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European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	

	

European	Journal	of	Chemistry	
ISSN	2153‐2249	(Print)	/	ISSN	2153‐2257	(Online)		2014	Eurjchem	Publishing	‐	Printed	in	the	USA	

http://dx.doi.org/10.5155/eurjchem.5.1.24‐32.870	

	
	

	

	

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

	 	 	

Synthesis	and	characterization	of	novel	pyrazolone	derivatives	

Magda	Ismail	Marzouk	a,*,	Galal	Hosni	Sayed	a,		
Mohamed	Said	Abd	ElHalim	b	and	Salma	Yehia	Mansour	a	

a	Heterocyclic	Synthetic	Laboratory,	Chemistry	Department,	Faculty	of	Science,	Ain	Shams	University,	Abbassia	11566,	Cairo,	Egypt	
b	Heterocyclic	Synthetic	Laboratory,	Chemistry	Department,	Faculty	of	Engineering,	Ain	Shams	University,	Abbassia	11566,	Cairo,	Egypt	

*Corresponding	author	at:	Heterocyclic	Synthetic	Laboratory,	Chemistry	Department,	Faculty	of	Science,	Ain	Shams	University,	Abbassia	11566,	Cairo,	Egypt.		
Tel.:	+2.0122.3309974.	Fax:	+2.02.24662917.	E‐mail	address:	magda_marzouk@sci.asu.edu.eg	(M.	Marzouk).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT

	
DOI:	10.5155/eurjchem.5.1.24‐32.870	

Received:	08	July	2013	
Received	in	revised	form:	26	August	2013	
Accepted:	26	August	2013	
Online:	31	March	2014	

KEYWORDS	

	 The	reactivity	of	hydrogen	atoms	at	C‐4	of	pyrazolone	3	towards	condensation	reactions	was
studied	 by	 its	 reaction	with	p‐anisaldehyde,	malononitrile	 and/or	 ethyl	 acetoacetate	 in	 the
presence	 of	 ammonium	 acetate	 and/or	 piperidine,	 glucose,	 phenyl	 isothiocyanate,	 2‐amino
thiazole	 and	 aniline	 to	 afford	 compounds	4‐6,	13,	15,	17	 and	18,	 respectively.	 Reaction	 of
amino	carbonitrile	4	with	ammonium	thiocyanate,	and	formamide	afforded	compound	7	and
pyrazolo[3,4‐b]pyridinylformamide,	9.	Reaction	of	compound	7	with	hydrazine	hydrate	gave
thiocyanato‐1,3,4‐thiadiazol‐2‐yl)‐1H‐pyrazolo[3,4‐b]pyridin‐6‐amine	 derivative,	 8.	 Acetyla‐
tion	of	amino	carbonitriles	4	and	5	afforded	compound	10	and	11,	respectively.	Reaction	of
compound	11	with	hydrazine	hydrate	afforded	azanediyl	compound	12.	The	pyrazolone	19
reacted	with	different	 nitrogen	 nucleophiles	 such	 as	 hydrazine	 hydrate,	 urea,	 thiourea	 and
hydroxylamine	hydrochloride	to	afford	compounds	22‐25.	The	reactivity	of	pyrazolone	19	as
an	 α,β‐unsaturated	 compound	 towards	 several	 carbon	 nucleophiles	 under	Michael	 reaction
was	 studied	 by	 its	 reaction	 with	 ethyl	 acetoacetate,	 ethyl	 cyanoacetate,	 and	 malononitrile
under	 different	 reaction	 conditions	 and	 pyrazolone	 3	 to	 afford	 compounds	 26‐32,
respectively.	 Synthesis	 of	 amino	 carbonitriles	5,	 pyrazolone	19	 and	pyrazolo[3,4‐c]pyrazole
22	were	 carried	out	under	microwave	 irradiation.	The	newly	 synthesized	 compounds	were
characterized	by	IR,	1H	NMR	and	mass	spectral	data.	Pyrazolone	

Malononitrile	
Azo	compounds		
Pyrazolo	pyrimidine	
Microwave	irradiation	
α,β‐Unsaturated	ketone	

	
1.	Introduction	
	

Pyrazolone	 is	 a	 five	membered	 lactam	 ring	 [1]	 containing	
two	 nitrogen	 atoms	 and	 one	 ketonic	 group	 in	 its	 structure.	
During	 the	discovery	of	pyrazolone,	 they	were	only	 known	as	
NSAIDs	 [2]	 but,	 since	 year	 2000,	 they	 play	 versatile	 role	 in	
several	complications	like	cerebral	ischemia	and	cardiovascular	
diseases	[3].	The	chemistry	of	pyrazolone	has	gained	increasing	
attention	due	to	its	diverse	pharmacological	properties	[4]	such	
as	 cytotoxic	 [5,6],	 anti‐inflammatory	 [7],	 antimicrobial	 [8,9],	
antioxidant	[10],	antiviral	[11],	oral	hypoglycemic	activity	[12]	
and	analgesic	[13,14].	Pyrazolones	are	believed	to	be	 involved	
in	 various	 biochemical	 and	 physiological	 reactions	 and	 thus	
scientific	 research	 programs	 are	 continually	 improvising	
synthetic	 techniques	 to	 prepare	 numerous	 pyrazolone	
derivatives.	For	the	last	decade	a	lot	of	work	has	been	going	on	
the	pyrazolone	nucleus.		

Scientists	have	developed	large	number	of	new	compounds	
related	 to	 this	 moiety	 and	 screened	 them	 for	 their	 different	
pharmacological	 activities	 to	 get	 a	 molecule	 of	 desired	
pharmacological	activity.	Although	earlier	many	of	pyrazolone	
derivatives	 were	 associated	 with	 adverse	 effects	 such	 as	
agranulocytosis,	skin	rashes	and	blood	dyscariasis,	etc.		
	
	

2.	Experimental	
	
2.1.	Instrumentation	
	

All	melting	points	were	measured	on	a	Gallenkamp	melting	
point	apparatus	and	are	uncorrected.	All	microwave	reactions	
were	carried	out	in	a	domestic	microwave	oven	(Galanza	950).	
The	 infrared	 spectra	were	 recorded	using	potassium	bromide	
disks	 on	 a	 Pye	 Unicam	 SP‐3‐300	 infrared	 spectrophotometer.	
1H	NMR	spectra	were	run	at	300	MHz,	on	a	Varian	Mercury	VX‐
300	 NMR	 spectrometer,	 using	 TMS	 as	 internal	 standard	 in	
deuterated	 chloroform	 or	 deuterated	 dimethyl	 sulphoxide.	
Chemical	 shifts	 are	 quoted	 δ	 in	 ppm.	 The	mass	 spectra	 were	
recorded	 on	 Shimadzu	 GCMS‐QP‐1000EX	mass	 spectrometers	
at	 70 eV.	 All	 the	 spectral	 measurements	 as	 well	 as	 elemental	
analyses	 were	 carried	 out	 at	 the	 Micro	 Analytical	 Center	 of	
Cairo	 University,	 Egypt,	 and	 the	 Main	 Defence	 Chemical	
Laboratory	 2.	 The	 antimicrobial	 activities	were	 carried	 out	 at	
Egyptian	 Petroleum	 Research	 Institute,	 Fermentation	
Biotechnology	Lab.	All	the	chemical	reactions	are	monitored	by	
TLC.		

	
	
	
	



Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	 25	
 

	

 
	

Scheme	1
	
	
2.2.	Synthesis	
	
2.2.1.	1,3‐Diphenyl‐1H‐pyrazol‐5(4H)‐one	(3)	
	

A	mixture	of	phenyl	hydrazine	(1)	(10.8 mL,	0.1	mol),	ethyl	
benzoylacetate	 (2)	 (19.2 mL,	 0.1 mol)	 in	 acetic	 acid	 (50 mL)	
was	 refluxed	 for	4 h,	 and	 left	 to	cool.	The	separated	solid	was	
filtered	off,	washed	with	ethanol,	dried	and	recrystallized	from	
acetic	 acid.	 Color:	 Yellow.	 Yield:	 90%.	 M.p.:	 138‐140	 °C	 (Lit.	
[15],	 135	 °C).	 FT‐IR	 (KBr,	,	 cm‐1):	 3055	 (CH	aromatic),	 2954,	
2911	 (CH	aliphatic),	1706	 (C=O).	 1H	NMR	(300	MHz,	CDCl3,	δ,	
ppm):	 7.94	 (d,	 2H,	 ArH),	 7.80	 (d,	 2H,	 ArH),	 7.34‐7.53	 (m,	 4H,	
ArH),	7.42	(t,	2H,	ArH),	3.87	(s,	2H,	CH2).	MS	(EI,	m/z	(%)):	236	
(M+·,	100),	194	(10.51),	105	(29.76),	103	(63.39),	91	(53.48),	78	
(7.19),	77	(84.85).	Anal.	calcd.	for	C15H12N2O:	C,	76.25;	H,	5.12;	
N,	11.86.	Found:	C,	76.36;	H,	5.14;	N,	12.01	%.	
	
