A novel and efficient synthesis of 1-hydroxyquinazolin-4-ones via tin(II) chloride induced cyclization of 2-nitrobenzamides and ketones

Article abstract of DOI:10.1055/s-2008-1067126

A mild, efficient and novel synthesis of 2,3-dihydro-1-hydroxyquinazolin- 4(1H)-ones via cyclization of 2-nitrobenzamides and ketones induced by tin(II) chloride dihydrate is described. This new method has the advantages of accessible starting materials, convenient manipulation, short reaction times, and high yields. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067126

2000
PAPER
A Novel and Efficient Synthesis of 1-Hydroxyquinazolin-4-ones via Tin(II)
Chloride Induced Cyclization of 2-Nitrobenzamides and Ketones
S
ynthesis of 1-Hyd
a
roxyquinaz
q
olin-4-onesing Shi,*a,b Guolan Dou,b Yao Zhoub
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, Suzhou
215123, P. R. of China
E-mail: dqshi@263.net
Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. of China
b
Received 27 February 2008; revised 1 April 2008
Here we wish to describe a method induced by tin(II)
chloride dihydrate for the preparation of 1-hydroxy-
quinazolin-4-ones 3 using 2-nitrobenzamides 1 and ke-
tones 2 as the starting materials (Scheme 1).
Abstract: A mild, efficient and novel synthesis of 2,3-dihydro-1-
hydroxyquinazolin-4(1H)-ones via cyclization of 2-nitrobenz-
amides and ketones induced by tin(II) chloride dihydrate is de-
scribed. This new method has the advantages of accessible starting
materials, convenient manipulation, short reaction times, and high
yields.
We began our study of the reaction showed in Scheme 1
by optimizing the reaction conditions for the preparation
of 3. A summary of the optimization experiments is pro-
vided in Table 1. The results showed that at 60 °C the re-
action proceeded smoothly in high yield. To find the
optimum ratio of substrate to reductive agent, the reaction
was carried out in ethanol using a 1:1 to 1:5 ratio of sub-
strate to reductive agent (Table 1, entries 5, 3, 6, 7, 8),
leading to 3a in 61%, 92%, 88%, 52%, and 45% yields,
respectively. We concluded the best ratio of substrate to
reductive agent was 1:2. Moreover, different organic sol-
vents were further investigated as shown in Table 1; we
concluded that ethanol was the best solvent for this
reaction.
Key words: tin(II) chloride dihydrate, 1-hydroxyquinazolin-4-one,
2-nitrobenzamide, ketone
Quinazolinone derivatives are interesting because of their
diverse range of biological activity as anticancer, diuretic,
anti-inflammatory, anticonvulsant, and antihypertensive
agents.1 Recently, these compounds have also been re-
ported as an Na+/Ca2+ exchanger inhibitor.2 The main syn-
thetic approaches to such compounds consist of the
condensation of imidates with anthranilic acid,3 the reac-
tion of anthranilamides with aldehydes,4 palladium-cata-
lyzed cyclization reaction of N-aryl-N¢-benzylureas,5 and
the aza-Wittig reactions of a-azido-substituted aromatic
imides.6 We have previously reported the synthesis of
quinazolin-4(3H)-ones7 and imidazo[1,2-c]quinazolines8
with the aid of a low-valent titanium reagent. However,
none of the compounds prepared by these methods con-
tained 1-hydroxyquinazolin-4-ones. Yamaguchi9 has re-
ported the synthesis of this kind of compound in the
presence of sodium amide, but with 1-hydroxyquinazolin-
4-ones as byproducts in low yields. The Raney nickel cat-
alyzed hydrogenation of 2,3-dihydro-3-(2-nitroben-
In order to demonstrate the efficiency and the applicabili-
ty of the present method, we performed the reaction of a
variety of 2-nitrobenzamides 1 and ketones 2 with tin(II)
chloride at 60 °C in ethanol. The results are summarized
in Table 2.
As shown in Table 2, when N-substituted 2-nitrobenz-
amides 1 and ketones 2 were treated with tin(II) chloride
under the same reaction conditions, only acetone gave the
corresponding products 3 in high yields (entries 1–8 vs
entries 9 and 10). However, when N-unsubstituted 2-ni-
trobenzamides 1 and ketones 2 were treated with tin(II)
chloride under same reaction conditions, other aliphatic
ketones (such as butan-2-one and pentan-3-one) can also
give the desired products 3 in high yields (entries 12 and
13). So we infer from these results that steric hindrance
plays a critical role in this reaction. However, when N-un-
zoyl)benzoxazole
to
1-hydroxy-3-(2-hydroxyphen-
yl)quinazoline-2,4(1H,3H)-dione, however, inaccessible
starting materials and low yield restrict this reaction.10
Therefore, a simple and efficient procedure is still strong-
ly desired for the synthesis of this important heterocyclic
compound.
O
O
R1
R2
R3
O
R1
SnCl2·2H2O
N
N
H
+
R2
R3
X
N
X
NO2
OH
1
2
3
Scheme 1
SYNTHESIS 2008, No. 13, pp 2000–2006
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067126; Art ID: F04308SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1-Hydroxyquinazolin-4-ones
2001
Table 1 Optimization of Reductive Solvent, Temperature, and
Substrate/Reductive Reagent Ratio in the Synthesis of 3a
Table 3 Reductive Cyclization of N-Unsubstituted 2-Nitrobenza-
mides and Substituted Acetophenones
O
O
Entry
Solvent
Temp (°C)
Ratio
Yield (%)
(substrate/SnCl2)
NH
NH2
Ar
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
DMF
THF
r.t.
