One-pot synthesis of quinazoline-2,4(1H,3H)-diones and 2- thioxoquinazolinones with the aid of low-valent titanium reagent

Article abstract of DOI:10.1002/jhet.121

(Chemical Equation Presented) An efficient, convenient, one-pot synthesis of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolinones was accomplished in good yields via the novel reductive cyclization of ethyl 2-nitrobenzoates with isocyanates or isothioc

Full text of DOI:10.1002/jhet.121

July 2009
One-Pot Synthesis of Quinazoline-2,4(1H,3H)-diones and
2-Thioxoquinazolinones with the Aid of Low-Valent
Titanium Reagent
645
Guo-Lan Dou, Man-Man Wang, Zhi-Bin Huang, and Da-Qing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical and
Materials Science, Soochow University, Suzhou 215123, People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received December 20, 2008
DOI 10.1002/jhet.121
Published online 7 July 2009 in Wiley InterScience (www.interscience.wiley.com).
An efficient, convenient, one-pot synthesis of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazoli-
nones was accomplished in good yields via the novel reductive cyclization of ethyl 2-nitrobenzoates
with isocyanates or isothiocyanates mediated by TiCl4/Zn system.
J. Heterocyclic Chem., 46, 645 (2009).
INTRODUCTION
1H-quinazoline-2,4-diones has been reported [13]. How-
ever, the reaction time is too long (24 h). A recent
report details the preparation of 2,4(1H,3H)-quinazoline-
diones and 2-thioxoquinazolines assisted by microwave
[14], but the yields of this protocol were a little lower.
It is found that all the methods mentioned earlier used
amino-compounds other than nitro-compounds as start-
ing materials. Therefore, we became interested in devel-
oping a novel and convenient synthetic method for the
preparation of quinazolinedione derivatives start with
nitro-compounds. Our initial studies showed that suc-
cessful synthesis of various quinazolinediones from 2-
nitrobenzamides and triphosgene [15]. As part of our
ongoing research for novel synthesis of quinazoline-
diones derivatives, herein, we describe a new one-pot
synthesis of quinazolinedione derivatives by treating
ethyl o-nitrobenzoates with isothiocyanates or isocya-
nates under low-valent titanium reagent (TiCl4/Zn).
It has been reported that quinazolinones show antihy-
pertonic, antirheumatic, antianaphylactic, antiasthmatic,
tranquilizing, neuro-stimulating, and benzodiazepine
binding activity [1,2]. The quinazolindione moiety, in
particular, is widely found in natural purine based, alka-
loids and many biologically active compounds [3]. For
example, 3-substituted quinazolinones, such as SGB-
1534 (1) and ketanserin (2) have been found to have
antihypertensive activities mediated via a-adrenoceptor
and serotonic receptor anatgonism [4], respectively. 6,7-
Dimethoxy-1H-quinazoline-2,4-dione is a key intermedi-
ate for the production of the following medicines (Pra-
zosin (Minipress) [5], Bunazosin (Detantol) [5], and
Doxazosin (Cardenalin) [5]. 7-Chloro-1H-quinazoline-
2,4-diones is also a key intermediate for the production
of the medicines such as FK366 [6] and KF31327 [7].
The quinazolinedione ring system can generally be
prepared by the reaction of anthranilic acid with urea
[8], anthranilamide with phosgene [9], and anthranilic
acid with potassium cyanate [10] or chlorosulfonyl iso-
cyanate [11]. However, these synthetic methods are con-
siderably limited because of the usage of drastic condi-
tions and uneasily starting materials. Different solid-
phase combinatorial synthesis of quinazolinediones was
reported in recent years, but these methods need long
reaction times, multiple steps, or both [12]. Carbon
dioxide reacted with 2-aminobenzonitriles assisted by
excess amount of DBU or DBN to give corresponding
RESULTS AND DISCUSSION
On the basis of our previous experience, we selected
ethyl 2-nitrobenzoate 1a and the 4-methylphenyl isothio-
cyanate 2a as model substrates to optimize the experi-
mental conditions for the proposed reductive cyclization
reaction (Scheme 1). The results are summarized in
Table 1.
As shown in Table 1, we briefly examined the effect
of different temperatures and ratio of 1a:TiCl4/Zn. The
C
V
2009 HeteroCorporation

646
G.-L. Dou, M.-M. Wang, Z.-B. Huang, and D.-Q. Shi
Vol 46
Scheme 1
Similarly, aryl isocyanates containing electron-donat-
ing and electron-withdrawing substituents were reacted
well with ethyl 2-nitrobenzoate, therefore, we can con-
clude that the electronic nature of the substituents has
no significant effect on this reaction, but severe steric
hindrance still play an important part in this reaction.
