untitled


European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2012	EURJCHEM	

DOI:10.5155/eurjchem.3.2.241‐246.597	

	
	

	

	

European	Journal	of	Chemistry	
Journal	homepage:	www.eurjchem.com	

	 	 	

Synthesis	of	some	new	S‐glycosyl	pyrimidine	and	condensed	pyrimidine	
derivatives	

Wesam	Saber	Shehab*	and	Enaiat	Kamel	Mohamed	

Department	of	Chemistry,	Faculty	of	Science,	Zagazig	University,	Zagazig,	44511,	Egypt	

*Corresponding	author	at:	Department	of	Chemistry,	Faculty	of	Science,	Zagazig	University,	Zagazig,	44511,	Egypt.		
Tel.:	+2.011.9720874;	fax:	+2.055.2285374.	E‐mail	address:	dr_wesam123@yahoo.com	(W.	Shehab).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT
Received:	10	February	2012	
Received	in	revised	form:	05	March	2012	
Accepted:	22	March	2012	
Online:	30	June	2012	

KEYWORDS	

	 Mercaptopyrimidine	(4) was	synthesized	by	the	reaction	of	isothiocyanate	and	acrylate	(1).	It
was	allowed	to	react	with	preacetylated	sugar	bromide	and/or	halomethylene	derivatives	to
produce	alkylated	pyrimidines	(5,7a‐d).	Hydrolysis	of	compound	(5)	produced	compound	(6).
Interacyclization	 of	 compounds	 (7a‐d)	 afforded	 thienopyrimidines	 (8a‐d).	 Moreover
oxidation	 of	 compound	 (7b)	 gave	 the	 corresponding	 thienopyrimidine	 dioxide	 (9).
Cyanoethylation	 of	 compound	 (4)	 afforded	 compound	 (10)	 that	 reacted	 with	 hydrazine
hydrate	to	give	pyrazolopyrimidine	(11).	Oxidation	of	compound	4	afforded	bisulphide	(12).
The	 cycloaddition	 product	 (13)	 was	 obtained	 by	 reaction	 of	 compound	 4	 with	 maleic
anhydride.	Pyrimidopyrimidine,	pyrimidopyridazine	and	tetrazolopyriminde	derivatives	(16‐
20)	were	obtained	by	reaction	of	4‐chloropyrimidine	(15)	with	thiourea,	benzilhydrazone	and
sodium	azide,	respectively.	N‐alkylated	pyrazolopyrimidine	(21)	was	obtained	by	reaction	of
compound	(15)	with	acetophenonehydrazone.	

S‐glycosyl	
Thienopyrimidine	
S‐alkyl	pyrimidine	
Pyrimidopyrimidine	
Mercaptopyrimidine	
Tetrazolopyrimindine	derivatives	

	
1.	Introduction	
	

Pyrimidines	and	heterocyclic	annulated	pyrimidines	exhibit	
interesting	biological	activities	as	medicinal	applications	[1‐3].	
A	variety	of	anticancer	drugs	made	from	pyrimidine	derivatives	
have	 clinical	 use	 currently,	 the	 hydrazinopyrimidine‐S‐
carbonitrile	 derivatives	 have	 antineoplastic	 activities	 [4].	
Moreover,	 pyrimidines	 and	 condensed	 pyrimidines	 are	
important	classes	of	heterocyclic	compounds	that	exhibit	broad	
spectrum	of	biological	activities	such	as	anticancer	 [5,6],	 anti‐
inflammatory,	 anti	 ‐allergic	 and	 analgesic	 activity	 [7‐9].	 In	
continuation	 of	 our	 efforts	 in	 this	 direction,	 we	 synthesized	
some	 new	 pyrimidine	 derivatives	 and	 condensed	 pyrimidine	
derivatives	for	biological	evaluations.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

Melting	 points	 are	 all	 uncorrected.	 The	 IR	 spectra	 (KBr)	
discs	were	recorded	on	a	Perkin‐Elmer	1650	spectrometer.	1H	
NMR	 spectra	 was	 determined	 on	 Bruker	 Ac‐300	 MHz	
instrument.	 Chemical	 shifts	 are	 expressed	 as		 (ppm)	 relative	
to	 tetramethylsilane	 (TMS)	 as	 internal	 standard	 and	DMSO‐d6	
as	 solvent.	 The	 elemental	 analysis	 was	 carried	 by	 the	 Micro‐
analytical	center,	Cairo	University.	
	
