Interaction of secondary amines with aromatic aldehydes-efficient method for synthesis of the functionalized heterocyclic amines

Article abstract of DOI:10.1007/s10593-007-0238-z

A method is proposed for the benzylation of secondary heterocyclic amines with functionalized derivatives of benzaldehyde in the presence of formic acid under conditions close to amination according to the Leuckart-Wallach reaction.

Full text of DOI:10.1007/s10593-007-0238-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 12, 2007
INTERACTION OF SECONDARY
AMINES WITH AROMATIC
ALDEHYDES – EFFICIENT
METHOD FOR SYNTHESIS
OF THE FUNCTIONALIZED
HETEROCYCLIC AMINES
Zh. V. Ignatovich1, K. N. Gusak1, T. V. Chernikhova1,
N. G. Kozlov2, and E. V. Koroleva1
A method is proposed for the benzylation of secondary heterocyclic amines with functionalized
derivatives of benzaldehyde in the presence of formic acid under conditions close to amination
according to the Leuckart–Wallach reaction.
Keywords: N-methylpiperazine, benzaldehyde derivatives, formic acid, pyrrolidine, reductive
amination.
The piperazine ring is a key structural fragment of a large group of compounds, the broad spectrum of
activity of which explains the interest in the development of rational methods of obtaining them [1-3]. One of the
variants of constructing compounds from piperazine is the synthesis of functionalized benzyl derivatives. Such
derivatives may be obtained by the direct alkylation of an amine with benzyl halides or by the reductive
amination of benzoic acid derivatives [4, 5]. We investigated the reaction of N-methylpiperazine, pyrrolidine,
and morpholine with p-substituted benzaldehydes in the presence of formic acid. The reaction represents in
essence the combination in one process of the preparation of a carbonyl derivative of an amine and its
subsequent reduction. However the problem in this case includes not only the selection of a reducing agent for
the imine formed in situ, but also the sensitivity of the of the functional groups in the aromatic compound
towards the reducing agent used. The Leuckart–Wallach reaction (the reducing agent is formic acid) is applied in
a more restricted manner than catalytic reduction with hydrogen [4]. Nonetheless this method enables
compounds containing functional substituents labile in catalytic reduction reactions to be used and provides a
satisfactory yield of tertiary amines.
Benzylamines 8-13 were obtained in preparative yield from secondary heterocyclic amines 1-3 and
functionalized benzaldehyde derivatives 4-7 using formic acid as reducing agent and conditions close to the
conditions of the Leuckart–Wallach reaction.
__________________________________________________________________________________________
1Institute of the Chemistry of New Materials, National Academy of Sciences of Belarus, Minsk 220141;
2
e-mail: evk@ichnm.basnet.by. Institute of Physical Organic Chemistry, National Academy of Sciences of
Belarus, Minsk 220072; e-mail: loc@foch.basnet.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 12, pp. 1820-1823, December, 2007. Original article submitted July 21, 2006.
1540
0009-3122/07/4312-1540©2007 Springer Science+Business Media, Inc.

1. HCOOH, ∆
2. NaOH
R
X
NH
OHC
+
1–3
HCOOH
4–7
+
N
X
CH
16
R
O
NC
X
H
X
NH
14
X
N
X
N
R
CH2
8–13
R
HC
N
X
15
1–3, 8–11, 14 X = NMe; 4 R = COOH; 5 R = COOMe; 6 R = NO2; 7 R = H;
8 R = COOH; 9 R = COOMe; 10 R = NO2; 11 R = H; 12 R = COOMe, X = – ;
13 R = COOMe, X = O
The most important side process in the reaction being investigated was the formylation of the amine with
the formation of formamide 14, the yield of which reached 25% when using difficultly soluble benzaldehyde
derivatives in the reaction. The product of the reduction of the aldehyde group of the initial benzaldehyde, the
corresponding benzyl alcohol, was formed in less than 10% yield. The formation of aminals 15 by stabilization
of the immonium ion 16, possibly by addition of a second molecule of amine, and noticed previously in
reactions for making amines according to Leuckart–Wallach, was not observed.
The presence of functional substituents in the aryl fragment of the benzylamine guarantees the
conversion by known and available methods to a wide range of derivatives of heterocyclic amines, which are
precursors of a large number of medicinal preparations, and also display high and varied biological activity
[5-7].
EXPERIMENTAL
1
The IR spectra were taken on a Nicolet Protege 460 Fourier spectrophotometer. The H and 13C NMR
spectra were recorded on a Bruker AC-500 (500 and 100 MHz respectively) and a Tesla BS-567 (100 MHz)
spectrometer in CDCl3 and D2O, internal standards were TMS and 2,2-dimethyl-2-silapentane-5-sulfonate. The
mass spectra were obtained on an Agilent Technologis 6850/5973 chromato-mass spectrometer in EI ionization
mode at an energy of 70 eV. Column chromatography was carried out on silica gel 40/100 µ (Czech Republic),
TLC on Kieselgel 60F254 plates (Merck) in the system chloroform–methanol, 85:15, visualization with iodine
and UV.
Interaction of Secondary Amines with Benzaldehyde Derivatives. Amine (0.1 mol) was mixed with
formic acid (0.5 mol) under ice cooling and the mixture left for 10-15 min to form the salt. The cooling was
removed, aldehyde (0.12 mol) was added in one batch, and the reaction mixture was heated under reflux with
stirring at 180-200oC for 6-8 h. At the end of the reaction, water (50 ml) was added to the reaction mixture,
1541

which was acidified to pH 3 with 10% HCl, and then extracted with ether (3×100 ml). The extract, which
contains mainly the formyl derivative of the amine and the initial aldehyde, was discarded. The aqueous
remainder was treated with 20% NaOH to pH 9, the desired reaction product extracted with ether and
chloroform, the combined extracts were dried over MgSO4, and evaporated in vacuum. The solid products were
recrystallized. To obtain analytically pure benzylamines 9-13 the solid reaction mixture after evaporation was
chromatographed on a column of silica gel (chloroform–methanol, gradient elution).
4-(4-Carboxybenzyl)-1-methylpiperazine (8) was isolated in 40% yield by evaporating the neutral
aqueous solution after exhaustive extraction of the reaction mixture with chloroform. Mp 228oC (dec.).
IR spectrum (KBr), ν, cm-1: 1296, 1350, 1461, 1643, 2820-3400. 1H NMR spectrum (D2O), δ, ppm (J, Hz): 2.81
(3H, s, CH3N); 2.5-3.4 (8H, CH2 piperazine); 3.72 (2H, s, CH2Ar); 7.38 (2H, d, J = 8.0, arom.); 7.88 (2H, d,
J = 8.0, arom.). 13C NMR spectrum (D2O), δ, ppm: 174.71 (COOH); 136.97; 135.80; 129.70; 128.79; 60.27
(CH2Ar); 52.35; 48.98 ((CH2)4); 42.50 (CH3). Mass spectrum, m/z (Irel), %: 234 [M]+ (40), 190 [M–COO]+ (30),
135 [HO2CC6H4CH2]+ (100), 99 [NC4H8NCH3]+ (70), 44 [CO2]+ (90). Found, %: C 66.78; H 7.65; N 12.10.
C13H18N2O2. Calculated, %: C 66.66; H 7.61; N 11.90.
4-(4-Methoxycarbonylbenzyl)-1-methylpiperazine (9). Yield 70%, oily liquid. IR spectrum (film), ν,
1
cm-1: 610, 755, 1280, 1735, 3200-3400. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.30 (3H, s, CH3N); 2.48
(8H, m, CH2 piperazine); 3.57 (2H, s, CH2Ar); 3.92 (3H, s, OCH3); 7.43 and 7.99 (4H, two d, J = 8.0, arom.).
13C NMR spectrum (D2O), δ, ppm: 45.99; 51.90; 53.06; 55.02; 62.52; 64.69; 128.81; 128.87; 129.46; 143.78;
167.05. Mass spectrum, m/z (Irel, %): 248 [M]+ (90), 177 (60), 149 [M–NC4H8NCH3]+ (100), 99 [NC4H8NCH3]+
(80). Found, %: C 67.54; H 7.98; N 11.59. C14H20N2O2. Calculated, %: C 67.74; H 8.06; N 11.29.
1-Methyl-4-(4-nitrobenzyl)piperazine (10). Yield 47%, oil. IR spectrum (film), ν, cm-1: 1420, 1535,
1
1650. H NMR spectrum, δ, ppm (J, Hz): 2.69 (3H, s, CH3N); 2.67 (8H, m, CH2 piperazine); 3.75 (2H, s,
CH2Ar); 7.89 and 7.99 (4H, two d, J = 8.0, arom.). Mass spectrum, m/z (Irel, %): 235 [M]+ (90), 136 [M–
N(CH2)4NMe]+ (100), 99 [N(CH2)4NMe]+ (90). Found, %: C 61.39; H 7.23; N 18.07. C12H17N3O2. Calculated,
%: C 61.29; H 7.19; N 17.87.
4-Benzyl-1-methylpiperazine (11) was isolated as an oily liquid, Rf 0.6 (chloroform–methanol, 9:1).
1
Yield 77%. IR spectrum (thin layer), ν, cm-1: 980, 1060, 1100, 1440. H NMR spectrum, δ, ppm (J, Hz): 2.26
(3H, s, CH3N); 2.44 (8H, m, CH2 piperazine); 3.49 (2H, s, CH2Ar); 7.27 (5H, m, arom.). Mass spectrum, m/z (Irel,
%): 190 [M]+ (70), 146 (20), 119 (45), 99 [NC4H8NCH3]+ (40), 91 [H2CC6H5]+ (100). Found, %: C 76.04;
H 9.49; N 15.03. C13H18N2. Calculated, %: C 75.80; H 9.42; N 14.83. (Synthesized for the first time and
characterized as the hydrochloride in [8].)
1-(4-Methoxycarbonylbenzyl)pyrrolidine (12). Oil, Rf 0.54 (chloroform–methanol, 9:1). Yield 50%.
1
IR spectrum (thin layer), ν, cm-1: 1730. H NMR spectrum, δ, ppm (J, Hz): 1.97, m and 2.97, m (8H, CH2
pyrrolidine); 3.87 (3H, s, OCH3); 4.11 (2H, s, CH2Ar); 7.41 and 7.95 (4H, two d, J = 8.0, arom.). Mass spectrum,
m/z (Irel, %): 219 [M]+ (100), 149 [M–C4H8N]+ (70), 121 [C6H4COOH]+ (45), 135 [M–C4H8NCH2]+ (90). Found,
%: C 71.48; H 7.70; N 6.51. C13H17NO2. Calculated, %: C 71.23; H 7.76; N 6.39.
1-(4-Methoxycarbonylbenzyl)morpholine (13) was isolated as an oil, Rf 0.55. Yield 50%. IR spectrum
1
(thin layer), ν, cm-1: 1740. H NMR spectrum, δ, ppm (J, Hz): 2.2, m and 3.48, m (8H, NC4H8O); 3.63 (2H, s,
CH2Ar); 3.81 (3H, s, OCH3); 7.32 and 7.80 (8H, two d, J = 8.5, arom.). Mass spectrum, m/z (Irel, %): 235 [M]+
(80), 149 [M-OC4H8N]+ (100), 121 [C6H4COOH]+ (45), 86 [OC4H8N]+ (65). Found, C 66.66; H 7.12; N 6.0.
C13H17NO3. Calculated, %: C 66.42; H 7.22; N 5.9.
4-Formyl-1-methylpiperazine (14) was isolated as an oily liquid, Rf 0.4 (chloroform–methanol, 9 : 1).
IR spectrum (film), ν, cm-1: 1040, 1460, 1690. 1H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s, CH3N); 2.34 and
2.39 (4H, two t, J = 5.1, (CH2)2NCH3); 3.36 and 3.53 (4H, two t, J = 5.0, (CH2)2NC(O)H); 7.99 (1H, s, HC=O).
Mass spectrum, m/z (Irel, %): 128 [M]+ (100), 99 [M–C(O) (80) H]+, 70 (80), 56 (75), 42 (75). Found, %:
C 56.60; H 9.22; N 21.50. C6H12N2O. Calculated, %: C 56.25; H 9.37; N 21.88. (According to [9, 10]:
bp 94-95oC (3 mm Hg). IR spectrum, ν, cm-1: 1660 (C=O); mass spectrum, m/z (Irel, %): 128 [M]+)
1542

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