Reactions of N-arylmaleimides with 3-amino-1,2,4-triazole and 2-aminobenzimidazole

Article abstract of DOI:10.1002/jhet.660

Figure represented. The reaction of 3-amino-1,2,4-triazole (1) with N-arylmaleimides leads to azolopyrimidines 4 and 5. The 2-aminobenzimidazole (2) in the reaction with 3 gives the pyrimidobenzimidazoles 6. In similar conditions, the reaction of amine 2 with maleic anhydride (7) leads to formation of 2-oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-4-carboxylic acid (8). The structures of 4, 5, 6, and 8 were proved by X-Ray and NOE NMR measurements. J. Heterocyclic Chem., (2011)

Full text of DOI:10.1002/jhet.660

888
Reactions of N-Arylmaleimides with 3-Amino-1,2,4-triazole and
2-Aminobenzimidazole
Vol 48
Roman V. Rudenko, Sergey A. Komykhov,* Vladimir I. Musatov,
Irina S. Konovalova, Oleg V. Shishkin, and Sergey M. Desenko
Scientific and Technological Complex "The Institute for Single Crystals,’’
National Academy of Science of Ukraine, Kharkiv 61001, Ukraine
*E-mail: komykov@isc.kharkov.com
Received August 6, 2010
DOI 10.1002/jhet.660
Published online 19 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of 3-amino-1,2,4-triazole (1) with N-arylmaleimides leads to azolopyrimidines 4 and 5.
The 2-aminobenzimidazole (2) in the reaction with 3 gives the pyrimidobenzimidazoles 6. In similar
conditions, the reaction of amine 2 with maleic anhydride (7) leads to formation of 2-oxo-1,2,3,4-tetra-
hydropyrimido[1,2-a]benzimidazole-4-carboxylic acid (8). The structures of 4, 5, 6, and 8 were proved
by X-Ray and NOE NMR measurements.
J. Heterocyclic Chem., 48, 888 (2011).
INTRODUCTION
dinucleophiles; according to these reports, the direction
of such reactions seems to be ambiguous (Scheme 1).
For example, it was reported [3] that refluxing of substi-
tuted 6-aminouracil (9) or its alkylthio derivative (10)
with maleic anhydride in acetonitril or dimethylforma-
mide leads to formation of corresponding pyrrolo[2,3-
d]pyrimidines (11, 12), whereas reaction of 9 or 10 with
maleimide occurs only as C-alkylation at position 5 of
pyrimidine ring leading to compounds 13 and 14,
respectively. Another report [4,5] describes the reaction
of 6-aminouracil (15) and its thio derivative (16) with
The interest to reactions of N-aryl imides of maleic
acid with different organic reagents is determined by
their high synthetic potential. There are many examples
of their use as dienophiles [1] in the Diels-Alder reac-
tions, leading to different bi- or tricyclic compounds.
Reactions of N-arylmaleimides with substituted thiour-
eas and thiosemicarbazides leading to thiazolidone
derivatives are broadly investigated [2].
Unfortunately, there are only a low number of reports
concerning the behavior of N-arylmaleimides with 1,3-
C
V
2011 HeteroCorporation

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Reactions of N-Arylmaleimides with 3-Amino-1,2,4-triazole and 2-Aminobenzimidazole
889
Scheme 1
N-aryl-substituted maleimides by refluxing in isopropa-
nol, which occurs as N-alkylation with participation of
amino group. There is formation of more comlicated
heterocyclic systems described by reactions of 6-amino-
uraciles and their analogs with maleic anhydride or mal-
eimide [3].
obtained. The situation becomes more complicated when
bielectrophilic component of such reaction has more
than two electrophilic centers (like compound 3). As an
instance, the reaction of amine 1 with 1,2-dibenzoyl-
ethylene could be mentioned [7] where three products
were obtained which structure corresponded to attack of
electrophile on all three endocyclic nitrogens in 3. Tak-
ing into account, the data given in Ref. 7 and polyelec-
trophilic nature of compound 3, by establishing the
structure of products described in Ref. 6 additional data
are necessary to be involved.
The reaction of aminoazoles containing the amidine
moiety, especially, 3-amino-1,2,4-triazole (1) and 2-ami-
nobenzimidazole (2), with N-aryl derivatives of malei-
mides was firstly reported at [6], according to which the
reaction leads to formation of azolopyrimidine deriva-
tives 4 and 6; the structure assignment was made based
The aim of this work was the investigation of behavior
of N-aryl maleimides in reactions with 3-amino-1,2,4-tria-
zole and 2-aminobenzimidazole. Taking into account the
described above results about the ambiguity in the direc-
tion of reactions of maleimides and maleic anhydride with
1
exclusively on H-NMR spectra in this case (Scheme 2).
Our previous research showed that in the reactions of
hererocyclic aminoazoles, like 1 and similar, with car-
bonyl bielectrophiles different isomeric products can be
Scheme 2
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R. V. Rudenko, S. A. Komykhov, V. I. Musatov, I. S. Konovalova, O. V. Shishkin, and S. M.
