Three-component condensation of 4-aryl-1,4-dihydrobenzo[4,5]imidazo[1,2-a] [1,3,5]triazin-2-amines with formaldehyde and primary amines

Article abstract of DOI:10.1134/S1070428011070177

Three-component cyclization of 4-aryl-1,4-dihydrobenzo[4,5]imidazo[1,2-a] [1,3,5]triazin-2-amines with formaldehyde and primary amines gave the corresponding 6-unsubstituted or 6-aryl-2-alkyl-2,3,4,6-tetrahydro-1H-[1,3,5] triazino[1',2':3,4][1,3,5]triazino[1,2-a]benzimidazoles.

Full text of DOI:10.1134/S1070428011070177

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 7, pp. 1074–1076. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.Yu. Potapov, A.S. Shestakov, V.N. Verezhnikov, Kh.S. Shikhaliev, 2011, published in Zhurnal Organicheskoi Khimii, 2011,
Vol. 47, No. 7, pp. 1057–1059.
Three-Component Condensation of 4-Aryl-1,4-dihydro-
benzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines
with Formaldehyde and Primary Amines
A. Yu. Potapov, A. S. Shestakov, V. N. Verezhnikov, and Kh. S. Shikhaliev
Voronezh State University, Universitetskaya pl. 1, Voronezh, 394006 Russia
e-mail: pistones@mail.ru
Received July 18, 2010
Abstract—Three-component cyclization of 4-aryl-1,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines
with formaldehyde and primary amines gave the corresponding 6-unsubstituted or 6-aryl-2-alkyl-2,3,4,6-tetra-
hydro-1H-[1,3,5]triazino[1′,2′:3,4][1,3,5]triazino[1,2-a]benzimidazoles.
DOI: 10.1134/S1070428011070177
Reactions of substituted guanidines [1] and
2-aminobenzimidazoles [2] with formaldehyde and
primary amines provide a synthetic route to hydro-
genated 1,3,5-triazine derivatives. In the present work
we performed analogous reaction with 4-aryl-1,4-dihy-
drobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines
IIIa–IIIf which are readily available via condensation
of 1-(1H-benzimidazol-2-yl)guanidine (I) with aro-
matic aldehydes IIa–IIf (Scheme 1). Martin et al. [3]
previously proposed two procedures for the synthesis
of these compounds, and the products were assigned
the structure of tautomeric 4-aryl-3,4-dihydrobenzo-
[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines IVa–IVf on
the basis of only IR spectra and elemental analyses.
1
We examined their H NMR spectra in DMSO-d6 and
found that the CH and NH proton signals appear as
two singlets, which corresponds to tautomeric structure
of 4-aryl-1,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]-
triazin-2-amines III, whereas the CH and NH protons
in the triazine ring of tautomers IV should resonate as
two doublets. The melting points of IIIa and IIIb coin-
cided with those reported in [3] for IVa and IVb.
Scheme 1.
Ar
Ar
N
NH
N
H2N
NH2
NH2
NH
N
N
N
ArCHO (IIa–IIf)
NH
NH
N
H
N
N
I
IIIa–IIIf
IVa–IVf
Ar = Ph (a), 4-MeOC6H4 (b), 2-MeOC6H4 (c), 4-FC6H4 (d), pyridin-3-yl (e), pyridin-4-yl (f).
Scheme 2.
Ar
Ar
N
N
NH2
NH
N
N
N
+
2CH2O
+
RNH2
NH
N
N
N
R
IIIa–IIId
V
VIa–VId
VIIa–VIId
III, VII, Ar = Ph (a), 4-MeOC6H4 (b), 2,5-(MeO)2C6H3 (c), 4-FC6H4 (d); VI, VII, R = PhCH2 (a), puridin-3-ylmethyl (b),
2-morpholinoethyl (c), PhCH2CH2 (d).
1074

