. Those ideas will be discussed in this

section and compared with some results from literature.

The nucleophilic nature of both reactants (aldehyde α-position and AgHF2) implies that

an oxidation must take place in order to form a new C—F bond. This principle is similar to

the described electrolytic fluorinations (see 4.1.5), but in our case, a chemical oxidant is used

instead. The oxidation of F− is impossible, because of its high standard potential (1/2 F2 + e−

→ F−: E0 = +2.87 V).75 Thus, the oxidation of the aldehyde seems much more probable. The

only obvious oxidant in the reaction mixture is silver(I), whose reduction is supported by the

observation of grey solids after completion of the reactions, which we interpret as elemental

silver (Ag+ + e− → Ag0: E0 = +0.80 V).72 The requirement for two equivalents of Ag+

suggests that the aldehyde undergoes a two-electron oxidation to an α-carbonyl cation. At

first glance, this seems rather unlikely because carbocations are destabilized by electron-

withdrawing groups in α-position. On the other hand, it would explain the observed order of

reactivity: diphenylacetaldehyde > 10a > 2,2-dialkylacetaldehyde ~ primary aldehydes, which

corresponds to the number of cation-stabilizing α-aromatic groups.

It is firmly anchored in our general chemical understanding that carbocations containing

a directly attached electron-withdrawing group should be highly unstable, and thus, should

not exist. However, there is a large number of examples, proving that such cations can indeed

be generated, studied, and used as intermediates in synthetic methods.76,77

Apart from the electrolytic methods described in 4.1.5, several ways to generate α-

carbonyl cations have been reported. For example, solvolysis of carbonyl compounds with a

good leaving group in α-position (e.g. OMs or OTf), loss of N2 from α-diazo carbonyl

compounds after reaction with an electrophile, or reactions of silver(I) salts with α-bromo

carbonyl compounds (Scheme 4.20).76


154

RR''

O

R'

RR''

O

R' OMs

RR''

O

R' Br

RR'

O

N2

RR'

O

E N2

RR'

O

E

-MsO-

Ag+

-AgBr

E+

-N2

Scheme 4.20. Reported methods for the generation of α-carbonyl cations.

Alternatively, the transformation of enolates to α-carbonyl radicals and α-carbonyl

cations via subsequent one-electron oxidation steps has been published. α,α-Diaryl

substituted ketones or aldehydes were treated with 2 equivalents of the one-electron oxidant

tris(1,10-phenanthroline)iron (III) hexafluorophosphate [Fe(phen)3](PF6)3 (Scheme 4.21).78 A

fast reaction was obtained, yielding the corresponding benzofurans via two one-electron

oxidation steps to the α-carbonyl cation, followed by cyclization, [1,2]-methyl shift, and

deprotonation.

Mes

MesR

O

Mes = 2,4,6-trimethylphenyl

Mes

MesR

O

MesR

O[Fe(phen)3]3+

-[Fe(phen)3]2+

[Fe(phen)3]3+

-[Fe(phen)3]2+

O

Mes

R1) [1,2]-CH3-shif t

2) -H+

O

Mes

R

Scheme 4.21. Generation of α-carbonyl cations by two one-electron oxidations.

The oxidizing agent [Fe(phen)3](PF6)3 is strong enough to effect both one-electron

transfers ([Fe(phen)3]3+ + e− → [Fe(phen)3]2+: E0 = +1.15 V).72

Interestingly, even an α-fluorination of ketones has been reported by Griesbaum and co-

workers, which was found to proceed via α-carbonyl cations (Scheme 4.22). Chloride

abstraction from 2-chlorooxiranes with AgBF4 gave epoxycarbenium ions in the first step.

Rearrangement to the corresponding α-keto cations and reaction with BF4− as fluoride source

gave the α-fluoroketones in good yields.79


155

O

Cl R'

R O

R'RH H

R

O

H

R'R

O

F

R'Ag+

-AgCl

BF4-

-BF3

R=R'=CH3:R=CH3, R'=Ph:R=Ph, R'=CH3:R=tBu, R'=H:

68%62%83%78%t

Scheme 4.22. Synthesis of α-fluoroketones via α-keto cations reported by Griesbaum.

It should be noted that the epoxide has different roles in the reaction of Griesbaum and

in our tandem reaction starting from α-methylstyrene oxide (see Scheme 4.16). In the reaction

of Griesbaum, the epoxide-carbonyl rearrangement takes place with an already ionized

species, leading directly to the α-carbonyl cation. In our case, the rearrangement leads to the

neutral aldehyde that has to be oxidized in an additional step.

Considering the widespread reports about the occurrence of α-carbonyl cations and the

order of reactivity that we observe for differently substituted aldehydes, we currently believe

that the α-fluorination of aldehydes with AgHF2 does indeed involve the oxidation of the

aldehydes to α-carbonyl cations. A two-step oxidation by two equivalents of Ag+ seems to be

the most probable oxidation process. However, as described in paragraph 3.2.3.2, we found

that Ag+ is able to abstract a hydride from a ruthenium-coordinated β-keto ester enolate

(Table 3.2, run 3). An alternative oxidation mechanism by hydride abstraction could thus be

considered also for the aldehydes in question here. The removal of the α-hydrogen as a

hydride by silver(I) would directly lead to an α-carbonyl cation, all set for the reaction with

fluoride.

Unfortunately, we were not able to assess the role of the ruthenium catalyst yet. The

asymmetric induction clearly shows that the chiral Ru/PNNP complex is involved in the

enantiodiscriminating step. Whether it is simply a Lewis acid for the coordination of the

aldehydes, or if there is a deeper involvement is not clear at present. For example, it is well

imaginable that an α-carbonyl cation could be stabilized in the coordination sphere of

ruthenium, probably by coordinating as an oxoallyl ligand. Furthermore, it could be possible

that ruthenium is involved in the redox processes during the catalytic cycle, with Ag+ acting

as terminal oxidant.


156


In sum, complex 9SbF6, prepared in situ from [RuCl2(PNNP)] (1) and AgSbF6 (1

equiv), catalyzes the asymmetric α-fluorination of 2-alkylphenylacetaldehydes 10a-d with

AgHF2 as fluorinating agent. The α-fluoroaldehydes were obtained in yields of up to 35%

(11b) and with enantioselectivities of up to 27% ee (11a).

CH3

H

O

H

O

H3C F

9SbF6 (5 mol%)


24% yield27% ee

10a 11a

The enantioselective α-fluorination of aldehydes was reported only with organocatalysts

up to date. Thus, our system constitutes the first transition metal-catalyzed version of this

reaction, although with inferior performance so far. Currently, the choice of substrates is

limited to aldehydes with both a phenyl and an alkyl group in α-position. Aldehydes with

different substitution patterns or carbonyl compounds with other carbonyl functional groups

than aldehydes are unreactive. Moreover, the reproducibility of the results is problematic. The

initially obtained 36% ee for 11a was not repeated.

What makes this reaction interesting from a fundamental point of view is its unusal

mechanism. From the clues we collected, and from published data, we assume that the

reaction involves an umpolung of the aldehyde by oxidation to an α-carbonyl cation, which is

then trapped by fluoride. The reagent AgHF2 combines both the oxidant Ag+ and the F−

source. The underlying concept of chemical oxidation followed by enantioselective

fluorination with F− could be developed into an attractive alternative to the α-fluorination of

carbonyl compounds with electrophilic N—F reagents. These reagents are expensive and

create large amounts of the corresponding amines as by-products. Therefore, especially for

industrial applications, there might be an interest in cheaper and more atom-economic

approaches for the α-fluorination of carbonyl compounds.

A major task for future work will be further mechanistic investigations directed at the

identification of catalytically active species, and the delineation of a well-defined catalytic

cycle. Also further substrate screenings will give a better understanding of the reaction. For

example, 2-alkyl-2-arylacetaldehydes with different aryl groups might be tested. Possible

variations include the steric bulk of the aryl group (e.g. naphthyl or mesityl), as well as its


157

electronic properties (e.g. OMe or NO2 substituents). A further goal will be the separation of

the oxidant from the fluoride source. For practical reasons, it would be an advantage to avoid

Ag+ as oxidant, because its salts are light-sensitive and hygroscopic. It would also be better to

use a less reactive fluoride source that could be handled in normal glassware. Furthermore,

having separate oxidants will allow to adjust the required oxidation potential to different

substrates in order to optimize the reactivities.

In a broader picture, the concept of asymmetric bond formation between a carbonyl α-

position and a nucleophile under oxidation might be extended to other substrates and other

C—X bond-forming nucleophiles, leading to potentially attractive alternatives of the

corresponding electrophilic α-heterofunctionalizations. Preliminary experiments in this

direction are reported in Appendix 6.4.


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[58] Zagipa, B.; Hidaka, A.; Cao, Y.; Fuchigami, T. J. Fluorine Chem. 2006, 127, 552 – 557.

[59] Kabore, L.; Chebli, S.; Faure, R.; Laurent, E.; Marquet, B. Tetrahedron Lett. 1990, 31, 3137 – 3140.

[60] Baba, D.; Yang, Y.-J.; Uang, B.-J.; Fuchigami, T. J. Fluorine Chem. 2003, 121, 93 – 96.


[62] Meinwald, J.; Labana, S. S.; Chadha, M. S. J. Am. Chem. Soc. 1963, 85, 582 – 585.

[63] Maruoka, K.; Nagahara, S.; Ooi, T.; Yamamoto, H. Tetrahedron Lett. 1989, 30, 5607 – 5610.

[64] Anderson, A. M.; Blasek, J. M.; Garg, P.; Payne, B. J.; Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527 –

1530.

[65] Karamé, I.; Lorraine Tommasino, M.; Lemaire, M. Tetrahedron Lett. 2003, 44, 7687 – 7689.

[66] Suda, K.; Kikkawa, T.; Nakajima, S.; Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554 – 9555.

[67] Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett. 1986, 27, 2715 – 2716.

[68] Davis, F. A.; Kasu, P. V. N.; Sundarababu, G.; Qi, H. J. Org. Chem. 1997, 62, 7546 – 7547.

[69] Tokunaga, M.; Aoyama, H.; Shirogane, Y.; Obora, Y.; Tsuji, Y. Catal. Today 2006, 117, 138 – 140.

[70] Stavber, S.; Planinšek, Z.; Zupan, M. J. Org. Chem. 1992, 57, 5334 – 5337.

[71] Steele, W. V.; O’Hare, P. A. G.; Appelman, E. H. Inorg. Chem. 1981, 20, 1022 – 1024.

[72] Vanýsek, P. In CRC Handbook of Chemistry and Physics (2007 – 2008)88th Ed.; Lide, D. R.; Ed.; Taylor

& Francis: Boca Raton, 2007; Vol. 8, pp 20 – 29. [73] Bonaccorsi, C.; Mezzetti, A. Organometallics 2005, 24, 4953 – 4960.

[74] Bonaccorsi, C. ETH, Ph.D. Thesis No. 16352, Zurich, Switzerland, 2005.

[75] Huheey, J. E. Anorganische Chemie; Walter de Gruyter: Berlin, 1988.

[76] For a review on carbocations substituted with electron-withdrawing groups, see: Creary, X. Chem. Rev.

1991, 91, 1625 – 1678.

[77] For a review on α-carbonyl cations, see: Creary, X.; Hopkinson, A. C.; Lee-Ruff, E. In Advances in

Carbocation Chemistry; Creary, X.; Ed.; Jai Press Ltd.: London, 1989; Vol. 1, pp 45 – 92.

[78] Röck, M.; Schmittel, M. J. Chem. Soc., Chem. Commun. 1993, 1739 – 1741.

[79] Griesbaum, K.; Keul, H.; Kibar, R.; Pfeffer, B.; Spraul, M. Chem. Ber. 1981, 114, 1858 – 1870.


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5 Experimental Part

5.1 General Procedures

Chemicals

All solvents used for synthetic purposes were of “puriss. p. a.” grade, purchased from

Fluka, Merck, J. T. Baker or Scharlau Chemie. The solvents for air- or moisture-sensitive

manipulations were freshly distilled from an appropriate drying agent under argon (EtOH

from Na/diethyl phthalate; toluene from Na; CH2Cl2 and 1,2-dichloroethane from CaH2; Et2O

and THF from Na/benzophenone; hexane from Na/benzophenone/tetraglyme; pentane from

Na/benzophenone/diglyme). Deuterated solvents for NMR spectroscopy were purchased from

Cambridge Isotope Laboratories (CD2Cl2) or Armar Chemicals (CDCl3). For sensitive

compounds, CD2Cl2 was dried by heating for 15 h over CaH2, then purified by vacuum

transfer and degassed by three freeze-pump-thaw cycles.

All commercial chemicals were obtained in “puriss. p. a.” grade from Fluka, Aldrich,

Acros, Abcr, VWR or Strem Chemicals, and were used without further purification, unless

stated otherwise.

The following chemicals were distilled prior to use: 2-Phenylpropionaldehyde, heptanal,

3-phenylpropionaldehyde, phenylacetaldehyde, and 2-ethylhexanal.

2-Diphenylphosphino-benzaldehyde,1 [RuCl2(PPh3)3],2 and Dess-Martin periodinane

(DMP)3,4 were prepared according to published procedures.

Several compounds were prepared and kindly provided by other members of the group:

Ethyl 2-methyl-3-oxo-3-phenylpropanoate (4d) by Aline Sondenecker,5 (R,R)-

[Ru(TsDPEN)(p-cymene)] by Yanyun Liu, 6 [RuCl2(PNNP)] complexes with substituted PAr2

moieties (Ar = Ph-4-CF3, Ph-3,5-(CF3)2, Ph-4-OMe) by Cristina Bonaccorsi.7

Instruments and Techniques

All manipulations with air- or moisture-sensitive materials were carried out at a

vacuum/argon line with standard Schlenk techniques, or in a glovebox (MBRAUN MB-150B-

G-II) under an atmosphere of purified nitrogen.

5 Experimental Part

162

Rotavapor: Büchi Rotavapor R-200, Vacuum Controller V-800, Heating Bath B-490. The

temperature of the heating bath was kept at or below 40 °C.

TLC: SiO2 Merck 60-F254. UV-detection at 254 nm. Stains: mostaïne (0.4 g Ce(SO4)2·4H2O,

10.0 g (NH4)6Mo7O24·4H2O, 10 mL H2SO4 conc., 180 mL water), KMnO4 (1.0 g KMnO4, 2.0

g Na2CO3, 100 mL water).

FC: SiO2: Fluka Silica Gel 60, particle size 0.04 – 0.063 mm. Air pressure < 0.3 bar. Al2O3:

Fluka Aluminium Oxide for Chromatography, particle size 0.05 – 0.15 mm, pH 7.0±0.5;

deactivated to Brockmann activity IV by addition of 10 w-% water.

NMR: The 1H, 13C{1H}, 19F and 31P{1H} NMR spectra were measured on the following

instruments (frequencies in MHz): Bruker Avance AC 200 (1H, 200.1; 19F, 188.3), Bruker

Avance DPX 250 (1H, 250.1; 13C{1H}, 62.5; 31P{1H}, 101.3), Bruker Avance DPX 300 (1H,

300.1; 13C{1H}, 75.5; 31P{1H}, 121.5), Bruker Avance DPX 400 (1H, 400.1; 13C{1H}, 100.6; 31P{1H}, 162.0), and Bruker Avance DPX 500 (1H, 500.2; 13C{1H}, 125.8; 31P{1H}, 202.5).

Two-dimensional and variable-temperature NMR spectra were recorded on the Bruker

Avance DPX 400 or DPX 500 instruments. 1H and 13C positive chemical shifts δ (in ppm) are

downfield from tetramethylsilane, and are referenced to the residual solvent signal. 19F NMR

signals are referenced to external CFCl3, and 31P NMR signals to external 85% H3PO4.

Coupling constants J are given in Hertz. If not specified, J represents JH,H. The multiplicity is

denoted by the following abbreviations: s: singlet; d: doublet; t: triplet; q: quartet; sept: septet;

m: multiplet; br: broad.

Achiral GC: Carlo Erba Instruments GC8000; column: Optima 5 (25 m x 0.25 mm, film 0.5

μm). Quantitative determination of conversions and yields by GC were carried out with n-

decane or n-dodecane as internal standards. The response factors fR of the analytes (starting

material and product) were calculated from the GC peak areas of calibration solutions

containing known molar amounts of analyte and internal standard:

s

s

x

xR n

AAnf ⋅=

Ax: Peak area of the analyte. nx: Moles of the analyte. As: Peak area of the internal standard. ns: Moles of the internal standard.

In the reaction mixtures, the amounts of starting material and product were determined by the

corresponding GC peak areas and the known molar amount of internal standard, according to

the following equation:

5 Experimental Part

163

Rss

xx fn

AAn ⋅⋅=

Chiral GC: Enantiomeric excesses were determined by chiral GC on a Thermo Finnigan

TraceGC ultra with a Thermo Finnigan AS2000 autosampler. Columns: Supelco α-DEX 120

(30 m x 0.25 mm, film 0.25 μm); Supelco β-DEX 120 (30 m x 0.25 mm, film 0.25 μm). Inlet:

Split injector (42 mL/min, 200 °C). Carrier: Helium (1.4 mL/min). Detector: FID (Air/H2

350/35, 250 °C). The retention time of the major enantiomer is given in italics.

Preparative HPLC: A Gilson system with the modules 306 Pump, 806 Manometric Module,

UV/VIS-156 detector and FC 204 Fraction Collector was used. Column: Chiralcel OD-H (25

cm x 2 cm, particle size 5 μm).

GC-MS: Thermo Finnigan TraceGC; column: Zebron ZB-5 (30 m x 0.25 mm, film 0.25 μm).

Inlet: Split injector (42 mL/min, 200 °C). Carrier: Helium (1.2 mL/min). Thermo Finnigan

TraceMS; EI-M; diagnostic peaks are given as m/z and the intensities in % of the base-peak.

MS: EI- and MALDI-MS were measured by the MS-service of the Laboratory of Organic

Chemistry (ETH Zürich). ESI-MS measurements were performed on a Finnigan TSQ

Quantum instrument by Luca Cereghetti (Prof. Peter Chen’s group, ETH Zürich).

M.p. A Gallenkamp Griffin MPA-350.BM2.5 melting point apparatus was used to determine

melting points, which are uncorrected.

EA: Elemental analyses were carried out by the Laboratory of Microelemental Analysis (ETH

Zürich); all measurements are within a deviation of ± 0.4% of the calculated values.

Polarimeter: Perkin Elmer 341; cell 1 dm, solvent CHCl3, c in g/100 mL.

Crystallography: X-ray structural measurements were carried out by Sebastian Gischig,

Francesco Camponovo and Pietro Butti on a Bruker CCD diffractometer: Bruker SMART

PLATFORM, with CCD detector, graphite monochromator, Mo Kα (0.71073 Å) radiation and

a low-temperature device (200 K). The single crystals were mounted in

perfluoropolyalkylether oil on top of a glass fiber and fixed with epoxidic glue. All

calculations were performed on PC systems with SHELXTL (ver. 6.12) and SHELXL-97.

The structures were solved either by Patterson or direct methods and successive interpretation

of the difference Fourier maps, followed by full-matrix least-squares refinement (against F2).

All non-hydrogen atoms were refined freely with anisotropic displacement parameters. The

contribution of the hydrogen atoms, in their calculated positions, was included in the

refinement using a riding model for the X-ray structures. Moreover, an empirical absorption

5 Experimental Part

164

correction using SADABS (ver. 2.03) was applied to all structures. Model plots were made

with ORTEP-32 for Windows.

5.2 Chapter 2

5.2.1 Ru/PNNP Complexes

(S,S)-(N,N’)-Bis[2-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine (12)

A solution of (S,S)-(+)-1,2-diaminocyclohexane (590 mg,

5.17 mmol) in ethanol (20 mL) was added to a suspension of 2-

diphenylphospino-benzaldehyde (3.0 g, 10.30 mmol, 2.0 equiv) in

ethanol (20 mL) and was stirred under argon at r.t. for 14 h. The

resulting light yellow solution was concentrated under reduced

pressure to yield the crude product as a yellow viscous oil. Crystallisation was induced by

dissolving the oil in hot ethanol and cooling to −20 °C for two d. The precipitate was

collected by filtration, washed twice with cold ethanol (0 °C), and dried in HV, giving the

pure product as an off-white solid. Yield: 3.13 g (4.75 mmol, 92%). The NMR spectroscopic

data are in agreement with reported values.8 1H NMR (250.1 MHz, CDCl3): δ 8.73 (d, 2 H, J = 4.0 Hz, HC=N), 7.78 (ddd, 2 H, J = 7.3,

3.9, 1.6 Hz, arom. H), 7.4 – 7.2 (m, 24 H, arom. H), 6.85 (ddd, 2 H, J = 7.4, 4.5, 1.4 Hz, arom.

H), 3.2 – 3.1 (m, 2 H, HC-N), 1.7 – 1.2 (m, 8 H, CH2). 31P{1H} NMR (101.3 MHz, CDCl3): δ

−13.5 (s, 2 P).

(OC-6-13-(S,S))-Dichloro{N,N’-bis[2-(diphenylphosphino)benzylidene]cyclohexane-1,2-

diamine}ruthenium(II) (trans-[RuCl2(PNNP)]) (1)

A solution of (S,S)-PNNP (12) (1.00 g, 1.52 mmol, 1.0

equiv) in toluene (10 mL) was added to a suspension of

[RuCl2(PPh3)3] (1.46 g, 1.52 mmol) in refluxing toluene (50 mL).

The dark red solution was heated to reflux for 15 h. After cooling

to r.t., the solution was concentrated under reduced pressure to a

volume of ca. 10 mL, then poured into vigorously stirred hexane (150 mL). The precipitate

was collected by filtration, recrystallized from CH2Cl2/hexane and dried in HV at 50 °C

N N

PPPh2 Ph2

N N

PPPh2 Ph2

Ru

Cl

Cl

5 Experimental Part

165

overnight, affording the pure product as a dark red solid. Yield: 1.033 g (1.243 mmol, 82%).

The spectral data are consistent with those reported in the literature.9 1H NMR (300.1 MHz, CD2Cl2): δ 9.00 – 8.96 (m, 2 H, HC=N), 7.75 (dd, 2 H, J = 7.5, 1.2 Hz,

arom. H), 7.56 (dd, 2 H, J = 7.5, 7.5 Hz, arom. H), 7.41 – 7.36 (m, 4 H, arom. H), 7.27 – 7.20

(m, 4 H, arom. H), 7.16 – 7.03 (m, 12 H, arom. H), 6.94 – 6.88 (m, 4 H, arom. H), 4.20 – 4.10

(m, 2 H, HC−N), 2.78 (br d, 2 H, J = 12.0 Hz, CH2), 2.18 – 2.00 (m, 4 H, CH2), 1.57 – 1.49

(m, 2 H, CH2). 31P{1H} NMR (121.5 MHz, CD2Cl2): δ 48.1 (s, 2 P).

(OC-6-42-A-(S,S),(S))-2-tert-Butoxycarbonylcyclopentanone{N,N’-bis[2-(diphenylphos-

phino)benzylidene]cyclohexane-1,2-diamine}ruthenium(II) Bis(hexafluorophosphate)

(2a)

Method a (in situ with (Et3O)PF6): [RuCl2(PNNP)] (1)

(30 mg, 36 μmol) and (Et3O)PF6 (18.3 mg, 74 μmol, 2.04

equiv) were dissolved in dry CD2Cl2 (0.8 mL) in an NMR tube

fitted with a Young-valve. The resulting solution was stirred at

r.t. for 14 h, and then, 2-tert-butoxycarbonylcyclopentanone

(4a) (6.5 μL, 36 μmol, 1.0 equiv) was added. The NMR spectroscopic analysis of the reaction

solution showed a mixture of 2a (92%) and [Ru(H2O)2(PNNP)]2+ (8%, by integration of the 31P NMR signals).

Method b (in situ with TlPF6): TlPF6 (30 mg, 86 μmol, 2.4 equiv) and 2-tert-

butoxycarbonylcyclopentanone (4a) (6.5 μL, 36 μmol, 1 equiv) were added to a solution of

[RuCl2(PNNP)] (1) (30 mg, 36 μmol, 1 equiv) in CD2Cl2 (0.8 mL). After stirring for 15 h at

r.t., the resulting suspension was filtered to remove TlCl and excess TlPF6.

