COMMUNICATION
The reductive amination of aldehydes and ketones by catalytic use of
dibutylchlorotin hydride complex{
Hirofumi Kato,a Ikuya Shibata,*b Yuta Yasaka,b Shinji Tsunoi,b Makoto Yasudaa and Akio Baba*a
Received (in Cambridge, UK) 25th July 2006, Accepted 14th August 2006
First published as an Advance Article on the web 29th August 2006
DOI: 10.1039/b610614e
system that is applicable to a wide range of carbonyls and amines,
including aliphatic examples, under mild conditions (Scheme 1).
Initially, we examined hydride sources and additives in reductive
aminations using a catalytic amount of Bu2SnClH, as shown in
Table 1. Triethylsilane (Et3SiH) did not give the desired amine 3a
in satisfactory yield (Table 1, entry 1). In contrast, diphenylsilane
(Ph2SiH2) completed the reaction within 15 min to afford 3a in
89% yield (Table 1, entry 2). The yields of 3a and 3b were increased
to quantitative by the addition of only 2 mol% of HMPA (Table 1,
entries 3 and 4). A similar effect to HMPA has been observed in
the equimolar reaction.5 However, because the use of hazardous
HMPA should be avoided, we investigated the affect of other
additives, such as DMPU, DMF and phosphine oxides. While
these additives did not give satisfactory results, pyridine N-oxide
worked well, giving amine 3b in 94% yield when combined with
PhSiH3 instead of Ph2SiH2 (Table 1, entry 6). Moreover, an
interesting effect was observed in the reaction with acetophenone
(1b). Although the system of Bu2SnClH–HMPA and PhSiH3 only
promoted the reaction of 1b with 58% yield (Table 1, entry 8), the
addition of pyridine N-oxide gave a higher yield of 89% (Table 1,
entry 9).
The reductive amination of aldehydes or ketones using Ph2SiH2
or PhSiH3 has been effectively promoted by the direct use of
Bu2SnClH–pyridine N-oxide as a catalyst; this method has
advantages in terms of its mild conditions and wide application
to various carbonyls and amines, including aliphatic examples.
The reductive amination of aldehydes and ketones is one of the
most useful routes to secondary amines, in which the three
components of carbonyl, amine and reductant are easily combined
in one pot.1 The advantage of this reaction is that there is no need
to isolate intermediate imines, in particular, in cases where
combinations of aromatic amines and aliphatic carbonyls would
give expectedly unstable imines. The choice of reductant is very
critical because the undesirable reduction of starting carbonyls
must be suppressed. A number of reducing agents have been
developed, sodium cyanoborohydride (NaBH3CN),2 sodium
triacetoxyborohydride (NaBH(OAc)3)3 and borane–pyridine
(BH3–Py)4 being the most commonly used. However, these
reagents have serious problems, requiring excess amounts of
starting amines and acidic conditions. We have already overcome
these problems by developing the Bu2SnClH system, which effects
the reductive amination with equimolar amounts of amines under
mild and neutral conditions.5,6 However, the use of aliphatic
amines caused the decomposition of the tin hydride. In addition,
an equimolar amount of environmentally hazardous tin reagent is
necessary, and so a catalytic application is desirable. Apodaca and
Xiao demonstrated reductive amination with phenylsilane
(PhSiH3) in the presence of a catalytic amount of Bu2SnCl2.7
More recently, Kangasmetsa and Johnson have improved the
same system by using microwave-assisted heating.8 They suggest
that Bu2SnClH, generated in situ, is an active species. However,
discussions on the effects of Bu2SnCl2 and by-product water are
unclear. Since Bu2SnClH has been already noted to be an elegant
reagent for reductive amination and easily available by redistribu-
tion between Bu2SnCl2 and Bu2SnH2, without forming any acidic
by-products,5 we have re-investigated the reaction by the direct use
of Bu2SnClH as the catalyst. Consequently, we found that the
addition of a small amount of pyridine N-oxide achieved a catalyst
Next, we applied the optimized system, using 2 mol% of
Bu2SnClH–pyridine N-oxide, to the reaction between aliphatic
ketones or aldehydes with amines (Table 2). In all entries, sub-
stoichiometric quantities of PhSiH3 performed the reactions, in
contrast to the microwave-assisted method that required two
equivalents of the silane to consume all the imine formed.8 This
result may indicate a different mechanism to the reduction. The
reductive amination of aliphatic ketones or aliphatic aldehydes
with aromatic amines readily took place to give high yields
(Table 2, entries 1–7). In particular, the reaction of the primary
aliphatic aldehyde 1g with 2a (Table 2, entry 7) demonstrates the
advantage of this catalyst system over the equimolar one because
only 30% yield of 3j was given, even with the stoichiometric use of
Bu2SnClH–HMPA. A stronger base, aliphatic amine 2c, could be
also applied without decomposition of the tin hydride and PhSiH3
(Table 2, entry 8), while facile decomposition of tin hydrides by the
amine has been reported.5 Even combinations of aliphatic ketone
and aliphatic amines were allowed, giving 3k and 3l (Table 2,
entries 8 and 9).
aDepartment of Applied Chemistry, Center for Atomic and Molecular
Technologies (CAMT), Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Fax: +81 6-6879-7387; Tel: +81 6-6879-7386
bResearch Center for Environmental Preservation, Osaka University,
2-4 Yamadaoka, Suita, Osaka 565-0871, Japan.
E-mail: shibata@epc.osaka-u.ac.jp; Fax: +81 6-6879-8978;
Tel: +81 6-6879-8975
{ Electronic supplementary information (ESI) available: Experimental
details, characterisation data and NMR spectra. See DOI: 10.1039/
b610614e
Scheme 1
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4189–4191 | 4189
Kato, Hirofumi
