Synthesis of quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-4(3H)-ones with the aid of a low-valent titanium reagent

Article abstract of DOI:10.1016/S0040-4039(03)00449-0

A short and facile synthesis of a series of quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-4(3H)-ones was accomplished in good yields via the novel reductive cyclization of o-nitrobenzamides and triethyl orthoformate, aldehydes or ketones promoted by TiCl₄/Zn.

Full text of DOI:10.1016/S0040-4039(03)00449-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3199–3201
Synthesis of quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-
4(3H)-ones with the aid of a low-valent titanium reagent
Daqing Shi,a,b,* Liangce Rong,b Juxian Wang,b Qiya Zhuang,b Xiangshan Wangb and Hongwen Hua
aDepartment of Chemistry, Nanjing University, Nanjing 210093, PR China
bDepartment of Chemistry, Xuzhou Normal University, Xuzhou 221009, PR China
Received 5 December 2002; revised 3 February 2003; accepted 14 February 2003
Abstract—A short and facile synthesis of a series of quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-4(3H)-ones was accom-
plished in good yields via the novel reductive cyclization of o-nitrobenzamides and triethyl orthoformate, aldehydes or ketones
promoted by TiCl4/Zn. © 2003 Published by Elsevier Science Ltd.
Low-valent titanium reagents have an exceedingly high
ability to promote reductive coupling of carbonyl com-
pounds and are attracting increasing interest in organic
synthesis. Many other functional groups can also be
coupled.1
pared from titanium tetrachloride and zinc powder in
anhydrous THF, the reductive cyclization products,
quinazolin-4(3H)-ones 3 were obtained in good yields
(Scheme 1). The results are summarized in Table 1.
Moreover, treatment of o-nitrobenzamides
4 and
Recently, we have reported the cyclodimerization of
a,b-unsaturated ketones and a,b-unsaturated nitriles
promoted by this reagent yielding functional
cyclopentanes2 and cyclopentenes,3 respectively.
ketones or aromatic aldehydes 5 with TiCl4–Zn in
anhydrous THF under the same reaction conditions
afforded 1,2-dihydroquinazolin-4(3H)-ones 6 in good
yields (Scheme 2).
Preparations of quinazolin-4(3H)-ones are in demand
because of their potential biological and pharmaceutical
activities.4 Unfortunately, synthetic methods for the
elaboration of this bicyclic system are not general in
scope, and involve multistep, and often low-yielding,
reaction sequences. The main synthetic approaches to
such compounds consist of preliminary amidation of
2-aminobenzonitrile, 2-aminobenzoic acid or ethyl 2-
aminobenzoate5 and the aza-Wittig reactions of a-
azido-substituted aromatic imides.6 Different one-pot
syntheses 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 200°C.7 Here we wish to describe a new method
induced by the TiCl4/Zn system for the preparation of
quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-
4(3H)-ones using o-nitrobenzamides as the starting
material.
Scheme 1.
Table 1. The synthesis of quinazolin-4(3H)-ones promoted
by TiCl4/Zn
Entry
X
Ar
Isolated yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
Cl
Cl
Cl
Cl
Cl
C6H5
84
84
86
79
90
93
91
87
83
4-CH3C6H4
4-ClC6H4
3-Cl-4-F-C6H3
C6H5
4-CH3C6H4
4-ClC6H4
4-BrC6H4
3-Cl-4-F-C6H3
When N-aryl-o-nitrobenzamides 1 and triethyl ortho-
formate 2 were treated with low-valent titanium pre-
* Corresponding author. Tel.: 86-516-3403163; fax: 86-516-3403164;
e-mail: dqshi@xznu.edu.cn
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00449-0

3200
D. Shi et al. / Tetrahedron Letters 44 (2003) 3199–3201
Scheme 2.
Table 2 summarizes our results. All reactions could be
carried out under mild conditions. However, N-phenyl-
o-nitrobenzamide failed to react with 3-pentanone,
cyclopentanone, benzaldehyde or acetophenone under
these conditions, although the reaction of o-nitrobenza-
mide 4 and the cyclic ketones 7 with the same reagent
system afforded 2,2-polymethylene-1,2-dihydroquina-
zolin-4(3H)-ones 8 (Scheme 3) and the results are sum-
marized in Table 3. However, o-nitrobenzamide failed
to react with acetophenone or 1-tetralone.
Figure 1. ORTEP diagram of 3a.
1
The structures of 3, 6 and 8 were confirmed by IR, H
NMR and elemental analysis.8 The structures of 3a and
Figure 2. ORTEP diagram of 8c.
Scheme 3.
8c were further confirmed by X-ray analysis (Fig. 1 and
Fig. 2).9
Table 3. The reductive cyclization of o-nitrobenzamides
and cyclic ketones
In summary, a series of quinazolin-4(3H)-ones and
1,2-dihydroquinazolin-4(3H)-ones were synthesized via
reductive cyclization of o-nitrobenzamides with triethyl
orthoformate, aldehydes or ketones induced by the
TiCl4/Zn system. The advantages of our method are the
easily accessible starting materials, convenient manipu-
lation and moderate to high yields.
Entry
X
n
Isolated yield (%)
8a
8b
8c
8d
H
Cl
H
1
1
2
2
84
89
63
83
Cl
Table 2. The synthesis of 1,2-dihydroquinazolin-4(3H)-ones promoted by TiCl4/Zn
Entry
X
R1
R2
R3
Isolated yield (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H
H
Cl
Cl
C6H5
4-CH3C6H4
4-BrC6H4
C6H5
4-CH3C6H4
4-ClC6H4
4-CH3C6H4
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
3,4-OCH2OC6H3
3,4-(OCH3)2C6H3
4-CH3C6H4
4-CH3OC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
H
H
H
H
H
81
88
83
85
89
86
79
82
91
89
92
92
93
80
87
H
H
H

D. Shi et al. / Tetrahedron Letters 44 (2003) 3199–3201
3201
Acknowledgements
2978, 1627, 1519, 1399, 1277, 1176, 1108, 1022, 813, 755,
1
697 cm−1. H NMR (400 MHz, CDCl3) lH: 1.49 (6H, s,
2×CH3), 2.38 (3H, s, CH3), 6.67–7.95 (8H, m, ArH).
Anal. C17H18N2O. Calcd C, 76.66; H, 6.81; N, 10.52.
Found C, 76.83; H, 6.59; N, 10.63%. Compound 8c,
2,2-penta-methylene-1,2-dihydroquinazolin-4(3H)-one
mp 224–225°C, wmax: 3367, 3109, 2924, 1652, 1484, 1382,
We are grateful to the Natural Science Foundation of
Jiangsu Education Committee (00KJB150008) for
financial support.
1270, 1178, 1145, 1040, 1004, 855, 760 cm−1 1H NMR
.
(400 MHz, CDCl3) lH: 1.47–1.48 (2H, m, CH2), 1.53–
1.60 (4H, m, 2×CH2), 1.83–1.84 (4H, m, 2×CH2), 6.19
(1H, br., s, NH), 6.65–7.87 (4H, m, ArH). Anal.
C13H16N2O. Calcd C, 72.19; H, 7.46; N, 12.95. Found C,
72.32; H, 7.28; N, 13.15%.
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Crystal data for 3a: C14H10N2O; M=222.24, colorless
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,
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8. Typical physical data for representative compounds:
Compound 3a, 3-phenylquinazolin-4(3H)-one mp 135–
137°C (lit.10 mp 138–139°C), wmax: 3030, 1672, 1610, 1473,
1402, 1262, 1181, 1111, 1024, 933, 913, 767, 699, 623
cm−1. 1H NMR (400 MHz, CDCl3) lH: 7.43–7.46 (2H, m,
ArH), 7.51–7.59 (4H, m, ArH), 7.77–7.85 (2H, m, ArH),
8.15 (1H, s, C2-H), 8.38 (1H, d, J=11 Hz, C5-H). Com-
pound 6b, 2,2-dimethyl-3-(4%-methylphenyl)-1,2-dihydro-
quinazolin-4(3H)-one mp 255–256°C, wmax: 3306, 3025,
,
10.387(1), b=10.954(2), c=10.827(2) A, i=110.77(1)°,
3
V=1151.8(4) A , Z=4, DC=1.247 g cm−3. F(000)=464,
,
v(MoKa)=0.080 mm−1. Intensity data were collected on
a Siemens P4 diffractometer with graphite-monochro-
,
mated MoKa radiation (u=0.71073 A) using ꢀ–2q scan
mode with 2.34°<q<25.00°. 2033 unique reflections were
measured and 1557 reflections with I>2|(I) were used in
the structure refinement. The structure was solved by
direct methods and expanded using Fourier techniques.
The final refinement was converged to R=0.0449 and
wR=0.1217.
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