Solvent-free direct reductive amination by catalytic use of an organotin reagent incorporated on an ionic liquid

Article abstract of DOI:10.1039/b912697j

An organotin reagent supported on an ionic liquid was used as a highly effective catalyst (down to 0.1 mol%) for the direct reductive amination of aldehydes and ketones using PhSiH₃; this solvent-free method facilitates purification of the products, thus minimizing the contamination by tin.

Full text of DOI:10.1039/b912697j

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Solvent-free direct reductive amination by catalytic use of an organotin
reagent incorporated on an ionic liquidw
´
Phuoc Dien Pham, Philippe Bertus and Stephanie Legoupy*
Received (in Cambridge, UK) 26th June 2009, Accepted 8th September 2009
First published as an Advance Article on the web 22nd September 2009
DOI: 10.1039/b912697j
An organotin reagent supported on an ionic liquid was used as a
highly effective catalyst (down to 0.1 mol%) for the direct
reductive amination of aldehydes and ketones using PhSiH3;
this solvent-free method facilitates purification of the products,
thus minimizing the contamination by tin.
In the course of developing task specific ionic liquids
(TSILs),11 we became interested in investigating the use of
organotin reagents supported on ionic liquids.12 In this
communication, we report our initial results for the catalytic
activity of ionic liquid-supported organotin reagents in the
direct solvent-free reductive amination reaction mediated by
phenylsilane. The use of organotin reagents immobilized on
ionic liquids (non-volatile properties) would have the
combined advantages of minimizing the product contamination
by tin residues and making the purification easier, by distillation.
In a first experiment, the organotin reagent supported on
ionic liquid 112c was used to study the reductive amination of
benzaldehyde (2a) with aniline (3a) using the phenylsilane as a
reductant in stoichiometric quantities (Table 1). The results
show that a catalytic amount of organotin reagent (Table 1,
entry 2 vs. 1) is required to promote the reduction. The
organotin catalyst is highly efficient, as lowering the catalyst
loading (to 1, 0.5 and 0.1 mol%; entries 3–5, respectively) still
afford high conversions within an acceptable reaction time
(2 h). The product 4a was conveniently isolated by a short path
distillation from the crude mixture.
The amine functionality occupies a very important role in
organic chemistry due to its prominence in biological and
naturally occurring molecules, such as alkaloids, amino acids,
nucleic acids and many more. One-pot reductive amination
between carbonyl compounds and primary or secondary
amines is one of the most efficient routes available to obtain
highly substituted amines; however, the choice of a suitable
chemoselective reducing agent that favours reaction with
imines (or iminiums) over parent carbonyls is of vital
importance. Various boron-based reagents have been developed
for this task,1 including NaBH3CN2 and NaBH(OAc)3.3
However, these reagents require the use of an excess of amine
and acidic conditions. Among the other methods used, the
recent use of organotin-catalyzed reductive amination by
phenylsilane is promising, since under these neutral conditions,
carbonyl compounds are not reduced. In this area, Apodaca
and Xiao used a catalytic amount of Bu2SnCl2 (2 mol%),4
whilst Baba et al. have proposed the catalytic use of
Bu2SnClH–pyridine-N-oxide (up to 2 mol%) for the reductive
Having demonstrated the efficiency of this direct solvent-
free reductive amination in our model system, the applicability
of this process to range of differently substituted aldehydes
was then investigated using the optimised conditions
(0.1 mol% of 1). Variously substituted aromatic aldehydes
were reacted in presence of aniline to afford the secondary
amines in good yields (Table 2, entries 1–3). It should be noted
that even sterically demanding reactions proceed with high
conversion (entry 4). Interestingly, the one-pot reduction of
aliphatic aldehyde with aromatic amine gave the desired
products in high yield (entries 5 and 6) and, in contrast with
Apodaca’s system,4 benzylamine reacted very well with
amination of aldehydes.5 In addition, Kangasmetsa et al. used
¨
microwave conditions, but used a higher amount of catalyst
(10 mol%).6 It should be noted that purification of the amine
has been performed by chromatography, leading to possible
tin contamination of the products.
Triorganotin derivatives display great potential as reagents
for organic and radical chemistry,7 but their use has been
avoided for the synthesis of pharmacologically active substances
due to their toxicity and the difficulties of removing residues
from the products. Recently, efforts have been made to
overcome these problems, leading, for example, to the use
of solid-phase synthetic methods,8 phosphonium grafted
organotins9 and other modified organotin reagents10 in the
Stille coupling reaction, in allylation reactions and in radical
reactions (dehalogenation, cyclisation, etc.) but not in reductive
amination.
Table 1 Reductive amination of carbonyl 2a with amine 3a by
organotin reagent 1
Entry
1/mol%
Time/h
Yield (%)a
`
Laboratoire de Synthese Organique, UCO2M, UMR CNRS 6011,
b
1
2
3
4
5
0
2
1
0.5
0.1
24
2
2
2
2
—
Universite´ du Maine, Avenue Olivier Messiaen,
72085 Le Mans Cedex 9, France.
E-mail: stephanie.legoupy@univ-lemans.fr;
Fax: +33 2 43 83 39 02; Tel: +33 2 43 83 30 96
w Electronic supplementary information (ESI) available: Experimental
details and characterisation data for the compounds in the tables. See
DOI: 10.1039/b912697j
80
83
83
84
a
b
After distillation. Traces.
ꢀc
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Chem. Commun., 2009, 6207–6209 | 6207

