Indian Journal of Chemistry Vol. 43B, June 2004, pp. 1355-1359

Note

A convenient synthesis of some novel pyrazole derivatives

EI-Saied A Aly*, Mohamed A EI-Borai & Mohamed A Barren

Chemistry Department , Faculty of Science, Tanta University, Tanta, Egypt

Received 13 March 2003; accepted (revised) 14 January 2004

A range of some nove l pyrazole deri vati ves has been prepared in moderate to good yield by the reaction of 3-aryl- l -phenyl - 1 H­pyrazole-4-carbaldehydes Ia,b as a starting material with some reagents such as acylglycine, benzamidine hydrochloride, malononitrile and ethyl azidoacetate giving the oxazolone deriva­tives (2a,b and 3a,b), dihydroimidazolone derivatives 6a,b, pyri ­dine derivatives (8a,b and 9a,b) and pyrrolopyrazole derivatives IIa,b, respectively. Structures of all the synthesized products have been confirmed by physical and spectroscopic data.

IPC: Int.CI.7 C 07 0231/00

Pyrazole and its synthetic analogues have been found to exhibit industrial , agricultural and biological appli­cations. I

-5 As a part of our continuing interest in syn­

thesis and reactivity of five- membered heterocyclic compounds ,6,7 recently , we have shown a new syn­thetic route for the synthesis of some novel pyrazole derivatives from 3-aryl-l-phenyl-1H-pyrazole-4-carbaldehydes la,b, which is obtained according to the literature procedure, ~

Reaction of la,b with benzoylglycine or acetylg ly­cine in acetic anhydride and in the presence of sodium acetate9

, IO resulted in the production of 4-(3 -aryl-l­phenyl-I H-pyrazol-4-ylmethylene)-2-phenyl(or methyl ) oxazol-5(4H)-ones 2a,b and 3a,b respectively in moderate to good yield. The alkaline hydrolysis of compounds 2a,b and 3a,b were carried out using dif­ferent alkaline media. It was found that hydrolysi s using aqueous 2% ethanolic sodium hydroxide solu­tion afforded 2-benzoylamino(or 2-acetylamino)-3-(3-aryl-l-phenyl-1H-pyrazol-4-yl)acrylic acids (4a,b and 4c,d, respectively) in an excellent yield . While, on carrying out hydrolysis using sodium acetate in boiling methanol , methyl 2-benzoylamino (or 2-acetylamino)-3-(3-aryl -l-phenyl- l H-pyrazol-4-yl) acrylates (Sa,b and Sc,d , respectively) were obtained in good yield.

We turned our attention to investigate the reaction of Ia,b with a mixture of benzamidine hydrochloride and ethyl chloroacetate in the presence of sodium bi-

carbonate in boiling n-propanol ll to afford 2-phenyl-5-(3-aryl-l-phenyl-1H-pyrazol-4-ylmethylene)-3H-4,5-dihydroimidazol-4-ones 6a,b. In order to obtain some cyanopyridine derivatives attached to the pyrazole ring, la,b were treated with malononitrile in boiling ethanol and in the presence of piperidine to gi ve 2-(3-aryl-l-phenyl-I H-pyrazol-4-ylmethylene)malononitriles 7a,b, which could be cyclized with acetone and am­monium acetate l 2 to give the desired 3-amjno-4-(3-aryl-l -phenyl-l H-pyrazol-4-yl)-6-methylpyridine-2-car­bonitriles 8a,b. But on carrying out the reaction of la,b with malononitrile and acetophenone l 3 in the presence of ammonium acetate, 2-amino-5-(3-aryl -l ­phenyl-l H-pyrazol-4-yl)-4-phenylnicotinonitriles 9a,b were obtained, which on treatment with formamide in boiling ethanol yielded 6-(3-aryl -l-phenyl-IH-pyra­zol-4-yl)-5-phenylpyrido[2,3-d] pyrimidin-4-ylamjnes IOa,b. Reaction of Ia,b with ethyl azidoacetate in ethanolic sodium hydroxide solution , followed by thermal cyclization l4 afforded ethyl 3-aryl-l-phenyl­I H,6H-pyrrolo[2,3-c ]pyrazole-5-carboxylates lla,b. Finally, by applying Aldol condensation on com­pounds la,b with cyc lohexanone in aqueous sodiu m hydroxide and dimethyl sulphoxide,15 2 ,6-bi s (3-aryl­I-phenyl-I H-pyrazol-4-yl methylene)cyclohexanones 12a,b were obtained as yellow crystals in good yields (Scheme I, Table I ).

