Synthesis of imidazo[1,2-c]quinazolin-5(6H)-ones and benzimidazo[1,2-c] quinazolin-6(5H)-ones with the aid of low-valent titanium reagent

Article abstract of DOI:10.1002/jhet.353

(Chemical Equation Presented) A short and facile synthesis of imidazo[1,2-c]quinazolin-5(6H)-ones and benzimidazo[1,2-c]quinazolin-6(5H)-ones was accomplished in good yields via the novel reductive cyclization of 2-(2-nitrophenyl)-imidazoles or 2-(2-nitrophenyl)benzoimidazoles with isocyanates promoted by low-valent titanium reagent.

Full text of DOI:10.1002/jhet.353

5
24
Synthesis of Imidazo[1,2-c]quinazolin-5(6H)-ones and
Benzimidazo[1,2-c]quinazolin-6(5H)-ones with the Aid of
Low-Valent Titanium Reagent
Vol 47
Xuan Zhao and Da-Qing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University, Suzhou 215123, People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received September 21, 2009
DOI 10.1002/jhet.353
Published online 2 April 2010 in Wiley InterScience (www.interscience.wiley.com).
A short and facile synthesis of imidazo[1,2-c]quinazolin-5(6H)-ones and benzimidazo[1,2-c]quinazo-
lin-6(5H)-ones was accomplished in good yields via the novel reductive cyclization of 2-(2-nitrophenyl)-
imidazoles or 2-(2-nitrophenyl)benzoimidazoles with isocyanates promoted by low-valent titanium
reagent.
J. Heterocyclic Chem., 47, 524 (2010).
INTRODUCTION
dazo[1,2-c]-quinazolin-5(6H)-one (4) that selectively
antagonized the a -adrenoceptor [10]. (Fig. 1).
1
Low-valent titanium reagents have an exceedingly
high ability to promote reductive coupling of carbonyl
compounds, and are attracting increasing interest in or-
ganic synthesis [1]. Many other functional groups can
also be coupled [2]. Recently, we have reported the
low-valent titanium induced intermolecular reductive
coupling reaction of carboxylic derivatives with aro-
matic ketones [3], the intramolecular reductive coupling
reaction of 4,4-dicyano-1,3-diaryl-1-butanone [4], the
cyclodimerization of a,b-unsaturated ketones [5], and
the intramolecular reductive coupling reaction of keto-
malononitriles [6].
The synthesis of quinazolinones is well studied, and
recent development in combinatorial chemistry made the
preparation of large number of quinazolinones in a short
time possible. Sequential cyclizations of 2-isothio- cyan-
atobenzonitrile and 2-isocyanatobenzonitrile with a-ami-
noketones resulted 6H-imidazo[1,2-c]quinazolinones
with high yields [11]. A series of 2-[(substituted- phe-
nylpiperazin-1-yl)methyl]- and 2-[(substitutedphenyl-
piperidin-1-yl)methyl]-2,3-dihydroimidzao[1,2-c]quina-
zolin-5(6H)-ones were synthesized by bromo-cycliza-
tion with NBS in THF at room temperature [10,12].
But many of these still suffer from drawbacks such as
drastic conditions, unsatisfactory yields, long-reaction
time, high temperature, complex manipulation, and
inaccessible starting materials.
