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European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	

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

DOI:10.5155/eurjchem.3.3.316‐321.612	

	
	

	

	

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

	 	 	

Synthesis	and	studies	of	pyrazolo[3,4‐b]pyridin‐4‐one	derivatives	

Hussain	Ali	Soleiman*,	Ali	Kamel	Khalafallah	and	Hana'a	Abd‐Ellatif	

Chemistry	Department,	Aswan	Faculty	of	Science,	South	Valley	University,	Aswan,	81111,	Egypt	

*Corresponding	author	at:	Chemistry	Department,	Aswan	Faculty	of	Science,	South	Valley	University,	Aswan,	81111,	Egypt.		
Tel.:	+20.97.3480447;	fax:	+20.97.3480450.	E‐mail	address:	hsoleiman2001@yahoo.com			(H.A.	Soleiman).	

	
	

	 	

	 	 	
ARTICLE	INFORMATION	 	 ABSTRACT
Received:	10	April	2012	
Received	in	revised	form:	10	July	2012	
Accepted:	10	July	2012	
Online:	30	September	2012	

KEYWORDS	

	 A	 series	 of	 isolated/fused	 of	 pyrazole,	 isoxazolo,	 pyrimidine,	 pyrimidine	 thione,	 spiro
thiazolodine	 and	 spiro	 β‐lactam	 derivatives	 incorporating	 to	 4‐acetyl‐5‐imino‐3‐methyl‐1‐
phenyl‐2‐pyrazoline	have	been	 synthesized	by	different	methods.	The	 structure	 of	 chemical
reactions	 based	 on	 chemical	 and	 spectroscopic	 evidence.	 The	 detailed	 synthesis	 and
spectroscopic	data	were	reported.	

Pyrazole	
Isoxazolo	
Pyrimidine	
Spiro	β‐lactam	
Pyrimidine	thione	
Spiro	thiazolodine	

	
1.	Introduction	
	

Pyrazole,	 isoxazole,	 pyrimidine,	 pyrimidinothione,	 spiro	
thiazolodine	 and	 Spiro	 β‐lactam	 derivatives	 incorporating	 4‐
acetyl‐5‐imino‐3‐methyl‐1‐phenyl‐2‐pyrazoline	are	biologically	
important	molecules	 and	natural	 products	 [1‐5].	 The	 reaction	
between	benzaldehyde,	aniline	and	cyclohexanone	was	studies	
as	 a	 model	 reaction	 in	 water	 in	 the	 presence	 of	 various	
amounts	of	first	generation	dendrimer	[6‐15].	It	was	found	that	
only	2	mol	%	of	the	catalyst	was	required	to	drive	the	reaction	
smoothly	to	completion.	The	scope	of	the	dendrimer	catalyzed	
Mannish	 reaction	 was	 extended	 to	 other	 aldehydes,	 ketones	
and	 anilines	 [16‐26].	 In	 a	 similar	 manner	 condensation	
between	 other	 substrates	 like	 1‐(5‐imino‐3‐methyl‐1‐phenyl‐
4,5‐dihydro‐1H‐pyrazol‐4‐yl)ethanone	 (1)	 also	 a	 short	 period	
of	 time	 with	 excellent	 yield	 and	 high	 purity	 and	 no	 more	
purification	was	 required.	 In	 a	 literature	 search,	 it	 has	 found	
that	Mannich	bases	had	antimicrobial	activities	[27,28]	besides	
various	 activities.	 The	 pyrazole	 nucleus	 is	 present	 in	 a	 wide	
variety	 of	 biologically	 interesting	 compounds,	 which	 exhibit	
anti‐hyperglycemic,	 analgesic,	 anti‐inflammatory,	 antipyretic,	
antibacterial,	hypoglycemic,	sedative‐hypnotic	activity	[29‐42].	
Pyrazoles	 and	 their	 derivatives	 are	 widely	 used	 as	
pharmaceutical	 [43‐45]	 and	 agrochemical	 agents	 [46]	 and	
consequently	 a	 large	 number	 of	 synthetic	 routes	 to	 pyrazoles	
has	been	reported	[47‐51].	However,	there	is	still	great	interest	
in	finding	milder	and	more	efficient	methods	to	these	valuable	
compounds.	 Amino	 pyrazole	 derivative	 and	 imino	 pyrazole	
derivative	undergo	various	reactions,	and	as	such	are	excellent	
and	 general	 starting	 materials	 for	 the	 development	 of	 the	
heterocyclic	compounds	synthesis.	
	