Experimental Section All melting points were taken on Gallen Kamp

apparatus and are uncorrected. Microanalysis were performed by Microanaly~ is unit , Faculty of Science, Cairo University , IR spectra (KBr) were recorded on a Pye Unicam SP 200G and SP 1200 spectrophotome­ter ; IH NMR spectra on a JEOL-IOOMHz and Varian T-90MHz with CDCI3 or DMSO-dr, as solvents usi ng TMS as internal reference (chemical shi fts in 0, ppm); and mass spectra on an MS/Z mass spectrometer f it­ted with a direct inlet system at 70eV.

4-(3-Aryl-I-phenyl-IH -pyrazol-4-ylmethylene)-2-phenyloxazol-S(4H)-ones 2a,b. A mjxture of la,b (0.01 mole) , benzoylglycine ( 1.79 g, 0 .01 mole) and sodium acetate (0 ,83 g, 0.0 I mole) in acetic anhydride (5 mL) was heated under reflux for 3 hL The reaction mixture was cooled and hydrolysed in ice-water and the solid product that formed was filtered , washed

1356

P

Ar

I Ph

10a,b

i HCONH,

NC

INDIAN J. CHEM. , SEC B, JUNE 2004

o Ar CHn

)) NyNH I Ph Ph

6a,b

+ NH2 CI II

Ph-C-NH2

I ~OCH'

Ar

I Ph

8a,b

CN

CN

I ~ ' CN Ar))CH=cf

~ I Ph

7a,b

::b 0 RCONH:::OOH A')j~CHO Cycloh'~ooo, Ar CHn ~C20' AcONa ~h DMSO, NaOH

'7J--( NVO 1a,b 0

t(~ I Ar = a, Ph Ar CHvCH Ar I R b, P-tOIYI)) t./ Ph I ~ 1 ~

j ~ , N

2a,b ; R = Ph I 1 3a,b; R = CH3 Ph

N3CH2COOEt Ph

I NaOH or .CH3COONa

Ar)jCH= y- COR'

I ~ NHCOR

~ I Ph

4a-d , Sa-d

4

a b c d

Ar

Ph p-Tol

Ph p-Tol

EtOH 12a,b

Ar)jCH=y-COOEt

I ~ N3 ~

I Ph

Ar

~COOEt

Toluene,. J ~ N reflux . '" H

I Ph

11a,b

R R' 5 Ar R R'

Ph OH a Ph Ph OMe Me OH b p-Tol Me OMe Ph OH c Ph Ph OMe Me OH d p-Tol Me OMe

Scheme I

with water till pH 7, then dried and recrystalli zed from carbon tetrachloride; IR: (1740-1760), (1635-1645). (1605-1610) and (1210-1230) cm-l due to C=O, C=C, C=N and C-O, respectively; lH NMR of

2b (DMSO-d6): 0 2.35 (s, 3H, CH3), 7.20 (s, IH, CH=C), 7.30-8.10 (m, 14H, ArH) and 8.40 (s, IH, CH-pyrazole) ; MS (EI) of 2a: mlz 39 1 (M+, 65 %), 258 (II %), 105 (94%), 77 (lOO%).

NOTES

Table I - Characterization data of compounds 2,3,4,5,6,7,8,9,10,11 and 12.