Desenko
Vol 48
Scheme 3
binucleophiles and amines 1 and 2 with bielectrophiles,
the structures 4-6, 17-21 (Scheme 3) could be considered.
values for protons of ABX system in 4 and 5 was not
more than 0.1 ppm. It is necessary to notice that analyti-
1
cal data and H-NMR data for compound 4a, which was
prepared similar to described in Ref. 6, were absolutely
consistent with described values. Compounds 4 showed
enhancement of the signal of triazole proton (at 8.33
ppm) by irradiation of the HX proton of ABX system
(the signal at 5.30 ppm) in the NOE experiment
(Scheme 5); compound 5 showed no such effect, which
is consistent with structures of 4 and 5 given above.
In addition, structures of 4c and 5d were confirmed
by its X-ray analysis (Fig. 1).
RESULTS AND DISCUSSION
Reaction of N-arylmaleimides (3) with 3-amino-1,2,4-
triazole (1) was carried out in different solvents: by
heating in dioxane (on conditions described in Ref. 6),
in ethanol and n-penthanol, in acetic acid and by melt-
ing together without solvent by 150–160ꢀC. As a result,
compounds 4a–g and 5a–g were prepared (Scheme 4). It
was established that when carrying out in dioxane or
isopropanol reaction leads regioselectively to formation
of compounds 4. Compounds 5 can be obtained selec-
tively by heating of 3 and 1 in acetic acid during not
more than 1 h; carrying out this reaction on this condi-
tions for a longer time led to mixtures of compounds 4
and 5. The same result was obtained by using of toluene
or dimethylformamide as a solvent. In all cases, accord-
ing to 1H-NMR data, the individual compounds were
isolated.
The tetrahydropyrimidine ring of the compound 5d
adopts asymmetric half-chair conformation (the pucker-
ing parameters [8] are S ¼ 0.48, H ¼ 43.4ꢀ, W ¼
21.3ꢀ). Deviations of the C(4) and C(5) atoms from the
mean plane of the remaining atoms of the ring are
˚
˚
ꢁ0.30 A and 0.18 A, respectively. The carbamide frag-
ment of the substituent at C(5) atom is visibly noncopla-
nar to the C(4)AC(5) endocyclic bond (the
C(4)AC(5)AC(6)AO(2) torsion angle is ꢁ65.9(3)ꢀ) due
to repulsion between hydrogen atoms (shortened intra-
˚
The structure of 4a–g and 5a–g was assigned based
on 1H-NMR including NOE experiments, NMR 13C,
mass-spectrometry. The 1H-NMR spectra of 4a–g and
5a–g were very similar and contained signals of ABX
system, protons of aromatic rings, secondary amino
groups, and triazole proton. It was noticed that the
molecular contact H(5). . .H(5NA) 2.13 A as compared
˚
with van der Waals radii sum [9] 2.34 A). The aryl
group adopts the ap-conformation relatively the
C(5)AC(6) bond (the C(5)AC(6)AN(5)AC(7) torsion
angle is ꢁ172.2(2)ꢀ) and it is turned with respect to the
C(6)AN(5) bond (the C(6AN(5)AC(7)AC(8) torsion
angle is ꢁ58.0(3). Such orientation of this substituent
leads to the appearance of the H(5NA). . .F(3) shortened
1
chemical shift values in the H-NMR spectra of products
obtained by heating in acetic acid (compounds 5) were
different from corresponding values for the products
obtained in alcohols or dioxane (4), especially, the
chemical shift values for triazole protons. For instance,
compounds 4 had a signal for triazole proton at 7.74–
7.76 ppm, whereas compounds 5 the corresponding sig-
nal was situated at 8.30–8.35 ppm. The difference in d
˚
˚
intramolecular contact 2.52 A (2.56 A), which cannot be
considered as hydrogen bond owing to very small value
of the NAH. . .F angle (108ꢀ). In the crystal phase mole-
cules of 5d form centrosymmetric dimers due to the
N(4)AH(4NA). . .N(3)0 (ꢁx, ꢁyþ1, ꢁzþ1) intermolecu-
ꢀ
˚
lar hydrogen bond (H. . .N 2.07 A NAH. . .N 166 ).
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Reactions of N-Arylmaleimides with 3-Amino-1,2,4-triazole and 2-Aminobenzimidazole
891
(the puckering parameters [8] are S ¼ 0.62, H ¼ 40.6ꢀ,
W ¼ 24.7ꢀ in A, S ¼ 0.61, H ¼ 42.2ꢀ, W ¼ 24.3ꢀ B).
Deviations of the C(4) and C(5) atoms from the mean
Scheme 4
˚
plane of the remaining atoms of the ring are ꢁ0.26 A
˚
and 0.36 A, respectively in both A and B molecules.