Good yields were also obtained when 3-methyl or 4-Cl-
substituted ethyl 2-nitrobenzoates were used. Mean-
while, it was found that isocyanates showed similar
reactivity trends with isothiocyanates.
results obtained from these experiments indicated that
the reaction temperatures had a significant influence on
the success of this reaction. At room temperature or
40ꢀC, no expected compound was detected (Table 1,
entries 1 and 2). To our delight at refluxed the reaction
proceeded smoothly in high yield (entry 4). To further
evaluate the influence of the ratio of 1a:TiCl4/Zn, this
reaction was carried out with different ratio. From the
results it is obvious that the best ratio is 1:3.
The structures of products 3 and 5 were confirmed by
1
IR, H NMR, 13C NMR, and HRMS.
In conclusion, a series of quinazoline-2,4(1H,3H)-dio-
nes and 2-thioxoquinazolinones were synthesized
induced by low-valent titanium reagent (TiCl4/Zn). The
protocol has been used for nitro-compounds other than
amino-compounds as starting materials, which is very
economic. Meanwhile, a variety of substrates can partic-
ipate in the procedure with good yields. Furthermore,
this method still has the advantages of short reaction
time and convenient manipulation.
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 ethyl 2-nitrobenzoates as well as
different isothiocyanates or isocyanates, was examined.
First of all, we performed the reaction of a variety of
ethyl 2-nitrobenzoates 1 and isothiocyanates 2 via TiCl4/
Zn system (Scheme 2, Table 2).
EXPERIMENTAL
As shown in Table 2, it can be seen that this protocol
can be applied not only to aliphatic isothiocyanates but
also to aromatic isothiocyanates with either electron-
withdrawing groups (such as halide groups) or electron-
donating groups (such as alkyl groups) under the same
conditions. Furthermore, it was particularly noteworthy
that the effects of substituted ethyl 2-nitrobenzoates
were also investigated. 4-Chloro and 3-methyl substitu-
tion can also give moderate to good yields. However,
the reductive cyclization was hindered by severe steric
hindrance. For instance, no expected product was
obtained when ethyl 2-nitrobenzoate was reacted with
2,6-di-i-pr-substituted aryl isothiocyanate.
THF was distilled from sodium-benzophenone immediately
before use. All reactions were conducted under N2 atmosphere.
Melting points are uncorrected. IR spectra were recorded on
Varian F-1000 spectrometer in KBr with absorptions in cmꢁ1
.
1H and 13C NMR were determined on Varian-400 MHz spec-
trometer in DMSO-d6 solution. J values are in Hz. Chemical
shifts are expressed in ppm downfield from internal standard
TMS.
General procedure for synthesis of thioxoquinazolineones
3. TiCl4 (0.3 mL, 3 mmol) was added dropwise using a sy-
ringe to a stirred suspension of zinc powder ( 0.384 g, 6
mmol) in freshly distilled anhydrous THF (10 mL) at RT
under a dry N2 atmosphere. After completion of the addition,
the mixture was refluxed for 2 h. The suspension of the low-
valent titanium reagent formed was cooled to RT and a solu-
tion of ethyl 2-nitrobenzoates (1 mmol) and isothiocycanates
(1 mmol) in THF (5 mL) was added dropwise. The reaction
mixture was then refluxed for 15 min under N2. After this pe-
riod, the TLC analysis of the mixture showed the reaction to
be completed. The reaction mixture was quenched with 5%
HCl (15 mL) and extracted with ClCH2CH2Cl (3 ꢂ 20 mL).
The combined extracts were washed with water (3 ꢂ 20 mL)
and dried over anhydrous Na2SO4. After evaporation of the
solvent under reduced pressure, the crude product was purified
by recrystallization from 95% ethanol.
A second part of the research was designed to synthe-
size quinazoline-2,4(1H,3H)-diones via the novel reductive
cyclization of ethyl 2-nitrobenzoates with isocyanates
under the same reaction conditions (Scheme 3, Table 3).
Table 1
Optimization for the reductive cyclization reaction.
Entry
Temperature (ꢀC)
Ratioa
Isolated yield (%)
1
2
3
4
5
6
7
8
r.t.
