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European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	

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

DOI:10.5155/eurjchem.3.3.287‐292.611	

	
	

	

	

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

	 	 	

Synthesis	and	studies	of	pyrazolo[3,4‐b]piperidin‐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:	01	July	2012	
Accepted:	08	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‐amino‐3‐methyl‐1‐
phenyl‐2‐pyrazoline	have	been	 synthesized	by	different	methods	of	 chemical	 reactions.	The
structure	 assignments	 of	 these	 compounds,	 based	 on	 chemical	 and	 spectroscopic	 evidence
were	deduced	from	their	IR,	1H	NMR,	elemental	analysis	and	mass	spectrometry.	

Pyrazole	
Isoxazolo		
Pyrimidine		
Spiro	β‐lactam	
Pyrimidine	thione	
Spiro	thiazolodine	

	
1.	Introduction	
	

Mannich	 reaction	 is	 a	 versatile	 reaction	 and	 was	 studied	
used	 widely	 in	 the	 synthesis	 of	 biologically	 important	
molecules	 and	 natural	 products	 [1‐5].	 The	 reaction	 between	
benzaldehyde,	 aniline	 and	 cyclohexanone	 as	 a	model	 reaction	
in	water	in	the	presence	of	various	amounts	of	first	generation	
dendrimer	[6‐14].	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	 Mannich	 reaction	 was	
extended	to	other	aldehydes,	ketones	and	anilines	[15‐25].	In	a	
similar	manner	condensation	between	other	substrates	like	4‐
acetyl‐5‐imino‐3‐methyl‐1‐phenyl‐2‐pyrazoline	(1)	also	a	short	
period	 of	 time	 with	 excellent	 yield	 and	 high	 purity	 and	 non	
more	 purification	 was	 required.	 As	 literature	 search,	 it	 has	
found	 that	Mannich	 bases	 had	 antimicrobial	 activities	 [26,27]	
besides	various	activities.	The	pyrazole	nucleus	is	present	in	a	
wide	 variety	 of	 biologically	 interesting	 compounds,	 which	
exhibit	 ant	 hyperglycemic,	 analgesic,	 anti‐inflammatory,	
antipyretic,	 antibacterial,	 hypoglycemic,	 sedative	 ‐	 hypnotic	
activity	 [28‐31].	 Pyrazoles	 and	 their	 derivatives	 are	 widely	
used	 as	 pharmaceutical	 [32,33]	 and	 agrochemical	 agents	 [34]	
and	 consequently	 a	 large	 number	 of	 synthetic	 routes	 to	
pyrazoles	 has	 been	 reported	 [35‐38].	 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	organic	synthesis.	

	
2.	Experimental	
	

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	90M	
Hz	spectrophotometer	using	DMSO	d6	as	a	solvent	and	TMS	as	
an	 internal	 standard	 chemical	 shifts	 are	 expressed	 as	 ppm	

units.	The	microanalysis	was	performed	by	the	micro	analytical	
centers	 at	 Cairo	 University.	Mass	 spectra	were	 obtained	 on	 a	
Shimadzu	GCMS	QP	1000	EX	mass	spectrometer	at	70	eV.		
	
2.1.	Synthesis	of	4‐acetyl‐5‐imino‐3‐methyl‐1‐phenyl‐2‐
pyrazoline	(1)		
	

The	compound	(1)	was	carried	out	according	to	Mohanty	et	
al.,	1977	[39].	
	
2.2.	Synthesis	of	4‐acetyl‐5‐amino‐3‐methyl‐1‐phenyl‐2‐
pyrazoline	(2)	
	

The	compound	1	 (2	g,	0.004	mol)	was	dissolved	 in	20	mL	
acetic	acid	with	1	g	zinc	dust,	reflux	for	2‐3	hr.	The	hot	mixture	
was	 filtrated	 to	 get	 off	 zinc	 dust	 residue.	 The	 filtrate	 was	
poured	 on	 ice/water	 with	 continuous	 stirring.	 The	 solid	
product	 was	 collected	 by	 filtration	 and	 crystallized	 from	 the	
diluted	acetic	acid	(Scheme	1,	Tables	1,	2).	
	