40
60
80
60
60
60
60
60
60
60
60
60
1:2
1:2
1:2
1:2
1:1
1:3
1:4
1:5
1:2
1:2
1:2
1:2
1:2
60
80
92
80
61
88
52
45
64
35
31
79
14
X
X
N
Me
X
NO2
SnCl2·2H2O
EtOH, 60 °C
1
OH
3
NH
5
+
O
3
O
4
Ar
Me
Ar
N
H
Me
5
4
6
Product
5a
X
Ar
Yield (%)
7
H
4-ClC6H4
Tol
67
53
57
8
5b
Cl
Cl
9
5c
4-ClC6H4
10
11
12
13
drate at room temperature afforded products 7 and the
MeCN
DCE
results are summarized in Table 4.
Furthermore, treatment of bis(2-nitrobenzamides) 8a–c
and acetone with tin(II) chloride dihydrate in ethanol at 60
°C gave the desired products 9a–c in good yields
(Table 5).
Table 2 Synthesis of Compounds 3
All the products were characterized by 1H and 13C NMR,
IR, and HRMS spectra. The structures of 3a, 5b, 7e, and
9a were further confirmed by X-ray diffraction analysis.11
The molecular structures of the products 3a, 5b, 7e, and
9a are shown in Figures 1–4.
Entry Product
X
R1
R2 R3
Yield
(%)
1
2
3a
3b
3c
3d
3e
3f
H
4-ClC6H4
Me Me
Me Me
Me Me
Me Me
Me Me
92
91
92
95
74
89
89
95
0
Cl Ph
A plausible mechanistic pathway to products 3, 5, 7, and
9 from 2-nitrobenzamides and ketones is illustrated in
Scheme 2, although the details are still unclear. In the ini-
tial step, 2-nitrobenzamides are reduced by tin(II) chloride
to A. The hydroxylamine compounds A then reacted with
3
Cl 4-Tol
4
Cl 4-MeOC6H4
Cl 4-ClC6H4
5
6
Cl 3-Cl-4-MeC6H3 Me Me
Table 4 Reductive Cyclization of N-Unsubstituted 2-Nitrobenz-
amides and Cyclic Ketones
7
3g
3h
3i
Cl 3-ClC6H4
Cl Bn
Me Me
Me Me
8
O
O
O
9
H
4-Tol
4-Tol
H
Et
Et
SnCl2·2H2O
NH2
NH
n
+
n
10
11
12
13
3j
H
Me 4-ClC6H4
Me Et
0
EtOH, r.t., 2 h
Y
X
NO2
X
N
Y
OH
3k
3l
Cl
Cl
Cl
97
92
0
7
1
6
H
Me Pr
Product
7a
X
Y
n
Yield (%)
3m
H
Ph Bn
H
H
2
3
2
1
2
3
82
75
99
80
95
80
7b
H
H
substituted 2-nitrobenzamides 1 were treated with substi-
tuted acetophenones 4, the desired products 3 were not
detected and quinazolinones 5 were obtained without ex-
ception (Table 3).
7c
H
Me
H
7d
Cl
Cl
Cl
7e
H
Moreover, the reaction of N-unsubstituted 2-nitrobenz-
amides 1 and cyclic ketones 6 with tin(II) chloride dihy-
7f
H
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York

2002
D. Shi et al.
PAPER
Table 5 Reductive Cyclization of Bis(2-nitrobenzamides) and Ace-
tone
O
O
O
n
SnCl2·2H2O
N
N
+
H
H
Me
Me
EtOH, 60 °C,
2 h
O2N
X
X
NO2
8
O
O
n
N
N
Figure 4 Molecular structure of 9a
N
X
X
N
aliphatic ketones or cyclic ketones to give the expected
products 3, 7, and 9. However, in the case of acetophe-
none, the lower reactivity than acetone allows the reduc-
tion of hydroxylamine A to amine B, then quinazolines 5
would be formed from the resulting amine and the amide
group.
OH
OH
9
Product
9a
X
n
2
2
3
Yield (%)
H
93
97
95
9b
Cl
Cl
In summary, a series of 1-hydroxyquinazolin-4-ones were
synthesized via cyclization of 2-nitrobenzamides and
ketones induced by tin(II) chloride. The advantages of this
new method are the easily accessible starting materials,
convenient manipulation, short reaction time, and high
yields.
9c
Reactions were carried via a SnCl2-mediated cyclization of 2-ni-
trobenzamides and ketones. Commercial solvents and reagents
were used as received. IR spectra were obtained on a Tensor 27
1
spectrophotometer. NMR spectra were recorded for H NMR and
13C NMR using Bruker DPX-400 MHz instrument, at 293 K unless
otherwise noted, with residue peaks of the solvents DMSO-d6 (d =
2.50 for 1H and d = 40.00 for 13C) used for reference. HRMS were
obtained on a TOF-MS instrument using EI ionization. X-ray crys-
tallographic analysis was performed with a Siemens Smart-1000
CCD diffractometer.
Figure 1 Molecular structure of 3a
Quinazolinones 3, 5, 7, and 9; General Procedure
A soln of 2-nitrobenzamide (3 mmol), ketone (3 mmol), and
SnCl2·2 H2O (6 mmol) in EtOH (20 mL) was stirred at 60 °C or r.t.
for 2 h. The mixture was quenched with 3% HCl (100 mL) and fil-
tered and the crude product was purified by recrystallization (EtOH)
to give the pure products 3, 5, 7, or 9.
