© 2017 bobby owen garrett

ENANTIOSELECTIVE HYDROGENATION OF UNFUNCTIONALIZED ALKENES USING

STACKPHOS

By

BOBBY OWEN GARRETT

A THESIS PRESENTED TO THE GRADUATE SCHOOL

OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF SCIENCE

UNIVERSITY OF FLORIDA

2017

3

ACKNOWLEDGMENTS

I would like to thank first Dr. Aponick for giving me the opportunity to be here; this has

truly been an experience I will always treasure. I’d also like to thank the University of Florida

and the Department of Chemistry for having a great place for people to gather and do science. I

would like to thank my friends along the way that have been with me through the different times

of my life. I hope that even if we don’t see each other every day in the future, that we can still

count on each other as friends. Lastly, I’d like to thank my family. I know the life I’ve lived is a

lot different from the experiences many in my family have had, but they always find a way to

keep me humble and kind.

4

TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...............................................................................................................3

LIST OF SCHEMES........................................................................................................................5

LIST OF FIGURES .........................................................................................................................6

LIST OF ABBREVIATIONS ..........................................................................................................7

ABSTRACT .....................................................................................................................................9

CHAPTER

1 INTRODUCTION ..................................................................................................................11

Phosphine Experimentation ....................................................................................................11 Atropisomeric Ligand .............................................................................................................12

Iridium Catalysis .....................................................................................................................13 Enantioselective Hydrogenation Using Iridium .....................................................................13 Motivation ...............................................................................................................................15

2 ENANTIOSELECTIVE HYDROGENATION USING STACKPHOS ................................16

Synthesis of Catalyst ...............................................................................................................16

Test Reactions .........................................................................................................................16 Ligand Study ...........................................................................................................................17

1,1-disubstituted Olefins .........................................................................................................18 Synthesis of Substrates ...........................................................................................................19

3 CONCLUSION.......................................................................................................................22

4 EXPERIMENTAL ..................................................................................................................23

1. General Procedure to Synthesize Ligand-Iridium Complex ...............................................24 2. General Procedure for Hydrogenation ................................................................................24

LIST OF REFERENCES ...............................................................................................................44

BIOGRAPHICAL SKETCH .........................................................................................................46

5

LIST OF SCHEMES

Scheme page

1-1 First homogeneous asymmetric hydrogenation. ................................................................11

1-2 Kagan and Knowles rhodium-catalyzed enantioselective hydrogenations. .......................12

1-3 Noyori and Crabtree selective hydrogenations. .................................................................13

1-4 Pfaltz enantioselective hydrogenation of stilbenes. ...........................................................14

1-5 Hydrogenation of minimally functionalized olefins. .........................................................14

2-1 Synthesis of precatalyst for enantioselective hydrogenation. ............................................16

2-2 First attempts of enantioselective hydrogenation. .............................................................16

2-3 Standard hydrogenation conditions, and various ligands used in the reaction. .................18

2-4 Synthesis of test substrates.................................................................................................20

6

LIST OF FIGURES

Figure page

1-1 (S)-StackPhos. ....................................................................................................................15

2-1 First attempts at 1,1-disubstituted hydrogenations. ...........................................................19

2-2 Class of compounds synthesized for hydrogenation. .........................................................20

7

LIST OF ABBREVIATIONS

BARF

BINAP

Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate

2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

br

C

COD

d

DABCO

DCM

DMAP

DMSO

dr

ee

g

h

1H NMR

HPLC

Broad

Celsius

Cyclooctadiene

Doublet

1,4-diazabicyclo[2.2.2]octane

Dichloromethane

4-Dimethylaminopyridine

Dimethylsulfoxide

Diastereomeric excess

Enantiomeric excess

Gram

Hour

Proton nuclear magnetic resonance

High pressure liquid chromatography

HRMS

L-DOPA

High resolution mass spectra

L-3,4-dihydroxyphenylalanine

M

m

MHz

min

mg

mL

Molar

Multiplet

Megahertz

Minute

Milligram

Milliliter

8

mmol

mol

PDC

PHOX

Millimoles

Mole

Pyridinium dichromate

Phosphinooxazolines

psi Pounds per square inch

q

s

t

TBSCl

THF

Quartet

Singlet

Triplet

Tert-butyldimethylsilyl chloride

Tetrahydrofuran

TLC Thin-layer chromatography

TMS Tetramethylsilane

9

Abstract of Thesis Presented to the Graduate School

of the University of Florida in Partial Fulfillment of the

Requirements for the Degree of Master of Science

ENANTIOSELECTIVE HYDROGENATION OF UNFUNCTIONALIZED ALKENES USING

STACKPHOS

By

Bobby Owen Garrett

May 2017

Chair: Aaron Aponick

Major: Chemistry

Ligand-promoted catalysis has played a vital role in the synthesis of complex molecules

due to its ability to accelerate chemical reactions. While there are many classes of ligands used

throughout many fields, P,N-ligands have emerged as highly effective ligands for several

enantioselective transformations. With the development of StackPhos in the Aponick lab in

2013, it was shown that this imidazole-based ligand could achieve high yields and

enantioselectivities in the A3 coupling. Consequently, work has begun both to study the scope of

reactions StackPhos can catalyze enantioselectively and to further study this ligand and

understand its reactivity. To this end, an enantioselective iridium-catalyzed hydrogenation of

unfunctionalized alkenes using StackPhos has been studied. Face selective reduction of alkenes

is one of the most powerful methods to create tertiary and quaternary chiral centers and

synthesize natural products and drug molecules. Initially, a model substrate was studied by

hydrogenating trans-α-methyl stilbene. Once it was confirmed that StackPhos itself was the best

ligand in our study in both reactivity and enantioselectivity, other substrates were tested. Due to

the observed poor reactivity of trans-α-methyl stilbene, it was decided to decrease the steric bulk

around the alkene by moving from a tri-substituted olefin to a 1,1-disubstitued olefin. This

indeed enabled higher conversion of certain substrates, but with others not reacting at all, likely

10

due to electronic effects. While the reactivity of 1,1-disubstituted alkenes was higher, bulky

substrates were still unable to be hydrogenated. Additionally, the enantioselectivity was difficult

to determine by HPLC due to the nonpolar nature of the compounds studied.

