Catalytic Asymmetric Hydrogenation:

Toward Chiral Diamines and Cyclohexanes

By

Joseph Pignatelli

A Thesis Submitted in Conformity with the Requirements for

the degree of Master of Science

Department of Chemistry

University of Toronto

© by Joseph Pignatelli (2011)

Catalytic Asymmetric Hydrogenation:

Toward Chiral Diamines and Cyclohexanes

Joseph Pignatelli

Master of Science

Department of Chemistry

University of Toronto

2011

Abstract

As the need for developing environmentally friendly chemistry continues to become

more apparent, catalytic asymmetric hydrogenation has risen to the forefront as a reliable and

eco-friendly method for enantioselective synthesis. We herein describe our progress toward the

synthesis of valuable structural motifs via hydrogenation: chiral 1,2-diamines, 1,3-diamines and

substituted cyclohexanes.

We propose a strategy whereby protected 1,2-diimine and 1,3-diimine surrogates can be

hydrogenated selectively and deprotected to furnish the desired chiral amines. Using this

strategy, it was demonstrated that imidazolone precursors could be hydrogenated with >20:1

diastereoselectivity to give latent 1,2-diamines, albeit with no enantiomeric excess.

We further propose that substituted benzene rings linked to an oxazolidinone

chiral-auxiliary can be diastereoselectively hydrogenated using a heterogeneous metal catalyst.

Following hydrogenation, the chiral cyclohexanes could be obtained in up to quantitative yield

and 99% diastereomeric excess.

ii

Acknowledgements

I would like to thank Prof. Vy Dong for her continued guidance and encouragement

throughout the length of my graduate studies. I am further indebted for her support in achieving

my personal goals and giving me the opportunity to work with a great group of people.

I give my thanks to Wilmer Alkhas for taking care of business around the lab and making

our lives that much easier. I also want to acknowledge my collaborator Charles Yeung and all of

my lab mates, thanks for the good times and the good company over the last year.

Lastly, I would like to give a big thank you to my friends and family, especially my dad

Antonio and my mother Francesca. Your support throughout my graduate studies has lessened

my load significantly, for that and everything else you do I will always be grateful. To my

friends, thank you for understanding the multitude of important obligations I had during this

time. Many more good memories are still to come.

iii

Table of Contents

Acknowledgments .........................................................................................................................iii

Table of Contents ...........................................................................................................................iv

List of Abbreviations .....................................................................................................................vi

List of Tables .................................................................................................................................ix

List of Figures .................................................................................................................................x

List of Appendices .......................................................................................................................xiii

Chapter 1: Synthesis of Chiral Diamines via Asymmetric Hydrogenation.....................................1

1.1 Introduction...........................................................................................................................1

1.1.1 Synthesis of Chiral Amines by Hydrogenation..........................................................1

1.1.2 Synthesis of Chiral Diamines......................................................................................2

1.2 Results and Discussion.........................................................................................................6

1.2.1 Toward Chiral 1,2-Diamines via 1,2-Diimine Hydrogenation...................................6

1.2.2 1,2-Diamines via Hydrogenation of Imidazolones...................................................12

1.2.3 Toward Chiral 1,3-Diamines via 1,3-Diimine Hydrogenation.................................16

1.3 Conclusions and Future Work............................................................................................20

1.4 Experimental Procedures....................................................................................................21

1.4.1 General Considerations.............................................................................................21

1.4.2 General Procedure A: Synthesis of 1,2-Diimine Precursors.....................................21

1.4.3 General Procedure B: Cyclic Thiourea Synthesis.....................................................22

1.4.4 General Procedure C: Synthesis of Imidazolones.....................................................22

1.4.5 General Procedure D: Hydrogenation of Imidazolones............................................22

iv

1.4.6 Characterization Data................................................................................................23

Chapter 2: Chiral Cyclohexanes by Asymmetric Hydrogenation..................................................32

2.1 Introduction.........................................................................................................................32

2.1.1 Hydrogenation of Heteroaromatics...........................................................................32

2.1.2 Selective Hydrogenation of Carbocyclic Aromatics.................................................39

2.2 Results and Discussion.......................................................................................................45

2.2.1 Substrate Synthesis...................................................................................................45

2.2.2 Hydrogenation of Fluoro-Substituted Arenes: Optimization of

Auxiliary Appendage and Substitution Pattern.........................................................48

2.2.3 Hydrogenation of Methoxy- and Hydroxy-Substituted Arenes:

Effects of Substitution Pattern and Auxiliary Rigidifcation.....................................52

2.2.4 Hydrogenation of Alkyl Substituted Arenes: Effects of Degree

and Pattern of Substitution........................................................................................55

2.2.5 Extending Selectivity Trends to the Design of New Substrates...............................59

2.3 Conclusions and Future Work............................................................................................60

2.4 Experimental Procedures....................................................................................................61

2.4.1 General Considerations.............................................................................................61

2.4.2 General Procedure A Auxiliary-Bound Arene Synthesis.........................................62

2.4.3 General Procedure B: Hydrogenation of Auxiliary-Bound Arenes..........................62

2.4.4 Characterization Data................................................................................................63

v

List of Abbreviations

δ chemical shift

1H-NMR proton NMR

13C-NMR carbon 13 NMR

BDPP bis(diphenylphosphino)pentane

BINAP 1,1’-binaphthalene-2,2’-diyl-bis-diphenylphosphine

Bn benzyl

br broad

CDCl3 deuterated chloroform

cod 1,5-cyclooctadiene

CTAB cetyltrimethylammonium bromide

Cy cyclohexyl

d doublet

dd doublet of doublets

dr diastereomeric ratio

dsp doublet of septets

DART Direct Analysis in Real Time

DCE 1,2-dichloroethane

DCM dichloromethane

(1R,1′R,2S,2′S)-DUANPHOS (1R,1′R,2S,2′S)-2,2′-Di-tert-butyl-2,3,2′,3

′-tetrahydro-1H,1′H-(1,1′)biisophosphindolyl

DOCEA dioctylcyclohexylethylamine

vi

DPPE 1,3-bis(diphenylphosphino)propane

ESI Electrospray Ionization

Et ethyl

EtOAc ethyl ecetate

g grams

GC-FID Gas Chromatography Flame Ionization Detector

GC-MS Gas Chromatography Mass Spectrometry

h hours

HRMS High Resolution Mass Spectrometry

Hz hertz

IR Infrared Spectroscopy

J coupling constant

JosiPhos (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]

L1 ligand one

L2 ligand two

LC-MS Liquid Chromatography Mass Spectrometry

M molar

Me methyl

MeDuPhos (+)-1,2-Bis[(2S,5S)-2,5-dimethylphospholano]benzene

mg milligrams

min minutes

ml millilitres

vii

mmol millimoles

MONOPHOS (R)-(−)-(3,5-Dioxa-4-phosphacyclohepta[2,1-a:3,4-

a′]dinaphthalen-4-yl)dimethylamine

mp melting point

NMR Nuclear Magnetic Resonance

NR no reaction

OMeBIPHEP (R)-(-)-2,2'-Bis[di(3,5-di-t-butyl-4-methoxyphenyl)

phosphino]-6-6'-dimethoxy-1,1'-biphenyl

ppm parts per million

p-TsOH para-toluenesulfonic acid

q quartet

rt room temperature

s singlet

SFC Supercritical Fluid Chromatography

t triplet

tt triplet of triplets

TLC Thin Layer Chromatography

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

TOA trioctylamine

t-Bu tertiary-butyl

XANTPHOS 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

viii

List of Tables

Table 1.1 Optimization of the Hydrogenation of 1.1a....................................................................8

Table 1.2: Attempted Asymmetric Hydrogenations of 1.1a..........................................................11

Table 1.3: Synthesized Imidazolone Precursors............................................................................13

Table 1.4: Attempted Hydrogenations of Imidazolone Substrates................................................13

Table 1.5: Synthesized Thiourea Precursors..................................................................................17

Table 1.6: Hydrogenation of Thiourea Precursors.........................................................................18

Table 1.7: Effect of Cyclic Thiourea Spike 1.5d on Hydrogenation of Cyclic urea 1.6a.............20

Table 2.1: Synthesized Auxiliary-bound Substrates......................................................................45

Table 2.2: Diastereoselectivities Obtained with Various Auxiliary Appendages..........................49

Table 2.3: Positional Effects on Diastereoselectivity with Fluorine..............................................50

Table 2.4: Positional Effects on Diastereoselectivity with Methoxy Groups................................52

Table 2.5: Hydrogenation of 2.1i With and Without Metal Additives..........................................54

Table 2.6: Hydrogenation of Methoxy- and Hydroxy-Arenes with t-Bu Appendage...................55

Table 2.7: Hydrogenation Optimization Studies with Substrate 2.1q...........................................57

ix

List of Figures

Figure 1.1: Hydrogenations of Enamides and Imines To Furnish Chiral Amines...........................1

Figure 1.2: Hydrogenation of Ciba-Giegy’s (S)-Metolachlor.........................................................2

Figure 1.3: Chiral Diamines of Interest...........................................................................................3

Figure 1.4: Synthetic Routes to Chiral 1,2-Diamines......................................................................3

Figure 1.5: Du Bois’ C-H bond amination route to 1,3-diamines...................................................4

Figure 1.6: Enantioselective Michael Additions en route to Chiral 1,3-Diamines.........................4

Figure 1.7: Enzymatic Desymmetrization of meso 1,3-Diamines..................................................5

Figure 1.8: Chiral 1,3-Diamines via Phosphoric Acid Aza-Mannich Reaction by Terada............5

Figure 1.9: Chiral 1,3-Diamines via Phosphoric Acid Aza-Mannich Reaction by Zhu.................6

Figure 1.10: Chiral 1,3-Diamines via Palladium Catalysis.............................................................6

Figure 1.11: Chiral 1,2-Diamines via Reduction of 1.1a................................................................7

Figure 1.12: First Reactivity Affording Hydrogenated Product 1.2a.............................................7

Figure 1.13: Synthesis of Novel 1,2-Diimine Precursors..............................................................11

Figure 1.14: Route to Latent Chiral 1,2-Diamines........................................................................12

Figure 1.15: Hydrogenations of 1.3c.............................................................................................14

Figure 1.16: Formation of Unsubstiuted Imidazolone 1.3d...........................................................15

Figure 1.17: Reactivity Differences of Substrates 1.3c and 1.3d..................................................16

Figure 1.18: Hydrogenation of Cyclic Ureas to 1,3-Diamine Precursors......................................16

Figure 1.19: Ligands for Asymmetric Hydrogenation of Cyclic Urea 1.6a.................................17

Figure 1.20: Hydrogenation of Cyclic Urea 1.6a in the Presence of Thiourea Spike 1.5a...........19

Figure 2.1: Murata’s Hydrogenation of 2-methylquinoxaline.......................................................33

x

Figure 2.2: Bianchini’s Hydrogenation of 2-methylquinoxaline...................................................33

Figure 2.3: Asymmetric Hydrogenation of 2-methylfuran............................................................33

Figure 2.4: Asymmetric Hydrogenation of Pyrazines by Lonza...................................................34

Figure 2.5: Asymmetric Hydrogenation of Quinolines.................................................................34

Figure 2.6: Asymmetric Transfer Hydrogenation of Quinolines...................................................35

Figure 2.7: Asymmetric Hydrogenation of Isoquinolines.............................................................35

Figure 2.8: First Asymmetric Hydrogenation of Protected Indoles...............................................36

Figure 2.9: Hydrogenation of Protected Indoles Setting a Second Chiral Center.........................36

Figure 2.10: Asymmetric Hydrogenation of Unprotected Indoles................................................37

Figure 2.11: Early Asymmetric Hydrogenations of Pyridines.......................................................37

Figure 2.12: Asymmetric Hydrogenations of Pyridium Ylides.....................................................38

Figure 2.13: Asymmetric Hydrogenations of Auxiliary-Bound Pyridines....................................38

Figure 2.14: Hydrogenation of 1-napthol and 2-napthol...............................................................39

Figure 2.15: Proposed Mechanism of Benzene Hydrogenation....................................................40

Figure 2.16: Alper’s Hydrogenations under Phase-Transfer Conditions.......................................41

Figure 2.17: Blum’s Hydrogenations under Phase-Transfer Conditions.......................................41

Figure 2.18: Lemaire’s Auxiliary-Based Hydrogenation with Phase-Transfer Conditions..........42

Figure 2.19: Lemaire’s Enantioselective Hydrogenations under Phase-Transfer Conditions.......42

Figure 2.20 Besson’s Diastereoselective Hydrogenation using a Proline-Derived Auxiliary.......43

Figure 2.21 Solladie-Cavallo’s Diastereoselective Hydrogenation of Phenols.............................43

Figure 2.22: Proposed Strategy for Selective Hydrogenation of Benzenes...................................44

Figure 2.23: Hydrogenation of meta-CF3 Substituted Arene.........................................................51

xi

Figure 2.24: X-ray Crystal Structure of 2.2h.................................................................................51

Figure 2.25: Hydrogenation with Attempted Rigidification by Hydrogenation Bonding.............54

Figure 2.26: Hydrogenation of Methyl-Substituted Arenes..........................................................56

Figure 2.27: Hydrogenation of dimethyl-substituted Arenes........................................................58

Figure 2.28: Hydrogenation of Arene 2.1t.....................................................................................59

Figure 2.29: Hydrogenation of Ester-Substituted Arene 2.1u.......................................................60

Figure 2.30: Proposed Elimination of the Chiral Auxiliary...........................................................61

xii

List of Appendices

Appendix A: 1H-NMR and

13C-NMR Spectra...............................................................................90

Appendix B: 19

F-NMR Spectra....................................................................................................143

Appendix C: GC-MS and GC-FID Traces...................................................................................146

Appendix D: Chiral SFC Traces..................................................................................................162

xiii

1

Chapter 1: Synthesis of Chiral Diamines via

Asymmetric Hydrogenation

1.1 Introduction

1.1.1 Synthesis of Chiral Amines by Hydrogenation

Hydrogenation is well a established and reliable method for the synthesis of chiral

amines.1,2

Seminal work by Kagan demonstrated that enamides could be successfully

hydrogenated to the chiral amine using a Rhodium/DIOP catalyst.3 Subsequent reports by

numerous groups have extended the scope of related asymmetric hydrogenations to include a

wide variety of enamides, which are now believed to facilitate enantioenduction by co-ordinating

to the transition metal catalyst.1 Modern typical procedures also involve the hydrogenation of

imines, where an electron-withdrawing protecting group is often used to activate the substrate

(Figure 1.1).1,2

(1)

(2)

Figure 1.1: Hydrogenations of Enamides and Imines to Furnish Chiral Amines

1. Xie, J-H.; Zhu, S-F.; and Zhou, Q-L., Chem Rev. 2011, 111, 1713–1760.

2 a) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753-819. b) Spindler, F.; Blaser, H.-U.

Enantioselective Hydrogenation of C=N Functions and Enamines; The Handbook of Homogeneous Hydrogenation.

De Vries, J. G.; Elsevier, C. J., eds. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany. 2007, Chapter

34, 1193-1214.

3 Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429-6433.

2

Of significance is the multi-ton production of Ciba-Geigy’s herbicide (S)-metolachlor,

which utilizes an Ir/Xyliphos catalyst to enantiselectively hydrogenate the imine functionality of

an intermediate structure (Figure 1.2).2b

(3)

Figure 1.2: Hydrogenation of Ciba-Giegy’s (S)-Metolachlor

Despite these advancements, to the best of our knowledge, there is no direct route to

chiral 1,2-diamines or 1,3-diamines via catalytic asymmetric hydrogenation. An extension of

hydrogenation methodologies to include these targets would be uniquely valuable because the

chemistry is intrinsically green in nature, rendering it attractive in both academia and especially

industry, where therapeutics are produced on a multi-ton scale. It is in this context which we

describe our advancements in chiral diamine synthesis.

1.1.2 Synthesis of Chiral Diamines

Chiral diamines are present in a myriad of chemically and biologically relevant molecules

(Figure 1.3).1,2,4

In particular, the chiral 1,2-diamine structural unit is prevalent in a number of

drug molecules and catalysts used in a range of oxidations, reductions and C-C bond forming

reactions.1 This has sparked the development of a variety of complementary strategies for their

synthesis; Figure 1.4 illustrates just a few of these many strategies.4,5

4 Kim, H.; So, S. M.; Chin, J.; Kim, B. M. Aldrichim. Acta 2008, 41, 77-88.

5 Yeung, C.S. Transition Metal Catalysis: Activation of CO2, C-H and C-O Bonds En Route to Carboxylic Acids,

Biaryls and N-Containing Heterocycles. Ph.D. Thesis, University of Toronto, Toronto, Canada, 2011.

3

Figure 1.3: Chiral Diamines of Interest

Figure 1.4: Synthetic Routes to Chiral 1,2-Diamines4,5

Chiral 1,3-diamines have found similar applications,6 yet there are much fewer methods

which can be called upon by the synthetic chemist to build this structural unit. Furthermore,

many of these methods are limited in scope. Some more recently developed strategies are

6 a) Jahn, T.; Ko¨nig, G. M.; Wright, A. D. Tetrahedron Lett. 1997, 38,3883. b) Vickery, K.; Bonin, A. M.; Fenton,

R. R.; O’Mara, S.; Russell, P. J.; Webster, L. K.; Hambley, T. W. J. Med. Chem. 1993, 36, 3663.

4

highlighted below. Du Bois has reported a rhodium catalyzed C-H bond amination which affords

the diamine with retention of stereochemistry (Figure 1.5).7

(4)

Figure 1.5: Du Bois’ C-H bond amination route to 1,3-diamines7

Du et.al have demonstrated a route to chiral 1,3-diamines via an enantioselective Michael

addition to nitroalkenes which gives 1,3-dinitroalkanes that can facilely be reduced to the desired

diamine (Figure 1.6).8

(5)

Figure 1.6: Enantioselective Michael Additions en route to Chiral 1,3-Diamines8

The Gotor group has also achieved an enzymatic desymmetrization meso 1,3-diamines to

afford the chiral variant (Figure 1.7).9

7 . Kurokawa, T.; Kim, M.; Bois, J. D., Angew. Chem. Int. Ed. 2009, 48, 2777-2779.

8 Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W., J. Am. Chem. Soc. 2006, 128, 7418-7419

9 Ríos-Lombardía, N.; Busto, E.; García-Urdiales, E.; Gotor-Fernández, V.; Gotor, V.,

J. Org. Chem. 2009, 74, 2571-2574.

5

(6)

Figure 1.7: Enzymatic Desymmetrization of meso 1,3-Diamines9

Two accounts of phosphoric acid catalyzed aza-mannich reactions have also been

reported by Terada10

(Figure 1.8) and Zhu11

(Figure 1.9). Recently, Menche and colleagues

reported a palladium catalyzed intramolecular allylic substitution which provides either 1,3-syn

or anti-tetrahydropyrimidinones as intermediates to be transformed into the corresponding free

amines (Figure 1.10).12

(7)

Figure 1.8: Chiral 1,3-Diamines via Phosphoric Acid Aza-Mannich Reaction by Terada10

10

Terada, M.; Machioka, K.; Sorimachi, K., Angew. Chem. Int. Ed. 2009, 48, 2553-2556. 11

Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546-5549. 12

Morgen, M.; Bretzke, S.; Pengfei, L.; Menche, D., Organic Letters, 2010, 12, 4494-4497.

6

(8)

Figure 1.9: Chiral 1,3-Diamines via Phosphoric Acid Aza-Mannich Reaction by Zhu11

(9)

Figure 1.10: Chiral 1,3-Diamines via Palladium Catalysis12

1.2 Results and Discussion

1.2.1 Toward Chiral 1,2-Diamines via 1,2-Diimine Hydrogenation

At the outset we envisaged that we could achieve diastereo- and enantioselective

hydrogenation of the spirocyclic diimine 1.1a (Figure 1.11) originally used by Corey for the

synthesis of 1,2-diamines.13

13

Corey, E.J; Imwinkelreid, R.; Pikul, S.; Xiang Y-B., J. Am. Chem. Soc., 1989, 111, 5493-5495.

