Synthesis of Some Quinazolinone Derivatives Functionalized with N-3 Heterocyclic Side Chain

Article abstract of DOI:10.1002/jhet.3197

A number of quinazolinone derivatives substituted at position-3 are prepared from 3, 1-benzoxazinone. Thus, treatment of 3, 1-benzoxazinon with cyanoacetohydrazide or thionocarbohydrazide gave the quinazolinone derivatives. The quinazolinones have been utilized as synthon for new pyridinone, azete, thiazole, thiazolidinone, thosemicarbazide, and thiosemicarbazone derivatives. The structures of the synthesized compounds were established on the basis of IR, ¹HNMR, mass spectral data, and elemental analyses.

Full text of DOI:10.1002/jhet.3197

Month 2018
Synthesis of Some Quinazolinone Derivatives Functionalized with N-3
Heterocyclic Side Chain
a
a
b
b
*
Ahmed S. A. Youssef, Magdy M. Hemdan, Fatma A. El-Mariah, and Heba E. Hashem
aDepartment of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt
bDepartment of Chemistry, College for Girls, Ain Shams University, Heliopolis, Cairo 11457, Egypt
*
E-mail: hebahashem89@yahoo.com
Received January 22, 2018
DOI 10.1002/jhet.3197
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A number of quinazolinone derivatives substituted at position-3 are prepared from 3, 1-benzoxazinone.
Thus, treatment of 3, 1-benzoxazinon with cyanoacetohydrazide or thionocarbohydrazide gave the
quinazolinone derivatives. The quinazolinones have been utilized as synthon for new pyridinone, azete, thi-
azole, thiazolidinone, thosemicarbazide, and thiosemicarbazone derivatives. The structures of the synthe-
sized compounds were established on the basis of IR, 1HNMR, mass spectral data, and elemental analyses.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
of potassium hydroxide produced dihydroazete derivative
3 as shown in Scheme 1. On the other hand, refluxing
compound 2 under similar conditions and in the presence
of elemental sulfur gave the thiazole derivative 5. The
structures of compounds 3 and 5 are evidenced from their
spectral and analytical data. Their IR spectra show
absorption bands characteristic for NH, C═O and C═S
The quinazoline ring system is found in many types of
bioactive natural and synthetic products. Many natural
products containing quinazoline moiety were found to
have different application in the medicinal field as
biologically active compounds [1–3], including
antimicrobial [4,5], antioxidant [6], anticancer [7,8],
antihypertensive [9], anti-HIV [10], anticonvulsant [11],
antitumor [12], and antiviral activities [13]. The present
work aimed to utilize 2-methyl-4H-benzo[d][3,1]oxazin-4-
one [14] with cyanoacetohydrazide or thiocarbono-
hydrazide as a source of bioactive quinazoline derivatives
functionalized with 3-heterocycles side chain.
1
groups. The HNMR spectrum of 3 shed further lights on
the proposed structure as it shows signals for NH, CH3,
and aromatic protons. The appearance of one broad singlet
signal for one NH proton and not two singlet signals for
two NH protons, as well as absence of a singlet signal in
the up field region for a methine proton is a good evidence
for the suggested cyclic structure 3 instead of the open
chain structure 4. 1HNMR spectrum of compound 5
showed its existence in dimethylsulphoxide solution as a
mixture of amine–imine tautomers 5a and 5b in the ratio
of 83:17%, respectively. The lower absorption frequency
of the carbonyl group as well as the higher δ value for the
signal of NH proton is in accordance with the existence of
compound 5 as its chelated form shown in Scheme 1. The
RESULTS AND DISCUSSION
Treatment of quinazolinone derivative 2 with equivalent
amounts of phenyl isothiocyanate by stirring at room
temperature in dimethylformamide and a catalytic amount
© 2018 Wiley Periodicals, Inc.

A. S. A. Youssef, M. M. Hemdan, F. A. El-Mariah, and H. E. Hashem
Vol 000
Scheme 1. Treatment of quinazolinone derivative 2 with equivalent amounts of phenyl isothiocyanate in different media.
microanalytical and spectral data support the structures of
Inspection of 1HNMR spectrum of compound 7 revealed
the synthesized compounds
(Experimental section).
Reaction of quinazolinone derivative 2 with phenyl
isothiocyanate and ethyl bromide by stirring at room
temperature in dimethyl formamide and a catalytic amount
of potassium hydroxide gave the adduct 6.
On the other hand, similar treatment with two molar
equivalents of ethyl chloroacetate instead of ethyl bromide
afforded the thiazolidinone derivative 7 in a good yield
(Scheme 2).
