Features of 2-, 3-aminopyridines and 2-aminopyrimidine condensation with 2-formylimidazoles

Article abstract of DOI:10.1023/A:1022578505237

Condensation of 2-, 3-aminopyridines and 2-aminopyrimidine with 1-vinyl- and 1-ethylimidazole-2-carbaldehydes and 1-vinyl-, 1-ethylbenzimidazole-2-carbaldehydes takes two paths depending on the reagents structure: either form Schiff bases or aminals of th

Full text of DOI:10.1023/A:1022578505237

Russian Journal of Organic Chemistry, Vol. 38, No. 11, 2002, pp. 1674 1680. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 11, 2002,
pp. 1731 1737.
Original Russian Text Copyright
2002 by Baikalova, Zyryanov, Afonin, Trofimov.
Features of 2-, 3-Aminopyridines and 2-Aminopyrimidine
Condensation with 2-Formylimidazoles
L. V. Baikalova, I. A. Zyryanov, A. V. Afonin, and B. A. Trofimov
Faworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences, Irkutsk, 664033 Russia
Received July 17, 2002
Abstract Condensation of 2-, 3-aminopyridines and 2-aminopyrimidine with 1-vinyl- and 1-ethylimidazole-
2-carbaldehydes and 1-vinyl-, 1-ethylbenzimidazole-2-carbaldehydes takes two paths depending on the
reagents structure: either form Schiff bases or aminals of the corresponding heterocyclic carbaldehydes.
The extensive search for easy and unconventional
synthetic procedures for preparation of versatile azole
and azine derivatives are obviously caused by their
presence as building blocks both in synthetic and
endogenic biologically active compounds [1 4].
Besides these classes of heterocycles attract stable
interest as polydentate ligands for synthesis of various
metal complexes significantly extending the range of
the pharmacological activity of compounds from
azole and azine series [5 7], and also the variety of
potential catalysts. In continuation of the studies on
condensation of amines and aldehydes of heterocyclic
series [8 10] we report here on results of investiga-
tion of reaction between 1-vinyl(ethyl)-2-formylimid-
azoles (I IV) with 2-, 3-aminopyridines (V, VI)
and 2-aminopyrimidine (VII). The main goal was
elucidating the effect of the heterocycle structure and
the character of its substituents on the direction of the
process because of the nucleophilic addition of
primary amines to aromatic aldehydes was known to
furnish not only Schiff bases but also aminals of the
corresponding aldehydes [11, 12].
original reagents within 8 16 h bases VIII, IX
formed in 60 70% yield. At boiling aldehydes I, II
with pyridine VI in various organic solvents (benzene,
ethanol, ether) arose an intractable mixture of reac-
tion products and initial reagents.
Benzimidazolecarbaldehydes III, IV react dif-
ferently with 3-aminopyridine (VI). With 2-formyl-
1-ethylbenzimidazole (IV) formed azomethine XI in
62% (in benzene) or 70% yield (at melting).
At the same time the reaction of 1-vinyl-2-formyl-
benzimidazole (III) with amine VI terminated at the
stage of the intermediate hemiaminal Xa that preci-
pitated from the solution (in benzene or ether) in
nearly quantitative yield (85 90%). We failed to shift
the equilibrium to the expected base X by changing
the reaction conditions. Only at long heating (26 h)
of the initial reagents III and VI in benzene we
1
detected by H NMR spectrum formation of about
20% of azomethine X alongside quite a number of
unidentified reaction products.
In contrast to 3-aminopyridine (VI) reaction of its
2-isomer V with aldehydes I IV takes two routes
providing azomethines and aminals simultaneously,
and the reaction products ratio depends essentially on
the azole (I IV) nature (Scheme 2).
