A facile synthesis of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones under microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(03)00696-3

Preparation of 2-amino-N-(1-H-benzimidazol-2-yl)benzamide and a variety of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters under microwave irradiation are described.

Full text of DOI:10.1016/S0040-4020(03)00696-3

Tetrahedron 59 (2003) 4757–4760
A facile synthesis of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-
quinazolinones under microwave irradiation
*
Hassan Hazarkhani and Babak Karimi
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P.O. Box 45195-159, Gava Zang, Zanjan, Iran
Received 17 February 2003; revised 7 April 2003; accepted 1 May 2003
Abstract—Preparation of 2-amino-N-(1-H-benzimidazol-2-yl)benzamide and a variety of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-
quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters under microwave irradiation are described. q 2003 Elsevier
Science Ltd. All rights reserved.
One of the most frequently encountered heterocycles in
medicinal chemistry is 4(3H)-quinazolinone with wide
applications including anticonvulsant,1 antihypertensive,2
antidiabetic,3 antibacterial,4 antitumor,5 antihistaminic,6
and antiinflammatory7 activities. On the other hand
heterocyclic molecules containing benzimidazole groups
is the another heterocyclic compounds that have been
exhibiting a broad spectrum of pharmacological activities.8
Important clinical examples of these heterocycles include
mebendazole,9 albendazole,10 astemizole,11 and omepra-
zole.12 Recent investigations on biological activity of
heterocycles containing benzimidazole ring clearly show
that they play an important role as selective neuropeptide
Along this line we have designed the synthesis of 3-(2-
benzimidazolyl)-2-alkyl-4(3H)-quinazolinones as new het-
erocyclic compounds that contain both benzimidazole and
YY1 receptor antagonists,13 factor Xa (FXa) inhibitors,14 5-
lipoxygenase inhibitors for use as novel antiallergic
quinazolinone moieties in their structures. These results
agents,15 poly(ADP-ribose) polymerase (PARP) inhibi-
encouraged us to prepare new polyheterocyclic systems,
which bear two or three different heterocyclic nuclei. For
tors16 and as human cytomegalovirus (HCMV) inhibitors.17
Furthermore, a literature search shows that the study of
this purpose, we have started from isatoic anhydride as a
polyheterocyclic systems based on a quinazolinone struc-
useful starting material that its applications in synthesis of
tural block has attracted intrest, owing to their potential
heterocycles have been well documented.21
useful biological activities. For example, 3-(1H-tetrazol-5-
yl)-4(3H)-quinazolinone sodium salt (MDL 427, A) and 3-
N-[(1H-imidazole-1-yl) alkyl]-4(3H)-quinazolinone (B)
have been introduced as antiallergic and antihypertensive
agents, respectively.18
When a mixture of isatoic anhydride and 2-aminobenzimi-
dazole in DMAC was irradiated with microwave (300 W
power) in the presence of a catalytic amount of p-
toluenesulfonic acid, the reaction was almost completed
within 2 min. Work-up of the reaction mixture shows that 2-
amino-N-(1-H-benzimidazol-2-yl)benzamide (1) was pre-
pared in 70% yield after recrystallization from 95% ethanol
Very recently, we reported a facile synthesis of new 6-alkyl
(Scheme 1). Interestingly, we have found that this reaction
benzimidazo[1,2-c]quinazolines using isatoic anhydride
is highly chemoselective in the preparation of amide 1, since
Microwave irradiation has been extensively used for the
rapid synthesis of a variety of heterocyclic compounds.19
and 2-(o-aminophenyl)benzimidazole under microwave
irradiation in N,N-dimethyl acetamide (DMAC).20
no detectable of either amides 3 or 4 is formed under the
described reaction conditions.
This new amide has three nucleophilic sites that can be
condensed with different electrophilic species for prep-
aration of a wide variety of quinazolinone based targets.
Herein, we wish to report the synthesis of 3-(2-benzimida-
*
Corresponding author. Tel.: þ98-241-4242235; fax: þ98-241-4248013;
e-mail: hazarkhani@iasbs.ac.ir
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00696-3

4758
H. Hazarkhani, B. Karimi / Tetrahedron 59 (2003) 4757–4760
Scheme 1.