The structures of compounds 6 and 7 are evidenced by
studying their spectral data. Their IR spectra exhibit
absorption bands correlated with CN and C═O groups; as
well as absorption bands for NH group in case of
3
and 5, respectively
the appearance of doublet-doublet signals at δ = 4.68,
4.80 ppm with coupling constant J = 15.9 Hz. This is a
good evidence for the magnetic nonequivalence for the
methylene protons of thiazolidinone ring.
Treatment of a solution of compound 2 in ethanol with an
equivalent amount of malononitrile and a catalytic amount
of pipridine yielded pyridindione derivative 8 as shown in
Scheme 3. The infrared spectrum of compound 8 showed
absorption bands due to vibrational coupling of the two
carbonyl groups of pyridine ring at 1779 and 1708 cm1.
1
Moreover, its HNMR displayed a geminal coupling of
the two methylene protons (Jgem = 14.1 Hz) which
suggests that they are magnetically nonequivalent. The
reaction of
2
with 1, 3-diphenyl-1H-pyrazole-4-
1
compound 6. Furthermore, their HNMR spectra which
carbaldehyde 9 in 10% alc. potassium hydroxide furnished
pyrazole derivative 10. The formation of compound 10 is
depicted in Scheme 4. Treatment of compound 10 with
hydrazine hydrate in boiling n-butanol produced a mixture
of amino quinazoline derivative 11 [15] and the pyrazole
show from low to high field signals for aromatic and
aliphatic protons, in addition to an exchangeable broad
singlet signal for NH proton of compound 6. These are in
accordance with their proposed structures.
Scheme 2. Reaction of quinazolinone derivative 2 with phenyl isothiocyanate and ethyl bromide or ethylchloroacetate by stirring at room temperature in
dimethyl formamide and a catalytic amount of potassium hydroxide gave the adduct 6 or thiazolidinone derivative 7, respectively.
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Quinazolinone Derivatives
Scheme 3
derivative 12. The structures of compounds 10 and 12 are
deduced from their analytical and spectral data. The higher
absorption value of carbonyl group at 1710 cmÀ1 in case of
compound 10 is in accordance with its existence as the
Scheme 5. The mechanism for the formation of compounds 11 and 12
from compound 10.
1
conjugated four membered cyclic imide. Their HNMR
spectra are in a good agreement with their proposed
structures (cf. experimental). Further support for the
suggested structures is gained from their mass spectra that
revealed their correct molecular ion peaks as well as some
of important peaks. The structure of compound 11 is
identified by direct comparison m.p., m.m.p., and tlc with
an authentic sample prepared by heating of an ethanolic
solution of compound 1 with hydrazine hydrate.
The proposed mechanism for the formation of compound
10 is illustrated in Scheme 4.
The mechanism for the formation of compounds 11 and
12 from compound 10 is presented in Scheme 5.
reaction of benzoxazinone 1 with thiocarbonohydrazide in
absolute ethanol in the presence of few drops of glacial
acetic acid produced quinazolinone derivative 13 in a
Further synthesis of quinazolinone derivatives were
achieved by reaction of benzoxazinone
1
with
thiocarbonohydrazide as shown in Scheme 6. Thus,
Scheme 4. The proposed mechanism for the formation of compound 10.
Journal of Heterocyclic Chemistry
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A. S. A. Youssef, M. M. Hemdan, F. A. El-Mariah, and H. E. Hashem
Vol 000
Scheme 6. Synthesis and reaction of quinazolinone derivative 13.
spectrum of compound 13 showed its existence in DMSO
solution as a mixture of thione–thiol tautomers 13a and
13b in approximately equal ratio; moreover, the lower
absorption frequency of carbonyl group, as well as the
higher δ value for the signal of Ha proton confirms
chelation shown in Scheme 6. 1HNMR spectrum of
compound 14 supports its existence as a tautomeric
mixture of 14a and 14b in 3:2 ratio, as it showed two
absorption singlet signals corresponding to the two
methyl protons as well as the extra exchangeable broad
signals due to OH proton for compound 14b. The higher
δ value for the signal of NH proton of compound 15 is in
accordance with its existence as the chelated form shown
in Scheme 6.