7

(10)

1.1a

Figure 1.11: Chiral 1,2-Diamines via Reduction of 1.1a13

Corey`s strategy involves condensation of benzil with cyclohexanone in the presence of

ammonium acetate to afford the spirocyclic compound, which is reduced with lithium in

ammonia and subjected to an acidic work-up to give the diamine in racemic form.13

In principle,

changing the reduction step to an asymmetric hydrogenation could lead to enantioenriched

products and circumvent the need for resolution. In our first efforts toward this goal we achieved

initial reactivity with a homogeneous catalytic system using [Rh(COD)2]BF4 and (±)-BINAP

under 30 bar H2 at ambient temperature; the mono-hydrogenated product was obtained in 62%

yield (Figure 1.12).

(11)

Figure 1.12: First Reactivity Affording Hydrogenated Product 1.2a

Upon further optimization (Table 1.1), a [Rh(COD)2]BF4/(±)BINAP system and a

modified system employed by Zhang and colleagues14

provided mono-reduced product 1.2a in

essentially quantitative yield, but surprisingly the second hydrogenation event was never

observed.

14

Wang, D-S.; Chen, Q-A.; Li, Y.; Yu, C-B.; Zhou Y-G.; Zhang X., J. Am. Chem. Soc., 2010, 132, 8909-8911.

8

Precatalyst/

Ligand

H2

Pressure

Solvent/

Temperature

Additive Time

(Yield)

[Rh(COD)Cl]2/(±)BINAP

10.3 bar

DCM (1mL)/60ºC

None

16 h (NR)

[Rh(COD)2]BF4/(±)BINAP 10.3 bar DCM (1mL)/60ºC None Overnight (NR)

[Ir(COD)Cl]2/(±)BINAP 30 bar DCM (1mL)/rt None Overnight (NR)

[Ir(COD)Cl]2/(±)BINAP 50 bar DCM (1.5mL)/rt None 20 h (NR)

[Ir(COD)Cl]2/L1 30 bar DCM (1mL)/rt None Overnight (NR)

[Ir(COD)Cl]2/XANTPHOS 30 bar DCM (1mL)/rt None Overnight (NR)

[Rh(COD)Cl]2/(±)BINAP 30 bar DCM (1mL)/rt None 16 h (NR)

[Rh(COD)Cl]2/(±)BINAP 50 bar DCM (1.5mL)/

60ºC

None 20 hr (NR)

[Rh(COD)Cl]2/(±)BINAP 50 bar DCM (1.5mL)/

60ºC

HCl 20 hr (complex

spectra, no

mono or di-

reduced

products by

LC-MS)

9

[Rh(COD)Cl]2/(±)BINAP 50 bar DCM (1.5mL)/

60ºC

HCl/Bu4NI 20 hr (complex

spectra, no

mono or di-

reduced

products by

LC-MS)

[Rh(COD)Cl]2/BDPP 30 bar DCM (1mL)/rt None Overnight (NR)

[Rh(COD)Cl]2/XANTPHOS 30 bar DCM (1mL)/rt None Overnight

(trace)

[Rh(COD)Cl]2/(±)BINAP 30 bar DCM (1mL)/rt None 24 h (48%

yield, 73%

conversion)

[Rh(COD)2]BF4/(±)BINAP 50 bar MeOH (1.5mL)/

60ºC

p-TsOH 13.5 hr (mix of

starting

material,

product and by-

products by

LC-MS, not

isolated)

[Rh(COD)2]BF4/(±)BINAP 50 bar MeOH (1.5mL)/

60ºC

AlCl3 13.5 hr mix of

starting material

and product and

by-products by

LC-MS, not

isolated)

[Rh(COD)2]BF4/(±)BINAP 30 bar MeOH (1mL)/rt None Overnight,

(62% yield)

[Rh(COD)2]BF4/(±)BINAP 50 bar MeOH

(1.5mL)/60ºC

None 17 h

(~quantitative)

[Rh(COD)2]BF4/DPPE 30 bar MeOH (1mL)/rt None Overnight (NR)

10

[Rh(COD)2]BF4/XANTPHOS 30 bar MeOH (1mL)/rt None Overnight (NR)

[Rh(COD)2]BF4/L2 30 bar MeOH (1mL)/rt None Overnight (NR)

Pd(OCOCF3)2/(±)BINAP 30 bar 1mL DCM,

0.5mL TFE/ rt

p-TsOH 4 h (90%)

Pd(OCOCF3)2/(±)BINAP 100 bar 1mL DCM, 0.5mL

TFE/ 120ºC

None 32.5 h

(Complex

mixture of by-

products)

L1 L2

Table 1.1: Optimization of the Hydrogenation of 1.1a

The matter was further complicated by the observation that the product 1.2a slowly

reoxidizes back to starting material on the bench. We also attempted and were unsuccessful at

reducing 1.2a with MeLi or LiAlH4.15

Proposing this might be a steric issue since di-reduction of

1.1a is observed with Li/NH3,13

analogues of the original diimine precursor 1.1a, 1.1b and 1.1c

(Figure 1.13), were synthesized in the hope that they may exhibit increased reactivity, but both of

these analogues could be hydrogenated quantitatively at only one imine as well using our

optimized conditions and with increased temperatures and hydrogen pressures.

15

Yeung, C.S.; Galligan, B.; Dong, V.M., Unpublished Work.

11

(12)

(13)

Figure 1.13: Synthesis of Novel 1,2-Diimine Precursors13

(see Supporting Information for

Hydrogenation Conditions)

This prompted an alternate approach; we postulated that if we could achieve

enantioselective mono-hydrogenation a subsequent diastereoselective reduction with Li/NH3

could furnish the chiral 1,2-diamines. Unfortunately, various chiral hydrogenation systems

afforded only racemic product (Table 1.2).

Substrate Precatalyst Ligand

Conditions Product

(Yield)

1a [RhCOD2]BF4 R-BINAP H2 (50 bar), MeOH

(1.5mL)/ 60ºC, 17 h

1.2a (91%)

1a [RhCOD2]BF4 R-MeO-

BIPHEP

H2 (50 bar), MeOH

(1.5mL)/ 60ºC, 18 h

1.2a (97%)

12

1a Pd(OCOCF3)2 R-BINAP H2 (50 bar), DCM

(1.5mL) TFE (1mL)/

60ºC, 4 h

1.2a (92%)

1a Pd(OCOCF3)2 (1R,1′R,2S,2′S)-

DuanPhos

H2 (50 bar), DCM

(1.5mL) TFE (1mL)/

60oC, 5 h

1.2a

(~quantitative)

Table 1.2: Attempted Asymmetric Hydrogenations of 1.1a

We reasoned from this that it is likely the products undergo racemization, in a manner

which may be connected to the observed re-oxidaton, and turned our sights toward a new model

system.

1.2.2 1,2-Diamines via Hydrogenation of Imidazolones

As an alternative strategy, we imagined that substituted imidazolones could serve as

viable precursors for the formation of chiral 1,2-diamines by hydrogenation. This was based on

precedent from an analogous substrate hydrogenated in industry (Figure 1.14).2b

(14)

Figure 1.14: Route to Latent Chiral 1,2-Diamines2b

With this goal in mind, we synthesized imidazolone substrates 1.3a-1.3c in a single step

(Table 1.3).16

16

Chawla, H.M.; Pathak, M.; Tetrahedron, 1990, 46, 1331-1342.

13

1.3

Product R Rʹ Yield

1.3a Ph Ph 43%

1.3b Bn Ph 4%

1.3c Ph Me 26%

Table 1.3: Synthesized Imidazolone Precursors

For ease of preparation, our initial studies made use of identically substituted alpha-

hydroxy ketones. Using a number of homogeneous hydrogenation conditions no reactivity was

ever observed for 1.3a or 1.3b (Table 1.4).

Substrate H2/ Temperature [M]/Ligand Solvent/Additive

1.3a 30 bar/rt Pd(OCOCF3)2/

(±)BINAP

(1 mL DCM/ 0.5 mL

TFE)/ None

1.3a 50 bar/60ºC [Rh(COD)Cl]2/

(±)BINAP

1.5 mL DCM/ None

1.3a 50 bar/60ºC [Rh(COD)2]BF4/

(±)BINAP

1.5 mL MeOH/ None

14

1.3a 50 bar/60ºC [Ir(COD)Cl]2/(±)

BINAP

1.5 mL DCM/ None

1.3a 70 bar/80ºC [Ir(COD)Cl]2/(±)

BINAP

1.5 mL DCM/ 1.1 eq p-

TsOH

1.3b 50 bar/60ºC [Rh(COD)Cl]2/

(±)BINAP

1.5 mL DCM/ None

Table 1.4: Attempted Hydrogenations of Imidazolone Substrates

In attempting homogeneous hydrogenation of 1.3c, reactivity was achieved via

unintentional generation of heterogeneous metal species in situ (Figure 1.15).

(15)

(16)

Figure 1.15: Hydrogenations of 1.3c

Though the desired product 1.4a was formed as a single diastereomer (eq 15), it was

found to be racemic by SFC analysis, as would be expected with heterogeneous conditions.

Undesired product 1.4b was also obtained as a single diastereomer (eq 16). To gain insight into

15

the cause of this lack of reactivity, substrate 1.3d was synthesized via a complimentary route

(Figure 1.16).17

(17)

Figure 1.16: Formation of Unsubstiuted Imidazolone 1.3d

We imagined that 1.3d, with its di-substituted double bond, should be hydrogenated

much more easily than the tetrasubstituted counterparts. If this substrate could not be

hydrogenated, it may suggest aromatic character in the imidazolone ring sufficient to thwart

reactivity. A catalytic system was quickly found which could hydrogenate the substrate with

excellent yields suggesting that the substitution of the double bond is the major cause of

unreactivity (Figure 1.17 eq 19). We attempted to apply this catalytic system to hydrogenation of

substrate 1.3c, but unfortunately even under more forcing conditions the substrate remained

unreactive (Figure 1.17 eq 18). It is likely that a combination of the high substitution of the

double bond and partial aromatic character renders these substrates resistant to hydrogenation.

17

Llopart, C.C; Ferrer, F.; Joule, J.A. Can. J. Chem.,2004, 82, 1649–1661.

16

(18)

(19)

Figure 1.17: Reactivity Differences of Substrates 1.3c and 1.3d

1.2.3 Toward Chiral 1,3-Diamines via 1,3-Diimine Hydrogenation

Previous work in the group identified a promising class of cyclic urea substrates which

underwent hydrogenation with iridium catalysts to form latent chiral 1,3-diamines (Figure

1.18).15

The cyclic urea where R = Bn proved to be the most effective at promoting asymmetric

induction and diastereoselectivity. Shown in Figure 1.19 are the chiral ligands which were most

selective.

(20)

Figure 1.18: Hydrogenation of Cyclic Ureas to 1,3-Diamine Precursors

17

Figure 1.19: Ligands for Asymmetric Hydrogenation of Cyclic Urea 1.6a. The reported

dr’s are a ratio of trans:cis as determined by NMR spectroscopy15

Encouraged by these results, we endeavoured to synthesize analogous thiourea substrates

which we reasoned could be used to achieve asymmetric induction. Four derivatives were

prepared (Table 1.5) and hydrogenated. Hydrogenation of each of these substrates under various

conditions (Table 1.6) afforded no reaction.

1.5

Urea Ketone Cyclic Thiourea Yield

1.5a 37%

1.5b 18%

18

1.5c 34%

1.5d 76%

Table 1.5: Synthesized Thiourea Precursors

Substrate H2/ Temperature [M]/Ligand Resulta

1.5a 10.3 bar/60ºC [Ir(COD)Cl]2/(±)

BINAP

No reaction

1.5a 10.3 bar/60ºC [Rh(COD)Cl]2/

(±)BINAP

No reaction

1.5b 10.3 bar/60ºC [Ir(COD)Cl]2/(±)

BINAP

No reaction

1.5c 10.3 bar/rt [Rh(COD)2]BF4/

(±)BINAP

No reaction

1.5d 13.7 bar/100ºC [Ir(COD)Cl]2/(±)

BINAP

Decomposition

19

1.5d 10.3 bar/100ºC [Ir(COD)Cl]2/(±)

BINAP

Decomposition

a: As determined by 1H-NMR

Table 1.6: Hydrogenation of Thiourea Precursors

What was surprising is that the allyl group of 1.5b survived the reaction conditions, under

which we would expect it to be easily hydrogenated. Also, under more forcing conditions, we

observed decomposition of starting materials by 1H-NMR. This prompted us to repeat the known

hydrogenation of 1.6a in the presence of these thioureas as a spike and observe if they affected

the reaction. In this experiment only starting material was recovered in the presence of 7.5 mol%

thiourea 1.5a (Figure 1.20). To determine whether this was a general effect the identities of the

spike, metal complex and ligands were varied and the experiments repeated. The results are

summarized in Table 1.7 below. Based on these findings it was hypothesized that the thiourea

substrate may poison the catalyst in situ in at least some cases. We will thus focus future efforts

on the analogous cyclic ureas which show much more promise for the synthesis of chiral 1,3-

diamines.

(21)

1.6a

Figure 1.20: Hydrogenation of Cyclic Urea 1.6a in the Presence of Thiourea Spike 1.5a

20

1.6a 1.6b

Precatalyst/Spike Ligand Resulta

[Ir(COD)Cl]2/No spike rac-BINAP Conversion to product

observed

[Ir(COD)Cl]2/1.5d rac-BINAP Conversion to product

observed

[Ir(COD)Cl]2/ No Spike DPPE Conversion to product

observed

[Ir(COD)Cl]2/1.5d DPPE Only starting material

observed

[Rh(COD)Cl]2/ No Spike rac-BINAP Conversion to product

observed

[Rh(COD)Cl]21.5d rac-BINAP Only starting material

observed

[Rh(COD)Cl]2/ No Spike DPPE Only starting material

observed

[Rh(COD)Cl]2/1.5d DPPE Only starting material

observed

a: As determined by crude 1H-NMR, exact conversions and yields not determined

Table 1.7: Effect of Cyclic Thiourea Spike 1.5d on Hydrogenation of Cyclic urea 1.6a.

1.3 Conclusions and Future Work

Future work towards 1,2-diamines via hydrogenation includes the possibility of achieving

dynamic kinetic resolution of spirocyclic diimines 1.1a-1.1c if racemization is indeed occurring.

21

Efforts toward 1,3-diamines will center on further optimizing the hydrogenations of the urea-

protected 1,3-diamine surrogates.

1.4 Experimental Procedures

1.4.1 General Considerations

Reagents were purchased from Sigma-Aldrich, Strem, or Alfa Aesar and

used without further purification. All solvents were purchased from Caledon or Fischer and

used as received unless otherwise noted. Reactions were monitored by thin-layer

chromatography (TLC) on EMD Silica Gel 60 F254 plates under UV light (254 μm) or

by Liquid-Chromatography-Mass Spectrometry. Solutions were concentrated under reduced

pressure on a Büchi rotary evaporator. Column chromatography was carried out on Silicycle

Silica-P Flash Silica Gel (40-63 μm). 1H and

13C NMR spectra were recorded on a Bruker AV-III

400 MHz spectrometer at room temperature. Data for 1H-NMR are reported as: chemical shift

(δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad),

coupling constant (Hz), integration. Data for 13

C-NMR are reported as: chemical shift (δ

ppm).

1.4.2 General Procedure A: Synthesis of 1,2-Diimine Precursors

Prepared by a modified literature procedure13

. To a 100 mL round-bottom flask was

added benzil (2.1 g,10 mmol), the ketone (10 mmol), ammonium acetate (8 g) and 20 mL acetic

acid. The resulting mixture was refluxed overnight. The solution was allowed to cool at which

time 20 mL of H2O was added and the mixture was extracted 3 x 50 mL CH2Cl2. The combined

organics were washed 1 x 50 mL NaCl and dried with magnesium sulphate. This solution was

concentrated under reduced pressure and the crude product obtained was purified by column

chromatography (eluent: 10% EtOAc/Hexanes v/v) to afford the desired products.

22

1.4.3 General Procedure B: Cyclic Thiourea Synthesis

Prepared by a modified literature procedure.15

In a 100 mL round-bottom flask was

charged the thiourea (7.07 mmol), pentane-2,4-dione (0.8 mL, 7.78 mmol), ethanol (10 mL), and

2 mL conc. HCl. The resulting suspension was heated to reflux overnight. The reaction mixture

was cooled to room temperature, diluted with 100 mL EtOAc and washed with 50 mL sat’d

NaHCO3. The aqueous phase was subsequently extracted with 3 x 50 mL EtOAc. The combined

organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product

was purified by column chromatography to afford the cyclic thiourea.

1.4.4 General Procedure C: Synthesis of Imidazolones

Based on a modified procedure of Chawla and Pathak.16

Into a one-neck round bottom

flask was charged an equimolar amount of the selected alpha-hydroxy ketone and urea. The

resulting mixture was stirred neat at 170oC for the indicated time. A thick gum is obtained which

is extracted 4 x 150 mL CHCl3. The extracts were combined, concentrated in vacuo, and the

obtained crude material was recrystallized from EtOH to afford the title compounds.

1.4.5 General Procedure D: Hydrogenation of Imidazolones

To 0.1 mmol of substrate in a 12x32 mm vial was added a stir bar, 0.1 mmol

imidazolone substrate, 5 mol % [Rh(COD)2]BF4 (2 mg, 0.005 mmol), 7.5 mol % ligand (0.075

mmol) and 1.5 mL of dry degassed THF. The vial was fitted with a slit cap and placed into a

CAT18 HEL reactor. The vessel was then pressurized to 50 bar, heated on a heat block to 60oC

and left for 13 hours. After 13 hours the vessel was vented and the products were purified by

flash chromatography (eluent 90% ethyl acetate/hexanes v/v).

23

1.4.6 Characterization Data

2,3-diphenyl-1,4-diazaspiro[4.4]nona-1,3-diene (1.1b): Synthesized with General Procedure A

using 10 mmol (0.88 mL) cyclopentanone. The product was obtained as a brown solid (1.7 g,

59%). Characterization data: 1H NMR (400 MHz, CDCl3) δ 7.52-7.49 (m, 4H), 7.45-7.42 (m,

3H), 7.36 (t, 4H, J= 7.3 Hz), 2.13-2.24, (m, 8H). 13

C NMR (100 MHz, CDCl3), δ 164.2, 133.0,

130.2, 129.1, 128.5, 111.8, 35.7, 26.5. IR (cm-1

): 3063, 2963, 1442, 1272, 1007, 764, 696.

HMRS (ESI, m/z): [M]+

calc.: 277.1699; found: 277.1707. mp = 97-99 oC.

2,2-dimethyl-4,5-diphenyl-2H-imidazole (1.1c): Synthesized with General Procedure A using

10 mmol (0.73 mL) acetone. The title compound was obtained as a dark brown solid (1.32 g,

53%). Characterization data: 1H NMR (400 MHz, CDCl3) δ 7.50-7.53 (m, 4H), 7.44-7.47 (m,

2H), 7.37 (t, 4H, J = 7.7), 1.67 (s, 6H). 13

C NMR (100 MHz, CDCl3) δ 164.4, 132.9, 130.4,

129.1, 128.5, 101.8, 24.4. IR (cm-1

): 2980, 2933, 2350, 2187, 1550, 1487, 1442, 1267, 1213,

1171, 972, 768, 702, 692. HMRS (ESI, m/z): [M]+

calc.: 249.1386; found: 249.1381.

mp = 67-68 oC.

24

2,3-diphenyl-1,4-diazaspiro[4.5]dec-1-ene (1.2a):To a 12x32 mm vial was added a stir bar,

1.1a (28.8 mg, 0.1 mmol) 5 mol % Pd(TFA)2, (1.6 mg, 0.005 mmol), 7.5 mol % rac-BINAP (4.7

mg, 0.0075 mmol) and p-toluene sulfonic acid hydrate (20.9 mg, 0.11 mmol). Trifluoroethanol

(0.5 mL) was sparged for 5 min and added to the vial followed by 1 mL of anhydrous CH2Cl2.

