Spectral characterization of novel 3-phenyl-2-substituted quinazoline and fused quinazoline derivatives

Article abstract of DOI:10.1080/00397911.2011.642924

3-phenyl-2-thioxo-quinazolin-4(3H)one 1 was utilized for the construction of some novel 2-substituted quinazolin-4(3H)one derivatives through the formation of 2-hydrazinyl quinazolinone, which was used as the key starting material for the synthesis of 2-heteryl quinazolines via the reaction with one carbon donors, -diketones and -ketoester. Infrared, 1H NMR, and mass spectra of the synthesized compounds were discussed. Some of them showed promising anti-inflammatory activity. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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Spectral Characterization of Novel 3-
Phenyl-2-Substituted Quinazoline and
Fused Quinazoline Derivatives
Mahmoud R. Mahmoud a , Wael S. I. Abou-Elmagd a , Salwa S.
Abdelwahab a & El-Sayed A. Soliman a
a Chemistry Department, Faculty of Science, Ain Shams University,
Abassia, Cairo, Egypt
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Mahmoud R. Mahmoud , Wael S. I. Abou-Elmagd , Salwa S. Abdelwahab & El-
Sayed A. Soliman (2013): Spectral Characterization of Novel 3-Phenyl-2-Substituted Quinazoline
and Fused Quinazoline Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:11, 1484-1490
To link to this article: http://dx.doi.org/10.1080/00397911.2011.642924
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Synthetic Communications1, 43: 1484–1490, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.642924
SPECTRAL CHARACTERIZATION OF NOVEL
3-PHENYL-2-SUBSTITUTED QUINAZOLINE AND
FUSED QUINAZOLINE DERIVATIVES
Mahmoud R. Mahmoud, Wael S. I. Abou-Elmagd,
Salwa S. Abdelwahab, and El-Sayed A. Soliman
Chemistry Department, Faculty of Science, Ain Shams University, Abassia,
Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract 3-phenyl-2-thioxo-quinazolin-4(3H)one 1 was utilized for the construction of
some novel 2-substituted quinazolin-4(3H)one derivatives through the formation of
2-hydrazinyl quinazolinone, which was used as the key starting material for the synthesis
of 2-heteryl quinazolines via the reaction with one carbon donors, -diketones and -ketoester.
1
Infrared, H NMR, and mass spectra of the synthesized compounds were discussed. Some
of them showed promising anti-inflammatory activity.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Anti-inflammatory; hydrazino;
quinazolin-4(3H)one; triazolthione
pyrazolone;
pyrazolo
quinazoline;
INTRODUCTION
The selective pressure exerted by antibiotic treatment has made many
pathogenic bacteria resistant to common antibiotics. New drugs are needed to resolve
this serious public health problem. Special attention was recently paid to the quinazo-
line derivatives. Many derivatives of this system showed antifungal,[1] antibacterial,[2]
antitumor,[3] anti-inflammatory,[4] anticonvulsant,[5–7] analgesic,[8,9] and antitubercu-
lar[10] activities. Moreover, quinazoline derivatives have been identified as a new class
of cancer chemotherapeutic agents with significant therapeutic efficiency against solid
tumors.[11–13]
Received October 9, 2011.
Address correspondence to Wael S. I. Abou-Elmagd, Chemistry Department, Faculty of Science,
Ain Shams University, Abassia, Cairo 11566, Egypt. E-mail: waelmagd97@yahoo.com
1484

QUINAZOLINE AND DERIVATIVES
1485
These diverse biological activities initiated our interest in the synthesis of some
quinazoline derivatives bearing other heterocycles that have a broad spectrum of
biological activities, like pyrazole, triazole, and oxadiazole.
RESULTS AND DISCUSSION
These findings prompted us to synthesize a variety of quinazolinone derivatives
via the reaction of anthranilic acid with arylisothiocyanate[14] with the aim of obtain-
ing more precise information about the course of the reaction and some interesting
pharmaceutical compounds. The key intermediate, 3-phenyl-2-thioxo- quinazolin-4
(3H)one 1, was prepared.[15] Structure 1 was confirmed by its low Rf value, high
melting point, and solubility in sodium hydroxide solution, beside the correct ana-
lytical and spectroscopic data. Full analysis of the mass spectrum of 1 shows the cor-
rect molecular ion peak at m=z ¼ 254 (69.49%), which upon loss of the hydrogen
radical yielded the cation (M ꢀ 1) at m=z ¼ 253 (100%) as the base peak.
Furthermore, acylation of compound 1 with lauroyl chloride in refluxing
pyridine afforded the N-acylation product 2. The structure 2 was substantiated from
the correct molecular weight determination and analytical and spectral data. The
=
infrared (IR) spectrum of 2 displayed tC
at 1737 cmꢀ1 and 1687 cmꢀ1, and no
O
band appeared for the NH group. Moreover, the electron-impact–mass (EI-MS)
spectrum shows the correct molecular ion peak at m=z ¼ 436 (0.04%).
When compound 1 was reacted with ethyl iodide in boiling ethanol in the
presence of sodium hydroxide, the S-alkylation product 2-(ethylthio)-3-phenyl-
quinazolin-4(3H)one 3 was obtained. The structure of 3 was confirmed from the
correct analytical and spectroscopic data.
The mass spectrum of 3 is completely in accord with the proposed structure.
The EI fragmentation pattern of 3 shows the correct molecular ion peak at m=
z ¼ 282 (30.61%), which upon loss of the ethyl radical afforded the daughter ion
at m=z ¼ 253 (45.22%). Loss of the thioethyl radical gave the cation at m=z ¼ 221
(44.79%).
Treatment of compound 1 with hydrazine hydrate (1:1) in refluxing dioxane
afforded 2-hydrazinyl-3-phenyl quinazolin-4(3H)one 4. The same product was
obtained upon treatment of 3 with hydrazine hydrate. The long duration of the reac-
tion (22 h) might be due to the presence of a bulky phenyl ring at position 3, which
might reduce the reactivity of the quinazolinone ring system at C-2 position. The
reaction of 1 with excess hydrazine hydrate yielded 2-hydrazinyl-4-hydrazono-
3-phenyl-3,4-dihydroquinazoline 5. The structures of 4 and 5 were confirmed from
the correct analytical and spectroscopic data.
The EI fragmentation pattern for the mass spectrum of 4 shows the correct
molecular ion at m=z ¼ 252 (70.2%).
The conversion of 1 and 3 to 4 could be summarized according to the mech-
anism shown in Scheme 2.
Compound 1 in the presence of excess hydrazine yielded 5, whose structure was
1
confirmed by IR and H NMR spectra.
The formation of compound 5 could be visualized as shown in Scheme 3.
It has been reported[16] that hydrazinopyrimidine can be considered as a key
starting material for the synthesis of diverse nitrogen bridgehead compounds. Thus,

1486
M. R. MAHMOUD ET AL.
Scheme 1.
Scheme 2.

QUINAZOLINE AND DERIVATIVES
1487
Scheme 3.
compound 4 was subjected to react with electrophilic reagents, such as b-diketones,
carbon disulfide, phenyl isothiocyanate, and ethylbenzoylacetate.
When compound 4 was allowed to react with acetyl acetone and=or benzoyl
acetone in boiling ethanol, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-phenyl quinazolin-4-
(3H)-one 6a and 2-(3-methyl-5-phenyl-1H-pyrazol-1-yl)-3-phenyl quinazolin-4
(3H)-one 6b were afforded, respectively. Structure 6 was substantiated from the
analytical and spectroscopic data.
Full analysis for the mass spectrum of 6a shows the correct molecular ion
peak at m=z ¼ 316 (100%), which represents the base peak. The mass spectrum of
compound 6b shows the molecular ion peak at m=z ¼ 378 (16.6%), which upon
loss of pyrazolyl moiety yielded the cation at m=z ¼ 221 (14.1%). The base peak
at m=z ¼ 77 (100%) represents the phenyl cation C6Hþ5 . Compound 4 was
converted to the pyrazole derivatives 6a and 6b according to the pathway shown
in Scheme 4.
Heterocyclic o-aminocarbonitriles including furans, pyrimidines, and quinazo-
lines reacted with carbon disulfide under different conditions to afford biologically
interesting fused thiazines and=or pyrimidinedithione. However, when compound
4 was treated with carbon disulfide in refluxing pyridine, it yielded 4-phenyl-1-
thioxo-1,2-dihydro[1,2,4]triazolo[4,3-a]quinazolin-5(4H)one 7. The structure of
compound 7 was deduced from the spectral data.
1
The H NMR indicates the presence of thiolactamÐthiolactim form. The EI
fragmentation pattern of the mass spectrum of compound 7 supported the assigned
structure, which shows the correct molecular ion peak at m=z ¼ 294 (54.1%).
Treatment of compound 4 with phenylisothiocyanate in refluxing pyridine
afforded the compound 7 as the sole product in fairly good yield. This is confirmed
by comparison with the previous product obtained from the reaction of 4 with carbon
disulfide M ¼ 294 (100%). The reaction of 4 with CS2 and=or phenylisothiocyanate to
give 7 could be summarized as shown in Scheme 5.
It was reported that the reaction of hydrazino-pyrimidine derivative with b-ketoe-
ster was claimed to afford the pyrazolone derivative.[16] Herein, when compound 4 was
allowed to react with ethyl benzoacetate in boiling ethanol, it afforded the condensation
product ethyl-3-[2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)hydrazono]-3-phenyl

