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Stereoselective Syntheses of 2-Imidazolines

Janssen, G.V.

2015

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StereoselectiveSyntheses of

2-Imidazolines

Guido Janssen

2015

c© 2015, G. V. Janssen, Amsterdam.

Cover design: Maus Bullhorst http://www.mausbaus.com

The work described in this thesis was financially supported by the DutchNational Research School Combination Catalysis Controlled by Chem-ical Design (NRSC–Catalysis).

ISBN: 978-94-6299-055-5

Printed by: Ridderprint BV

VRIJE UNIVERSITEIT

StereoselectiveSyntheses of

2-Imidazolines

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctor aande Vrije Universiteit Amsterdam,

op gezag van de rector magnificusprof.dr. F.A. van der Duyn Schouten,

in het openbaar te verdedigenten overstaan van de promotiecommissie

van de Faculteit der Exacte Wetenschappenop dinsdag 28 april 2015 om 15.45 uur

in de aula van de universiteit,De Boelelaan 1105

door

Guido Viktor Janssen

geboren te Nijmegen

promotoren: prof.dr.ir. R.V.A Orruprof.dr. K. Lammertsma

copromotoren: dr. J.C. Slootwegdr. E. Ruijter

UNLESS

SOMEONE LIKE YOU CARES A WHOLE AWFUL LOT,NOTHING IS GOING TO GET BETTER. IT’S NOT.

the LORAXby Dr. Seuss

Contents

List of Abbreviations 9

1 Introduction 111.1 General Introduction . . . . . . . . . . . . . . . . . . . . . . 121.2 Application of 2-Imidazolines . . . . . . . . . . . . . . . . . 131.3 Synthesis of 2-Imidazolines . . . . . . . . . . . . . . . . . . 291.4 Outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381.5 References and Notes . . . . . . . . . . . . . . . . . . . . . . 40

2 Catalytic Enantioselective Approach toward 2-Imidazolines 472.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 482.2 Alternative Chiral Phosphoric Acids . . . . . . . . . . . . . 552.3 Catalytic Asymmetric Imidazoline-3CR . . . . . . . . . . . 632.4 Experimental Section . . . . . . . . . . . . . . . . . . . . . . 732.5 References and Notes . . . . . . . . . . . . . . . . . . . . . . 84

3 Diastereoselective 1,3-cycloadditions 873.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 883.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . 923.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013.4 Experimental Section . . . . . . . . . . . . . . . . . . . . . . 1013.5 References and Notes . . . . . . . . . . . . . . . . . . . . . . 110

4 Chiral Auxiliaries in the Imidazoline-3CR 1134.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . 1194.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1274.4 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1274.5 Experimental Section . . . . . . . . . . . . . . . . . . . . . . 130

4.6 References and Notes . . . . . . . . . . . . . . . . . . . . . . 146

5 Chemoselective Addition of Isocyanides to N-tert-butanesulfin-imines 1495.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505.2 Results and Discussion . . . . . . . . . . . . . . . . . . . . . 1565.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645.4 Experimental Section . . . . . . . . . . . . . . . . . . . . . . 1645.5 References and Notes . . . . . . . . . . . . . . . . . . . . . . 173

Summary 177

Samenvatting 185

Dankwoord 193

List of Publications 198

List of AbbreviationsADF Amsterdam density functional programACDC Asymmetric Counterion–Directed CatalysisBINAM 1,1’-binaphthyl-2,2’-diamineBINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphthaleneBINOL 1,1’-bi-2-naftolBPA BINOL-based phosphoric acid diestersbr broad (spectral)COSMO conductor-like screening modeld doublet (in NMR)DCM dichloromethanedba dibenzylideneacetoneDFT density functional theoryDiPEA N,N-diisobutylethylamineDPP diphenylphosphatedr diastereomeric ratioee enantiomeric excessESI electrospray ionisation (in mass spectrometry)EWG electron-withdrawing groupGGA generalized gradient approximationHMDS hexamethyldisilazaneh hoursHOMO highest occupied molecular orbitalHPLC high performance liquid chromatographyHRMS high resolution mass spectrometryIBS imidazoline binding siteIR infraredI.S. internal standardJ coupling constant (in NMR)LUMO lowest unoccupied molecular orbitalm multipletM molarMCR multicomponent reactionMeOH methanolmL mililitermp melting point (range)NBD norbornadieneNHC N -heterocyclic carbeneNMR nuclear magnetic resonancePG protective groupPMP para-methoxyphenylPNP para-nitrophenylppm parts per millionRf retention factor (in chromatography)rt room temperatures singlet (in NMR)SAOP statistical average of (model) orbital potentialsept septet (in NMR)

9

STOs slater type orbitalst triplet (in NMR)Tf triflyl, trifluoromethanesulfonylTFPB tetrakis(3,5-bistrifluoromethylphenyl)borateTHF tetrahydrofuranTLC thin layer chromatographyTMS trimethylsilylTMSCl trimethylsilyl chlorideTosMIC tosylmethyl isocyanideTRIP 3,3’-Bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’-diyl

hydrogenphosphateTS transition stateTs tosyl, 4-toluenesulfonylUV ultravioletVAPOL 2,2’-’diphenyl-(4-biphenanthrol)vs. versusZORA zeroth-order regular approximation

10

Chapter 1

Introduction

N

NR2

R1

R3

R4

Synthesis

Biological activity

Natural products

Catalysis

2-imidazolines

Abstract

This chapter contains the reported syntheses and application of 2-imidazolines.First, the application of several biologically active naturally occurring 2-imidazolines as well as synthetic 2-imidazolines in medicinal chemistry is de-scribed. Then, the application of 2-imidazolines in asymmetric transition metalcatalysis and organocatalysis is highlighted, which is followed by an overview ofknown syntheses for the generation of (chiral) 2-imidazolines. Finally the scopeof this thesis is outlined.

Chapter 1

1.1 General Introduction

Cyclic compounds represent an important class in chemistry.Within this class several subclasses exist based on the atomspresent in the ring. For example, isocyclic compounds have onlyatoms of one element in the ring (e.g. A and B, Figure 1.1). Cyc-lic compounds with at least two different elements in the ring areknown as heterocyclic compounds (e.g. C and D). We speak oforganic heterocycles when at least one of the ring atoms is a car-bon (e.g. C), atom while inorganic heterocycles do not contain anycarbon in the ring (e.g. D).

NB

NBN

BHH

H

HH

H

Borazineinorganic heterocycle

cyclopentadieneorganic carbocycle, isocyclic

N

Pyridineorganic heterocycle

NN N

NN

NH2

(3-aminophenyl)pentazoleisocyclic

A B C D

Figure 1.1: Different cyclic compounds

The chemistry of organic heterocyclic compounds is one of themost complex branches of organic chemistry. It is equally interest-ing for its synthetic and theoretical implications and for the biolo-gical and industrial significance of heterocyclic chemistry.1,2 Thering sizes in this class of compounds range from highly strainedthree-membered rings up to macrocycles containing more than 80atoms.3,4

The research described in this thesis deals with the synthesisof 2-imidazolines, which belong to the five membered hetero-cycles. This chapter underlines the importance of 2-imidazoline-containing structures in the fields of biology (paragraph 1.2.2 and1.2.1) and catalysis (paragraph 1.2.3). Moreover, this chapter de-scribes known synthethic routes in paragraph 1.3

The imidazoline core contains two nitrogen, three carbon

12

Introduction

atoms, and one double bond arranged in a N-C-N-C-C fashion.The various regioisomeric imidazolines mutually differ in the loc-ation of the double bond (Figure 1.2). Among the imidazolines,2-imidazolines (A) are the most widely studied.

N

HN

N

HN

NH

HN

A 2-imidazoline

B 3-imidazoline

C 4-imidazoline

Figure 1.2: Imidazoline core structures.

1.2 Application of 2-Imidazolines

1.2.1 Natural Products

The abundance of the 2-imidazoline scaffold in natural products israther low compared to other structural motifs. A possible explan-ation for this observation is that 2-imidazolines are relatively eas-ily aromatized to the corresponding imidazoles. This is the reasonwhy 2-imidazoline-containing natural products are often isolatedalongside with the corresponding imidazoles.

