Enantioselective α-arylation of carbonyls via Cu(I)-bisoxazoline catalysis

Article abstract of DOI:10.1021/ja206050b

The enantioselective α-arylation of both lactones and acyl oxazolidones has been accomplished using a combination of diaryliodonium salts and copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction and retention of enolizable α-carbonyl benzylic stereocenters, a valuable synthon for the production of medicinal agents.

Full text of DOI:10.1021/ja206050b

COMMUNICATION
pubs.acs.org/JACS
Enantioselective r-Arylation of Carbonyls via Cu(I)-Bisoxazoline
Catalysis
James S. Harvey, Scott P. Simonovich, Christopher R. Jamison, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S Supporting Information
b
Scheme 1. Proposed Mechanism for Carbonyl r-Arylation
ABSTRACT: The enantioselective R-arylation of both
lactones and acyl oxazolidones has been accomplished using
a combination of diaryliodonium salts and copper catalysis.
These mild catalytic conditions provide a new strategy for
the enantioselective construction and retention of enoliz-
able R-carbonyl benzylic stereocenters, a valuable synthon
for the production of medicinal agents.
he enantioselective R-arylation of carbonyls has become a
T
mainstay transformation in chemical synthesis, primarily
driven by the research efforts of Buchwald and Hartwig.1,2 These
seminal studies have delivered a number of transition metal-
catalyzed protocols that directly produce quaternary carbon
stereocenters adjacent to a series of carbonyl moieties including
ketones, lactones, esters, imides, and amides. Slower to develop,
however, have been methods that enable the enantioselective
production of enolizable R-carbonyl benzylic stereocenters
(methine stereocenters), presumably due to the propensity for
postreaction racemization when elevated temperatures or basic
conditions are employed.3 Notable recent progress has been
made, however, through the work of (i) Fu and co-workers,4 who
have shown that nickel-catalyzed Kumada and Negishi couplings
can afford R-aryl carbonyl products with excellent enantiocontrol
(eq 1), and (ii) our own laboratory’s combined use of copper and
organic catalysis with iodonium salts for the direct asymmetric
R-arylation of aldehydes (eq 2).5
As an outgrowth of these latter studies, we postulated that a
broadly expanded array of carbonyl systems might be readily
accessible using chiral copper catalysts in the presence of
iodonium salts with silylketene acetals (eq 3). As a critical
advantage, this new mechanistic approach would allow access
to a range of carbonyl adducts that contain enolizable benzylic
stereocenters, a significant challenge for asymmetric arylation
chemistry. Herein, we describe the successful execution of these
ideals and present an operationally trivial protocol to generate
R-carbonyl methine-bearing stereogenicity without postreaction
racemization.
Design Plan. We elected to employ silylketene acetals and N,
O-aminals as suitable enolic substrates, given their synthetic
accessibility6 and well-established capacity to combine with
electrophilic coupling partners.7 As outlined in Scheme 1, we
proposed that oxidative insertion of a ligand-bound copper(I)
complex into a suitable diaryliodonium salt8 would result in a
highly electrophilic chiral copper(III) species,9,10 which would be
intercepted by the silylated nucleophile. Subsequent reductive
elimination and silyl hydrolysis yields the desired R-arylated
Received: July 1, 2011
Published: August 17, 2011
r
2011 American Chemical Society
13782
dx.doi.org/10.1021/ja206050b J. Am. Chem. Soc. 2011, 133, 13782–13785
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Evaluation of CuBox Catalysts and Iodonium
Counterions
Table 2. Scope of the Iodonium Aryl-Coupling
Componenta,b
entry
catalyst
none
X
temp (°C)
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8c
OTf
OTf
OTf
OTf
OTf
PF6
PF6
PF6
23
23
23
23
23
23
0
0
77
<2
60
77
98
98
98
(CuOTf)2PhMe
1
2
3
3
3
3
59
87
89
91
93
0
a NMR yield. b Determined by chiral HPLC analysis, absolute config-
uration determined by chemical correlation or by analogy. c Performed
with 1:1 toluene/CH2Cl2. Ox = oxazolidone.
carbonyl product and regenerates the copper(I) catalyst. As was
the case with our previous organocatalytic studies, we recognized
that aryliodonium salts are nontoxic, readily accessible, and air
and moisture stable, valuable characteristics with respect to the
development of a broadly useful transform.8c
From the outset, we rationalized that bidentate coordination at
copper would be important to facilitate high levels of enantios-
electivity. As such, we sought to incorporate an N-acyl oxazoli-
done into our substrates that would both act as a directing group
for copper and as a latent source of functionality for further
transformations.11
a Absolute configuration assigned by chemical correlation or by analogy.
b Enantiomeric excess determined by chiral HPLC analysis of the
isolated product. c Performed at 0 °C. d Symmetrical diaryliodonium
hexafluorophosphate was used. Ox = oxazolidone.
As shown in Table 1, we were delighted to find that exposure
of the propyl oxazolidone-derived silylketene N,O-aminal to
diphenyliodonium triflate in the presence of 5 mol % (CuOTf)2-
PhMe, produced the corresponding R-arylation adduct in high
yield (entry 2, 77% yield).12 Although previous reports have
demonstrated that silylenol ethers can undergo direct arylation
using noncatalytic conditions with iodonium salts, we observed
no detectable reaction when our protocol was performed in the
absence of copper salts.13 With this validation of our catalysis
proposal in hand, we next turned our attention to the develop-
ment of an enantioselective variant via the examination of a series
of well-known chiral ligand sets.14 As revealed in Table 1, both
the isopropyl and phenyl substituted bisoxazoline (Box)15 de-
rived Cu(I) complexes (2 and 3, respectively) produced the
desired R-arylation product with useful efficiency (60À77%
yield); however, notably superior levels of enantiocontrol were
observed with catalyst 3 (87% ee). Changing the iodonium salt to
the corresponding PF6 counterion, using a mixed medium
(CH2Cl2/toluene) and lowering the reaction temperature to
0 °C, resulted in further improvements to provide the R-phenyl
oxazolidone product in 98% yield and 93% ee, a protocol that was
employed in subsequent scope studies.
As outlined in Table 2, we have found that a broad range of aryl
and heteroaryl rings can be enantioselectively coupled with
silylketene acetals using this Cu(I)Box-mediated technology.
While symmetrical diaryliodonium triflates can be successfully
employed in this context, we have found that the more practical
approach of Gaunt to generate ArÀCu(III)-XY systems from
nonsymmetrical aryl-mesityl reagents is preferred.9b Both elec-
tron-deficient (entries 2À3 and 11, 80À96% yield, 91À95% ee)
and electron-rich arenes (entries 4À5 and 10, 89À96% yield,
90À94% ee) were found to be suitable coupling partners. More-
over, a broad range of meta- and para-substituted aryl rings
with diverse steric and electronic properties (ethers, esters, and
halides) can be readily exploited in this protocol (entries 2À4, 6,
13783
dx.doi.org/10.1021/ja206050b |J. Am. Chem. Soc. 2011, 133, 13782–13785

Journal of the American Chemical Society
COMMUNICATION
Table 3. Scope of the Silylketene Acetal Coupling
Componenta,b
We have also found that this R-arylation protocol is tolerant of
enolic coupling partners that display a wide range of functional
groups, including arenes and olefins (Table 3, entries 7À11, 83À
95% yield, 88À95% ee) as well as ethers, esters, and carbamates
(entries 3, 9À11, 91À94% yield, 91À93% ee). Notably, our mild
R-arylation strategy is fully selective for the enolic R-position in
the presence of other nucleophilic heterocycles such as indoles
(entry 13, 65% yield, 89% ee), a system that has previously been
shown to undergo arylation in the presence of similar Cu(III)aryl
intermediates.9a Importantly, sterically demanding β-branched
substrates are accommodated with little effect on yield or enan-
tioselectivity (entry 4À6, 74À90% yield, 84À92% ee). Finally,
other nonoxazolidone-based nucleophiles readily undergo cou-
pling via this procedure in high yield and selectivity (entries 12,
14À15, 76À89% yield, 88À91% ee).
To further demonstrate the value of this new R-arylation
strategy, we implemented this technology in a unique and expe-
ditious route to a known oral nonsteroidal anti-inflammatory
medicinal agent ((S)-naproxen, see Supporting Information).
This demonstration reveals that a variety of similar drug-like
molecules could be produced in a rapid and enantioselective
fashion for the purposes of medicinal agent testing.16
In conclusion, we have developed a new technology that
allows the direct and enantioselective R-arylation of enolate equi-
valents using a readily available catalyst from commercial sources.
Further investigations into (i) the mechanism of this transforma-
tion and (ii) developing models for induction are currently
underway in our laboratory.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
’ ACKNOWLEDGMENT
This manuscript is dedicated to Professor D. A. Evans on the
occasion of his 70th birthday. Financial support was provided by
NIHGMS (R01 GM078201-05) and kind gifts from Merck,
Amgen, Abbott Research Laboratories, and Bristol-Myers Squibb.
a Absolute configuration assigned by chemical correlation or analogy.
b Enantiomeric excess determined by chiral HPLC analysis. c Performed
at 23 °C. d Reaction performed at À5 °C with CH2Cl2/toluene (2:1) as
solvent. e Performed at À10 °C with CH2Cl2/toluene (2:1). f 25 mol % 3
CH2Cl2/toluene (2:1). i Performed at À20 °C. j Mesityl iodonium
hexafluorophosphate was employed. k Performed at À10 °C. Ox =
oxazolidone.
’ REFERENCES
g
employed at 10 °C. Performed at À10 °C. h Performed at 5 °C with
(1) For racemic R-arylation of carbonyl compounds using Pd
catalysis see:(a) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999,
40, 2355. (b) Martín, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007,
46, 7236. (c) Vo, G. C.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008,
47, 2127.
(2) For asymmetric R-arylation of carbonyl compounds, see:(a)
García-Fortanet, J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,
47, 8108. (b) Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2009, 131, 9900. (c) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 195. (d) Hartwig and Liu have constructed R-methine
stereogenic centers using a chiral auxiliary:Liu, X.; Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 5182.
10À11, 80À96% yield, 90À95% ee). It is important to note that
the iodonium moiety is chemoselectively targeted by the copper
catalyst in preference to other halogen substituents (entry 6).
In addition to aryl rings, we were delighted to find that hetero-
aromatic systems such as thiophenes and indoles were suitable
coupling partners (entries 9 and 12, 75À88% yield, 90À94% ee),
a useful outcome given the utility of these systems within the
realm of medicinal agent discovery.
(3) Alemꢀan, J.; Cabrera, S.; Maerten, E.; Overgaard, J.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2007, 46, 5520.
13784
dx.doi.org/10.1021/ja206050b |J. Am. Chem. Soc. 2011, 133, 13782–13785

Journal of the American Chemical Society
COMMUNICATION
(4) (a) Dai, X.; Strotman, N. A.; Fu, G. C. J. Am. Chem. Soc. 2008,
130, 3302. (b) Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int.
Ed. 2009, 48, 154. (c) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 1264. (d) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11027.
(5) (a) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011,
133, 4260. (b) For examples of R-carbonyl arylation via SOMO
catalysis see:Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2009, 131, 11640.
(6) (a) Yu, J.-Q.; Wu, H.-C; Corey, E. J. Org. Lett. 2005, 7, 1415. (b)
Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem.
Soc. 2005, 127, 3774.
(7) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. L. Chem. Rev.
2002, 102, 2227.
(8) For reviews on diaryliodonium salts, see:(a) Merritt, E. A.;
Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.(b) Varvoglis, A.
The Organic Chemistry of Polycoordinated Iodine; VCH Publishers: New
York, 1992. (c) Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315.
(9) For examples of copper-catalyzed arylation reactions, see:(a)
Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172. (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (c)
Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2011, 50, 463. (d) Ryan, J. H.; Stang, P. J.
Tetrahedron Lett. 1997, 38, 5061.
(10) For studies on the mechanism of copper-catalyzed
arylation, see:(a) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940.
(b) Beringer, F. M.; Geering, E. J.; Kuntz, I.; Mausner, M. J. Phys. Chem.
1956, 60, 141.
(11) Boyd, E.; Coulbeck, E.; Coumbarides, G. S.; Chavda, S.;
Dingjan, M.; Eames, J.; Flinn, A.; Motevalli, M.; Northen, J.; Yohannes,
Y. Tetrahedron Asymm 2007, 18, 2515.
(12) A range of other Lewis acids including Pd(OAc)2, AuCl PPh3,
3
AgOTf, Ni(OTf)2, Sc(OTf)3, and Zn(OTf)2 gave <2% product.
(13) Typically noncatalytic processes require the use of fluoride ion
or equivalent, see:(a) Chen, K.; Koser, G. F. J. Org. Chem. 1991,
56, 5764. (b) Iwama, T.; Birman, V. B.; Kozman, S. A.; Rawal, V. H.
Org. Lett. 1999, 1, 673.
(14) A range of other chiral ligands were employed all of which
resulted in lower selectivity and or reactivity than bisoxazoline derived
ligands, e.g. BINOL (41% yield, 25% ee), DIOP (<2% yield)
(15) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(b) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am.
Chem. Soc. 2001, 123, 4480. (c) Evans, D. A.; Johnston, J. N. Org. Lett.
1999, 1, 865. (d) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 5985.
(16) By demonstrating a new and rapid route to (S)-naproxen via
enantioselective catalysis, we do not to intend to infer that this would be
a competitive process for the known manufacturing route. Instead we
illustrate this synthesis as a useful strategy to generate R-aryl carbonyl
containing drug-like molecules for implementation in medicinal-agent
testing programs.
(17) During the course of this work, we became aware that the Gaunt
lab at Cambridge University were involved in similar studies. The Gaunt
group graciously agreed to publish their results in a back-to-back format
with our own results. We thank them for their collegiality and generosity.
13785
dx.doi.org/10.1021/ja206050b |J. Am. Chem. Soc. 2011, 133, 13782–13785