A green and facile synthesis of 2-alkylsulfanyl-3H-quinazolin-4-one

Article abstract of DOI:10.14233/ajchem.2013.13593

Reaction of 2-thioquinazolinone (1) with various alkylating agents like dimethyl sulphate, diethyl sulphate and benzyl chloride in the presence of K₂CO₃ as a mild base, by a simple physical grinding, microwave irradiation and PEG-600 under solvent-free conditions for 10-15 min at room temperature, followed by processing, gave respectively 2-methylsulfanyl-3H-quinazolin-4-one (2a, i.e., R = CH₃), 2-ethylsulfanyl-3H-quinazolin-4-one (2b, i.e., R = C₂H₅) and 2-benzyl sulfanyl-3H-quinazolin-4-one (2c, i.e., R = PhCH₂Cl). It appears from this study that green syntheses such as solid phase synthesis (physical grinding) and microwave irradiation gives better yields, quality and in less reaction time the products over conventional methods involving green solvents like ethanol, PEG-600 etc. The entire sequences of reactions have been carried out using eco-friendly solvents and green conditions.

Full text of DOI:10.14233/ajchem.2013.13593

Asian Journal of Chemistry; Vol. 25, No. 5 (2013), 2644-2646
http://dx.doi.org/10.14233/ajchem.2013.13593
A Green and Facile Synthesis of 2-Alkylsulfanyl-3H-quinazolin-4-one
*
B. SRINIVASA REDDY , A. NAIDU and P.K. DUBEY
Department of Chemistry, J.N.T. University, Hyderabad, College of Engineering, Kukatpally, Hyderabad-500 085, India
*Corresponding author: E-mail: srinivasjntu123@gmail.com
(Received: 14 February 2012;
Accepted: 15 November 2012)
AJC-12420
Reaction of 2-thioquinazolinone (1) with various alkylating agents like dimethyl sulphate, diethyl sulphate and benzyl chloride in the
presence of K2CO3 as a mild base, by a simple physical grinding, microwave irradiation and PEG-600 under solvent-free conditions for
10-15 min at room temperature, followed by processing, gave respectively 2-methylsulfanyl-3H-quinazolin-4-one (2a, i.e., R = CH3),
2-ethylsulfanyl-3H-quinazolin-4-one (2b, i.e., R = C2H5) and 2-benzyl sulfanyl-3H-quinazolin-4-one (2c, i.e., R = PhCH2Cl). It appears
from this study that green syntheses such as solid phase synthesis (physical grinding) and microwave irradiation gives better yields,
quality and in less reaction time the products over conventional methods involving green solvents like ethanol, PEG-600 etc. The entire
sequences of reactions have been carried out using eco-friendly solvents and green conditions.
Key Words: 2-Thioquinazolinone, Alkylating agent (DMS/DES/PhCH2Cl), PEG-600, Ethanol, K2CO3, M.W.
Preparation of 2-alkylsulfanyl-3H-quinazolin-4-one (2)
from 2-thioquinazolinone (1)
INTRODUCTION
The quinazolinone ring system forms an important class
of N-heterocyclic compounds as it is present in a large number
of compounds with useful biological properties such as antiin-
flammatory1,2, anticonvulsant3, hypotensive4 and antimalarial5
types. 2-Thioquinazolinones possess good analgesic activities6.
2-Substituted quinazolin-4(3H)-ones exhibit a wide range of
pharmacological properties7,8, such as good antimicrobial
activity against different species of gram positive bacteria9,
gram-negative bacteria10, pathogenic fungi11,12, antitubercular
i) In solid phase: A mixture of 2-thioquinazolinone (1)
(1.78 g, 10 mM), K2CO3 (2.76 gms, 20 mM) and alkylating
agent (10 mM) were ground together for about 10-15 min in a
mortar and pestle at room temperature to obtain a homogeneous
mixture. The latter was then treated with ice-cold water (ca.
30-40 mL). The separated solid was filtered, washed with water
(2 × 10 mL) and dried to obtain crude 2-alkylsulfanyl-3H-
quinazolin-4-one (2). The crude product was recrystallized
from ethanol to obtain pure 2 (a-c) (Table-1).
activity13,14 and antitumor chemotherapeutic agent15,16
.
ii) In solution phase: 1) In PEG-600: A mixture of 1
(1.78 g, 10 mM), alkylating agent (10 mM) and PEG-600 (20
mL) was stirred at room temperature for 2 h.At the end of this
period, the mixture was poured into ice-cold water (ca. 50
mL). The separated solid was filtered, washed with water (2 ×
10 mL) and dried. The crude product was recrystallized from
ethanol to obtain pure 2 (a-c) (Table-1).
EXPERIMENTAL
All the reagents used in this work were obtained from
commercial suppliers. Solvents were freshly distilled before
being used. Melting points were determined using a Buchi
melting point B-545 apparatus and are uncorrected. TLC
analyses were done on glass plates coated with silica gel GF-
254 and spotting was done using iodine/UV lamp. IR spectra
were recorded on a Perkin-Elmer model 446 instrument in
2) In ethanol: A mixture of 1 (1.78 g, 10 mM), K2CO3
(2.76 g, 20 mM) ethanol (50 mL) and the alkylating agent (10
mM) was stirred at RT for 2 h. The progress of reaction was
monitored on TLC for the disappearance of 1. After the
completion of the reaction (ca. 2 h), the excess ethanol was
rotary evaporated and the residual mixture poured into
ice-cold water (2 × 20 mL). The separated solid was filtered,
washed with water (20 mL) and dried. The crude product
was recrystallized from ethanol to obtain pure 2 (a-c) (Table-
1).
1
KBr phase. H NMR were recorded in CDCl3/DMSO using
400 MHz Varian Gemini spectrometer and mass spectra were
recorded on a LC-MS spectrometer, model HP-5989A. Experi-
ments under microwave irradiation were carried out by using
the commercially available CEM discover microwave reactor.
Elemental analyses were performed by Varian 3LV analyzer
series CHN analyzer.