40
60
1:3
1:3
1:3
1:3
1:1
1:2
1:4
1:5
0
0
10
93
0
Scheme 2
Reflux
Reflux
Reflux
Reflux
Reflux
57
83
80
a Ratio of 1 and TiCl4/Zn system.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
One-Pot Synthesis of Quinazoline-2,4(1H,3H)-diones and 2-Thioxoquinazolinones
with the Aid of Low-Valent Titanium Reagent
647
Table 2
Synthesis of 2-thioxoquinazolinones.
Entry
X
Y
R
Products
Yields (%)a
1
2
H
H
H
H
4-CH3C6H4
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
93
90
78
86
71
72
86
83
86
89
82
0
3
4
H
H
H
H
3-CH3C6H4
C6H5CH2
C6H5
5
H
Cl
Cl
Cl
Cl
H
6
7
H
H
4-ClC6H4
3-CH3C6H4
C6H5CH2
C6H5
8
9
H
CH3
CH3
CH3
H
10
11
12
H
H
4-ClC6H4
3-ClC6H4
2,6-di-i-PrC6H4
3j
3k
3l
H
a Isolated yield.
ArH), 7.21–7.23 (m, 1H, ArH), 7.34–7.38 (m, 2H, ArH), 7.44–
7.45 (m, 1H, ArH), 7.93 (t, J ¼ 8.4 Hz, 1H, ArH), 13.06 (s,
1H, NH). 13C NMR (DMSO-d6): 20.84, 114.99, 115.14,
124.39, 125.92, 128.77, 128.90, 129.16, 129.56, 133.31,
138.95, 139.92, 140.43, 159.13, 176.49.
2-Thioxo-3-p-tolyl-2,3-dihydroquinazolin-4(1H)-one (3a).
This compound was obtained as solid with mp >300ꢀC (ref.
16; 304ꢀC); IR (KBr) m: 3244, 1661, 1621, 1532, 1488, 1408,
1269, 1232, 1200, 1023, 990, 807, 759, 709, 692 cmꢁ1 1H
.
NMR (DMSO-d6): 2.37 (s, 3H, CH3), 7.13–7.15 (m, 2H, ArH),
7.26–7.28 (m, 2H, ArH), 7.35 (t, J ¼ 7.6 Hz, 1H, ArH), 7.43–
7.45 (m, 1H, ArH), 7.76–7.80 (m, 1H, ArH), 7.94–7.96 (m,
1H, ArH), 13.03 (s, 1H, NH).
HRMS [Found: m/z 302.0281 (Mþ), calcd for
C15H11N2OS35Cl: M, 302.0281].
3-Benzyl-7-chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (3h). This compound was obtained as solid with mp 258–
260ꢀC (ref. 21; 255–257ꢀC); IR (KBr) m: 3204, 1652, 1616,
1528, 1481, 1431, 1385, 1334, 1307, 1289, 1254, 1163, 1150,
3-Phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3b).
This compound was obtained as solid with mp >300ꢀC (ref.
17; 307ꢀC); IR (KBr) m: 3245, 1661, 1622, 1532, 1487, 1406,
1075, 948, 917, 862, 761, 726, 698 cmꢁ1 1H NMR (DMSO-
.
1
1266, 1105, 988, 759, 691 cmꢁ1. H NMR (DMSO-d6): 7.26–
d6): 5.65 (s, 2H, CH2), 7.22–7.26 (m, 1H, ArH), 7.28–7.33 (m,
4H, ArH), 7.37–7.40 (m, 1H, ArH), 7.44 (s, 1H, ArH), 7.96 (t,
J ¼ 8.4 Hz, 1H, ArH), 13.08 (s, 1H, NH).
7.28 (m, 2H, ArH), 7.33–7.37 (m, 1H, ArH), 7.38–7.42 (m,
1H, ArH), 7.45–7.50 (m, 3H, ArH), 7.76–7.80 (m, 1H, ArH),
7.96 (t, J ¼ 7.6 Hz, 1H, ArH), 12.99 (s, 1H, NH).
HRMS [Found: m/z 302.0293 (Mþ), calcd for
C15H11N2OS35Cl: M, 302.0281].
2-Thioxo-3-m-tolyl-2,3-dihydroquinazolin-4(1H)-one (3c).
This compound was obtained as solid with mp 282–284ꢀC
(ref. 18; 286–289ꢀC); IR (KBr) m: 3246, 1665, 1622, 1530,
8-Methyl-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (3i). This compound was obtained as solid with mp 152–
153ꢀC; IR (KBr) m: 3263, 1692, 1617, 1524, 1492, 1469,
1488, 1403, 1270, 1238, 1203, 913, 798, 772, 691 cmꢁ1
.