2.	Experimental	
	
2.1.	Instrumentation		
	

All	 melting	 points	 are	 uncorrected.	 IR	 spectra	 were	
recorded	 on	 a	 Pye	 Unicam	 SP‐1100	 Spectrophotometer	 KBr	
disc.	 1H	 NMR	 spectra	 were	 recorded	 on	 a	 Varian	 EM‐390	 90	
MHz	spectrophotometer	using	DMSO‐d6	 as	 a	 solvent	 and	TMS	
as	 an	 internal	 standard	 chemical	 shifts	 are	 expressed	 as	 ppm	
units.	 Mass	 spectra	 were	 obtained	 on	 a	 Shimadzu	 GCMS	 QP	
1000	EX	mass	spectrometer	at	70	eV.	The	microanalyses	were	
performed	by	the	microanalytical	centers	at	Cairo	University.		
	
2.2.	Synthesis	of	1‐(5‐imino‐3‐methyl‐1‐phenyl‐4,5‐dihydro‐
1H‐pyrazol‐4‐yl)ethanone	(1)	
	

The	compound	1	was	carried	out	according	to	Mohanty	et	
al.,	1977	[52]	(Tables	1,	2).	
	
2.3.	Synthesis	of	3‐methyl‐1‐phenyl‐5,6‐dihydro‐1H‐pyrazolo	
3,4‐b]pyridin‐4(3aH)‐one	(2)	

	
A	 solution	 of	 compound	 (2.15	 g,	 0.01	 mol)	 in	 DMF	 as	 a	

solvent	 in	presence	of	piperidine	(0.85	mL,	0.01	mol)	and	HCl	
(0.5	 mL,	 0.05	mol)	 with	 paraformaldehyde	 (0.3	 g,	 0.01	 mol).	
The	 reaction	mixture	was	 heated	 under	 reflux	 for	 3	 hr.	 Then	
left	to	cool	and	was	poured	on	ice/water	with	the	stirring.	The	
solid	 product	 so	 formed	 was	 collected	 by	 filtration	 and	
crystallized	 from	 the	 diluted	 dimethyl‐formamide	 (Scheme	 1,	
Tables	1,	2).	
	
2.4.	Synthesis	of	5‐benzylidene‐3‐methyl‐1‐phenyl‐5,6‐
dihydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(3a),		
5‐(4‐methoxybenzylidene)‐3‐methyl‐1‐phenyl‐5,6‐dihydro‐
1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(3b),		
5‐(4‐hydroxybenzylidene)‐3‐methyl‐1‐phenyl‐5,6‐dihydro‐
1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(3c)		
	

A	solution	of	compound	2	(1.135	g,	0.005	mol)	in	DMF	was	
treated	with	aromatic	aldehyde	compounds	(3a:	0.53	mL,	0.005		

	



Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	 317	
 

	

 
	

Scheme	1
	

	
mol;	3b:	0.68	mL,	0.005	mol;	3c:	0.61	g,	0.005	mol)	in	presence	
of	 piperidine	 as	 catalyst.	 The	 reaction	 mixture	 was	 heated	
under	reflux	for	4	hr.,	then	left	to	cool	and	poured	on	ice/water.	
The	 solid	 product	 so	 formed	 was	 collected	 by	 filtration	 and	
crystallized	 from	 the	 diluted	 dimethyl‐formamide	 (Scheme	 1,	
Tables	1,	2).	
	
2.5.	Synthesis	of	1‐(8‐methyl‐3,6‐diphenyl‐3a,4‐dihydro	
dipyrazolo[3,4‐b:3',4'‐d]pyridin‐2(3H,6H,8aH)‐yl)ethanone	
(4a),	1‐(3‐(4‐methoxyphenyl)‐8‐methyl‐6‐phenyl‐3a,4‐
dihydrodipyrazolo[3,4‐b:3',4'‐d]pyridin‐2(3H,6H,8aH)‐yl)	
ethanone	(4b),	1‐(3‐(4‐hydroxyphenyl)‐8‐methyl‐6‐phenyl‐
3a,4‐dihydrodipyrazolo[3,4‐b:3',4'‐d]pyridin‐2	(3H,6H,8aH)‐
yl)ethanone	(4c)	

	
A	 solution	of	 compounds	3a‐c	 (3a:	 0.94	 g,	 0.003	mol;	3b:	

0.99	g,	0.003	mol;	3c:	1.03	g,	0.003	mol)	in	dimethyl	formamide	

was	treated	with	hydrazine	monohydrate	(0.15	mL,	0.003	mol)	
in	presence	of	(4	drops)	of	acetic	acid	as	a	catalyst.	The	reaction	
mixture	was	heated	under	reflux	for	8	hr,	then	left	to	cool	and	
poured	 on	 ice/water.	 The	 solid	 product	 so	 formed	 was	
collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	 DMF	
(Scheme	1,	Tables	1,	2).	
	
2.6.	Synthesis	of	8‐methyl‐2,3,6‐triphenyl‐2,3,3a,4,6,8a‐
hexahydrodipyrazolo[3,4‐b:3',4'‐d]pyridine	(5a),		
3‐(4‐methoxyphenyl)‐8‐methyl‐2,6‐diphenyl‐2,3,3a,4,6,8a‐
hexahydrodipyrazolo[3,4‐b:3',4'‐d]pyridine	(5b),		
3‐(4‐hydroxyphenyl)‐8‐methyl‐2,6‐diphenyl‐2,3,3a,4,6,8a‐
hexahydrodipyrazolo[3,4‐b:3',4'‐d]pyridine	(5c)	
	

A	 solution	 of	 compounds	3a‐c	 (3a:	 0.3	 g,	 0.0009	mol,	3b:	
0.29	 g,	 0.0009	 mol;	 3c:	 0.3	 g,	 0.0009	 mol)	 in	 dimethyl	
formamide	was	treated	with	phenyl	hydrazine	(0.1	mL,	0.0009		



318	 Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	
	
	
Table	1.		Characterization	of	compounds	(2‐11).	

Comp.	No.	 Yield,	%	 M.P.,	oC	 Color	 Mol.	Formula,		(M.wt.,	g)	
Elemental	Analysis,	%	
Calculated	(Found)	 Mass,	m/z	

C H	 N	

2	 63	 120‐122	 Light	beige	 C13H13N3O
(227.27)	

68.71
(68.72)	

5.77	
(5.72)	

18.49	
(18.50)	

227	

3a	 35	 134‐136	 Reddish	brown	
C20H17N3O
(315.37)	

76.19
(76.20)	

5.39	
(5.40)	

13.30	
(13.5)	 316	

3b	 46	 114‐116	 Dark	red	 C21H19N3O2

(345.40)
73.04
(73.05)

5.50	
(5.52)	

12.17	
(12.15)	

345	

3c	 99	 148‐150	 Light	brown	
C20H17N3O2	
(331.37)	

72.50	
(72.48)	

5.31	
(5.30)	

12.68	
(12.66)	 331	

4a	 50	 150‐152	 Light	brown	 C22H21N5O	
(371.44	)	

71.15	
(71.17)	

5.66	
(5.65)	

18.86	
(18.85)	

359	

4b	 25	 145‐147	 Reddish	brown	 C23H23N5O2

(401.47)	
68.81
(65.82)	

5.77	
(5.72)	

17.44	
(17.44)	 400	

4c	 30	 140‐142	 Dark	beige	
C22H21N5O2

(387.44)	
68.20
(68.2)	

5.46	
(5.41)	

18.00	
(18.00)	 389	

5a	 83	 200‐202	 Brown	 C26H23N5

(405.50)	
77.03
(77.05)	

5.67	
(5.69)	

17.28	
(17.30)	 403	

5b	 48	 114‐116	 Brown	
C27H25N5O	
(435.53)	

74.46	
(74.48)	

5.79	
(5.72)	

16.09	
(16.07)	 436	

5c	 34	 >180	 Dark	brown	 C26H23N5O	
(421.50)

74.09	
(74.11)

5.50	
(5.48)	

16.62	
(16.62)	

422	

6a	 80	 152‐154	 Dark	brown	 C20H18N4O	
(330.39)	

72.72	
(72.71)	

5.45	
(5.45)	

16.96	
(16.95)	 331	

6b	 40	 132‐135	 Brown	 C21H20N4O2

(360.42)	
69.98
(69.90)	

5.59	
(5.56)	

15.55	
(15.56)	

360	

6c	 52	 210‐212	 Reddish	brown	
C20H18N4O2

(346.39)	
69.35
(69.35)	

5.24	
(5.19)	

16.17	
(16.17)	 347	

7a	 45	 138‐140	 Dark	red	 C21H19N5O
(357.41)	

70.58
(70.59)	

5.32	
(5.30)	

19.60	
(19.62)	

359	

7b	 25	 109‐111	 Dark	brown	 C22H21N5O2	
(387.45)	

68.20	
(68.03)	

5.46	
(5.66)	

18.08	
(18.03)	 387	

7c	 76	 118‐220	 Brown	 C21H19N5O2	
(373.41)	

67.55	
(66.56)	

5.13	
(5.09)	

18.75	
(18.76)	

375	

8a	 58	 170‐172	 Light	greenish	yellow	 C21H19N5S
(373.48)	

67.56
(67.55)	

5.09	
(5.08)	

18.76	
(18.75)	 371	

8b	 63	 212‐214	 Light	brown	
C21H19N5OS
(389.47)	

64.78
(64.77)	

4.88	
(4.86)	

17.99	
(17.98)	 387	

8c	 40	 119‐120	 Dark	brown	 C22H21N5OS
(403.50)

65.50
(64.50)

5.21	
(5.21)	

17.36	
(17.36)	

403	

9a	 99	 122‐124	 Dark	brown	
C21H21N5O	
(359.43)	

70.19	
(70.20)	

5.84	
(5.90)	

19.49	
(19.50)	 359	

9b	 96	 158‐160	 Dark	brown	 C19H16N4O2	
(332.36)

68.67	
(68.70)

4.81	
(4.82)	

16.86	
(16.88)	

330	

9c	 94	 130‐132	 Brown	 C23H18N4O2	
(382.42)	

72.25	
(72.30)	

4.71	
(4.73)	

14.65	
(14.66)	 381	

10a	 70	 166‐164	 Dark	brown	 C23H23N5O2S
433.53	)	

63.74
(63.76)	

5.31	
(5.32)	

16.16	
(16.16)	

433	

10b	 20	 110‐112	 Brown	 C21H18N4O3S
(406.46)	

62.06
(62.07)	

4.43	
(4.44)	

13.79	
(13.80)	 405	

10c	 40	 160‐???	 Dark	brown	 C25H20N4O3S
(456.52)	

65.78
(65.80)	

4.38	
(4.40)	

12.20	
(12.30)	

455	

11a	 20	 190‐192	 Light	brown	 C23H22N5O2Cl	
(435.91)	

63.44	
(64.45)	

5.05	
(5.06)	

16.09	
(16.10)	 434	

11b	 20	 175‐177	 Dark	brown	 C21H17N4O3Cl	
(408.84)	

61.76	
(61.77)	

4.16	
(4.17)	

13.72	
(13.73)	 407	

11c	 50	 165‐167	 Brown	 C25H19N4O3Cl
(458.90)	

65.43
(65.48)	

4.17	
(4.20)	

12.21	
(12.00)	 458	

	
	
mol)	 in	 presence	 of	 3	 drops	 of	 piperidine	 as	 catalyst.	 The	
reaction	mixture	was	heated	under	reflux	for	8	hr,	 then	left	 to	
cool	and	was	poured	on	ice/water.	The	solid	product	so	formed	
was	 collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	
DMF	(Scheme	1,	Tables	1,	2).	
	
2.7.	Synthesis	of	8‐methyl‐3,6‐diphenyl‐3a,4,6,8a‐
tetrahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(6a),	
3‐(4‐methoxyphenyl)‐8‐methyl‐6‐phenyl‐3a,4,6,8a‐
tetrahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(6b),	
3‐(4‐hydroxyphenyl)‐8‐methyl‐6‐phenyl‐3a,4,6,8a‐
tetrahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(6c)	
	

A	solution	of	compounds	3a‐c	(3a:	0.22	g,	0.0007	mol;	3b:	
0.22	 g,	 0.0007	 mol;	 3c:	 0.24	 g,	 0.0007	 mol)	 in	 dimethyl	
formamide	 as	 a	 solvent	 was	 treated	 with	 hydroxylamine	
hydrochloride	(0.05	g,	0.0007	mol),	 in	 the	presence	of	sodium	
hydroxide	as	a	catalyst.	The	reaction	mixture	was	heated	under	

reflux	for	8	hr,	 then	left	 to	cool	and	was	poured	on	 ice/water.	
The	 solid	 product	 so	 formed	 was	 collected	 by	 filtration	 and	
crystallized	from	the	diluted	DMF	(Scheme	1,	Tables	1,	2).	
	
2.8.	Synthesis	of	9‐methyl‐4,7‐diphenyl‐3,4,4a,5,7,9a‐
hexahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]pyrimidin‐2‐
one	(7a),	4‐(4‐methoxyphenyl)‐9‐methyl‐7‐phenyl‐3,4,4a,	
5,7,9a‐hexahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]	
pyrimidin‐2‐one	(7b),	4‐(4‐hydroxyphenyl)‐9‐methyl‐7‐
phenyl‐3,4,4a,5,7,9a‐hexahydro‐2H‐pyrazolo[4',3':5,6]	
pyrido[4,3‐d]pyrimidin‐2‐one	(7c)		
	

A	 solution	of	 compounds	3a‐c	 (3a:	 1.57	 g,	 0.005	mol;	3b:	
1.59	g,	0.005	mol;	3c:	1.72	g,	0.005	mol)	in	dimethyl	formamide	
was	 treated	 with	 urea	 (0.3	 g,	 0.005	 mol)	 in	 the	 presence	 of	
sodium	 hydroxide	 as	 a	 catalyst.	 The	 reaction	 mixture	 was	
heated	under	reflux	for	8	hr,	 then	 left	 to	cool	and	was	poured	
on	ice/water.		



Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	 319	
 

	

 
	

Scheme	2
	
	

The	 solid	 product	 so	 formed	 was	 collected	 by	 filtration	 and	
crystallized	from	the	diluted	DMF	(Scheme	1,	Tables	1,	2).	
	
2.9.	Synthesis	of	9‐methyl‐4,7‐diphenyl‐3,4,4a,5,7,9a‐
hexahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]pyrimidine‐2‐
thione	(8a),	4‐(4‐methoxyphenyl)‐9‐methyl‐7‐phenyl‐3,4,4a,	
5,7,9a‐hexahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]	
pyrimidine‐2‐thione	(8b),	4‐(4‐hydroxyphenyl)‐9‐methyl‐7‐
phenyl‐3,4,4a,5,7,9a‐hexahydro‐2H‐pyrazolo[4',3':5,6]	
pyrido[4,3‐d]pyrimidine‐2‐thione	(8c)		
	

A	solution	of	compounds	3a‐c	(3a:	0.5	g,	0.001	mol;	3b:	0.4	
g,	0.001	mol;	3c:	0.34	g,	0.001	mol)	in	dimethyl	formamide	was	
treated	 with	 thiourea	 (0.1	 g,	 0.001	 mol)	 in	 the	 presence	 of	
sodium	 hydroxide	 as	 a	 catalyst.	 The	 reaction	 mixture	 was	
heated	under	reflux	for	8	hr,	 then	left	 to	cool	and	was	poured	
on	 ice/water.	 The	 solid	 product	 so	 formed	 was	 collected	 by	
filtration	 and	 crystallized	 from	 the	 diluted	 DMF	 (Scheme	 1,	
Tables	1,	2).	

2.10.	Synthesis	of	5‐((4‐(dimethylamino)phenyl)imino)‐3‐
methyl‐1‐phenyl‐5,6‐dihydro‐1H‐pyrazolo[3,4‐b]pyridin‐4	
(3aH)‐one	(9a),	5‐((4‐hydroxyphenyl)imino)‐3‐methyl‐1‐
phenyl‐5,6‐dihydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	
(9b),	5‐((2‐hydroxynaphthalen‐1‐yl)imino)‐3‐methyl‐1‐
phenyl‐5,6‐dihydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	
(9c)	
	

A	 solution	 of	 compound	 2	 (0.5	 g,	 0.002	mol)	 in	 dimethyl	
formamide	 was	 treated	 with	 nitroso	 compounds	 (9a:	 0.33	 g,	
0.002	 mol;	 9b:	 0.24	 g,	 0.002	 mol;	 9c:	 0.34	 g,	 0.002	 mol)	 in	
presence	 of	 2	 drops	 of	 piperidine	 as	 a	 catalyst.	 The	 reaction	
mixture	was	heated	under	 reflux	 for	8‐10	hr,	 then	 left	 to	 cool	
and	was	poured	on	ice/water.	The	solid	product	so	formed	was	
collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	 DMF	
(Scheme	1,	Tables	1,	2).	
	
