1
1
but also unreactive toward imines, whereas Bu
2
SnClH has
been shown to reduce imines readily.12 Indeed, organotin
hydride species generated in situ from organotin oxides
Table 3. Direct Reductive Amination of Aldehydes with
1
3
Microwave Heating
and polysiloxanes have been identified as being responsible
for tin-catalyzed reactions even in the presence of stoichio-
metric amounts of siloxanes and would support Bu
as a possible in situ generated catalytic reductant. Regenera-
tion of Bu SnClH would thus occur from the intermediate
tin amide complex during the catalytic cycle by the action
of PhSiH
or siloxane (2).14 The proposed mechanism does
lend itself to testing; the first step in the pathway indicates
that the active tin intermediate is Bu SnClOH; this material
can be prepared readily by simple hydrolysis of Bu
To test the possibility of Bu SnClOH being an initial active
tin species, N-benzylidinaniline was reacted with phenylsilane
under various conditions.16 When the reduction was con-
2
ducted in the presence 10 mol % of freshly prepared Bu -
SnClOH, the imine was fully converted to the expected
secondary amine, indicating that at least the first steps in
the proposed mechanism could be viable.17
2
SnClH
2
yielda
R3 (%)
3
entry
R1
R2
1
2
3
4
2-(OH)-4-(CH3O)C6H3 PhCH2CH2
2-(OH)-4-(CH3O)C6H3 morpholine
2-(OH)-4-(CH O)C H cyclohexyl
2-(OH)-4-(CH3O)C6H3 L-(CH3)2CHCH-
NH2)COOCH3
(CH3)2CH
(CH3)2CH
(CH3)2CH
H
61
81
67
41
2
1
5
2
SnCl
2
.
3
6
3
H
H
2
(
5
6
7
cyclohexyl
PhCH2CH2
4-(morpholinyl-4-CH2)-
C6H4CH2
morpholine
H
H
H
63
70
74
8
9
4-(CH3O)C6H4
4-(CH O)C H
74
85
69
3
6
4
PhCH CH
2
2
H
b
10
2-(CH3O)C6H4
N-Boc-piperazine
Considering the mechanism, this reveals the possibility
that primary and secondary alkylamines could be considered
as potential substrates provided imine formation could be
forced to near completion. Our earlier orienting experiments
on the reductive alkylation of anilines (Table 1, entry 4)
a
Isolated yield of analytically pure product. b The yield was increased
from 23% when reaction was performed at 50 °C instead of 100 °C.
indicated that 10 mol % of Bu
2
SnCl
2
gave near-quantitative
by extraction or cation exchange methods as analytically pure
samples. Even the sterically demanding imine formed from
2-hydroxy-4-methoxybenzaldehyde and L-valine methyl ester
was readily reduced and obtained in 41% isolated yield.
It was noted that during addition of phenylsilane to the
reaction mixture as expected a slight gas evolution occurred.
However, the initial pressure levels measured inside the
microwave vessel during reaction were similar to those
obtained during reductive alkylation of anilines.
imine formation. Pleasingly, a test reaction between 2-phen-
ylethylamine and isobutyraldehyde, using the optimized
microwave conditions, resulted in the expected N-isobu-
tylphenethylamine (entry 6). This was obtained as a single
product in 70% yield after simple extraction.
A series of primary and secondary amines were then
alkylated with a range of aryl and alkyl aldehydes using the
above conditions (Table 3). All reaction products were
obtained as expected in moderate to good yields and isolated
The series of successful transformations demonstrate that
the rate of imine formation is greatly accelerated evidenced
1
8
by the lack of tertiary amine formation. However, whether
Bu SnCl improves the rate of formation of carbinol amine
or the succeeding dehydration step or both is not clear at
(
9) (a) Grady, G. L.; Kuivila, H. G. J. Org. Chem. 1969, 34, 2014. (b)
Lipowich, J.; Bowman, S. A. J. Org. Chem. 1973, 38, 162.
10) (a) Reifenberg, G. H.; Considine, W. J. Organometallics 1993, 12,
2
2
(
3
015. (b) Kuivila, H. G.; Beumel, Jr. O. F. J. Am. Chem. Soc. 1961, 83,
246, (c) Stern, A.; Becker, E. I. J. Org. Chem. 1962, 27, 4052.
1
9
1
the moment.
(
11) Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda, H.;
Sonoda, N. J. Org. Chem. 1995, 60, 2677.
12) Shibata, I.; Moriuchi-Kawakami, T.; Tanizawa, D.; Suwa, T,;
Sugiyama, E.; Matsuda, H.; Baba, A. J. Org. Chem. 1998, 63, 383.
In summary, a highly efficient microwave-accelerated
protocol for direct catalytic reductive amination has been
developed. The microwave-accelerated protocol expands the
scope of the reaction beyond those previously reported, and
the simple extractive ion-exchange isolation steps allow a
fast-throughput synthesis of secondary and tertiary amines.
(
(
13) (a) Hays, D. S., Fu, G. C. J. Org. Chem. 1996, 61, 4-5. (b) Hays,
D. S., Csholl. M. Fu, G. C. J. Org. Chem. 1996, 61, 6751-6752. Hayashi,
K.; Iyoda, J.; Shiihara, J. Organomet. Chem. 1967, 10, 81-94.
(14) PhSiH3 and other silanes have been reported to rapidly convert tin
amides to tin hydrides; Hays, D. S., Fu, G. C. J. Org. Chem. 1997, 62,
7
071.
Supporting Information Available: Spectroscopic and
analytical data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Gibbons, A. J.; Sawyer, A. K.; Ross, A. J. Org. Chem. 1961, 26,
2
304. It was also reported that dibutylchlorotin hydroxide readily loses water
to form bis(dibutylchlorotin) oxide.
16) A solution of imine (1 mmol) and PhSiH3 (2 mmol) in THF was
(
reacted in the presence of 10 mol % of Bu2SnClOH or 10 mol % HCl (4
M in dioxane) or both to rule out possible catalytic involvement of HCl.
The reactions were monitored by H NMR following the disappearance of
OL0522844
1
imine proton signal at δ 8.49 ppm and appearance of CH2 signal at δ 4.34
ppm. When Bu2SnClOH was dried under reduced pressure for longer time,
the catalytic activity was lost. For the imine reduction experiments, freshly
prepared tin hydroxide was used; the characteristic IR frequency for O-H
(18) In control experiments, reacting 4-methoxybenzaldehyde (1.5 mmol)
and cyclohexylamine (1.5 mmol) in the presence of (a) 2 mol % Bu2SnCl2
and 1.1 equiv of PhSiH3 (7 min, 100 °C, 150 W) or (b) preforming imine
in the presence of Bu2SnCl2 (7 min, 100 °C, 150 W) followed by reduction
with PhSiH3 (7 min, 100 °C, 150 W) resulted in a significant amount of
tertiary amine (40% and 11%, respectively). Optimized conditions gave
the secondary amine as a single product in 67% isolated yield (Table 3
entry 3).
-
1
stretching at 3421 cm was absent after drying.
17) Another possible explanation for why 1 mol of water is needed could
(
be that it hydrolyses the tin amide intermediate releasing Bu2SnClOH from
which Bu2SnClH is regenerated according to the proposed mechanism
(Scheme 1).
(19) Stetin, C.; de Jeso, B.; Pommier, J. C. Synth. Commun. 1982, 12, 495.
Org. Lett., Vol. 7, No. 25, 2005
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