The carbamide fragment of the substituent at the C(5)
atom is almost coplanar to the N(3)AC(5) endocyclic
bond (the N(3)AC(5)AC(6)AO(2) torsion angle is
8.1(5)ꢀ A, 8.3(5)ꢀ B). The o-chlorophenyl group is prac-
tically coplanar to the carbamide fragment (the
N(3)AC(5)AC(6)AO(2) torsion angle is 6.4(7)ꢀ A,
5.6(7) B). Such position of this group is stabilized by
the C(12)AH(12). . .O2 intramolecular hydrogen bond
ꢀ
˚
(H. . .O 2.13 A C-H. . .O 126 in molecule A, H. . .O
ꢀ
˚
2.15 A C-H. . .O 126 in B). The o-chlorophenyl substit-
uent is disordered over two position due to the rotation
around the C(7)AN(5) bond with populations 60:40% in
molecules A and B. In the crystal phase, molecules 4c
form dimers between molecules A and B due to the
N(4)AH(4NA). . .N(2B)0 (x, yꢁ1, z) intermolecular
ꢀ
˚
hydrogen bond (H. . .N 2.02 A, NAH. . .N 164 ). In the
crystal form hydrophilic cavity which contain water
molecules (Fig. 2).
We also studied the reaction of 2-aminobenzimidazole
(2) with N-arylmaleimides (3) by heating in dimethylfor-
mamide or dioxane (Scheme 6). The single product (6)
was isolated; its analytical data were consistent with
given in [6]. According to NMR data including NOE
experiments (Scheme 6), the structure of 6 was assigned
1
as given on Scheme 4. The H-NMR spectra of 6 con-
tained except signals of ABX system and aryl rings,
additionally signals for ABDC system of benzimidazole
ring. The enhancement of one of the signals of benzim-
idazole moiety (7.43 ppm) by irradiation of HX proton
(signal at 5.38 ppm) in the NOE experiment (Scheme 6)
allowed to propose the structure of 6 as shown on
Scheme 6.
Finally, we investigated the reaction of amine 2 with
maleic anhydride (7). Heating of components in dime-
thylformamide during 5 led to formation of 2-oxo-
1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-4-carbox-
Scheme 5
These dimers form the infinite chains along [0 1 0] crys-
tallographic direction due to the N(5)AH(5NA). . .O(2)0
(x, yꢁ1, z) intermolecular hydrogen bond (H. . .O0 2.12
0
ꢀ
˚
A, NAH. . .O 170 ).
The compound 4c is observed in the crystal phase
with water solvent molecules with the 1:1 ratio. Two
molecules (A and B) with some differences in geometri-
cal parameters are observed in the asymmetric part of
the unit cell. The tetrahydropyrimidine ring in both iso-
mers adopts almost identical half-chair conformation
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R. V. Rudenko, S. A. Komykhov, V. I. Musatov, I. S. Konovalova, O. V. Shishkin, and S. M.
Desenko
Vol 48
Figure 1. Molecular structures of compounds 4c and 5d, respectively with numerations of nonhydrogen atoms used in the structural analysis.
The crystals of 4c (C12H10N5O2Cl1ꢂH2O) are monoclinic. At
ylic acid (8), Scheme 7. The structure assignment was
˚
293 K, a ¼ 13.385(1), b ¼ 13.268(1), c ¼ 18.043(1) A, b ¼
achieved by use of the same approach as for compound
6: the irradiation of the methine proton (signal at 5.46
ppm) in the NOE experiment showed the enhancement
of the signal at 7.38 ppm (of the benzimidazole proton).
´
3
˚
90.13(4), V ¼ 3204.2(3)A , Mr ¼ 615.40, Z ¼ 8w, space
group P21/n, dcalc ¼ 1.276 g/cm3, l (MoKa) ¼ 0.254 mmꢁ1
,
F(000) ¼ 1264. Intensities of 19076 reflections (5534 inde-
pendent, Rint ¼0.061) were measured on the «Xcalibur-3» dif-
fractometer (graphite monochromated MoKa radiation, CCD
detector, x-scaning, 2Hmax ¼ 50ꢀ).
The structures were solved by direct method using
EXPERIMENTAL
SHELX97 package [10]. The restrains for the bond lengths
3
˚
˚
(CArACAr 1.38 A, Csp -Cl 1.79 A) in the disordered fragments
were applied during refinement of the structure 4c. Positions
of the hydrogen atoms were located from electron density dif-
ference maps and refined by ‘‘riding’’ model with Uiso ¼ nUeq
of the carrier atom (n ¼ 1.5 for methyl group and n ¼ 1.2 for
General. Melting points were determined with a Kofler ap-
paratus. The yields of 3a–e are given after their crystallization.
1
The H- and 13C-NMR spectra were recorded in DMSO-d6 at
200 MHz (50 MHz for 13C) on a Varian Mercury VX-200
spectrometer, internal standard was Si(CH3)4. The EI mass
spectra were obtained on Varian 1200L with electron energy
70 eV.
X-ray
diffraction
study. The
crystals
of
5d
Scheme 6
(C13H10F3N5O2) are monoclinic. At 293 K, a ¼ 20.517(1), b
´
˚
3
˚
¼ 4.884(1), c ¼ 14.135(1) A, b ¼ 97.02(1), V ¼ 1406 (1) A ,
Mr ¼ 325.26, Z ¼ 4, space group P21/c, dcalc ¼ 1.537 g/cm3,
l(MoKa¼ 0.135 mmꢁ1, F(000) ¼ 664. Intensities of 7738
reflections (2421 independent, Rint ¼0.037) were measured on
the «Xcalibur-3» diffractometer (graphite monochromated
MoKa radiation, CCD detector, x-scaning, 2Hmax ¼ 50ꢀ).