2.2.2.	6‐Amino‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1H‐
pyrazolo[3,4‐b]pyridine‐5‐carbonitrile	(4)		
	

A	mixture	of	pyrazolone	3	(2.36 g,	0.01 mol),	malononitrile	
(0.66 g,	0.01 mol),	ammonium	acetate	(2.31 g,	0.03 mol,),	and	p‐
anisaldehyde	(1.36 mL,	0.01 mol)	was	fused	for	15 h	at	140‐170	
°C,	 the	 reaction	 mixture	 was	 poured	 onto	 water,	 to	 give	 the	
solid	 product	 4	 which	 was	 washed	 with	 water	 (3×30 mL),	
dried,	 and	 recrystallized	 from	 benzene:ethanol	 (2:1)	 (Scheme	
1).	Color:	Brown.	Yield:	86.3	%.	M.p.:	248‐250	°C.	FT‐IR	(KBr,	,	
cm‐1):	 3451,	 3338	 (NH2),	 2202	 (C≡N),	 1604	 (C=N).	 1H	 NMR	
(300	MHz,	DMSO,	δ,	ppm),	δ:	7.06‐7.14	(m,	14H,	ArH),	5.02	(s,	
2H,	 NH2	 D2O	 exchangeable),	 3.82	 (s,	 3H,	 OCH3).	 MS	 (EI,	m/z	
(%)):	417	(M+·,	0.80),	330	(74.22),	287	(24.48),	121	(100),	77	
(32.72).	Anal.	 calcd.	 for	C26H19N5O:	C,	74.80;	H,	4.59;	N,	16.78.	
Found:	C,	74.95;	H,	4.72;	N,	16.68	%.	
	

2.2.3.	6‐Amino‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1,4‐
dihydropyrano[2,3‐c]pyrazole‐5‐carbonitrile	(5)	
	

Method	 A:	 A	 mixture	 of	 pyrazolone	 3	 (2.36 g,	 0.01 mol),	
malononitrile	 (0.66 g,	 0.01 mol),	 and	p‐anisaldehyde	 (1.36 mL,	
0.01 mol)	in	presence	of	1 mL	piperidine	was	fused	for	15 h	at	
140	 °C.	 After	 cooling,	 the	 solid	 product	 was	 washed	 with	
ethanol,	 filtered	 off,	 dried,	 and	 crystallized	 from	 benzene:	
ethanol	(2:1)	(Scheme	1).	Color:	Brown.	Yield:	14	%.	M.p.:	288‐
290	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3400,	 3376	 (NH2),	 2206	 (C≡N),	
1600	(C=N).	 1H	NMR	(300	MHz,	DMSO,	δ,	ppm):	6.97‐7.44	(m,	
16H,	14ArH,	NH2),	3.83	(s,	1H,	benzilic),	3.70	(s,	3H,	OCH3).	MS	
(EI,	m/z	 (%)):	 420	 (6.83,	M+·),	 408	 (27.95),	 360	 (22.67),	 247	
(10.25),	 95	 (23.91),	 55	 (100).	 Anal.	 calcd.	 for	 C26H20N4O2:	 C,	
74.27;	H,	4.79;	N,	13.33.	Found:	C,	74.41;	H,	4.98;	N,	13.54	%.	

Method	 B:	 A	 mixture	 of	 pyrazolone	 3	 (2.36 g,	 0.01 mol),	
malononitrile	 (0.66 g,	 0.01 mol),	 and	p‐anisaldehyde	 (1.36 mL,	
0.01 mol)	 in	 presence	 of	 1 mL	 piperidine	 was	 heated	 under	
microwave	 irradiation	 for	 2	 min,	 at	 power	 180	 Watt.	 After	
cooling,	the	solid	product	was	washed	with	ethanol,	filtered	off,	
dried,	and	crystallized	from	benzene:ethanol	(2:1).		
	
2.2.4.	4‐(4‐Methoxyphenyl)‐6‐methyl‐1,3‐diphenyl‐1H‐
pyrazolo[3,4‐b]pyridine	(6)	
	

A	 mixture	 of	 pyrazolone	 3	 (2.36 g,	 0.01 mol),	 ethyl	
acetoacetate	 (2.94 mL,	 0.01 mol,),	 ammonium	 acetate	 (2.31 g,	
0.03 mol),	 and	 p‐anisaldehyde	 (1.36 mL,	 0.01 mol)	 was	 fused	
for	15 h	at	140	°C.	After	cooling,	the	solid	product	was	washed	
with	 water,	 filtered	 off,	 dried,	 and	 crystallized	 from	
benzene:petroleum	 ether	 (60‐80	 °C)	 (2:1)	 (Scheme	 1).	 Color:	
Brown.	Yield:	50	%.	M.p.:	246‐248	°C.	FT‐IR	(KBr,	,	cm‐1):	3058	
(CH	aromatic),	2958	(CH	aliphatic),	1635	(C=N),	1601	(C=C).		



26	 Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	
	

1H	 NMR	 (300	 MHz,	 DMSO,	 δ,	 ppm):	 6.88‐8.11	 (m,	 15H,	
ArH),	 3.81	 (s,	 3H,	OCH3),	 3.30	 (s,	 3H,	 CH3).	MS	 (EI,	m/z	 (%)):	
391	(21.7,	M+·),	354	(100),	353	(82.6),	188	(26.1),	77	(95.7),	68	
(13.0).	 Anal.	 calcd.	 for	 C26H21N3O:	 C,	 79.77;	 H,	 5.41;	 N,	 10.73.	
Found:	C,	79.91;	H,	5.60;	N,	10.96	%.	
	
2.2.5.	(6‐Amino‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1H‐
pyrazolo[3,4‐b]pyridin‐5‐yl)(iminomethyl)	
thiocyanatomethanethioimidate	(7)	
	

A	 mixture	 of	 pyrazolopyridine‐5‐carbonitrile	 4	 (4.17 g,	
0.01 mol),	 ammonium	 thiocyanate	 (2.28 g,	 0.03 mol),	 in	 acetic	
acid	 (10 mL)	was	 refluxed	 for	 10 h,	 the	 reaction	mixture	was	
poured	onto	water,	 filtered	off,	washed	with	water,	 dried	and	
recrystallized	from	ethanol	(Scheme	1).	Color:	Brown.	Yield:	92	
%.	M.p.:	222‐224	°C.	FT‐IR	(KBr,	,	cm‐1):	3457,	3338	(NH,	NH2),	
2207	 (C≡N),	 1602	 (C=N).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	
6.94‐7.95(m,	 14H,	 ArH),	 5.69	 (s,	 4H,	 2NH,	 NH2	 D2O	
exchangeable),	3.78	(s,	3H,	OCH3).	MS	(EI,	m/z	(%)):	535	(20.0,	
M+·)	376	(16.7),	195	(16.7),	103	(100),	104	(46.7),	79	(26.7),	78	
(36.7),	77(96.7).	Anal.	calcd.	for	C28H21N7OS2:	C,	62.78;	H,	3.95;	
N,	18.30;	S,	11.97.	Found:	C,	62.92;	H,	4.15;	N,	12.13;	S,	11.94	%.	
	
2.2.6.	4‐(4‐Methoxyphenyl)‐1,3‐diphenyl‐5‐(5‐thiocyanato‐
1,3,4‐thiadiazol‐2‐yl)‐1H‐pyrazolo[3,4‐b]pyridin‐6‐amine	
(8)	
	

A	 mixture	 of	 (iminomethyl)	 thiocyanatomethanethio‐
imidate	 7	 (5.35 g,	 0.01 mol),	 hydrazine	 hydrate	 (0.5 mL,	
0.01 mol),	in	absolute	ethanol	(20 mL)	was	refluxed	for	2 h,	the	
reaction	 mixture	 was	 concentrated,	 and	 the	 separated	 solid	
was	 filtered	 off,	 dried	 and	 crystallized	 from	 ethanol:benzene	
(1:1)	(Scheme	1).	Color:	Dark	brown.	Yield:	35	%.	M.p.:	225‐227	
°C.	FT‐IR	 (KBr,	,	 cm‐1):	3324	 (NH2),	1602	 (C=N),	1252	 (C=C).	
1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 7.02‐8.05	 (m,	 14H,	 ArH),	
5.63	(s,	2H,	NH2	D2O	exchangeable),	3.87	(s,	3H,	OCH3).	MS	(EI,	
m/z	(%)):	533	(0.01,	M+·),	516	(14.3),	210	(17.1),	119	(45.7),	93	
(25.7),	 60	 (25.7),	 58	 (17.1),	 57	 (100).	 Anal.	 calcd.	 for	
C28H19N7OS2:	 C,	 63.02;	 H,	 3.59;	 N,	 18.37;	 S,	 12.02.	 Found:	 C,	
63.28;	H,	4.13;	N,	19.02;	S,	12.25	%.	
	
