Synthesis of Benzoxazolylthiomethyl and Benzthiazolylthiomethyl Quinazolin-4(3 h)-ones

Article abstract of DOI:10.1080/10426507.2015.1025905

o-Aminophenol (1a, X = O) or o-aminothiophenol (1b, X = S) was reacted with carbon disulfide in ethanol containing KOH under reflux to obtain 2-mercaptobenzoxazole (2a, X = O) and 2-mercaptobenzthiazole (2b, X = S), respectively. Condensation of 2a and 2b each with chloroacetic acid gave 2-(benzoxazol-2-ylthio)acetic acid (3a, X = O) and 2-(benzthiazol-2-ylthio)acetic acid (3b, X = S) respectively which with anthranilamide gave 2-((benzoxal-2-ylthio)methyl) quinazolin-4(3H)-one (5a, X = O) and 2-((benzthiazol-2-ylthio)methyl)quinazolin-4(3H)-one (5b, X = S) respectively. The products 5a,b could be prepared in three other routes involving the general sequences 6→2→5, 6→7→5 and 8→9→5.

Full text of DOI:10.1080/10426507.2015.1025905

This article was downloaded by: [University of Sydney]
On: 01 May 2015, At: 07:54
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of benzoxazolylthiomethyl and
benzthiazolylthiomethyl quinazolin-4(3H)-ones
a
a
a
Mohammad Rafeeq , Chittireddy Venkata Ramana Reddy & Pramod Kumar Dubey
a
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad College of
Engineering, Kukatpally, Hyderabad, Telangana, India-500085.
Accepted author version posted online: 20 Mar 2015.
Click for updates
To cite this article: Mohammad Rafeeq, Chittireddy Venkata Ramana Reddy & Pramod Kumar Dubey (2015): Synthesis of
benzoxazolylthiomethyl and benzthiazolylthiomethyl quinazolin-4(3H)-ones, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2015.1025905
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1025905
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Synthesis of benzoxazolylthiomethyl and benzthiazolylthiomethyl quinazolin-4(3H)-ones
Mohammad Rafeeq*, Chittireddy Venkata Ramana Reddy and Pramod Kumar Dubey
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad
College of Engineering, Kukatpally, Hyderabad, Telangana, India-500085.
E-mail ID: mohammadrafeeq8@gmail.com
Abstract: o-Aminophenol (1a, X=O) or o-aminothiophenol (1b, X=S) was reacted with carbon
disulfide in ethanol containing KOH under reflux to obtain 2-mercaptobenzoxazole (2a, X=O)
and 2-mercaptobenzthiazole (2b, X=S) respectively. Condensation of 2a and 2b each with
chloroacetic acid gave 2-(benzoxazol-2-ylthio)acetic acid (3a, X=O) and 2-(benzthiazol-2-
ylthio)acetic acid (3b, X=S) respectively which with anthranilamide gave 2-((benzoxal-2-
ylthio)methyl) quinazolin-4(3H)-one (5a, X=O) and 2-((benzthiazol-2-ylthio)methyl)quinazolin-
4
(3H)-one(5b, X=S) respectively. The products 5a-b could be prepared in three other routes
involving the general sequences 6 5, 6 5 and 8 5.
2
7
9
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Key words: Anthranilamide, quinazolin-4(3H)-one, benzoxazole, benzthiazole, TBAB
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
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 anti-
1
-2
3
4
5
inflammatory , anticonvulsant , hypotensive and anti-malarial types. 2-Thioquinazolinones
6
possess good analgesic activities . 2-Heterylquinazolin-4(3H)-ones exhibit a wide range of
7
, 8
pharmacological properties , such as good antimicrobial activity against different species of
9
10
11, 12
gram-positive bacteria , gram-negative bacteria and pathogenic fungi
. In view of this wide
range of pharmacological activities, the quinazolinone derivatives have been the target of a large
1
3-16
number of organic synthetic efforts
.
1
7
It was reported from our laboratory earlier that treatment of 2-(4-oxo-3,4-dihydro-
quinazolin-2-ylsulfanyl)-propionic acid with with o-phenylenediamine in refluxing 6N aq.HCl
for 12 h gave 2-[1-(1H-benzimidazol-2-yl)-ethylsulfanyl] quinazolin-4(3H)-one. In another
1
8
report , also from our laboratory, condensation of 2-((chloromethyl) quinazolin-4(3H)-One with
2
-mercaptoquinazolin-4(3H)-one in dimethylformamide containing K CO as a base and TBAB
2
3
as a phase transfer catalyst for 2-3 h gave bisquinazolin-4(3H)-one derivatives i.e 2-(4-Oxo-3,4-
1
9
dihydroquinazolin-2-ylsulfinylmethyl)quinazolin-4(3H)-one. Patil
et al. synthesized 2-
by
substituted-1H-benz(d)imidazol-2-ylsulfinyl)methyl-3-substitutedquinazolin-4(3H)-ones
condensing 2-chloromethylquinazolin-4(3H)-one with 2-mercaptobenzimidazole in 5N NaOH
dissolved in ethanol as a solvent for 10-12 h.
In view of the literature information given above, it seems only limited work has been
done on the preparation of 2-alkylthioheteryl derivatives of quinazolin-4(3H)-one. The present
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
work is concerned with the synthesis of benzoxazolylthiomethyl, benzthiazolylthiomethyl 2-
substitutions of quinazolin-4(3H)-ones.
Results and discussions
Commercially available o-aminophenol (1a) or o-aminothiophenol (1b) were each treated,
independently, with carbon disulfide in isopropyl alcohol containing KOH giving
2
0-22
benzo[d]oxazole-2-thiol(2a) or benzo[d]thiazole-2-thiol(2b) respectively by reported
procedure. The latter, were, again, reacted with 2-chloroacetic acid in aq. KOH at RT for 1 h
giving (benzo[d]oxazol-2-ylthio) acetic acid (3). The structures of all new compounds
synthesized in this work have been established on the basis of their spectroscopic data.
(Experimental).
Condensation of 3a (i.e. 3, X=O) with anthranilamide (4) under refluxing conditions in
aq. HCl for 10 h gave a product which has been characterized as 2-((benzo[d]oxazol-2-
ylthio)methyl)quinazolin-4(3H)-one (5a).
In an alternative approach, reaction of 2 with 6 under different conditions in the presence
of bases at RT for 3-4 h gave 5, which were found to be identical in m.p., m.m.p., TLC and IR
with that of the same products obtained in the route described above, (i.e. 3+ 4
The preparation of 5 from 2 and 6 has been studied under different conditions and the
results are shown in Table 1.
5).
It is obvious from Table 1, that for the condensation of 2(a-b) with 6, 5% methanolic
NaOH seems to offer the best conditions giving 5 in the highest yield.
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
In a yet alternative approach, 5 could be prepared by the condensation of dithiocarbonic
acid o-ethyl ester i.e. S-[2-(4-oxo-3, 4-dihydroquinazolin-2-yl) ethyl] ester (7) with 1 in refluxing
toluene containing traces of acetic acid as catalyst for 2-3 h. The former compound. i.e. 7, in
turn, was synthesized by the reaction of 2-chloromethylquinazolin-4(3H)-one (6) with potassium
o-ethyl dithiocarbonate in ethanol at RT for 3 h. (Scheme 1).
The conversion of 7 to 5 seems to follow the mechanism given in Scheme 2
1
7
The mechanism seems to follow the strategy as reported earlier in the case of
condensation of 7 with o-phenylenediamine. Here, the nucleophilic attack by the amino group of
1
on the xanthate carbon of 7 yielding the intermediate 7A that loses of ethanol to form 7B. The
latter, then, undergoes ring closure involving a second but intramoleular, nucleophilic attack by
the hydroxyl/thio group on the xanthate carbon to form 7C which changes to 7D. This
intermediate then undergoes loss of elements of H S in a bid to aromatize to form the final
2
product 5.
In another alternative method, 5 could also be synthesized from 4 by reaction with chloroacetyl
chloride in benzene, triethylamine as catalyst at RT for 1-2 h yielding 2-(2-
chloroacetylamino)benzamide (8) which on treatment with 2 in aq. K CO gave 9 followed by
2
3
refluxation in acetic acid for 3 h as shown in Scheme 1.