	
	



320	 Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	
	
	
Table	2.	IR	and	1H	NMR	spectral	data	of	compounds	(2‐11).	
Comp.	No	 IR	(cm‐1)	 1H	NMR	(δ,	ppm)		
2	 1707‐1704	(C=O),	1629	(C=N)		 1.20	(s,	3H,	CH3),	2.39	(t,	J =	7.00	Hz,	2H,	CH2CO),	2.79	(s,	1H,	CHCO),	3.70‐3.90	(t,	J	=	7.30	Hz,	2H,	CH2N),	

7.09‐7.99	(m,	5H,	Ar‐H+).	

3b	 3069	(OH),	1656	(C=O),	590	(C=N)		 0.80	(s,	3H,	CH3),	1.19	(s,	1H,	CH),	3.35	(s,	1H,	CHCO),	7.12‐8.00	(m,	9H,	Ar‐H+),	8.71	(s,	2H,	CH2N),		
9.90	(s,	3H,	CH3)	

3c	 1704‐1717	(C=O),	3069	(OH),		
1597	(C=N)		

1.18	(s,	3H,	CH3),	1.60	(s,	1H,	CH),	2.89	(s,	1H,	CHCO),	3.39	(s,	2H,	CH2N),	6.96‐7.94	(m,	9H,	Ar‐H+),	
9.78	(s,	1H,	OH)	

4a	 1707	(C=O),	1627	(C=N)		 1.24	(s,	3H,	CH3),	2.11	(s,	1H,	CHCN),	2.35	(q,	J =	7.30	Hz,	1H,	CHCH),	2.74‐2.89	(d,	J	=	7.00	Hz,	1H,	CHPh),	
3.38‐3.85	(d,	J	=	7.00	Hz,	2H,	CH2N),	3.93	(s,	3H,	OCH3),	6.50‐8.00	(m,	10H,	Ar‐H+)	

4c	 3055	(OH),	1706	(C=O),		
1599	(C=N),			

0.76	(s,	3H,	CH3),	3.37	(s,	3H,	CH3O),	7.12‐8.00	(m,	14H,	Ar‐H+	+	heterocyclic	nuclei),	8.50	(s,	1H,	OH)
	
	

5a	 1590‐1599	(C=N)		 0.77	(s,	3H,	CH3),	1.17	(s,	1H,	CHCN),	1.50	(q,	J	=	7.30	Hz,	1H,	CHCHPh),	2.17‐2.32	(d,	J	=	7.00	Hz,	1H,	CHN),	
3.35	(d,	J	=	7.00	Hz,	2H,	CH2N),	7.43‐7.98	(m,	15H,	Ar‐H+)	

6c	 3045	(OH),	1597	(C=N)		 0.75	(s,	3H,	CH3),	6.50‐8.00	(m,	14H,	Ar‐H+	+	heterocyclic	nuclei),	8.50	(s,	1H,	OH)	
	
	

7c	 3428	(NH),	3075	(OH),	1708‐1707	
(C=O),	1599	(C=N),			

0.76	(s,	3H,	CH3),	3.33	(br,	1H,	NH),	6.00‐7.80	(m,	14H,	Ar‐H+	+	Heterocyclic	nuclei),	8.50	(s,	1H,	OH)	

8c	 3427	(NH),	1608	(C=N)		 0.70	(s,	3H,	CH3),	1.17	(s,	1H,	CHCN),	2.16	(q,	J	=	7.30	Hz,	1H,	CHCH),	2.34	(d,	J	=	7.00	Hz,	1H,	CHN),		
3.35	(s,	1H,	NH),	3.83	(d,	J	=	7.00	Hz,	2H,	CH2N),	3.35	(s,	3H,	OCH3),	7.43‐7.99	(m,	9H,	Ar‐H+)	

9c	 3060	(OH),	1705‐1708	(C=O),		
1625	(C=N)		

0.87	(s,	3H,	CH3),	2.37	(s,	1H,	CHCO),	3.43	(s,	2H,	CH2N),	7.43‐7.99	(m,	11H,	Ar‐H+),	8.93	(s,	1H,	OH)	

10a	 1709	(C=O),	1626‐1598	(C=N)		 0.77	(s,	3H,	CH3),	1.19 (s,	1H,	CHCO),	2.14	(s,	2H,	SCH2),	2.89	(s,	2H,	CH2N),	3.33	(s,	6H,	CH3N),		
7.75‐7.89	(m,	9H,	Ar‐H+)		

10c	 3427‐3060	(OH),	1627	(C=O),	
1492	(C=N)		

1.25	(s,	3H,	CH3),	6.50‐8.00	(m,	16H,	Ar‐H+ +	Heterocyclic	nuclei),	4.27	(s,	1H,	OH)	

11c	 3428‐3060	(OH),	1626‐1598	(C=N)	 0.78	(s,	3H,	CH3),	3.38	(s,	1H,	CHCl),	7.10‐8.00	(m,	14H,	Ar‐H+	+	Heterocyclic	nuclei),	7.87	(s,	1H,	OH)	
	

	
	
2.11.	Synthesis	of	3'‐(4‐(dimethylamino)phenyl)‐3‐methyl‐1‐
phenyl‐3a,6‐dihydrospiro[pyrazolo[3,4‐b]pyridine‐5,2'‐
thiazolidine]‐4,4'(1H)‐dione	(10a),	3'‐(4‐hydroxyphenyl)‐3‐
methyl‐1‐phenyl‐3a,6‐dihydrospiro[pyrazolo[3,4‐b]pyridine‐
5,2'‐thiazolidine]‐4,4'(1H)‐dione	(10b),	3'‐(2‐hydroxy	
naphthalen‐1‐yl)‐3‐methyl‐1‐phenyl‐3a,6‐dihydrospiro	
[pyrazolo[3,4‐b]pyridine‐5,2'‐thiazolidine]‐4,4'(1H)‐dione	
(10c)		
	

A	 solution	of	 compounds	9a‐c	 (9a:	 0.72	 g,	 0.002	mol;	9b:	
0.74	g,	0.002	mol;	9c:	0.8	g,	0.002	mol)	in	dimethyl	formamide	
was	 treated	 with	 thioglycolic	 acid	 (0.2	 mL,	 0.002	 mol)	 in	
presence	 of	 2	 drops	 of	 piperidine	 as	 a	 catalyst.	 The	 reaction	
mixture	was	heated	under	 reflux	 for	8‐10	hr,	 then	 left	 to	 cool	
and	was	poured	on	ice/water.	The	solid	product	so	formed	was	
collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	 DMF	
(Scheme	1,	Tables	1,	2).	
	
2.12.	Synthesis	of	3‐chloro‐1‐(4‐(dimethylamino)phenyl)‐3'‐
methyl‐1'‐phenyl‐3a',6'‐dihydrospiro[azetidine‐2,5'‐
pyrazolo[3,4‐b]pyridine]‐4,4'(1'H)‐dione	(11a),	3‐chloro‐1‐
(4‐hydroxyphenyl)‐3'‐methyl‐1'‐phenyl‐3a',6'‐dihydrospiro	
[azetidine‐2,5'‐pyrazolo[3,4‐b]pyridine]‐4,4'(1'H)‐dione	
(11b),	3‐chloro‐1‐(2‐hydroxynaphthalen‐1‐yl)‐3'‐methyl‐1'‐
phenyl‐3a',6'‐dihydrospiro[azetidine‐2,5'‐pyrazolo[3,4‐b]	
pyridine]‐4,4'(1'H)‐dione	(11c)	
	

A	 solution	of	 compounds	9a‐c	 (9a:	 0.72	 g,	 0.002	mol;	9b:	
0.74	g,	0.002	mol;	9c:	0.8	g,	0.002	mol)	in	dimethyl	formamide	
was	treated	with	chloroacetylchloride	(0.23	mL,	0.002	mol)	 in	
presence	of	2	drops	of	triethylamine	as	a	catalyst.	The	reaction	
mixture	was	heated	under	 reflux	 for	8‐10	hr,	 then	 left	 to	 cool	
and	was	poured	on	ice/water.	The	solid	product	so	formed	was	
collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	 DMF	
(Scheme	1,	Tables	1,	2).	