As a result of these studies we established that
unlike the previously performed condensations of
azoles aminoderivatives with aldehydes I IV which
yielded only azomethines [8 10], 2-aminoazines V
VII addition to imidazolecarbaldehydes can furnish
as final products alongside Schiff bases also aminals
depending on the structure of initial reagents
(Scheme 1). For instance, the reaction of 3-amino-
pyridine VI with imidazolecarbaldehydes I, II
resulted exclusively in new azomethines, 3-[1-vinyl-
(ethyl)imidazol-2-yl]methyleneaminopyridines (VIII,
IX). The reaction proceeded under fairly severe con-
ditions: at melting ( 95 C) of equimolar amounts of
At heating in benzene equimolar amounts of
2-aminopyridine (V) and 1-vinyl(ethyl)-2-formyl-
imidazoles (I, II) mostly azomethines XII, XIII were
isolated in low yield ( 30%). The insignificant
amounts of aminals XVI, XVII (up to 5%) were
1
detected by H NMR spectra. Under similar condi-
tions 2-formylbenzimidazoles III, IV with 2-amino-
pyridine afford prevailingly aminals 2-[1-vinyl(ethyl)-
1070-4280/02/3811-1674$27.00 2002 MAIK Nauka/Interperiodica

FEATURES OF 2-, 3-AMINOPYRIDINES
1675
Scheme 1.
I, VIII, R = CH=CH2; II, IX, R = Et.
Scheme 2.
XII, XVI, R1 = CH=CH2, R2 = R3 = H; XIII, XVII, R1 = Et, R2 = R3 = H; XIV, XVIII, R1 = CH=CH2, R2,
R3 (CH)4; XV, XIX, R1 Et, R2, R3
(CH)4.
=
=
=
benzimidazol-2-yl]methylenediaminopyridines (XVIII, 2-aminopyridine (V) and condensation under con-
XIX) in an yield not exceeding 30 40%, and the cor-
responding azomethines XIV, XV as minor products
(3 5%). At the increased reaction time (24 h) and at
melting of the initial reagents at 95 C both reaction
paths are conserved but the yield of azomethines XII,
XIII grows to 45 and 64% respectively, and that of
aminals XVIII, XIX falls to 10 17%. Therewith in
both cases the amount of aminals XVI, XVII and
azomethines XIV, XV arising also as side products
remains the same ( 5%). At double excess of
ditions of base catalysis (KOH, benzene) we succeed-
ed in obtaining aminals XVIII, XIX in 69% yield.
As in the general case [11, 12] azomethines formation
in the reaction under study is reversible, and in water
solutions it strongly shifts to the initial compounds.
Aminals apparently arise from addition of the second
amine molecule to the intermediately forming hemi-
aminal, for in reaction of the corresponding azo-
methine with amine we failed to obtain the expected
aminal, and only the initial reagents were recovered.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

1676
BAIKALOVA et al.
The condensation of 2-aminopyrimidine (VII) with
imidazolecarbaldehydes I IV at heating to 60 70 C
in ethanol results exclusively in previously unknown
Azomethines synthesized VIII, IX, XI are yellow
crystalline compounds, and Schiff bases X, XII, XIII
are yellow oily substances. Aminals XVIII XXIII
are colorless crystals, sparingly soluble in most
organic solvents, save compounds XVIII, XIX.
Hemiaminal Xa is a colorless powder insoluble in
benzene, ether, and in ethanol, chloroform, carbon
tetrachloride, and DMSO it immediately dissociates
into the initial amine VI and aldehyde III. The struc-
ture of compounds synthesized was established
aminals
2-[vinyl(ethyl)imidazol-2-yl]methylenedi-
aminopyrimidines (XX XXIII). The maximum yields
(57 and 76% respectively) of aminals XX, XXI was
obtained from 2-formylimidazoles I, II in ethanol in
20 h. Under similar conditions the yields of diamines
XXII, XXIII prepared from benzimidazolecarb-
aldehydes III, IV amount only to 25 36%. The use
as solvent of methanol, benzene, dioxane, or con-
densation in reagents melt, or changing the ratio
pyrimidine aldehyde to 2: 1 resulted in decreased
yield of compounds XX XXIII.
1
relaying on H NMR, IR, UV, and mass spectra.
Characteristics of the compounds are listed in Table1.