2.3.	Synthesis	of	3‐methyl‐1‐phenyl‐5,6,7,7a‐tetrahydro‐1H‐
pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(3)	
	

A	 solution	of	 compound	2	 (1.78	g,	 0.008	mol)	 in	dimethyl	
formamide	was	 treated	with	paraformaldehyde	 (0.25	g,	 0.008	
mol)	 and	 piperidine	 (0.82	mL,	 0.009	mol)	 and	 HCl	 (0.41	mL,	
0.01	mol).	The	reaction	mixture	was	heated	under	reflux	for	3	
hr,	 then	 left	 to	 cool	 and	 was	 poured	 into	 ice/water	 with	 the	
stirring.	The	solid	product	so	formed	was	collected	by	filtration	
and	crystallized	from	the	diluted	DMF	(Scheme	1,	Tables	1,	2).	
	
2.4.	Synthesis	of	5‐benzylidene‐3‐methyl‐1‐phenyl‐5,6,7,7a‐
tetrahydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(4a),	5‐
(4‐methoxybenzylidene)‐3‐methyl‐1‐phenyl‐5,6,7,7a‐
tetrahydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(4b),	5‐
(4‐hydroxybenzylidene)‐3‐methyl‐1‐phenyl‐5,6,7,7a‐
tetrahydro‐1H‐pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	(4c)	



288	 Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	
	
	

N
N N

H

O

Ph

H3C

N
N NH

CH3

O

Ph

H3C

N
N NH2

CH3

O

Ph

H3C
NH

OCH2/HCl

N
N NH2

CH3

O

Ph

H3C

N
N N

H

O

Ph

H3C OHC

X

N
N N

H

O

Ph

H3C

H
C

X

N
N N

H

N

Ph

H3C

N

COCH3 X

N
N N

H

N

Ph

H3C

N

Ph X

N
N N

H

N

Ph

H3C

O

X

N
N N

H

N

Ph

H3C

NH

X

N
N N

H

N

Ph

H3C

NH

X

Zn/AcO

+
DMF/pip.

H2NNH2.H2O

DMF/G.CH3COOH

H2N.NHPh

DMF/pip.

H2N.OH.HCl

DMF/NaOH

H2NCONH2

DMF/NaOH

DMF/NaOH

H2NCSNH2

(4a - c)

O

S

( 1 ) ( 2 )

( 3 )

(4a - c)

(5a - c)

(6a - c)

(7a - c)

(8a - c)

(9a - c)

/ DMF

( 3 )

a, X = H
b, X = p-OCH3
c, X = p-OH

	
	

Scheme	1
	
	

A	solution	of	compound	3	 (1.17	g,	0.005	mol)	was	treated	
with	 aromatic	 aldehyde	 compounds	 (4a:	 0.54	mL,	 0.005	mol;	
4b:	0.68	mL,	0.005	mol;	4c:	0.61	g,	0.005	mol)	in	the	presence	
of	 3	 drops	 piperidine	 as	 a	 catalyst.	 The	 reaction	mixture	was	
heated	under	reflux	for	4	hr,	 then	left	 to	cool	and	was	poured	
on	 ice/water	 with	 stirring.	 The	 solid	 product	 so	 formed	 was	
collected	 by	 filtration	 and	 crystallized	 from	 the	 diluted	 DMF	
(Scheme	1,	Tables	1,	2).	
	
2.5.	Synthesis	of	1‐(8‐methyl‐3,6‐diphenyl‐3,3a,4,5,5a,6‐
hexahydrodipyrazolo[3,4‐b:3',4'‐d]pyridin‐2(8aH)‐yl)	
ethanone	(5a),	1‐(3‐(4‐methoxyphenyl)‐8‐methyl‐6‐phenyl‐
3,3a,4,5,5a,6‐hexahydrodipyrazolo[3,4‐b:3',4'‐d]	pyridin‐2	

(8aH)‐yl)ethanone	(5b),	1‐(3‐(4‐hydroxyphenyl)‐8‐methyl‐6‐
phenyl‐3,3a,4,5,5a,6‐hexahydrodipyrazolo[3,4‐b:3',4'‐d]	
pyridin‐2(8aH)‐yl)ethanone	(5c)	
	

A	 solution	of	 compounds	4a‐c	 (4a:	 0.31	 g,	 0.001	mol;	4b:	
0.34	g,	0.001	mol;	4c:	0.33	g,	0.001	mol)	in	dimethyl	formamide	
was	treated	with	hydrazine	monohydrate	(0.05	mL,	0.001	mol)	
in	the	presence	of	4	drops	of	acetic	acid.	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).	
	



Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	 289	
 

	
Table	1.	Characterization	of	compounds	(3‐12).	

Comp.	No.	 Yield,	%	 M.P.,	oC	 Color	 Mol.	Formula,		
(M.wt.,	g)	

Elemental	Analysis,	%	
Calculated	(Found)	 Mass,	

m/z	
C H N	

3	 66	 208‐210	 Light	yellow	 C13H15N3O	
(229.28)	

68.12	
(68.15)	

6.55	
(6.57)	

18.3	
(18.5)	

228	

4a	 59	 166‐168	 Greenish	yellow C20H19N3O
(317.39)	

75.70
(75.72)	

5.99	
(6.00)	

13.24	
(13.25)	

315

4b	 98	 130‐132	 Latency	 C21H21N3O2

(347.42)	
72.62
(72.64)	

6.05	
(6.06)	

12.10	
(12.12)	

346

4c	 92	 138‐140	 Light	beige C20H19N3O2

(333.39)	
72.07
(72.08)	

5.70	
(5.80)	

12.61	
(12.62)	

331

5a	 83	 140‐142	 Brown	 C22H23N5O	
(373.46)	

70.77	
(70.76)	

6.16	
(6.15)	

18.76	
(18.76)	

374	

5b	 61	 158‐160‐	 Dark	brown	 C23H25N5O2	
(403.48)	

68.48	
(68.47)	

6.20	
(6.10)	

17.36	
(17.35)	

404	

5c	 75	 160‐162‐	 Light	brown C22H23N5O2

(389.46)	
67.86
(67.84)	

5.91	
(5.90)	

17.99	
(17.97)	

390

6a	 50	 166‐168	 Brown	 C26H25N5

(407.52)	
76.65
(76.66)	

6.14	
(6.15)	

17.19	
(17.20)	

408

6b	 79	 190‐192	 Brown	 C27H23N5O
(433.51)	

74.82
(74.83)	

5.31	
(5.32)	

16.16	
(16.17)	

433

6c	 40	 144‐146	 Dark	beige	 C26H25N5O	
(423.52)

73.75	
(73.75)

5.91	
(5.89)	

16.54	
(16.52)	

423	

7a	 81	 154‐156	 Light	orange	 C20H20N5O	
(346.41)	

72.28	
(72.30)	

6.02	
(6.02)	

21.08	
(21.08)	

346	

7b	 66	 100‐102	 Reddish	brown	 C21H22N4O2	
(362.43)	

69.61	
(69.60)	

6.07	
(6.06)	

15.46	
(15.45)	

362	

7c	 70	 120‐122	 Dark	beige C20H20N4O2

(348.40)	
68.96
(68.95)	

5.74	
(5.74)	

16.09	
(16.09)	

349

8a	 50	 225‐227	 Reddish	brown C21H21N5O
(359.43)	

70.78
(70.77)	

5.84	
(5.83)	

19.49	
(19.48)	

357

8b	 84	 150‐152	 Reddish	brown C22H23N5O2

(389.46)	
67.86
(67.84)	

5.90	
(5.70)	

17.99	
(17.99)	

389

8c	 50	 139‐140	 Dark	beige	 C21H21N5O2	
(375.43)	

67.20	
(66.20)	

5.60	
(5.50)	

18.66	
(18.66)	

375	

9a	 40	 176‐178	 brown	 C21H21N5S	
(375.49)	

67.20	
(67.20)	

5.60	
(5.70)	

18.66	
(18.67)	

374	

9b	
	

80	 141‐143	 Beige	 C22H23N5OS
(405.52)	

65.16
(65.00)	

5.72	
(5.70)	

17.27	
(17.50)	

405

9c	 38	 139‐140	 Yellow	 C21H21N5OS
(391.49)	

64.45
(64.43)	

5.37	
(5.35)	

17.90	
(17.90)	

391

10a	 98	 163‐165	 Beige	 C21H23N5O
(361.45)	

69.80
(70.00)	

6.37	
(6.40)	

19.39	
(19.40)	

360

10b	 40	 168‐170	 Brown	 C19H18N4O2	
(334.38)

68.26	
(68.27)

5.38	
(5.39)	

16.76	
(16.77)	

334	

10c	 98	 149‐151	 Brown	 C23H20N4O2	
(384.44)	