Compd m.p. Yi eld Mol. formula. % N Compd m.p. Yield Mol. formula °C (%) (Mol Wt.) Calcd °C (%) (Mol Wt.)

(Found)

2a 196-98 55 C2sH I7N)02 10.73 6b 370-71 52 C26H20N40 (39 I .43) (10.60) (404.48)

2b 200-01 60 C26H19N)02 10.36 7a 190-91 83 CI9HI2N4 (405.45) (10.60) (296.33)

3a 135 50 C2oH1SN)02 12.75 7b 178-79 85 C2oHI 4N4 (329 .35) (13.00) (3 10.36)

3b 98- 100 55 C21H17N30 2 12.23 8a 232-33 50 C22H17Ns (343.39) (12 .50) (351.41)

4a 198-200 90 C2sHI9N303 10.26 8b 145-46 55 C23H 19N5 (409.44) (10.00) (365.44)

4b 205-07 93 C26H21N303 9.92 9a 180-8 1 90 C27HI9NS (423.47) (9.60) (4 13.49)

4c 140-42 80 C2oH17NP3 12.09 9b 195-96 95 C2sH21NS (347.37) ( 11.80) (427.5 1)

4d 100-02 75 C2 1HI9N303 11.62 lOa 235-36 80 C28H20N6 (361.40) (11.10) (440.51)

5a 215-16 78 C26H21N30 3 9.92 lOb 160-61 82 C29H22 N6 (423.47) (9.60) (454.54)

5b 232-33 80 C27H23N303 9.60 lla 208-09 30 C2oH17N30 2 (437.49) (9.80) (331.38)

5c 150-51 70 C21H I9N303 11.62 lIb 198-99 35 C21HI9N30 2 (36 1.37) (12.00) (345.40)

5d 125-26 74 C22H21NP3 I 1.19 12a 260-62 85 C3sH30N40 (375.42) ( I 1.00) (558.69)

6a 312- 13 50 C2sH IsN40 14.35 12b 240-41 90 C4oH34N40 (390.44) (14.50) (586.74)

% N Calcd

(Found)

13.85 ( 13.60)

18.91 ( 18.60)

18.05 (17 .90)

19.93 (20. 10)

19. 16 ( 19.50)

16.94 (16.60)

16.38 ( 16.20)

19.08 ( 19.38)

18.49 ( 18.92)

12.68 (12.90)

12.17 (12.50)

10.03 (9.90)

9.55 (9.80)

1357

4-(3-Aryl-l-phenyl-IH -pyrazol-4-ylmethylene)-2-methyloxazol-5(4H)-ones 3a,b. The procedure is the same as described fo r synthesis of compounds 2a,b in which acetylglyci ne was used instead of ben­zoylglyci ne. The reaction mj xture was heated under reflux fo r 5 hr and the product that obtained was re­crystalli zed from ethanol: IR: ( l745- l760), (1620-1640), (1600- 1610) and (1210-1240) cm- l due to C=O, C=C, C=N and e-o, respectively; MS (EI) of 3a: mlz 329 (M+, 12%), 258 (14%),247 (100%) and 77 (46%).

lH NMR (DMSO-d6) of 4b: b 2_35 (s, 3H, CH3), 7.20 (s, 1 H, CH=C) , 7.40-8.10 (m, 14 H, ArH), 8.60 (s, IH, CH-pyrazole), 9.50 (s , IH, NH) and 9_90 (s , IH, COOH); MS (EI) of 4b: mlz 423 (M+, 100%), 406 (22%),378 (12%), 258 (16%), 105 (13%), 77 (76%).

