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European	Journal	of	Chemistry	4	(2)	(2013)	168‐171	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2013	EURJCHEM	

DOI:10.5155/eurjchem.4.2.168‐171.762	

	
	

	

	

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

	 	 	

Utility	of	(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acetic	acid	hydrazide		
in	the	synthesis	of	some	heterocyclic	nitrogen	compounds	

Mamdouh	Adly	Hassan	a,	Maghrabi	Ali	Seleem	b	,	Ahmed	Mohamed	Mosallem	Younes	b,		
Mohamed	Mobark	Taha	b	and	Abou‐Bakr	Haredi	Abdel‐Monsef	b,*	

a	Pharmaceutical	Chemistry	Department,	Faculty	of	Pharmacy,	Sinai	University,	45518,	Arish,	Egypt	
b	Chemistry	Department,	Faculty	of	Science,	South	Valley	University,	Qena,	83523,	Egypt	

*Corresponding	author	at:	Chemistry	Department,	Faculty	of	Science,	South	Valley	University,	Qena,	83523,	Egypt.		
Tel.:	+20.96.5211281;	fax:	+20.96.5211279.	E‐mail	address:	bakooos2004@yahoo.com	(A.H.	Abdel‐Monsef).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT	
Received:	01	March	2013	
Received	in	revised	form:	30	March	2013	
Accepted:	30	March	2013	
Online:	30	June	2013	

KEYWORDS	

	 An	efficient	synthesis	of	(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acetic	acid	hydrazide	(3)
has	been	achieved	and	described.	The	obtained	hydrazide	(3)	was	used	 in	building	of	 some
interesting	heterocycles	 such	 as,	 triazole,	 oxadiazole,	pyrazole,	phthalazine,	 and	 indol‐2‐one
rings	at	position	3.	The	structures	of	the	obtained	compounds	were	confirmed	by	IR,	1H	NMR,
13C	NMR,	MS	spectral	and	elemental	analysis.	

Isatine			
Acetic	acid	
Phthalimide	
Phenylisothiocyanate	
Quinazoline‐2,4‐dione	
Tetrachlorophthalic	anhydride	

	
1.	Introduction	
	

Quinazolines	are	made	up	of	two	fused	six	member	simple	
aromatic	 rings	 which	 represents	 one	 of	 the	 most	 important	
class	 of	 heterocycles	 possessing	 wide	 spectrum	 of	 biological	
activities	 and	 it	 considered	 the	 building	 block	 of	 many	
biologically	active	compounds	 that	possess	antibacterial	 [1‐8],	
anti‐inflammatory	 [1,2,7]	 and	 antifungal	 [5,9,10].	 Quinazoline	
and	pyrimidine	derivatives	are	 incorporated	 in	a	wide	variety	
of	 pharmaceuticals.	 In	 addition,	 quinazoline	 and	 pyrimidine	
derivatives	are	attracting	important	applications	in	the	field	of	
medicinal	 chemistry;	 the	pyrimidine	 ring	 is	present	 in	 a	 large	
number	 of	 biological	 important	 compounds	 [11].	 This	
encouraged	 us	 to	 synthesize	 new	 quinazoline	 derivatives	
attached	 to	 interesting	 heterocycles	 such	 as	 triazole,	
oxadiazole,	pyrazole	and	phthalazine	rings.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

Melting	 points	 were	 uncorrected	 and	 determined	 on	 an	
electric	melting	point	apparatus	(Kofler).	The	IR	spectra	(KBr)	
were	recorded	on	a	Shimadzu	408	spectrometer.	The	 1H	NMR	
spectra	 were	 recorded	 using	 300	 MHz	 Varian	 EM	 390	
spectrometer;	chemical	shifts	are	reported	in	ppm	with	TMS	as	
an	 internal	standard	and	are	given	 in	δ	units.	Electron	 impact	
mass	 spectra	 were	 obtained	 at	 70	 eV	 with	 Shimadzu	 GC‐MS	
(QP‐2010	plus).	13C	NMR	spectra	were	measured	on	a	JEOL	ECX	
instrument	 400	 MHz	 in	 DMSO‐d6	 and	 carried	 out	 at	 Jacobs	
University	Bremen,	Germany.	Elemental	analyses	were	carried	
out	at	the	Microanalysis	Unit	at	Cairo	University.	The	purity	of	
the	compounds	was	detected	by	TLC.	