3-Benzyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3d).
This compound was obtained as solid with mp 233–234ꢀC
(ref. 19; 230–231ꢀC); IR (KBr) m: 3198, 3130, 1650, 1622,
1533, 1487, 1426, 1403, 1340, 1170, 1147, 1074, 958, 754,
1409, 1240, 1213, 1090, 1016, 987, 795, 757, 735, 691 cmꢁ1
.
1H NMR (DMSO-d6): 2.12 (s, 3H, CH3), 6.15 (s, 2H, ArH),
6.57 (t, J ¼ 7.6 Hz, 1H, ArH), 7.15 (d, J ¼ 7.2 Hz, 1H, ArH),
7.38 (t, J ¼ 8.8 Hz, 1H, ArH), 7.51 (d, J ¼ 7.6 Hz, 1H, ArH),
7.65–7.69 (m, 1H, ArH), 8.04 (dd, J1 ¼ 2.4 Hz, J2 ¼ 6.8 Hz,
1H, ArH), 10.19 (s, 1H, NH). 13C NMR (DMSO-d6): 17.67,
114.57, 116.52, 116.74, 120.67, 120.73, 121.82, 123.18,
126.55, 133.19, 136.57, 147.77, 168.38.
707, 691 cmꢁ1
.
7-Chloro-3-phenyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-
one (3e). This compꢀound was obtained as solid with mp 286–
288ꢀC (ref. 20; 289 C); IR (KBr) m: 3185, 1661, 1616, 1528,
1479, 1385, 1337, 1276, 1260, 1217, 1191, 1123, 1075, 925,
HRMS [Found: m/z 268.0670 (Mþ), calcd for C15H12N2OS:
M, 268.0670].
1
861, 845, 751, 692 cmꢁ1. H NMR (DMSO-d6): 7.27–7.29 (m,
2H, ArH), 7.38–7.51 (m, 5H, ArH), 7.94–7.96 (m, 1H, ArH),
13.09 (s, 1H, NH).
7-Chloro-3-(4-chlorophenyl)-2-thioxo-2,3-dihydroqui-nazo-
lin-4(1H)-one (3f). This compound was obtained as solid with
mp 274–276ꢀC (ref. 20; 273ꢀC); IR (KBr) m: 3195, 1657,
1617, 1530, 1491, 1386, 1279, 1257, 1219, 1193, 1090, 1022,
Scheme 3
992, 924, 856, 815, 756, 680 cmꢁ1
.
7-Chloro-2-thioxo-3-m-tolyl-2,3-dihydroquinazolin-4(1H)-
one (3g). This compound was obtained as solid with mp 230–
231ꢀC (ref. 21; 230–232ꢀC); IR (KBr) m: 3193, 1659, 1617,
1525, 1479, 1385, 1258, 1192, 926, 880, 781, 757, 696 cmꢁ1
.
1H NMR (DMSO-d6): 2.34 (s, 3H, CH3), 7.06–7.08 (m, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

648
G.-L. Dou, M.-M. Wang, Z.-B. Huang, and D.-Q. Shi
Vol 46
Table 3
Synthesis of quinazoline-2,4(1H,3H)-diones.
Entry
X
Y
Z
R
Products
Yield (%)a
1
2
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
4-ClC6H4
3-ClC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
89
84
92
75
90
66
77
94
90
93
91
0
3
4
H
H
4-CH3C6H4
3-CH3C6H4
3-ClC6H4
5
H
6
7
H
3-CH3C6H4
4-ClC6H4
3-ClC6H4
4-CH3C6H4
3-CH3C6H4
cyclohexy
4-CH3C6H4
2,6-di-i-PrC6H4
CH3
CH3
CH3
CH3
CH3
H
8
9
10
11
12
13
5j
5k
5l
H
5m
a Isolated yield.
7.35 (m, 1H, ArH), 7.51–7.52 (m, 3H, ArH), 7.71 (t, J ¼ 8.0
Hz, 1H, ArH), 7.94 (d, J ¼ 8.0 Hz, 1H, ArH), 11.61 (s, 1H,
NH).