Experimental section
Melting points are uncorrected and were determined in open capillary tubes in sulphuric acid
bath. TLC was run on silica gel – G and visualization was done using iodine or UV light. IR
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1
spectra were recorded using Perkin – Elmer 1000 instrument in KBr pellets. H NMR spectra
were recorded in DMSO – d using TMS as internal standard using an instrument operating at
6
4
00 MHz.
Preparation of 3 from 2
A mixture of 2-mercaptobenzoxazole (2a, X=O) and 2-mercaptobenzthiazole (2b, X=S) (10
mmol), 2-chloroacetic acid (10 mmol), K CO (10 mmol) and DMF (10 mL), TBAB as a PTC
2
3
was stirred for 1-2 h at RT. After completion of reaction, the mixture was cooled to RT and
treated with acetic acid until neutralised. The separated solid was filtered, washed with water
(2×40 mL) and dried to obtain crude 3a-b. The latter on recrystallization from suitable solvent
gave pure 3a-b.
°
-1
3
1
8
a: white colour solid (1.55 g, 73 %), M.p. 178-80 C; IR (KBr): 3200-3000 cm (broad, –NH-),
-1
1
700, 1665 cm (strong, sharp, C=O ); H-NMR (DMSO-d /TMS): δ 4.00 (s, 2H, -CH ), 7.30-
6
2-
.00 (m, 4H, aryl protons), 12.75 (s, 2H, D O exchangeable protons, –NH- and –COOH); LC-
2
+
MS: m/z 210[M+H] . Elemental Analysis: C, 51.67; H, 3.37; N, 6.69; O, 22.94; S, 15.33. Found:
C, 51.64; H, 3.35; N, 6.73; O, 22.91; S, 15.36.
°
°
3
b white colour solid (1.85 g, 80 %), M.p. 226-227 C (228-230 C lit ); IR (KBr): 3200-3000
-1
-1
1
cm (broad, –NH-), 1700, 1665 cm (strong, sharp, two, C=O ); H-NMR (DMSO-d /TMS): δ
6
4
.10 (s, 2H, -CH ), 7.20-8.00 (m, 4H, aryl protons), 12.65 (s, 2H, D O exchangeable protons, –
2- 2
+
NH- and –COOH); LC-MS : m/z 224 [M+H] . Elemental Analysis: C, 47.98; H, 3.13; N, 6.22;
O, 14.20; S, 28.47. Found: C, 47.95; H, 3.16; N, 6.25; O, 14.22; S, 28.48.
Preparation of 5 from 3 and 4
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A mixture of 3 (5 mmol), o-aminobenzamide (4) (0.68g, 5 mmol) and aq. HCl (6N, 50 mL) was
refluxed for 8-10 h. At the end of this period, the reaction mixture was diluted with water (50
mL) and the pH adjusted to ≥ 7.0 with aq. ammonia. The separated solid was filtered, washed
with water (2×10 mL) and dried.
o
-1
5
a: Yield=2.5 g (80 %); M.p. =190-192 C (MeOH). IR (KBr): 3200 cm (–NH), 1657
-1
1
cm (–NHC=O); H NMR (DMSO-d )  4.53 (s, 2H, -CH -), 7.14-8.11 (m, 8H, aryl protons),
6
2
1
3
1
1
2.65 (b, s, 1H, D O, –NH-); C-NMR (DMSO-d /TMS) δ 34.8(CH ), 114.0, 121.1, 121.6,
2 6 2
25.8, 126.6, 126.8, 134.4, 139.4, 148.4, 149.7, 153.9 (aromatic carbons) and 161.1(C=O),
+
LCMS: m/z 310 [M+H] . C H N O S, Elemental Analysis: C, 62.12; H, 3.58; N, 13.58; O,
1
6
11
3
2
1
5
1
0.34; S, 10.37. Found: 62.09; H, 3.63; N, 13.61; O, 10.32; S, 10.36.
o
-1
b: Yield: 2.45 g (76 %); M.p. =163-165 C (MeOH); IR (KBr): 3241 cm (broad, NH & OH),
-1
1
671 cm (strong, C=O); H NMR (DMSO-d ):  4.53 (s, 2H, -CH -), 7.14-8.11 (m, 8H, aryl
6
2
1
3
protons), 12.65 (broad, s, 1H, D O exchangeable proton, –NH-); C-NMR spectrum (DMSO-
2
d /TMS) showed signals at δ 34.3(CH ), 114.4, 121.1, 121.8, 125.7, 126.5, 126.8, 134.3, 139.5,
6
2
+
1
48.5, 149.8, 153.8(aromatic carbons) and 161.7(C=O). LC-MS: m/z 325 [M+H] . Chemical
Formula: C H N OS , Elemental Analysis: C, 59.06; H, 3.41; N, 12.91; O, 4.92; S, 19.71.