2.2.	Synthesis	
	
2.2.1.	Ethyl	2‐(4‐chlorophenyl)	1‐4‐mercapto‐6‐phenyl	
pyrimidine‐5‐carboxylate	(4)	
	

A	 solution	 of	 p‐chlorobenzoylthiocyanate	 (3)	 (0.01	 mol)	
(prepared	by	refluxing	p‐chlorobenzoyl	chloride	(0.01	mol)	and	
ammonium	 isothiocyanate	 (0.01	mol)	 in	 dry	 acetone	 (20	mL)	

for	 2	 h.)	 was	 added	 to	 ethyl‐3‐amino‐3‐	 phenylacrylate	 (0.01	
mol)	 (prepared	 by	 bubbling	 ammonia	 gas	 into	 ethylbenzoyl	
acetate	(0.01	mol)	for	3	h	at	room	temperature)	in	dry	acetone.	
The	 reaction	 mixture	 was	 refluxed	 for	 4	 h	 filtered	 off	 and	
cooled.	 The	 solid	 obtained	 was	 filtered	 off,	 dried	 and	
recrystallized	 from	 ethanol	 95%	 to	 give	 yellow	 crystals,	 4	
(Scheme	 1).	 Yield:	 92%.	 M.p.:	 210‐212	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	
3450‐3350	(NH),	1725	(C=O,	ester),	1200	(C=S).	1H	NMR	(300	
MHz,	 DMSO‐d6,	 ,	 ppm):	 1.36	 (t,	 3H,	 CH3CH2),	 4.39	 (q,	 2H,	
CH3CH2),	 7.50‐8.39	 (m,	 9H,	 Ar‐H),	 13.20	 (br,	 1H,	 SH).	 Anal.	
calcd.	 for	 C19H15ClN2O2S:	 C,	 61.53;	 H,	 4.08;	 N,	 7.55;	 S,	 8.65.	
Found:	C,	61.49;	H	3.98;	N,	7.50;	S,	8.59%.	
	
2.2.2.	2‐(Acetoxymethyl)‐6‐(2‐(4‐chlorophenyl)‐5‐(ethoxy	
carbonyl)‐6‐phenylpyrimidin‐4‐ylthio)tetrahydro‐2H‐pyran‐
3,4,5‐triyl	triacetate	(5)	
	

A	solution	of	compound	4	(0.01	mol)	in	aqueous	potassium	
hydroxide	(0.01	mol)	in	distilled	water	(10	mL)	was	added	to	a	
solution	 of	 2,3,4,6‐tetra‐o‐acetyl‐‐D‐glucopyranosyl	 bromide	
(0.01	 mol)	 in	 acetone	 (30	 mL).	 The	 reaction	 mixture	 was	
stirred	 for	 4	 h	 at	 room	 temperature.	 The	 mixture	 was	
evaporated	 under	 reduced	 pressure	 and	 the	 residue	 was	
washed	with	distilled	water	to	remove	the	potassium	bromide	
formed.	 The	 solid	 product	 was	 dried	 and	 recrystallized	 from	
ethanol	 affording	 pale	 gray	 crystals	 (Scheme	 1).	 Yield:	 35%.	
M.p.:	170‐172	oC.	IR	(KBr,	ν,	cm‐1):	1745	(C=O,	acetoxy	groups),	
1725	(C=O,	ester),	1636	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	,	
ppm):	1.87,	1.92,	1.95	and	2.02	(4s,	12H,	4CH3C=O),	1.37	(t,	3H,	
CH3CH2),	4.03	(m,	2H,	H‐5'	and	H‐6''),	4.28	(m,	1H,	H‐6'),	4.38	
(q,	2H,	CH3CH2),	5.06	(t,	1H,	H‐4'),	5.61	(t,	1H,	H‐2'),	5.69	(t,	1H,	
H‐3'),	6.21	(d,	1H,	H‐1'),	7.30‐8.41	(m,	9H,	Ar‐H).	Anal.	calcd.	for	
C33H33ClN2O11S:	 C,	 56.53;	 H,	 4.74;	 N,	 4.00;	 S,	 4.57.	 Found:	 C,	
56.50;	H,	4.69;	N,	3.98;	S,	4.52%.	
	



242	 Shehab	and	Mohamed	/	European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	
	
	 	

Cl

O

OEt

Ph

Ar

C

N

N

H

O

SC

CAr

H2N

O

O

OEt
C

S

Ar

Ph

NH

AcO

OAc

O

H
OAc

H OAc

H

Br

HH

O

OEt
C

SHAr

Ph

N

N

COOEt

SHAr

Ph

N

N

NH2 O

OEtPh
NH3

O O

OEtPh

Ar =

6 5

MeOH/TEA

Dry acetone

4

Acetone
+

4 3

2

1

+
Room temperature

-H2O

N

KOH

OAc

O

OAc

HOAc

H

S

OAc

H

O

OEt

Ph

Ar

C

N

N

H

OH

O

OH

HOH

H

S

OH

H

 

Scheme	1	
	
	
2.2.3.	Ethyl	2‐(4‐chlorophenyl)‐4‐phenyl‐6‐(3,4,5‐trihydroxy‐
6‐(hydroxymethyl)	tetrahydro‐2H‐pyran‐2‐yl	thio)	
pyrimidine‐5‐carboxylate	(6)	
	