In the IR spectra of azomethines VIII XIII the
absorption bands of the stretching vibrations of the
azomethine bond (N=CH) is observed in the more
1
shortwave region (1630 1615 cm ) that the cor-
responding band in the spectra of azomethines
prepared from the same aldehydes I IV and amino-
1
azoles (1602 1598 cm ). Therewith the bands of
stretching and bending vibrations of NH2 group of
azines V, VI appearing respectively at 3450 3300 and
1
1640 1630 cm are absent in the spectra of bases
XX, R1 = CH=CH2, R2 = R3 = H; XXI, R1 = Et,
R2 = R3 = H; XXII, R1 = CH=CH2, R2, R3 =
(CH)4; XXIII, R1 = Et, R2, R3 = (CH)4.
VIII XIII. Unlike the spectrum of 3-aminopyridine
1
(VI) containing a broad band at 3410 3310 cm of
NH2 group vibrations, in the IR spectrum of hemi-
aminal Xa a narrow strong band is observed at
1
The attempt to prepare aminals XX XXIII under
3375 cm and a wide band with a maximum at
1
conditions of base catalysis (KOH, K2CO3) failed:
3055 cm ; the former band corresponds to NH
1
the isolated mixture according to H NMR data con-
vibrations, the latter to those of associated hydroxy
group. The conservation of the vinyl substituent in
Xa molecule is confirmed by the presence in the
tained up to 7% of the corresponding aminal XX
XXIII and the initial reagents.
IR spectrum of absorption bands at
975 cm .
1643 and
Thus the direction of nucleophilic additions to
carbonyl group of imidazolecarbaldehydes I IV of
2-, 3-aminopyridines and 2-aminopyrimidine are
essentially governed by azine character. With low-
basic 2-aminopyrimidine (VII) condensation affords
only aminals of heteroaldehydes. 2-Aminopyridine
(V) reacts with 2-formylimidazoles along two paths
giving rise simultaneously to azomethines and
aminals in a ratio depending on the electronic struc-
ture of the aldehyde component. 3-Aminopyridine
(VI) with highly basic heterocyclic carbaldehydes
I, II, IV [13] yields azomethines. The reaction of less
basic aldehyde of this series, 1-vinyl-2-formylbenz-
imidazole (III), with amine VI is incomplete and is
finished at the stage of the corresponding hemiaminal
Xa formation. It is presumable that like the hydration
process of the corresponding aldehydes I, III [14],
the dehydration at the stage of hemiaminal conversion
into azomethine is in some way catalyzed by the
heterocyclic fragment of the carbaldehyde and there-
fore occurs more readily with heterocycles I, II, IV
as stronger bases.
1
The IR spectra of aminals XVIII XXIII are
characterized by a narrow strong absorption band of
NH groups in the region 3235 3210 cm . The
1
stretching vibrations of the rings belonging to amine
and aldehyde moieties appear as very strong absorp-
1
tion bands at 1600 and 1585 cm which correspond
to overall absorption from aromatic and heterorings.
It should also be noted that the absorption bands of
vinyl groups in all compounds obtained from 1-vinyl-
imidazole(benzimidazole)carbaldehydes I, III con-
serve their position ( 1650 1640 and
960
1
950 cm ).
Difference in UV spectra of azomethines and
aminals reflects specific features of their structure.
For instance, the spectrum of aminal XXI appears as
superimposed spectra of the corresponding azole III
and 2-aminopyrimidine (VII). The longwave band in
1
the solution spectrum at 34150 cm is observed
virtually at the same frequency as the band of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

FEATURES OF 2-, 3-AMINOPYRIDINES
Table 1. Yields and characteristics of compounds synthesized
1677
mp,
[bp, C]
(p, mm Hg)
C
Found, %
H
Calculated, %
H
Compd.
no.