3-(4-Chlorophenyl)-2,3-dihydro-1-hydroxy-2,2-dimethyl-
quinazolin-4(1H)-one (3a)
Solid; mp 203–205 °C.
Figure 2 Molecular structure of 5b
IR (KBr): 3238, 3053, 2989, 2938, 1632, 1578, 1494, 1470, 1426,
1391, 1312, 1274, 1232, 1175, 1104, 1085, 1047, 1014, 980, 950,
870, 822, 761, 719, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.58 (s, 1 H, OH), 7.72 (d,
J = 7.2 Hz, 1 H, ArH), 7.57–7.52 (m, 3 H, ArH), 7.30–7.23 (m, 3 H,
ArH), 7.03–6.99 (m, 1 H, ArH), 1.33 (s, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.13, 151.39, 138.82,
138.50, 130.12, 129.62, 129.29, 129.06, 128.22, 120.52, 115.24,
113.98, 80.53, 23.28.
HRMS: m/z [M]+ calcd for C16H1535ClN2O2: 302.0822; found:
302.0834.
Crystal data11
CCDC-682915; C16H15ClN2O2; M = 302.75, colorless block crys-
tals, 0.35 × 0.29 × 0.24 mm, monoclinic, space group P21/c,
a = 7.211(9) Å, b = 17.13(2) Å, c = 12.062(15) Å, b = 94.591(19)°,
Figure 3 Molecular structure of 7e
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Hydroxyquinazolin-4-ones
2003
O
O
R1
R1
SnCl2·2H2O
N
N
H
H
X
NO2
X
NH
OH
O
1, 8
A
R2
R3
O
O
R1
R1
R3
N
N
H
X
NH2
X
N
R2
B
OH
O
3, 7, 9
Me
O
Ar
R1
R3
N
X
N
R2
H
5
Scheme 2
V = 1485(3) Å3, Z = 4, Dc = 1.354 g·cm–1, F(000) = 632, m (MoKa) =
0.263 mm–1. Intensity data were collected on a diffractometer with
graphite monochromated MoKa radiation (l = 0.71073 Å) using w
scan mode with 2.07° < q < 25.01°. 2585 unique reflections were
measured and 1170 reflections with I > 2s(I) were used in the re-
finement. The structure was solved by direct methods and expanded
using Fourier techniques. The final cycle of full-matrix least
squares technique to R1 = 0.0896 and wR2 = 0.1913.
J1 = 1.6 Hz, J2 = 8.4 Hz, 1 H, ArH), 2.36 (s, 3 H, CH3), 1.33 (s, 6 H,
2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.49, 151.68, 139.06,
137.85, 136.17, 130.10, 129.91, 120.78, 115.60, 114.24, 80.83,
23.58, 21.15.
HRMS: m/z [M]+ calcd for C17H1735ClN2O2: 316.0979; found:
316.0990.
7-Chloro-2,3-dihydro-1-hydroxy-3-(4-methoxyphenyl)-2,2-
dimethylquinazolin-4(1H)-one (3d)
Solid; mp 143–144 °C.
7-Chloro-2,3-dihydro-1-hydroxy-2,2-dimethyl-3-phenyl-
quinazolin-4(1H)-one (3b)
Solid; mp 214–216 °C.
IR (KBr): 3198, 2983, 2965, 2897, 1637, 1597, 1508, 1468, 1456,
1434, 1388, 1369, 1300, 1250, 1218, 1194, 1168, 1152, 1116, 1079,
1029, 899, 858, 827, 771, 689 cm–1.
IR (KBr): 3231, 2996, 2943, 1627, 1600, 1492, 1437, 1389, 1373,
1311, 1281, 1224, 1191, 1179, 1114, 1083, 1016, 1000, 894, 860,
823, 772, 762, 702, 665 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.79 (s, 1 H, OH), 7.71 (d,
J = 8.0 Hz, 1 H, ArH), 7.19 (d, J = 2.0 Hz, 1 H, ArH), 7.15 (d,
J = 8.8 Hz, 2 H, ArH), 7.03 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1 H, ArH),
7.00 (d, J = 8.8 Hz, 2 H, ArH), 3.80 (s, 3 H, CH3O), 1.33 (s, 6 H,
2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.67, 159.11, 151.69,
139.06, 131.37, 129.92, 120.75, 115.59, 114.70, 114.23, 80.92,
55.77, 23.54.
1H NMR (400 MHz, DMSO-d6): d = 9.81 (s, 1 H, OH), 7.72 (d,
J = 8.0 Hz, 1 H, ArH), 7.50–7.40 (m, 3 H, ArH), 7.25 (d, J = 7.2 Hz,
2 H, ArH), 7.21 (d, J = 2.0 Hz, 1 H, ArH), 7.04 (dd, J1 = 2.0 Hz,
J2 = 8.0 Hz, 1 H, ArH), 1.34 (s, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 162.01, 150.27, 137.70,
134.15, 132.68, 132.12, 129.28, 127.51, 120.73, 116.43, 114.92,
80.18, 23.22.
HRMS: m/z [M]+ calcd for C16H1535ClN2O2: 302.0822; found:
302.0824.
HRMS: m/z [M]+ calcd for C17H1735ClN2O3: 332.0928; found:
332.0942.