1
6
11
3
2
Found: C, 59.08; H, 3.39; N, 12.93; O, 4.95; S, 19.66.
Preparation of 5 from 6 and 2 using triethylamine and acetone
A mixture of 2-((chloromethyl) quinazolin-4(3H)-One (6) (10 mmol), 2 (10 mmol),
triethylamine (TEA) (1.6 mL, 10 mmol) and acetone (25 mL) was stirred at RT for 3-4 h. After
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
completion of the reaction, as monitored by TLC, the mixture was poured into ice-cold water
(
2×10 mL). The separated product was filtered, washed with water (2×10 mL), dried to obtain.
Pure 5a-b (MeOH), identical in mp, mmp and TLC with that of the same product obtained in the
route described above, i.e. 3+4 5.
a: Yield = 2.4 g (75 %); M.p. = 198-200 C (MeOH).
o
5
o
5
b: Yield = 2.7 g (83 %); M.p. = 163-165 C (MeOH).
Preparation of 5 from 6 and 2 under PTC conditions
A mixture of 6 (1.93, 10 mmol), 2 (10 mmol), K CO (1.92 g, 15 mmol), TBAB (5 mmol) as a
2
3
PTC catalyst and DMF (10 mL) was stirred at RT for 3-4 h. After completion of the reaction, as
monitored by TLC, the mixture was poured into ice-cold water (100 mL). The separated product
was filtered, washed with water (2×25 mL) and dried to obtain 5a-b. Pure 5a-b (MeOH),
identical in mp, mmp and TLC with that of the same product obtained in the route described
above, i.e. 3+4
5
o
5
a: Yield = 2.30 g (73 %); M.p. = 190-192 C (MeOH).
o
5
b: Yield = 2.7 g (83 %); M.p. = 163-165 C (MeOH).
Preparation of 5 from 7 and 1
A mixture of 7 (2.8g, 10 mmol), 1 (10 mmol), acetic acid (1.2 mL, 10 mmol) and toluene (30
°
mL) was refluxed at 110 C in an oil-bath for 6-8 h, until the reaction was complete as shown by
periodic TLC for disappearance of the starting material. At the end of this period, toluene was
distilled off and the residue treated with aq. NaOH (1N, 50 mL) at RT. The separated solid was
filtered, washed with water (2×15 mL) and dried to obtain 5a-b. Pure 5a-b (MeOH), identical in
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
mp, mmp and TLC with that of the same product obtained in the route described above, i.e.
3
5
+4
5
o
a: Yield =2.1 g (77 %), M.p. = 190-192 C (MeOH).
o
5
b: Yield = 2.7 g (83 %); M.p. = 163-165 C (MeOH).
Preparation of 7 from 6
A mixture of 6 (10 mmol), potassium ethoxydithiocarbamate (10 mmol) and ethanol (30 mL)
was refluxed for 2 h. Then, the reaction mixture was cooled to RT and the separated KBr salt
was filtered and washed with ethanol (20 mL). The ethanolic filtrate was distilled off and the
residue diluted with water (20 mL). The separated solid was filtered, washed with water (20 mL)
and dried to obtain crude 7.
°
°
lit.17
-1
7
: Yield: 2.1 g (80 %); M.p.156-158 C (157-159 C
) ; IR (KBr): 3200-3100 cm (broad, –
-1
-1
NH-), 1660 cm (strong, sharp, C=O of the amide group), 1180 cm (broad, C=S of the xanthate
1
group); H-NMR (DMSO-d6/TMS):  1.20 (t, 3H, -CH ), 4.40 ( 2H, -CH -), 4.50 (s, 2H, -CH -),
3
2
2
7
.20-8.50 (m, 4H, aryl protons) 12.58 (broad s, 1H, D O exchangeable proton, –NH); LC-MS:
2
+
m/z 281[M+H] .
Preparation of 9 from 8 and 2
A mixture of 2-(2-chloroacetylamino)benzamide (8) (2.12 gm, 10 mmol), 2 (10 mmol), K CO
2
3
(1.92 g, 15 mmol), TBAB (0.25g.) and DMF (10 mL) was stirred at RT for 2 h. After completion
of the reaction, as monitored by TLC, the mixture was poured into ice-cold water (100 mL). The
separated product was filtered, washed with water (2×25 mL) and dried to obtain 9a-b.