Yield, %
Formula
C
N
C
N
VIII
IX
Xa
XI
XII
62
72
83
62
45
95 97
64 66
97 99
126 128
62 63
66.49
65.83
68.36
71.74
66.33
5.04
6.38
5.25
5.30
5.44
28.21
27.96
21.53
22.42
28.39
C11H10N4
C11H12N4
C15H13N4O
C15H13N4
C11H10N4
66.67
66.00
67.92
72.00
66.67
5.05
6.00
4.91
5.60
5.05
28.28
28.00
21.13
22.40
28.28
[184 186 (3)]
[186 187 (5)]
119 121
151 153
219 221
182 185
193 195
201 203
XIII
XVIII
XIX
XX
XXI
64
69
61
57
76
25
36
65.58
69.94
69.42
57.14
56.35
62.57
62.01
6.09
5.50
6.49
4.76
5.73
4.99
5.59
28.02
24.61
24.27
38.10
37.36
32.26
32.17
C11H12N4
C20H18N6
C20H20N6
C14H14N8
C14H16N8
C18H16N8
C18H18N8
66.00
70.18
69.77
57.35
56.76
62.79
62.43
6.00
5.26
5.80
4.73
5.41
4.65
5.20
28.00
24.56
24.42
38.36
37.84
32.56
32.37
XXII
XXIII
1
2-aminopyrimidine (VII) (34300 cm ). At the same
time in the solution spectra of compounds with an
azomethine bond the longwave maximum is displaced
to higher frequencies due to extension of the conjuga-
signal of azomethine proton Haz is observed down-
field ( 9.05, 9.09 ppm) compared to the signal of
similar proton in the spectra of Schiff bases VIII, IX
where the amine moiety originates from 3-amino-
pyridine (VI) (Haz 8.53 ppm) (Table 2). The spatial
arrangement of molecules XII, XIII is also com-
patible with the presence of second intermolecular
hydrogen bond between the proton of CHaz= N bond
and endocyclic nitrogen of pyridine ring A; this
1
tion system: 32100 and 30250 cm for bases XI, XII
respectively in contrast to the spectra of the initial
azines containing absorption bands at 34800 (V) and
1
34200 cm (VI) [15].
1
In the H NMR spectra of bases XII, XIII, VIII
suggestion rationalizes the large
value of azo-
XI the signals of NH2 groups present in the original
3-aminopyridine (VI) (3.69 ppm) and 2-amino-
pyridine (V) (5.85 ppm) disappear, and instead arises
a proton signal from the azomethine group in the
region 8.53 9.09 ppm (Table 2) in agreement with
the published data on the azomethines of azole series
[8 10].
methine proton in these compounds.
1
In the H NMR spectra of aminals XX XXIII,
XVIII, XIX the signals of NH2 groups observed in
the original 2-amnopyrimidine (VII) at 6,56 ppm and
in 2-aminopyridine (V) at 5.85 ppm are lacking, and
signals appear belonging to NH ( 6.00 7.58 ppm)
and CH ( 7.27 7.72 ppm) groups (Table 3). These
signals were distinguished by recording spectra in
DMSO at 80 C, therewith the NH signals sifted
upfield by 0.3 ppm whereas the CH signals did not
move.
Note the downfield position of the signal from HX
proton in the spectra of compounds XII (8.38 ppm),
VIII (8.34 ppm), X (8.1 ppm) (Table 1) as compared
to the 2-substituted 1-vinylimidazoles ( 6.6 7.0 ppm)
[16 18]. The same shift was observed in the spectra
of azomethines prepared from 2-aminobenzimidazoles
and 5-amino-3-(2-pyrrolyl)pyrazoles, and it testifies
to the participation of HX atom in an intramolecular
hydrogen bond with a nitrogen of the azomethine
group [8 10]. This situation suggests prevalence of
mutual cis-,trans-orientation of azomethine and vinyl
groups (E-isomer, A, B).
EXPERIMENTAL
1H NMR spectra were registered on spectrometer
Bruker DPX-400 at 20 25 and 70 80 C from solu-
tions in DMSO-d6 and CDCl3, internal reference
HMDS. IR spectra were recorded on spectrometer
Bruker IFS 25 from samples pelletized with KBr or as
mulls in mineral oil. Mass spectra were measured on
1
In the H NMR spectra of azomethines prepared
with the use of 2-aminopyridine, XII, XIII, the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

FEATURES OF 2-, 3-AMINOPYRIDINES
1679
GC-MS spectrometer LKB-2091 (BROMMA) with
direct sample admission into the ion source (vaporizer
The reaction mixture was boiled for 26 h in a flask
connected to the Dean-Stark trap. After evaporation
temperature 250 C), ionizing energy 60 eV. Syntheses to a volume of 10 ml the reaction mixture was poured
were carried out in anhydrous solvents.
into 30 ml of ether, the precipitate formed was
washed with cold benzene and dried. Yield 0.75 g.