11

CHAPTER 1

INTRODUCTION

Enantioselective Hydrogenation: In natural product and drug synthesis, one of the most

vital considerations is how to establish the specified chiral centers. There are many ways to set

chiral centers, and enantioselective hydrogenation is a powerful method used. Hydrogenation of

double bonds is a simple, and straightforward method to produce chiral compounds in an atom-

economical way. High functional group tolerance is observed and often provides desired

compounds with quantitative yields in excellent enantioselectivities.1 While expensive transition

metals such as rhodium and iridium are generally required, they can often be used in less than

1% catalyst loading due to their high turnover rate. The first observed homogenous asymmetric

hydrogenation was pioneered by Knowles at Monsanto in 1968.2 He used an a chiral version of

Wilkinson’s catalyst by replacing triphenylphosphine with chiral phosphine 3 and obtained

minimal selectivity (Scheme 1-1). This was an important preliminary result because the transfer

of ligand chirality to catalyst facial selectivity was achieved in this hydrogenation process.

Scheme 1-1. First homogeneous asymmetric hydrogenation.

Phosphine Experimentation

Significantly higher selectivities were first observed by Kagan in 1971 and Knowles in

1972 with rhodium-catalyzed hydrogenation using ligands 6 and 9 respectively but using a

different substrate (Scheme 1-2).3,4 This moved the field forward by displaying the ability of

rhodium-based catalyst systems to potentially provide high levels of selectivity. In 1975,

12

Knowles would use the bidentate ligand 12 to make L-DOPA, a drug for Parkinson’s Disease, in

an industrial scale.5

Scheme 1-2. Kagan and Knowles rhodium-catalyzed enantioselective hydrogenations.

Atropisomeric Ligand

In 1980, Noyori reported a 99% ee hydrogenation of the enamine 13 (Scheme 1-3).6

These hydrogenations were highly effective, but required a directing group to obtain good

selectivity. However, Noyori’s work showed that BINAP could display a more generalized

reactivity as opposed to the specific ligand-substrate relationship in selectivity observed in earlier

reports.

13

Iridium Catalysis

Crabtree demonstrated in 1986 that iridium salts could be used as hydrogenation catalysts

as well. He reduced unsaturated menthol 15 with 99% yield and 96:4 dr using what is now

called Crabtree’s catalyst at 1.2 atm.7 However, an alcohol directing group was required in order

to get high selectivity.

Scheme 1-3. Noyori and Crabtree selective hydrogenations.

Enantioselective Hydrogenation Using Iridium

In 1998, the Pfaltz group hydrogenated a series of tri-substituted, unfunctionalized

alkenes. They were able to obtain excellent enantioselectivities by modifying the Crabtree

catalyst using their PHOX-type bidentate P, N ligand instead of tri-cyclohexylphosphine and

pyridine (Scheme 1-4).8

14

Scheme 1-4. Pfaltz enantioselective hydrogenation of stilbenes.

Under their first set of conditions using the iridium-PHOX catalyst with the tetrafluoroborate

anion, only 50% yield was obtained. They found that using a more non-coordinating anion like

BARF dramatically increased the yield to 99% at only 0.3 mol% catalyst loading while retaining

99% ee. When more coordinating anions such as tetrafluoroborate and halides were used, lower

reactivity was observed. Even at 0.05 mol% catalyst loading, they were able to obtain the

product 18 in full conversion, granted at a reduced enantioselectivity. To demonstrate the power

of this method, Pfaltz and coworkers submitted -tocotrienyl acetate 19 to their reaction

conditions using the pyridine-phosphinite ligand 20.9 They selectively obtained 21 as 98% of the

(R,R,R) isomer in quantitative yields (Scheme 1-5).

Scheme 1-5. Hydrogenation of minimally functionalized olefins.

15

Motivation

Because of the aforementioned reactivity of P,N ligands and the high selectivity

observed, hydrogenation using different chiral P,N ligands could afford similar success. Such a

ligand was developed in the Aponick Lab in 2013, namely StackPhos (Figure 1-1.).10 StackPhos

is an axially chiral imidazole-based biaryl P, N-ligand developed in 2013. Many reports exist

using P, N-ligands and iridium catalytic systems, however, most ligands have point chirality or

are axially chiral 6,6-biaryl ligands. Our scaffold has an atropisomeric 6,5-biaryl based system

utilizing aryl-aryl stacking which provides steric and electronic features unique to StackPhos.

This would create a different catalytic environment and could give improved results.

Figure 1-1. (S)-StackPhos.

16

CHAPTER 2

ENANTIOSELECTIVE HYDROGENATION USING STACKPHOS

Synthesis of Catalyst

The first task at hand was to synthesize the hydrogenation catalyst incorporating StackPhos in

order to perform enantioselective hydrogenation (Scheme 2-1).

Scheme 2-1. Synthesis of precatalyst for enantioselective hydrogenation.

Test Reactions

StackPhos was made via the reported procedure.10 The desired metal salt 22 was

obtained quantitatively as a red solid after one hour of stirring (Scheme 2-1). Our test substrate

was trans--methyl stilbene 17 and we subjected it to the reaction conditions for 24 h garnering

only trace amounts of the desired compound 18 (Scheme 2-2).

