Solvent-free one-pot reduction of imines generated in situ from aldehydes and aniline by tributyltin hydride on silica gel

Article abstract of DOI:10.1246/cl.2002.274

Imines generated in situ from aldehydes and aniline can be reduced using tributyltin hydride on silica gel under solvent-free conditions to provide the corresponding amines in good yields.

Full text of DOI:10.1246/cl.2002.274

274
Chemistry Letters 2002
Solvent-Free One-Pot Reduction of Imines Generated in situ from Aldehydes and Aniline
by Tributyltin Hydride on Silica Gel
Ryoichi Hiroi, Norikazu Miyoshi, and Makoto Wadaꢀ
Department of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,
1-1 Minamijosanjima, Tokushima 770-8502
(Received October 25, 2001; CL-011049)
Imines generated in situ from aldehydes and aniline can be
reduced using tributyltin hydride on silica gel under solvent-free
conditions to provide the corresponding amines in good yields.
Table 1. Reduction of imines prepared in situ from carbonyl
compounds and aminesa
One-pot reduction of imines prepared in situ from carbonyl
compounds and primary amines is one of the convenient routes to
various secondary amines.1 In exploring the reaction, various
modified borohydride derivatives including sodium cyanoboro-
hydride (NaBH3CN),2a,b sodium triacetoxy borohydride
(NaBH(OAc)3)2c and other ones2d,e have been developed.
However, owing to some drawbacks of the requirement of excess
amounts of amines and the overalkylation of product amines, it is
desirable to focus alternative metal hydrides except borohydride
derivatives for reductive amination of carbonyl compounds.
Tributyltin hydride (Bu3SnH) is widely used in organic
synthesis,3 and although the reducing ability of Bu3SnH is low, it
is well-known that Bu3SnH only reduces aldehydes and ketones
by using several accelerators such as high pressure,4 Lewis acids
or transition metal catalysts,5 high coordination of Bu3SnH with
HMPA or Bu4NF,6 and MeOH solvent.7 Most conventionally
used Bu3SnH systems can not be used for reductive aminations
because the reagent bears no selectivity for imines over carbonyl
compounds,6c;8 although most recently, reductive amination of
carbonyl compounds with primary ammonium salts was per-
formed by Bu3SnH in DMF at room temperature.9
Herein, we describe the synthetic utility of Bu3SnH reduction
on silica gel, namely, solvent-free one-pot reduction of imines
generated in situ from aldehydes and aniline by Bu3SnH on silica
gel.10
Needless to say, in general, imino group is less reactive than
carbonyl group, in fact, the reduction of pre-prepared benzalde-
hyde N-phenyl imine with Bu3SnH did not take place in organic
solvents except HMPA11 or without solvents. However, on the
basis of the enhancement of the reducing ability of Bu3SnH by
silica gel,12 we found that the reduction of pre-prepared
benzaldehyde N-phenyl imine using Bu3SnH proceeded at room
temperature on dried silica gel (Nacalai Tesque silica gel 60, 230–
400 mesh, 1200 mg, dried by heat gun in flask) without any
solvents to afford the corresponding phenyl benzyl amine in 70%
yield. In the continuation of this work, under the same reaction
conditions, the mixture of benzaldehyde and aniline on silica gel
was treated with Bu3SnH to give the product in 88% yield (Entry
2) as shown in Table 1, indicating that water produced in this
system seems to accelerate the reaction similarly to the case of
reduction of aldehydes with Bu3SnH on silica gel,12c;13 although
the yield decreased to 62% (Entry 1) when SiO2 (800 mg) was
used as shown in Table 1. Reductive amination of benzaldehyde
with aniline was achieved in quantitative yield (Entry 3) using
SiO2 (1600 mg).14
The reaction proceeded smoothly with aliphatic aldehydes as
well as aromatic aldehydes giving the expected products in good
yields (Entries 4, 5, 6, and 7). In the case of cinnamaldehyde, the
1,2-reduction took place exclusively in moderate yield (Entry 8).