71.87	
(71.88)	

5.20	
(5.21)	

14.58	
(14.59)	

384	

11a	 20	 150‐152	 Brown	 C23H25N5O2S
(435.54)	

63.44
(63.45)	

5.74	
(5.75)	

16.09	
(16.09)	

435

11b	 30	 120‐122	 Brown	 C21H20N4O3S
(408.47)	

61.76
(61.78)	

4.90	
(4.93)	

13.72	
(13.73)	

406

11c	 25	 125‐127	 Light	brown C25H22N4O3S
(458.53)	

65.50
(65.52)	

4.80	
(4.82)	

12.22	
(12.23)	

458

12a	 15	 145‐146	 Brown	 C23H24N5O2Cl	
(437.93)	

63.15	
(63.16)	

5.49	
(5.50)	

16.01	
(16.03)	

436	

12b	 18	 200‐202	 Brown	 C21H19N4O3Cl	
(410.86)	

61.46	
(61.48)	

4.63	
(4.65)	

13.60	
(13.90)	

412	

12c	 10	 145‐147	 Brown	 C25H21N4O3Cl	
(460.92)	

65.21	
(65.22)	

4.56	
(4.57)	

12.17	
(12.18)	

460	

	
	
2.6.	Synthesis	of	8‐methyl‐2,3,6‐triphenyl‐2,3,3a,4,5,5a,6,8a‐
octahydrodipyrazolo[3,4‐b:3',4'‐d]pyridine	(6a),		
3‐(4‐methoxyphenyl)‐8‐methyl‐2,6‐diphenyl‐2,3,3a,4,5,5a,6,	
8a‐octahydrodipyrazolo[3,4‐b:3',4'‐d]	pyridine	(6b),	3‐(4‐
hydroxyphenyl)‐8‐methyl‐2,6‐diphenyl‐2,3,3a,4,5,5a,6,8a‐
octahydrodipyrazolo[3,4‐b:3',4'‐d]	pyridine	(6c)	
	

A	 solution	of	 compounds	4a‐c	 (4a:	 0.31	 g,	 0.001	mol;	4b:	
0.34	g,	0.001	mol;	4c:	0.33	g,	0.001	mol)	in	dimethyl	formamide	
was	 treated	with	phenyl	hydrazine	(0.1	mL,	0.001	mol)	 in	 the	
presence	 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,4,5,5a,6,8a‐
hexahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(7a),	
3‐(4‐methoxyphenyl)‐8‐methyl‐6‐phenyl‐3a,4,5,5a,6,8a‐
hexahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(7b),	
3‐(4‐hydroxyphenyl)‐8‐methyl‐6‐phenyl‐3a,4,5,5a,6,8a‐
hexahydro‐3H‐isoxazolo[3,4‐d]pyrazolo[3,4‐b]pyridine	(7c)	
	

A	 solution	of	 compounds	4a‐c	 (4a:	 0.31	 g,	 0.001	mol;	4b:	
0.34	g,	0.001	mol;	4c:	0.33	g,	0.001	mol)	in	dimethyl	formamide	
was	 treated	with	 hydroxyl	 amine	 hydrochloride	 (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).	
	
	
	



290	 Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	
	
	 	
Table	2.	IR,	1H	NMR	spectral	data	of	compound	(3‐12).	
Comp.	No	 IR	(cm‐1)	 1H	NMR	(δ,	ppm)	
3	 3063	(NH),	1706	(C=O),		

1596	(C=N)		
0.86	(s,	3H,	CH3),	1.24	(d,	J =	7.00	Hz,	1H,	NCHN),	2.16	(t,	J =	7.30	Hz,	2H,	CH2CO),	2.35	(d,	J =	7.00,	1H,	
CHCO),	2.73	(t,	J	=	7.30	Hz,	2H,	CH2N),	3.37	(s,	1H,	NH),	7.24‐7.97	(m,	5H,	Ar‐H+)	
	

4c	 3392	(OH),	3068‐3063	(NH),		
1640‐1623	(C=O)	

0.79	(s,	3H,	CH3),	1.23	(s,	1H,	CHPh),	2.16	(d,	J	=	7.00	Hz,	1H,	NCHN),	2.34	(d,	J	=	7.00	Hz,	1H,	CHCO),	3.73	
(s,	2H,	CH2N),	8.65	(s,	1H,	NH),	6.7‐8.1	(m,	9H,	Ar‐H+),	9.8	(s,	1H,	OH)	
	