The vial was capped with a slit screw cap and placed inside a HEL Cat 18 reactor. The reactor

was purged once with hydrogen gas before the reactor was pressurized to 50 bar at ambient

temperature. The reaction was left for overnight, upon which time a dark red solution is obtained.

The mixture was immediately purified by column chromatography (gradient eluent: 20%

EtOAc/Hex- 8%MeOH/EtOAc, v/v) to obtain 1.2a in ~quantitative yield as a light orange oil.

Characterization data: 1H NMR (400 MHz, CDCl3) δ 7.62-7.68 (m, 2H), 7.22-7.32, (m, 8H),

5.45, (s, 1H), 1,42-2.1 (m, 12H). 13

C NMR (100 MHz, CDCl3) δ 167.8, 141.8, 132.9, 130.3,

129.3, 128.7, 128.4, 128.3, 128.1, 92.2, 71.2, 39.7, 38.8, 25.7, 23.7, 23.7. HMRS (ESI, m/z):

[M]+

calc.: 291.1855; found: 291.1846.

2,3-diphenyl-1,4-diazaspiro[4.4]non-1-ene (1.2b): To a 12x32 mm vial was added a stir bar,

1.1b (27.4 mg, 0.1 mmol) 5 mol % Pd(TFA)2, (2 mg, 0.005 mmol), 7.5 mol % rac-BINAP (4.7

mg, 0.0075 mmol) and 1.5 mL dry and degassed MeOH. The vial was capped with a slit screw

25

cap and placed inside a HEL Cat 18 reactor. The reactor was purged once with hydrogen gas

before the reactor was pressurized to 50 bar at ambient temperature and heated to 60ºC. The

reaction was left for 5 h and then purified by column chromatography (gradient eluent: 20%

EtOAc/Hex- 8%MeOH/EtOAc, v/v) to obtain 24.6 mg (89%) 1.2b as a yellow oil.

Characterization data: 1H NMR (400 MHz, CDCl3) δ 7.63-7.66 (2H, m) 7.21-7.55 (8H, m) 5.42,

(1H, s), 1.70-2.32 (8H, m). 13

C NMR (100 MHz, CDCl3) δ 168.1, 141.4, 132.7, 130.4, 129.3,

129.1, 128.7, 128.5, 128.2, 128.1, 100.3, 71.4, 41.1, 40.7, 25.0, 24.9. HMRS (ESI, m/z): [M]+

calc.: 277.1699; found: 277.1707.

2,2-dimethyl-4,5-diphenyl-2,5-dihydro-1H-imidazole (1.2c): To a 12x32 mm vial was added a

stir bar, 1.1c (24.8 mg, 0.1 mmol) 5 mol % [Rh(COD)2]BF4 (2 mg, 0.005 mmol), 7.5 mol % rac-

BINAP (4.7 mg, 0.0075 mmol) and 1.5 mL dry and degassed MeOH. The vial was capped with a

slit screw cap and placed inside a HEL Cat 18 reactor. The reactor was purged once with

hydrogen gas before the reactor was pressurized to 50 bar at 60ºC. The reaction was determined

to be complete by LC-MS after 18 hr. The mixture was immediately purified by column

chromatography (gradient eluent: 20% EtOAc/Hex did not elute the product, it was flushed with

MeOH to obtain 1.2c (19 mg, 76%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (2H,

m), 7.25-7.31 (8H, m), 5.48 (1H, s), 1.62 (3H, s), 1.49 (3H, s). 13

C NMR (100 MHz, CDCl3) δ

168.2, 141.3, 132.6, 130.4, 129.3, 128.7, 128.4, 128.2, 128.1, 90.1, 71.9, 29.9, 29.7. HMRS (ESI,

m/z): [M]+

calc.: 251.1542; found: 251.1536.

26

1,4,5-triphenyl-1H-imidazol-2(3H)-one (1.3a): Synthesized using General Procedure C with 10

mmol (1.36 g) phenyl urea and 10 mmol (2.12 g) benzoin. The title compound was obtained as a

white solid (1.35 g, 43% yield). Characterization data was consistent with the literature.16

1-benzyl-4,5-diphenyl-1H-imidazol-2(3H)-one (1.3b): Synthesized using General Procedure C

with 10 mmol (1.5 g) benzyl urea and 10 mmol (2.12 g) benzoin. The title compound was

obtained as a white solid (138 mg, 4% yield). Characterization data was consistent with the

literature.16

4,5-dimethyl-1-phenyl-1H-imidazol-2(3H)-one (1.3c): Synthesized using General Procedure C

with 20 mmol (2.72 g) phenyl urea and 20 mmol (1.76 g) acetoin. The title compound was

obtained as a white solid (975 mg, 26% yield). Characterization data was consistent with the

literature.16

27

1-phenyl-1H-imidazol-2(3H)-one (1.3d): Based on a modified procedure by Joule.16

To a one

neck-round bottom flask was added 1.3e (4 g, 17.8 mmol) and 40 mL 2.5 M HCl. After stirring

for 20 h, the solution was neutralized with aqueous sodium bicarbonate and the solids were

filtered to give the titled compound as a white solid (2.76 g, 97%). Characterization data was

consistent with the literature.16

1-(2,2-dimethoxyethyl)-3-phenylurea (1.3e): Based on a procedure by Joule.17

To a one-neck

round bottom flask was added 20.95 mmol (2.28 mL) phenylisocyanate to 20.95 mmol (2.25

mL) aminoacetaldehyde dimethyl acetal over 5 minutes on an ice bath. The reaction was allowed

to warm to room temperature and stir for 1 h until a yellow mass was obtained. The crude

material was flash chromatographed (gradient eluent: 0-50% Ethyl Acetate/Hexane v/v) to give

4g (85%) of the title compound as a white solid. Chracterization data was consistent with the

literature.17

28

4,5-dimethyl-1-phenylimidazolidin-2-one (1.4a). Synthesized with General Procedure D using

(R)-MonoPHOS as the ligand. The title compound was isolated as a brown gum. 1H NMR (400

MHz, CDCl3) δ 7.42, (m, 1H), 7.35 (m, 1H), 7.11 (m, 1H), 4.72 (br.s, 1H), 4.36 (m,1H), 3.98 (m,

1H), 1.23 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, 6.7 Hz). 13

C NMR (100 MHz, CDCl3) δ 159.5, 138.4,

128.9, 124.1, 122.1, 55.8, 49.0, 15.9, 12.7. HMRS (ESI, m/z): [M]+

calc.: 191.11844; found:

191.11778. IR (cm-1

): 2924, 2856, 1751, 1688, 1611, 1495, 1454, 1401, 1257, 1196, 1114, 852,

756, 701.

1-cyclohexyl-4,5-dimethylimidazolidin-2-one (1.4b). Synthesized with General Procedure D

using (R,R)-MeDuPHOS as the ligand and isolated as a brown solid (12 mg, 61%). 1H NMR

(400 MHz, CDCl3) δ 4.30 (br.s, 1H), 3.67-3.80 (m, 2H), 3.52 (m, 1H), 1.57-1.90 (m, 7H), 1.33-

1.88 (m, 12H). 13

C NMR (100 MHz, CDCl3) δ 161.9, 53.6, 52.8, 50.3, 32.6, 30.8, 26.4, 26.3,

25.9, 15.9, 15.5. HMRS (ESI, m/z): [M]+

calc.: 197.16539; found: 197.16651. IR (cm-1

): 3218,

2932, 2855, 1749, 1685, 1611, 1589, 1494, 1453, 1432, 1400, 1349, 1256, 1196, 1161, 1113,

1030, 1004, 850, 771, 756, 735, 702. mp = 102.-104oC.

29

1-phenylimidazolidin-2-one (1.4c): Synthesized using General Procedure D with (±)BINAP as

ligand. Isolated as a white solid (16 mg, 98%). Characterization data was consistent with the

literature.17

1,4,6-trimethylpyrimidine-2(1H)-thione (1.5a): Synthesized with general procedure B using 1-

methylthiourea (637 mg, 7.07 mmol). After the described work-up the compound was

chromatographed (eluent 10% MeOH/EtoAc). The title compound was obtained as a yellow

solid (405 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 6.44 (s, 1H), 3.99 (s, 1H), 2.45 (s, 3H), 2.39

(s, 3H). 13

C NMR (100 MHz, CDCl3) δ 184.1,168.1, 156.8, 111.7, 39.9, 24.7, 22.0. IR (cm-1

):

2185, 2150, 1601, 1531, 1420, 1368, 1350, 1216, 1132, 1066, 1023, 959, 874, 834, 748, 734.

HMRS (ESI, m/z): [M]+

calc.: 155.0637; found: 155.0632. mp = 153-154 oC.

1-allyl-4,6-dimethylpyrimidine-2(1H)-thione (1.5b): Synthesized with general procedure B

using 1-allylthiourea (821 mg, 7.07 mmol). After the described work-up the compound was

chromatographed (eluent 100% EtoAc). The title compound was isolated as a yellow solid (230

mg, 18%). 1H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 6.05 (m, 1H), 5.36 (d, 2H, J = 5.3 Hz),

30

5.32 (d, 1H, J = 10.6 Hz), 5.16 (d, 1H, J = 17.3 Hz), 2.46 (s, 3H), 2.38 (s, 3H). 13

C NMR (100

MHz, CDCl3) δ 184.1, 168.4, 157.1, 129.9, 118.3, 111.9, 54.3, 24.8, 21.0,. IR (cm-1

): 3083, 2930,

2149,1638, 1604, 1526, 1465, 1417, 1395, 1374, 1333, 1283, 239, 1187, 1158, 1121, 1086, 1031,

1010, 993, 865, 782. [M]+

calc.: 181.0793; found: 181.0801. mp = 90-92 oC.

1-benzyl-4,6-dimethylpyrimidine-2(1H)-thione (1.5c): Synthesized with general procedure B

using 1-benzylurea (1.17 g, 7.07 mmol). After the described work-up the compound was

chromatographed (eluent 4% MeOH/EtoAc). The title compound was isolated as a red solid (550

mg, 34%). 1H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 6.05 (m, 1H), 5.36 (d, 2H, J = 5.3 Hz),

5.32 (d, 1H, J = 10.6 Hz), 5.16 (d, 1H, J = 17.3 Hz), 2.46 (s, 3H), 2.38 (s, 3H). 13

C NMR (100

MHz, CDCl3) δ 184.1, 168.4, 157.1, 129.9, 118.3, 111.9, 54.3, 24.8, 21.0. IR (cm-1

): 3030, 2929,

2156, 1604, 1524, 1496, 1452, 1416, 1349, 1243, 1185, 1138, 1076, 951, 832, 785, 692. [M]+

calc.: 231.0950; found: 231.0942. mp = 84-85 oC.

4,6-dimethyl-1-phenylpyrimidine-2(1H)-thione (1.5d): Synthesized with general procedure B

using 1-phenylthiourea (1.46 g, 7.07 mmol). After the described work-up the compound was

chromatographed (eluent 100 EtoAc%). The title compound was isolated as a yellow solid (1.16

g mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.50 (m, 1H), 7.20 (m, 2H), 2.45 (s,

31

3H), 2.02 (s, 3H) . 13

C NMR (100 MHz, CDCl3) δ, 185.1, 169.7, 157.4, 141.5, 130.4, 129.3,

126.9, 110.9, 25.1, 22.4. IR (cm-1

): 3032, 2150, 1609, 1590, 1518, 1489, 1422, 1370, 1334, 1270,

1112, 1007, 992, 923, 895, 854, 761, 742, 717, 693. [M]+

calc.: 217.0793; found: 217.0799. mp =

decomp. 180oC.

32

Chapter 2: Chiral Cyclohexanes by

Asymmetric Hydrogenation

2.1 Introduction

2.1.1 Hydrogenation of Heteroaromatics

Continuing developments of asymmetric hydrogenation methodologies have allowed the

hydrogenation of alkenes, imines, enamines, ketones as well as heteroaromatics with outstanding

yields and enantioselectivities.18-21

Of these classes, heteroaromatics are particularly challenging

- their stability renders them poorly reactive, they typically lack secondary coordinating groups,

and unprotected heteroatoms are known to poison many hydrogenation catalysts.21

Despite these

challenges advancements have been made in many heteroaromatic substrate classes. 192021

In 1987 the Murata group demonstrated the first homogenous asymmetric hydrogenation

of 2-methylquinoxaline with a chiral rhodium catalyst and obtained a minimal 3% ee

(Figure 2.1).22

Though not synthetically useful, this seminal result demonstrated proof of

principle. Just over a decade later Bianchini and coworkers reported the hydrogenation of the

identical quinoxaline with an improved 90% ee at 53.7% conversion (Figure 2.2).23

18

Burgess, K.; Ciu, X. Chem Rev. 2005, 105, 3272-3296 19

Xie, J-H.; Zhou, S-F.; Q-L, Zhou. Chem Rev. 2011, 111, 1713-60. 20

Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40-73. 21

Zhou, Y.G. Acc. Chem. Res. 2007, 40, 1357–1366. 22

Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26, 763–766. 23

Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M. Organometallics. 1998, 17, 3308–3310.

33

(1)

Figure 2.1: Murata’s Hydrogenation of 2-methylquinoxaline22

(2)

Figure 2.2: Bianchini’s Hydrogenation of 2-methylquinoxaline23

In the interim between Murata and Bianchini’s reports, Takaya et al. extended

enantioselective hydrogenation to include furans. In their 1995 report they demonstrate that 2-

methylfuran can be hydrogenated at 100 bar H2 with a chiral ruthenium catalyst to give 50% ee

with full conversion to the desired product (Figure 2.3).24

(3)

Figure 2.3: Asymmetric Hydrogenation of 2-methylfuran24

24

Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya, H. J. Org. Chem. 1995, 60, 357–363.

34

In 1996 Lonza patented the asymmetric hydrogenation of N-(tert-butyl)pyrazine-2-

carboxamide using a chiral Rh/Josiphos complex to afford the corresponding product in 78% ee

(Figure 2.4).25

(4)

Figure 2.4: Asymmetric Hydrogenation of Pyrazines by Lonza25

More recently quinolines have been investigated by the Zhou group.26

One representative

study uses a chiral iridium catalyst with iodine as an additive, which is presumed to oxidize the

Ir(I) complex to a more reactive Ir(III) complex that is believed to be the active species

(Figure 2.5).9a

Asymmetric hydrogenation of quinolines has also been achieved by via transfer

hydrogenation by the Rueping group.10

Using the Hantzsch ester and chiral phosphoric acids,

they were able to obtain the desired products between 10-88% ee (Figure 2.6).27

(5)

Figure 2.5: Asymmetric Hydrogenation of Quinolines26a

25

Fuchs, R., 1997, Eur. Pat. Appl. EP 803502, (Chem. Abstr., 1998, 128, 13286). 26

a)Wang, W-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125,10536–10537. b)

Wang, D-W.; Wang, X-B.; Wang, D-S.; Lu, S-M.; Zhou, Y-G.; Li, Y-X. J. Org. Chem. 2009, 74, 2780-2787. 27

Rueping, M.; Antonchick, A. P.; Theissmann, T.A. Angew. Chem., Int. Ed. 2006, 45, 3683–3686.

35

(6)

Figure 2.6: Asymmetric Transfer Hydrogenation of Quinolines27

The asymmetric hydrogenation of isoquinolines has also been explored by the Zhou

group. It was found that chloroformates could be used as to activate the substrate towards

hydrogenation, affording the chiral products in up to 85% yield and 80% ee (Figure 2.7).28

(7)

Figure 2.7: Asymmetric Hydrogenation of Isoquinolines28

Indoles have also been successfully hydrogenated with high enantiselectivity. In 2000

Kuwano et al. achieved the first asymmetric hydrogenation of protected indoles using a

homogeneous [Rh(PhTRAP)]SbF6 catalyst (Figure 2.8).29

A subsequent report in 2006 by

Kuwano extended the hydrogenation of indoles to include the synthesis of a second chiral center

28

Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Chin. J. Catal. 2005, 26, 287–290. 29

Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614–

7615.

36

(Figure 2.9).30

For these 2,3-disubstituted indoles, an analogous system was used, replacing

rhodium with ruthenium.

(8)

(9)

Figure 2.8: First Asymmetric Hydrogenation of Protected Indoles29

(10)

Figure 2.9: Hydrogenation of Protected Indoles Setting a Second Chiral Center30

A contribution by the Zhang group in 2010 details the use of a Pd-catalyzed system

which was used to set two stereocenters but instead using unprotected indoles (Figure 2.10).31

The selectivity observed is believed to be achieved via dynamic kinetic resolution of the

protonated intermediate.

30

Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653–2655. 31

Wang, D-S.; Chen Q-A.; Li, W.; Yu, C-B.; Zhou, Y-G.; Zhang, X. J. Am. Chem. Soc. 2010,

132, 8909–8911.

37

(11)

Figure 2.10: Asymmetric Hydrogenation of Unprotected Indoles31

The hydrogenation of pyridine derivatives is also highly desirable for the synthesis of

chiral piperdines. Early attempts using homogenous and chirally-modified heterogeneous

catalysis provided poor enantioselectivities (Figure 2.11).32,33

Later, Charette demonstrated that

pyridinium ylides could be hydrogenated with ee’s ranging from 50-90% (Figure 2.12).34

(12)

(13)

Figure 2.11: Early Asymmetric Hydrogenations of Pyridines32,33

32

Studer, M.; Wedemeyer-Exl, C.; Spindler, F.; Blaser, H.-U. Monatsh. Chem. 2000, 131, 1335-1343. 33

Blaser, H.-U.; Honig, H.; Studer, M. J. Mol. Catal. A: Chem. 1999, 139, 253–257. 34

Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005,127, 8966–8967.

38

(14)

Figure 2.12: Asymmetric Hydrogenations of Pyridium Ylides34

In 2004, Glorius reported the diastereoselective hydrogenation of auxiliary-bound

pyridines using heterogeneous catalysis (Figure 2.13).35

It was hypothesized that the auxiliary

becomes conformationally locked by forming a hydrogen bond with a protonated pyridine,

projecting the isopropyl group such that one face of the heteroarene is blocked and leaving the

other open to hydrogenation. The attractiveness of this method is furthered by the ability to

remove the chiral auxiliary under the same reaction conditions and recover it upon work-up.

Inspired by this work, we ventured to use similar concepts to achieve the elusive goal of

asymmetric hydrogenation of benzene derivatives.

(15)

Figure 2.13: Asymmetric Hydrogenations of Auxiliary-Bound Pyridines35

35

Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W. Angew. Chem., Int. Ed. 2004,43, 2850–2852.

39

2.1.2 Selective Hydrogenation of Carbocyclic Aromatics

Early work in hydrogenation of carbocylic aromatics by Meyers et al. in 1964 demonstrated that

hydrogenations of 1-napthol and 2-napthol with 5% Rh/Al2O3 provided the corresponding

decalols and decalones.36

Hydrogenations of 1-napthol in methanol or ethanol were found to be

selective for the decalols which were formed in a 13.3:2.3:1 diastereomeric ratio with the cis, cis

isomer predominating. Hydrogenations in acetic acid formed the decalone with approximately

2.3:1 selectivity.19

Similar trends were observed for 2-napthol, but the isomeric ratio of the

decalol products were not determined (Figure 2.14). Subsequent to this report, a 1974 study by

Bennett revealed that arene-exchange takes place with Ruthenium complexes in aromatic

solvents. In general, it was found that electron-rich arenes displaced the metal-bound arene more

efficiently.37

This and subsequent work38

supported the accepted Horiuti-Polanyi mechanism39

for the hydrogenation of benzene (Figure 2.15).

