HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 4, 2016, pp. 649-663
Received, 18th November, 2015, Accepted, 22nd February, 2016, Published online, 26th February, 2016.
DOI: 10.3987/COM-15-13370

■ Synthesis of Some Novel Thiadiazoles and Thiazoles Linked to Pyrazole Ring

Magda A. Abdallah, Sobhi M. Gomha,* Mohamad R. Abdelaziz, and Nany S. Eldin Serag

Department of Organic Chemistry, Cairo University, Giza-Haram 12613, Egypt

Abstract

The novel compound namely ethyl 3-(1-(2-(2-cyanoacetyl)- hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate 3 was used as key intermediate for synthesizing the thioanilide derivative 4 and the arylidene derivatives 6. The reaction of 4 with a number of haloketones and haloesters furnished the respective thiazole derivatives 8, 10 and 11a,b. Moreover, the reaction of 4 with N-aryl-2-oxopropane hydrazonoyl chloride 13 and ethyl (N-arylhydrazono)chloroacetate 17 in absolute ethanol in the presence of triethylamine at reflux afforded a new series of thiadiazoles 15 and 19, respectively. The mechanisms that account for formation of products 15 and 19 were discussed. Also, the structures of all the newly synthesized products were confirmed based on elemental analysis, spectral data and by alternative methods.

1,3,4-Thiadiazole derivatives have attracted considerable interest owing to their wide spectra of biological activities such as antibacterial, antifungal, antihepatitis B viral, antileishmanial, anti-inflammatory, analgesic, CNS depressant, anticancer, antioxidant, antidiabetic, molluscicidal, antihypertensive, diuretic, analgesic, antitubercular, and anticonvulsant activities.1–11 In addition, many pyrazole derivatives have attracted considerable attention in the recent years due to their diverse biological activities.12–20
In continuation to our interest in the chemical and pharmacological properties of pyrazole and thiadiazole derivatives, we report herein a facile synthetic strategy for preparation of some new 1,3,4-thiadiazole and thiazole derivatives linked to pyrazole moiety. The biological activities of the synthesized products will be reported in extended work.
The required starting compound 3 was prepared by reaction of ethyl 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate 1 with cyanoacetic acid hydrazide 2 in EtOH containing drops of concentrated HCl under reflux for 6 h (Scheme 1). The structural assignment of the compound 3 was based on both elemental analysis and spectral data (IR, 1H NMR, Mass). For example, the IR spectrum of compound 3 revealed four characteristic absorption bands at ʋ 1692, 1729, 3263 and 2228 cm-1 assignable to the ester, amide carbonyl groups, -NH and nitrile groups. The 1H NMR spectrum of 3 exhibited two singlet signals at δ 2.94, 11.19 ppm assigned for the –CH2- and the -NH protons, in addition to the expected signals assigned for the aromatic and ester protons. The mass spectrum of 3 showed a molecular ion peak at its expected value.
Compound 3 was then used as precursor for synthesis of the thioanilide derivative 4. Thus, reaction of compound 3 with phenyl isothiocyanate in dimethylformamide in the presence of potassium hydroxide followed by acidification of the produced potassium salt with hydrochloric acid afforded product 4 (Scheme 1). The structure of product 4 was established via microanalysis and spectral data (IR, 1H NMR, Mass). For example, the IR spectrum of thioanilide 4 revealed two absorption bands at ʋ 1721, 1693cm-1 for the two carbonyl groups, in addition to the presence of three absorption bands at ʋ 3431, 3185 and 2219 cm-1 assigned for the two NH and nitrile groups. Moreover, the 1H NMR spectrum of product 4 revealed the absence of signal at δ 2.94 ppm for the CH2 group and instead appeared two singlet signals for the protons of NH and the –SH groups, in addition to the expected signals attributed to the protons of methyl, amide NH, ester and aryl groups (see experimental section).

The mass spectrum of product 4 exhibited a molecular ion peak at m/z = 550 which is consistent with the assigned structure.
In addition to the utility of compound 3 in preparation of the thioanilide 4, we also used it in synthesis of some novel arylidene derivatives. Thus, reaction of compound 3 with a number of benzaldehyde derivatives 5a-g in EtOH in the presence of piperidine under reflux for 6 h (monitored by TLC) furnished the respective arylidene derivative 6 (Scheme 1). The structure of products 6a-g was established via elemental analysis and spectral (IR, 1H NMR, Mass) data. For example, the IR spectra of products 6 revealed in each case the characteristic absorption bands as in compound 3, except ʋ value of the nitrile group decreases as it is conjugated with the arylmethylene double bond (ArCH=). Also, the 1H NMR spectra showed the absence of the singlet signal of the protons of CH2 group, and instead revealed the characteristic signal assigned for the olefinic proton (ArCH= ) near δ 8.3 ppm, in addition to the other expected signals for the aromatic, NH, Me and EtOCO- protons.

