Facile synthesis of substituted quinazolin-4-(3H)-ones using low-valence titanium reagent

Article abstract of DOI:10.1081/SCC-120034156

A short and facile synthesis of a series of 3-aryl quinazolin-4-(3H)-ones was accomplished in good yields via the intermolecular reductive coupling reaction of N-aryl-2-nitrobenzamide and triethyl orthoformate promoted by TiCl₄/Zn.

Full text of DOI:10.1081/SCC-120034156

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 10, pp. 1759–1765, 2004
Facile Synthesis of Substituted
Quinazolin-4-(3H)-ones Using
Low-Valence Titanium Reagent
1
1
Daqing Shi,1,2,3, Liangce Rong, Juxian Wang,
*
Qiya Zhuang,1 Xiangshan Wang,1 and Hongwen Hu2
1Department of Chemistry, Xuzhou Normal University,
Xuzhou, P.R. China
2Department of Chemistry, Nanjing University, Nanjing, P.R. China
3Key Laboratory of Biotechnology on Medical Plant,
Jiangsu, Xuzhou, P.R. China
ABSTRACT
A short and facile synthesis of a series of 3-aryl quinazolin-4-(3H)-ones
was accomplished in good yields via the intermolecular reductive
coupling reaction of N-aryl-2-nitrobenzamide and triethyl orthoformate
promoted by TiCl4/Zn.
Key Words: Quinazolin-4-(3H)-ones; Low-valence titanium; Synthesis.
*
Correspondence: Daqing Shi, Department of Chemistry, Xuzhou Normal University,
Xuzhou 221116, P.R. China.
1759
DOI: 10.1081/SCC-120034156
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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INTRODUCTION
In the early seventies, three groups of investigators[1–3] established that
low-valence titanium, prepared by the reaction of strong reducing agents on
titanium trichloride or titanium tetrachloride in tetrahydrofuran, can abstract
oxygen from ketones or aldehydes, leading to formation of olefins. An increas-
ing interest in the reaction induced by low-valence titanium reagents is
observed and a large number of functional groups can be reduced.[4–8]
Recently, we reported the cyclodimerization of a,b-unsaturated ketones and
a,b-unsaturated nitrile compounds promoted by this reagent, yield functional
cyclopentanes[9] and cyclopentenes,[10] respectively.
Quinazolin-4-(3H)-one is an alkaloid.[11,12] Substituted quinazolin-4-
(3H)-ones possess a wide range of pharmacological activities. 2-Methyl-
3-o-toly-quinazolin-4-(3H)-one is a potent hypnotic agent and other quina-
zolin-4-(3H)-ones have been reported to exhibit analgesic, antibacterial,
anticancer, anesthetic, anticonvulsant, anti-inflammatory, antimalarial, and
antiparasitic, diuretic, sedative and tranquilizing properties [for selected
examples, see Refs.[13–20]]. The main synthetic approaches to such
compounds consist of preliminary amidation of 2-amninobenzonitrile,
2-aminobenzoic acid, or ethyl 2-aminobenzoate[21–23] and thermolysis of
4-amilino-1,2,3-benzotriazimes.[24] Different one-pot synthesis have been
described, but the condensation of 2-aminobenzoic acid with amides or
nitriles requires either high temperature or must be affected in a sealed
tube at 2008C.[25–27] Unfortunately, synthetic methods for the elaboration
of this bicyclic system are not general in scope, and involve often low-
yielding multistep and reaction sequences. We wish to report here a facile
synthesis of 3-arylquinazolin-4-(3H)-ones in fairly high yields via the reac-
tion of N-aryl-2-nitrobenzamide and triethyl orthoformate promoted by low-
valence titanium.
When N-aryl-2-nitrobenzamide (1) and triethyl orthoformate (2) were
treated with low-valence titanium, prepared from titanium tetrachloride and
zinc powder in anhydrous THF, the intermolecular reductive coupling product
(3) are obtained in moderate yields (Sch. 1). The results are summarized in
Table 1.
Scheme 1.

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Table 1. The synthesis of 3-arylquinazolin-4-(3H)-
ones promoted by low-valence titanium.
Entry
X
Ar
Yield (%)a
3a
3b
3c
3d
3e
3f
H
H
C6H5
4-CH3C6H4
4-ClC6H4
84
84
86
79
90
93
91
87
83
H
H
3-Cl-4-F-C6H3
C6H5
Cl
Cl
Cl
Cl
Cl
4-CH3C6H4
4-ClC6H4
4-BrC6H4
3g
3h
3i
3-Cl-4-F-C6H3
aIsolated yield.
1
All the products 3a–i were characterized by IR, H NMR spectral anal-
ysis, and elemental analysis. The structure of 3a was confirmed by x-ray
analysis.a The x-ray crystal structure of 3a is given in Fig. 1.
In conclusion, we believe that the above work provides a useful method
for preparing 3-arylquinazolin-4-(3H)-ones. The remarkable advantage of this
reaction is neutral and mild reaction conditions and simple operation. Further
studies to develop other new uses of the low-valence titanium reagent are now
in progress.
EXPERIMENTAL
THF was distilled from sodium benzophenone immediately prior to use.
All reactions were conducted under a nitrogen atmosphere. Melting points are
1
uncorrected. H NMR spectra were recorded on an Inova-400 instrument as
CDCl3 solutions using TMS as internal standard. IR spectra were determined
on Tensor 27 spectrometer. Elemental analyses were performed on Perkin–
Elmer 2400 II instrument. X-ray diffraction was measure on a Siemens P4
diffractometer.
aX-ray crystallography for 3a: Empirical formula C14H10N2O, FW ¼ 222.24,
˚
˚
3
T ¼ 297(2) K, moloclinic, space group P2(1)/c, a ¼ 12.080(2) A, b ¼ 7.793(1) A,
3
˚
˚
c ¼ 11.599(1) A, b ¼ 97.56(1)8, V ¼ 1082.4(2) A , Z ¼ 4, Dc ¼ 1.364 mg/m ,
l(Mo Ka) ¼ 0.71073 A, m ¼ 0.088 mm21, F(0 0 0) ¼ 464. 1708 , u , 25.258,
˚
R ¼ 0.0358, wR ¼ 0.0851, S ¼ 0933. Largest diff. Peak and hole: 0.130 and
23
˚
20.117e A
.

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Shi et al.
Figure 1. The x-ray crystal structure of 3a.
General Procedure for the Synthesis of
3-Arylquinazolin-4(3H)-ones (3)
TiCl4 (2.2 mL, 20 mmol) was added dropwise using a syringe to a stirred
suspension of zinc dust (2.6 g, 40 mmol) in freshly distilled anhydrous THF
(15 mL) at room temperature under a dry nitrogen atmosphere. After com-
pletion of the addition, the mixture was refluxed for 2 hr. The suspension of
the low-valence titanium reagent formed was cooled to room temperature
and a solution of N-aryl-2-nitrobenzamide (5 mmol) and triethyl orthoformate
(10 mmol) in THF (10 mL) was added dropwise. The mixture was refluxed
5 hr under N2 (the reaction was monitored by TLC). The reaction mixture
was quenched with 10% HCl (50 mL) and extracted with CHCl3
(3 Â 50 mL). The combined extracts were washed, with water (3 Â 50 mL)
and dried over anhydrous Na2SO4. After evaporation of the solvent under
reduced pressure, the crude products 3a–i were purified by recrystallization
from 95% ethanol.
3a. M.p. 135–1378C (lit.[28] m.p. 138–1398C); IR (KBr, n, cm21): 3030,
1672, 1610, 1473, 1402, 1262, 1181, 1111, 1024, 933, 913, 767, 699, 623;
1H NMR (CDCl3, d, ppm): 7.43–7.46 (2H, m, Ar-H), 7.51–7.59 (4H, m,
Ar-H), 7.77–7.85 (2H, m, Ar-H), 8.15 (1H, s, C2-H), 8.38 (1H, d,
J ¼ 11 Hz, C5-H).
3b. M.p. 147–1498C (lit.[28] m.p. 148–1498C); IR (KBr, n, cm21): 3030,
1689, 1600, 1514, 1471, 1323, 1293, 1192, 1114, 1025, 917, 836, 817, 770,
1
749, 694, 615; H NMR (CDCl3, d, ppm): 2.44 (3H, s, CH3), 7.26–7.37
(4H, m, Ar-H), 7.54–7.58 (1H, m, Ar-H), 7.76–7.81 (2H, m, Ar-H), 8.13
(1H, s, C2-H), 8.38 (1H, d, J ¼ 6.8 Hz, C5-H).
3c. M.p. 183–1838C (lit.[29] m.p. 180–1818C); IR (KBr, n, cm21): 3030,
1695, 1614, 1490, 1467, 1293, 1257, 1178, 1093, 1012, 918, 828, 765, 695; 1H
NMR (CDCl3, d, ppm): 7.38–7.40 (2H, m, Ar-H), 7.53–7.59 (3H, m, Ar-H),
7.77–7.85 (2H, m, Ar-H), 8.10 (1H, s, C2-H), 8.37 (1H, d, J ¼ 8.8 Hz, C5-H).