7-Chloro-2,3-dihydro-1-hydroxy-2,2-dimethyl-3-(4-methylphe-
nyl)quinazolin-4(1H)-one (3c)
Solid; mp 208–210 °C.
7-Chloro-3-(4-chlorophenyl)-2,3-dihydro-1-hydroxy-2,2-di-
methylquinazolin-4(1H)-one (3e)
Solid; mp 202–204 °C.
IR (KBr): 3205, 2982, 2896, 1629, 1595, 1509, 1438, 1385, 1364,
1311, 1282, 1259, 1222, 1193, 1108, 1083, 1035, 1017, 1003, 897,
873, 859, 813, 772, 721, 692 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.80 (s, 1 H, OH), 7.71 (d,
J = 8.4 Hz, 1 H, ArH), 7.27 (d, J = 8.0 Hz, 2 H, ArH), 7.19 (d,
J = 1.6 Hz, 1 H, ArH), 7.11 (d, J = 8.0 Hz, 2 H, ArH), 7.03 (dd,
IR (KBr): 3315, 2997, 2986, 2900, 1649, 1591, 1490, 1436, 1389,
1366, 1310, 1288, 1266, 1213, 1191, 1115, 1090, 1033, 1015, 1004,
941, 924, 896, 858, 816, 767, 723, 688 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.84 (s, 1 H, OH), 7.72 (d,
J = 8.4 Hz, 1 H, ArH), 7.53 (d, J = 8.8 Hz, 2 H, ArH), 7.30 (d,
J = 8.4 Hz, 2 H, ArH), 7.21 (d, J = 1.6 Hz, 1 H, ArH), 7.04 (dd,
J1 = 1.6 Hz, J2 = 8.0 Hz, 1 H, ArH), 1.34 (s, 6 H, 2 CH3).
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York

2004
D. Shi et al.
PAPER
13C NMR (100 MHz, DMSO-d6): d = 161.53, 151.68, 139.31,
137.66, 133.17, 132.37, 129.96, 129.64, 120.89, 115.31, 114.37,
80.93, 23.52.
HRMS: m/z [M]+ calcd for C16H1435Cl2N2O2: 336.0432; found:
336.0434.
1H NMR (400 MHz, DMSO-d6): d = 9.41 (s, 1 H, OH), 8.40 (s, 1 H,
NH), 7.62 (d, J = 8.0 Hz, 1 H, ArH), 7.07 (s, 1 H, ArH), 6.92 (d,
J = 8.4 Hz, 1 H, ArH), 1.85–1.58 (m, 2 H, CH2), 1.31 (s, 3 H, CH3),
0.90 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.54, 151.89, 138.42,
128.93, 119.42, 114.89, 113.23, 77.19, 29.30, 22.65, 8.20.
7-Chloro-3-(3-chloro-4-methylphenyl)-2,3-dihydro-1-hydroxy-
2,2-dimethylquinazolin-4(1H)-one (3f)
Solid; mp 220–221 °C.
HRMS: m/z [M]+ calcd for C11H1335ClN2O2: 240.0666; found:
240.0658.
IR (KBr): 3232, 2947, 2921, 2862, 1636, 1602, 1534, 1492, 1437,
1388, 1373, 1311, 1283, 1232, 1190, 1175, 1083, 1052, 1019, 1003,
912, 861, 825, 810, 773, 706, 691, 668 cm–1.
7-Chloro-2,3-dihydro-1-hydroxy-2-methyl-2-propylquinazolin-
4(1H)-one (3l)
Solid; mp 177–179 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.83 (s, 1 H, OH), 7.72 (d,
J = 8.0 Hz, 1 H, ArH), 7.45 (d, J = 8.4 Hz, 1 H, ArH), 7.34 (d,
J = 1.2 Hz, 1 H, ArH), 7.20 (d, J = 1.6 Hz, 1 H, ArH), 7.16 (dd,
J1 = 1.2 Hz, J2 = 8.0 Hz, 1 H, ArH), 7.04 (dd, J1 = 1.6 Hz, J2 = 8.4
Hz, 1 H, ArH), 2.38 (s, 3 H, CH3), 1.35 (s, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.54, 151.68, 139.29,
137.67, 136.04, 133.74, 131.96, 130.66, 129.97, 129.29, 120.87,
115.30, 114.35, 80.96, 23.45, 19.75.
IR (KBr): 3384, 3100, 2965, 2872, 1659, 1600, 1466, 1450, 1415,
1369, 1306, 1291, 1276, 1198, 1186, 1159, 1145, 1085, 1024, 991,
922, 868, 837, 805, 776, 737, 687, 627 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.41 (s, 1 H, OH), 8.44 (s, 1 H,
NH), 7.62 (d, J = 8.0 Hz, 1 H, ArH), 7.06 (s, 1 H, ArH), 6.92 (d,
J = 8.0 Hz, 1 H, ArH), 1.78–1.30 (m, 7 H, CH3 and CH2CH2), 0.86
(t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.41, 151.83, 138.41,
128.93, 119.42, 114.94, 113.18, 76.86, 23.04, 16.59, 14.27.
HRMS: m/z [M]+ calcd for C17H1635Cl2N2O2: 350.0589; found:
350.0589.
HRMS: m/z [M]+ calcd for C12H1535ClN2O2: 254.0822; found:
254.0831.
7-Chloro-3-(3-chlorophenyl)-2,3-dihydro-1-hydroxy-2,2-di-
methylquinazolin-4(1H)-one (3g)
Solid; mp 192–193 °C.
