A simple protocol for direct reductive amination of aldehydes and ketones using potassium formate and catalytic palladium acetate

Article abstract of DOI:10.1055/s-2003-37509

A method for direct reductive amination of aldehydes and ketones, including α,β-unsaturated carbonyl compounds, has been developed, which requires potassium formate as reductant and palladium acetate as catalyst. Suitable amines include both primary and secondary aliphatic and aromatic amines.

Full text of DOI:10.1055/s-2003-37509

LETTER
555
A Simple Protocol for Direct Reductive Amination of Aldehydes and Ketones
Using Potassium Formate and Catalytic Palladium Acetate
D
irec
t
Reductive
a
A
mination
s
of
A
ldehy
u
des and Ket
d
one
s
eb Basu,* Satadru Jha, Md. Mosharef H. Bhuiyan, Pralay Das
Department of Chemistry, North Bengal University, Darjeeling 734 430, India
Fax +91(353)581546; E-mail: basu_nbu@indiatimes.com
Received 29 October 2002
vestigate whether potassium formate, which is soluble in
Abstract: A method for direct reductive amination of aldehydes
and ketones, including α,β-unsaturated carbonyl compounds, has
been developed, which requires potassium formate as reductant and
palladium acetate as catalyst. Suitable amines include both primary
and secondary aliphatic and aromatic amines.
polar organic solvents and in water, with activation by
palladium salt could significantly reduce the C-N double
bond of the imine formed in the direct reductive amination
reaction. We report herein our observation, which consti-
tutes a one-pot reductive amination protocol for aldehydes
and ketones, including conjugated ones, with the aid of
potassium formate and catalytic palladium acetate.
Key words: reductive amination, potassium formate, palladium
acetate, one-pot reaction
The direct reductive amination of carbonyl compounds1 is
a useful organic transformation for preparing primary,
secondary and tertiary amines. The carbonyl compound
initially reacts with ammonia or amine to form an imine,
which then undergoes reduction in presence of hydrogen
or hydride ion (Scheme 1). The term ‘direct reductive am-
ination’ is used to describe a reaction in which a mixture
of the carbonyl compound and the amine is treated with
suitable reducing agent in a one-pot operation.1b Several
reductive systems are known to effect the reduction of the
C–N double bond of the imine. The Borch reduction,2 one
of the early methods, involves sodium cyanoborohydride,
[NaBH3CN], as the reductant. However, use of excess re-
agent (up to 5-fold) along with toxic cyanide as the by-
product limits its wide applications. The alternative sodi-
um triacetoxyborohydride, [NaBH(OAc)3],3 has not been
successful for aromatic and unsaturated ketones. Other
reagents include ZnCl2–Zn(BH4)2;4 NiCl2–NaBH4;5 Ti(i-
PrO)4–polymethylhydrosiloxane;6 Ti(i-PrO)4–NaBH4;7
Bu3SnH;8 Bu2SnClH and Bu2SnIH;9 decaborane;10 silica
gel–Zn(BH4)2;11 Et3SiH–trifluoroacetic acid;12 pyridine–
BH3;13 phenylsilane–dibutyltin dichloride.14 All these
methods require stoichiometric or excess quantities of the
hydrides, which are generally highly reactive and expen-
sive as well. Furthermore, use of tin hydrides in some pro-
tocols is not recommended for large-scale preparation as
the residual insoluble tin compounds pose a great risk in
its elimination. On the other hand, use of formic acid as
the source of hydrogen, called the Wallach reaction, or
ammonium salts of formic acid, called the Leuckart reac-
tion, often yields the N-formyl derivative of the amine in-
stead of the free amine.15 Recently, we16a and other
groups16b have shown that potassium formate promoted
by palladium acetate can reduce efficiently the conjugated
C-C double bond. It therefore appeared reasonable to in-
Scheme 1
To examine the scope of this reaction, a variety of alde-
hydes and ketones were reductively aminated with ali-
phatic and aromatic amines (Table 1). Both primary and
secondary amines, such as morpholine (entries 2 and 6)
have been used. Reactions with substrates bearing poten-
tially reducible functional groups including chloro (entry
3), bromo and nitro (entry 7) yielded anticipated products
without detectable reductive side products. Although ace-
tophenone is a difficult case for some reductive amination
protocols, use of excess potassium formate (2–4 mmol)
and a slight excess of palladium acetate (5 mol%) gave re-
ductive amination of the ketones at a rate comparable to
that of other substrates. The process is equally effective
for heteroaromatic systems (entry 5). Reductive amina-
tion of cinnamaldehyde (entry 12) with cyclohexyl amine,
however, proceeded with concomitant reduction of the C–
C double bond. Unlike the Leukart reaction or the
Wallach reaction, no N-formyl derivatives were formed in
this protocol.
It is well known that aldehydes generally form imines
faster than ketones. In this protocol, separate conditions
were employed for imine preparation prior to addition of
reducing agent. Whereas the aldehydes (except cinnamal-
dehyde) were reacted with amines in presence of activated
molecular sieves (4 Å), the imines from the ketones were
prepared on a surface of silica gel following the procedure
of Ranu et. al.11 However the imines prepared by using
either molecular sieves or silica gel were directly taken in
dimethyl formamide and subjected to reduction by adding
palladium acetate (2–5 mol%) and potassium formate
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0555,0557,ftx,en;D24402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