It is noteworthy that the imine derived from 2-chlorobenzalde-
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
275
Synthesis,’’ ed. by B. M. Trost and I. Fleming, Pergamon, Oxford
(1991), Vol. 8, p 25.
hyde also reacted selectively with Bu3SnH in spite of having a
chloro group (Entry 9), although it is known that Bu3SnH can also
act as a dehalogenating agent.3 Secondary amine, N-methylanilne
was usable as a substrate and the corresponding tertiary amine
was obtained in moderate yield (Entry 10). Reductive amination
of acetophenone with aniline led to the product in 45% yield
(Entry 11). Unfortunately, the use of aliphatic primary amines
prevented the reductive amination from smooth reaction
proceeding. It seems that the aliphatic amines reduce the
availability of reaction sites on the silica gel because the basicity
of aliphatic amines is stronger than that of aniline.
2
3
a) R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc., 93,
2897 (1971). b) C. F. Lane, Synthesis, 1975, 135. c) A. F. Abdel-Magid,
K. G. Carson, B. D. Harris, C. A. Maryanoff, and R. D. Shah, J. Org.
Chem., 61, 3849 (1996). d) R. J. Mattson, K. M. Pham, D. J. Leuck, and
K. A. Cowen, J. Org. Chem., 55, 2552 (1990). e) A. Pelter and R. M.
Rosser, J. Chem. Soc., Perkin Trans., 1, 717 (1984).
a) W. P. Neumann, Synthesis, 1987, 665. b) M. Pereyre, P. J. Quintard,
and A. Rahm, ‘‘Tin in Organic Synthesis,’’ Butterworth, London (1987).
M. D. Castaining and A. Rahm, J. Org. Chem., 51, 665 (1986).
a) H. X. Zhang, F. Guibe, and G. Balavoine, Tetrahedron Lett., 29, 619
(1988). b) K. Kikukawa, H. Umekawa, F. Wada, and T. Matsuda, Chem.
Lett., 1998, 881. c) J. C. Cochran, B, S. Bronk, K. M. Terrence, and
H. K. Phillips, Tetrahedron Lett., 31, 6621 (1990).
4
5
Four experiments were performed in order to investigate the
mechanism of the reductive amination: 1) The reaction did not
take place at all on ODS-silica gel. 2) The imine from
benzaldehyde and aniline was obtained in quantitative yield on
silica gel. 3) Benzyl alcohol was not obtained at all in the
benzaldehyde (2.0 mmol)—aniline (1.0 mmol) reaction using
Bu3SnH (1.0 mmol). 4) No tin-containing compounds were
isolated when the extract was evaporated, indicating that they
were strongly bound to the silica gel. Our suggested reaction
mechanism is shown in Scheme 1. We propose that hydrogen
bonding between the imino group and the acidic silanol group
exerts the predominant activating effect, and a six-membered
transition state involving the silanol coordination to tin and
hydrogen bonding to the imino group can be invoked, allowing
the selective reduction of the imine to proceed smoothly. From a
synthetic perspective, our results indicate several synthetic
utilities of the present reaction: 1) The reaction is an organic
solvent-free reaction. 2) The chemoselective reaction is promoted
on the surface of silica gel without any additional catalysts, and no
side reaction such as the reduction of starting aldehyde or
overalkylation was detected. 3) A pre-prepared imine is not
necessary. 4) Isolation of the desired product is facilitated because
the used tin compound is trapped on silica gel. 5) Thus, the present
method offers considerable advantages in terms of simplicity and
high efficiency.
6
a) I. Shibata, T. Yoshida, A. Baba, and H. Matsuda, Chem. Lett., 1991,
307. b) I. Shibata, T. Yoshida, A. Baba, and H. Matsuda, Chem. Lett.,
1989, 619. c) I. Shibata and A. Baba, J. Syn. Org. Chem. Jpn., 56, 280
(1998).
J.-P. Quintard and M. Pereyre, J. Organometal. Chem., 82, 103 (1974).
Halogen substituted one such as n-Bu2SnClH-HMPA worked well in
the reductive aminations of various carbonyl compounds with aromatic
amines. I. Shibata, T. Suwa, E. Sugiyama, and A. Baba, Synlett, 1998,
1081.