In the NMR data, diagnostic H, C, and P atoms are labelled according to Figure 2.14. 1H NMR (250.1 MHz, CD2Cl2,): T = 298 K: δ 9.03 (d, 1 H, JP,H = 9.0 Hz, HbC=N), 8.83 (s, 1

H, Hb’C=N), 7.94 (dd, 1 H, J = 7.2, 3.2 Hz, benzylidene-Hc), 7.89 (dd, 1 H, J = 7.4, 4.3 Hz,

benzylidene-Hc’), 7.8 – 6.8 (m, 25 H, arom. H), 6.72 (dd, 1 H, J = 8.8, 8.8 Hz, arom. H), 3.78

(dd, 1 H, J = 11.0, 9.1 Hz, C(O)CHdCOO), 3.40 – 3.32 (m, 1 H, HaC–N), 3.00 (br d, 1 H, J =

11.4 Hz, CHH’), 2.52 – 2.42 (m, 2 H, CH2), 2.42 – 2.35 (m, 1 H, Ha’C–N), 1.96 (br d, 1 H, J =

13.6 Hz, CHH’), 1.92 – 1.83 (m, 1 H, CHH’), 1.67 – 1.62 (m, 2 H, CH2), 1.46 – 1.37 (m, 1 H,

CHH’), 1.36 – 1.25 (m, 3 H, CH2), 1.25 – 1.16 (m, 1 H, CHH’), 1.21 (s, 9 H, C(CH3e)3), 1.00

– 0.90 (m, 1 H, CHH’), 0.82 – 0.71 (m, 1 H, CHH’). T = 183 K: δ 3.50 (br dd, 1 H, J = 9.0,

9.0 Hz, C(O)CHdCOO). 31P{1H} NMR (101.3 MHz, CD2Cl2): T = 298 K: δ 61.2 (d, 1 P, JP,P’

O

OO

RuP

N

N

P

H

(PF6)2

5 Experimental Part

166

= 29.1 Hz, Pap), 51.3 (d, 1 P, JP,P’ = 29.1 Hz, Peq), –144.3 (sept, 2 P, JP,F = 711 Hz, PF6−). T =

183 K: δ 61.6 (d, 1 P, JP,P’ = 28.5 Hz, Pap), 52.7 (d, 1 P, JP,P’ = 28.5 Hz, Peq). 13C{1H} NMR

(125.8 MHz, CD2Cl2,): δ 227.3 (Ci=O), 175.2 (CjOO), 170.9 (d, 1 C, JC,P = 4.8 Hz, C=N),

168.6 (d, 1 C, JC,P = 4.9 Hz, C=N), 139.6 – 125.5 (36 C, arom. C), 90.8 (OC(CH3)3), 78.0

(Ca’–N), 70.0 (Ca–N), 55.5 (C(O)CdHCOO), 32.2 (CH2), 31.5 (CH2), 28.1

(C(O)CH2CH2CkH2), 27.9 (C(CH3)3), 27.2 (CH2), 24.9 (CH2), 24.1 (CH2), 19.5 (CH2). MS

(HiResMALDI): m/z 943.2759 [M-H]+ (calcd. for C54H55N2O3P2Ru+: 943.2740).

(OC-6-42-A-(S,S))-2-tert-Butoxycarbonylcyclopentanoato{N,N’-bis[2-(diphenylphos-

phino)benzylidene]cyclohexane-1,2-diamine}ruthenium(II) Hexafluorophosphate (3a)

A solution of [RuCl2(PNNP)] (1) (200 mg, 0.241 mmol)

and (Et3O)PF6 (120 mg, 0.484 mmol, 2.0 equiv) in CH2Cl2 (10

mL) was stirred at r.t. for 16 h. Then, 2-tert-

butoxycarbonylcyclopentanone (4a) (52 μL, 0.287 mmol, 1.2

equiv) in CH2Cl2 (1 mL) was added, and the resulting solution

was stirred for 3 h at r.t.. After adding triethylamine (38 μL, 0.273 mmol, 1.13 equiv) and

stirring for further 15 min, the crude reaction mixture was filtered through a short plug of

SiO2 with CH2Cl2 as eluent. After evaporation of the solvent, the orange product was

triturated four times with hexane/CH2Cl2 (20:1) and dried in HV overnight. The analytically

pure product was obtained as an orange solid. Yield: 216 mg (0.199 mmol, 82%). Diagnostic

H, C, and P atoms in the NMR data are labelled according to Figures 2.18 and 2.21.

M.p. 210 – 215 °C (decomp). 1H NMR (500.2 MHz, CD2Cl2, 298 K): δ 8.89 (s, 1 H,

Hb’C=N), 8.69 (d, 1 H, JP,H = 9.5 Hz, HbC=N), 7.79 (dd, 1 H, J = 7.2, 4.1 Hz, benzylidene-

Hc’), 7.66 – 7.58 (m, 4 H, arom. H), 7.53 – 7.48 (m, 3 H, arom. H), 7.46 – 7.34 (m, 7 H, arom.

H), 7.21 – 7.15 (m, 6 H, arom. H), 7.03 – 6.90 (m, 4 H, arom. H), 6.89 (ddd, 2 H, J = 7.6, 7.6,

1.8 Hz, arom. H), 6.52 (dd, 1 H, J = 8.7, 8.7 Hz, arom. H), 3.80 – 3.71 (m, 1 H, HaC–N), 2.58

– 2.50 (m, 1 H, CHH’), 2.43 – 2.35 (m, 1 H, CHH’), 2.30 – 2.21 (m, 1 H, Ha’C–N), 2.04 (ddd,

1 H, J = 13.3, 7.6, 6.1 Hz, CHH’), 1.98 – 1.86 (m, 2 H, CH2), 1.77 – 1.66 (m, 2 H, CH2), 1.62

– 1.53 (m, 1 H, CHH’), 1.33 – 1.22 (m, 3 H, CH2), 1.21 – 1.13 (m, 3 H, CH2), 1.11 (s, 9 H,

C(CH3e)3). 31P{1H} NMR (101.3 MHz, CD2Cl2): T = 298 K: δ 63.4 (d, 1 P, JP,P’ = 31.2 Hz,

Pap), 52.5 (d, 1 P, JP,P’ = 31.2 Hz, Peq), –144.3 (sept, 1 P, JP,F = 711 Hz, PF6−). T = 183 K: δ

64.6 (d, 1 P, JP,P’ = 31.0 Hz, Pap), 52.8 (d, 1 P, JP,P’ = 31.0 Hz, Peq). 13C{1H} NMR (125.8

MHz, CD2Cl2): δ 192.0 (C=Ci–O), 168.3 (CjOO), 166.7 (d, 1 C, JC,P = 3.1 Hz, C=N), 163.5

O

OO

RuP

N

N

P

PF6

5 Experimental Part

167

(d, 1 C, JC,P = 5.2 Hz, C=N), 138.2 – 126.4 (36 C, arom. C), 93.1 (Cd=C–O), 79.4

(OC(CH3)3), 78.2 (C–N), 68.7 (C–N), 38.9 (CH2), 32.2 (CH2), 31.9 (CH2), 29.3 (C(CH3)3),

28.8 (CH2), 25.0 (CH2), 24.2 (CH2), 20.2 (CH2). EA: Calcd. for C54H55F6N2O3P3Ru (1088.0):

C, 59.61; H, 5.09; N, 2.57; found: C, 59.86; H, 5.20; N, 2.54.

5.2.2 Determination of the pKaaq of Complex 2a

Triphenylphosphonium Tetrafluoroborate ((HPPh3)BF4)

A solution of HBF4 in Et2O (54 w-%, 0.47 mL, 3.41 mmol, 1.5

equiv) was added to a CH2Cl2 solution (3 mL) of triphenylphosphine

(600 mg, 2.29 mmol), cooled to 0 °C. After 5 min, the mixture was

allowed to reach r.t.. Addition of hexane (1 mL) gave a white

precipitate that was collected by filtration, washed twice with hexane,

and dried in HV. Yield: 375 mg (1.07 mmol, 47%). 1H NMR (250.1 MHz, CD2Cl2) δ 9.04 (d, 1 H, JP,H = 529 Hz, HP), 7.94 – 7.71 (m, 15 H,

arom. H). 31P{1H} NMR (101.3 MHz, CD2Cl2) δ 4.48 (s, 1 P).

pKa Determination: Deprotonation of 2a with PPh3

[RuCl2(PNNP)] (1) (18 mg, 21.7 μmol) and (Et3O)PF6 (10.9 mg, 44 μmol, 2.03 equiv)

were dissolved in dry CD2Cl2 (0.6 mL), and the resulting solution was stirred at r.t. for 8 h.

After adding 2-tert-butoxycarbonylcyclopentanone (4a) (50 μL of a solution of 40 μL 4a in

0.5 mL CD2Cl2, 22 μmol, 1.02 equiv), the solution was stirred for additional 16 h.

Triphenylphosphine was added (50 μL of a solution of 56.8 mg PPh3 in 0.5 mL CD2Cl2, 21.7

μmol, 1.0 equiv), and the reaction mixture was analyzed by 31P{inverse-gated 1H} NMR

spectroscopy.

The chemical shifts δ(PPh3) = –5.482 and δ(HPPh3+) = 4.847 for the use in eq 2.3 were

determined by independent measurements using similar concentrations in CD2Cl2 as in the

deprotonation experiment. The ratio of the integrals of complexes 3a and 2a, as well as the

PPh3↔HPPh3+ equilibrium chemical shift were obtained from both the Fourier spectrum and

from a Lorentzian line fit.

Fourier spectrum: Ratio [3a]/[2a] = 0.186, δeq = –5.05.

Lorentzian line fit: Ratio [3a]/[2a] = 0.232, δeq = –4.702.

P H BF4-

5 Experimental Part

168

The equilibrium constant Keq was calculated by using the exact expression (eq 2.1), and

the approximations from eq 2.4. The following table gives the resulting pKaaq values of 2a

from the different calculation methods of Keq.

eq 2.1 eq 2.4

([3a]/[2a])2 eq 2.4

([HPPh3+]/[PPh3])2 average

Fourier spectrum 4.82 4.19 5.45

Lorentzian fit 4.45 4.00 4.91 4.6±0.5

pKa Determination: Protonation of 3a with (HPPh3)BF4

Complex 3a (37.3 mg, 34.3 μmol) and (HPPh3)BF4 (12.0 mg, 34.3 μmol, 1.0 equiv)

were dissolved in CD2Cl2 (0.6 mL), and the reaction mixture was analyzed by 31P{inverse-

gated 1H} NMR spectroscopy. The equilibrium signal between PPh3 and HPPh3+ did not reach

complete coalescence and exhibited a broad shoulder, which was used for the integration in

the Fourier spectrum, as well as for the average chemical shift δeq.

The chemical shifts δ(PPh3) = –5.466 and δ(HPPh3+) = 4.477 were determined by

independent measurements using similar concentrations as in the protonation experiment.

Fourier spectrum: [3a]/[2a] = 0.155, [HPPh3+]/[PPh3] = 0.168, δeq = –5.10.

Lorentzian line fit: [3a]/[2a] = 0.175, δeq = –5.10.

eq 2.1 eq 2.4

([3a]/[2a])2 eq 2.4

([HPPh3+]/[PPh3])2 average

Fourier spectrum 4.32 4.35 4.28

Lorentzian fit 4.91 4.24 5.57 4.6±0.5

Diphenylammonium Tetrafluoroborate ((Ph2NH2)BF4)

HBF4 in Et2O (54 w-%, 1.6 mL, 11.9 mmol, 1.0 equiv) was added to a solution of

diphenylamine (2.0 g, 11.8 mmol) in Et2O (10 mL) at 0 °C under an argon atmosphere. A

white solid precipitated, which was collected by filtration under argon, washed twice with

Et2O (10 mL each), and dried in HV. Yield: 2.756 g (10.7 mmol, 91%). 1H NMR (250.1 MHz, CD2Cl2) δ 9.7 (br s, 2 H, Ph2NH2

+), 7.53 (br s, 10 H, arom. H).

pKa Determination: Deprotonation of 2a with Ph2NH

A mixture of [RuCl2(PNNP)] (1) (20 mg, 24.1 μmol), TlPF6 (20 mg, 57.3 μmol, 2.4

equiv), and 2-tert-butoxycarbonylcyclopentanone (4a) (4.4 μL, 24.3 μmol, 1.0 equiv) in

CD2Cl2 (0.6 mL) was stirred at r.t. for 15 h. After filtration, diphenylamine (4.1 mg, 24.2

5 Experimental Part

169

μmol, 1.0 equiv) was added and the solution was analyzed by 31P NMR spectroscopy.

Separate signals of 2a and 3a were obtained, whose integrals were used in the approximation

Keq ≈ ([3a]/[2a])2. Fourier spectrum: [3a]/[2a] = 0.054, Lorentzian line fit: [3a]/[2a] = 0.087.

pKa Determination: Protonation of 2a with (Ph2NH2)BF4

3a (26 mg, 23.9 μmol) and (Ph2NH2)BF4 (6.2 mg, 24.1 μmol, 1.0 equiv) were dissolved

in CD2Cl2 (0.6 mL), and the reaction mixture was analyzed by 31P NMR spectroscopy. The

high-frequency doublet of 2a appeared at an equilibrium chemical shift of δeq 61.30, which

was used in the approximation Keq ≈ ([3a]/[2a])2. Fourier spectrum: [3a]/[2a] = 0.040,

Lorentzian line fit: [3a]/[2a] = 0.038.

The calculated pKaaq values for 2a from both the deprotonation and the protonation

experiment are given in the following table:

Fourier spectrum Lorentzian fit average

2a + Ph2NH 3.31 2.90

3a + (Ph2NH2)BF4 3.57 3.61 3.3±0.3

5.3 Chapter 3

5.3.1 Substrate Synthesis

Di-tert-butyl Adipate

Adipoyl chloride (8.0 mL, 54.9 mmol) was added

during 10 min to a solution of N,N-dimethylaniline (22.2 mL,

175.1 mmol, 3.2 equiv) and tert-butanol (16.7 mL, 175.5

mmol, 3.2 equiv) in Et2O (10 mL). After stirring for 18 h at r.t., a NaCl solution (sat., ca. 50

mL) was added, and stirring was continued for 3 h. Then, further NaCl solution (sat., ca. 50

mL) was added, and the phases were separated. The aqueous phase was extracted twice with

Et2O (50 mL each). The combined organic phases were washed with a 2 M HCl solution

twice (100 mL each), 1 M NaOH solution (100 mL), and with a NaCl solution (sat., 100 mL),

dried (Na2SO4), and concentrated under reduced pressure. The pure product was obtained as a

colorless oil by vacuum distillation (0.01 mbar, bp. 55 – 62 °C). Yield: 12.693 g (49.1 mmol,

90%). Analytical data are in agreement with literature values.10

O

OO

O

5 Experimental Part

170

TLC (hexane/EtOAc 8:1): Rf = 0.28 (KMnO4). 1H NMR (300.1 MHz, CDCl3): δ 2.27 – 2.19

(m, 4 H, CH2COOtBu), 1.68 – 1.58 (m, 4 H, CH2CH2COOtBu), 1.45 (s, 18 H, CH3).

2-tert-Butoxycarbonylcyclopentanone (4a)

Sodium hydride (60 w-% dispersion in mineral oil; 1.6 g, 40.0

mmol, 2.07 equiv) was washed oil-free with two portions of dry hexane

(20 mL each) in a 3-necked flask fitted with a reflux condenser and an

addition funnel. After drying the sodium hydride in HV, it was suspended in dry toluene (16

mL) and tert-butanol (85 μL, 0.89 mmol, 0.05 equiv), and the mixture was heated to reflux. A

solution of di-tert-butyl adipate (5.0 g, 19.4 mmol) in toluene (30 mL) was added through the

addition funnel to the hot suspension during 2 h. After stirring at reflux for further 14 h, a

thick yellow suspension was obtained. A solution of acetic acid (10% in water) was added

until the pH reached 6 – 7. The mixture was diluted with water (20 mL), then extracted three

times with Et2O (80 mL each). The combined organic phases were washed with a NaHCO3

solution (sat., 150 mL) and with water (150 mL), dried (Na2SO4), and concentrated under

reduced pressure. The crude product was purified by vacuum distillation (0.27 mbar, bp. 52 –

54 °C), giving pure 4a as a colorless liquid. Yield: 2.578 g (14.0 mmol, 72%). The spectral

data are in agreement with literature values.11

TLC (hexane/EtOAc 8:1): Rf = 0.19 (KMnO4). 1H NMR (300.1 MHz, CDCl3): δ 3.05 (dd, 1

H, J = 8.9, 8.9 Hz, C(O)CHCOO, keto tautomer), 2.32 – 2.20 (m, 4 H, CH2, keto and enol

tautomers), 2.18 – 2.08 (m, 1 H, CH2, keto and enol tautomers), 1.92 – 1.80 (m, 1 H, CH2,

keto and enol tautomers), 1.52 (s, 9 H, C(CH3)3, enol tautomer (ca. 6%)), 1.47 (s, 9 H,

C(CH3)3, keto tautomer (ca. 94%)).

5.3.2 Catalytic Fluorination of β-Keto Esters

General Procedure

A solution of [RuCl2(PNNP)] (1) (20.0 mg, 0.024 mmol, 0.1 equiv) and (Et3O)PF6 (12.2

mg, 0.049 mmol, 0.205 equiv) in CH2Cl2 (2 mL; 1.5 mL for reactions in CH2Cl2/Et2O (1:1))

was stirred at r.t. overnight. A color change from red to brown indicated the formation of the

catalytically active complex. The substrate (0.24 mmol, 1 equiv) was added, and the mixture

was diluted with CH2Cl2 (1 mL) or with Et2O (1.5 mL) for reactions in CH2Cl2/Et2O (1:1).

After 10 min, N-fluorobenzenesulfonimide (NFSI, 82 mg, 0.26 mmol, 1.08 equiv) was added,

O O

O

5 Experimental Part

171

and the reaction was monitored by TLC. After completion, the reaction was quenched by

adding tetrabutylammonium chloride (20 mg, 0.072 mmol, 0.3 equiv) to deactivate the

catalyst. The solvent was evaporated under reduced pressure, and the oily residue was

subjected to FC on SiO2. Yields refer to isolated products unless otherwise stated.

Conversions were determined by 1H NMR spectroscopy as the ratio between the product and

the sum of the starting material and product.

(R)-2-tert-Butoxycarbonyl-2-fluorocyclopentanone (5a)

Prepared according to the general procedure from β-keto ester 4a

(44 mg, 0.24 mmol). In CH2Cl2: Yield 44 mg (0.218 mmol, 91%), 88% ee.

In CH2Cl2/Et2O (1:1): Yield 46 mg (0.227 mmol, 94%), 93% ee.

Analytical data are in agreement with literature values.12

TLC (hexane/EtOAc 10:1): Rf = 0.15 (KMnO4). [α]D20 +107.5 (c = 1.37, CHCl3), 91% ee. 1H

NMR (CDCl3, 200.1 MHz): δ 2.66 – 2.04 (m, 6 H, CH2), 1.53 (s, 9 H, C(CH3)3). 19F NMR

(CDCl3, 188.3 MHz): δ –162.7 (dd, 1 F, JF,H = 21.0, 17.2 Hz). Chiral GC: β-DEX column,

90 °C isotherm; retention times tR = 74.3 (S) and 75.7 min (R). The absolute configuration of

the major enantiomer was determined to be R by an X-ray study of the camphanic ester 18.

(R)-2-Ethoxycarbonyl-2-fluorocyclopentanone (5b)

Prepared according to the general procedure from β-keto ester 4b (38

mg, 0.24 mmol). In CH2Cl2: Yield 34.6 mg (0.199 mmol, 82%), 58% ee. In

CH2Cl2/Et2O (1:1): Yield 35.3 mg (0.203 mmol, 84%), 65% ee. Analytical

data are consistent with those reported in the literature.13

TLC (hexane/EtOAc 10:1): Rf = 0.10 (KMnO4). [α]D20 +169.0 (c = 1.53, CHCl3), 99.7% ee.

1H NMR (CDCl3, 250.1 MHz): δ 4.32 (q, 2 H, J = 7.1 Hz, CH3CH2), 2.68 – 2.10 (m, 6 H,

CH2), 1.34 (t, 3 H, J = 7.1 Hz, CH3CH2). 19F NMR (CDCl3, 188.3 MHz): δ –164.0 (dd, 1 F,

JF,H = 20.5, 20.5 Hz). Chiral GC: β-DEX column, 90 °C isotherm; retention times tR = 58.6

(S) and 62.5 (R) min. The absolute configuration of the major enantiomer is R by comparison

of the sign of optical rotation with the structurally related (R)-5a.

(R)-Ethyl 2-Fluoro-2-methyl-3-oxobutanoate (5c)

Prepared according to the general procedure from β-keto ester 4c (35

mg, 0.24 mmol). In CH2Cl2: 91% conversion, 59% ee. In CH2Cl2/Et2O (1:1):

O

OEt

O

F

O O

OEtF

O O

OF

5 Experimental Part

172

96% conversion, 77% ee. The product was not isolated. The conversion was determined by

NMR spectroscopy. Analytical data are in agreement with literature values.14

TLC (hexane/EtOAc 8:1): Rf = 0.23 (KMnO4). 1H NMR (CD2Cl2, 250.1 MHz): δ 4.24 (q, 2

H, J = 7.1 Hz, OCH2CH3), 2.32 (d, 3 H, J = 4.3 Hz, C(O)CH3), 1.69 (d, 3 H, J = 22.3 Hz,

CH3CF), 1.30 (t, 3 H, J = 7.1 Hz, OCH2CH3). 19F NMR (CD2Cl2, 188.3 MHz): δ –157.7 (qq,

1 F, J = 22.6, 4.5 Hz). Chiral GC: β-DEX column, 70 °C isotherm; retention times tR = 16.2

(R) and 17.2 min (S). The absolute configuration is R (by correlation with reported data).14,15

Ethyl 2-Methyl-2-fluoro-3-oxo-3-phenylpropanoate (5d)

Prepared according to the general procedure from β-keto ester 4d

(50 mg, 0.24 mmol). In CH2Cl2: Yield 26 mg (0.116 mmol, 48%), 69%

ee. In CH2Cl2/Et2O (1:1): Yield 36 mg (0.161 mmol, 65%), 24% ee.


TLC (hexane/EtOAc 10:1): Rf = 0.27 (KMnO4). 1H NMR (CDCl3, 300.1 MHz): δ 8.09 –

8.05 (m, 2 H, arom. H), 7.64 – 7.58 (m, 1 H, arom. H), 7.51 – 7.46 (m, 2 H, arom. H), 4.27

(dq, 2 H, J = 1.0, 7.2 Hz, CH3CH2), 1.89 (d, 3 H, J = 22.5 Hz, CH3CF), 1.22 (t, 3 H, J = 7.0

Hz, CH3CH2). 19F NMR (CDCl3, 188.3 MHz): δ –151.8 (br q, 1 F, J = 22.4 Hz). Chiral GC:

β-DEX column, 110 °C isotherm; retention times tR = 88.2 and 89.5 min.

Catalytic Fluorination of 4a with Enolato Complex 3a as Catalyst

NFSI (79 mg, 0.251 mmol, 1.05 equiv vs. 3a+4a) was added to a solution of enolato

complex 3a (26 mg, 24 μmol, 0.1 equiv) and β-keto ester 4a (39 μL, 0.216 mmol, 0.9 equiv)

in CH2Cl2 (3 mL), and the mixture was stirred for 24 h at r.t.. Then, tetrabutylammonium

chloride (20 mg, 72 μmol, 0.3 equiv) was added, and the solvents were evaporated. The crude

product was filtered through SiO2 with hexane/EtOAc 10:1, giving 44 mg of a 1.85 : 1

mixture of 5a + 4a. Conversion: 65%, enantiomeric excess of 5a: 47% ee. Analytical data of

the product are identical to those of the standard catalytic run.

O

OEt

O

F

5 Experimental Part

173

5.3.3 Stoichiometric Reactions with Complexes 2a and 3a

Stoichiometric Fluorination of Complex 2a

To a solution of 2a (prepared by method a or b, as described above) was added NFSI

(11.7 mg, 37 μmol, 1.03 equiv). After stirring for 24 h, the reaction was quenched by adding

tetrabutylammonium chloride (30 mg, 108 μmol, 3 equiv). The solvent was evaporated under

reduced pressure and the residue was purified by FC on SiO2 (hexane/EtOAc, 10:1), yielding

pure 5a. Analytical data of the product are identical to those of the standard catalytic run.