THREE-COMPONENT CONDENSATION OF 4-ARYL-1,4-DIHYDRO-BENZO[4,5]IMIDAZO...
1075
Scheme 3.
Py
Py
Py
N
N
N
H
CH2O (V)
NH2
N
N
N
N
N
CH2
CH2
NH
NH
NH
N
N
N
IIIe, IIIf
A
CH2
N
N
N
2H2CO
RNH2 (VIa, VIc)
H
N
N
NH2
NH
N
N
N
Py
–PyCHO
NH
NH
N
N
N
N
R
B
VIIe, VIIf
III, Py = pyridin-3-yl (e), pyridin-4-yl (f); VIa, VIIe, R = PhCH2; VIc, VIIf, R = 2-morpholinoethyl.
Reactions of 4-aryl-1,4-dihydrobenzo[4,5]imidazo-
[1,2-a][1,3,5]triazin-2-amines IIIa–IIId with formal-
dehyde (V) and primary amines VIa–VId lead to
fusion of a new triazine ring to the existing one with
formation of 2-alkyl-6-aryl-2,3,4,6-tetrahydro-1H-
[1,3,5]triazino[1′,2′:3,4][1,3,5]triazino[1,2-a]benzimid-
azoles VIIa–VIId (Scheme 2). The reaction occurred
most smoothly when a mixture of equimolar amounts
of the reactants was heated in boiling dioxane con-
taining a small amount (10%) of dimethylformamide.
The products separated from the reaction mixture on
cooling (yield 54–85%). Unlike initial 4-aryl-1,4-dihy-
drobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines
The subsequent three-component condensation of B
with formaldehyde and primary amine yields final
product VIIe or VIIf (Scheme 3).
Compounds VIIa–VIIf were isolated as white crys-
talline substances which were poorly soluble in most
organic solvents and soluble in DMF and DMSO on
heating.
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by TLC on Silufol UV-254 plates
using chloroform–methanol (5 : 1) as eluent. The
1H NMR spectra were recorded on a Bruker AC-300
spectrometer (300 MHz) from solutions in DMSO-d6
using tetramethylsilane as internal reference. The mass
spectra (electron impact, 70 eV) were obtained on
an LKB 9000 instrument. The elemental compositions
were determined on a Carlo Erba NA 1500 analyzer.
1
IIIa–IIId, the H NMR spectra of VIIa–VIId lacked
signals assignable to protons of exo- and endocyclic
amino groups, but contained two singlets belonging to
methylene protons and signals from protons in the
corresponding aliphatic amine fragments and NH
group in the newly formed triazine ring.
When the above three-component condensation was
performed with 4-[pyridin-3(or 4)-yl]-1,4-dihydro-
benzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amines IIIe
and IIIf, the only isolated products were those contain-
ing no pyridine fragment, 2-alkyl-2,3,4,6-tetrahydro-
1H-[1,3,5]triazino[1′,2′:3,4][1,3,5]triazino[1,2-a]benz-
imidazoles VIIe and VIIf. Unlike compounds VIIa–
2-Alkyl-6-aryl-2,3,4,6-tetrahydro-1H-[1,3,5]tri-
azino[1′,2′:3,4][1,3,5]triazino[1,2-a]benzimidazoles
VIIa–VIIf (general procedure). A mixture of
0.005 mol of compound IIIa–IIIf, 0.011 mol of
a 40% solution of formaldehyde (V), 0.005 mol of
amine VIa–VId, and 5 ml of dioxane containing 10%
of DMF was heated for 30 min under reflux. The
precipitate was filtered off and recrystallized from
dimethylformamide.
1
VIId which displayed in the H NMR spectra signals
from the C6H proton (δ 6.6–7.0 ppm) and protons in
the aromatic ring attached to C6, in the spectra of VIIe
and VIIf we observed only a singlet at δ 5.3 ppm due
to methylene protons (C6H2). Presumably, loss of the
pyridine fragment occurs via opening of the triazine
ring with formation of intermediate A, rotation about
the C–N bond therein, and cyclization to triazinobenz-
imidazole B with elimination of pyridinecarbaldehyde.
2-Benzyl-6-phenyl-2,3,4,6-tetrahydro-1H-[1,3,5]-
triazino[1′,2′:3,4][1,3,5]triazino[1,2-a]benzimid-
azole (VIIa). Yield 1.5 g (76%), mp 237–239°C.
1H NMR spectrum, δ, ppm: 3.60 s (2H, PhCH2), 4.25 s
and 4.35 s (2H each, 1-H, 3-H), 6.60 s (1H, 6-H),
6.58–6.91 m (7H, Harom), 6.93 t (1H, C6H4, J = 8.0 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011