(16)

Figure 2.14: Hydrogenation of 1-napthol and 2-napthol36

36

Meyers, A.I.; Beverung, W.; Garcia-Munoz, G. J. Org. Chem. 1964, 29, 3427–3429. 37

Bennett, M.A.; Smith, A.K. J. Chem. Soc. Dalton. Trans., 1974, 233-241. 38

a) Saeys, M.; Reyniers, M-F.; Neurock M.; Marin, G,B. J. Phys. Chem. B 2005, 109, 2064-2073 b) Tanimoto, M.;

Naito, S. J. Chem. Soc., Faraday Trans 1.1987, 83, 2475-2486. c) Bouchy, A.; Roussy, G.; Gault, F.G.; Ledoux,

M.J. J. Chem. Soc., Faraday Trans. 1, 1978, 74, 2652-2666. 39

Horiuti, J.; Polanyi, M. Trans. Faraday Soc.1934, 30, 1164.

40

Figure 2.15: Proposed Mechanism of Benzene Hydrogenation

Metal-hydride addition occurs in a syn fashion across one face of arene, but at each stage

of the cycle, it is possible to have dissociation and reassociation of another molecule of starting

material, or any of the partially hydrogenated intermediates. In general, the cis kinetic products

are favoured, but trans products can be obtained when a partially hydrogenated intermediate re-

coordinates and is hydrogenated from the opposite face of a previous hydrogenation. This is a

useful and intuitive mechanism, but many studies contribute to the overall picture that this

mechanism is not totally general, and can vary depending on the substrate and catalyst system.40

Alongside these fundamental studies, many examples of diastereoselective benzene

hydrogenations were developed. Many groups have used phase transfer catalysis to achieve this.

Alper and colleagues reported diastereoselective hydrogenations of naphthalene and 4-

methylanisole using phase transfer conditions (where cetyltrimethylammonium bromide (CTAB)

is the phase-transfer reagent) and a rhodium precatalyst (Figure 2.16).41

Soon after, Blum

reported a stereoselective hydrogenation of p-xylene also using phase transfer conditions (Figure

40

a) Thiel, P.A.; Polta, J.A.; Flynn D.K. Surface Science, 1987, 185, L497-L505. b) Dunworth, W.P.; Nord, F.F.; J.

Am. Chem. Soc., 1952, 74, 1459-1462. c) Tetenyi, P.; Paal, Z. Z. Phys. Chem. N. F, 1972, 80, 63. d) Tetenyi, P. J.

Catal., 1994, 147, 601-603. e) Thybaut, J. W.; Saeys, M.; Marin, G. B. Chem. Eng. J., 2002, 90, 117-129. f)

Lindfors, L. P.; Salmi, T. Ind. Eng. Chem. Res. 1993, 32, 34-42. 41

Janurrklewlcz, K.R.; Alper, H. Organometallics, 1983, 2, 1055-1057.

41

2.17).42

They use Maitlis’ test and light-scattering experiments to support the contention that the

system is homogeneous, though by modern standards this evidence would be considered

insufficient.43

(17)

(18)

Figure 2.16: Alper’s Hydrogenations under Phase-Transfer Conditions

(19)

Figure 2.17: Blum’s Hydrogenations under Phase Transfer Conditions

Phase-transfer systems were then extended to the synthesis of enantioenriched products.

Lemaire used an appended chiral auxiliary and trioctylamine (TOA) to furnish a chiral

42

Blum, J.; Amer, I.; Zoran, A.; Sasson, y.; Tetrahedron Lett., 1983, 38, 4139-4142. 43

Widegren, J.A.; Finke, R.G. J. Mol. Catal. A, 2002, 198, 317–341.

42

cyclohexanol in 10% ee (Figure 2.18).44

In the same study, they supplanted the auxiliary with a

chiral phase transfer catalyst dioctylcyclohexylethylamine (DOCEA) as the inducer of

enantioselectivity. Using this system, they report two examples with enantioinduction

(Figure 2.19).44

(20)

Figure 2.18: Lemaire’s Auxiliary-Based Hydrogenation with Phase-Transfer Conditions

(21)

(22)

Figure 2.19: Lemaire’s Enantioselective Hydrogenations under Phase-Transfer Conditions

Concurrent with these reports, Besson developed the hydrogenation of various o-toluic

acid derivatives with low to excellent diasteroselectivities using chiral auxiliaries.45

One

particular study uses proline methylester as the auxiliary to hydrogenate o-toluic carboxylic acids

with up to 68% de by optimizing: 1) the heterogeneous metal support 2) amine additives 3)

44

Nasar, K.; Fache, F.; Beziat, J-C.; Besson, M.; Gallezot, P.; Lemiare, M. J. Mol. Catal., 1994, 87, 107-115. 45

a) Bachiller-Baeza, B.; Rodriguez-Ramos, I.; Guerrero-Ruiz, A.; Besson, M.; Pinel, C. J. Mol.

Catal. A., 2000, 164, 147-155. b) Besson, M.; Gallezot, P.; Neto, S.; Pinel, C. Chem.

Commun., 1998, 1431-1432.

43

thermal preactivation of the catalyst (Figure 2.20).46

The authors found that thermal preactivation

was beneficial for catalysts supported on alumina, and that an amine additive N-

ethyldicyclohexylamine was more beneficial for carbon-based supports; this lead to the

postulation that the amine adsorbs onto the acidic sites of the alumina support, away from active

site of the catalyst.

(23)

Figure 2.20 Besson’s Diastereoselective Hydrogenation using a Proline-Derived Auxiliary

A more recent report by Solladie-Cavallo demonstrates the hydrogenation of

trisubstituted phenols, with 4 examples ranging between 60-79% of all cis product without the

use of a chiral auxiliary as a controller of selectivity (Figure 2.21).47

(24)

Figure 2.21 Solladie-Cavallo’s Diastereoselective Hydrogenation of Phenols

With these studies in mind, we set out to achieve a more general and highly selective

hydrogenation of benzene rings. We noted that the current methodologies which rely on chiral

46

Besson, M.; Gallezot, P.; Pinel, C.; Neto, S. Heterogeneous Catalysis and Fine Chemicals IV,

1997, 108, 215-222. 47

Solladie-Cavallo, A.; Baram, A.; Choucair, E.; Norouzi-Arasi, H.; Schmitt, M.; Garin, F.; J.

Mol. Catal. A., 2007, 92-98.

44

auxiliaries are generally limited in scope, and that in some cases these methodologies require

treatments of the catalysts and amine additives to achieve selectivity. Furthermore,

hydrogenations of auxiliary-bound heteroaromatics, such as pyridines or furans, rely upon a

“locking mechanism” such as a hydrogen-bond35

(see Figure 2.13) or metal chelation to ensure

hydrogenation of a single face.48

These controls are not readily available for the hydrogenation

of benzenes, though in the course of these studies it has been suggested that dipole minimization

may have an effect on the orientation of a chiral auxiliary and thus may be exploited to increase

selectivity.49

We thus propose that, using a chiral oxazolidione, we can achieve highly selective

hydrogenations of a variety of functionalized benzene rings and investigate the effects of ring

electronics, polarity, degree and pattern of substitution and the nature of the auxiliary (Figure

2.22). In doing this, we demonstrate a general and novel method for controlling the selectivity of

benzene hydrogenations using an “unlocked” chiral auxiliary and discover trends which impart

selectivity, to be used in subsequent investigations.

(25)

Figure 2.22: Proposed Strategy for Selective Hydrogenation of Benzenes

48

Sebek, M; Holz, J.; Borner, A.; Jahnisch, K. Synlett, 2009, 3, 461-465. 49

Prashad, M.; Liu, Y.; Kim, H-Y.; Repic, O.; Blacklock T.J. Tetrahedron Asymmetry, 1999, 10,

3479-3482.

45

2.2 Results and Discussion

2.2.1 Substrate Synthesis

The desired auxiliary-bound arenes could be obtained via an Ullmann-type copper

catalyzed coupling50

between an enantiopure oxazolidinone auxiliary and the chosen iodoarene.

The substrates were generally obtained in moderate to excellent yields (Table 2.1). Of note, as

the steric demands of the reaction increase (bulky groups at R1 and RA) the reaction efficiency

decreases, with the result that ortho-substituted iodoarenes were not compatible with the t-butyl

appended oxazolidinone.

R1 R2 R3 R4 RA Yield Product

H

F

H

H

Cy

40%

2.1a

H

F

H

H

Bn

61%

2.1b

H

F

H

H

t-Bu

67%

2.1c

50

Klapars, A.; Antilla, J.C.; Huang, X.; Buchwald, S.L.; J. Am. Chem. Soc.. 2001, 123, 7727-

7729.

46

H

F

H

H

i-Pr

91%

2.1d

F

H

H

H

i-Pr

81%

2.1e

H

H

F

H

i-Pr

84%

2.1f

H

H

F

H

t-Bu

56%

2.1g

H

CF3

H

H

t-Bu

38%

2.1h

OMe

H

H

H

i-Pr

53%

2.1i

H

OMe

H

H

i-Pr

72%

2.1j

47

H

H OMe H i-Pr 76%

2.1k

H

H

OMe

H

t-Bu

76%

2.1l

H

OMe

H

H

t-Bu

39%

2.1o

H

Me

H

H

t-Bu

45%

2.1p

H

H

Me

H

t-Bu

38%

2.1q

H

Me

Me

H

t-Bu

45%

2.1r

H

Me

H

Me

t-Bu

25%

2.1s

48

H

CF3 H CF3 t-Bu 52%

2.1t

H

H

CO2Et

H

t-Bu

48%

2.1u

a The bromoarene was substituted for the iodoarene.

Table 2.1: Synthesized Auxiliary-bound Substrates

The purpose and results of the hydrogenation reactions will be discussed based on

substrate class.

2.2.2 Hydrogenation of Fluoro-Substituted Arenes: Optimization of

Auxiliary Appendage and Substitution Pattern

In using fluorinated benzenes, we imagined there might exist the opportunity for the

creation of valuable fluorine-substituted cyclohexanes, since the arene C-F bond is typically

most resistant to dehalogenation compared to other carbon-halogen bonds. Furthermore, this

would introduce a convenient probe for diastereoselectivity by 19

F-NMR. Upon hydrogenation of

substrate 2.1d, we were encouraged to observe only two isomers by 19

F-NMR with a 1.9:1

diastereomeric ratio, albeit with 65% defluorinated product by GC-MS. (Table 2.2). With this

knowledge in hand, we quickly set out to determine which auxiliary appendage would maximize

selectivity, and determined that a t-butyl group provided the greatest diastereoselectivity (5.4:1)

presumably because of its increased steric bulk (2.2c). While this may seem intuitive, it is worthy

of mention considering that in Glorius’ account on pyridine hydrogenation a change of the

oxazolidinone appendage from i-propyl to t-butyl did not significantly alter selectivity,

49

suggesting that steric bulk plays a larger role in a system such as ours, with freely-rotating

auxiliaries.35

Substrate

Fluorinated

Product

(Overall Yield)a

Percent

Defluorinationb

Diastereoselectivityc

2.1a

2.2a (49%)

76%

2.1:1

2.1b

2.2b (94%)

Not determined

2.5:1d

2.1c

2.2c (95%)

88%

5.4:1

2.1d

2.2d (85%)

65%

1.9:1

Reaction Conditions: H2 50 bar, rt, 1.5 mL THF, 40 mg 5%/Rh/Al2O3. a: Includes defluorinated product

b:Determined by GC-MS

c: Determined by

19F-NMR (identity of major isomer undetermined)

d: H2 80 bar, 50

oC

Table 2.2: Diastereoselectivities Obtained with Various Auxiliary Appendages

We next endeavoured to move the fluorine atom around the ring to determine the

relationship between the substitution pattern of an electron-withdrawing substituent and

diastereoselectivity (Table 2.3). For this study, the isopropyl auxiliary was used as the tert-butyl

auxiliary was incompatible with ortho-substituted iodoarenes.

50

Substrate Fluorinated

Product

(Overall Yield)a

Percent

Defluorinationb

Diastereoselectivityc

2.1e

2.2e (99%)

71%

1.7:1

2.1d

2.2d (85%)

65%

1.9:1

2.1f

2.2f (91%)

61%

7.2:1

2.1g

2.2g (56%)

70%

15.2:1

Reaction Conditions: H2 (50 bar), 5% Rh/Al2O3, THF, rt. a: Includes defluorinated product

b: Determined by GC-

MS. c: Determined by

19F-NMR (identity of major isomer undetermined)

Table 2.3: Positional Effects on Diastereoselectivity with Fluorine

The ortho- and meta- substituted fluoroarenes gave similar results in this study. However,

a diasteromeric ratio of 7.2:1 was obtained in hydrogenation of the para-fluoro arene 2.1f to give

the cyclohexane products and could be increased further to 15.2:1 when substituted with the t-

butyl appended oxazolidinone.

During these investigations of various effects on diastereoselectivty, we simultaneously

set out to determine which diastereomer was formed as the major product. We reasoned that in

our hydrogenations the major isomer was the cis isomer following literature precedent.25-30

We

51

further reasoned that the major cis isomer was likely the isomer obtained from hydrogenation of

the arene from the face opposite the bulky auxiliary appendage. Evidence of this hypothesis was

provided when we hydrogenated the strongly electron withdrawing meta-CF3 substituted arene

2.1h. We were delighted to obtain the product in a 10:1:0.15 diastereomeric ratio and in 90%

overall yield (Figure 2.23).

(26)

2.1h 2.2h

Figure 2.23: Hydrogenation of meta-CF3 Substituted Arene

The major isomer (by 1H-NMR) was crystallized out and its X-ray crystal structure

confirmed that the major diastereomer was as predicted: hydrogenation from the face opposite

the t-butyl group gives the major product shown (Figure 2.24).

Figure 2.24: X-ray Crystal Structure of 2.2h

This increase in selectivity relative to the meta-fluoro substituted arene may be explained

by: 1) increased steric bulk substituting a trifluoromethyl group for a fluoro group and 2)

increased electron-withdrawing character of the trifluoromethyl group, imposing a greater dipole

52

moment. These two factors would result in favoring one rotamer over others to reduce steric

strain and dipole moments, allowing the auxiliary to more effectively block one face of the

arene, freeing the other for hydrogenation.

With these hypotheses, we next investigated electron-rich arenes and looked for

selectivity trends.

2.2.3 Hydrogenation of Methoxy- and Hydroxy-Substituted Arenes:

Effects of Substitution Pattern and Auxiliary Rigidifcation

In our exploration of electron-rich arenes, we took the same approach as was used

previously and hydrogenated arenes that were methoxy-substituted in positions, ortho, meta and

para to the auxiliary. Of note, these more electron-rich arenes were more difficult to reduce than

their electron-deficient counterparts and thus required more forcing conditions. Various solvents:

THF, methylene chloride, acetic acid and methanol were investigated to maximize reactivity and

selectivity. In solvents other than THF, reactivity was totally lost, thus we continued with THF

for the remainder of our studies. Tabulated below are the obtained results:

Substrate

Product

(Percent Yield)

Diastereoselectivitya

2.1i

2.2i (99%)

1.9:1 (trace amounts of the 2 other

isomers detected)

2.1j

2.2j (99%)

2:1:0.76

53

2.1k

2.2k (87%)

4.9:1

2.1l

2.2l (77%)b

12.5:1

Reaction Conditions: H2 (80 bar), 5% Rh/Al2O3, THF, 50

oC.

a: Determined by GC-FID and GC-MS (identity of

major isomer undetermined) b: 22% remaining starting material

Table 2.4: Positional Effects on Diastereoselectivity with Methoxy Groups

Interestingly, hydrogenation of the para-substituted fluoroarene was moderately more

selective than the analogous methoxyarene. Furthermore, additional isomers were detected by

GC-MS using the ortho- and meta- methoxyarene substrates that were not detected by using the

fluoroarenes. Though it might be expected that the methoxybenzenes benefit from increased

steric strain, the results suggest that electronic factors may have greater influence on selectivity.

We also proposed two methods to increase selectivity with the ortho methoxy-substituted

arenes using the above-mentioned rotational locking strategy. One strategy involves adding a

lewis acidic metal to the hydrogenation reaction; it may be possible to form a chelate between

the lone pair of the auxiliary carbonyl and the lone pair from the methoxy group in the manner

illustrated above Table 2.5. Different metal additives were screened and in some cases the

solvent was switched to dichloromethane, a less coordinating solvent than THF, to reduce

competition for the metal center. Unfortunately, the alterations attempted procured a total loss of

reactivity (Table 2.5).

54

2.1i 2.2i

[M] Solvent Diastereoselectivity

None THF 1.9:1

NaOTf THF No conversion

None DCM No conversion

MgCl2 DCM No conversion

Table 2.5: Hydrogenation of 2.1i With and Without Metal Additives

We then proposed a second strategy: deprotection of the methoxy group affords the

phenol (the free phenol is not tolerated in substrate synthesis) which can possibly form an

internal hydrogen bond to the carbonyl of the oxazolidinone. Deprotection with BBr3 afforded

the necessary precursor which was hydrogenated to afford the cyclohexanol as a disappointing

mixture of all four isomers (1.4: 1: 0.27: 0.23) in 80% yield (Figure 2.25).

(27)

2.1i 2.1m (68%) 2.2m

80% yield (1.4: 1: 0.27: 0.23) dr

Figure 2.25: Hydrogenation with Attempted Rigidification by Hydrogenation Bonding

55

Since these attempts were unsuccessful, we decided to hydrogenate meta-substituted

hydroxyl- and methoxy- arenes with our auxiliary of choice to probe the selectivity of the

reaction with a freely-rotating auxiliary (Table 2.6).

Substrate

Hydrogenated

Product

(Percent Yield)

Diastereoselectivitya

2.1n

2.2n (82%)

3.3:1b

2.1o

2.2o (63%)c

4:1

Reaction Conditions: H2 (80 bar), 5% Rh/Al2O3, THF, 50oC.

a: Determined by GC-FID and GC-MS (identity of

major isomer undetermined) b: H2 (50 bar), rt. Determined by

1H-NMR

c: 36% starting material remained

Table 2.6: Hydrogenation of Methoxy- and Hydroxy-Arenes with t-Bu Appendage

Modest diasteromeric ratios were obtained in keeping with the trend that substrates with

strong electron-withdrawing substituents increase selectivity. We next decided to investigate

methyl-substituted arenes, which would impart little electronic bias and allow us to more directly

probe the effects of: 1) increasing the number of substituents on the ring and 2) more complex

substitution patterns.

2.2.4 Hydrogenation of Alkyl Substituted Arenes: Effects of Degree

and Pattern of Substitution

In general, alkyl substituted arenes were highly reactive but typically gave lower

selectivities than substituents that alter the electronics of the ring more conspicuously (Figure

56

2.26). This seems to support the hypothesis that substituents which induce a dipole are required

for increased diastereoselectivities.

(28)

2.1p 2.2p (97%, 1.7: 1: 0.22 :0.16)

(29)

2.1q 2.2q (99%, 3.1:1)

Figure 2.26: Hydrogenation of Methyl-Substituted Arenes

Despite the low diastereoselectivities obtained, we decided to optimize our reaction

conditions using substrate 2.1q since methyl-substituted arenes are the least electronically

biasing of our substrates. Our standard conditions were forcing, at pressures up to 80 bar and

high temperatures, so we aimed to make these conditions milder for greater practicality and the

potential for increased diastereoselectivities (Table 2.7).

Not surprisingly, at elevated pressures and temperatures (80 bar, 50oC) selectivity is

decreased. In contrast, it appears that hydrogenations under 50 bar or 40 bar of H2 were counter-

intuitively more selective than those at lower pressures. Despite this finding it is nevertheless of

practical value that these hydrogenations can proceed smoothly at much lower pressures (6.9

bar). Also of note is that among the metals tested, 5% Rh/Al2O3 was the most reactive and its use

was thus continued in further investigations.

57

Table 2.7: Hydrogenation Optimization Studies with Substrate 2.1q

While we were excited to have achieved mild hydrogenations of mono-methylated

arenes, the optimized conditions were not broadly applicable to less reactive tri-substituted

arenes. For example, while substrate 2.1r could be readily hydrogenated at 6.9 bar, substrate 2.1s

could not (Figure 2.27).