A literature survey reavealed that quinazolinones
show antihypertonic, antirheumatic, antiana-phylactic,
antiasthmatic, tranquilizing, neuro-stimulating, and ben-
zodiazepine binding activity [7,8]. For example, 3-sub-
stituted quinazolinones, such as SGB-1534 (1) [9] and
ketanserin (2) have been found to have antihypertensive
activities mediated via a-adrenoceptor and serotonic re-
ceptor anatgonism, respectively. Addition of a (2-
methoxyphenyl)piperazine side chain at the 2- or 3-posi-
tion of the angular tricyclic 2,3-dihydroimidazo[1,2-
c]quinazoline ring system of SGB-1534 resulted in the
formation of potent antihypertensive agents such as
Therefore, the development of more efficient methods
for the preparation of this kind of compounds is still an
active ongoing research area, and there is scope for fur-
ther improvement toward milder reaction conditions and
improved yields. In recent years, our interest has been
focused on the synthesis of quinazolines uing low-valent
titanium reagent. We have previously reported the syn-
thesis of quinazolines [13], quinazoline-2,4-diones [14],
imidazo[1,2-c]quinazolines [15], 2-thioxoquinazolinones,
imidazo[1,2-c]quinazolin-5-amines, and benzimidazo[1,2-c]
quinazolin-5-amines [16] by the reaction of nitro-
2-[[4-(2-methoxyphenyl)-piperazin-1-yl]methyl]-2,3-dihy-
droimidazo[1,2-c]-quinazolin-5(6H)-one (3) and 3-[[4-(2-
methoxyphenyl)piperazin-1-yl]methyl]-2,3-dihydroimi-
V
C
2010 HeteroCorporation

May 2010
Synthesis of Imidazo[1,2-c]quinazolin-5(6H)-ones and Benzimidazo[1,2-c]quinazolin-
525
6(5H)-ones with the Aid of Low-Valent Titanium Reagent
Table 1
Optimization for the reductive cyclization reaction.
ꢀ
Temperature ( C)
Entry
TiCl
4
/M
Isolated yield (%)
1
2
3
4
5
r.t.
40
TiCl
TiCl
TiCl
4
/Zn
/Zn
/Zn
42
55
89
34
48
4
4
reflux
reflux
reflux
TiCl
TiCl
4
/Fe
/Mg
4
2-(2-nitrophenyl)imidazoles or 2-(2-nitrophenyl) benzoi-
midazoles was examined.
First of all, we performed the reaction of a variety
of 2-(2-nitrophenyl)imidazoles 1 and isocyanates 2
via TiCl /Zn system in anhydrous THF (Scheme 2,
Figure 1. SGB-1534 (1), Ketanserin (2).
4
compounds with orthoformates, triphosgene, aldehydes,
ketones, and isothiocyanates, respectively, induced by
low-valent titanium reagent.
Table 2).
Furthermore, treatment of 2-(2-nitrophenyl)benzoimi-
dazoles 4 and isocyanates 2 with TiCl /Zn in anhydrous
4
As our earlier works goes, herein, we wish to describe
a method induced by low-valent titanium reagent for the
preparation of imidazo[1,2-c]quinazolin-5(6H)-ones and
benzimidazo[1,2-c]quinazolin-6(5H)-one using 2-(2-
nitrophenyl)imidazole, 2-(2-nitrophenyl)benzoimidazole
and isocyanates as starting materials.
THF under the same reaction conditions, the reductive
cyclization
products benzimidazo[1,2-c]quinazolin-
(5H)-ones 5 were obtained in good yields (Scheme 3).
6
The results are summarized in Table 3.
As shown in Table 1 and Table 2, for series of 1 and
, either the aromatic ring containing weak electron-
2
withdrawing groups (such as halides) or electron-donat-
ing groups (such as alkyl group), reacted well to give
the corresponding products 3 in high yields under the
same reaction conditions. So we concluded that no
obvious effects from the electronic or nature of the aro-
matic ring substrates were observed in the above
reactions.
RESULTS AND DISCUSSION
On the basis of our previous experience, we selected
2
-(2-nitrophenyl)-4,5-diphenyl-1H-imidazoles 1a and the
-isocyanato-4-methylbenzene 2a as model substrates to
optimize the experimental conditions for the proposed
reductive cyclization reaction (Scheme 1). The results
are summarized in Table 1.
1
Because the nitro compounds are easy to be reduced
to amines by low-valent titanium reagent [17], we think
this reaction may proceed through the intermediate
amine 6. As shown in Scheme 4, the nitro compound
was reduced by low-valent titanium to generate amine
As shown in Table 1, we briefly examined the effect
of different temperatures and low-valent titanium sys-
tems. The results obtained from these experiments indi-
cated that the reaction temperatures had a significant
influence on the success of this reaction. To our delight
at refluxed the reaction proceeded smoothly in high
yield (entry 3). To further evaluate the influence of low-
valent titanium system, this reaction was carried out
with different low-valent titanium reagents. From the
6
, which was then reacted with isocyanates to give inter-
mediate 7. Finally, the expected products 3 were pro-
duced by addition and elimination.
