Synthesis and characterization of novel quinazoline-substituted 1,3,4-thiadiazolium-5-thiolates

Article abstract of DOI:10.1080/10426507.2010.525768

Novel 3-[4-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)benzoyl]-2- substituted-1,3,4-thiazolium-5-thiolate 7(a-j) and 3-{4-[(6-bromo-2- phenylquinazolin-4-yl)amino] benzoyl}-2-substituted-1,3,4-thiadiazolium-5- thiolate 12(a-j) were synthesized from 6-brom

Full text of DOI:10.1080/10426507.2010.525768

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Phosphorus, Sulfur, and Silicon and the
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Synthesis and Characterization of
Novel Quinazoline-Substituted 1,3,4-
Thiadiazolium-5-thiolates
Shahrukh T. Asundaria a , Keshav C. Patel a & Kalpesh M. Mehta a
a Department of Chemistry, Veer Narmad South Gujarat University,
Surat, Gujarat, India
Version of record first published: 04 Aug 2011.
To cite this article: Shahrukh T. Asundaria , Keshav C. Patel & Kalpesh M. Mehta (2011): Synthesis and
Characterization of Novel Quinazoline-Substituted 1,3,4-Thiadiazolium-5-thiolates, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:7, 1554-1562
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Phosphorus, Sulfur, and Silicon, 186:1554–1562, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.525768
SYNTHESIS AND CHARACTERIZATION OF NOVEL
QUINAZOLINE-SUBSTITUTED
1,3,4-THIADIAZOLIUM-5-THIOLATES
Shahrukh T. Asundaria, Keshav C. Patel,
and Kalpesh M. Mehta
Department of Chemistry, Veer Narmad South Gujarat University, Surat,
Gujarat, India
GRAPHICAL ABSTRACT
Abstract Novel 3-[4-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)benzoyl]-2-substituted-
1,3,4-thiazolium-5-thiolate 7(a–j) and 3-{4-[(6-bromo-2-phenylquinazolin-4-yl)amino]
benzoyl}-2-substituted-1,3,4-thiadiazolium-5-thiolate 12(a–j) were synthesized from 6-bromo-
2-phenyl-4H-3,1-benzoxazin-4-one (1). The structures of the newly synthesized compounds
were confirmed by spectral data and elemental analysis.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Carbodithioic acid; mesoionic; quinazoline; 1,3,4-thiadiazolium-5-thiolate
INTRODUCTION
A literature survey revealed that mesoionic compounds are one of the most important
classes of heterocyclic compounds.1–3 The compounds containing a bisheterocyclic system
Received 10 August 2010; accepted 19 September 2010.
The authors are thankful to Atul Limited, Valsad and Ami Organics, Sachin, for providing useful chemicals.
Address correspondence to Keshav C. Patel, Department of Chemistry, Veer Narmad South Gujarat Univer-
sity, Udhna-Magdalla Road, Surat 3950 07 Gujarat, India. E-mail: shahrukhsun@gmail.com
1554

1,3,4-THIADIAZOLIUM-5-THIOLATES
1555
displayed much better antibacterial activity than monoheterocyclic compounds.4 Recently
there have been broad developments in investigations of both the synthesis and study of
the chemical and biological properties of mesoionic compounds, and attention has been
increasingly paid to the synthesis of bisheterocyclic compounds.5–7 Thiadiazolium deriva-
tives were found to possess a vast array of synthetic as well as biological importance.8–10
Quinazoline derivatives are interesting because of their diverse range of biological activities
and synthetic applications.11–13
In a search for novel compounds with pharmaceutical value and to expand the appli-
cations of quinazoline and thiadiazole in organic synthesis, we report herein the synthesis
of novel quinazoline-substituted 1,3,4-thiadiazolium-5-thiolate derivatives.
RESULTS AND DISCUSSION
In the present investigation, 3-[4-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-
yl)benzoyl]-2-substituted-1,3,4-thiadiazolium-5-thiolate 7(a–j) and 3-{4-[(6-bromo-
2-phenylquinazolin-4-yl)amino]benzoyl}-2-substituted-1,3,4-thiadiazolium-5-thiolate
12(a–j) were synthesized from 4-(6-bromo-4-oxo-2-phenylquinazolin-3-(4H)-yl) benzoic
acid (2) and 6-bromo-2-phenylquinazolin-4(3H)-one (3), respectively. Scheme 1 shows
synthesis of compounds 2 and 3. 4-(6-Bromo-2-phenyl-4-oxoquinazoline-3(4H)-yl)
benzohydrazide (5) was synthesized from compound (2) according to a literature method.14
The hydrazino group of compounds (5) and (10) was reacted with carbon disul-
fide and potassium hydroxide to give the corresponding hydrazino carbodithioic acid
O
O
N
O
N
OH
Br
Br
O
N
4-aminobenzoic acid
2
1
NH3
O
Br
NH
N
3
Scheme 1 Synthesis of 4-(6-bromo-4-oxo-2-phenylquinazolin-3-(4H)-yl) benzoic acid (2) and 6-bromo-2-
phenylquinazolin-4(3H)-one (3).

1556
S. T. ASUNDARIA ET AL.
O
O
O
N
Cl
O
N
OH
Br
N
Br
SO2Cl
N
4
2
O
NH2
O
N
NH
CS2 / KOH
Br
NH2NH2H2O
N
5
O
R
O
NH
S K
O
N
N
O
N
NH
O
S
S
Br
N
R
Br
S
N
N
Cl
7(a-j)
6
(a) R = C6H5 (b) R = ClCH2 (c) R = CH3 (d) R = 2-NO2-C6H4 (e) R = 3-NO2-C6H4
(f) R = 4-NO2-C6H4 (g) R = 2-Cl-5-NO2-C6H3 (h) R = 4-OCH3-3-NO2-C6H3
(i) R = 4-Cl-C6H4 (j) R = 3-Cl-5-NO2-C6H3
Scheme 2 Synthesis of 3-[4-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)benzoyl]-2-substituted-1,3,4-thia
diazolium-5-thiolate 7(a–j).
derivatives, which, on cyclization with different acid chloride derivatives, gave substituted-
1,3,4-thiadiazolium-5-thiolate 7(a–j) and 12(a–j). The hydrazine group of compounds (5)
and (10) was used to build the 1,3,4-thiadiazolium-5-thiolate ring. Both aliphatic and aro-
matic acid chloride derivatives were used for the cyclization process. The rate of cyclization
was not affected by the nature of the acid chloride derivatives. It is noteworthy that potas-
sium dithioformates (H C S S−K+) can also be used as cyclizing agents in the process.15
The structures of the compounds 7(a–j) and 12(a–j) were determined by elemental analysis,
infrared (IR), and nuclear magnetic resonance (NMR) spectra. Examination of the elemen-
tal data revealed that the elemental contents were consistent with the predicted formulas
shown in Schemes 2 and 3.

1,3,4-THIADIAZOLIUM-5-THIOLATES
1557
Cl
O
Br
Br
N
POCl3
PABA
6 -7 h
NH
N
N
8
3
O
O
HN
N
HN
NH NH2
Br
OH
Br
SOCl2
N
CS2/KOH
N
NH2NH2H2O
N
10
9
S
O
N
O
N
C
HN
N
HN
S K
S
Br
NH
NH
Br
N
N
R
R-COCl
S
N
12(a-j)
11
(a) R = C6H5 (b) R = ClCH2 (c) R = CH3 (d) R = 2-NO2-C6H4 (e) R = 3-NO2-C6H4
(f) R = 4-NO2-C6H4 (g) R = 2-Cl-5-NO2-C6H3 (h) R = 4-OCH3-3-NO2-C6H3
(i) R = 4-Cl-C6H4 (j) R = 3-Cl-5-NO2-C6H3
Scheme 3 Synthesis of 3-{4-[(6-bromo-2-phenylquinazolin-4-yl)amino]benzoyl}-2-substituted-1,3,4-thiadiaz
olium-5-thiolate.
The IR spectra showed bands at 550–646 cm−1 (C Br), 1655–1690 cm−1 (C O
amide), 1313–1385 cm−1 (C S thiadiazole), and 1583–1617 cm−1 (CN quinazoline). In
addition, compounds 7(a–j) showed absorption bands at 1678–1690 cm−1 (C O quina-
zoline) and compound 12(a–j) showed absorption bands at 1296–1324 cm−1 due to C N
stretching of the NH group. Furthermore, compounds 7(a–j) and 12(a–j) contain different
substitutions at C-2 of the thiadiazole ring. IR spectral characteristics of all of the synthe-
sized compounds were consistent with their proposed structures. The 1H-NMR spectra of
compounds 12(a–j) showed signals in the range of δ 9.80–9.85 ppm for N H protons. The
aromatic protons of compounds 7(a–j) and 12(a–j) appeared as multiplets in the range of
δ 7.10–8.79 ppm. Other signals were consistent with the predicted structures. Further, the
13C NMR spectra exhibited confirmatory signals for the carbon of C S of the thiadiazole
ring of around δ 164.0 ppm, and the carbon at C-2 of the thiadiazole ring appeared between
δ 136.5–137.7 ppm. The signals for the carbonyl carbon directly attached to the thiadiazole
ring appeared between δ 176.0–178.0 ppm. The carbonyl group (C O) directly attached at

1558
S. T. ASUNDARIA ET AL.
N-3 of the thiadiazole ring is electron withdrawing in character; therefore, the 13C NMR
values of C-2 and C-5 of the thiadiazole ring varied from literature values.16 For compounds
7(a-j), the signals for the carbonyl carbon of quinazoline and C S of the thiadiazole ring
were found in close proximity to each other.
EXPERIMENTAL
Melting points were determined by an open capillary method and were uncorrected.
The IR spectra were recorded on a Shimadzu Fourier transform infrared (FTIR) instrument
(Shimadzu, Japan) using KBr pellets. NMR spectra were recorded on a Bruker Avance
II NMR at 400 MHz at SAIF, Chandigarh, using tetramethylsilane (TMS) as the internal
standard and DMSO-d6 as a solvent. Thin-layer chromatography (TLC) was performed
on E-Merck precoated 60 F254 plates and the spots were rendered visible by exposure to
ultraviolet (UV) light. Some selected NMR spectra for 7a and 12a are shown in Figures
S1–S4 (Supplemental Materials). Physical characterization data are summarized in Table
1 and IR and NMR spectra for 7a–j and 12a–j are presented in Table 2.
General Procedure for 7(a–j) as Exemplified for 7a
4-(6-Bromo-2-phenyl-4-oxoquinazoline-3(4H)-yl)benzohydrazide (5) was synthe-
sized from anthranilic acid by the reported procedure.14,17
Potassium 2-{[4-(6-bromo-2-phenyl-4-oxoquinazoline-3(4H)-yl) phenyl]
carbonyl} hydrazine carbodithioic acid (6). Carbon disulfide (0.60 mL, 0.01 mol)
was added dropwise to the solution of 4-(6-bromo-2-phenyl-4-oxoquinazolin-3(4H)-
yl)benzohydrazide (2.17 g, 0.005 mol) and potassium hydroxide (0.28 g, 0.005 mol) in
ethanol (25 mL) and the mixture was stirred for 1 h at room temperature. The precipitates
were treated with ether (30 mL). The solid that separated was filtered, washed with ether,
and dried.
◦
1
Yield: 65%; m.p. 210–213 C. IR (KBr): 1687, 1635, 1605, 1338, 632; H NMR
(400 MHz, DMSO-d6): δ 7.42–8.00 (m, 12H, Ar H), 9.82 (s, 1H, CONH), 9.94 (s, 1H,
CSNH). 13C NMR (100 MHz, DMSO-d6): δ 120.6, 121.9, 122.3, 125.5, 128.5, 128.7,
129.4, 130.0, 131.2, 131.7, 132.8, 135.7, 136.4, 149.2, 151.8, 162.7, 165.7, 196.8. Anal.
Calcd. (%) for C22H14O2N4S2BrK: C, 48.09; H, 2.57; N, 10.20; S, 11.67. Found: C, 48.13;
H, 2.45; N, 10.29; S, 11.76.
3-[4-(6-Bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)benzoyl]-2-phenyl-1,3,
4-thiazolium-5-thiolate (7a). To a stirred solution of 2-{[4-(6-bromo-2-phenyl-4-
oxoquinazoline-3(4H)-yl) phenyl] carbonyl} hydrazine carbodithioic acid (1.24 g, 0.005
mol) in water was added benzoyl chloride (0.58 mL, 0.005 mol). The reaction mixture was
stirred for 2 h at room temperature. The yellowish solid that separated was filtered, washed
repeatedly with cold water, and recrystallized from ethanol.
Following the above procedure, compounds 7(b–j) were prepared by using
chloroacetyl chloride, acetyl chloride, 2-nitrobenzoyl chloride, 3-nitrobenzoyl chloride,
4-nitrobenzoyl chloride, 2-chloro-5-nitrobenzoyl chloride, 4-methoxy-3-nitrobenzoyl
chloride, 4-chlorobenzoyl chloride, and 3-chloro-5-nitrobenzoyl chloride as acid chlorides
and the products were purified by crystallization from ethanol.

1559

1560

1,3,4-THIADIAZOLIUM-5-THIOLATES
1561
General Procedure for 12(a–j) as Exemplified for 12a
6-Bromo-4-chloro-2-phenyl quinazoline (8) was synthesized according to the previ-
ously reported procedure.18
4-[(6-Bromo-2-phenylquinazoline-4-yl)amino]benzoic acid (9). A mixture
of 6-bromo-4-chloro-2-phenylquinazoline (3.19 g, 0.01 mol), 4-aminobenzoic acid (1.37
g, 0.01 mol), and potassium carbonate (1.38 g, 0.01 mol) in isopropyl alcohol (15.0 mL)
was heated to 90–95 ◦C for 6 h. After completion of the reaction, the mixture was cooled
to room temperature and poured into cold water. The solid product obtained was filtered
and dried and recrystallized from methanol. Yield: 83%; m.p. 230–233 ◦C. IR (KBr): 2950
(br), 1705, 1610, 1310, 625; 1H-NMR (400 MHz, DMSO-d6): δ 7.42–7.95 (m, 12H, Ar-H),
9.79 (s, 1H, NH), 10.98 (s, 1H, COOH). 13C-NMR (100 MHz, DMSO-d6): δ 110.3, 112.9,
118.0, 118.3, 125.3, 125.8, 128.1, 129.6, 131.2, 131.4, 133.4, 137.0, 139.3, 150.2, 151.5,
166.4, 167.5; Anal. Calcd. (%) for C21H14O2N3Br: C, 60.02; H, 3.36; N, 10.00; Found: C,
59.91; H, 3.27; N, 9.93.
4-[(6-Bromo-2-phenylquinazoline-4-yl)amino] benzo hydrazine (10). 4-
[(6-Bromo-2-phenylquinazoline-4-yl)amino]benzoic acid (4.20 g, 0.01 mol) and thionyl
chloride (1.10 mL, 0.015 mol) were refluxed for 2 h. The excess thionyl chloride was dis-
tilled off. The resultant mixture was cooled and dissolved in ethanol (40 mL). The excess
of the hydrazine hydrate (5.0 mL) was added slowly with constant stirring. The reaction
mixture was kept under reflux conditions for 6 h. The solution was poured into ice. The
solid product obtained was filtered off and recrystallized from ethanol. Yield: 67%; m.p.
190–193 ◦C. IR (KBr): 3346, 3272, 1645, 1593, 1310, 580; 1H NMR (400 MHz, DMSO-
d6): δ 4.80 (s, 2H, NHNH2), 7.53–8.15 (m, 12H, Ar H), 9.87 (s, 1H, NH), 10.14 (s, 1H,
NHNH2); 13C-NMR (100 MHz, DMSO-d6): δ 110.4, 113.8, 114.6, 118.3, 126.1, 128.8,
129.7, 130.7, 131.1, 131.8, 133.5, 137.8, 139.4, 149.9, 150.8, 165.7, 166.3. Anal. Calcd.
(%) for C21H16ON5Br: C, 58.08; H, 3.71; N, 16.13. Found: C, 58.13; H, 3.82; N, 16.21.
Potassium 2-({4-[(6-bromo-2-phenylquinazoline-4-yl)amino]phenyl}carbo
nyl)hydr azine carbodithioic acid (11). To a stirred solution of 4-[(6-bromo-2-
phenylquinazoline-4-yl)amino]benzo hydrazine (2.17 g, 0.005 mol) and potassium
hydroxide (0.28 g, 0.005 mol) in absolute alcohol (25 mL), carbon disulfide (0.60 mL, 0.01
mol) was added dropwise and the mixture was stirred for 1 h at room temperature. The
yellowish-colored precipitate was treated with ether. The solid that separated was filtered,
washed with ether, and dried.
Yield: 73%; m.p. 227–230 ◦C. IR (KBr): 3262, 1640, 1597, 1342, 1318, 586;
1H NMR (400 MHz, DMSO-d6): δ 7.68–8.12 (m, 12H, Ar-H), 9.80 (s, 1H, NH), 9.97
(s, 1H, CONH), 10.18 (s, 1H, CSNH); 13C-NMR (100 MHz, DMSO-d6): δ 110.7, 114.2,
114.7, 117.8, 126.0, 129.0, 129.6, 130.3, 131.4, 131.8, 132.6, 136.9, 140.4, 150.2, 151.6,
165.5, 165.8, 193.6. Anal. Calcd. (%) for C22H15ON5S2BrK: C, 48.17; H, 2.76; N, 12.77;
S, 11.69. Found: C, 48.29; H, 2.69; N, 12.85; S, 11.76.
3-{4-[(6-Bromo-2-phenylquinazolin-4-yl)amino]benzoyl}-2-phenyl-1,3,4-
thiadiazolium-5-thiolate (12a). To a stirred solution of potassium salt of 2-({4-[(6-
bromo-2-phenylquinazoline-4yl) amino]phenyl}carbonyl)hydrazine carbodithioic acid
(0.005 mol) in water (50 mL) was added benzoyl chloride (0.005 mol). The reaction
mixture was stirred for 2 h at room temperature. The yellowish solid that separated was
filtered, washed repeatedly with cold water, and recrystallized from ethanol.
Following the above procedure, compounds 12(b-j) were synthesized by using
chloroacetyl chloride, acetyl chloride, 2-nitrobenzoyl chloride, 3-nitrobenzoyl chloride,

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S. T. ASUNDARIA ET AL.
4-nitrobenzoyl chloride, 2-chloro-5-nitrobenzoyl chloride, 4-methoxy-3-nitrobenzoyl chlo-
ride, 4-chlorobenzoyl chloride, and 3-chloro-5-nitrobenzoyl chloride as acid chloride
derivatives and the products were purified by crystallization from ethanol.
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