3.	Results	and	discussion	
	

Our	 approach	 to	 the	 development	 of	 some	 synthetic	
applications	of	1‐phenyl‐3‐methyl‐5‐pyrazolone	is	based	on	the	
generation	 of	 building	 blocks	 containing	 fused,	 isolated,	 and	
Spiro	heterocyclic	compounds,	each	of	which	can	be	selectively	
reacted	 [51].	 We	 have	 recently	 shown	 like	 reaction	 of	 1‐(5‐
imino‐3‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)ethan‐
one	 (1)	 wheras	 we	 have	 obtained	 an	 available	 compound	 2,	
Scheme	1.	The	structure	of	 compound	2	was	 confirmed	by	 IR	
spectra	 which	 revealed	 the	 presence	 of	 peaks	 at	 1656‐1707	
(C=O)	 and	 1596‐1629	 cm‐1	 (C=N),	 also	 1H	 NMR	 spectra	 of	
compound	2	 revealed	 the	 presence	 of	 signals	 peaks	 at	 1.2	 (s,	
3H,	CH3),	2.39	(t,	2H,	CH2CO),	2.79	(s,	1H,	CHCO),	3.7‐3.9	(t,	2H,	
CH2N)	 and	 7.09‐7.99	 (m,	 5H,	 Ar‐H+)	 ppm,	 the	mass	 spectrum	
showed	the	molecular	ion	peak	at	m/z	=	227.28.	

The	 active	 methylene	 group	 in	 compound	 2	 condensed	
with	 different	 aromatic	 aldehydes	 (benzaldehyde,	
anisaldehyde,	p‐hydroxy‐benzaldehyde)	in	dimethylformamide	
under	 piperidine	 as	 catalyst	 to	 yield	 the	 corresponding	 5‐
aryldino‐4‐tetrahydropyridinone	 derivatives	 (3a‐c)	 Scheme	 1.	
The	 structures	 of	 compounds	 3a‐c	 were	 confirmed	 by	 IR	
spectra,	1H	NMR	spectra.	

The	 activity	 of	 exocyclic	 C=C	 conjugated	 with	 the	 α‐
carbonyl	 group	 in	 compound	 3a‐c	 were	 determined	 by	 the	
reaction	with	hydrazines,	hydroxyl	 amine	hydrochloride,	urea	
and	 thiourea,	 to	 yield	 the	 compounds	 4‐8a‐c,	 Scheme	 1.	 The	
nature	 of	 the	 products	 obtained	 such	 as	 N‐acetyl	 pyrazolo	
pyridine	 derivatives	 was	 confirmed	 by	 IR	 spectra,	 1H	 NMR	
spectra,	 and	 the	 mass	 spectra.	 The	 structure	 of	 isoxazolo‐
pyridine	derivatives	6a‐c,	pyridopyrimidinone	derivatives	7a‐c	
and	also	pyrimidine	thiano	derivatives	8a‐c	was	confirmed	by	
IR	spectra,	1H	NMR	spectra	and	mass	spectra.	

Other	Schiff's	base	compounds	were	prepared	through	the	
condensation	 of	 3‐methyl‐1‐phenyl‐5,6‐dihydro‐1H‐pyrazolo	



Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	316‐321	 321	
 

[3,4‐b]pyridin‐4(3aH)‐one	(2)	with	nitroso	compounds	such	as	
(a)	p‐nitroso,	N,N‐dimethyl	aniline,	(b)	p‐nitrosophenol	and	(c)	
α‐nitroso‐β‐naphthol	in	the	presence	of	dimethylformamide	as	
solvent	 under	 piperidine	 as	 catalyst,	 afforded	 to	 compounds	
9a‐c	 (Scheme	 2)..	 Schiff's	 base	 compounds	 9a‐c	 reacted	 with	
thioglycolic	 acid	 in	 dimethylformamide	 under	 piperidine	 as	
catalyst	to	yield	the	corresponding	N‐thiazole	derivatives	10a‐c	
(Scheme	2).	Also,	when	 Schiff's	base	 compounds	9a‐c	 reacted	
with	 chloroacetylchloride	 in	 dimethylformamide	 under	
triethylamine	as	catalyst	to	yield	the	corresponding	N‐β‐lactam	
derivatives	11a‐c	(Scheme	2).	
	
4.	Conclusions	
	

We	 have	 reported	 the	 development	 of	 some	 synthetic	
applications	of	1‐phenyl‐3‐methyl‐5‐pyrazolone	is	based	on	the	
generation	 of	 building	 blocks	 containing	 fused,	 isolated	 and	
spiro	 pyrazole,	 isoxazole,	 pyrimidine,	 pyrimidinothione,	
thiazolodine	and	β‐lactam	derivatives	incorporating	4‐acetyl‐5‐
imino‐3‐methyl‐1‐phenyl‐2‐pyrazoline.	
	
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