Dibutyltin chloride hydride complex as a novel reductant for chemoselective reductive amination

Article abstract of DOI:10.1055/s-1998-1895

Imine-selective reducing agent Bu₂SnClH-HMPA (I) performed effective reductive amination of carbonyl compounds. Various functionalized amines could be prepared in a one-pot procedure. Noteworthy is that highly chemoselective reactions were achieved with the co-existence of other functionalities such as halogen, carbon-carbon double bond and hydroxyl groups.

Full text of DOI:10.1055/s-1998-1895

October 1998
SYNLETT
1081
Dibutyltin Chloride Hydride Complex as a Novel Reductant for Chemoselective Reductive
Amination
Ikuya Shibata, Toshihiro Suwa, Erika Sugiyama and Akio Baba*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, 2-1 Yamada-Oka, Suita, Osaka 565-0871, Japan
Fax: +81-6-879-7387; E-mail: baba@ap.chem.eng.osaka-u.ac.jp
Received 8 July 1998
Abstract: Imine-selective reducing agent Bu SnClH-HMPA (I)
2
performed effective reductive amination of carbonyl compounds.
Various functionalized amines could be prepared in a one-pot procedure.
Noteworthy is that highly chemoselective reactions were achieved with
the co-existence of other functionalities such as halogen, carbon-carbon
double bond and hydroxyl groups.
Reductive amination of aldehydes is one of the most convenient routes
to various secondary amines, in which three components of carbonyls,
1
amines and reductants are treated in one portion. By this procedure, a
wide range of functionalized amines can be prepared because
intermediate imines, in particular unstable ones, do not have to be
isolated. The choice of the reductant is very critical since the
undesirable reduction of the carbonyls must be depressed to form
intermediate imines. Sodium cyanoborohydride (NaBH CN) has been
3
2
used because of its wide applicability. However, there are some
drawbacks because of the requirement of excess amounts of amines and
inapplication to weak bases such as aromatic amines. To solve these
3
problems, modified borohydrides have been developed. However,
alternative metal hydride reagents have scarcely been focused so far. We
have provided a set of organotin hydrides by the introduction of a
halogen substituent or a ligand on the tin atom to achieve highly
4
chemoselective reductions of multifunctionalized substrates. The five-
5
coordinated tin hydride, Bu SnClH-HMPA (I), easily formed in situ
2
6
from Bu SnClH and HMPA, has been revealed to reduce imines even
in the presence of carbonyls. This high imine-selectivity indicates that
2
7
the reagent I would be a good candidate for the reductive amination. We
present here the first use of tin hydrides for reductive amination of
aldehydes and ketones under mild and neutral conditions (Scheme 1).
The characteristic features are as follows. 1) Effective reactions
proceeded in particular for the case using aromatic amines as starting
substrates. 2) Stoichiometric amounts of substrates and tin reductant
were adequate. 3) Co-existence of other functionalities was allowed in
the starting carbonyls 1 and amines 2.
not produced under these conditions. Instead of 2a, the use of more
weakly basic p-chloroaniline 2b also gave the corresponding secondary
amine 3ab in good yield (entry 2). Next, other aromatic aldehydes were
examined. In entry 3, the reducing system (I) did not affect the bromine
9
functionality at all, which is generally reducible by trialkyltin hydrides.
In the reaction of 1c, the hydroxy group on the aromatic ring did not
affect the reaction at all (entry 4). The reaction using 2-furylaldehyde 1d
also afforded the amine 3d (entry 5). In the case of aliphatic aldehyde
1e, the reactions proceeded smoothly to give N-alkyl arylamines 3ea and
3eb (entries 6 and 7). Unsaturated aldehyde 1f was converted to N-allyl
phenylamines 3f by the regioselective 1,2-addition to the intermediate
unsaturated imine (entry 8). Ketones were also reactive to give branched
amines. Cyclic ketone 1g gave 3g (entry 9). In the case of functionalized
ketones such as 1h and 1i, effective amination of the carbonyl group
took place to give 3h and 3i, where undesired side reaction such as ring
cleavage of epoxide did not proceed at all (entries 10 and 11).
Scheme 1
Table 1 summarizes the reductive aminations of various carbonyl
compounds by using Bu SnClH-HMPA (I). The three reagents, the tin
hydride I, carbonyl compound 1 and aniline 2a were successively added
to THF solvent. Initially, we examined the reductive aminations of
benzaldehyde 1a. The reaction with aniline 2a proceeded smoothly to
2
8
give the corresponding secondary amines, 3aa in good yield (entry 1).
Benzyl alcohol derived from the reduction of starting material 1a was

1082
LETTERS
SYNLETT
In this way, compared with NaBH CN, tin reagent I was especially
Matsuda, H. J. Org. Chem. 1992, 57, 4049. (c) Kawakami,
Shibata, I.; Baba, A.; Matsuda, H. J. Org. Chem.1993, 58,
7608.(d) Kawakami, T.; Shibata, I.; Baba, A. J. Org. Chem. 1996,
61, 82. (e) Kawakami, T.; Miyatake, M.; Shibata, I.; Baba, A.;
Matsuda, H. J. Org. Chem. 1996, 61, 376.
T.;
3
useful in the reaction using weakly basic aromatic amines. For the
formation of imine intermediates, promoters such as acids and
10
dehydrating agents were not necessary. Probably, tin reagent I not
only acted as a reductant of imino groups but also accelerated the
11
formation of imines. In all cases, highly chemoselective reactions
(5) By the addition of HMPA to Bu SnClH, a large upfield shift was
2
119
were achieved even with the co-existence of aryl halides, vinyl halides,
hydroxyl group, double bonds and epoxide functionalities.
Functionalized amines were prepared effectively in a one-pot procedure.
We are now further investigating the development of the reductant to
apply to a wide range of corbonyl compounds and amines.
detected in
Sn NMR spectra, which indicates the clear
formation of tin hydride I as a five coordinated complex.
Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda, H.;
Sonoda, N. J. Org. Chem. 1995, 60, 2677.
(6) Bu SnClH was prepared by the redistribution between Bu SnCl
2
2
2
and Bu SnH . Neumann, W. P.; Pedain, J. Tetrahedron Lett., 1964,
2
2
Acknowledgements. This work was financially supported by the Grant-
in-Aid for Scientific Research from Ministry of Education, Science and
Culture. Thanks are due to Mr. H. Moriguchi, Faculty of Engineering,
Osaka University for assistance in obtaining HRMS spectra.
5, 2461.
(7) Shibata, I; Suwa, T.; Moriuchi-Kawakami, T.; Tanizawa, D.;
Sugiyama, E.; Matsuda, H.; Baba, A. J. Org. Chem. 1998, 63, 383.
(8) Representative procedure is as follows. To the solution of
Bu SnH (0.5 mmol) and Bu SnCl (0.5 mmol) in 1 mL of THF
2
2
2
2
References and Notes
was added HMPA (1 mmol). The mixture was stirred at room
temperature for 10 min. To the solution were added 1a (1 mmol)
and aniline 2a (1 mmol), and the mixture was stirred at 0°C until
(1) Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic
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York, 1991; p. 25.
-1
the Sn-H absorption (1862 cm ) disappeared in the IR spectrum.
After quenching with MeOH (5 mL), volatiles were removed
under reduced pressure. The residue was subjected to column
chromatography (Fuji-gel FL100DX) eluting with hexane-EtOAc
(9:1) to give pure product 3aa.
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(11) Tin chloride, Bu SnCl catalyzes the formation of imines. Stetin,
2 2
C.; Jeso, de B.; Pommier, J. C. Syn. Commun. 1982, 496.