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3d. M.p. 212–2148C; IR (KBr, n, cm21): 3030, 1699, 1612, 1500, 1474,
1324, 1259, 871, 822, 771, 752, 717, 692; H NMR (CDCl3, d, ppm): 7.33–
1
7.35 (2H, m, Ar-H), 7.54–7.61 (2H, m, Ar-H), 7.79–7.86 (2H, m, Ar-H), 8.11
(1H, s, C2-H), 8.37 (1H, d, J ¼ 7.2 Hz, C5-H), Elemental analysis: found (%):
C, 61.38; H, 2.73, Calcd for C24H8ClFN2O (274.68): C, 61.22; H, 2.94.
3e. M.p. 196–1988C; IR (KBr, n, cm21): 3030, 1677, 1606, 1454,
1
1387, 1255, 1078, 899, 863, 781, 749, 698; H NMR (CDCl3, d, ppm):
7.42–7.43 (2H, m, Ar-H), 7.51–7.59 (4H, m, Ar-H), 7.78 (1H, s, C8-H),
8.16 (1H, s, C2-H), 8.35 (1H, d, J ¼ 8.4 Hz, C5-H), Elemental analysis:
found (%): C, 65.58; H, 3.34, Calcd for C14H9ClN2O (256.69): C, 65.51;
H, 3.53.
3f. M.p. 191–1928C; IR (KBr, n, cm21): 3030, 1677, 1597, 1513, 1464,
1
1387, 1257, 1132, 1078, 1057, 951, 920, 899, 864, 831, 781, 765, 691; H
NMR (CDCl3, d, ppm): 2.45 (3H, s, CH3), 7.26–7.30 (2H, m, Ar-H), 7.35–
7.37 (2H, m, Ar-H), 7.50 (1H, d, J ¼ 8.4 Hz, C6-H), 7.77 (1H, s, C8-H),
8.13 (1H, s, C2-H), 8.30 (1H, d, J ¼ 8.4 Hz, C5-H), Elemental analysis:
found (%): C, 66.73; H, 4.01, Calcd for C15H11ClN2O (270.71): C, 66.55;
H, 4.09.
3g. M.p. 211–2138C; IR (KBr, n, cm21): 3033, 1692, 1610, 1489,
1408, 1302, 1257, 1175, 1082, 896, 834, 814, 789, 776; 1H NMR
(CDCl3, d, ppm): 7.38 (2H, d, J ¼ 8.0 Hz, Ar-H), 7.52–7.55 (3H, m, Ar-
H), 7.79 (1H, s, C8-H), 8.12 (1H, s, C2-H), 8.29 (1H, d, J ¼ 8 Hz, C5-H),
Elemental analysis: found (%): C, 57.91; H, 2.53, Calcd for
C14H8Cl2N2O: C, 57.76; H, 2.77.
3h. M.p. 237–2388C; IR (KBr, n, cm21): 3030, 1690, 1607, 1485, 1258,
1
1069, 1009, 897, 855, 814, 768, 694, 625; H NMR (CDCl3, d, ppm): 7.31
(2H, d, J ¼ 8.4 Hz, Ar-H), 7.52 (1H, d, J ¼ 8.8 Hz, C6-H), 7.69 (2H, d,
J ¼ 8.4 Hz, Ar-H), 7.78 (1H, s, C8-H), 8.11 (1H, s, C2-H), 8.29 (1H, d,
J ¼ 8.8 Hz, C5-H), Elemental analysis: found (%): C, 50.35; H, 2.16, Calcd
for C14H8BrClN2O (335.58): C, 50.11; H, 2.40.
3i. M.p. 198–2008C; IR (KBr, n, cm21): 3030, 1697, 1610, 1503, 1257,
1
824, 780; H NMR (CDCl3, d, ppm): 7.32–7.35 (2H, m, Ar-H), 7.53–7.55
(2H, m, Ar-H), 7.80 (1H, s, C8-H), 8.12 (1H, s, C2-H), 8.29 (1H, d,
J ¼ 8.8 Hz, C5-H), Elemental analysis: found (%): C, 54.58; H, 2.13, Calcd
for C14H7Cl2FN2O (309.12): C, 54.40; H, 2.28.
ACKNOWLEDGMENTS
We are grateful to the Education Committee Nature Science Foundation
of Jiangsu Province and the Key Laboratory of Organic Synthesis, Suzhou
University for financial support.

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Received in Japan October 6, 2003

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