The utility of thioanilide compound 4 as building block for constructing thiazole ring was explored via its reaction with active haloketones and haloesters. Thus, reaction of compound 4 with chloroacetone (7), ethyl chloroacetate (9), 3-chloro-2,4-pentanedione (11a), ethyl 2-chloro-3-oxobutanoate (11b) under reflux in ethanol in the presence of triethylamine led to formation of the corresponding thiazole derivatives 8, 10 and 12a,b, respectively (Scheme 2 ).
The structure assigned for the products 8, 10 and 12a,b was confirmed by elemental and spectral data (see experimental). It was suggested that the above reactions start with S-alkylation followed by in situ intramolecular cyclization of the intermediate by elimination of either ethanol molecule or water to give the final thiazole derivatives 8, 10 and 12a,b.21, 22
The thioanilide derivative 4 was then used as key intermediate for synthesis of some novel thiadiazole derivatives via its reaction with hydrazonoyl halides 13a-e. Thus, reaction of thioanilide derivative 4 with N'-aryl-2-oxo-propanehydrazonoyl chlorides 13a-e in EtOH in the presence of triethylamine under reflux afforded in each case one isolable product (TLC analysis) which was identified to be 15 and not the other possible structure 16 (Scheme 3). The structure assigned for the products 15 was elucidated on the basis of microanalyses and spectral (IR, 1H NMR, Mass) data. For example, the IR spectra of products 15 revealed in each case three characteristic absorption bands at ʋ 1720, 1690 and 1652 cm-1 due to the three carbonyl groups, in addition to the presence of two absorption bands at ʋ 3423 and 2219 cm-1 attributed to the amide-NH and the nitrile groups. Moreover, the 1H NMR spectra of products 15, exhibited in each case the disappearance of the signals due to the protons of the -NH and –SH groups and instead displayed a signal at δ 2.72 ppm due to the acetyl group of the thiadiazole moiety. The mass spectra of products 15 showed in each case a molecular ion peak at the correct molecular weight. To account for formation of products 15 it was suggested that reaction of 4 with the nitrilimine, formed in situ by treatment of 13 with triethylamine, results in formation of the non-isolable intermediate 14 via 1,3-nucleophilic addition, which underwent cyclization by elimination of aniline molecule to give the thiadiazole derivative 15 (Scheme 3 ).
To provide further evidence that reaction of thioanilide 4 with hydrazonoyl chlorides 13 gave products 15 and not 16, we synthesized the latter by an equivocal method as outlined in Scheme 3. Thus, treatment of the thiazole derivative 8 with benzenediazonium chloride in ethanol in the presence of basic catalyst (NaOAc) at low temperature (0-5 oC) afforded the coupling product 16a.23 Which is completely different from 15a (mp, mixed mp., IR). The structure of product 16a was confirmed by both elemental and spectral data (IR, 1H NMR, Mass) (see experimental section).
Also, reaction of thioanilide derivative 4 with another type of hydrazonoyl chloride, namely ethyl 2-chloro-2-(2-arylhydrazono)ethanoate 17a-f in refluxing ethanol in the presence of triethylamine, afforded in each case a single isolable product. There are two expected cyclization routes leading to either the 1,3,4-thiadiazole structure 19 or 1,3-thiazolone structure 20 can be suggested for the reaction product via loss of either aniline or EtOH molecule from the intermediate 18, respectively, as outlined in Scheme 4.

However in all cases, the reaction proceeded via loss of aniline similar to the mechanism depicted in Scheme 3, and the reaction product was proved, in each case, to be 1,3,4-thiadiazole 19, based on elemental analysis and spectral data (IR, MS, 1H NMR and 13C NMR) which are in support with structure 19 rather than 20. For example, the IR spectra of products 19a-f revealed in each case three characteristic absorption bands near ʋ 1724, 1712 and 1654 cm-1 due to the carbonyl group of the two ester and the amide groups, in addition to the presence of two absorption bands at ʋ 3427 and 2223 cm-1 attributed to the amide-NH and the nitrile groups. The 1H NMR spectra of product 19, exhibited in each case the disappearance of the signal due to the protons of PhNH- and thiol groups and instead displayed the signals characteristic for the ester group (EtOCO) of the thiadiazole moiety.
