Synthesis of novel benzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazoline derivatives

Article abstract of DOI:10.3184/030823407X209741

Cyclocondensation of 2-(1H-benzimidazol-2-yl)anilines 1a,b with carbon disulfide in the presence of potassium f-butoxide in boiling DMF afforded the corresponding benzimidazo[1,2-c]quinazoline-6(5H)-thiones 2a,b. Treatment of these compounds with hydrazine hydrate at reflux in ethanol gave the hydrazine derivatives 3a,b which were subsequently cyclised to the title compounds 4a-f on heating with orthoesters in ethanol.

Full text of DOI:10.3184/030823407X209741

JOURNAL OF CHEMICAL RESEARCH 2007
MAy, 257–258
RESEARCH PAPER 257
Synthesis of novel benzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazoline
derivatives
Abolghasem Davoodnia, M. Momen Heravi, Ehsan Golshani, Mehdi Bakavoli*
and Leila Dehabadi
Department of Chemistry, School of Sciences, Islamic Azad University, 91735-413 Mashhad, Iran
Cyclocondensation of 2-(1H-benzimidazol-2-yl)anilines 1a,b with carbon disulfide in the presence of potassium
t-butoxide in boiling DMF afforded the corresponding benzimidazo[1,2-c]quinazoline-6(5H)-thiones 2a,b. Treatment
of these compounds with hydrazine hydrate at reflux in ethanol gave the hydrazine derivatives 3a,b which were
subsequently cyclised to the title compounds 4a–f on heating with orthoesters in ethanol.
Keywords: fused benzimidazoles, 1,2,4-triazoles, quinazolines
Benzimidazole derivatives show a variety of biological
activities such as antibacterial, antitumor, antiviral and
antitubercular activity.1-4 These compounds are an important
class of nitrogen heterocycles and they constitute useful
intermediates in organic synthesis.5 In connection with our
interest in the synthesis of nitrogen and sulfur heterocycles of
biological significance,6 we recently reported the synthesis of
some new polyheterocyclic compounds.7 Arising from these
studies, we now report the synthesis of some novel pentacyclic
fused benzimidazole derivatives from benzimidazole
intermediates.
orthoesters in ethanol (Scheme 1). The structural assignments
of compounds 4a–f was based upon the spectral and
microanalytical data (see Experimental section). For example,
1
the H NMR spectrum of 4a did not show the NH2 and NH
signals of the precursor 3a but showed a sharp 1H signal at
δ = 9.8 ppm from the triazole ring, indicating the formation of
the pentacyclic compound 4a.
In conclusion, we describe the synthesis of a novel
heterocyclic ring system through heterocyclisation of the
hydrazines 3a,b with orthoesters in boiling ethanol.
Experimental
The melting points were measured on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300
Shimadzu spectrophotometer. The 1H NMR (100 MHz) spectra were
recorded on a Bruker AC 100 spectrometer. The 13C NMR (125 MHz)
spectra were recorded on a Bruker Avance DRX -500 spectrometer.
The mass spectra were obtained on a Varian Mat CH-7 instrument at
70 eV. Elemental analysis was performed on a ThermoFinnigan Flash
EA microanalyser.
Results and discussion
Our approach is based on the use of 2-(1H-benzimidazol-
2-yl)anilines (1a,b) as starting materials. Reaction of
these compounds with carbon disulfide in the presence of
potassium t-butoxide in boiling DMF gave the corresponding
benzimidazo[1,2-c]quinazolin-6(5H)-thiones (2a,b) in high
yield. The synthesis of this heterocyclic ring system from
cyclocondensation of 1a,b with several electrophilic reagents
such as acetic acid, acetone and isocyanates has been reported
earlier.8
The thione derivatives 2a,b were then refluxed with
hydrazine hydrate in ethanol to give the hydrazine derivatives
3a,b. These compounds were subsequently cyclised to new
pentacyclic fused benzimidazoles 4a–f when heated with
The benzimidazol-2-ylanilines 1a,b were prepared as described by
Zaikia and Joullié.9
Typical procedure for the preparation of 2
A mixture of 2-(1H-benzimidazol-2-yl)aniline 1a (2.09 g, 10 mmol)
and carbon disulfide (1.2 ml, 20 mmol) in DMF (10 ml) containing
potassium t-butoxide (1.12 g, 10 mmol) was heated under reflux for
8 hours. After cooling the reaction mixture, water was added, the
precipitate was filtered and recrystallised from ethanol to give 1.88 g
R
R
R
R
N
N
N
CS2
DMF
t-BuOK
N
H
NH
H2N
1a,b
2a,b
S
N2H4
EtOH
R
R
R
R
N
N
N
N
R'C(OEt)3
EtOH
N
N
N
NH
N
R'
NH2
4a-f
3a,b
1-3: a, R = H; b, R = Me
a, R = R' = H
d, R = Me, R' = H
b, R = H, R' = Me e, R = R' = Me
c, R = H, R' = Et
f, R = Me, R' = Et
Scheme 1
* Correspondent. E-mail: mbakavoli@yahoo.com
PAPER: 07/4530