7
8
9
T. Suwa, E. Sugiyama, I. Shibata, and A. Baba, Synlett, 2000, 556.
10 Organic reactions on supported reagents have recently received
considerable attention from synthetic chemists because of their high
efficiency, environmentally benign conditions, and convenient work-up
procedures.10a{10c In particular, silica gel has been shown to be the most
useful inorganic solid for effecting a variety of functional group
transformations.10d{10e a) ‘‘Supported Reagents: Preparation, Analysis,
and Application,’’ ed. by J. H. Clark, A. P. Kybett, and D. J.
Macquarrie, VCH, New York (1992). b) ‘‘Solid Supports and Catalysts
in Organic Synthesis,’’ ed. by K. Smith, Ellis Horwood, Chichester
(1992). c) ‘‘Catalysis of Organic Reactions by Supported Inorganic
Reagents,’’ ed. by J. H. Clark, VCH, New York (1994). d) T.
Nishiguchi, J. Syn. Org. Chem. Jpn., 51, 308 (1993). e) H. Kotsuki, T.
Shimanouchi, R. Oshima, and S. Fujiwara, Tetrahedron, 54, 2709
(1998).
11 T. Kawakami, T. Sugimoto, I. Shibata, A. Baba, H. Matsuda, and N.
Sonoda, J. Org. Chem., 60, 2677 (1995).
12 Recently, we reported solvent-mediated chemoselective reduction of
aldehydes using Bu3SnH in CH3OH, H2O-CH3OH, H2O-THF, or H2O
without additional catalysts.12a Consequently, we suggested that
hydrogen bonding to carbonyl group and tin had the predominant
activating effect to promote the reaction. These facts prompted us to try
the reaction on silica gel support because silica gel has many hydroxyl
groups in its structure as a form of silicic acid, a so-called Brꢀnsted
acid,12b and wefoundthe organicsolvent-freechemoselective reduction
of aldehydes using Bu3SnH and H2O supported on silica gel12c although
it had been reported that Bu3SnH had reduced aldehydes to give the
corresponding alcohols in the presence of a cyclohexane slurry of dried
silica gel.12d Thus, it was demonstrated that silica gel enhanced the
reducing ability of Bu3SnH. a) K. Kamiura and M. Wada, Tetrahedron
Lett., 40, 9059 (1999). b) A. Mckillop and D. W. Young, Synthesis,
1979, 401 and 481. c) K. Kamiura, N. Miyoshi, and M. Wada,
Unpublished results. We disclose the results in full elsewhere. d)
N. Y. M. Fung, P. Mayo, J. H. Schaule, and A. C. Weedon, J. Org.
Chem., 43, 3977 (1978).
Scheme 1.
This work was supported by a Grant-in-Aid for Scientific
Research (B)(No. 11554024) from the Ministry of Education,
Science, Sports and Culture, Japan. We are grateful to Mitsubishi
Chemical Corporation for the financial support of this project.
13 In the case of addition of water (for example, 2.0 equimolar amounts),
the yield decreased.
14 A typical procedure is described as follows: Bu3SnH (0.291 g,
1.0 mmol) was added at ambient temperature to a mixture of
benzaldehyde (0.106 g, 1.0 mmol) and aniline (0.930 g, 1.0 mmol) on
the dried silica gel (by heat gun, 1600 mg). The reaction mixture was
stirred at the same temperature for only 1 h, and then the organic
materials were extracted with diethyl ether (30 ml ꢁ 3). After evapora-
tion of the solvent, the residue was purified by thin-layer chromato-
graphy on silica gel (hexane: AcOEt ¼ 5 : 1) to afford the
corresponding product, benzyl phenyl amine (0.183 g, 100% yield).
This paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 75th birthday. We express our sincere
gratitude to Professor Teruaki Mukaiyama for his stimulating
guidance and encouragement.
References and Notes
1
R. O. Hutchins and M. K. Hutchins, in ‘‘Comprehensive Organic