556
B. Basu et al.
LETTER
Table 1 Direct Reductive Amination of Aldehydes and Ketones with HCO2K and Catalytic Pd(OAc)2
Entry
Substrate 1
Amine 2
Conditiona/Temp./ Product3
Yield (%)b
Time (h)
1
2
A/40 °C/3
A/40 °C/4
68
62
3
4
5
6
7
8
9
A/50 °C/5
A/40 °C/3
A/40 °C/3
A/50 °C/5
A/50 °C/5
B/50 °C/5
B/60 °C/6
67
75
86
67
56
70
76
10
11
12
B/60 °C/6
B/60 °C/6
B/50 °C/5
83
80
69
a Conditions A: Aldehyde + Amine in DMF with MS (4 Å) and stirred at r.t. for 3–5 h; B: Ketone + Amine intimately mixed on activated silica
and stirred at r.t. for 5–6 h.
b Yield are reported after chromatographic purification (2–3 runs). Satisfactory spectral data were obtained for all the amines (products).
(2–3 equiv) and heated at 40–60 °C for 3–6 hours.17 The
References
products were obtained after purification on column chro-
matography. In general, the reaction procedure is very
simple and the reaction condition appears to be mild.
(1) For a recent review, see: (a) Tarasevich, V. A.; Kozlov, N.
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Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D.
J. Org. Chem. 1996, 61, 3849.
In summary, the method described here can be useful for
preparing all classes of amines from suitable carbonyl
compounds and the amines. Furthermore, the method can
be of importance in view of cheap reducing agent, which
decomposes to environmentally friendly chemicals. Since
palladium catalysed hydride addition is probably the
cause of the C–N double bond reduction, the possibility
for asymmetric reductive amination in presence of a chiral
ligand might be explored.
(2) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
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Acknowledgement
Financial support from the Department of Science & Technology,
New Delhi (Grant No. SP/S1/G13/97) is gratefully acknowledged.
We are thankful to Professor B. C. Ranu, Department of Oragnic
Chemistry, Indian Association for the Cultivation of Science, Cal-
cutta 700 032, India for his help in doing some of the experiments.
(11) Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63,
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Synlett 2003, No. 4, 555–557 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Direct Reductive Amination of Aldehydes and Ketones
557
(13) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem.
1995, 60, 5995.
0.1 mmol). The mixture was then heated at 40 °C for 3 h to
complete the reaction (TLC) and after cooling it was diluted
with ice-cold water (15 mL). The mixture was extracted with
ether (3 × 20 mL). The combined extract was washed with
brine, dried (Na2SO4), and evaporated to leave the crude
product, which was purified by column chromatography
over silica gel. Elution with ethyl acetate–hexanes (1:19;
Rf 0.26) furnished N-cyclohexyl p-methoxybenzyl amine 4
(815 mg, 75%) as an oil: IR(neat): 1246, 1300, 1510, 1610,
2851, 2925 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.05–
1.31 (m, 6 H), 1.61 (br, 1 H), 1.70–1.92 (m, 4 H), 2.43–2.50
(m, 1 H), 3.73 (s, 2 H), 3.78 (s, 3 H), 6.84 (d, 2 H, J = 8.3
Hz), 7.22 (d, 2 H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3):
δ = 24.9, 26.2, 33.4, 50.3, 55.2, 56.0, 113.7, 129.2, 132.9,
158.4.
(14) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
(15) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th
ed.; John Wiley and Sons: New York, 2001, Chap. 16, 1187.
(16) (a) Basu, B.; Bhuiyan, M. M. H.; Jha, S. Synth. Commun.
2003, 33, 289. (b) Arcadi, A.; Bernocchi, E.; Cacchi, S.;
Marinelli, F. Synlett 1991, 27.
(17) General Procedure for Aldehydes. For the aldehydes
(listed in Table 1) except cinnamaldehyde:
A solution of p-anisaldehyde (680 mg, 5 mmol) and
cyclohexylamine (500 mg, 5 mmol) in dry DMF (5 mL) was
magnetically stirred at r.t. for 4 h, in presence of molecular
sieves (4 Å). To the resulting reaction mixture were added
HCOOK (840 mg, 10 mmol) and palladium acetate (22 mg,
Synlett 2003, No. 4, 555–557 ISSN 0936-5214 © Thieme Stuttgart · New York