3-(4-Chlorophenyl)-8-methyl-2-thioxo-2,3-dihydroquinazo-
lin-4(1H)-one (3j). This compound was obtained as solid with
mp 182–184ꢀC; IR (KBr) m: 3060, 1705, 1617, 1514, 1404,
1247, 1213, 1165, 1075, 808, 762, 701 cmꢁ1. 1H NMR (DMSO-
d6): 2.57 (s, 3H, CH3), 7.24–7.28 (m, 1H, ArH), 7.33–7.35 (m,
2H, ArH), 7.54–7.56 (m, 2H, ArH), 7.62 (d, J ¼ 8.0 Hz, 1H,
ArH), 7.83 (d, J ¼ 7.6 Hz, 1H, ArH), 11.90 (s, 1H, NH). 13C
NMR (DMSO-d6): 17.44, 116.56, 124.26, 124.58, 125.32,
129.04, 131.01, 132.69, 136.88, 138.03, 138.45, 159.79, 176.29.
HRMS [Found: m/z 302.0281 (Mþ), calcd for
C15H11N2OS35Cl: M, 302.0281].
General procedure for synthesis of quinazolinedione
5. TiCl4 (0.3 mL, 3 mmol) was added dropwise using a sy-
ringe to a stirred suspension of zinc powder ( 0.384 g, 6
mmol) in freshly distilled anhydrous THF (10 mL ) at RT
under a dry N2 atmosphere. After completion of the addition,
the mixture was refluxed for 2 h. The suspension of the low-
valent titanium reagent formed was cooled to RT and a solu-
tion of ethyl 2-nitrobenzoates (1 mmol) and isocyanates (1
mmol) in THF (5 mL) was added dropwise. The reaction mix-
ture was then refluxed for 15 min under N2. After this period,
the TLC analysis of the mixture showed the reaction to be
completed. The reaction mixture was quenched with 5% HCl
(15 mL) and extracted with ClCH2CH2Cl (3 ꢂ 20 mL). The
combined extracts were washed with water (3 ꢂ 20 mL) and
dried over anhydrous Na2SO4. After evaporation of the solvent
under reduced pressure, the crude product was purified by
recrystallization from 95% ethanol.
3-p-Tolylquinazoline-2,4(1H,3H)-dione (5c). This com-
pound was obtained as solid with mp 260–262ꢀC (ref. 24; 265–
266ꢀC); IR (KBr) m: 3199, 3129, 3069, 3005, 1721, 1665, 1608,
1512, 1490, 1448, 1288, 1153, 1023, 869, 815, 791, 754 cmꢁ1. 1H
NMR (DMSO-d6): 2.37 (s, 3H, CH3), 7.10–7.19 (m, 2H, ArH),
7.21–7.24 (m, 2H, ArH), 7.27–7.29 (m, 2H, ArH), 7.68–7.72 (m,
1H, ArH), 7.93 (d, J ¼ 7.2 Hz, 1H, ArH), 11.54 (s, 1H, NH).
3-m-Tolylquinazoline-2,4(1H,3H)-dione (5d). This com-
pound was obtained as solid with mp 256–258ꢀC (ref. 23;
252–252.6ꢀC); IR (KBr) m: 3255, 1721, 1668, 1620, 1607,
1490, 1433, 1398, 1272, 1157, 922, 812, 785, 758, 697 cmꢁ1
.
1H NMR (DMSO-d6): 2.36 (s, 3H, CH3), 7.10–7.13 (m, 2H,
ArH), 7.22–7.25 (m, 3H, ArH), 7.37 (t, J ¼ 7.6 Hz, 1H, ArH),
7.71 (t, J ¼ 8.0 Hz, 1H, ArH), 7.94 (d, J ¼ 8.0 Hz, 1H, ArH),
11.56 (s, 1H, NH).
7-Chloro-3-(3-chlorophenyl)quinazolinee-2,4(1H,3H)-dione
(5e). This compound was obtained as solid with mp >300ꢀC
(ref. 23; 312ꢀC); IR (KBr) m: 3232, 3188, 1736, 1656, 1616,
1594, 1480, 1432, 1370, 1169, 1089, 945, 867, 837, 759, 718
cmꢁ1 1H NMR (DMSO-d6): 7.25–7.35 (m, 3H, ArH), 7.52–
.
7.53 (m, 3H, ArH), 7.95 (d, J ¼ 8.4 Hz, 1H, ArH), 11.74 (s,
1H, NH).
