Amination of functionally substituted benzaldehydes in the presence of sodium tetrahydroborate: New preparation method for benzylamines

Full text of DOI:10.1134/S1070428007100326

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 10, pp. 1573−1574. © ©Pleiades Publishing, Ltd., 2007.
Original Russian Text © Zh.V. Ignatovich, K.N. Gusak, N.G. Kozlov, E.V. Koroleva, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43,
No. 10, pp. 1575−1576.
SHORT
COMMUNICATIONS
Amination of Functionally Substituted
Benzaldehydes in the Presence of Sodium Tetrahydroborate:
New Preparation Method for Benzylamines
Zh. V. Ignatovich, K. N. Gusak, N. G. Kozlov, and E. V. Koroleva
Institute of the Chemistry of new materials, National Academy of Sciences of Belarus, Minsk, 220141 Belarus
e-mail: evk@ichnm.basnet.by
Received February 7, 2007
DOI: 10.1134/S1070428007100326
Reductive amination of benzaldehydes derivatives
with heterocyclic amines results commonly in a low yield
of tertiary amines save the methods using catalytic
hydrogenation under pressure [1]. We found that in reac-
tion of N-methylpiperazine (Ia) or morpholine (Ib) with
amines endowed with versatile biological activity and
also are precursors of many drugs [2, 3].
Reaction of secondary amines with 4-methoxy-
carbonylbenzaldehyde. To a solution of 1.6 g (0.01 mol)
of 4-methoxycarbonylbenzaldehyde in 10 ml of methanol
cooled to 0 ÷ –5°C was added at stirring 1 ml (0.01 mol)
of amine I, after 40 min 0.6 ml (0.02 mol) of acetic acid
was added, the mixture was thus maintained for 1 h, then
it was heated at 60°C for 2 h. Then at cooling was added
4
-methoxycarbonylbenzaldehyde (II) in the presence
of sodium tetrahydroborate and acetic acid benzylamines
IV and V formed in up to 90% yield (see Scheme).
Iminium salt III formed in reaction of amine and
aldehyde in the presence of acetic acid is reduced with
sodium tetrahydroborate into the corresponding tertiary
benzylamine IV and V. Therewith we did not detect any
probable side reduction of initial methyl-4-formyl-
benzoate or of aromatic part of the benzylamine. Benzyl-
amines thus obtained are separated from the reaction
mixture by extraction and do not require additional
purification.
by portions 2.96 g (0.08 mol) of NaBH . The reaction
4
mixture was stirred at 60–70°C for 10–12 h, evaporated
in a vacuum, water was added, and the reaction mixture
was acidified with diluted hydrochloric acid to pH 1,
and the solution was extracted with ethyl acetate (3 ×
5
0 ml). The extract was rejected, the water solution was
alkalinized with 30% water solution of NaOH till pH 7–
, and the reaction product was extracted into ethyl
acetate (3×50 ml), the extract was dried with Na SO ,
8
The presence of a functional substituent in the aryl
fragment of the benzylamine ensures access by known
methods to a wide range of derivatives of heterocyclic
2
4
and on evaporating the solvent we obtained practically
pure (by TLC data) product.
Scheme.
_
(
(
1) AcOH,
2) NaBH4
AcO
+
X
NH +OHC
Iа, Ib
CO Me
X
N CH
CO Me
2
2
IIIа, IIIb
II
X
N H2C
CO Me
2
IV, V
X = NMe (Ia, IIIa, IV), O (Ib, IIIb, V).
1573

1574
IGNATOVICH et al.
1-Methyl-4-(4-methoxycarbonylbenzyl)piperazine
registered on a spectrometer Bruker AC-500 (500 MHz)
(
(
(
IV). Yield 90%, oily light-yellow fluid. IR spectrum
in CDCl , internal reference TMS. Mass spectra were
3
–1
1
film) ν, cm : 620, 765, 1275, 1725. H NMR spectrum
CDCl ), δ, ppm: 2.30 s (3H, CH –N), 2.48 s (8H, CH
2
measured on a GC-MS instrument Agilent Technologies
6850/5973 in an electon impact ionization mode, ionizing
electrons energy 70 eV. TLC was performed on Kieselgel
60F254 plates (Merck) in a system chloroform–methanol,
85:15, development in iodine vapor or under UV
irradiation.
3
3
of piperazine), 3.57 s (2H, CH Ar), 3.92 s (3H, OMe),
7
z (I , %): 248[M] (90) 177 (60), 149 [M –
NC H NCH ] (100), 99 [NC H NCH ] (80). Found,
2
.43 d and 7.99 d (4H , J 8.0 Hz). Mass spectrum, m/
arom
+
rel
,
+
+
4
8
3
4
8
3
%
%
: C 67.54; H 7.98; N 11.59. C H N O . Calculated,
14 20 2 2
The study was carried out under a financial support
of Belarus’ Republic Foundation for Basic Research
(grant X07-110).
: C 67.74; H 8.06; N 11.29.
-(4-Methoxycarbonylbenzyl)morpholine (V).
Yield 80%, colorless oily fluid. IR spectrum (thin film),
1
–1
1
ν, cm : 1740. H NMR spectrum, δ, ppm: 2.49 m and
.77 m (8H, NC H O), 3.49 s (2H, CH Ar), 3.95 s (3H,
REFERENCES
3
4
8
2
1
2
. Regnier, G.L., Cavenary, R.J., Laubie, M.J., and LeDoua-
ry, J.C. , J. Med. Chem., 1968, vol. 11, p. 1151.
. Horton, D.A., Bourne, G.T., and Smythe, M.L., Chem. Rev.,
OMe),7.42 d and 8.0 d (8Harom, J 6.0 Hz). Mass spectrum,
m/z (I , %): 235 [M] (55), 204 [M – OCH ] (45), 149
+
+
rel
3
+
+
[
[
M – OC H NCH ] (100), 121 [C H COOH] (25), 86
4 8 2 6 4
OC H N] (35).
2
003, vol. 103, p. 901.
+
4
8
3. Leopoldo, M., de, Giorgio, P., Berardi, F., Lacivita, E.,
Colabuto, N.A., Perrone, R., and Tortorella, V., J. Med.
Chem., 2002, vol. 45, p. 5727.
IR spectra were recorded on a Fourier spectro-
1
photometer Nicolet Protégé-460. H NMR spectra were
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 10 2007