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Table 2 Reductive amination of various aldehydes 2 with primary
amines 3
Table 4 Direct reductive amination of cyclohexanone
Yield
1/mol% Time/h (%)a
Entry R1
R2
7
Yield
Time/h (%)a
Entry R1 (2)
R2 (3)
4
1
2
3
4
(CH2)2O(CH2)2 (3d) 7a
N-phenylpiperazine (3h) 7b
0.5
0.5
0.1
0.1
8
10
2
64
65
82
89
1
2
3
4
5
6
7
8
9
Ph (2a)
(4-NO2)C6H4 (2b) Ph (3a)
(4-MeO)C6H4 (2c) Ph (3a)
Ph (3a)
4a
4b
4c
2
8
2
3
4
4
4
3
3
84
68b
83
80
73
88
86
89
82
Ph
Ph
H (3a)
Me (3f)
7c
7d
4
Ph (2a)
(2-t-Bu)C6H4 (3b) 4d
(2-t-Bu)C6H4 (3b) 4e
Ph (3a)
Bn (3c)
Ph (3a)
a
After distillation.
C7H15 (2d)
Cyclopentyl (2e)
Ph (2a)
Furan-2-yl (2f)
PhCHQCH (2g) Ph (3a)
4f
4g
4h
4i
that the reduction of isolated imine 8 to amine 4a has a low
conversion under anhydrous conditions. Indeed a low (11%)
yield of 4a was obtained compared to 84% yield under direct
reductive amination (entry 1, Table 5 vs. entry 5, Table 1),
confirming the important role of water in the reaction. When
the reduction of the imine was performed using 1 (0.1 mol%)
in the presence of one equivalent of water (Table 5, entry 2),
the desired amine was isolated in high yield, but with a longer
reaction time (12 h), confirming the important role of water in
the reaction. Additionally, the reduction of isolated imine did
not proceed in the absence of 1, either in the presence or
absence of water (Table 5, entries 3 and 4) showing that
PhSiH3 alone is not able to reduce the imine.
a
b
After distillation. The reaction was performed at 40 1C.
benzaldehyde (entry 7). The heterocyclic aldehyde 2f was also
used to afford 4h (entry 8) in excellent yield (89%). In the case
of cinnamaldehyde (entry 9), the reduction took place in good
yield (82%) without reduction of the CQC double bond. The
products obtained had minimal amounts of tin.13
These results prompted us to investigate the reduction of
benzaldehyde and various secondary cyclic and acyclic amines
using the same organotin reagent, 1 (Table 3). As above,
the reaction could not be promoted in the absence of the
organotin reagent (entry 1), whilst the reductive amination of
benzaldehyde with cyclic and acyclic secondary amines can be
achieved in good yield to afford the corresponding tertiary
amines as tin-free products, as measured by ICP-MS.13
In comparison with the reported tin-catalyzed methods,4–6
we were pleased to find that the direct reductive amination of
cyclohexanone proceeded successfully with a range of primary
and secondary amines to afford the corresponding amine
products, 7, in good yields (Table 4). However, the reaction
requires a higher amount of catalyst and a longer reaction
time when using cyclic amines (entries 1 and 2). In contrast,
the yields obtained with acyclic amines were increased
(entries 3 and 4).
On the basis of the above results, we propose the plausible
catalytic cycle described in Scheme 1. In a first step, the
treatment of organotin reagent 1 with phenylsilane results in
organotin hydride species I.14 Next, it is strongly possible that
imine or iminium salt intermediates are reduced by the
organotin moiety with the assistance of water to give the
corresponding amine and organotin hydroxide species II. In
the final stage, PhSiH3 reacts with II to regenerate the
organotin species I.15 The mechanism recently proposed by
Baba et al.5 for the reductive amination of primary amines
involving imine-coordinated tin species cannot be extended to
the reductive amination to secondary amines and therefore
cannot be applicable here.
In summary, we have developed an efficient method for the
reductive amination of aldehydes and ketones with various
primary and secondary cyclic and acyclic amines, to afford the
corresponding secondary and tertiary amines in high yields
under solvent-free conditions by using an organotin reagent
As already reported in the other tin-catalyzed reductive
amination of carbonyl compounds with silanes, we have found
Table 3 Reduction of benzaldehyde with secondary amines
Table 5 Reduction of isolated N-benzylidineaniline with phenylsilane
Yield
(%)a
Entry R1
R2
5
1/mol%
Time/h
Yield
(%)a
Entry
1/mol%
Additive
Time/h
b
1
2
3
4
5
(CH2)2O(CH2)2 (3d)
(CH2)2O(CH2)2 (3d)
(CH2)5 (3e)
Ph
Bn
0
18
2
2
2
4
—
5a
5b
5c
5d
0.1
0.1
0.1
0.1
78
76
82
82
1
2
3
4
0.1
0.1
0
None
2
12
24
24
11
81
0
Water (1 equiv.)
None
Water (1 equiv.)
Me (3f)
Bn (3g)
0
0
a
b
After distillation. Traces of 5a.
a
After distillation.
ꢀc
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6208 | Chem. Commun., 2009, 6207–6209

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´
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ꢀc
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Chem. Commun., 2009, 6207–6209 | 6209