2-(4-Chlorophenyl)-2,3-dihydro-2-methylquinazolin-4(1H)-one
(5a)
IR (KBr): 3198, 2981, 2939, 2871, 1633, 1599, 1475, 1435, 1388,
1372, 1309, 1281, 1261, 1225, 1189, 1172, 1156, 1082, 1020, 1003,
909, 881, 869, 828, 806, 784, 772, 705 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.85 (s, 1 H, OH), 7.72 (d,
J = 8.4 Hz, 1 H, ArH), 7.54–7.51 (m, 2 H, ArH), 7.39 (s, 1 H, ArH),
7.29–7.25 (m, 1 H, ArH), 7.21 (d, J = 2.0 Hz, 1 H, ArH), 7.05 (dd,
J1 = 2.0 Hz, J2 = 8.4 Hz, 1 H, ArH), 1.36 (s, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.49, 151.69, 140.16,
139.36, 133.73, 131.14, 130.53, 129.97, 129.45, 128.79, 120.92,
115.25, 114.39, 80.98, 23.64, 23.44.
Solid; mp 213–214 °C.
IR (KBr): 3242, 3174, 3031, 2943, 1636, 1615, 1522, 1491, 1454,
1432, 1388, 1327, 1270, 1221, 1202, 1150, 1097, 1011, 989, 826,
792, 743, 717, 695 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.83 (s, 1 H, NH), 7.69 (s, 1 H,
NH), 7.49 (t, J = 8.4 Hz, 3 H, ArH), 7.37 (d, J = 8.4 Hz, 2 H, ArH),
7.22 (t, J = 7.6 Hz, 1 H, ArH), 6.76 (d, J = 8.0 Hz, 1 H, ArH), 6.60
(t, J = 7.6 Hz, 1 H, ArH), 1.63 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 164.20, 147.41, 147.20,
133.90, 132.26, 128.45, 127.74, 127.62, 117.54, 115.44, 114.80,
70.35, 30.91.
HRMS: m/z [M]+ calcd for C16H1435Cl2N2O2: 336.0432; found:
336.0446.
HRMS: m/z [M]+ calcd for C15H1335ClN2O: 272.0716; found:
272.0737.
3-Benzyl-7-chloro-2,3-dihydro-1-hydroxy-2,2-dimethyl-
quinazolin-4(1H)-one (3h)
7-Chloro-2,3-dihydro-2-methyl-2-(4-methylphenyl)quinazolin-
4(1H)-one (5b)
Solid; mp 244–246 °C.
Solid; mp 196–198 °C.
IR (KBr): 3221, 3032, 3001, 2975, 2870, 1630, 1597, 1496, 1455,
1440, 1394, 1368, 1352, 1312, 1277, 1252, 1186, 1115, 1085, 1023,
1008, 975, 872, 857, 808, 774, 739, 698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.68 (s, 1 H, OH), 7.77 (d,
J = 8.4 Hz, 1 H, ArH), 7.36–7.22 (m, 5 H, ArH), 7.15 (d, J = 1.6 Hz,
1 H, ArH), 7.03 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1 H, ArH), 4.83 (s, 2
H, CH2), 1.36 (s, 6 H, 2 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.89, 151.46, 139.92,
138.94, 129.86, 128.82, 127.27, 127.18, 120.71, 115.13, 114.08,
80.68, 44.98, 22.28.
IR (KBr): 3243, 3175, 3020, 2926, 1638, 1607, 1524, 1511, 1479,
1451, 1422, 1379, 1363, 1317, 1274, 1238, 1222, 1192, 1157, 1101,
1074, 1019, 989, 960, 899, 848, 831, 815, 779, 717, 688 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.86 (s, 1 H, NH), 7.87 (s, 1 H,
NH), 7.47 (d, J = 8.0 Hz, 1 H, ArH), 7.34 (d, J = 8.0 Hz, 2 H, ArH),
7.11 (d, J = 8.0 Hz, 2 H, ArH), 6.78 (s, 1 H, ArH), 6.60 (d, J = 8.4
Hz, 1 H, ArH), 2.22 (s, 3 H, CH3), 1.64 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 163.51, 148.67, 144.73,
138.17, 136.89, 129.70, 129.12, 125.46, 117.32, 114.32, 113.83,
70.75, 31.01, 20.95.
HRMS: m/z [M]+ calcd for C17H1735ClN2O2: M, 316.0979; found:
316.0965.
Crystal data11
7-Chloro-2-ethyl-2,3-dihydro-1-hydroxy-2-methylquinazolin-
4(1H)-one (3k)
Solid; mp 184–186 °C.
CCDC-682916; C16H15ClN2O; M = 286.75, colorless block crys-
tals, 0.38 × 0.26 × 0.20 mm, monoclinic, space group P21/c,
a = 12.2843(8) Å, b = 9.3487(6) Å, c = 12.3510(7) Å,
b = 101.7300(10)°, V = 1388.79(15) Å3, Z = 4, Dc = 1.371 g·cm–1,
F(000) = 600, m (MoKa) = 0.272 mm–1. Intensity data were collect-
ed on a diffractometer with graphite monochromated MoKa radia-
tion (l = 0.71073 Å) using w scan mode with 1.69° < q < 25.01°.
IR (KBr): 3226, 2970, 2881, 1655, 1601, 1439, 1383, 1296, 1252,
1208, 1188, 1158, 1082, 1040, 1022, 872, 857, 821, 778, 697, 666,
624 cm–1.
