International Journal of Organic Chemistry
Vol. 2  No. 2 (2012) , Article ID: 20379 , 10 pages DOI:10.4236/ijoc.2012.22021

An Efficient and Convenient Synthesis of Certain 2-Thioxothiazole,2-oxo-1,2-dihydropridine, 2-Oxo-2H-pyran,2,4-diaminothiophene and Pyrazolo[5,1-c][1,2,4]triazine Derivatives Containing Antipyrine Moiety

Seif-Eldin Nasr Ayyad1,2, Fathy Muhammad Abdelaziz El-Taweel2*, Abdel-Ghani Ali Elagamey2, Tahani Mahmoud El-Mashad2

1Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, KSA

2Department of Chemistry, Faculty of Science, New Damietta Branch, Mansoura University, New Damietta, Egypt

Email: *

Received February 18, 2012; revised March 9, 2012; accepted March 23, 2012

Keywords: Thioxothiazoles; Pyridine; Thiophene; Pyrazolotriazines


2-Thioxothiazole derivatives 5a-c were prepared by reacting a mixture of 1a-c, CS2/KOH and 4-(2-chloroacetyl)-1, 5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (3). Reacting 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) with mercaptoacetic acid, arylidenemalononitriles 8 and (E)- 3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (12) give 4-oxo-4,5-dihydrothiazole 6, 2-oxo-1,2-dihydropyridine 10 and 2-oxo-2H-pyran 15 respectively. Heating a mixture of 5c, malononitrile and elemental sulfur yield 2,4-diaminothiophene 19. Coupling of 5c with the diazotized aminopyrazole 20 and aryldiazonium salts 23 give pyrazolo[5,1-c][1,2,4] triazines 22 and arylhydrazones 25 respectively.

1. Introduction

Diverse pharmacological properties have been associated with thiazole derivatives [1-3]. These pharmacological activities have been attracted special attention to prepare a new class of thiazole derivatives carrying antipyrinyl moiety because of their applications in the field of pharmaceuticals [4-6] and antibacterials [7-9]. The present work reports the synthesis of certain thiazole derivatives containing antipyrine moiety using readily available starting materials.

2. Experimental

All melting points are uncorrected and have been measured on a Griffin & George MBF010T (London) apparatus. Recorded yields correspond to the pure products. IR (KBr) spectra were recorded on a Perkin Elmer SP- 880 spectrometer and from samples of sufficient solubility. 1H-NMR spectra were measured on a Varian 270 MHz spectrometer on DMSO-d6 as solvent and TMS as an internal standard. Chemical shifts are reported in δ units (ppm).

Microanalyses were performed on a LECO CHN-932 elemental analyzer and carried out in the Microanalytical Data Units at Cairo and Mansoura Universities.

General procedure for preparation of 4,4’-(2-thioxothiazole-3,4-(2H)-diyl)bis(1,5-dimethy l-2-phenyl-1H-pyrazol-3(2H)-one)(5a),2-(4-chlorophenoxy)-N-(-(1,5-di-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide(5b) and 2-cyan o-N-(4- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2 H)-yl)acetamide(5c)

A solution of 4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (1a) or 2-(chlorophenoxy)acetohydrazide (1b) or 2-cyanoacetohydrazide (1c) (0.01 mol) in dimethylformamide (30 mL) containing potassium hydroxide (0.01 mol) and (0.01 mol) of carbon disulfide was stirred at room temperature for 6 h. To this solution (0.01 mol) of 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3 (2H)-one (2) was added, then the solution was stirred again overnight, poured on ice and neutralized with dilute hydrochloric acid. The precipitates formed were collected by filtration and crystallized from ethanol to give 5a-c respectively.

4,4’-(2-Thioxothiazole-3,4-(2H)-diyl)bis(1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one)(5 a)

Colorless crystals, m.p. 265˚C - 267oC, yield 70%. - IR(γ/cm–1): 1660 (antipyrinyl C=O), 1240(C=S). -1H-NMR (DMSO-d6, δ/ppm): 2.16, 2.21 (2s, 6H, 2CH3), 3.02, 3.35 (2s, 6H, 2N-CH3), 7.07 (s, 1H, thiazole H-5), 7.16 - 7.50 (m, 10H, aryl H). -C25H23N5S2O2 (489.62) Calcd. C 61.33, H 4.74, N 14.30. Found C 61.43, H 5.2, N 14.12.

