Pharmaceutical Chemistry Journal
Vol. 34, No. 7, 2000
REACTIONS OF SODIUM BOROHYDRIDE IN ACETIC ACID:
REDUCTIVE AMINATION OF CARBONYL COMPOUNDS
1
1
1
1
1
A. V. Panfilov, Yu. D. Markovich, A. A. Zhirov, I. P. Ivashev, A. T. Kirsanov,
and V. B. Kondrat’ev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 7, pp. 34 – 35, July, 2000.
Original article submitted October 25, 1999.
Sodium borohydride is widely used for the reduction of
carbonyl-containing compounds to alcohols. Previously [1],
we demonstrated that sodium borohydride can be also suc-
cessfully employed for the reductive amination of carbonyl
compounds by inorganic acid salts of ammonia and primary
and secondary amines. The purpose of this work was to study
the interaction of carbonyl compounds with ammonia, pri-
mary amines, and sodium borohydride in acetic acid accord-
ing to the scheme
action between cyclohexanone (initial carbonyl) and aniline
(initial amine). The proposed structures of the synthesized
compounds were confirmed by the data of IR spectrometry,
mass spectroscopy, elemental analyses, and TLC.
It was experimentally established that the optimum mo-
lar ratio of components in the initial carbonyl com-
pound – amine – sodium borohydride mixture is 1 : 1.1 : 1.1,
respectively. Acetic acid is used both as the reagent and as
the solvent for preparing a 10% solution of the initial car-
bonyl compound.
R
R
NaBH4
2
2
CH
N
H
R
C
O + R NH
2
(
CH COOH), ÷
1
R
The reductive amination reaction using complex hy-
drides is sufficiently well studied [2] and can be adequately
described by the following scheme:
1
R
3
3
Ià In
1
Ia: R + R = C H (cyclo), R =H;
2
5
10
1
Ib: R + R = C H (cyclo), R =CH ;
2
5
10
3
OH
1
c: R + R = C H (cyclo), R =Ph;
2
1
H O
2
5
10
O + H N
NH
1
Id: R + R = C H (cyclo), R =C H (cyclo);
2
2
5
10
6 11
1
Ie: R + R = C H (cyclo), R =C H -i;
2
5
10
3
7
+H O
2
1
If: R + R = C H (cyclo), R =C H ;
2
5
10
2 5
1
Ig: R + R = C H (cyclo), R =H;
2
4
8
2
1
Ih: R = Ph, R =R =H;
II
1
Ii: R = Ph, R =H, R =CH ;
1
Ij: R = Ph, R =H, R =C H ;
1
Ik: R = Ph, R =H, R =C H -i;
2
Il: R = Ph, R =H, R =Ph;
1
Im: R = Ph, R =CH , R =H;
2
In: R=R =Ph, R =CH .
2
3
2
2
5
N
2
3
7
1
III
2
3
1
3
reduction
N
N
H
The yields of compounds Ia – In vary from 25 to 80%. In
addition, the reaction mass contains the products of the car-
bonyl group reduction to alcohol, but their yields do not ex-
ceed 10 – 15%. The reductive amination process is con-
ducted at a temperature of 15°C, the reaction time not ex-
ceeding 3 h. The initial compounds were cyclic ketones,
acetophenone, and benzaldehyde.
The proposed method was used to obtain the series of
primary and secondary amines presented in Table 1. The ma-
ximum yields of substituted amines were observed in the re-
III
IV
In the first stage, the carbonyl compound interacts with
the initial amine to form an intermediate product II which,
eliminating water, converts into azomethine III. The second
stage consists in the reduction of compound III by various re-
ducing agents.
As is known, one mole of sodium borohydride reacts
with 3 moles of acetic acid to form sodium triacetoxyboro-
hydride [3]:
1
“Belvitaminy” Joint-Stock Company, Belgorod, Russia.
NaBH + 3CH COOH ® NaBH(CH COO) + 3H .
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3
3
3
2
371
0
091-150X/00/3407-0371$25.00 © 2000 Kluwer Academic/Plenum Publishers