1
All the products were characterized by H-NMR and
IR.
In conclusion, a series of imidazo[1,2-c]quinazolin-
5(6H)-ones and benzimidazo[1,2-c]quinazolin-6(5H)-
ones were synthesized induced by low-valent titanium
results it is obvious that the best system is TiCl /Zn.
4
Having established an optimal condition for the proto-
col, we performed a more detailed examination of the
substrates. Thus, the behavior of a variety of substrates,
which include different isocyanates as well as different
reagent (TiCl /Zn). The process was carried out only
4
Scheme 2
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

5
26
X. Zhao and D.-Q. Shi
Vol 47
Table 2
The synthesis of imidazo[1,2-c]quinazolin-5(6H)-ones 3.
Table 3
The synthesis of benzimidazo[1,2-c]quinazolin-6(5H)-ones 5.
a
a
Compd.
Ar
X
R
Yield/%
Compd.
X
Y
R
Yield/%
3
a
Ph
Ph
H
Cl
Cl
Cl
H
4-CH
4-CH
4-CH
4-ClC
4-ClC
3
3
3
C
C
C
6
6
6
H
H
H
4
4
4
89
85
88
92
83
5a
5b
5c
5d
H
H
H
Cl
4-ClC
4-ClC
6
H
H
4
90
81
87
89
3b
6
4
3
c
4-CH
4-CH
6 4
4-BrC H
3
C
6
H
4
H
Cl
CH
H
3
4-CH
4-CH
3
C
C
6
6
H
H
4
3d
3
OC
6
H
4
6
H
H
4
4
3
4
3
e
6
a
Isolated yield.
a
Isolated yield.
1
6
H-NMR (400 MHz, DMSO-d ) d: 7.23–7.29 (m, 3H, ArH),
one step to generate diversity on the imidazo[1,2-c]qui-
nazolines. The yields are higher and the reaction times
are shorter than the protocol we reported earlier [14].
The short reaction times (0.5 h) and simple reaction
conditions make this protocol attractive.
7.33–7.37 (m, 2H, ArH), 7.43–7.47 (m, 7H, ArH), 7.55–7.59 (m,
H, ArH), 8.26 (d, J ¼ 8.0 Hz, 1H, ArH), 11.75 (s, 1H, NH).
-Chloro-2,3-diphenylimidazo[1,2-c]quinazolin-5(6H)-one
1
9
ꢀ ꢀ
(
3b): white solid, m.p. >300 C (Lit [14] >300 C). IR (KBr)
m: 3160, 1706, 1596, 1553, 1480, 1443, 1378, 1335, 803, 779,
ꢁ1
7
49, 702 cm
1
.
H-NMR (400 MHz, DMSO-d ) d: 7.23–7.25 (m, 3H, ArH),
6
7
.34–7.36 (m, 1H, ArH), 7.43–7.45 (m, 7H, ArH), 7.92–7.94
(
m, 1H, ArH), 8.16–8.17 (m, 1H, ArH), 11.84 (s, 1H, NH).
-Chloro-2,3-di(4-methylphenyl)imidazo[1,2-c]quinazolin-
EXPERIMENTAL
9
ꢀ ꢀ
(6H)-one (3c): white solid, m.p. >300 C (Lit [14] >300 C). IR
5
(
1
THF was distilled from sodium-benzophenone immediately
KBr) m: 3220, 1706, 1598, 1551, 1480, 1443, 1370, 1334,
2
prior to use. All reactions were conducted under N atmos-
phere. Melting points are uncorrected. IR spectra were
recorded on Tensor 27 spectrometer in KBr with absorptions
ꢁ
1
280, 1234, 1073, 813, 797, 749, 760 cm .
1
H-NMR (300 MHz, DMSO-d
(s, 3H, CH
), 7.05 (d, J ¼ 7.8 Hz, 2H, ArH), 7.19–7.35 (m,
H, ArH), 7.55–7.59 (m, 1H, ArH), 8.15 (d, J ¼ 2.1 Hz, 1H,
ArH), 11.79 (s, 1H, NH).