7-Chloro-3-m-tolylquinazoline-2,4(1H,3H)-dione (5f). This
compound was obtained as solid with mp >300ꢀC (ref.17;
>300ꢀC); IR (KBr) m: 3230, 3185, 1736, 1652, 1593, 1429,
1370, 1262, 1159, 1089, 944, 871, 815, 726, 702 cmꢁ1 1H
.
3-(4-Chlorophenyl)quinazoline-2,4(1H,3H)-dione (5a). This
compound was obtained as solid with mp 298–299ꢀC (ref. 22;
301–302ꢀC); IR (KBr) m: 3201, 3070, 2938, 1732, 1674, 1493,
1448, 1406, 1282, 1156, 1090, 1016, 872, 825, 757, 741, 688
NMR (DMSO-d6): 2.35 (s, 3H, CH3), 7.10–7.13 (m, 2H, ArH),
7.24–7.29 (m, 3H, ArH), 7.37 (d, J ¼ 7.6 Hz, 1H, ArH), 7.93–
7.95 (m, 1H, ArH), 11.68 (s, 1H, NH).
cmꢁ1
.
1H NMR (DMSO-d6): 7.23 (d, J ¼ 7.2 Hz, 2H, ArH),
3-(4-Chlorophenyl)-8-methylquinazoline-2,4(1H,3H)-dione
(5g). This compound was obtained as solid with mp 282–
284ꢀC; IR (KBr) m: 3327, 3233, 1721, 1655, 1534, 1493,
7.38–7.39 (m, 2H, ArH), 7.54–7.55 (m, 2H, ArH), 7.71 (t, J ¼
8.0 Hz, 1H, ArH), 7.95 (d, J ¼ 8.0 Hz, 1H, ArH), 11.59 (s,
1H, NH).
1405, 1225, 1092, 1059, 1019, 819, 760 cmꢁ1 1H NMR
.
(DMSO-d6): 2.39 (s, 3H, CH3), 7.14 (t, J ¼ 7.6 Hz, 1H, ArH),
7.33 (d, J ¼ 8.8 Hz, 1H, ArH), 7.38–7.40 (m, 2H, ArH), 7.55–
7.56 (m, 3H, ArH), 10.84 (s, 1H, NH).
HRMS [Found: m/z 286.0510 (Mþ), calcd for
C15H11N2O235Cl: M, 286.0509].
3-(3-Chlorophenyl)quinazoline-2,4(1H,3H)-dione (5b). This
compound was obtained as solid with mp 265–266ꢀC (ref. 23;
260.5–261.5ꢀC); IR (KBr) m: 3248, 3204, 3065, 2938, 1734,
1652, 1594, 1493, 1437, 1400, 1340, 1275, 1168, 731, 688
cmꢁ1 1H NMR (DMSO-d6): 7.22–7.25 (m, 2H, ArH), 7.33–
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
One-Pot Synthesis of Quinazoline-2,4(1H,3H)-diones and 2-Thioxoquinazolinones
with the Aid of Low-Valent Titanium Reagent
649
REFERENCES AND NOTES
3-(3-Chlorophenyl)-8-methylquinazoline-2,4(1H,3H)-dione
(5h). This compound was obtained as solid with mp 280–282ꢀC;
IR (KBr) m: 3233, 3089, 1726, 1665, 1605, 1506, 1476, 1405,
[1] Francis, J. E.; Cash, W. D.; Barbaz, W. D.; Bernard, P. S.;
Lovell, R. A.; Mazzenga, G. C.; Friedmann, R. C.; Hyun, J. L.; Braun-
walder, A. F.; Loo, P. S.; Bennett, D. A. J Med Chem 1991, 34, 281.
[2] (a) Cianci, C.; Chung, T. D. Y.; Menwell, N.; Putz, H.;
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 Hetrocycl Chem 1990, 27, 723; (c) Kottke, K.; Kuehmstedt, H.;
Graefe, I.; Wehlau, H.; Knocke, D. DD 253623 (1988); Chem Abstr
1988, 109, 17046; (d) Liu, K. C.; Hu, M. K. Arch Pharm (Weinheim,
Ger) 1986, 319, 188; (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.
1330, 1266, 1147, 1088, 898, 785, 753, 691 cmꢁ1 1H NMR
.
(DMSO-d6): 2.40 (s, 3H, CH3), 7.15 (t, J ¼ 7.6 Hz, 1H, ArH),
7.35–7.36 (m, 1H, ArH), 7.52–7.57 (m, 4H, ArH), 7.82 (d, J ¼
8.0 Hz, 1H, ArH), 10.86 (s, 1H, NH). 13C NMR (DMSO-d6):
17.87, 115.18, 123.01, 124.77, 126.06, 128.80, 128.96, 129.96,
131.08, 133.56, 136.94, 137.92, 138.85, 150.94, 150.97.