3-(1-Vinylimidazol-2-yl)methyleneamino-
pyridine (VIII). To a melt of amine VI (0.3 g,
3.19 mmol) was added at stirring aldehyde I (0.4 g,
3.19 mmol) The reaction mixture was heated at
95 C for 8 h with simultaneous distillation of
liberating water at 10 15 mm Hg into a cooled trap.
The solid yellow substance obtained was ground with
50 ml of hexane. The precipitate obtained was filtered
off, washed with hexane and ether, dried. Yield 0.5 g.
2-(1-Ethylbenzimidazol-2-yl)methylenediamino-
pyridine (XIX) was similarly synthesized from a
mixture of 0.56 g (3.19 mmol) of aldehyde IV and
0.6 g (6.38 mmol) of amine V. Yield 0.67 g.
2-(1-Vinylimidazol-2-yl)methylenediamino-
pyrimidine (XX). To a solution of 2.57 g (21 mmol)
of aldehyde I in 30 ml of ethanol was added at stir-
ring 2 g (21 mmol) of amine VII. The reaction mix-
ture was boiled for 20 h. Then the solvent was
evaporated to a volume of 20 ml, the precipitate was
filtered off, washed with ethanol and ether, and dried.
Yield 1.75 g.
3-(1-Ethylimidazol-2-yl)methyleneamino-
pyridine (IX) was prepared in a similar way from
1.5 g (16 mmol) of amine VI and 2 g (16 mmol) of
aldehyde II within 16 h. Yield 2.3 g.
3-(1-Vinylbenzimidazol-2-yl)hydroxymethylene-
aminopyridine (Xa). To a solution of 0.54 g (3.19
mmol) of aldehyde III in 5 ml of benzene was added
dropwise at stirring a solution of 0.3 g (3.19 mmol)
of pyridine VI in 5 ml of benzene. The reaction
mixture with the precipitate which separated within
1 min was stirred at room temperature for 2 h. The
precipitate was filtered off, washed with benzene and
ether, and dried. Yield 0.7 g.
Likewise was synthesized 2-(1-ethylimidazol-2-yl)-
methylenediaminopyrimidine (XXI) from a mixture
of 2.0 g (16 mmol) of aldehyde II and 1.53 g
(16 mmol) of amine VII. The precipitate was filtered
off, washed with acetone and ether. Yield 1.8 g,
m/z 296.
Likewise was prepared 2-(1-vinylbenzimidazol-
2-yl)methylenediaminopyrimidine (XXII) from
a mixture of 3.6 g (21 mmol) of aldehyde III and 2 g
(21 mmol) of amine VII within 24 h. Yield 0.9 g.
3-(1-Ethylbenzimidazol-2-yl)methyleneamino-
pyridine (XI). To a solution of 0.56 g (3.19 mmol)
of aldehyde IV in 10 ml of benzene was added by
portions 0.3 g (3.19 mmol) of amine VI. The reaction
mixture was boiled for 24 h, the solvent was
evaporated till the volume of the mixture was 5 ml,
and it was cooled. The yellow solution formed was
poured into 20 ml of ether, the precipitate was filtered
off and dried. Yield 0.5 g.
Likewise was prepared 2-(1-ethylbenzimidazol-2-
yl)methylenediaminopyrimidine (XXIII) from a
mixture of 3.65 g (21 mmol) of aldehyde IV and 2 g
(21 mmol) of amine VII. Yield 1.3 g.
The constants, yields, and elemental analyses of
compounds synthesized are given in Table 1.
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2-(1-Vinylimidazol-2-yl)methyleneamino-
pyridine (XII). To a melt of amine V (1.93 g,
20.5 mmol) was added aldehyde I (2.5g, 20.5mmol).
The reaction mixture was heated at 95 C for 12 h
with simultaneous distillation of liberating water into
a cooled trap. Then the residue was subjected to
vacuum distillation. Yield 1.83 g.
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