2.2.7.	N‐(5‐cyano‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1H‐
pyrazolo[3,4‐b]pyridin‐6‐yl)formamide	(9)		
	

A	 mixture	 of	 pyrazolopyridine‐5‐carbonitrile	 4	 (4.17 g,	
0.01 mol),	formic	acid	(5 mL),	formamide	(10 mL),	and	dimethyl	
formamide	 (5 mL)	was	 refluxed	 for	 12 h,	 the	 reaction	mixture	
was	 poured	 onto	 water	 to	 give	 solid	 which	 was	 filtered	 off,	
washed	 with	 water,	 dried	 and	 recrystallized	 from	 benzene	
(Scheme	1).	Color:	Green.	Yield:	76.4	%.	M.p.:	230‐232	°C.	FT‐IR	
(KBr,	 ,	 cm‐1):	 3428	 (NH),	 2208	 (C≡N),	 1670	 (C=O),	 1604	
(C=N).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 7.02‐8.20	 (m,	 15H,	
14ArH,	 ‐CH),	 5.73	 (s,	 1H,	 NH	 D2O	 exchangeable),	 3.87	 (s,	 3H,	
OCH3).	MS	(EI,	m/z	(%)):	445	(0.01,	M+·),	386	(21.4),	354	(21.4),	
238	 (16.7),	 194	 (26.2),	 119	 (23.8),	 106	 (23.8),	 93	 (31.0),	 77	
(100).	 Anal.	 calcd.	 for	 C27H19N5O2:	 C,	 72.80;	 H,	 4.30;	 N,	 15.72.	
Found:	C,	73.13;	H,	4.70;	N,	15.90	%.	
	
2.2.8.	General	procedure	for	compounds	10	and	11	
	

A	mixture	of	amino	carbonitrile	4	and/or	5	(0.01 mol)	and	
acetic	 anhydride	 (20 mL)	 was	 refluxed	 for	 5 h,	 the	 reaction	
mixture	 was	 poured	 onto	 water,	 the	 separated	 solid	 was	
filtered	 off,	washed	with	water,	 dried	 and	 recrystallized	 from	
benzene:ethanol	(2:1)	(Scheme	2).	

N‐(5‐cyano‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1H‐pyrazolo	
[3,4‐b]pyridin‐6‐yl)acetamide	 (10):	 Color:	 Brown.	 Yield:	 85.45	
%.	 M.p.:234‐236	 °C.	 FT‐IR	 (KBr,,	 cm‐1):	 3436	 (NH),	 2216	
(C≡N),	 1712	 (C=O).	 1H	 NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 7.01‐
8.10	 (m,	 15H,	 14ArH,	 NH),	 3.92	 (s,	 3H,	 OCH3),	 1.26	 (s,	 3H,	
COCH3).	MS	 (EI,	m/z	 (%)):	459	 (16.7	%,	M+·),	 355	 (19.4),	 279	

(16.7),	135	(27.8),	121	(50.0),	119	(22.2),	93	(22.2),	78	(16.7),	
77	(100).	Anal.	calcd.	for	C28H21N5O2:	C,	73.19;	H,	4.61;	N,	15.24.	
Found:	C,	73.17;	H,	4.50;	N,	15.36	%.		

N‐(5‐cyano‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1,4‐dihydro	
pyrano[2,3‐c]pyrazol‐6‐yl)acetamide	 (11):	 Color:	 Dark	 brown.	
Yield:	55.88	%.	M.p.:	>300	°C.	FT‐IR	(KBr,	,	cm‐1):	3421	(NH),	
2211	 (C≡N),	 1714	 (C=O),	 1598	 (C=N).	 1H	 NMR	 (300	 MHz,	
CDCl3,	 δ,	 ppm):	 6.47‐7.90	 (m,	 15H,	 14	 ArH,	 NH),	 3.94	 (s,	 1H,	
benzilic),	 3.78	 (s,	 3H,	OCH3),	 2.07	 (s,	 3H,	 COCH3).	MS	 (EI,	m/z	
(%)):	431	(7.8,	[M	‐	CH3O·]+),	236	(19.6),	126	(13.7),	84	(25.5),	
70	 (27.5),	 64	 (100),	 55	 (23.5),	 53	 (37.3).	 Anal.	 calcd.	 for	
C28H22N4O3:	C,	72.71;	H,	4.79;	N,	12.11.	Found:	C,	72.65;	H,	4.58;	
N,	12.90	%.	
	
2.2.9.	6,6'‐(1,1’(Hydrazine‐1,2‐diylbis(ethane‐1,1‐diyl))	
bis(azanediyl))bis(4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1,4‐
dihydropyrano[2,3‐c]pyrazole‐5‐carbonitrile)	(12)	
	

A mixture	 of	 pyrazoloacetamide	 11	 (4.62 g,	 0.01 mol)	
hydrazine	 hydrate	 (0.5 mL,	 0.01 mol)	 in	 absolute	 ethanol	
(50 mL)	was	refluxed	for	2 h,	the	reaction	mixture	was	poured	
onto	 ice:HCl	 (1:3).	 The	 solid	 that	 separated	 was	 filtered	 off,	
washed	 with	 water,	 dried	 and	 recrystallized	 from	
benzene:ethanol	(2:1)	(Scheme	1).	Color:	Pale	brown.	Yield:	22	
%.	 M.p.:	 280‐282	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3336	 (NH),	 2207	
(C≡N),	 1600	 (C=N).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 6.83‐
7.79	(m,	28H,	ArH),	3.83	(s,	2H,	benzilic),	3.69	(m,	2H,	2CHNH),	
3.49	 (s,	 6H,	 2OCH3),	 2.73	 (s,	 4H,	 4NH	 D2O	 exchangeable),	
1.04(d,	 6H,	 2CH3).	 MS	 (EI,	 m/z	 (%)):	 926	 (18.8,	 M+2),	 319	
(15.6),	234	(15.6),	128	(12.5),	112	(18.8),	84	(40.6),	78	(40.6),	
77	(62.5),	60	(46.9),	58	(56.3),	56	(75.0),	55	(100).	Anal.	calcd.	
for	C56H48N10O4:	C,	72.71;	H,	5.23;	N,	15.14.	Found:	C,	72.53;	H,	
5.34;	N,	15.20	%.	
	
2.2.10.	4‐(2,3,4,5,6‐Pentahydroxyhexylidene)‐1,3‐diphenyl‐
1H‐pyrazol‐5(4H)‐one	(13)	
	

A	mixture	of	pyrazolone	3	(2.36 g,	0.01 mol),	glucose	(2.3 g,	
0.01 mol)	 in	H2O	 (1 mL),	 ethanol	 (5 mL),	 and	DMF	 (5 mL)	was	
heated	 on	 water	 bath	 for	 4 h,	 the	 solid	 that	 separated	 after	
cooling	 and	 evaporating	 the	 solvent	 was	 filtered	 off,	 washed	
with	 water	 (30 mL),	 dried	 and	 crystallized	 from	
benzene:ethanol	 (3:1)	 (Scheme	 2).	 Color:	 Green.	 Yield:	 95	%.	
M.p.:	 190‐192	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3380	 (OH),	 3066	 (CH	
aromatic),	2930	(CH	aliphatic),	1696	(C=O).	1H	NMR	(300	MHz,	
DMSO,	 δ,	 ppm):	 7.77‐7.93	 (m,	 4H,	 ArH),	 7.49‐7.62	 (m,	 5H,	
5ArH),	 7.30‐7.37	 (m,	 2H,	 1ArH,=CH),	 4.60,	 4.92,	 5.96,	 6.07	 (s,	
5H,	 5OH,	 D2O	 exchangeable),	 4.03‐4.16	 (m,	 1H,	 =CHCHOH),	
3.77‐3.86	 (m,	 2H,	 CH2OH),	 3.61‐3.67	 (m,	 3H,	 glucose	moiety).	
MS	(EI,	m/z	(%)):	398	(0.06,	M+·),	24.7	(20.12),	236	(13.36),	91	
(100),	 92	 (16.16),	 76	 (14.01).	 Anal.	 calcd.	 for	 C21H22N2O6:	 C,	
63.31;	H,	5.57;	N,	7.03.	Found:	C,	63.50;	H,	5.77;	N,	7.15	%.	
	