POTAPOV et al.
1076
7.28 d (1H, C6H4, J = 8.0 Hz), 7.31–7.69 m (5H, Ph),
7.93 s (1H, 4-H). Found, %: C 73.25; H 5.67; N 21.26.
m/z 394 [M]+. C24H22N6. Calculated, %: C 73.07;
H 5.62; N 21.30. M 394.48.
and 4.35 s (2H each, 1-H, 3-H), 6.68 s (1H, 6-H),
6.53–6.76 m (7H, Harom), 6.77 t (1H, Harom, J = 8.0 Hz),
6.88–7.24 m (5H, Harom), 7.55 s (1H, 4-H). Found, %:
C 70.30; H 5.49; N 19.78. m/z 426 [M]+. C25H23FN6.
Calculated, %: C 70.41; H 5.44; N 19.70. M 426.50.
6-(4-Methoxyphenyl)-2-(pyridin-3-ylmethyl)-
2,3,4,6-tetrahydro-1H-[1,3,5]triazino[1′,2′:3,4]-
[1,3,5]triazino[1,2-a]benzimidazole (VIIb). Yield
2-Benzyl-2,3,4,6-tetrahydro-1H-[1,3,5]triazino-
[1′,2′:3,4][1,3,5]triazino[1,2-a]benzimidazole (VIIe).
Yield 1.2 g (75%), mp 256–258°C. 1H NMR spectrum,
δ, ppm: 3.58 s (2H, PhCH2), 4.25 s and 4.35 s (2H
each, 1-H, 3-H), 5.30 s (2H, 6-H), 6.55–6.93 m (5H,
1
1.45 g (68%), mp 253–255°C. H NMR spectrum, δ,
ppm: 3.78 s (3H, CH3O), 4.04 s (2H, N2CH2), 4.30 s
and 4.38 s (2H each, 1-H, 3-H), 6.60 s (1H, 6-H),
6.85–7.02 m (3H, C5H4N, Harom), 7.07–7.56 m (6H,
H
arom), 6.95 m (2H, C6H4), 7.15 t (1H, C6H4, J =
8.0 Hz), 7.25 d (1H, C6H4, J = 8.0 Hz), 7.56 s (1H,
4-H). Found, %: C 67.68; H 5.66; N 26.48. m/z 318
[M]+. C18H18N6. Calculated, %: C 67.91; H 5.70;
N 26.40. M 318.38.
H
arom), 7.76 d (1H, C5H4N, J = 8.0 Hz), 7.95 s (1H,
4-H), 8.46 d (1H, C5H4N, J = 8.0 Hz), 8.65 s (1H,
C5H4N). Found, %: C 67.81; H 5.49; N 23.10. m/z 425
[M]+. C24H23N7O. Calculated, %: C 67.75; H 5.45;
N 23.04. M 425.50.
2-(2-Morpholinoethyl)-2,3,4,6-tetrahydro-1H-
[1,3,5]triazino[1′,2′:3,4][1,3,5]triazino[1,2-a]benz-
imidazole (VIIf). Yield 1.1 g (64%), mp 248–250°C.
1H NMR spectrum, δ, ppm: 2.35 br.t (2H, 2-CH2CH2),
2.55 m (4H, CH2NCH2), 2.85 t (2H, 2-CH2, J =
7.5 Hz), 3.55 m (4H, CH2OCH2), 4.25 s and 4.35 s (2H
each, 1-H, 3-H), 5.30 s (2H, 6-H), 6.94 m (2H, C6H4),
7.15 t (1H, C6H4, J = 8.0 Hz), 7.25 d (1H, C6H4, J =
8.0 Hz), 7.56 s (1H, 4-H). Found, %: C 59.63; H 6.82;
N 28.64. m/z 341 [M]+. C17H23N7O. Calculated, %:
C 59.81; H 6.79; N 28.72. M 341.42.
6-(2,5-Dimethoxyphenyl)-2-(2-morpholinoethyl)-
2,3,4,6-tetrahydro-1H-[1,3,5]triazino[1′,2′:3,4]-
[1,3,5]triazino[1,2-a]benzimidazole (VIIc). Yield
1
1.3 g (54%), mp 178–180°C. H NMR spectrum, δ,
ppm: 2.40 t (2H, 2-CH2CH2), 2.55 m (4H, CH2NCH2),
2.85 t (2H, 2-CH2, J = 8.0 Hz), 3.55 m (4H,
CH2OCH2), 3.69 s and 3.72 s (3H each, CH3O), 4.25 s
and 4.35 s (2H each, 1-H, 3-H), 6.60 s (1H, 6-H),
6.70 d (1H, C6H4, J = 8.0 Hz), 6.77 t (1H, C6H4, J =
8.0 Hz), 6.74 d (1H, Harom, J = 8.0 Hz), 6.93 m (2H,
C6H4), 7.03 s (1H, Harom), 7.21 d (1Harom, J = 8.0 Hz),
7.85 s (1H, 4-H). Found, %: C 62.74; H 6.51; N 20.48.
m/z 477 [M]+. C25H31N7O3. Calculated, %: C 62.88;
H 6.54; N 20.53. M 477.57.
REFERENCES
1. Potapov, A.Yu., Shikhaliev, Kh.S., Kryl’skii, D.V., and
Peshkov, M.D., Izv. Vyssh. Uchebn. Zaved., Ser. Khim.
Khim. Tekhnol., 2004, vol. 47, p. 151.
2. Shikhaliev, Kh.S., Potapov, A.Yu., and Kryl’skii, D.V.,
Izv. Ross. Akad. Nauk, Ser. Khim., 2007, p. 355.
3. Martin, D., Graubaum, H., Kempter, G., and Ehrlich-
6-(4-Fluorophenyl)-2-(2-phenylethyl)-2,3,4,6-
tetrahydro-1H-[1,3,5]triazino[1′,2′:3,4][1,3,5]tri-
azino[1,2-a]benzimidazole (VIId). Yield 1.8 g (85%),
1
mp 219–221°C. H NMR spectrum, δ, ppm: 2.55 t
(2H, PhCH2), 2.85 t (2H, 2-CH2, J = 8.5 Hz), 4.25 s
mann, W., J. Prakt. Chem., 1981, vol. 323, p. 303.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 7 2011