Scheme 2.
zolyl)-2-alkyl-4-(3H)-quinazolinones through the reaction
of 1 with a set of orthoesters under microwave irradiation.
We have carried out the reaction of 2-amino-N-benzimida-
zolyl benzamide (1) with triethylorthoformate under
microwave irradiations. For this purpose a mixture of the
amide (5 mmol), triethylorthoformate (7.5 mmol), p-tolue-
nesulfonic acid (0.25 mmol) and DMAC (1–2 ml) in a tall
beaker was covered with a stemless funnel and placed in a
microwave oven and irradiated with 600 W power for 4 min
(irradiation sequences were interrupted with a cooling
period in between). Then the reaction mixture was allowed
to cool to room temperature and poured in a large volume of
cool water to give precipitate.
1. Experimental
1.1. Typical procedure for preparation of 2-amino-N-(1-
H-benzimidazol-2-yl)benzamide (1)
A mixture of isatoic anhydride (1.63 g, 10 mmol), 2-
aminobenzimidazole (1.35 g, 10 mmol), p-toluenesulfonic
acid (0.05 g, 0.25 mmol) and N,N-dimethylacetamide
(DMAC, 1–2 ml) in a tall beaker was covered with stemless
funnel, placed in microwave oven and irradiated with
300 W power for 30 s (evolution of CO2 was observed). The
reaction mixture was cooled and irradiated again for 90 s
with interruptions in between. Then, the reaction mixture
was allowed to cool to room temperature and poured in cool
water (250 ml). The precipitate formed was filtered and
washed with water. Recrystallization from ethanol (95%)
gave 2-amino-N-benzimidazolyl benzamide (1) as white
crystals, 1.76 g, 70%, mp 220–28C.
The precipitate was filtered off and recrystallized from
ethanol (95%) to afford pure 3-benzimidazolyl-4(3H)-
quinazolinone (4a) in 94% yield (Scheme 2). Reaction of
2-amino-N-(1-H-benzimidazol-2-yl)benzamide (1) with
triethyl orthoacetate, triethyl orthopropionate, trimethyl
orthobutyrate and trimethyl orthovalerate under similar
reaction conditions gave the 2-methyl, 2-ethyl, 2-propyl and
2-butyl-3-benzimidazolyl-4(3H)-quinazolinones (4b-e) in
high yields, respectively (Scheme 2). The work on the
preparation of other types of substituted quinazolinones and
the study of their biological activities are on going in our
laboratories.
1.2. General procedure for preparation of 3-(2-
benzimidazolyl)-2-alkyl-4(3H)-quinazolinones (4a-e)
A mixture of 2-amino-N-benzimidazolyl benzamide (1)
(1.26 g, 5 mmol), orthoester (7.5 mmol), p-toluenesulfonic
acid (0.05 g, 0.25 mmol) and N,N-dimethylacetamide
(DMAC, 1–2 ml) in a tall beaker was covered with stemless
funnel, placed in microwave oven and irradiated with
600 W power for 30 s. The reaction mixture was cooled and
irradiated again for 4–5 min with interruptions in between.
Then, the reaction mixture was allowed to cool to room
temperature and poured into cool water (250 ml). The
In summary we have reported a facile, rapid and useful
synthesis of new substituted quinazolinones under micro-
wave irradiation. The yield of reactions is high and work up
of the product is easy.

H. Hazarkhani, B. Karimi / Tetrahedron 59 (2003) 4757–4760
4759
precipitates formed were filtered and washed with water.
Recrystallization from 95% ethanol or absolute ethanol
gave 3-(2-benzimidazolyl)-2-alkyl-4(3H)-quinazolinones in
good to high yields.
136.06, 127.88, 127.83, 127.06, 126.91, 123.24, 120.14,
27.99, 11.13 ppm. MS (20 eV) m/z (relative intensity): 290
(Mþ, 37.3), 261 (12.2), 235 (42.1), 176 (24.2), 133 (100),
119 (40.2), 92 (18.5), 76 (22.8), 57 (15.6). CHN analysis:
%C (calcd 70.33, found 70.01), %H (calcd 4.80, found
4.80), %N (calcd 19.30, found 18.95).