2-Benzoylamino( or 2-acetylamino )-3-(3-aryl-l­phcnyl-1l1-pyrazol-4-yl)acrylic acids 4a-d. A solu­tion of 2a,b or 3a,b (0.01 mole) in ethanoli c sodi um hydroxide (10%, 50 mL) was heated under reflux for 3 hr. It was concentrated , diluted with water (100 mL), acidified with 2% hydroch loric acid . The solid that resulted was fi itered, dried and recrystalli zed from ethanol; IR (1690-l700), (1665-1680) , (1635-1645), (1595 -1 605) and (3200-3300) cm-l due to COO, C=O, C=C, C=N and NH, respectivel y;

Methyl 2-bel1zoylamino(or 2-acetylamino)-3-(3-aryl-l-phenyl-IH -pyrazc-I-4-yl)acrylates Sa-d. A suspension of 2a,b and 3a,b (0.0 I mole) in methanol (30 mL) and sodium acetate (0.82 g, 0_01 mole) was heated under reflux for 30 hr. The reaction mj xture was concentrated , cooled and the so lid thu s obtained was collected by fi ltration , dried and recrystallized from ethanol;

IR : (1735 -1740). (17 10-1730), (1630- 1640), (1600-1605) and (32 10-3220) cm- l due to COO, C=O, C=C, C=N and NH, respectively; lH NMR (CDCI3) of Sa: b 3.85 (s, 3H, OCH3) , 7.10 (s, JH, CH=C), 7.30-8 .20 (m, IS H, ArH), 8.45 (s , 1 H, CH-pyrazole) and 9.60 (s, IH, NH); lH NMR (CDCl3) of 5b: b 2.35 (s, IH, CH3), 3.85 (s, 3H, OCH3), 7.20 (s , 1 H, CH=C), 7.30-8. 10 (m, 14H, ArH) , 8.30 (s , lH, CH-pyrazole) and

1358 INDIAN J. CHEM., SEC B, JUNE 2004

9.60 (s, I H, NH); MS (EI) of Sa: mlz 423 (M+, 12%), 392 (14%), 303 (16%), 105 (100%), 77 (44%); MS (El) of Sb: mlz 437 (M+, 10%), 406 (15 %), 317 (22%),246 (14%),105 (100%),77 (48%).

2-Phenyl-S-(3-aryl-l-phenyl-IH -pyrazol-4-ylme­thylene)-3H-4,S-dihydroimidazol-4-ones 6a,b. A mixture of la,b (0.01 mole) , benzamidine hydrochlo­ride dihydrate (3.48 g, 0.02 mole) and ethyl chloroacetate (2.26 mL, 0.02 mole) in n-propanol (20 mL) was heated under reflux with sti rring for I hr. The product that formed was collected by filtration , washed with methanol , dried and recrystallized from n-butanol; IR: (1700-1710), (1625-1635), (1600-1605) and (3100-3120) cm-I due to C=O, C=C, C=N and NH, respectively; MS (El) of 6a: 390 (M+, 64%), 389 (41 %), 362 (13%), 258 (10%), (105, 10%), 77 (100%); MS (EI) of 6b: 404 (M+, 100%),376 (26%), 274 (38%),191 (12%), 105 (13%), 77 (60%).

2-(3-Aryl-l-phenyl-IH -pyrazol-4-ylmethylene)­malononitriles 7a,b. A mixture of la,b (0.01 mole) , malononitrile (0.66 g, 0.01 mole) in absolute ethanol (20 mL) and a few drops of piperidine was heated under reflux for 4 hr. After cooling, the solid product that separated was collected by filtration, dried and recrystallized from ethanol; IR: (2240-2250), (1635-1640) and (1600-1605) cm-I due to C=N, C=C and C=N, respectively; MS (EI) of 7a: mlz 296 (M+, 100%), 295 (35%), 270 (21 %),77 (56%); MS (EI) of 7b: mlz 311 (M++l, 100%),310 (M+, 87%), 285 (23%),9 1 (11 %), 77 (38%).