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
o
-1 (
9
1
8
3
a: Yield = 2.30 g (74 %); M.p. = 113-115 C (EtOH); IR (KBr) 3200-3100 cm NH & NH ),
2
-1
1
700 cm (C=O); H NMR (DMSO-d )  4.44 (s, 2H, -CH ), 7.36-8.00 (m, 8H, aryl protons)
6
2-
13
.08 (b, s, 2H, D O, -NH ) and 12.44 (b, s, 1H, D O, –NH); C-NMR (DMSO-d /TMS) δ
2
2
2
6
8.5(CH ), 110.2, 119.1, 123.2, 123.5, 124.4, 124.8, 126.9, 132.3, 137.0, 141.5, 151.9(aromatic
2
+
carbons) and 172.1 (C=O); LC-MS m/z 327 [M+H] . Chemical Formula: C H N O S,
16
13
3
3
Elemental Analysis: C, 58.70; H, 4.00; N, 12.84; O, 14.66; S, 9.80. Found: C, 58.72; H, 4.04; N,
1
2.82; O, 14.64; S, 9.80.
b: Yield: 2.8 g (81 %); M.p. = 131-132 C (Chloroform). IR (KBr): 3200-3100 cm (very
o
-1
9
-1
1
broad, NH & NH ) , 1665 cm (strong, C=O); H NMR (DMSO-d ):  4.36 (s, 2H, -CH ), 7.30-
2
6
2-
8
.00 (m, 8H, aryl protons) 8.18 (broad s, 2H, D O exchangeable protons, -NH ) and 12.43
2 2
1
3
13
(
broad, singlet, 1H, D O; The C-NMR spectrum (DMSO-d /TMS) The C-NMR spectrum
2
6
(
DMSO-d /TMS) δ 38.3(CH ), 110.2, 119.1, 123.2, 123.5, 124.4, 124.8, 126.9, 132.3, 137.0,
6 2
1
41.5, 151.9 (Aromatic Carbons) and 172.1(C=O). Chemical Formula: C H N O S , Elemental
16 13 3 2 2
Analysis: C, 55.96, H, 3.82, N, 12.24, O, 9.32, S, 18.67. Found; C, 55.98, H, 3.84, N, 12.27, O,
+
9
.35, S, 18.64; LC-MS: m/z 344 [M+H] .
Preparation of 5 from 9
A mixture of 9 (3.27 g, 10 mmol) and AcOH (20 mL) was refluxed for 3-4 h. After completion
of the reaction, as monitored by TLC, the mixture was poured into ice-cold water (50 mL), and
the pH of the mixture was adjusted to ≥ 7.0 with acetic acid. The separated solid was filtered,
washed with water (2×25 mL) and dried to obtain 5a-b. Pure 5a-b (MeOH), identical in mp,
mmp and TLC with that of the same product obtained in the route described above, i.e.
3
+4
5
10
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
o
5
5
a: Yield = 2.25 g (72 %); M.p. = 190-192 C (MeOH).
o
b: Yield = 2.18 g (77 %); M.p. = 163-165 C (MeOH).
Conclusion
The title compounds 2-((benzo[d]oxazol-2-ylthio)methyl)quinazolin-4(3H)-one (4a), 2-
((benzo[d]oxazol-2-ylthio)methyl)quinazolin-4(3H)-one (4b) have been synthesized by three
different routes. Of all the methodologies discussed, the condensation of 6 with 2 in MeOH as
solvent using NaOH as base appears to be the better and efficient route for the product obtained,
compare to the other two routes.
Acknowledgement
The authors are indebted to the University Grants Commission, Govt. of India, New Delhi, for
the sanction of Major Research Project (to Dr. Ch.VRR). They are also thankful to the authorities
of Jawaharlal Nehru Technological University Hyderabad for providing laboratory facilities.
11
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
References
[
1]. Alagarasamy, M.; Meena, S.; Revathi, R.; Kumar, S.V.; Ramesh, K.V. Arkivoc
2
006, (xvi), 149-159.
2]. Ozaki, K.; Yamada, Y.; Oninell, T.; Ishizuka, T.; Iwasawa,Y. J. Med .Chem. 1985,
8, 568-576.
3]. Bonola, G.; Dare, P.; Mgistretti, M. J.; Massarani, E.; Setnikar, I. J. Med. Chem.
968, 11, 1136-1139.
4]. Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968, 11, 130-136.
[
[
2
1
[
[
[
5]. Bhargava, P. N.; Chaurasia, M. R. J. Med. Chem. 1968, 11, 404-405.
6]. Reddy, P. S. N.; Venugopal, K. N.; Rao, G. K.; Pai, P. N. S. Indian J. Heterocycl. Chem.
2
007, 12, 243-246.
7]. Buyuktimkin, x.; Ekinci, A. C.; Buyuktimkin, N.; Otuk G.; J. Pharm. Sci. 1992, 81,
092-1094.
8]. Murgan, V.; Thomas, C.; Ramasarma, G.V.S.; Kumar, E. P. Indian J. Pharm. Sci.
003, 65, 386-389.
9]. Zhou, Y.; Murthy, D. E.; Sun, Z.; Gregor, V. E. Tetrahedron. Lett. 2004, 45, 8049-
051.
[
[
[
[
1
2
8
10]. Fatmah, A. M. A.; Lalila, A. A.; Mahmoud, N. N.; El-Sayed, E. H.; Abdel-Aziz, A. A.
M.; El-Azab, A. S.; Abdel-Hamide, S. G. Al-Omar, M. A.; Al-Obaid, A. M.; El-
Subbagh, H. I. Bioorg. Med. Chem. Lett. 2010, 18, 2849-2863.
[
11]. Pandeya, S. N.; Sriram, D.; Nath, G.; De Clerck. E. Pharm. Acta. Helv. 1999, 74, 11-17.
12
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[
[
12]. Grover, G.; Kini, S. G. Eur. J. Med. Chem. 2006, 41, 256-262.
13]. Chandrika, P. M.; Yakaiah, T.; Rao, A. R. R.; Narasiah, B.; Reddy, N. C.; Sridhar, V.;
Rao, J.V. Eur. J. Med. Chem. 2008, 43, 846-852.
[
[
[
14]. Cao, S.L.; Feng, Y. P.; Jiang, Y.V.; Liu, S.Y.; Ding, G.Y.; Li, R. T. Bioorg. Med.
Chem. Lett. 2005, 15, 1915-1917.
15]. Nagwa, M.; Abdel, G.; Hanan, H.; Georgey, R. M.; Youssef, N. A.; El-Sayed. Eur. J. Med.
Chem. 2010, 45, 6058-6067.
16]. Foote, K. M.; Mortlock, A. A.; Heron, N. M.; Jung, F. H.; Hill, G. B.; Pasquet, G.; Brady,
M. C.; Green, S.; Heaton, S. P.; Kearney, S.; Keen, N. J.; Odedra, R.; Wedge, S. R.;
Wikinson, R.W. Bioorg. Med. Chem. Lett. 2008, 18, 1901-1904.
[
[
17]. Reddy, B. S.; Naidu, A.; Dubey, P. K. Phosphorus Sulfur Silicon Relat. Elem., 2012,
1
87, 598– 605.
18]. Reddy, B. S.; Naidu, A.; Dubey, P. K. Indian J. Heterocycl. Chem.; 2011, 20,
09-112.
1
[
[
19]. Patil, A.; Swastika, G.; Sanjay, S. J. Chem. Sci.. 2010, 122, 443–450.
20]. Fauzia, M.; Shafi, S.; Zaman, M. S.; Nitin, P. K.; Vikrant, S. R.; Chaitanya, M.;
Naveen, M.; Inshad, A. K.; Alam. M. S. Eur. J. Med. Chem, 2008, 76, 274-283.
21]. Mahesh, K. N. D.; Dubey, P. K, Indian J. Chem. 2012, 1619.
[
[
22]. Sebrell , L. B.; Boord, C.E., J. Am. Chem. Soc., 1923, 45, 2390– 2399.
13
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1 Preparation of 5(a-b) from 6 and 2(a-b) by under different condition:
S.No.
Solvent used
Water
Base used
Time (h)
Yield of 4(%)
1
2
3
4
5
6
7
8
9
(5%) K CO (5 mole %)
4
4
4
3
3
3
2
3
3
3
3
55
60
60
70
90
80
80
75
60
70
70
2
3
Water
(5%) NaOH (5 mole %)
(5%) KOH (5 mole %)
____
Water
PEG 600
MeOH
Acetonitrile
DMF
NaOH (5 mole %)
TEA (5 mole %)
K CO (5 mole %)
2
3
MeOH
Piperidine (5 mole %)
Pyridine (5 mole %)
TEA (5 mole %)
MeOH
1
1
0
1
DCM
CHCl3
TEA (5 mole %)
14
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 1
15
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 2
16
ACCEPTED MANUSCRIPT