-Chloro-2,3-bis(4-methoxyphenyl)imidazo[1,2-c]quinazo-
6 3
) d: 2.24 (s, 3H, CH ), 2.38
ꢁ
1
1
3
in cm
00 MHz or UNITY INOVA 400 MHz spectrometer in
DMSO-d solution. J values are in Hz. Chemical shifts are
. H-NMR spectra were determined on NMRststem-
7
3
6
9
expressed in ppm downfield from internal standard TMS.
General procedure for the synthesis of 3 and 5 is repre-
ꢀ
ꢀ
lin-5(6H)-one (3d): white solid, m.p. >300 C (Lit [14] >300 C). IR
(
1
KBr) m: 3210, 1703, 1614, 1594, 1554, 1520, 1491, 1366,
sented as follows. TiCl (0.3 mL, 3 mmol) was added drop-
4
ꢁ1
330, 1287, 1246, 1171, 1037, 828, 750, 740 cm
1
.
wise using a syringe to a stirred suspension of zinc powder
(0.384 g, 6 mmol) in freshly distilled anhydrous THF (10 mL)
at r.t. under a dry N atmosphere. After completion of the
H-NMR (400 MHz, DMSO-d ) d: 3.73 (s, 3H, CH O), 3.33
6
3
(
8
s, 3H, CH O), 6.85 (d, J ¼ 8.8 Hz, 2H, ArH), 6.99 (d, J ¼
3
2
.4 Hz, 2H, ArH), 7.34–7.36 (m, 3H, ArH), 7.42 (d, J ¼ 8.8
addition, the mixture was refluxed for 2 h. The suspension of
the low-valent titanium reagent formed was cooled to r.t. and
a solution of 2-(2-niteophenyl)imidazole or 2-(2-nitrophenyl)
benzoimidazole (1 mmol) and isocycanates (1 mmol) in THF
Hz, 2H, ArH), 7.58 (d, J ¼ 8.8 Hz, 1H, ArH), 8.16 (s, 1H,
ArH), 11.79 (s, 1H, NH).
2
,3-Bis(4-bromophenyl)imidazo[1,2-c]quinazolin-5(6H)-one
ꢀ
ꢀ
(
3
1
3e): white solid, m.p. >300 C (Lit [14] >300 C). IR (KBr) m:
(
5 mL) was added dropwise. The reaction mixture was then
refluxed for 30 min under N . After this period, the TLC anal-
227, 3172, 3073, 1709, 1594, 1572, 1550, 1492, 1478, 1392,
ꢁ1
2
072, 959, 744, 727, 694 cm
1
.
ysis of the mixture showed the reaction to be completed. The
reaction mixture was quenched with 5% HCl (15 mL) and
H-NMR (400 MHz, DMSO-d ) d: 7.33–7.41 (m, 6H, ArH),
6
7
2
.49–7.51 (m, 2H, ArH), 7.53–7.57 (m, 1H, ArH), 7.61–7.63 (m,
H, ArH), 8.22 (d, J ¼ 8.0 Hz, 1H, ArH), 11.79 (s, 1H, NH).
Bezimidazo[1,2-c]quinazolin-6(5H)-one (5a): white solid, m.p.
extracted with ClCH CH
extracts were washed with water (3 ꢂ 20 mL) and dried over
2
2
Cl (3 ꢂ 20 mL). The combined
anhydrous Na SO . After evaporation of the solvent under
2
4
ꢀ
ꢀ
>
300 C (Lit [14] >300 C). IR (KBr) m: 3150, 3077, 2916,
reduced pressure, the crude product was purified by recrystalli-
zation from 95% ethanol.
2
,3-Diphenylimidazo[1,2-c]quinazolin-5(6H)-one (3a): white
ꢀ
ꢀ
Scheme 4
solid, m.p. >300 C (Lit [14] >300 C). IR (KBr) m: 3160, 1706,
ꢁ
1
596, 1553, 1480, 1443, 1378, 1335, 803, 779, 749, 702 cm .