The first example of 2-imidazoline containing natural productswere isolated in 1960 from the bacteria Streptomyces racemochromo-genous novo sp. and named racemomycins (1, Figure 1.3). In thesestructures, the cis-2-imidazoline is connected to a N-gulosaminesugar moiety, which is in turn connected to a β-lysine peptidicside chain. The difference between the racemomycin congeners(racemomycins A–E) is the number of β-lysine residues in the pep-tidic side chain.5,6 The biological activities of the Racemomycinsinclude antimicrobal as well as antiviral properties that can be en-hanced by modification of the peptide side chain.7

A class of imidazoline-containing structures are derived fromtryptophan.8 These compounds were first discovered in 1988 byTsuji and Rinehart who isolated 4,5-dihydrotopsentins 2 from the

13

Chapter 1

A: R1 = H, R2 = COOB: R1 = COO , R2 = H

N

HN

O

NH

NHBr

N

HN

HN

OH

O

NH

O

HO O

HN

OHO

NH2

O

NH2H

HNH

Racemomycins 1 (1960)antibiotic

4,5-dihydrotopsentins 2 (1988)R = Br or HAntitumor, antiviral, antiinflammatory

N

HN

NH2

NH

Br

Br

discodermindole 3 (1991)antitumor properties

N

N

H

Me

HN

R1 R2O

NH

Br

clatramides 5 (1996)antibiotic

H

n

A: n = 1C: n = 2B: n = 3D: n = 4E: n = 5

R

NH

CO2

NMe

NNH2

R

X

Y

trachicladindoles 4 (1991)

Figure 1.3: Natural occuring 2-imidazolines

Caribbean deep-sea sponges of the family Halichondriidae. The cor-responding imidazoles were also isolated from the same sponge,illustrating their close connection in biosynthesis.9 In the fol-lowing years 4,5-dihydrotopsentins 2 were isolated from severalspecies of sea sponges10,11 and received considerable attentionbecause of their wide range of bioactivities.12 Because of theseactivities, Denis et al. developed a total synthesis for these com-pounds using a condensation reaction of diamine 8 with 3-indolyl-α-ketothioamides13 7 as key step (see paragraph 1.3.1) to constructthe imidazoline core.14

During the search for new anti-tumor compounds from marineorganisms, Sun et al. isolated in 1991 the structurally similar dis-codermindole 3 form the sea sponge Discodermia polydiscus found

14

Introduction

NH

RNH

R

OMeS

NI

Amberlyst A 21MeOH, rt. 48 h

NH

NH3Cl

NH3Cl

HNN

NH

NH R6 7 2

O8

Scheme 1.1: Total synthesis of 4,5-dihydrotepsins 2

on the Bahamas.15 This compound was also found in the SouthAustralian marine sponge Trachicladus laevispirulifer together withthe trachicladindoles A–G 4 that are structurally very similar im-idazolinium salts. Two closely related biosynthetic pathways aresuggested starting from tryptophan to arrive both at the discoder-mindoles 3 and trachicladindoles 4.16

A final example of 2-imidazoline-containing natural productsare clatramides A and B (5, Figure 1.3), isolated from the Carribeansea sponge Agelas clathrodes. These compounds show antifungalactivity against the Aspergillus niger,17 and are derived from his-tidine. Likely, the biosynthetic pathway includes methylation ofthe imidazole ring, and an amidation to introduce the pyrrolegroup.18

1.2.2 Biological activity

The 2-imidazoline scaffold is biologically active in a range of ap-plications. They are reported as enzyme inhibitors, nuclear factorκB inhibitors, imidazoline binding site (IBS) agonists and as p53–MDM2 interaction inhibitors. The popularity of the 2-imidazolinescaffold in medicinal chemistry is furthermore illustrated by thenumber of patents in this field. Since 2006, 27 patents on biologic-ally active 2-imidazoline derivatives were filed.19 This paragraphdescribes the two most important applications: (1) the imidazolinebinding site agonists and (2) the p53–MDM2 interaction inhibit-ors.

15

Chapter 1

Imidazoline Binding Sites

The imidazoline binding sites were discovered three decades agoby Bousquet et al.20 The major sites of action were found tobe the noradrenergic terminals in rostral ventrolateral medulla(RVLM),21 a part of the brain that regulates the autonomous bodyfunctions such as blood pressure, swallowing and breathing.22

Three main classes of IBS exist:23–25 i.e. the I1 imidazoline re-ceptor that facilitates the symphato-inhibitory actions to lowerblood pressure, the I2 receptor that functions as an important al-losteric binding site of monoamine oxidase, and the I3 receptorthat is a regulator for insulin secretion from pancreatic β cells.26

These properties make 2-imidazolines interesting compounds fortreatment of cardiovascular diseases. Figure 1.4 shows some im-idazolines with their preferred binding site.

O

ONH

N

11 Idazoxan (I3)

NH

NNH

Cl

Cl

9 Clonidine (I1)

NH

N O

10 Cirazoline (I2)

NH

NNH

NN

Me

OMe

Cl

12 Moxinidine (I1)

NH

N

13 Metrazoline (I2)

NHN

O

14 Efaroxan (I3)

Figure 1.4: Relevant 2-imidazolines and preferred binding site.

p53–MDM2 Interaction Inhibitors

Next to the IBS agonists, 2-imidazolines are known to inhibitthe interaction between the protein p53 and its regulator murinedouble minute 2 protein (MDM2, HDM2 in humans). The proteinp53 was discovered in 1979 in a study of the role of viruses in can-cer. p53 was found as a complex with viral tumor antigens,27,28

and has since then been subject in cancer inhibition. In its free

16

Introduction

form, p53 is able to inhibit the formation of tumors by trigger-ing DNA repair of damaged cells during the cell-cycle, or whenthat fails, induce cell-cycle arrest followed by apoptosis (Figure1.5).29–32

Figure 1.5: p53 mode of action.

Directly blocking the p53-MDM2 protein-protein interaction isan attractive approach in cancer treatment, as targeting MDM2by an inhibitor increases the level of p53.33,34 The first success-ful compounds to inhibit this interaction were peptide derivat-ives. Unfortunately due to their poor cell membrane permeab-ility, these compounds show only modest cellular activity.35,36

Therefore, the focus changed to small molecules for the inhibi-tion of the protein-protein interaction. Active compounds for thispurpose are spirooxindoles, piperidones, 1,4-diazepines and 2-imidazolines.35 The cis-imidazolines 15–17 (Figure 1.6) were dis-covered by Hoffmann–La Roche in 2004 as very potent inhibit-ors.37 These compounds, called nutlins, contain a 2-imidazolinecore that carries two haloaryl moieties and a C2-aryl group, that ispara-methoxy and orthoalkoxy substituted. These groups mimicthe three p53 amino acid residues (Leu26 and Trp23 for thehaloaryl groups, and Phe19 for the ortho-alkoxy group) respons-ible for the binding interaction and fit perfectly into the hydro-phobic pockets of the MDM2 binding site.38

Structure based optimization led to the development of 19(Scheme 1.2) which is threefold more active than nutlin-3a (Kd =10.7 nM) and is the first MDM2 inhibitor in clinical trials.39,40 Thisincreased activity was obtained through introduction of a sulf-onyl group on the urea part for better binding and introduction of

17

Chapter 1

N

N

Cl

Cl

NO NH

O

O

O

N

N

Br

Br

NO N

O

O

OH

N

N

Cl

Cl

NO

O

O

N

O

15 Nutlin-1IC50 = 260 nM

16 Nutlin-2IC50 = 140 nM

17 Nutlin-3aIC50 = 90 nM

Figure 1.6: Nutlins described by Hoffmann–La Roche.

two methyl groups on the imidazoline backbone to prevent oxid-ation of the imidazoline core to the corresponding imidazole. Thepara-methoxy group on the C2-aryl, prone to metabolism, was ex-changed for a tert-butyl group to prevent degradation while keep-ing the hydrophobic interaction intact. Finally, the isopropyl etherwas replaced for an ethyl ether to reduce the molecular weight.39

18

Introduction

N

N

Cl

Cl

NO NH

O

O

O

N

N

Cl

Cl

NO N

O

SO

O

RG-7112 (RO5045337)(Kd = 10.7 nM to MDM2)

Nutlin-3a 18IC50 = 90 nM

Optimization

N

N

Cl

Cl

OO

O

O

Me

Me

NHAc

MDM2 Ki = 600 nM

N

N

Cl

Cl

S

N

O

NH

O

MDM2 IC50 = 260 nM

N

N

Cl

Cl

S

N

O

NH

O

Me

MDM2 IC50 = 92 nM

N

N

Cl

Cl

S

N

O

Me

MDM2 IC50 = 9.2 nM

ON

O

Increasepotency

Increasestability

Annulation

20

19

21

2223

Scheme 1.2: Optimization of small molecule p53-MDM2 interaction in-hibitors based on the Nutlins.

In a different study, Hu et al. modified the amide part witha carbamate group to arrive at Nutlin analogue 20 that showsa similar binding activity as Nutlin-3a.41 While in search for aneven more potent compound, Soga et al. found that the dihydroim-idazothiazole 21 core has also great potential. Lead optimizationdelivered compound 23 that is ten-fold more active that nutlin-3a.42,43

The inhibition of the MDM2-p53 interaction by 2-imidazolines

19

Chapter 1

is an attractive approach for future cancer treatment, as nutlin-3ahas shown to be a potent and selective small-molecule MDM2 ant-agonist, which has a considerable promise in pre-clinical studies.

1.2.3 Application in Catalysis

Another field in which imidazolines have become popular is thefield of transition-metal catalysis, as they emerged as versatile(chiral) ligands. In the relatively new field of organocatalysis, 2-imidazolines are applied as organocatalysts in several reactions,such as cycloadditions and addition reactions.

Since it would go beyond the purpose of this chapter to givean complete literature overview, this section highlights some im-portant examples of 2-imidazolines in catalysis.

Transition-Metal Catalysis

Being structurally analogous to the 2-oxazolines,44–49 2-imidazolines have been developed as versatile ligands incoordination chemistry and enantioselective transition–metalcatalysis.50 Compared to the 2-oxazolines 24, 2-imidazolines

N

OR2

R1R3

N

NR2

R1R3

R4 Additional electronic andsteric fine-tuning

24 25TM(L)n TM(L)n

Chirality for asymmetric catalysis

**

Figure 1.7: 2-oxazolines vs. 2-imidazolines.

25 are better sigma donors via the sp2-N atom and as a con-sequence, the corresponding transition metal-complexes areusually more stable. Additionally, 2-imidazolines have an ad-ditional functionalization possibility at the imidazoline nitrogenatom. Functionalization of this position with different substitu-ents allows fine-tuning of the electronic properties as well as the

20

Introduction

steric and conformational environment of the ligand (Figure 1.7).Finally, for asymmetric catalysis, chirality can be introduced inthe backbone of the ring.

2-Imidazolines coordinate in a monodentate fashion to trans-ition metals, via the sp2 nitrogen atom (Figure 1.8 A). A bidentatecan be created by linking two imidazolines via a linker (B). Al-ternatively, a bidentate ligand can also be created by linking anexternal donor atom (X) to the imidazoline (C). Finally, a pincerligand can be created by using a linker that contains a donor atom(D). In terms of enantioselectivity, the best results have been re-ported with ligands of type C and D.50

X

N

NR

XTM(L)n

N

NR

TM(L)n

A B C D

N

NR

TM(L)n

N

NR

N

NR

TM(L)n

N

NR

Figure 1.8: Coordination modes of imidazolines A) monodentate, B)bidentate via the imidazoline nitrogen and, C) bidentate via the nitro-gen atoms of two linked imidazolines and D) tridentate via the two im-idazoline imine nitrogen atoms and an external donor atom (X) presentin the linker.

Within the class B ligands, the phosphino-imidazoline lig-ands (e.g. in catalyst 28, Scheme 1.3) have since their first re-port in 200151 been successfully applied in iridium and rhodiumcatalytic asymmetric hydrogenation reactions of olefins. In gen-eral, they perform better in terms of activity and selectivity thantheir analogous oxazoline ligands.52,53 Catalyst 28 (Scheme 1.3)was developed for the rhodium catalyzed hydrogenation of α,β-unsaturated ureido esters 26 that are intermediates in the syn-thesis of analogues of amidonitril 29, a selective inhibitor ofcathepsin S. This is a serine protease involved in inflammation.54

While the two cyclohexyl groups on phosphorus in 28 are es-sential for a good activity, the naphtalene moiety is responsible for

21

Chapter 1

the restriction of the phosphine conformation resulting in a enanti-oselective reaction. This ligand in combination with Rh(NBD)2BF4gives the required enantiomer of 6 differently substituted α,β-unsaturated urea esters 26 in 99% ee with a catalyst loading of 0.6mol%.

ON

O

NH

CO2Me

R 0.6 mol% cat.H2

MeOH, 30 °CO

N

O

NH

CO2Me

R

N

N

Ph

PhPCyCy Rh

CyO

cat.:

R = aromatic, alkyl 6 examples, 99% ee

ON N

H

O

O

HN

N

CN

NO

26 27 amidonitril 29

28

Scheme 1.3: Enantioselective hydrogenation of unsaturated ureas.

Recently Nakamura et al. explored the application of C2-symmetric bis-imidazoline pincer complexes 33 and 37 (Scheme1.4 and 1.5). In both catalytic systems, the two imidazoline moiet-ies are connected through a linker containing a meta-phenyl. Thisallows, upon coordination with palladium, for CH activation ofthe ‘ortho’ carbon atom of the phenyl ring, leading to the forma-tion of the bis(imidazoline)Pd(II) pincer complexes.

The first example describes the enantioselective allylation ofisatin–derived ketimines 30 (Scheme 1.4). Catalyst 33 was foundas the optimal catalyst for this transformation. The tert-butylgroup on the phenylene linker as well as the sterically demand-ing trimethylbenzoyl groups were essential, most likely to forcethe ligand in the appropriate conformation in order to obtain abetter selectivity. Using this method, a range of isatin–derived ke-timines was succesfully allylated in high yields (84–96%) and withexcellent ee’s (82–95%).55

22

Introduction

N

N N

NPh

Ph

PdPh

Ph Br

cat:

OOO ONO

NBoc

Tr

Si(OMe)3

NO

Tr

BocHN5 mol% cat.AgF (1.0 equiv.)

THF, -30 °C

R

R30

32

333184–96% yield82–95% ee

Scheme 1.4: Palladium catalyzed enantioselective allylation of isatin–derived ketimines.

In the second example, the versatility of 2-imidazoline pin-cer ligands was demonstrated in the enantioselective palladium-catalyzed decarboxylative cyanoalkylation of imines (Scheme 1.5),using a structurally similar bisimidazoline ligand (37), which af-forded β-cyanoamines (36) in good yield (70–83%) and ee (72–90%).56

CN

CO2H

NR2

R1

5 mol% cat.AgOTf (5 mol%)

THF, 0 °C R1

NHR2

CNCO2

N

N N

NPh

Ph

PdPh

Ph

Ac Ac

Br

cat:

R1 = aromaticR2 = 2-py-SO2

11 examples, 72-90% ee34 35 36 37

Scheme 1.5: Enantioselective decarboxylative cyanoalkylation ofimines.

Given the multitude of applications of 2-imidazoline–derivedchiral ligands, they have emerged as a successful group of lig-ands in enantioselective catalysis. However, when more enanti-oselective synthesis routes are available, the full potential of chiral2-imidazolines as ligands in asymmetric catalysis can be explored.

23

Chapter 1

Organocatalysis

The use of 2-imidazolines as organocatalysts in asymmetric cata-lysis is relatively new and has not been significantly explored. Thelikely reason for this is that the enantioselectivities in the first ex-amples were low, and high catalyst loadings were required for rateacceleration. The 2-imidazolines, however, have great potential asorganocatalysts due to their (Brønsted) basicity and nucleophili-city (Figure 1.9 A) as well as their Brønsted acidity of the salts(Figure 1.9 B).57

N

N

HX

N

N

A B

Nucleophile,Brønsted base Brønsted acid,

H-bond donor

R1

R2R3

R4

R1

R2R3

R4

Figure 1.9: A) Brønsted base and nucleophile, B) Brønsted acid.

The first asymmetric reaction mediated by 2-imidazolines wasreported by Göbel et al. in 2003 (Figure 1.6).58 They envisionedthe protonated, chiral Phebim bis-imidazoline 42 as chiral H-bonddonor for the activation of the carbonyl groups of 39 creating achiral environment and activating it for the Diels–Alder reactionwith diene 38. Although the resulting 19-nor steroids 40 and 41were formed with a significant rate acceleration, they were ob-tained in a moderate ee of 47% (R = Me) and a poor ee of 7% (R= Et), even when a stoichiometric amount of 2-imidazoline wasused.

24

Introduction

MeO

O

O

R 100 mol% cat.

CH2Cl2, -80 °CMeO

H

H

R

OH

OHN

N N

HN

Ph

Ph Ph

Ph

H H

cat: 2 TFPB

TFPB = tetrakis(3,5-bistrifluoromethylphenyl)borate

40 R = Me: 47% ee41 R = Et: 7% ee

38 39

42

Scheme 1.6: Organocatalytic Diels–Alder reaction using diprotonatedbis(imidazoline) 42.

A few years later, Göbel et al. extended their concept in theDiels–Alder reaction with a modified catalyst, namely bisamidine47. When examined in the reaction between cyclopentadiene 43and methyl vinyl ketone 44, a 2000-fold rate acceleration wasfound. However in CDCl3, the ee remained low (∼ 12%) at tem-peratures ranging from room temperature to –70 ◦C.59 Appar-ently, these bis-imidazolines are quite effective in the rate acceler-ation of Diels–Alder reactions, but they do not provide the desiredenantiocontrol.

O1 mol% cat.

CHCl3

O

O

HN

N N

HN

Ph

PhPh

Ph

H H

TFPBcat:

4746 46ee = ~ 12%43 44

Scheme 1.7: Diels–Alder reaction of cyclopentadiene and methyl vinylketone.

In 2005 Lectka et al. reported the successful application ofmono-imidazoline 51 as nuclophilic organocatalyst in the transselective Staudinger lactam synthesis by a reaction between in-situ generated ketenes from acid chlorides 4960 and imines 48(Scheme 1.8).61 Remarkably, this result contrasts the complete

25

Chapter 1

cis-selectivity obtained with chincona alkaloid-based organocata-lysts.62,63 The initial nucleophilic attack of the charged catalyst 51on the ketene is proposed to afford the (Z)-enolate selectively be-cause of ion pairing with the bulky counterion, affording the trans-lactam when reacted with imine 48 (Scheme 1.9). With a neutralcatalyst, the thermodynamically more stable (E)-enolate is formedaffording the cis-lactam. However, because a symmetric catalystis used the products are obtained as racemic mixtures.

Cl O

R

NTs

EtO2C H

10 mol% cat.base

toluene 0 °C N N Ph

SO3

NR4

NTs O

REtO2C

cat:

R = Heptylup to 1:50 cis:trans48 49 50

51

Scheme 1.8: Organocatalytic formation of trans-β-lactams.

O•

R H

Nu

OR

HNu

OH

R

Nu Nu

Favored

neutral Nu

charged NuO•

R H

Nu

OR

HNu

OH

R

Nu Nu

Favored

NR4NR4

Scheme 1.9: Proposed explanation for the complete switch in diaste-reoselectivity.

A report in which a chiral mono-imidazoline was used asasymmetric organocatalyst, is the 2-imidazoline-catalyzed asym-metric Morita-Baylis-Hillman reaction that was reported by Tanet al. in 2006.64 Anticipating on the nucleophilic properties of

26

Introduction

chiral mono-imidazoline 55, they demonstrated that 55 wasable to react in the same way (1,4-addition to 53) as 1,4-diazabicyclo[2.2.2]octane (DABCO) or Et3P, normally used ascatalyst in this reaction. Unfortunately, the reaction required 50mol% catalyst to reach full conversion with reaction times rangingfrom three days to two weeks, while the products were obtainedin only moderate to reasonable ee (47-78%).

H

O

R1

O

R250 mol% cat.

toluene, rt

OH

R1R2

O

NN

PhR

cat:

R = 2-naphtyl52 53 54

55

R1 = EWGR2 = Me, Et, Cy

47-78% ee

Scheme 1.10: Mono-imidazoline catalyzed Morita-Baylis-Hillman reac-tion.

RNO2

1-2

O

OMe

O 5 mol% cat.

toluene, -10 °C 1-2

O OOMe

R HNO2

Ph OH

O10 mol% cat.Br+ source

toluene, -40 °C

O OPh

Br

A)

B)

cat: 61, 1% ee 62, 61% ee 63, 89% ee

cat: 61, 6% ee 62, 28% ee 63, 69% ee

56 57 58

59 60

Scheme 1.11: Comparison of 2-imidazolines catalysts 61, 62 and 63 (Fig-ure 1.10) in the: A) conjugate addition of β-ketoester to nitroolefins, andB) the bromolactonization of e-vinyl carboxylic acids.

Murai et al. investigated how to increase the enantioselectiv-ity of 2-imidazoline catalysts.65 In their studies on the enanti-oselective conjugate addition of β-ketoesters 56 to nitroolefins 57

27

Chapter 1

(Scheme 1.11A) they found that C3-symmetric tris-imidazoline 63as catalyst gave a much higher ee (89%) when compared to C2-symmetric bis-imidazoline 62 (61% ee) and mono-imidazoline 61(1% ee). The same trend was observed in the intramolecular 2-imidazoline catalyzed bromolactonization of e-vinyl carboxylicacids 59 to afford tetrahydropyran-2-ones 60 (Scheme 1.11B).Catalysts 61, 62 and 63 gave ee’s of 6%, 28% and 69%, showingthe superiority of 63.66,67

HN

NPh

Ph

H

HHN

NPh

Ph

H

HN

N

Ph

PhHN

NPh

Ph

HN

N

Ph

Ph

NHN

Ph PhUndesirable reaction site Desirable reaction site

61 62 63

Figure 1.10: Difference in reaction sites of 2-imidazolines organocata-lysts.

Further investigations showed that this third imidazoline unitis indeed beneficial. Kinetic experiments on the conjugate addi-tion showed a significant rate enhancement for the bis- and tris-imidazolines 62 and 63 over the reaction with mono-imidazoline61. This indicated that two imidazoline rings must be involvedin the activation of the substrate. Furthermore, because there is alarge difference in enantioselectivity between 62 and 63, they con-cluded that there are two active reaction sites, namely a desirablereaction site surrounded by two imidazoline rings responsible forthe enantioselective reaction, and an undesirable reaction site re-sponsible for a less selective reaction (Figure 1.10).68

To summarize, the concept of 2-imidazoline based organocata-lysts is relatively new and therefore not yet widely explored.However, the field is emerging and with more fundamental in-sight in the modes of activation the application of 2-imidazolineswill be more successful in the future.

28

Introduction

1.3 Synthesis of 2-Imidazolines

A plethora of synthetic methods using different starting materi-als has been developed since the first publication of 2-imidazolinecompounds in 1888.69 Some of the early methods are still beingused and were already reviewed in 1954.70 During the past twodecades the development of synthetic methods for 2-imidazolinesfocused more on diastereoselective and enantioselective reactions.On the other hand, the traditional methods have been modifiedand optimized as well for better efficiency.71–73

1.3.1 Condensation of 1,2-Diamines

One of the first and most widely applied method for the synthesisof 2-imidazolines 65 is the condensation of 1,2-diaminoethanes 64with a C1-carbon source (Scheme 1.12).

NH2

NH2R

R"C1 source"

N

HNR

R64 65

Scheme 1.12: General reaction scheme for synthesis of 2-imidazolinesby condensation of 1,2-diamines with a C1 carbon source.

Typical C1-sources include carboxylic acids,74–78 cyanides,79,80

esters,81 and aldehydes.82,83 The main advantage of this method isthe facile introduction of chirality when using enantiopure diam-ines. The continued popularity of this method is illustrated inparagraph 1.2.3, as most of the ligands and organocatalysts weresynthesized using this method. However, a shortcoming is thelack of stereocontrol when C2-unsymmetric 1,2-diamines are ap-plied. To overcome this limitation, Casey et al. developed an ana-logous one-pot reaction starting from β-aminoalcohols 66 (Scheme1.13).84

29

Chapter 1

OHR1

R2 NH2

R3COX OHR1

R2 NH

O

R3

SOCl2ClR1

R2 NH

O

R3

ClR1

R2 N

Cl

R3

SOCl2or PCl5

ClR1

R2 NH

NHR4

R3

R4NH2

N

NR1

R2R3

R4

NaOH

66 67 68

71 70 69

Scheme 1.13: Synthesis of chiral trans-2-imidazolines from cis β-hydroxyamines.

Although this approach is more labour-intensive, using(chiral) 1,2-aminoalcohols rather than 1,2-diamines, it provides aperfect platform to overcome the regioselectivity issue. The keystep in this approach is the selective amidation of 66, using an acidchloride. At this point the regioselectivity is established and fourmore steps are required to construct the imidazoline ring. Next,the alcohol in 67 was exchanged for a chloride to obtain 68. Theamidine part of the imidazoline is constructed by transformationof the amide in 68 to imidoylchoride 69 followed by reaction withan amine. Subsequent treatment with sodium hydroxide inducedcyclization by SN2 substitution of the chloride, and resulted in thedesired optically pure trans-2-imidazoline 71.

1.3.2 Imine-Isocyanide Reactions for the Synthesisof 2-Imidazolines

In the 1970s van Leusen85 and Schöllkopf86 independently de-veloped a base-promoted Mannich reaction between metallatedisocyanides and imines to deliver 2-imidazolines 74 and 77(Scheme 1.14 and 1.15). The procedure of Schöllkopf involves theα-lithiation of isocyanides 72 using n-butyllithium, that react withimines 73 (Scheme 1.14).

30

Introduction

NCH

R1H

NR2

R4R3

1) n-BuLi2) H2O

N

NR3

R4

R1H

R2

72 73 74

Scheme 1.14: Reaction between α-lithiated isocyanides with imines de-veloped by Schöllkopf.

Van Leusen used the same approach but employed tosyl-methyl isocyanide (TosMIC) derivatives 75, that are deprotonatedwith NaH, as the isocyanide input for the synthesis of 4-tosyl-2-imidazolines 77. Aromatization to the desired imidazoles 78 wasachieved by elimination of the 4-tosyl group using K2CO3.

Ts

NCTs

R1H

NR2

R3

1) NaH2) H2O

N

NR3

R1H

R2

75 7677

K2CO3

N

NR3

R1H

R2

78

Scheme 1.15: Imidazole synthesis by van Leusen.

Where van Leusen used isolated imines in the reaction, Siskoet al. were able to perform the reaction in a multicomponent fash-ion using amines, aldehydes and a range of TosMIC analogues inone pot.87,88 This MCR was successfully applied in combinatorialchemistry as it led to the discovery of pyrroloimidazoles as neuriteoutgrowth stimulators.89

Catalytic Asymmetric Imine-Isocyanide Reactions

In recent years, the demand for chiral 2-imidazolines led to thedevelopment of several asymmetric catalytic procedures for thisreaction. The first catalytic diastereoselective Mannich-type reac-tion was reported in 1996 by Hayashi et al. using Au(I)-catalysis,

31

Chapter 1

and they succeeded in the diastereoselective formation of cis-2-imidazolines (d.r. > 90:10) by reacting isocyanoacetates with N-sulfonylimines.90 The trans-isomer on the other hand, was formedpreferentially (d.r. = 95:5) in the presence of RuH2(PPh3)4 asshown by Lin et al. in 1997.91 More recently, other catalysts such asNHC-CuCl92 and palladium pincer complexes93 were developedfor the trans selective synthesis of 2-imidazolines.