Stoichiometric Fluorination of Complex 2a in the Presence of Additives

To a solution of 2a (prepared by method b) was added the appropriate additive (0.32

mmol, 9 equiv, see Table 3.10) and NFSI (11.7 mg, 37 μmol, 1.03 equiv). After stirring at r.t.

for 24 h, the reaction was quenched with tetrabutylammonium chloride (30 mg, 108 μmol, 3

equiv), and the solvent was evaporated under reduced pressure. The product 5a was purified

by FC on SiO2 (hexane/EtOAc, 10:1). Analytical data of the product are identical to those of

the standard catalytic run.

Stoichiometric Fluorination of Complex 3a

NFSI (12 mg, 38 μmol, 1.04 equiv) was added to a solution of enolato complex 3a (40

mg, 37 μmol, 1 equiv) in CH2Cl2 (1.5 mL). After stirring for 24 h at r.t., tetrabutylammonium

chloride (30 mg, 108 μmol, 2.9 equiv) was added, and the solvent was evaporated under

reduced pressure. Purification by FC on SiO2 (hexane/EtOAc, 10:1) gave 5a (6.0 mg, 30

μmol, 81%, 97% ee). Analytical data of the product are identical to those of the standard

catalytic run.

5.3.4 Derivatisation of Catalysis Product (R)-5a

(1R,2R)-2-tert-Butoxycarbonyl-2-fluoro-cyclopentanol (17)

(R,R)-[Ru(TsDPEN)(p-cymene)] (23 mg, 38 μmol, 1.8 mol%) was

added to a solution of (R)-2-tert-butoxycarbonyl-2-fluorocyclopentanone

(5a) (429 mg, 2.12 mmol, 88% ee) in iPrOH (18 mL). After stirring the

resulting solution for 21 h at r.t., Et2O (15 mL) was added, and the stirring was continued for

OH O

OF

5 Experimental Part

174

3 h. Evaporation of the solvents gave the crude product, which was purified by FC on SiO2

with hexane/TBME 5:1 as eluents, affording pure alcohol 17 as a light yellow liquid. Yield:

327 mg (1.60 mmol, 75%).

TLC (hexane/TBME 5:1): Rf = 0.12 (mostaïne). [α]D20 –13.9 (c = 1.06, CHCl3). 1H NMR

(200.1 MHz, CDCl3,): δ 4.33 (br ddd, 1 H, J = 13.8, 8.6, 4.0 Hz, CHOH), 2.94 (d, 1 H, J = 3.8

Hz, OH), 2.5 – 1.7 (m, 6 H, CH2), 1.51 (s, 9 H, C(CH3)3). 19F NMR (188.3 MHz, CDCl3): δ –

156.1 (br ddd, 1 F, J = 35.3, 23.0, 13.0 Hz). 13C{1H} NMR (75.5 MHz, CDCl3): δ 170.0 (d, 1

C, JC,F = 25.1 Hz, COOtBu), 102.4 (d, 1 C, JC,F = 191.1 Hz, CF), 83.2, 78.6 (d, 1 C, JC,F =

29.5 Hz, CHOH), 33.4 (d, 1 C, JC,F = 23.1 Hz, CH2CF), 32.5 (d, 1 C, JC,F = 1.9 Hz, CH2),

28.0, 20.5. EA: Calcd. for C10H17FO3 (204.24): C, 58.81; H, 8.39; found: C, 58.54; H, 8.41.

(1S)-(–)-Camphanic Acid (1R,2R)-2-tert-Butoxycarbonyl-2-fluoro-cyclopentyl Ester (18)

(1S)-(–)-Camphanic acid chloride (430 mg, 1.98 mmol, 2.3

equiv) was added to a solution of alcohol 17 (177 mg, 0.87 mmol) in

pyridine (10 mL). TLC (hexane/EtOAc 4:1) indicated complete

conversion after stirring for 3 h at r.t.. The reaction mixture was then

poured into aqueous HCl (10%, 50 mL) and extracted twice with

CH2Cl2 (60 mL each). The combined organic layers were washed twice with 0.1 M HCl (100

mL each) and with water (100 mL), then dried (Na2SO4), and concentrated under reduced

pressure. FC on SiO2 (hexane/EtOAc 4:1) gave diastereomerically pure ester 18 as a white

solid. Yield: 325 mg (0.85 mmol, 98%).

TLC (hexane/EtOAc 4:1): Rf = 0.22 (mostaïne). M.p. 109 – 113 °C. [α]D20 –27.6 (c = 1.10,

CHCl3). 1H NMR (300.1 MHz, CDCl3): δ 5.38 (br ddd, 1 H, J = 14.7, 5.3, 5.3 Hz,

CHOC(O)), 2.50 – 2.20 (m, 3 H, CHH’), 2.15 – 1.75 (m, 6 H, CH2), 1.69 – 1.60 (m, 1 H,

CHH’), 1.50 (s, 9 H, C(CH3)3), 1.09 (s, 3 H, CH3), 1.02 (s, 3 H, CH3), 0.94 (s, 3 H, CH3). 19F

NMR (188.3 MHz, CDCl3): δ −155.9 (br ddd, 1 F, J = 29.8, 21.1, 14.7 Hz). 13C{1H} NMR

(75.5 MHz, CDCl3): δ 177.8, 167.1 (d, 1 C, JC,F = 25.1 Hz, COOtBu), 166.2, 101.5 (d, 1 C,

JC,F = 192.1 Hz, CF), 90.8, 83.1, 80.4 (d, 1 C, JC,F = 33.4 Hz, CHOC(O)), 54.8, 54.2, 33.1 (d,

1 C, JC,F = 22.3 Hz, CH2CF), 30.6, 30.3 (d, 1 C, JC,F = 1.7 Hz, CH2), 28.9, 27.9, 20.3 (d, 1 C,

JC,F = 1.3 Hz, CH2), 16.8, 16.7, 9.6. EA: Calcd. for C20H29FO6 (384.44): C, 62.49; H, 7.60;

found: C, 62.65; H, 7.68.

O O

OF

O

O

O

5 Experimental Part

175

5.3.5 Attempted Synthesis of a Ruthenium(III) β-Keto Ester Complex

Attempted Oxidation of [Ru(OEt2)2(PNNP)]2+ (6)

[RuCl2(PNNP)] (1) (20 mg, 24 μmol) and (Et3O)PF6 (12.2 mg, 49 μmol, 2.04 equiv)

were dissolved in CD2Cl2 (1 mL) and stirred at r.t. for 16 h. AgPF6 (18.7 mg, 74 μmol, 3.1

equiv) was added, and the suspension was stirred in the dark for 4.5 h. Then, the suspension

was filtered into an NMR tube fitted with a Young-valve. β-Keto ester 4a was added first in

stoichiometric amounts (4.2 μL, 23 μmol, 1.0 equiv), later in excess (35 μL, 0.193 mmol, 8.0

equiv). Optionally, various amounts of triethylamine were added. The reaction mixtures were

analyzed by NMR spectroscopy after each step (see paragraph 3.2.3.1)

Attempted Oxidation of Enolato Complex 3a

An appropriate one-electron oxidant (1 equiv) was added to a solution of the enolato

complex 3a (20 mg, 18.4 μmol) in CD2Cl2 (0.7 mL) at r.t.. The resulting solution was

analyzed by NMR spectroscopy (see Table 3.1).

(OC-6-42-A-(S,S))-2-tert-Butoxycarbonyl-2-cyclopenten-1-one{N,N’-bis[2-(diphenylphos-

phino)benzylidene]cyclohexane-1,2-diamine}ruthenium(II) Bis(hexafluorophosphate)

(19)

A solution of complex 3a (30 mg, 27.6 mmol) in CD2Cl2

(0.6 mL) was added to tritylium hexafluorophosphate

(Ph3C)PF6 (10.7 mg, 27.6 mmol, 1.0 equiv). The color of the

solution immediately changed from orange to bright yellow.

The NMR spectroscopic analysis of the reaction mixture

showed the formation of pure 19 besides the secondary reaction product triphenylmethane

(characteristic 1H NMR signal: δ 5.59 (s, 1 H, Ph3CH)). Diagnostic H and C atoms in the

NMR data are labelled according to the X-ray crystal structure numbering (Figure 3.12). 1H NMR (CD2Cl2, 500.2 MHz): δ 8.90 (s, 1 H, H19C=N), 8.90 (d, 1 H, JP,H = 9.0 Hz,

H26C=N), 8.38 (dd, 1 H, J = 2.5, 2.5 Hz, H48), 7. 95 – 7.91 (m, 2 H, arom. H), 7.78 – 7.68 (m,

3 H, arom. H), 7.65 – 7.58 (m, 3 H, arom. H), 7.53 – 7.38 (m, 6 H, arom. H), 7.29 – 7.20 (m, 7

H, arom. H), 7.11 – 7.06 (m, 4 H, arom. H), 6.96 (ddd, 2 H, J = 7.8, 7.8, 2.3 Hz, arom. H),

6.59 (br dd, J = 8.8, 8.8 Hz, arom. H), 3.57 (br dd, 1 H, J = 10.3, 10.3 Hz, H25C−N), 2.83 (br

d, 1 H, J = 10.5 Hz, H24), 2.77 (ddd, 1 H, J = 22.5, 5.8, 2.0 Hz, H47), 2.50 (ddd, 1 H, J = 22.5,

O

OO

RuP

N

N

P

(PF6)2

5 Experimental Part

176

4.5, 2.0 Hz, H47’), 2.46 (br d, 1 H, J = 12.5 Hz, H21), 2.22 (dd, 1 H, J = 21.0, 5.5 Hz, H46),

2.11 (br ddd, 1 H, J = 10.9, 10.9, 2.1 Hz, H20C−N), 1.97 (br d, 1 H, J = 13.0 Hz, H22), 1.89

(br d, 1 H, J = 13.0 Hz, H23), 1.83 (dd, 1 H, J = 21.0, 5.5 Hz, H46’), 1.67 (dddd, 1 H, J = 11.8,

11.8, 11.8, 2.3 Hz, H21’), 1.22 – 1.13 (m, 1 H, H23’), 1.12 – 1.04 (m, 1 H, H24’), 0.81 (br ddd, 1

H, J = 13.0, 13.0, 13.0 Hz, H22’). 31P{1H} NMR (CD2Cl2, 202.5 MHz): δ 63.2 (d, 1 P, JP,P’ =

29.3 Hz, P2), 50.4 (d, 1 P, JP,P’ = 29.3 Hz, P1), –144.3 (sept, 2 P, JP,F = 711 Hz, PF6−). 13C{1H}

NMR (CDCl3, 75.5 MHz): δ 215.5 (C45=O), 188.3 (C=C48), 169.4 (d, 1 C, JC,P = 4.8 Hz,

C19=N), 167.1 (d, 1 C, JC,P = 5.1 Hz, C26=N), 165.7 (C50OOtBu), 139.1 – 124.0 (arom. C),

131.9 (C49COOtBu) 88.6 (OC51(CH3)3), 77.5 (C20−N), 69.3 (C25−N), 37.8 (C46H2), 31.9

(C21H2), 31.0 (C24H2), 29.2 (C47H2), 27.9 (C(CH3)3), 24.6 (C22H2), 23.7 (C23H2). MS

(MALDI): m/z 941 ([M-H]+, 43), 885 ([M-H-tBu]+, 100).

5.3.6 Ru/PNNP Complexes of the Reaction Products 5a and NSI−

Coordination of 5a to the Ru/PNNP Fragment, [Ru(5a)(PNNP)](PF6)2 (21a-e)

Using racemic 5a: TlPF6 (30.2 mg, 86.8 μmol, 2.4

equiv) was added to a solution of [RuCl2(PNNP)] (1) (30.0

mg, 36.1 μmol, 1 equiv) in dry CD2Cl2 (0.8 mL). After 2

min, racemic α-fluoro-β-keto ester 5a (8.1 mg, 40.0 μmol,

1.1 equiv) was added and the mixture was stirred at r.t. for

15 h. The resulting suspension was filtered to remove TlCl and excess TlPF6, and analyzed by

NMR spectroscopy. The 31P and 19F NMR spectra show the signals of a mixture of five

complexes 21a-e, together with [RuCl(PNNP)]+ (9), free 5a and several unidentified

complexes. Diagnostic NMR signals are given below. 31P{1H} NMR (121.5 MHz, CD2Cl2): [RuCl(PNNP)]+ (9), 44% of total integration: δ 59.4 (br

d, 1 P, JP,P’ = 27.7 Hz), 50.0 (br d, 1 P, JP,P’ = 27.7 Hz). 19F NMR (188.3 MHz, CD2Cl2): 5a:

δ −162.7 (dd, 1 F, JF,H = 21.0, 17.2 Hz, 47%); 21a: δ −162.3 (br dd, 1 F, JF,H = 22.4, 22.4 Hz,

28%); 21b: δ −163.3 (br dd, 1 F, JF,H = 23.3, 23.3 Hz, 5%); 21c: δ −164.3 (br dd, 1 F, JF,H =

18.1, 18.1 Hz, 17%); 21d: δ −164.9 (br dd, 1 F, JF,H = 16.8, 16.8 Hz, 12%); 21e: δ −165.3 (br

dd, 1 F, JF,H = 21.6, 21.6 Hz, 7%).

Using (R)-5a (91% ee): The reaction was carried out as above, using (R)-5a (8.0 mg,

39.6 μmol, 1.1 equiv). A mixture of the three complexes 21a (38%), 21c (14%), and 21e

O

OO

RuP

N

N

P

F

(PF6)2

5 Experimental Part

177

(4%), together with [RuCl(PNNP)]+, free 5a (44%) and several unidentified complexes was

detected by NMR analysis. The 19F NMR data of complexes 21a,c,e are identical to those

reported above.

Tetraphenylphosphonium Bis(phenylsulfonyl)amide ((Ph4P)NSI)

A 0.1 M NaOH solution was added to a suspension of

dibenzenesulfonimide (NHSI, 400 mg, 1.35 mmol) in deionised

water (5 mL) until all NHSI was dissolved and the pH reached 7 – 8.

This solution was added to tetraphenylphosphonium bromide (564

mg, 1.35 mmol, 1.0 equiv) dissolved in a mixture of deionized water (10 mL) and EtOH (10

mL). A white solid started to precipitate, whose crystallization was completed at 5 °C

overnight. Then, the solids were collected by filtration, washed twice with water/EtOH 5:1,

and dried in HV, giving the pure product as a white crystalline solid. Yield: 694 mg (1.09

mmol, 81%).

M.p. 178 – 180 °C. 1H NMR (250.1 MHz, CD2Cl2): δ 7.92 (ddd, 4 H, J = 7.7, 7.7, 1.7 Hz,

para-H of Ph4P+), 7.82 – 7.70 (m, 12 H, arom. H of Ph4P+ and NSI−), 7.62 (dd, 8 H, J = 12.8,

7.5 Hz, arom. H of Ph4P+), 7.36 – 7.23 (m, 6 H, arom. H of NSI−). 31P{1H} NMR (101. 3

MHz, CD2Cl2): δ 23.3 (s, 1 P). 13C{1H} NMR (100.6 MHz, CD2Cl2): δ 147.0, 136.1 (d, 1 C,

JC,P = 3.0 Hz, Ph4P+), 134.8 (d, 1 C, JC,P = 10.3 Hz, Ph4P+), 131.0 (d, 1 C, JC,P = 12.9 Hz,

Ph4P+), 130.1, 128.0, 127.0, 117.9 (d, 1 C, JC,P = 89.7 Hz, Ph4P+). EA: Calcd. for

C36H30NO4PS2 (635.74): C, 68.01; H, 4.76; N, 2.20; found: C, 67.89; H, 4.61; N, 2.11.

Coordination of NSI− to the Ru/PNNP Fragment, [Ru(NSI)(PNNP)]PF6 (20a-c)

From [Ru(OEt2)2(PNNP)]2+ and (Ph4P)NSI:

[RuCl2(PNNP)] (1) (20 mg, 24.1 μmol) and (Et3O)PF6 (12.3

mg, 49.6 μmol, 2.06 equiv) were dissolved in CD2Cl2 (0.6 mL)

in an NMR tube fitted with a Young-valve. The resulting

solution was stirred at r.t. for 15 h, then (Ph4P)NSI (15.3 mg,

24.1 μmol, 1.0 equiv) was added. NMR spectroscopic analysis of the reaction mixture showed

three new compounds (20a, 20b, and 20c, ratio 1.2:1:1.7) with AB spin patterns in the 31P

NMR spectrum, together with several broad unidentified signals. Diagnostic signals in the 1H

NMR spectrum are the imine protons (HC=N) and a HC−N cyclohexane proton of the PNNP

ligand.

SNS

O O OO

Ph4P

SN

O

S ORu

P

N

N

P

PF6O

O

Ph

Ph

5 Experimental Part

178

1H NMR (300.1 MHz, CD2Cl2): 20a: δ 9.01 (d, 1 H, JP,H = 9.6 Hz, HC=N), 8.62 (s, 1 H,

HC=N), 5.30 – 5.19 (m, 1 H, HC−N); 20b: δ 9.08 (d, 1 H, JP,H = 9.6 Hz, HC=N), 8.55 (s, 1 H,

HC=N), 4.83 – 4.72 (m, 1 H, HC−N) 20c: δ 9.12 (d, 1 H, JP,H = 10.2 Hz, HC=N), 8.73 (s, 1 H,

HC=N), 4.14 – 4.04 (m, 1 H, HC−N). 31P{1H} NMR (121.5 MHz, CD2Cl2): 20a: δ 61.6 (d, 1

P, JP,P’ = 30.1 Hz), 43.8 (d, 1 P, JP,P’ = 30.1 Hz); 20b: δ 62.4 (d, 1 P, JP,P’ = 30.0 Hz), 42.1 (d,

1 P, JP,P’ = 30.1 Hz); 20c: δ 48.7 (d, 1 P, JP,P’ = 27.9 Hz), 47.2 (d, 1 P, JP,P’ = 27.8 Hz).

From Enolato Complex 3a and NFSI: N-fluorobenzenesulfonimide (NFSI, 6.0 mg, 19.0

μmol, 1.04 equiv) was added to a solution of 3a (20 mg, 18.4 μmol) in CD2Cl2 (0.6 mL). The

reaction mixture was analyzed by NMR spectroscopy and by ESI MS. The NMR spectra

showed quantitative conversion to the products 20a and 20b (ratio 1.4:1). The 1H and 31P

NMR data are identical to those reported above. 19F NMR (CD2Cl2, 188.3 MHz): δ −73.2 (d, 6 F, JP,F = 711 Hz, PF6

−), –162.7 (dd, 1 F, J =

21.0, 17.2 Hz, free 5a). MS (ESI): m/z 1056 (M+, 100), 759 ([Ru(PNNP)]+, 17).

5.3.7 Determination of Exchange Rates in the Equilibrium 2a↔3a

CD2Cl2 solutions of 2a were prepared in situ by method b (see above). Then, β-keto

ester 4a (52 uL, 0.29 mmol, 8 equiv), fluorinated β-keto ester 5a (58 mg, 0.29 mmol, 8

equiv), or Et2O (0.1 mL) were added as appropriate. The exchange rate constants were

determined by line width analysis of a Lorentz line fit in 31P NMR spectra. At exchange rates

below coalescence, eq 5.1 describes the line width at half maximum W2a for complex 2a.

(5.1)

The transverse relaxation time T2,2a can be derived from the natural line width W0,2a by

T2,2a = (π·W0,2a)−1, when the contributions of instrumental factors to the line broadening are

neglected. Thus, eq 1 transforms to a simple expression for the rate constant k1 (eq 5.2).

(5.2)

An analogous equation is obtained for k−1, which leads to eq 5.3 under the reasonable

assumption that the natural line widths for complexes 2a and 3a (W0,2a and W0,3a) are similar.

(5.3)

⎟⎟⎠

⎞⎜⎜⎝

⎛+=

2a2a

,21

11T

kWπ

( ) π⋅−= 2a2a ,01 WWk

( ) π⋅−=− − 3a2a WWkk 11

5 Experimental Part

179

The individual rate constants k1 and k−1 can be calculated from eq 5.3 and the 2a:3a

ratio. The data from all measurements are collected in the following table:

run Additive Integral

2aa Integral

3aa 2a:3a (%) W2a (Hz) W3a (Hz) k1 (s−1) k−1 (s−1)

1 - 130 11.9 92:8 4.4 14.5 3.2 34.9

2 - 3240 330 91:9 2.7 10 2.6 25.5

3 - 4040 320 93:7 3.1 12.1 2.4 30.7

4 - 3050 285 91:9 2.5 9 2.1 23

5 - 2930 300 91:9 2.5 10 2.7 26.2

6 Et2O 2725 300 90:10 2.3 6.8 1.7 15.9

7 Et2O 2630 383 97:13 2.4 7.8 2.9 20

8 4a (8 equiv) 2900 320 90:10 2.6 10.2 3.0 26.9

9 5a (8 equiv) 3160 300 91:9 2.5 11.5 3.1 31.7

10 4a (8 equiv)+ Et2O 2720 400 87:13 2.7 11 4.5 31

11 4a (8 equiv)+ Et2O 3910 570 87:13 3.7 15.5 6.3 43.3

12 5a (8 equiv)+ Et2O 6800 1100 86:14 6.5 25 11 69

13 5a (8 equiv)+ Et2O 4160 860 83:17 5.4 25.4 21 79 a Relative integrals in arbitrary units, obtained from Lorentz line fits of 31P NMR spectra.

5.3.8 Low-Temperature Protonation of 3a with CSA

A solution of enolato complex 3a (15 mg, 13.8 μmol) in dry CD2Cl2 (0.4 mL) was

cooled to −90 °C (hexane/N2(l)) in an NMR tube fitted with a Young-valve. A solution of

(DL)-10-camphorsulfonic acid (CSA, 3.2 mg, 13.8 μmol, 1.0 equiv) in CD2Cl2 (0.1 mL) was

added dropwise along the cold glass wall of the NMR tube. After shaking quickly, the tube

was inserted into the NMR probe-head, precooled at −90 °C. 1H and 31P NMR spectra were

recorded upon warming the sample stepwise.

pKa Estimation of 2a from Protonation of 3a with CSA

The above low-temperature protonation of 3a was used to estimate the pKaaq value of

2a, as a fast equilibrium between 2a and 3a was observed at 0 °C. The following

characteristic signals appeared at equilibrium chemical shifts in the 1H NMR and in the 31P

NMR spectrum:

Imine doublet 1H NMR: δeq 8.807 (pure 2a: δ 9.010, pure 3a: δ 8.675 at 0 °C). 31P NMR doublet: δeq 63.026 (pure 2a: δ 61.328, pure 3a: δ 63.648 at 0 °C).

5 Experimental Part

180

With two different reference pKa values, the following pKaaq values were calculated:

reference pKa

CH3SO3H 1H NMR 31P NMR average

1.62 1.24 0.74 1.0±0.4

−1.92 −2.30 −2.80 −2.8±0.4

5.4 Chapter 4

5.4.1 Reactivity of Ru/PNNP Complexes Towards meso-Epoxides

Abstraction of One Chloro Ligand

TlPF6 (5.0 mg, 14.3 μmol, 1.08 equiv) or (Et3O)PF6 (3.4 mg, 13.3 μmol, 1.03 equiv)

was added to a solution of [RuCl2(PNNP)] (1) (11.0 mg, 13.2 μmol) in dry CD2Cl2 (0.8 mL).

The mixture was stirred at r.t. for 15 h, then filtered (in the case of (Et3O)PF6: transferred)

into an NMR tube. The appropriate meso-epoxide (7a-d) was added, and the solution was


Abstraction of Two Chloro Ligands

AgSbF6 (9.5 mg, 27.6 μmol, 2.09 equiv) or (Et3O)PF6 (6.8 mg, 27.0 μmol, 2.07 equiv)

was added to a solution of [RuCl2(PNNP)] (1) (11.0 mg, 13.2 μmol) in dry CD2Cl2 (0.8 mL).