	
2.2.	Synthesis		
	
2.2.1.	1‐[(2,4‐Dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐
methylcarbonyl]‐4‐phenylthiosemicarbazide	(4)	
	

To	a	mixture	of	hydrazide	3	(Scheme	1)	(2	g,	0.008	mol)	in	
absolute	 ethanol	 (20	 mL)	 phenyl	 isothiocyanate	 (0.011	 mol)	
was	 added	 and	 the	 reaction	mixture	was	 heated	 under	 reflux	
for	 4	 hrs.,	 then	 left	 to	 cool.	 The	 solid	 that	 separated	 was	
collected	 by	 filtration	 crystallized	 from	 ethanol	 to	 afford	
compound	4	 (1.7	 g,	 0.004	mol)	 as	white	 crystals	 (Scheme	 2).	
Yield:	1.7	g,	54	%.	M.p.:	220	oC.	FT‐IR	(KBr,	ν,	cm‐1):	3339,	3304,	
3292,	 3265	 (NH’s),	 1733,	 1661,	 1635	 (C=O’s).	 1H	 NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	4.7	(s,	2H,	CH2),	7.1‐7.9	(m,	9H,	arom.),	
9.3	 (s,	 1H,	NH),	 9.7	 (s,	 1H,	NH),	 10.4	 (s,	 1H,	NH),	 11.6	 (s,	 1H,	
NH).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	41.7,	113.6,	115.2,	
120.8,	 122.7,	 124.4,	 125.9,	 127.3,	 128.1,	 135.2,	 138.9,	 139.3,	
150.2,	 162,	 167.	 MS	 (m/z,	 %):	 369	 (3.0	 %).	 Anal.	 calcd.	 for	
C17H15N5O3S:	C,55.28;	H,4.08;	N,18.96.	Found:	C,	 55.48;	H,	4.2;	
N,	19.02%.	
	
2.2.2.	3‐(5‐Mercapto‐4‐phenyl‐4H‐[1,2,4]triazol‐3‐ylmethyl)‐
1H‐quinazoline‐2,4‐dione	(5)	
	

Compound	4	was	refluxed	in	NaOH	solution	(10	mL)	for	6	
hrs.	The	mixture	was	 left	 to	 cool,	 filtered,	 and	 the	 filtrate	was	
acidified	with	dil.	HCl.	The	solid	obtained	was	 filtered	off,	and	
crystallized	 from	 benzene/ethanol	 to	 give	 compound	 5	 as	
white	crystals	(Scheme	2).	M.p.:	>300	oC.	 	FT‐IR	(KBr,	ν,	cm‐1):	
3126	(NH),	2510	(SH),	1721,	1663	(C=O’s).	1H	NMR	(300	MHz,	
DMSO‐d6,	δ,	ppm):	4.9	(s,	2H,	CH2),	7.1‐7.9	(m,	9H,	arom.),	11.6	
(s,	1H,	NH),	13.8	(s,	1H,	SH).	



Hassan	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	168‐171	 169	
 

	 	

 
	

Scheme	1	
	
	

 
	

Scheme	2
	
	

13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	35.5,	113.2,	115.2,	120.8,	
122.7,	 127.3,	 127.9,	 129.4,	 133,	 135.3,	 139.2,	 148.2,	 148.5,	
161.3,	 167.9	%).	 Anal.	 calcd.	 for	 C17H13N5O2S:	 C,58.11;	H,3.73;	
N,19.93.	Found:	C,	58.31;	H,	3.75;	N,	20.8%.	
	
2.2.3.	3‐((5‐oxo‐5H‐[1,2,4]triazolo[3,4‐a]isoindol‐3‐yl)	
methyl)quinazoline‐2,4(1H,3H)‐dione	(6)	
	

Heating	 of	 the	 hydrazide	 3	 (1	 g,	 0.004	 mol)	 with	
phthalimide	 (0.75	g,	 0.005	mol)	 in	DMF	 (20	mL)	under	 reflux	
for	 14	 hours	 gave	 after	 cooling	 a	 solid	 product	 which	 was	
filtered	off	and	crystallized	 from	benzene	 to	give	compound	6	
as	yellow	crystals	(Scheme	2).	Yield:	0.4	g,	59	%.	M.p.:	224	oC.	
FT‐IR	(KBr,	ν,	cm‐1):	3200	(NH),	1774,	1752,	1603	(C=O’s).	MS	
(m/z,	%):	345	(1.46	%).	Anal.	calcd.	for	C18H11N5O3:	C,	62.62;	H,	
3.21;	N,	20.28.	Found:	C,	62.9;	H,	3.24;	N,	20.51%.	
	
2.2.4.	3‐Amino‐1‐[2‐(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐
yl)‐acetyl]‐5‐phenyl‐1H‐pyrazole‐4‐carbonitrile	(7)	
	

Benzylidine	 malononitrile	 (0.27	 g,	 0.002	 mol)	 in	 ethanol	
(20	mL)	and	piperidine	as	a	catalyst	was	added	to	hydrazide	3	
(0.4	g,	0.002	mol)	and	the	reaction	mixture	was	refluxed	for	9	
hrs.,	the	formed	solid	product	was	filtered	off	and	recrystallized	
from	 ethanol	 to	 afford	 compound	 7	 (0.16	 g,	 0.0004	 mol)	 as	
white	crystal	(Scheme	3).	Yield:	0.16	g,	66	%.	M.p.:	>300	oC.	FT‐
IR	 (KBr,	 ν,	 cm‐1):	 3300	 (NH),	 3198	 (ν	NH2),	 2250	 (CN),	 1741,	
1637	(C=O’s).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	4.9	(s,	2H,	
CH2),	 7.2‐7.92	 (m,	 9H,	 arom.),	 11.5	 (s,	 2H,	 NH2),	 11.7	 (s,	 1H,	
NH).	13C	NMR	(100	MHz,	DMSO‐d6,	δ,	ppm):	41.4,	113.4,	115.2,	
118.8,	 119.3,	 122.6,	 126.8,	 127,	 127.3,	 128.7,	 129.9,	 133.9,	
135.1,	139.2,	144,	150,	161.7,	168.	Anal.	calcd.	 for	C20H14N6O3:	
C,62.17;	H,3.65;	N,21.75.	Found:	C,	62.38;	H,	3.67;	N,	22.02%.	

	
	

2.2.5.	(2,4‐Dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acetic	acid	
(2‐oxo‐1,2‐dihydro‐indol‐3‐ylidene)‐hydrazide		(8)	
	

Treatment	 of	 hydrazide	 3	 (0.4	 g,	 0.002	 mol)	 with	 isatine	
(0.25	g,	0.002	mol)	in	acetic	acid	(20	mL)	and	reflux	for	9	hrs.	
afforded	 compound	 8	 (0.3	 g,	 0.001	 mol)	 as	 yellow	 crystals	
(Scheme	3).	Yield:	0.3	g,	50	%.	M.p.:	298	oC.	FT‐IR	(KBr,	ν,	cm‐1):	
3306,	 3222,	 3165	 (NH’s),	 1733,	 1752,	 1635	 (C=O’s).	 1H	 NMR	
(300	MHz,	DMSO‐d6,	 δ,	ppm):	5.1	 (s,	2H,	CH2),	 6.9‐7.9	 (m,	8H,	
arom.),	11.2	(s,	1H,	NH),	11.67	(s,	1H,	NH),	12.6	(s,	1H,	NH).	13C	
NMR	 (100	MHz,	 DMSO‐d6,	 δ,	 ppm):	 40.3,	 111.1,	 113.4,	 115.3,	
119.4,	 120.8,	 122.5,	 122.8,	 127.4,	 131.7,	 135.3,	 139.3,	 142.5,	
149.9,	 161.7,	 162.4,	 199.6,	 205.3.	 MS	 (m/z,	 %):	 363	 (6.0	 %).	
Anal.	 calcd.	 for	C18H13N5O4:	C,59.50;	H,3.61;	N,19.28.	Found:	C,	
59.71;	H,	3.63;	N,	20.32%.	
	
2.2.6.	3‐[2‐Oxo‐2‐(5,6,7,8‐tetrachloro‐1,4‐dioxo‐3,4‐dihydro‐
1H‐phthalazin‐2‐yl)‐ethyl]‐1H‐quinazoline‐2,4‐dione	(9)	
	

Tetrachlorophthalic	 anhydride	 (1.2	 g,	 0.004	mol)	 in	 acetic	
acid	(20	mL)	was	added	 to	hydrazide	3	 (1	g,	0.004	mol),	 then	
the	 reaction	mixture	was	 refluxed	 for	9	hrs.,	 the	 formed	solid	
product	was	filtered	off	and	recrystallized	from	dioxane	to	give	
compound	9	 as	white	 crystals	 (Scheme	3).	 Yield:	 1.2	 g,	 57	%.	
M.p.:	 >310	 oC.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3304	 (NH),	 1661,	 1635	
(C=O’s).	1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	4.7	(s,	2H,	CH2),	
7.0‐7.9	 (m,	 4H,	 arom.),	 11.2	 (s,	 1H,	NH),	 11.6	 (s,	 1H,	NH).	MS	
(m/z,	%):	 502	 (1.27%).	 Anal.	 calcd.	 for	 C18H8Cl4N4O5:	 C,43.06;	
H,1.61;	N,11.16.	Found:	C,	43.28;	H,	1.63;	N,	11.92%.	
	
	
	
	
	
	



170	 Hassan	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	168‐171	
	

	

 
	

Scheme	3	
	
	

 
	

Scheme	4
	
	

 
	

Scheme	5
	
	

2.2.7.	Acetic	acid	N'‐[2‐(2,4‐dioxo‐1,4‐dihydro‐2H‐
quinazolin‐3‐yl)‐acetyl]‐hydrazide	(10)	

	
Refluxing	of	hydrazide	3	(0.5	g,	0.002	mol)	with	acetic	acid	

(20	mL)	for	8	hrs.	On	cooling,	 the	separated	solid	was	filtered	
off	and	crystallized	from	acetic	acid	to	give	compound	10	(0.4	g,	
0.0015	mol)	 as	white	 crystals	 (Scheme	 3).	 Yield:	 0.4	 g,	 66	%.	
M.p.:	 >300	 oC.	 FT‐IR	 (KBr,	 ν,	 cm‐1):	 3304,	 3282,	 3265	 (NH’s),	
1733,	 1732,	 1635	 (C=O’s).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	1.9	(s,	3H,	CH3),	4.5	(s,	2H,	CH2),	7.1‐7.9	(m,	4H,	arom.),	
9.8	(s,	1H,	NH),	10.1	(s,	1H,	NH),	11.5	(s,	1H,	NH).	13C	NMR	(100	
MHz,	DMSO‐d6,	δ,	ppm):	20.9,	41.6,	114.1,	115.7,	123.1,	127.9,	
135.7,	139.9,	150.4,	162.3,	166.3,	168.4.	MS	(m/z,	%):	276	(3.0	
%).	Anal.	calcd.	for	C12H12N4O4:	C,52.18;	H,4.37;	N,20.28.	Found:	
C,	52.39;	H,	4.39;	N,	20.35	%.	
	
	
	

3.	Results	and	discussion	
	

In	 this	work,	we	were	 able	 to	 introduce	 the	 amino	 group	
which	 is	 present	 in	 glycine	 ethyl	 ester	 hydrochloride	 into	 the	
sulphonyloxy	system	in	N‐phenylsulphonyloxyphthalimide	1	to	
obtain	 (2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acetic	 acid	
ethyl	 ester	2	 which	 on	 treatment	with	 hydrazine	 hydrates	 in	
ethanol	 	 gave	 the	 hydrazide	 3	 (Scheme	 1)	 [12].	 Scheme	 4	
outlines	 the	 synthetic	 pathway	 used	 to	 obtain	 (2,4‐dioxo‐1,4‐
dihydro‐2H‐quinazolin‐3‐yl)‐acetic	 acid	 hydrazide	3	 [12].	 The	
route	outlined	 in	Scheme	2	shown	 that	hydrazide	3	 used	as	a	
starting	 material	 for	 synthesis	 of	 some	 new	 quinazoline	
derivatives	 attached	 to	 interesting	 heterocycles	 such	 as	
triazole,	oxadiazole,	pyrazole	and		phthalazine	rings	which	have	
biological	effects	[13,14],	and		many	applications	were	they	are	
used	as	fungicidal	and	bacterial	reagents	[15].		

	
	



Hassan	et	al.	/	European	Journal	of	Chemistry	4	(2)	(2013)	168‐171	 171	
 

	

 
	

Scheme	6
	
	
Scheme	 5	 and	 6	 outline	 the	 synthetic	 pathway	 used	 to	

synthesis	 1‐[(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐met‐
hylcarbonyl]‐4‐phenylthiosemicarbazide	 4	 and	 3‐((5‐oxo‐5H‐
[1,2,4]triazolo[3,4‐a]isoindol‐3‐yl)methyl)quinazoline‐2,4(1H,	
3H)‐dione	 (6).	 Scheme	 3	 shows	 the	 results	 of	 treatment	 of	
hydrazide	3	with	benzylidine	malononitrile,	isatine,	tetrachloro	
phthalic	 anhydride	 and	 acetic	 acid.	 Treatment	 of	 hydrazide	3	
with	benzylidine	malononitrile	in	ethanol	under	reflux	gave	3‐
amino‐1‐[2‐(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acet‐
yl]‐5‐phenyl‐1H‐pyrazole‐4‐carbonitrile,	 7,	 which	 contains	
pyrazole	 ring.	 As	 a	 part	 of	 our	 program	 aimed	 to	 synthesize	
new	 rings	 attached	 to	 quinazoline	 ring	 as	 we	 notice	 in	
compounds	8	and	9	which	contain	indol‐2‐one	and	phthalazine	
rings,	respectively,	by	reacting	of	hydrazide	3	with	isatine	and	
tetrachlorophthalic	 anhydride,	 respectively.	 Treatment	 of	
hydrazide	3	with	acetic	acid	under	reflux	gave	acetic	acid	N'‐[2‐
(2,4‐dioxo‐1,4‐dihydro‐2H‐quinazolin‐3‐yl)‐acetyl]‐hydrazide,	
10.	
	