2-(4-Chlorophenoxy)-N-(-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl) acetamide(5b)

Colorless crystals, m.p. 215˚C - 217˚C, yield 70%. - IR(γ/cm–1): 3480 (NH), (C=O), 1660 (antipyrinyl C=O). -1H-NMR(DMSO-d6, δ/ppm): 2.94 (s, 3H, CH3), 3.32 (s, 3H, N-CH3), 4.73 (s, 2H, CH2), 6.91 - 7.79 (m, aryl H), 10.34 (s, 1H, NH). -C22H19N4ClS2O3(486.59) Calcd. C 54.31, H 3.94, N 11.50. Found C 54.16, H 4.05, N 11.43.

2-Cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazo l-3(2H)-yl)acetamide(5c)

was prepared according to the literature procedure [4].

Preparation of N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)-2-thiox othiazol-3(2H)-2-(4-oxo-4,5-dihydrothiazol-2-yl)acetamide(6)

A solution of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) (0.01 mol) and mercaptoacetic acid (0.01 mol) in dry pyridine (30 mL) was refluxed for 6 h. The solvent was removed in vacuo. The product was collected by filtration, crystallized from ethanol/DMF, to give 6 as brown crystals, no melt ν/300˚C, yield 60%. - IR(γ/cm–1): 3450, 3420 (NH, OH), 1685 (C=O), 1670 (antipyrinyl C=O). -1H-NMR(DMSO-d6, δ/ppm): 2.52 (s, 3H, CH3), 3.11 (s, 3H, N-CH3), 4.77 (s, 2H, CH2), 7.42 - 7.56 (m, 7H, aryl H), 8.9, 10.40 (2s, 2H, 1H, OH and 1H, NH). -C19H17N5S3O3 (459.57) Calcd. C 49.66, H 3.73, N 15.24. Found C 49.63, H 4.03, N 14.75.

Preparation of (E)-3-aryl-2-cyano-N-(4-(1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-p yrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acrylamides(7a, b)

A solution of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) (0.01 mol) in ethanol (50 mL) was treated with the appropriate aromatic aldehydes (0.01 mol) and few drops of piperidine. The reaction mixture was refluxed for 2 h and then the solvent was concentrated to its half volume. The solid products were collected by filtration, crystallized from ethanol and identified as (7a, b).

(E)-2-Cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl2,3-dihydro-1H-pyrazol-4-yl)-2-thioxoth iazol-3-(2H)-yl)-3-(4-hydroxyphenyl) acrylamide(7a)

Colorless crystals, m.p. 236˚C - 238˚C, yield 65%. -IR (γ/cm–1): 3450, 3383 (OH, NH), 2212 (conjugated CN), 1670 (amidic C=O), 1658 (antipyrinyl C=O). -C24H19N5S2O3 (489.58) Calcd. C 58.88, H 3.91, N 14.3; Found C 59.04, H 3.82, N 14.10.

(E) 3-(3-Chlorophenyl)-2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl2,3-dihydro-1H-pyra zol-4-yl)-2-thioxothiazol-3-(2H)-yl)acrylamide(7b)

Pale yellow, m.p. 200˚C - 202˚C, yield 63%. -IR(γ/ cm–1): 3560, 3441, 3389 (NH), 2206 (conjugated CN), 1676 (C=O), 1651 (antipyrinyl C=O). -1H-NMR(DMSOd6, δ/ppm): 2.41 (s, 3H, CH3), 3.27 (s, 3H, N-CH3), 7.41- 7.54 (m, 7H, 6H, aryl H + 1H, NH), 8.31 (s, 1H, ylidenic H). -C24H18ClN5S2O2 (508.02) Calcd. C 56.74, H 3.57, N 13.79; Found C 56.82, H 3.48, N 13.67.

Synthesis of 6-amino-4-aryl-1-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxo-thiazol-3(2H)-yl-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitriles(10b)

Method A:

A solution of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxo thiazol-3(2H)-yl)acetamide (5c) (0.01 mol) in ethanol (50 mL) containing (0.1 mL) of piperidine, was treated with (0.01 mol) of arylidenemalononitriles 8. The reaction mixture was refluxed for 3 h, then left to cool. The solid products formed were collected by filtration and crystallized from ethanol to give (10a, b).