258 JOURNAL OF CHEMICAL RESEARCH 2007
of 2a as white crystals (75%). The thione 2b was similarly prepared
from 1b.
11,12-Dimethylbenzimidazo[1,2-c][1,2,4]triazolo[4,3-a]
quinazoline (4d): White crystals (0.93 g, 81%), m.p. 352–354°С.
1H NMR ([2H6]DMSO, TMS): δ 2.3 (s, 3H, CH3), 2.4 (s, 3H, CH3),
7.6–8.6 (m, 6H, aromatic ring H), 9.8 (s, 1H, CH of triazole ring).
MS: m/z 287 (M+, 4), 286 (6), 285 (25), 284 (96), 283 (100), 282
(68), 268 (29), 254 (21), 140 (19), 125 (12), 113 (13), 83 (15), 69
(19), 55 (35), 42 (37). Found: C, 70.91; H, 4.64; N, 24.25. Calc. for
C17H13N5 (287): C, 71.06; H, 4.56; N, 24.37%.
3,11,12-Trimethylbenzimidazo[1,2-c][1,2,4]triazolo[4,3-
a]quinazoline (4e): White crystals (0.94 g, 78%), m.p. 339–341°С.
1H NMR ([2H6]DMSO, TMS): δ 2.4 (s, 3H, CH3), 2.5 (s, 3H, CH3),
3.0 (s, 3H, CH3), 7.6–8.7 (m, 6H, aromatic ring H). MS: m/z 301 (M+,
5), 299 (38), 298 (100), 297 (98), 296 (36), 282 (15), 254 (20), 240
(15), 147 (8), 114 (10), 89 (8), 56 (20), 42 (26). Found: C, 71.53;
H, 5.21; N, 23.05. Calc. for C18H15N5 (301): C, 71.74; H, 5.02; N,
23.24%.
Benzimidazo[1,2-c]quinazoline-6(5H)-thione (2a): M.p. 305–
307°С (Lit.10 308–310°С). FT IR (KBr, νmax/cm-1) 3190 (NH). 1H
NMR ([2H6]DMSO, TMS): δ 7.5–8.5 (m, 8H, aromatic rings), 9.4
(broad, 1H, NH). MS: m/z 251 (M+, 4), 250 (10), 249 (19), 248 (53),
247 (100), 246 (96), 215 (12), 188 (13), 157 (15), 123 (32), 100 (15),
89 (28), 62 (18).
9,10-Dimethylbenzimidazo[1,2-c]quinazoline-6(5H)-thione (2b):
White crystals (2.18 g, 78%), m.p. 294–296°С. FTIR (KBr, νmax/cm-1):
1
3200 (NH). H NMR ([2H6]DMSO, TMS): δ 2.1 (s, 3H, CH3), 2.2
(s, 3H, CH3), 7.4–8.5 (m, 6H, aromatic rings), 9.1 (broad, 1H, NH).
MS: m/z 279 (M+, 8), 278 (15), 276 (83), 275 (100), 215 (10), 245
(31), 187 (14), 121 (17), 100 (12), 89 (37), 64 (19). Found: C, 68.32;
H, 4.88; N, 14.81. Calc. for C16H13N3S (279): C, 68.79; H, 4.69;
N, 15.04%.
3-Ethyl-11,12-dimethylbenzimidazo[1,2-c][1,2,4]triazolo[4,3-
a]quinazoline (4f): White crystals (0.92 g, 73%), m.p. 308–310°С.
1H NMR ([2H6]DMSO, TMS): δ 1.48 (t, J = 7 Hz, 3H, CH3), 2.4
(s, 3H, CH3), 2.5 (s, 3H, CH3), 2.7 (q, J = 7 Hz, 2H, CH2), 7.6-8.7
(m, 6H, aromatic ring H). MS: m/z 315 (M+, 8), 314 (37), 313 (97),
312 (100), 311 (98), 297 (25), 254 (36), 240 (26), 154 (21), 114 (24),
100 (20), 82 (31), 56 (32), 42 (22). Found: C, 72.22; H, 5.51; N,
22.13. Calc. for C19H17N5 (315): C, 72.36; H, 5.43; N, 22.21%.
Typical procedure for the preparation of 3
A mixture of benzimidazo[1,2-c]quinazolin-6(5H)-thione 2a (2.51 g,
10 mmol) and hydrazine hydrate (2.0 ml) in ethanol (15 ml) was
heated under reflux for 10 hours. The reaction mixture was cooled to
room temperature and the precipitate was filtered and recrystallised
