dibutyltin dichloride enabled reductive amination of this
ketone at a rate comparable to that of the other substrates
of this behavior, control reactions were performed in the
absence of catalyst and carbonyl compound. Addition of
phenylsilane to a solution of cyclohexylamine in THF
resulted in mild gas evolution and some phenylsilane
decomposition. This effect was much more pronounced when
phenylsilane was added to a solution of cyclohexylamine
and 1 equiv of water in THF. Alkylamine-promoted oxidation
of phenylsilane with the water produced from imine con-
densation may play a role in the lack of reductive amination
observed with cyclohexylamine and benzylamine.21
(entry 13).
Reductive amination of 4-methoxybenzaldehyde with
primary and secondary alkylamines was also examined
Table 3). Reactions with both cyclic and acyclic secondary
(
Table 3. Direct Reductive Amination Using Alkylaminesa
Imines are in some cases reduced by the same reductants
2
2
used in direct reductive aminations. To examine this
possibility, N-benzylidineaniline was treated with phenyl-
silane under various conditions (Table 4). In the presence
yield, %b
Table 4. Reduction of N-Benzylidineaniline with Phenylsilane
entry
amine
piperidine
1
2
3
4
5c
6
7
70
78
67
49
13d
e
morpholine
N-phenylpiperazine
diethylamine
piperidine
cyclohexylamine
benzylamine
entry Bu SnCl , mol % additive (equiv) time, h yield, %a
2
2
1
2
3
4
2
none
water (1)
none
19
4
19
19
nr
89
nr
nr
e
2
0
0
a
Because of exothermicity, reactions were performed with cooling from
b
a room temperature water bath and dropwise phenylsilane addition. Isolated
water (1)
c
yield of chromatographed, analytically pure product. Reaction was
d
1
a
performed in the absence of Bu2SnCl2.
H NMR of the crude reaction
mixture revealed remaining aldehyde and fully decomposed phenylsilane.
H NMR of the crude reaction mixture showed imine formation and
Isolated yield of chromatographed product. Reactions were monitored
for completion by 1H NMR of the crude mixture: nr ) less than 5%
conversion.
e
1
phenylsilane decomposition.
of 2 mol % of dibutyltin dichloride, only trace reduction,
with no detectable decomposition of phenylsilane, was
observed (entry 1). In an attempt to duplicate the exact
conditions of the direct reductive amination reaction, imine
reduction was performed in the presence of both dibutyltin
dichloride and 1 equiv of water (entry 2). Complete
consumption of the imine was observed, and the secondary
amine product was isolated in good yield. No reaction
occurred in the absence of dibutyltin dichloride, either in
the presence or absence of water (entries 3 and 4).
amines gave the anticipated products in moderate yields
(entries 1-4). Interestingly, reductive amination with pip-
eridine also proceeded in the absence of dibutyltin dichloride,
although in significantly lower yield (entries 1 and 5). In
contrast, reactions with primary alkylamines gave the cor-
responding imines with complete consumption of phenyl-
1
silane, as determined by H NMR of the crude reaction
mixtures (entries 6 and 7).
Unlike reductive aminations with anilines, exothermicity
and vigorous gas evolution were consistently observed upon
adding phenylsilane to reaction mixtures containing either
primary or secondary alkylamines. To determine the origin
Other species have been found which behave as reductive
amination catalysts, although none were as effective as
dibutyltin dichloride. For example, metal salts (scandium
triflate and zinc iodide), a Bronsted acid (hydrogen chloride),
and another diorganotin (dibutyltin oxide) catalyzed the
reductive amination of 4-methoxybenzaldehyde with aniline
in the presence of phenylsilane. Efforts are underway to
evaluate the mechanistic implications of these observations
(16) Catalysis of a variety of organic reactions by diorganotins has been
reported. For some recent examples, see: (a) Iwasaki, F.; Maki, T.;
Onomura, O.; Nakashima, W.; Matsumura, Y. J. Org. Chem. 2000, 65,
9
96. (b) Orita, A.; Sakamoto, K.; Hamada, Y.; Mitsutome, A.; Otera, J.
Tetrahedron 1999, 55, 2899. (c) Whitesell, J. K.; Apodaca, R. Tetrahedron
Lett. 1996, 37, 2525. (d) Whitesell, J. K.; Apodaca, R. Tetrahedron Lett.
1
996, 37, 3955.
17) Stetin, C.; de Jeso, B.; Pommier, J. C. Synth. Commun. 1982, 12,
95.
18) General experimental procedure: A solution of carbonyl com-
2
3
(
and to identify more active catalysts.
4
The direct reductive amination protocol reported here
offers some advantages over other methods. Because little,
(
pound (1.5 mmol, 1 equiv) in tetrahydrofuran (0.3 mL) was treated with
an amine (1.5 mmol, 1 equiv), followed by dibutyltin dichloride (9 mg,
0
.03 mmol, 0.02 equiv). After 1-2 min at room temperature, the resulting
mixture was treated with organosilane (1.7 mmol, 1.1 equiv). Upon
completion, the reaction was diluted with chromatography solvent (with
added dichloromethane or ethyl acetate to dissolve solid material) and
chromatographed.
(20) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 3381.
(21) Dehydrogenative coupling of hydroxylic compounds with silicon
hydrides in the presence of amine bases is a known process. For a review,
see: Lukevics, E.; Dzinatara, M. J. Organomet. Chem. 1985, 295, 265.
(22) For examples, see refs 1a and 8a.
(19) THF was selected as a solvent because of its ability to form
concentrated solutions with a variety of potential substrates.
Org. Lett., Vol. 3, No. 11, 2001
1747