Asymmetric alkynylation of aldehydes catalyzed by an In(III)/BINOL complex

Article abstract of DOI:10.1021/ja053946n

Asymmetric alkynylation of both aromatic and aliphatic aldehydes using catalytic amounts of In(III)/BINOL is described. Dual activation of both substrates due to the "bifunctional character" of the indium(III) catalyst enables a broad range of substrate generality with high enantioselectivity (83 to > 99% ee). Copyright

Full text of DOI:10.1021/ja053946n

Published on Web 09/20/2005
Asymmetric Alkynylation of Aldehydes Catalyzed by an In(III)/BINOL Complex
Ryo Takita, Kenichiro Yakura, Takashi Ohshima,† and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received June 15, 2005; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. InBr3/BINOL ComplexsCatalyzed Asymmetric
Alkynylation of Various Aldehydes
The alkynylation of aldehydes is one of the most useful carbon-
carbon bond-forming reactions because of the versatility of the
corresponding propargylic alcohols.1a There are highly enantio-
selective alkynylations of aldehydes that use stoichiometric amounts
of corresponding metal reagents, such as organolithium and
organozinc reagents, with catalytic amounts of chiral ligands or
chiral Lewis acids.1 Given the recent strong demand for an
environmentally benign process with high total efficiency, the in
situ catalytic generation of metal nucleophiles and their use in
carbon-carbon bond-forming reactions is currently a major interest
in organic synthesis.2,3a Thus, the use of only catalytic amounts of
chiral metal salts to achieve truly catalytic asymmetric reactions
using terminal alkynes directly as a substrate is eagerly anticipated.
Carreira and co-workers reported the first sophisticated example
of a catalytic system of Zn(OTf)2, N-methylephedrine, and Et3N,
giving the corresponding products in a highly enantioselective
manner.3 Aromatic aldehydes, however, cannot be used in this
catalytic system due to the Cannizzaro reaction.3a Herein, we
describe a catalytic asymmetric alkynylation of both aromatic and
aliphatic aldehydes promoted by a chiral In(III)/BINOL complex.
We previously reported a new catalytic system for the alkynyl-
ation of aldehydes and ketones with the combination of indium(III)
salts and i-Pr2NEt.4,5 This catalytic system was developed based
on our concept of bifunctional catalysis, such as heterobimetallic
catalysis and Lewis acid-Lewis base catalysis.6 As a new entry of
bifunctional catalysts, we focused on the “bifunctional character”
of indium(III), which acts as both a hard Lewis acid7 and an
effective activator of alkynyl groups.8 That is, the success of this
catalysis is attributed to the dual activation of soft nucleophiles
(alkynes) and hard electrophiles (carbonyl compounds) by in-
dium(III) salts. The dual activation was successfully confirmed by
in situ IR and NMR spectroscopic studies.4 The effective activation
of both substrates enables the reaction to proceed under very mild
conditions for a broad range of substrates, including ketones. These
fascinating results prompted us to further develop asymmetric
variants to produce versatile optically active propargylic alcohols.
Initial studies on the development of the asymmetric reaction
conditions revealed that the use of BINOL as a chiral ligand had
high enantioselectivity in the addition of phenylacetylene (2a) to
cyclohexanecarboxaldehyde (1a); in the presence of 10 mol % of
InBr3,9 10 mol % of (R)-BINOL10 (1:1 ratio), and 50 mol % of
i-Pr2NEt in CH2Cl2 at 40 °C, the propargylic alcohol 3aa was
obtained in 96% ee, although the chemical yield was moderate
(46%, after 7 h). Further optimization of reaction conditions led to
the finding that the use of Cy2NMe instead of i-Pr2NEt effectively
accelerated the reaction,11,12 giving the product in 84% yield and
98% ee (after 7 h).
a Aldehyde 1c was slowly added over 22 h. b The reaction was performed
under air atmosphere. c InBr3 (2 mol %), (R)-BINOL (2 mol %), and
Cy2NMe (10 mol %) were used (10 M CH2Cl2).
The generality of this catalytic system (10 mol % of InBr3 and
(R)-BINOL, and 50 mol % of Cy2NMe in CH2Cl2 at 40 °C) was
examined, as summarized in Table 1. Even using the less reactive
alkylacetylene 2b instead of phenylacetylene (2a), good chemical
yield was obtained with excellent enantioselectivity (entry 2),
although a longer reaction time was required. The reaction with
isovaleraldehyde (1b) also proceeded under the same conditions,
† Current Address: Department of Chemistry, Graduate School of Engineering
Science, Osaka University.
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J. AM. CHEM. SOC. 2005, 127, 13760-13761
10.1021/ja053946n CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
well as further investigations, including catalytic alkynylation of
ketones, are ongoing.
Acknowledgment. This work was supported by Grant-in-Aid
for Encouragements for Young Scientists (A), and Grant-in-Aid
for Specially Promoted Research from JSPS and MEXT. R.T.
thanks the JSPS Research Fellowship for Young Scientists.
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
Figure 1. (+)-Nonlinear effects in asymmetric alkynylation catalyzed by
(1) For reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2004, 4095. (b) Pu, L. Tetrahedron 2003, 59, 9873.
(2) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
13632 and references therein.
an In(III)/BINOL complex.
and the corresponding products were obtained with high enantio-
meric excess (entries 3 and 4). Even for the very easily enolizable
aldehyde, hydrocinnamaldehyde (1c), slow addition of the aldehyde
prevented side reactions, such as self-condensation, providing the
desired product in good yield and excellent enantioselectivity (entry
5).
(3) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. (b)
Fa¨ssler, R.; Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc. Natl.
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Furthermore, the optimized conditions were also applicable to
aromatic aldehydes, which are quite challenging substrates for
existing catalytic systems due to a competitive Cannizzaro reaction.
The addition of phenylacetylene (2a) to benzaldehyde (1d) pro-
ceeded smoothly to give the corresponding product 3da in 84%
yield and 95% ee after 24 h. The use of the alkyl- and alkenyl-
acetylenes also produced high enantioselectivity (entries 7-9). In
addition, benzaldehyde derivatives with the electron-donating
substituent or electron-withdrawing substituent gave satisfactory
yields and high enantioselectivity (entries 10-12). Heteroaromatic
aldehydes, such as 3-furaldehyde (1g) or 3-thiophenecarboxaldehyde
(1h), can also be utilized as electrophiles (entries 13 and 14). The
use of trimethylsilylacetylene or 3-trimethylsiloxy-1-propyne as an
alkyne has been unsuccessful. It is noteworthy, however, that this
catalytic system has broad generality for both aromatic and aliphatic
aldehydes, as well as phenylacetylene, alkenylacetylenes, and
alkylacetylenes.
The reaction proceeded under air atmosphere, giving the pro-
pargylic alcohol 3da in comparable yield and enantioselectivity
(entry 15). The catalyst loading could also be decreased, and 2 mol
% of InBr3, (R)-BINOL, and 10 mol % of Cy2NMe provided 3da
in 85% yield and 96% ee after 48 h (entry 16).
On the basis of the previous mechanistic studies,4 dual activation
of both substrates is crucial, even in this asymmetric catalytic
process. The precise mechanism, however, is not clear, especially
whether one or two indium metals are involved in the reaction.
When the reaction was performed using nonenantiopure BINOL,
rather strong positive nonlinear effects13 were observed between
the enantiomeric excess of BINOL and the product (Figure 1),
suggesting that the bimetallic mechanism is involved in the catalytic
cycle.14
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(9) InBr3 used in this manuscript was purchased from Aldrich.
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(11) The use of other amines (i.e., Et3N, pentamethylpiperidine, diisopropyl-
amine, TMEDA, and pyridine) gave less satisfactory results.
(12) For recent representative examples of the beneficial effects of Cy2NMe
in metal-catalyzed enantioselective reactions, see: (a) Imbos, R.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 184. (b) Lo, M. M.-
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(14) The monometallic mechanism cannot be completely excluded by only
positive nonlinear effects. For the proposed bimetallic or monometallic
mechanism, see Supporting Information.
In conclusion, we developed a catalytic asymmetric alkynylation
of aldehydes promoted by the In(III)/BINOL complex and Cy2NMe.
Dual activation of both substrates due to the “bifunctional character”
of In(III) would make possible a broad range of substrate generality
with high enantioselectivity. More precise mechanistic studies as
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