The mixture was stirred at r.t. for 3 h, then filtered (in the case of (Et3O)PF6: transferred) into

an NMR tube. The appropriate meso-epoxide (7a-d) was added, and the solution was


5.4.2 Ring-Opening Hydrofluorination of meso-Epoxides

trans-2-Fluoro-cyclopentanol (8a)

A solution of [RuCl2(PNNP)] (1) (40.0 mg, 0.048 mmol, 0.2 equiv) and

(Et3O)PF6 (25.0 mg, 0.101 mmol, 0.42 equiv) in dry CH2Cl2 (3 mL) was stirred

at r.t. for 14 h. Then, the catalyst solution was added to AgHF2 (72.0 mg, 0.49

mmol, 2.02 equiv) in a Teflon® tube. A solution of cyclopentene oxide (7a) (21 μL, 20.4 mg,

0.242 mmol) and decane (internal standard for GC analysis, 50 μL, 0.26 mmol) in CH2Cl2 (1

OH

F

5 Experimental Part

181

mL) was added dropwise during 2 h by syringe pump. The mixture was stirred at r.t. for

additional 24 h. Samples of the reaction mixture (0.1 mL) were diluted with hexane (5 mL),

and filtered for GC analysis. Conversion: 95%. Yield: 11%. NMR spectroscopic data are in

agreement with literature values.17

TLC (hexane/EtOAc 3:1): Rf = 0.28 (mostaïne), slow decomposition on SiO2. Achiral GC:

tR = 3.4 min (cyclopentene oxide), 6.3 min (2-fluoro-cyclopentanol), 12.8 min (decane). 1H

NMR (200.1 MHz, CDCl3): δ 4.88 (dddd, 1 H, 2JF,H = 52.0 Hz, 3JH,H = 5.2, 2.6, 2.6 Hz,

CHF), 4.40 – 4.25 (m, 1 H, CHOH), 2.24 – 1.78 (m, 6 H, CH2). 19F NMR (188.3 MHz,

CDCl3): δ −180.1 (dddd, 1 F, 2JF,H = 52.0 Hz, 3JF,H = 31.4, 25.8, 17.1 Hz). Chiral GC: α-

DEX column, 55 °C isotherm; retention times tR = 35.9 and 40.1 min; 25% ee.

trans-2-Fluoro-cyclohexanol (8b)

A solution of [RuCl2(PNNP)] (1) (20.0 mg, 0.024 mmol, 0.2 equiv) and

(Et3O)PF6 (12.2 mg, 0.049 mmol, 0.42 equiv) in dry CH2Cl2 (3 mL) was stirred

at r.t. for 7 h. Then, the catalyst solution was added to AgHF2 (21.0 mg, 0.143

mmol, 1.2 equiv) in a Teflon® tube. A solution of cyclohexene oxide (7b) (12 μL, 11.7 mg,

0.119 mmol) and decane (internal standard for GC analysis, 30 μL, 0.15 mmol) in CH2Cl2 (1

mL) was added dropwise during 17 h by syringe pump. The mixture was stirred at r.t. for

additional 24 h. Samples of the reaction mixture (0.1 mL) were diluted with hexane (5 mL)

and filtered for GC analysis. Conversion: 100%. Yield: 8%. Spectral data are in agreement

with literature values.18

TLC (hexane/EtOAc 4:1): Rf = 0.22 (mostaïne). Achiral GC: tR = 7.2 min (cyclohexene

oxide), 8.7 min (2-fluoro-cyclohexanol), 12.8 min (decane). 1H NMR (200.1 MHz, CDCl3): δ

4.30 (dddd, 1 H, 2JF,H = 51.4 Hz, 3JH,H = 10.5, 8.3, 4.9 Hz, CHF), 3.80 – 3.56 (m, 1 H,

CHOH), 2.35 (br s, 1 H, OH), 2.20 – 1.95 (m, 2 H, CH2), 1.89 – 1.65 (m, 2 H, CH2), 1.59 –

1.20 (m, 4 H, CH2). 19F NMR (188.3 MHz, CDCl3): δ −182.1 (br d, 1 F, 2JF,H = 51.4 Hz).

Chiral GC: α-DEX column, 55 °C isotherm; retention times tR = 43.3 and 45.8 min; 10% ee.

F

OH

5 Experimental Part

182

5.4.3 Synthesis of 2-Alkylphenylacetaldehydes

2-Phenylbutan-1-ol

LiAlH4 (1.802 g, 47.5 mmol, 0.97 equiv) was suspended in dry Et2O

(20 mL) in a 3-necked flask fitted with an addition funnel and a reflux

condenser. A solution of (rac)-2-phenylbutyric acid (8.0 g, 48.7 mmol) in

dry Et2O (70 mL) was added dropwise during 75 min, which kept the mixture at a gentle

reflux. After stirring at r.t. for further 14 h, the conversion was complete as indicated by TLC.

Water was added at 0 °C until the evolution of gas stopped and a grey suspension was formed.

A H2SO4 solution (10%) was added until the mixture became homogeneous. The phases were

separated, and the aqueous phase was extracted twice with Et2O (60 mL each). The combined

organic phases were washed with a NaHCO3 solution (sat., 100 mL) and with a NaCl solution

(sat., 100 mL), dried (Na2SO4), and concentrated under reduced pressure to give a light

yellow oil. The product was used in the next step without purification. Yield: 6.923 g (46.1

mmol, 95%). Analytical data are in agreement with literature values.19

TLC (hexane/TBME 4:1): Rf = 0.11 (mostaïne). 1H NMR (300.1 MHz, CDCl3): δ 7.4 – 7.2

(m, 5 H, arom. H), 3.82 – 3.70 (m, 2 H, CH2OH), 2.76 – 2.65 (m, 1 H, CHPh), 1.79 (ddq, 1 H, 2JH,H = 14.7 Hz, 3JH,H = 5.7, 7.5 Hz, CHH’CH3), 1.61 (ddq, 1 H, 2JH,H = 14.7 Hz, 3JH,H = 9.2,

7.5 Hz, CHH’CH3), 0.87 (dd, 3 H, J = 7.4, 7.4 Hz, CH3).

2-Phenylbutyraldehyde (10b)

A solution of 2-phenylbutan-1-ol (325 mg, 2.16 mmol) in CH2Cl2 (10

mL) was added to a solution of Dess-Martin periodinane (1.01 g, 2.38

mmol, 1.1 equiv) in CH2Cl2 (10 mL). After stirring for 45 min at r.t., a white

precipitate had formed and TLC indicated complete conversion. Et2O (50 mL) and then a 1.3

M NaOH solution (20 mL) were added under vigorous stirring, causing the precipitate to

dissolve after 15 min. The layers were separated and the organic phase was washed with a 1.3

M NaOH solution (40 mL) and with water (40 mL), dried (Na2SO4), and concentrated under

reduced pressure. The crude product was purified by bulb-to-bulb distillation in a Kugelrohr

apparatus (9 mbar, 110 °C). Yield: 280 mg (1.89 mmol, 87%). Analytical data are in


TLC (hexane/EtOAc 4:1): Rf = 0.52 (mostaïne). 1H NMR (300.1 MHz, CDCl3): δ 9.70 (d, 1

H, J = 2.1 Hz, CHO), 7.43 – 7.20 (m, 5 H, arom. H), 3.43 (ddd, 1H, J = 7.4, 7.4, 2.1 Hz,

OH

H

O

5 Experimental Part

183

CHCHO), 2.14 (ddq, 1 H, 2JH,H = 14.2 Hz, 3JH,H = 7.2, 7.2 Hz, CHH’), 1.79 (ddq, 1 H, 2JH,H =

14.6 Hz, 3JH,H = 7.4, 7.4 Hz, CHH’), 0.93 (dd, 3 H, J = 7.5, 7.5 Hz, CH3). GC-MS: tR = 11.9

min; m/z 48 (M+, 34), 119 ([M-CHO]+, 84), 91 (C7H7+, 100).

General Procedure for the Synthesis of 2-Alkyl-2-phenyloxiranes (24a,c,d)20

KOtBu (1.2 equiv), trimethylsulfonium iodide (1.2 equiv) and the appropriate aryl alkyl

ketone 23 (1 equiv) were placed in a 2-necked flask fitted with a reflux condenser and heated

to 70 °C. The heterogeneous mixture was stirred mechanically from time to time. When TLC

indicated complete substrate conversion, the condenser was replaced by a micro-distillation

apparatus and the product was distilled under vacuum directly from the reaction mixture.

2-Methyl-2-phenyloxirane (24a)

Prepared in analogy to the general procedure at 60 °C from acetophenone

(23a) (5 mL, 5.150 g, 42.9 mmol), KOtBu (5.79 g, 51.6 mmol, 1.2 equiv) and

trimethylsulfonium iodide (10.50 g, 51.5 mmol, 1.2 equiv) within 2.5 h.

Distillation: 0.5 mbar, bp. 36 °C. Yield: 3.115 g (23.2 mmol, 54%). Analytical data are in


TLC (hexane/EtOAc 3:1): Rf = 0.57 (mostaïne). 1H NMR (300.1 MHz, CDCl3): δ 7.42 –

7.28 (m, 5 H, arom. H), 3.00 (d, 1 H, J = 5.4 Hz, OCHH’), 2.83 (d, 1 H, J = 5.4 Hz, OCHH’),

1.75 (s, 3 H, CH3). GC-MS: tR = 9.9 min; m/z 134 (M+, 77), 133 ([M-H]+, 89), 105 ([M-

CHO]+, 100), 77 (C6H5+, 86). The GC trace shows a mixture of the oxirane and 2-

phenylpropionaldehyde, indicating that a thermal Meinwald-rearrangement takes place in the

GC inlet.

2-Isopropyl-2-phenyloxirane (24c)

Prepared according to the general procedure from isobutyrophenone

(23c) (3 mL, 2.946 g, 19.9 mmol), KOtBu (2.68 g, 23.9 mmol, 1.2 equiv) and

trimethylsulfonium iodide (4.87 g, 23.9 mmol, 1.2 equiv) within 75 min.

Distillation: 0.30 mbar, bp. 41 – 43 °C. Yield: 2.493 g (15.4 mmol, 77%). Analytical data are

in agreement with literature values.22



2.12 (qq, 1 H, J = 6.8, 6.8 Hz, CH(CH3)2), 0.99 (d, 3 H, J = 6.8 Hz, CH(CH3)(CH’3)), 0.98 (d,

3 H, J = 6.8 Hz, CH(CH3)(CH’3)). GC-MS: tR = 12.8 min; m/z 162 (M+, 91), 91 (C7H7+, 100).

O

O

5 Experimental Part

184

2-tert-Butyl-2-phenyloxirane (24d)

Prepared according to the general procedure from 2,2-dimethyl-

propiophenone (23d) (2.5 mL, 2.418 g, 14.9 mmol), KOtBu (2.0 g, 17.8

mmol, 1.2 equiv) and trimethylsulfonium iodide (3.65 g, 17.9 mmol, 1.2

equiv) within 4 h. Distillation: 0.29 mbar, bp. 47 – 51 °C. Yield: 1.907 g (10.8 mmol, 73%).




1.03 (s, 9 H, C(CH3)3). GC-MS: tR = 13.7 min; m/z 177 ([M+H]+, 20), 175 ([M-H]+, 100), 91

(C7H7+, 68).

General Procedure for the Synthesis of 2-Alkylphenylacetaldehydes (10c,d)24

BF3·OEt2 (1.5 equiv) was added dropwise during 2 min to a solution of the appropriate

oxirane 24 in toluene (0.15 M). The mixture was stirred at r.t. until TLC indicated complete

conversion. Water was added, the layers were separated, and the aqueous phase was extracted

three times with Et2O. The combined organic phases were washed wih water, dried (Na2SO4),

and concentrated under reduced pressure. The crude product was purified by bulb-to-bulb

distillation in a Kugelrohr apparatus.

3-Methyl-2-phenylbutyraldehyde (10c)

Prepared according to the general procedure from 2-isopropyl-2-

phenyl-oxirane (24c) (484 mg, 2.98 mmol) and BF3·OEt2 (0.55 mL, 4.38

mmol, 1.5 equiv) in toluene (20 mL) within 40 min. Bulb-to-bulb

distillation: 8 – 10 mbar, 140 °C. Yield: 407 mg (2.51 mmol, 84%). The NMR spectroscopic

data are consistent with those reported in the literature.23


H, J = 3.3 Hz, CHO), 7.43 – 7.15 (m, 5 H, arom. H), 3.21 (dd, 1 H, J = 9.5, 3.3 Hz, CHCHO),

2.45 (dqq, 1 H, J = 9.5, 6.7, 6.6 Hz, CH(CH3)2), 1.07 (d, 3 H, J = 6.6 Hz, CH(CH3)(CH’3)),

0.80 (d, 3 H, J = 6.7 Hz, CH(CH3)(CH’3)). GC-MS: tR = 13.0 min; m/z 162 (M+, 36), 133

([M-CHO]+, 81), 91 (C7H7+, 100).

O

H

O

5 Experimental Part

185

3,3-Dimethyl-2-phenylbutyraldehyde (10d)

Prepared according to the general procedure from 2-tert-butyl-2-

phenyl-oxirane (24d) (525 mg, 2.98 mmol) and BF3·OEt2 (0.55 mL, 4.38

mmol, 1.5 equiv) in toluene (20 mL) within 1 h. Bulb-to-bulb distillation: 6

– 8 mbar, 170 °C. Yield: 417 mg (2.37 mmol, 79%). Analytical data are in agreement with

literature values.23


H, J = 3.5 Hz, CHO), 7.43 – 7.24 (m, 5 H, arom. H), 3.32 (d, 1 H, J = 3.5 Hz, CHCHO), 1.06

(s, 9 H, C(CH3)3). GC-MS: tR = 14.3 min; m/z 176 (M+, 2), 120 ([M-C4H8]+, 100), 91 (C7H7+,

90).

3-Phenylbutan-2-ol

Magnesium turnings (616 mg, 25.3 mmol, 1.1 equiv) were suspended

in dry Et2O (4 mL) in a 3-necked flask fitted with a reflux condenser and an

addition funnel. A solution of methyl iodide (1.6 mL, 3.648 g, 25.7 mmol,

1.12 equiv) in dry Et2O (5 mL) was added dropwise during 15 min. The formation of the

Grignard reagent started immediately and heated the solution to reflux. When the addition

was completed, the solution was heated to reflux for further 20 min, then cooled to r.t.. A

solution of 2-phenylpropionaldehyde (10a) (3.085 g, 23.0 mmol) in dry Et2O (12 mL) was

added dropwise during 30 min, which kept the solution at a gentle reflux. After stirring at r.t.

for 14 h, a solution of NH4Cl (sat., 20 mL) was added, and the layers were separated. The

aqueous phase was extracted twice with Et2O (25 mL each). The combined organic phases

were washed with water (50 mL), dried (Na2SO4), and concentrated under reduced pressure.

The crude product was obtained as a light yellow oil and was used in the next step without

further purification. Yield: 3.355 g (22.3 mmol, 97%). The 1H NMR spectrum showed the

formation of two diastereoisomers (A and B) in the ratio A : B = 1.7 : 1, whose signals are in

agreement with literature data.25

TLC (hexane/EtOAc 4:1): Rf = 0.24 (mostaïne). 1H NMR (200.1 MHz, CDCl3):

Diastereoisomer A: δ 7.45 – 7.18 (m, 5 H, arom. H), 4.00 – 3.86 (m, 1 H, CH(OH)CH3), 2.86

– 2.71 (m, 1 H, CH(Ph)CH3), 1.37 (d, 3 H, J = 6.9 Hz, CH(Ph)CH3), 1.14 (d, 3 H, J = 6.4 Hz,

CH(OH)CH3). Diastereoisomer B: δ 7.45 – 7.18 (m, 5 H, arom. H), 3.96 – 3.83 (m, 1 H,

CH(OH)CH3), 2.80 – 2.65 (m, 1 H, CH(Ph)CH3), 1.31 (d, 3 H, J = 7.1 Hz, CH(Ph)CH3), 1.28

(d, 3 H, J = 6.1 Hz, CH(OH)CH3).

H

O

OH

5 Experimental Part

186

3-Phenylbutan-2-one (25)

A solution of 3-phenylbutan-2-ol (351 mg, 2.34 mmol) in CH2Cl2 (10

mL) was added to a solution of Dess-Martin periodinane (1.090 g, 2.57

mmol, 1.1 equiv) in CH2Cl2 (10 mL). After stirring at r.t. for 40 min, TLC

indicated complete conversion and the mixture was added to Et2O (50 mL). A 1.3 M NaOH

solution (20 mL) was added, and stirring was continued for 10 min. Then, the layers were

separated and the organic phase was washed with a 1.3 M NaOH solution (40 mL), and twice

with water (40 mL each), dried (Na2SO4), and concentrated under reduced pressure.

Purification was accomplished by bulb-to-bulb distillation in a Kugelrohr apparatus (10 mbar,

120 °C), giving 25 as a light yellow liquid. Yield: 287 mg (1.937 mmol, 83%). Analytical

data are in agreement with literature values.25


7.20 (m, 5 H, arom. H), 3.76 (q, 1 H, J = 7.0 Hz, CHCH3), 2.07 (s, 3 H, C(O)CH3), 1.41 (d, 3

H, J = 7.0 Hz, CHCH3). GC-MS: tR = 11.5 min; m/z 148 (M+, 45), 105 ([M-COCH3]+, 100).

2-Phenylpropionic Acid Ethyl Ester (26)

A solution of (rac)-2-phenylpropionic acid (1.8 mL, 1.975 g, 13.1

mmol) and conc. H2SO4 (0.4 mL, 0.736 g, 7.2 mmol, 0.55 equiv) in

ethanol (10 mL) was heated to reflux. After 5 h, the solution was cooled to

r.t. and concentrated under reduced pressure to 1/3 of the initial volume. After pouring into

ice-cooled water (40 mL), the mixture was extracted three times with Et2O (40 mL each). The

combined organic phases were washed twice with water (100 mL each), dried (Na2SO4), and

concentrated under reduced pressure. The crude product was purified by vacuum distillation

(0.1 mbar, bp. 33 – 35 °C), furnishing 26 as a colorless liquid. Yield: 1.938 g (10.9 mmol,

83%). Analytical data are in agreement with literature values.26


7.20 (m, 5 H, arom. H), 4.19 (dq, 1 H, 2JH,H = 14.2 Hz, 3JH,H = 7.1 Hz, OCHH’CH3), 4.14 (dq,

1 H, 2JH,H = 14.2 Hz, 3JH,H = 7.1 Hz, OCHH’CH3), 3.75 (q, 1 H, J = 7.1 Hz, CHCH3), 1.54 (d,

3 H, J = 7.1 Hz, CHCH3), 1.25 (dd, 3 H, J = 7.1, 7.1 Hz, OCHH’CH3). GC-MS: tR = 13.5

min; m/z 178 (M+, 54), 105 ([M-CO2Et]+, 100).

O

OEt

O

5 Experimental Part

187

5.4.4 Ruthenium Catalyzed α-Fluorination of Aldehydes

General Procedure

AgSbF6 (8.2 mg, 24.0 μmol, 0.05 equiv) was added to a solution of [RuCl2(PNNP)] (1)

(20.0 mg, 24.0 μmol, 0.05 equiv) in dry 1,2-dichloroethane (2 mL). The mixture was stirred

for 15 h in the dark, giving a brown suspension. The appropriate aldehyde 10 (0.48 mmol, 1

equiv) was added, then the suspension was filtered into a Teflon® tube containing AgHF2 (168

mg, 1.14 mmol, 2.4 equiv), diluted with 1,2-dichloroethane (1 mL), and stirred at 60 °C in the

dark for 24 h. After cooling to r.t., the reaction mixture was filtered through a short plug of

Al2O3 with CH2Cl2 as eluent, and concentrated under reduced pressure. A CH2Cl2 solution of

the residue was used for GC-MS and chiral GC analysis. Yields were determined by

integration of the 19F NMR signals, using a known amount of octafluoronaphthalene as an

internal standard (19F NMR signals at δ −145.1 and −153.6). A delay time of d1 > 30 s was

applied between pulses to ensure the complete relaxation of the fluorine nuclei in different

chemical environments.

2-Fluoro-2-phenylpropionaldehyde (11a)

From 2-phenylpropionaldehyde: Prepared according to the general

procedure from aldehyde 10a (64 mg, 0.48 mmol). Yield: 17.8 mg (0.117

mmol, 24%). Acetophenone was identified as side-product by 1H NMR

spectroscopy and GC-MS. The NMR spectral data of the product are consistent with reported

values.27,28 1H NMR (CDCl3, 200.1 MHz): δ 9.74 (d, 1 H, JF,H = 4.9 Hz, CHO), 7.62 – 7.15 (m, 5 H,

arom. H), 1.82 (d, 3 H, JF,H = 22.7 Hz, CH3). 19F NMR (CDCl3, 188.3 MHz): δ –160.9 (dq, 1

F, JF,H = 22.7, 4.9 Hz). GC-MS: Product: tR = 8.8 min; m/z 152 (M+, 9), 123 ([M-CHO]+,

100), 103 ([M-CHO-HF]+, 81). Starting material: tR = 10.3 min; m/z 134 (M+, 8), 105 ([M-

CHO]+, 100). Acetophenone: tR = 9.6 min; m/z 120 (M+, 27), 105 ([M-CH3]+, 100), 77

(C6H5+, 73). Chiral GC: α-DEX column, 56 °C isotherm; retention times tR = 48.9 and 50.3

min; 27% ee.

Tandem Meinwald rearrangement – α-Fluorination from α-methylstyrene oxide:

AgSbF6 (8.2 mg, 24.0 μmol, 0.05 equiv) was added to a solution of [RuCl2(PNNP)] (1) (20.0

mg, 24.0 μmol, 0.05 equiv) in 1,2-dichloroethane (2 mL) and stirred for 15 h in the dark.

After filtration, a solution of α-methylstryrene oxide (24a) (66 mg, 0.49 mmol) in 1,2-

H

O

F

5 Experimental Part

188

dichloroethane (0.5 mL) was added and stirred at r.t. for 1.5 h. Then, the solution was added

to AgHF2 (169 mg, 1.15 mmol, 2.4 equiv) in a Teflon® tube, protected from light, and stirred

at 60 °C for 24 h. A conversion of 50% was estimated from GC-MS measurements.

Analytical data of the product are identical to the ones described above.

2-Fluoro-2-phenylbutyraldehyde (11b)

Prepared according to the general procedure from aldehyde 10b (71

mg, 0.48 mmol). Yield: 28.0 mg (0.168 mmol, 35%). Propiophenone was

identified as a side-product by 1H NMR spectroscopy and GC-MS. 1H NMR (CDCl3, 200.1 MHz): δ 9.77 (d, 1 H, JF,H = 5.6 Hz, CHO), 7.65 – 7.20 (m, 5 H,

arom. H), 2.40 – 2.00 (m, 2 H, CH2), 0.99 (dd, 3 H, J = 7.4, 7.4 Hz, CH3). 19F NMR (CDCl3,

188.3 MHz): δ –175.6 (ddd, 1 F, JF,H = 26.1, 23.2, 5.6 Hz). GC-MS: Product: tR = 10.7 min;

m/z 166 (M+, 3), 137 ([M-CHO]+, 100), 117 ([M-CHO-HF]+, 78). Propiophenone: tR = 11.7

min; m/z 134 (M+, 14), 105 ([M-C2H5]+, 100), 77 (C6H5+, 57). Chiral GC: α-DEX column,

66 °C isotherm; retention times tR = 54.3 and 55.9 min; 23% ee.

2-Fluoro-3-methyl-2-phenylbutyraldehyde (11c)

Prepared according to the general procedure from aldehyde 10c (79

mg, 0.49 mmol). Yield: 27.6 mg (0.153 mmol, 31%). 1H NMR (CDCl3, 200.1 MHz): δ 9.77 (d, 1 H, JF,H = 6.7 Hz, CHO), 7.60 –

7.15 (m, 5 H, arom. H), 2.63 – 2.40 (m, 1 H, CH(CH3)2), 1.12 (d, 3 H, J = 6.8 Hz,

CH(CH3)(CH’3)), 0.82 (d, 3 H, J = 7.0 Hz, CH(CH3)(CH’3)). 19F NMR (CDCl3, 188.3 MHz):

δ –189.8 (dd, 1 F, JF,H = 31.9, 6.7 Hz). GC-MS: tR = 12.0 min; m/z 180 (M+, 5), 151 ([M-

CHO]+, 100), 131 ([M-CHO-HF]+, 74). Chiral GC: α-DEX column, 75 °C isotherm;

retention times tR = 49.9 and 51.1 min; 18% ee.

