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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