1.3. Spectral data
1.3.1. 2-Amino-N-benzimidazolyl benzamide (1). From
95% ethanol, mp 220–28C. IR (KBr) n 3337 (broad), 3190,
3063, 2967, 2878, 1645, 1606, 1575, 1525, 1421, 1348,
1278, 1228, 1163, 1020, 916, 881, 858, 746, 693 cm21. 1H
NMR (DMSO-d6, 500 MHz) d 12.01 (broad s, 2H), 7.95–
7.93 (d, 1H, J¼8.0 Hz), 7.43–7.40 (m, 2H), 7.19–7.16 (m,
1H), 7.12–7.10 (m, 2H), 6.80–6.77 (broad s, 2H), 6.75–
6.73 (d, 1H, J¼8.3 Hz), 6.54–6.51 (t, 1H, J¼7.5 Hz) ppm.
13C NMR (DMSO-d6, 125 MHz) d 172.23, 151.15, 150.20,
133.93, 133.08, 130.72, 122.09, 117.02, 115.42, 115.07,
113.32 ppm. MS (20 eV) m/z (relative intensity): 252 (Mþ,
37.3), 236 (35.4), 134 (14.6), 120 (100), 92 (60.2), 65 (45.8).
CHN analysis: %C (calcd 66.66, found 66.21), %H (calcd
4.79, found 4.78), %N (calcd 22.21, found 21.85).
1.3.5. 3-(2-Benzimidazolyl)-2-propyl-4(3H)-quinazoli-
none (4d). 1.14 g, 75%, from absolute ethanol, mp 211–
148C. IR (KBr) n 3306–3171 (broad), 2959, 2932, 2867,
1
1687, 1668, 1608, 1533, 1460, 1433, 1275, 770 cm 21. H
NMR (CDCl3, 500 MHz) d 11.29 (broad s, 1H), 7.67–7.47
(m, 4H), 7.22–7.12 (broad s, 2H), 6.99–6.98 (m, 2H),
2.43–2.40 (t, 2H, J¼7.5 Hz), 1.75–1.71 (quartet, 2H,
J¼7.5 Hz), 0.85–0.82 (t., 3H, J¼7.3 Hz) ppm. 13C NMR
(CDCl3, 125 MHz) d 163.10, 156.19, 147.18, 141.97,
141.34, 135.44, 133.47, 127.25, 127.05, 125.82, 124.20,
123.26, 119.62, 118.87, 112.17, 34.45, 28.83, 22.26,
13.91 ppm. MS (20 eV) m/z (relative intensity): 304 (Mþ,
47.3), 276 (28.4), 261 (22.5), 235 (20.3), 176 (20.5), 133
(100), 119 (40.2), 92 (15.8), 76 (45.8), 57 (16.5). CHN
analysis: %C (calcd 71.04, found 70.85), %H (calcd 5.30,
found 5.29), %N (calcd 18.41, found 18.01).
1.3.2. 3-(2-Benzimidazolyl)-4(3H)-quinazolinone (4a).
1.23 g, 94%, from 95% ethanol, mp 300–28C. IR (KBr) n
3383–3229 (broad), 3071, 1691, 1622, 1510, 1440, 1386,
1259, 901, 760, 743 cm21. 1H NMR (DMSO-d6, 500 MHz)
d 13.06 (s, 1H), 9.02 (s, 1H), 8.34–8.33 (d, 1H, J¼7.8 Hz),
7.98–7.95 (t, 1H, J¼7.5 Hz), 7.83–7.81 (d, 1H, J¼8.0 Hz),
7.71–7.68 (t, 2H, J¼7.2 Hz), 7.65–7.64 (d, 1H, J¼7.3 Hz),
7.30–7.27 (t, 2H, J¼7.5 Hz). 13C NMR (DMSO-d6,
125 MHz) d 160.25, 147.56, 144.87, 144.48, 141.05,
136.46, 134.49, 129.14, 128.54, 127.57, 123.84, 123.06,
122.09, 119.55, 113.46 ppm. MS (20 eV) m/z (relative
intensity): 262 (Mþ, 100), 234 (80.5), 134 (10.6), 118
(12.2), 102 (10.5), 76 (11.8), 50 (15.6). CHN analysis: %C
(calcd 68.69, found 68.45), %H (calcd 3.84, found 3.80),
%N (calcd 21.36, found 21.42).