A	mixture	of	compound	5	(0.01	mol)	in	methanol	(30	mL),	
1	 mL	 of	 triethylamine	 (TEA)	 and	 few	 drops	 of	 water	 were	
stirred	 overnight	 at	 room	 temperature,	 the	 solvent	 was	 then	
removed	 under	 vacum,	 and	 the	 residue	 was	 washed	 with	
chloroform.	 The	 remaining	 residue	 was	 recrystallized	 from	
ethanol	giving	gray	crystals	(Scheme	1).	Yield:	25%.	M.p.:	180‐
182	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	 3420‐3395	 (very	 broad	 band)	 (OH),	
1735	 (C=O,	ester).	 1H	NMR	(300	MHz,	DMSO‐d6/D2O,	,	ppm):	
1.40	(t,	3H,	CH3CH2),	3.68	(m,	1H,	H5),	4.39	(q,	2H,	CH3CH2),	4.48	
(m,	2H,	H6'.6''),	5.02	(d,	1H,	H‐4'),	5.16	(d,	1H,	H‐2'),	5.44	(d,	1H,	
H‐3'),	5.61	(d,	1H,	H‐1'),	4.40‐8.41	(m,	9H,	Ar‐H).	Anal.	calcd.	for	
C25H25ClN2O7S:	 C,	 56.34;	 H,	 4.73;	 N,	 5.26;	 S,	 6.02	 Found:	 C,	
56.29;	H,	4.70;	N,	5.27;	S,	6.00%.	
	
2.2.4.	Synthesis	of	compounds	7a‐d	
	

A	 mixture	 of	 compound	 4	 (0.01	 mol)	 and	 appropriate	
alkylating	 agent	 (benzyl	 chloride,	 ethyl	 bromoacetate,	
chloroacetamide	 and	phenacyl	 bromide)	 and	 triethylamine	 (3	
drops)	 in	 ethanol	 was	 refluxed	 for	 30	 min.	 The	 precipitate	
obtained	 upon	 cooling	 and	 dilution	with	 water	 was	 collected	
and	crystallized	from	suitable	solvent	(Scheme	2).	

Ethyl	 4‐(benzylthio)‐2‐(4chlorophenyl)‐6‐phenyl	 pyrimidine‐
5‐carboxylate	(7a):	A	pale	yellow	crystal.	Yield:	85%.	M.p.:	110‐
112	oC.	IR	(KBr,	ν,	cm‐1):	1738	(C=O,	ester).	1H	NMR	(300	MHz,	
DMSO‐d6,	,	ppm):	1.2	(t,	3H,	CH3	CH2),	4.3	(q,	2H,	CH3CH2),	4.7	
(S,	 2H,	 SCH2),	 7.0‐8.4	 (m,	 14H,	 Ar‐H).	 Anal.	 calcd.	 for	
C26H21ClN2O2S:	 C,	 67.74;	 H,	 4.59;	 N,	 6.08;	 S,	 6.96.	 Found:	 C,	
67.69;	H,	4.61;	N,	6.12;	S,	6.98%.	

Ethyl	 2‐(4‐Chlorophenyl)‐4‐(2‐ethoxy‐2‐oxoethylthio)‐6‐
phenylpyrimidine‐5‐carboxylate	 (7b):	 A	 pale	 yellow	 powder.	
Yield:	 87%.	 M.p.:	 120‐122	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	 1712	 (C=O,	
ester),	 1698	 (C=O,	 ketonic).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 ,	
ppm):	1.1	(t,	3H,	CH3CH2),	1.3	(t,	3H,	CH3H2),	3.2	(S,	2H,	SCH2),	
4.2	(q,	2H,	CH3CH2),	4.4	(q,	2H,	CH3CH2),	7.2‐8.2	(m,	9H,	Ar‐H).	
Anal.	calcd.	for	C23H2ClN2O4S:	C,	60.46;	H,	4.63;	N,	6.13;	S,	7.02.	
Found:	C,	60.44;	H,	4.59;	N,	6.11;	S,	7.00%.	

Ethyl	 4‐(2‐amino‐2‐oxoethylthio)‐2‐(4‐chlorophenyl)‐6‐
phenylpyrimidine‐5‐carboxylate	 (7c):	 Yellow	 crystal.	 Yield:	
75%.	 M.p.:	 130‐132	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	 1725	 (C=O,	 ester),	
1649	(C=O,	amide).	1H	NMR	(300	MHz,	DMSO‐d6,	,	ppm):	1.3	(t,	
3H,	CH3CH2),	3.8	 (S,	2H,	SCH2),	4.3	 (q,	2H,	CH3CH2),	6.8	 (s,	2H,	
NH2),	 7.2‐8.4	 (m,	 9H,	 Ar‐H).	 Anal.	 calcd.	 for	 C21H18ClN3O3S:	 C,	
58.94;	H,	4.24;	N,	9.82;	S,	7.49.	Found:	C,	58.89;	H,	4.21;	N,	9.79;	
S,	7.44%.	