Method B:

6-Amino-4-aryl-1-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thiox othiazol-3(2H)-yl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles(10b)

were also prepared by reacting (E)-3-aryl-2-cyano-N-(4-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)2-thioxothiazol-3(2H)-yl)acrylamides (7a, b) with malononitrile in ethanolic-piperidine.

6-Amino-1-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazo l-3(2H)-yl-4-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(10a)

Faint brown crystals, m.p. 254˚C - 256˚C, yield 63%. - IR(γ/cm–1): 3500, 3380(OH, NH2), 2223(conjugated CN), 1700 (C=O), 1652 (antipyrinyl C=O). -C27H19N7S2O3 (553.62) Calcd. C 58.58, H 3.46, N 17.78; Found C 58.64, H 3.38, N 18.03.

6-Amino-4-(3-chlorophenyl)-1-(4-(1,5-dimethyl-3-oxo- 2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile(10b)

Brown cryctals, m.p. 230˚C - 232˚C, yield 60%. –IR (γ/cm–1): 3448, 3387 (NH2), 2206 (conjugated CN), 1740 (C=O), 1672 (C=O antipyrinyl). -1H-NMR (DMSO-d6, δ/ppm): 2.34 (s, 3H, CH3), 3.30 (s, 3H, N-CH3), 7.11 - 7.74 (m, 10Haryl H), 8.10 (s, 2H, NH2). -C27H18ClN7S2O2 (572.06) Calcd. C 56.69, H 3.17, N 17.17; Found C 56.83, H 3.34, N 17.32.

N-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-6-(furan-2-yl)-2- oxo-2H-pyran-3-carboxamide(15)

A solution of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) (0.01 mol) and (0.01 mol) of (E)-3- (dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (12) in ethanol (50 mL) was treated with acetic acid (1 mL) was refluxed for 3 h and then left to cool. The solid formed was collected by filtration and crystallized from ethanol to give 15 as faint brown crystals, m.p. 170˚C - 172˚C, yield 60%. -IR(γ/cm–1): 3450 (NH), 1743 (C=O amidic), 1652 (antipyrinyl C=O). -1H-NMR(DMSO-d6, δ/ppm): 2.35 (s, 3H, CH3), 3.33 (s, 3H, N-CH3), 6.70 (s, 1H, thiazoleH-5), 6.90 (d, J = 8 Hz, 1H, pyroneH-5), 7.21 - 8.0 (m, 8H, aryl H), 8.20 (d, J = 8 Hz, 1H, pyroneH-4), 9.6 (s, 1H, NH). -C24H18N4S2O5 (505.55) Calcd. C 56.91, H 3.58, N 11.06; Found C 57.01, H 3.48, N 11.35.

Preparation of 2,4-diamino-5-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)thiophene-3-carboxamide(19)

A solution of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) (0.01 mol) and (0.01 mol) of malononitrile and elemental sulfur (0.01 mol) in ethanol (50 mL) containing (0.1 mL) of triethylamine was refluxed for 2 h and then left to cool to room temperature. The precipitate formed was collected by filtration, crystallized from ethanol to give 19 as faint brown crystals, m.p. 220˚C - 222˚C, yield 65%. -IR(γ/cm–1): 3527, 3380 (NH2), 2223 (conjugated CN), 1702 (C=O amidic),1654 (antipyrinyl C=O). -1H-NMR (DMSO-d6, δ/ppm): 2.29 (s, 3H, CH3), 3.03 (s, 3H, N-CH3), 7.22 - 7.782 (m, 10H, 5H, arylH, 5H, 2NH2 + 1H, NH). -C20H17N7S3O2 (483.59) Calcd. C 49.67, H 3.54, N 20.27; Found C 49.75, H 3.63, N 20.35.