The reaction of thiosemicarbazide derivative 13 with
aromatic aldehydes, namely, 2-chloroquinoline-3-
carbaldehyde and 4-methoxybenzaldehyde afforded the
thiosemicarbazone derivatives 16 and 18, respectively
(Scheme 7). Treatment of the thiosemicarbazone derivative
16 with hydrazine hydrate or phenyl hydrazine furnished
the fused tetrazinoquinazoline derivatives 17a and 17b,
respectively. Similar treatment of thiosemicarbazone
derivative 18 with hydrazine hydrate gave tetrazine
derivative 19. The microanalytical and spectral data of
compounds 16–19 confirm their suggested structures
rigidly (Experimental section).
The appearance of extra signals for methyl protons in the
1HNMR spectra of compounds 16 and 18 suggest their
existence as Syn/Anti sterioisomers in the ratios of 2:3 and
1:4, respectively. On the other hand, the higher δ values
for the signals of CH3 protons of the anti-isomer and the
imino methane proton of the syn-isomer as compared with
the counterpart isomers of compound 16 may be due to
good yield. Compound 13 is used as useful building block
for the synthesis of further quinazoline derivatives
functionalized with a 3-substitued side chain. Treatment
of a solution of compound 13 in dry benzene with
benzoyl chloride yielded the thiosemicarbazide derivative
14. Boiling of the thiosemicarbazide 14 in a mixture of
an equimolar ratio of acetic and hydrochloric acids
afforded the thiadiazole derivative 15 in a good yield.
The structures of compounds 13–15 were substantiated
from their microanalytical and spectral data. 1HNMR
Scheme 7. Treatment of quinazolinone 13 with different aldehyde.
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Quinazolinone Derivatives
location of these protons in the deshielding region of both
quinoline and quinazoline rings.
The higher δ value for the signals of NHb proton
suggests the existence of compound 16 and 18 as their
chelation forms as shown in Scheme 7.
The lower absorption frequency of carbonyl group as
well as the higher δ value of NHa proton of compound
19, suggests its existence as the chelated form shown in
Scheme 7.
4-(2-Methyl-4-oxoquinazolin-3(4H)-ylamino)-3-phenyl-2-
thioxo-2,3-dihydro-thiazole-5-carbonitrile (5).
To
a
solution of 2 (0.01 mol) in dimethyl formamide (20 mL),
phenyl isothiocyanate (0.01 mol), elemental sulfur
(0.01 mol) and catalytic amount of potassium hydroxide
was added. The reaction mixture was heated under reflux
for 6 h. The solvent was distilled off under reduced
pressure and the residue was poured onto ice/HCl. The
solid obtained was filtered off and recrystallized to give
compound 5. Yield. 56%; yellow crystals; m.p. <300°C
(EtOH); IR (KBr) (υ, cmÀ1): 3395, 3114 (NH), 3078,
3020 (CHarom), 2966, 2829 (CHalkyl), 2216 (CN), 1624
EXPERIMENTAL
1
(C═O), 1612 (C═N), 1231 (C═S); H NMR (DMSO-d6)
δ: 2.91 (s, 3H, CH3), 2.99 (s, 1H, CHa), 7.59–8.26 (m,
18H, Ar-H), 14.6 (br.s, 1H, NH, exchangeable); MS
(70 eV) m/z (%): 391 (M.+, 1), 316 (1), 225 (26), 224
(100), 199 (1), 167 (3), 160 (1), 135 (1), 118 (1), 105 (3),
104 (32), 91 (1), 76 (13), 52 (1); Anal. calcd for
C19H13N5OS2 (391.47): C, 58.29; H, 3.35; N, 17.89.
Found: C, 58.38; H, 3.11; N, 17.61%.
All melting points are uncorrected and were measured
on
a
Gallenkamp
electric
melting
point
apparatus (London, UK). The infrared spectra were
recorded using potassium bromide disks on a FTIR
Thermo Electron Nicolet 7600 (Waltham, MA) infrared
spectrometer at the central laboratory of faculty of
1
science Ain shams University. HNMR spectra were run
at 300 MHz on a GEMINI 300 BB NMR spectrometer
using tetramethylsilane (TMS) as internal standard in
deuterated dimethylsulphoxide (DMSO-d6) at the main
defense chemical laboratory. The mass spectra were
recorded on Shimadzu GCMS-QP-1000EX mass
spectrometer (Kyoto, Japan) operating at 70 eV at the
Regional center for Mycology and Biotechnology of Al-
Azhar University. The elemental analyses were performed
on a perkin-Elemer 2400 CHN elemental analyzer at the
Micro analytical center of Cairo University. The reactions
were monitored by the thin layer chromatography on
Merck Kiesel gel 60 F254 aluminum backed plates. The
spots were detected by UV irradiation at 254–365 nm.