6c	 3411‐3150	(OH),	3064	(NH),		
1707	(C=O),	1598	(C=N)		
	

0.78	(s,	3H,	CH3),	2.3	(s,	1H,	NH),	6.7‐8.0	(m,	20H,	Ar‐H+ +	Heterocycle	nuclei),	7.98	(s,	1H,	OH)
	

7a	 3064‐3061	(NH),		
1599‐1598	(C=N)		

0.77	(s,	3H,	CH3),	3.34	(s,	1H,	NH),	7.42‐7.82	(m,	16H,	Ar‐H+ +	Heterocycle	nuclei)	
	
	

7b	 3391‐3150	(NH),	1598	(C=N)		
	
	

0.78	(s,	3H,	CH3),	2.14	(s,	1H,	NH),	3.84	(s,	3H,	OCH3),	6.5‐8.0	(m,	15H,	Ar‐H+	+	Heterocycle	nuclei)
	

8b	 3062	(NH),	1706	(C=O),		
1601‐1599	(C=N)		

0.78	(s,	3H,	CH3),	1.17	(d,	J	=	7.00	Hz,	2H,	NCHNH),	2.14	(q,	J	=	7.30	Hz,	1H,	CHCH),	2.33	(d,	J	=	7.00	Hz,	
1H,	CHCN),	2.74	(d,	J	=	7.00	,	1H,	CHN),	2.9	(s,	2H,	NH),	3.35	(s,	3H,	OCH3),	3.69	(t,	J	=	7.30	Hz,	2H,	CH2N),	
7.16‐7.96	(m,	9H,	Ar‐H+)	

8c	 3416‐3150	(OH,	NH),		
1708	(C=O),	1598	(C=N)		

0.78	(s,	3H,	CH3),	3.93	(s,	2H,	NH),	6.0‐7.97 (m,	16H,	Ar‐H+ +	Heterocycle	nuclei)	
	
	

9a	 3061	(NH),	1599	(C=N)		
	
	

0.78	(s,	3H,	CH3),	1.18	(q,	J	=	7.30	Hz,	1H,	CHCH),	2.13	(d,	J =	7.00	Hz,	1H,	NCHN),	2.33	(d,	J	=		7.00	Hz,	1H,	
CHCN),	2.7	(d,	J	=	7.00	Hz,	1H,	CHN),	2.9	(d,	2H,	CH2N),	3.31	(s,	2H,	NH),	7.42‐7.98	(m,	10H,	Ar‐H+)	

9b	 3391‐3150	(OH),	3068	(NH),		
1597	(C=N)		

0.75	(s,	3H,	CH3),	1.18	(q,	J	=	7.30	Hz,	1H,	CHCH),	2.14	(d,	J	=		7.00	Hz,	1H,	NCHN),	2.35	(d,	J	=		7.00	Hz,	1H,	
CHN),	2.68	(d,	J	=	 	7.00	Hz,	2H,	CH2N),	3.31	(br,	1H,	NH),	3.33	(br,	1H,	NHCS),	3.35	(s,	3H,	OCH3),	7.18‐
7.97	(m,	10H,	Ar‐H+	+	Heterocycle	nuclei)		

10c	 3425‐3150	(NH,	OH),		
1625‐1614	(C=N)		

0.75	(s,	3H,	CH3),	1.17	(d,	J	=	7.00	Hz,	1H,	NCHN),	2.38	(d,	J	=	7.00	Hz,	1H,	CHCO),	2.89	(s,	2H,	CH2N),	3.36	
(s,	1H,	NH),	6.89‐7.48	(m,	11H,	Ar‐H+),	7.96	(s,	1H,	OH)	
	

11b	 3414‐3150	(NH,	OH),	1706	(C=O),		
1601‐1598	(C=N)		
	

0.76	(s,	3H,	CH3),	3.35	(s,	1H,	NH),	6.0‐7.8	(m,	15H,	Ar‐H+ +	Heterocycle	nuclei),	7.96	(s,	1H,	OH)
	

11c	 3411‐3150	(OH),	3064‐3061	(NH),		
1751‐1710	(C=O)	
	

