COMMUNICATION
DOI: 10.1002/chem.201101668
One-Pot Synthesis of Chiral Aziridines by a Domino Reaction by Using
Desulfonylative Formation on the N-Tosyl Imine of Chloroacetaldehyde with
an Asymmetric Mannich Reaction as a Key Step
Yujiro Hayashi,* Tatsuya Urushima, Daisuke Sakamoto, Kou Torii, and
Hayato Ishikawa[a]
Aziridine is a versatile building block in organic synthesis
because of its facile transformation to other useful com-
pounds by ring-expansion and ring-opening reactions. Aziri-
dine is also found as a key structural unit in natural prod-
ucts. Thus, the development of an efficient method for the
preparation of chiral aziridines is synthetically important.[1]
There are several successful asymmetric, catalytic aziridina-
tions, such as nitrene addition to alkene and carbene addi-
tion to imine catalyzed by organometallic reagents. Organo-
catalysts[2] are known to catalyze aziridination, most of
which involve the reaction of a,b-enal or a,b-enone with hy-
droxyamine derivatives through an iminium ion intermedi-
ate.[3]
cause imines derived from chloroacetaldehyde possess a-hy-
drogens, their Mannich reaction is expected to be very diffi-
cult. Just recently, we have found that the asymmetric cata-
lytic Mannich reaction of imines derived from aliphatic alde-
hydes with a-hydrogens is catalyzed by diarylprolinol silyl
ether 1.[6,7] In this communication, we describe the successful
synthesis of chiral aziridine derivatives by an asymmetric
Mannich reaction catalyzed by 1, followed by intramolecular
cyclization in a one-pot operation.
Recently, we have reported the one-pot synthesis of chiral
b,g-epoxyaldehyde through uninterrupted sequential reac-
tions including an asymmetric aldol reaction of chloroacetal-
dehyde as a key step.[4] If the asymmetric Mannich reaction
of the imine derived from chloroacetaldehyde and unmodi-
fied aldehyde proceeds, followed by an intramolecular nu-
cleophilic substitution, a chiral aziridine derivative would be
generated (Scheme 1). The Mannich reaction of imines de-
rived from aliphatic aldehydes with a-hydrogens is thought
to be difficult because of the equilibrium between imine and
enamine,[5] and there are only four examples of the organo-
catalyst-mediated, asymmetric cross-Mannich reaction of an
unmodified aldehyde as the Mannich donor and imines de-
rived from aliphatic aldehydes with a-hydrogens.[5d,f,h] Be-
First, we chose N-(2-chloroethylidene)-p-toluenesulfona-
mide as the imine, which can be obtained from N-(2-chloro-
1-phenylsulfonylethyl)-p-toluenesulfonamide (7) by treat-
ment with a base. a-Amidosulfone 7 was prepared from an
aqueous solution of chloroacetaldehyde, p-toluenesulfona-
mide (TsNH2), and PhSO2Na·2H2O in aqueous formic acid
(Scheme 2).
Because all of the trials for the isolation of the desired
imine were unsuccessful as a result of its rapid degradation,
we investigated the domino reaction of the in situ desulfon-
AHCTUNGTREGyNNNU lative generation of N-Ts imine and the enantioselective
Mannich reaction.[8] The reaction was performed as follows:
organocatalyst, base, a-amidosulfone 7 and aldehyde were
all mixed together in the presence of solvent at 08C, and the
reaction mixture was stirred for 24 h. Because trifluorometh-
yl-substituted diarylprolinol silyl ether 1 gave good results in
Scheme 1.
[a] Prof. Dr. Y. Hayashi, T. Urushima, D. Sakamoto, K. Torii,
Dr. H. Ishikawa
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science, Kagurazaka, Shinjuku-ku
Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
Supporting information for this article is available on the WWW
Scheme 2.
Chem. Eur. J. 2011, 17, 11715 – 11718
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11715