2-Fluoro-3,3-dimethyl-2-phenylbutyraldehyde (11d)

Prepared according to the general procedure from aldehyde 10d (85

mg, 0.48 mmol). Yield: 12.1 mg (0.063 mmol, 13%). 2,2-dimethylpropio-

phenone was identified as a side-product by 1H NMR spectroscopy and GC-

MS. 1H NMR (CDCl3, 200.1 MHz): δ 9.96 (d, 1 H, JF,H = 8.2 Hz, CHO), 7.55 – 7.23 (m, 5 H,

arom. H), 1.08 (s, 9 H, C(CH3)3). 19F NMR (CDCl3, 188.3 MHz): δ –170.6 (d, 1 F, JF,H = 8.2

H

O

F

H

O

F

H

O

F

5 Experimental Part

189

Hz). GC-MS: Product: tR = 13.2 min; m/z 194 (M+, 1), 165 ([M-CHO]+, 36), 138 ([M-C4H8]+,

100). 2,2-Dimethylpropiophenone: tR = 12.9 min; m/z 162 (M+, 4), 105 ([M-C4H9]+, 100), 77

(C6H5+, 23). Chiral GC: No separation of the enantiomers was achieved on α-DEX and β-

DEX columns.

5.5 References Experimental Part

[1] Hoots, J. E.; Rauchfuss, T. B.; Wrobleski, D. A. Inorg. Synth. 1982, 21, 175 – 179.

[2] Hallman, P. S.; Stephenson, T. A.; Wilkinson, G. Inorg. Synth. 1946, 12, 237 – 240.

[3] Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155 – 4156.

[4] Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.

[5] Krapcho, A. P.; Diamanti, J.; Cayen, C.; Bingham, R. Org. Synth. 1973, Coll. Vol. 5, 198 – 201.

[6] Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285

– 288.


[8] Stoop, R. M.; Bachmann, S.; Valentini, M.; Mezzetti, A. Organometallics 2000, 19, 4117 – 4126.

[9] Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087 – 1089.

[10] Babler, J. H.; Sarussi, S. J. J. Org. Chem. 1987, 52, 3464 – 3466.

[11] Henderson, D.; Richardson, K. A.; Taylor, R. J. K., Saunders, J. Synthesis 1983, 996 – 997.

[12] Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530 –

14531.

[13] Cahard, D.; Audouard, C.; Plaquevent, J.-C.; Roques, N. Org. Lett. 2000, 2, 3699 – 3701.

[14] Kitazume, T.; Kobayashi, T. J. Fluorine Chem. 1986, 31, 357 – 361.

[15] Perseghini, M. ETH, Ph.D. Thesis No. 15195, Zurich, Switzerland, 2003.

[16] Takeuchi, Y.; Satoh, A.; Suzuki, T.; Kameda, A.; Dohrin, M.; Satoh, T.; Koizumi, T.; Kirk, K. L. Chem.

Pharm. Bull. 1997, 45, 1085 – 1088.

[17] Shellhamer, D. F.; Briggs, A. A.; Miller, B. M.; Prince, J. M.; Scott, D. H.; Heasley, V. L. J. Chem. Soc.,

Perkin Trans. 2 1996, 973 – 977.

[18] Bruns, S.; Haufe, G. J. Fluorine Chem. 2000, 104, 247 – 254.

[19] Stratakis, M.; Kalaitzakis, D.; Stavroulakis, D.; Kosmas, G.; Tsangarakis, C. Org. Lett. 2003, 5, 3471 –

3474.

[20] Toda, F.; Kanemoto, K. Heterocycles 1997, 46, 185 – 188.

[21] Zhang, Y.; Wu, W. Tetrahedron: Asymmetry 1997, 8, 2723 – 2725.

[22] Tian, J.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435 – 2446.

[23] Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353 – 3361.

[24] Ibarra, C. A.; Arias, S.; Fernández, M. J.; Sinisterra, J. V. J. Chem. Soc., Perkin Trans. 2 1989, 503 – 508.

[25] Arjona, O.; Pérez-Ossorio, R.; Pérez-Rubalcaba, A.; Quiroga, M. L. J. Chem. Soc., Perkin Trans. 2 1981,

597 – 603.

5 Experimental Part

190

[26] Mueller, R.; Yang, J.; Duan, C.; Pop, E.; Geoffroy, O. J.; Zhang, L. H.; Huang, T.-B.; Denisenko, S.;

McCosar, B. H.; Oniciu, D. C.; Bisgaier, C. L.; Pape, M. E.; Freiman, C. D.; Goetz, B.; Cramer, C. T.;

Hopson, K. L.; Dasseux, J.-L. H. J. Med. Chem. 2004, 47, 6082 – 6099.

[27] Oldendorf, J.; Haufe, G. J. Prakt. Chem. 2000, 342, 52 – 57.

[28] Purrington, S. T.; Lazaridis, N. V.; Bumgardner, C. L. Tetrahedron Lett. 1986, 27, 2715 – 2716.

6 Appendix

191

6 Appendix

6.1 List of Abbreviations

°C degree Celsius

Ac acetyl

acac acetylacetonate

aHF anhydrous HF

Ar aryl

arom. aromatic

BINAP 2,2´-bis(diphenylphosphino)-1,1´-binaphthyl

BINOL 1,1’-bi-2-naphthol

Boc tert-butyloxycarbonyl

BOX bis(oxazoline)

cat. catalytic

conv. conversion

COSY correlation spectroscopy

CSA (DL)-10-camphorsulfonic acid

d day(s)

DCE 1,2-dichloroethane

de diastereomeric excess

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide

EA elemental analysis

ee enantiomeric excess

EI electron ionization

eq equation

equiv equivalent(s)

ESI electrospray ionization

6 Appendix

192

Et ethyl

EWG electron-withdrawing group

EXSY exchange spectroscopy

FC flash column chromatography

F-TEDA 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane

bis(tetrafluoroborate)

GC gas chromatography

h hour(s)

Hacac acetylacetone

HMQC heteronuclear multiple quantum correlation

HPLC high performance liquid chromatography

HV high vacuum (10−2 – 10−3 mbar)

Hz Hertz iPr iso-propyl

IR infrared spectroscopy

LDA lithium diisopropylamide

M.p. melting point

MALDI matrix-assisted laser desorption ionization

Me methyl

min minute(s)

MS mass spectrometry

n.d. not determined

NFSI N-fluorobenzenesulfonimide

NHSI dibenzenesulfonimide

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

NOESY nuclear Overhauser effect spectroscopy

Np naphthyl

NSI− dibenzenesulfonamide anion

Ph phenyl

ppm parts per million

py pyridine

r.t. room temperature

rac racemic

6 Appendix

193

SET single-electron transfer

T temperature

TADDOL α,α,α’,α’-tetraaryl-1,3-dioxolan-4,5-dimethanol

TBME tert-butylmethylether tBu tert-butyl

Tf trifluoromethylsulfonyl

THF tetrahydrofuran

TLC thin layer chromatography

Ts toluene-4-sulfonyl

TsDPEN N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine

6 Appendix

194

6.2 List of Numbered Compounds

1 [RuCl2(PNNP)] 2a dicarbonyl complex [Ru(4a)(PNNP)](PF6)2 3a enolato complex [Ru(4a−H+)(PNNP)]PF6 4 β-keto esters 4a 2-tert-butoxycarbonylcyclopentanone 4b 2-ethoxycarbonylcyclopentanone 4c ethyl 2-methyl-3-oxobutanoate 4d ethyl 2-methyl-3-oxo-3-phenylpropanoate 5a-d α-fluoro-β-keto esters 6 [Ru(OEt2)2(PNNP)](PF6)2 7 meso-epoxides 7a cyclopentene oxide 7b cyclohexene oxide 7c cis-2,3-epoxybutane 7d cis-stilbene oxide 8a-d fluorohydrins 9 [RuCl(PNNP)]+ 10 2-alkylphenylacetaldehydes 10a 2-phenylpropionaldehyde 10b 2-phenylbutyraldehyde 10c 3-methyl-2-phenylbutyraldehyde 10d 3,3-dimethyl-2-phenylbutyraldehyde 11a-d α-fluoroaldehydes 12 PNNP ligand 13 α-acetyl-N-benzyl-δ-valerolactame 14 β-keto acid complex 15 dicarbonyl complex [Ru(13)(PNNP)](PF6)2 16 enolato complex [Ru(13−H+)(PNNP)]PF6 17 (1R,2R)-2-tert-butoxycarbonyl-2-fluoro-cyclopentanol 18 (1S)-(–)-camphanic acid ester of 17 19 α-alkylidene-β-keto ester complex [Ru(4a−H−)(PNNP)](PF6)2 20a-c [Ru(NSI)(PNNP)]+ 21a-e [Ru(5a)(PNNP)]2+ 22a-b camphorsulfonate complex [Ru(CSA−)(PNNP)]+ 23a,c,d aryl alkylketones 24a,c,d oxiranes 25 3-phenylbutan-2-one 26 2-phenylpropionic acid ethyl ester

6 Appendix

195

6.3 Crystallographic Data

6.3.1 Enolato Complex 3a

Crystal Data and Structure Refinement:

Empirical formula C108H110F12N4O6P6Ru2,

2.22 (CCl2) Formula weight 2362.38 Temperature 200(2) K Wavelength 0.71073 Å Crystal system, space group Triclinic, P−1 Unit cell dimensions a = 14.9279(11) Å alpha = 78.0510(10)°

b = 16.6872(12) Å beta = 74.0360(10)° c = 23.5871(17) Å gamma = 79.2880(10)°

Volume 5474.5(7) Å3 Z, Calculated density 2, 1.433 Mg/m3 Absorption coefficient 0.549 mm−1 F(000) 2420 Crystal size 0.80 x 0.42 x 0.23 mm Theta range for data collection 1.72 to 26.37° Limiting indices −18<=h<=18, −20<=k<=20, −29<=l<=29 Reflections collected / unique 49537 / 22319 [R(int) = 0.0265] Completeness to theta = 26.37 99.6% Absorption correction Empirical Max. and min. transmission 0.8842 and 0.6679 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 22319 / 5 / 1351 Goodness-of-fit on F2 1.041 Final R indices [I>2sigma(I)] R1 = 0.0497, wR2 = 0.1364 R indices (all data) R1 = 0.0573, wR2 = 0.1418 Largest diff. peak and hole 2.254 and −0.726 e·Å−3

Atomic coordinates (x 104) and equivalent isotropic displacement parameters Ueq (Å2 x 103). Disordered

CH2Cl2 molecules are omitted:

Atom x y z Ueq Atom x y z Ueq

Ru(1) 7188(1) 2054(1) 7399(1) 19(1) Ru(2) 7049(1) 2766(1) 2967(1) 22(1) P(1) 8623(1) 1962(1) 6734(1) 21(1) P(2) 6560(1) 943(1) 7345(1) 21(1) P(3) 8579(1) 2753(1) 2427(1) 26(1) P(4) 6608(1) 1642(1) 2775(1) 24(1) P(5) 2451(1) 1957(1) 9357(1) 48(1) P(6) 2016(1) 2940(1) 4876(1) 42(1) F(1) 2044(3) 1174(2) 9764(2) 127(2) F(2) 2975(3) 2001(2) 9850(2) 96(1) F(3) 2912(3) 2740(2) 8981(2) 96(1) F(4) 1951(3) 1910(3) 8873(2) 134(2) F(5) 1568(2) 2549(2) 9675(1) 75(1) F(6) 3341(2) 1385(2) 9034(1) 73(1)

F(7) 2657(3) 2347(2) 5262(2) 120(2) F(8) 2639(2) 3643(2) 4812(1) 64(1) F(9) 2688(3) 2659(3) 4293(2) 123(2) F(10) 1370(3) 3562(2) 4505(2) 104(1) F(11) 1401(2) 2239(2) 4922(2) 90(1) F(12) 1348(2) 3235(3) 5459(2) 96(1) O(1) 6516(1) 2688(1) 6738(1) 23(1) O(2) 7523(2) 3191(1) 7524(1) 24(1) O(3) 7426(2) 4572(2) 7398(1) 43(1) O(4) 6518(2) 3401(1) 2253(1) 29(1) O(5) 7207(2) 3901(1) 3196(1) 29(1) O(6) 7018(2) 5285(1) 3122(1) 38(1) N(1) 7718(2) 1648(2) 8136(1) 24(1) N(2) 5947(2) 2233(2) 8068(1) 24(1)

6 Appendix

196

N(3) 7388(2) 2356(2) 3771(1) 25(1) N(4) 5687(2) 2859(2) 3531(1) 24(1) C(1) 8727(2) 2873(2) 6148(1) 26(1) C(2) 8322(2) 2940(2) 5674(2) 34(1) C(3) 8302(3) 3653(2) 5260(2) 43(1) C(4) 8675(3) 4325(2) 5311(2) 47(1) C(5) 9075(3) 4267(2) 5781(2) 46(1) C(6) 9111(3) 3552(2) 6195(2) 37(1) C(7) 9195(2) 1093(2) 6339(1) 26(1) C(8) 9174(2) 305(2) 6671(2) 29(1) C(9) 9679(3) -377(2) 6426(2) 40(1)

C(10) 10219(3) -270(2) 5844(2) 47(1) C(11) 10254(3) 514(2) 5509(2) 44(1) C(12) 9744(2) 1196(2) 5755(2) 34(1) C(13) 9559(2) 1944(2) 7100(1) 26(1) C(14) 10459(2) 2026(2) 6734(2) 36(1) C(15) 11218(3) 1974(3) 6974(2) 46(1) C(16) 11088(3) 1832(3) 7586(2) 50(1) C(17) 10213(2) 1733(2) 7953(2) 38(1) C(18) 9429(2) 1785(2) 7720(2) 27(1) C(19) 8557(2) 1659(2) 8181(1) 28(1) C(20) 6959(2) 1573(2) 8706(1) 29(1) C(21) 7259(3) 1520(3) 9283(2) 42(1) C(22) 6407(3) 1475(3) 9819(2) 57(1) C(23) 5679(3) 2229(3) 9744(2) 51(1) C(24) 5348(3) 2271(3) 9181(2) 39(1) C(25) 6173(2) 2301(2) 8629(1) 30(1) C(26) 5097(2) 2227(2) 8061(1) 27(1) C(27) 4812(2) 1966(2) 7589(1) 25(1) C(28) 3905(2) 2260(2) 7534(2) 31(1) C(29) 3558(2) 1994(2) 7127(2) 34(1) C(30) 4097(2) 1415(2) 6793(2) 34(1) C(31) 4996(2) 1091(2) 6861(2) 29(1) C(32) 5370(2) 1365(2) 7253(1) 23(1) C(33) 6977(2) 297(2) 6762(1) 24(1) C(34) 6928(2) -551(2) 6882(2) 31(1) C(35) 7190(3) -1004(2) 6415(2) 37(1) C(36) 7493(3) -628(2) 5838(2) 40(1) C(37) 7541(3) 216(2) 5716(2) 37(1) C(38) 7283(2) 671(2) 6178(2) 28(1) C(39) 6337(2) 198(2) 8037(1) 27(1) C(40) 5439(3) 154(2) 8404(2) 36(1) C(41) 5313(3) -323(3) 8972(2) 52(1) C(42) 6073(3) -768(3) 9170(2) 54(1) C(43) 6967(3) -748(3) 8803(2) 47(1) C(44) 7102(3) -266(2) 8241(2) 36(1) C(45) 6374(2) 3480(2) 6635(1) 24(1) C(46) 5812(3) 3900(2) 6186(2) 34(1) C(47) 5755(4) 4825(2) 6179(2) 55(1) C(48) 6329(3) 4936(2) 6587(2) 41(1) C(49) 6653(2) 4066(2) 6864(2) 29(1) C(50) 7214(2) 3893(2) 7279(2) 28(1) C(51) 7981(3) 4566(2) 7828(2) 45(1) C(52) 7510(4) 4154(4) 8446(2) 68(1) C(53) 8976(3) 4163(3) 7616(2) 60(1)

C(54) 7953(5) 5477(3) 7810(3) 90(2) C(55) 8732(2) 3731(2) 1916(2) 33(1) C(56) 8389(3) 3879(3) 1409(2) 43(1) C(57) 8387(3) 4645(3) 1045(2) 56(1) C(58) 8702(4) 5283(3) 1193(2) 62(1) C(59) 9032(3) 5146(3) 1696(2) 58(1) C(60) 9059(3) 4371(2) 2057(2) 42(1) C(61) 9265(2) 1960(2) 1986(2) 33(1) C(62) 9818(3) 2127(3) 1411(2) 46(1) C(63) 10370(3) 1486(3) 1133(2) 63(1) C(64) 10374(4) 678(3) 1421(3) 67(1) C(65) 9836(3) 506(3) 1994(2) 55(1) C(66) 9288(3) 1145(2) 2274(2) 40(1) C(67) 9372(2) 2687(2) 2906(2) 29(1) C(68) 10320(3) 2747(2) 2637(2) 38(1) C(69) 10964(3) 2686(3) 2972(2) 45(1) C(70) 10678(3) 2581(2) 3586(2) 43(1) C(71) 9756(2) 2508(2) 3860(2) 35(1) C(72) 9081(2) 2543(2) 3530(2) 29(1) C(73) 8148(2) 2405(2) 3909(2) 28(1) C(74) 6536(2) 2249(2) 4281(1) 27(1) C(75) 6642(2) 2268(2) 4904(2) 32(1) C(76) 5720(3) 2167(2) 5379(2) 40(1) C(77) 4940(3) 2827(3) 5233(2) 43(1) C(78) 4820(3) 2826(2) 4613(2) 37(1) C(79) 5729(2) 2921(2) 4139(1) 28(1) C(80) 4899(2) 2829(2) 3425(2) 30(1) C(81) 4798(2) 2585(2) 2888(2) 29(1) C(82) 3956(2) 2883(2) 2720(2) 36(1) C(83) 3778(3) 2628(2) 2246(2) 41(1) C(84) 4415(3) 2045(2) 1954(2) 42(1) C(85) 5242(3) 1727(2) 2126(2) 36(1) C(86) 5457(2) 2001(2) 2588(2) 28(1) C(87) 7199(2) 1097(2) 2148(2) 29(1) C(88) 7186(3) 254(2) 2189(2) 41(1) C(89) 7500(4) -102(3) 1673(2) 58(1) C(90) 7817(4) 375(3) 1130(2) 61(1) C(91) 7834(3) 1210(3) 1089(2) 51(1) C(92) 7515(3) 1571(2) 1601(2) 37(1) C(93) 6387(2) 812(2) 3416(1) 28(1) C(94) 5497(3) 624(2) 3713(2) 34(1) C(95) 5374(3) 15(2) 4218(2) 42(1) C(96) 6133(3) -425(2) 4415(2) 45(1) C(97) 7022(3) -248(2) 4124(2) 43(1) C(98) 7154(3) 376(2) 3628(2) 36(1) C(99) 6292(2) 4188(2) 2190(2) 30(1) C(100) 5789(3) 4603(2) 1711(2) 42(1) C(101) 5492(4) 5493(3) 1815(2) 69(2) C(102) 6070(3) 5636(2) 2218(2) 44(1) C(103) 6430(3) 4771(2) 2488(2) 32(1) C(104) 6904(2) 4602(2) 2948(2) 28(1) C(105) 7400(3) 5279(2) 3635(2) 37(1) C(106) 6769(3) 4900(3) 4212(2) 46(1) C(107) 8413(3) 4868(3) 3547(2) 51(1) C(108) 7357(4) 6199(2) 3629(2) 56(1)

6 Appendix

197

Bond lengths (Å). Calculated distances to hydrogen atoms and disordered CH2Cl2 molecules are omitted:

Bond Å Bond Å Bond Å

Ru(1)–N(1) 2.044(2) Ru(1)–O(1) 2.082(2) Ru(1)–N(2) 2.097(3) Ru(1)–O(2) 2.144(2) Ru(1)–P(2) 2.2681(8) Ru(1)–P(1) 2.2803(8) Ru(2)–N(3) 2.045(3) Ru(2)–O(4) 2.067(2) Ru(2)–N(4) 2.100(3) Ru(2)–O(5) 2.144(2) Ru(2)–P(4) 2.2647(8) Ru(2)–P(3) 2.2868(9) P(1)–C(13) 1.826(3) P(1)–C(1) 1.829(3) P(1)–C(7) 1.834(3)

P(2)–C(33) 1.825(3) P(2)–C(39) 1.827(3) P(2)–C(32) 1.839(3) P(3)–C(67) 1.825(3) P(3)–C(55) 1.828(3) P(3)–C(61) 1.833(4) P(4)–C(87) 1.826(3) P(4)–C(93) 1.827(3) P(4)–C(86) 1.853(3) P(5)–F(4) 1.548(4) P(5)–F(1) 1.566(4) P(5)–F(3) 1.576(3) P(5)–F(2) 1.589(3) P(5)–F(6) 1.590(3) P(5)–F(5) 1.598(3) P(6)–F(9) 1.566(3) P(6)–F(12) 1.572(3) P(6)–F(7) 1.575(4) P(6)–F(10) 1.578(4) P(6)–F(11) 1.586(3) P(6)–F(8) 1.586(3)

O(1)–C(45) 1.281(4) O(2)–C(50) 1.259(4) O(3)–C(50) 1.332(4) O(3)–C(51) 1.473(4) O(4)–C(99) 1.282(4)

O(5)–C(104) 1.259(4) O(6)–C(104) 1.341(4) O(6)–C(105) 1.472(4) N(1)–C(19) 1.290(4) N(1)–C(20) 1.501(4) N(2)–C(26) 1.276(4) N(2)–C(25) 1.483(4) N(3)–C(73) 1.283(4) N(3)–C(74) 1.501(4) N(4)–C(80) 1.280(4) N(4)–C(79) 1.476(4) C(1)–C(2) 1.386(5)

C(1)–C(6) 1.397(5) C(2)–C(3) 1.376(5) C(3)–C(4) 1.380(6) C(4)–C(5) 1.379(6) C(5)–C(6) 1.380(5) C(7)–C(8) 1.386(4) C(7)–C(12) 1.390(5) C(8)–C(9) 1.382(5) C(9)–C(10) 1.383(6)

C(10)–C(11) 1.382(6) C(11)–C(12) 1.386(5) C(13)–C(18) 1.396(5) C(13)–C(14) 1.396(5) C(14)–C(15) 1.381(5) C(15)–C(16) 1.380(6) C(16)–C(17) 1.371(5) C(17)–C(18) 1.406(4) C(18)–C(19) 1.467(4) C(20)–C(21) 1.525(4) C(20)–C(25) 1.543(5) C(21)–C(22) 1.528(5) C(22)–C(23) 1.516(7) C(23)–C(24) 1.523(5) C(24)–C(25) 1.526(5) C(26)–C(27) 1.463(4) C(27)–C(28) 1.382(4) C(27)–C(32) 1.410(4) C(28)–C(29) 1.387(5) C(29)–C(30) 1.370(5) C(30)–C(31) 1.389(5) C(31)–C(32) 1.389(4) C(33)–C(38) 1.379(5) C(33)–C(34) 1.397(4) C(34)–C(35) 1.391(5) C(35)–C(36) 1.366(6) C(36)–C(37) 1.389(5) C(37)–C(38) 1.385(5) C(39)–C(40) 1.386(5) C(39)–C(44) 1.398(5) C(40)–C(41) 1.392(5) C(41)–C(42) 1.375(6) C(42)–C(43) 1.379(6) C(43)–C(44) 1.383(5) C(45)–C(49) 1.383(4) C(45)–C(46) 1.511(4) C(46)–C(47) 1.526(5) C(47)–C(48) 1.509(5) C(48)–C(49) 1.513(4) C(49)–C(50) 1.411(4) C(51)–C(53) 1.506(6) C(51)–C(54) 1.506(6) C(51)–C(52) 1.515(7) C(55)–C(56) 1.384(5)