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-Hydroxyquinazolin-4-ones
2005
1344 unique reflections were measured and 1116 reflections with
I > 2s(I) were used in the refinement. The structure was solved by
direct methods and expanded using Fourier techniques. The final
cycle of full-matrix least squares technique to R1 = 0.0451 and
wR2 = 0.1098.
7¢-Chloro-1¢-hydroxyspiro[cyclopentane-1,2¢(1¢H)-quinazolin]-
4¢(3¢H)-one (7d)
Solid; mp 208–210 °C.
IR (KBr): 3320, 3165, 3072, 3030, 2943, 1656, 1606, 1572, 1466,
1376, 1330, 1291, 1255, 1182, 1159, 1137, 1094, 1007, 954, 905,
818, 791, 709, 667 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.52 (s, 1 H, OH), 8.78 (s, 1 H,
NH), 7.55 (d, J = 2.4 Hz, 1 H, ArH), 7.48 (dd, J1 = 2.4 Hz, J2 = 8.4
Hz, 1 H, ArH), 7.16 (d, J = 8.4 Hz, 1 H, ArH), 2.16–2.09 (m, 2 H,
2 CH), 1.71–1.60 (m, 6 H, 6 CH).
13C NMR (100 MHz, DMSO-d6): d = 161.66, 152.68, 138.33,
129.08, 120.05, 115.82, 113.84, 85.27, 34.81, 24.21.
HRMS: m/z [M]+ calcd for C12H1335ClN2O2: 252.0666; found:
252.0663.
7-Chloro-2-(4-chlorophenyl)-2,3-dihydro-2-methylquinazolin-
4(1H)-one (5c)
Solid; mp 271–272 °C.
IR (KBr): 3230, 3174, 3020, 1639, 1606, 1524, 1479, 1453, 1422,
1361, 1322, 1270, 1240, 1200, 1157, 1097, 1081, 1011, 990, 962,
900, 859, 834, 787, 720, 689 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.95 (s, 1 H, NH), 7.96 (s, 1 H,
NH), 7.50–7.46 (m, 3 H, ArH), 7.40 (d, J = 8.4 Hz, 2 H, ArH), 6.79
(d, J = 1.6 Hz, 1 H, ArH), 6.63 (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, 1 H,
ArH), 1.64 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 164.20, 147.41, 147.20,
133.89, 132.26, 128.46, 127.74, 127.62, 117.54, 115.44, 114.80,
70.35, 30.91.
7¢-Chloro-1¢-hydroxyspiro[cyclohexane-1,2¢(1¢H)-quinazolin]-
4¢(3¢H)-one (7e)
Solid; mp 206–208 °C.
IR (KBr): 3263, 3161, 2929, 2862, 1662, 1601, 1507, 1439, 1374,
1306, 1281, 1259, 1218, 1157, 1111, 1082, 1012, 984, 912, 888,
874, 840, 779, 707, 669 cm–1.
1¢-Hydroxyspiro[cyclohexane-1,2¢(1¢H)-quinazolin]-4¢(3¢H)-one
(7a)
1H NMR (400 MHz, DMSO-d6): d = 9.49 (s, 1 H, OH), 8.46 (s, 1 H,
NH), 7.62 (d, J = 8.0 Hz, 1 H, ArH), 7.10 (d, J = 2.0 Hz, 1 H, ArH),
6.96 (dd, J 1 = 2.0 Hz, J2 = 8.0 Hz, 1 H, ArH), 1.87–1.80 (m, 2 H,
2 × CH), 1.72–1.58 (m, 7 H, 7 × CH), 1.08–1.05 (m, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 161.35, 151.64, 138.46,
128.95, 119.85, 115.68, 113.87, 76.07, 31.26, 24.74, 20.96.
Solid; mp 195–197 °C.
IR (KBr): 3267, 3170, 3081, 2929, 2862, 1656, 1608, 1558, 1540,
1507, 1469, 1429, 1387, 1342, 1313, 1288, 1276, 1255, 1151, 1110,
910, 819, 789, 759, 701 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.22 (s, 1 H, OH), 8.30 (s, 1 H,
NH), 7.63 (d, J = 7.6 Hz, 1 H, ArH), 7.46–7.41 (m, 1 H, ArH), 7.14
(d, J = 8.4 Hz, 1 H, ArH), 6.94–6.89 (m, 1 H, ArH), 1.85–1.79 (m,
2 H, 2 CH), 1.70–1.52 (m, 7 H, 7 CH), 1.08–1.04 (m, 1 H, CH).
HRMS: m/z [M]+ calcd for C13H1535ClN2O2: 266.0822; found:
266.0827.
13C NMR (100 MHz, DMSO-d6): d = 162.17, 150.47, 133.60,
126.86, 120.13, 117.16, 114.85, 75.52, 31.29, 24.88, 21.03.
Crystal data11
CCDC-682917; C13H15ClN2O2; M = 265.71, colorless block crys-
tals, 0.48 × 0.35 × 0.33 mm, triclinic, space group P1,
a = 12.484(5) Å, b = 12.873(5) Å, c = 17.065(6) Å, a = 91.005(5)°,
b = 106.187(4)°, g = 101.340(4)°, V = 2574.6(16) Å3, Z = 8,
Dc = 1.371 g·cm–1, F(000) = 1112, m (MoKa) = 0.292 mm–1. Inten-
sity data were collected on a diffractometer with graphite mono-
chromated MoKa radiation (l = 0.71073 Å) using w scan mode
with 1.62° < q < 25.01°. 8950 unique reflections were measured and
4418 reflections with I > 2s(I) were used in the refinement. The
structure was solved by direct methods and expanded using Fourier
techniques. The final cycle of full-matrix least squares technique to
R1 = 0.0515 and wR2 = 0.1139.