Scheme 2-2. First attempts of enantioselective hydrogenation.

Decreasing the amount of solvent used from 2 mL to 0.3 mL in order to increase

concentration and heating to 50 °C afforded 37% conversion to the product by 1HNMR. In

Scheme 2-2, only racemic StackPhos had been used in the hydrogenations. From this point

forward, enantiopure Iridium complexes of StackPhos in the range of 95-99% ee were used.

17

With non-racemic catalyst, hydrogenation of 17 gave 33% conversion and 18 in 83% ee. This

result was exciting due to the observed high enantioselectivity, but also because this is the first

example of an elevated temperature reaction utilizing StackPhos. This may indicate that while

the free ligand would racemize at this temperature in the time allotted, StackPhos does not

racemize when complexed to iridium in this way.

Ligand Study

Intrigued by these results, but unsatisfied about heating an enantioselective

transformation for reactivity, changes in reaction conditions were required. The concentration of

the reaction had been increased to as high as possible considering the difficulties in handling the

reaction effectively and dissolving the reagents. We didn’t want to let the reaction go for longer

than 24 h since that was already as long or longer than literature precedents. In further reactions,

we increase the standard pressure of hydrogen to 1000 psi from 725 psi to potentially provide

more reactivity. The other commonly used solvent in these transformations, toluene, was tested

but only provided a 10% conversion. We reduced the catalyst loading, which increased the

conversion to 37%. Having exhausted all other means, modification of the ligand was deemed

necessary and several ligands obtained from other group members were used to test for

reactivity. Me-StackPhos was obtained from Sourabh Mishra in 97% ee as well as racemic

phenanthroline ligand 24. The para-fluoro ligand 23 was obtained from Ji Liu as the racemate.

Benzimidazole ligand 25 was synthesized from an intermediate given by Dr. Cardoso. After

submission to the reaction conditions, Me-StackPhos was the only one besides StackPhos to

show significant yield at 24% and the ee was slightly lower at 67% (Scheme 2-3).

18

Scheme 2-3. Standard hydrogenation conditions, and various ligands used in the reaction.

1,1-disubstituted Olefins

These data showed that reactivity and selectivity of our ligand would probably be

problematic with tri-substituted olefins. As such, it was decided to move to less substituted

olefins since less sterically hindered olefins display increased reactivity. Specifically, the 1,1-

disubstituted alkene moiety was chosen since it is the least hindered alkene that gives a chiral

center upon hydrogenation. Our first attempts to hydrogenate terminal olefins were made with

test substrate -methyl styrene 26 and to our delight, we observed 88% conversion to n-

isopropylbenzene after only 16 h. Hydrogenation of -methyl styrene at 7 M and 0.004%

catalyst loading was attempted and 88% conversion was observed after 24 h. Since n-

isopropylbenzene isn’t chiral and methyl groups aren’t bulky, hydrogenations on two bulkier

compounds were attempted. Both 27 and 28 reacted poorly with minimal product observed for

27 and no product observed for 28 (Figure 2-1).

19

Figure 2-1. First attempts at 1,1-disubstituted hydrogenations.

Synthesis of Substrates

Since sterically bulky groups as both substituents of the alkenes seemed unreasonable as

a test substrate, it was decided to make a set of compounds that had an aryl group on one side

and a small alkyl chain on the other side, namely an ethyl group. This type of substrate was

chosen for several reasons: facial differentiation would occur more easily due to the large

difference in steric bulk between an aryl group and an ethyl group, electronic effects of a

substituent on the aryl ring could potentially be tested to explain differences in reactivity, a chiral

center should enable determination of the facial selectivity of the process. The synthesis of

alkenes of this type would be a simple three-step procedure from either a benzoic acid or a

benzaldehyde. If starting with a benzoic acid, formation of the Weinreb amide11 followed by a

reaction with a Grignard reagent would allow access to the ethyl ketone.12 Starting from the

aldehyde, Grignard addition followed oxidation by pyridinium dichromate13 would yield the

ethyl ketone. The ethyl ketone can undergo the Wittig reaction to obtain the desired alkene

(Scheme 2-4).14

20

Scheme 2-4. Synthesis of test substrates.

The first in this series was the unsubstituted benzene 34. However, problems arose

because the compound was extremely volatile (Figure 2-2). To remedy that, 35 was synthesized

and full conversion was obtained at both 1000 psi and 500 psi. Unfortunately, the product was

too non-polar to study the enantioselectivity by HPLC. The rest of the series was synthesized,

compounds 36-41 using the methods described previously, and complete conversion was

observed for each compound with the exception of the methoxy-substituted benzene.

Figure 2-2. Class of compounds synthesized for hydrogenation.

A potential explanation could be that the electron-donating nature of a methoxy group

inhibits the reactivity of that compound towards hydrogenation. To determine the reactivity of

21

the system is with these compounds, 37 was hydrogenated at 250 psi for 24 h and at atmospheric

pressure for 48 h to give 80% and 78% conversion respectively. However, chiral HPLC

conditions for separation of these compounds could not be determined.

22

CHAPTER 3

CONCLUSION

The enantioselective hydrogenation of 1,1-disubstituted alkenes has been demonstrated

using StackPhos as the chiral ligand. Less bulky, and more electron deficient substrates could be

hydrogenated at lower pressures reliably. Determining the enantioselectivity of this reaction was

difficult due to the non-polar nature of the substrates making them unsuitable to analyze via

traditional chiral HPLC. However, the first example of StackPhos garnering high selectivity at

an elevated temperature has been described, supporting the idea that StackPhos would racemize

more slowly if coordinated strongly as a bidentate ligand to a metal. StackPhos performed far

better than other ligands tested that have varied groups substituted on the imidazole ring.

