Enantioselective α-arylation of N-acyloxazolidinones with copper(II)-bisoxazoline catalysts and diaryliodonium salts

Article abstract of DOI:10.1021/ja206047h

A new strategy for the catalytic enantioselective α-arylation of N-acyloxazolidinones with chiral copper(II)-bisoxazoline complexes and diaryliodonium salts is described. The mild catalytic conditions are operationally simple, produce valuable synthetic building blocks in excellent yields and enantioselectivities, and can be applied to the synthesis of important nonsteroidal anti-inflammatory agents and their analogues.

Full text of DOI:10.1021/ja206047h

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pubs.acs.org/JACS
Enantioselective r-Arylation of N-Acyloxazolidinones with
Copper(II)-bisoxazoline Catalysts and Diaryliodonium Salts
Aurꢀelien Bigot, Alice E. Williamson, and Matthew J. Gaunt*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom
S Supporting Information
b
ABSTRACT: A new strategy for the catalytic enantioselec-
tive R-arylation of N-acyloxazolidinones with chiral copper-
(II)-bisoxazoline complexes and diaryliodonium salts is
described. The mild catalytic conditions are operationally
simple, produce valuable synthetic building blocks in ex-
cellent yields and enantioselectivities, and can be applied to
the synthesis of important nonsteroidal anti-inflammatory
agents and their analogues.
he arylation of enolate derivatives is a strategic CÀC
T
bond-forming process that has found widespread application
in organic synthesis (eq 1).1 While transition metal catalysts have
facilitated major breakthroughs in enolate arylation, the devel-
opment of corresponding catalytic enantioselective methods
remains a significant challenge. Pioneering studies from the
Buchwald and Hartwig laboratories have resulted in transition
metal-catalyzed enantioselective enolate arylations which form
all-carbon stereogenic centers.2 Conversely, related processes to
generate tertiary R-aryl carbonyl compounds have not been
forthcoming, presumably due to problems of product racemiza-
tion under the necessary basic reaction conditions. Fu and co-
workers realized an alternative solution to this problem with their
mild nickel-catalyzed cross coupling of R-halocarbonyls with
aryl-organometallic reagents to deliver R-aryl carbonyls in high
enantioselectivity.3 Aryl-boranes,3a aryl-zinc,3b aryl-silane,3c and
aryl Grignard reagents3d can all be used with certain types of
R-halocarbonyl to deliver the enantioenriched products. Despite
these pioneering advances, the demonstrated importance of the
R-aryl carbonyl motif (in both pharmaceutical molecules and
chiral building blocks) necessitates the development of new
catalytic enantioselective methods for their preparation.
Recently, our laboratory discovered that copper catalysts
facilitate regioselective biaryl bond formation between diarylio-
donium salts and simple arenes (eq 2).4,5 While the mechanism
of these reactions remains unclear, we consider the reactive species
to be a copper-activated aromatic electrophile. As a logical extension
of this catalyst activation mode, we questioned whether the action of
a chiral copper catalyst on a diaryliodonium salt would form an aryl
electrophile species suitable for participation in an enantioselective
arylation (eq 2).6 Koser et al. had reported an R-arylation of an
enolsilane with diaryliodonium fluorides, a reaction that we specu-
lated might be compatible with our enantioselective copper-
catalyzed arylation blueprint (eq 3).7 Herein, we describe a copper-
catalyzed enantioselective arylation of an enolate equivalent with
diaryliodonium triflates (eq 4). This mild and operationally simple
process delivers versatile R-arylcarbonyl products in excellent yields
and enantioselectivities, is tolerant of a range of functionality, and
can be applied to the enantioselective synthesis of important
therapeutic agents. During the course of our investigations, an
elegant report by MacMillan and Allen described a related catalytic
enantioselective process, which arylates aldehydes through the
intermediacy of a chiral enamine.8
At the outset of our studies, we selected silylketenimides 1,
derived from N-acyloxazolidinones, as appropriate substrates for
our designed catalytic enantioselective arylation process.9 N-acyl-
oxazolidinones possess several favorable features: (1) the derived
silylketenimides can be formed as single (Z)-isomers, (2) the
presence of the Lewis basic carbonyl oxygen of the oxazolidinone
could rigidify a transition state via stabilizing interactions with a
Received: June 29, 2011
Published: August 17, 2011
r
2011 American Chemical Society
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Table 1. Optimization of Catalytic Enantioselective Arylation
Table 2. Scope of N-Acyloxazolidinone Componenta,b
mol %
yield ee 3a
solvent temp (°C) (%)a (%)
entry
Ar
X
catalyst, R
1
2
Ph, 2a OTf
Ph, 2a OTf
À
À
CH2C12
CH2C12
rt
50
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
À
À
55
38
À
75
15
28
33
60
71
82
14
90
94
À
À
3
Ph, 2a OTf 10, Cu(OTf)2 CH2C12
Ph, 2a OTf 10, i-Pr, 4a CH2C12
Ph, 2a OTf 10, t-Bu, 4b CH2C12
Ph, 2a OTf 10, Ph, 4c CH2C12
À
4
44
À
5
6
91
91
93
87
90
70
93
95
91
92
7
Ph, 2a OTf 10, Ph, 4c
Ph, 2a OTf 10, Ph, 4c
Ph, 2a OTf 10, Ph, 4c
Ph, 2a OTf 10, Ph, 4c
dioxane
EtOAc
hexane
PhMe
8
9
10
11 Ph, 2b BF4
10, Ph, 4c CH2C12
12 Mes, 2c OTf 10, Ph, 4c CH2C12
13 Mes, 2c OTf 10, Ph, 4c CH2C12
14 Mes, 2c OTf
15b Mes, 2c OTf
5, Ph, 4c
5, Ph, 4c
CH2C12
CH2C12
rt
rt
a NMR yields based on 1,3,5-trimethoxybenzene as internal standard.
b 1.2 equiv of 1a used, yield of isolated product after chromatography.
chiral copper complex, (3) R-functionalized N-acyloxazolidinones
are less susceptible to postreaction racemization than other
carbonyl compounds, and (4) the products resulting from aryla-
tion can be readily transformed into useful intermediates, includ-
ing carboxylic acids, esters, ketones, aldehydes, and alcohols, in a
single step. The seminal studies of Evans and co-workers provided
a fundamental understanding of related R,β-unsaturated systems
and demonstrated their utility as electrophiles in a rich variety of
copper(II)-bisoxazoline-catalyzed processes.10 In contrast, our
proposed copper-catalyzed enantioselective arylation would re-
quire silylketenimide 1 to function as the nucleophile. To the best
of our knowledge, silylketenimides derived from N-acyloxazolidi-
nones have not previously been used as enolate equivalents in
enantioselective copper-catalyzed transformations.
Before commencing our investigations into an enantioselec-
tive arylation, we first had to establish the viability of copper
catalysts in this process. A control reaction between silylketenimide
1a and diphenyliodonium triflate 2a, in the absence of a copper salt,
failed to produce any arylation product 3a at both room temperature
and 50 °C (Table 1, entries 1, 2). However, in the presence of
10 mol % Cu(OTf)2, a moderate yield of the desired arylated
product 3a was observed at room temperature (entry 3), confirming
our hypothesis that copper salts could catalyze this transformation.
When we conducted the same experiment with a preformed chiral
catalyst, generated from Cu(OTf)2 and (S,S)-diisopropyl-bisoxazo-
line (to form 4a, entry 4), we were delighted to find that the reaction
gave 38% yield of product 3a in a 44% enantiomeric excess. This
prompted us to assess other bisoxazoline catalysts, and we found
that both yield and enantioselectivity were significantly improved by
a See Supporting Information for details. b Yield and ee of isolated
product are quoted as an average over two experiments.
91% ee.11 Intriguingly, the enantioselectivity remained high across a
range of solvents, although reactivity was greatly affected compared
to the original dichloromethane reaction medium (entries 7À10).
Notably, the enantiomeric excess was reduced when the counterion
of the diphenyliodonium salt was changed from triflate to tetra-
fluoroborate (entry 11). Further assessment of the reaction condi-
tions (entries 12À15) showed that using (PhÀIÀMes)OTf (2c)
led to higher conversion, presumably owing to the increased
solubility of this salt, compared to symmetric salt 2a.
The use of the nontransferring mesityl ligand is also advanta-
geous as only one equivalent of the transferring aryl group is
required, an important feature if valuable aryl coupling partners
are employed.4,8,12 Our optimized reaction involved treatment of
1.2 equiv of 1a with 5 mol % of Cu(OTf)2 diphenyl-bisoxazoline
3
(4c) and 1 equiv of (PhÀIÀMes)OTf (2c) in dichloromethane
at room temperature for 2 h to afford 3a in 94% yield and 92% ee
(entry 15).13
We next explored the capacity of this new reaction (Table 2).
Modified alkyl substrates (1bÀd) performed well, although
isopropyl derivative 1c gave only a moderate yield, presumably
owing to a greater steric impact when compared to the cyclo-
propyl unit (1d). Substrates displaying remote functionality,
such as alkyl bromides, protected nitrogen functionality, alkenes,
and heterocyclic substituents, afforded the products in high yield
and ee (3eÀh). Reaction of benzyloxy-substituted silylketeni-
mide 1i gave the arylated mandelic acid derivative 3i in excellent
yield and ee. We were also able to generate the protected
changing the catalyst to Cu(OTf)2 (R,R)-diphenyl-bisoxazoline
3
(4c, entry 6), resulting in the formation of 3a in 75% yield and
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Table 3. Scope of Diaryliodonium Salt Component in the Copper-Catalyzed Enantioselective Arylationa,b
a See Supporting Information for details. b Yield and ee of isolated product are quoted as an average over at least two experiments. c Reaction with 10 mol %
catalyst 4c at 10 °C for 20 h. d Reaction on 2 g scale with 2 mol % catalyst 4c for 6 h.
arylglycine product 3j in moderate ee (53%). While we have not
yet been able to improve this result, it provides a new entry into
an important class of amino acids. Notably, these results
demonstrate that our new methodology can be extended to
N-acyloxazolidinones containing R-heteroatoms, valuable func-
tionality for a range of synthetic applications.
Finally, we also showed that aryl-substituted silylketenimide 1k
undergoes the reaction in good yield (77%) and moderate ee
(59%). The ee can be upgraded by crystallization from methanol to
produce 3k in 50% yield and 92% ee. Surprisingly, in comparison to
other substrates, the sense of enantioinduction is reversed in the
arylation of silylketenimide 1k.14 To the best of our knowledge, this
is the first example of a catalytic enantioselective arylation to install
an R-carbonyl tertiary stereogenic center bearing two different aryl
groups. We believe that these compounds may find broad utility as
building blocks in drug discovery.
The catalytic enantioselective arylation reaction produces analo-
gues of nonsteroidal anti-inflammatory drugs, an important class
of pharmaceuticals for the treatment of pain and associated
inflammation,15 as well as being implicated in other disease areas.16
Furthermore, enantioenriched R-aryl carbonyl compounds are
versatile building blocks for a wide range of synthetic applications.
Therefore, we next examined the compatibility of the reaction with
other diaryliodonium salts (Table 3).5 The unsymmetric diaryl
iodonium salts that are used in this process can be readily prepared
in a one-pot procedure from the corresponding aryl iodide and
mesitylene5,17 and are bench stable solids. Aryl groups displaying
halogens, electron-rich and electron-deficient substituents, and useful
functionality could all be introduced through this simple arylation
process (3lÀr). Transferring a fluoropyridine group proved challen-
ging, with only moderate yield and ee observed under a range of
reaction conditions (3s). We found that aryl groups bearing ortho-
methyl substituents gave a moderate yield of arylated product 3t, but
in low ee, suggesting that the enantiodetermining step is influenced
by the steric properties of the aryl group. Pleasingly, however, the less
sterically encumbered ortho-fluorophenyl group was transferred in
excellent ee (3u). When the new arylation process was conducted
on a larger scale, between silylketenimide 1a and diaryliodonium
salt 2n, we found that the catalyst loading could be reduced to 2
mol % while still affording 3v in 99% yield and 93% ee. Hydrolysis
of the oxazolidinone 3v completed a short synthesis of (S)-
ibuprofen in just three chemical transformations from commercial
materials and provides a versatile strategy for the preparation of
related molecules of therapeutic interest.18 We also demonstrated
the compatibility of different silylketenimides (1f, 1i) with other
diaryliodonium salts, forming the versatile products 3w and 3x in
high yield and ee.
In summary, we have developed a new transformation that
enables the R-arylation of N-acyloxazolidinones with diaryliodo-
nium salts.19 The reaction proceeds in high yield and enantios-
electivity and is catalyzed by a chiral copper(II)-complex derived
from a commercially available bisoxazoline ligand. We have
demonstrated that the catalytic enantioselective arylation has a
broad substrate scope, is operationally simple and scalable, and
can be applied to the synthesis of pharmaceuticals and their novel
analogues. In line with our original hypotheses,4 we currently
favor a copper(III)-mediated aryl transfer, although at this stage
we cannot rule out other mechanisms. Further investigations into
the mechanism and extension of this asymmetric catalytic
activation mode are ongoing and will be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and full
b
characterization are provided for all compounds, and crystallographic
information for 3k (PDF, CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
(11) Hydrolysis of the oxazolidinone in 3a with LiOH, H2O2 gave
2-phenylpropionic acid. Comparison of its optical rotation with an
authentic sample enabled us to establish the absolute configuration of
Corresponding Author
mjg32@cam.ac.uk.
the arylation products. We found that Cu(OTf)2 (R,R)ÀPh-bisoxazo-
3
line gave the (R)-stereocenter in 3a; by analogy we base the absolute
stereochemistry of arylated products 3aÀ3x on this assignment.
(12) Sanford and co-workers also used this approach in the Pd-
catalyzed arylation of C-H bonds, see:(a) Kalyani, D.; Deprez, N. R.;
Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330.
(b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234.
(13) We also found that no formation of products was observed in
the absence of the chiral copper catalyst 4c when the reaction was
conducted at 50, 70, or 90 °C.
’ ACKNOWLEDGMENT
We are grateful to the Marie Curie Foundation for fellowship
(to A.B.), Phillip & Patricia Brown for Next Generation Fellow-
ship (to M.J.G.) and studentship (A.E.W.), the EPSRC and ERC
for fellowships (M.J.G.), and Novartis and AstraZeneca for
unrestricted research donations. We acknowledge the EPSRC
Mass Spectrometry Service at the University of Swansea.
(14) The absolute configuration was determined by X-ray diffrac-
tion: CCDC 831502.
(15) Mack, D. J.; Brichacek, M.; Plichta, A.; Njardarson, J. T. Top 200
Pharmaceutical Products by Worldwide Sales in 2009; Department of
Chemistry, University of Arizona; http://cbc.arizona.edu/njardarson/
group/top-pharmaceuticals-poster.
(16) Woodman, T. J.; Wood, P. J.; Thompson, A. S.; Hutchings,
T. J.; Steel, G. R.; Jiao, P.; Threadgill, M. D.; Lloyd, M. D. Chem.
Commun. 2011, 47, 7332.
(17) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349,
2610.
(18) The gram-scale synthesis of (S)-ibruprofen using the highly
modular copper(II)-catalyzed enantioselective arylation highlights the
utility of the process for the preparation of useful quantities of drug-like
molecules of potential use in medicinal chemistry programmes.
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