1.3.6. 3-(2-Benzimidazolyl)-2-butyl-4(3H)-quinazolinone
(4e). 1.10 g, 70%, from absolute ethanol, mp 226.2288C. IR
(KBr) n 3325–3167 (broad), 2951, 2936, 2871, 1691, 1664,
1610, 1537, 1460, 1437, 1275, 770 cm21. 1H NMR (CDCl3,
500 MHz) d 11.50 (broad s, 1H), 7.56–7.49 (m, 4H), 7.13
(broad s, 2H), 7.06–7.03 (t, 2H), 2.53–2.50 (t, 2H,
J¼7.7 Hz), 1.73–1.67 (quintet, 2H, J¼7.5 Hz), 1.26–1.19
(sex. 2H, J¼7.5 Hz), 0.78–0.75 (t, 3H, J¼7.25 Hz) ppm.
13C NMR (CDCl3, 125 MHz) d 163.24, 156.23, 147.24,
141.93, 135.29, 127.29, 126.99, 125.88, 124.09, 123.48,
119.80, 119.02, 34.44, 28.85, 22.19, 13.70 ppm. MS (20 eV)
m/z (relative intensity): 318 (Mþ, 47.3), 290 (15.5), 261
(25.6), 235 (22.4), 176 (15.8), 133 (14.6), 119 (40.2), 92
(20.1), 76 (45.8). CHN analysis: %C (calcd 71.68, found
71.30), %H (calcd 5.70, found 5.45), %N (calcd 17.60,
found 17.23).
1.3.3. 3-(2-Benzimidazolyl)-2-methyl-4(3H)-quinazoli-
none (4b). 1.31 g, 95%, from absolute ethanol, mp 237–
98C. IR (KBr) n 3295 (broad), 3040, 2994, 1668, 1620,
1571, 1487, 1410, 1394, 1336, 1275, 959, 758, 746,
1
696 cm21. H NMR (DMSO-d6, 500 MHz) d 8.50–8.48
Acknowledgements
(d, 1H, J¼8.2 Hz), 8.24–8.23 (d, 1H, J¼7.8 Hz), 7.49–7.44
(m, 3H), 7.23–7.21 (m, 2H), 7.13–7.10 (t, 1H, J¼7.5 Hz),
3.39 (s, 1H), 2.75 (s, 3H). 13C NMR (DMSO-d6, 125 MHz)
d 174.09, 169.07, 152.41, 140.72, 132.68, 131.59, 130.96,
124.32, 123.53, 122.94, 120.51, 112.82, 26.08 ppm. MS
(20 eV) m/z (relative intensity): 276 (Mþ, 37.3), 162 (25.4),
133 (100), 119 (40.2), 92 (28.2), 76 (31.8), 43 (60.5). CHN
analysis: %C (calcd 69.55, found 69.25), %H (calcd 4.38,
found 4.35), %N (calcd 20.28, found 20.01).
The authors are grateful to Institute for Advanced Studies in
Basic Sciences (IASBS) for partial support of this work.
References
1. (a) Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.;
Traber, J. Eur. J. Med. Chem. 1984, 19, 381. (b) Gupta, C. M.;
Bhaduri, A. P.; Khanna, N. M. J. Med. Chem. 1968, 11, 392.
2. (a) Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem.
1968, 11, 130. (b) Hussain, M. A.; Chiu, A. T.; Price, W. A.;
Timmermans, P. B.; Shefter, E. Pharm. Res. 1988, 5, 242.
3. Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
4. Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Lin-gardo, L.
J. Med. Chem. 1999, 42, 4705.
1.3.4. 3-(2-Benzimidazolyl)-2-ethyl-4(3H)-quinazolinone
(4c). 1.30 g, 90%, from absolute ethanol, mp 137–98C. IR
(KBr) n 3584–3056 (broad), 2978–2932, 1695, 1656, 1598,
.