23

CHAPTER 4

EXPERIMENTAL

General. All reactions were performed under nitrogen atmosphere unless otherwise

stated. Reaction flasks were dried in the oven and anhydrous solvents were transferred via

syringe directly into the flask. Anhydrous dichloromethane (DCM), diethyl ether,

tetrahydrofuran (THF), acetonitrile, and toluene were purified using a mBraun solvent

purification system. Reagents were purchased from Aldrich or Oakwood and used without any

further purification. Analytical thin layer chromatography (TLC) was performed with 250 µm

Silica Gel 60 F254 pre-coated plates (EMD Chemicals Inc.). Flash chromatography utilized

230-400 Mesh 60Å Silica Gel (Whatman Inc.). Proton nuclear magnetic resonance (1HNMR)

spectra were recorded with Varian Unity Inova 500MHz and Varian Mercury 300 MHz

spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) downfield relative to

tetramethylsilane (TMS, 0.0 ppm) or (CDCl3, 7.26 ppm). Coupling constants (J) are reported in

Hz. Multiplicities reported use the following abbreviations: s, singlet; d, doublet; t, triplet; q,

quartet; m, multiplet; br, broad. Carbon-13 nuclear magnetic resonance (13C NMR) spectra were

obtained using a Varian Unity Mercury 300 spectrometer at 75 MHz. Chemical shifts are

reported in ppm relative to the carbon resonance of CDCl3 (77.00 ppm). Infrared spectra were

obtained on a Bruker Vector 22 IR spectrometer at 4.0 cm-1 resolution and are reported in

wavenumbers. High resolution mass spectra (HRMS) were obtained by Mass Spectrometry Core

Laboratory of University of Florida, and are reported as m/e (relative ratio). Accurate masses are

reported for the molecular ion (M+) or a suitable fragment ion.

24

1. General Procedure to Synthesize Ligand-Iridium Complex

To a flask of NaBARF (20 mg, 0.0225 mmol) and [Ir(COD)Cl]2 (50 mg, 0.0075 mmol) was

added a solution of ligand (0.015 mmol) in dichloromethane (0.5 mL). The resulting orange

solution was stirred at room temperature for 1 h. The solution was filtered through a plug of

silica and concentrated to give the desired compound as a red or orange crystalline solid.8

2. General Procedure for Hydrogenation

To a test tube (13x100 mm) was added an iridium catalyst (0.00107 mmol), the precursor alkene

(0.330 mmol), and dichloromethane (0.3 mL) to form a red solution. The test tube was placed

inside a Parr bomb, sealed, vented with hydrogen, then pressurized to 1000 psi and stirred for 24

h. The reaction mixture was concentrated by carefully blowing a stream of nitrogen into the test

tube, dissolved in hexanes, filtered through a plug of silica, and concentrated to give the

compound as a colorless or pale yellow oil.8

25

Prepared according to a previous report in the Aponick group.10 Spectroscopic data matches the

reported values.

Prepared by a similar procedure.10 To a solution of 1-(1H-benzo[d]imidazol-2-yl)naphthalen-2-ol

provided by Dr. Cardoso (332 mg, 1.28 mmol) and triethylamine (0.178 mL, 1.28 mmol) in

DCM (10 mL) was added TBSCl (192 mg, 1.28 mmol) at room temperature for 1.5 h and

quenched with water (2 mL). The crude compound was extracted with DCM (3 x 1 mL), dried

over MgSO4 and the solvent removed under pressure. The solid residue was purified by flash

chromatography (5-20% ethyl acetate/hexanes) to yield 356 mg (74%) of 42 as a white solid. 1H

NMR (300 MHz, CDCl3) δ 8.62 (d, J= 6 Hz, 1H), 7.95 (m, 2H), 7.76 (br, 2H), 7.51 (quint, J=

6Hz, 2H), 7.38 (m, 2H), 7.26 (d, J= 9 Hz, 1H), 0.99 (s, 6H), 0.95 (s, 9H).

26

Prepared by a similar procedure.10 Compound 42 (356 mg, 0.953 mmol) dissolved in THF (5

mL) was added dropwise to a suspension of sodium hydride (24 mg, 1.0 mmol) in THF (5 mL) at

-78 °C. After ten minutes of stirring, pentafluorobenzyl bromide (0.144 mL, 0.953 mmol) was

added dropwise to the solution. The reaction was allowed to warm to room temperature and stir

for 18 h at which point the solution was cooled to 0 °C and water was added. The organic phase

was separated and the aqueous phase extracted with ethyl acetate (3 x 1 mL). The combined

organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue

was purified by flash chromatography (5-20% ethyl acetate/hexanes) to yield 122 mg (23%) of

43 as an oil. 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J= 6 Hz, 2H), 7.82 (d, J= 3 Hz, 1H), 7.50

(m, 1H), 7.38 (m, 5H), 7.19 (d, J= 6 Hz, 2H), 5.35 (q, J= 6 Hz, 1H), 1.59 (s, 6H), 0.78 (s, 9H).

Prepared by a similar procedure.10 To a solution of 43 (582 mg, 1.05 mmol) in methanol (30

mL) was added potassium carbonate (290 mg, 2.10 mmol) at room temperature and stirred for 30

min. To the solid was added ethyl acetate and water, then the organic layer was removed and the

aqueous layer extracted with ethyl acetate. After drying with magnesium sulfate and

27

concentrating under reduced pressure, the deprotected alcohol was obtained as a brown solid and

used as crude in the next step.

To a solution of the compound and DMAP (12.8 mg, 0.105 mmol) in dichloromethane (30 mL)

was added triethylamine (0.146 mL, 1.05 mmol) and triflic anhydride (0.176 mL, 1.05 mmol) at

room temperature for 6 h. The reaction was then concentrated and purified by flash

chromatography (5-10% ethyl acetate/hexanes) to yield 420 mg (70%) of 44. 1H NMR (300

MHz, CDCl3) δ 8.26 (d, J= 6 Hz, 1H), 8.08 (d, J= 6 Hz, 2H), 7.70 (m, 3H), 7.58 (m, 4H), 5.43

(q, J= 12 Hz, 6H).

Prepared by a similar procedure.10 To nickel(II)-1,2-bis(diphenylphosphino)ethane dichloride

(38.5 mg, 0.073 mmol) dissolved in dimethylformamide (4 mL), diphenylphosphine (0.256 mL,

1.47 mmol) was added to the solution and stirred at 130°C for 30 min. DABCO (329 mg, 2.93

mmol) and 44 (420 mg, 0.73 mmol) were then dissolved in dimethylformamide (3 mL), added to

the dark red solution, and stirred at 130°C for 14 h. The dimethylformamide was then removed

via distillation at reduced pressure and the compound was purified via flash chromatography (5-

20% ethyl acetate/hexanes gradient) to yield 177 mg (40%) 25 as a pale yellow solid. 1H NMR

(300 MHz, CDCl3) δ 8.01 (d, J= 6 Hz, 1H), 7.93 (d, J= 6 Hz, 2H), 7.66 (d, J= 3 Hz, 1H), 7.55

(m, 9H), 7.31 (m, 6H), 7.03 (d, J= 6Hz, 1H), 5.30 (q, J= 6 Hz, 2H).

28

Prepared according to general procedure 1 to yield 20.4 mg (73%) of the desired compound. 1H

NMR (500 MHz, CDCl3) δ 8.06 (m, 2H), 7.92 (d, J= 10 Hz, 1H), 7.74 (m, 14H), 7.52 (m, 11H),

7.33 (t J= 10 Hz, 1H), 7.05 (t, J= 10 Hz, 2H), 5.18 (br, 1H), 4.90 (d, J= 20 Hz, 1H), 4.50 (d, J=

30 Hz, 1H), 4.10 (br, 1H), 3.31 (br, 1H), 2.81 (br, 1H), 2.42 (br, 1H), 2.11(m, 1H), 2.04 (br, 2H),

1.76 (br, 1H), 0.87 (br, 1H); HRMS (ESI) calcd for C52H40F5IrN2P [M-BARF]+ 1011.2479,

found 1011.2512.


NMR (500 MHz, CDCl3) δ 8.09 (dd J= 10, 5 Hz, 2H), 7.88 (d J= 5 Hz, 1H), 7.73 (m, 17H), 7.55

(m, 9H), 7.18 (t, J=10 Hz, 2H), 7.03 (m, 4H), 5.19 (br, 1H), 4.86 (d, J= 20 Hz, 1H), 4.59 (d, J=

20 Hz, 1H), 4.07 (br, 1H), 3.19 (m, 1H), 2.85 (br, 1H), 2.40 (br, 1H), 2.09 (m, 1H), 2.04 (m, 3H),

1.89 (br, 1H), 0.87 (m, 1H).

29

Prepared according to general procedure 1 but at half the molarity to yield 12 mg (91%) of the

desired compound.


NMR (500 MHz, CDCl3) δ 8.79 (t J= 5, Hz, 2H), 8.18 (d J= 10 Hz, 1H), 8.02 (m, 4H), 7.92 (t J=

5 Hz, 1H), 7.88 (t, J= 10 Hz, 1H), 7.77 (m, 6H), 7.63 (m, 1H), 7.56 (m, 7H), 7.18 (m, 2H), 7.04

(br, 2H), 5.61 (d, J= 20 Hz, 1H), 5.01 (br, 1H), 4.92 (d, J= 20 Hz, 1H), 4.60 (br, 1H), 4.18 (m,

1H), 3.21 (br, 1H), 2.98 (m, 1H), 2.43 (m, 1H), 1.97 (m, 2H), 1.61 (br, 1H), 1.42 (br, 1H), 0.89

(br, 1H).

30

Prepared according to general procedure 1 but at four times the molarity to yield 50.1 mg (92%)

of the desired compound. 1H NMR (500 MHz, CDCl3) δ 8.31 (d J= 10 Hz, 2H), 8.18(d J= 10

Hz, 1H), 7.82 (m, 13H), 7.62 (m, 9H), 7.33 (t, J= 5 Hz, 1H), 7.21 (t, J= 5 Hz, 2H), 7.05 (t, J= 5

Hz, 2H), 5.55 (br, 1H), 5.23 (t, J= 5 Hz, 1H), 5.01 (q, J= 20 Hz, 2H), 4.21 (br, 1H), 3.10 (br,

1H), 2.73 (d, J= 20 Hz, 1H), 2.01 (br, 1H), 1.82 (br, 1H), 1.58 (br, 1H), 0.99 (br, 1H).

Prepared according to general procedure 2. 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 10H), 3.00

(m, 2H), 2.80 (m, 1H), 1.30 (d J= 6 Hz, 3H).