Further evidence for the formation of products 19 from the reaction of thioanilide 4 with hydrazonoyl chlorides 17 was achieved by synthesizing the other possible products 20 by an equivocal procedure. Thus, reaction of the thiazolone derivative 10 with benzenediazonium chloride in ethanol in the presence of sodium acetate as basic catalyst at low temperature (0-5 oC) afforded product 20a24 (Scheme 4). The structure of product 20a was established on the basis of elemental analysis and spectral data (IR, 1H NMR, Mass) (see Experimental section).

The stereochemistry of Me-C=N-NH in all the synthesized compounds is anti-form according to our previous work based on NOE difference experiments and the minimum energy conformations MM2 force field calculations.25 The stereochemistry of the second double bond in compounds 4, 6a-g, 8, 10, 12a,b, 15a-e,16,19a-f and 20 is E-form to decrease steric hindrance. The stereochemistry of the hydrazo-double bond in compound 20 is E-form due to the stability caused with formation of hydrogen bond with carbonyl group of the thiazolone moiety.
In this study, novel thioanilide derivative was synthesized and used as a key intermediate for the synthesis of a new series of thiadiazoles via its reaction with N-aryl-2-oxopropane hydrazonoyl chloride and ethyl (N-arylhydrazono) chloroacetate. The mechanisms that account for formation of products were discussed. Also, the structures of all the newly synthesized products were confirmed based on elemental analysis, spectral data and by alternative methods.

EXPERIMENTAL
Melting points were measured on an Electrothermal IA 9000 series digital melting point apparatus. IR spectra were recorded in potassium bromide discs on PyeUnicam SP 3300 and Shimadzu FTIR 8101 PC infrared spectrophotometers. NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer operating at 300 MHz (1H NMR) and run in deuterated dimethyl sulfoxide (DMSO-d6). Chemical shifts were related to that of the solvent. 13C NMR was recorded on a BRUKER spectrometer at 75 MHz. Mass spectra was recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Elemental analyses were measured by using a German made Elementarvario LIII CHNS analyzer. Hydrazonoyl halides 13 and 1726-30 were prepared as reported in the respective literature.

Synthesis of (E)-ethyl 3-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (3). To a solution of 2-cyanoacetohydrazide 2 (1.0 g, 10 mmol) and ethyl 3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate (1) (3.34 g, 10 mmol) in absolute EtOH (30 mL) three drops of conc. HCl were added and the reaction mixture was refluxed for 6 h. then left to cool. The solid product formed was collected by filtration, dried and recrystallized from EtOH to give 3. Yield 83%; yellow microcrystals; mp 188-190 °C; IR (KBr): v 1692, 1729 (2C=O), 2228 (CN), 3263 (NH) cm-1; 1H NMR (DMSO-d6): δ 1.16 (t, J = 7.2 Hz, 3H, CH3), 1.90 (s, 3H, CH3), 2.94 (s, 2H, CH2), 4.22 (q, J = 7.2 Hz, 2H, CH2), 7.29-7.37 (m, 10H, ArH), 11.19 (s, 1H, D2O exchangeable, NH); MS m/z (%): 415 (M+, 42), 361 (73), 214 (100), 116 (58), 59 (74). Anal. Calcd for C23H21N5O3 (415.44): C, 66.49; H, 5.09; N, 16.86. Found C, 66.30; H, 5.02; N, 16.74%.
Synthesis of ethyl 3-((E)-1-(2-((E)-2-cyano-3-(phenylamino)-3-thioxopropanoyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (4). To an ice-cold suspension of finely powdered potassium hydroxide (1.1 g, 0.02 mol) in dry DMF (5 mL), ethyl 3-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (3) (4.15 g, 0.01 mol) and then the phenyl isothiocyanate (1.35, 0.01 mol) were added in portions with stirring. After complete addition, stirring was continued at room temperature for an over-night. The reaction mixture was then poured into ice/cold H2O and acidified with concentrted HCl. The obtained precipitate was filtered, washed with H2O, dried, and crystallized from EtOH to give the product 4 in 80% yield as yellow solid, mp 185-187 oC; IR(KBr) (cm-1) 3431, 3185 (2NH), 2219 (CN), 1721, 1693 (2CO); 1H NMR (DMSO-d6): δ 1.19 (t, J = 7.2 Hz, 3H, CH3), 1.91 (s, 3H, CH3), 4.25 (q, J = 7.2 Hz, 2H, CH2), 7.16-7.88 (m, 15H, ArH ), 10.57, 11.19 (2s, 2H, D2O exchangeable, 2NH), 13.52 (s, 1H , SH); MS m/z (%): 550 (M+, 100), 397 (64), 285 (39), 165 (42), 77 (90), 59 (81). Anal. Calcd. for C30H26N6O3S (550.63): C, 65.44; H, 4.76; N, 15.26; Found. C, 65.27; H, 4.59; N, 15.08%.