Vol. 25, No. 5 (2013)
A Green and Facile Synthesis of 2-Alkylsulfanyl-3H-quinazolin-4-one 2645
TABLE-1
PREPARATION OF 2 FROM 1 UNDER DIFFERENT CONDITIONS
Green solvent (solution phase)
Solid phase
Temp.
Microwave irradiation
S. Subs-
No. trate
PEG-600
Ethanol
Reagent
Product
Time
(min)
Yield*
(%)
Time
(min)
130
Yield*
(%)
Time
(min)
Yield Time
* (%) (min)
Temp/
Wattage
Yield*
(%)
DMS
10-15
10-15
10-15
RT
RT
RT
80
90
90
65
60
70
130
130
140
70
60
60
5
5
5
RT/450W
RT/450W
RT/450W
82
80
73
2a
2b
2c
1
1
DES
130
Ph-CH2-Cl
140
m.p. of 2a 220-222 ºC. (Lit.17 m.p. 224-225 ºC). m.p. of 2b 202-204 ºC. (Lit.18 m.p. 205-207 ºC); m.p. of 2c 176-177 ºC. (Lit.19 m.p. 178-180 ºC).
*Yields refer to processed crude products, RT = Room temperature.
Under microwave irradiating conditions: Mixture of 1
(1.78 g, 10 mM) and alkylating agent (10 mM) was taken in a
10 mL CEM-reaction tube sealed by rubber stopper and
subjected to microwave irradiation for 5 min at 130 ºC in the
commercial micro-wave reactor.After that, the tube was cooled
and the completion of reaction was checked by TLC then
poured into ice-cold water (2 × 20 mL). The separated solid
was filtered, washed with water (2 × 10 mL) and dried. The
crude product was recrystallized from ethanol to obtain pure
2 (a-c) (Table-1).
Physical grinding/
K2CO3/ RT/ 10-15 mins
O
N
O
N
Alkylating agent/
Ethanol/ K2CO3/ RT/ 2-3 hrs
NH
NH
SH
S
(2 a-c)
R
(1)
Alkylating agent/
PEG-600/ RT/ 2-3 hrs
RESULTS AND DISCUSSION
Reaction of 1 with various alkylating agents like dimethyl
sulphate, diethyl sulphate and benzyl chloride (PhCH2Cl) in
the presence of K2CO3 as a mild base, by a simple physical
grinding of the reaction mixture in a mortar and pestle under
solvent-free conditions for 10-15 min at room temperature,
followed by processing, gave respectively 2-methylsulfanyl-
3H-quinazolin-4-one (2a, i.e., R = CH3), 2-ethylsulfanyl-3H-
quinazolin-4-one (2b, i.e., R = C2H5) and 2-benzyl sulfanyl-
3H-quinazolin-4-one (2c, i.e., R = PhCH2Cl), as the products
identical with the one reported in the earlier methods17-19 in all
respects (m.p. m.m.p and co-tlc analysis).
Alkylating agent/
Microwave irradiation
450 W / 5 mins
2a, R=CH3
2b, R=CH2 CH3
2c, R=Ph-CH2
Scheme-I
The reaction was also carried out in PEG-600 as a solvent.
Thus, treatment of 1, independently, with each of dimethyl
sulphate, diethyl sulphate and benzyl chloride (PhCH2Cl) in
PEG-600 at room temperature for 2 h without the use of any
base, followed by simple processing, gave respectively, 2a (i.e.,
2, R = CH3), 2b (i.e., 2, R = C2H5) and 2c (i.e., 2, R = PhCH2)
identical with the same products obtained above (Scheme-I).
It is obvious from the above results that PEG-600 is a very
efficient solvent for the alkylation of 1 resulting in the formation
of 2(a-c) respectively. Mechanistic explanation20 of these results
is that, probably PEG-600 dissolves the substrates 1 and the
reagent (i.e. the alkylting agent, dimethyl sulfate, diethyl sulfate,
etc.), bringing them together thereby providing an effective
means for chemical reaction to occur. Further, PEG-600 is
The reaction was also carried out in ethanol as a solvent.
Thus, treatment of 1, independently, with each of dimethyl
sulphate, diethyl sulphate and benzyl chloride (PhCH2Cl) in
ethanol at room temperature for 2 h K2CO3 as a base, followed
by simple processing, gave respectively, 2a (i.e., 2, R = CH3),
2b (i.e., 2, R = C2H5) and 2c (i.e., 2, R = PhCH2) identical with
the same products obtained above (Scheme-I).
Plausible mechanism:
O
O
O
N
O
O
O
O
O
NH
SH
O
O
O
N
O
N
O
O
O
O
H
O
O
NH
NH
SH
RT / 1-2 h
+
PEG-600
S
O
O
O
O
O
O
O
(PEG-600 with chelating hydrogen)
O
O