Figure 2. Cavity in the crystal of 4c containing water.
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Reactions of N-Arylmaleimides with 3-Amino-1,2,4-triazole and 2-Aminobenzimidazole
893
Scheme 7
other hydrogen atoms. Positions of the hydrogen atoms on the
water molecules could not be detected.
7-Oxo-N-(2-chlorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo
[4,3-a]pyrimidine-5-carboxamide (4c). Colorless crystals,
Full-matrix least-squares refinement of the structures against F2
in anisotropic approximation for nonhydrogen atoms using 7738
(5d), 19076 (4c) reflections were converged to: wR2 ¼ 0.142 (R1
¼ 0.049 for 1390 reflections with F > 4r(F), S ¼ 0.882) for struc-
ture 5d and wR2 ¼ 0.264 (R1 ¼ 0.093 for 2200 reflections with
F > 4r(F), S ¼ 0.785) for structure 4c. The final atomic coordi-
nates and crystallographic data for molecules 5d and 4c have been
deposited to with the Cambridge Crystallographic Data Centre,
UK, and are available on request quoting the deposition numbers
CCDC 773608 for 4c and CCDC 773609 for 5d).
3
m.p. > 300ꢀC. 1H-NMR (DMSO-d6) d 2.83 (1H, dd, JAX
¼
2
3
3.0, JAB ¼ 16.8 Hz, HA), 3.33 (1H, dd, JBX ¼ 7.4 Hz, HB),
5.44 (1H, dd, HX), 7.37–7.18 (2H, m, ArH), 7.62–7.48 (2H, m,
ArH), 8.33 (1H, s, 2-H), 10.18 (1H, s, NHCOAr), 11.5 (1H, br
s, 8-HNH).
7-Oxo-N-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro[1,2,4]
triazolo[4,3-a]pyrimidine-5-carboxamide (4d). Colorless crys-
tals, m.p. < 300ꢀC. 1H-NMR (DMSO-d6): d 2.81 (1H, dd,
2
3
3JAX ¼ 3.1, JAB ¼ 16.8 Hz, 6-HA), 3.33 (1H, dd, JBX ¼ 7.5
Hz, 6-HB), 5.42 (1H, dd 5-HX), 7.54–7.45 (2H, m, ArH), 7.78–
7.67 (2H, m, ArH), 8.31 (1H, s, 2-H), 11.80–10.0 (2H, br s,
NHCOAr þ 8-HNH). 13C-NMR (DMSO-d6): d 33.4, 51.7,
125.9 (1C, q, 1J(13C19F) ¼ 271 Hz, CF3), 125.0 (1C, q,
2J(13C19F) ¼ 30.3 Hz, CAr-CF3), 126.3, (1C, q, 3J(13C19F) ¼
4.8 Hz, m-CAr), 127.3, 129.9, 132.9, 134.0, (CAr), 139.4,
149.2, 165.6, 167.4.
General procedure for the synthesis of 7-oxo-N-aryl-
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-5-carboxa-
mide 4a–g. A mixture of the 3-amino-1,2,4-triazole (1, 0.42 g,
0.005 mol) and corresponding N-arylmaleimide (3, 0.005 mol)
in 10 mL of appropriate solvent was refluxed for 3 h. After
cooling, the precipitate formed was filtered off and recrystal-
lized from acetone and air-dried.
7-Oxo-N-(5-chloro-2-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]
triazolo[4,3-a]pyrimidine-5-carboxamide (4e). Colorless crystals,
7-Oxo-N-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrim-
idine-5-carboxamide (4a). Colorless crystals, m.p. > 300ꢀC.
1
3
m.p. > 300ꢀC. H-NMR (DMSO-d6): d 2.77 (1H, dd, JAX
¼
3
2
2
3
1H-NMR (DMSO-d6): d 2.81 (1H, dd, JAX ¼2.9, JAB ¼ 16.7
2.8 Hz, JAB ¼ 16.9 Hz, 6-HA), 3.30 (1H, dd, JBX ¼ 7.5 Hz,
6-HB), 3.87 (3H, s, CH3O), 5.50 (1H, dd, 5-HX), 7.22–7.06
(2H, m, ArH), 7.98–7.93 (1H, m, o-ArH), 8.32 (1H, s, 2-H),
10.0 (1H, br s, NHCOAr), 11.3 (1H, br s, 8-HNH); m/z (EI, rel.
%): 321 (2) [Mþ], 157 (10), 155 (20), 140 (36), 138 (34), 137
(29), 127 (13), 84 (100).
3
Hz, HA), 3.33 (1H, dd, JBX ¼7.5 Hz, 16.7 Hz, HB), 5.30 (1H,
dd, HX), 7.12–7.04 (1H, m, p-ArH), 7.36–7.27 (2H, m, m-
ArH), 7.57–7.52 (2H, m, o-ArH), 8.33 (1H, s, 2-H), 10.52
(1H, s, NHCOAr), 11.5 (1H, br. s, 8-H, NH). 13C-NMR
(DMSO-d6): d 33.5, 52.3, 119.5, 123.9, 128.6, 128.6, 137.9,
139.4, 149.3, 165.8, 166.0. Anal. Calcd. for C12H11N5O2: C,
56.03; H, 4.31; N, 27.22%. Found: C, 55.1; H, 4.2; N, 26.8.