from ethanol to give 3a (1.99 g, 80%) as white crystals.
6-Hydrazinobenzimidazo[1,2-c]quinazoline (3a): M.p. 206–208°С.
FT IR (KBr, νmax/cm-1): 3150–3300 (NH and NH2). 1H NMR
([2H6]DMSO, TMS): δ 7.1–8.7 (m, 10H, aromatic rings and NH2),
10.8 (br. s, 1H, NH). MS: m/z 249 (M+, 4), 248 (16), 247 (13), 246
(72), 245 (100), 244 (96), 228 (39), 216 (93), 215 (91), 188 (14), 140
(12), 100 (24), 89 (42), 76 (16), 64 (27). Found: C, 67.74; H, 4.62; N,
28.02. Calc. for C14H11N5 (249): C, 67.46 H, 4.45; N, 28.10%.
6-Hydrazino-9,10-dimethylbenzimidazo[1,2-c]quinazoline (3b):
Received 12 March 2007; accepted 5 May 2007
Paper 07/4530 doi: 10.3184/030823407X209741
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Typical procedure for the preparation of 4
A mixture of 6-hydrazinobenzimidazo[1,2-c]quinazoline 3a (1.0 g,
4 mmol) and triethyl orthoformate (1.6 ml, 10 mmol) in ethanol (15 ml)
was heated under reflux for 1 hours. After completion of the reaction,
which was monitored by TLC, the mixture was cooled and the
precipitate was filtered off and recrystallised from ethanol to give 4a
(0.73 g, 70%) as white crystals.
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362°С. NMR ([2H6]DMSO, TMS): δH 7.5–8.7 (m, 8H, aromatic ring
H), 9.8 (s, 1H, triazole CH). δC 112.0, 118.8, 119.3, 122.9, 123.7,
125.7, 128.1, 128.3, 128.4, 128.5, 131.8, 138.5, 142.3, 143.4, 145.5.
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226 (15), 199 (8), 125 (7), 100 (10), 88 (11), 79 (13), 56 (10). Found:
C, 69.37; H, 3.66; N, 26.88. Calc. for C15H9N5 (259): C, 69.49; H,
3.50; N, 27.01%.
3-Methylbenzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazoline
(4b): White crystals (0.82 g, 75%), m.p. 346–348°С. NMR
([2H6]DMSO, TMS): δH 3.1 (s, 3H, CH3), 7.6–8.8 (m, 8H, aromatic
rings). δC 23.6, 115.1, 117.6, 119.4, 122.8, 123.6, 125.2, 127.1, 127.3,
127.4, 129.3, 131.7, 141.9, 143.8, 146.9, 148.6. MS: m/z 273 (M+, 5),
271 (7), 270 (28), 269 (100), 268 (69), 227 (29), 125 (8), 100 (15), 88
(16), 75 (13). Found: C, 70.21; H, 4.18; N, 25.49. Calc. for C16H11N5
(273): C, 70.32; H, 4.06; N, 25.63%.
3-Ethylbenzimidazo[1,2-c][1,2,4]triazolo[4,3-a]quinazoline (4c):
White crystals (0.8 g, 70%), m.p. 319–321°С. NMR ([2H6]DMSO,
TMS): δH 1.55 (t, J = 6 Hz, 3H, CH3), 3.3 (q, J = 6 Hz, 2H, CH2),
7.6–8.7 (m, 8H, aromatic ring H). δC: 9.8, 28.4, 115.4, 117.6, 119.4,
122.9, 123.6, 125.1, 127.2, 127.3, 127.5, 128.8, 131.7, 141.7, 143.8,
146.9, 152.1. MS: m/z 287 (M+, 5), 286 (8), 285 (18), 284 (71), 283
(100), 282 (66), 281(20), 268 (14), 227 (13), 140 (13), 125 (10), 100
(14), 88 (15), 75 (14), 56 (19). Found: C, 71.13; H, 4.43; N, 24.28.
Calc. for C17H13N5 (287): C, 71.06; H, 4.56; N, 24.37%.
5
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PAPER: 07/4530