Reaction of 3 with aromatic aldehydes 5a-g:
General procedure: A mixture of 3 (0.415 g, 1 mmol), and the appropriate aromatic benzaldehyde derivative 5 (1 mmol) in 20 mL absolute EtOH in the presence of and 0.5 mL piperidine, was refluxed for 4-6 h (monitored by TLC). The reaction mixture was left to cool and the formed solid was filtered off, washed with water, dried and recrystallized from DMF to give 6a-g.
Ehyl 3-((E)-1-(2-((Z)-2-cyano-3-phenylacryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6a). Yield 72%; yellow solid; mp 213-215 oC; IR(KBr) (cm-1) 3412, 3182 (2NH), 2218 (CN), 1725, 1673 (2CO); 1H NMR (DMSO-d6): δ 1.17 (t, J = 7.2 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2), 6.98-7.68 (m, 15H, ArH ), 8.66 (s, 1H, CH=), 11.26 (s, 1H, D2O exchangeable, NH); MS m/z (%): 503 (M+, 63), 416 (37), 284 (100), 192 (60), 77 (74). Anal. Calcd for C30H25N5O3 (503.55): C, 71.56; H, 5.00; N, 13.91. Found C, 71.42; H, 4.87; N, 13.79%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(p-tolyl)acryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6b). Yield 77%; yellow solid; mp 181-183 oC; IR(KBr) (cm-1) 3412, 3182 (2NH), 2218 (CN), 1725, 1673 (2CO); 1H NMR (DMSO-d6): δ 1.07 (t, J = 7.2 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 2.25 (s, 3H, CH3), 4.20 (q, J = 7.2 Hz, 2H, CH2), 7.06-7.82 (m, 14H, ArH ), 8.64 (s, 1H, CH=), 11.15 (s, 1H, D2O exchangeable, NH); MS m/z (%): 517 (M+, 61), 442 (47), 318 (100), 230 (63), 63 (79). Anal. Calcd for C31H27N5O3 (517.58): C, 71.94; H, 5.26; N, 13.53. Found C, 71.86; H, 5.17; N, 13.38%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(4-methoxyphenyl)acryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6c). Yield 77%; yellow solid; mp 230-232 oC; IR(KBr) (cm-1) 3424, 3174 (2NH), 2219 (CN), 1718, 1670 (2CO); 1H NMR (DMSO-d6): δ 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 4.17 (q, J = 7.2 Hz, 2H, CH2), 6.96-7.95 (m, 14H, ArH ), 8.58 (s, 1H, CH=), 11.25 (s, 1H, D2O exchangeable, NH); MS m/z (%): 533 (M+, 73), 421 (50), 318 (100), 258 (82), 77 (95). Anal. Calcd for C31H27N5O4 (533.58): C, 69.78; H, 5.10; N, 13.13. Found C, 69.66; H, 5.04; N, 13.02%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(2-methoxyphenyl)acryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6d). Yield 68%; yellow solid; mp 186-188 oC; IR(KBr) (cm-1) 3408, 3193 (2NH), 2218 (CN), 1720, 1674 (2CO); 1H NMR (DMSO-d6): δ 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.21 (q, J = 7.2 Hz, 2H, CH2), 7.17-7.38 (m, 14H, ArH ), 8.64 (s, 1H, CH=), 11.15 (s, 1H, D2O exchangeable, NH); MS m/z (%): 533 (M+, 73), 421 (50), 318 (100), 258 (82), 77 (95). MS m/z (%): 533 (M+, 47), 318 (83), 237 (72), 193 (37), 127 (60), 59 (100). Anal. Calcd for C31H27N5O4 (533.58): C, 69.78; H, 5.10; N, 13.13. Found C, 69.64; H, 5.02; N, 13.10%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(4-chlorophenyl)-2-cyanoacryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6e). Yield 79%; yellow solid; mp 250-252 oC; IR(KBr) (cm-1) 3422, 3190 (2NH), 2221 (CN), 1723, 1682 (2CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.91 (s, 3H, CH3), 4.24 (q, J = 7.2 Hz, 2H, CH2), 7.31-7.58 (m, 14H, ArH ), 8.65 (s, 1H, CH=), 11.19 (s, 1H, D2O exchangeable, NH); MS m/z (%): 539 (M+ + 2, 30), 537 (M+, 100), 340 (42), 251 (38), 153 (72), 95 (69). Anal. Calcd for C30H24ClN5O3 (537.16): C, 66.97; H, 4.50; N, 13.02. Found C, 66.75; H, 4.38; N, 12.91%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(3-nitrophenyl)acryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6f). Yield 71%; yellow solid; mp 203-205 oC; IR(KBr) (cm-1) 3417, 3210 (2NH), 2223 (CN), 1724, 1680 (2CO); 1H NMR (DMSO-d6): δ 1.07 (t, J = 7.2 Hz, 3H, CH3), 1.69 (s, 3H, CH3), 4.24 (q, J = 7.2 Hz, 2H, CH2), 6.85-17-7.95 (m, 14H, ArH ), 8.69 (s, 1H, CH=), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 548 (M+, 57), 412 (72), 318 (100), 250 (49), 77 (86). Anal. Calcd for C30H24N6O5 (548.55): C, 65.69; H, 4.41; N, 15.32. Found C, 65.49; H, 4.35; N, 15.18%.