7-Oxo-N-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo
[4,3-a]pyrimidine-5-carboxamide (4b). Colorless crystals,
7-Oxo-N-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]
triazolo[4,3-a]pyrimidine-5-carboxamide (4f). Colorless crys-
1
3
tals, m.p. > 300ꢀC. H-NMR (DMSO-d6): d 2.81 (1H, dd, JAX
2
3
¼ 2.7, JAB ¼ 16.8 Hz, 6-HA), 3.32 (1H, dd, JBX ¼ 7.5 Hz, 6-
HB), 3.71 (6H, s, 2*CH3O), 5.26 (1H, dd, 5-HX), 6.91 (1H, m,
m-ArH), 7.05 (1H, m, o-ArH), 7.28 (1H, m, o0-ArH) 8.33 (1H,
s, 2-H), 10.36 (1H, br s, NHCOAr), 11.4 (1H, br s, 8-HNH).
7-Oxo-N-(3-fluoro-4-methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]
triazolo[4,3-a]pyrimidine-5-carboxamide (4g). Colorless crys-
tals, m.p. 296–297ꢀC. 1H-NMR (DMSO-d6): d 2.18 (3H, s,
1
3
m.p. > 300ꢀC. H-NMR (DMSO-d6): d 2.84 (1H, dd, JAX
¼
3.1 Hz, 2JAB ¼16.8 Hz, HA), 3.34 (1H, dd, 3JBX ¼ 7.3 Hz, HB),
5.29 (1H, dd, HX), 7.22–7.13 (2H, m, m-ArH), 7.62–7.54 (2H,
m, o-ArH), 8.34 (1H, s, 2-H), 10.57 (1H, s, NHCOAr), 11.5
(1H, br s, 8-H, NH). 13C-NMR (DMSO-d6): d 33.7, 52.4,
115.45 (d, J(13C19F) ¼ 22.7 Hz, m-CAr), 121.3 (d, J(13C19F)
2
3
4
2
3
¼ 8.0 Hz, o-CAr), 134.5 (d, J(13C19F) ¼ 2.2 Hz, CAr), 139.8,
CH3), 2.81 (1H, dd, JAX ¼ 2.9 Hz, JAB ¼ 16.8 Hz, 6-HA),
1
3
149.5, 158.4 (d, J(13C19F) ¼ 241 Hz, p-CAr), 166.1, 166.2. m/z
3.33 (1H, dd, JBX ¼ 7.6 Hz, 6-HB), 5.28 (1H, dd, 5-HX),
(EI, rel. %): 191 (2), 137 (19), 135 (16), 121 (23), 84 (100).
7.29–7.15 (2H, m, ArH), 7.50–7.43 (1H, m, ArH), 8.32 (1H, s,
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Vol 48
3
2-H), 10.62 (1H, br s, NHCOAr), 11.5 (1H, br s, 8-HNH); m/z
(EI, rel. %): 289 (5) [Mþ], 137 (6), 124 (13), 84 (100).
General procedure for the synthesis of 5-oxo-N-aryl-
4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxa-
mide 5a–g. A mixture of the 3-amino-1,2,4-triazole (1, 0.42 g,
0.005 mol) and of the corresponding N-arylmaleimide (3,
0.005 mol) in 1 mL of appropriate solvent was refluxed for 1
h. After cooling, mixture was diluted of acetone. The precipi-
tate formed was filtred off and air-dried.
> 300ꢀC. 1H-NMR (DMSO-d6) dH 2.84 (1H, dd, JAX ¼ 1.8
2
3
Hz, JAB ¼ 16.9 Hz, 6-HA), 3.52 (1H, dd, JBX ¼ 8.1 Hz, 6-
HB), 5.31 (1H, dd, 7-HX), 7.07–6.94 (2H, m, ArH), 7.20–7.18
(2H, m, ArH), 7.77 (1H, s, 2-H), 10.53 (1H, br s, NHCOAr),
11.3 (1H, br s, 4-HNH); m/z (EI, rel. %): 293 (33), 291 (100)
[Mþ], 138 (68), 137 (100), 84 (37), 83 (85). Anal. Calcd. for
C12H10ClN5O2: C, 49.41; H, 3.46; N, 24.01%. Found: C, 49.2;
H, 3.5; N, 24.1.
General procedure for the synthesis of 2-oxo-N-aryl-
1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-4-carboxamide
6a–g. A mixture of the 2-aminobenzimidazole (2, 0.4 g, 0.003
mol) and of the corresponding N-arylmaleimide (3, 0.003 mol)
in 1 mL of DMF was refluxed for 10 min. After cooling, mix-
ture was diluted of acetone, the precipitate formed was filtred
off and air dried.
5-Oxo-N-phenyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]py-
rimidine-7-carboxamide (5a). Colorless crystals, m.p.