1.17	(s,	3H,	CH3),	3.34	(s,	1H,	NH),	6.0‐7.6	(m,	17H,	Ar‐H+ +	Heterocycle	nuclei),	7.82	(s,	1H,	OH)
	

12c	 3428‐3061	(NH),	1709‐1706	(C=O)		 0.78	(s,	3H,	CH3),	1.17	(d,	J	=	7.00	Hz,	1H,	NCHN),	1.19	(d,	J	=	7.00	Hz,	1H,	CHCO),	2.15	(s,	2H,	CH2N),	2.36	
(s,	1H,	NH),	3.38	(s,	1H,	CHCl),	7.10‐7.48	(m,	11H,	Ar‐H+),	7.87	(s,	1H,	OH)	
	

	
	
2.8.	Synthesis	of	9‐methyl‐4,7‐diphenyl‐3,4,4a,5,6,6a,7,9a‐
octahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]pyrimidin‐2‐
one	(8a),	4‐(4‐methoxyphenyl)‐9‐methyl‐7‐phenyl‐3,4,4a,	
5,6,6a,7,9a‐octahydro‐2H‐pyrazolo[4',3':5,6]	pyrido[4,3‐d]	
pyrimidin‐2‐one	(8b),	4‐(4‐hydroxyphenyl)‐9‐methyl‐7‐
phenyl‐3,4,4a,5,6,6a,7,9a‐octahydro‐2H‐pyrazolo[4',3':5,6]	
pyrido[4,3‐d]pyrimidin‐2‐one	(8c)		
	

A	 solution	of	 compounds	4a‐c	 (4a:	 0.31	 g,	 0.001	mol;	4b:	
0.34	g,	0.001	mol;	4c:	0.33	g,	0.001	mol)	in	dimethyl	formamide	
was	 treated	with	 urea	 (0.06	 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).	
	
2.9.	 Synthesis	 of	 9‐methyl‐4,7‐diphenyl‐3,4,4a,5,6,6a,7,9a‐
octahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]pyrimidine‐2‐
thione	 (9a),	 4‐(4‐methoxyphenyl)‐9‐methyl‐7‐phenyl‐3,4,4a,	
5,6,6a,7,9a‐octahydro‐2H‐pyrazolo[4',3':5,6]pyrido[4,3‐d]	
pyrimidine‐2‐thione	 (9b),	 4‐(4‐hydroxyphenyl)‐9‐methyl‐7‐
phenyl‐3,4,4a,5,6,6a,7,9a‐octahydro‐2H‐pyrazolo[4',3':5,6]	
pyrido[4,3‐d]pyrimidine‐2‐thione	(9c)		
	

A	 solution	of	 compounds	4a‐c	 (4a:	 0.31	 g,	 0.001	mol;	4b:	
0.34	g,	0.001	mol;	4c:	0.33	g,	0.001	mol)	in	dimethyl	formamide	
was	treated	with	thiourea	(0.076	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‐5,6,7,7a‐tetrahydro‐1H‐pyrazolo[3,4‐b]	
pyridin‐4(3aH)‐one	(10a),		5‐((4‐hydroxyphenyl)imino)‐3‐
methyl‐1‐phenyl‐5,6,7,7a‐tetrahydro‐1H‐pyrazolo[3,4‐b]	
pyridin‐4(3aH)‐one	(10b),	5‐((2‐hydroxynaphthalen‐1‐yl)	
imino)‐3‐methyl‐1‐phenyl‐5,6,7,7a‐tetrahydro‐1H‐pyrazolo	
[3,4‐b]pyridin‐4(3aH)‐one	(10c)		
	

A	 solution	 of	 compound	 3	 (0.5	 g,	 0.002	mol)	 in	 dimethyl	
formamide	was	treated	with	nitroso	compounds	(10a:	0.32	mL,	
0.002	mol;	10b:	0.24	g,	0.002	mol;	10c:	0.34	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	2,	Tables	1,	2).	
	