3-Amino-4-(3-aryl-l-phenyl-IH -pyrazol .. 4-yl)-6-methylpyridine-2-carbonitriles 8a,b. A mixture of 7a,b (0.0 1 mole), acetone (0.6 mL, 0.01 mole) and ammonium acetate (1.23 g, 0.015 mole) in absolute ethanol (20 mL) was heated under reflux for 4 hr. Af­ter cooling, the product that obtained was collected by filtration, dried and recrystallized from benzene; IR: (3480-3490) and (2240-2250) cm- I due to NH2 and C=N, respectively; MS (EI) of 8b: mlz 365 (M+, 13%), 350 (44%),339 (16%), 338 (50%), 233 (10%), 77 (100%).

2-Amino-S-(3-aryl-l-phenyl-IH -pyrazol-4-yl)-4-phenylnicotinonitriles 9a,b. A mixture of la,b (0.01 mole) , acetophenone (1.2 mL, 0.01 mole) , malononi­trile (0.66 g, 0.01 mole) and ammonium acetate (7.7 g, 0.1 mole) in absolute ethanol (10 mL) was heated under reflux on a water-bath for 2 hr. After cooling, the solid that separated was collected by filtration, dried and recrystallized from n-butanol; IR: (3490-3500), (2245-2250), (1630-1635) and (1600-1605) cm-I due to NH2, C=N, C=C and C=N, respectively;

MS (El) of 9a: mlz 413 (M+, 13%), 397 (25%), 373 (15 %),245 (18%),77 (100%).

6-(3-Aryl-l-phenyl-IH -pyrazol·4-yl)-S-phenyl­pyrido[2,3-d]pyrimidin-4-ylamines 10a,b. A mix­ture of 9a,b (0.01 mole) and formamide (10 mL, 0.01 mole) was heated under reflux for 3 hr. The reaction mixture was cooled, diluted with water and the solid that formed was collected by filtration , dried and re­crystallized from ethanol; IR: (3480-3490) , (1635-1640 and (1605-1610) cm- I due to NH2, C=C and C=N respectively; MS (EI) of lOa: mlz 440 (M+, 10%), 377 (16%), 337 (75 %), 311 (55%),277 (63%), 249 (57%), 233 (100%).

Ethyl 3-Aryl-l-phenyl-1H,6H-pyrrolo[2,3-c ]pyra­zole-S-carboxylates 11a,b. Ethyl azidoacetate (10.3 g, 0.08 mole) was added to a mixture of la,b (0.02 mole) and sodium ethoxide (1.84 Na in 20 mL abs. EtOH) dropwi se with stirring at a rate which main­tained the temperature below ODC. Stirring was con­tinued at room temperature until TLC indicated that all the aldehyde has been consumed . The reaction mixture was poured onto ice-cold water and the solid separated was taken in toluene (30 mL) and heated under reflux for 1 hr. The resulting product was col­lected by filtration and recrystallized from ethanol; IR: (3260-3270), (1670-1680), (1635-1640) and (1595-1600) cm- I due to NH, C=O, C=C, C=N, re­spectively ; MS (EI) of 11a: mlz 331 (M+, 11 %), 316 (64%), 286 (16%), 285 (71 %), 105 (18%),77 (100%).

2,6-Bis(3-aryl-l-phenyl-IH -pyrazol-4-ylmethyl­ene)cyclohexanones l2a,b. A mixture of la,b (0.01 mole), cyclohexanone (1.9 mL, 0.02 mole) in aqueous dimethylsulfoxide (50%, 10 mL) and aqueous sodium hydroxide (20%, 10 mL) was heated with stirring at 100D C for 5 hr. The reaction mixture was cooled and neutralized with dilute hydrochloric acid, then the resulting product was collected by filtration, washed with w3ter and recrystallized from e·hanol; IR: (1705-1715) cm- I due to C=O; MS (EI) of 2a: mlz 558 (M+, 15%),531 (36%),530 (23%), 232 (20%), 77 (100%).

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NOTES 1359

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