>
1
3
300ꢀC. H-NMR (DMSO-d6): d 2.88 (1H, dd, JAX ¼ 2.0 Hz,
2JAB ¼ 16.8 Hz, 6-HA), 3.51 (1H, dd, JBX ¼ 8.2 Hz, 6-HB),
3
5.25 (1H, dd, 7-HX), 7.14–7.07 (1H, m, p-ArH), 7.37–7.29
(2H, m, m-ArH), 7.59–7.55 (2H, m, o-ArH), 7.77 (1H, s, 2-H),
10.52 (1H, s, NHCOAr), 11.5 (1H, br s, 4-HNH). Anal. Calcd.
for C12H11N5O2: C, 56.03; H, 4.31; N, 27.22%. Found: C,
54.5; H, 4.3; N, 26.6.
2-Oxo-N-phenyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimid-
azole-4-carboxamide (6a). Coloress crystals, m.p. > 300ꢀC.
1H-NMR (DMSO-d6): d 2.92 (1H, d, JAB ¼ 16.7 Hz, 3-HA),
2
3
5-Oxo-N-(2-chlorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo
[1,5-a]pyrimidine-7-carboxamide (5b). Colorless crystals, m.p.
3.50 (1H, dd, JBX ¼ 7.8 Hz, 3-HB), 5.38 (1H, d, 4-HX), 7.18–
7.03 (3H, m, ArH), 7.37–7.26 (2H, m, ArH), 7.49–7.39 (2H,
m, ArH), 7.61–7.51 (2H, m, ArH), 10.63 (1H, s, NHCOAr),
11.5 (1H, br s, 1-HNH). 13C-NMR (DMSO-d6): d 33.4, 51.9,
108.3, 117.0, 119.5, 120.5, 121.4, 123.8, 128.4, 132.3, 137.7,
141.7, 148.3, 166.0, 166.8. Anal. Calcd. for C17H14N4O2: C,
66.66; H, 4.61; N, 18.29%. Found: C, 66.6; H, 4.5; N, 18.1.
2-Oxo-N-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-
a]benzimidazole-4-carboxamide (6b). Coloress crystals, m.p.
3
> 300ꢀC. 1H-NMR (DMSO-d6) dH 2.87 (1H, dd, JAX ¼ 1.8
2
3
Hz, JAB ¼ 16.8 Hz, 6-HA), 3.55 (1H, dd, JBX ¼ 8.5 Hz, 6-
HB), 5.48 (1H, dd, 7-HX), 7.38–7.20 (2H, m, ArH), 7.67–7.50
(2H, m, ArH), 7.79 (1H, s, 2-H), 10.20 (1H, br s, NHCOAr),
11.50 (1H, br s, 4-HNH). Anal. Calcd. for C12H10ClN5O2: C,
49.41; H, 3.46; N, 24.01%. Found: C, 48.9; H, 3.4; N, 24.2.
5-Oxo-N-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-[1,2,4]
triazolo[4,3-a] pyrimidine-7-carboxamide (5c). Colorless crys-
tals, m.p. > 300ꢀC. 1H-NMR (DMSO-d6): d 2.78 (1H, dd,
> 300ꢀC. 1H-NMR (DMSO-d6): d 2.89 (1H, d, JAB ¼ 16.8
2
3
Hz, 3-HA), 3.47 (1H, dd, JBX ¼ 7.8 Hz, 3-HB), 3.72 (3H, s,
2
3
3JAX ¼ 1.8 Hz, JAB ¼ 16.8 Hz, 6-HA), 3.57 (1H, dd, JBX
¼
CH3O), 5.34 (1H, d 4-HX), 6.92–6.84 (2H, m, ArH), 7.17–7.08
(2H, m, ArH), 7.51–7.37 (4H, m, ArH), 10.36 (1H, s,
NHCOAr), 11.4 (1H, br s, 1-HNH); Anal. Calcd. for
C18H16N4O3: C, 64.28; H, 4.79; N, 16.66%. Found: C, 63.8;
H, 4.8; N, 16.4.
8.2 Hz, 6-HB), 5.39 (1H, dd, 7-HX), 7.54–7.44 (2H, m, ArH),
7.77–7.66 (2H, m, ArH), 7.78 (1H, s, 2-H), 10.26 (1H, br s,
NHCOAr), 11.50 (1H, br s, 4-HNH). 13C-NMR (DMSO-d6): d
33.5, 54.6, 123.1 (1C, q, 1J(13C19F) ¼ 274 Hz, CF3), 124.6
(1C, q, 2J(13C19F) ¼ 29.8 Hz, CAr-CF3), 126.1, (1C, q,
3J(13C19F) ¼ 5.1 Hz, m-CAr), 127.0, 129.3, 132.7, 133.8, (1C,
2-Oxo-N-(2-chlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]
benzimidazole-4-carboxamide (6c). Coloress crystals, m.p. >
q, J(13C19F) ¼ 2.0 Hz, CAr), 150.1, 150.6, 165.7, 167.3.