Metal H2

Pressure

Temperature Time Diastereoselectivity

5% Rh/Al2O3

80 bar

50°C

14 hr

2:1

5% Rh/Al2O3

50 bar

rt

12 hr

3.1:1

Pd(OH)2/C

50 bar

rt

12 hr

No reaction

[Rh(COD)2]BF4

50 bar

rt

12 hr

Poor Conversion

5% Rh/Al2O3

40 bar

rt

12 hr

3.1:1

5% Rh/Al2O3

10 bar

rt

12 hr

2.2:1

5% Rh/Al2O3

6.9 bar

rt

12 hr

2.3:1

5% Rh/Al2O3

6.9 bar

rt

3 hr

2.1:1

58

(30)

2.1r 2.2r (95%, 19.5:1)

(31)

2.1s 2.2s (x = 6.9, 0%)

(x = 50, 79%, 2.3:1)

Figure 2.27: Hydrogenation of dimethyl-substituted Arenes

Though hydrogenation of 2.1s was unsuccessful at 6.9 bar, we were pleased to find that

product 2.2r could be obtained in 19.5:1 diastereomeric ratio and in 95% yield. At 50 bar, we

were able to obtain product 2.2s in 79% yield and in a diastereomeric ratio of 2.3:1 (other trace

isomers observed by GC-MS). The very high selectivities afforded by substrate 2.1r may arise

because an all-cis isomer is kinetically favoured and thermodynamically favoured (allows for the

placement of all groups equatorial) and suggests that 1,3,5-substituted arenes may be good

candidates for future study. The diastereoselectivities afforded with substrate 2.1s seem to

indicate that more highly substituted substrates afford greater selectivities (2.3:1 for 2.1s

compared to the 1.7:1:0.22:0.16 shown for 2.1p above). While this unfortunately results in

decreased reactivity, the increase in selectivity is significant and overcomes the selectivity which

may be lost by using more forcing conditions.

59

At this time in our study, we felt we were able to draw the following inferences: 1)

electronically biasing substituents are critical for gaining selectivity, which possibly occurs by

influencing the conformation of the auxiliary 2) increased substitution decreases reactivity and

increases selectivity, possibly for steric reasons, and 3) substitution pattern is an important factor,

with para-substituted and 1,3,5-trisubstituted arenes being most selective. This likely rises from

the fact that the substrates tested were all symmetric, reducing the number of possible isomers

and in the case of 1,3,5-trisubstituted arenes it is likely that the major isomer arises from

hydrogenation of the face opposite the auxiliary to give cis products, as it is favoured both

kinetically and thermodynamically. With these thoughts, we extended our methodology to other

functional groups and took advantage of these trends when selecting substrates.

2.2.5 Extending Selectivity Trends to the Design of New Substrates

With these selectivity trends, we designed the bis(trifluoro)-substituted substrate 2.1t,

which has both the 1,3,5-substitution pattern and a strong dipole moment to bolster selectivity.

Upon hydrogenation, we were pleased to observe the tri-substituted cyclohexane in 94% yield

and >99:1 diasteroselectivity by GC-MS (Figure 2.28). Interestingly arene 2.1t required forcing

conditions to achieve reactivity, in spite of the fact that it bears two electron-withdrawing groups.

(32)

2.1t 2.2t (94%, >99:1 dr)

Figure 2.28: Hydrogenation of Arene 2.1t

60

We decided next to look at para- ester-substituted arenes since esters are both electron-

withdrawing and can withstand hydrogenation. Upon hydrogenation of 2.1u, product 2.2u was

obtained in 82% yield and 6.4:1 dr (Figure 2.29).

(33)

2.1u 2.2u (82%,6.4:1 dr)

Figure 2.29: Hydrogenation of Ester-Substituted Arene 2.1u

Research efforts toward exploiting our selectivity hypotheses and extending our

methodology to include new functionalities are continuing.

2.3 Conclusions and Future Work

In conclusion, we demonstrate that selectivity can be achieved in the hydrogenation of

differentially substituted benzenes using rotationally unlocked chiral auxiliaries. Our studies

revealed the following trends: 1) electronically biasing substituents are critical for gaining

selectivity 2) increased substitution decreases reactivity and increases selectivity 3) substitution

pattern is an important factor, with para-substituted and 1,3,5-trisubstituted arenes being most

selective of those investigated and 4) increasing the steric bulk of the chiral auxiliary increases

selectivity using oxazolidinones. In discovering and exploiting these trends, we were able to

stereoselectively hydrogenate a variety of differentially substituted and functionalized benzene

rings with good to excellent yields and with five substrates providing stereoselectivities of 10:1

dr or greater. Insight into the identity of the major stereoisomer was provided by x-ray

61

crystallography, which demonstrated that hydrogenation was occurring from the face opposite

the chiral auxiliary appendage.

Future work will focus on: discovering more reactive catalyst systems, the expansion of

the substrate scope to include anilines and looking for ways to predictably increase selectivity.

Further, we aim to remove the attached auxiliary. One possible route might involve a direct base-

mediated elimination of the oxazolidinone (Figure 2.30). Another possibility is opening the

oxazolidinone to the resulting amino alcohol, quaternizing the amine and then eliminating. We

are also looking for a method to remove the auxiliary which would preserve the newly formed

stereocenter.

Figure 2.30: Proposed Elimination of the Chiral Auxiliary

2.4 Experimental Procedures

2.4.1 General Considerations

Reagents were purchased from Sigma-Aldrich, Strem, or Alfa Aesar and

used without further purification. All solvents were purchased from Caledon or Fischer and

used as received unless otherwise noted. Reactions were monitored by thin-layer

chromatography (TLC) on EMD Silica Gel 60 F254 plates under UV light (254 μm) or

by Liquid-Chromatography-Mass Spectrometry. Solutions were concentrated under reduced

62

pressure on a Büchi rotary evaporator. Column chromatography was carried out on Silicycle

Silica-P Flash Silica Gel (40-63 μm). 1H and

13C NMR spectra were recorded on a Bruker AV-III

400 MHz spectrometer at ambient temperature. Data for 1H-NMR and

19F-NMR are reported as:

chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet, br = broad , sp = septet), coupling constant (Hz), integration. Data for 13

C NMR are

reported as: chemical shift (δ ppm) with coupling constants where applicable.

2.4.2 General Procedure A Auxiliary-Bound Arene Synthesis:

In the glovebox, 1 dr vial with a teflon cap was charged with x% CuI, 1 equiv trans-(±)-

diaminocyclohexane, 1 equiv iodoarene, 1.1 equiv auxiliary and 2.2 equiv potassium phosphate

in dry and degassed 1,4-dioxane. The vial was then tightly capped, brought out of the glovebox,

and allowed to stir at 95oC. When the iodoarene was fully consumed as judged by LC-MS, the

crude was subjected to flash chromatography (eluent 0-50% ethylacetate in hexanes) to afford

the auxiliary-bound arene.

2.4.3 General Procedure B: Hydrogenation of Auxiliary-Bound

Arenes:

To a 12x32 mm vial was added a stir bar, x mg 5% Rh/Al2O3, y mmol of auxiliary-bound

arene and 1.5 mL THF. The vial was fitted with a slit cap and placed into a CAT18 HEL reactor.

The vessel was then pressurized and heated on a heat block to the appropriate temperature. After

the indicated amount of time the vessel was vented, passed through a silica column

(approximately 2 cm in length and 1.5 cm in width) using approximately 15 mL of 100% ethyl

acetate as the elutent and concentrated.

63

2.4.4 Characterization Data

(S)-4-cyclohexyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1a): Synthesized using General

Procedure A Using: CuI (0.024 mmol, 4.56 mg, 12%), trans-(±)-diaminocyclohexane (0.24

mmol, 29 µl) 3-chlorofluoroiodobenzene (0.2 mmol, 23.5 µl, 1 equiv), (S)-4-

cyclohexyloxazolidin-2-one (0.238 mmol, 40.3 mg, 1.2 equiv), potassium phosphate (0.476

mmol, 101mg, 2.4 equiv) in 1.5 mL 1,4-dioxane.Isolated as a white solid (21 mg, 40%) after

20.5 h. 1H NMR (400 MHz, CDCl3) 7.30-7.38 (m, 2H), 7.23 (m, 1H), 6.88 (m, 1H), 4.28-4.43

(m, 3H), 1.65-1.83 (5H, m), 0.96-1.28 (6H, m). 13

C NMR (100 MHz, CDCl3) δ 163.1 (d, JC-F

=

245.5 Hz), 155.6, 138.6 (d, JC-F

= 10 Hz), 130.3 (d, JC-F

= 9.2 Hz), 116.8 (d, JC-F

= 3.6 Hz), 111.7

(d, JC-F

= 22.5 Hz), 109.0 (d, JC-F

= 25.3 Hz), 63.4, 60.2, 37.9, 28.4, 26.2, 26.0, 25.4, 24.8. HRMS

(ESI, m/z): [M]+

calc.: 264.1394; found: 264.1391. IR (cm-1

): 2926, 2854, 1748, 1612, 1590,

1495, 1452, 1404, 1364, 1314, 1277, 1208, 1117, 1040, 979, 857, 774, 754. m.p = 104-107oC.

(S)-4-benzyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1b): Synthesized using General Procedure

A: Using: CuI (0.0525 mmol, 9.99 mg, 12%), trans-(±)-diaminocyclohexane (0.525 mmol, 63

64

µl) 3-fluoroiodobenzene (0.5 mmol, 58.7 µl, 1 equiv), (S)-4-benzyloxazolidin-2-one (0.525

mmol, 142.3 mg, 1.2 equiv), and potassium phosphate (1.05 mmol, 223 mg, 2.1 equiv) in 1.5 mL

1,4-dioxane. Isolated as a brown oil (83 mg, 61%) after 19.5 h. 1H NMR (400 MHz, CDCl3)

7.45-7.25 (m, 6H), 7.11-7.15 (m, 1H), 6.90 (m, 1H), 4.64 (m, 1H), 4.34 (t, 1H, J = 8.3 Hz), 4.21

(dd, 1H, J = 9 Hz, 4.4 Hz), 3.14 (dd, 1H, J = 13.8 Hz, 3.6 Hz), 2.80 (dd, 1H, J = 14.3 Hz, 9.3

Hz). 13

C NMR (100 MHz, CDCl3) δ 163.2 (d, JC-F

= 245.2 Hz), 155.1, 138.4 (d, JC-F

= 10.8 Hz),

134.9, 130.5 (d, JC-F

= 9.6 Hz), 129.2, 129.1, 127.5, 116.1 (d, JC-F

= 2.8 Hz), 111.8 (d, JC-F

= 21.3

Hz), 108.6 (d, JC-F

= 26.5 Hz), 65.9, 57.0, 37.6. HRMS (ESI, m/z): [M]+

calc.: 272.1081; found:

272.1086. IR (cm-1

): 3029, 2917, 1748, 1611, 1589, 1493, 1454, 1399, 1316, 1195, 1160, 1114,

1072, 1031, 1004, 993, 850, 773, 755, 734, 702.

(S)-4-(tert-butyl)-3-(3-fluorophenyl)oxazolidin-2-one (2.1c): Synthesized using General

Procedure A: Using: CuI (0.0238 mmol, 4.53 mg, 12%), trans-(±)-diaminocyclohexane (0.238

mmol, 28.5 µl) 3-fluoroiodobenzene (0.2 mmol, 23.5 µl, 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-

one (0.238 mmol, 34.2 mg, 1.2 equiv), and potassium phosphate (0.476 mmol, 101 mg, 2.1

equiv) in 1.5 mL 1,4-dioxane. Isolated as a white solid (32 mg, 67.4%) after 70 h. 1H NMR (400

MHz, CDCl3) 7.34 (m, 1H), 7.22 (m, 2H), 6.91 (tdd, 1H, J = 8.2 Hz, 1.2 Hz, 0.5 Hz) 4.44 (t, 1H,

J = 8.6 Hz), 4.33 (dd, 1H, J = 9.4 Hz, 3.4 Hz), 4.21 (dd, 1H, J = 8.5 Hz, 3.5 Hz), 0.85 (s, 9H). 13

C

NMR (100 MHz, CDCl3) δ 162.9 (d, JC-F

= 246 Hz), 156.4, 140.5 (d, JC-F

= 9.9 Hz), 130.2 (d, JC-

F = 9.6 Hz), 119.5 (d, J

C-F = 3Hz), 112.8 (d, J

C-F = 20.4 Hz 111.6 (d J

C-F = 24.5 Hz), 65.0, 64.4,

65

36.1, 25.9. IR (cm-1

): 3078, 2966, 1610, 1591, 1488, 1455, 1405, 1370, 1298, 1289, 1275, 1222,

1177, 1155, 1119, 1056, 1030, 1014, 1001, 980, 931, 879, 865, 848, 807, 782. mp = 97-98ºC

(S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1d): Synthesized using General

Procedure A: Using: CuI (0.055 mmol, 10.5 mg, 12%), trans-(±)-diaminocyclohexane (0.55

mmol, 66 µl) 3-fluoroiodobenzene (0.5 mmol, 58.7 µl, 1 equiv), (S)-4-isopropyloxazolidin-2-one

(0.6 mmol, 77.5 mg, 1.2 equiv), and potassium phosphate (0.55 mmol, 233.5 mg, 2.1 equiv) in

1.5 mL 1,4-dioxane. Isolated as a brown oil (77.5 mg, 69%) after 17.5 h. 1H NMR (400 MHz,

CDCl3) δ 7.29-7.36 (m, 2H), 7.22 (m, 1H), 6.88 (m, 1H), 4.41 (m, 2H), 4.25 (m, 1H), 2.18 (m,

1H), 0.93 (d, 3H, J = 7.2 Hz) 0.85 (d, 3H, J = 6.9 Hz). 13

C NMR (100 MHz, CDCl3) δ 163.1 (d,

JC-F

= 248 Hz), 155.8, 138.4 (d, JC-F

= 10.4 Hz), 130.3 (d, JC-F

= 8.8 Hz), 116.9 (d, JC-F

= 3 Hz),

111.9 (d, JC-F

= 21.3 Hz), 109.1 (d, JC-F

= 25.6 Hz), 62.4, 60.3, 27.5, 17.7, 14.2. HRMS (ESI,

m/z): [M]+

calc.: 224.10868; found: 224.10795. IR (cm-1

): 2962, 1746, 1610, 1591, 1495, 1455,

1404, 1392, 1323, 1204, 1145, 1116, 1051 1010, 972, 866, 807, 777, 753, 726, 704.

(S)-3-(2-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1e): Synthesized using General

Procedure A: Using: CuI (0.15mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 2-fluoroiodobenzene (0.3 mmol, 35µl, 1 equiv), (S)-4-isopropyloxazolidin-2-one (0.36

66

mmol, 46.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2 mL 1,4-

dioxane. Isolated as clear oil (54.1 mg, 80.7%) after 17 h. 1H NMR (400 MHz, CDCl3) δ 7.30-

7.34 (m, 2H), 7.21 (dd, 1H, J = 1.4 Hz, 8.2 Hz), 6.87 (td, 1H, J = 8.3 Hz, 2.5 Hz), 4.41, (m, 1H),

4.25 (m, 1H), 2.17 (m, 1H), 0.92 (d, 3H, J = 7.1 Hz), 0.84 (d, 3H, J = 6.9 Hz). 13

C NMR (100

MHz, CDCl3) δ 162.9 (d, JC-F

= 246 Hz), 155.6, 138.5 (d, JC-F

= 10.4 Hz), 130.3 (d, JC-F

= 9.4

Hz), 116.9 (d, JC-F

= 3.5 Hz), 118.2 (d, JC-F

= 20.8 Hz), 109.1 (d, JC-F

= 25.8 Hz), 62.5, 60.3, 27.5,

17.7, 14.2. HRMS (DART-MS, m/z): [M]+

calc.: 224.10868; found: 224.10759. IR (cm-1

): 2963,

1746, 1611, 1590, 1494, 1455, 1404, 1392, 1324, 1278, 1214, 1194, 1141, 1112, 1056, 1011,

979, 927, 865, 806, 776, 753, 726, 685.

(S)-3-(4-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1f): Synthesized using General

Procedure A: Using: CuI (0.15mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 4-fluoroiodobenzene (0.3 mmol, 35µl, 1 equiv), (S)-4-isopropyloxazolidin-2-one (0.36

mmol, 46.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2 mL 1,4-

dioxane. Isolated as a clear oil (56.2 mg, 84%) after 2 h. 1H NMR (400 MHz, CDCl3) δ 7.37-7.44

(m, 2H), 7.04-7.11 (m, 2H), 4.33-4.45 (m, 2H), 4.23 (dd, 1H, J = 8 Hz, 4.5 Hz), 2.06 (dsp, 1H, J

= 3.5 Hz, 7 Hz), 0.90 (d, 3H, J = 7.1 Hz), 0.84 (d, 3H, J = 6.9 Hz). 13

C NMR (100 MHz, CDCl3)

δ 160.1 (d, JC-F

= 245 Hz), 156.2, 132.8 (d, JC-F

= 3 Hz), 124.4 (d, JC-F

= 8.1 Hz), 116.0, (d, JC-F

= 22.8 Hz), 62.6, 60.9, 27.7, 17.6, 14.3. HRMS (DART-MS, m/z): [M]+

calc.: 224.10868; found:

67

224.10950. IR (cm-1

): 2964, 1742, 1604, 1509, 1425, 1405, 1393, 1371, 1323, 1220, 1147, 1119,

1054, 995, 961, 833, 761.

(S)-4-(tert-butyl)-3-(4-fluorophenyl)oxazolidin-2-one (2.1g): Synthesized using General

Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 4-fluoroiodobenzene (0.3 mmol, 34.6 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one

(0.36 mmol, 51.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2

mL 1,4-dioxane. Isolated as a white solid (40.6 mg, 56 %) after 12 h. 1H NMR (400 MHz,

CDCl3) 7.37 (m, 2H), 7.08 (m, 2H), 4.44 (t, 1H, J = 9.0 Hz), 4.31 (dd, 1H, J = 4.1 Hz, 9.1 Hz),

4.17 (dd, 1H, J = 9 Hz, 4.1 Hz), 0.83 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 161.8, 158.1 (d,

JC-F

= 232 Hz), 143.9 (d, JC-F

= 3.7 Hz), 126.3 (d, JC-F

= 8.8 Hz), 116.0 (d, JC-F

= 22.7 Hz), 65.6,

64.4, 35.7, 25.8. HRMS (DART-MS, m/z): [M]+

calc.: 238.12433 found: 238.12512. IR (cm-1

):

2962, 2870, 1737, 1603, 1509, 1476, 1423, 1405, 1370, 1221, 1130, 1053, 842, 760. mp = 124-

125oC.

(S)-4-(tert-butyl)-3-(3-(trifluoromethyl)phenyl)oxazolidin-2-one (2.1h): Synthesized using

General Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane

(1.5 mmol, 180 µl) 3-iodotrifluoromethylbenzene (0.3 mmol, 43.4 µl , 1 equiv), (S)-4-(tert-

68

butyl)oxazolidin-2-one (0.36 mmol, 51.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol,

127.4 mg, 2 equiv) in 2 mL 1,4-dioxane. Isolated as a yellow oil (32.5 mg, 37.7%) after 15 h. 1H

NMR (400 MHz, CDCl3) 7.70 (m, 2H), 7.49 (m, 2H), 4.47 (t, 1H, J = 9Hz), 4.36 (dd, 1H, J = 9.1

Hz, 3.4 Hz), 4.30 (dd, 1H, 8.8 Hz, 3.3 Hz), 0.85 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 162.9 (d,

JC-F

= 246.7 Hz), 156.4, 139.6, 131.5 (q, J = 32.4 Hz), 129.7, 127.4, 122.5 (m), 120.5 (m), 64.8,

64.5, 36.1, 25.9. HRMS (EI, m/z): [M]+

calc.: 287.1133 found: 287.1141. IR (cm-1

): 2967, 1747,

1613, 1595, 1496, 1455, 1402, 1371, 1358, 1327, 1270, 1198, 1167, 1127, 1095, 1071, 1032,

1003, 973, 891, 799, 759, 736, 693.