1488
M. R. MAHMOUD ET AL.
Scheme 4.
Scheme 5.

QUINAZOLINE AND DERIVATIVES
1489
propanoate 8 and no pyrazolone derivative 9 was obtained. The spectroscopic data of
the product obtained confirm structure 8.
Furthermore, the EI fragmentation pattern of the mass spectrum of 8 con-
firmed the assigned structure. On the other hand, ring closure of the latter compound
8 in the HCl=AcOH mixture led to the construction of a new pyrazolone ring linked
to the quinazoline nucleus with the formation of 9. The structure of 9 was illustrated
from their analytical and spectral data.
EXPERIMENTAL
Melting points are measured on an electrothermal melting-point apparatus.
Elemental analyses were carried out at the microanalytical unit at Cairo Univeristy.
The IR spectra were measured on a Unicam SP-1200 spectrometer using the KBr
wafer technique. The 1H NMR spectra were measured in dimethylsulfoxide
(DMSO-d6) on a Varian Plus instrument (300 MHz). Mass spectra were recorded
on a Shimadzu GC-MS QP-1000EX instrument operating at 70 eV.
General Procedure for the Preparation of 1[15]
A mixture of anthranilic acid (0.02 mol, 2.74 g) and phenyl isothiocyanate
(0.02 mol, 2.5 ml) in dry toluene (30 ml) was heated under reflux for 4 h. The product
deposited during reflux was collected by suction, washed by ethanol, dried, and then
recrystallized from dioxane to give 3-phenyl-2-thioxo quinazolin-4(3H)-one 1.
3-Phenyl-2-thioxo quinazolin-4(3H)-one (1, C14H10N2OS)
Pale yellow crystalsꢀ(186% yield); mp: 305–306 ꢁC. IR: tmax 3243 (NH), 1663
ArH), 13.01 (s, 1H, NH, exchangeable). MS: m=z (%) 254 (Mꢂþ, 69), 253 (100),
119 (26), 92 (25), 90 (16), 77 (26), 64 (15). Anal. calcd. for C14H10N2OS (254): C,
66.14; H, 3.93; N, 11.02; S, 12.59. Found: C, 66.19; H, 4.07; N, 11.43; S, 12.71.
.
1H NMR (DMSO-d6): d (ppm) 7.26–7.97 (m, 9H,
=
=
(C O), 1621 (C N) cm
General Procedure for Hydrazinolysis of 1 or 3
An equimolar amount of 1 or 3 (0.003 mol) and hydrazine hydrate (0.003 mol)
in ethanol (30 ml) were refluxed for 6 h. The solid product formed was filtered off and
recrystallized from ethanol to give 2-hydrazinyl-3-phenyl quinazolin-4(3H)-one 4.
2-Hydrazinyl-3-phenyl quinazolin-4(3H)-one (4, C14H12N4o)
Colorless crystals (50% yield); mp: 205–207 ꢁC. IR: tmax 3472, 3303, 3173
ꢀ1
.
1H NMR (DMSO-d6): d (ppm) 4.2 (br.s, 2H,
=
(NH2, NH), 1648 (C O) cm
NH2, exchangeable), 7.08–7.92(m, 9H, ArH), 8.17 (br.s, 1H, NH, exchangeable).
MS: m=z (%) 252 (Mꢂþ, 65.4), 251 (20), 222 (41), 221 (49), 207 (24), 133 (25), 120
(42), 119 (42), 118 (22), 104 (28), 92 (52), 91 (41), 77 (100). Anal. calcd. for
C14H12N4O (252): C, 66.66; H, 4.76; N, 22.22. Found: C, 66.90; H, 4.95; N, 22.53.
Complete experimental details can be found online in the Supplemental Materials.

1490
M. R. MAHMOUD ET AL.
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