untitled


European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	

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

DOI:10.5155/eurjchem.3.2.129‐137.579	

	
	

	

	

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

	 	 	

Convenient	synthesis	of	some	new	pyrazolo[5,1‐c]triazines,	isoxazolo[3,4‐d]	
pyrimidine	and	pyridine	derivatives	containing	benzofuran	moiety	

Abdou	Osman	Abdelhamid*,	Abdelgawad	Ali	Fahmi	and	Amna	Ali	Mohamed	Alsheflo	

Department	of	Chemistry,	Faculty	of	Science,	Cairo	University,	Giza	12613,	Egypt	

*Corresponding	author	at:	Department	of	Chemistry,	Faculty	of	Science,	Cairo	University,	Giza	12613,	Egypt.		
Tel.:	+202.35676573;	fax:	+202.35727556.	E‐mail	address:	abdelhamid45@gmail.com		(A.O.	Abdelhamid).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT
Received:	26	December	2011	
Received	in	revised	form:	04	February	2012	
Accepted:	04	February	2012	
Online:	30	June	2012	

KEYWORDS	

	 Pyrazolo[5,1‐c][1,2,4]triazine,	 [1,2,4]triazolo[3,4‐c][1,2,4]triazine,	 benzo[4,5]‐imidazo[2,1‐
c][1,2,4]triazine,	 isoxazole,	 isoxazolo[3,4‐d]pyridazine,	 pyrazole,	 pyridine,	 substituted	 urea
and	 phenyl	 carbamate	 derivatives	 containing	 benzofuran	 moiety	 were	 synthesized	 via
reaction	 of	 sodium	 salt	 of	 5‐hydroxy‐l‐benzofuran‐2‐ylpropenone	 or	 1‐(benzofuran‐2‐yl)‐3‐
(dimethylamino)prop‐2‐en‐1‐one	with	diazotized	heterocyclic	amines,	hydroximoyl	chlorides
and	 active	 methylene	 compounds.	 The	 structures	 of	 all	 the	 newly	 synthesized	 compounds
were	 confirmed	 by	 elemental	 analyses,	 spectral	 data,	 and	 alternative	 synthetic	 routes,
whenever	possible.	

Triazines	
Pyridines	
Pyrazoles	
Isoxazoles	
Hydrazones	
Benzoimidazo[2,1‐c][1,2,4]triazine	

	
1.	Introduction	
	

The	 considerable	 biological	 and	 medicinal	 activities	 of	
pyrazolotriazines	 and	 triazolotriazines,	 as	 adenine	 analogues,	
antagonists,	antischistosomal	and	antitumor	agents	 [1‐3]	have	
stimulated	interest	in	the	synthesis	of	these	ring	systems.	Also,	
some	 pyrazoloazines	 are	 found	 to	 be	 useful	 in	 agricultural	
applications	as	herbicides	and	plant	growth	regulants	 [4],	and	
in	 medicinal	 applications	 as	 antibiotics	 [5],	 antilipemics	 and	
cardiotonics	[6],	central	nervous	system	agents	[7],	anxiolytics	
[8],	 treatment	of	 influenza	[9],	antidepressants	and	antihyper‐
tensives	 [10],	 and	 its	 antileishmanial	 and	 antitrypanosomal	
activities	[11].		

In	 continuation	 of	 our	 interest	 in	 the	 synthesis	 of	
heterocycles	[12‐16],	we	report	herein	a	convenient	method	for	
the	 synthesis	 of	 pyrazolo[5,l‐c]triazines,	 [l,2,4]triazolo[4,3‐c]	
triazine,	 benzo[4,5]imidazo[2,1‐c]triazine,	 isoxazole,	 isoxazolo	
[3,4‐d]pyrimidine,	 pyridines,	 and	 pyrazoles	 containing	
benzofuran	moiety.	
	
2.	Experimental	
	
2.1.	Instrumentation	
	

All	 melting	 points	 were	 determined	 on	 an	 electrothermal	
apparatus	and	are	uncorrected.	The	 IR	spectra	were	recorded	
(KBr	discs)	on	a	Shimadzu	FT‐IR	8201	PC	spectrophotometer.	
The	 1H	 NMR	 spectra	 were	 recorded	 in	 CDCl3	 and	 (CD3)2SO	
solutions	 on	 a	 Varian	 Gemini	 300	 MHz	 spectrometer	 and	
chemical	 shifts	are	expressed	 in		 ppm	units	using	TMS	as	an	
internal	reference.	The	mass	spectra	were	recorded	on	a	GC‐MS	
QP1000	EX	Shimadzu.	Elemental	analyses	were	 carried	out	at	
the	Microanalytical	Center	of	Cairo	University.		
	

2.2.	Pyrazolo[5,1‐c]triazines	(6a‐c),	triazolo[3,4‐c][1,2,4]	
triazine	(10)	and	benzo[4,5]imidazo[2,1‐c][1,2,4]triazine	
(11)	

	
A	 solution	 of	 the	 appropriate	 of	 5‐phenylpyrazole‐3‐

diazonium	 chloride	 (3a),	 4‐phenylpyrazole3‐diazonium	
chloride	 (3b),	 4‐cyanopyrazole‐3‐diazonium	 chloride	 (3c),	
triazole‐3‐diazonium	 nitrate	 or	 benzimidazole‐2‐diazonium	
sulphate	 was	 added	 to	 a	 cold	 mixture	 of	 the	 appropriate	
sodium	 salt	 of	 1‐(benzofuran‐2‐yl)‐3‐hydroxyprop‐2‐en‐1‐one	
(2),	 (which	 is	 prepared	 from	 benzofuran‐2‐ylethanone	 and	
ethyl	 formate	 in	 presence	 of	 sodium	 methoxide),	 or																					
1‐(benzofuran‐2‐yl)‐3‐(dimethylamino)prop‐2‐en‐1‐one	 (7)	 (5	
mmol)	 and	 sodium	 acetate	 (0.65	 gm,	 5	mmol)	 in	 ethanol	 (40	
mL)	at	0‐5	 °C,	while	 stirring	 for	30	min.	The	 reaction	mixture	
was	 stirred	 for	 further	 3	 h.	 The	 resulting	 solid	was	 collected	
and	 recrystallized	 from	 the	 proper	 solvent	 to	 give	 the	
corresponding	6a‐c,	10	and	11,	respectively,	(Scheme	1‐3).	

(Benzofuran‐2‐yl)(8‐phenylpyrazolo[5,1‐c][1,2,4]triazin‐3‐
yl)methanone	 (6a):	 Yellow	 crystals.	 Crystallization	 from	
ethanol.	Yield:	91%.	M.p.:	258‐260	°C.	FT‐IR	(KBr,	cm‐1):	3018	
(CH),	 1645	(CO),	 1612	(C=N),	 1556	(C=C).	 1H	NMR	 (300	
MHz,	DMSO‐d6,	δ,	ppm):	7.43‐8.20	 (m,	8H,	ArH's	and	pyrazole	
H‐5),	 8.57‐8.59	 (m,	 3H,	 ArH's),	 8.80	 (s,	 1H,	 ArH).	MS	 (EI,	m/z	
(%)):	341	(M+,	100),	313	(87),	284	(16),	257	(23),	227	(9),	154	
(54),	145	(32),	142	(69),	128	(52),	113	(27),	101	(24),	76	(87),	
62	(34).	Anal.	calcd.	for	C20H12N4O2	(340.33):	C,	70.58;	H,	3.55;	
N,	16.46.	Found:	C,	70.75;	H,	3.41;	N,	16.59%.	

(Benzofuran‐2‐yl)(7‐phenylpyrazolo[5,1‐c][1,2,4]triazin‐3‐
yl)methanone	(6b):	Orange	crystals.	Crystallization	from	AcOH.	
Yield:	 92%.	 M.p.:	 233‐235	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3032	 (CH),	
1646	 (CO),	 1612	 (C=N),	 1541	 (C=C).	 1H	 NMR	 (300	 MHz,	
DMSO‐d6,	δ,	ppm):	7.42‐8.62	(m,	10H,	ArH's	and	pyrazole	H‐5),	
9.24	(s,	1H,	ArH's),	9.81	(s,	1H,	ArH).		

	



130	 Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	
	

	

O

O

CH3

+ HCOOC2H5
O

O

ONa
1 2

MeONa

N
H

N
N2Cl

X

3

O

O

N
N

HN

N

X

HO
O

O

N
N

N

N

Ph

HO

45

H

O

O

N
N

N

N

X6

Y

Y

Y

Y

a, X = C6H5 Y = H
b, X = H Y = C6H5
c, X = H Y = CN

- H2O

	
	

Scheme	1
	
	
MS	 (EI,	m/z	 (%)):	 341	 (M+,	 100),	 312	 (22),	 285	 (26),	 256	

(16),	229	(9),	156	(17),	145	(59),	142	(70),	128	(41),	101	(22),	
76	(26),	62	(33).	Anal.	calcd.	for	C20H12N4O2	(340.33):	C,	70.58;	
H,	3.55;	N,	16.46.	Found:	C,	70.57;	H,	3.68;	N,	16.38%.	

4‐(Benzofuran‐2‐carbonyl)‐pyrazolo[5,1‐c][1,2,4]triazine‐8‐
carbonitrile	(6c):	Yellow	crystals.	Crystallization	 from	ethanol.	
Yield:	 89%.	 M.p.:	 302‐304	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 2223	 (CN),	
1640	 (CO),	 1563	 (C=C).	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	6.68	(s,	1H,	pyrazole	H‐5),	7.36‐8.14	(m,	5H,	ArH's),	9.24	
(s,	 1H,	 ArH's).	MS	 (EI,	m/z	 (%)):	 290	 (M+1,	 3),	 289	 (M+,	 15),	
179	 (13),	 145	 (27),	 142	 (15),	 114	 (6),	 101	 (5),	 88	 (100),	 76	
(25),	 64	 (17),	 62	 (63).	 Anal.	 calcd.	 for	 C15H7N5O2	 (289.25):	 C,	
62.29;	H,	2.44;	N,	24.21.	Found:	C,	62.38;	H,	2.52;	N,	24.40%.	

([1,2,4]Triazolo[3,4‐c][1,2,4]triazin‐6‐yl)(benzofuran‐2‐yl)	
methanone	 (10):	 Yellow	 crystals.	 Crystallization	 from	 AcOH.	
Yield:	 89%.	 M.p.:	 220‐222	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3065	 (CH),	
1642	 (CO),	 1529	 (C=C)	 .	 1H	 NMR	 (300	 MHz,	 DMSO‐d6,	 δ,	
ppm):	6.70‐8.20	 (m,	5H,	ArH's),	9.24	 (s,	1H,	ArH),	9.46	 (s,	1H,	
ArH).	MS	(EI,	m/z	 (%)):	265	(M+,	63),	237	(16),	182	(19),	155	
(100),	145	(25),	127	(27),	113	(17),	100	(20),	88	(93),	75	(21),	
62	(63).	Anal.	calcd.	for	C13H7N5O2	(265.23):	C,	58.87;	H,	2.66;	N,	
26.41.	Found:	C,	58.67;	H,	2.55;	N,	26.31%.	

Benzofuran‐2‐yl‐benzo[4,5]imidazo[2,1‐c][1,2,4]triazin‐4‐yl‐
methanone	(11):	Buff	crystals.	Crystallization	from	AcOH.	Yield:	
90%.	M.p.:	>	300	°C.	FT‐IR	(KBr,	cm‐1):	3065	(CH),	1712	(CO),	
1529	(C=C).	 1H	NMR	(300	MHz,	DMSO‐d6,	δ,	ppm):	7.20‐7.54	
(m,	8H,	ArH's),	7.55	(s,	1H,	ArH),	7.96	(s,	1H,	ArH).	MS	(EI,	m/z	
(%)):	314	(M+,	3),	286	(8),	221	(6),	166	(6),	164	(11),	152	(6),	
130	 (8),	 120	 (12),	 119	 (21),	 105	 (25),	 104	 (46),	 98	 (12),	 97	

(21),	 91	 (56),	 83	 (17),	 77	 (49),	 65	 (16).	 Anal.	 calcd.	 for	
C18H10N4O2	(314.3):	C,	68.79;	H,	3.21;	N,	17.83.	Found:	C,	68.94;	
H,	3.35;	N,	17.95%.	
	
2.3.	Arylhydrazones	(12a)	and	(12b)	
	

Benzenediazonium	chloride	or	4‐methylbenzenediazonium	
chloride	 (5	 mmol)	 was	 added	 dropwise	 with	 continuous	
cooling	and	stirring	to	a	stirred	solution	of	the	appropriate	2	or	
7	 (5	mmol),	 in	 ethanol	 (15	mL)	 at	 0‐5	 °C;	 containing	 sodium	
acetate	 (0.65	 g,	 5	 mmol)	 as	 a	 buffer	 solution.	 The	 reaction	
mixture	was	stirred	for	3	h.	The	reaction	mixture	was	left	on	a	
refrigerator	 overnight.	 The	 resulting	 solid,	 was	 collected,	
washed	 with	 water	 and	 recrystallized	 to	 give	 12a	 and	 12b,	
respectively,	(Scheme	4).	

2‐(2‐Phenylhydrazono)‐3‐(benzofuran‐2‐yl)‐3‐oxopropanal	
(12a):	 Red	 crystals.	 Crystallization	 from	 ethanol.	 Yield:	 94%.	
M.p.:	 140‐142	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3089	(CH),	 1654	(CO),	
1529	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.28‐7.93	(m,	
10H,	ArH's),	9.98	 (s,	1H,	 ‐CHO),	14.39	 (s,	br.,	1H,	NH).	MS	 (EI,	
m/z	(%)):	292	(M+,	26),	263	(13),	209	(21),	180	(9),	172	(62),	
145	 (70),	 118	 (15),	 92	 (88),	 89	 (100),	 77	 (55),	 62	 (34).	Anal.	
calcd.	for	C17H12N2O3	(292.29):	C,	69.86;	H,	4.14;	N,	9.58.	Found:	
C,	69.77;	H,	4.22;	N,	9.68%. 

2‐(2‐p‐Tolylhydrazono)‐3‐(benzofuran‐2‐yl)‐3‐oxopropanal	
(12b):	 Orange	 crystals.	 Crystallization	 from	 ethanol.	 Yield:	
95%.	 M.p.:	 144‐146	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3082	 (CH),	 1654	
(CO),	1540	(C=C).		

	



Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	 131	
 

	

O

O

N
H3C

CH3

7

N
H

N
N2Cl

Ph

+

3a

O

O

N
N N

H
N

N

CH3
CH3

Ph
8

O

O

N

N

N

N

N

CH3

CH3

Ph

9

H
O

O

N
N

N N

Ph

6a

- N(CH3)2

	
	

Scheme	2
	
	
1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	2.34	(s,	3H,	CH3),	7.28‐

7.93	 (m,	9H,	ArH's),	 9.98	 (s,	1H,	 ‐CHO),	14.39	 (s,	 br.,	 1H,	NH).	
MS	 (EI,	m/z	 (%)):	 307	 (M+1,	 8),	 306	 (M+,	 38),	 186	 (46),	 170	
(35),	169	(9),	172	(62),	145	(70),	118	(15),	92	(88),	89	(100),	
77	 (100),	157	 (11),	 138	 (40),	 121	 (77),	 115	 (10),	 93	 (13),	 65	
(13).	Anal.	calcd.	 for	C18H14N2O3	(306.32):	C,	70.58;	H,	4.61;	N,	
9.15.	Found:	C,	70.67;	H,	4.82;	N,	9.28%. 
	
2.4.	Pyrazoles	(13a)	and	(13b)	
	
Method	A		
	

Equimolar	 amounts	 of	 each	 of	 2‐(2‐phenylhydrazono)‐3‐
(benzofuran‐2‐yl)‐3‐oxopropanal	 (12a)	or	2‐(2‐p‐tolylhydrazo	
no)‐3‐(benzofuran‐2‐yl)‐3‐oxopropanal	 (12b)	 and	 hydrazine	
hydrate	 (4	 mmol	 for	 each)	 in	 ethanol	 (10	 mL)	 were	 heated	
under	 reflux	 for	 4	 h.	 The	 resulting	 solid,	 so	 formed,	 after	
cooling	was	recrystallized	 from	the	proper	solvent	 to	give	 the	
corresponding	13a	and	13b,	respectively,	(Scheme	4).	
	
Method	B	
	

A	 solution	 of	 the	 appropriate	 arendiazonium	 chloride	 (5	
mmol	 for	 each)	 was	 added	 dropwise	 to	 a	 stirred	 solution	 of							
3‐(benzofuran‐2‐yl)‐1H‐pyrazole	 (14)	 (0.9	 g,	 5	 mmol)	 in	
ethanolic	solution	(15	mL)	at	0‐5	°C,	containing	sodium	acetate	
as	 a	buffer	 solution.	The	 reaction	mixture	was	stirred	 for	3	h.	
and	 was	 left	 on	 a	 refrigerator	 overnight.	 The	 resulting	 solid,	
was	 collected,	 washed	 with	 water	 and	 recrystallized	 to	 give	
products	 identical	 in	 all	 respects	 with	 12a	 and	 12b,	
respectively,	(Scheme	4).	

1‐(3‐(Benzofuran‐2‐yl)‐4H‐pyrazol‐4‐ylidene)‐2‐phenyl	
hydrazine	 (13a):	 Yellow	 crystals.	 Crystallization	 from	 AcOH.	
Yield:	84%.	M.p.:	222‐224	 °C.	FT‐IR	 (KBr,	 cm‐1):	1630	(C=N),	
1540	(C=C).	MS	(EI,	m/z	 (%)):	287	(M+‐1,	10),	237	(12),	213	
(13),	 199	 (10),	 165	 (32),	 149	 (100),	 130	 (18),	 124	 (15),	 104	
(44),	100	 (15),	97	 (26),	90	 (27),	76	 (55),	65	 (53).	Anal.	 calcd.	
for	 C17H12N4O	 (288.3):	 C,	 70.82;	 H,	 4.20;	 N,	 19.43.	 Found:	 C,	
70.95;	H,	4.32;	N,	19.38%. 

1‐(3‐(Benzofuran‐2‐yl)‐4H‐pyrazol‐4‐ylidene)‐2‐p‐tolyl	
hydrazine	 (13b):	 Gray	 crystals.	 Crystallization	 from	 EtOH.	

Yield:	98%.	M.p.:	198‐200	 °C.	FT‐IR	 (KBr,	 cm‐1):	1614	(C=N),	
1574	(C=C).	MS	(EI,	m/z	(%)):	305	(M++2,	0.2),	214	(100),	145	
(32),	 118	 (27),	 89	 (20),	 71	 (23),	 63	 (13).	 Anal.	 calcd.	 for	
C18H14N4O	(302.33)	C,	71.51;	H,	4.67;	N,	18.53.	Found:	C,	71.64;	
H,	4.78;	N,	18.37%.	
	
2.5.	3‐(Benzofuran‐2‐yl)‐1H‐pyrazole	(14)	
	

Equimolar	 amounts	 of	 1‐(benzofuran‐2‐yl)‐3‐(dimethyl	
amino)prop‐2‐en‐1‐one	(7)	and	hydrazine	hydrate	(5	mmol	for	
each)	in	ethanol	(10	mL)	containing	tow	drops	piperidine	as	a	
catalyst	were	boiled	under	reflux	for	4	h.	The	resulting	solid,	so	
formed,	 after	 cooling	was	 recrystallized	 to	 give	14	 as	 a	 beige	
crystals	 (Scheme	 4).	 Crystallization	 from	 EtOH	 Yield:	 69.4%.	
M.p.:	142‐144	°C.	FT‐IR	(KBr,	cm‐1):	3136	(NH),	1620	(C=N),	
1539	(C=C).	MS	 (EI,	m/z	 (%)):	 184	 (M+,	 100),	 155	 (25),	 149	
(50),	138	(25),	135	(19),	102	(25),	78	(19),	75	(19),	69	(36),	60	
(33),	 57	 (63).	 Anal.	 calcd.	 for	 C11H8N2O	 (184.19):	 C,	 71.73;	H,	
4.38;	N,	15.21.	Found:	C,	71.89;	H,	4.51;	N,	15.35%. 
	
2.6.	Isoxazoles	(17a‐c)	
	
Method	A		
	

Triethylamine	 (0.5	 g,	 0.75	 mL,	 5	 mmol)	 was	 added	
dropwise	 to	 equimolar	 a	 mount	 of	 7	 and	 the	 appropriate	
hydroximoyl	chlorides	15a‐c	(5	mmol,	each)	in	dry	toluene	(20	
mL)	while	 stirring.	 The	 reaction	mixture	was	 stirred	 for	 6	 h;	
evaporate	the	solvent	and	then	triturated	with	petroleum	ether	
(40‐60	 oC).	 The	 resulting	 solid	 was	 collected	 and	 crystallized	
gave	17a‐c,	respectively,	(Scheme	5).	
	
Method	B	
	

Equimolar	 amount	 of	7	 and	 the	 appropriate	 hydroximoyl	
chloride	15a‐c	(5	mmol,	for	each)	in	dry	toluene	(20	mL)	were	
heated	under	reflux	for	18	h.	The	reaction	mixture	was	filtered	
off	 and	 the	 filtrate	 was	 evaporated	 and	 triturated	 with	
petroleum	 ether	 (40‐60	 oC).	 The	 resulting	 solid	was	 collected	
and	 crystallized	 to	 give	products	 identical	 in	 all	 aspects	 (M.p.,	
mixed	m.p.	and	spectra)	with	17a‐c,	(Scheme	5).	



132	 Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	
	

	

O

R ONa

N
H

NN

N2NO3

O

R

N
N N

N
N

2
7

3d

10

R = benzofuran-2-yl

N
H

N
N2HSO4

O

R

N
N N

N

3e

11

O

R N
CH3

CH3

3d

3e

	
	

Scheme	3
	
	
Benzofuran‐2‐yl‐(4‐benzoyl‐isoxazol‐3‐yl)‐methanone	 (17a):	

Brown	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 80%.	 M.p.:	
178‐180	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3066	(CH),	1651	(CO),	 1623	
(C=N),	1550	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.22‐
7.75	 (m,	8H,	 ArH's),	 9.34	 (d,	 2H,	 J	 =	8	Hz,	ArH's),	 8.67	 (s,	 1H,	
isoxazole	H‐5).	MS	(EI,	m/z	 (%)):	317	(M+,	62),	315	(M‐1,	45),	
301	(16),	287	(18),	285	(18),	237	(84),	194	(12),	166	(16),	161	
(35),	133	 (20),	108	 (14),	90	 (11),	77	 (12),	63	 (9).	Anal.	 calcd.	
for	 C19H11NO4	 (317.29):	 C,	 71.92;	 H,	 3.49;	 N,	 4.41.	 Found:	 C,	
72.12;	H,	3.56;	N,	4.62%. 

Benzofuran‐2‐yl‐[4‐(furan‐2‐oyl)‐isoxazol‐3‐yl]‐methanone	
(17b):	Brown	 crystals.	 Crystallization	 from	AcOH.	Yield:	79%.	
M.p.:	 142‐144	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3093	(CH),	 1685	(CO),	
1639	(C=N),	1554	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
6.61	(d,	1H,	J	=	5	Hz,	furan‐H‐4),	7.22‐7.66	(m,	6H,	ArH's),	7.77	
(s,	1H,	furan	H‐5),	8.75	(s,	1H,	isoxazole	H‐5).	MS	(EI,	m/z	(%)):	
307	(M+,	26),	290	(16),	246	(10),	218	(5),	171	(20),	152	(13),	
143	 (100),	128	 (28),	 115	 (74),	 101	 (19),	 89	 (12),	 77	 (25),	 65	
(15),	 51	 (14).	 Anal.	 calcd.	 for	 C17H9NO5	 (307.26):	 C,	 66.45;	 H,	
2.95;	N,	4.56.	Found:	C,	66.65;	H,	3.11;	N,	4.68%. 

Benzofuran‐2‐yl‐[4‐(thien‐2‐oyl)‐isoxazol‐3‐yl]‐methanone	
(17c):	 Beige	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 79%.	
M.p.:	 110‐112	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3093	(CH),	 1672	(CO),	
1554.	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	6.61	(d,	1H,	J	=	
5	Hz,	furan‐H‐4),	7.22‐7.66	(m,	6H,	ArH's),	7.77	(d,	1H,	J	=	5	Hz,	
furan	H‐5),	 8.75	 (s,	1H,	 isoxazole	H‐5).	MS	 (EI,	m/z	 (%)):	322	
(M+,	 6),	 307	 (6),	 291	 (10),	 275	 (18),	 265	 (16),	 249	 (46),	 213	
(14),	187	(12),	148	(20),	121	(42),	92	(45),	77	(16),	72	(100),	
65	(15).	Anal.	calcd.	 for	C17H9NO4S	(323.32):	C,	63.15;	H,	2.81;	
N,	4.33;	S,	9.92.	Found:	C,	63.27;	H,	2.72;	N,	4.57;	S,	10.12%.	
	
2.6.	Isoxazolo[3,4‐d]pyridazines	(18a‐c)	
	

Equimolar	 a	 mount	 of	 each	 of	 the	 appropriate	 isoxazoles	
17a‐c	(5	mmol)	and	hydrazine	hydrate	(1	mL,	99%)	in	ethanol	
(20	mL)	was	boiled	under	reflux	for	2h.	The	resulting	solid	was	
collected	 and	 crystallized	 to	 give	 isoxazolo[3,4‐d]pyridazines	
18a‐c,	(Scheme	5).	

7‐(Benzofuran‐2‐yl)‐4‐phenylisoxazolo[3,4‐d]pyridazine	
(18a):	 Brown	 crystals.	 Crystallization	 from	AcOH.	 Yield:	 93%.	
M.p.:	 >	 300	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3066	 (CH),	 .1631	 (C=N),	

1566	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	6.61	(d,	1H,	J	=	
5	Hz,	furan‐H‐3),	7.22‐7.66	(m,	9H,	ArH's),	8.75	(s,	1H,	isoxazole	
H‐5).	MS	(EI,	m/z	(%)):	313	(M+,	7),	254	(6),	222	(8),	220	(17),	
205	(50),	192	(15),	190	(22),	187	(10),	179	(88),	175	(27),	160	
(14),	149	(10),	145	(46),	130	(26),	119	(27),	108	(22),	107	(27),	
91	(100),	77	(24),	65	(14).	Anal.	calcd.	for	C19H11N3O2	(313.31):	
C,	72.84;	H,	3.54;	N,	13.41.	Found:	C,	73.00;	H,	3.41;	N,	13.59%.	

7‐(Benzofuran‐2‐yl)‐4‐(furan‐2‐yl)isoxazolo[3,4‐d]pyridazine	
(18b):	Brown	crystals.	 Crystallization	 from	AcOH.	Yield:	98%.	
M.p.:	 >	 320	 oC.	 FT‐IR	 (KBr,	 cm‐1):	 3066	 (CH),	 1631	 (C=N),	
1566	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	6.61	(d,	1H,	J	=	
5	Hz,	furan‐H‐4),	7.22‐7.66	(m,	6H,	ArH's),	7.77	(s,	1H,	furan	H‐
5),	8.75	(s,	1H,	 isoxazole	H‐5).	MS	(EI,	m/z	(%)):	303	(M+,	13),	
232	(14),	162	(5),	119	(100),	91	(19).	Anal.	calcd.	for	C17H9N3O3	
(303.27):	C,	67.33;	H,	2.99;	N,	13.86.	Found:	C,	67.52;	H,	3.11;	N,	
14.00%.	

7‐(Benzofuran‐2‐yl)‐4‐(thien‐2‐yl)isoxazolo[3,4‐d]pyridazine	
(18c):	 Brown	 crystals.	 Crystallization	 from	AcOH.	 Yield:	 98%.	
M.p.:	 >	 320	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3070	 (CH),	 1620	 (C=N),	
1561	(C=C)	.	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	7.22‐7.93	(m,	
8H,	ArH's),	 8.75	 (s,	 1H,	 isoxazole	H‐5).	MS	 (EI,	m/z	 (%)):	319	
(M+,	0.5),	240	(2),	220	(36),	208	(4),	122	(100),	108	(5),	84	(5),	
69	(6),	57	(7).	Anal.	calcd.	for	C17H9N3O2S	(319.34):	C,	63.94;	H,	
2.84;	N,	 13.16;	 S,	 10.04.	 Found:	 C,	 64.12;	H,	 3.00;	N,	 13.25;	 S,	
10.24%.	
	
2.7.	Pyridines	(19‐21)	and	(23)	
	

Equimolar	 amounts	 of	 7,	 the	 appropriate	 ethyl	
acetoacetate,	 acetylacetone,	 ethyl	 cyanoacetate	 or	 benzoyl‐
acetonitrile	and	ammonium	acetate	(5	mmol	for	each)	in	acetic	
acid	 (10	mL)	were	 boiled	 under	 reflux	 for	 4	 h.	 The	 resulting	
solid,	 after	 cooling	 was	 collected	 and	 recrystallized	 from	 the	
appropriate	 solvent	 to	 give	 19‐21	 and	 23,	 respectively,	
(Scheme	6).	

Ethyl	 6‐(benzofuran‐2‐yl)‐2‐methylpyridine‐3‐carboxylate	
(19):	 Beige	 crystals.	 Crystallization	 from	 EtOH.	 Yield:	 81%.	
M.p.:	 126‐128	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3058,	 2974	 (CH),	 1712	
(C=O),	1639	(C=N),	1581	(C=C).		

	
	



Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	 133	
 

	

O O
ONa + ArN2Cl

O
O

N

CHO

H
N Ar

O N

N
HN Ar

N

O O

N CH3

H3C

+ ArN2Cl

O N
NH

ArN2Cl

N2H4.H2O

a, Ar = C6H5
b, Ar = 4-CH3C6H4

7

2

12

1314 	
	

Scheme	4
	
	
1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 1.32	 (t,	 3H,	 J	 =	 7	 Hz,	

CH2CH3),	2.49	(s,	3H,	CH3),	4.29	(q,	2H,	J	=	7	Hz,	CH2CH3),	7.28‐
8.29	 (m,	 7H,	 ArH's).	 Anal.	 calcd.	 for	 C17H15NO3	 (281.31):	 C,	
72.58;	H,	5.37;	N,	4.98.	Found:	C,	72.73;	H,	5.49;	N,	5.13%.	

1‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)ethanone	 (20):	
Beige	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 79%.	 M.p.:	
210‐212	°C.	FT‐IR	(KBr,	cm‐1):	3058,	2920	(CH),	1702	(C=O),	
1639	(C=N),	1542	(C=C).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
2.48	 (s,	 3H,	 CH3),	 2.49	 (s,	 3H,	 CH3),	 7.10‐7.95	 (m,	 7H,	 ArH's).	
Anal.	 calcd.	 for	C16H13NO2	 (251.28):	 C,	 76.48;	H,	 5.21;	N,	 5.57.	
Found:	C,	76.62;	H,	5.41;	N,	5.78%.	

Ethyl	 2‐amino‐6‐(benzofuran‐2‐yl)pyridine‐3‐carboxylate	
(21):	 Yellow	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 85%.	
M.p.:	 177‐179	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3448,	3274	(NH2),	 3058	
(CH),	1681	(C=O),	1631	(C=N),	1589	(C=C).	1H	NMR	(300	
MHz,	CDCl3,	δ,	ppm):	1.13	(t,	3H,	J	=	7	Hz,	CH2CH3),	4.29	(q,	2H,				
J	=	7	Hz,	CH2CH3),	7.26‐8.21	(m,	9H,	ArH's	and	NH2).	Anal.	calcd.	
for	 C16H14NO3	 (282.29):	 C,	 68.07;	 H,	 5.00;	 N,	 9.92.	 Found:	 C,	
68.24;	H,	5.12;	N,	9.80%.	

(2‐Amino‐6‐(benzofuran‐2‐yl)pyridin‐3‐yl)(phenyl)methan‐
one	 (23):	 Brown	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	
76%.	M.p.:	 284‐286	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3413,	3274	(NH2),	
3101	(CH),	1645	(C=O),	1618	(C=N),	1550	(C=C).	MS	 (EI,	
m/z	 (%)):	315	 (M+1,	2),	 314	 (M+,	13),	312	 (7),	236	 (13),	 235	
(98),	234	(14),	233	(100),	154	(47),	153	(82),	152	(45),	76	(47),	
64	(9).	Anal.	calcd.	for	C20H14N2O2	(314.34):	C,	76.42;	H,	4.49;	N,	
8.91.	Found:	C,	76.57;	H,	4.58;	N,	9.12%.	
	
2.8.	6‐(Benzofuran‐2‐yl)‐2‐methylpyridine‐3‐carbo	
hydrazide	(25)	
	

Equimolar	amounts	of	19	and	hydrazine	hydrate	 (5	mmol	
for	each)	in	ethanol	(10	mL)	were	heated	under	reflux	for	4	h.	
The	resulting	solid,	so	formed,	after	cooling	was	recrystallized	
to	give	25	as	beige	crystals.	Crystallization	from	EtOH,	(Scheme	
6).	Yield:	94%.	M.p.:	199‐200	°C.	FT‐IR	(KBr,	cm‐1):	3448,	3274,	
3147	 (NH,	 NH2),	 3058,	 2970	 (CH),	 1681	 (C=O),	 1620	
(C=N),	1551	(C=C).	 1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	2.70	
(s,	3H,	CH3),	6.34	(s,	br.,	3H,	NH,	NH2),	7.12‐7.95	(m,	7H,	ArH's).	
MS	(EI,	m/z	(%)):	276	(M+,	18),	252	(10),	236	(100),	208	(13),	
190	(11),	180	(24),	152	(27),	139	(9),	90	(88),	88	(14),	76	(17),	
63	(12).	Anal.	calcd.	for	C15H13N3O2	(267.28):	C,	67.40;	H,	4.90;	
N,	15.72.	Found:	C,	67.65;	H,	5.14;	N,	15.89%.	
	
	
	

2.9.	2‐(6‐Benzofuran‐2‐yl‐2‐methyl‐pyridine‐3‐carbonyl)‐5‐
methyl‐2,4‐dihydro‐pyrazol‐3‐one	(26)	
	

Equimolar	 amounts	of	25	 and	ethyl	 acetoacetate	 (5	mmol	
for	each)	 in	acetic	acid	(10	mL)	and	were	heated	under	reflux	
for	 2	 h.	 The	 resulting	 solid,	 so	 formed,	 after	 cooling	 was	
recrystallized	to	give	26	as	yellow	crystals.	Crystallization	from	
AcOH,	 (Scheme	 6).	 Yield:	 83%.	 M.p.:	 314‐316	 °C.	 FT‐IR	 (KBr,	
cm‐1):	 3058,	 2924	 (CH),	 1705	 (C=O),	 1604	 (C=N),	 1546	
(C=C).	 1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 2.06	 (s,	 3H,	 CH3),	
2.71	(s,	3H,	CH3),	3.41	(dd,	1H),	3.63	(dd,	1H),	7.12‐7.95	(m,	7H,	
ArH's).	MS	 (EI,	m/z	 (%)):	 334	 (M+1,	 22),	 333	 (M+,	 100),	 290	
(14),	249	 (14),	118	 (24),	117	 (10),	91	 (6),	68	 (8).	Anal.	 calcd.	
for	C19H15N3O3	 (333.34):	C,	 68.46;	H,	4.54;	N,	12.61.	Found:	C,	
68.54;	H,	4.67;	N,	12.84%.	
	
2.10.	2‐(6‐Benzofuran‐2‐yl‐2‐methyl‐pyridine‐3‐carbonyl)‐5‐
methyl‐4‐(phenyl‐hydrazono)‐2,4‐dihydro‐pyrazol‐3‐one	
(27)	
	
Method	A	
	

To	 a	 stirred	 solution	 of	 26	 (1.3	 g,	 5	 mmol)	 in	 ethanolic	
solution	(15	mL)	at	0‐5	°C;	containing	sodium	acetate	(0.65	g)	
as	a	buffer	solution,	a	prepared	solution	of	benzene	diazonium	
chloride	(as	usual	manner,	5	mmol)	was	added	dropwise	while	
cooling	and	stirring.	The	reaction	mixture	was	stirred	 for	3	h.	
The	 resulting	 solid,	 was	 collected,	 washed	 with	 water	 and	
recrystallized	 from	DMF	 to	give	as	a	orange	crystals,	 (Scheme	
6).	Yield:	87%.	M.p.:	256‐258	°C.	FT‐IR	(KBr,	cm‐1):	3480	(NH)	
3058,	2924	(CH),	1720	(C=O),	1615	(C=N),	1589	(C=C).	1H	
NMR	(300	MHz,	CDCl3,	δ,	ppm):	2.00	 (s,	3H,	CH3),	2.61	 (s,	3H,	
CH3),	6.89‐7.95	(m,	12H,	ArH's),	10.72	(s,	br.,	1H,	NH).	MS	(EI,	
m/z	 (%)):	 438	 (M+1,	 32),	 437	 (M+,	 100),	 422	 (60),	 346	 (39),	
331	 (7),	 273	 (18),	 245	 (13),	 217	 (10),	 93	 (24),	 66	 (7).	 Anal.	
calcd.	 for	 C25H19N5O3	 (437.45):	 C,	 68.64;	 H,	 4.38;	 N,	 16.01.	
Found:	C,	68.82;	H,	4.45;	N,	16.23%.	
	
Method	B	
	

A	mixture	of	ethyl	2‐(2‐phenylhydrazono)‐3‐oxobutanoate	
(28)	 (1.17	g,	5	mmol))	and	25	 (1.38	g,	5	mmol)	 in	acetic	acid	
(15	mL)	was	boiled	under	reflux	for	2h.	The	resulting	solid,	was	
collected,	washed	with	water	and	recrystallized	gave	a	product	
identical	 in	all	aspects	(M.p.,	mixed	m.p.	and	spectra)	with	27,	
which	obtained	by	method	A.	
	



134	 Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	
	
	 	

	
	

Scheme	5
	
	
2.11.	Azido(6‐(benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)	
methanone	(29)	
	

A	 stirred	 solution	 of	25	 (1.38	 g,	 5	mmol)	 in	 hydrochloric	
acid	(15	mL,	6.0	M)	at	0‐5	°C,	sodium	nitrite	was	added	portion	
wise	tell	effervescence	ended.	The	reaction	mixture	was	stirred	
for	1	h.	The	resulting	solid,	was	collected,	filtered,	washed	with	
water	 and	 recrystallized	 from	 ethanol	 to	 give	 29	 as	 yellow	
crystals,	(Scheme	6).	Yield:	82%.	M.p.:	260‐263	°C.	FT‐IR	(KBr,	
cm‐1):	 3058,	 2924	 (CH),	 2136	 (azide),	 1789	 (C=O),	 1566	
(C=C).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 2.71	 (s,	 3H,	 CH3),	
7.01‐7.95	(m,	7H,	ArH's).	MS	(EI,	m/z	 (%)):	268	(M+,	17),	251	
(51),	224	(79),	196	(38),	181	(20),	167	(20),	155	(91),	153	(35),	
141	 (11),	 126	 (100),	114	 (31),	 101	 (38),	 88	 (37),	 75	 (49),	 63	
(46).	Anal.	calcd.	 for	C15H10N4O2	(278.27):	C,	64.74;	H,	3.62;	N,	
20.13.	Found:	C,	64.95;	H,	3.71;	N,	20.24%.	
	
2.12.	Urea	derivatives	(30a‐c),	(31)	and	pyridin‐3‐yl)	
quinazoline‐2,4(1H,3H)‐dione	(32)	
	

A	mixture	of	29	 (1.36	g,	5	mmol)	and	appropriate	aniline,			
p‐toluidine,	 p‐anisidine,	 3‐amino‐5‐phenylpyrazole	 or	
anthranilic	 acid	 (or	 methyl	 anthranilate)	 (5	 mmol)	 in	 dry	
dioxane	 (20	mL)	was	 refluxed	 for	 4	 h.	 The	 resulting	 solid,	 so	
formed,	was	collected	and	recrystallized	to	give	30a‐c,	31	and	
32,	respectively,	(Scheme	7).	

1‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)‐3‐phenylurea	
(30a):	 White	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 92%.	
M.p.:	 282‐284	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3290	(NH),	 3070	(CH),	
1708	(C=O),	 1643	(C=N),	 1604	(C=C).	 1H	 NMR	 (400	MHz,	
DMSO‐d6,	δ,	ppm):	2.11	(s,	3H,	CH3),	6.98	(t,	1H,	J	=	7	Hz,	ArH),	
7.01‐7.35	 (m,	 7H,	 ArH's	 and	 2	 NH),	 7.46‐7.50	 (m,	 2H,	 ArH's),	
7.86‐7.88	 (m,	1H,	ArH),	 8.37‐9.24	 (m,	3H,	ArH's).	MS	 (EI,	m/z	
(%)):	344	(M+1,	4),	343	(M+,	28),	250	(26),	224	(100),	195	(23),	
180	(25),	168	(16),	155	(18),	152	(17),	126	(20),	119	(19),	93	
(15),	76	 (20),	 63	 (30).	Anal.	 calcd.	 for	C21H17N3O2	 (343.38):	C,	
73.45;	H,	4.99;	N,	12.24.	Found:	C,	73.56;	H,	5.11;	N,	12.40%.	

1‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)‐3‐p‐tolylurea	
(30b):	White	 crystals.	 Crystallization	 from	 AcOH.	 Yield:	 93%.	
M.p.:	 302‐306	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3560	(NH),	 3066	(CH),	
1705	 (C=O),	 1643	 (C=N),	 1543	 (C=C).	 1H	 NMR	 (400	MHz,	
DMSO‐d6,	δ,	ppm):	2.18	 (s,	3H,	CH3),	2.48	(s,	3H,	CH3),	7.03	(t,	

2H,	J	=	8	Hz,	ArH),	7.21‐7.36	(m,	7H,	ArH's	and	2	NH),	7.86‐7.88	
(m,	1H,	ArH),	8.19	(s,	1H,	ArH),	8.3	(d,	1H,	J	=	8	Hz,	ArH),	9.04	
(s,	1H,	ArH).	MS	(EI,	m/z	(%)):	358	(M+1,	4),	357	(M+,	20),	250	
(33),	 224	 (100),	 195	 (23),	 180	 (22),	 167	 (11),	 155	 (27),	 152	
(22),	134	(44),	126	(34),	106	(100),	91	(21),	76	(49),	65	(19).	
Anal.	calcd.	for	C22H19N3O2	(357.41):	C,	73.93;	H,	5.36;	N,	11.76.	
Found:	C,	74.15;	H,	5.51;	N,	11.56%.	

1‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)‐3‐(4‐methoxy	
phenyl)urea	 (30c):	 White	 crystals.	 Crystallization	 from	 AcOH.	
Yield:	 93%.	M.p.:	 302‐306	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3275	 (NH),	
3062	(CH),	1705	(C=O),	1643	(C=N),	1577(C=C).	 1H	NMR	
(400	 MHz,	 DMSO‐d6,	 δ,	 ppm):	 2.44	 (s,	 3H,	 CH3),	 3.66	 (s,	 3H,	
OCH3),	7.03	(t,	2H,	J	=	8	Hz,	ArH),	7.21‐7.36	(m,	7H,	ArH's	and	2	
NH),	7.86‐7.88	(m,	1H,	ArH),	8.19	(s,	1H,	ArH),	8.3	(d,	1H,	J	=	8	
Hz,	ArH),	9.04	(s,	1H,	ArH).	MS	(EI,	m/z	(%)):	375	(M+2,	1),	373	
(M+,	17),	250	(63),	225	(11),	224	(95),	195	(16),	181	(22),	168	
(23),	155	(20),	149	(25),	134	(21),	126	(17),	122	(55),	108	(39),	
106	 (20),	 80	 (33),	 78	 (22),	 76	 (14),	 62	 (49).	 Anal.	 calcd.	 for	
C22H19N3O3	(373.4):	C,	70.76;	H,	5.13;	N,	11.25.	Found:	C,	70.85;	
H,	5.04;	N,	11.37%.	

1‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)‐3‐(3‐phenyl‐
1H‐pyrazol‐5‐yl)urea	 (31):	White	 crystals.	 Crystallization	 from	
AcOH.	 Yield:	 93%.	 M.p.:	 302‐306	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3275	
(NH),	 3062	(CH),	 1705	(C=O),	 1643	(C=N),	 1577	(C=C).	
1H	NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.48	(s,	3H,	CH3),	5.62	(s,	
1H,	 pyrazole	H‐4),	 7.21‐7.36	 (m,	 12H,	 ArH's	 and	 3	NH),	 7.86‐
7.88	(m,	1H,	ArH),	8.3	(d,	1H,	J	=	8	Hz,	ArH),	9.04	(s,	1H,	ArH).	
MS	(EI,	m/z	 (%)):	409	(M+,	0.2),	250	(58),	224	(100),	197	(7),	
185	(48),	180	(16),	168	(10),	159	(30),	130	(11),	127	(22),	101	
(26),	 88	 (10),	 106	 (20),	 76	 (27),	 62	 (19).	 Anal.	 calcd.	 for	
C24H19N5O2	 (409.44):	 C,	 70.40;	 H,	 4.68;	 N,	 17.10.	 Found:	 C,	
70.32;	H,	4.84;	N,	17.25%.	

3‐(6‐(Benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)quinazoline‐
2,4(1H,3H)‐dione	 (32):	 White	 crystals.	 Crystallization	 from	
AcOH.	 Yield:	 89%.	 M.p.:	 288‐290	 °C.	 FT‐IR	 (KBr,	 cm‐1):	 3431	
(OH),	3273	(NH),	3058	(CH),	1619	(C=N),	1570	(C=C).	1H	
NMR	(400	MHz,	DMSO‐d6,	δ,	ppm):	2.47	(s,	3H,	CH3),	7.13‐7.72	
(m,	9H,	ArH's),	8.08	(d,	1H,	J	=	8	Hz,	ArH),	8.22	(d,	1H,	J	=	8	Hz,	
ArH),	10.49	(s,	br.,	1H,	NH).	MS	(EI,	m/z	 (%)):	370	(M+1,	27),	
369	(M+,	100),	250	(10),	182	(28),	167	(12),	154	(13),	144	(7),	
127	(18).	Anal.	calcd.	for	C22H15N3O3	(369.37):	C,	71.54;	H,	4.09;	
N,	11.38.	Found:	C,	71.35;	H,	4.21;	N,	11.12%.	



Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	 135	
 

	 	

O

O

N CH3
H3C

N

O

O

R

N CH3

CH3

O

R N NH2

O

O

R
N
H

O

CN

R

N NH2R

O

N CNR

R =

719

20
21 22

23

24

i

ii

iii

iv

i = Ethyl acetoacetate
ii = Acetylacetone
iii = Ethyl cyanoacetate
iv = Benzoylacetonitrile
v = N2H4.H2O

vi = PhN2Cl
vii = NaNO2/ HCl

N

N
H

O
NH2

R

25

N

N3

O

R

29

N

N

O

R N

O

N

N

O

R N

O

N
HN Ph

i

v

vi

25

N
NH

Ph

OC2H5

OO

26

27
28

vii

	

Scheme	6
	
	
2.13.	Phenyl	6‐(benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl	
carbamate	(33)	
	

A	mixture	of	29	(1.36	g,	5	mmol)	and	phenol	in	dry	benzene	
(20	mL)	was	 refluxed	 for	 4	 h.	 The	 resulting	 solid,	 so	 formed,	
was	 collected	 and	 recrystallized	 to	 33	 as	 white	 crystals.	
Crystallization	 from	AcOH,	 (Scheme	7).	 Yield:	 92%.	M.p.:	 308‐
310	°C.	FT‐IR	(KBr,	cm‐1):	3274	(NH),	3058	(CH),	1678	(CO),	
1620	 (C=N),	 1569	 (C=C).	 1H	 NMR	 (400	 MHz,	 DMSO‐d6,	 δ,	
ppm):	2.10	(s,	3H,	CH3),	6.70‐7.67	(m,	13H,	ArH's	and	NH).	MS	
(EI,	m/z	 (%)):	 345	 (M+1,	 0.8),	 344	 (M+,	 0.28),	 250	 (45),	 224	
(47),	195	(17),	180	(37),	167	(20),	154	(10),	145	(98),	126	(22),	
88	(100),	76	(63),	62	(47).	Anal.	calcd.	for	C21H16N2O3	(344.36):	
C,	73.24;	H,	4.68;	N,	8.13.	Found:	C,	73.35;	H,	4.82;	N,	8.00%.	
	
3.	Results	and	discussion	
	

Treatment	 of	 the	 diazotized	 3‐amino‐5‐phenylpyrazole	
(3a)	with	each	of	1‐(benzofuran‐2‐yl)‐3‐(dimethylamino)prop‐
2‐en‐1‐one	 (7)	 and	 sodium	 salt	 of	 5‐hydroxy‐l‐benzofuran‐2‐
ylpropenone	 (2)	 in	 ethanolic	 sodium	 acetate	 solution	 gave	
(benzofuran‐2‐yl)(7‐phenylpyrazolo[5,1‐c][1,2,4]triazin‐3‐yl)	
methanone	 (6a)	 in	 good	 yield	 (Scheme	 1).	 Analogously,	
treatment	 of	 the	 appropriate	 dazonium	 salt	 of	 heterocyclic	
amines	3b,	c	with	2	or	7	 in	ethanolic	sodium	acetate	afforded	
(benzofuran‐2‐yl)(8‐phenylpyrazolo[5,l‐c][l,2,4]triazin‐3‐yl)	

methanone	 (6b)	 and	 3‐benzofuran‐2‐carbonyl)‐pyrazolo[5,l‐c]	
[l,2,4]triazine‐8‐carbonitrile	(6c)	(Scheme	1).	

Structure	6a	was	elucidated	by	elemental	analysis,	spectral	
data	 and	 alternative	 synthesis.	 The	 formation	 of	6a	 accorded	
via	 coupling	 diazonium	 chloride	 3a	 with	 2	 to	 form	 the	
intermediate	4	which	converted	to	another	intermediate	5.	The	
later	 afforded	 the	 final	 product	 6	 through	 elimination	 of	 a	
molecule	 of	 water.	 Meanwhile,	 treatment	 of	 1‐(benzofuran‐2‐
yl)‐3‐(dimethylamino)prop‐2‐en‐1‐one	 [17]	 (7)	 with	 3a	 in	
ethanolic	 sodium	 acetate	 as	 a	 buffer	 solution	 gave	 product	
identical	in	all	respects	(M.p.,	mixed	m.p.	and	spectra)	with	6a,	
(Scheme	2).	

Treatment	 of	 2	 or	7	 with	 the	 appropriate	 1,2,4‐triazol‐3‐
yldiazonium	 nitrate	 (3d)	 or	 benzimidazol‐2‐diazonium	
sulphate	 in	 cold	 solution	 of	 ethanolic	 sodium	 acetate	 gave	
([l,2,4]triazolo[3,4‐c][1,2,4]triazin‐6‐yl)benzofuran‐2‐yl)met‐
hanone	 (10)	 and	 benzo[4,5]imidazo[2,1‐c][1,2,4]triazin‐3‐yl‐
benzofuran‐2‐yl‐methanone	 (11),	 respectively	 in	 good	 yield	
(Scheme	3).	

Treatment	 of	 2	 or	 7	 with	 benzenediazonium	 chloride	 in	
ethanol	containing	sodium	acetate	as	a	buffer	solution	yielded	
2‐(2‐phenylhydrazono)‐3‐(benzofuran‐2‐yl)‐3‐oxopropanal	
(12a)	 (Scheme	4).	 Structure	12a	was	 confirmed	by	elemental	
analysis,	 spectral	 data	 and	 chemical	 transformations.	 1H	NMR	
spectrum	 of	 12a	 showed	 signal	 at	 7.26‐8.20	 ppm	 (m,	 10H,	
ArH’s),	9.75	ppm	(s,	1H,	‐CHO)	and	14.39	ppm	(s,	br.,	1H,	NH).		



136	 Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	
	

	

	

Scheme	7	
	
	
Compound	 12a	 was	 reacted	 with	 hydrazine	 hydrate	 in	

boiling	 ethanol	 under	 reflux	 gave	 1‐(3‐(benzofuran‐2‐yl)‐4H‐
pyrazol‐4‐ylidene)‐2‐phenylhydrazine	 (13a)	 (Scheme	 4).	 The	
structure	 13a	 was	 confirmed	 by	 elemental	 analysis,	 spectral	
data	and	alternative	synthetic	route.	Thus,	compound	7	reacted	
with	 hydrazine	 hydrate	 gave	 3‐(benzofuran‐2‐yl)‐1H‐pyrazole	
(14).	The	later	was	reacted	with	benzenediazonium	chloride	in	
ethanolic	sodium	acetate	solution	to	afford	product	identical	in	
all	aspects	(M.p.,	mixed	m.p.	and	spectra)	with	12a.	Similar,	p‐
toluenediazonium	 chloride	 reacted	 with	 2	 or	 7	 in	 ethanolic	
sodium	acetate	gave	12b,	which	converted	to	pyrazole	13b	by	
heating	with	hydrazine	hydrate.	

Next,	 treatment	 of	 compound	 2	 with	 2‐chloro‐2‐
(hydroxyimino)‐1‐phenylethanone	 15a	 in	 toluene	 (15	mL)	 at	
room	 temperature	 in	 presence	 of	 triethylamine	 gave	 one	
isolable	 product	 formulated	 as	 3,4‐diacylisoxazole	 16	 or	 4,5‐
diacylisoxazole	 17	 (Scheme	 5).	 Structure	 of	 the	 product	 was	
confirmed	 by	 elemental	 analysis,	 spectral	 data	 and	 chemical	
transformation.	Thus,	treatment	of	the	product	with	hydrazine	
hydrate	gave	isoxazolo[3,4‐d]pyridazine	18a	(Scheme	5).	From	
the	above	result,	the	product	is	formulated	as:	benzofuran‐2‐yl‐
(4‐benzoyl‐isoxazol‐3‐yl)‐methanone	 (17a).	 Analogously,	 7	
reacted	 with	 each	 of	 15b	 and	 15c	 in	 toluene	 in	 presence	 of	
triethylamine	 afforded	 isoxazoles	 17b	 and	 17c,	 respectively.	
Compounds	 17b	 and	 17c	 reacted	 with	 hydrazine	 hydrate	 in	
boiling	ethanol	gave	 isoxazolo[3,4‐d]pyridazines	18b	and	18c,	
respectively.	

Treatment	 of	 1‐(benzofuran‐2‐yl)‐3‐(dimethylamino)prop‐
2‐en‐1‐one	 (7)	 with	 each	 of	 ethyl	 acetoaetate,	 acetylacetone,	
ethyl	cyanoacetate,	or	benzoylacetonitrile	in	boiling	acetic	acid	
containing	 ammonium	 acetate	 under	 reflux	 gave	 ethyl	 6‐
(benzofuran‐2‐yl)‐2‐methylpyridine‐3‐carboxylate	 (19),	 1‐(6‐
(benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)	 ethanone	 (20),	 ethyl	
2‐amino‐6‐(benzofuran‐2‐yl)pyridine‐3‐carboxylate	(21),	ethyl	
and	 (2‐amino‐6‐(benzofuran‐2‐yl)pyridin‐3‐yl)	 (phenyl)	
methanone	(23),	respectively	(Scheme	6).	Structure	22	and	24	
were	 ruled	 on	 the	 basis	 of	 spectroscopic	 data.	 Thus,	 the	 IR	
spectrum	 showed	 the	 absence	 of	 bands	 between	 2100‐and	
2300	 cm‐1	 due	 to	 the	 absence	 of	 CN	 group	 but	 showed	 the	
presence	of	bands	at	3448	and	3274	cm‐1	due	to	the	presence	of	

an	amino	group.	Also,	1H‐NMR	spectrum	of	21	revealed	signals	
at	1.32	ppm	(t,	3H)	and	4.31	ppm	(q,	2H),	indicate	the	presence	
of	 ethoxy	 group	 (cf.	 Experimental	 part).	 Structure	 19	 was	
confirmed	 by	 elemental	 analysis,	 spectral	 data	 and	 chemical	
transformation.	Thus,	it	reacted	with	hydrazine	hydrate	to	give	
6‐(benzofuran‐2‐yl)‐2‐methylpyridine‐3‐carbohydrazide	 (25)	
in	a	good	yield.	Compound	25	reacted	with	ethyl	acetacetate	or	
with	 sodium	 nitrite	 in	 the	 presence	 of	 hydrochloric	 acid	 to	
afford	 2‐(6‐benzofuran‐2‐yl‐2‐methyl‐pyridine‐3‐carbonyl)‐5‐
methyl‐2,4‐dihydro‐pyrazol‐3‐one	 (26)	 and	 azido‐(6‐
(benzofuran‐2‐yl)	 ‐2‐methylpyridin‐3‐yl)methanone	 (29)	
(Scheme	6).	

Meanwhile,	26	reacted	with	benzenediazonium	chloride	in	
a	cold	solution	of	ethanol	containing	sodium	acetate	as	a	buffer	
solution	 to	 give	 2‐(6‐benzofuran‐2‐yl‐2‐methyl‐pyridine‐3‐
carbonyl)‐5‐methyl‐4‐(phenyl‐hydrazono)‐2,4‐dihydro‐
pyrazol‐3‐one	 (27).	 The	 structure	 of	 compound	 27	 was	
confirmed	 by	 alternative	 synthesis	 by	 treatment	 of	 the	
hydrazide	25	with	ethyl	3‐oxo‐2‐(phenyl‐hydrazono)butanoate	
(28)	in	boiling	acetic	acid	to	afford	a	product	which	was	found	
identical	 in	all	aspects	(M.p.,	mixed	m.p.,	and	spectra)	with	27	
previously	prepared.	

Azido(6‐(benzofuran‐2‐yl)‐2‐methylpyridin‐3‐yl)	
methanone	 (29)	 can	 be	 converted	 into	 the	 substituted	 ureas,	
30a‐c,	 31	 and	 3‐(6‐(benzofuran‐2‐yl)‐2‐methylpyridin‐3‐
yl)quinazoline‐2,4(1H,3H)‐dione	 (32)	 by	 its	 boiling	 with	 the	
appropriate	 aromatic	 amines,	 3‐amino‐5‐phenylpyrazole	 or	
methyl	 anthranilate	 (anthranilic	 acid)	 in	 dry	 dioxane,	
respectively.	 Also,	 phenyl	 6‐(benzofuran‐2‐yl)‐2‐methyl‐
pyridin‐3‐ylcarbamate	 (33)	 can	 obtained	 by	 boiling	 29	 with	
phenol	in	dry	benzene	(Scheme	7).	
		
4.	Conclusions	

	
The	 studies	 described	 above	 clearly	 demonstrate	 that	 the	

new	 pyrazolo[5,l‐c]triazines,	 [l,2,4]triazolo[4,3‐c]triazine,	
benzo[4,5]‐imidazo[2,1‐c][1,2,4]triazine,	 isoxazoles,	 isoxazolo	
[3,4‐d]pyrimidine	 pyridines,	 urea	 derivatives	 and	 carbamate	
derivative	containing	benzofuran	moiety	can	be	synthesized	in	
a	 good	 yields	 via	 sodium	 salt	 of	 1‐(benzofuran‐2‐yl)‐3‐



Abdelhamid	et	al.	/	European	Journal	of	Chemistry	3	(2)	(2012)	129‐137	 137	
 

hydroxyprop‐2‐en‐1‐one	 or	 1‐(benzofuran‐2‐yl)‐3‐(dimethyl	
amino)prop‐2‐en‐1‐one.		
	
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