1575, 1529, 1496, 1348, 1275, 743 cm21 1H NMR
(DMSO-d6, 500 MHz) d 12.60 (broad s, 1H), 8.18–8.16
(d, 1H, J¼7.5 Hz), 7.91–7.88 (t, 1H, J¼7.3 Hz), 7.76–7.74
(d, 1H, J¼8.0 Hz), 7.70 (m, 2H), 7.59–7.56 (t, 1H,
J¼7.3 Hz), 7.31 (m, 2H), 2.48–2.46 (q, 2H, J¼7.1 Hz),
1.17–1.14 (t, 3H, J¼7.1 Hz) ppm. 13C NMR (DMSO-d6,
125 MHz) d 161.86, 157.45, 147.45, 143.06, 141.05,
5. (a) Baek, D. J.; Park, Y. K.; Heo, H. I.; Lee, M.; Yang, Z.;
Choi, M. Bioorg. Med. Chem. Lett. 1998, 8, 3287. (b) Webber,
S. E.; Bleckman, T. M.; Attard, J.; Deal, J. G.; Kathardekar,

4760
H. Hazarkhani, B. Karimi / Tetrahedron 59 (2003) 4757–4760
V.; Welsh, K. M.; Webber, S.; Janson, C.; Matthews, D. A.;
Whitlow, M.; Trinh, L.; Post, J.; Liang, A.; Morrissey, M. M.;
Shaw, K. J. Bioorg. Med. Chem. Lett. 2000, 10, 963.
16. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.;
Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.;
Srinivasan, S.; Golding, B. T. J. Med. Chem. 2000, 43, 4084.
17. Zhu, Z.; Lippa, B.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 2000, 43, 2430.
Smith, W. W.; Freer, S. T.; Jordan, S. R.; Bacquet, R. J.;
Howland, E. F.; Booth, C. L. J.; Ward, R. W.; Hermann, S. M.;
White, J.; Morse, C. A.; Hilliard, J. A.; Bartlett, C. A. J. Med.
Chem. 1993, 36, 733.
6. Omar, A. M. E.; El-Din, S. A. S.; Labouta, I. M.; El-Tambary,
A. A.; Alexandria, J. Pharm. Sci. 1991, 5, 94.
7. Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson,
D. A.; Cottam, H. B. J. Med. Chem. 1999, 42, 3860.
8. Nawrocka, W. Boll. Chim. Farm. 1996, 135, 18.
9. Winstanley, P. Lancet 1998, 352, 1080.
18. (a) William, B. W.; Andrew, S. T. Jr.; Peter, S. C.; Joseph,
W. M.; Jeffery, B. P. J. Med. Chem. 1987, 30, 2277. (b) Cross,
P. E.; Dickinson, R. P.; Parry, M. J.; Randall, M. J. J. Med.
Chem. 1985, 28, 1427. (c) Norton, P. P.; Larry, E. B.; Shyam,
S.; Jon, E. L.; Emily, H. M.; Edward, L. O. J. Med. Chem.
1986, 29, 2403.
10. Carpio, A. J. Neurol. Neurosurg. Psychiat. 1999, 66, 411.
11. Al-Muhaimeed, H. J. Int. Med. Res. 1997, 25, 175.
12. Richter, J. E. Am. J. Gastroenterol. 1997, 92, 34.
13. Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman,
D. M.; Arnold, M. B.; Schober, D. A.; Gackenheimer, S. L.;
Bruns, R. F.; Hipskind, P. A.; Britton, T. C.; Cantrell, D. R.
J. Med. Chem. 1998, 41, 2709.
¨
19. For a review see: (a) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225. (b) Rad-Moghadam,
K.; Khajavi, M. S. J. Chem. Res. (S) 1998, 702. (c) Khajavi,
M. S.; Mohammadi, A. A.; Sadat Hosseini, S. S. Synth.
Commun. 2001, 31, 3647.
14. Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.;
Matsumoto, H.; Taguchi, T.; Inagaki, N.; Nagai, H.; Satoh,
T. Bioorg. Med. Chem. 2000, 8, 373.
20. Khajavi, M. S.; Rad-Moghadam, K.; Hazarkhani, H. Synth.
Commun. 1999, 29, 2617.
21. For a review of chemistry of isatoic anhydride see: Coppola,
G. M. Synthesis 1980, 505.
15. Zhao, Z. S.; Arnaiz, D. O.; Griedel, B.; Sakata, S.; Dallas, J. L.;