C(55)–C(60) 1.387(5) C(56)–C(57) 1.384(6) C(57)–C(58) 1.382(7) C(58)–C(59) 1.368(7) C(59)–C(60) 1.394(6) C(61)–C(62) 1.384(5) C(61)–C(66) 1.387(5) C(62)–C(63) 1.386(6) C(63)–C(64) 1.377(8) C(64)–C(65) 1.373(7) C(65)–C(66) 1.383(6) C(67)–C(68) 1.396(5) C(67)–C(72) 1.398(5) C(68)–C(69) 1.381(5) C(69)–C(70) 1.375(6) C(70)–C(71) 1.367(5) C(71)–C(72) 1.418(4) C(72)–C(73) 1.464(5) C(74)–C(75) 1.528(4) C(74)–C(79) 1.544(4) C(75)–C(76) 1.529(5) C(76)–C(77) 1.508(6) C(77)–C(78) 1.521(5) C(78)–C(79) 1.514(5) C(80)–C(81) 1.462(5) C(81)–C(82) 1.396(5) C(81)–C(86) 1.401(5) C(82)–C(83) 1.379(5) C(83)–C(84) 1.379(6) C(84)–C(85) 1.384(5) C(85)–C(86) 1.397(5) C(87)–C(92) 1.376(5) C(87)–C(88) 1.394(5) C(88)–C(89) 1.390(6) C(89)–C(90) 1.370(7) C(90)–C(91) 1.380(7) C(91)–C(92) 1.388(5) C(93)–C(94) 1.380(5) C(93)–C(98) 1.395(5) C(94)–C(95) 1.391(5) C(95)–C(96) 1.371(6) C(96)–C(97) 1.371(6) C(97)–C(98) 1.391(5) C(99)–C(103) 1.386(5) C(99)–C(100) 1.505(5)

C(100)–C(101) 1.519(6) C(101)–C(102) 1.527(6) C(102)–C(103) 1.514(5) C(103)–C(104) 1.407(5) C(105)–C(106) 1.516(6) C(105)–C(107) 1.518(6) C(105)–C(108) 1.522(5)

6 Appendix

198

Bond angles (°). Angles involving hydrogen atoms and disordered CH2Cl2 molecules are omitted:

Angle deg (°) Angle deg (°) Angle deg (°)

N(1)–Ru(1)–O(1) 167.61(9) N(1)–Ru(1)–N(2) 80.60(10) O(1)–Ru(1)–N(2) 91.28(9) N(1)–Ru(1)–O(2) 79.70(9) O(1)–Ru(1)–O(2) 90.70(8) N(2)–Ru(1)–O(2) 87.64(9) N(1)–Ru(1)–P(2) 102.30(7) O(1)–Ru(1)–P(2) 85.76(6) N(2)–Ru(1)–P(2) 82.59(7) O(2)–Ru(1)–P(2) 169.52(6) N(1)–Ru(1)–P(1) 94.59(7) O(1)–Ru(1)–P(1) 92.40(6) N(2)–Ru(1)–P(1) 172.17(7) O(2)–Ru(1)–P(1) 85.40(6) P(2)–Ru(1)–P(1) 104.58(3) N(3)–Ru(2)–O(4) 166.67(10) N(3)–Ru(2)–N(4) 81.14(10) O(4)–Ru(2)–N(4) 89.98(10) N(3)–Ru(2)–O(5) 78.64(9) O(4)–Ru(2)–O(5) 91.21(8) N(4)–Ru(2)–O(5) 88.06(9) N(3)–Ru(2)–P(4) 103.45(7) O(4)–Ru(2)–P(4) 85.10(6) N(4)–Ru(2)–P(4) 82.58(7) O(5)–Ru(2)–P(4) 169.93(7) N(3)–Ru(2)–P(3) 94.34(8) O(4)–Ru(2)–P(3) 93.48(7) N(4)–Ru(2)–P(3) 172.94(7) O(5)–Ru(2)–P(3) 85.72(7) P(4)–Ru(2)–P(3) 103.83(3) C(13)–P(1)–C(1) 104.63(14) C(13)–P(1)–C(7) 96.15(14) C(1)–P(1)–C(7) 104.28(15)

C(13)–P(1)–Ru(1) 110.81(11) C(1)–P(1)–Ru(1) 111.64(10) C(7)–P(1)–Ru(1) 126.58(10)

C(33)–P(2)–C(39) 103.78(14) C(33)–P(2)–C(32) 101.11(14) C(39)–P(2)–C(32) 102.99(14) C(33)–P(2)–Ru(1) 126.31(10) C(39)–P(2)–Ru(1) 114.78(11) C(32)–P(2)–Ru(1) 104.74(10) C(67)–P(3)–C(55) 104.41(16) C(67)–P(3)–C(61) 97.44(15) C(55)–P(3)–C(61) 104.62(16) C(67)–P(3)–Ru(2) 111.52(11) C(55)–P(3)–Ru(2) 110.32(11) C(61)–P(3)–Ru(2) 126.08(11) C(87)–P(4)–C(93) 103.87(15) C(87)–P(4)–C(86) 98.97(15) C(93)–P(4)–C(86) 105.14(15) C(87)–P(4)–Ru(2) 125.73(11) C(93)–P(4)–Ru(2) 114.63(10) C(86)–P(4)–Ru(2) 105.78(10)

F(4)–P(5)–F(1) 91.5(3)

F(4)–P(5)–F(3) 92.9(3) F(1)–P(5)–F(3) 175.5(3) F(4)–P(5)–F(2) 179.3(2) F(1)–P(5)–F(2) 88.6(3) F(3)–P(5)–F(2) 87.0(2) F(4)–P(5)–F(6) 89.0(2) F(1)–P(5)–F(6) 90.24(19) F(3)–P(5)–F(6) 88.96(18) F(2)–P(5)–F(6) 90.37(19) F(4)–P(5)–F(5) 91.24(19) F(1)–P(5)–F(5) 91.0(2) F(3)–P(5)–F(5) 89.78(19) F(2)–P(5)–F(5) 89.41(18) F(6)–P(5)–F(5) 178.7(2)

F(9)–P(6)–F(12) 179.1(2) F(9)–P(6)–F(7) 90.3(3)

F(12)–P(6)–F(7) 89.9(3) F(9)–P(6)–F(10) 91.4(3) F(12)–P(6)–F(10) 88.3(2) F(7)–P(6)–F(10) 177.6(3) F(9)–P(6)–F(11) 89.06(19) F(12)–P(6)–F(11) 91.82(19) F(7)–P(6)–F(11) 92.5(2) F(10)–P(6)–F(11) 89.2(2) F(9)–P(6)–F(8) 89.63(17)

F(12)–P(6)–F(8) 89.49(18) F(7)–P(6)–F(8) 88.26(19)

F(10)–P(6)–F(8) 90.13(18) F(11)–P(6)–F(8) 178.5(2)

C(45)–O(1)–Ru(1) 121.13(18) C(50)–O(2)–Ru(1) 123.66(19) C(50)–O(3)–C(51) 124.0(3) C(99)–O(4)–Ru(2) 120.6(2)

C(104)–O(5)–Ru(2) 123.3(2) C(104)–O(6)–C(105) 124.1(3) C(19)–N(1)–C(20) 116.9(3) C(19)–N(1)–Ru(1) 128.0(2) C(20)–N(1)–Ru(1) 112.43(18) C(26)–N(2)–C(25) 120.0(3) C(26)–N(2)–Ru(1) 129.7(2) C(25)–N(2)–Ru(1) 110.11(19) C(73)–N(3)–C(74) 116.3(3) C(73)–N(3)–Ru(2) 128.2(2) C(74)–N(3)–Ru(2) 112.38(19) C(80)–N(4)–C(79) 120.1(3) C(80)–N(4)–Ru(2) 129.9(2) C(79)–N(4)–Ru(2) 109.92(19)

C(2)–C(1)–C(6) 118.2(3) C(2)–C(1)–P(1) 119.6(2) C(6)–C(1)–P(1) 121.8(3) C(3)–C(2)–C(1) 120.9(3) C(2)–C(3)–C(4) 120.8(4) C(5)–C(4)–C(3) 118.8(3) C(4)–C(5)–C(6) 121.0(4) C(5)–C(6)–C(1) 120.3(3)

C(8)–C(7)–C(12) 119.2(3) C(8)–C(7)–P(1) 117.2(2) C(12)–C(7)–P(1) 123.0(3) C(9)–C(8)–C(7) 120.9(3)

C(8)–C(9)–C(10) 119.6(3) C(11)–C(10)–C(9) 120.1(3)

C(10)–C(11)–C(12) 120.2(4) C(11)–C(12)–C(7) 120.0(3)

C(18)–C(13)–C(14) 119.4(3) C(18)–C(13)–P(1) 123.1(2) C(14)–C(13)–P(1) 117.3(2)

C(15)–C(14)–C(13) 121.3(3) C(16)–C(15)–C(14) 119.5(3) C(17)–C(16)–C(15) 120.1(3) C(16)–C(17)–C(18) 121.5(3) C(13)–C(18)–C(17) 118.3(3) C(13)–C(18)–C(19) 128.2(3) C(17)–C(18)–C(19) 113.5(3) N(1)–C(19)–C(18) 130.8(3) N(1)–C(20)–C(21) 116.6(3) N(1)–C(20)–C(25) 106.8(2) C(21)–C(20)–C(25) 111.8(3) C(20)–C(21)–C(22) 110.3(3) C(23)–C(22)–C(21) 110.2(4) C(22)–C(23)–C(24) 110.3(3) C(23)–C(24)–C(25) 110.9(3) N(2)–C(25)–C(24) 115.1(3) N(2)–C(25)–C(20) 104.2(2) C(24)–C(25)–C(20) 111.2(3) N(2)–C(26)–C(27) 124.6(3) C(28)–C(27)–C(32) 120.1(3) C(28)–C(27)–C(26) 116.6(3) C(32)–C(27)–C(26) 122.8(3) C(27)–C(28)–C(29) 120.1(3) C(30)–C(29)–C(28) 120.3(3) C(29)–C(30)–C(31) 120.2(3) C(32)–C(31)–C(30) 120.7(3) C(31)–C(32)–C(27) 118.6(3) C(31)–C(32)–P(2) 121.1(2) C(27)–C(32)–P(2) 120.3(2)

C(38)–C(33)–C(34) 119.0(3) C(38)–C(33)–P(2) 118.7(2) C(34)–C(33)–P(2) 122.2(2)

C(35)–C(34)–C(33) 119.9(3) C(36)–C(35)–C(34) 120.7(3) C(35)–C(36)–C(37) 119.7(3) C(38)–C(37)–C(36) 120.0(3) C(33)–C(38)–C(37) 120.8(3) C(40)–C(39)–C(44) 118.7(3) C(40)–C(39)–P(2) 121.9(3) C(44)–C(39)–P(2) 119.0(3)

C(39)–C(40)–C(41) 120.2(4) C(42)–C(41)–C(40) 120.5(4) C(41)–C(42)–C(43) 119.9(4) C(42)–C(43)–C(44) 120.0(4)

6 Appendix

199

C(43)–C(44)–C(39) 120.7(4) O(1)–C(45)–C(49) 131.6(3) O(1)–C(45)–C(46) 118.4(3) C(49)–C(45)–C(46) 110.0(3) C(45)–C(46)–C(47) 105.2(3) C(48)–C(47)–C(46) 108.3(3) C(47)–C(48)–C(49) 104.6(3) C(45)–C(49)–C(50) 125.3(3) C(45)–C(49)–C(48) 111.7(3) C(50)–C(49)–C(48) 122.9(3) O(2)–C(50)–O(3) 120.0(3) O(2)–C(50)–C(49) 127.0(3) O(3)–C(50)–C(49) 113.0(3) O(3)–C(51)–C(53) 110.7(3) O(3)–C(51)–C(54) 101.4(3) C(53)–C(51)–C(54) 110.6(4) O(3)–C(51)–C(52) 110.7(3) C(53)–C(51)–C(52) 112.0(4) C(54)–C(51)–C(52) 110.9(4) C(56)–C(55)–C(60) 118.6(3) C(56)–C(55)–P(3) 118.6(3) C(60)–C(55)–P(3) 122.2(3)


C(61)–C(62)–C(63) 119.9(4) C(64)–C(63)–C(62) 120.9(5) C(65)–C(64)–C(63) 119.7(4) C(64)–C(65)–C(66) 119.6(4)

C(65)–C(66)–C(61) 121.3(4) C(68)–C(67)–C(72) 118.6(3) C(68)–C(67)–P(3) 118.4(3) C(72)–C(67)–P(3) 123.0(2)


C(92)–C(87)–C(88) 120.0(3)

C(92)–C(87)–P(4) 117.3(3) C(88)–C(87)–P(4) 121.7(3)


C(93)–C(94)–C(95) 120.1(3) C(96)–C(95)–C(94) 120.6(4) C(97)–C(96)–C(95) 119.9(4) C(96)–C(97)–C(98) 120.1(4) C(97)–C(98)–C(93) 120.3(4) O(4)–C(99)–C(103) 131.7(3) O(4)–C(99)–C(100) 118.1(3) C(103)–C(99)–C(100) 110.2(3) C(99)–C(100)–C(101) 105.1(3)

C(100)–C(101)–C(102) 106.7(3) C(103)–C(102)–C(101) 103.9(3) C(99)–C(103)–C(104) 125.3(3) C(99)–C(103)–C(102) 110.8(3)

C(104)–C(103)–C(102) 123.7(3) O(5)–C(104)–O(6) 119.9(3)

O(5)–C(104)–C(103) 126.8(3) O(6)–C(104)–C(103) 113.3(3) O(6)–C(105)–C(106) 110.7(3) O(6)–C(105)–C(107) 112.2(3)

C(106)–C(105)–C(107) 112.4(3) O(6)–C(105)–C(108) 101.7(3)

C(106)–C(105)–C(108) 109.7(3) C(107)–C(105)–C(108) 109.6(4)

6.3.2 β-Keto Acid Complex 14


Empirical formula C50H48BF6N2O5P3Ru Formula weight 1075.69 Temperature 200(2) K Wavelength 0.71073 Å Crystal system, space group Monoclinic, P21/n Unit cell dimensions a = 12.0460(5) Å alpha = 90° b = 20.6031(9) Å beta = 92.7020(10)°

c = 20.3481(9) Å gamma = 90° Volume 5044.5(4) Å3 Z, Calculated density 4, 1.416 Mg/m3 Absorption coefficient 0.475 mm−1 F(000) 2200 Crystal size 0.475 x 0.475 x 0.321 mm Theta range for data collection 1.41 to 26.03° Limiting indices −14<=h<=14, −25<=k<=25, −25<=l<=25

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Reflections collected / unique 44016 / 9948 [R(int) = 0.0385] Completeness to theta = 26.03 99.9% Refinement method Full-matrix least-squares on F^2 Data / restraints / parameters 9948 / 9 / 736 Goodness-of-fit on F2 1.116 Final R indices [I>2sigma(I)] R1 = 0.0545, wR2 = 0.1548 R indices (all data) R1 = 0.0631, wR2 = 0.1606 Largest diff. peak and hole 0.921 and -0.466 e·Å−3

Atomic coordinates (x 104) and equivalent isotropic displacement parameters Ueq (Å2 x 103):


Ru(1) 4328(1) 2172(1) 2107(1) 29(1) P(1) 6076(1) 1748(1) 2314(1) 34(1) P(2) 3943(1) 1940(1) 1032(1) 35(1) N(1) 3556(2) 1431(2) 2574(2) 33(1) N(2) 2702(3) 2530(2) 2059(2) 33(1) O(1) 5023(2) 3045(1) 1780(2) 43(1) O(2) 4519(2) 2573(2) 3090(2) 45(1) O(3) 4726(4) 3334(3) 3863(2) 96(2) C(1) 7017(3) 2388(2) 2636(2) 40(1) C(2) 7492(4) 2810(2) 2196(3) 53(1) C(3) 8153(4) 3327(3) 2429(3) 64(2) C(4) 8312(4) 3428(3) 3093(3) 65(2) C(5) 7815(4) 3023(3) 3531(3) 59(1) C(6) 7168(3) 2500(2) 3304(2) 46(1) C(7) 6883(4) 1281(2) 1737(2) 46(1) C(8) 6371(4) 744(2) 1452(3) 57(1) C(9) 6955(6) 336(3) 1060(3) 79(2) C(10) 8051(6) 456(4) 961(4) 100(3) C(11) 8560(5) 975(4) 1248(4) 96(3) C(12) 8002(4) 1392(3) 1638(3) 68(2) C(13) 6087(3) 1134(2) 2958(2) 40(1) C(14) 7115(4) 895(2) 3195(3) 52(1) C(15) 7188(4) 371(3) 3625(3) 63(1) C(16) 6239(5) 82(3) 3827(3) 68(2) C(17) 5218(4) 314(2) 3599(3) 59(1) C(18) 5123(4) 841(2) 3164(2) 42(1) C(19) 3969(3) 1013(2) 2980(2) 41(1) C(20) 2306(3) 1508(2) 2546(2) 38(1) C(21) 1689(4) 1131(2) 3066(3) 50(1) C(22) 451(4) 1284(3) 3016(3) 62(1) C(23) 242(4) 2002(2) 3084(3) 58(1) C(24) 810(3) 2369(2) 2553(3) 49(1) C(25) 2065(3) 2235(2) 2590(2) 38(1) C(26) 2226(4) 2903(2) 1633(2) 41(1) C(27) 2729(4) 3117(2) 1031(2) 45(1) C(28) 2411(5) 3722(3) 783(3) 64(1) C(29) 2802(7) 3939(3) 203(3) 89(2) C(30) 3491(7) 3554(3) -145(3) 91(2) C(31) 3808(5) 2942(3) 90(3) 64(1) C(32) 3446(4) 2720(2) 683(2) 43(1) C(33) 4979(4) 1703(2) 457(2) 44(1) C(34) 4805(4) 1220(3) -8(2) 57(1)

C(35) 5602(5) 1094(4) -463(3) 75(2) C(36) 6563(5) 1433(4) -448(3) 80(2) C(37) 6755(5) 1906(4) 16(3) 76(2) C(38) 5967(4) 2053(3) 467(3) 57(1) C(39) 2816(3) 1365(2) 848(2) 38(1) C(40) 1885(4) 1509(3) 446(2) 49(1) C(41) 1092(4) 1034(3) 310(3) 60(1) C(42) 1218(4) 421(3) 571(3) 60(1) C(43) 2136(4) 269(2) 973(3) 54(1) C(44) 2935(4) 745(2) 1108(2) 48(1) C(45) 5045(4) 3558(2) 2089(3) 54(1) C(46) 5557(5) 4146(2) 1817(4) 78(2) C(47) 5305(7) 4663(3) 2397(5) 114(3) C(48) 5153(6) 4311(3) 3019(4) 85(2) C(49) 4581(4) 3688(3) 2754(3) 66(2) C(50) 4619(4) 3149(3) 3227(3) 57(1) B(1) 1417(5) 4294(3) 2618(3) 49(1) F(1) 2194(3) 4653(2) 2309(2) 102(1) F(2) 703(3) 4016(2) 2149(2) 71(1) F(3) 1981(3) 3810(1) 2981(2) 62(1) F(4) 809(3) 4671(2) 3022(2) 83(1) P(3) 4519(2) 1855(1) 4984(2) 83(1) F(5) 4783(15) 1918(17) 5755(10) 137(9) F(6) 3380(9) 1695(5) 4762(6) 205(5) O(6) 4810(19) 2434(9) 4788(6) 101(7) O(5) 5520(20) 1587(19) 4675(10) 204(16) F(5') 4408(13) 2059(17) 5712(8) 140(9) O(5') 5003(12) 1200(6) 5028(10) 93(5) O(6') 5010(20) 2259(9) 4566(8) 121(9) B(4) 2389(14) 1261(10) 5030(9) 30(5) P(4) 2389(14) 1261(10) 5030(9) 30(5) F(7) 2612(5) 660(3) 4722(3) 81(2) F(8) 1229(6) 1456(3) 4661(3) 104(3) F(9) 2415(17) 1272(15) 5672(13) 45(7) F(7') 2612(5) 660(3) 4722(3) 81(2) F(8') 1229(6) 1456(3) 4661(3) 104(3) P(5) 1710(20) 958(12) 5055(8) 137(11) O(8) 1980(30) 1292(15) 5689(11) 88(12) O(9) 880(30) 464(19) 4870(30) 310(60) P(5') 1350(9) 718(8) 4829(6) 75(4) O(8') 1002(16) 398(11) 5370(8) 73(6) O(9') 630(20) 381(18) 4304(12) 122(12)

6 Appendix

201

Bond lengths (Å). Calculated distances to hydrogen atoms are omitted:


Ru(1)–N(1) 2.046(3) Ru(1)–N(2) 2.091(3) Ru(1)–O(1) 2.106(3) Ru(1)–O(2) 2.168(3) Ru(1)–P(2) 2.2651(10) Ru(1)–P(1) 2.2994(10) P(1)–C(13) 1.821(5) P(1)–C(7) 1.833(4) P(1)–C(1) 1.837(4)

P(2)–C(33) 1.818(4) P(2)–C(39) 1.827(4) P(2)–C(32) 1.844(4) N(1)–C(19) 1.277(5) N(1)–C(20) 1.512(5) N(2)–C(26) 1.274(5) N(2)–C(25) 1.484(5) O(1)–C(45) 1.230(6) O(2)–C(50) 1.224(6) O(3)–C(50) 1.348(7) C(1)–C(6) 1.383(6) C(1)–C(2) 1.392(7) C(2)–C(3) 1.399(7) C(3)–C(4) 1.371(8) C(4)–C(5) 1.378(8) C(5)–C(6) 1.397(7) C(7)–C(8) 1.379(7) C(7)–C(12) 1.392(7) C(8)–C(9) 1.375(7) C(9)–C(10) 1.368(10)

C(10)–C(11) 1.351(11)

C(11)–C(12) 1.367(8) C(13)–C(18) 1.390(6) C(13)–C(14) 1.397(6) C(14)–C(15) 1.388(7) C(15)–C(16) 1.370(8) C(16)–C(17) 1.379(7) C(17)–C(18) 1.403(6) C(18)–C(19) 1.466(6) C(20)–C(25) 1.529(6) C(20)–C(21) 1.532(6) C(21)–C(22) 1.523(6) C(22)–C(23) 1.510(7) C(23)–C(24) 1.509(7) C(24)–C(25) 1.535(5) C(26)–C(27) 1.460(7) C(27)–C(28) 1.392(6) C(27)–C(32) 1.405(6) C(28)–C(29) 1.368(8) C(29)–C(30) 1.370(9) C(30)–C(31) 1.396(8) C(31)–C(32) 1.381(7) C(33)–C(34) 1.382(7) C(33)–C(38) 1.392(7) C(34)–C(35) 1.389(7) C(35)–C(36) 1.352(9) C(36)–C(37) 1.368(9) C(37)–C(38) 1.385(8) C(39)–C(40) 1.388(6) C(39)–C(44) 1.389(6) C(40)–C(41) 1.386(7)


B(1)–F(4) 1.368(6) B(1)–F(1) 1.369(6) B(1)–F(2) 1.379(6) B(1)–F(3) 1.398(6) P(3)–O(6) 1.310(17) P(3)–O(6') 1.347(14) P(3)–F(6) 1.461(10) P(3)–O(5') 1.472(14) P(3)–O(5) 1.489(18) P(3)–F(5') 1.551(17) P(3)–F(5) 1.59(2) F(6)–B(4) 1.606(16) B(4)–F(9) 1.31(3) B(4)–F(7) 1.42(2) B(4)–F(8) 1.605(19) P(5)–O(9) 1.46(2) P(5)–O(8) 1.485(19) P(5')–O(8') 1.37(2) P(5')–O(9') 1.51(3)

Bond angles (°). Angles involving hydrogen atoms are omitted:


N(1)–Ru(1)–N(2) 80.74(12) N(1)–Ru(1)–O(1) 168.81(12) N(2)–Ru(1)–O(1) 93.96(12) N(1)–Ru(1)–O(2) 83.44(13) N(2)–Ru(1)–O(2) 88.06(12) O(1)–Ru(1)–O(2) 86.55(12) N(1)–Ru(1)–P(2) 102.39(9) N(2)–Ru(1)–P(2) 83.13(9) O(1)–Ru(1)–P(2) 86.63(9) O(2)–Ru(1)–P(2) 168.46(9) N(1)–Ru(1)–P(1) 93.68(9) N(2)–Ru(1)–P(1) 171.81(10) O(1)–Ru(1)–P(1) 90.48(8) O(2)–Ru(1)–P(1) 85.34(8) P(2)–Ru(1)–P(1) 104.02(4) C(13)–P(1)–C(7) 96.3(2) C(13)–P(1)–C(1) 105.0(2) C(7)–P(1)–C(1) 105.6(2)

C(13)–P(1)–Ru(1) 111.80(14) C(7)–P(1)–Ru(1) 126.15(15) C(1)–P(1)–Ru(1) 109.71(13)