(S)-4-isopropyl-3-(2-methoxyphenyl)oxazolidin-2-one (2.1i): Synthesized using General

Procedure A: Using: CuI (0.06 mmol, 11.4 mg, 12%), trans-(±)-diaminocyclohexane (0.6 mmol,

72 µl) 2-iodoanisole (0.5 mmol, 117 mg, 1 equiv), (S)-4-isopropyloxazolidin-2-one (0.6 mmol,

77.5 mg, 1.2 equiv), and potassium phosphate (1.2 mmol, 255 mg, 2.1 equiv) in 1.5 mL 1,4-

dioxane. Isolated as a yellow oil (62.3 mg, 53%) after 18 h.1H NMR (400 MHz, CDCl3) 7.25-

7.36 (m, 2H), 6.93-7.02 (m, 2H), 4.33-4.37 (m, 2H), 4.20 (dd, 1H, J = 7.8 Hz, 5.1 Hz), 3.86 (s,

3H), 1.77 (m, 1H), 0.91 (d, 3H, J = 6.8 Hz), 0.84 (d, 3H, J = 7.2 Hz). 13

C NMR (100 MHz,

CDCl3) δ 157.6, 155.1, 129.6, 128.9, 125.0, 121.0, 112.1, 63.7, 61.1, 55.7, 28.8, 17.8. HRMS

(ESI, m/z): [M]+

calc.: 236.1281; found: 264.1289. IR (cm-1

): 2963, 2876, 1744, 1610, 1590,

1494, 1455, 1403, 1392, 1323, 1277, 1214, 1144, 1114, 1051, 1011, 979, 865, 806, 776, 753,

726, 704.

69

(S)-4-isopropyl-3-(3-methoxyphenyl)oxazolidin-2-one (2.1j): Synthesized using General

Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 3-iodoanisole (0.3 mmol, 35.7 µl, 1 equiv), (S)-4-isopropyloxazolidin-2-one (0.36 mmol,

46.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2.1 equiv) in 2 mL 1,4-

dioxane. Isolated as a yellow oil (51 mg, 72.3%) after 17 h.1H NMR (400 MHz, CDCl3) 7.28 (t,

1H, J = 8.2 Hz), 7.10 (t, 1H, J = 2.2 Hz), 6.99 (dd, 1H, J = 1.6 Hz, 8.2 Hz), 6.73 (dd, 1H, J = 8.4

Hz, 2.3 Hz), 4.39 (m, 2H), 4.22 (m, 1H), 3.81 (s, 3H), 2.16 (dsp, 1H, J = 7.1 Hz, 2.7 Hz), 0.90

(d, 3H, J = 71. Hz), 0.85 (d, 3H, J = 6.9 Hz) 13

C NMR (100 MHz, CDCl3) δ 160.3, 155.9, 138.0,

129.8, 114.2, 110.6, 108.4, 62.4, 60.6, 55.4, 27.6, 17.7, 14.3. HRMS (DART-MS, m/z): [M]+

calc.: 236.12867; found: 264.12933. IR (cm-1

): 2961, 1744, 1602, 1491, 1457, 1403, 1392, 1323,

1292, 1220, 1177, 1144, 1116, 1051, 975, 854, 772, 726, 690.

(S)-4-isopropyl-3-(4-methoxyphenyl)oxazolidin-2-one (2.1k): Synthesized using General

Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 4-iodoanisole (0.3 mmol, 70.2 mg, 1 equiv), (S)-4-isopropyloxazolidin-2-one (0.36

mmol, 46.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2.1 equiv) in 2 mL

70

1,4-dioxane. Isolated as a yellow oil (56.9 mg, 76%) after 2 h. 1H NMR (400 MHz, CDCl3) 7.32

(m, 2H), 6.92 (m, 2H), 4.40 (t, 1H, J = 8.6 Hz), 4.32 (m, 1H) 4.20 (dd, 1H, J = 8.4 Hz. 5.1 Hz),

3.80 (s, 3H), 2.04 (dsp, 1H, J = 7.2 Hz, 3.6 Hz), 0.88 (d, 3H, J = 7.1 Hz), 0.86 (d, 3H, J = 6.8 Hz)

13C NMR (100 MHz, CDCl3) δ 157.4, 156.6, 129.6, 124.7, 114.5, 62.7, 61.3, 55.5, 27.8, 17.7,

14.4. HRMS (DART-MS, m/z): [M]+

calc.: 236.12867; found: 264.12867. IR (cm-1

): 3329, 2958,

1724, 1514, 1412, 1322, 1248, 1181, 1121, 1063, 1035, 991, 962, 927, 833, 763.

(S)-4-(tert-butyl)-3-(4-methoxyphenyl)oxazolidin-2-one (2.1l): Synthesized using General

Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)-diaminocyclohexane (1.5 mmol,

180 µl) 4-iodoanisole (0.3 mmol, 70.2 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (0.36

mmol, 51.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2 mL 1,4-

dioxane. Isolated as a white solid (39.3 mg, 52.3%) after 12 h. 1H NMR (400 MHz, CDCl3) 7.29

(m, 2H), 6.90 (m, 2H), 4.42 (t, 1H, J = 9.3 Hz), 4.29 (dd, 1H, J = 9.2 Hz, 4.5 Hz), 4.13 (dd, 1H, J

= 8.9 Hz, 4.6 Hz), 3.80 (s, 3H), 0.83 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 157.8, 157.4, 131.8,

126.2, 114.4, 65.8, 64.4, 55.5, 35.5, 25.8. HRMS (DART-MS, m/z): [M]+

calc.: 250.14432

found: 250.14504. IR (cm-1

): 2961, 1736, 1513, 1409, 1369, 1295, 1247, 1218, 1175, 1126,

1056, 1032, 962, 831, 760. mp = 149-150oC.

71

(S)-4-(tert-butyl)-3-(2-hydroxyphenyl)oxazolidin-2-one (2.1m): To a one-neck round bottom

flask on an ice bath was added 42.5 mg (0.18 mmol) 2.1i dissolved in 15 mL DCM. The flask

was put under argon and a solution of 1M BBr3 (0.1 mL, 1 mmol) was syringed into the flask

drop-wise over 5 min. After 30 min, the reaction was shown to be complete by LC-MS. The

reaction was quenched with H2O, and then added to a separatory funnel to be washed with 2x 30

mL H2O and 1x 30 mL NaCl. After drying with MgSO4 the crude was concentrated under

reduced pressure and flash chromatographed using a 0-50% gradient of hexanes in ethyl acetate

to afford the title compound as a clear oil (24.5 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 7.59

(br.s, 1H), 7.18 (m, 1H), 7.10 (dd, 1H, J = 8.1 Hz, 1.5 Hz), 7.05 (dd, 1H, J = 8.3 Hz, 1.5 Hz),

6.95 (m, 1H), 4.58 (t, 1H, J = 9 Hz), 4.50 (dd, 1H, J = 9 Hz, 3.8 Hz), 4.35 (dd, 1H, J = 8 Hz, 4.4

Hz), 1.96 (m, 1H), 0.86 (d, 3H, J = 6.9 Hz), 0.84 (d, 3H, J = 6.9Hz).13

C NMR (100 MHz, CDCl3)

δ 157.7, 151.0, 128.3, 124.3, 123.4, 121.1, 120.8, 64.7, 61.9, 28.3, 17.4, 14.6. HRMS (ESI, m/z):

[M]+

calc.: 222.1124 found: 222.1118. IR(cm-1

): 3209, 2966, 1723, 1600, 1514, 1485, 1460,

1426, 1394, 1370, 1283, 1227, 1148, 1051, 999, 964, 852, 756.

72

(S)-4-(tert-butyl)-3-(3-hydroxyphenyl)oxazolidin-2-one (2.1n): To a one-neck round bottom

flask on an ice bath was added 92 mg (0.36 mmol) 2.1m dissolved in 15 mL DCM. The flask

was put under argon and a solution of 1M BBr3 (432 µl, 0.432 mmol) was syringed into the flask

drop-wise over 5 min. After 30 min, the reaction was shown to be complete by LC-MS. The

reaction was quenched with H2O, and then added to a separatory funnel to be washed with 2x 30

mL H2O and 1x 30 mL NaCl. After drying with MgSO4 the crude was concentrated under

reduced pressure and flash chromatographed using 40% hexanes in ethyl acetate to afford the

title compound as a white solid (55.8 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.19 (t, 1H, J = 8

Hz), 7.02 (t, 1H, J = 2.2 Hz), 6.86 (m, 1H), 6.65 (dd, 1H, J = 8.3 Hz, 0.6 Hz), 4.44 (t, 1H, J = 9.1

Hz), 4.32 (dd, 1H, J = 9.3 Hz, 3.7 Hz), 4.20 (dd, 1H, J = 9 Hz, 3.8 Hz), 0.84 (s, 9H). 13

C NMR

(100 MHz, CDCl3) δ 157.2, 156.7, 139.7, 129.8, 115.6, 113.5, 112.2, 65.3, 64.6, 35.9, 25.8.

HRMS (DART-MS, m/z): [M]+

calc.: 236.12867 found: 236.12801. IR(cm-1

): 3302, 2963, 1716,

1594, 1486, 1415, 1222, 1198, 1124, 1057, 978, 854, 779, 761, 692. mp = 180-182oC.

(S)-4-(tert-butyl)-3-(3-methoxyphenyl)oxazolidin-2-one (2.1o): Synthesized using General

Procedure A: Using: CuI (1.5 mmol, 285.7 mg, 50%), trans-(±)-diaminocyclohexane (5 mmol,

600 µl) 3-iodoanisole (3 mmol, 357 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (3.3 mmol,

73

472.5 mg, 1.1 equiv), and potassium phosphate (6 mmol, 1.27 g, 2 equiv) in 10 mL 1,4-dioxane.

Isolated as a yellow solid (290 mg, 39%) after 16.5 h. 1H NMR (400 MHz, CDCl3) 7.26 (t, 1H,

8.7 Hz), 6.96-7.03 (m, 2H), 6.75 (dd, 1H, J = 8.2 Hz, 2.3 Hz), 4.40 (t, 1H, J = 8.4 Hz), 4.28 (dd,

1H, J = 9 Hz, 3.6 Hz), 4.22 (dd, 1H, J = 8.7 Hz, 3.4 Hz), 3.79 (s, 3H), 0.83 (s, 9H).13

C NMR

(100 MHz, CDCl3) δ 160.1, 156.8, 140.1, 129.7, 116.5, 111.4, 110.6, 65.1, 64.4, 55.4, 35.8, 25.8.

HRMS (ESI, m/z): [M]+

calc.: 250.1437 found: 250.1428. IR (cm-1

): 2962, 1743, 1602, 1489,

1400, 1368, 1292, 1218, 1198, 1122, 1045, 975, 759. mp = 89-91oC.

(S)-4-(tert-butyl)-3-(m-tolyl)oxazolidin-2-one (2.1p): Synthesized using General Procedure A:

Using: CuI (0.25 mmol, 47.6 mg, 50%), trans-(±)-diaminocyclohexane (2.5 mmol, 300 µl) 3-

iodotoluene (0.5 mmol, 64.2 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (0.6 mmol, 85.9

mg, 1.2 equiv), and potassium phosphate (1 mmol, 212.3 mg, 2 equiv)c in 2 mL 1,4-dioxane.

Isolated as a thick yellow oil (52.6 mg, 45%) after 17 h. H NMR (400 MHz, CDCl3) 7.27-7.22

(m, 2H), 7.18 (m, 1H), 7.02 (m, 1H), 4.41 (t, 1H, J = 89 Hz), 4.29 (dd, 1H, J = 9.2 Hz, 3.9 Hz),

4.22 (dd, 1H, J = 3.9 Hz, 8.8 Hz) 2.35 (s, 3H), 0.83 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ

157.0, 139.0, 138.9, 128.8, 126.9, 125.3, 121.5, 65.3, 64.375, 35.8, 25.8, 21.4. HRMS (DART-

MS, m/z): [M]+

calc.: 234.14940 found: 234.14848. IR(cm-1

): 2964, 1748, 1611, 1590, 1494,

1455, 1404, 1324, 1216, 1113, 1057, 1012, 979, 866, 807, 777, 685, 667.

74

(S)-4-(tert-butyl)-3-(p-tolyl)oxazolidin-2-one (2.1q): Synthesized using General Procedure A:

Using: CuI (1.5 mmol, 285.7 mg, 50%), trans-(±)-diaminocyclohexane (15 mmol, 1.8 mL) 4-

iodotoluene (3 mmol, 654.1 mg , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (3.6 mmol, 515.5

mg, 1.2 equiv), and potassium phosphate (6 mmol, 1.27 g, 2 equiv) in 12 mL 1,4-dioxane.

Isolated as a white solid (268 mg, 38%) after 4 h. H NMR (400 MHz, CDCl3) 7.27 (m, 2H), 7.17

(m, 2H), 4.42 (t, 1H, J = 8.7 Hz), 4.29 (dd, 1H, J = 8.7 Hz, 4.4 Hz), 4.19 (dd, 1H, J = 9.3 Hz, 4.1

Hz), 2.34 (s, 3H), 0.83 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 157.2, 136.3, 136.0, 129.7, 124.5,

65.4, 64.4, 35.7, 25.9, 21.0. HRMS (DART-MS, m/z): [M]+

calc.: 234.14940 found: 234.14898.

IR(cm-1

): 2962, 1760, 1732, 1513, 1400, 1364, 1290, 1215, 1201, 1129, 1049, 963, 821, 761,

736. mp = 130-132oC

(S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1r): Synthesized using General

Procedure A but with a round-bottom flask under argon in place of a vial Using: CuI (1.18

mmol, 224.7 mg, 50%), trans-(±)-diaminocyclohexane (3.5 mmol, 420 µl), 3,4-dimethyl-

iodobenzene (2.36 mmol, 336 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (2.6 mmol, 372

75

mg, 1.1 equiv), and potassium phosphate (4.63 mmol, 982 mg, 2 equiv) in 10 mL 1,4-dioxane.

Isolated as a white solid (270 mg, 46.2%) after 17.75 h. 1H NMR (400 MHz, CDCl3) 7.15 (br.s,

1H), 7.06 (m, 1H), 4.35 (t, 1H, J = 9.2 Hz), 4.21 (dd, 1H, J = 4.4 Hz, 9 Hz), 4.14 (dd, 1H, J = 4

Hz, 8.8 Hz), 2.20 (s, 3H), 2.18 (s, 3H), 0.77 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 157.4, 137.6,

136.8, 134.8, 130.3, 126.1, 122.1, 65.5, 64.6, 35.8, 26.0, 20.1, 19.5. HRMS (DART-MS, m/z):

[M]+

calc.: 248.16505 found: 248.16584. IR(cm-1

): 2958, 1745, 1709, 1605, 1579, 1505, 1487,

1475, 1407, 1366, 1274, 1220, 1142, 1114, 837, 757. mp = 102-103oC.

(S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1s): Synthesized using General

Procedure A: Using: CuI (1.5 mmol, 285.7 mg, 50%), trans-(±)-diaminocyclohexane (15 mmol,

1.8 mL) 3,5-dimethyl-iodobenzene (3 mmol, 426.3 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-

one (3.2 mmol, 458.2 mg, 1.07 equiv), and potassium phosphate (6 mmol, 1.27 g, 2 equiv) in 10

mL 1,4-dioxane. Isolated as a yellow solid (268 mg, 38%) after 4 h. 1H NMR (400 MHz, CDCl3)

δ 7.02 (br.s, 2H), 6.84 (br.s, 1H), 4.40 (t, 1H, J = 9.1 Hz), 4.28 (dd, 1H, J = 9.5 Hz, 4 Hz), 4.19

(dd, 1H, J = 8.9 Hz, 3.9 Hz), 2.30 (s, 6H), 0.82 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 157.1,

138.8, 138.7, 127.9, 122.3, 65.3, 64.4, 35.8, 25.8, 21.3. HRMS (DART-MS, m/z): [M]+

calc.:

248.1645 found: 248.1634. mp = 115-116oC.

76

(S)-3-(3,5-bis(trifluoromethyl)phenyl)-4-(tert-butyl)oxazolidin-2-one (2.1t): Synthesized

using General Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±)

diaminocyclohexane (1.5 mmol, 180 µl) 3,5-di(trifluoromethyl)iodobenzene (0.3 mmol, 53.2 µl,

1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one (0.36 mmol, 51.5 mg, 1.2 equiv), and potassium

phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2 mL 1,4-dioxane. Isolated as a yellow solid (52.2

mg, 52 %) after 4 h. 1H NMR (400 MHz, CDCl3) 7.97 (s, 2H), 7.69 (s, 1H), 4.49 (t, 1H, J = 8.9

Hz), 4.39 (dd, 1H, J = 2.9 Hz, 16.5 Hz), 4.37 (dd, 1H, J = 14 Hz, 3.1 Hz), 0.88 (s, 9H). 13

C NMR

(100 MHz, CDCl3) δ 155.9, 140.7, 132.5 (q, JC-F

= 33.6 Hz), 123.0 (m),122.9 (d, JC-F

= 273 Hz),

118.9 (m), 64.5, 64.4, 36.4, 25.9. HRMS (DART-MS, m/z): [M]+

calc.: 356.10852 found:

356.10915. IR (cm-1

): 2966, 1752, 1618, 1475, 1403, 1387, 1278, 1183, 1131, 1106, 1061, 980,

890, 846, 757, 698, 682. mp = 77-81oC.

(S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)benzoate (2.1u): Synthesized using General

Procedure A: Using: CuI (0.15 mmol, 28.5 mg, 50%), trans-(±) diaminocyclohexane (1.5 mmol,

180 µl) ethyl 3-iodobenzoate (0.3 mmol, 50.5 µl , 1 equiv), (S)-4-(tert-butyl)oxazolidin-2-one

77

(0.36 mmol, 51.5 mg, 1.2 equiv), and potassium phosphate (0.6 mmol, 127.4 mg, 2 equiv) in 2

mL 1,4-dioxane. Isolated as a brown solid (42 mg, 48 %) after 4 h. 1H NMR (400 MHz, CDCl3)

8.06 (m, 2H), 7.55 (m, 2H), 4.45 (t, 1H, J = 8.8 Hz). 4.40-4.29 (m, 4H), 1.39 (t, 3H, J = 7.1 Hz),

0.85 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 165.9, 156.2, 143.1, 130.5, 127.4, 122.9, 64.5, 64.4,

61.0, 36.3, 25.9, 14.3. HRMS (DART-MS, m/z): [M]+

calc.: 292.15488 found: 292.15527. IR

(cm-1

): 2963, 1748, 1712, 1605, 1514, 1477, 1398, 1368, 1269, 1195, 1107, 1059, 853, 772, 760,

702. mp = 101-104oC.

(4S)-4-cyclohexyl-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2a): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 10 mg (0.038 mmol) 2.1a. After 3 h,

5.4 mg of crude material was isolated as a clear oil in a mixture of approximately 3:1

defluorinated to fluorinated product as determined by GC-MS. 1H NMR (400 MHz, CDCl3) δ

4.57-4.42 (m, 1H), 4.15-4.10 (m, 3H), 3.70 (m, 1H), 3.44 (m, 1H), 2.40-0.96 (m, 34H). 13

C NMR

(100 MHz, CDCl3) δ 157.9, 91.6, 91.4, 89.6, 63.6, 63.6, 63.5, 59.2, 59.2, 54.3, 40.3, 40.2, 31.4,

30.1, 28.8, 28.5, 26.4, 26.3, 26.3, 26.2, 25.9, 25.9, 25.6, 25.6, 25.6, 25.4, 24.5, 21.1, 20.9.

HRMS (DART-MS, m/z): [M]+

calc.: 270.18693 found: 270.18819 (fluorinated) and 252.19676

(defluorinated). Two isomers of fluorinated product are detected by both GC-MS and 19

F-NMR,

the latter of these provides the diasteromeric ratio. 19

F-NMR (373 MHz, CDCl3) δ -169.11 (d, J =

49 Hz), -169.87 (d, J = 48.2 Hz) with signals integrated in a 1:2.1 ratio respectively.

78

(4S)-4-(cyclohexylmethyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2b): Synthesized using

General Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 20.8 mg (0.0767 mmol) 2.1b.