Because of the demand for enantioselective methods, severalresearch groups further explored the synthetic potential of thisreaction for the catalytic enantioselective synthesis of chiral 2-imidazolines. The first example was reported by Lin et al. in 1999,who were inspired by the highly enantioselective synthesis ofoxazolines, via a reaction between methyl isocyanoacetate andaldehydes, catalyzed by chiral ferrocenylphosphine–gold com-plexes.94 This approach was successfully translated to the re-action between N-tosylaldimines 79 and ethyl isocyanoacetate80 (Scheme 1.16).95 The best performing catalyst system was0.5 mol% Me2SAuCl in combination with ligand 82, giving cis-imidazolines 81 preferably (> 90:10) in good ee’s (up to 88%).

NTs

ArEtO2C NC

AuClSMe2 (0.5 mol %)ligand (0.5 mol %)

CH2Cl2, 25 °C N

NTs

H

Ar

EtO2C

FePPh2

PPh2

N

N

ligand:

79 80 81

82dr (trans:cis) up to 4:96ee up to 88 %

Scheme 1.16: Catalytic enantioselective synthesis of cis-2-imidazolines.

A complementary catalytic method was reported by Szabó etal. Using chiral BINOL-based palladium pincer complexes 85the same reaction was observed, however, in this case with apreference for the formation of the trans-isomer of imidazoline84 (Scheme 1.17) with comparable ee’s, however, the diastereose-lectivity is lower (4:1).96

32

Introduction

NTs

ArMeO2C NC

1 mol % cat.

THF, 20 °C, 18 h N

NTs

H

Ar

MeO2C

ligand:

79 83 84

85dr (trans:cis) up to 4:1ee up to 86 %

PdOO

OP

OO

OP

I

Scheme 1.17: Catalytic enantioselective synthesis of 2-imidazolines.

In search for better enantioselectivities, Zhang et al. reportedthe first organocatalytic synthesis of 2-imidazolines using cin-chona derived alkaloids, again using methyl isocyanoacetate 83and N-sulfonylimines 79 as starting materials (Scheme 1.18).97

They reasoned that the chiral bifunctional catalyst 86 could activ-ate the acidic α-carbon atom of methyl isocyanoacetate 83 by de-protonation, and at the same time activate the imine by hydrogenbonding. This approach proved successful and afforded the de-sired 2-imidazolines in a d.r. up to 99:1 in favor of the trans-isomer.The obtained ee’s range from 5 to 70% and are highly dependenton the steric bulk of the aromatic ring on the imine carbon atom.The electron-withdrawing tosyl group on the imine proved essen-tial for the reaction to proceed as for example p-methoxyaniline orbenzylamine-derived imines led only to trace amounts of product.

N

Ar

Ts

MeO2C NC10 mol% cat

toluene, 4Å MS, rt48–72 h

N

NTs

Ph

MeO2C

dr (cis:trans) up to 99:1ee 5–70% N

HO

AcO N

cat: 86

79 83 84

Scheme 1.18: Organocatalytic synthesis of 2-imidazolines fromaldimines and isocyanoacetates.

In all the catalytic enantioselective examples shown, only α-

33

Chapter 1

unsubstituted glycine–derived isocyanoacetates were used. Na-kamura et al. aimed for the synthesis of 2-imidazolines bear-ing a quaternary stereogenic center on the 4-position, derivedfrom the application of α-substituted isocyanoacetates 88 withsulfonylimines 87 (Scheme 1.19).98 After screening several or-ganocatalysts, cinchona alkaloid–derived catalyst 90 proved to bethe best. A bifunctional role for the catalyst was proposed inwhich the quinucleine nitrogen atom deprotonates the α-acidicisocyanide, while at the same time the thiourea moiety activatesthe imine. Essential for the propriate orientation of the catalystwhen bonded to imine 87, is the 2-pyridyl group on the sulf-onylimine. At the same time, the ee shows a correlation withthe steric bulk on the ester as the ee increases when the esterbecomes more sterically demanding (methylester 66% vs. mes-itylester 82%).

NSO2Py

Ar

NC

CO2MesR

cat. 10 mol%4 Å molsieves

toluene, -20 °C N

NSO2Py

Ar

RMesO2C

N

MeO

HN

HN

S

CF3

CF3

N

cat:

dr (trans:cis) up to 99:1ee up to 90%

87 88 89 90

Scheme 1.19: Organocatalytic synthesis of 2-imidazolines from iminesand α-substituted isocyanoacetates.

So far only aldimines are reported in the reaction with iso-cyano acetates and no reports on the enantioselective reactionwith ketimines are available to date. This is most likely be-cause of their relatively low reactivity, together with the diffi-culty in enantiocontrol. However, Ortín and Dixon recently re-ported that cinchona alkaloid–derived aminophosphine ligand94, in combination with silver(I) oxide, is efficiently able to cata-lyze the reaction of isocyanoacetate esters 92 with benzophenone-derived N-diphenylphosphinoyl protected ketimines 91 to pro-

34

Introduction

duce 2-imidazolines 93 in high ee (93–99%) using 20 mol% catalyst(Scheme 1.20A).99 Again the combination of the protecting groupon the imine, as well as the steric bulk on the ester of the isocy-anide, was crucial for obtaining the products in high ee and d.r.,which limits the scope of the reaction.

NP

Ar R1

O

PhPh

CN CO2CHPh2

Ag2O (5 mol%)94 (20 mol%)

M.S. (4A),EtOAc60 h, –20 °C

NN

O

PPh2

N

H

NH

O

PPh2N

OMeN

NO

O

CN CO2Me

Ag2O (10 mol%)98 (20 mol%)

THF, 24 h, 24 °CN

N

MeO2C

OHO

N

MeO2C

19 examples,ee = 93 – 99%dr = 73:23 – 99:1

94

9813 examples,ee = 91 – 99%dr = 99:1

A

ON

N

O CO2Me

2.0 eq.

91 93

95 97

96

83

N

N

Ph2HCC2O

R1PAr

OPh

Ph

B

R1 = Me, Et

92

Scheme 1.20: Preparation of 2-imidazolines using silver-aminophosphine catalyst systems.

Following this report, Zhao et al. further expanded the scopeof this reaction to cyclic α-iminoesters 95 and methyl isocyano-acetate 83 using a slightly modified catalyst system 98 (Scheme1.20B).100 The fused imidazoline intermediate 96, however, un-dergoes a second reaction with the cyclic ester affording 5-oxazolesubstituted 2-imidazolines 97 diastereoselectively in high ee’s (91–99%).

The same reaction as the one reported by Ortín with compar-

35

Chapter 1

able results, appeared somewhat later in the literature (Scheme1.20A).101 The only difference is in fact the catalyst: copper in-stead of silver, a modified cinchona alkaloid based ligand (99) andCs2CO3 as catalytic base to promote the reaction (Scheme 1.21).

NP

Ar Me

O

PhPh

CN CO2CHPh2

Cu(OTf)2 (10 mol%)99 (10 mol%)Cs2CO3 (20 mol%)

M.S. (5A), THF3–48 h, –20 °C

NN

ON

N

H

15 examples,ee = 91 – 99%dr = 81:19 – 92:8

9991 93N

N

Ph2HCC2O

MePAr

OPh

Ph

CF3

92

Scheme 1.21: Enantioselective copper catalyzed addition of isocyano-acetates to N-diphenylphosphinoyl protected ketimines.

MCR Approach (O3-CR)

Despite the successful enantioselective catalytic systems de-scribed in the previous paragraph, all examples are limited inscope and require protective groups on the imines. As a con-sequence, the applicability of these reactions is limited and, es-pecially in combinatorial chemistry, these methods are not veryuseful. To overcome this problem, our group developed in 2003a multicomponent variant of this reaction starting from amines,aldehydes or ketones and α-acidic isocyanides (Scheme 1.22).

36

Introduction

R1NH2

O

R3R2

EWG NC

R4

Na2SO4(AgOAc)

CH2Cl2, rt N

NR1

R3 R2

R4EWG

100 105

NR1H

R3

R2EWGN

R4

C

NHR1

R2

R3 N

R4 EWG

CN

NR1H

EWGR4

R3R2

101103 104

1,2-proton shift

102

Scheme 1.22: Multicomponent approach for the synthesis of 2-imidazolines.

In the initially reported reaction, the imine is formed in situby stirring a solution of an aldehyde or ketone and an amine inCH2Cl2 in the presence of a drying agent (Na2SO4). Subsequentaddition of the α-acidic isocyanide 100 resulted in the formation ofa wide range of 2-imidazolines in moderate to excellent yields.102

The mechanism is proposed to be similar as the one studied bySchöllkopf in the 1970s,86 i.e. a Mannich type addition of depro-tonated isocyanide 102 to (protonated) imine 101, followed bycyclization to 104, that undergoes a 1,2-proton shift to yield im-idazoline 105. Contrary to the reaction reported by Schöllkopf,no additional base is required to deprotonate the isocyanide, mostlikely because the imine is basic enough to perform this deproton-ation.