C(33)–P(2)–C(39) 102.7(2) C(33)–P(2)–C(32) 102.0(2) C(39)–P(2)–C(32) 105.2(2) C(33)–P(2)–Ru(1) 124.21(14) C(39)–P(2)–Ru(1) 116.79(14) C(32)–P(2)–Ru(1) 103.65(15) C(19)–N(1)–C(20) 116.8(3) C(19)–N(1)–Ru(1) 129.2(3) C(20)–N(1)–Ru(1) 112.2(2) C(26)–N(2)–C(25) 120.7(3) C(26)–N(2)–Ru(1) 129.4(3) C(25)–N(2)–Ru(1) 109.7(2) C(45)–O(1)–Ru(1) 124.9(3) C(50)–O(2)–Ru(1) 125.8(4)

C(6)–C(1)–C(2) 119.3(4)

C(6)–C(1)–P(1) 121.3(4) C(2)–C(1)–P(1) 119.1(3) C(1)–C(2)–C(3) 120.2(5) C(4)–C(3)–C(2) 120.0(5) C(3)–C(4)–C(5) 120.1(5) C(4)–C(5)–C(6) 120.4(5) C(1)–C(6)–C(5) 120.0(5)

C(8)–C(7)–C(12) 119.2(4) C(8)–C(7)–P(1) 116.8(4) C(12)–C(7)–P(1) 123.6(4) C(9)–C(8)–C(7) 120.2(5)

C(10)–C(9)–C(8) 119.9(6) C(11)–C(10)–C(9) 120.0(6)

C(10)–C(11)–C(12) 121.5(6) C(11)–C(12)–C(7) 119.1(6)

C(18)–C(13)–C(14) 118.8(4) C(18)–C(13)–P(1) 122.7(3) C(14)–C(13)–P(1) 118.0(4)

6 Appendix

202


C(34)–C(33)–C(38) 119.1(4) C(34)–C(33)–P(2) 123.2(4)

C(38)–C(33)–P(2) 117.6(4) C(33)–C(34)–C(35) 120.2(5) C(36)–C(35)–C(34) 120.4(6) C(35)–C(36)–C(37) 120.1(5) C(36)–C(37)–C(38) 120.9(6) C(37)–C(38)–C(33) 119.3(5) C(40)–C(39)–C(44) 119.2(4) C(40)–C(39)–P(2) 123.6(4) C(44)–C(39)–P(2) 117.2(3)

C(41)–C(40)–C(39) 119.7(5) C(42)–C(41)–C(40) 120.6(4) C(41)–C(42)–C(43) 120.6(5) C(42)–C(43)–C(44) 118.9(5) C(39)–C(44)–C(43) 121.0(4) O(1)–C(45)–C(46) 120.7(5) O(1)–C(45)–C(49) 127.6(5) C(46)–C(45)–C(49) 111.7(5) C(45)–C(46)–C(47) 99.7(5) C(48)–C(47)–C(46) 109.6(5) C(47)–C(48)–C(49) 100.4(6) C(50)–C(49)–C(45) 116.8(4) C(50)–C(49)–C(48) 113.6(5) C(45)–C(49)–C(48) 106.3(5) O(2)–C(50)–O(3) 119.8(6) O(2)–C(50)–C(49) 125.7(5) O(3)–C(50)–C(49) 114.4(5)

F(4)–B(1)–F(1) 111.5(5) F(4)–B(1)–F(2) 108.5(5) F(1)–B(1)–F(2) 108.8(5) F(4)–B(1)–F(3) 110.4(4) F(1)–B(1)–F(3) 107.6(4)

F(2)–B(1)–F(3) 110.0(4) O(6)–P(3)–O(6') 27.5(9) O(6)–P(3)–F(6) 111.9(11) O(6')–P(3)–F(6) 112.3(12) O(6)–P(3)–O(5') 137.9(12) O(6')–P(3)–O(5') 114.8(10) F(6)–P(3)–O(5') 100.1(8) O(6)–P(3)–O(5) 88.6(18) O(6')–P(3)–O(5) 64.8(17) F(6)–P(3)–O(5) 123.4(13) O(5')–P(3)–O(5) 50.2(15) O(6)–P(3)–F(5') 94.7(14) O(6')–P(3)–F(5') 119.7(16) F(6)–P(3)–F(5') 103.5(9) O(5')–P(3)–F(5') 104.0(13) O(5)–P(3)–F(5') 127.7(9) O(6)–P(3)–F(5) 100.5(14) O(6')–P(3)–F(5) 119.9(16) F(6)–P(3)–F(5) 117.7(10) O(5')–P(3)–F(5) 87.4(13) O(5)–P(3)–F(5) 108.6(10) F(5')–P(3)–F(5) 19.8(10) P(3)–F(6)–B(4) 136.3(11) F(9)–B(4)–F(7) 117(2) F(9)–B(4)–F(8) 116.2(16) F(7)–B(4)–F(8) 101.0(11) F(9)–B(4)–F(6) 110.3(17) F(7)–B(4)–F(6) 100.1(13) F(8)–B(4)–F(6) 110.3(11) O(9)–P(5)–O(8) 131(3)

O(8')–P(5')–O(9') 99.3(14)

Hydrogen bond between O(3) and O(6):

D–H...A d(D–H) (Å) d(H...A) (Å) d(D...A) (Å) Angle D–H–A (°)

O(3)–H(3A)…O(6) 1.135(16) 1.515(18) 2.641(17) 170(8) O(3)–H(3A)…O(6') 1.135(16) 1.551(19) 2.651(17) 161(6)

6.3.3 Camphanic Acid Ester 18


Empirical formula C20H29FO6 Formula weight 384.43 Temperature 293(2) K Wavelength 0.71073 Å Crystal system, space group Orthorhombic, P 21 21 21 Unit cell dimensions a = 6.4686(11) Å alpha = 90°

b = 13.640(2) Å beta = 90° c = 23.973(4) Å gamma = 90°

Volume 2115.1(6) Å3 Z, Calculated density 4, 1.207 Mg/m3 Absorption coefficient 0.094 mm−1

6 Appendix

203

F(000) 824 Crystal size 0.82 x 0.41 x 0.34 mm Theta range for data collection 1.70 to 24.71° Limiting indices −7<=h<=7, −15<=k<=16, −23<=l<=28 Reflections collected / unique 10879 / 3603 [R(int) = 0.0196] Completeness to theta = 24.71 100.0% Absorption correction None Max. and min. transmission 0.9689 and 0.9272 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3603 / 0 / 250 Goodness-of-fit on F2 1.036 Final R indices [I>2sigma(I)] R1 = 0.0394, wR2 = 0.1047 R indices (all data) R1 = 0.0459, wR2 = 0.1101 Absolute structure parameter 0.2(9) Largest diff. peak and hole 0.150 and −0.140 e·Å−3

Atomic coordinates (x 104) and equivalent isotropic displacement parameters Ueq (Å2 x 103):


F(1) 9004(2) 3469(1) 10123(1) 83(1) O(1) 6969(2) 5099(1) 10278(1) 66(1) O(2) 4502(3) 4483(2) 9731(1) 92(1) O(3) 8399(2) 5021(1) 8950(1) 53(1) O(4) 11043(2) 6048(1) 8853(1) 89(1) O(5) 9000(3) 7196(1) 8147(1) 64(1) O(6) 8572(4) 8186(1) 7412(1) 115(1) C(1) 9599(3) 4397(1) 9325(1) 47(1) C(2) 10683(3) 3598(2) 9007(1) 65(1) C(3) 9138(5) 2790(2) 8936(1) 94(1) C(4) 7276(4) 3034(2) 9285(1) 75(1) C(5) 7951(3) 3858(1) 9664(1) 51(1) C(6) 6243(3) 4506(2) 9891(1) 54(1) C(7) 5666(4) 5813(2) 10581(1) 67(1)

C(8) 4777(6) 6555(2) 10182(1) 100(1) C(9) 7193(6) 6270(2) 10979(1) 107(1) C(10) 3970(6) 5278(2) 10896(1) 101(1) C(11) 9318(3) 5807(1) 8741(1) 48(1) C(12) 7909(3) 6323(1) 8342(1) 47(1) C(13) 8024(4) 7469(2) 7666(1) 69(1) C(14) 6326(3) 6757(2) 7562(1) 62(1) C(15) 5499(5) 6783(2) 6967(1) 94(1) C(16) 4755(4) 7033(2) 8028(1) 87(1) C(17) 5855(4) 6714(2) 8568(1) 75(1) C(18) 7351(3) 5816(1) 7786(1) 56(1) C(19) 9253(5) 5504(2) 7460(1) 93(1) C(20) 5855(5) 4955(2) 7851(1) 108(1)

Bond lengths (Å). Calculated distances to hydrogen atoms are omitted:


F(1)–C(5) 1.400(2) O(1)–C(6) 1.318(2) O(1)–C(7) 1.478(3) O(2)–C(6) 1.190(3) O(3)–C(11) 1.324(2) O(3)–C(1) 1.462(2) O(4)–C(11) 1.194(2) O(5)–C(13) 1.367(3) O(5)–C(12) 1.460(2) O(6)–C(13) 1.206(3)


C(11)–C(12) 1.498(3)


6 Appendix

204

Bond angles (°). Angles involving hydrogen atoms are omitted:


C(6)–O(1)–C(7) 123.18(17) C(11)–O(3)–C(1) 117.78(14) C(13)–O(5)–C(12) 105.58(16) O(3)–C(1)–C(2) 110.86(16) O(3)–C(1)–C(5) 103.70(14) C(2)–C(1)–C(5) 104.24(16) C(3)–C(2)–C(1) 106.20(18) C(2)–C(3)–C(4) 108.0(2) C(3)–C(4)–C(5) 105.5(2) F(1)–C(5)–C(4) 109.43(17) F(1)–C(5)–C(6) 107.03(15) C(4)–C(5)–C(6) 116.08(18) F(1)–C(5)–C(1) 105.09(15) C(4)–C(5)–C(1) 103.93(16) C(6)–C(5)–C(1) 114.72(15) O(2)–C(6)–O(1) 125.4(2) O(2)–C(6)–C(5) 123.95(19)

O(1)–C(6)–C(5) 110.59(17) O(1)–C(7)–C(8) 110.41(19) O(1)–C(7)–C(9) 102.1(2) C(8)–C(7)–C(9) 111.9(2)

O(1)–C(7)–C(10) 109.88(19) C(8)–C(7)–C(10) 111.3(3) C(9)–C(7)–C(10) 110.9(2) O(4)–C(11)–O(3) 123.93(18) O(4)–C(11)–C(12) 125.59(18) O(3)–C(11)–C(12) 110.47(15) O(5)–C(12)–C(11) 107.09(15) O(5)–C(12)–C(17) 104.42(17) C(11)–C(12)–C(17) 117.73(16) O(5)–C(12)–C(18) 101.67(14) C(11)–C(12)–C(18) 118.89(16) C(17)–C(12)–C(18) 104.98(17) O(6)–C(13)–O(5) 120.8(2)

O(6)–C(13)–C(14) 131.5(2) O(5)–C(13)–C(14) 107.76(16) C(13)–C(14)–C(15) 113.7(2) C(13)–C(14)–C(18) 99.63(17) C(15)–C(14)–C(18) 119.8(2) C(13)–C(14)–C(16) 101.7(2) C(15)–C(14)–C(16) 115.9(2) C(18)–C(14)–C(16) 103.41(16) C(17)–C(16)–C(14) 103.49(19) C(12)–C(17)–C(16) 101.64(17) C(19)–C(18)–C(20) 110.5(2) C(19)–C(18)–C(14) 113.73(18) C(20)–C(18)–C(14) 113.75(19) C(19)–C(18)–C(12) 112.34(17) C(20)–C(18)–C(12) 113.78(19) C(14)–C(18)–C(12) 91.66(15)

6.3.4 α-Alkylidene-β-keto Ester Complex 19


Empirical formula C54H54F12N2O3P4Ru,

2 (CH2Cl2) Formula weight 1401.79 Temperature 200(2) K Wavelength 0.71073 Å Crystal system, space group Triclinic, P−1 Unit cell dimensions a = 11.5110(7) Å alpha = 96.8860(10)°

b = 13.8903(8) Å beta = 93.7550(10)° c = 20.6616(12) Å gamma = 113.0850(10)°

Volume 2994.2(3) Å3 Z, Calculated density 2, 1.555 Mg/m3 Absorption coefficient 0.630 mm−1 F(000) 1424 Crystal size 0.55 x 0.17 x 0.16 mm Theta range for data collection 1.00 to 26.02° Limiting indices −14<=h<=14, −17<=k<=16, −25<=l<=25 Reflections collected / unique 26500 / 11770 [R(int) = 0.0252] Completeness to theta = 26.02 99.7% Absorption correction Empirical Max. and min. transmission 0.9060 and 0.7221 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 11770 / 0 / 739 Goodness-of-fit on F2 1.021 Final R indices [I>2sigma(I)] R1 = 0.0504, wR2 = 0.1290 R indices (all data) R1 = 0.0559, wR2 = 0.1337 Largest diff. peak and hole 1.260 and -0.758 e·Å−3

6 Appendix

205

Atomic coordinates (x 104) and equivalent isotropic displacement parameters Ueq (Å2 x 103). CH2Cl2

molecules are omitted:


Ru(1) 208(1) 2035(1) 2824(1) 20(1) P(1) 765(1) 1210(1) 1941(1) 22(1) P(2) 285(1) 1082(1) 3632(1) 25(1) O(1) –1744(2) 1045(2) 2600(1) 26(1) O(2) –73(2) 3053(2) 2165(1) 25(1) O(3) –1160(2) 3637(2) 1489(1) 34(1) N(1) 1957(2) 3275(2) 3026(1) 23(1) N(2) –172(2) 2962(2) 3580(1) 26(1) C(1) –461(3) 822(3) 1237(2) 27(1) C(2) –362(4) 1468(3) 762(2) 35(1) C(3) –1374(4) 1249(4) 282(2) 49(1) C(4) –2485(4) 383(4) 275(2) 52(1) C(5) –2605(4) –272(3) 737(2) 48(1) C(6) –1604(3) –56(3) 1223(2) 37(1) C(7) 1223(3) 96(3) 1959(2) 28(1) C(8) 715(4) –827(3) 1505(2) 39(1) C(9) 1191(5) –1602(3) 1538(2) 48(1) C(10) 2152(4) –1463(3) 2012(2) 47(1) C(11) 2676(4) –540(3) 2465(2) 41(1) C(12) 2211(3) 239(3) 2435(2) 34(1) C(13) 2202(3) 2105(3) 1656(2) 27(1) C(14) 2554(3) 1751(3) 1074(2) 33(1) C(15) 3652(4) 2355(3) 834(2) 40(1) C(16) 4435(4) 3336(3) 1187(2) 42(1) C(17) 4118(3) 3702(3) 1770(2) 37(1) C(18) 2999(3) 3092(3) 2020(2) 27(1) C(19) 2835(3) 3591(3) 2652(2) 28(1) C(20) 2041(3) 4046(3) 3627(2) 27(1) C(21) 3090(3) 5149(3) 3688(2) 33(1) C(22) 3035(4) 5865(3) 4299(2) 39(1) C(23) 1751(4) 5925(3) 4270(2) 41(1) C(24) 694(4) 4825(3) 4235(2) 38(1) C(25) 723(3) 4087(3) 3633(2) 28(1) C(26) –994(3) 2679(3) 3982(2) 32(1) C(27) –1732(3) 1577(3) 4057(2) 33(1) C(28) –2921(4) 1336(4) 4275(2) 45(1) C(29) –3638(4) 321(4) 4393(2) 54(1) C(30) –3147(4) –435(4) 4331(2) 50(1)

C(31) –1950(4) –199(3) 4125(2) 40(1) C(32) –1241(3) 802(3) 3974(2) 30(1) C(33) 328(3) –229(3) 3525(2) 29(1) C(34) 1095(4) –494(3) 3953(2) 35(1) C(35) 1056(4) –1510(3) 3874(2) 45(1) C(36) 228(4) –2272(3) 3368(2) 50(1) C(37) –533(4) –2017(3) 2944(2) 46(1) C(38) –482(3) –996(3) 3016(2) 36(1) C(39) 1522(3) 1844(3) 4312(2) 29(1) C(40) 1250(4) 2190(3) 4917(2) 38(1) C(41) 2235(4) 2903(4) 5390(2) 51(1) C(42) 3466(4) 3246(4) 5253(2) 53(1) C(43) 3761(4) 2885(3) 4663(2) 44(1) C(44) 2790(3) 2185(3) 4193(2) 34(1) C(45) –2526(3) 1226(3) 2254(2) 28(1) C(46) –3926(3) 543(3) 2161(2) 43(1) C(47) –4504(4) 1022(4) 1671(2) 51(1) C(48) –3412(3) 1955(3) 1539(2) 39(1) C(49) –2305(3) 2087(3) 1868(2) 29(1) C(50) –1076(3) 2961(2) 1857(2) 25(1) C(51) –50(4) 4620(3) 1389(2) 39(1) C(52) 539(6) 5321(3) 2038(2) 66(1) C(53) 864(5) 4294(4) 1030(3) 62(1) C(54) –691(5) 5111(4) 955(2) 60(1) P(3) 3717(1) 7245(1) 613(1) 46(1) F(1) 3990(4) 8382(3) 970(3) 139(2) F(2) 3515(4) 6124(3) 279(3) 132(2) F(3) 2270(3) 6996(3) 465(2) 82(1) F(4) 3400(4) 6816(4) 1283(2) 116(1) F(5) 5175(3) 7473(3) 780(3) 120(2) F(6) 4060(5) 7751(5) –13(2) 144(2) P(4) 6750(1) 3977(1) 3312(1) 66(1) F(7) 5856(6) 4500(5) 3514(3) 163(2) F(8) 7748(8) 3584(8) 3133(2) 245(5) F(9) 6545(5) 4056(6) 2576(2) 174(3)

F(10) 5640(10) 2959(6) 3157(4) 282(6) F(11) 6956(5) 3823(5) 4040(2) 135(2) F(12) 7835(9) 5069(7) 3478(5) 276(5)

Bond lengths (Å). Calculated distances to hydrogen atoms and CH2Cl2 molecules are omitted:


Ru(1)–N(1) 2.047(3) Ru(1)–N(2) 2.083(3) Ru(1)–O(1) 2.107(2) Ru(1)–O(2) 2.172(2) Ru(1)–P(2) 2.2692(8) Ru(1)–P(1) 2.2973(8) P(1)–C(13) 1.821(3) P(1)–C(7) 1.823(3) P(1)–C(1) 1.828(3)

P(2)–C(39) 1.823(3) P(2)–C(33) 1.829(3) P(2)–C(32) 1.851(3) O(1)–C(45) 1.235(4) O(2)–C(50) 1.235(4) O(3)–C(50) 1.305(4) O(3)–C(51) 1.508(4) N(1)–C(19) 1.284(4) N(1)–C(20) 1.511(4)

N(2)–C(26) 1.277(4) N(2)–C(25) 1.482(4) C(1)–C(2) 1.389(5) C(1)–C(6) 1.395(5) C(2)–C(3) 1.389(5) C(3)–C(4) 1.367(7) C(4)–C(5) 1.373(7) C(5)–C(6) 1.391(5) C(7)–C(8) 1.385(5)

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206

C(7)–C(12) 1.388(5) C(8)–C(9) 1.393(5) C(9)–C(10) 1.367(6)

C(10)–C(11) 1.384(6) C(11)–C(12) 1.389(5) C(13)–C(14) 1.391(5) C(13)–C(18) 1.401(5) C(14)–C(15) 1.377(5) C(15)–C(16) 1.383(6) C(16)–C(17) 1.378(5) C(17)–C(18) 1.407(5) C(18)–C(19) 1.462(4) C(20)–C(21) 1.518(5) C(20)–C(25) 1.541(4) C(21)–C(22) 1.532(5) C(22)–C(23) 1.511(5) C(23)–C(24) 1.524(5) C(24)–C(25) 1.525(4) C(26)–C(27) 1.464(5) C(27)–C(28) 1.395(5)

C(27)–C(32) 1.398(5) C(28)–C(29) 1.388(6) C(29)–C(30) 1.372(7) C(30)–C(31) 1.393(5) C(31)–C(32) 1.394(5) C(33)–C(34) 1.389(5) C(33)–C(38) 1.390(5) C(34)–C(35) 1.385(5) C(35)–C(36) 1.391(6) C(36)–C(37) 1.370(6) C(37)–C(38) 1.385(5) C(39)–C(40) 1.384(5) C(39)–C(44) 1.396(5) C(40)–C(41) 1.400(5) C(41)–C(42) 1.368(6) C(42)–C(43) 1.377(6) C(43)–C(44) 1.384(5) C(45)–C(49) 1.465(5) C(45)–C(46) 1.500(5) C(46)–C(47) 1.527(5)

C(47)–C(48) 1.478(5) C(48)–C(49) 1.339(5) C(49)–C(50) 1.463(5) C(51)–C(53) 1.502(6) C(51)–C(52) 1.502(6) C(51)–C(54) 1.506(5)

P(3)–F(6) 1.545(4) P(3)–F(2) 1.546(4) P(3)–F(1) 1.561(4) P(3)–F(3) 1.563(3) P(3)–F(4) 1.580(4) P(3)–F(5) 1.586(3) P(4)–F(10) 1.469(7) P(4)–F(8) 1.501(4) P(4)–F(12) 1.520(7) P(4)–F(7) 1.526(4) P(4)–F(9) 1.548(4) P(4)–F(11) 1.559(4)

Bond angles (°). Angles involving hydrogen atoms and CH2Cl2 molecules are omitted:


N(1)–Ru(1)–N(2) 80.72(10) N(1)–Ru(1)–O(1) 166.46(9) N(2)–Ru(1)–O(1) 90.85(9) N(1)–Ru(1)–O(2) 80.70(9) N(2)–Ru(1)–O(2) 87.67(9) O(1)–Ru(1)–O(2) 88.44(8) N(1)–Ru(1)–P(2) 101.44(7) N(2)–Ru(1)–P(2) 82.43(8) O(1)–Ru(1)–P(2) 87.81(6) O(2)–Ru(1)–P(2) 169.35(6) N(1)–Ru(1)–P(1) 93.86(7) N(2)–Ru(1)–P(1) 172.70(8) O(1)–Ru(1)–P(1) 93.54(6) O(2)–Ru(1)–P(1) 86.62(6) P(2)–Ru(1)–P(1) 103.55(3) C(13)–P(1)–C(7) 97.40(15) C(13)–P(1)–C(1) 104.44(15) C(7)–P(1)–C(1) 106.12(15)

C(13)–P(1)–Ru(1) 111.76(11) C(7)–P(1)–Ru(1) 124.85(11) C(1)–P(1)–Ru(1) 110.06(10)

C(39)–P(2)–C(33) 104.28(15) C(39)–P(2)–C(32) 105.47(15) C(33)–P(2)–C(32) 101.33(16) C(39)–P(2)–Ru(1) 113.09(11) C(33)–P(2)–Ru(1) 126.32(11) C(32)–P(2)–Ru(1) 104.07(11) C(45)–O(1)–Ru(1) 125.4(2) C(50)–O(2)–Ru(1) 128.1(2) C(50)–O(3)–C(51) 124.3(3) C(19)–N(1)–C(20) 116.9(3) C(19)–N(1)–Ru(1) 128.9(2)

C(20)–N(1)–Ru(1) 112.23(19) C(26)–N(2)–C(25) 120.4(3) C(26)–N(2)–Ru(1) 129.2(2) C(25)–N(2)–Ru(1) 110.29(19)

C(2)–C(1)–C(6) 118.4(3) C(2)–C(1)–P(1) 121.3(3) C(6)–C(1)–P(1) 119.6(3) C(1)–C(2)–C(3) 121.0(4) C(4)–C(3)–C(2) 119.7(4) C(3)–C(4)–C(5) 120.4(4) C(4)–C(5)–C(6) 120.4(4) C(5)–C(6)–C(1) 119.9(4)

C(8)–C(7)–C(12) 119.4(3) C(8)–C(7)–P(1) 124.0(3) C(12)–C(7)–P(1) 116.3(3) C(7)–C(8)–C(9) 119.5(4)

C(10)–C(9)–C(8) 120.9(4) C(9)–C(10)–C(11) 120.2(4)

C(10)–C(11)–C(12) 119.4(4) C(7)–C(12)–C(11) 120.7(4)

C(14)–C(13)–C(18) 119.3(3) C(14)–C(13)–P(1) 117.7(3) C(18)–C(13)–P(1) 122.8(2)