To methyltriphenylphosphonium bromide (2.036 g, 5.67 mmol) in diethyl ether (20 mL) at 0°C

was added n-butyl lithium solution in hexanes (2.27 mL, 5.67 mmol) and stirred until the

solution turned orange (half an hour). To the resulting orange solution, ketone (0.503 mL, 3.78

mmol) was slowly added and solids immediately formed. The reaction was then stirred at room

31

temperature for 16 h. The reaction mixture was concentrated and a column was ran with 100%

hexanes to yield 208 mg (42%) as a pale yellow oil. Spectra matches previously reported data.17

1H NMR (300 MHz, CDCl3) δ 7.52 (m, 1H), 7.38 (m, 4H), 5.39 (d, J= 3 Hz, 1H), 5.18 (d, J= 3

Hz, 1H), 2.63 (t, J= 6 Hz, 3H), 1.22 (q, J= 6 Hz, 2H).



solution turned orange (half an hour). To the resulting orange solution, ketone (712 mg, 3.78



hexanes to yield the compound as a pale yellow oil. Spectra matches previously reported data.15

1H NMR (300 MHz, CDCl3) δ 7.57 (5H), 5.42 (s, 1H), 5.26 (s, 1H), 2.68 (t, J= 9 Hz, 1H), 2.02

(m, 6H), 1.55 (m, 6H).

To methyltriphenylphosphonium bromide (2.46 mg, 6.9 mmol) in diethyl ether (23 mL) at 0°C

was added n-butyl lithium solution in hexanes (4.31 mL, 6.9 mmol) and stirred until the solution

turned orange (half an hour). To the resulting orange solution, ketone (752 mg, 4.6 mmol) was

slowly added and solids immediately formed. The reaction was then stirred at room temperature

for 16 h. The reaction mixture was concentrated and a column was ran with 100% hexanes to

32

yield 403 mg (54%) as a yellow oil. Spectra matches previously reported data.17 1H NMR (300

MHz, CDCl3) δ 7.39 (d, J=6 Hz, 2H), 6.87 (d, J=6 Hz, 2H), 5.22 (s, 1H), 4.99 (s, 1H), 3.82 (s,

3H), 2.52 (q, J= 6 Hz, 2H), 1.11 (t, J= 6 Hz, 3H).

To methyltriphenylphosphonium bromide (3.24 g, 9.1 mmol) in benzene (45 mL) at 0°C was

added n-butyl lithium solution in hexanes (5.7 mL, 9.1 mmol) and stirred until the solution

turned orange (half an hour). To the resulting orange solution, ketone (1.22 g, 6.1 mmol) was



yield 284 mg (23%) as a pale yellow oil. Spectra matches previously reported data.17 1H NMR

(300 MHz, CDCl3) δ 7.61 (d, J=6 Hz, 2H), 7.53 (d, J=6 Hz, 2H), 5.36 (s, 1H), 5.18 (s, 1H), 2.55

(q, J= 6 Hz, 2H), 1.3 (t, J= 6 Hz, 3H).

To methyltriphenylphosphonium bromide (1.39 g, 3.9 mmol) in diethyl ether (15 mL) at 0°C was





33

yield 95.5 mg (22%) as a yellow oil. Spectra matches previously reported data.19 1H NMR (300

MHz, CDCl3) δ 7.42 (m, 4H), 5.39 (s, 1H), 5.19 (s, 1H), 2.60 (q, J= 6 Hz, 2H), 1.21 (t, J= 6 Hz,

3H).







MHz, CDCl3) δ 7.26 (m, 4H), 5.25 (s, 1H), 5.01 (s, 1H), 2.48 (q, J= 6 Hz, 2H), 1.33 (s, 9H), 1.10

(t, J= 6 Hz, 3H).


added n-butyl lithium solution in hexanes (2.06 mL, 3. 3mmol) and stirred until the solution




34



3H).

To methyltriphenylphosphonium bromide (893 mg, 2.5 mmol) in diethyl ether (10 mL) at 0°C

was added n-butyl lithium solution in hexanes (1.56 mL, 2.5 mmol) and stirred until the solution






3H).

Prepared according to general procedure 2. Spectra matches previously reported data.17 1H NMR

(300 MHz, CDCl3) δ 7.42 (m, 4H), 7.32 (m, 6H), 2.73 (m, 1H), 1.75 (m, 2H), 1.38 (d, J= 6 Hz,

3H), 0.98 (t, J= 6 Hz, 3H).

35


(300 MHz, CDCl3) δ 7.82 (m, 3H), 7.62 (m, 1H), 7.43 (m, 3H), 2.80 (m, 1H), 1.75 (m, 2H), 1.38

(d, J= 6 Hz, 3H), 0.87 (t, J= 6 Hz, 3H).



solution turned orange (half an hour). To the resulting orange solution, ketone (666 mg, 3.78



hexanes to yield 478 mg (73%) as a yellow oil. Spectra matches previously reported data.16 1H

NMR (300 MHz, CDCl3) δ 7.68 (d, J= 6 Hz, 2H), 7.01 (d, J= 6 Hz, 2H), 5.36 (s, 1H), 5.00 (s,

1H), 3.97 (s, 3H), 1.77 (m, 1H), 1.08 (m, 4H).


(300 MHz, CDCl3) δ 7.58 (d, J= 6 Hz, 2H), 7.35 (d, J= 6 Hz, 2H), 2.68 (m, 1H), 1.63 (m, 2H),

1.28 (d, J= 6 Hz, 3H), 0.86 (t, J= 6 Hz, 3H).

36



1.28 (d, J= 6 Hz, 3H), 0.86 (t, J= 6 Hz, 3H).



1.41 (s, 9H), 1.32 (d, J= 6 Hz, 3H), 0.92 (t, J= 6 Hz, 3H).



1.22 (d, J= 6 Hz, 3H), 0.83 (t, J= 6 Hz, 3H).