2646 Reddy et al.
Asian J. Chem.
O
O
N
O
O S
O
O
H3C
CH3
NH
SCH3
NH
O
S
O
O
+
+
CH3
Dimethyl sulphate
or
N
S
O
Diethyl sulphate/ Cl-CH2
able to extract the hydrogen from the -SH of quinazolinone
and is able to retain it in its claws by chelation through several
lone pairs of electrons in its oxygen containing chain. The
sulphanyl anion from the substrate 1 then attacks the positively
polarized methyl carbon of the alkylating agent bringing about
product (2) formation. This role of PEG-600 is very similar to
that of the crown ethers or that of the proton sponge (i.e. 1,8-
dimethylaminonaphthalene). The latter acts as a very strong
base due to its ability to extract hydrogen from an acidic
substrate and then retain it by chelation through lone pair of
electrons on the two nitrogen atoms of the two amino groups
(Scheme-I).
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In conclusion, green and simple syntheses of 2-alkylsulfanyl-
3H-quinazolin-4-one (2a-c) from 1 are described. It appears
from this study that Green syntheses such as solid phase
synthesis (physical grinding) and micro wave irradiation gives
better yields, quality and in less reaction time the products
over conventional methods involving green solvents like
ethanol, PEG-600 etc. The entire sequence of reactions shown
in Scheme-I have been carried out using eco-friendly solvents
and green conditions.
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ACKNOWLEDGEMENTS
The authors are thankful to the authorities of Jawaharlal
Nehru Technological University Hyderabad for providing
laboratory facilities.