1
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis of Imidazo[1,2-c]quinazolin-5(6H)-ones and Benzimidazo[1,2-c]quinazolin-
527
6(5H)-ones with the Aid of Low-Valent Titanium Reagent
2
1
849, 1722, 1614, 1592, 1541, 1479, 1450, 1427, 1382, 1330,
ꢁ
Ed Engl 1996, 35, 2443; (e) Zhou, L. H.; Tu, S. J.; Shi, D. Q.; Dai, G.
Y. W.; Chen, X. Synthesis 1998, 851; (f) Mariappan, P.; Gadthula, S.;
Surisetti, S. Tetrahedron Lett 2001, 42, 7123.
1
292, 1226, 1148, 928, 756, 699 cm
1
.
6
H-NMR (400 MHz, DMSO-d ) d: 7.34–7.50 (m, 4H, ArH),
[
3] Shi, D. Q.; Chen, J. X.; Chai, W. Y.; Chen, W. X.; Kao, T.
Y. Tetrahedron Lett. 1993, 34, 2963.
4] Shi, D. Q.; Mu,L. L.; Lu, Z. S.; Dai, G. Y. Synth Commun
997, 27, 4121.
[5] Zhou, L. H.; Shi, D. Q.; Dai, G. Y.; Chen, W. X. Tetrahe-
dron Lett 1997, 38, 2729.
6] Shi, D. Q.; Rong, L. C.; Shi, C. L.; Zhuang, Q. Y.; Wang,
X. S.; Tu, S. J.; Hu, H. W. Synthesis 2005, 717.
7] Francis, J. E.; Cash, W. D.; Barbaz, W. D.; Bernard, P.
7
.62–7.66 (m, 1H, ArH), 7.84 (d, J ¼ 7.6 Hz, 1H, ArH), 8.29
(
d, J ¼ 7.6 Hz, 1H, ArH), 8.35 (d, J ¼ 8.0 Hz, 1H, ArH),
1.95 (s, 1H, NH).
,10-Dichlorobenzimidazo[1,2-c]quinazolin-6(5H)-one (5b):
[
1
1
9
ꢀ
ꢀ
white solid, m.p. >300 C (Lit [14] >300 C). IR (KBr) m: 3156,
3
1
7
089, 2928, 1713, 1626, 1614, 1547, 1510, 1480, 1415, 1392,
324, 1300, 1267, 1232, 1209, 1160, 1099, 877, 867, 779,
[
ꢁ
1
48, 713, 688 cm
1
.
H-NMR (400 MHz, DMSO-d
[
6
) d: 7.35–7.39 (m, 2H, ArH),
S.; Lovell, R. A.; Mazzenga, G. C.; Friedmann, R. C.; Hyun, J. L.;
Braunwalder, A. F.; Loo, P. S.; Bennett, D. A. J Med Chem 1991,
7
.66–7.69 (m, 1H, ArH), 8.12 (s, 1H, ArH), 8.25 (d, J ¼ 8.0
Hz, 1H, ArH), 8.42 (s, 1H, ArH), 12.12 (s, 1H, NH).
,10-Dimethylbenzimidazo[1,2-c]quinazolin-6(5H)-one (5c):
34, 281.
9
[
8] (a) Cianci, C.; Chung, T. D. Y.; Menwell, N.; Putz, H.;
ꢀ
ꢀ
white solid, m.p. >300 C (Lit [14] >300 C). IR (KBr) m: 3156,
066, 2975, 2913, 2842, 1720, 1624, 1596, 1551, 1511, 1479, 1455,
Hagen, M.; Colonno, R. J.; Krystal, M. Antiviral Chem Chemother
1996, 7, 353; (b) Gineinah, M. M.; Ismaiel, A. M.; El-Kerdawy, M.
M. J Het Chem 1990, 27, 723; (c) Liu, K. C.; Hu, M. K. Arch Pharm
(Weinheim) 1986, 319, 188; (d) Kottke, K.; Kuehmstedt, H.; Graefe,
I.; Wehlau, H.; Knocke, D. DD 253623 (1988), Chem Abstr 1988,
3
1
ꢁ
1
380, 1344, 1291, 1230, 1159, 994, 914, 878, 744, 665 cm .