HRMS [Found: m/z 286.0510 (Mþ), calcd for
C15H11N2O235Cl: M, 286.0509].
8-Methyl-3-p-tolylquinazoline-2,4(1H,3H)-dione (5i). This
compound was obtained as solid with mp 284–286ꢀC; IR
(KBr) m: 3228, 3083, 1712, 1659, 1613, 1506, 1469, 1411,
1329, 1269, 1168, 1108, 1069, 887, 814, 790, 766 cmꢁ1 1H
.
[3] Johne, S. Pharmazie 1982, 36, 583.
NMR (DMSO-d6): 2.38 (s, 3H, CH3), 2.40 (s, 3H, CH3), 7.14
(t, J ¼ 7.6 Hz, 1H, ArH), 7.18–7.20 (m, 2H, ArH), 7.28–7.30
(m, 2H, ArH), 7.54 (d, J ¼ 7.2 Hz, 1H, ArH), 7.82 (d, J ¼ 8.0
Hz, 1H, ArH), 10.78 (s, 1H, NH). 13C NMR (DMSO-d6):
17.83, 21.43, 115.17, 122.91, 124.67, 126.06, 129.39, 130.01,
133.81, 136.79, 138.13, 138.81, 151.17, 163.00.
[4] (a) Nagano, H.; Takagi, M.; Kubodera, N.; Matsunaga, I.;
Nabata, H.; Ohba, Y.; Sakai, K.; Hata, S.; Uchida, Y. Eur Pat 89065
(1983) Chugai Pharmaceutical Co., Ltd.; Chem Abstr 1984, 100, 6547;
(b) Imagawa, J.; Sakai, K. Eur J Pharmacol 1986, 131, 257.
[5]
Merck Index; Merck: Whitehouse Station, NJ, 1996; Vol.
12, pp 7897, 1512, 3489.
HRMS [Found: m/z 266.1056 (Mþ), calcd for C16H14N2O2:
M, 266.1055].
[6] (a) Goto, S.; Tsuboi, H.; Kagara, K. Chem Express 1993, 8,
761; (b) Kagara, K.; Goto, S.; Tsuboi, H. Jpn. Pat. 25, 767, 1989;
Kagara, K.; Goto, S.; Tsuboi, H. Chem Abstr 1989, 111, 97274.
[7] Mohri, S. J Synth Org Chem Jpn 2001, 59, 514.
[8] (a) Pastor, G.; Blanchard, C.; Montginoul, C.; Torreilles, E.;
Giral, L.; Texier, A. Bull Soc Chim Fr 1975, 1331; (b) Khalifa, M.;
Osman, A. N.; Ibrahim, M. G.; Ossman, A. R. E.; Ismail, M. A. Phar-
mazie 1982, 37, 115.
8-Methyl-3-m-tolylquinazoline-2,4(1H,3H)-dione (5j). This
compound was obtained as solid with mp 240–241ꢀC; IR
(KBr) m: 3236, 1722, 1663, 1606, 1507, 1407, 1329, 1269,
1
1150, 803, 780, 759, 699 cmꢁ1. H NMR (DMSO-d6): 2.36 (s,
3H, CH3), 2.40 (s, 3H, CH3), 7.10–7.16 (m, 3H, ArH), 7.24–
7.25 (m, 1H, ArH), 7.37 (t, J ¼ 7.6 Hz, 1H, ArH), 7.54 (d, J
¼ 7.2 Hz, 1H, ArH), 7.81 (d, J ¼ 8.0 Hz, 1H, ArH), 10.80 (s,
1H, NH). 13C NMR (DMSO-d6): 17.17, 20.80, 114.49, 122.28,
124.04, 125.37, 126.03, 128.67, 128.78, 129.39, 135.69,
136.16, 138.26, 138.16, 150.44, 150.47.
HRMS [Found: m/z 266.1055 (Mþ), calcd for C16H14N2O2:
M, 266.1055].
3-Cyclohexyl-8-methylquinazoline-2,4(1H,3H)-dione (5k).
This compound was obtained as solid with mp 244–245ꢀC; IR
(KBr) m: 3222, 3189, 3079, 2935, 2852, 1703, 1650, 1607,
1506, 1474, 1417, 1376, 1329, 1276, 1188, 1116, 1081, 1023,
[9] Michman, M.; Patai, S.; Wiesel, Y. Org Prep Proced Int
1978, 10, 13.