2.2.11.	5‐Oxo‐N,1,3‐triphenyl‐4,5‐dihydro‐1H‐
pyrazole‐4‐carbothioamide	(15)	
	

A	 mixture	 of	 pyrazolone	 3	 (2.36 g,	 0.01 mol)	 and	 phenyl	
isothiocyanate	(0.6 mL,	0.01 mol)	in	dry	acetone	(50 mL)	in	the	
presence	of	piperidine	 (0.5 mL)	was	heated	on	water	bath	 for	
4 h.	 The	 separated	 solid	 after	 pouring	 onto	 ic:eHCl	 (1:2)	 was	
filtered	 off,	 washed	 with	 water,	 dried	 and	 crystallized	 from	
ethanol	(Scheme	2).	Color:	Yellow.	Yield:	25.3%.	M.p.:	180‐182	
°C.	FT‐IR	(KBr,	,	cm‐1):	3063	(NH),	3034	(CH	aromatic),	2912	
(CH	aliphatic),	1711	(C=O).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	
8.64	 (s,	 1H,	 OH,	 D2O	 exchangeable),	 6.91‐8.08	 (m,	 15H,	 ArH),	
1.60	 (s,	 1H,	 NH,	 D2O	 exchangeable).	 MS	 (EI,	 m/z	 (%)):	 373	
(3.33,	M+2),	371	(40.86,	M+.),	279	(22.20),	278	(100),	93	(21.48),	
77	 (56.96).	 Anal.	 calcd.	 for	 C22H17N3OS:	 C,	 71.14;	 H,	 4.61;	 N,	
11.31;	S,	8.63.	Found:	C,	70.83;	H,	5.32;	N,	11.32;	S	8.71	%.	
	
	



Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	 27	
 

	

N

N

Ph

Ph

O

(CHOH)4CH2OH

13

N

N

Ph

Ph

O

3

N

N

Ph

S

Ph

O

NHPh

N

N

Ph

S

Ph

O

NHPh

B

HCl

15
14

PhNCS N2H4

N
N N

H

N

Ph

Ph

Ph

S

16

N

N

Ph

Ph

O

N

S

N
N

17

N

N

Ph

Ph

O

PhN
N

Glucose/DMF

EtOH/AcOH

Acetone/piperidine

NaNO2/HCl

2-Amino thiazole

NaNO2/HCl

Aniline

N

N

Ph

Ph

O

Ar

p-Anisaldehyde

EtOH/piperidine
Ar = C6H4(4-OCH3)

19

N

N

Ph

Ph

OH

PhN
N

18

N

N

Ph

S

Ph

OH

NHPh

 
	

Scheme	2	
	
	
2.2.12.	2,4,6‐Triphenyl‐1,2‐dihydropyrazolo[3,4‐c]pyrazole‐
3‐(6H)‐thione	(16)	
	

A	 mixture	 of	 pyrazolidine‐4‐carbothioamide	 15	 (3.71 g,	
0.01 mol)	 hydrazine	 hydrate	 (0.5 mL,	 0.01 mol)	 in	 absolute	
ethanol	 (50 mL)	 was	 refluxed	 for	 10 h.	 After	 cooling	 the	
reaction	mixture	was	poured	onto	 ice:HCl	(1:3),	 the	separated	
solid	 was	 filtered	 off,	 washed	 with	 water,	 dried	 and	
recrystallized	from	benzene	(Scheme	2).	Color:	White.	Yield:	65	
%.	 M.p.:	 235‐237	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3011	 (NH),	 1597	
(C=N),	 1454	 (NCS).	 1H	 NMR	 (300	MHz,	 DMSO,	 δ,	 ppm):	 7.23‐
7.91	 (m,	 16H,	 15ArH,	NH).	MS	 (EI,	m/z	 (%)):	368	 (8.00,	M+·),	
260	(100),	108	(12.0),	97	(26.0),	85	(32.0),	83	(30.0),	68	(24.0),	
55	(46.0).	Anal.	calcd.	for	C22H16N4S:	C,	71.71;	H,	4.38;	N,	15.21;	
S,	8.70.	Found:	C,	71.92;	H,	4.51;	N,	15.34;	S,	8.90	%.	
	
2.2.13.	1,3‐Diphenyl‐4‐(thiazol‐2‐yldiazenyl)‐1H‐pyrazol‐
5(4H)‐one	(17)	
	

2‐Aminothiazole	 (0.1	 g,	 0.001mol)	 was	 dissolved	 in	 conc.	
HCl	(5	mL)	and	the	solution	was	then	cooled	to	0‐5	°C.	Sodium	
nitrite	(0.069 g,	0.001mol)	 in	water	(3	mL)	was	then	added	 to	
this	solution	dropwise	with	vigorous	stirring	during	about	1 h,	
while	cooling	at	0‐5	 °C.	The	clear	diazonium	salt	 solution	was	
then	 added	 dropwise	 to	 a	 well	 cooled	 (0‐5	 °C)	 and	 stirred	
solution	of	pyrazolone	3	(0.236 g,	0.001mol)	in	sodium	acetate	
(1 g,	 dissolved	 in	5 mL	 of	 25%	aqueous	 ethanol).	 Stirring	was	
continued	 for	 4h	 at	 0‐5	 °C	 and	 the	 precipitated	 product	
separated	upon	dilution	with	cold	water	 (25	mL)	was	 filtered	
off,	washed	with	water	 several	 times,	dried	and	recrystallized	
from	 ethanol:benzene	 (1:1)	 (Scheme	 2).	 Color:	 White.	 Yield:	
80.2	 %.	M.p.:	 182‐184	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 1712	 (C=O),	
1663	 (C=N).	 1H	NMR	 (300	MHz,	 CDCl3,	 δ,	 ppm):	 8.23‐8.24	 (d,	
1H,	 NCH),	 7.52‐8.07	 (m,	 4H,	 ArH),	 7.50‐7.51	 (d,	 1H,	 =CH‐S),	
7.04‐7.25	(m,	6H,	ArH),	3.87	(s,	1H,	CH).	MS	(EI,	m/z	(%)):	347	

(62.7,	 M+·),	 236	 (16.4),	 129	 (100),	 84	 (19.4),	 78	 (19.4),	 77	
(74.6),	55	(4.5).	Anal.	calcd.	for	C18H13N5OS:	C,	62.23;	H,	3.77;	N,	
20.16;	S,	9.23.	Found:	C,	62.41;	H,	3.92,	N,	20.19;	S,	9.41	%.	
	
2.2.14.	1,3‐Diphenyl‐4‐(phenyldiazenyl)‐1H‐pyrazol‐5‐ol	
(18)	
	

Aniline	 (0.093 mL,	 0.001mol)	 in	 conc.	 HCl	 (3.6 mL)	 and	
water	 (1	mL)	was	 cooled	 in	 ice	 bath	 at	 0‐5	 °C	 and	 diazotized	
with	 the	 solution	 of	 sodium	 nitrite	 (0.345 g)	 in	water	 (2 mL).	
The	cold	diazonium	solution	was	added	slowly	to	a	well	stirred	
solution	pyrazolone	3	(0.236 g,	0.001 mol)	in	pyridine	(20 mL).	
The	 reaction	 mixture	 was	 stirred	 for	 another	 2 h.	 The	 crude	
product	was	 filtered	off,	dried	and	recrystallized	from	ethanol	
(Scheme	2).	Color:	Orange.	Yield:	55	%.	M.p.:	160‐162	°C.	FT‐IR	
(KBr,	 ,	 cm‐1):	 3435	 (OH),	 1650	 (C=O).	 1H	 NMR	 (300	 MHz,	
CDCl3,	δ,	ppm):	14.07	(s,	1H,	OH	D2O	exchangeable),	7.22‐8.28	
(m,	 15H,	 ArH).	MS	 (EI,	m/z	 (%)):	340	 (72.6,	M+·),	 263	 (26.0),	
235	 (28.3),	 220	 (6.0),	 77	 (100),	 78	 (7.5).	 Anal.	 calcd.	 for	
C21H16N4O:	C,	74.10;	H,	4.74;	N,	16.46.	Found:	C,	74.23;	H,	4.91;	
N,	16.53	%.	
	
2.2.15.	4‐(4‐Methoxybenzylidene)‐1,3‐diphenyl‐1H‐Pyrazol‐
5(4H)‐one	(19)	
	

Method	A:	A	mixture	of	pyrazolone	3	 (2.36 g,	0.01 mol),	p‐
anisaldehyde	 (1.36 mL,	 0.01 mol)	 in	 ethanol	 (70 mL)	 in	
presence	 of	 piperidine	 (1 mL)	 was	 refluxed	 for	 2 h.	 A	 white	
powder	 was	 formed	 during	 reflux.	 After	 cooling,	 the	 white	
powder	 was	 filtered	 off,	 washed	 with	 ethanol,	 dried	 and	
crystallized	 from	 ethanol	 (Scheme	 2).	 Color:	 White.	 Yield:	
81.6%.	 M.p.:	 218‐220	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3054	 (CH	
aromatic),	2950	(CH	aliphatic),	1714	(C=O).	1H	NMR	(300	MHz,	
DMSO,	δ,	ppm):	6.76‐8.04	(m,	14H,	ArH),	5.13	(s,	1H,	CH),	3.86	
(s,	3H,	OCH3).	



28	 Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	
	

	 	

 
	

Scheme	3
	
	
MS	(EI,	m/z	(%)):	354	(71.7,	M+·),	247	(36.1),	236	(42.8),	78	

(8.6),	57	(13.9),	56(100).	Anal.	 calcd.	 for	C23H18N2O2:	C,	77.95;	
H,	5.12;	N,	7.90.	Found:	C,	78.19;	H,	5.30;	N,	8.13	%.	

Method	B:	A	mixture	of	pyrazolone	3	 (2.36 g,	0.01 mol),	p‐
anisaldehyde	 (1.36 mL,	 0.01 mol)	 in	 presence	 of	 piperidine	
(1 mL)	was	 heated	 under	microwave	 irradiation	 for	 2	min	 at	
power	180.	 After	 cooling,	 the	 separated	 solid	was	 filtered	 off,	
washed	with	ethanol,	dried	and	recrystallized	from	ethanol.			
	
2.2.16.	4‐(4‐Methoxyphenyl)‐1,3‐diphenyl‐1,3a,4,5‐
tetrahydropyrazolo[3,4‐c]pyrazole	(22)	
	

Method	 A:	 A	 mixture	 of	 pyrazolone	 19	 (3.54 g,	 0.01 mol),	
hydrazine	 hydrate	 (0.5 mL,	 0.01 mol)	 in	 ethanol	 (30 mL)	 was	
refluxed	 for	 2 h.	 the	 reaction	 mixture	 was	 then	 poured	 onto	
ice:HCl	(1:3),	the	solid	product	that	formed	was	filtered	off	and	
washed	with	water	(4	×	30 mL),	dried	and	recrystallized from	
benzene	 (Scheme	3).	 Color:	 Purple.	 Yield:	 98%.	M.p.:	 185‐187	
°C.	FT‐IR	(KBr,	,	cm‐1):	3623	(NH),	3056,	3030	(CH	aromatic),	
1569	(C=N).	1H	NMR	(300	MHz,	DMSO,	δ,	ppm):	8.12	(s,	1H,	NH,	
D2O	 exchangeable),	 6.76‐8.04	 (m,	 14H,	 ArH),	 5.13	 (s,	 1H,	
CHC=N),	 3.82(s,	 1H,	 CH‐NH),	 3.68	 (s,	 3H,	 OCH3).	 MS	 (EI,	m/z	
(%)):	 370	 (0.5,	M+2),	 355	 (24.1),	 354	 (100),	 353	 (30.2),	 247	
(47.5),	 221	 (33.2),	 77	 (44.8).	 Anal.	 calcd.	 for	 C23H20N4O:	 C,	
74.98;	H,	5.47;	N,	15.21.	Found:	C,	75.14;	H,	5.62;	N,	15.35	%.	

Method	 B:	 A	 mixture	 of	 pyrazolone	 19	 (3.54 g,	 0.01 mol),	
hydrazine	 hydrate	 (0.5 mL,	 0.01 mol)	 was	 heated	 under	
microwave	 irradiation	 for	 4	 min	 at	 power	 360	 Watt.	 The	
separated	 solid	 was	 filtered	 off	 and	 washed	 with	 water	 (4	 ×	
30 mL),	dried	and	recrystallized	from	benzene.		
	
2.2.17.	4‐(4‐Methoxyphenyl)‐1,3‐diphenyl‐4,5‐dihydro‐1H‐
pyrazolo[3,4‐d]pyrimidin‐6(3aH)‐one	(23)	
	

A	 mixture	 of	 pyrazolone	 19	 (3.54 g,	 0.01 mol),	 and	 urea	
(0.6 g,	0.01 mol)	 in	glacial	acetic	acid	(20 mL)	was	refluxed	for	
5 h.	 The	 separated	 solid	 after	 pouring	 on	 crushed	 ice	 was	
filtered	 off,	 washed	 with	 water,	 dried	 and	 crystallized	 from	
benzene	(Scheme	3).	Color:	Yellow.	Yield:	45	%.	M.p.:	143‐145	
°C.	FT‐IR	(KBr,	,	cm‐1):	3625	(NH),	1723	(C=O),	1602	(C=N).	1H	
NMR	(300	MHz,	CDCl3,	δ,	ppm):	6.76‐8.07	(m,	14H,	ArH),	5.17	

(s,	 1H,	 CHNH),	 3.91	 (s,	 3H,	 OCH3),	 3.78	 (s,	 1H,	 NH	 D2O	
exchangeable),	 3.72	 (s,	 1H,	 CH).	MS	 (EI,	m/z	 (%)):	355	 (12.4,	
[M‐CHNO·]+),	247	 (20.7),	236	 (59.9),	77	 (100),	78	 (9.1).	 	Anal.	
calcd.	 for	 C24H20N4O2:	 C,	 72.71,	 H;	 5.08,	 N;	 14.13.	 Found:	 C,	
72.90;	H,	5.21;	N,	14.31	%.	
	
2.2.18.	1‐(4‐(4‐Methoxyphenyl)‐1,3‐diphenyl‐1,4‐
dihydropyrazolo[4,3‐e][1,3]thiazin‐6‐yl)thiourea	(24)	
	

A	mixture	of	pyrazolone	19	(3.54 g,	0.01 mol)	and	thiourea	
(0.76 g,	0.01 mol)	in	glacial	acetic	acid	(20 mL)	was	refluxed	for	
5 h.	The	reaction	mixture	was	poured	on	crushed	ice	to	give	a	
yellow	 solid	which	was	 filtered	 off,	washed	with	water,	 dried	
and	crystallized	from	benzene:ethanol	(1:1)	(Scheme	3).	Color:	
Yellow.	Yield:	60.15	%.	M.p.:	205‐207	 °C.	FT‐IR	 (KBr,	,	 cm‐1):	
3380,	3276	(NH,	NH2),	1614	(C=N).	1H	NMR	(300	MHz,	CDCl3,	δ,	
ppm):	 6.79‐7.96	 (m,	 14H,	 ArH),	 5.16	 (s,	 1H,	 benzilic),	 3.69	 (s,	
3H,	OCH3),	3.08	(s,	3H,	NH,	NH2	D2O	exchangeable).	MS	(EI,	m/z	
(%)):	 471	 (23.3,	 M+·),	 236	 (26.7),	 235	 (30.0),	 91	 (30.0),	 77	
(100).	Anal.	calcd.	for	C25H21N5OS2:	C,	63.67;	H,	4.49;	N,	14.85;	S,	
13.60.	Found:	C,	63.82;	H,	4.60;	N,	14.93;	S,	13.81	%.	
	
2.2.19.	3‐(4‐Methoxyphenyl)‐4,6‐diphenyl‐3a,6‐dihydro‐3H‐
pyrazolo[3,4‐c]isoxazole	(25)	
	

A	 mixture	 of	 pyrazolone	 19	 (3.54 g,	 0.01 mol)	 and	
hydroxylamine	hydrochloride	(0.69 g,	0.01 mol)	 in	presence	of	
pyridine	(10 mL)	was	refluxed	for	6 h,	the	separated	solid	after	
cooling	was	filtered	off,	dried	and	crystallized	from	petroleum	
ether	80‐100	°C	 (Scheme	4).	Color:	Pale	yellow.	Yield:	70.1	%.	
M.p.:	 112‐115	 °C.	 FT‐IR	 (KBr,	 ,	 cm‐1):	 3058	 (CH	 aromatic),	
2952	 (CH	aliphatic),	1600	 (C=N).	 1H	NMR	(300	MHz,	CDCl3,	δ,	
ppm):	6.74‐8.55	(m,	14H,	ArH),	3.91	(d,	1H,	CH‐O),	3.83	(s,	3H,	
OCH3),	 2.85	 (d,	 1H,	 CH‐C=N).	MS	 (EI,	m/z	 (%)):	 354	 (42,	 [M‐
CH3O·]+),	247	(17.4),	235	(49.9),	77	(100),	57	(3.5).	Anal.	calcd.	
for	C23H19N3O2:	C,	74.78;	H,	5.18;	N,	11.37.	Found:	C,	75.10;	H,	
5.25;	N,	11.56	%.	
	