Ethyl	 2‐(4‐chlorophenyl)‐4‐(2‐oxo‐2‐phenylethylthio)‐6‐
phenylpyrimidine‐5‐carboxylate	 (7d):	 Yellow	 crystal.	 Yield:	
80%.	M.p.:	 135‐138	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	 1712	 (C=O,	ketonic),	
1698	(C=O,	ester).	1H	NMR	(300	MHz,	DMSO‐d6,	,	ppm):	1.3	(t,	
3H,	CH3CH2),	4.2	(q,	2H,	CH3CH2),	4.6	(s,	2H,	SCH2),	7.0‐8.4	(m,	
14,	 Ar‐H).	 Anal.	 calcd.	 for	 C27H21ClN2O3S:	 C,	 66.32;	 H,	 4.33;	N,	
5.73;	S,	6.56.	Found:	C,	66.21;	H,	4.19;	N,	5.52,	S,	6.41%.	
	
2.2.5.	Synthesis	of	compounds	8a‐d	
	

A	mixture	of	appropriate	pyrimidine	(7a‐d)	(0.01	mol)	and	
sodium	 ethoxide	 (0.01	 mol)	 in	 ethanol	 (30	 mL)	 was	 heated	
under	 reflux	 for	 30	min.	 The	 precipitate	 formed	 after	 cooling	
and	 acidification	 with	 hydrochloric	 acid	 (3	 mL,	 60%)	 was	
collected	and	crystallized	from	suitable	solvent	(Scheme	2).	

	
	



Shehab	and	Mohamed	/	European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	 243	
 

	

 
	

Scheme	2	
	
	
2‐(4‐Chlorophenyl)‐4,6‐diphenylthieno	 [2,3‐d]	pyrimidin‐5‐ol	

(8a):	A	colorless	crystals.	Yield:	42%.	M.p.:	220‐222	oC.	IR	(KBr,	
ν,	cm‐1):	3500	(OH),	1610	(C=N).	1H	NMR	(300	MHz,	DMSO‐d6,	
,	ppm):	7.0‐8.2	(m,	14H,	Ar‐H),	10.1	(s,	1H,	OH).	Anal.	calcd.	for	
C24H15ClN2OS:	C,	69.48;	H,	3.64;	N,	6.75;	S,	7.73.	Found:	C,	69.49;	
H,	3.65;	N,	6.76;	S,	7.74%.	

Ethyl	 2‐(4‐chlorophenyl)‐5‐hydroxy‐4‐phenylthieno[2,3‐d]	
pyrimidine‐6‐carboxyate	 (8b):	 Colorless	 crystals.	 Yield:	 50%.	
M.p.:	210‐212	oC.	IR	(KBr,	ν,	cm‐1):	3300‐3200	(OH),	1725	(C=O,	
ester),	1692	(C=O,	PH).	 1H	NMR	(300	MHz,	DMSO‐d6,	,	ppm):	
1.34	(t,	3H,	CH3CH2),	4.21	(q,	2H,	CH3CH2),	7.2‐8.4	(m,	9H,	Ar‐H),	
10.0	 (s,	 1H,	 OH).	 Anal.	 calcd.	 for	 C21H15ClN2O3S:	 C,	 61.39;	 H,	
3.68;	N,	6.82;	S,	7.80.	Found:	C,	61.35;	H,	3.66;	N,	6.80;	S,	7.79%.	

2‐(4‐Chlorophenyl)‐5‐hydroxy‐4‐phenylthieno[2,3‐d]	
pyrimidine‐6‐carboxyate	 (8c):	 Colorless	 crystals.	 Yield:	 65%.	
M.p.:	240‐242	oC.	IR	(KBr,	ν,	cm‐1):	3500‐3100	(OH,	NH2),	1665	
(C=O,	 amide).	 1H	NMR	 (300	MHz,	DMSO‐d6,	,	 ppm):	3.42	 (br,	
2H,	NH2),	7.56‐8.12	(m,	9H,	Ar‐H),	10.2	(s,	1H,	OH).	Anal.	calcd.	
for	C19H12ClN3O2S:	C,	59.76;	H,	3.17;	N,	11.00;	S,	8.40.	Found:	C,	
59.74;	H,	3.09;	N,	11.04;	S,	8.39%.	

	

(2‐(4‐Chlorophenyl)‐5‐hydroxy‐4‐phenylthieno[2,3‐d]	
pyrimidine‐6‐yl)(Phenyl)	methanone	 (8d):	 Pale	 yellow	 crystals.	
Yield:	50%.	M.p.:	215‐218	oC.	IR	(KBr,	ν,	cm‐1):	3400	(OH),	1720	
(C=O).	1H	NMR	(300	MHz,	DMSO‐d6,	ppm):	7.21‐8.70	(m,	14H,	
Ar‐H),	10.2	(s,	1H,	OH).	Anal.	calcd.	For	C25H15ClN2O2S:	C,	67.79;	
H,	 3.41;	 N,	 6.32;	 S,	 7.24.	 Found:	 C,	 67.71;	 H,	 3.39;	 N,	 6.31;	 S,	
7.22%.	
	