Genaral method for synthesis of 4-amino-N-(4-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-7-substituted pyrazolo[5,1-c][1,2,4] trazine-3-carboxami des (22a,b) and 2-(arylhydrazono)-N- (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihyd o-1H-pyrazol- 4-yl)-2-thioxothiazol-3(2H)-yl)-2-(4-oxo-4,5-dihydrothiazol-yl)acetamides(24a-c)

To a cold solution of 2-cyano-N-(4-(1,5-dimethyl-3- oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) (0.01 mol) in water-ethanol mixture (1:1) containing saturated solution of sodium acetate (10 mL), the diazotized 4-(5-amino-1H-pyrazol- 3-yl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one (20) (prepared from 4-(5-amino-1H-pyrazol-3-yl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one hydrochloride (0.01 mol) and (0.01 mol) of sodium nitrite) or the aryldiazonium salts 23 (prepared from primary aromatic amine hydrochloride) (0.01 mol) and the equivalent amount of sodium nitrite was added dropwise with stirring. The reaction mixture was left in the refrigerator overnight. The resulting solids were collected by filtration and crystallized from the proper solvents to give (22a, b) and (24a-c) repectively.

4-Amino-7-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N-(4-(1,5-dimeth yl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide(22a)

Brown crystals, from ethanol/DMF, m.p. 220˚C - 222˚C, yield 75%. -IR(γ/cm1): 3500 - 3370 (NH2, NH), 1705 (amidic C=O), 1670 (antipyrinyl C=O). -C31H27N11S2O3 (665.75) Calcd. C 55. 93, H 4.09.46, N 23.14; Found C 56.03, H 4.11, N 23.34.


Brown crystals, from ethanol, m.p. 180˚C - 182˚C, yield 80%. -IR(γ/cm–1): 3507 - 3385 (NH2, NH), 1703 (C=O amidic), 1675 (antipyrinyl C=O). -1H-NMR (DMSOd6, δ/ppm): 2.33 (s, 3H, CH3), 3.30 (s, 3H, N-CH3), 6.2 (s, 1H, pyrazoleH-4), 6.65 (s, 1H, thiazole H-5), 7.31 - 7.90 (m, 12H, 10H, aryl H + 2H, NH2). -C26H21N9S2O2  (555.64) Calcd. C 56.20, H 3. 81, N 22.69; Found C 56.42, H 3.61, N 22.41.

2-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-ylamino)-2-oxo-N- p-tolylacetohydrazonoyl cyanide(24a)

Red crystals, from ethanol, m.p.160˚C - 162˚C, yield 75%. -IR(γ/cm–1): 3455 (NH), 2210 (conjugated CN), 1700 (C=O amidic), 1660 (antipyrinyl C=O), 1630 (C=N), 1590 (N=N). -1H-NMR (DMSO-d6, δ/ppm) :2.33 (s, 3H, CH3), 2.52 (s, 3H, CH3), 3.32(s, 3H, N-CH3) 6.65 (s, 1H, thiazole H-5), 7.14 - 7.56 (m, 10H, aryl H), 9.25, 10.17 (2S, 2H, 2NH). -C24H21N7S2O2 (503.61) Calcd. C 57. 24, H 4. 20, N 19.47; Found C 57.28, H 4.34, N 19.56.

N-(4-Chlorophenyl)-2-(4-(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-ylamino)-2-oxoacetohydra-zonoyl cyanide(24b)

Reddish brown crystals, from ethanol, m.p. 180˚C - 182˚C, yield 75%. -IR(γ/cm1): 3449 (NH), 2214 (conjugated CN), 1741 (C=O amidic), 1677, m.p. 170˚C - 172˚C, yield 60%. -IR(γ/cm1): 3450 (NH), 1743 (C=O amidic), 1652 (antipyrinyl C=O). -1H-NMR(DMSO-d6, δ/ppm): 2.35 (s, 3H, CH3), 3.33 (s, 3H, N-CH3), 6.70 (s, 1H, thiazoleH-5), 6.90 (d, J = 8 Hz, 1H, pyroneH-5), 7.21 - 8.0 (m,8H, aryl H), 8.20(d, J = 8 Hz, 1H, pyroneH-4), 9.6 (s, 1H, NH). -C24H18N4S2O5 (505.55) Calcd. C 56. 91, H 3.58, N 11.06; Found C 57.01, H 3.48, N 11.35.

N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yla-mino)-2-oxoacetohydr azonoyl cyanide(24c)

Brown crystals, from ethanol, m.p. 175˚C - 1177˚C, yield 65%. -IR(γ/cm1): 3500 (NH), 2210 (conjugated CN), 1700 (C=O amidic), 1665 (antipyrinyl C=O), 1630 (C=N), 1600 (N=N). -C28H25 N9S2O2 (599.69) Calcd.C 56.08, H 4.20, N 21.02; Found C 56.13, H 4.34, N 21.33.