Using CH2Cl2 as the solvent, the reaction initially proceededwith 9-isocyanofluorene or (α-functionalized) isocyanoacetates incombination with a range of aldehydes and amines.102 In fur-ther studies the reaction was extended to p-nitrobenzyl isocyanideand ketones could also be used. However, this required 2 mol%AgOAc as catalyst. Ag(I) most likely coordinates to the terminalisocyanide carbon atom, increasing the α-acidity of the isocyanideas well as the NC electrophilicity.103 A subsequent solvent studyshowed that the reaction rate could be increased when more polar

37

Chapter 1

solvents were used. Furthermore, using MeOH as solvent, the useof silver catalysts was not strictly necessary.104

This reaction was applied for the combinatorial synthesis of4-aminoquinoline 2-imidazolines 109 by Chibale et al. in 2008(Scheme 1.23). The synthesized library was successfully evalu-ated in an in vitro SAR study against two strains of Plasmodiumfalciparum and Trypanosoma brucei (best ED50 = 33 nM) that are re-sponsible for the transmission of human malaria.105

NCl

HNNH2

CN CO2Me

RCHO

MeOH, 45 °C, 2h

43–99% yield

NCl

HNN

N

R

CO2Men

106a–c

107a–e

108 109a–n

n

Scheme 1.23: Application of the O3-CR to search for 2-imidazolinesactive against malaria.

1.4 Outline

Several methods are available for the synthesis of optically pure2-imidazolines as shown in this chapter. However, it also becameclear that these methods have certain drawbacks. Most of themrequire specific substrates or are limited in scope. In this thesisseveral approaches are explored to circumvent these limitations.An overview of our investigations is shown in Scheme 1.24.

38

Introduction

NR

RR

EWG NC

N

NR

H

RR

EWGR

R

Chapter 3 N

NR

R

RH

EWGH

R = SO

EWG NC

EWG

Chapter 4

R = SO

Chapter 5

R

HN

OAlkyl

NS

AgX*

Chapter 2

HNR

NC

EWG

SO

N

NH

H

R

EWGEWG EWG

RNC EWG

N R

Scheme 1.24: Investigated approaches for the enantioselective syn-thesis of 2-imidazolines.

In chapter 2 we present the findings from our study to cata-lyze the MCR described in paragraph 1.3.2 enantioselectively.In chapter 3 the development of a trans-selective 1,3-dipolarcycloaddition to produce tetrasubstituted 2-imidazolines is de-scribed, that is based on the extension of the previously de-veloped imidazoline-3CR. Next to the development and optim-ization study, an extensive computational study is also presentedthat allowed us to rationalize the obtained results.106 In chapter4 the enantioselective synthesis of 2-imidazolines using an chiralauxiliary is described. Optimization of the reaction conditions ledto the isolation of unprecedented isocyanides that we were ableto transform to optically pure 2-imidazolines. We also presentthe application of this isocyanide in the Ugi and Passerini reac-

39

Chapter 1

tion.107 Chapter 5, deals with the unexpected reactivity of alkyl-sulfinylimines that were obtained when expanding the scope ofthe reaction in chapter 4.108

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45

Chapter 2

CatalyticEnantioselectiveApproach toward2-Imidazolines

Abstract

In this chapter we present the enantioselective imidazoline-3CR using acombination of metal and organocatalysis. Ketones, amines and α-acidic isocy-anides are reacted to give enantioenriched 2-imidazolines using C2-symmetricBINOL-based phosphoric acid silver(I) salts. In addition, we present ourfindings in the synthesis of a new class of chiral anions for the application incatalysis.

Chapter 2

2.1 Introduction

Catalysis for the introduction of chirality has emerged as a power-ful tool in asymmetric synthesis.1,2 One of the advantages ofasymmetric catalysis over other methods such as the use of chiralstarting materials or chiral auxiliaries, is the amount of optic-ally pure material needed for the efficient generation of enantio-enriched products. While a stoichiometric amount of chiral ma-terials is required in these approaches, catalysis requires only sub-stoichiometric amounts of chiral material to produce large quant-ities of enantio-enriched product.

Asymmetric catalysis can be divided in three sub-classes. Thefirst and most abundant is transition metal catalysis, relying onchirality transfer from chiral ligands during the catalytic cycle.Chiral ligands bonded directly to the metal are thus responsiblefor controlling the product chirality.3,4 However, rational liganddesign is difficult due to the complex nature of asymmetric cata-lysis resulting in high cost and effort for the identification andpreparation of the optimal catalysts. Furthermore, the use ofnoxious and/or scarce metals, which, although only present intrace amounts, can contaminate the final organic product. Theadditional lack of orthogonality with a wide range of functionalgroups, and in some cases the need to operate under rigorouslyanhydrous or anaerobic conditions, make transition-metal cata-lysis not suitable for every application.

Biocatalysis, the second class, uses enzymes to perform enanti-oselective transformations.5–7 Enzymes isolated from cells or evenwhole cells containing enzymes, are used as catalysts in this ap-proach. Although a lot of progress is made in this field, often ob-served drawbacks of biocatalysis are narrow substrate scope andinsufficient stability of the enzymes under the operating condi-tions.

Alternatively, the third approach uses low molecular weightmetal-free molecules as catalysts and is nowadays generallyknown as organocatalysis.8 One of the first reports on organocata-lysis stems from 1971, in which proline was used as asymmet-ric organocatalyst for the intramolecular asymmetric Aldol reac-

48

Catalytic Enantioselective Approach toward 2-Imidazolines

tion of triketones.9,10 The concept was further elaborated someyears later by Wynberg and Staring who reported on the asym-metric chincona alkaloid catalyzed formation of 4-substituted 2-oxetanones.11,12 Although at first this new concept was ignored,it has emerged as a powerful tool in asymmetric synthesis since2000.13,14 The difference with transition metal catalysis is themode of activation the substrates. Where in transition-metal cata-lysis the substrates are activated by coordination of the metal cata-lyst, organocatalysts offer the possibility to either covalently ac-tivate substrates forming reactive intermediates, such as enam-ines and iminium ions in the case of secondary amine based cata-lysts,15 or by activation through hydrogen bonding or protonationin Brønsted acid catalysis (Figure 2.1).16

XR2

R1 H

H

Y

Y

XR2

R1 HY

XR2

R1 H

Y

A B C

Figure 2.1: Brønsted acid activation of substrates. A) Double hydrogen-bond activation, B) single hydrogen-bond activation and C) Brønstedacid activation.

The concept of combining Brønsted acid organocatalysis withtransition-metal catalysis has recently emerged as a successfulapproach in asymmetric catalysis.17–21 It allows for new enan-tioselective catalytic transformations pursuing enantiocontrol bymeans of chiral anions rather than chiral ligands (Figure 2.2).

M+L x- M+ x-L

Ligand control Anion control

Figure 2.2: Ligand vs. anion controlled asymmetric catalysis.

49

Chapter 2

The concept can be described by two definitions. The first isnamed Dual (Cooperative) Catalysis and was introduced by Jac-obsen in 2004: “The dual catalytic approach takes advantage of sim-ultaneous activation of the electrophile as well as the nucleophile bytwo different but compatible catalysts”.22 This means that two sep-arate catalysts are required to activate the substrates, while in thesecond definition, named Asymmetric Counterion–Directed Cata-lysis (ACDC) by List in 2006, the definition reads: “Asymmetriccounterion–directed catalysis refers to the induction of enantioselectivityin a reaction proceeding through a cationic intermediate by means of ionpairing with a chiral, enantiomerically pure anion provided by the cata-lyst”.21 This means that one catalyst delivers both the cation foractivation of a reactant as well as the anion to form the final chiralion pair. As a consequence this definition also includes element-ary Brønsted acid organocatalysis. However, it must be noted thatthese definitions cannot be seen totally separated from each other.In most examples an interplay between the two concepts cannotbe completely excluded. In the context of this thesis we refer toACDC also when the active catalyst is formed by a combinationof two compounds.

Cooperative catalysis and ACDC are particularly powerful be-cause a relatively small set of chiral anions is capable of catalyzinga range of reactions. Essential in this approach are the chiral C2-symmetric BINOL-based phosphoric acid diesters (BPAs 1, Figure2.3). These phosphoric acids were developed by Akiyama andTerada in 200423,24 and have successfully been applied in severalkey organocatalytic transformations since then.16,25,26

OP

O O

OH

R

R

OP

O O

NH

R

R

Tf

1 2

R

R3

OO

S

S

NH

OO

OO

Figure 2.3: Examples of BINOL-based phosphoric acids. (R = Ar,Si(Ph)3).

50


In order to achieve an efficient chirality transfer during cata-lytic reactions, two aspects are of importance. First, it is essen-tial to have suitable substituents on the 3- and 3’-positions of thebinaphtol backbone (Figure 2.3). The role of these substituentsis the creation of a chiral pocket around the anionic center ofthe phosphoric acid. Therefore, these groups often need to berather bulky. The second important aspect for catalyst activityis the acidity of the phosphoric acid. While the pKa of the par-ent phosphoric acid (around 3.0) is sufficient for most reactions, alower pKa is required for efficient protonation in other reactions.26

Therefore catalysts such as N-triflyl phosphoric amides 227,28 andbis(sulfuryl)imides 329 having alternative acid functionalities thatlower the pKa were developed. However, it must be noted that theacidity is most important in catalytic reactions where the phos-phoric acid has a double role as both activator and chiral coun-terion.