Compounds 1 and 2 were synthesized following the
methods mentioned in the literatures [5,16–18].
2-Cyano-3-(ethylthio)-N-(2-methyl-4-oxoquinazolin-3(4H)-
yl)-3-(phenylamino)-acrylamide (6). To a stirred solution
of 2 (0.01 mol) in dimethyl formamide (20 mL); phenyl
isothiocyanate (0.01 mol) and a catalytic amount of
potassium hydroxide were added. The stirring at room
temperature was continued for 6 h. Ethyl bromide
(0.01 mol) was added drop wise; the reaction mixture was
stirred for further 2 h. A solid product was obtained that
was filtered off and recrystallized to give compound 6.
Yield: 40%; yellow crystals; m.p. 210–212°C (toluene);
IR (KBr) (υ, cmÀ1): 3184 (NH), 3064 (CHarom), 2969,
2930 (CHalkyl), 2197 (CN), 1704 (C═O), 1597 (C═N);
1H NMR (DMSO-d6) δ: 1.04 (t, 3H, CH2CH3,
J = 7.2 Hz), 2.07 (s, 3H, CH3), 2.44 (q, 2H, CH2CH3,
J = 7.5 Hz), 7.19–8.09 (m, 9H, Ar-H), 11.32 (br.s,
1H, NHPh, exchangeable), 13.15 (br.s, 1H, NHCO,
exchangeable); MS (70 eV) m/z (%): 405 (M+., 12),
344 (2), 313 (11), 246 (2), 233 (100), 170 (4), 160 (4),
116 (10);
4-(2-Methyl-4-oxoquinazolin-3(4H)-ylamino)-1-phenyl-2-
thioxo-1,2-dihydroazete-3-carbonitrile (3).
To a stirred
solution of 2 (0.01 mol) in dimethyl formamide (20 mL)
at room temperature, phenyl isothiocyanate (0.01 mol)
and catalytic amount of potassium hydroxide were added.
The stirring is continued for further 6 h, poured onto
ice/HCl. The solid product that obtained was filtered off
and recrystallized from ethyl alcohol to give compound 3.
Yield: 92%; yellow crystals; m.p. 208–210°C; IR (KBr)
(υ, cmÀ1): 3348, 3262 (NH), 3059 (CHarom), 2927
(CHalkyl), 2175 (CN), 1713 (C═O), 1637 (C═N), 1266
Anal. calcd for C21H19N5O2S (405.47): C, 62.21; H,
4.72; N, 17.27. Found: C, 61.93; H, 4.51; N, 16.90%.
Ethyl
ylimino)-2-(4-oxo-3-phenyl thiazolidin-2-ylidene) ethoxy)
acetate (7).
2-(-2-cyano-1-(2-methyl-4-oxoquinazolin-3(4H)-
To a stirred solution of 2 (0.01 mol) in
dimethyl formamide (20 mL), phenyl isothiocyanate
(0.01 mol) and catalytic amount of potassium hydroxide
were added. The reaction mixture was stirred at room
temperature for 6 h. Then, ethyl chloroacetate (0.02 mol)
was added drop wise. The reaction mixture was stirred
for further 3 h and was poured onto ice water; the solid
obtained was filtered off and recrystallized to give
compound 7. Yield: 94%; Orange crystals; m.p.
142–144°C (EtOH); IR (KBr) (υ, cmÀ1): 3063 (CHarom),
2988, 2954 (CHalkyl), 2205 (CN), 1755, 1736, 1725
1
(C═S); H NMR (DMSO-d6) δ: 2.02 (s, 3H, CH3), 7.02–
7.27 (m, 4H, Ar-H), 7.35 (br.s, 1H, NH, exchangeable),
7.73–8.13 (m, 5H, Ar-H);
MS (70 eV) m/z (%): 361 (M.+ +2, 1), 318 (5), 242 (71),
224 (37), 196 (5), 183 (3), 131 (2), 117 (9), 90 (23), 76
(12), 65 (11), 52 (3); Anal. calcd for C19H13N5OS
(359.4): C, 63.49; H, 3.65; N, 19.49. Found: C, 63.16; H,
3.44; N, 19.33%.