37

To methyltriphenylphosphonium bromide (478 g, 1.34 mmol) in diethyl ether (20 mL) at 0°C


solution turned orange (half an hour). To the resulting orange solution, ketone (164.3 mg, 0.89



hexanes to yield 69.6 mg (43%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (m, 4H),

7.79 (d J= 3 Hz, 1H) 7.63 (m, 2H), 5.62 (s, 1H), 5.38 (s, 1H), 2.84 (q, J= 6 Hz, 2H), 1.38 (t, J= 6

Hz, 3H).

Prepared according to general procedure 2. 1H NMR (300 MHz, CDCl3) δ 7.59 (m, 2H), 7.29

(m, 2H), 6.68 (m, 1H), 1.63 (dd, J= 6 Hz, 2H), 1.28 (d, J= 6 Hz, 3H), 0.87 (t, J= 6 Hz, 3H).

To aldehyde (0.89 mL, 7.3 mmol) in diethyl ether (35 mL) in a flamed dried flask at 0° C was

added 3M ethylmagnesium bromide in THF (3.67 mL, 11 mmol). The resulting pale yellow

solution was then allowed to stir at room temperature for 2 hours. The reaction was quenched at

0°C with 1M hydrochloric acid and was extracted with ethyl acetate. The resulting organic layer

38

was dried with brine and sodium sulfate. Upon concentration under reduced pressure, 1.11 g

(100%) of a colorless oil was obtained as the product. 1H NMR (300 MHz, CDCl3) δ 7.39 (d,

J=6 Hz, 2H), 6.99 (d, J=6 Hz, 2H), 4.63 (br, 1H), 3.92 (s, 3H), 2.53 (br, 1H), 1.88 (m, 2H), 1.02

(t, J= 6 Hz, 3H).

To a solution of oxalyl chloride in dichloromethane at -78°C was added DMSO dropwise. After

1 h the alcohol was added dropwise. After 30 min triethylamine was added dropwise and the

reaction was allowed to warm to room temperature and stirred overnight. The reaction

concentrated under reduced pressure and flash chromatography (10% ethyl acetate/hexanes) gave

751.7 mg (63%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=6 Hz, 2H),

6.94 (d, J=6 Hz, 2H), 3.85 (s, 3H), 2.96 (q, J= 6 Hz, 2H), 1.22 (t, J= 6 Hz, 3H).

To alcohol (1.16 g, 5.7 mmol) in dichloromethane (30 mL) was added pyridinium dichromate

(3.22 g, 8.6 mmol) and stirred for 16 h at room temperature. The resulting brown solution was

filtered over celite and concentrated under reduced pressure to yield 627.2 mg (54%) as a pale

yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=6 Hz, 2H), 7.75 (d, J=6 Hz, 2H), 3.03 (q,

J= 6 Hz, 2H), 1.24 (t, J= 6 Hz, 3H).

39

To alcohol (765 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridinium dichromate


filtered over celite and concentrated under reduced pressure to yield 435 mg (57%) as a pale


J= 6 Hz, 2H), 1.81 (t, J= 6 Hz, 3H).





J= 6 Hz, 2H), 1.79 (s, 9H), 1.39 (t, J= 6 Hz, 3H).




40

yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.01 (t, J=6 Hz, 2H), 7.15 (t, J=6 Hz, 2H), 2.98 (q, J=

6 Hz, 2H), 1.22 (t, J= 6 Hz, 3H).

To Weinreb amide (409 mg, 1.6 mmol) in diethyl ether (10 mL) in a flamed dried flask at 0° C

was added 3M ethylmagnesium bromide in THF (1.1 mL, 3.3 mmol). The resulting pale yellow



was dried with brine and sodium sulfate. Upon concentration under reduced pressure, 355 mg

(100%) of the desired compound a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.95 (d J= 6 Hz,

2H), 7.73 (d J= 6 Hz, 2H), 3.09 (q, J= 6 Hz, 2H), 1.36 (t, J= 6 Hz, 3H).

To aldehyde (801 mg, 5.7 mmol) in diethyl ether (30 mL) in a flamed dried flask at 0° C was

added 3M ethylmagnesium bromide in THF (3.8 mL, 11.4 mmol). The resulting pale yellow




(79%) of a colorless oil was obtained as the product. 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J=6

41

Hz, 2H), 7.47 (d, J=6 Hz, 2H), 4.69 (br, 1H), 1.80 (q, J= 6 Hz, 2H), 1.58 (br, 1H), 0.98 (t, J= 6

Hz, 3H).

To Weinreb amide (456 mg, 2.1 mmol) in diethyl ether (3 mL) in a flamed dried flask at 0° C

was added 3M ethylmagnesium bromide in THF (2.24 mL, 6.7 mmol). The resulting pale

yellow solution was then allowed to stir at room temperature for 2 hours. The reaction was

quenched at 0°C with 1M hydrochloric acid and was extracted with ethyl acetate. The resulting

organic layer was dried with brine and sodium sulfate. Upon concentration under reduced

pressure, 164 mg (42%) of the desired compound a colorless oil. 1H NMR (300 MHz, CDCl3) δ

8.59 (s, 1H), 8.17 (d J= 3 Hz, 1H) 8.09 (d J= 3 Hz, 1H), 7.97 (m, 2H), 7.67 (m, 2H), 3.24 (q, J=

6 Hz, 2H), 1.02 (t, J= 6 Hz, 3H).






42

(11%) of a colorless oil was obtained as the product. 1H NMR (300 MHz, CDCl3) δ 7.62 (d J= 6

Hz, 2H), 7.47 (t, J=6 Hz, 2H), 4.69 (br, 1H), 1.82 (br, 3H), 0.96 (t, J= 6 Hz, 3H).