After 3 h, 20 mg of crude material was isolated as a clear oil in a mixture of defluorinated and

fluorinated product (ratio of defluorinated to fluorinated not determined). 1

H NMR (400 MHz,

CDCl3) δ 4.29 (m, 1H), 3.39 (m, 1H), 3.85(m, 1H), 3.70 (m, 1H), 3.44 (m, 1H), 1.74-0.94 (m,

23H). 13

C NMR (100 MHz, CDCl3) δ 157.7, 67.8, 54.1, 52.9, 42.3, 34.5, 34.3, 32.5, 31.7, 30.2,

26.3, 26.2, 25.9, 25.9, 25.4. HRMS (DART-MS, m/z): [M]+

calc.: 284.2026 found: 284.2020

(fluorinated) and 266.2102 (defluorinated). Two isomers of fluorinated product are detected by

19F-NMR, which provides the diasteromeric ratio.

19F-NMR (373 MHz, CDCl3) δ -169.21 (d, J =

47.9 Hz), -169.85 (d, J = 49.2 Hz) with signals integrated in a 1:2.5 ratio respectively.

(4S)-4-(tert-butyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2c): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 16 mg (0.0672 mmol) 2.1c. After 7 h,

15.5 mg of crude material was isolated as a clear oil in a mixture of approximately 88%

defluorinated to 12% fluorinated product as determined by GC/MS. 1

H NMR (400 MHz, CDCl3)

δ 4.15 (m, 4H), 3.34 (m, 1H), 1.88-1.70 (m, 7H), 3.70 (m, 1H), 0.96 (s, 9H), 0.91 (s, 1H). 13

C

NMR (100 MHz, CDCl3) δ 158.3, 66.5, 66.3, 65.1, 65.1, 58.3, 35.2, 29.9, 29.1, 26.4, 26.2, 25.5,

79

25.1, 24.7. HRMS (ESI, m/z): [M]+

calc.: 244.1707 found: 244.1709 (fluorinated) and 226.2

(defluorinated). Two isomers of fluorinated product are detected by both GC-MS and 19

F-NMR,

the latter of these provides the diasteromeric ratio. 19

F-NMR (373 MHz, CDCl3) δ -169.64 (d, J =

47.8 Hz), -169.88 (d, J = 48.3 Hz) with signals integrated in a 1:5.4 ratio respectively.

(4S)-3-(3-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2d): Synthesized using General

Procedure B using 50 mg 5% Rh/Al2O3 and 50 bar H2 and 18.5 mg (0.083 mmol) 2.1d. After 8.5

h, 16 mg of crude material was isolated as a clear oil in a mixture of approximately 65%

defluorinated to 35% fluorinated product as determined by GC/MS.1H NMR (400 MHz, CDCl3)

δ 4.04 (m, 3H), 3.66 (m, 1H), 1.88-1.44 (m, 9H), 1.07 (m, 1H), 0.84 (m, 7H).

13C NMR (100 MHz, CDCl3) δ 157.9, 68.5, 67.1, 62.6, 62.5, 59.3, 54.2, 31.7, 31.4, 30.9, 30.0,

29.6, 29.5, 25.9, 25.8, 25.3, 24.7, 20.9, 18.1, 13.8. HRMS (ESI, m/z): [M]+

calc.: 230.15563

found: 230.15869 (fluorinated) and 212.16410 (defluorinated). Two isomers of fluorinated

product are detected by both GC-MS and 19

F-NMR, the latter of these provides the diasteromeric

ratio. 19

F-NMR (373 MHz, CDCl3) δ -169.75 (d, J = 47.5 Hz), -170.51 (d, J = 50.4 Hz) with

signals integrated in a 1:1.9 ratio respectively.

(4S)-3-(2-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2e): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 25.5 mg (0.11 mmol) 2.1e. After 3 h,

80

26 mg of crude material was isolated as a clear oil in a mixture of approximately 71%

defluorinated to 29% fluorinated product as determined by GC/MS.1H NMR (400 MHz, CDCl3)

δ 4.09 (m, 2H), 3.66 (m, 1H), 3.76 (m, 1H), 3.45 (m, 1H), 2.09-1.12 (m, 11H), 0.90 (m, 6H).

13C NMR (100 MHz, CDCl3) δ 157.9, 91.5, 91.3, 89.6, 62.6, 62.5, 59.3, 59.3, 54.2, 51.5, 51.3,

37.7, 37.5, 31.8, 31.7, 31.4, 30.0, 29.7, 29.6, 29.5, 28.4, 25.9, 25.8, 25.3, 21.0, 20.9, 18.1, 13.9.

HRMS (ESI, m/z): [M]Na+

calc.: 252.1370 [M]Na+

found: 252.1374 (fluorinated) and [M]+

212.1639 (defluorinated). Two isomers of fluorinated product are detected by 19

F-NMR, which

provides the diasteromeric ratio. 19

F-NMR (373 MHz, CDCl3) δ -169.76 (d, J = 48.1 Hz), -

170.51 (d, J = 48.1 Hz) with signals integrated in a 1:1.7 ratio respectively.

(S)-3-(4-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2f): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 28.1 mg (0.125 mmol) 2.1f. After 3 h,

26.2 mg of crude material was isolated as a clear oil in a mixture of approximately 61%

defluorinated to 39% fluorinated product as determined by GC/MS. 1

H NMR (400 MHz, CDCl3)

δ 4.17 (m, 3H), 3.76 (m, 2H), 3.42 (m, 1H), 2.12-1.12 (m, 19H), 2.09-1.12 (m, 11H), 0.90 (m,

10H).13

C NMR (100 MHz, CDCl3) δ 158.2, 157.9, 88.1, 86.4, 62.6, 62.5, 59.3, 58.5, 54.2, 52.7,

31.4, 30.3, 30.3, 30.120, 30.085, 30.034, 29.9, 29.6, 25.9, 25.888, 25.848, 25.3, 23.7, 18.2, 18.1,

13.8, 13.7. HRMS (ESI, m/z): [M]+

calc.: 230.15563 found: 230.15542 (fluorinated) and

212.16466 (defluorinated). Two isomers of fluorinated product were detected by GC-MS; which

was used to determine the approximate diastereomeric ratio of 7.2:1 because of ambiguity in 19

F-

NMR and GC-FID.

81

(S)-4-(tert-butyl)-3-(4-fluorocyclohexyl)oxazolidin-2-one (2.2g): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3 and 50 bar H2 and 28.6 mg (0.12 mmol) 2.1g. After 3 h,

25.8 mg of crude material was isolated as a white solid in a mixture of approximately 70%

defluorinated to 30% fluorinated product as determined by GC-MS. 1

H NMR (400 MHz, CDCl3)

δ 4.12 (m, 3H), 3.34 (m, 1H), 3.06 (m, 1H), 2.95 (tt, 1H, J = 12 Hz, 3.9 Hz), 2.39-1.16 (m, 18H),

0.90 (m, 11H).13

C NMR (100 MHz, CDCl3) δ 158.3, 87.6, 85.8, 66.2, 65.8, 65.2, 65.1, 58.3,

56.9, 30.9, 29.9, 29.1, 26.4, 26.1, 25.5, 25.4, 25.1, 23.6. HRMS (ESI, m/z): [M]+

calc.:

244.17128 found: 244.17195 (fluorinated) and 226.18139 (defluorinated). Two isomers of

fluorinated product were detected by GC-MS, and GC-FID analysis was performed to obtain a

diastereomeric ratio of 15.2:1. mp = 108-110ºC

(S)-4-(tert-butyl)-3-((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxazolidin-2-one (2.2h):

Synthesized using General Procedure B using 30 mg 5% Rh/Al2O3, 50 bar H2, 22.4 mg (0.078

mmol) 2.1s. After 20 h, 20.6 mg of product (90%) was isolated as a white solid and as a mixture

of diastereomers (10:1:0.15). Diasteromeric ratios were determined by GC-FID analysis. The

title compound was identified to be the major component of the diasteromeric mixture via

crystallization by slow diffusion of hexanes into benzene and subsequent X-ray crystal analysis.

82

The obtained crystals were verified by 1H-NMR to be the major diasteromer.

1H NMR (400

MHz, CDCl3) δ 4.22 (t, 1H, J = 8.9 Hz), 4.16 (dd, J = 9.4 Hz, 3.2 Hz), 3.36 (dd, 1H, J = 8.7 Hz,

3.3 Hz) 3.01 (tt, 1H, J = 3.7 Hz, 11.8 Hz), 2.44 (dq, 1H, J = 3.6 Hz, 12.5 Hz), 2.17-1.83 (m, 4H),

1.38-1.17 (m, 2H), 0.96 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 158.1, 127.0 (q, JC-F

= 277.5

Hz), 66.2, 65.1, 56.5, 42.0 (q, JC-F

= 27.2 Hz), 35.3, 28.8, 27.5 (m) 25.4, 24.3, 23.8 (m). HRMS

(DART-MS, m/z): [M]+

calc.: 294.16809 found: 294.16753. mp = 140-141ºC

(4S)-4-isopropyl-3-(2-methoxycyclohexyl)oxazolidin-2-one (2.2i): Synthesized using General

Procedure B using 50 mg 5% Rh/Al2O3,80 bar H2, 14.4 mg (0.06 mmol) 2.1i and with the

reaction warmed to 50ºC. After 39 h, 16 mg of the title compound was isolated as a yellow oil

and a mixture of diastereomers (1.9:1) by GC-MS and GC-FID analysis. 1H NMR (400 MHz,

CDCl3) δ 4.13 (m, 3H), 3.71 (m, 2H), 3.26 (s, 3H), 2.29 (m, 1H), 1.86-1.33 (m, 12H), 0.86 (m,

8H). 13

C NMR (100 MHz, CDCl3) δ 159.0, 63.157, 63.0, 59.8, 58.0, 57.7, 56.5, 55.8, 55.6, 29.8,

27.5, 26.5, 26.4, 25.6, 25.4, 24.3, 18.9, 18.7, 18.457, 18.3, 13.7, 13.6. HRMS (DART-MS, m/z):

[M]+

calc.: 242.17562 found: 242.17648

83

(4S)-4-isopropyl-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2j): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3, 80 bar H2, 23.8 mg (0.1 mmol) 2.1j and with the

reaction warmed to 50ºC. After 24 h, 24 mg of of the titled product was isolated as a yellow oil

and a mixture of diastereomers (2:1:0.76) by GC-MS and GC-FID analysis. 1H NMR (400 MHz,

CDCl3) δ 4.15 (t, 1H, J = 9 Hz), 4.06 (m, 1H), 3.80-3.53 (m, 2H), 3.20 (m, 1H), 2.75-1.25 (m,

10H), 0.89 (m, 6H). 13

C NMR (100 MHz, CDCl3) δ 157.9, 62.6, 62.6, 60.6, 58.9, 58.9, 55.9,

52.0, 49.0, 37.4, 35.7, 31.1, 31.1, 30.9, 29.8, 29.7, 29.0, 28.1, 22.1, 22.0, 19.8, 19.8, 18.2, 17.9,

14.0, 13.8, 13.7. HRMS (DART-MS, m/z): [M]+

calc.: 242.17562 found: 242.17619.

(S)-4-isopropyl-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2k): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3, 80 bar H2, 28.5 mg (0.12 mmol) 2.1k and with the

reaction warmed to 50ºC. After 24 h, 21 mg of the titled product was isolated as a clear oil and a

mixture of diastereomers (4.9:1) by GC-FID and GC-MS analysis. 1H NMR (400 MHz, CDCl3)

δ 4.10 (m, 2H), 3.80 (m, 1H), 3.44 (m, 1H), 3.34 (s, 1H), 3.31 (s, 2H), 2.17-1.25 (m, 12H),

0.92-0.86 (m, 7H). 13

C NMR δ (100 MHz, CDCl3) δ 158.2, 73.4, 62.5, 58.4, 55.7, 53.5, 29.8,

28.9, 28.7, 26.1, 23.9, 18.3, 13.7. HRMS (DART-MS, m/z): [M]+

calc.: 242.17562 found:

242.17640.

84

(S)-4-(tert-butyl)-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2l): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3,80 bar H2, 23.6 mg (0.095 mmol) 2.1l and with the

reaction warmed to 50ºC. After 24 h, 24 mg of crude material was isolated as a white solid and a

mixture of diastereomers (12.5:1) by GC-FID and GC-MS analysis with 23% starting material

remaining. 1H NMR (400 MHz, CDCl3) δ 4.15 (m, 3H), 3.81 (s,1H), 3.39 (m, 1H), 3.35 (m, 1H),

3.29 (s, 3H), 3.06 (1H, tt, J = 3.7 Hz, 12.3 Hz), 2.63 (qd, 1H, J = 13.2 Hz, 3.7 Hz), 2.26 (qd, 1H,

J = 3.7 Hz, 13.2 Hz), 2.06 (m, 2H), 1.78-1.26 (m, 6H), 0.96 (s, 10H), 0.83 (s, 3H). 13

C NMR

(100 MHz, CDCl3) δ 158.3, 73.1, 65.7, 65.2, 57.7, 55.5, 29.3, 29.2, 25.8, 25.6, 24.2, 23.9. HRMS

(DART-MS, m/z): [M]+

calc.: 256.19127 found: 256.19076. mp 72-74ºC

(4S)-3-(2-hydroxycyclohexyl)-4-isopropyloxazolidin-2-one (2.2m): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3,80 bar H2, 15 mg (0.067 mmol) 2.1m and with the

reaction warmed to 50ºC. After 14.5 h, 12.3 mg (80%) of the title compound was isolated as a

yellow gum and a mixture of diastereomers (1.4: 1: 0.27: 0.23) by GC-MS and GC-FID. 1H

NMR (400 MHz, CDCl3) δ 4.30-4.20 (m, 2H), 4.11 (m, 1H), 3.89-3.73 (m, 1H), 3.30-3.09 (m,

1H), 2.11-1.24 (m, 10H), 0.92 (m, 6H). 13

C NMR (100 MHz, CDCl3) δ 160.1, 158.9, 69.7, 69.5,

63.5, 62.7, 61.9, 60.9, 58.8, 58.7, 35.2, 33.3, 29.9, 29.1, 28.6, 26.0, 25.1, 24.4, 24.1, 18.6, 18.2,

18.1, 14.1, 13.8,. HRMS (DART-MS, m/z): [M]+

calc.: 228.15997 found: 298.16034.

85

(4S)-4-(tert-butyl)-3-(3-hydroxycyclohexyl)oxazolidin-2-one (2.2n): Synthesized using

General Procedure B using 40 mg 5% Rh/Al2O3, 50 bar H2, and 23.5 mg (0.1 mmol) 2.1o. After

14 h, 20 mg (82%) of the title product was isolated as a clear oil and a mixture of diastereomers

(3.3:1) by GC-FID and GC-MS analysis. 1H NMR (400 MHz, CDCl3) δ 4.16 (m, 3H), 3.48 (m,

1H), 3.35 (m, 1H), 3.00 (m, 1H), 2.46-2.12 (m, 3H), 2.06-1.17 (m, 15H), 0.97 (s, 2H), 0.965 (s,

4H), 0.95 (s, 5H). 13

C NMR (100 MHz, CDCl3) δ 158.3, 70.4, 70.0, 67.4, 66.3, 66.2, 65.1, 65.1,

55.9, 53.4, 52.3, 39.2, 38.3, 36.1, 35.2, 35.2, 34.7, 34.6, 31.7, 30.9, 28.6, 27.7, 25.5, 25.4, 25.4,

22.5, 22.2, 19.7. HRMS (DART-MS, m/z): [M]+

calc.: 242.17562 found: 242.17627.

(4S)-4-(tert-butyl)-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2o): Synthesized using

General Procedure B using 40 mg 5% Rh/Al2O3,80 bar H2, 23.4 mg (0.1 mmol) 2.1m and with

the reaction warmed to 60ºC. After 24 h, 24 mg of crude was isolated as a white solid and a

mixture of diastereomers (4:1) by GC-MS and GC-FID analysis with 37% starting material

remaining. 1H NMR (400 MHz, CDCl3) δ 4.43 (t, 1H, J = 9 Hz), 4.31 (dd, 1H, J = 5 Hz, 3.7 Hz),

4.18 (m, 5H), 3.81 (s, 3H), 3.35 (m, 6H), 3.26 (s, 1H), 3.00-2.96 (m, 3H), 2.31 (m, 2H), 2.12-

86

1.82 (m, 8H), 1.72 (s, 3H), 1.43-1.11 (m, 5H), 0.96 (s, 16H), 0.90 (s, 1H), 0.85 (s, 9H). 13

C NMR

(100 MHz, CDCl3) δ 160.1, 158.28, 158.25, 78.8, 78.5, 66.0, 65.2, 65.1, 65.1, 64.4, 56.1, 55.7,

55.4, 53.4, 35.9, 35.6, 35.2, 34.7, 30.8, 30.7, 28.9, 28.2, 25.8, 25.4, 24.7, 22.4, 22.2. HRMS

(DART-MS, m/z): [M]+

calc.: 256.19127 found: 256.19063. mp = 63-65ºC

(4S)-4-(tert-butyl)-3-(3-methylcyclohexyl)oxazolidin-2-one (2.2p): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3, 50 bar H2, 24.3 mg (0.104 mmol) 2.1p. After 14 h, 24

mg of the title product (97%) was isolated as a white solid and a mixture of diastereomers. GC-

FID and GC-MS analysis confirms a diastereomeric ratio of: (1.7: 1: 0.22 :0.16). 1H NMR (400

MHz, CDCl3) δ 4.19 (t, 1H, J = 8.7 Hz), 4.13 (dd, 1H, J = 9.3 Hz, 3.2 Hz), 3.34 (m, 1H), 2.98

(m, 1H), 1.89-1.56 (m, 6H), 1.38-1.11 (m, 2H), 0.94 (m, 14H). 13

C NMR (100 MHz, CDCl3) δ

158.3, 66.3, 66.3, 65.1, 58.0, 58.0, 38.3, 37.5, 35.2, 33.8, 33.1, 32.8, 29.3, 28.4, 25.7, 25.4, 22.4,

22.2. HRMS (DART-MS, m/z): [M]+

calc.: 240.19635 found: 240.19694. mp 61-63ºC.

(S)-4-(tert-butyl)-3-(4-methylcyclohexyl)oxazolidin-2-one (2.2q): Synthesized using General

Procedure B using 40 mg 5% Rh/Al2O3, 100 psi H2, 23.3 mg (0.104 mmol) 2.1q. After 3 h, 23.7

mg of the title product (99%) was isolated as a white solid and a mixture of diastereomers.

Diasteromeric ratios were determined by 1H NMR (400 MHz, CDCl3) δ 4.18 (t, 1H, J = 8.9 Hz),

87

4.13 (dd, 1H, J = 3.3 Hz, 9.3 Hz), 3.34 (dd, 1H, J = 8.9 Hz, 3.4 Hz), 2.93 (m, 1H), 2.63 (dq, 1H, J

= 4.2 Hz, 12.8 Hz), 1.88-1.41 (m, 8H), 0.96 (s, 8H). 13

C NMR (100 MHz, CDCl3) δ 158.3, 66.3,

66.1, 65.0, 58.5, 58.2, 35.2, 34.9, 34.7, 31.7, 31.4, 29.6, 28.7, 26.3, 25.5, 24.1, 23.5, 22.2, 17.3.

HRMS (DART-MS, m/z): [M]+

calc.: 240.19635 found: 240.19694. mp = 90-92ºC

(4S)-4-(tert-butyl)-3-(3,4-dimethylcyclohexyl)oxazolidin-2-one (2.2r): Synthesized using

General Procedure B using 30 mg 5% Rh/Al2O3, 50 bar H2, 24.7 mg (0.1 mmol) 2.1r. After 15 h,

20 mg of the title product (79%) was isolated as a white solid and a mixture of diastereomers.