To illustrate the potential of ACDC, we present a two selec-ted examples. The first example is one of the early successful re-ports by Toste et al. in 2007 on the gold-catalyzed intramolecu-lar hydroalkoxylation of δ-allenols 4 (Scheme 2.1), that gave onlypoor ee’s (0–8% ee) using chiral diphosphine ligands.30 The chiralcounter ion approach, on the other hand, proved to be muchmore effective. Using BPA silver salts 7 as the chiral anion sourcein combination with a gold catalyst, ee’s up to 97% were ob-tained. The role of the silver ion in 7 is to activate the precatalystdppm(AuCl)2 by chloride abstraction. Next, the gold catalyst isable to coordinate to allene 4, creating cationic complex 5 (Scheme2.1). At this point the cationic complex is likely to form an ion pairwith the binaphtyl phosphate anion of 7. Subsequent nucleophilicintramolecular attack of the alcohol on the activated allene affordsthe desired products 6 in high yield and ee.

51

Chapter 2

•OH 2.5 mol% dppm(AuCl)2

5 mol% 7e

Solvent

OH

OP

O O

OAg

R

R

7e, R = 2,4,6-i-Pr-C6H2

4 6

Solvent = CH3NO2

acetone

CH2Cl2

THF

benzene

60% yield, 18% ee

71% yield, 37% ee

76% yield, 65% ee

83% yield, 76% ee

90% yield, 97% ee

•OH

Au7e

5

Scheme 2.1: Intramolecular chiral counter-ion directed enantioselectivehydroalkoxyalation of δ-allenols 4

Not surprisingly, a clear trend in selectivity in relation to thesolvent polarity was observed. The less polar the solvent, thehigher the enantioselectivity. This underlines that the choice ofsolvent is also crucial for the ee, and can be explained by the factthat the phosphate anion of 7e forms a contact ion pair with thecationic intermediate 5 in apolar solvents, while the ion pairs aresolvent-shared or even solvent-separated in more polar solvents(Figure 2.4). It is evident that the larger distance between the twoions becomes, the lower the influence of the chiral anion will be.

+-

+

- +-

contact solvent-shared solvent-separated

Figure 2.4: Different types of ion-pairs depending on solvent polarity.

52


In 2007, Rüping et al. reported the asymmetric addition of acet-ylenes 9 to imines 8 using ACDC (Scheme 2.2).31 In this reactionboth substrates need to be activated in order to react. For thispurpose the authors used phosphoric acids 1 and silver acetate asbinary catalyst system. Their proposed mechanism is shown inScheme 2.3 and consists of two connected catalytic cycles (I andII). In cycle I, imine 14 is protonated by phosphoric acid 1 result-ing in the chiral ion pair 11. Simultaneously, in the second catalyticcycle, silver acetate and alkyne 13 react to give the nucleophilic sil-ver acetylide 12, that subsequently attacks the iminium ion of 11 inan enantioselective manner to afford product 16. Their survey ofdifferent catalysts nicely points out the importance of steric bulkon the 3 and 3’ position of the phosphoric acids. While catalyst1a (R = Ph) gave a poor ee of 14%, catalyst 1d, having larger 3/3’substituents (R = 9-anthracenyl), afforded product 16 in 82% ee.

N

HEtO

O

PMP

Ph

1a–d (10 mol%)AgOAc (5 mol%)

toluene, 10–12 h, 30 °C Ph

NHPMP

OEt

O

8 9 10

OP

O O

OH

R

R

R = phenyl 1-naphtyl

9-phenanthryl

9-anthracenyl

14% ee

10% ee

72% ee

82% ee

1a

1b

1c

1d

Scheme 2.2: Ag(I) chiral anion–controlled catalysis of for the alkynyla-tion of imines (PMP = p-methoxyphenyl).

53

Chapter 2

R

R

Ag

NHR

CO2RR

*

NR

HRO2C

NR

HRO2C

H

POO

O O*

POO

O OH*

AgOAcHOAc

POO

O OH*

POO

O OH*

I II

1112

1

13

16

141

1

15

NR

HRO2C

H

17

III

racemic backgroundreaction

OAc

POO

O OAg*

Scheme 2.3: Proposed catalytic cycle for the enantioselective silver-catalyzed alkynylation of imines.

Although the method was successfully developed, no full se-lectivity was obtained (highest ee = 91%). We speculate that theequilibrium between silver acetate and 1 may be responsible forthis. Acetic acid forms upon silver exchange from acetate to phos-phoric acid 1, that can activate a third (non-selective) catalyticcycle (Scheme 2.3, III). In this cycle, imine 14 is protonated byacetic acid creating an achiral ion pair 17 that leads to reduced se-lectivities. Because of this equilibrium it cannot be excluded thata mixture of acetic acid, silver acetate, 1 and 15 exists, facilitatingthe unselective background reaction.

We envisioned that the same approach would be feasibleto catalyze the imidazoline-3CR enantioselectively (Section 1.3.2,

54


Chapter 1). Similarly to the example by Rüping et al., theimidazoline-3CR is also catalyzed by silver(I) salts and also in-volves the activation of imines by protonation. We therefore ex-pect that this strategy should give comparable results in the MCR.The results of this investigation are described in section 2.3.

Simultaneously to this investigation we aimed for the expan-sion of available binaphtyl-based chiral anions. The availability ofmore efficient and more readily accessible anions is beneficial forthe exploration and optimization of new catalytic reactions. Ourefforts in this area are described in section 2.2.

2.2 Alternative Chiral Phosphoric Acids

2.2.1 Introduction

As discussed above, the most widely used catalysts for ACDC areBPAs 1. The chirality of these acids is located in the binaphtylbackbone of the catalyst, that consequently requires large stericbulk on the 3 and 3’ positions to create a chiral pocket aroundthe phosphoric acid for efficient chirality transfer during the reac-tion.25 Frequently used (bulky) substituents include (substituted)aromatic rings, halogens, alkyl groups and silanes.32 The syn-thesis of these catalysts, however, require four steps from opticallypure BINOL.23,24

In the case of more bulky substituents the method is even moreelaborate and requires more steps.33 We envisioned that stericbulk attached to the atoms adjacent to the phosphorus atom in-stead of the 3/3’ position of the naphthyl backbone, might presentpresent a much more effective approach. Nitrogen and carbonanalogues (18 and 19, Figure 2.5) provide this possibility. Calcu-lation (HF/3-21G(d))34 of the optimized structures indeed showsthat the directing groups are closer to the anionic center (Figure2.6).

55

Chapter 2

Ar

Ar

OP

O O

OH NP

N O

OH

Ar

Ar

PO

OH

Ar

Ar

Ar

Ar

1 18 19

Figure 2.5: BINOL-based phosphoric acids 1 and analogous structures.

Figure 2.6: Calculated structures (HF/3-21G*) of BINOL-based phos-phoric acid 1a (left), the nitrogen analogue 18a (R = Ph) (Middle) andcarbon analogue 19a (R = Ph) (Right). The geometry of 1a is overlaid ingreen in the middle and right structures for reference.

Moreover, replacing the oxygen atoms by nitrogen or carbonshould allow for modulation of the acidity of the catalyst. WhileBPAs are relatively acidic (pKa = 3.0–4.0 in DMSO)35,36, the pKa ofanalogues 18 and 19 are expected to be considerably higher.37

Phenyl-substituted phosphordiamidic acid 18a is accessible ina three-step synthesis starting from commercially available 1,1’-binaphthyl-2,2’-diamine 20 (BINAM, Scheme 2.4).38 The first stepis introduction of the directing groups on nitrogen that is accom-plished by a palladium–catalyzed Buchwald-Hartwig aminationto give diamine 21a. Phosphorylation of 21a using POCl3 affordsphosphoramidic acid chloride 22a, that is subsequently hydro-lyzed in an aqueous solution of 1M LiOH in H2O/CH3CN to af-ford the desired phosphoric acid 18a.

For the synthesis of the carbon-analogue 19 on the other hand,no synthetic procedure has been described in the literature.

56


NHPhNHPh

NH2NH2

Pd2(DBA)3, (+/-)BinapNaOtBu, DBU, PhBr

(tol) ∆ 90%

POCl3

(pyridine) 80% NP

NPh

Ph

Cl

O

1M LiOH(H2O/CH3CN);then H+/H2O

85%

NP

NPh

Ph

OH

O

20 21a 22a

18a

Scheme 2.4: Reported synthesis for the chiral phosphordiamidic acid18a.

2.2.2 Results and Discussion

We started with the synthesis of phosphordiamidic acids (R)-18a–d using the reported method by Ishihara et al.38 The Buchwald-Hartwig amination, employing a mixture of NaOtBu and DBU asbase, Pd2(dba)3 as the palladium source and (±)-BINAP as theligand, proceeds in moderate to excellent yields (Table 2.1). Thereaction between bromobenzene and (R)-BINAM provided (R)-21a in quantitative yield after 2 hours at reflux (entry 1). Onthe other hand, p-substituted electron-deficient bromobenzenes(p-fluoro bromobenzene and p-nitro bromobenzene, entries 2 and3) required longer reaction times and gave lower yields ((R)-21b,88% and (R)-21c, 50%). Sterically demanding 2,4,6-triisopropylbromobenzene reacted even slower and gave (R)-21d in 38% yieldafter 16 hours (entry 4).