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A. S. A. Youssef, M. M. Hemdan, F. A. El-Mariah, and H. E. Hashem
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(C═O), 1632 (C═N); 1H NMR (DMSO-d6) δ: 1.15 (t, 3H,
OCH2CH3, J = 7.2 Hz), 2.12 (s, 3H, CH3), 4.12 (s, 2H,
OCH2CO), 4.09 (q, 2H, OCH2CH3, J = 7.2 Hz), 4.68,
4.80 (dd, 2H, SCH2CO, Jgem = 15.9 Hz), 7.2–8.13
(m, 9H, Ar-H); MS (70 eV) m/z (%): 505 (M.++2, 2),
503 (M+., 20), 400 (3), 384 (1), 339 (3), 288 (4), 186 (3),
159 (4), 119 (8), 117 (13), 104 (26), 103 (18), 77
(100), 41 (9); Anal. calcd for C25H21N5O5S (503.53): C,
59.63; H, 4.20; N, 13.91. Found: C, 59.88; H, 3.94; N,
13.76%.
5-(1,3-Diphenyl-1H-pyrazol-4-yl)-3H-pyrazol-3-one (12).
Yield: 90%; yellow crystals; m.p. 210–212°C (EtOH); IR
(KBr) (υ, cmÀ1): 3053 (CHarom), 1723 (C═O), 1618
(C═N); 1H NMR (DMSO-d6) δ: 4.53 (s, 1H, CH═),
7.12–8.85 (m, 10H, Ar-H), 9.14 (s, 1H, pyrazolo-H); MS
(70 eV) m/z (%): 305 (M.+, 2), 244 (3), 223 (5), 219 (4),
194 (3), 159 (3), 106 (9), 81 (22), 77 (100), 64 (15), 44
(83); Anal. calcd for C18H12N4O (300.31): C, 71.99; H,
4.03; N, 18.66. Found: C, 71.81; H, 3.76; N, 18.39%.
4-(2-Methyl-4-oxoquinazolin-3(4H)-yl) thiosemicarbazide
4-Hydroxy-1-(2-methyl-4-oxoquinazolin-3(4H)-yl)-2,
(13).
To a solution of benzoxazinone 1 (0.01 mol) in
6-dioxo-1,2,5,6-tetrahydro pyridine-3-carbonitrile (8).
A
ethanol (30 mL), thiocarbonohydrazide (0.01 mol) and few
drops of glacial acetic acid were added. The reaction
mixture was refluxed for 6 h. The solvent was distilled
under reduced pressure, and the residue was poured onto
crushed ice. The solid obtained was filtered off and
recrystallized to give compound 13. Yield: 80%; colorless
crystals; m.p. 238–240°C; (EtOH); IR (KBr) (υ, cmÀ1):
3271, 3177, 3112 (NH, NH2), 3063 (CHarom), 2948
(CHalkyl), 1629 (C═O), 1607 (C═N), 1219 (C═S); 1H
NMR (DMSO-d6) δ: 2.22 (s, 3H, CH3), 5.49 (br.s, 2H,
NH2, exchangeable), 6.47 (t, 1H, ArH, J = 7.2), 6.70 (d,
1H, ArH J = 8.0), 7.11–7.21 (m, 1H, Ar-H, J = 7.5), 7.65
(d, 1H, ArH, J = 6.8), 13.33 (br.s, 1H, NHa, exchangeable),
for 13a: 12.66 (br.s, 1H, NH, exchangeable), for 13b: 5.23
(br.s, 1H, SH, exchangeable); MS (70 eV) m/z (%): 249
(M.+, 1), 190 (1), 160 (3), 146 (64), 132 (3), 118 (7), 105
(3), 104 (4), 76 (7), 56 (26).; Anal. calcd for C10H11N5OS
(249.29): C, 48.18; H, 4.45; N, 28.09. Found: C, 47.87;
H, 4.33; N, 27.85%.
mixture of compound
2 (0.01 mol), malononitrile
(0.01 mol) was refluxed in ethanol (30 mL) and few
drops of piperidine for 6 h. The solvent was distilled
under reduced pressure, and the residue was poured
onto crushed ice. The solid obtained was filtered off
and recrystallized to give compound 8. Yield: 40%;
brown crystals; m.p. 232–234°C; (ethanol/pet. ether
(40–60°C)); IR (KBr) (υ, cmÀ1): 3343 (OH), 3068,
3040 (CHarom), 2939, 2865 (CHalkyl), 2202 (CN), 1779,
1708 (C═O), 1600 (C═N); 1H NMR (DMSO-d6) δ:
2.04 (s, 3H, CH3), 3.90, 4.03 (AB quartet, 2H, CH2,
Jgem = 14.1, 10.8 Hz), 7.53–8.13 (m, 4H, Ar-H), 13.3
(br. s, 1H, OH, exchangeable); MS (70 eV) m/z (%):
310 (M.+, 1), 266 (3), 199 (6), 140 (5), 128 (13), 112
(12), 103 (33), 100 (100), 81 (21); Anal. calcd for
C15H10N4O4 (310.26):C, 58.07; H, 3.25; N, 18.06.
Found: C, 57.79; H, 2.85; N, 17.92%.
3-(4-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-oxoazet-1(2H)-yl)-2-
methylquinazolin-4(3H)-one (10).
A
mixture of
1-Benzoyl-4-(2-methyl-4-oxoquinazolin-3(4H)-yl)
thiosemicarbazide (14). A mixture of compound 13 (3
compound 2 (0.01 mol) and 1,3-diphenyl-1H-pyrazole-4-
carbaldehyde (9) (0.01 mol) was refluxed in 10% alc.
KOH (30 mL) for 8 h. Acidifying the ice cooled reaction
mixture with dilute HCl gave solid product that was
filtered off and recrystallized from ethyl acetate to give
compound 10. Yield: 78%; pale yellow crystals; mp 224–
226°C; IR (KBr) (υ, cmÀ1): 3060 (CHarom), 2927, 2857
mmole) and benzoyl chloride (3 mmole) in dry benzene
(30 ml) was refluxed for 8 h. A solid product was
obtained after cooling the reaction mixture to room
temperature that was filtered off and recrystallized from
ethanol to give compound 14. Yield: 95%; colorless
crystals; m.p. 202–204°C; IR (KBr) (υ, cmÀ1): 3272,
3176, 3112 (NH), 3070 (CHarom), 2949, 2782 (CHalkyl),
1
(CHalkyl), 1710 (C═O), 1624 (C═N); H NMR (DMSO-
d6) δ: 2.20 (s, 3H, CH3), 4.53 (, 1H, CH═), 7.27–7.88
(m, 14H, Ar-H), 8.49 (s, 1H, pyrazolo-H); MS (70 eV)
m/z (%): 445 (M.+, 100), 428 (5), 370 (27), 326 (11), 279
(7), 241 (24), 233 (18), 172 (36), 140 (25), 82 (23); Anal.
calcd for C27H19N5O2 (445.47): C, 72.80; H, 4.30; N,
15.72. Found: C, 72.62; H, 4.11; N, 15.43%.
1
1683, 1630 (C═O), 1601, 1549 (C═N), 1218 (C═S); H
NMR (DMSO-d6) δ: 2.18 (s, 3H, CH3), 2.12 (s, 3H,
CH3), 7.56 (t, 3H, ArH, J = 7.6), 7.66 (t, 2H, ArH,
J = 7.2), 7.97 (d, 4H, ArH, J = 8.8), 11.76 (br.s, 1H,
OH, exchangeable), 13.37 (br.s, 2H, NHa, exchangeable),
13.70 (br.s, 1H, NHb, exchangeable); MS (70 eV) m/z (%):
353 (M.+, 1.4), 333 (3), 310 (5), 260 (13), 224 (64), 196
(16), 127 (24), 105 (100), 91 (17), 77 (83); Anal. calcd for
C17H15N5O2S (353.4): C, 57.78; H, 4.28; N, 19.82. Found:
C, 57.51; H, 4.09; N, 19.48%.
Action of Hydrazine Hydrate on Pyrazole Derivative 10.
A mixture of 10 (0.01 mol) and hydrazine hydrate
(0.01 mol) in n-butanol (30 mL) was refluxed for 4 h.
The solvent was distilled under reduced pressure and the
residue was poured onto ice cold water. The solid
obtained was filtered off and fractionally recrystallized to
give 11 as white crystals from pet. ether 60–80°C m.p.
146–148°C (lit. [15] m.p. 145°C). The residual part was
then recrystallized from ethanol to give 12.
2-Methyl-3-(5-phenyl-1,3,4-thiadiazol-2-ylamino)
quinazolin-4(3H)-one (15). Compound 14 (3 mmole) was
heated with a mixture of equal volumes of acetic and
hydrochloric acids (30 ml) for 2 h. Cool the reaction
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Month 2018
Quinazolinone Derivatives
mixture to room temperature and poured onto crushed ice.
solid product was obtained, filtered off, and
General procedure.
A mixture of compound 16 (3
A
mmole) and hydrazine hydrate (3 mmole) or phenyl
hydrazine (3 mmole) was refluxed in ethanol or n-
butanol (20 mL) for 6 h. The solvent was evaporated
and the residue was treated with cold water. The solid
product was filtered off and recrystallized from the
suitable solvents to give compounds 17a and 17b,
respectively.
recrystallized from acetic acid to give compound 15.
Yield: 91%; colorless crystals; m.p. 118–120°C; IR (KBr)
(υ, cmÀ1): 3211 (NH), 3070 (CHarom), 2892 (CHalkyl),
1
1671 (C═O), 1602, 1581 (C═N); H NMR (DMSO-d6) δ:
2.47 (s, 3H, CH3), 6.88–6.94 (m, 1H, Ar-H), 7.48–7.51
(m, 2H, Ar-H), 7.58–7.62 (m, 3H, Ar-H), 7.77 (d, 1H,
ArH, J = 7.6), 7.92 (d, 2H, ArH, J = 6.8), 12.94 (br.s,
1H, NH, exchangeable); MS (70 eV) m/z (%):335 (M+.,
3), 320 (9), 306 (10), 214 (1), 176 (1), 123 (1), 121 (2),
105 (16), 76 (15), 52 (13)., Anal. calcd for C17H13N5OS
(335.38): C, 60.88; H, 3.91; N, 20.88. Found: C, 60.61;
H, 3.76; N, 20.59%.
General procedure. To a solution of thiosemicarbazide
derivative 13 (3 mmole) in ethanol (30 mL), 2-
chloroquinoline-3-carbaldehyde or 4-methoxybenzaldehyde
(3 mmole) and few drops of glacial acetic acid were added.
The reaction mixture was refluxed for 8–12 h (TLC).
Cooling to ambient temperature, the solid products obtained
were filtered off and recrystallized from the suitable
solvents to give compounds 16 or 18.
3-(2((2-Chloroquinolin-3-yl) methylene) hydrazinyl)-6-
methyl-2H-1,2,4,5-tetrazino [1,6-c]quinazoline (17a).
Yield: 68%; pale yellow crystals; mp 218–220°C (ethyl
alcohol); IR (KBr) (υ, cmÀ1): 3389, 3286, 3187 (NH),
3030 (CHarom), 2973, 2931 (CHalkyl), 1614, 1583 (C═N);
1H NMR (DMSO-d6) δ: 2.42 (s, 3H, CH3), 5.70 (br.s, 2H,
2NH, exchangeable), 7.43–7.62 (m, 7H, Ar-H), 7.87 (d,
1H, ArH, J = 8.0 Hz), 7.99 (s, 1H, Ar-H), 8.25 (s, 1H,
CH═N); MS (70 eV) m/z (%): 402 (M.+, 4), 367 (6), 360
(7), 341 (29), 285 (10), 240 (3), 213 (12), 204 (9), 198 (2),
189 (4), 162 (5), 157 (2), 118 (12), 104 (10), 76 (11);
Anal. calcd for C20H15ClN8 (402.84): C, 59.63; H, 3.75; N,
27.82. Found: C, 59.28; H, 3.66; N, 27, 61%.
3-(2((2-Chloroquinolin-3-yl)methylene)hydrazinyl)-6-
1-((2-Chloroquinolin-3-yl)
methylene)-4-(2-methyl-4-
methyl-2-phenyl-2H-1,2,4,5
tetrazino[1,6-c]quinazoline
oxoquinazolin-3(4H)-yl)-thiosemicarbazide (16).
Yield:
(17b).
Yield: 63%; yellow crystals; mp 244–246°C
85%; orange crystals; m.p. 288–290°C (acetic acid); IR
(KBr) (υ, cmÀ1): 3163 (NH), 3047 (CHarom), 2945, 2894
(CHalkyl), 1696 (C═O), 1660, 1611 (C═N), 1218 (C═S);
1H NMR (DMSO-d6) 7.20 (t, 1H, ArH, J = 7.6), 7.33 (d,
1H, ArH, J = 8.4), 7.52 (t, 1H, ArH, J = 7.2), 7.72 (d, 1H,
ArH, J = 8.0), 7.79 (t, 1H, ArH, J = 7.6), 7.98 (t, 1H,
ArH, J = 7.2), 8.09 (d, 1H, ArH, J = 8.8), 8.16 (d, 1H,
ArH, J = 8.0), 8.90 (d, 1H, ArH, J = 8.0), 4.34 (br.s, 1H,
NHa, exchangeable), 12.04 (br.s, 1H, NHb, exchangeable)
for Syn isomer: δ: 2.22 (s, 3H, CH3), 8.52 (s, 1H, CH═N),
for Anti isomer: 2.41 (s, 3H, CH3), 8.61 (s, 1H, CH═N);
MS (70 eV) m/z (%): 422 (M.+, 1), 262 (1), 260 (1), 248
(3), 224 (14), 218 (4),188 (4), 174 (4), 170 (80), 162 (2),
77 (71), 74 (13), 64 (12).; Anal. calcd for C20H15ClN6OS
(422.89): C, 56.80; H, 3.58; N, 19.87. Found: C, 57.04;
H, 3.29; N, 19.53%.
(MeOH); IR (KBr) (υ, cmÀ1): 3330, 3171 (NH), 3036
1
(CHarom), 2977, 2945 (CHalkyl), 1610, 1581 (C═N); H
NMR (DMSO-d6) δ: 2.42 (s, 3H, CH3), 5.73 (br.s, 1H,
NH, exchangeable), 7.21–7.29 (m, 3H, Ar-H), 7.53 (d,
2H, ArH, J = 7.6 Hz), 7.76 (t, 2H, ArH, J = 7.2 Hz), 7.95
(t, 2H, ArH, J = 7.2 Hz), 8.06 (d, 2H, ArH, J = 8.4 Hz),
8.12 (d, 2H, ArH, J = 7.2 Hz), 8.47 (s, 1H, Ar-H), 8.81
(s, 1H, CH═N); MS (70 eV) m/z (%): 478 (M.+, 1.77),
409 (33), 351 (14), 261 (14), 244 (59), 219 (15), 136
(34), 102 (72), 89 (100), 77 (80); Anal. calcd for
C26H19ClN8 (478.94): C, 65.20; H, 4.00; N, 23.40.
Found: C, 64.89; H, 3.71; N, 23.22%.
3-(6-(4-Methoxyphenyl)-1,
ylamino)-2-methyl-quinazolin-4(3H)-one
2-dihydro-1,2,4,5-tetrazin-3-
(19).
To
compound 18 (3 mmole) in ethanol (30 mL), hydrazine
hydrate (3 mmole) was added. The reaction mixture was
refluxed for 5 h. A solid product was obtained after
cooling to room temperature, filtered off and
recrystallized from diluted ethanol to give compound 19.
Yield: 70%; yellow crystals; m.p. 150–152°C; IR (KBr)
(υ, cmÀ1): 3271, 3175, 3110 (NH), 3061 (CHarom), 2938
(CHalkyl), 1623 (C═O), 1602, 1583(C═N); 1H NMR
(DMSO-d6) δ: 2.22 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
5.50 (br.s, 2H, 2NH, exchangeable), 7.02–7.80 (m, 8H,
Ar-H), 13.40 (br.s, 1H, 1NH, exchangeable), MS
(70 eV) m/z (%): 364 (M.+ +1, 2), 256 (2), 215 (2), 203
(4), 174 (4), 159 (1), 148 (2), 118 (3), 105 (36), 83 (65),
76 (18), 52 (9); Anal. calcd for C18H17N7O2 (363.37):
C, 59.50; H, 4.72; N, 26.98. Found: 59.14; H, 4.46; N,
26.60.
1-(4-Methoxybenzylidene)-4-(2-methyl-4-oxoquinazolin-
3(4H)-yl)-thiosemicarbazide (18).
Yield: 80%; colorless
crystals; m.p. 210–212°C (EtOH); IR (KBr) (υ, cmÀ1):
3114 (NH), 3067 (CHarom), 2941 (CHalkyl), 1675 (C═O),
1
1607, 1586 (C═N), 1258 (C═S); H NMR (DMSO-d6) δ:
7.07–7.10 (m, 4H, Ar-H), 7.83–7.86 (m, 4H, Ar-H), 5.50
(br.s, 1H, NHa, exchangeable), 9.69 (s, 1H, CH═), 13.66
(br.s, 1H, NHb, exchangeable) for Syn isomer: 2.22 (s,
3H, CH3), 3.76 (s, 3H, OCH3); for Anti isomer: 2.31 (s,
3H, CH3), 3.79 (s, 3H, OCH3); MS (70 eV) m/z (%): 367
(M.+, 1), 329 (2), 264 (14), 241 (5), 158 (6), 131 (50),
100 (29), 76 (14), 58 (83), 44 (100); Anal. calcd for
C18H17N5O2S (367.42): C, 58.84; H, 4.66; N, 19.06.
Found: C, 58.69; H, 4.31; N, 18.80%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, M. M. Hemdan, F. A. El-Mariah, and H. E. Hashem
Vol 000
[11] Laddha, S. S.; Bhatnagar, S. P. Phosphorus Sulfur Silicon Relat
Elem 2008, 183, 2262.
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