To a solution of carboxylic acid (1.0 g, 4.97 mmol) in benzene (20 ml) was added thionyl

chloride (0.86 mL, 11.71 mmol) and refluxed for 1 h. The mixture was concentrated under

reduced pressure and dissolved in dichloromethane (20 mL). Then, N,O-

Dimethylhydroxylamine hydrochloride (530 mg, 5.48 mmol) and pyridine (0.89 mL, 11.05

mmol) were added to the reaction. After 14 h the solution was quenched with saturated sodium

carbonate solution and washed with water and brine before being dried with sodium sulfate,

filtered, and concentrated under reduced pressure to yield 409 mg (32%) Weinreb amide as a

colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.00 (d J= 6 Hz, 2H), 7.73 (t, J= 6 Hz, 2H), 3.53 (s,

3H), 3.37 (s, 3H).






43

(82%) of a colorless oil was obtained as the product. 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=6

Hz, 2H), 7.39 (d, J=6 Hz, 2H), 4.68 (t, J= 3 Hz, 1H), 1.88 (br, 3H), 1.03 (t, J= 6 Hz, 3H).






(95%) of a colorless oil was obtained as the product. 1H NMR (300 MHz, CDCl3) δ 7.43 (m,

2H), 7.15 (t, J=6 Hz, 2H), 4.70 (br, 1H), 2.90 (br, 3H), 1.02 (t, J= 6 Hz, 3H).

To a solution of carboxylic acid (1.032 g, 6.0 mmol), N,O-Dimethylhydroxylamine

hydrochloride (1.755 g, 18.0 mmol), and triethylamine (2.51 mL, 18.0 mmol) in toluene (30 mL)

at 0°C was added a solution of phosphine trichloride (0.261 mL, 3.0 mmol) in toluene (5 mL).

The reaction was then heated to 60°C for 1 h. The reaction mixture was then quenched with

saturated sodium carbonate solution and extracted with ethyl acetate. The resulting organic layer

was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 150

mg (25%) Weinreb amide as a colorless oil.

44

LIST OF REFERENCES

1. a) Zhao, D.; Candish, L.; Paul, D.; Glorius, F. ACS Catal. 2016, 6, 5978–5988. b) Verendel, J.

J.; Paimes, O.; Dieguez, M.; Andersson, P. G. Chem. Rev. 2014, 114, 2130−2169.

2. Knowles, W. S.; Sabacky, M. J. Chem. Commun. 1968, 1445-1446.

3. Dang, T.; Kagan, H. J. Chem. Soc., Chem. Commun. 1971, 188, 481.

4. Knowles, W. S.; Sabacky, M; Vineyard, B. J. Chem. Soc., Chem. Commun. 1972, 10-11.

5. Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998-2007.

6. Noyori, T.; Ito, K.; Miyashita, A; Takaya, H.; Yasuda, A; J. Am. Chem. Soc. 1980, 102, 7932-

7934.

7. Davis, M.; Crabtree, R. J. Org. Chem. 1986, 51, 2655-2661.

8. Pfaltz, A.; Lightfoot, A.; Schnider, P. Angew. Chem. Int. Ed. 1998, 37, 2897-2899.

9. Bell, S.; Wüstenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz, A. Science, 2006, 311,

642–644.

10. Aponick, A.; Cardoso, F. S. P.; Abboud, K. A. J. Am. Chem. Soc. 2013, 135, 14548-14551.

11. Padwa, A.; Cochran, J. E.; Kappe, C. O. J. Org. Chem., 1996, 61, 3706–3714.

12. Ochiai, K.; Takita, S.; Kojima, A.; Eiraku, T.; Iwase, K.; Kishi, T.; Ohinata, A.; Yageta, Y.;

Yasue, T.; Adams, D. R.; Kohno, Y. Bioorg Med Chem Lett 2013, 23, 375-381.

13. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-402.

14. Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134, 10357−10360.

15. Hansen, A. L.; Ebran, J.; Gogsig, T. M.; Skrydstrup, T. J. Org. Chem., 2007, 72, 6464–6472.

16. Barton, D. H. R.; Bohe, L.; Lusinchi, X. Tetrahedron, 1990, 5273-5284.

17. Mazuela, J.; Verendel, J. J.; Coll, M.; Schaffner, B.; Borner, A.; Andersson, P. G.; Pamies, O.;

Dieguez, M. J. Am. Chem. Soc. 2009, 131, 12344–12353.

18. Takagi, R.; Igata, N.; Yamamoto, K.; Kojima, S. Journal of Molecular Catalysis A: Chemical

2010, 321, 71–76.

19. McIntyre S.; Hormann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Adv. Synth. Catal. 2005, 347,

282 – 288.

20. Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2003, 1091-1096.

45

21. Singh, R. P.; Kamble, R. M.; Chandra, K. L.; Saravanan, P.; Singh, V. K. Tetrahedron 2001,

57, 241-247.

22. Kataoka, N.; Shelby, Q.; Stambuli, J.P.; Hartwig, J. F. J. Org. Chem., 2002, 67, 5553–5566.

46

BIOGRAPHICAL SKETCH

Bobby Owen Garrett was born in Birmingham, Alabama in 1990. He attended high

school at Corner High School in Warrior, Alabama. After high school, he attended Auburn

University on scholarship and obtained his bachelor’s degree in chemistry graduating Cum

Laude in 2013. He was an active researcher in organic chemistry at Auburn for two years under

Dr. Peter Livant and also obtained a minor in political science. He then accepted an offer to

enroll in the University of Florida Chemistry Graduate Program. There he worked on

enantioselective catalysis under Dr. Aaron Aponick where he obtained his master’s degree in

May of 2017.

© 2017 bobby owen garrett

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