300ꢀC. H-NMR (DMSO-d6): d 2.92 (1H, d, JAB ¼ 16.9 Hz,
4
1
2
3
5-Oxo-N-(5-chloro-2-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]
triazolo[4,3-a] pyrimidine-7-carboxamide (5d). Colorless crys-
tals, m.p. > 300ꢀC. 1H-NMR (DMSO-d6): d 2.83 (1H, dd,
3-HA), 3.52 (1H, dd, JBX ¼ 8.1 Hz, 3-HB), 5.60 (1H, d, 4-
HX), 7.37–7.08 (4H, m, ArH), 7.64–7.40 (4H, m, ArH), 10.25
(1H, s, NHCOAr), 11.4 (1H, br s, 1-HNH); m/z (EI, rel. %):
342 (39) [Mþ], 340 (13) [Mþ], 186 (11), 158 (7), 144 (28),
133 (39), 131 (12), 127 (15), 126 (16), 90 (100). Anal. Calcd.
for C17H13ClN4O2: C, 59.92; H, 3.85; N, 16.44%. Found: C,
59.5; H, 3.84; N, 16.4
3JAX ¼ 1.8, JAB ¼ 17.1 Hz, 6-HA), 3.49 (1H, dd, JBX ¼ 8.4
Hz, 6-HB), 3.87 (3H, s, CH3O), 5.60 (1H, dd, 7-HX), 7.20–
7.07 (2H, m, ArH), 7.78 (1H, s, 2-H), 8.00 (1H, m, o-ArH),
10.0 (1H, br s, NHCOAr), 11.5 (1H, br s, 4-HNH). 13C-NMR
(DMSO-d6): d 33.6, 54.8, 56.1, 112.8, 120.8, 123.8, 124.2,
127.5, 148.4, 150.3, 150.7, 166.0, 166.9; m/z (EI, rel. %): 323
(9) [Mþ], 321 (27) [Mþ], 138 (98), 137 (100), 110 (47), 109
(36), 84 (48).
2
3
2-Oxo-N-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyri-
mido[1,2-a]benzimida-zole-4-carboxamide (6d). Coloress crys-
tals, m.p. > 300ꢀC. H-NMR (DMSO-d6): d 2.87 (1H, d, JAB
1
2
3
¼ 16.7 Hz, 3-HA), 3.56 (1H, dd, JBX ¼ 7.9 Hz, 3-HB), 5.53
5-Oxo-N-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[4,3-a]pyrimidine-7-carboxamide (5e). Colorless crystals,
m.p. > 300ꢀC. 1H-NMR (DMSO-d6): d 2.13 (3H, s, CH3),
(1H, d, 4-HX), 7.22–7.08 (2H, m, ArH), 7.54–7.35 (4H, m,
ArH), 7.79–7.61 (2H, m, ArH), 10.36 (1H, s, NHCOAr), 11.5
(1H, br s, 1-HNH); Anal. Calcd. for C18H13F3N4O2: C, 57.76;
H, 3.5; N, 14.97%. Found: C, 57.6; H, 3.6; N, 14.9.
3
2
2.24 (3H, s, CH3), 2.85 (1H, dd, JAX ¼ 2.2 Hz, JAB ¼ 16.9
3
Hz, 6-HA), 3.52 (1H, dd, JBX ¼ 8.1 Hz, 6-HB), 5.33 (1H, dd,
2-Oxo-N-(4-chlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]
benzimidazole-4-carboxamide (6e). Coloress crystals, m.p. >
7-HX), 7.06–6.92 (2H, m, ArH), 7.22–7.18 (1H, m, ArH), 7.78
(1H, s, 2-H), 9.87 (1H, br s, NHCOAr), 11.3 (1H, br s, 4-
HNH). 13C-NMR (DMSO-d6): d 17.7, 20.5, 34.1, 55.1, 124.9,
125.4, 130.9, 131.9, 132.5, 135.1, 150.3, 150.9 166.64,
166.65.; m/z (EI, rel. %): 285 (8) [Mþ], 138 (68), 137 (100),
84 (39), 83 (85).
1
2
300ꢀC. H-NMR (DMSO-d6): d 2.91 (1H, d, JAB ¼ 16.8 Hz,
3
3-HA), 3.49 (1H, dd, JBX ¼ 7.8 Hz, 3-HB), 5.35 (1H, d, 4-
HX), 7.14–7.05 (2H, m, ArH), 7.45–7.31 (4H, m, ArH), 7.61–
7.52 (2H, m, ArH), 10.74 (1H, s, NHCOAr), 11.4 (1H, br s, 1-
HNH). 13C-NMR (DMSO-d6): d 33.3, 51.9, 108.3, 117.1,
120.6, 121.0, 121.4, 127.6, 128.4, 132.3, 136.6, 141.7, 148.3,
166.1, 167.0; m/z (EI, rel. %): 342 (24) [Mþ], 340 (8) [Mþ],
5-Oxo-N-(3-chlorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo
[4,3-a]pyrimidine-7-carboxamide (5f). Colorless crystals, m.p.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Reactions of N-Arylmaleimides with 3-Amino-1,2,4-triazole and 2-Aminobenzimidazole
895
186 (39), 158 (14), 144 (59), 133 (84), 131 (21), 127 (28), 126
(27), 90 (100). Anal. Calcd. for C17H13ClN4O2: C, 59.92; H,
3.85; N, 16.44%. Found: C, 59.3; H, 3.8; N, 16.3.