57

Chapter 2

Table 2.1: Buchwald-Hartwig amination of (R)-21 with severalbromobenzenes.

NH2NH2

Ar-Br, NaOtBu, DBUPd2(dba)3 (2.5 mol%)(+/-)-BINAP (5 mol%)

Toluene, reflux

NHArNHAr

(R)-20 (R)-21

Entry Ar Time (h) Product Yield (%)a

1 Ph 2 h (R)-21a quant.2 4-F-C6H4 16 h (R)-21b 883 4-NO2-C6H4 3 h (R)-21c 504 2,4,6-triisopropylphenyl 16 h (R)-21d 38

a Isolated yield.

Unfortunately, the subsequent phosphorylation of the substi-tuted BINAM-products (R)-21b–21d appeared to be troublesome.Using the reported conditions (POCl3, in pyridine at 110 ◦C) wasonly successful for (R)-21a (R = Ph), affording phosphordiamidicacid chloride 22a in 40% yield. The electron-poor diamine 21band sterically demanding (R)-21d were unreactive under theseconditions and only starting material was recovered (Scheme 2.5A). This lack of reactivity can be rationalized by the fact that theelectron-deficient aromatic groups reduces the nucleophilicity ofthe amine nitrogen for 21b, while sterics prevent phosphoryla-tion for (R)-21d. To increase the nucleophilicity, we lithiated theamines (R)-21b and (R)-21d by reacting them with n-butyllithiumbefore a mixture of pyridine and POCl3 was added (Scheme 2.5B). Again, mostly starting material was recovered, although ac-companied by decomposition products.

Because POCl3 did not react with (R)-21b/d or lithiated (R)-21b/d, we used the more electrophilic PCl3 as phosphorylationagent (Scheme 2.6).39 Consequently, this approach requires an ad-ditional oxidation of the phosphorus atom, in order to arrive atthe phosphoramidic acids 18.

We treated the amines (R)-21b and (R)-21d with PCl3 in the

58


NH

NHR

R

POCl3 (1.1 equiv)

110 °Cpyridine, 16h

n-BuLi (2.1 equiv)

–78 °CTHF, 1h

N

NR

R

LiLi

POCl3 (1.1 equiv) pyridine (10 equiv)

–78 °C to rtTHF, 16h

N

NR

R

PO

Cl

XA

B

(R)-21b(R)-21d

(R)-23b(R)-23d

(R)-22b(R)-22d

Scheme 2.5: Attempted conditions for the phosphorylation of (R)-21

N

NR

R

P Br(R)-21b(R)-21d

PCl3, Et3N

THF, –78 °C to rt N

NR

R

P Cl

X

(R)-21b(R)-21d

Xn-BuLi, then PCl3

THF, –78 °C to rt

PBr3, Et3N

THF, –78 °C to rtX

Xn-BuLi, then PBr3

THF, –78 °C to rt

(R)-24b(R)-24d

(R)-25b(R)-25d

A

B

Scheme 2.6: Attempted strategies for the phosphorylation of 21

presence of Et3N to capture HCl generated during the reaction(Scheme 2.6 A). Also using this approach, no reaction was ob-served and only starting material was obtained. Lithiation of theamines 21 using n-BuLi prior to the addition of PCl3 was also un-successful. Even the use of the highly reactive PBr3 under theseconditions, unfortunately, did not lead to any reaction (Scheme2.6 B).

In view of time and the difficulties we faced during the phos-phorylation, we decided to abandon the development of this syn-

59

Chapter 2

thetic route. Instead, we decided to investigate the imidazoline-3CR (see Section 2.3) using the commercially available BINOL-based phosphoric acids to obtain a proof of principle. Because weplanned to use the silver salt of the phosphoric BPAs as catalystin this investigation, we converted several commercially availableBPAs to the corresponding silver salts.

Generation of the Silver Salts

Although the generation of silver BPAs was reported on gram-scale in the past by treatment of silver carbonate in CHCl3,40 wefaced difficulties in the isolation of the product when we per-formed the reaction on a 10 mg scale. We therefore applied adifferent strategy, i.e. based on a method for the synthesis of sil-ver(I) diphenyl phosphate (AgDPP) (Scheme 2.7).41 The reportedmethod begins with diphenyl phosphate acid chloride that uponhydrolysis (NaOH/H2O) affords an aqueous solution of the di-phenyl phosphate anion. The required phosphate silver salt pre-cipitates, upon treatment of this solution with AgNO3. It was forus more convenient to begin with diphenyl phosphate 26 (DPP).Upon deprotonation with 0.5 equiv Na2CO3 in water, the DPP an-ion dissolved. Precipitation of AgDPP was then achieved by treat-ment with an aqueous solution of AgNO3 (1.0 equiv) that afforded27 (85%) after filtration (Scheme 2.7).

POPhO

PhO OH

1) Na2CO3 (0.5 equiv)2) AgNO3 (1.0 equiv)

H2O, rt, 15 minP

OPhO

PhO O Ag85%

26 27

Scheme 2.7: Generation of silver(I) diphenyl phosphate.

Treatment of the BINOL–based phosphoric acid (R)-1e (R/R’= 2,4,6-iPrC6H2), however, afforded a suspension after deproton-ation with Na2CO3 in water. Apparently, the sodium salt of (R)-1e is only slightly soluble in water. We therefore carefully addedacetonitrile as co-solvent in order to fully dissolve the sodium salt.

60


When this solution was subsequently treated with AgNO3, filtra-tion afforded only a few percent of the required silver salt. Mostlikely the silver salt is partially soluble in the water/acetonitrilemixture. Indeed, when the acetonitrile was evaporated from thefiltrate, the remaining part of the silver salt (R)-7e also precipit-ated. After filtration the combined yield of (R)-7e was 90% (Table2.2, entry 1).

The same procedure was followed for two other BPAs havingdifferent 3/3’-substituents that afforded the silver salts (R)-7f (R= SiPh3) and (R)-7g (R = 3,5-(F3C)C6H3) in 83 and 92% yield, re-spectively (entries 2 and 3). For structure (R)-29, having an altern-ative C2-symmetric backbone, the silver salt generation was lessefficient (67% yield, entry 4).

61

Chapter 2

Table 2.2: Silver salt generation.

OP

O O

OH

R

R

Na2CO3

H2O/CH3CN OP

O O

ONa

R

R

AgNO3

H2O OP

O O

OAg

R

R(R)-1 (R)-28 (R)-7

Entry Product Yield

1 (R)-7eO

PO O

OAg

iPr

iPriPr

iPr

iPr iPr

90

2 (R)-7fO

PO O

OAg

SiPh3

SiPh3

83

3 (R)-7gO

PO O

OAg

CF3

CF3

CF3

CF3

92

4 (R)-29 PhPh OP

O O

OAg 67

2.2.3 Conclusion

In conclusion, the synthesis of a series of BINAM-based phos-phoric acids appeared to be problematic. Although the Buchwald-

62


Hartwig reaction to introduce the directing groups did work,the phosphorylation using several phosphorylation agents failed,most likely due to insufficient reactivity of the amine nitrogenatoms due to sterics or reduced nucleophilicity as a result of elec-tron withdrawing R-groups on nitrogen. For the generation ofphosphoric acid diester silver salts, we have developed an ef-ficient method with a precipitation reaction using silver nitrate.This method was successful for a selection of phosphoric acids.

2.3 Catalytic Asymmetric Imidazoline-3CR

2.3.1 Introduction

As discussed above, we envisioned the silver(I)-catalyzedimidazoline-3CR (2.8) as a suitable reaction for ACDC and thusaim for an enantioselective reaction. Similarly to the reaction re-ported by Rüping et al., the nucleophilic reaction partner (an iso-cyanide) is activated by silver, while the electrophilic imine is ac-tivated by protonation (Scheme 2.9).

The proposed mechanism of this reaction begins with the ac-tivation of isocyanide 32 by silver(I).42,43 The activated isocyanide34 is then deprotonated by in situ formed imine 35 resulting in ni-trilium ion 36 and iminium ion 37. The important aspect in thesubsequent step is the ion pairing between the 37 and the chiralcounter ion (X*�). This enables the subsequent attack of the de-protonated isocyanide 36 on this chiral ion pair 37 to occur enan-tioselectively. With the new stereocenter established, cyclizationof 38 proceeds by intramolecular nucleophilic attack of the aminenitrogen atom to the isocyanide carbon atom to afford interme-diate 39. The subsequent 1,2-proton shift finally regenerates thecatalyst and at the same time, affords the desired 2-imidazoline33. In the case of aldehydes or prochiral ketones (R2 6= R3 in 31,Scheme 2.8) two stereocenters are formed during the reaction. Al-though without chiral catalyst the reaction has a preference for theformation of the trans diastereomer, the obtained d.r.’s are mostlypoor.44

63

Chapter 2

R1NH2

O

R3R2

EWG NC

stereoselective syntheses of 2-imidazolines...chapter 1 introduction n r n 2 r1 r3 r4 synthesis...

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