2.11.	Synthesis	of	3'‐(4‐(dimethylamino)phenyl)‐3‐methyl‐1‐
phenyl‐1,6,7,7a‐tetrahydrospiro[pyrazolo[3,4‐b]pyridine‐
5,2'‐thiazolidine]‐4,4'(3aH)‐dione	(11a),	3'‐(4‐hydroxy	
phenyl)‐3‐methyl‐1‐phenyl‐1,6,7,7a‐tetrahydrospiro	
[pyrazolo[3,4‐b]pyridine‐5,2'‐thiazolidine]‐4,4'(3aH)‐dione	
(11b),	3'‐(2‐hydroxynaphthalen‐1‐yl)‐3‐methyl‐1‐phenyl‐
1,6,7,7a‐tetrahydrospiro[pyrazolo[3,4‐b]pyridine‐5,2'‐
thiazolidine]‐4,4'(3aH)‐dione	(11c)		
	

A	 solution	 of	 compounds	 10a‐c	 (10a:	 0.73	 g,	 0.002	 mol;	
10b:	 0.66	 g,	 0.002	 mol;	 10c:	 0.77	 g,	 0.002	 mol)	 in	 dimethyl	
formamide	was	 treated	with	 thioglycolic	 acid	 (0.18	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	2,	Tables	1,	2).	



Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	 291	
 

	 	

N
N N

H

O

Ph

H3C

N
N N

H

O

Ph

H3C N N

CH3

CH3

H3C

H3C

NO

ON OH

N
N N

H

O

Ph

H3C N OH

NO

HO

N
N N

H

O

Ph

H3C N

HO

N
N N

H

O

Ph

H3C N N

CH3

CH3

S
O

N
N N

H

O

Ph

H3C N N

CH3

CH3

O
Cl

N
N N

H

O

Ph

H3C N OH

S
O

N
N N

H

O

Ph

H3C N

S
O

N
N N

H

O

Ph

H3C N OH

O
Cl

N
N N

H

O

Ph

H3C N

O
Cl

OH

OH

HSCH2COOH

DMF/pip.

ClCOCH2Cl

DMF/NEt3

HSCH2COOH

DMF/pip.

ClCOCH2Cl

DMF/NEt3

HSCH2COOH

DMF/pip.

ClCOCH2Cl

DMF/NEt3

DMF/pip.

DMF/pip.

DMF/pip.

( 3 )

(10a)

(10b)

(10c)

(11a)

(11b)

(12a)

(12b)

(12c)

(11c)

	
	

Scheme	2
	
	
2.12.	Synthesis	of	3‐chloro‐1‐(4‐(dimethylamino)phenyl)‐3'‐
methyl‐1'‐phenyl‐1',6',7',7a'‐tetrahydrospiro[azetidine‐2,5'‐
pyrazolo[3,4‐b]pyridine]‐4,4'(3a'H)‐dione	(12a),	3‐chloro‐1‐
(4‐hydroxyphenyl)‐3'‐methyl‐1'‐phenyl‐1',6',7',7a'‐	
tetrahydrospiro[azetidine‐2,5'‐pyrazolo[3,4‐b]pyridine]‐4,4'	
(3a'H)‐dione	(12b),	3‐chloro‐1‐(2‐hydroxynaphthalen‐1‐yl)‐
3'‐methyl‐1'‐phenyl‐1',6',7',7a'‐tetrahydrospiro	[azetidine‐
2,5'‐pyrazolo[3,4‐b]pyridine]‐4,4'(3a'H)‐dione	(12c)	
	

A	 solution	 of	 compounds	 10a‐c	 (10a:	 0.73	 g,	 0.002	 mol;	
10b:	 0.66	 g,	 0.002	 mol;	 10c:	 0.77	 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	2,	(Tables	1,	2).	
	
	
	
	

3.	Results	and	discussion	
	

By	 using	 4‐acetyl‐5‐imino‐3‐methyl‐1‐phenyl‐2‐pyrazoline	
(1)	 [38],	 we	 could	 synthesize	 the	 new	 compound	 4‐acetyl‐5‐
amino‐3‐methyl‐1‐phenyl‐2‐pyrazoline	 (2),	 Scheme	 1	 which	
has	been	considered	as	starting	material	for	the	synthesis	of	all	
newly	 compounds	 involved	 in	 this	 our	 research	 project.	 The	
structure	 of	 compound	2	was	 confirmed	 by	 IR	 spectra	which	
revealed	the	presence	of	peaks	at	3350	cm‐1	(NH2),	at	1670	cm‐1	

(C=O),	at	1600	cm‐1	(C=N),	also	1H	NMR	spectra	of	compound	2	
revealed	the	presence	of	signals	peaks	at	1.4	(s,	3H,	CH3),	2.25	
(s,	3H,	CH3CO),	2.65	 (s,	1H,	CHN),	2.85(s,	1H,	CHCO),	4.20	(br,	
2NH,	 NH2),	 and	 7.00‐8.00	 (m,	 5H,	 Ar‐H+)	 ppm,	 the	 mass	
spectrum	showed	the	molecular	ion	peak	at	m/z	=	229.28.	