Ethyl 3-((E)-1-(2-((Z)-2-cyano-3-(2,4-dichlorophenyl)acryloyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (6g). Yield 77%; yellow solid; mp 240-242 oC; IR(KBr) (cm-1) 3420, 3216 (2NH), 2226 (CN), 1721, 1682 (2CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.65 (s, 3H, CH3), 4.20 (q, J = 7.2 Hz, 2H, CH2), 7.33-7.86 (m, 13H, ArH ), 8.64 (s, 1H, CH=), 11.19 (s, 1H, D2O exchangeable, NH); MS m/z (%): 571 (M+, 100), 418 (59), 318 (88), 235 (73), 125 (42), 77 (82). Anal. Calcd for C30H23Cl2N5O3 (571.12): C, 62.94; H, 4.05; N, 12.23. Found C, 62.75; H, 3.83; N, 12.11%.
Reaction of thioanilide derivatives 4 with active α-haloketones and α-haloesters
General procedure: To a mixture of thioanilide 4 (0.55 g, 1 mmol) and the appropriate chloroacetone (7), ethyl chloroacetate (9), 3-chloropentane-2,4-dione (11a), and ethyl 2-chloro-3-oxobutanoate (11b) (1 mmol) in EtOH (20 mL), was added triethylamine (0.5 mL) at room temperature. The reaction mixture was heated under reflux until all the starting material was consumed (2–6 h, monitored by TLC). The solid that formed, after cooling, was filtered and recrystallized from DMF to give the corresponding thiazole derivatives 8, 10 and 12a,b, respectively.
Ethyl 3-((E)-1-(2-((E)-2-cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)acetyl)hydrazono)-ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (8). Yield 75%; yellow solid; mp 213-315 oC; IR(KBr) (cm-1) 3429 (NH), 2220 (CN), 1720, 1671 (2CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.10 (s, 3H, CH3), 4.23 (q, J = 7.2 Hz, 2H, CH2), 6.42 (s, 1H, thiazole-H5), 7.14-7.73 (m, 15H, ArH ), 11.14 (s, 1H, D2O exchangeable, NH); MS m/z (%): 588 (M+, 64), 406 (70), 348 (64), 218 (39), 77 (100), 59 (83). Anal. Calcd for C33H28N6O3S (588.68): C, 67.33; H, 4.79; N, 14.28; Found C, 67.23; H, 4.71; N, 14.14%.
Ethyl 3-((E)-1-(2-((E)-2-cyano-2-(4-oxo-3-phenylthiazolidin-2-ylidene)acetyl)hydrazono)ethyl)-1,5-diphenyl -1H-pyrazole-4-carboxylate (10). Yield 74%; yellow solid; mp 242-244 oC; IR(KBr) (cm-1) 3428 (NH), 2220 (CN), 1728, 1671, 1658 (3CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.83 (s, 3H, CH3), 4.11 (s, 2H, CH2), 4.24 (q, J = 7.2 Hz, 2H, CH2), 7.14-7.73 (m, 15H, ArH ), 11.05 (s, 1H, D2O exchangeable, NH); 13C NMR (DMSO-d6): δ 13.4, 15.3 (CH3), 31.5, 62.3 (CH2), 82.4, 116.7, 118.3, 120.2, 124.3, 126.2, 127.3, 127.8, 128.0, 128.4, 129.3, 130.1, 135.6, 138.3, 140.8, 143.8, 145.4, 148.1, 157.2, 160.5, 162.5, 164.9, 171.0; MS m/z (%): 590 (M+, 100), 426 (64), 356 (39), 212 (53), 51 (72). Anal. Calcd for C32H26N6O4S (590.65): C, 65.07; H, 4.44; N, 14.23; Found C, 65.02; H, 4.35; N, 14.18%.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-4-methyl-3-phenylthiazol-2(3H)-ylidene)-2-cyanoacetyl)-hydrazono)-ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (12a). Yield 69%; yellow solid; mp 182-184 oC; IR(KBr) (cm-1) 3423 (NH), 2221 (CN), 1723, 1697, 1649 (3CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.42 (s, 3H, CH3), 4.23 (q, J = 7.2 Hz, 2H, CH2), 7.11-7.79 (m, 15H, ArH ), 11.07 (s, 1H, D2O exchangeable, NH); MS m/z (%): 630 (M+), 468 (38), 357 (96), 319 (100), 77 (86), 51 (72). Anal. Calcd for C35H30N6O4S (630.72): C, 66.65; H, 4.79; N, 13.32; Found C, 66.47; H, 4.66; N, 13.25%.