[10] Lange, N. A.; Sheibley, F. E. Org Synth 1943, 2, 79.
[11] Vorbrueggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50,
6549.
[12] (a) Okuzumi, T.; Nakanishi, E.; Tsuji, T.; Makino, S. Tetra-
hedron 2003, 59, 5603; (b) Choo, H. P.; Kim, M.; Lee, S. K.; Kim, S.
W.; Chung, I. K. Bioorg Med Chem 2002, 10, 517; (c) Buckman, B.
O.; Mohan, R. Tetrahedron Lett 1996, 37, 4439; (d) Gordeev, M. F.;
Hui, H. C.; Gordon, E. M.; Patel, D. V. Tetrahedron Lett 1997, 38,
1729; (e) Smith, A. L.; Thomson, C. G.; Leeson, P. D. Bioorg Med
Chem Lett 1996, 6, 1483.
915, 793, 754 cmꢁ1
.
1H NMR (DMSO-d6): 1.17 (t, J ¼ 12.8
[13] Mizuno, T.; Ishino, Y. Tetrahedron 2002, 58, 3155.
[14] Li, Z. G.; Huang, H.; Sun, H. B.; Jiang, H. L.; Liu, H. J
Comb Chem 2008, 10, 484.
Hz, 1H, CH2), 1.26–1.36 (m, 2H, CH2), 1.58–1.67 (m, 3H,
CH2), 1.78–1.82 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.38–2.44
(m, 2H, CH2), 4.71–4.77 (m, 1H, CH), 7.08 (t, J ¼ 7.2 Hz,
1H, ArH), 7.46 (d, J ¼ 7.2 Hz, 1H, ArH), 7.78 (d, J ¼ 7.6
Hz, 1H, ArH), 10.53 (s, 1H, NH). 13C NMR (DMSO-d6):
16.95, 25.11, 25.99, 28.33, 52.85, 114.34, 122.12, 123.62,
125.25, 135.74, 137.78, 151.07, 162.34.
[15] 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.
[16] Alagarsamy, V.; Solomon, V. R.; Dhanabal, K. Bioorg Med
Chem 2007, 15, 235.
HRMS [Found: m/z 258.1367 (Mþ), calcd for C15H18N2O2:
M, 258.1368].
[17] Mayoral, J.; Melendez, E.; Merchan, F.; Sanchez, J. Synthe-
sis 1981, 12, 962.
[18] Alagarsamy, V.; Gridhar, R.; Yadav, M. R. Biol Pharm
Bull 2005, 28, 1531.
6-Chloro-3-p-tolylquinazoline-2,4(1H,3H)-dione (5l). This
compound was obtained as solid with mp 291–293ꢀC (ref. 25;
291–293ꢀC); IR (KBr) m: 3336, 1700, 1695, 1595, 1528, 1478,
[19] Alagarsamy, V.; Solomon, V. R.; Murugan, M. Bioorg Med
Chem 2007, 15, 4009.
1
1409, 1312, 1295, 1254, 1231, 1079, 815, 773, 743 cmꢁ1. H
[20] Lakhan, R.; Singh, R. L. Farmaco Ed Sci 1988, 43, 745.
[21] Dou, G. L.; Wang, M. M.; Shi, D. Q. J Comb Chem, to
appear.
NMR (DMSO-d6): 2.37 (s, 3H, CH3), 7.17–7.19 (m, 2H, ArH),
7.24–7.29 (m, 3H, ArH), 7.74–7.76 (m, 1H, ArH), 7.85–7.86
(m, 1H, ArH), 11.67 (s, 1H, NH).
[22] Azizian, J.; Mehrdad, M.; Jadidi, K.; Sarrafi, Y. Tetrahedron
Lett 2000, 41, 5265.
Acknowledgments. The authors are grateful to the ‘‘Surpassing
Project’’ Foundation of Jiangsu Province and the Key Laboratory
of Biotechnology on Medical Plants of Jiangsu Province for fi-
nancial support.
[23] Kisber; Glagolewa, Zhur. Obsh Khim 1953, 23, 1028.
[24] Taub, B.; Hino, J. B. J Org Chem 1961, 26, 5238.
[25] Garin, J.; Melendez, E.; Merchan, F. L.; Tejero, T.; Villarroya, E.
Synthesis 1983, 5, 406.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet