Synthesis and cytotoxicity screening of piperazine-1-carbodithioate derivatives of 2-substituted quinazolin-4(3H)-ones

Article abstract of DOI:10.1002/ardp.200800148

A new series of piperazine-1-carbodithioate derivatives of 2-substituted quinazolin-4(3H)-ones were synthesized via a five-steps procedure starting from 2-amino-5-methylbenzoic acid. The cytotoxicity of the resulting compounds against A-549 (human lung ca

Full text of DOI:10.1002/ardp.200800148

182
Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
Full Paper
Synthesis and Cytotoxicity Screening of Piperazine-1-
carbodithioate Derivatives of 2-Substituted Quinazolin-4(3H)-
ones
Sheng-Li Cao1, Yan-Wen Guo2, Xian-Bo Wang2, Mei Zhang1, Yu-Ping Feng3, Yu-Yang Jiang3, 4
Yue Wang3, 4, Qian Gao1, and Jian Ren1
,
1 Department of Chemistry, Capital Normal University, Beijing, China
2 School of Science, Beijing Technology Institute, Beijing, China
3 Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education;
Department of Chemistry, Tsinghua University, Beijing, China
4 Key Laboratory of Chemical Biology, Guangdong Province; Graduate School at Shenzhen, Tsinghua
University, Shenzhen, China
A new series of piperazine-1-carbodithioate derivatives of 2-substituted quinazolin-4(3H)-ones
were synthesized via a five-steps procedure starting from 2-amino-5-methylbenzoic acid. The
cytotoxicity of the resulting compounds against A-549 (human lung cancer), HCT-8 (human
colon cancer), HepG2 (human liver cancer), and K562 (human myelogenous leukaemia) cell lines
was determined by the MTT assay. Preliminary screening results of these compounds are
reported.
Keywords: Dithiocarbamate / Cytotoxicity / Quinazolin-4(3H)-one / Screening / Synthesis /
Received: August 13, 2008; accepted: November 14, 2008
DOI 10.1002/ardp.200800148
Introduction
Quinazolin-4(3H)-one analogs of folic acid have drawn
considerable attention in the search for antifolates and
antitumor agents [1]. In recent years, classical as well as
Figure 1. Structure of compound 1.
non-classical antifolates, which differ in either contain-
ing the L-glutamic acid moiety or not, have been increas-
ingly reported in the literature [2–8]. On the other hand,
synthesized, 1 (Fig. 1), containing the 4-fluorophenylpi-
dithiocarbamate has proved to be an effective pharmaco-
phore with cancer chemopreventive and antitumor activ-
ity [9–15]. In our previous paper, the synthesis of a series
of 2-methylquinazolin-4(3H)-one derivatives bearing
dithiocarbamate side chains was described together with
their in-vitro antitumor activity via the MTT assay [16].
Preliminary results showed that among the compounds
perazine-1-carbodithioate moiety, possessed significant
in-vitro cytotoxicity against human myelogenous leukae-
mia K562 and human cervical cancer HeLa cell lines with
IC50 values of 0.5 and 12.0 lM, respectively [16, 17].
We noted reports that substituents at the C2 position
of quinazolin-4(3H)-one derivatives acting as antifolate
antitumor agents had much to do with their biological
activity [18, 19]. Therefore, a new series of 2-substituted-
quinazolin-4(3H)-one derivatives bearing 4-substituted-
piperazine-1-carbodithioate side chains 8a–z (Scheme 1
and Table 1) have been designed with the aim of investi-
gating the effect of the substituents both at the C2 posi-
tion of quinazolin-4(3H)-one and the N4 position of piper-
azine on the antitumor activity in search for more effec-
Correspondence: Sheng-Li Cao, Department of Chemistry, Capital Nor-
mal University, Beijing 100048, China.
E-mail: sl_cao@sohu.com
Fax: +86 10 68902493
Abbreviations: 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-tetrazolium bro-
mide (MTT); N-bromosuccinimide (NBS)
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
Piperazine-1-carbodithioate Derivatives
183
Reagents and conditions: a) RCOCl, pyridine, THF, reflux 5 h; b) Ac2O, reflux 1.5 h; c) HCONH2, 150 – 1558C, 3 h; d) NBS, (PhCO)2O2,
CHCl3, m N n, reflux 3 h; e) CS2, K3PO4, DMF, rt, 2 h.
Scheme 1. Synthetic route to compounds 8a–z.
Table 1. Percent growth inhibition of compounds 8a–z against
A-549, HCT-8, HepG2, and K562 cell lines at the concentration
Results and discussion
of 5 lg/mL.
As shown in Scheme 1, the reaction of 2-amino-5-methyl-
benzoic acid 2 with different acyl chlorides in dry tetra-
hydrofuran using pyridine as acid-binding agent yielded
N-acylated products 3. Heating 3 with an excess of acetic
anhydride under reflux for 1.5 h produced benzoxazin-4-
ones 4, which were converted into 2-substituted quinazo-
lin-4(3H)-ones 5 by heating together with formamide at
150-1558C. Bromination of 5 in chloroform with N-bro-
mosuccinimide (NBS) gave bromomethyl compounds 6,
of which four viz., 6e–h have been reported elsewhere
[20]. Finally, the target compounds 8a–z were prepared
according to the established method [16, 21] by the reac-
tion of compounds 6 with CS2 and various 1-substitued-
piperazines (7a–d) in the presence of anhydrous K3PO4.
The structures of the synthesized compounds were con-
Com-
R1
R2
% Inhibition at 5 lg/mL
pound
A-549 HCT-8 HepG2 K562
8a
8b
8c
8d
8e
8f
CF3
CF3
CF3
CF3
Et
Me
–1.0
–3.0
1.2
1.3
12.4
10.6
17.1
–1.0
29.9
20.5
–37.0
6.8
2.7
5.0
0.1
8.4
0.9
1.4
5.4
4.6
PhCH2 –11.0
Ph
4-FPh
Me
PhCH2
Ph
4-FPh
Me
PhCH2
Ph
4-FPh
Me
PhCH2 –20.1
Ph
4-FPh
Me
PhCH2
Ph
4-FPh
Me
PhCH2 –23.6 –13.0
Ph
4-FPh
4-FPh
–2.2
–6.4
6.2
–8.7
–2.9
1.4
1.5
–4.7
–6.5
–5.0
–5.1
–9.8
17.7
Et
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
Et
Et
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
PhCH2
PhCH2
PhCH2
PhCH2
Ph
Ph
Ph
Ph
4-ClPh
–3.9
4.7
13.5 17.6
20.6
6.5
6.7
5.8
6.5
80.4 –15.6 –12.8
–3.8 –21.4
10.0 –16.2
16.3
–9.7
–3.4
12.9
10.5
–6.3
–6.7
9.5
14.3 13.1
1
firmed by MS, H-NMR, and elemental analysis, and the
data are given in the experimental section.
–27.3
–6.5
–10.9
–6.4
–0.5
7.5
–11.3
11.5
3.8
4.3
7.3
3.9
The newly synthesized compounds 8a–z were prelimi-
narily screened at the single concentration of 5 lg/mL
using the colorimetric MTT (3-(4,5-dimethylthiazo-2-yl)-
2,5-diphenyl-tetrazolium bromide) assay [21] to test their
in-vitro cytotoxicity against A-549 (human cell lung can-
cer), HCT-8 (human colon cancer), HepG2 (human liver
cancer), and K562 (human myelogenous leukaemia) cell
lines. The cytotoxicity of the compounds tested was esti-
mated in terms of percent growth inhibition compared
with untreated control cells. From the data listed in
Table 1, it was disappointing to note that all but two of
the compounds did not show significant inhibitory activ-
ity. The two compounds that demonstrated inhibition,
namely 8k and 8x, inhibited the growth of A-549 and
11.1
28.6 39.1
8t
–4.7
–14.9
8.2
–7.7
2.0
8.9
4.2
7.9
8u
8v
8w
8x
8y
8z
–0.9 11.3
–13.4 12.3
23.7 12.0
–22.9
–2.1
8.8
66.7
–0.8 –12.1
–2.0 16.8
–9.5
44.7
0.3
6.1
2-Furanyl 4-FPh
tive antitumor agents. We now report the synthesis of
these compounds together with their screening results
of inhibitory activity against A-549, HCT-8, HepG2, and
K562 tumor cell lines.
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184
S.-L. Cao et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
reduced pressure, water (100 mL) was added into the residue,
and the resulting mixture was acidified to pH 2–3 with dilute
hydrochloride. The formed precipitate was collected by filtra-
tion and recrystallized from appropriate solvent to afford com-
pounds 3a–d.
HCT-8 cells by 80.4% and 66.7%, respectively. In contrast
with the 2-methyl-quinazolin-4(3H)-one derivatives previ-
ously reported [16], no compound within the new series
8a–z displayed obvious inhibitory activity against K562
cells. These results indicate that the substituents at the
C2 position of quinazolin-4(3H)-one instead of those at
the N4 position of piperazine markedly influence the
cytotoxic activity of this type of compounds.
In summary, a new series of piperazine-1-carbodi-
thioate derivatives of 2-substituted quinazolin-4(3H)-ones
were synthesized and the screening results revealed that
the replacement of methyl at the C2 position of quinazo-
lin-4(3H)-one with other alkyl, aryl, or heteroaryl group
led to a decrease in cytotoxic activity.
2-(Butyramido)-5-methylbenzoic acid 3a
Yield: 80.3%, m.p.: 115.1–116.08C (from EtOH / H2O, 9 : 1). ESI-MS
m/z: 222 [M + H]+. 1H-NMR (CDCl3) d: 1.04 (t, J = 7.3 Hz, 3H,
CH3CH2), 1.82 (m, 2H, CH3CH2CH2), 2.35 (s, 3H, CH3), 2.47 (t, J =
7.4 Hz, 2H, CH2CH2), 7.41 (d, J = 8.6 Hz, 1H, Ar-H), 7.94 (s, 1H, Ar-
H), 8.64 (d, J = 8.6 Hz, 1H, Ar-H), 10.94 (s, 1H, NH), 11.70 (br s, 1H,
COOH). Anal. Calcd. for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 64.97; H, 6.72; N, 6.41.
2-(Isobutyramido)-5-methylbenzoic acid 3b
Yield: 94.6%, m.p.: 162.3–163.28C (from ethanol / H2O, 3 : 1). ESI-
1
MS m/z: 220 [M – H]– . H-NMR (CDCl3) d: 1.32 (d, J = 6.9 Hz, 6H,
This work was supported by grants from the Education Com-
mittee of Beijing City (Grant No. KM200710028008) and the
Natural Science Foundation of Beijing City (Grant No.
7042006). The authors are grateful to the National Center for
Pharmaceutical Screening, Institute of Materia Medica, Chi-
(CH3)2CH), 2.36 (s, 3H, CH3), 2.65 (m, 1H, (CH3)2CH), 7.43 (d, J =
8.6 Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 8.67 (d, J = 8.6 Hz, 1H, Ar-H),
10.93 (s, 1H, NH). Anal. Calcd. for C12H15NO3: C, 65.14; H, 6.83; N
6.33. Found: C, 65.20; H, 6.79; N, 6.33.
nese Academy of Medical Sciences, and Peking Union Medical 2-(4-Chlorobenzamido)-5-methylbenzoic acid 3c
Yield: 83.7%, m.p.: 233.2–233.58C (from ethyl acetate / ethanol,
2 : 1). ESI-MS m/z: 288 [M – H]– . 1H-NMR (DMSO-d6) d: 2.32 (s, 3H,
CH3), 7.49 (d, J = 8.8 Hz, 1H, Ar-H), 7.66 (d, J = 8.4 Hz, 2H, Ar-H),
7.86 (s, 1H, Ar-H), 7.94 (d, J = 8.4 Hz, 2H, Ar-H), 8.53 (d, J = 8.8 Hz,
1H, Ar-H). Anal. Calcd. for C15H12ClNO3: C, 62.19; H, 4.17; N, 4.83.
Found: C, 61.99; H, 4.20; N, 4.66.
College for performing antitumor activity screening of our
compounds.
The authors have declared no conflict of interest.
2-(Furan-2-carboxamido)-5-methylbenzoic acid 3d
Experimental
Yield: 86.5%, m.p.: 202.4–202.88C (from acetone / H2O, 1 : 1). ESI-
MS m/z: 244 [M – H]– . 1H-NMR (DMSO-d6) d: 2.33 (s, 3H, CH3), 6.76
(m, 1H, furan-H), 7.28 (d, J = 3.1 Hz, 1H, furan-H), 7.47 (d, J =
8.5 Hz, 1H, Ar-H), 7.88 (s, 1H, furan-H), 8.00 (s, 1H, Ar-H), 8.58 (d, J
Melting points were determined on an XT4A microscopic melt-
ing point apparatus (Keyi Electrooptical, Beijing, China) or WRS-
1B digital melting point apparatus (Shenguang, Shanghai,
China) and are uncorrected. 1H-NMR spectra were recorded on a
Bruker AC-200P spectrometer (Bruker, Zꢀrich, Switzerland) at
200 MHz using tetramethylsilane (TMS) as internal standard.
Electrospray ionization (ESI) mass spectra were recorded on a
Bruker Daltonics Esquire-LC 00136 mass spectrometer (Bruker
Daltonics, Bremen, Germany); chemical ionization (CI) mass
spectra were recorded on a Finnigan Trace DSQ mass spectrome-
ter (Thermo Finnigan, USA); electron impact (EI) mass spectra
were recorded on a Micromass GCT mass spectrometer (Micro-
mass, Manchester, UK). Elemental analyses were performed by
Institute of Chemistry, Chinese Academy of Science, on a Flash
EA 1112 elemental analyzer (Thermo Electron. Waltham, MA,
USA). Column chromatography was carried out on silica gel
(200-300 mesh). 2-Amino-5-methylbenzoic acid 2 was prepared
according to the reported method [22], and other commercially
available reagents were used without further purification.
=
8.5 Hz, 1H, Ar-H), 12.08 (s, 1H, NH). Anal. Calcd. for
C13H11NO4 N H2O: C, 59.31; H, 4.98; N, 5.32. Found: C, 59.07; H,
4.95; N, 5.35.
General procedure for the synthesis of 2-substituted
6-methylbenzoxazin-4-ones 4a–d
A
mixture of 2-(N-acylamino)-5-methylbenzoic acid 3a–e
(18 mmol) and acetic anhydride (26 mL) was heated under reflux
for 1.5 h. After removing excess acetic anhydride under reduced
pressure, the residue solidified to afford crude products 4a and
4b. In the preparation of 4c and 4d, the reaction mixtures were
cooled to room temperature and left refrigerated overnight. The
separated precipitate was collected by filtration to give the
crude products 4c and 4d. The crude products were recrystal-
lized from appropriate solvents to give compounds 4a–d.
6-Methyl-2-propyl-4H-benzo[d][1,3]oxazin-4-one 4a
Yield: 86.4%, m.p.: 70.9–71.08C (from cyclohexane). ESI-MS m/z:
204 [M + H]+. 1H-NMR (CDCl3) d: 1.04 (t, J = 7.4 Hz, 3H, CH3CH2),
1.86 (m, 2H, CH3CH2CH2), 2.47 (s, 3H, CH3), 2.66 (t, J = 7.5 Hz, 2H,
CH2CH2), 7.46 (d, J = 8.2 Hz, 1H, benzoxazinone 8-H), 7.60 (dd, J =
8.2 Hz and 1.6 Hz, 1H, benzoxazinone 7-H), 8.64 (d, J = 1.6 Hz, 1H,
benzoxazinone 5-H). Anal. Calcd. for C12H13NO2: C, 70.92; H, 6.45;
N, 6.89. Found: C, 70.51; H, 6.35; N, 6.93.
General procedure for the synthesis of 5-methyl-2-(N-
acylamino)benzoic acids 3a–d
To a stirred solution of 2-amino-5-methylbenzoic acid 2 (3.02 g,
20 mmol) and pyridine (25 mmol) in tetrahydrofuran (34 mL)
was added dropwise acyl chloride (21 mmol) in tetrahydrofuran
(42 mL). The reaction mixture was heated under reflux for 5 h.
After removing about 2/3 volume of tetrahydrofuran under
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Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
Piperazine-1-carbodithioate Derivatives
185
2-Isopropyl-6-methyl-4H-benzo[d][1,3]oxazin-4-one 4b
Yield: 88.9%, m.p.: 51.6–51.98C (from petroleum ether). ESI-MS
m/z: 204 [M + H]+. 1H-NMR (CDCl3) d: 1.36 (d, J = 6.9 Hz, 6H,
(CH3)2CH), 2.46 (s, 3H, CH3), 2.93 (m, 1H, (CH3)2CH), 7.47 (d, J =
8.2 Hz, 1H, benzoxazinone 8-H), 7.59 (d, J = 8.2 Hz, 1H, benzoxazi-
none 7-H), 7.97 (s, 1H, benzoxazinone 5-H). Anal. Calcd. for
C12H13NO2 N 1/6 H2O: C, 69.88; H, 6.52; N, 6.79. Found: C, 69.70; H,
6.52; N, 6.61.
2-(Furan-2-yl)-6-methylquinazolin-4(3H)-one 5d
Yield: 56.5%, m.p.: 260.4–261.48C (from methanol). ESI-MS m/z:
227 [M + H]+. 1H-NMR (DMSO-d6) d: 2.32 (s, 3H, CH3), 6.72 (m, 1H,
furan-H), 7.21 (d, J = 3.4 Hz, 1H, furan-H), 7.36 (d, J = 8.4 Hz, 1H,
quinazolinone 8-H), 7.73 (d, J = 8.4 Hz, 1H, quinazolinone 7-H),
7.95 (s, 1H, quinazolinone 5-H), 8.33 (s, 1H, furan-H), 12.64 (s, 1H,
NH). Anal. Calcd. for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38.
Found: C, 69.11; H, 4.51; N, 12.35.
General procedure for the synthesis of 2-substituted
2-(4-Chlorophenyl)-6-methyl-4H-benzo[d][1,3]oxazin-4-
6-bromomethylquinazolin-4(3H)-ones 6a–d
2-Substituted 6-methylquinazolin-4(3H)-one 5a–d (14 mmol), N-
bromosuccinimide (NBS) (16 mmol) and benzoyl peroxide
(0.2 mmol) were dissolved in trichloromethane (70 mL; for 5c,
150 mL of trichloromethane was used). The resulting mixture
was refluxed under the irradiation of 100-W tungsten lamp for
3 h. After cooling to room temperature, the separated solid was
filtered and recrystallized from acetic acid to afford compounds
6a–d.
one 4c
Yield: 91.1%, m.p.: 190.6–190.88C (from ethyl acetate / ethanol,
2 : 1). ESI-MS m/z: 272 [M + H]+. 1H-NMR (CDCl3) d: 2.50 (s, 3H, CH3),
7.47 (d, J = 8.6 Hz, 2H, Ar-H), 7.60 (m, 2H, benzoxazinone 8-H and
7-H), 8.02 (s, 1H, benzoxazinone 5-H), 8.22 (d, 2H, J = 8.6 Hz, Ar-H).
Anal. Calcd. for C15H10ClNO2: C, 66.31; H, 3.71; N, 5.16. Found: C,
66.11; H, 3.74; N, 4.99.
2-(Furan-2-yl)-6-methyl-4H-benzo[d][1,3]oxazin-4-one 4d
Yield: 80.4%, m.p.: 154.7–155.08C (from cyclohexane). ESI-MS m/
6-Bromomethyl-2-propylquinazolin-4(3H)-one 6a
Yield: 66.7%, m.p.: A3308C. ESI-MS m/z: 281, 283 [M + H]+. 1H-NMR
(DMSO-d6) d: 0.96 (t, J = 7.4 Hz, 3H, CH3CH2), 1.78 (m, 2H,
CH3CH2CH2), 2.69 (t, J = 7.5 Hz, 2H, CH2CH2), 4.88 (s, 2H, CH2Br),
7.66 (d, J = 8.4 Hz, 1H, quinazolinone 8-H), 7.93 (d, J = 8.4 Hz, 1H,
quinazolinone 7-H), 8.20 (s, 1H, quinazolinone 5-H). Anal. Calcd.
for C12H13BrN2O: C, 51.26; H, 4.66; N, 9.96. Found: C, 51.49; H,
4.87; N, 10.31.
1
z: 228 [M + H]+. H-NMR (CDCl3) d: 2.48 (s, 3H, CH3), 6.61 (m, 1H,
furan-H), 7.34 (dd, J = 3.4 and 0.6 Hz, 1H, furan-H), 7.65 (m, 3H,
benzoxazinone 8-H, 7-H and furan-H), 8.01 (s, 1H, benzoxazinone
5-H). Anal. Calcd. for C13H9NO3: C, 68.72; H, 3.99; N, 6.16. Found:
C, 69.09; H, 4.04; N, 6.17.
General procedure for the synthesis of 2-substituted
6-methylquinazolin-4(3H)-ones 5a–d
A mixture of 2-substituted 6-methylbenzoxazin-4-one 4a–e and
formamide (40 mL) was stirred at 150-1558C for 3 h. After cool-
ing to room temperature, water (100 mL) was added into the
reaction mixture and the formed solid was collected by filtra-
tion and was recrystallized from appropriate solvent to afford
compounds 5a–d.
6-Bromomethyl-2-isopropylquinazolin-4(3H)-one 6b
Yield: 50.5%, m.p.: A3308C. ESI-MS m/z: 281, 283 [M + H]+. 1H-NMR
(DMSO-d6) d: 1.27 (d, J = 6.7 Hz, 6H, (CH3)2CH), 2.91 (m, 1H,
(CH3)2CH), 4.86 (s, 2H, CH2Br), 7.63 (d, J = 8.2 Hz, 1H, quinazoli-
none 8-H), 7.85 (d, J = 8.2 Hz, 1H, quinazolinone 7-H), 8.16 (s, 1H,
quinazolinone 5-H). Anal. Calcd. for C12H13N2OBr N H2O: C, 50.46;
H, 4.76; N, 9.81. Found: C, 50.50; H, 4.62; N, 9.66.
6-Methyl-2-propylquinazolin-4(3H)-one 5a
Yield: 70.5%, m.p.: 244.3–244.88C (from acetic acid). ESI-MS m/z:
203 [M + H]+. 1H-NMR (CDCl3) d: 1.11 (t, J = 7.3 Hz, 3H, CH3CH2),
1.93 (m, 2H, CH3CH2CH2), 2.53 (s, 3H, CH3), 2.81 (t, J = 7.6 Hz, 2H,
CH2CH2), 7.63 (m, 2H, quinazolinone 7-H and 8-H), 8.09 (s, 1H,
quinazolinone 5-H). Anal. Calcd. for C12H14N2O N 1/10 AcOH: C,
70.46; H, 7.02; N, 13.36. Found: C, 70.46; H, 7.02; N, 13.45.
6-Bromomethyl-2-(4-chlorophenyl)quinazolin-4(3H)-one
6c
1
Yield: 55.3%, m.p.: 282.8–283.68C. EI-MS m/z: 348, 350 [M+]. H-
NMR (DMSO-d6) d: 4.87 (s, 2H, CH2Br), 7.62 (d, J = 8.7 Hz, 2H, Ar-H),
7.73 (d, J = 8.4 Hz, 1H, quinzolinone 8-H), 7.89 (d, J = 8.4 Hz, 1H,
quinazolinone 7-H), 8.18 (m, 3H, quinazolinone 5-H and Ar-H).
Anal. Calcd. for C15H10ClNO2Br: C, 51.53; H, 2.88; N, 8.01. Found:
C, 51.73; H, 3.01; N, 8.09.
2-Isopropyl-6-methylquinazolin-4(3H)-one 5b
Yield: 69.4%, m.p.: 244.3–244.88C (from acetic acid). ESI-MS m/z:
203 [M + H]+. 1H-NMR (DMSO-d6) d: 1.26 (d, J = 6.7 Hz, 6H,
(CH3)2CH), 2.42 (s, 3H, CH3), 2.88 (m, 1H, (CH3)2CH), 7.52 (d, J =
8.2 Hz, 1H, quinazolinone 8-H), 7.60 (d, J = 8.2 Hz, 1H, quinazoli-
none 7-H), 7.88 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C, 71.12; H, 7.00; N,
13.64.
6-(Bromomethyl)-2-(furan-2-yl)quinazolin-4(3H)-one 6d
Yield: 60.7%, m.p.: 265–2678C. EI-MS m/z: 304, 306 [M+]. 1H-NMR
(DMSO-d6) d: 4.87 (s, 2H, CH2Br), 6.77 (m, 1H, furan-H), 7.63 (d, J =
3.4 Hz, 1H, furan-H), 7.69 (d, J = 8.4 Hz, 1H, quinazolinone 8-H),
7.88 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 7.80 (s, 1H, furan-H),
8.19 (s, 1H, quinazolinone 5-H). Anal. Calcd. for C13H9N2O2Br: C,
51.17; H, 2.97; N, 9.18. Found: C, 51.40; H, 2.97; N, 9.14.
2-(4-Chlorophenyl)-6-methylquinazolin-4(3H)-one 5c
Yield: 73.4%, m.p.: 311–3128C (from acetic acid). ESI-MS m/z: 271
[M + H]+.1H-NMR (DMSO-d6) d: 2.47 (s, 3H, CH3), 7.63 (m, 4H, quina-
zolinone 7-H, 8-H and Ar-H), 7.96 (s, 1H, quinazolinone 5-H), 8.19
(d, J = 8.7 Hz, 2H, Ar-H). Anal. Calcd. for C15H11ClN2O: C, 66.55; H,
4.10; N, 10.35. Found: C, 66.50; H, 4.12; N, 10.06.
General procedure for the synthesis of compounds
8a–z
A suspension of 1-substituted piperazine 7a–d (2.4 mmol), car-
bon disulfide (0.72 mL, 12 mmol) and anhydrous potassium
phosphate (0.51 g, 2.4 mmol) in N,N-dimethylformamide (15 mL)
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186
S.-L. Cao et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
was stirred at room temperature for 30 min. Then, bromo-
methyl compound 6 (2 mmol) was added and the stirring was
continued for 2 h. The reaction mixture was poured into water
(100 mL) and the formed solid was collected by filtration and
purified by column chromatography (CC) on silica gel or recrys-
tallization from appropriate solvent to give compounds 8a–z.
H), 4.34 (br s, 2H, piperazine-H), 4.71 (s, 2H, CH2S), 7.63 (d, J =
8.4 Hz, 1H, quinazolinone 8-H), 7.77 (d, J = 8.4 Hz, 1H, quinazoli-
none 7-H), 8.23 (s, 1H, quinazolinone 5-H), 11.69 (br s, 1H, NH).
Anal. Calcd. for C17H22N4OS2 N 4/3 H2O: C, 52.82; H, 6.43; N, 14.49.
Found: C, 52.84; H, 6.13; N, 14.86.
(2-Ethyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
benzylpiperazine-1-carbodithioate 8f
(2-(Trifluoromethyl)-3,4-dihydro-4-oxoquinazolin-6-
yl)methyl 4-methylpiperazine-1-carbodithioate 8a
Yield: 64.7%, m.p.: 228.9–230.48C (CC, eluent: dichloromethane
/ methanol, 95 : 5). CI-MS m/z: 403 [M + H]+.1H-NMR (CDCl3) d: 2.37
(s, 3H, NCH3), 2.58 (t, J = 4.8 Hz, 4H, piperazine-H), 4.04 (br s, 2H,
piperazine-H), 4.31 (br s, 2H, piperazine-H), 4.74 (s, 2H, CH2S),
7.80 (d, J = 8.5 Hz, 1H, quinazolinone 8-H), 7.92 (d, J = 8.5 Hz, 1H,
quinazolinone 7-H), 8.32 (s, 1H, quinazolinone 5-H). Anal. Calcd.
for C16H17F3N4OS2: C, 47.75; H, 4.26; N, 13.92. Found: C, 47.72; H,
4.29; N, 13.88.
Yield: 65.8%, m.p.: 195.0–196.58C (CC, eluent: dichloromethane
/ methanol, 95 : 5). ESI-MS m/z: 439 [M + H]+. 1H-NMR (DMSO-d6) d:
1.23 (t, J = 7.5 Hz, 3H, CH3CH2), 2.45 (s, 4H, piperazine-H), 2.57 (q, J
= 7.5 Hz, 2H, CH3CH2), 3.51 (s, 2H, CH2Ph), 3.90 (br s, 2H, pipera-
zine-H), 4.24 (br s, 2H, piperazine-H), 4.69 (s, 2H, CH2S), 7.31 (s,
5H, Ar-H), 7.55 (d, J = 8.3 Hz, 1H, quinazolinone 8-H), 7.76 (d, J =
8.3 Hz, 1H, quinazolinone 7-H), 8.07 (s, 1H, quinazolinone 5-H).
Anal. Calcd. for C23H26N4OS2: C, 62.98; H, 5.97; N, 12.77. Found: C,
62.61; H, 6.05; N, 12.77.
(2-(Trifluoromethyl)-3,4-dihydro-4-oxoquinazolin-6-
(2-Ethyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
yl)methyl 4-benzylpiperazine-1-carbodithioate 8b
phenylpiperazine-1-carbodithioate 8g
Yield: 48.1%, m.p.: 201–2038C (CC, eluent: dichloromethane /
methanol, 98 : 2). CI-MS m/z: 479 [M + H]+. 1H-NMR (DMSO-d6) d:
2.49 (s, 4H, piperazine-H), 3.55 (s, 2H, CH2Ph), 3.93 (br s, 2H, piper-
azine-H), 4.24 (br s, 2H, piperazine-H), 4.77 (s, 2H, CH2S), 7.31 (s,
5H, Ar-H), 7.76 (d, J = 8.5 Hz, 1H, quinazolinone 8-H), 7.91 (d, J =
8.5 Hz, 1H, quinazolinone 7-H), 8.18 (s, 1H, quinazolinone 5-H).
Yield: 86.6%, m.p.: 246–2478C (CC, eluent: dichloromethane /
methanol, 99 : 1). CI-MS m/z: 425 [M + H]+. 1H-NMR (DMSO-d6) d:
1.24 (t, J = 7.5 Hz, 3H, CH3CH2), 2.62 (q, J = 7.5 Hz, 2H, CH3CH2),
3.30 (br s, 4H, piperazine-H), 4.09 (br s, 2H, piperazine-H), 4.40 (br
s, 2H, piperazine-H), 4.75 (s, 2H, CH2S), 6.82 (t, J = 7.2 Hz, 1H, Ar-
H), 6.95 (d, J = 7.9 Hz, 2H, Ar-H), 7.25 (t, J = 7.9 Hz, 2H, Ar-H), 7.57
(d, J = 8.4 Hz, 1H, quinazolinone 8-H), 7.81 (d, J = 8.4 Hz, 1H, qui-
nazolinone 7-H), 8.11 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C22H24N4OS2: C, 62.23; H, 5.70; N, 13.20. Found: C, 62.36; H, 5.82;
N, 13.10.
1
Anal. Calcd. for C22H21F3N4OS2 N /3 H2O: C, 54.53; H, 4.51; N, 11.56.
Found: C, 54.46; H, 4.45; N, 11.97.
(2-(Trifluoromethyl)-3,4-dihydro-4-oxoquinazolin-6-
yl)methyl 4-phenylpiperazine-1-carbodithioate 8c
(2-Ethyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-(4-
fluorophenyl)piperazine-1-carbodithioate 8h
Yield: 54.8%, m.p.: 231–2328C (CC, eluent: dichloromethane /
1
methanol, 98 : 2). CI-MS m/z: 465 [M + H]+. H-NMR (DMSO-d6) d:
3.29 (br s, 4H, piperazine-H), 4.08 (br s, 2H, piperazine-H), 4.38 (br
s, 2H, piperazine-H), 4.80 (s, 2H, CH2S), 6.81 (t, J = 7.2 Hz, 1H, Ar-
H), 6.94 (d, J = 8.1 Hz, 2H, Ar-H), 7.24 (t, J = 7.8 Hz, 2H, Ar-H), 7.75
(d, J = 8.4 Hz, 1H, quinazolinone 8-H), 7.92 (d, J = 8.4 Hz, 1H, qui-
nazolinone 7-H), 8.21 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C21H19F3N4OS2 N ꢁH2O: C, 53.26; H, 4.26; N, 11.83. Found: C,
53.28; H, 4.26; N, 11.92.
Yield: 84.3%, m.p.: 251.1–251.38C (from trichloromethane /
methanol, 9 : 1). ESI-MS m/z: 442.1 [M+]. 1H-NMR (DMSO-d6) d: 1.24
(t, J = 7.5 Hz, 3H, CH3CH2), 2.62 (q, J = 7.5 Hz, 2H, CH3CH2), 3.21 (br
s, 4H, piperazine-H), 4.08 (br s, 2H, piperazine-H), 4.38 (br s, 2H,
piperazine-H), 4.74 (s, 2H, CH2S), 7.02 (m, 4H, Ar-H), 7.57 (d, J =
8.4 Hz, 1H, quinazolinone 8-H), 7.81 (d, J = 8.4 Hz, 1H, quinazoli-
none 7-H), 8.11 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C22H23FN4OS2: C, 59.70; H, 5.24; N, 12.66. Found: C, 59.78; H, 5.26;
N, 12.64.
(2-(Trifluoromethyl)-3,4-dihydro-4-oxoquinazolin-6-
yl)methyl 4-(4-fluorophenyl)piperazine-1-carbodithioate
8d
Yield: 67.0%, m.p.: 251.2–252.68C (CC, eluent: dichloromethane
/ methanol, 98 : 2). CI-MS m/z: 483 [M + H]+. 1H-NMR (DMSO-d6) d:
3.22 (s, 4H, piperazine-H), 4.08 (br s, 2H, piperazine-H), 4.38 (br s,
2H, piperazine-H), 4.81 (s, 2H, CH2S), 7.03 (m, 4H, Ar-H), 7.73 (d, J
= 8.3 Hz, 1H, quinazolinone 8-H), 7.95 (d, J = 8.3 Hz, 1H, quinazo-
linone 7-H), 8.23 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C21H18F4N4OS2: C, 52.27; H, 3.76; N, 11.61. Found: C, 52.27; H,
3.86; N, 11.68.
(3,4-Dihydro-4-oxo-2-propylquinazolin-6-yl)methyl 4-
methylpiperazine-1-carbodithioate 8i
Yield: 33.2%, m.p.: 225.5–226.08C (CC, eluent: dichloromethane
/ methanol, 96 : 4). ESI-MS m/z: 377 [M + H]+. 1H-NMR (CDCl3) d:
1.08 (t, J = 6.8 Hz, 3H, CH3CH2), 1.92 (m, 2H, CH3CH2CH2), 2.33 (s,
3H, NCH3), 2.51 (br s, 4H, piperazine-H), 2.77 (t, J = 7.2 Hz, 2H,
CH2CH2), 3.97 (br s, 2H, piperazine-H), 4.35 (br s, 2H, piperazine-
H), 4.72 (s, 2H, CH2S), 7.65 (d, J = 8.3 Hz, 1H, quinazolinone 8-H),
7.81 (d, J = 8.3 Hz, 1H, quinazolinone 7-H), 8.27 (s, 1H, quinazoli-
none 5-H), 11.86 (br s, 1H, NH). Anal. Calcd. for C18H24N4OS2: C,
57.42; H, 6.42; N, 14.88. Found: C, 57.28; H, 6.44; N, 14.90.
(2-Ethyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
methylpiperazine-1-carbodithioate 8e
(3,4-Dihydro-4-oxo-2-propylquinazolin-6-yl)methyl 4-
Yield: 87.5%, m.p.: 202–2048C (CC, eluent: dichloromethane /
methanol, 9 : 1). ESI-MS m/z: 363 [M + H]+. 1H-NMR (CDCl3) d: 1.43
(t, J = 7.6 Hz, 3H, CH3CH2), 2.32 (s, 3H, NCH3), 2.50 (s, 4H, pipera-
zine-H), 2.82 (q, J = 7.6 Hz, 2H, CH3CH2), 3.91 (br s, 2H, piperazine-
benzylpiperazine-1-carbodithioate 8j
Yield: 85.8%, m.p.: 186.3–186.88C (from ethyl acetate). ESI-MS m/
z: 452 [M+]. 1H-NMR (CDCl3) d: 1.07 (t, J = 7.3 Hz, 3H, CH3CH2), 1.90
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Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
Piperazine-1-carbodithioate Derivatives
187
(m, 2H, CH3CH2CH2), 2.53 (br s, 4H, piperazine-H), 2.76 (t, J =
7.6 Hz, 2H, CH2CH2), 3.54 (s, 2H, CH2Ph), 3.93 (br s, 2H, pipera-
zine-H), 4.35 (br s, 2H, piperazine-H), 4.71 (s, 2H, CH2S), 7.30 (s,
5H, Ar-H), 7.63 (d, J = 8.4 Hz, 1H, quinazolinone 8-H), 7.80 (d, J =
8.4 Hz, 1H, quinazolinone 7-H), 8.25 (s, 1H, quinazolinone 5-H),
11.90 (br s, 1H, NH). Anal. Calcd. for C24H28N4OS2: C, 63.68; H,
6.24; N, 12.38. Found: C, 63.56; H, 6.30; N, 12.19.
(3,4-Dihydro-2-isopropyl-4-oxoquinazolin-6-yl)methyl 4-
phenylpiperazine-1-carbodithioate 8o
Yield: 61.2%, m.p.: 227.3–228.98C (from DMF / H2O, 2 : 1). ESI-MS
1
m/z: 439 [M + H]+. H-NMR (DMSO-d6) d: 1.26 (d, J = 6.9 Hz, 6H,
(CH3)2CH), 2.90 (m, 1H, (CH3)2CH), 3.29 (br s, 4H, piperazine-H),
4.11 (br s, 2H, piperazine-H), 4.35 (br s, 2H, piperazine-H), 4.75 (s,
2H, CH2S), 6.82 (t, J = 6.9 Hz, 1H, Ar-H), 6.95 (d, J = 7.9 Hz, 2H, Ar-
H), 7.25 (t, J = 7.9 Hz, 2H, Ar-H), 7.58 (d, J = 8.4 Hz, 1H, quinazoli-
none 8-H), 7.81 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.12 (s, 1H,
quinazolinone 5-H). Anal. Calcd. for C23H26N4OS2: C, 62.98; H,
5.97; N, 12.77. Found: C, 62.84; H, 6.06; N, 12.82.
(3,4-Dihydro-4-oxo-2-propylquinazolin-6-yl)methyl 4-
phenylpiperazine-1-carbodithioate 8k
Yield: 69.6%, m.p.: 230.5–231.38C (CC, eluent: dichloromethane
/ methanol, 99 : 1). ESI-MS m/z: 439 [M + H]+. 1H NMR (CDCl3) d:
1.08 (t, J = 6.4 Hz, 3H, CH3CH2), 1.92 (m, 2H, CH3CH2CH2), 2.78 (t, J
= 5.9 Hz, 2H, CH2CH2), 3.30 (br s, 4H, piperazine-H), 4.13 (br s, 2H,
piperazine-H), 4.46 (br s, 2H, piperazine-H), 4.75 (s, 2H, CH2S),
6.92 (m, 3H, Ar-H), 7.29 (m, 2H, Ar-H), 7.67 (d, J = 8.4 Hz, 1H, qui-
nazolinone 8-H), 7.83 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.29
(s, 1H, quinazolinone 5-H), 11.60 (br s, 1H, NH). Anal. Calcd. for
C23H26N4OS2: C, 62.98; H, 5.97; N, 12.77. Found: C, 62.82; H, 6.05;
N, 12.76.
(3,4-Dihydro-2-isopropyl-4-oxoquinazolin-6-yl)methyl-4-
(4-fluorophenyl)piperazine-1-carbodithioate 8p
Yield: 59.9%, m.p.: 243.9–246.38C (from DMF / H2O, 2 : 1). ESI-MS
1
m/z: 457 [M + H]+. H-NMR (DMSO-d6) d: 1.26 (d, J = 6.8 Hz, 6H,
(CH3)2CH), 2.90 (m, 1H, (CH3)2CH), 3.21 (br s, 4H, piperazine-H),
4.16 (br s, 2H, piperazine-H), 4.28 (br s, 2H, piperazine-H), 4.74 (s,
2H, CH2S), 7.02 (m, 4H, Ar-H), 7.58 (d, J = 8.4 Hz, 1H, quinazoli-
none 8-H), 7.80 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.11 (s, 1H,
quinazolinone 5-H). Anal. Calcd. for C23H25N4OS2: C, 60.50; H,
5.52; N, 12.27. Found: C, 60.48; H, 5.53; N, 12.21.
(3,4-Dihydro-4-oxo-2-propylquinazolin-6-yl)methyl 4-(4-
fluorophenyl)piperazine-1-carbodithioate 8l
Yield: 74.6%, m.p.: 216.7–218.38C (from DMF / H2O, 2 : 1). ESI-MS
m/z: 456 [M+]. 1H-NMR (DMSO-d6) d: 0.93 (t, J = 6.8 Hz, 3H, CH3CH2),
1.74 (m, 2H, CH3CH2CH2), 2.61 (t, J = 7.2 Hz, 2H, CH2CH2), 3.21 (br
s, 4H, piperazine-H), 4.10 (br s, 2H, piperazine-H), 4.37 (br s, 2H,
piperazine-H), 4.74 (s, 2H, CH2S), 7.03 (m, 4H, Ar-H), 7.56 (d, J =
8.2 Hz, 1H, quinazolinone 8-H), 7.80 (d, J = 8.2 Hz, 1H, quinazoli-
none 7-H), 8.11 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C23H25FN4OS2: C, 60.50; H, 5.52; N, 12.27. Found: C, 60.41; H, 5.53;
N, 12.30.
(2-Benzyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
methylpiperazine-1-carbodithioate 8q
Yield: 26.8%, m.p.: 208.6–209.48C (CC, eluent: dichloromethane
/ methanol, 95 : 5). ESI-MS m/z: 425 [M + H]+. 1H-NMR (DMSO-d6) d:
2.19 (s, 3H, NCH3), 2.38 (br s, 4H, piperazine-H), 3.93 (br s, 3H,
piperazine-H and CH2Ph), 4.22 (br s, 2H, piperazine-H), 4.71 (s,
2H, CH2S), 7.31 (m, 5H, Ar-H), 7.56 (d, J = 8.4 Hz, 1H, quinazoli-
none 8-H), 7.78 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.07 (s, 1H,
quinazolinone 5-H). Anal. Calcd. for C22H24N4OS2 N ꢁH2O: C,
60.94; H, 5.81; N, 12.92. Found: C, 61.14; H, 5.67; N, 13.11.
(3,4-Dihydro-2-isopropyl-4-oxoquinazolin-6-yl)methyl 4-
methylpiperazine-1-carbodithioate 8m
(2-Benzyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
benzylpiperazine-1-carbodithioate 8r
Yield: 70.6%, m.p.: 242.9–243.98C (CC, eluent: dichloromethane
/ methanol, 95 : 5). ESI-MS m/z: 377 [M + H]+. 1H-NMR (DMSO-d6) d:
1.26 (d, J = 6.5 Hz, 6H, (CH3)2CH), 2.20 (s, 3H, NCH3), 2.40 (br s, 4H,
piperazine-H), 2.89 (m, 1H, (CH3)2CH), 3.91 (br s, 2H, piperazine-
H), 4.23 (br s, 2H, piperazine-H), 4.71 (s, 2H, CH2S), 7.58 (d, J =
8.4 Hz, 1H, quinazolinone 8-H), 7.81 (d, J = 8.4 Hz, 1H, quinazoli-
none 7-H), 8.09 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C18H24N4OS2: C, 57.42; H, 6.42; N, 14.88. Found: C, 57.47; H, 6.56;
N, 14.72.
Yield: 82.7%, m.p.: 176–1788C (CC, eluent: dichloromethane /
methanol, 95 : 5). ESI-MS m/z: 500 [M+]. 1H-NMR (DMSO-d6) d: 2.44
(s, 4H, piperazine-H), 3.50 (s, 2H, CH2Ph), 3.93 (br s, 4H, pipera-
zine-H and CH2Ph), 4.24 (br s, 2H, piperazine-H), 4.69 (s, 2H,
CH2S), 7.31 (s, 5H, Ar-H), 7.35 (s, 5H, Ar-H), 7.55 (d, J = 8.4 Hz, 1H,
quinazolinone 8-H), 7.77 (d, J = 8.4 Hz, 1H, quinazolinone 7-H),
8.08 (s, 1H, quinazolinone 5-H). Anal. Calcd. for C28H28N4OS2 N 1/3
H2O: C, 66.37; H, 5.70; N, 11.06. Found: C, 66.65; H, 5.69; N, 11.30.
(3,4-Dihydro-2-isopropyl-4-oxoquinazolin-6-yl)methyl 4-
(2-Benzyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-
benzylpiperazine-1-carbodithioate 8n
phenylpiperazine-1-carbodithioate 8s
Yield: 62.7%, m.p.: 215.1–216.98C (from DMF / H2O, 2 : 1). ESI-MS
1
m/z: 453 [M + H]+. H-NMR (DMSO-d6) d: 1.25 (d, J = 6.8 Hz, 6H,
Yield: 72.6%, m.p.: 218.9–221.68C (from DMF / H2O, 2 : 1). ESI-MS
1
(CH3)2CH), 2.45 (br s, 4H, piperazine-H), 2.90 (m, 1H, (CH3)2CH),
3.51 (s, 2H, CH2Ph), 3.92 (br s, 2H, piperazine-H), 4.24 (br s, 2H,
piperazine-H), 4.70 (s, 2H, CH2S), 7.31 (s, 5H, Ar-H), 7.56 (d, J =
8.4 Hz, 1H, quinazolinone 8-H), 7.78 (d, J = 8.4 Hz, 1H, quinazoli-
none 7-H), 8.09 (s, 1H, quinazolinone 5-H). Anal. Calcd. for
C24H28N4OS2 N ꢂH2O: C, 63.06; H, 6.28; N, 12.26. Found: C, 62.98;
H, 6.23; N, 12.27.
m/z: 486 [M+]. H-NMR (DMSO-d6) d: 3.28 (br s, 4H, piperazine-H),
3.94 (s, 2H, CH2Ph), 4.07 (br s, 2H, piperazine-H), 4.36 (br s, 2H,
piperazine-H), 4.74 (s, 2H, CH2S), 6.82 (t, J = 7.3 Hz, 1H, Ar-H), 6.95
(d, J = 7.9 Hz, 1H, Ar-H), 7.30 (m, 7H, Ar-H), 7.58 (d, J = 8.4 Hz, 1H,
quinazolinone 8-H), 7.82 (d, J = 8.4 Hz, 1H, quinazolinone 7-H),
8.11 (s, 1H, quinazolinone 5-H). Anal. Calcd. for C27H26N4OS2: C,
66.64; H, 5.39; N, 11.51. Found: C, 66.77; H, 5.47; N, 11.44.
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S.-L. Cao et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 182–189
(2-Benzyl-3,4-dihydro-4-oxoquinazolin-6-yl)methyl 4-(4-
fluorophenyl)piperazine-1-carbodithioate 8t
(2-(4-Chlorophenyl)-3,4-dihydro-4-oxoquinazolin-6-
yl)methyl4-(4-fluorophenyl)piperazine-1-carbodithioate
Yield: 62.5%, m.p.: 202.6–204.18C (from DMF / H2O, 2 : 1). ESI-MS
m/z: 504 [M+]. 1H-NMR (DMSO-d6) d: 3.20 (br s, 4H, piperazine-H),
3.93 (s, 2H, CH2Ph), 4.07 (br s, 2H, piperazine-H), 4.35 (br s, 2H,
piperazine-H), 4.73 (s, 2H, CH2S), 7.01 (m, 4H, Ar-H), 7.30 (m, 5H,
Ar-H), 7.57 (d, J = 8.4 Hz, 1H, quinazolinone 8-H), 7.80 (d, J =
8.4 Hz, 1H, quinazolinone 7-H), 8.10 (s, 1H, quinazolinone 5-H).
Anal. Calcd. for C27H25FN4OS2: C, 64.26; H, 4.99; N, 11.10. Found:
C, 64.27; H, 5.05; N, 11.20.
8y
Yield: 50.2%, m.p.: 315–3178C (from DMF / H2O, 2 : 1). ESI-MS m/z:
525 [M + H]+. H-NMR (DMSO-d6) d: 3.22 (br s, 4H, piperazine-H),
1
4.21 (br m, 4H, piperazine-H), 4.78 (s, 2H, CH2S), 7.01 (m, 4H, Ar-
H), 7.62 (d, J = 8.6 Hz, 2H, Ar-H), 7.71 (d, J = 8.4 Hz, 1H, quinazoli-
none 8-H), 7.87 (d, J =8.4 Hz, 1H, quinazolinone 7-H), 8.17 (m, 3H,
quinazolinone 5-H and Ar-H). Anal. Calcd. for C26H22ClFN4OS2: C,
59.47; H, 4.22; N, 10.67. Found: C, 59.19; H, 4.25; N, 10.50.
(2-(Furan-2-yl)-3,4-dihydro-4-oxoquinazolin-6-
yl)methyl4-(4-fluorophenyl)piperazine-1-carbodithioate
(3,4-Dihydro-4-oxo-2-phenylquinazolin-6-yl)methyl 4-
methylpiperazine-1-carbodithioate 8u
8z
Yield: 41.7%, m.p.: 275.8–275.98C (CC, eluent: dichloromethane
/ methanol, 95 : 5). ESI-MS m/z: 411 [M + H]+. 1H-NMR (DMSO-d6) d:
2.36 (s, 3H, NCH3), 2.44 (br s, 4H, piperazine-H), 3.95 (br s, 2H,
piperazine-H), 4.26 (br s, 2H, piperazine-H), 4.76 (s, 2H, CH2S),
7.58 (m, 3H, Ar-H), 7.71 (d, J = 8.4 Hz, 1H, quinazolinone 8-H),
7.85 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.18 (m, 3H, quinazoli-
Yield: 54.6%, m.p.: 253.0–253.88C (from DMF / H2O, 2 : 1). ESI-MS
m/z: 481 [M + H]+. 1H-NMR (DMSO-d6) d: 3.22 (br s, 4H, piperazine-
H), 4.16 (br s, 2H, piperazine-H), 4.33 (br s, 2H, piperazine-H), 4.76
(s, 2H, CH2S), 6.75 (m, 1H, furan-H), 7.05 (m, 4H, Ar-H), 7.60 (d, J =
3.3 Hz, 1H, furan-H), 7.66 (d, J = 8.4 Hz, 1H, quinazolinone 8-H),
7.84 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 7.97 (s, 1H, furan-H),
8.15 (s, 1H, quinazolinone 5-H). Anal. Calcd. for C24H21FN4O2S2 N
1/5 H2O: C, 59.53; H, 4.45; N, 11.57. Found: C, 59.55; H, 4.36; N,
11.59.
1
none 5-H and Ar-H). Anal. Calcd. for C21H22N4OS2 N /3 H2O: C,
60.55; H, 5.48; N, 13.45. Found: C, 60.74; H, 5.43; N, 13.44.
(3,4-Dihydro-4-oxo-2-phenylquinazolin-6-yl)methyl 4-
benzylpiperazine-1-carbodithioate 8v
References
Yield: 82.6%, m.p.: 228.1–229.08C (CC, eluent: dichloromethane
/ methanol, 97 : 3). ESI-MS m/z: 486 [M+].1H-NMR (DMSO-d6) d: 2.46
(br s, 4H, piperazine-H), 3.51 (s, 2H, CH2Ph), 3.92 (br s, 2H, pipera-
zine-H), 4.24 (br s, 2H, piperazine-H), 4.73 (s, 2H, CH2S), 7.31 (m,
5H, Ar-H), 7.55 (m, 3H, Ar-H), 7.69 (d, J = 8.4 Hz, 1H, quinazoli-
none 8-H), 7.84 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.12 (m, 3H,
quinazolinone 5-H and Ar-H). Anal. Calcd. for C27H26N4OS2: C,
66.64; H, 5.39; N, 11.51. Found: C, 66.64; H, 5.45; N, 11.47.
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Yield: 32.7%, m.p.: 261.5–262.38C (from DMF). ESI-MS m/z: 473 [M
+ H]+. 1H-NMR (DMSO-d6) d: 3.29 (s, 4H, piperazine-H), 4.08 (br s,
2H, piperazine-H), 4.38 (br s, 2H, piperazine-H), 4.78 (s, 2H, CH2S),
6.80 (t, J = 7.2 Hz, 1H, Ar-H), 6.93 (d, J = 8.2 Hz, 2H, Ar-H), 7.23 (t, J
= 7.8 Hz, 2H, Ar-H), 7.57 (m, 3H, Ar-H), 7.70 (d, J = 8.4 Hz, 1H, qui-
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65.86; H, 5.11; N, 12.01.
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Yield: 46.3%, m.p.: 263.3–264.18C (from DMF). CI-MS m/z: 491 [M
+ H]+. 1H-NMR (DMSO-d6) d: 3.22 (s, 4H, piperazine-H), 4.08 (br s,
2H, piperazine-H), 4.39 (br s, 2H, piperazine-H), 4.78 (s, 2H, CH2S),
6.99 (m, 4H, Ar-H), 7.56 (m, 3H, Ar-H), 7.70 (d, J = 8.4 Hz, 1H, qui-
nazolinone 8-H), 7.86 (d, J = 8.4 Hz, 1H, quinazolinone 7-H), 8.20
(m, 3H, quinazolinone 5-H and Ar-H), 12.56 (br s, 1H, NH). Anal.
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63.59; H, 4.83; N, 11.37.
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com