(E)-Ethyl 2-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-methyl-3-phenyl-2,3-dihydrothiazole-5-carboxylate (12b). Yield 73%; yellow solid; mp 320-322 oC; IR(KBr) (cm-1) 3426, 3170 (2NH), 2221 (CN), 1720, 1677, 1651 (3CO); 1H NMR (DMSO-d6): δ 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.20 (s, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2), 7.04-7.89 (m, 20H, ArH ), 11.16, 11.47 (2s, 2H, D2O exchangeable, 2NH); MS m/z (%): 707 (M+, 52), 670 (70), 576 (66), 369 (38), 77 (45), 64 (100). Anal. Calcd for C40H33N7O4S (707.23): C, 67.88; H, 4.70; N, 13.85; Found C, 67.69; H, 4.63; N, 13.76%.
Reaction of the thioanilide derivative 4 with hydrazonoyl chlorides 13a-e and 17a-f
General procedure: To a solution of the thioanilide derivative 4 (0.550 g, 1 mmol) in absolute EtOH (20 mL), the appropriate hydrazonoyl chlorides 13a-e or 17-f (1 mmol) was added, in the presence of triethylamine (0.3 mL). The reaction mixture were refluxed for 4 h (monitored by TLC), allowed to cool and the solid formed was filtered off, washed with ethanol, dried and recrystallized from EtOH to give the corresponding thiadiazole derivatives 15a–e and 19a-f, respectively.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoacetyl)-hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15a). Yield 70%; brown solid; mp 210-212 oC; IR(KBr) (cm-1) 3423 (NH), 2219 (CN), 1720, 1690, 1652 (3CO); 1H NMR (DMSO-d6): δ 1.19 (t, J = 7.2 Hz, 3H, CH3), 1.86 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.27 (q, J = 7.2 Hz, 2H, CH2), 7.02-7.95 (m, 15H, ArH ), 11.14 (s, 1H, D2O exchangeable, NH); 13C NMR (DMSO-d6): δ 13.2, 14.9, 23.2 (CH3), 61.8 (CH2), 92.4, 116.1, 119.1, 120.4, 121.5, 125.7, 125.9, 127.3, 128.1, 129.2, 129.7, 131.3, 131.9, 133.6, 137.5, 140.2, 143.6, 147.4, 155.2, 167.3, 169.8, 193.6; MS m/z (%): 617 (M+, 9), 571 (13), 482 (12), 295 (30), 118 (28), 80 (100), 64 (55). Anal. Calcd for C33H27N7O4S (617.68): C, 64.17; H, 4.41; N, 15.87. Found C, 64.13; H, 4.28; N, 15.81%.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-3-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoacetyl)-hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15b). Yield 73%; brown solid; mp 193-195 oC; IR(KBr) (cm-1) 3414 (NH), 2219 (CN), 1723, 1688, 1656 (3CO); 1H NMR (DMSO-d6): δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 2.27 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.27 (q, J = 7.2 Hz, 2H, CH2), 6.96-7.45 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 631 (M+, 24), 590 (32), 489 (28), 318 (61), 135 (100), 86 (87), 64 (88). Anal. Calcd for C34H29N7O4S (631.70): C, 64.64; H, 4.63; N, 15.52. Found C, 64.48; H, 4.90; N, 15.40%.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-3-(4-chlorophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoacetyl)- hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15c). Yield 73%; brown solid; mp 220-222 oC; IR(KBr) (cm-1) 3421 (NH), 2219 (CN), 1726, 1680, 1656 (3CO); 1H NMR (DMSO-d6): δ 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2), 7.11-7.55 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 653 (M++2, 15), 651 (M+, 39), 572 (33), 495 (38), 369 (25), 77 (41), 64 (100). Anal. Calcd for C33H26ClN7O4S (651.15): C, 60.78; H, 4.02; N, 15.04. Found C, 60.57; H, 3.82; N, 15.01%.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-3-(4-bromophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoacetyl)- hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15d). Yield 74%; brown solid; mp 206-208 oC; IR(KBr) (cm-1) 3380 (NH), 2220 (CN), 1724, 1667, 1651 (3CO); 1H NMR (DMSO-d6): δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 2.71 (s, 3H, CH3), 4.20 (q, J = 7.2 Hz, 2H, CH2), 6.99-7.45 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 697 (M++2, 19), 695 (M+, 21), 572 (63), 458 (65), 160 (73), 80 (24), 64 (100). Anal. Calcd for C33H26BrN7O4S (695.10): C, 56.90; H, 3.76; N, 14.08. Found C, 56.75; H, 3.59; N, 14.02%.