HRMS: m/z [M]+ calcd for C13H16N2O2: 232.1212; found:
232.1222.
1¢-Hydroxyspiro[cycloheptane-1,2¢(1H¢)-quinazolin]-4¢(3¢H)-
one (7b)
Solid; mp 200–201 °C.
IR (KBr): 3209, 3075, 2924, 1656, 1607, 1507, 1469, 1389, 1199,
1152, 1069, 857, 759 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.22 (s, 1 H, OH), 8.42 (s, 1 H,
NH), 7.59 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1 H, ArH), 7.41–7.38 (m, 1
H, ArH), 7.06 (d, J = 7.6 Hz, 1 H, ArH), 6.88–6.84 (m, 1 H, ArH),
2.11 (dd, J1 = 8.4 Hz, J2 = 14.4 Hz, 2 H, CH2), 1.81 (dd, J1 = 9.2 Hz,
J2 = 14.4 Hz, 2 H, CH2), 1.59–1.48 (m, 8 H, 4 × CH2).
HRMS: m/z [M]+ calcd for C14H18N2O2: 246.1368; found:
246.1380.
7¢-Chloro-1¢-hydroxyspiro[cycloheptane-1,2¢(1¢H)-quinazolin]-
4¢(3¢H)-one (7f)
Solid; mp 223–225 °C.
IR (KBr): 3296, 3109, 3090, 2928, 2904, 1651, 1603, 1600, 1440,
1370, 1306, 1281, 1225, 1199, 1153, 1072, 1020, 963, 935, 867,
830, 782, 700 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.50 (s, 1 H, OH), 8.57 (s, 1 H,
NH), 7.59 (d, J = 8.0 Hz, 1 H, ArH), 7.03 (d, J = 2.0 Hz, 1 H, ArH),
6.99 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1 H, ArH), 2.10 (dd, J1 = 8.4 Hz,
J2 = 14.0 Hz, 2 H, CH2), 1.81 (dd, J1 = 8.4 Hz, J2 = 14.4 Hz, 2 H,
CH2), 1.59–1.48 (m, 8 H, 4 CH2).
1¢-Hydroxy-4-methylspiro[cyclohexane-1,2¢(1¢H)-quinazolin]-
4¢(3¢H)-one (7c)
Solid; mp 202–204 °C.
IR (KBr): 3263, 3085, 2909, 2871, 1664, 1606, 1517, 1468, 1431,
1388, 1348, 1311, 1265, 1152, 1112, 1020, 1000, 902, 875, 801,
762, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.22 (s, 1 H, OH), 8.28 (s, 1 H,
NH), 7.62 (d, J = 7.2 Hz, 1 H, ArH), 7.43 (t, J = 8.0 Hz, 1 H, ArH),
7.13 (d, J = 8.4 Hz, 1 H, ArH), 6.90 (t, J = 7.6 Hz, 1 H, ArH), 1.91–
0.88 (m, 9 H, 4 CH2, CH), 0.87 (s, 3 H, CH3).
HRMS: m/z [M]+ calcd for C14H1735ClN2O2: 280.0979; found:
280.0989.
2,3-Dihydro-3-{2-[1,4-dihydro-1-hydroxy-2,2-dimethyl-4-oxo-
quinazolin-3(2H)-yl]ethyl}-1-hydroxy-2,2-dimethylquinazolin-
4(1H)-one (9a)
HRMS: m/z [M]+ calcd for C14H18N2O2: 246.1368; found:
246.1360.
Solid; mp 223–225 °C.
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York

2006
D. Shi et al.
PAPER
IR (KBr): 3464, 3254, 2997, 2969, 2905, 1638, 1616, 1571, 1473,
1405, 1363, 1318, 1301, 1265, 1193, 1181, 1015, 985, 940, 868,
758, 698, 671 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.50 (s, 2 H, 2 OH), 7.72 (d,
J = 7.6 Hz, 2 H, ArH), 7.47 (t, J = 7.6 Hz, 2 H, ArH), 7.17 (d,
J = 8.4 Hz, 2 H, ArH), 6.96 (t, J = 7.6 Hz, 2 H, ArH), 3.64–3.55 (m,
4 H, 2 CH2), 1.54 (s, 12 H, 4 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.37, 151.22, 138.68,
129.58, 120.57, 115.19, 113.94, 80.36, 40.26, 22.40.
HRMS: m/z [M]+ calcd for C23H2635Cl2N4O4: 492.1331; found:
492.1334.
Acknowledgment
13C NMR (100 MHz, DMSO-d6): d = 162.56, 150.22, 134.12,
127.44, 120.72, 116.19, 114.73, 80.06, 41.63, 22.52.
We are grateful to the Foundation of Key Laboratory of Organic
Synthesis of Jiangsu Province for financial support.
HRMS: m/z [M]+ calcd for C22H26N4O4: 410.1954; found:
410.1877.
References
Crystal data11
(1) (a) Chan, J. H.; Hong, J. S.; Kuyper, L. F.; Jones, M. L.;
Baccanari, D. P.; Tansik, R. L.; Boytos, C. M.; Rudolph, S.
K.; Brown, A. D. J. Heterocycl. Chem. 1997, 34, 145.
(b) Gackenheimer, S. L.; Schaus, J. M.; Gehlert, D. R.
J. Pharmacol. Exp. Ther. 1996, 732, 113. (c) Dempcy, R.
Q.; Skibo, E. B. Biochemistry 1991, 30, 8480.
CCDC-682918; C22H28N4O5; M = 428.48, colorless block crystals,
0.42 × 0.23 × 0.19 mm, monoclinic, space group P21/c,
a = 8.627(3) Å, b = 10.972(4) Å, c = 23.345 (8) Å, b = 99.898(5)°,
V = 2176.8(13) Å3, Z = 4, Dc = 1.307 g·cm–1, F(000) = 1062,
m (MoKa) = 0.0936 mm–1. Intensity data were collected on a dif-
fractometer with graphite monochromated MoKa radiation
(l = 0.71073 Å) using w scan mode with 2.566° < q < 20.623°. 3819
unique reflections were measured and 1775 reflections with
I > 2s(I) were used in the refinement. The structure was solved by
direct methods and expanded using Fourier techniques. The final
cycle of full-matrix least squares technique to R1 = 0.0620 and
wR2 = 0.1520.
(d) Campbell, S. F.; Davey, M. J. Drug Design Delivery
1986, 83. (e) Imagawa, J.; Sakai, K. Eur. J. Pharmacol.
1986, 131, 257.
(2) Hasegawa, H.; Muraoka, M.; Matsui, K.; Kojima, A. Bioorg.
Med. Chem. Lett. 2003, 13, 3471.
(3) (a) Ried, W.; Sinharray, A. Chem. Ber. 1963, 96, 3306.
(b) Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.;
Kang, G. L.; Hamel, E. J. Med. Chem. 1990, 33, 1721.
(c) Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707.
(4) Connoly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153.
(5) (a) Schlapbach, A.; Heng, R.; Padova, F. D. Bioorg. Med.
Chem. Lett. 2004, 14, 357. (b) Ferraccioli, R.; Carenzi, D.
Synthesis 2003, 1383.
(6) (a) Takeuchi, H.; Haguvara, S.; Eguchi, S. Tetrahedron
1989, 45, 6375. (b) Takeuchi, H.; Matsushita, Y.; Eguchi, S.
J. Org. Chem. 1991, 56, 1535. (c) Molina, P.; Alajarin, M.;
Vidal, A. Tetrahedron Lett. 1988, 29, 3849.
(7) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.; Wang,
X. S.; Hu, H. W. Tetrahedron Lett. 2003, 44, 3199.
(8) Shi, D. Q.; Wang, J. X.; Shi, C. L.; Rong, L. C.; Zhuang, Q.
Y.; Hu, H. W. Synlett 2004, 1098.
7-Chloro-3-{2-[7-chloro-1,4-dihydro-1-hydroxy-2,2-dimethyl-
4-oxoquinazolin-3(2H)-yl]ethyl}-2,3-dihydro-1-hydroxy-2,2-
dimethylquinazolin-4(1H)-one (9b)
Solid; mp 254–256 °C.
IR (KBr): 3273, 2980, 2944, 2867, 1626, 1597, 1558, 1538, 1437,
1389, 1362, 1296, 1251, 1183, 1148, 1111, 1080, 1019, 1004, 944,
899, 868, 859, 838, 803, 774, 744, 695, 682, 666 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.75 (s, 2 H, 2 OH), 7.73–7.68
(m, 2 H, ArH), 7.13 (s, 2 H, ArH), 7.00 (d, J = 8.4 Hz, 2 H, ArH),
3.63 (s, 4 H, 2 CH2), 1.54 (s, 12 H, 4 CH3).
13C NMR (100 MHz, DMSO-d6): d = 161.73, 151.26, 138.95,
129.56, 120.61, 114.82, 113.98, 80.50, 41.62, 22.55.
(9) Yamaguchi, K. Bull. Chem. Soc. Jpn. 1976, 49, 1366.
(10) Sam, J.; Richmond, C. W. J. Heterocycl. Chem. 1964, 1,
245.
7-Chloro-3-{3-[7-chloro-1,4-dihydro-1-hydroxy-2,2-dimethyl-
4-oxoquinazolin-3(2H)-yl]propyl}-2,3-dihydro-1-hydroxy-2,2-
dimethylquinazolin-4(1H)-one (9c)
(11) Crystallographic data for the structures of 3a (CCDC-
682915), 5b (CCDC-682916), 7e (CCDC-682917), and 9a
(CCDC-682918) have been deposited at the Cambridge
Crystallographic Data Centre. Copies of available material
can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033; email: deposit@ccdc.cam.ac.uk].
Solid; mp 230–232 °C.
IR (KBr): 3271, 3143, 2996, 2864, 1621, 1599, 1567, 1442, 1372,
1334, 1312, 1275, 1252, 1203, 1178, 1156, 1135, 1084, 1059, 1044,
1022, 1006, 939, 864, 805, 770, 690, 668, 614 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.71 (s, 2 H, 2 OH), 7.68 (d,
J = 8.0 Hz, 2 H, ArH), 7.11 (s, 2 H, ArH), 6.98 (d, J = 7.2 Hz, 2 H,
ArH), 3.55 (t, J = 7.2 Hz, 4 H, 2 CH2), 1.87–1.82 (m, 2 H, CH2),
1.47 (s, 12 H, 4 CH3).
Synthesis 2008, No. 13, 2000–2006 © Thieme Stuttgart · New York