2.2.6.	6‐(4‐Chlorophenyl)‐3‐hydroxy‐4‐phenylthieno[2,3‐d]	
pyrimidine	dioxide	(9)	
	

Potassium	permanganate	(0.01	mol)	was	added	in	portions	
to	a	solution	of	compound	7b	(0.01	mol)	in	chloroform	(20	mL)	
and	concentrated	H2SO4	(1	mL)	[10].	The	reaction	mixture	was	
left	at	room	temperature	overnight,	 then	ethanol	(10	mL)	was	
added	 and	 filtered	 off.	 The	precipitate	 obtained	was	 collected	
by	 filtration,	 dried	 and	 recrystallized	 from	 ethanol	 yield	 a	
colorless	crystals	(Scheme	2).	Yield:	25%.	M.p.:	120‐122	oC.	 IR	
(KBr,	ν,	cm‐1):	3500	(OH).	1H	NMR	(300	MHz,	DMSO‐d6,	,	ppm):	
7.23	(s,	1H,	 thiophene	proton),	8.28‐8.70	 (m,	9H,	Ar‐H),	11.52	
(br,	1H,	OH).	Anal.	calcd.	for	C18H11ClN2O3S:	C,	58.30;	H,	2.99;	N,	
7.55;	S,	5.65.	Found:	C,	58.29;	H,	2.10;	N,	7.53;	S,	8.66%.	



244	 Shehab	and	Mohamed	/	European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	
	
	 	

 
	

Scheme	3
	
	
2.2.7.	Ethyl	2‐(4‐chlorophenyl)‐4‐((2‐cyanoethyl)thio)‐6‐
phenylpyrimidine‐5‐carboxylate	(10)	
	

A	mixture	of	compound	4	(0.01	mol)	and	acrylonitrile	(0.01	
mol)	 and	 triethylamine	 (4	 drops)	 in	 ethanol	 (20	 mL)	 was	
heated	 under	 reflux	 for	 2	 h.	 After	 cooling	 the	 precipitate	was	
collected	 and	 crystallized	 from	 ethanol	 to	 give	 white	 crystal	
(Scheme	 2).	 Yield:	 40%.	 M.p.:	 118‐120	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	
2220	(CN),	1725	(C=O,	ester).	1H	NMR	(300	MHz,	DMSO‐d6,	,	
ppm):	 1.3	 (t,	 3H,	 CH3CH2),	 4.2	 (q,	 2H,	 CH3CH2),	 4.6	 (m,	 4H,	
2CH2),	7.2‐8.2	 (m,	9H,	Ar‐H).	Anal.	 calcd.	 for	C22H18ClN3O2S:	C,	
62.33;	H,	4.28;	N,	9.91.	Found:	C,	62.40;	H,	4.23;	N,	9.90.	
	
2.2.8.	6‐(4‐Chlorophenyl)‐4‐(cyanomethylthio)‐6‐phenyl	
pyrimidine‐5‐carboxylate	(11)	
	

A	 mixture	 of	 compound	 10	 (0.01	 mol)	 and	 hydrazine	
hydrate	(0.01	mol)	 in	n‐butanol	(20	mL)	was	refluxed	for	2	h.	
The	 precipitate	 obtained	 upon	 cooling	 was	 collected	 and	
crystallized	 from	butanol	 to	give	colorless	 crystal	 (Scheme	2).	
Yield:	 60%.	M.p.:	 230‐232	 oC.	 1H	NMR	 (300	MHz,	DMSO‐d6,	,	
ppm):	4.61	(br,	1H,	NH),	7.2‐8.38	(m,	9H,	Ar‐H),	10.91	(br,	1H,	
OH).	 Anal.	 calcd.	 for	 C17H11ClN4O:	 C,	 63.26;	 H,	 3.44;	 N,	 17.36.	
Found:	C,	63.24;	H,	3.45;	N,	17.34%.	
	
2.2.9.	Diethyl	6,6'‐disulfanediyl	bis(2‐(4‐chlorophenyl)‐4‐
phenylpyrimidine‐5‐carboxylate	(12)	
	

Iodine	 (0.01	mol)	 was	 added	 to	 a	 suspension	 solution	 of	
compound	4	(0.01	mol)	in	acetic	acid	(20	mL)	and	stirred	for	4	
h.	 The	 white	 solid	 that	 obtained	 was	 filtered	 off	 and	
recrystallized	 from	 benzene	 afforded	 a	 colourless	 crystals	
(Scheme	 2).	 Yield:	 52%.	 M.p.:	 140‐142	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	

1710	 (C=O).	 1H	NMR	 (300	MHz,	DMSO‐d6,	,	 ppm):	1.4	 (t,	 6H,	
2CH3CH2),	 4.49	 (q,	 4H,	 2CH3CH2),	 7.34‐8.05	 (m,	 18H,	 Ar‐H).	
Anal.	 calcd.	 for	 C38H28Cl2N4O4S2:	 C,	 61.70;	 H,	 3.82;	 N,	 7.57;	 S,	
8.67.	Found:	C,	61.69;	H,	3.84;	N,	7.56;	S,	8.65%.	
	
2.2.10.	2'‐(4‐Chlorophenyl)‐4'‐phenyl‐2H,5'H‐spiro[furan‐
3,6'‐thieno[2,3‐d]	pyrimidine]‐2,5,5'(4H)‐trione	(13)	
	

A	 mixture	 of	 compound	 4	 (0.01	 mol),	 maleic	 anhydride	
(0.01	mol)	and	few	drops	of	piperidine	(PIP)	in	(20	mL)	xylene	
was	 refluxed	 for	 16	 h.	 The	 solid	 product	 that	 obtained	 after	
cooling	 was	 collected	 by	 filtration,	 dried	 and	 recrystallized	
from	 toluene	 to	 afford	 pale	 gray	 crystals	 (Scheme	 2).	 Yield:	
35%.	 M.p.:	 260‐262	 oC.	 IR	 (KBr,	 ν,	 cm‐1):	 1810‐1702	 (br),	
(2C=O)	 anhydride	 and	 (C=O).	 1H	NMR	 (300	MHz,	DMSO‐d6,	,	
ppm):	3.82	(s,	2H,	CH2),	7.38‐7.98	(m,	9H,	Ar‐H).	Anal.	calcd.	for	
C21H11ClN2O4S:	 C,	 59.65;	 H,	 2.62;	 N,	 6.63;	 S,	 7.58.	 Found:	 C,	
59.67;	H,	2.61;	N,	6.60;	S,	7.56%.	
	
2.2.11.	Ethyl	4‐chloro‐2‐(4‐chlorophenyl)‐6‐phenyl	
pyridimine‐5‐carboxylate	(15)	
	

Chlorine	 gas	 was	 bubbled	 through	 a	 suspension	 of	
compound	4	(0.01	mol)	in	acetic	acid	(20	mL,	25%)	for	about	4	
h	 [11].	 The	 resulting	 product	 was	 collected	 by	 filtration,	
washed	with	water,	dried	and	recrystallized	from	benzene	as	a	
colorless	 crystal	 (Scheme	 3).	 Yield:	 75%.	M.p.:	 100‐102	 oC.	 IR	
(KBr,	 ν,	 cm‐1):	 1725	 (C=O,	 ester),	 1620	 (C=N).	 1H	 NMR	 (300	
MHz,	 DMSO‐d6,	 ,	 ppm):	 1.3	 (t,	 3H,	 CH3CH2),	 4.40	 (q,	 2H,	
CH3CH2),	7.2‐8.0	(m,	9H,	Ar‐H).	Anal.	calcd.	for	C19H14Cl2N2O2:	C,	
61.14;	H,	3.78;	N,	7.51.	Found:	C,	61.10;	H,	3.77;	N,	7.50%.	
	
	



Shehab	and	Mohamed	/	European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	 245	
 

 

 
	

Scheme	4	
	
	
2.2.12.	7‐(4‐Chlorophenyl)‐2‐mercapto‐5‐phenylpyrimido	
[4,5‐d]	pyrimidin‐4	(3H)‐one	(16)	
	

A	mixture	 of	 compound	15	 (0.01	mol)	 and	 thiourea	 (0.01	
mol)	 in	 ethanol	 (30	 mL)	 in	 the	 presence	 of	 triethylamine	 (3	
drops)	 was	 refluxed	 for	 3	 h.	 The	 solid	 that	 separated	 after	
cooling	and	pouring	 into	water	was	collected	by	 filtration	and	
recrystallized	from	ethanol	to	give	brown	crystals	(Scheme	3).	
Yield:	65%.	M.p.:	220‐222	oC.	IR	(KBr,	ν,	cm‐1):	3440	(NH),	1665	
(C=O),	1080	(SH).	 1H	NMR	(300	MHz,	DMSO‐d6,	,	ppm):	7.20‐
8.98	(m,	10H,	Ar‐H	+	NH	proton),	12.2	(s,	1H,	SH).	Anal.	calcd.	
for	C18H11ClN4OS:	C,	58.94;	H,	3.02;	N,	15.27;	S,	8.74.	Found:	C,	
58.90;	H,	3.00;	N,	15.29;	S,	8.70.	
	
2.2.13.	7‐(4‐Chlorophenyl)‐3,4,5‐triphenylpyrimido[4,5‐c]	
pyridazine	(18)	
	

A	 mixture	 of	 compound	 15	 (0.01	 mol)	 and	
benzilmonohydrazone	 (0.01	 mol)	 in	 ethanol	 (30	 mL)	 in	
presence	of	TEA	(3	drops)	was	refluxed	for	2	h.	The	solid	that	
separated	after	cooling	and	pouring	into	water	was	collected	by	
filtration	and	 crystallized	 from	ethanol	 to	 give	yellow	crystals	
(Scheme	3).	 Yield:	 60%.	M.p.:	 200‐202	 oC.	 1H	NMR	 (300	MHz,	
DMSO‐d6,	 ,	 ppm):	 7.21‐8.41	 (m,	 19H,	 Ar‐H).	 Anal.	 calcd.	 for	
C30H19ClN4:	C,	76.51;	H,	4.07;	N,	11.90.	Found:	C,	76.50;	H,	4.02;	
N,	11.89%.	
	
2.2.14.	Ethyl	5‐(4‐chlorophenyl)‐7‐phenyltetrazolo	[1,5‐c]	
pyrimidine‐8‐carboxylate	(20)	
	

A	 mixture	 of	 compound	 15	 (0.01	mol)	 and	 sodium	 azide	
(0.01	mol)	 in	 ethanol	 (30	mL)	was	 refluxed	 for	4	h.	The	 solid	
that	 separated	 after	 cooling	 and	 pouring	 into	 water	 was	
collected	 by	 filtration	 and	 crystallized	 from	 ethanol	 to	 give	
yellow	 crystals	 (Scheme	 3).	 Yield:	 60%.	 M.p.:	 280‐282	 oC.	 IR	
(KBr,	 ν,	 cm‐1):	 1690	 (C=O).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 ,	
ppm):	1.4	 (t,	3H,	CH3CH2),	 4.40	(q,	2H,	CH3CH2),	7.10‐8.12	 (m,	
9H,	 Ar‐H).	 Anal.	 calcd.	 for	 C19H14ClN5O2:	 C,	 60.09;	 H,	 3.72;	 N,	
18.44.	Found:	C,	60.02;	H,	3.71;	N,	18.45%.	
	
2.2.15.	6‐(4‐Chlorophenyl)‐4‐phenyl‐2‐(1‐phenylvinyl)‐1H‐
pyrazolo[3,4‐d]pyrimidin‐3	(2H)‐one	(21)	
	

A	 mixture	 of	 compound	 15	 (0.01	 mol)	 and	
acetophenonehydrazone	 (0.01	 mL)	 and	 a	 drops	 of	 TEA	 in	
ethanol	(20	mL)	was	refluxed	for	6	h.	The	reaction	mixture	was	
cooled,	neutralized	by	hydrochloric	acid	poured	into	ice	water,	
filtered	 off,	 dried	 and	 recrystallized	 from	 ethanol	 to	 give	 a	

yellow	 crystal	 (Scheme	 4).	 Yield:	 65%.	 M.p.:	 190‐192	 oC.	 IR	
(KBr,	 ν,	 cm‐1):	 3440	 (NH),	 1675	 (C=O).	 1H	 NMR	 (300	 MHz,	
DMSO‐d6,	,	ppm):	4.0	(s,	H,	NH),	4.61	(s,	2H,	=CH2),	7.14‐7.79	
(m,	14H,	Ar‐H).	Anal.	calcd.	for	C25H17ClN4O:	C,	70.67;	H,	4.03;	N,	
13.19.	Found:	C,	70.65;	H,	4.01;	N,	13.15%.	
	
3.	Results	and	discussion	
	

The	 present	 work	 involves	 the	 synthesis	 of	 some	 new	
pyrimidine	 and	 condensed	pyrimidine	derivatives.	 Ethyl	 2‐(4‐	
chlorophenyl)1‐4‐mercapto‐6‐phenylpyrimidine‐5‐carboxylate	
(4)	 which	 was	 readily	 synthesized	 by	 the	 interaction	 of	
isothiocyanate	 (2)	 with	 unsaturated	 amino	 ester	 (1)	
presumably	 via	 the	 non‐isolable	 acyclic	 compound	 3	 that	
undergo	intramolecular	cyclodehydration	affording	the	ethyl	2‐
(4‐chlorophenyl)1‐4‐mercapto‐6‐phenylpyrimidine‐5‐
carboxylate	(4)	(Scheme	1).	

In	 an	 attempt	 to	 prepare	 nucleoside	 derivatives	 from	 the	
reaction	 of	 ethyl	 2‐(4‐chlorophenyl)1‐4‐mercapto‐6‐
phenylpyrimidine‐5‐carboxylate	(4)	and	2,3,4,6‐tetra‐O‐acetyl‐
α‐D‐glycopyranosyl	 bromide	 in	 the	 presence	 of	 aqueous	
potassium	 hydroxide	 led	 to	 the	 formation	 of	 S‐glycosyl	
derivative	5.	 The	 formation	 of	 compound	5	 is	 proved	 by	 the	
disappearance	of	ν(SH)	in	IR	spectra	and	appearance	of	signals	
at	 δ	 1.87,	 1.92,	 1.95,	 2.02	 ppm	 due	 to	 the	 four	methyl	 of	 the	
acetyl	 groups	 .	Hydrolysis	of	 compound	5	 using	 triethylamine	
in	 methanol	 afforded	 the	 deacylated	 compound	 6	 which	
showed	 in	 IR	 spectra	 the	 disappearance	 of	 the	 acetyl	 groups	
and	 appearance	 of	 bands	 at	 3420‐3395	 cm‐1	 for	 resulting	 of	
free	hydroxyl	groups.	

The	synthetic	strategy	toward	thienopyrimidine	is	based	on	
bulding	a	thiophene	ring	into	a	pyrimidine	ring	with	two	ortho	
substituents	 one	 electrophilic	 (C=O)	 and	 one	 potentially	
nucleophilic	(SH)	by	its	reaction	with	halomethylene	to	form	a	
thiophene	 ring	with	 appropriate	 functionalities.	 This	 result	 is	
usually	 achieved	 in	 one	 operation	 by	 a	 series	 of	 constitutive	
reactions,	 alkylation	 followed	 by	 ring	 closure	 at	 the	
electrophilic	center	and	subsequent	aromatization	(8a‐d).	

Thus,	 when	 ethyl	 2‐(4‐chlorophenyl)	 1‐4‐mercapto‐6‐
phenylpyrimidine‐5‐carboxylate	(4)	was	allowed	to	react	with	
activated	 halomethylene	 compounds	 (benzyl	 chloride,	 ethyl	
bromoacetate,	 chloroacetamide	 and/or	 phenacyl	 bromide)	
afforded	 the	 corresponding	 4‐alkylthiopyrimidine	 derivatives	
(7a‐d)	 which	 converted	 to	 thienopyrimidine	 (8a‐d)	 upon	
refluxing	in	basic	medium.	

Oxidative	 cyclization	 of	 compound	 7b	 using	 potassium	
permengenate	 in	 acidic	 medium	 afforded	 thienopyrimidine	
dioxide	 (9).	While,	 alkylation	 of	 ethyl	 2‐(4‐chlorophenyl)	 1‐4‐



246	 Shehab	and	Mohamed	/	European	Journal	of	Chemistry	3	(2)	(2012)	241‐246	
	
mercapto‐6‐phenylpyrimidine‐5‐carboxylate	 (4)	 with	
acrylonitrile	 in	 pyrimidine	 afforded	 4‐cyanoethylmercapto	
pyrimidine	 derivative	 (10)	 which	 proved	 its	 structure	 by	
reaction	 with	 hydrazine	 hydrate	 [12]	 giving	 pyrazolo‐
pyrimidine	 (11).The	 IR	 spectra	 of	 compound	 11	 showed	 the	
disappearance	of	the	(C=O)	group	and	the	(CN)	group.	1H	NMR	
of	compound	11	 showed	a	signal	at		 6.41	ppm	characterized	
for	 NH	 group	 of	 pyrazole	 ring.	 Oxidation	 of	 ethyl	 2‐(4‐
chlorophenyl)	 1‐4‐mercapto‐6‐phenylpyrimidine‐5‐carboxy‐
late	 (4)	 using	 iodine	 in	 acetic	 acid	 [13]	 gives	disulphide	 (12).	
Spiro	 compound	 13	 was	 also	 obtained	 by	 addition	 of	
compound	4	 to	maleic	 anhydride	 in	 refluxing	 xylene	 and	 few	
drops	of	piperdine	(Scheme	2).	

Reaction	 of	 compound	 4	 with	 chlorine	 gas	 in	 acetic	 acid	
[14,15]	 gave	 chloropyrimidine	 (15).	 The	 conversion	 of	
compound	4	 into	 compound	15	 may	 be	 proceed	 through	 the	
formation	 of	 pyrimidine‐4‐sulphonyl	 chloride	 (14)	 which	
liberated	 sulfurdioxide	 to	 give	 compound	 15	 which	 reacted	
with	thiourea	affording	the	pyrimidopyrimidine	(16),	while	the	
condensation	of	compound	15	with	benzilmonohydrazone	gave	
the	 corresponding	 pyrimidopyridazine	 (18)	 via	 the	 initial	
formation	 of	 non‐isolated	 open	 form	 (17)	 that	 underwent	
intramolecular	 cyclocondensation	 [16‐18].	 The	 reaction	 of	
compound	 15	 with	 sodium	 azide	 gave	 the	 corresponding	
tetrazolopyrimidine	 (20)	 presumably	 via	 the	 formation	 of	
azide	form	(19).	The	structure	of	compound	20	was	proved	by	
the	disappearance	of	azido	group	in	IR	spectrum	(Scheme	3).	

Finally,	 synthesis	 of	 6‐(4‐chlorophenyl)‐4‐phenyl‐2‐(1‐
phenylvinyl)‐1H‐pyrazolo[3,4‐d]pyrimidine‐3(2H)‐one	 (21)	
was	 achieved	 by	 refluxing	 chloropyrimidine	 (15)	 with	
acetophenonehydrazone	 in	 ethanol	 in	 the	 presence	 of	 TEA	
(Scheme	4).	The	reaction	may	be	proceeding	via	the	formation	
of	 acyclic	 intermediate,	 followed	 by	 Ene‐rearrangement	 then	
ring	cyclization	as	shown	in	the	following	mechanism.	
	
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