The	structure	of	compound	3	was	confirmed	by	IR	spectra	
which	 revealed	 the	 presence	 of	 peaks	 at	 3063	 (NH),	 1706	
(C=O),	 1596	 (C=N)	 cm‐1,	 also	 1H	NMR	 spectra	 of	 compound	3	
revealed	the	presence	of	signals	peaks	at	0.86	(s,	3H,	CH3),	1.24	
(d,	J	=	7.00	Hz,	1H,	NCHN),	2.16	(t,	J	=	7.30	Hz,	2H,	CH2O),	2.35	
(d,	J	=	7.00	Hz,	H,	CHCO),	2.73	(t,	J	=	7.30	Hz,	2H,	CH2N),	3.37	(s,	



292	 Soleiman	et	al.	/	European	Journal	of	Chemistry	3	(3)	(2012)	287‐292	
	
1H,	 NH),	 and	 7.24‐7.97	 (m,	 5H,	 Ar‐H+)	 ppm	 and	 the	 mass	
spectra	showed	the	molecular	ion	peak	at	m/z	228.	

The	 active	 methylene	 group	 in	 compound	 3	 condensed	
with	different	aromatic	aldehydes	(benzaldehyde,	anisaldehyde	
and	 p‐hydroxybenzaldehyde)	 in	 dimethylformamide	 under	
piperidine	as	catalyst	to	yield	the	corresponding	5‐aryldino‐4‐
piperidinone	 derivatives	 (4a‐c),	 respectively	 (Scheme	 1).	 The	
structure	of	compounds	4a‐c	was	confirmed	by	IR	spectrum,	1H	
NMR	spectrum	and	mass	spectra	 (Tables	1,	2).	The	activity	of	
exocyclic	 C=C	 conjugated	 with	 the	 α‐carbonyl	 group	 in	
compounds	 4a‐c	 were	 determined	 by	 the	 reaction	 with	
hydrazines,	 hydroxylamine	 hydrochloride,	 urea	 and	 thiourea,	
to	 yield	 the	 compounds	 5‐9a‐c,	 (Scheme	 1).	 The	 isoxazolo	
piperidino	derivatives	 (7a	 and	7b),	 the	piperidine	derivatives	
(8b,	 c)	 and	 the	 pyrimidine	 thione	 derivatives	 (9a,	 9c)	 were	
confirmed	by	micro‐analytical	and	spectroscopic	data.	

The	 compounds	 (10a‐c)	 were	 prepared	 by	 the	
condensation	 of	 3‐methyl‐1‐phenyl‐5,6,7,7a‐tetrahydro‐1H‐
pyrazolo[3,4‐b]pyridin‐4(3aH)‐one	 (3)	 with	 nitroso	
compounds	 such	 as	 (a)	 p‐nitroso	N,N‐dimethyl	 aniline,	 (b)	 p‐
nitroso	phenyl	and	(c)	α‐nitroso‐β‐naphthol	in	the	presence	of	
dimethylformamide	 as	 solvent	 under	 piperidine	 as	 catalyst	
(Scheme	 2).	 When	 Schiff's	 base	 compounds	 (10a‐c)	 reacted	
with	 thioglycolic	 acid	 in	 dimethylformamide	 under	 piperidine	
as	 catalyst	 yielded	 the	 corresponding	 N‐thiazole	 derivatives	
(11a‐c),	(Scheme	2).	By	the	reaction	of	Schiff's	base	compounds	
(10a‐c)	with	chloroacetylchloride	in	dimethylformamide	under	
triethylamine	as	catalyst	yielded	the	corresponding	N‐β‐lactam	
derivatives	(12a‐c)	(Scheme	2).	
	
4.	Conclusion		
	

The	 present	 study	 deals	 with	 the	 development	 of	 some	
synthetic	 applications	 of	 3‐methyl‐1‐phenyl‐5‐pyrazolone	 and	
is	based	on	the	generation	of	building	blocks	containing	 fused	
isolated	and	spiro	heterocyclic	compounds.	

	
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