4.	Conclusion	
	

The	 synthesis	 of	 new	 quinazolindione	 derivatives	 was	
achieved	 and	 structural	 verification	was	 achieved	 by	 spectral	
and	physical	analysis.		
	
Acknowledgments	

	
The	 authors	 are	 grateful	 to	 the	 spirit	 of	 Prof.	 Dr.	 Youssef	

Hassan	Ebeed,	Faculty	of	Science,	South	Valley	University,	Rami	
Al‐Oweini	 and	 Ibrahim	 Mohamed	 Ismael	 for	 their	 help	 in	
analysis	of	some	samples.	
	
References	
	
[1]. Bakhite,	E.	A.;	Radwan,	S.	M.;	El‐deen,	A.	M.	K.	J.	Chin.	Chem.	Soc.	2000,	

47(5),	1105‐1114.		
[2]. Younes,	M.	I.;	Abbas,	H.	H.;	Metwally,	S.	A.	M.	Pharmazine	1999,	46(2),	

98‐100.		
[3]. Rideout,	J.	L.;	Krenitesky,	T.	A.;	Chao,	E.	Y.;	Elion,	G.	B.;	Williams,	R.	B.;	

Latter	,	V.	S.	J.	Med.	Chem.	1983,	26(10),	1489‐1494.		
[4]. Rideout,	J.	L.;	Krenitesky,	T.	A.;	Koszalka.	G.	W.;	Coln,	N.	K.;	Chao,	E.	Y.;	

Elion,	G.	B.;	Latter,	V.	S.;	Williams,	R.	B.	J.	M.	Chem.	1982,	25(9),	1040‐
1044.		

[5]. Marie,	M.	 G.;	 Aly,	 D.	M.;	Mishrikey,	M.	M.	Bull.	Chem.	Soc.	 Jpn.	1992,	
65(12),	3419‐3422.		

[6]. Krenitesky,	T.	A.;	Rideout,	J.	L.;	Koszalka,	G.	W.;	Inmmon,	R.	B.;	Chao,	E.	
Y.;	Elion,	G.	B.	J.	Med.	Chem.	1982,	25(1),	32‐35.		

[7]. Gatta,	F.;	Perotti,	F.;	Gradoni,	L.;	Gramiccia,	M.;	Orsini,	S.;	Palazzo,	G.;	
Rossi,	V.	Eur.	J.	Med.	Chem.	1990,	30,	419‐424.		

[8]. Ugarkar,	B.	G.;	Cottam,	H.	B.;	Mekernan,	P.	A.;	Robins,	R.	K.;	Revankar,	
G.	R.	J.	Med.	Chem.	1984,	27(8),	1026‐1030.		

[9]. Makara,	G.	M.;	Ewing,	W.;	winter,	E.	J.	Org.	Chem.	2001,	66(17),	5783‐
5787.		

[10]. Mishara,	B.;	Muddin,	N.	Indian	J.	Chem.	1989,	28B,	337‐346.		
[11]. Ostrowski,	S.;	Swat,	J.;	Makosza,	M.	Arkivoc	2000,	1(6),	905‐908.		
[12]. Hassan,	 M.	 A.;	 Seleem,	 M.	 A.;	 Younes,	 A.	 M.	 M.;	 Taha,	 M.	 M.;	 Abdel‐

Monsef,	A.	H.	Eur.	J	Chem.	2013,	4(2),	121‐123.		
[13]. Ram,	V.;	Pandey,	H.	N.	Chem.	Pharm.	Bull.	(Jpn.)	1974,	22,	2778‐2783.		
[14]. Parmar,	S.;	Chaudhary,	M.;	Chaudhary,	S.;	Kumar,	S.;	Spiro,	H.	J.	Pharm.	

Sci.	1977,	66,	971‐975.		
[15]. Jain,	R.;	Shukla,	A.	Indian	J.	Chem.	Soc.	1990,	67,	575‐579.