7.35 (2H, m, ArH), 11.8 (2H, br s, 1-HNHþCOOH). 13C-NMR
(DMSO-d6): d 32.9, 50.3, 108.9, 117.0, 120.7, 121.4, 132.7,
141.6, 147.6, 166.2, 170.0. Anal. Calcd. for C11H9N3O3: C,
57.14; H, 3.92; N, 18.17%. Found: C, 57.5; H, 4.2; N, 17.9.
2-Oxo-N-(2,4-dimethylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]
benzimidazole-4-carboxamide (6f). Coloress crystals, m.p. >
300ꢀC. 1H-NMR (DMSO-d6): d 2.07 (3H, s, CH3), 2.22 (3H,
2
s, CH3), 2.91 (1H, d, JAB ¼ 17.2 Hz, 3-HA), 3.52 (1H, dd,
REFERENCES AND NOTES
3JBX ¼ 8.2 Hz, 3-HB), 5.47 (1H, d, 4-HX), 7.22–6.9 (5H, m,
ArH), 7.54–7.37 (2H, m, ArH), 9.93 (1H, s, NHCOAr), 11.5
(1H, br s, 1-HNH); m/z (EI, rel. %): 334 (74) [Mþ], 186 (41),
159 (44), 158 (53), 144 (93), 133 (100), 131 (27), 121 (63),
117 (45), 90 (70). Anal. Calcd. for C19H18N4O2: C, 68.24; H,
5.43; N, 17.76%. Found: C, 68.1; H, 5.4; N, 17.6.
[1] About reactions of N-aryl maleimides as dienophiles see (a)
Meinwald, J.; Emerman, S. L.; Yang, N. C.; Bu¨chi, G. J Am Chem
Soc 1955, 77, 4401; (b) Blomquist, A. T.; Verdol, J. A. J Am Chem
Soc 1955, 77, 1806; (c) Blomquist, A. T.; Verdol, J. A. J Am Chem
Soc 1956, 78, 109; (d) Tsuchiya, T.; Arai, H.; Igeta, H. Tetrahedron
1973, 29, 2747.
2-Oxo-N-(4-carboxy)-1,2,3,4-tetrahydropyrimido[1,2-a]benz-
imidazole-4-carboxamide (6g). Coloress crystals, m.p.
[2] Shimo, T.; Matsuda, Y.; Iwanaga, T.; Shinmyozu, T.;
Somekawa, K. Heterocycles 2007, 71, 1053.
´
[3] Cobo, J.; Sanchez, A.; Nogueras, M. Tetrahedron 1998, 54,
>
1
2
300ꢀC. H-NMR (DMSO-d6): d 2.95 (1H, d, JAB ¼ 17.0 Hz,
3
3-HA), 3.51 (1H, dd, JBX ¼ 8.1 Hz, 3-HB), 5.41 (1H, d, 4-
5753.
HX), 7.15–7.07 (2H, m, ArH), 7.46–7.38 (2H, m, ArH), 7.68–
7.63 (2H, m, ArH), 7.90–7.85 (2H, m, ArH), 10.92 (1H, s,
NHCOAr), 12.0 (2H, br s, 1-HNHþCOOH). Anal. Calcd. for
C18H18N4O4: C, 61.71; H, 4.03; N, 15.99%. Found: C, 60.9;
H, 4.1; N, 15.7.
[4] Velchinskaya, E.; Petsushak, B.; Rogal, A. Chem Hetero-
cycl Compd (Engl. Transl.), 2007, 43, 695.
[5] Vel’chinskaya, E. V.; Kuz’menko, I. I.; Kulik, L. S. Phar-
maceutical Chemistry J 1999, 33, 155.
[6] Kovygin, Y. A.; Krylski, D. V.; Zorina, A. V.; Shikhaliev,
K. S. Chem Heterocycl Compd (Engl. Transl.), 2004, 40, 1222.
[7] (a) Desenko, S. M.;Chem Heterocycl Compd (Engl.
Transl.), 1900, 26, 1362; (b) Desenko, S. M.; Orlov, V. D.; Lipson, V.
V.; Kaganovsky, A. A.; Tue, Z. V.; Ivkov, S. M. Doklady Akademii
Nauk Ukrainskoy SSR, Ser. B (Russian), 1990, No. 7, 45.
[8] Zefirov, N. S.; Palyulin, V. A.; Dashevskaya, E. E. J Phys
Org Chem 1990, 3, 147.
2-Oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-4-car-
boxylic acid (6h). A mixture of the 2-aminobenzimidazole (2,
0.4 g, 0.003 mol) and of the maleic anhydride (3, 0.3 g, 0.003
mol) in 1 mL of DMF was refluxed for 5 min. After cooling,
mixture was diluted of acetone, the precipitate formed was fil-
tred off and air dried.
Coloress crystals, m.p. > 300ꢀC. 1H-NMR (DMSO-d6): d
2
3
2.90 (1H, d, JAB ¼ 16.8 Hz, 3-HA), 3.42 (1H, dd, JBX ¼ 7.8
[9] Zefirov, Y. V. Kristallografiya (Russian), 1997, 42, 936.
[10] Sheldrick, G. M. Acta Crystallogr 2008, A64, 112.
Hz, 3-HB), 5.49 (1H, d, 4-HX), 7.16–7.04 (2H, m, ArH), 7.44–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet