Catalytic asymmetric hiyama cross-couplings of racemic α-bromo esters

Article abstract of DOI:10.1021/ja8009428

The first catalytic asymmetric cross-coupling of α-halo carbonyl compounds with aryl metal reagents has been developed, thereby generating synthetically useful α-aryl carboxylic acid derivatives in good enantiomeric excess. The method can also be applied to enantioselective alkenylation reactions. Copyright

Full text of DOI:10.1021/ja8009428

Published on Web 02/27/2008
Catalytic Asymmetric Hiyama Cross-Couplings of Racemic r-Bromo Esters
Xing Dai, Neil A. Strotman, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 6, 2008; E-mail: gcf@mit.edu
Table 1. Asymmetric Hiyama Reactions: Effect of Reaction
Enantioenriched R-aryl carboxylic acids are an important class
Parametersa
of target molecules, due in large part to their bioactivity.1 The
catalytic asymmetric cross-coupling of an R-halo acid derivative
with an aryl metal reagent represents a potentially attractive route
to this family of structures, but to date no progress has been
described toward the achievement of this objective. Indeed, until
recently there were virtually no examples of efficient arylations of
secondary R-halo carbonyl compounds by a Group 10 catalyst to
generate even racemic products.2 In this report, we establish that a
nickel/diamine catalyst accomplishes asymmetric Hiyama reactions
of R-bromo esters with aryl silanes to provide R-aryl esters in good
enantiomeric excess (ee) (eq 1).3,4
a The yield was determined by GC versus a calibrated internal
standard.
Table 2. Asymmetric Hiyama Reactions: Phenylations of
R-Bromo Estersa
In 2007, we reported that Ni/norephedrine is an effective catalyst
for Hiyama arylations of a variety of secondary R-halo carbonyl
compounds (e.g., eq 2).2 Unfortunately, the cross-coupling products
were essentially racemic (<5% ee).5
However, through adjustment of the reaction parameters, we
were able to develop a method that achieves stereoconvergent
asymmetric Hiyama couplings of R-halo esters with organosilanes
(e.g., Table 1, entry 1). The chiral ligand, fluoride activator, and
silane each plays an important role in determining the efficiency
of the cross-coupling process (entries 2-5), as does the steric
demand of R1 (entries 6-10). A good, but decreased, yield is
observed when the catalyst loading is lowered, with little change
in the ee (entry 11).
An array of racemic R-bromo esters can be cross-coupled with
PhSi(OMe)3 with good enantioselectivity in the presence of NiCl2‚
a All data are the average of two experiments. Isolated yields are reported.
b The 2,6-diisopropylphenyl ester was used.
glyme and diamine 1 (Table 2). The highest ee’s are obtained with
smaller alkyl substituents (e.g., Me f i-Bu; entries 1-4). In the
case of a bulky i-Pr group, relatively little of the desired product is
generated if a BHT ester is employed; use of a less hindered aryl
ester leads to cross-coupling, albeit in moderate ee (entry 5).
Functional groups such as esters, ethers, olefins, and unactivated
alkyl bromides are compatible with the reaction conditions (entries
6-10).6 It is noteworthy that both of the catalyst components are
air-stable and that the cross-couplings proceed at room temperature.
This method for catalytic asymmetric Hiyama reactions is not
limited to phenylations of R-bromo esters. Substituted aryl silanes,
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10.1021/ja8009428 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Asymmetric Hiyama Reactions: Arylations of R-Bromo
Estersa
knowledge, with regard to asymmetric cross-couplings of alkyl
electrophiles, there have been no prior reports of success with
organosilanes or with arylations/vinylations, nor have diamines been
employed as chiral ligands. Additional investigations are underway.
Acknowledgment. We thank Dr. Stefan Sommer for prelimi-
nary studies and Dr. Chudi Ndubaku for a helpful suggestion.
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
Merck Research Laboratories, and Novartis.
a All data are the average of two experiments. Isolated yields are
reported.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Table 4. Asymmetric Hiyama Reactions: Alkenylations of
R-Bromo Estersa
References
(1) For leading references to their pharmacology, see: Landoni, M. F.; Soraci,
A. Curr. Drug Metab. 2001, 2, 37-51.
(2) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed. 2007, 46,
3556-3558.
(3) For reviews of the Hiyama reaction, see: (a) Denmark, S. E.; Sweis, R.
F. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Dieder-
ich, F., Eds.; Wiley-VCH: New York, 2004; Chapter 4. (b) Hiyama, T.;
Shirakawa, E. Top. Curr. Chem. 2002, 219, 61-85.
(4) See the following for previous reports of catalytic asymmetric cross-
couplings of alkyl electrophiles. (a) R-Halo amides: Fischer, C.; Fu, G.
C. J. Am. Chem. Soc. 2005, 127, 4594-4595. (b) Benzylic halides: Arp,
F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483. (c) Allylic
halides: Son, S.; Fu, G. C. J. Am. Chem. Soc., ASAP. In each case, a
chiral pybox ligand and an alkylzinc reagent are employed.
(5) The susceptibility of R-aryl carbonyl compounds to racemization can
complicate the development of catalytic asymmetric methods for their
synthesis. For example, to date, highly enantioselective arylations of
enolates have been limited to the formation of quaternary stereocenters.
For an early study, see: Ahman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki,
M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919. For
leading references, see: Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 195-200.
(6) Notes: (a) In a gram-scale reaction, the cross-coupling illustrated in entry
1 of Table 2 proceeds in 80% yield and 90% ee. (b) The ee of the product
correlates linearly with the ee of the ligand. (c) The ee of the product is
constant during the course of the reaction. (d) In the absence of an
organosilane, no phenylation by TBAT is observed.
(7) Notes: Under our standard conditions, (a) a cross-coupling with (4-
CF3)C6H4Si(OMe)3 furnished racemic product, perhaps due to the lability
of the R stereocenter (in the case of aryl groups that are not electron-
poor, control experiments establish that racemization of the product does
not occur); (b) a reaction with (1-naphthyl)Si(OMe)3 was unsuccessful;
(c) (4-F)C6H4Si(OMe)3 underwent cross-coupling in moderate yield (44%)
and ee (63%).
a All data are the average of two experiments. Isolated yields are
reported.
including one that bears a benzylic chloride, undergo cross-coupling
in good ee (Table 3).7
Furthermore, the catalyst system can be applied without modi-
fication to highly enantioselective alkenylations of R-bromo esters
(Table 4). Thus, vinyltrimethoxysilane (entry 1), as well as more
substituted vinylsilanes (entries 2 and 3), can be employed as
coupling partners.8
The BHT ester can be reduced to a primary alcohol without
racemization (eq 3). If a carboxylic acid is desired, an oxidatively
cleavable aryl ester may be used (eq 4; see entry 10 of Table 1).9
In conclusion, we have developed the first catalytic asymmetric
cross-couplings of R-halo carbonyl compounds with aryl metal
reagents, thereby generating synthetically useful R-aryl carboxylic
acid derivatives in good ee; this method can also be applied
to enantioselective alkenylation reactions. To the best of our
(8) Under our standard conditions, n-hexyltrimethoxysilane and allyltri-
methoxysilane did not participate in asymmetric Hiyama cross-couplings
in good ee/yield.
(9) Hydrolysis of BHT esters generally requires vigorous reaction conditions.
For an example, see: Hattori, T.; Hayashizaka, N.; Miyano, S. Synthesis
1995, 41-43.
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