The diasteromeric ratio was determined to be 2.3:1 by GC-MS and GC-FID analysis. 1

H NMR

(400 MHz, CDCl3) δ 4.18 (t, 1H, J = 8.8 Hz), 4.12 (dd, 1H, J = 3.3 Hz, 9 Hz), 3.37 (m, 1H),

1.71-1.36 (m, 6H), 0.95 (m, 15H). 13

C NMR (100 MHz, CDCl3) δ 158.3, 66.1, 65.0, 58.3, 35.4,

35.2, 35.0, 32.9, 32.6, 32.0, 31.7, 31.1, 25.4, 23.3, 22.7, 19.8, 19.7, 11.5. HRMS (DART-MS,

m/z): [M]+

calc.: 254.2114 found: 254.2106. mp = 92-94ºC.

(4S)-4-(tert-butyl)-3-(3,5-dimethylcyclohexyl)oxazolidin-2-one (2.2s): Synthesized using

General Procedure B using 30 mg 5% Rh/Al2O3, 100 psi H2, 24.7 mg (0.1 mmol) 2.1s. After 4.75

h, 24 mg of the title product (94%) was isolated as a white solid and a mixture of diastereomers

88

(19.5:1) by GC-MS and GC-FID analysis. 1H NMR (400 MHz, CDCl3) δ 4.19 (t, 1H, J = 9 Hz),

4.13 (dd, 1H, J = 3.2Hz, 9 Hz), 3.33 (dd, 1H, J = 8.8 Hz, 3.2 Hz), 3.02 (m, 1H), 2.04 (q, 1H, J =

12.6 Hz), 1.83 (m, 1H), 1.68-1.55 (m, 4H), 1.43-1.26 (m, 3H), 0.94 (s, 9H), 0.67 (q, 1H, J = 12.6

Hz). 13

C NMR (100 MHz, CDCl3) δ 158.3, 66.3, 65.1, 57.7, 42.7, 37.7, 36.9, 35.261, 32.4, 32.1,

25.5, 22.2, 22.1. HRMS (DART-MS, m/z): [M]+

calc.: 254.21200 found: 254.21322. mp = 89-

90ºC.

(4S)-3-(3,5-bis(trifluoromethyl)cyclohexyl)-4-(tert-butyl)oxazolidin-2-one (2.2t): Synthesized

using General Procedure B using 30 mg 5% Rh/Al2O3, 80 bar H2, 18 mg (0.0506 mmol) 2.1t.

After 35 h, 17.1 mg of the title product (94%) was isolated as a white solid in >99:1 selectivity

by GC-MS and GC-FID. 1H NMR (400 MHz, CDCl3) δ 4.25 (t, 1H, J = 9 Hz), 4.18 (dd, 1H, J =

9.3, 3.3 Hz), 3.38 (dd, 1H, J = 8.7 Hz, 3.3 Hz), 3.08 (m, 1H), 2.60 (q, 1H, J = 12.4 Hz), 2.17-2.10

(m, 5H), 1.98 (m, 1H), 1.43 (m, 1H) 0.97 (s, 9H). 13

C NMR (100 MHz, CDCl3) δ 157.9, 126.4 (q,

JC-F

= 278.8 Hz), 66.1, 65.2, 55.0, 40.7 (m), 35.2, 27.7 (m), 26.752, 25.4 (m), 23.0 (m). HRMS

(DART-MS, m/z): [M]NH

4+

calc.: 379.18202 found: 379.18364. mp = 200-203ºC.

89

(S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)cyclohexanecarboxylate (2.2u): Synthesized

using General Procedure B using 40 mg 5% Rh/Al2O3, 50 bar H2, 29.1 mg (0.1 mmol) 2.1u.

After 14 h, 29.1 mg of the title product (82%) was isolated as a white solid in 6.4:1 by GC-MS

and GC-FID analysis. 1H NMR (400 MHz, CDCl3) δ 4.15 (m, 4H), 3.35 (dd, 1H, J = 3.4 Hz, 8.6

Hz), 3.03 (tt, 1H, J = 12 Hz, 3.7 Hz), 2.58 (m, 1H), 2.49 (dq, 1H, J = 12.4 Hz, 4.4 Hz), 2.34 (m,

2H), 2.10 (m, 1H), 1.77 (m, 1H), 1.65 (m, 1H), 1.43 (m, 2H), 1.28 (t, 3H, J = 7.2 Hz), 0.95 (s,

9H). 13

C NMR (100 MHz, CDCl3) δ 174.1, 158.2, 65.8, 65.1, 60.5, 57.6, 38.2, 35.2, 27.4, 26.9,

26.5, 26.1, 25.5, 25.4, 14.3. HRMS (DART-MS, m/z): [M]+

calc.: 298.20183 found: 298.20175.

mp = 130-133ºC.

90

Additional NMR Spectra

1H-NMR and

13C NMR Spectra

1H-NMR of 2,3-diphenyl-1,4-diazaspiro[4.4]nona-1,3-diene (1.1b)

13C-NMR of 2,3-diphenyl-1,4-diazaspiro[4.4]nona-1,3-diene (1.1b)

91

1H-NMR of 2,2-dimethyl-4,5-diphenyl-2H-imidazole (1.1c)

13C-NMR of 2,2-dimethyl-4,5-diphenyl-2H-imidazole (1.1c)

92

1H-NMR of 2,3-diphenyl-1,4-diazaspiro[4.5]dec-1-ene (1.2a)

13C-NMR of of 2,3-diphenyl-1,4-diazaspiro[4.5]dec-1-ene (1.2a)

93

1H-NMR of 2,3-diphenyl-1,4-diazaspiro[4.4]non-1-ene (1.2b)

13C-NMR of 2,3-diphenyl-1,4-diazaspiro[4.4]non-1-ene (1.2b)

94

1H-NMR of 2,2-dimethyl-4,5-diphenyl-2,5-dihydro-1H-imidazole (1.2c):

13C-NMR of 2,2-dimethyl-4,5-diphenyl-2,5-dihydro-1H-imidazole (1.2c):

95

1H-NMR of 4,5-dimethyl-1-phenylimidazolidin-2-one (1.4a)

13C-NMR of 4,5-dimethyl-1-phenylimidazolidin-2-one (1.4a)

96

1H-NMR 4,5-dimethyl-1-cyclohexyllimidazolidin-2-one (1.4b)

13C-NMR 4,5-dimethyl-1-cyclohexyllimidazolidin-2-one (1.4b)

97

1H-NMR of 1,4,6-trimethylpyrimidine-2(1H)-thione (1.5a)

13C-NMR of 1,4,6-trimethylpyrimidine-2(1H)-thione (1.5a)

98

1H-NMR of

1-allyl-4,6-dimethylpyrimidine-2(1H)-thione (1.5b)

13C-NMR of

1-allyl-4,6-dimethylpyrimidine-2(1H)-thione (1.5b)

99

1H-NMR of 1-benzyl-4,6-dimethylpyrimidine-2(1H)-thione (1.5c)

13C-NMR of 1-benzyl-4,6-dime thylpyrimidine-2(1H)-thione (1.5c)

100

1H-NMR of 4,6-dimethyl-1-phenylpyrimidine-2(1H)-thione (1.5d)

13

C-NMR of 4,6-dimethyl-1-phenylpyrimidine-2(1H)-thione (1.5d)

101

1H-NMR (S)-4-cyclohexyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1a)

13C-NMR (S)-4-cyclohexyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1a)

102

1H-NMR (S)-4-benzyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1b)

13C-NMR (S)-4-benzyl-3-(3-fluorophenyl)oxazolidin-2-one (2.1b)

103

1H-NMR (S)-4-(tert-butyl)-3-(3-fluorophenyl)oxazolidin-2-one (2.1c)

13C-NMR (S)-4-(tert-butyl)-3-(3-fluorophenyl)oxazolidin-2-one (2.1c)

104

1H-NMR (S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1d)

13C-NMR (S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1d)

105

1H-NMR (S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1e)

13C-NMR (S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1e)

106

1H-NMR of (S)-3-(4-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1f)

13C-NMR of (S)-3-(4-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1f)

107

1H-NMR (S)-4-(tert-butyl)-3-(4-fluorophenyl)oxazolidin-2-one (2.1g):

13C-NMR (S)-4-(tert-butyl)-3-(4-fluorophenyl)oxazolidin-2-one (2.1g):

108

1H-NMR of (S)-4-(tert-butyl)-3-(3-(trifluoromethyl)phenyl)oxazolidin-2-one (2.1h)

13C of (S)-4-(tert-butyl)-3-(3-(trifluoromethyl)phenyl)oxazolidin-2-one (2.1h)

109

1H-NMR (S)-4-isopropyl-3-(2-methoxyphenyl)oxazolidin-2-one (2.1i)

13C-NMR (S)-4-isopropyl-3-(2-methoxyphenyl)oxazolidin-2-one (2.1i)

110

1H-NMR (S)-4-isopropyl-3-(3-methoxyphenyl)oxazolidin-2-one (2.1j):

13C-NMR (S)-4-isopropyl-3-(3-methoxyphenyl)oxazolidin-2-one (2.1j):

111

1H-NMR of (S)-4-isopropyl-3-(4-methoxyphenyl)oxazolidin-2-one (2.1k):

13C-NMR of (S)-4-isopropyl-3-(4-methoxyphenyl)oxazolidin-2-one (2.1k):

112

1H-NMR of (S)-4-(tert-butyl)-3-(4-methoxyphenyl)oxazolidin-2-one (2.1l):

13C-NMR of (S)-4-(tert-butyl)-3-(4-methoxyphenyl)oxazolidin-2-one (2.1l):

113

1H-NMR of (S)-4-(tert-butyl)-3-(2-hydroxyphenyl)oxazolidin-2-one (2.1m)

13C-NMR of (S)-4-(tert-butyl)-3-(2-hydroxyphenyl)oxazolidin-2-one (2.1m)

114

1H-NMR of (S)-4-(tert-butyl)-3-(3-hydroxyphenyl)oxazolidin-2-one (2.1n)

13C-NMR of (S)-4-(tert-butyl)-3-(3-hydroxyphenyl)oxazolidin-2-one (2.1n)

115

1H-NMR of (S)-4-(tert-butyl)-3-(3-methoxyphenyl)oxazolidin-2-one (2.1o):

13C-NMR of (S)-4-(tert-butyl)-3-(3-methoxyphenyl)oxazolidin-2-one (2.1o):

116

1H-NMR of (S)-4-(tert-butyl)-3-(m-tolyl)oxazolidin-2-one (2.1p)

13C-NMR of

1H-NMR of (S)-4-(tert-butyl)-3-(m-tolyl)oxazolidin-2-one (2.1p)

117

1H-NMR of (S)-4-(tert-butyl)-3-(p-tolyl)oxazolidin-2-one (2.1q)

13C-NMR of (S)-4-(tert-butyl)-3-(p-tolyl)oxazolidin-2-one (2.1q)

118

1H NMR of (S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1r)

13C-NMR of (S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1r)

119

1H-NMR of (S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1s)

13C-NMR of (S)-4-(tert-butyl)-3-(3,4-dimethylphenyl)oxazolidin-2-one (2.1s)

120

1H-NMR of (S)-3-(3,5-bis(trifluoromethyl)phenyl)-4-(tert-butyl)oxazolidin-2-one (2.1t)

13C-NMR of (S)-3-(3,5-bis(trifluoromethyl)phenyl)-4-(tert-butyl)oxazolidin-2-one (2.1t)

121

1H-NMR of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)benzoate (2.1u)

13C-NMR of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)benzoate (2.1u)

13C-NMR of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)benzoate (2.1u)

122

1H-NMR of (4S)-4-cyclohexyl-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2a)

13C-NMR of (4S)-4-cyclohexyl-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2a)

123

1H-NMR of (4S)-4-(cyclohexylmethyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2b)

13C-NMR of (4S)-4-(cyclohexylmethyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2b)

124

1H-NMR of (4S)-4-(tert-butyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2c)

13C-NMR of (4S)-4-(tert-butyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2c)

125

1H-NMR of (4S)-3-(3-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2d)

13C-NMR of (4S)-3-(3-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2d)

126

1H-NMR of (4S)-3-(2-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2e)

13C-NMR of (4S)-3-(2-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2e)

127

1H-NMR of (S)-3-(4-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2f)

13C-NMR of (S)-3-(4-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2f)

128

1H-NMR of (S)-4-(tert-butyl)-3-(4-fluorocyclohexyl)oxazolidin-2-one (2.2g)

13C-NMR of (S)-4-(tert-butyl)-3-(4-fluorocyclohexyl)oxazolidin-2-one (2.2g)

129

1H-NMR (S)-4-(tert-butyl)-3-((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxazolidin-2-one (2.2h)

13C-NMR

(S)-4-(tert-butyl)-3-((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxazolidin-2-one

(2.2h)

130

1H-NMR of (4S)-4-isopropyl-3-(2-methoxycyclohexyl)oxazolidin-2-one (2.2i)

13C-NMR of (4S)-4-isopropyl-3-(2-methoxycyclohexyl)oxazolidin-2-one (2.2i)

131

1H-NMR of (4S)-4-isopropyl-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2j)

13C-NMR of (4S)-4-isopropyl-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2j)

132

1H-NMR of (S)-4-isopropyl-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2k)

13C-NMR of (S)-4-isopropyl-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2k)

133

1H-NMR of (S)-4-(tert-butyl)-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2l)

13C-NMR of (S)-4-(tert-butyl)-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2l)

134

1H-NMR of (4S)-3-(2-hydroxycyclohexyl)-4-isopropyloxazolidin-2-one (2.2m)

13C-NMR of (4S)-3-(2-hydroxycyclohexyl)-4-isopropyloxazolidin-2-one (2.2m)

135

1H-NMR of (4S)-4-(tert-butyl)-3-(3-hydroxycyclohexyl)oxazolidin-2-one (2.2n)

13C-NMR of (4S)-4-(tert-butyl)-3-(3-hydroxycyclohexyl)oxazolidin-2-one (2.2n)

136

1H-NMR of (4S)-4-(tert-butyl)-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2o)

13C-NMR of (4S)-4-(tert-butyl)-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2o)

137

1H-NMR of (4S)-4-(tert-butyl)-3-(3-methylcyclohexyl)oxazolidin-2-one (2.2p)

13C-NMR of (4S)-4-(tert-butyl)-3-(3-methylcyclohexyl)oxazolidin-2-one (2.2p)

138

1H-NMR of (S)-4-(tert-butyl)-3-(4-methylcyclohexyl)oxazolidin-2-one (2.2q)

13C-NMR of (S)-4-(tert-butyl)-3-(4-methylcyclohexyl)oxazolidin-2-one (2.2q)

139

1H-NMR of (4S)-4-(tert-butyl)-3-(3,4-dimethylcyclohexyl)oxazolidin-2-one (2.2r)

13C-NMR of (4S)-4-(tert-butyl)-3-(3,4-dimethylcyclohexyl)oxazolidin-2-one (2.2r)

140

1H-NMR of (4S)-4-(tert-butyl)-3-(3,5-dimethylcyclohexyl)oxazolidin-2-one (2.2s)

13C-NMR of (4S)-4-(tert-butyl)-3-(3,5-dimethylcyclohexyl)oxazolidin-2-one (2.2s)

141

1H-NMR of (4S)-3-(3,5-bis(trifluoromethyl)cyclohexyl)-4-(tert-butyl)oxazolidin-2-one (2.2t)

13C-NMR of (4S)-3-(3,5-bis(trifluoromethyl)cyclohexyl)-4-(tert-butyl)oxazolidin-2-one

(2.2t)

142

1H-NMR of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)cyclohexanecarboxylate (2.2u)

13C-NMR of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)cyclohexanecarboxylate (2.2u)

143

19F-NMR Spectra

19F-NMR of (4S)-4-cyclohexyl-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.1a)

19F-NMR of (4S)-4-(cyclohexylmethyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2b)

144

19F-NMR of (4S)-4-(tert-butyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2c)

19F-NMR of (S)-3-(3-fluorophenyl)-4-isopropyloxazolidin-2-one (2.1d)

145

19F-NMR of (4S)-3-(2-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2e)

146

GC-MS and GC-FID Assays

GC-MS of (4S)-4-cyclohexyl-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2a):

Defluorinated Product

GC-MS of (4S)-4-(tert-butyl)-3-(3-fluorocyclohexyl)oxazolidin-2-one (2.2c):

Defluorinated Product

GC-MS of (4S)-3-(3-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2d):

Defluorinated Product

147

GC-MS of (4S)-3-(2-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2e):

Defluorinated Product

GC-MS of (S)-3-(4-fluorocyclohexyl)-4-isopropyloxazolidin-2-one (2.2f):

Defluorinated Product

148

GC-MS of (S)-4-(tert-butyl)-3-(4-fluorocyclohexyl)oxazolidin-2-one (2.2g):

GC-FID of (S)-4-(tert-butyl)-3-(4-fluorocyclohexyl)oxazolidin-2-one (2.2g):

149

GC-MS (S)-4-(tert-butyl)-3-((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxazolidin-2-one (2.2h):

GC-FID (S)-4-(tert-butyl)-3-((1R,3S)-3-(trifluoromethyl)cyclohexyl)oxazolidin-2-one (2.2h):

150

GC-MS of (4S)-4-isopropyl-3-(2-methoxycyclohexyl)oxazolidin-2-one (2.2i):

GC-FID of (4S)-4-isopropyl-3-(2-methoxycyclohexyl)oxazolidin-2-one (2.2i):

151

GC-MS (4S)-4-isopropyl-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2j):

GC-FID (4S)-4-isopropyl-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2j):

152

GC-MS (S)-4-isopropyl-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2k):

GC-FID (S)-4-isopropyl-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2k):

153

GC-MS of (S)-4-(tert-butyl)-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2l):

GC-FID of (S)-4-(tert-butyl)-3-(4-methoxycyclohexyl)oxazolidin-2-one (2.2l):

154

GC-MS of (4S)-3-(2-hydroxycyclohexyl)-4-isopropyloxazolidin-2-one (2.2m):

GC-FID of (4S)-3-(2-hydroxycyclohexyl)-4-isopropyloxazolidin-2-one (2.2m):

155

GC-MS (4S)-4-(tert-butyl)-3-(3-hydroxycyclohexyl)oxazolidin-2-one (2.2n):

GC-FID (4S)-4-(tert-butyl)-3-(3-hydroxycyclohexyl)oxazolidin-2-one (2.2n):

156

GC-MS of (4S)-4-(tert-butyl)-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2o):

GC-FID of (4S)-4-(tert-butyl)-3-(3-methoxycyclohexyl)oxazolidin-2-one (2.2o):

157

GC-MS of (4S)-4-(tert-butyl)-3-(3-methylcyclohexyl)oxazolidin-2-one (2.2p):

GC-FID of (4S)-4-(tert-butyl)-3-(3-methylcyclohexyl)oxazolidin-2-one (2.2p):

158

GC-MS of (4S)-4-(tert-butyl)-3-(3,4-dimethylcyclohexyl)oxazolidin-2-one (2.2r):

GC-FID of (4S)-4-(tert-butyl)-3-(3,4-dimethylcyclohexyl)oxazolidin-2-one (2.2r):

159

GC-MS (4S)-4-(tert-butyl)-3-(3,5-dimethylcyclohexyl)oxazolidin-2-one (2.2s):

160

GC-MS of (4S)-3-(3,5-bis(trifluoromethyl)cyclohexyl)-4-(tert-butyl)oxazolidin-2-one (2.2t):

GC-FID of (4S)-3-(3,5-bis(trifluoromethyl)cyclohexyl)-4-(tert-butyl)oxazolidin-2-one (2.2t):

161

GC-MS of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)cyclohexanecarboxylate (2.2u):

GC-FID of (S)-ethyl 4-(4-(tert-butyl)-2-oxooxazolidin-3-yl)cyclohexanecarboxylate (2.2u):

162

Chiral-SFC Traces

Hydrogenation of 1.1a using Rh/(R)-BINAP

Hydrogenation of 1.1a using Rh/(R)-OMeBIPHEP

163

Hydrogenation of 1.1a using Pd/(R)-BINAP

Hydrogenation of 1.1a using Pd/(1R,1′R,2S,2′S)-DuanPhos