	
	
	



Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	 29	
 

	

 
	

Scheme	4
	
	
2.2.20.	1‐(6‐Hydroxy‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1,4‐
dihydropyrano[2,3‐c]pyrazol‐5‐yl)ethanone	(26)		
	

A	 mixture	 of	 pyrazolone	 19	 (0.708 g,	 0.002 mol),	 ethyl	
acetoacetate	 (0.26 mL,	 0.002 mol,)	 in	 sodium	 ethoxide	 (1%)	
solution	 was	 refluxed	 for	 6 h.	 The	 mixture	 was	 poured	 onto	
ice:HCl	(1:3),	the	separated	solid	was	filtered	off,	washed	with	
water,	dried	and	recrystallized	from	ethanol	(Scheme	4).	Color:	
Pale	 yellow.	 Yield:	 73.17	 %.	 M.p.:	 140‐142	 °C.	 FT‐IR	 (KBr,	 ,	
cm‐1):	3629	(OH),	1713	(C=O),	1601	(C=N).	1H	NMR	(300	MHz,	
DMSO,	δ,	ppm):	6.84‐8.68	(m,	14H,	ArH),	6.00	(s,	1H,	OH,	D2O	
exchangeable),	5.21	(s,	1H,	benzilic),	3.91	(s,	3H,	OCH3),	3.71(s,	
3H,	COCH3).	MS	(EI,	m/z	 (%)):	440	 (9.4,	 [M	+2·]+),	354	 (71.8),	
353	(34.1),	352	(21.2),	268	(100),	267	(45.9),	251	(28.2),	249	
(58.8),	 172	 (15.3),77	 (40.0),	 78	 (11.8).	 Anal.	 calcd.	 for	
C27H22N2O4:	C,	73.96;	H,	5.06;	N,	6.39.	Found:	C,	74.14;	H,	5.20;	
N,	6.51	%.	
	
2.2.21.	1‐(6‐Hydroxy‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1H‐
pyrazolo[3,4‐b]pyridin‐5yl)ethanone	(27)	
	

A	 mixture	 of	 pyrazolone	 19	 (0.708 g,	 0.002 mol),	
ammonium	 acetate	 (2 g),	 and	 ethyl	 acetoacetate	 (0.26 mL,	

0.002 mol,)	 was	 fused	 for	 7 h	 at	 170	 °C.	 After	 cooling,	 the	
reaction	mixture	 was	 triturated	with	 petroleum	 ether	 (60‐80	
°C)	 to	 give	 an	 orange	 solid	 which	 was	 recrystallized	 from	
petroleum	 ether	 60‐80	 °C	 (Scheme	 4).	 Color:	 Orange.	 Yield:	
66.66%.	M.p.:136‐138	°C.	FT‐IR	(KBr,	,	cm‐1):	3055	(OH)	1706	
(C=O).	1H	NMR	(300	MHz,	CDCl3,	δ,	ppm):	14.89	(s,	1H,	OH,	D2O	
exchangeable),	 7.12‐7.91	 (m,	 14H,	 ArH),	 3.76	 (s,	 3H,	 OCH3),	
3.60	(s,	3H,	COCH3).	MS	(EI,	m/z	(%)):	435	(3.4,	M+·),	289	(2.9),	
276	 (9.1),	171	 (7.4),	121	 (100).	Anal.	 calcd.	 for	C27H21N3O3:	C,	
74.47;	H,	4.86;	N,	9.65.	Found:	C,	74.51;	H,	4.93;	N,	9.72	%.	
	
2.2.22.	4‐(4‐Methoxyphenyl)‐6‐oxo‐1,3‐diphenyl‐1,6‐dihydro	
pyrano[2,3‐c]pyrazole‐5‐carbonitrile	(28)	
	

A	 mixture	 of	 pyrazolone	 19	 (0.708 g,	 0.002 mol),	 ethyl	
cyanoacetate	 (0.226 mL,	 0.002 mol)	 in	 sodium	 ethoxide	 (1%)	
solution	 was	 refluxed	 for	 6 h.	 The	 mixture	 was	 poured	 onto	
ice:HCl	(1:3),	the	separated	solid	was	filtered	off,	washed	with	
water,	dried	and	recrystallized	from	ethanol	(Scheme	4).	Color:	
Pale	 green.	 Yield:	 35.16%.	 M.p.:	 136‐138	 °C.	 FT‐IR	 (KBr,	 ,	
cm‐1):	 2208	 (C≡N),	 1706	 (C=O),	 1665	 (C=N),	 1621	 (C=C).	 1H	
NMR	(300	MHz,	DMSO,	δ,	ppm):	7.25‐7.82	(m,	14H,	ArH),	3.79	
(s,	 3H,	OCH3).	MS	 (EI,	m/z	 (%)):	354	 (9.4,	 [M‐C3H3NO·]+),	 236	



30	 Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	
	
(44.2),	105	(23.2),	91	(42.0),	85	(32.6),	69	(42.0),	57	(100),	51	
(282).	 Anal.	 calcd.	 for	 C26H17N3O3:	 C,	 74.45;	 H,	 4.09;	 N,	 10.02.	
Found:	C,	74.62;	H,	4.13;	N,	10.21	%.	
	
2.2.23.	2‐((3‐Methoxyphenyl)(5‐oxo‐1,3‐diphenyl‐4,5‐
dihydro‐1H‐pyrazol‐4‐yl)methyl)malononitrile	(29)	
	

A	 mixture	 of	 pyrazolone	 19	 (3.54 g,	 0.01 mol)	 and	
malononitrile	 (0.66 g,	 0.01 mol)	 in	 ethanol	 (30 mL)	 in	 the	
presence	 of	 piperidine	 (1 mL)	 was	 refluxed	 for	 10 h.	 After	
cooling,	 solid	 crystals	were	 produced	which	were	 filtered	 off,	
dried	 and	 recrystallized	 from	 ethanol:benzene	 (2:1)	 (Scheme	
4).	Color:	Brown	crystals.	Yield:	69	%.	M.p.:	211‐213	°C.	FT‐IR	
(KBr,	,	cm‐1):	3328	(OH),	2189,	2153	(C≡N),	1639	(C=O),	1601	
(C=N).	1H	NMR	(300	MHz,	DMSO,	δ,	ppm):	18.11	(s,	1H,	OH	D2O	
exchangeable),	6.76‐8.03	(m,	14H,	ArH),	5.12	(d,	1H,	CHCHCN),	
3.68	(s,	3H,	OCH3),	3.15	(d,	1H,	CHCHCN).	MS	(EI,	m/z	(%)):	420	
(3.1,	M+·),	236	(3.1),	84	(100),	70	(15.5),	57	(37.6).	Anal.	calcd.	
for	C26H20N4O2:	C,	74.27;	H,	4.79;	N,	13.33.	Found:	C,	73.95;	H,	
4.64;	N,	13.24	%.		
	
2.2.24.	[5‐Amino‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐1,4‐
dihydro‐9‐oxa‐1,2,6,8‐tetraaza‐cyclopenta[b]naphthalen‐7‐
yl]	acetonitrile	(30)	
	

A	 mixture	 of	 pyrazolone	 19	 (0.708 g,	 0.002 mol),	
malononitrile	 (0.132 g,	 0.002 mol)	 in	 sodium	 ethoxide	 (1%)	
solution	 was	 refluxed	 for	 6 h.	 The	 mixture	 was	 poured	 onto	
ice:hydrochloric	acid,	 the	solid	 that	separated	was	 filtered	off,	
washed	 with	 water,	 dried	 and	 recrystallized	 from	 benzene	
(Scheme	4).	Color:	 Pale	 yellow.	Yield:	40	%.	M.p.:	 117‐119	 °C.	
FT‐IR	 (KBr,	 ,	 cm‐1):	 3424,	 3322	 (NH2),	 2213	 (C≡N),	 1642	
(C=N),	 1602	 (C=C).	 1H	NMR	 (300	MHz,	 DMSO,	 δ,	 ppm):	 7.07‐
7.83	 (m,	 15H,	 14ArH,	 1H	 benzilic),	 6.00	 (s,	 2H,	 NH2	 D2O	
exchangeable),	3.82	(s,	2H,	CH2CN),	3.35	(s,	3H,	OCH3).	MS	(EI,	
m/z	(%)):	443	(54.5,	 [M‐CHNO·]+),	295	(45.5),	138	(45.5),	122	
(54.5),	 109	 (72.7),	 108	 (63.6),	 93	 (27.2),	 67	 (72.7)52	 (100).	
Anal.	calcd.	for	C29H22N6O2:	C,	71.59;	H,	4.56;	N,	17.27.	Found:	C,	
71.61;	H,	4.71;	N,	17.41	%.	
	
2.2.25.	[5‐Amino‐4‐(4‐methoxyphenyl)‐1,3‐diphenyl‐4,9‐
dihydro‐1H‐pyrazolo[4’,3’:5,6]pyrido[2,3‐d]pyrimidin‐7‐
yl]acetonitrile	(31)	
	

A	 mixture	 of	 pyrazolone	 19	 (0.708 g,	 0.002 mol),	
malononitrile	(0.132 g,	0.002 mol)	and	ammonium	acetate	(2 g)	
was	fused	for	7 h	at	170	°C.	After	cooling,	the	solid	was	washed	
with	 water,	 filtered	 off,	 dried,	 and	 recrystallized	 from	
benzene:ethanol	(1:2)	(Scheme	4).	Color:	Pale	yellow.	Yield:	40	
%.	M.p.:	190‐192	°C.	FT‐IR	(KBr,	,	cm‐1):	3428,	3321	(NH,	NH2),	
2203	 (C≡N),	 1599	 (C=C).	 1H	NMR	 (300	MHz,	DMSO,	 δ,	 ppm):	
7.05‐8.32	(m,	14H,	ArH),	5.95	(s,	1H,	benzilic),	5.70	(s,	2H,	NH2	
D2O	exchangeable),	5.66	(s,	1H,	NH	D2O	exchangeable),	3.84	(s,	
3H,	OCH3),	3.67	(s,	2H,	CH2CN).	MS	(EI,	m/z	(%)):	435	(10.6,	[M‐
C2H4N2·]+),	 435	 (10.6),	 236	 (36.2),	 160	 (12.8),	 93	 (51.1),	 84	
(36.2),	78	(29.8),	77	(100),	56	(55.3).	Anal.	calcd.	for	C29H23N7O:	
C,	71.74;	H,	4.77;	N,	20.19.	Found:	C,	71.82;	H,	4.93;	N,	20.23	%.		
	
2.2.26.	4‐((5‐Hydroxy‐1,3diphenyl‐1H‐pyrazol‐4‐yl)(4‐
methoxyphenyl)methyl)‐1,3‐diphenyl‐1H‐pyrazol‐5‐ol	(32)	
	

Pyrazolone	 19	 (3.54 g,	 0.01 mol)	 was	 added	 at	 room	
temperature	with	stirring	to	a	mixture	of	pyrazolone	3	(2.36 g,	
0.01 mol),	 and	 sodium	 ethoxide	 (0.5 g	 sodium	 in	 10 mL),	 then	
the	mixture	was	stirred	for	another	1 h	at	100	°C.	The	mixture	
was	 poured	 onto	 ice:hydrochloric	 acid	 (1:3),	 the	 separated	
solid	 was	 filtered	 off,	 washed	 with	 water,	 dried	 and	
recrystallized	from	ethanol	(Scheme	4).		Color:	Red.	Yield:	90.4	
%.	M.p.:178‐180	°C.	FT‐IR	(KBr,	,	cm‐1):	3448	(OH),	3058	(CH	
aromatic),	2928	(CH	aliphatic),	1603	(C=N).	1H	NMR	(300	MHz,	
DMSO,	 δ,	 ppm):	 8.62	 (s,	 2H,	OH	D2O	 exchangeable),	 6.85‐7.89	

(m,	24H,	ArH),	5.23	(s,	1H,	benzilic),	3.89	(s,	3H,	OCH3).	MS	(EI,	
m/z	 (%)):	590	 (0.01,	M+·),	 236	 (60.6),	 149	 (100),	 148	 (33.3),	
135	 (12.1),	 121	 (21.2),	 92	 (16.7),	 77	 (45.5).	 Anal.	 calcd.	 for	
C38H30N4O3:	C,	77.27;	H,	5.12;	N,	9.49.	Found:	C,	77.32;	H,	5.27;	
N,	9.62	%.	
	
2.3.	Antimicrobial	activities	
	

The	 synthesized	 compounds	 were	 evaluated	 for	 their	
antimicrobial	activities	using	the	agar	diffusion	technique	[16].	
All	Chemical	compounds	were	dissolved	in	DMF	(5000	ppm).	

The	 tested	 compounds	 were	 evaluated	 against	 Gram	 ‐ve	
bacteria	(Pseudomonas	aeruginosa	ATCC	10145	and	Escherichia	
coli	 ATCC	 23282),	 Gram	 +ve	 bacteria	 (Bacillus	 subtilis	 ATCC	
6633,	 Micrococcus	 luteus	 ATCC	 25922)	 and	 Yeast	 (Candida	
albicans	 IMRU	3669	 and	Filamentous	niger	 ATCC	16404).	 The	
bacteria	 and	 yeast	 were	 grown	 on	 nutrient	 agar	 while	 the	
fungus	was	grown	on	Czapek’s	Dox	agar	medium.	

The	 negative	 control	 DMF	 was	 showed	 no	 antimicrobial	
activity	 against	 the	 tested	 microorganism,	 and	 the	 positive	
control	 was	 Erythromycin	 for	 bacteria	 and	Metronidazole	 for	
yeast	and	fungus.			

All	examination	were	done	in	duplicates	and	the	listed	are	
the	average	of	the	obtained	results.	
	
3.	Results	and	discussion	
	
3.1.	Synthesis	
	

The	 starting	 material	 pyrazolone	 3	 was	 prepared	 by	
literature	known	procedure	[17]	using	ethyl	benzoyl	acetate	1	
as	 β‐keto	 ester	 and	 phenyl	 hydrazine,	 2.	 In	 principle,	 for	
compounds	 unsubstituted	 at	 pyrazole	 C‐4,	 three	 isomers	 are	
possible,	 assigned	 as	 1H‐pyrazol‐5‐ol	 (A),	 2,4‐dihydro‐3H‐
pyrazol‐3‐one	 (B)	 and	 1,2‐dihydro‐3H‐pyrazol‐3‐one	 (C)	
(Scheme	5).	

	

 
	

Scheme	5	
	
The	IR	spectra	of	3	displayed	band	at	1706	cm−1	due	to	C=O	

absorption	 at	 position	 5	 and	 the	 1H	NMR	 spectrum	devoid	 of	
exchangeable	 NH	 or	 OH	 which	 indicated	 that	 pyrazolone	 3	
exists	 in	 the	 keto	 form	 in	 either	 the	 solid	 state	 or	 the	 liquid	
state.		

The	 reactivity	 of	 hydrogen	 atoms	 at	 C‐4	 is	 the	 most	
outstanding	 chemical	 property	 of	 pyrazolone	 3	 towards	
condensation	reactions	(Scheme	1).	

Amino	carbonitriles	4	 and	5	and	pyrazolopyridine	6	were	
synthesized	 via	 a	 multicomponent	 reaction	 of	 pyrazolone	 3	
with	p‐anisaldehyde	and	active	methylene	compounds	such	as	
malononitrile	 and/or	 ethyl	 acetoacetate	 in	 the	 presence	 of	
ammonium	 acetate	 and/or	 piperidine	 at	 140‐170	 °C.	 The	
appearance	of	 the	 cyano	and	 the	amino	 functions	 in	 the	 IR	of	
the	reaction	products	support	 the	 structures	of	compounds	4,	
and	5.		

It	has	been	reported	that	amino	carbonitriles	reacted	with	
ammonium	 thiocyanate	 [18]	 in	 boiling	 acetic	 acid	 to	 give	
(thioxo	 pyrimidinyl)	 thiourea	 derivatives,	 while	 in	 our	
investigation	 we	 isolated	 the	 amino(iminomethyl)thiocyanato	
methanethioimidate	 7	 through	 two	 consecutive	 additions	 of	
two	molecules	of	ammonium	thiocyanate	 to	compound	4.	The	
structure	 of	 compound	7	was	 confirmed	by	 IR	which	 showed	
band	 at	 2207	 (C≡N),	 and	 also	 its	 reaction	 with	 hydrazine	
hydrate	to	afford	pyrazolo[3,4‐b]pyridin‐6‐amine	derivative	8.	
	



Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	 31	
 

	 	
Table	1.	Microwave	synthesis	of	compounds	5,	19	and	22.	
Compound	no	 Power	(Watt)	 Time	(min) Yield	(%)	MW/Conventional	
5	 180	 4 50/14
19	 180	 2	 90/82	
22	 360	 4	 99/98	
	
	
Table	2.	The	Antimicrobial	activities	of	compounds	8,	23,	27	and	31	*.	
Compound		
no	

Bacillus	subtilis	 Micrococcus	lutes	 Pseudonomus	aerugino Escherichia	coli Candida	albicans	 Filamentous niger

8	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	
23	 ‐	 ‐	 17.0 20.0 ‐ ‐	
27	 36.0	 27.0	 27.0	 32.0	 21.0	 17.0	
31	 23.0	 21.0	 18.0 22.0 20.0 15.0	
Erythromycin	 32.0	 32.0	 30.0	 44.0	 ‐	 ‐	
Metronidazole	 ‐	 ‐	 ‐	 ‐	 27.0	 25.0	
DMF	 ‐	 ‐	 ‐	 ‐	 ‐	 ‐	
*	Erythromycin	was	used	as	a	standard	against	Gram	positive	and	Gram	negative	bacteria,	while	metronidazole	was	used	as	a	standard	against	fungi,	and	the	
negative	controle	was	DMF.	

	
	
Treatment	of	compound	4	with	formamide	in	the	presence	

of	 formic	 acid	 and	 DMF	 afforded	 the	 open	 structure	
pyrazolo[3,4‐b]pyridinylformamide	9.	

Acetylation	 of	 compounds	4	 and	5	 with	 acetic	 anhydride	
afforded	 the	 acetylated	 compounds	 pyrazolo[3,4‐b]pyridin‐6‐
yl)acetamide	 (10)	 and	 dihydropyrano[2,3‐c]‐pyrazol‐6‐
yl)acetamide	 11,	 respectively.	 The	 structures	 of	 these	
compounds	were	confirmed	by	spectroscopic	data	and	also	the	
reaction	of	compound	11	with	hydrazine	hydrate	to	give	the	bis	
compound	 12.	 The	 hydrazine	 hydrate	 is	 an	 ambident	
nucleophile	therefore	one	molecule	of	it	attacks	two	molecules	
of	 compound	11	 followed	 by	 hydrogenation	 to	 afford	 the	 bis	
compound	12	(Scheme	1).	

Condensation	 of	 pyrazolone	 3	 with	 glucose	 in	
ethanol/DMF/drops	 of	 AcOH	 mixture	 furnished	 the	 penta	
hydroxy	hexylidene	pyrazolone	derivative	13.	

The	 active	methylene	 group	 of	 pyrazolone	3	 reacted	with	
phenyl	isothiocyanate	[19]	in	the	presence	of	piperidine	to	give	
an	 intermediate	 thiolate	anion	14	which	upon	 treatment	with	
dilute	hydrochloric	acid	furnished	functionalized	thioamide	15	
(Scheme	2).	

Compound	15	 is	a	versatile	multifunctional	reagent	which	
reacted	 with	 hydrazine	 hydrate	 to	 afford	 pyrazolo[3,4‐
c]pyrazolethione	16.	

Novel	 4‐thiazolyl	 diazenyl‐1H‐pyrazol‐5‐one	 (17)	 and	
4‐(phenyldiazenyl)‐1H‐pyrazol‐5‐ol	(18)	have	been	obtained	as	
red	 and	 orange	 dyes	 respectively	 via	 the	 diazonium	 cation	
resulting	 from	 the	 interaction	 of	 nitrite	 with	 pyrazolone	 3	
followed	by	coupling	with	2‐aminothiazole	and	aniline	(Scheme	
2).		

The	pyrazolone	3	was	reacted	with	p‐anisaldehyde	[17]	in	
the	presence	of	piperidine	to	give	the	pyrazolone	19	according	
to	 Knoevenagel	 condensation	 reaction	which	 is	 an	 important	
tool	for	the	formation	of	new	carbon‐carbon	bonds.	

To	 show	 the	 synthetic	 potentiality	 of	 compound	 19,	 the	
reactivity	of	compound	19	with	different	nitrogen	nucleophiles	
such	 as	 hydrazine	 hydrate,	 urea,	 thiourea	 and	 hydroxylamine	
hydrochloride	was	examined	(Scheme	3,4).	

Reactions	 of	 compound	 19	 with	 hydrazine	 hydrate	 and	
urea	 afforded	 pyrazolo[3,4‐c]pyrazole	 (22)	 and	 pyrazolo[3,4‐
d]pyrimidinone	 (23)	 via	 β‐attack	 on	 the	 C=C	 moiety	 in	
compound	19	 to	 give	 the	non‐isolable	 intermediates	20,	21a,	
which	 underwent	 1,5	 and	 1,6	 intramolecular	 dipolar	
cyclization.	

Reaction	of	thiourea	with	compound	19	via	β‐attack	on	the	
C=C	moiety	in	compound	19	gave	the	non‐isolable	intermediate	
21b	 which	 underwent	 1,6	 intramolecular	 dipolar	 cyclization	
through	 the	 sulfur	 atom,	 followed	 by	 the	 loss	 of	 ammonia	
through	the	reaction	with	another	molecule	of	thiourea	to	give	
pyrazolo[4,3‐e][1,3]thiazinyl	thiourea	(24).	

Hydroxylamine	hydrochloride	was	reacted	with	compound	
19	in	the	presence	of	pyridine	to	give	pyrazolo[3,4‐c]isoxazole	
(25).	

In	this	work,	we	aim	to	study	the	reactivity	of	compound	19	
as	 α,β‐unsaturated	 compound	 towards	 several	 carbon	
nucleophiles	under	Michael	reaction	(Scheme	4).	

The	 formation	 of	 pyrano[2,3‐c]	 pyrazolyl	 ethanone	 (26)	
and	pyrazolo[3,4‐b]pyridinyl	 ethanone	 (27)	 seems	 to	proceed	
by	the	addition	of	the	nucleophile	ethyl	acetoacetate	on	the	β‐
carbon	of	the	electrophile	(19)	in	a	conjugate	addition	reaction	
in	the	presence	of	sodium	ethoxide	and/or	ammonium	acetate	
followed	 by	 6‐exo‐dig	 cyclization	 and	 dehydrogenation.	
Similarly	 compound	 28	 is	 formed	 by	 the	 addition	 of	 ethyl	
cyanoacetate	 to	 pyrazolone	 3	 in	 the	 presence	 of	 sodium	
ethoxide.	

The	 addition	 of	 malononitrile	 to	 compound	 19	 in	 the	
presence	 of	 piperidine	 afforded	 the	 adduct	 compound	 29	
which	exists	in	the	keto/enol	forms	which	was	inferred	from	its	
spectroscopic	data.	IR	spectrum	showed	bands	at	1639	cm‐1	for	
C=O,	 and	 3328	 cm‐1	 due	 to	 OH,	 1H	 NMR	 spectrum	 showed	 δ	
18.11	ppm	for	OH.					

On	 the	 other	 hand,	 the	 addition	 of	 malononitrile	 to	
compound	 19	 in	 the	 presence	 of	 sodium	 ethoxide	 and/or	
ammonium	 acetate	 afforded	 compounds	 30	 and	 31.	
Malononitirile	 was	 added	 to	 the	 β‐carbon	 of	 compound	 19	
followed	 by	 nucleophilic	 addition	 of	 the	 hydroxyl	 and/or	 the	
amino	groups	to	the	cyano	group	through	6‐exo‐dig	cyclization, 
then	 another	 molecule	 of	 malononitrile	 was	 attacked	 by	 the	
formed	 amino	 group	 followed	 by	 cyclization	 and	 hydrogen	
transfer	to	give	compounds	30	and	31,	respectively.	

Stirring	 of	 compound	 19	 with	 pyrazolone	 (3)	 in	 the	
presence	 of	 sodium	 ethoxide	 afforded	 hydroxy	 pyrazolyl	
pyrazolol	(32).	

It	 was	 observed	 that	 microwave	 irradiation	 method	 was	
practically	superior	to	conventional	heating	method	in	terms	of	
higher	 yields,	 rapid,	 and	 environmentally	 benign	 process.	We	
carried	out	some	of	the	reactions	using	microwave	 irradiation	
to	improve	the	yield	and	the	time	of	the	reactions.	Synthesis	of	
amino	 carbonitriles	 (5),	 pyrazolone	 (19)	 and	 pyrazolo[3,4‐
c]pyrazole	 (22)	 under	 microwave	 irradiation	 showed	
improvement	 in	 the	yield	and	the	time	of	the	reactions	(Table	
1).	 Formation	 of	 compounds	 5,	 19	 and	 22	 under	 microwave	
irradiation	 produced	 the	 products	 in	 good	 yield	 within	 2‐4	
minutes.	 The	 reactions	 were	 carried	 out	 under	 solvent	 free	
conditions	to	avoid	problems	associated	with	solvent	use	such	
as	cost,	handling	and	specifically	safety,	because	of	fire	hazard	
due	to	occurrence	of	sparks	in	microwave	ovens.	The	reactions	
were	 less	effective	and	 took	 two	hours	 to	be	completed	when	
carried	out	in	ethanol	under	reflux.		
	
3.2.	Antimicrobial	activities	
	



32	 Marzouk	et	al.	/	European	Journal	of	Chemistry	5	(1)	(2014)	24‐32	
	

Compound	 27	 showed	 higher	 reactivity	 towards	 Bacillus	
subtilis	 than	 the	 reference	 and	 high	 reactivity	 towards	 Gram						
‐ve	 bacteria,	 Gram	 +ve	 bacteria	 and	 fungi.	 Compound	 31	
showed	moderate	 reactivity	 towards	Gram	 ‐ve	bacteria,	Gram	
+ve	 bacteria	 and	 fungi.	 Compound	 8	 showed	 no	 reactivity	
towards	Gram	‐ve	bacteria,	Gram	+ve	bacteria	and	fungi	(Table	
2).		
	
4.	Conclusion	
	

Pyrazolone	3	is	an	active	compound	towards	condensation	
reactions.	Pyrazolone	19	acts	as	an	α,β‐unsaturated	compound	
towards	different	carbon	and	nitrogen	nucleophiles.	Microwave	
irradiation	 method	 was	 practically	 superior	 to	 conventional	
heating	 method	 in	 terms	 of	 higher	 yields,	 rapid,	 and	
environmentally	benign	process.	
	
Acknowledgements	
	

Technical	 support	 from	Department	 of	 Chemistry,	 Faculty	
of	Science,	Ain	Shams	University	is	gratefully	acknowledged.	
	
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