DOI: 10.1002/chem.201501351
Communication
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Asymmetric Synthesis
Catalytic Enantioselective Reaction of a-Phenylthioacetonitriles
with Imines using Chiral Bis(imidazoline)–Palladium Catalysts
Masaru Kondo,[a] Natsumi Kobayashi,[a] Tsubasa Hatanaka,[b] Yasuhiro Funahashi,[b] and
Shuichi Nakamura*[a]
Abstract: The catalytic enantioselective reaction of a-phe-
nylthioacetonitriles with imines has been developed. The
reaction of various imines proceeds in good yields and di-
astereo- and enantioselectivities in the presence of chiral
bis(imidazoline)–palladium catalysts. The obtained prod-
ucts can be converted into b-aminonitrile or b-aminoa-
mide compounds without loss of enantiopurity.
Scheme 1. Enantioselective reaction of a-phenylthioacetonitriles with imines
in the presence of palladium catalyst.
The development of catalytic enantioselective CÀC bond form-
ing reactions is an important topic in organic chemistry. In par-
ticular, the reaction of imines with nucleophiles, which can be
easily transformed into various functional groups, has attracted
a great deal of interest, as it provides efficient access to various
chiral amine derivatives.[1] In this context, a-carbanions of a-
thioacetonitriles, which are well known as cyanoalkyl anion
equivalents[2] and formyl anion equivalents,[3] are powerful
building blocks for the preparation of synthetically useful
chiral compounds. Although the racemic reaction of a-thioace-
tonitriles with electrophiles were reported,[4] there are no re-
Figure 1. Biologically active compounds incorporating the a-thio-b-amino-
acetonitrile moiety.
ports on enantioselective reactions using a-thioacetonitriles as
nucleophiles.[5] Recently, we developed an efficient activating
minidase inhibitor,[8] b-lactamase inhibitor,[9] and botulinum
neurotoxin inhibitor (Figure 1).[10]
method for nitrile compounds and a highly enantioselective re-
action of a-carbanions of nitriles with imines by using palladi-
um pincer complexes with 1,3-bis(imidazolin-2-yl)benzene
(Phebim) ligand.[6,7] Herein, we report the first highly enantiose-
lective reaction of a-phenylthioacetonitriles with imines using
bis(imidazoline)–palladium pincer complexes as a chiral Lewis
acid catalyst (Scheme 1).
We first examined the enantioselective reaction of a-phenyl-
thioacetonitrile 2a (1.5 equiv) with various imines 1a–c by
using 5 mol% of palladium catalysts 4a–e and AgOAc at 08C
(Table 1).
Although the reaction of 2a with N-Boc or N-diphenylphos-
phoryl (DPP) imines 1b or c afforded products 3b and c in low
yield (Table 1, entries 2 and 3), the reaction with N-(p-toluene-
sulfonyl)imine 1a gave product 3a in high yield with good
enantioselectivity but with low diastereoselectivity (Table 1,
entry 1). Encouraged by this result, we next investigated the
effect of the catalyst structure on stereoselectivity. The reaction
using bis(imidazoline)–palladium catalysts 4b–e, with R2 =me-
sityl or 1-naphthyl and R1 =acetyl or p-tosyl, afforded product
3a with better diastereo- and enantioselectivity than that from
the reaction using 4a (Table 1, entries 4–7). Catalyst 4b
emerged as the most suitable catalyst for this reaction, yielding
product 3a in good yield and stereoselectivity (80% yield,
d.r.=93:7, 96% ee; Table 1, entry 4). The reaction in the pres-
ence of silver acetylacetonate (Ag(acac)) instead of AgOAc was
carried out at À308C, giving 3a in high yield with high diaster-
eo- and enantioselectivity (Table 1, entry 8). Furthermore, the
The coordination of palladium to cyanides in a-phenylthio-
acetonitriles enhances their acidity of the a-proton, followed
by the reaction of a-cyano carbanions with imines, giving
chiral a-thio-b-aminoacetonitriles, which are precursors for
some biologically active compounds, such as influenza neura-
[a] M. Kondo, N. Kobayashi, Prof. Dr. S. Nakamura
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5245
[b] Prof. Dr. T. Hatanaka, Prof. Dr. Y. Funahashi
Department of Chemistry, Graduate School of Science
Osaka University
1-1 Machikaneyama, Toyonaka, Osaka 560-0043 (Japan)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 1 – 6
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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