C(15)–C(14)–C(13) 121.9(3) C(14)–C(15)–C(16) 119.1(3) C(17)–C(16)–C(15) 120.4(3) C(16)–C(17)–C(18) 121.1(3) C(13)–C(18)–C(17) 118.3(3) C(13)–C(18)–C(19) 128.1(3) C(17)–C(18)–C(19) 113.6(3) N(1)–C(19)–C(18) 131.2(3) N(1)–C(20)–C(21) 116.0(3)

N(1)–C(20)–C(25) 107.0(2) C(21)–C(20)–C(25) 111.3(3) C(20)–C(21)–C(22) 110.8(3) C(23)–C(22)–C(21) 110.1(3) C(22)–C(23)–C(24) 110.5(3) C(23)–C(24)–C(25) 110.4(3) N(2)–C(25)–C(24) 115.7(3) N(2)–C(25)–C(20) 104.1(3) C(24)–C(25)–C(20) 111.2(3) N(2)–C(26)–C(27) 124.2(3) C(28)–C(27)–C(32) 120.0(4) C(28)–C(27)–C(26) 117.4(3) C(32)–C(27)–C(26) 122.4(3) C(29)–C(28)–C(27) 120.4(4) C(30)–C(29)–C(28) 119.9(4) C(29)–C(30)–C(31) 120.2(4) C(30)–C(31)–C(32) 120.7(4) C(31)–C(32)–C(27) 118.7(3) C(31)–C(32)–P(2) 120.8(3) C(27)–C(32)–P(2) 120.5(3)

C(34)–C(33)–C(38) 119.3(3) C(34)–C(33)–P(2) 122.0(3) C(38)–C(33)–P(2) 118.6(3)


C(39)–C(40)–C(41) 120.1(4)

6 Appendix

207

C(42)–C(41)–C(40) 119.7(4) C(41)–C(42)–C(43) 121.1(4) C(42)–C(43)–C(44) 119.3(4) C(43)–C(44)–C(39) 120.8(3) O(1)–C(45)–C(49) 128.7(3) O(1)–C(45)–C(46) 123.1(3) C(49)–C(45)–C(46) 108.2(3) C(45)–C(46)–C(47) 105.0(3) C(48)–C(47)–C(46) 104.4(3) C(49)–C(48)–C(47) 113.3(3) C(48)–C(49)–C(50) 125.7(3) C(48)–C(49)–C(45) 109.0(3) C(50)–C(49)–C(45) 125.3(3) O(2)–C(50)–O(3) 123.7(3) O(2)–C(50)–C(49) 123.8(3) O(3)–C(50)–C(49) 112.5(3) C(53)–C(51)–C(52) 113.6(4) C(53)–C(51)–C(54) 110.5(4)

C(52)–C(51)–C(54) 111.8(4) C(53)–C(51)–O(3) 108.8(3) C(52)–C(51)–O(3) 109.8(3) C(54)–C(51)–O(3) 101.5(3)

F(6)–P(3)–F(2) 94.2(3) F(6)–P(3)–F(1) 86.7(3) F(2)–P(3)–F(1) 176.9(3) F(6)–P(3)–F(3) 93.7(2) F(2)–P(3)–F(3) 91.8(2) F(1)–P(3)–F(3) 91.1(2) F(6)–P(3)–F(4) 175.6(3) F(2)–P(3)–F(4) 90.1(3) F(1)–P(3)–F(4) 88.9(3) F(3)–P(3)–F(4) 87.0(2) F(6)–P(3)–F(5) 88.1(2) F(2)–P(3)–F(5) 87.6(2) F(1)–P(3)–F(5) 89.4(3) F(3)–P(3)–F(5) 178.2(2)

F(4)–P(3)–F(5) 91.3(3) F(10)–P(4)–F(8) 97.9(6) F(10)–P(4)–F(12) 176.0(7) F(8)–P(4)–F(12) 86.0(6) F(10)–P(4)–F(7) 88.4(6) F(8)–P(4)–F(7) 173.6(5)

F(12)–P(4)–F(7) 87.6(5) F(10)–P(4)–F(9) 85.7(4) F(8)–P(4)–F(9) 86.4(2)

F(12)–P(4)–F(9) 93.9(5) F(7)–P(4)–F(9) 94.1(3)

F(10)–P(4)–F(11) 92.0(4) F(8)–P(4)–F(11) 90.9(2) F(12)–P(4)–F(11) 88.6(5) F(7)–P(4)–F(11) 88.8(3) F(9)–P(4)–F(11) 176.2(3)

6.4 Copper(II)-Mediated Oxidative α-Amination of 2-

Phenylpropionaldehyde

At one point during our search for mechanistic clues in the Ru/PNNP-catalyzed α-

fluorination of aldehydes, we decided to study some reactions from the literature concerning

the one-electron oxidation of enolates. By studying these reactions with our substrate 2-

phenylpropionaldehyde (10a), we hoped to obtain mechanistic hints for the α-fluorination

(see 4.2.3). The unexpected results from those experiments led to an interesting and promising

side-project, which is described in this appended section.

6.4.1 Literature Examples for One-Electron Oxidation of Enolates

Braslau and co-workers reported the one-electron oxidation of tert-butyl propionate

enolate with copper(II) chloride in the presence of the radical scavenger 2,2,6,6-

tetramethylpiperidine-N-oxide (TEMPO).1 The TEMPO adduct was isolated in 52% yield

(Scheme 6.1).

6 Appendix

208

OtBu

O

OtBu

OLi

OtBu

O O tBu

O

ON

LDA

THF-78 °C

CuCl2(1 equiv)

TEMPO

52%

Scheme 6.1. Trapping of an α-carbonyl radical by TEMPO.

Another reaction sequence was published by Jahn and Rudakov.2 Oxidation of a

nitronate with CuCl2 leads to an α-nitro radical that is trapped by an intramolecular terminal

alkene (Scheme 6.2). The resulting primary radical then recombines with a chlorine atom

from a second equivalent of the oxidant CuCl2.

Ar OLi

O2N

Ar'+

THF

-78 °COAr Ar'

NO

O

OAr Ar'

NO2

OAr Ar'

NO2

OAr Ar'

NO2Cl

CuCl2

-CuCl-Cl-

CuCl2

-CuCl

Scheme 6.2. Oxidation of a nitronate and radical-trapping by chlorine.

Similar α-oxidations of carbonyl compounds have been reported with oxidants other

than CuCl2, e.g. FeCl3 or (Cp2Fe)PF6.3,4,5 We then tried stoichiometric reactions analogous to

the examples above, but with 2-phenylpropionaldehyde (10a) as substrate. Our goal was to

find out whether the aldehyde was able to follow a similar reaction pathway.

6.4.2 Attempted Radical Trapping of 2-Phenylpropionaldehyde (10a)

As a first attempt, we tried a protocol similar to the one of Braslau (see Scheme 6.1). 2-

Phenylpropionaldehyde (10a) was added to a THF solution of LDA, freshly prepared from

diisopropylamine and n-BuLi. Then, TEMPO (1.0 equiv) and the oxidant CuCl2 (1.1 equiv)

were added at 0 °C (Scheme 6.3). In contrast to the published reaction with tert-butyl

propionate, no adduct of 10a with TEMPO was observed. Instead, the main product was the

enamine 27 from condensation of 10a with diisopropylamine. As side-products, small

amounts of the secondary alcohol 28 and the primary alcohol 29 were detected.

6 Appendix

209

1) LDA (1.2 equiv)THF, -78°C -> 0°C

2) CuCl2 (1.1 equiv)TEMPO (1.0 equiv)

PhH

N PhOHPh

OH+

27major product

28 29

+H

O

10a

Scheme 6.3. Attempted TEMPO-trapping of 10a after oxidation with CuCl2.

Alcohol 28 results from nucleophilic addition of n-BuLi to 10a, if the formation of LDA

was not quantitative. Unexpectedly, small amounts of 10a were reduced to alcohol 29. It is

not clear at present which species acts as reducing agent in this reaction. Aldehyde 10a

obviously behaves differently than the ester studied by Braslau, as no α-oxidation was

observed with CuCl2 and TEMPO.

In a next model reaction, we employed conditions analogous to the nitronate oxidation

by Jahn and Rudakov (see Scheme 6.2). After deprotonation of 10a by LDA at −78 °C, CuCl2

(2.5 equiv) was added at 0°C. To our surprise, the major reaction product after 5 h at 0 °C was

identified as aldehyde 30, containing a diisopropylamino substituent in α-position (Scheme

6.4). Only traces of the expected α-chloro aldehyde 31 were observed, together with alcohols

28 and 29. The aminoaldehyde 30 was isolated in 21% yield after column chromatography.

H

O1) LDA (1.2 equiv)THF, -78°C -> 0°C

2) CuCl2 (2.5 equiv)

3021% yield

PhO

HN

PhH

O

Cl

+ + 28 + 29

10a 31

Scheme 6.4. Unexpected oxidative α-amination of 2-phenylpropionaldehyde.

This reaction has some intriguing features. Aldehyde 10a undergoes a direct α-

amination with a simple amine. The amine plays a dual role: First, it is used as amide base for

the formation of the lithium enolate of 10a, and secondly, it is itself the α-aminating agent

forming a new C—N bond. Most of all, there is a striking similarity to the α-fluorination of 2-

alkylphenylacetaldehydes by AgHF2. Also in the observed α-amination, two originally

nucleophilic centers are joined under oxidative conditions to form a new bond.

The α-amination of carbonyl compounds is usually accomplished with electrophilic

aminating agents, such as haloamines, O-substituted hydroxylamines, azides, diazonium salts,

or dialkylazodicarboxylates.6 Some of those reagents suffer drawbacks from a practical point

6 Appendix

210

of view, because they are highly reactive (azides, diazonium salts). The reaction of carbonyl

compounds with dialkylazodicarboxylates gives hydrazines, which are sometimes difficult to

cleave. However, they are widely and successfully used, and were applied also in our group

for the Ti(IV)-catalyzed amination of 1,3-dicarbonyl compounds.7

Browsing the literature, we found a publication about the efficient α-amination of an

ester with secondary amines, describing a similar observation. Bergman et. al. reported the α-

oxidation of methyl indole-3-acetate by FeCl3 (2 equiv), giving a resonance-stabilized α-

carbonyl cation, which is then trapped by the amine (Scheme 6.5).8,9

NH

OMe

O

NH

OMe

O

N

OMe

O

H

N

OMe

O

NH

OMe

OR2NR2NH

HN

OMe

O

H

FeCl3 FeCl3

R = iPr:Et:Me:

90%60%48%

Scheme 6.5. Published α-amination of methyl indole-3-acetate.

We decided to briefly study the copper(II)-mediated α-amination of 2-

phenylpropionaldehyde (10a), taking its reaction with LDA and CuCl2 as a starting point. The

following paragraphs describe the initial screening and optimization of the reaction

conditions, the use of oxidants other than CuCl2, and the attempts to disconnect the dual role

of the amine.

6.4.3 Screening of Reaction Conditions

In an initial screening of reaction conditions, we varied the amount of oxidant CuCl2,

the amount of base, and the temperature at which the oxidant was added. The results are

summarized in Table 6.1. The optimal outcome is achieved with 1.2 equivalents of LDA, and

the addition of CuCl2 (2.2 equiv) at 0 °C. After 2 h, the reaction is continued at room

temperature, and the α-aminated aldehyde 30 is isolated in 51% yield after 14 h (entry 1).

Interestingly, with only one equivalent of CuCl2, no α-oxidized product is obtained (entry 2).

6 Appendix

211

This observation is in parallel with the α-fluorination, where two equivalents of the reagent

AgHF2 give better results than only one.

Table 6.1. Initial screening of reaction conditions for the α-amination of 10a.

H

OO

HN

1) LDA, THF-78°C -> 0°C

2) CuCl2,temperature (T)

+ by-products

10a 30

entry LDA (equiv)

CuCl2 (equiv)

T (°C)

30 yield (%) by-products

1 1.2 2.2 0 51 29+31

2 1.2 1.0 0 trace 27+28+29

3 1.1 2.2 r.t. 16 n.d.

4 1.1 2.2 −78 33 n.d.

5 2.2 2.2 0 - 29

6 1.1 + iPr2NH (1.1) 2.2 0 35 29

The change to room temperature or to −78 °C for the CuCl2 addition leads to a decrease

of the yield to 16% and 33%, respectively (entries 3, 4). No amination at all is observed when

2.2 equivalents of LDA are used (entry 5), but a respectable 35% yield is obtained with a

mixture of LDA (1.1 equiv) and diisopropylamine (1.1 equiv) as bases (entry 6).

6.4.3.1 Screening of Other Oxidants

We then tested whether copper(II) salts other than CuCl2 might be used. With CuBr2,

the aminoaldehyde 30 was observed in the reaction mixture, but along with the formation of

large amounts of side-products. Among them are alcohol 29, enamine 27, and a compound

that presumably is the product of α-bromination. No α-oxidation takes place with CuF2, CuO,

or CuCO3/Cu(OH)2 (1:1) as oxidants.

Switching to iron(III), we tried the ferrocenium salt (Cp2Fe)PF6, as well as FeCl3 and

FeF3. The α-amination product was observed in none of the cases. Instead, aldehyde reduction

to alcohol 29 occurred to various extents. When FeF3 (2.2 equiv) was used as oxidant, 29 was

6 Appendix

212

isolated in 28% yield after chromatographic purification. Its formation is inexplicable to us at

the moment, as it is not clear how a hydride can be formed under the reaction conditions.

6.4.3.2 Separation of Base and Amine

On one hand, the combined role of diisopropylamine as lithium amide base and

aminating agent is elegant and convenient. On the other hand, it limits the scope of the

method to amines, which are able to form stable lithium amides. To overcome this restriction,

we tested several other bases in the deprotonation of 10a, followed by addition of

diisopropylamine (1.1 equiv) as aminating agent and CuCl2 (2.2 equiv) as oxidant. As shown

in Table 6.2, lithium 2,2,6,6-tetramethylpiperidide (LiTMP) as base gave only traces of the

desired α-aminated product 30 (entry 1). The main product in that reaction is the enamine

formed from aldehyde 10a and tetramethylpiperidine.

Table 6.2. α-Amination of 10a with separate base and amine.

H

O

1) Base (1.1 equiv), THF,temperature (T)

2) i -Pr2NH (1.1 equiv)

3) CuCl2 (2.2 equiv)0°C -> r.t.

products

10a

entry base T (°C) products

1 LiTMP 0 TMP-enamine + 31 + 30 (traces)

2 NaH 0 31

3 LiH 0 31

4 LiHMDS −78 32 (25% isolated) + 29 (traces)

The use of sodium and lithium hydride (entries 2 and 3) leads to α-chlorination (31)

instead of α-amination. With lithium hexamethyldisilazide (LiHMDS) yet another outcome is

observed (entry 4). The major product, isolated in 25% yield, is α-methyl benzyl cyanide

(32), the nitrile derived from aldehyde 10a. On the basis of a published, similar

transformation of aldehydes with ammonia and CuCl2,10 the formation of 32 might be

rationalized by the oxidation of an N-trimethylsilyl imine with two equivalents of CuCl2

(Scheme 6.6).

6 Appendix

213

PhH

O LiHMDS

H

NMe3Si SiMe3

PhX

-Me3SiX H

NSiMe3

PhCPhN2 CuCl2

-Me3SiCl-2 CuCl-HCl10a 32

Scheme 6.6. Formation of nitrile 32 by reaction of aldehyde 10a with LiHMDS and CuCl2.

The screening of bases has shown that the α-amination does not work when an

independent base and diisopropylamine are used instead of LDA. Overcoming this limitation

certainly is a major goal for future investigations. Concerning the scope of amines, reactions

with the lithium amides derived from the primary amines aniline and 1-aminopentane, as well

as with NaNH2 were not encouraging, as no α-amination was obtained.

In conclusion, the reaction of 2-phenylpropionaldehyde (10a) with LDA and CuCl2

represents a convenient method for the direct α-amination of an aldehyde using a simple

secondary amine. The reaction works best with 2.2 equivalents of CuCl2 at 0 °C, giving the α-

diisopropylamino aldehyde 30 in 51% isolated yield.

6.4.4 Literature Comparison and Outlook

Apart from the example with indol-esters by Bergman et. al. (Scheme 6.5), a similar

oxidative amination has been studied by Dembech and Ricci. They reported the reaction of

alkyl or aryl cuprates with lithium amides in the presence of O2.11,12 It was proposed that the

organocuprate, prepared from R1Li and Cu(I)CN, reacts with the lithium amide R2R3NLi to

give a stable dimeric amidocuprate cluster (Scheme 6.7). Purging with oxygen at −78 °C

produces the coupled tertiary amine.

R1Li + CuCN R1Cu(CN)LiR2

NLi

R3

R1 Li N

Li(CN)Cu Cu(CN)LiN R1Li

R2

R3

R2

R3

R1 Li N

Li(CN)Cu Cu(CN)LiN R1Li

R2

R3

R2

R3O2

R2NR1

R3

Scheme 6.7. Oxidative coupling of organocuprates and lithium amides.

6 Appendix

214

Dembech and Ricci suggested that aminyl radicals are produced by O2, which then react

with the alkyl or aryl ligand on copper. This methodology was later taken up by Knochel and

co-workers, who prepared highly substituted tertiary arylamines via the oxidative coupling of

aryl amidocuprates. Instead of O2, they employed 2,3,5,6-tetrachloro-1,4-benzoquinone

(chloranil) as oxidant.13,14 However, to the best of our knowledge, neither Ricci nor Knochel

applied the oxidative amination of organocuprates for the α-amination of carbonyl

compounds.

It might well be that our α-amination of 2-phenylpropionaldehyde (10a) proceeds via

clusters containing the aldehyde enolate and diisopropylamine (or -amide) as ligands. Unless

acetonitrile is used as solvent, Cu(II) is a rather weak oxidant (Cu2+ + e− → Cu+: E0 = +0.15

V)15 and is thus generally acting as an inner-sphere oxidant upon coordinated ligands.16 The

reaction mechanism might therefore be different from the α-fluorination, even though the

observed product of C—X bond formation with a nucleophile is analogous.

For the α-amination, a logical course of action for the future will be to study the

coordination chemistry of copper in our system. This may include the stepwise preparation of

defined complexes of Cu(I), followed by the addition of an oxidant. As a further goal, the

reaction might be run with catalytic amounts of copper, probably by using a copper salt under

an atmosphere of O2. With that approach, the use of chiral Cu(I) complexes could be

envisioned, which might ultimately lead to the development of an enantioselective version of

the oxidative α-amination.

6.4.5 Experimental Procedure

2-Diisopropylamino-2-phenylpropionaldehyde (30)

A 1.6 M solution of n-BuLi in hexane (0.56 mL, 0.90 mmol, 1.2

equiv) was added dropwise over 10 min to a solution of diisopropylamine

(125 μL, 90.3 mg, 0.89 mmol, 1.2 equiv) in dry THF (3 mL) at −45 °C.

The solution was stirred for 1 h at −45 °C and for 15 min at 0 °C. Then, it

was cooled to −78 °C and a solution of 2-phenylpropionaldehyde (10a) (100 μL, 100 mg,

0.75 mmol) in THF (1 mL) was added dropwise during 10 min. The solution was stirred at

−78 °C for additional 30 min and at 0 °C for 15 min. CuCl2 (220 mg, 1.64 mmol, 2.2 equiv)

was added in one portion, and stirring was continued at 0 °C for 2 h, and then at r.t. for further

14 h. During that time, the color of the solution changed from dark brown to yellow, and then

O

HN

6 Appendix

215

to dark green. The reaction mixture was filtered through a short plug of Al2O3 with CH2Cl2 as

eluent, then the solution was concentrated under reduced pressure. FC on deactivated SiO2

(1% NEt3 in hexane/EtOAc 50:1) with hexane/EtOAc 50:1 as eluent, gave aldehyde 30 as a

light yellow oil. Yield: 88 mg (0.38 mmol, 51%).

TLC (hexane/EtOAc 50:1): Rf = 0.22 (mostaïne). 1H NMR (300.1 MHz, CDCl3): δ 9.82 (s, 1

H, CHO), 7.61 – 7.54 (m, 2 H, arom. H), 7.46 – 7.22 (m, 3 H, arom. H), 3.16 (qq, 2 H, J = 6.9,

6.9 Hz, CH(CH3)2), 1.71 (s, 3 H, C(Ph)CH3), 1.20 (d, 6 H, J = 6.9 Hz, CH(CH3)2), 1.17 (d, 6

H, J = 6.9 Hz, CH(CH’3)2). 13C{1H} NMR (75.5 MHz, CDCl3): δ 200.1 (CHO), 141.7, 128.6,

128.0, 127.5, 74.7 (CCHO), 47.8 (CH(CH3)2), 25.3 (CH(CH3)2)), 23.6 (CH(C’H3)2), 19.5

(C(Ph)CH3). MS (EI): m/z 204.1747 ([M-CHO]+, 49), 162.1279 ([M-CHO-C3H6]+, 33),

120.0810 ([M-CHO-(C3H6)2]+, 46), 42.0408 (C3H6+, 100). EA: Calcd. for C15H23NO

(233.35): C, 77.21; H, 9.93; N, 6.00; found: C, 77.46; H, 9.91; N, 6.08.

6.4.6 References Appendix 6.4

[1] Braslau, R.; Burill II, L. C.; Siano, M.; Naik, N.; Howden, R. K.; Mahal, L. K. Macromolecules 1997, 30,

6445 – 6450.

[2] Jahn, U.; Rudakov, D. Org. Lett. 2006, 8, 4481 – 4484.

[3] Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124 – 4125.

[4] Jahn, U.; Müller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212 – 5213.

[5] Jahn, U.; Hartmann, P.; Kaasalainen, E. Org. Lett. 2004, 6, 257 – 260.

[6] For a review, see: Erdik, E. Tetrahedron 2004, 60, 8747 – 8782.

[7] Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658 – 664.

[8] Bergman, J.; Bergman, S.; Lindström, J.-O. Tetrahedron Lett. 1989, 30, 5337 – 5340.

[9] Bergman, J.; Bergman, S.; Lindström, J.-O. Tetrahedron Lett. 1998, 39, 4119 – 4122.

[10] Misono, A.; Osa, T.; Koda, S. Bull. Chem. Soc. Jpn. 1967, 40, 912 – 919.

[11] Alberti, A.; Canè, F.; Dembech, P.; Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61, 1677 –

1681.

[12] Canè, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G. Synthesis 1997, 545 – 548.

[13] Del Amo, V.; Dubbaka, S. R.; Krasovski, A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 7838 – 7842.

[14] Kienle, M.; Dubbaka, S. R.; Del Amo, V.; Knochel, P. Synthesis 2007, 1272 – 1278.

[15] Vanýsek, P. In CRC Handbook of Chemistry and Physics (2007-2008) 88th Ed.; Lide, D. R., Ed.; Taylor

& Francis: Boca Raton, 2007; Vol. 8, pp 20 – 29.

[16] Eberson, L. Electron Transfer Reactions in Organic Chemistry; Springer: Berlin, 1987; pp 101 – 117.

6 Appendix

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6 Appendix

217

6.5 Curriculum Vitae

Name Althaus

First Name Martin

Date of Birth October 10th, 1979

Nationality Swiss

Citizenship Lauperswil BE

06/2004 – 02/2008 Laboratory of Inorganic Chemistry, ETH Zurich, Switzerland.

Ph.D. thesis under the supervision of Prof. Dr. Antonio Togni and Prof.

Dr. Antonio Mezzetti. Title of the thesis: “Asymmetric C—F Bond

Formation Catalyzed by Ruthenium PNNP Complexes”.

Laboratory teaching assistant for first semester chemistry students

during three years. Supervision of two students in their 7th semester

research projects.

01/2004 – 05/2004 F. Hoffmann-La Roche Ltd., Basel, Switzerland. Industrial

internship in the division of process research and development.

04/2003 – 07/2003 Laboratory of Organic Chemistry, ETH Zurich, Switzerland.

Diploma thesis “Novel Schiff-Base Ligands Derived from [2.2]Para-

cyclophane: Syntheses and Applications in Transition-Metal Catalysis“

under the supervision of Prof. Dr. Erick M. Carreira.

11/1999 – 11/2003 ETH Zurich, Switzerland. Studies of chemistry (Dipl. Chem. ETH),

including one semester at Imperial College of Science, Technology,

and Medicine, London, GB.

08/1995 – 06/1999 High School, Kantonsschule Zofingen, Type C (natural sciences).

Zurich, February 2008

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