Ethyl 3-((E)-1-(2-((E)-2-(5-acetyl-3-(4-nitrophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-2-cyanoacetyl)-hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (15e). Yield 70%; brown solid; mp 237-239 oC; IR(KBr) (cm-1) 3426 (NH), 2223 (CN), 1724, 1660, 1656 (3CO); 1H NMR (DMSO-d6): δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.23 (q, J = 7.2 Hz, 2H, CH2), 7.10-7.69 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 662 (M+, 17), 369 (75), 318 (47), 158 (68), 64 (100). Anal. Calcd for C33H26N8O6S (662.67): C, 59.81; H, 3.95; N, 16.91. Found C, 59.73; H, 3.91; N, 16.78%.
(E)-Ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-phenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19a). Yield 70%; brown solid; mp 232-234 oC; IR(KBr) (cm-1) 3427 (NH), 2223 (CN), 1724, 1712, 1654 (3CO); 1H NMR (DMSO-d6): δ 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.32 (t, J = 7.4 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2), 4.36 (q, J = 7.4 Hz, 2H, CH2), 6.96-7.88 (m, 15H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); 13C NMR (DMSO-d6): δ 12.2, 13.5, 14.9 (CH3), 61.8, 62.1 (CH2), 91.3, 114.9, 119.3, 120.2, 121.7, 123.1, 123.7, 125.6, 127.5, 128.6, 129.2, 130.4, 131.4, 132.6, 138.3, 140.6, 142.1, 147.9, 151.4, 165.2, 168.5, 172.3; MS m/z (%): 647 (M+, 20), 573 (32), 119 (20), 91 (29), 64 (100). Anal. Calcd for C34H29N7O5S (647.70): C, 63.05; H, 4.51; N, 15.14. Found C, 63.01; H, 4.38; N, 15.05%.
(E)-Ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-(p-tolyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19b). Yield 74%; brown solid; mp 312-314 oC; IR(KBr) (cm-1) 3421 (NH), 2223 (CN), 1729, 1715, 1652 (3CO); 1H NMR (DMSO-d6): δ 1.05 (t, J = 7.2 Hz, 3H, CH3), 1.31 (t, J = 7.4 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.20 (q, J = 7.2 Hz, 2H, CH2), 4.37 (q, J = 7.4 Hz, 2H, CH2), 7.30-7.44 (m, 14H, ArH ), 11.15 (s, 1H, D2O exchangeable, NH); MS m/z (%): 661 (M+, 16), 555 (24), 476 (32), 135 (14), 80 (65), 64 (100). Anal. Calcd for C35H31N7O5S (661.73): C, 63.53; H, 4.72; N, 14.82. Found C, 63.44; H, 4.59; N, 14.75%.
(E)-Ethyl 4-(4-chlorophenyl)-5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)-ethylidene)hydrazinyl)-2-oxoethylidene)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19c). Yield 77%; brown solid; mp 220-222 oC; IR(KBr) (cm-1) 3427 (NH), 2223 (CN), 1723, 1710, 1652 (3CO); 1H NMR (DMSO-d6): δ 1.05 (t, J = 7.2 Hz, 3H, CH3), 1.21 (t, J = 7.4 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2), 4.36 (q, J = 7.4 Hz, 2H, CH2), 6.99-7.73 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 683 (M++2, 12), 681 (M+, 30), 572 (48), 473 (52), 369 (44), 125 (55), 77 (72), 64 (100). Anal. Calcd for C34H28ClN7O5S (681.16): C, 59.86; H, 4.14; N, 14.37. Found C, 59.63; H, 4.07; N, 14.24%.
(E)-Ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-(4-methoxyphenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19d). Yield 74%; brown solid; mp 213-215 oC; IR(KBr) (cm-1) 3425 (NH), 2220 (CN), 1722, 1712, 1648 (3CO); 1H NMR (DMSO-d6): δ 1.05 (t, J = 7.2 Hz, 3H, CH3), 1.23 (t, J = 7.4 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.26 (q, J = 7.2 Hz, 2H, CH2), 4.36 (q, J = 7.4 Hz, 2H, CH2), 6.92-7.68 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 677 (M+, 21), 480 (35), 318 (100), 261 (74), 106 (54), 77 (86). Anal. Calcd for C35H31N7O6S (677.73): C, 62.03; H, 4.61; N, 14.47. Found C, 61.91; H, 4.52; N, 14.30%.
(E)-Ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-(4-nitrophenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19e). Yield 77%; brown solid; mp 248-250 oC; IR(KBr) (cm-1) 3429 (NH), 2225 (CN), 1729, 1715, 1648 (3CO); 1H NMR (DMSO-d6): δ 1.08 (t, J = 7.2 Hz, 3H, CH3), 1.23 (t, J = 7.4 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 4.26 (q, J = 7.2 Hz, 2H, CH2), 4.38 (q, J = 7.4 Hz, 2H, CH2), 7.14-7.89 (m, 14H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 692 (M+, 8), 369 (16), 444 (100), 371 (17), 80 (33), 64 (100). Anal. Calcd for C34H28N8O7S (692.18): C, 58.95; H, 4.07; N, 16.18. Found C, 58.86; H, 4.03; N, 16.12%.
(E)-Ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-(2,4-dichlorophenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (19f). Yield 71%; brown solid; mp 260-262 oC; IR(KBr) (cm-1) 3428 (NH), 2220 (CN), 1723, 1710, 1653 (3CO); 1H NMR (DMSO-d6): δ 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.32 (t, J = 7.4 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 4.27 (q, J = 7.2 Hz, 2H, CH2), 4.39 (q, J = 7.4 Hz, 2H, CH2), 6.90-7.43 (m, 13H, ArH ), 11.16 (s, 1H, D2O exchangeable, NH); MS m/z (%): 715 (M+, 41), 658 (45), 484 (43), 369 (30), 80 (29), 64 (100). Anal. Calcd for C34H27Cl2N7O5S (715.12): C, 56.99; H, 3.80; N, 13.68. Found C, 56.76; H, 3.69; N, 13.58%.
Synthesis of compounds 16a and 20a
To a solution of thiazole derivative 8 or thiazolone 10 (1 mmol) in EtOH (20 mL) was added sodium acetate trihydrate (0.138 g, 1 mmol), and the mixture was cooled to 0-5 oC in an ice bath. To the resulting cold solution was added portionwise a cold solution of benzenediazonium chloride [prepared by diazotizing aniline (0.091 mL, 1 mmol) dissolved in hydrochloric acid (6 M, 1 mL) with a solution of sodium nitrite (0.07 g, 1 mmol) in water (2 mL)]. After complete addition of the diazonium salt, the reaction mixture was stirred for a further 30 min in an ice bath. The solid that separated was filtered off, washed with water and finally recrystallized from DMF to give the corresponding products 16a and 20a, respectively.
Ethyl 3-((E)-1-(2-((E)-2-cyano-2-(4-methyl-3-phenyl-5-((E)-phenyldiazenyl)thiazol-2(3H)-ylidene)-acetyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (16a). Yield 67%; yellow solid; mp 284-286 °C; IR(KBr) (cm-1) 3391 (NH), 2218 (CN), 1724, 1655 (2CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.82 (s, 3H, CH3), 2.16 (s, 3H, CH3), 4.27 (q, J = 7.2 Hz, 2H, CH2), 7.10-7.88 (m, 20H, ArH ), 11.15 (s, 1H, D2O exchangeable, NH); MS m/z (%): 692 (M+, 31), 482 (50), 214 (100), 77 (86). Anal. Calcd for C39H32N8O3S (692.23): C, 67.61; H, 4.66; N, 16.17. Found C, 67.53; H, 4.47; N, 16.05%.
Ethyl 3-((E)-1-(2-((E)-2-cyano-2-((E)-4-oxo-3-phenyl-5-(2-phenylhydrazono)thiazolidin-2-ylidene)-acetyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate (20a). Yield 69%; yellow solid; mp 262-264 °C; IR(KBr) (cm-1) 3431, 3233 (2NH), 2221 (CN), 1744, 1668, 1649 (3CO); 1H NMR (DMSO-d6): δ 1.09 (t, J = 7.2 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 4.23 (q, J = 7.2 Hz, 2H, CH2), 7.37-7.82 (m, 20H, ArH ), 10.47, 11.13 (2s, 2H, D2O exchangeable, 2NH); MS m/z (%): 694 (M+, 32), 418 (36), 390 (61), 276 (49), 77 (100), 51 (51). Anal. Calcd for C38H30N8O4S (694.21): C, 65.69; H, 4.35; N, 16.13. Found C, 65.58; H, 4.39; N, 16.04%.

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