Preparation of N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2- (4-oxo-4,5-dihydrothiazol-2-yl)-2-(2-p-tolylhydrazono)acetamide(25)

A solution of 2-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-ylamino) -2-oxo-N-p-tolylacetohydrazonoyl cyanide (24a) (0.01 mol) and (0.01 mol) of mercatoacetic acid in dry pyridine (30 mL) was refluxed for 6 h. The solvent evaporated under reduced pressure, then triturated with ethanol. The solid product was collected by filtration, crystallized from ethanol/1,4-dioxan,to give 25. The same product also prepared by reacting N-(4-(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)2-(4-oxo-4,5-dihydrothiazol-2-yl)acetamide (6) with aryl diazonium salt (23a).

Dark brown crystals, m.p. 245˚C - 247˚C, yield 60%. - IR(γ/cm–1): 3450 (NH), 1705 (C=O amidic), 1665 (antipyrinyl C=O), 1630 (C=N), 1600 (N=N). -C26H23 N7S3O2 (577.71) Calcd. C 54.06, H 4.01, N 16.97; Found C 54.13, H 4.23, N 17.04.

3. Results and Discussion

It has been found that, treatment of 4-amino-1,5-dimethyl- 2-phenyl-1H-pyrazol-3(2H)-one (1a) or 2-(chlorophenoxy) acetohydrazide (1b) or 2-cyanoacetohydrazide (1c) with carbon disulfide in dimethylformamide containing equivalent amount of potassium hydroxide give the non-isolable potassium salts 2a-c. The latter were alkylated with 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3

(2H)-one (2) to yield products with water elimination. 2- Thioxothiazole structures 5a-c were assigned as reaction products based on their analytical and spectral data. The 2-thioxothiazole derivatives 5a-c were presumably formed through the intermediacy of 4 (cf. Scheme 1).

The chemical reactivity of 2-cyano-N-(4-(1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) [4] towards different reagents was studied. Thus, compound 5c reacted with mercaptoacetic acid in dry pyridine to afford N-(4-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)2-thioxothiazol-3(2H)-yl)-2-(4-oxo-4,5-dihydrothiazol-2yl)acetamide (6). IR specrum of 6 indicates the absence of signal due to cyano group. 1H-NMR spectrum of 6 exhibits two signlets at δ = 8.9, 10.4 ppm for OH and NH in addition to aromatic protons. Thus, the N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)2-thioxothi azol-3(2H)-yl)-2-(4-oxo-4,5-dihydrothiazol-2-yl) acetamide structure 6 was established as reaction product (cf. Scheme 2).

Scheme 1. Formation of 2-thioxothiazoles 5.

Scheme 2. Formation of 2-(4-oxo-4,5-dihydrothiazol-2-yl)acetamide 6.

Condensation of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) with aromatic aldehydes in ethanol and in presence of piperidine as catalyst to afford (E)-3- aryl-2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acrylamides (7a, b).

Refluxing of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxo thiazol-3(2H)-yl)acetamide (5c) with the arylidenemalononitriles 8 in ethanol containing catalytic amount of piperidine resulted in the formation of the 6-amino-4-aryl-1-(4-(1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-oxo-1,2-dihydropyridine-3,5-dica rbonitriles (10a, b) or 2-amino-4-aryl-6-(4-(1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl-2-thioxothiazol-3(2H)-ylamino)-4H-pyran-3,5-dicarbonitriles (11a, b). The pyridine structures 10a, b were suggested as reaction products based on their elemental analysis and spectral data. If the reaction products were 2-amino-4-aryl-6-(4- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol4-yl-2-thioxothiazol-3(2H)-ylamino)-4H-pyran-3,5-dicarbonitriles (11a, b), one would expect 4H-pyran signals at δ = 4.5 - 5.0 ppm. In addition, 6-amino-4-aryl-1-(4-(1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-oxo-1,2-dihydropyridine-3,5-dica rbonitriles(10a, b) were also prepared via reacting (E)-3-aryl-2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acrylamides (7a, b) with malo nonitrile in ethanolic-piperidine. 6-Amino-4-aryl-1-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-oxo- 1,2-dihydropyridine-3,5-dicarbonitriles (10a, b) were proposed to be formed through Michael type addition of the active methylene group in the 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) to the pideficient center in (E)-3-aryl-2-cyano-N-(4-(1,5-dime-thyl-3-oxo- 2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl) acrylamides (7a, b) to give Michael adduct 9 which cyclized and readily eliminate one molecule of hydrogen to yield 6-amino-4-aryl-1-(4-(1,5-dimethyl-3- oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxthiazol- 3(2H)-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (10a, b) (cf. Scheme 3).

The reactivity of 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) towards enaminones were also studied. Thus, 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) was reacted with (E)-3-(dimethylamino)- 1-(furan-2-yl)prop-2-en-1-one (12) in ethanol catalysed by aceticacid to afford N-(4-(1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-6-(furan-2-yl)-2-oxo-2H-pyran-3-carboxamide (15) or 1-(4-(1,5-dihydro-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-yl)-2-thioxothiazol-3-(2H)-6-(furan-2-yl)-2oxo-1,2-dihydr opyridine-3-carbonitrile (16). Structure 15 was preferred over possible 16 by IR specrum which clearly indicates the presence of cyano group. Compound 15 was assumed to be obtained by first addition of the active methylene group in 5c to the activated double bond to give the adduct 13 which readily eliminate dimethylamine to give the intermediate 14. The latter cyclized to 15.

On the other hand, compound 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl) acetamide 5c was reacted with a mixture of reacted with a mixture of malononitrile and elemental sulfur to afford 2,4-diamino-5-cyano-N-(4-(1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -2-thioxothiazol-3-(2H)-yl)thiophene-3-carboxamide (19) Compound 19 is proposed to be formed by adding the active methylene group in malononitrile to the cyano

Scheme 3. Reaction of 2-thioxothiazole 5c with arylidenemalononitriles.

group in 2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)-2-thioxothia zol-3(2H)-yl) acetamide 5c to give the intermediate 17, which reacted with elemental sulfur and then cyclized to yield 19 (cf. Scheme 4).

In recent puplications , it has been reported that [5,10], diazotized aminopyrazoles or arene diazonium salts were used as starting materials for synthesis of pyrazolotriazines [5,10]. In the present work, diazotized 4-(5-amino- 1H-pyrazol-3-yl)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)- one (20) [11,12] coupled with the thiazole 2-cyano-N- (4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) in aqueous ethanolic-sodium acetate to afford 4-amino-7-(1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) -N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl) pyrazolo[5,1-c][1,2,4] triazine-3-carboxamide (22a) and 4-amino-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-7-phenyl pyrazolo [5,1-c][1,2,4] trazine-3-carboxamide (22b). IR spectra of 22a, b showed no signals attributable to cyano group. 4-Amino-7-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-2-thioxothiazol-3(2H)-yl) pyrazolo[5,1-c][1,2,4]triazine-3-carboxam ide (22a) and 4-amino-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)2-thioxo thiazol-3(2H)-yl)-7-phenyl pyrazolo [5,1-c][1,2,4]trazine-3-carboxamide (22b) were suggested to be formed via reacting the diazonium salt 20 with the active methylene group in 2-cyano-N-(4-(1,5-dimethyl-3-oxo- 2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) to give the intermediates 21 which cyclized via addition of highly nucleophilic pyrazole NH to the cyano group to affod 4-Amino-7-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-2-thioxothiazol-3(2H)-yl)pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide (22a) and 4-amino-N-(4-(1,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)2-thioxothiazol-3(2H)-yl)-7-phenyl pyrazolo [5,1-c][1,2, 4]trazine-3-carboxamide (22b) respectively. Coupling of

Scheme 4. Formation of 2-oxo-3H-pyran 15 and 2,4-diaminothiophne 19.

Scheme 5. Formation of pyrazolotriazines 22a, b; arylhydrazones 24 and 25.

2-cyano-N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)acetamide (5c) with aryl diazonium salts 23 yield 2-(arylhydrazono)- N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-(4-oxo-4,5-dihydrothiazol-2-yl)acetamides (24a-c).

2-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-yl)-2-thioxothiazol-3(2H)-ylamino)-2-oxo-Np-tolylacetohydrazonoyl cyanide (24a) reacted with mercaptoaceticacid to give N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2-(4-oxo-4,5-dih ydrothiazol-2-yl)-2-(2-p-tolylhydrazono) acetamide (25). The same product was prepared from reaction of N-(4-(1,5-dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)-2-thioxothiazol-3(2H)-yl)-2(4-oxo-4,5-dihydrothiazol-2-yl)acetamide (6) with p-tolyldiazonium chloride (cf. Scheme 5).


  1. W. S. H. Hamama, M. A. Ismail, S. Shaaban and H. H. Zoorob, “Prgress in the Chemistry of 4-Thiazolidinones,” Journal of Heterocyclic Chemistry, Vol. 45, No. 4, 2008, pp. 930-956. doi:10.1002/jhet.5570450401
  2. M. R. Mahmoud, H. M. F. Madkour, E. A. El-Bordanyand and E. A. Soliman, “Synthesis and Reactions of (Z)-2-Imino-5-(3,4,5-trimethoxy benzylidene)thiazolidin- 4(H)one,” European Journal of Chemistry, Vol. 2, No. 4, 2011, pp. 475-479. doi:10.5155/eurjchem.2.4.475-479.193
  3. K. A. M. El-Bayouki, W. M. Basyouni, Y. A. Mohamed, M. M. Aly and S. Y. Abbas, “Novel Synthesis of 4(3H)- Quinazolinones Containing Biologically Active Thiazole, Pyridinones and Chromene of Expected Antitumor and Antifungal Activities,” European Journal of Chemistry, Vol. 2, No. 4, 2011, pp. 455-462. doi:10.5155/eurjchem.2.4.455-462.171
  4. F. M. A. El-Taweel, Elagamey, A. A. El-Kenawy and M. A. Waly, “Novel Synthesis of Thiazole, Pyridine, Thiophene and Thieno[2,3-b]pyridine Derivatives,” Phosphorus, Sulfur and Silicon, Vol. 176, No. 1, 2001, pp. 215- 225. doi:10.1080/10426500108055120
  5. S. Bondock, R. Rabie, H. A. Etman and A. A. Fadda, “Synthesis and Antimicrobial Activity of Some New Heterocycles Incorporating Antipyrine Moiety,” European Journal of Medicinal Chemistry, Vol. 43, No. 10, 2008, pp. 2122-2129. doi:10.1016/j.ejmech.2007.12.009
  6. M. Jain, R. Sakhuja, P. Khanna, S. Bhagatand and S. C. A. Jain, “Facile Synthesis of Novel Unsymmetrical Bis-spiro [indole-pyrazolinyl-thiazolidine]-2,4-diones,” Arkivoc, Vol. 15, 2008, pp. 54-64.
  7. H. M. Al-Matar, K. D. Khalil, M. F. Al-Kanderi and M. H. Elnagdi, “Studies on 3-Oxoalkanenitriles: Novel Rearrangement Reactions Observed in Studies of the Chemistry of 3-Heteroaryl-3-oxoalkanenitriles as Novel Routes to 2-Dialkylaminopyridines,” Molecules, Vol. 17, No. 1, 2012, pp. 897-909. doi:10.3390/molecules17010897
  8. A. M. Asiri and S. Khan, “Synthesis and Anti-Bacterial Activities of Some Novel Schiff Bases Derived from Aminophenazone,” Molecules, Vol. 15, No. 10, 2010, pp. 6850- 6858. doi:10.3390/molecules15106850
  9. A. A. H. Abdel-Rahman, A. H. A. Ahmed and M. M. M. Ramiz, “Synthesis and Anti-HBV Activity of 4-Aminoantipyrine Derivatives,” Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010, pp. 72-78. doi:10.1007/s10593-010-0472-7
  10. M. A. Gouda, “Utility of 3-Amino-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine in Heterocyclic Synthesis,” Journal of Heterocyclic Chemistry, Vol. 48, No. 1, 2011, pp. 1-10. doi:10.1002/jhet.481
  11. F. M. A. El-Taweel, “Heterocyclic Amidines: Synthesis of New Azaindene Derivatives,” Alexanderia Journal of Pharmaceutical Science, Vol. 12, No. 1, 1998, pp. 11-15.
  12. T. M. A. Elmaati and F. M. A. El-Taweel, “Routes to Pyrazolo[3,4-e][1,4]thiazepine, Pyrazolo[1,5-a]pyrimidine and Pyrazole Derivatives,” Journal of the Chinese Chemical Society, Vol. 50, No. 3, 2003, pp. 413-418.


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