1
H-NMR (400 MHz, DMSO-d ) d: 2.38 (s, 3H, CH ), 2.39
6
3
(
s, 3H, CH
ArH), 8.12 (s, 1H, ArH), 8.27 (d, J ¼ 8.0 Hz, 1H, ArH), 11.91
s, 1H, NH).
-Chlorobenzimidazo[1,2-c]quinazolin-6(5H)-one (5d): white
3
), 7.33–7.38 (m, 2H, ArH), 7.61–7.64 (m, 2H,
109, 17046; (e) Kathawala, F.; Hardtmann, G. E. Ger Offen 2,146,076
(
1972), Chem Abstr 1972, 77, 48501; (f) Kathawala, F.; Hardtmann,
(
G. E. Ger Offen 2,261,095 (1971), Chem Abstr 1973, 79, 66385.
[9] (a) Nagano, H.; Takagi, M.; Kubodera, N.; Matsunaga, I.;
Nabat, H.; Ohba, Y.; Sakai, K.; Hata, S. I.; Uchida, Y. Eur. Pat.
2
ꢀ
ꢀ
solid, m.p. >300 C (Lit [14] >300 C). IR (KBr) m: 3204, 3037,
2
1
6
922, 1712, 1611, 1551, 1476, 1436, 1385, 1328, 1238, 1167,
146, 1110, 1081, 1059, 1008, 939, 911, 881, 825, 758, 714,
8
9065,1983, ChugaiPharmaceutical Co., Ltd; Chem Abstr 1984, 100,
6547. (b) Imagawa, J.; Sakai, K. Eur J Pharmacol 1986, 131, 257.
10] Chern, J. W.; Yen, M. H.; Lu, G. Y.; Shiau, C. Y.; Lai, Y.
J.; Chan, C. H. J Med Chem 1993, 36, 2196.
ꢁ1
87 cm
1
.
[
H-NMR (400 MHz, DMSO-d ) d: 7.35–7.37 (m, 1H, ArH),
6
7
.41–7.49 (m, 2H, ArH), 7.63–7.66 (m, 1H, ArH), 7.82–7.84
m, 1H, ArH), 8.17–8.18 (m, 1H, ArH), 8.30–8.32 (m, 1H,
[
[
11] Langer, P.; Bodtke, A. Tetrahedron Lett 2003, 44, 5965.
12] Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S.
(
ArH), 12.04 (s, 1H, NH).
W.; Yen, M. H.; Chien, S. L.; Rong J. K. J Med Chem 1998, 41,
128.
13] Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.;
Wang, X. S.; Hu, H. W. Tetrahedron Lett 2003, 44, 3199.
14] Shi, D. Q.; Dou, G. L.; Li, Z. Y.; Ni, S. N.; Li, X. Y.;
Wang, X. S.; Wu, H.; Ji, S. J. Tetrahedron 2007, 63, 9764.
15] Shi, D. Q.; Wang, J. X.; Shi, C. L.; Rong, L. C.; Zhuang,
3
Acknowledgment. Financial support from the Foundation of
Key Laboratory of Organic Synthesis of Jiangsu Province is
gratefully acknowledged.
[
[
[
REFERENCES AND NOTES
Q. Y.; Hu, H. W. Synlett 2004, 1098.
[
[
1] McMurry, J. E. Chem Rev 1989, 89, 1513.
[16] Dou, G. L.; Wang, M. M.; Shi, D. Q. J Comb Chem 2009,
2] (a) McMurry, J. E.; Fleming, M. P. J Org Chem 1976, 41,
11, 151.
8
96; (b) McMurry, J. E. Acc Chem Res 1983, 16, 405; (c) Lenoir, D.
[17] Ceorge, J.; Chandraseharan, S. Synth Commun 1983, 13,
495–499.
Synthesis 1989, 883; (d) F u¨ rstner, A.; Bogdanovi, B. Angew Chem Int
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet