HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 8, 2014, pp. 1827-1843
Received, 2nd May, 2014, Accepted, 24th June, 2014, Published online, 3rd July, 2014.
DOI: 10.3987/COM-14-13020

■ Synthesis of Novel Thiazole and 1,3,4-Thiadiazole Derivatives Incorporating Phenylsulfonyl Moiety

Ahmed E. M. Mekky, Ahmed F. Darweesh, Amani A. Salman, and Ahmad M. Farag*

Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

Reaction of 1-(benzothiazol-2-yl)-2-phenylsulfonyl-1-ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)-1-ethanone (2) with phenyl isothiocyanate afforded the corresponding potassium salts 3 and 4, respectively. The potassium salts 3 and 4 were converted into the corresponding (Z)-1-(benzothiazol-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl) propenone (5) and (Z)-1-(1-methylbenzimidazole-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)propenone (6), respectively upon acidification with HCl. The latter products were used as versatile building blocks for novel 1,3,4-thiadiazole derivatives via their reactions with the appropriate hydrazonyl halides. They have been also utilized for the synthesis of thiazole ring systems incorporating phenylsulfonyl moiety.

INTRODUCTION
Benzothiazole and benzimidazole derivatives are recognized as important heterocycles due to their diverse pharmacological properties.1 Their derivatives have attracted continuing interest because of their varied biological activities such as antiviral,2-5 antibacterial,6,7 antifungal,8-11 antitumour,12-15 anticancer,16,17 antitubercular,18,19 antimalarial,20 anticonvulsant,21 antihelminthic agentsin veterinary medicine,22-24 analgesic,25,26 anti-inflammtory,27,28 antidiabetic agents,29 anti-HIV,30,31 anticoagulative agents,32,33 antihypertensive,34,35 antineoplastic,36,37 anxiolytic agents.38,39 Many of their derivatives are now included in many of commercialized drugs.40-42 On the other hand, β-ketosulfone moiety displays a broad range of synthetic potentiality.43,44 In continuation of our research work aiming at the synthesis of a variety of heterocycles for biological screening,45-60 we report here on the utility of (Z)-1-(benzothiazol-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)propenone (5) and (Z)-1-(1-methylbenzimidazole-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)propenone (6) as reactive intermediates, for the synthesis of the 1,3,4-thiadiazole and 1,3-thiazole heterocycles incorporating phenylsulfonyl moiety of potential biological activity.
RESULTS AND DISCUSSION
Treatment of 1-(benzothiazol-2-yl)-2-(phenylsulfonyl)ethanone (1)46 and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (2)46 with phenyl isothiocyanate, in DMF in the presence of potassium hydroxide, at rt afforded the corresponding potassium salts 3 and 4, respectively. Treatment of these intermediate salts with HCl afforded, in each case, a single product (as examined by TLC). The reaction products were identified as (Z)-1-(benzothiazol-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)prop-2-en-1-one (5) and (Z)-1-(1-methylbenzimidazole-2-yl)-3-mercapto-3-(phenylamino)-2-(phenylsulfonyl)prop-2-en-1-one (6), respectively (Scheme 1). The IR spectra of compounds 5 and 6 showed, in each case, a band near 3345 cm-1 due to NH group and strong absorption bands at 1685 and 1680 cm-1 due to carbonyl functions.

Compounds 5 and 6 were assigned the (Z) configuration which is stabilized by hydrogen bonding rather than the (E) configuration which could suffer from steric hindrance. Compounds 5 and 6 react with 2-bromoacetophenone (7a) and 2-bromo-4′-chloroacetophenone (7b), in EtOH under conventional heating and under microwave conditions in the presence of an equivalent amount of triethylamine, to afford the corresponding polysubstituted thiazole derivatives 8a,b and 9a,b, respectively (Scheme 2). The IR spectra of the isolated products 8a and 9a showed strong absorption bands at 1685 and 1678 cm-1, respectively due to carbonyl functions. The 1H NMR spectra of 8a and 9a revealed in each case a characteristic singlet signal near δ 6.65 due to thiazole proton. Their mass spectra showed, in each case, a peak corresponding to the molecular ion (see Experimental Section).
Similarly, compounds 5 and 6 reacted with ethyl chloroacetate to afford, in each case, a single product identified as (Z)-2-(2-(benzothiazol-2-yl)-2-oxo-1-(phenylsulphonyl)ethylidene)-3-phenylthiazolidin-4-one (11) and (Z)-2-(2-(1-methylbenzimiazol-2-yl)-2-oxo-1-(phenylsulphonyl)ethylidene)-3-phenyl-thiazolidin-4-one (12), respectively (Scheme 2). The 1H NMR spectra of isolated products revealed multiplet signals in the range δ 7.21-8.14 and 7.20-7.94, respectively characteristic for aromatic protons. Their IR spectra showed bands at 1695, 1655 cm-1 for compound 11 and at 1678, and 1635 cm-1 for compound 12, due to two carbonyl functions. The mass spectra of the reaction products revealed, in each case, a peak corresponding to the molecular ion.

In a similar manner, compounds 5 and 6 reacted with chloroacetonitrile and with chloroacetone to afford the products identified as (Z)-2-(4-amino-3-phenylthiazol2-(3H)-ylidene-1-(benzothiazol-2-yl)-2-(phenylsulfonyl)ethanone (14), (Z)-2-(4-amino-3-phenylthiazol-2-(3H)-ylidene-1-(1-methylbenzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (15), (Z)-1-(benzothiazol-2-yl)-2-(4-methyl-3-phenylthiazol-2-(3H)- ylidene)-2-phenylsulphonyl)ethanone (17) and (Z)-1-(benzimidazol-2-yl)-2-(4-methyl-3-phenylthiazol-2-(3H)ylidene)-2-(phenylsulphonyl)ethanone (18), respectively (Scheme 2). The IR spectra of the isolated products 14 and 15, revealed, in each case, bands near 3331 and 3325 cm-1 due to NH2 group. The 1H NMR spectrum of compound 17, taken as an example, revealed singlet signals at δ 1.73 and 5.79 due to CH3 and CH-thiazole ring protons, respectively and a multiplet signal in region δ 6.91-8.14 due to aromatic protons.
A plausible mechanism illustrating the formation of compounds 8, 9, 11, 12, 14, 15, 17 and 18 is depicted in Scheme 3.

Treatment of compounds 5 and 6 with 2-oxo-N-arylpropanehydrazonyl chlorides 19a-d, afforded in each case, only one isolable product (as examined by TLC) (Scheme 4). The elemental analyses and spectral data of the reaction products were in complete agreement with the 1,3,4-thiadiazole structures 20a-d and 21a-d. For example, the IR spectra of the isolated products revealed, in each case, the appearance of the carbonyl absorption bands near 1675, 1645 cm-1 for compounds 20a-d and 1665, 1625 cm-1 in case of compounds 21a-d. Their mass spectra revealed, in each case, a peak corresponding to the molecular ion.

When compounds 5 and 6 were treated with N-phenylbenzohydrazonyl chloride (22) they afforded the corresponding (Z)-1-(benzothiazol-2-yl)-2-(3,5-diphenyl-1,3,4-thiadiazole-2-(3H)ylidene)-2-(phenyl-sulfonyl)ethanone (23) and (Z)-2-(3,5-diphenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (24), respectively (Scheme 5).

In a similar manner, compounds 5 and 6 react with the hydrazonyl halides 25a-c, under the same reaction conditions, to afford, in each case, a single product. The isolated products were identified as (Z)-ethyl 4-aryl-5-(2-(benzothiazol-2-yl)-2-oxo-1-((phenylsulfonyl)ethylidene)-4,5-dihyro-1,3,4-thiadiazole-2-carboxylate derivatives 26a-c, and (Z)-ethyl 4-aryl-5-(2-(1-methylbenzimidazol-2-yl)-2-oxo-1-((phenylsulfonyl)ethylidene)-4,5-dihyro-1,3,4-thiadiazole-2-carboxylate derivatives 27a-c, respectively (Scheme 6). The structures of the reaction products were confirmed on the basis of their elemental analyses and spectral data. For example, the IR spectra of the isolated products revealed, in each case, the appearance of two strong carbonyl absorption bands near 1680 and 1654 cm-1. Their mass spectra revealed, in each case, a peak corresponding to the molecular ion (see Experimental Section).
Compounds 5 and 6 reacted also with the hydrazonyl halides 28 and 31 and afforded the corresponding (Z)-1-(benzothiazol-2-yl)-2-(5-benzoyl-3-phenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-2-(phenylsulfonyl)-ethanone (29), (Z)-1-(1-methyl-1H-benzimidazol-2-yl)-2-(5-benzoyl-3-phenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-2-(phenylsulfonyl)ethanone (30), (Z)-5-(2-(benzothiazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethy-lidene)-N-4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (32) and (Z)-5-(2-(1-methyl-1H-benzimidazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-N-4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (33), respectively (Scheme 6). The IR spectra of the isolated products 32 and 33 revealed, in each case, an absorption band near 3395 cm-1 due to NH function. The 1H NMR spectrum of compound 32 showed, in addition to aromatic proton multiplet in the region 6.80-8.15 ppm, a D2O- exchangeable signal at 10.60 ppm due to NH proton

A general reasonable mechanism for the reaction of compounds 5 and 6 with the hydrazonyl halides 19a-d, 22, 25a-c, 28 and 31 leading to the formation of the products 20, 21, 23, 24, 26, 27, 29, 30, 32 and 33 is shown in Scheme 7.

EXPERIMENTAL
Melting points were determined in open glass capillaries with a Gallenkamp apparatus. The IR spectra were recorded using KBr disks on a Pye Unicam SP 3-300 or a Shimadzu FTIR 8101 PC IR spectrophotometer. The NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 and 75 MHz for 1H and 13C NMR spectra, respectively, using CDCl3 and DMSO-d6 as solvents. Chemical shifts were related to that of the solvent. Mass spectra (EI) were obtained at 70 eV with a Shimadzu GCMQP 1000 EX spectrometer. TLC analyses were performed using pre-coated silica gel 60778 plates (Fluka), and the spots were visualized with UV light at 254 nm. Fluka silica gel 60741 (70–230 mesh) was used for flash column chromatography. Microwave experiments were carried out using a CEM Discover LabMate microwave apparatus (300 W with ChemDriver Software).
1-(Benzothiazol-2-yl)-2-(phenylsulfonyl)ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (2) were prepared according to our reported procedure.46

Reaction of 1-(benzothiazol-2-yl)-2-(phenylsulfonyl)ethanone (1) and 1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (2) with phenyl isothiocyanate.
General procedure:
To a stirred solution of KOH (0.56 g, 10 mmol) in DMF (20 mL), the appropriate ketosulfone 1 or 2 (l0 mmol) was added. After stirring for 30 min, phenyl isothiocyanate (1.35 g, 10 mmol) was added to the resulting mixture. Stirring was continued for 6 h, then poured over crushed ice containing HCl. The formed solid product was filtered off, washed with water, dried and finally recrystallized from EtOH/DMF to afford 1-(benzothiazol-2-yl)-3-mercapto-3-phenylamino-3-phenylsulphonylprop-2-en-1-one (5) and 1-(1-methylbenzimidazol-2-yl)-3-mercapto-3-phenylamino-3-phenylsulphonylprop-2-en-1-one (6), respectively.
(Z)-1-(Benzothiazol-2-yl)-3-mercapto-3-phenylamino-3-phenylsulfonylprop-2-en-1-one (5): Yield (60%), mp 113-115 °C; IR (KBr) vmax/cm–1: 3345 (NH), 2580 (SH), 1685 (CO); 1H NMR (DMSO-d6) δ 4.21 (s, 1H, D2O-exchangable, NH), 6.57-8.14 (m, 14H, ArH), 11.3 (s, 1H, D2O-exchangable, SH); MS (m/z, %): 452 (M+, 100%); Anal. Calcd for C22H16N2O3S3 (452.57): C, 58.39; H, 3.56; N, 6.19; S, 21.26%. Found: C, 58.43; H, 3.49; N, 6.12; S, 21.19%.
(Z)-1-(1-Methylbenzimidazol-2-yl)-3-mercapto-3-phenylamino-3-phenylsulphonylprop-2-en-1-one (6): Yield (54%), mp 117-119 °C; IR (KBr) vmax/cm–1: 3346 (NH), 2570 (SH), 1680 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 4.21 (s, 1H, D2O-exchangable, NH), 6.39-7.93 (m, 14H, ArH), 11.3 (s, 1H, D2O-exchangable, SH); MS (m/z, %): 449 (M+, 100%); Anal. Calcd for C23H19N3O3S2 (449.55): C, 61.45; H, 4.26; N, 9.35; S, 14.27%. Found: C, 61.43; H, 4.29; N, 9.31; S, 14.30%.
Reaction of compounds 5 and 6 with α-haloketones 7a,b, ethyl bromoacetate, chloroacetonitrile and chloroacetone.
(A) Thermal method
General procedure:
To a solution of compounds 5 and 6 (1 mmol) and the appropriate α-haloketones 7, ethyl chloroacetate, chloroacetonitrile or chloroacetone (1 mmol), in EtOH (20 mL), was added triethylamine (0.5 mL). The reaction mixture was refluxed for 6 h, and then allowed to cool. The formed solid product was filtered off, washed with EtOH, dried and finally recrystallized from DMF/H2O to afford the corresponding thiazole derivatives 8a,b, 9a,b, 11, 12, 14, 15, 17 and 18, respectively.
(B) Microwave method (MW)
General procedure:
An ethanolic mixture of compounds 5 or 6 (1 mmol) and the appropriate α-haloketones 7, ethyl chloroacetate, chloroacetonitrile or chloroacetone (1 mmol) and few drops of triethylamine were added in a process vial. The vial was capped properly and irradiated with microwave under pressurized conditions (17.2 bars, 150 °C) for 30 min. The reaction mixture was evaporated under reduced pressure and residual solid was taken in ethanol then collected by filtration, washed with ethanol, dried and finally recrystallized from the proper solvent to afford the products 8a, 9a, 11 and 12, respectively.
(Z)-1-(Benzothiazol-2-yl)-2-(3,4-diphenylthiazol-2-(3H)-ylidene)-2(phenylsulfonyl)ethanone (8a): Yield: 88% (microwave); 73% (thermal), mp 170-172 °C; IR (KBr) vmax/cm–1: 1685 (CO); 1H NMR (DMSO-d6) δ 6.65 (s, 1H, thiazol-5-CH), 6.86-8.14 (m, 19H, ArH); 13C NMR (DMSO-d6) δ 107.11, 118.80, 120.95, 121.60, 124.15, 124.28, 125.27, 128.09, 128.45, 128.51, 128.76, 129.33, 129.80, 129.84, 131.16, 133.43, 137.23, 137.49, 142.19, 144.20, 155.10, 156.54, 162.69, 182.37; MS (m/z, %): 552 (M+, 100%); Anal. Calcd for C30H20N2O3S3 (552.69): C, 65.19; H, 3.65; N, 5.07; S, 17.40%. Found: C, 65.23; H, 3.59; N, 5.01; S, 17.31%.
(Z)-1-(Benzothiazol-2-yl)-2-(4-(4-chlorophenyl)(3-phenyl)thiazol-2-(3H)-ylidene)-2-(phenylsulfonyl)-ethanone (8b): Yield (84%), mp 179-181 °C; IR (KBr) vmax/cm–1: 1695 (CO); 1H NMR (DMSO-d6) δ 6.65 (s, 1H, thiazole-5-H), 6.83-8.14 (m, 18H, ArH); MS (m/z, %): 586 (M+); Anal. Calcd for C30H19ClN2O3S3 (587.13): C, 61.37; H, 3.26; N, 4.77; S, 16.38%. Found: C, 61.33; H, 3.23; N, 4.69; S, 16.34%.
(Z)-1-(1-Methylbenzimidazol-2-yl)-2-(3,4-diphenylthiazol-2-(3H)-ylidene)-2-(phenylsulfonyl)- ethanone (9a): Yield: 90% (microwave); 75% (thermal), mp 190-192 °C; IR (KBr) vmax/cm–1: 1678 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.65 (s, 1H, thiazole-5- CH), 7.20-7.97 (m, 19H, ArH); 13C NMR (DMSO-d6) δ 32.11, 107.16, 113.29, 114.87, 118.80, 120.95, 121.60, 122.71, 124.15, 124.28, 125.27, 128.09, 128.45, 128.51, 128.76, 129.33, 129.80,129.84, 131.16, 133.43, 134.53, 137.49, 139.11, 142.19, 144.20, 156.57, 182.30; MS (m/z, %): 549 (M+, 100%); Anal. Calcd for C31H23N3O3S2 (549.66): C, 67.74; H, 4.22; N, 7.64; S, 11.67%. Found: C, 67.71; H, 4.19; N, 7.69; S, 11.73%.
(Z)-2-(4-(4-Chlorophenyl)-3-phenylthiazol-2-(3H)-ylidene)-1-(1-methylbenzimidazol-2-yl)- 2-(phenylsulfonyl)ethanone (9b): Yield (84%), mp 188-190 °C; IR (KBr) vmax/cm–1: 1681 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.65 (s, 1H, thiazole-5-H), 6.93-7.94 (m, 18H, ArH); MS (m/z, %): 584 (M+, 100%); Anal. Calcd for C31H22ClN3O3S2 (584.11): C, 63.74; H, 3.80; N, 7.19; S, 10.98%. Found: C, 63.69; H, 3.76; N, 7.13; S, 10.91%.
(Z)-2-(2-(Benzothiazol-2-yl)-2-oxo-1-(phenylsulphonyl)ethylidene)-3-phenylthiazolidin-4-one (11): Yield: 93% (microwave); 76% (thermal), mp 236-238 °C; IR (KBr) vmax/cm–1: 1695 and 1655 (CO); 1H NMR (DMSO-d6) δ 4.11 (s, 2H, thiazole-5-H), 7.21-8.14 (m, 14H, ArH); MS (m/z, %): 492 (M+, 100%); Anal. Calcd for C24H16N2O4S3 (492.59): C, 58.52; H, 3.27; N, 5.69; S, 19.53%. Found: C, 58.50; H, 3.23; N, 5.75; S, 19.54%.
(Z)-2-(2-(1-Methylbenzimiazol-2-yl)-2-oxo-1-(phenylsulphonyl)ethylidene)-3-phenylthiazolidin-4-one (12): Yield: 83% (microwave); 64% (thermal), mp 200-202 °C; IR (KBr) vmax/cm–1: 1678 and 1635 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3) 4.11 (s, 2H, thiazole-5-CH), 7.20-7.94 (m, 14H, ArH); MS (m/z, %): 489 (M+, 100%); Anal. Calcd for C25H19N3O4S2 (489.57): C, 61.33; H, 3.91; N, 8.58; S, 13.10%. Found: C, 61.24; H, 3.95; N, 8.60; S, 13.11%.
(Z)-2-(4-Amino-3-phenylthiazol-2-(3H)-ylidene-1-(benzothiazo-2-yl)-2-(phenylsulfonyl)ethanone (14): Yield (85%), mp 282-284 °C; IR (KBr) vmax/cm–1: 3331 (NH2), 1640 (CO); 1H NMR (DMSO-d6) δ 5.20 (s, 2H, NH2), 5.76 (s, 1H, thiazole-5-CH), 6.91-8.14 (m, 14H, ArH); MS (m/z, %): 491 (M+, 100%); Anal. Calcd for C24H17N3O3S3 (491.61): C, 58.64; H, 3.49; N, 8.55; S, 19.57%. Found: C, 58.68; H, 3.45; N, 8.48; S, 19.50%.
(Z)-2-(4-Amino-3-phenylthiazol-2-(3H)-ylidene-1-(1-methylbenzimidazo-2-yl)-2-(phenylsulfonyl)-ethanone (15): Yield (85%), mp 246-248 °C; IR (KBr) vmax/cm–1: 3325 (NH2), 1635 (CO); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 5.20 (s, 2H, D2O-exchange, NH2), 5.76 (s, 1H, thiazole-5-CH), 6.91-7.83 (m, 14H, ArH); MS (m/z, %): 488 (M+, 100%); Anal. Calcd for C25H20N4O3S2 (488.58): C, 61.46; H, 4.13; N, 11.47; S, 13.13%. Found: C, 61.43; H, 4.16; N, 11.49; S, 13.11%.
(Z)-1-(Benzothiazol-2-yl)-2-(4-methyl-3-phenylthiazol-2-(3H)ylidene-2-(phenylsulphonyl)ethanone (17): Yield (80%), mp 181-183 °C; IR (KBr) vmax/cm–1: 1638 (CO); 1H NMR (DMSO-d6) δ 1.73 (s, 3H, CH3), 5.79 (s, 1H, thiazole-5-CH), 6.91-8.14 (m, 14H, ArH); 13C NMR (DMSO-d6) δ 20.05, 107.15, 118.76, 121.00, 121.64, 124.23, 124.32, 125.28, 128.81, 129.27, 129.83, 131.11, 133.54, 137.26, 139.03, 142.30, 144.65, 155.29, 156.55, 162.71, 182.28; MS (m/z, %): 490 (M+, 100%); Anal. Calcd for C25H18N2O3S3 (490.62): C, 61.20; H, 3.70; N, 5.71; S, 19.61%. Found: C, 61.13; H, 3.64; N, 5.65; S, 19.55%.
(Z)-1-Methyl-(benzimidazol-2-yl)-2-(4-methyl-3-phenylthiazol-2-(3H)-ylidene)-2-(phenylsulphonyl)-ethanone (18): Yield (83%), mp 170-172 °C; IR (KBr) vmax/cm–1: 1636 (CO); 1H NMR (DMSO-d6) δ 1.71 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 5.79 (s, 1H, thiazole-5-CH), 6.35-7.83 (m, 14H, ArH); 13C NMR (DMSO-d6) δ 19.87, 32.12, 107.16, 113.29, 114.87, 118.80, 121.60, 124.15, 124.28, 125.27, 128.51, 129.33, 129.80, 131.16, 133.40, 134.42, 137.53, 139.15, 142.11, 144.20, 156.55, 182.30; MS (m/z, %): 487 (M+, 100%); Anal. Calcd for C26H21N3O3S2 (487.59): C, 64.04; H, 4.34; N, 8.62; S, 13.15%. Found: C, 64.09; H, 4.28; N, 8.59; S, 13.09%.

Reaction of compounds 5 and 6 with hydrazonyl halides 19a-d, 22, 25a-c, 28 and 31.
(A) Thermal method
General procedure:
To a mixture of compounds 5 or 6 (1 mmol) in EtOH (20 mL), triethylamine (0.5 mL), the appropriate hydrazonyl halide 19a-d, 22, 25a-c, 28 or 31 (1 mmol) was added portion wise over a period of 30 min. The reaction mixture was stirred at room temperature for 12 h, during which hydrazonyl halide went into solution and a yellowish-red colored product precipitated. The solid product was filtered off, washed with water, dried and finally recrystallized from EtOH/DMF to afford the corresponding 1,3,4-thiadiazole derivatives 20a-d, 21a-d, 23, 24, 26a-c, 27a-c, 29, 30, 32 and 33, respectively.
(B) Microwave method
General procedure:
To a mixture of compounds 5 or 6 (1 mmol) and the appropriate hydrazonyl halide 22 or 25a (1 mmol) few drops of triethylamine were added in a process vial. The vial was capped properly and irradiated by microwave under pressurized conditions (17.2 bars, 150 oC) for 20 min. A yellowish-red colored product was formed. The solid product was filtered off, washed with water, dried and recrystallized from EtOH/DMF to afford the corresponding 1,3,4-thiadiazole derivatives 23, 24, 26a and 27a, respectively.
(Z)-2-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2-(3H)-ylidene)-1-(benzothiazol-2-yl)-2-(phenylsulphonyl)-ethanone (20a): Yield (81%), mp 210-212 °C; IR (KBr) vmax/cm–1: 1675, 1645 (CO), 1598 (C=N); 1H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 7.23-8.14 (m, 14H, ArH); 13C NMR (DMSO-d6) δ 24.7, 102.35, 114.33, 118.71, 119.79, 122.53, 123.43, 124.18, 126.93, 127.23, 128.63, 129.52, 132.98, 136.55, 142.54, 143.74, 152.02, 151.32, 155.50, 182.34, 192.87; MS (m/z, %): 519 (M+, 100%); Anal. Calcd for C25H17N3O4S3 (519.62): C, 57.79; H, 3.30; N, 8.09; S, 18.51%. Found: C, 57.71; H, 3.23; N, 8.00; S, 18.44%.
(Z)-2-(5-Acetyl-3-p-tolyl-1,3,4-thiadiazol-2(3H)-ylidene)-1(benzothiazol-2-yl)-2-(phenylsulfonyl)-ethanone (20b): Yield (76%), mp 258-260 °C; IR (KBr) vmax/cm–1: 1675, 1637 (CO), 1606 (C=N); 1H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 2.42 (s, 3H, CH3) 7.23-8.14 (m, 13H, ArH); MS (m/z, %): 533 (M+, 100%); Anal. Calcd for C26H19N3O4S3 (533.64): C, 58.52; H, 3.59; N, 7.87; S, 18.03%. Found: C, 58.47; H, 3.51; N, 7.80; S, 17.98%.
(Z)-2-(5-Acetyl-3-(4-chlorophenyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(benzothiazol-2-yl)-2-(phenyl-sulfonyl)ethanone (20c): Yield (78%), mp 228-230 °C; IR (KBr) vmax/cm–1: 1673, 1642 (CO), 1603 (C=N); 1H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 7.34-8.14 (m, 13H, ArH); MS (m/z, %): 553 (M+, 100%); Anal. Calcd for C25H16ClN3O4S3 (554.06): C, 54.19; H, 2.91; N, 7.58; S, 17.36%. Found: C, 54.11; H, 2.87; N, 7.53; S, 17.29%.
(Z)-2-(5-Acetyl-3-(4-methoxyphenyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-(benzothiazol-2-yl)-2-(phenylsulfonyl)ethanone (20d): Yield (73%), mp 186-188 °C; IR (KBr) vmax/cm–1: 1671, 1645 (CO), 1596 (C=N); 1H NMR (DMSO-d6) δ 2.22 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 7.14-8.13 (m, 13H, ArH); MS (m/z, %): 549 (M+, 100%); Anal. Calcd for C26H19N3O5S3 (549.64): C, 56.81; H, 3.48; N, 7.65; S, 17.50%. Found: C, 56.78; H, 3.41; N, 7.57; S, 17.48%.
(Z)-2-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2-(3H)-ylidene)1-(1-methylbenzimidazol-2-yl-)-2-(phenylsulphonyl)ethanone (21a): Yield (79%), mp 202-204 °C; IR (KBr) vmax/cm–1: 1665, 1625 (CO), 1588 (C=N); 1H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 6.67-7.79 (m, 14H, ArH); MS (m/z, %): 516 (M+, 100%); Anal. Calcd for C26H20N4O4S2 (516.59): C, 60.45; H, 3.90; N, 10.85; S, 12.41%. Found: C, 60.36; H, 3.86; N, 10.78; S, 12.37%.
(Z)-2-(5-Acetyl-3-p-tolyl-1,3,4-thiadiazol2(3H)-ylidene)-1-(1-methylbenzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (21b): Yield (75%), mp 210-212 °C; IR (KBr) vmax/cm–1: 1667, 1623 (CO), 1597 (C=N); 1H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3), 2.32 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 6.98-7.89 (m, 13H, ArH); MS (m/z, %): 530 (M+, 100%); Anal. Calcd for C27H22N4O4S2 (530.62): C, 61.12; H, 4.18; N, 10.56; S, 12.09%. Found: C, 61.06; H, 4.08; N, 10.49; S, 12.02%.
(Z)-2-(5-Acetyl-3-(4-chlorophenyl)1,3,4thiadiazol-2(3H)-ylidene)-1-(1-methylbenzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (21c): Yield (80%), mp 296-298 °C; IR (KBr) vmax/cm–1: 1666, 1630 (CO), 1605 (C=N); 1H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 7.11-7.99 (m, 13H, ArH); 13C NMR (DMSO-d6): δ 24.74, 32.07, 106.62, 111.73, 114.32, 121.43, 123.95, 126.45, 127.94, 129.23, 129.43, 134.02, 137.06, 139.41, 140.82, 142.31, 145.22, 146.31, 153.37, 160.05, 182.34, 190.53; MS (m/z, %): 550 (M+, 100%); Anal. Calcd for C26H19ClN4O4S2 (551.04): C, 56.67; H, 3.48; N, 10.17; S, 11.64%. Found: C, 56.70; H, 3.46; N, 10.13; S, 11.71%.
(Z)-2-(5-Acetyl-3-(4-methoxyphenyl)1,3,4-thiadiazol-2(3H)-ylidene)-1-(1-methylbenzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (21d): Yield (80%), mp 181-183 °C; IR (KBr) vmax/cm–1: 1664, 1627 (CO), 1593 (C=N); 1H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 4.02 (s, 3H, NCH3), 6.84-7.99 (m, 13H, ArH); MS (m/z, %): 546 (M+, 100%); Anal. Calcd for C27H22N4O5S2 (546.62): C, 59.33; H, 4.06; N, 10.25; S, 11.73%. Found: C, 59.24; H, 4.00; N, 10.17; S, 11.67%.
(Z)-1-(Benzothiazol-2-yl)-2-(3,5-diphenyl-1,3,4-thiadiazole-2-(3H)ylidene)-2-(phenylsulfonyl)ethanone (23): Yield: 89% (microwave); 72% (thermal), mp 254-256 °C; IR (KBr) vmax/cm–1: 1665 (CO), 1630 (C=N); 1H NMR (DMSO-d6) δ 6.80-8.14 (m, 19H, ArH); MS (m/z, %): 553 (M+, 100%); Anal. Calcd for C29H19N3O3S3 (553.67): C, 62.91; H, 3.46; N, 7.59; S, 17.37%. Found: C, 62.86; H, 3.39; N, 7.50; S, 17.28%.
(Z)-2-(3,5-Diphenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (24): Yield: 92% (microwave); 78% (thermal), mp 188-190 °C; IR (KBr) vmax/cm–1: 1661 (CO), 1595 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.80-7.92 (m, 19H, ArH); MS (m/z, %): 550 (M+, 100%); Anal. Calcd for C30H22N4O3S2 (550.65): C, 65.44; H, 4.03; N, 10.17; S, 11.65%. Found: C, 65.45; H, 3.97; N, 10.11; S, 11.57 %.
(Z)-Ethyl 5-(2-(benzothiazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-4-phenyl-4,5,di-hydro-1,3,4-thiadiazole-2-carboxylate (26a): Yield: 94% (microwave); 77% (thermal), mp 252-254 °C; IR (KBr) vmax/cm–1: 1680, 1654 (CO), 1598 (C=N); 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J = 7.2 Hz, CH3) 4.25 (q, 2H, J = 7.2 Hz, CH2), 6.80-8.14 (m, 14H, ArH); 13C NMR (DMSO-d6) δ 14.19, 61.30, 113.25, 118.60, 118.98, 119.84, 121.91, 122.90, 124.15, 124.27, 125.32, 128.34, 129.24, 129.51, 133.40, 139.60, 143.03, 147.25, 155.11, 159.70, 162.73, 182.30; MS (m/z, %): 549 (M+, 100%); Anal. Calcd for C26H19N3O5S3 (549.64): C, 56.81; H, 3.48; N, 7.65; S, 17.50%. Found: C, 56.76; H, 3.41; N, 7.59 S, 17.44%.
(Z)-Ethyl 5-(2-(benzothiazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-p-tolyl-4,5-di-hydro-1,3,4-thiadiazole-2-carboxylate (26b): Yield (79%), mp 249-251 °C; IR (KBr) vmax/cm–1: 1680, 1653 (CO), 1605 (C=N); 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J = 7.2 Hz, CH3), 2.32 (s, 3H, CH3), 4.25 (q, 2H, J = 7.2 Hz, CH2), 6.82-8.14 (m, 13H, ArH); MS (m/z, %): 563 (M+, 100%); Anal. Calcd for C27H21N3O5S3 (563.67): C, 57.53; H, 3.76; N, 7.45; S, 17.07 %. Found: C, 57.45, H, 3.70; N, 7.38 S, 16.99%.
(Z)-Ethyl 5-(2-(benzothiazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-4-chlorophenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate (26c): Yield (81%), mp 264-266 °C; IR (KBr) vmax/cm–1: 1680, 1654 (CO), 1604 (C=N); 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J = 7.2 Hz, CH3), 4.25 (q, 2H, J = 7.2 Hz, CH2), 6.88-8.14 (m, 13H, ArH); MS (m/z, %): 583 (M+, 100%); Anal. Calcd for C26H18ClN3O5S3 (584.09): C, 53.46; H, 3.11; N, 7.19; S, 16.47%. Found: C, 53.37; H, 3.02; N, 7.11; S, 16.40%.
(Z)-Ethyl 5-(2-(1-methylbenzimidazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-p-phenyl-4,5,-dihydro-1,3,4-thiadiazole-2-carboxylate (27a): Yield 92% (microwave); 71% (Thermal), mp 245-247 °C; IR (KBr) vmax/cm–1: 1678, 1652 (CO), 1601 (C=N); 1H NMR (DMSO-d6): δ 1.25 (t, 3H, J = 7.2 Hz, CH3), 4.02 (s, 3H, NCH3), 4.25 (q, 2H, J = 7.2 Hz, CH2), 6.80-7.83 (m, 14H, ArH); 13C NMR (DMSO-d6): δ 14.16, 32.19, 61.31, 113.40, 118.66, 119.07, 122.75, 122.93, 124.11, 124.30, 128.44, 128.54, 129.11, 133.60, 134.19, 138.30, 141.23, 142.12, 147.01, 155.83, 159.75, 164.11, 182.32; MS (m/z, %): 546 (M+, 100%); Anal. Calcd for C27H22N4O5S2 (546.62): C, 59.33; H, 4.06; N, 10.25; S, 11.73%. Found: C, 59.27; H, 4.01; N, 10.19 S, 11.68%.
(Z)-Ethyl 5-(2-(1-methylbenzimidazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-p-tolyl-4,5-dihyro-1,3,4-thiadiazole-2-carboxylate (27b): Yield (77%), mp 235-237 °C; IR (KBr) vmax/cm–1: 1682, 1651 (CO), 1607 (C=N); 1H NMR (DMSO-d6) δ 1.29 (t, 3H, J = 7.2 Hz, CH3), 2.33 (s, 3H, CH3), 4.02 (s, 3H, NCH3), 4.25 (q, 2H, J = 7.2 Hz, CH2), 6.72-8.14 (m, 13H, ArH); MS (m/z, %): 560 (M+, 100%); Anal. Calcd for C28H24N4O5S2 (560.64): C, 59.98; H, 4.31; N, 9.99; S, 11.44%. Found: C, 59.89; H, 4.27; N, 9.90; S, 11.37%.
(Z)-Ethyl 4-(4-chlorophenyl)-5-(2-(1-methylbenzimidazol-2-yl)-2-oxo-1-(phenylsulfonyl)-ethylidene)- 4,5-dihydro-1,3,4,thiadiazole-2-carboxylate (27c): Yield (80%), mp > 300 °C; IR (KBr) vmax/cm–1: 1678, 1652 (CO), 1601 (C=N); 1H NMR (DMSO-d6) δ 1.29 (t, 3H, J = 7.2 Hz, CH3), 4.02 (s, 3H, NCH3), 4.23 (q, 2H, J = 7.2 Hz, CH2), 6.85-7.98 (m, 13H, ArH); MS (m/z, %): 580 (M+, 100%); Anal. Calcd for C27H21ClN4O5S2 (581.06): C, 55.81; H, 3.64; N, 9.64; S, 11.04%. Found: C, 55.75; H, 3.56; N, 9.58; S, 10.97%.
(Z)-1-(Benzothiazol-2-yl)-2-(5-benzoyl-3-phenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-2-(phenylsulfonyl)ethanone (29): Yield (78%), mp 202-204 °C; IR (KBr) vmax/cm–1: 1670, 1652 (CO), 1609 (C=N); 1H NMR (DMSO-d6) δ 6.89-8.14 (m, 19H, ArH); 13C NMR (DMSO-d6) δ 110.05, 118.67, 118.98, 119.84, 120.77, 121.91, 122.90, 124.15, 124.27, 125.32, 128.34, 128.63, 129.02, 129.24, 129.51, 133.40, 137.81, 139.60, 143.03, 147.25, 155.11, 162.73, 182.30, 185.19; MS (m/z, %): 581 (M+, 100%); Anal. Calcd for C30H19N3O4S3 (581.68): C, 61.94; H, 3.29; N, 7.22; S, 16.54%. Found: C, 61.88; H, 3.21; N, 7.15; S, 16.48%.
(Z)-2-(5-Benzoyl-3-phenyl-1,3,4-thiadiazole-2-(3H)-ylidene)-1-(1-methyl-1H-benzimidazol-2-yl)-2-(phenylsulfonyl)ethanone (30): Yield (82%), mp 212-214 °C; IR (KBr) vmax/cm–1: 1673, 1648 (CO), 1590 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.80-7.90 (m, 19H, ArH); MS (m/z, %): 578 (M+, 100%); Anal. Calcd for C31H22N4O4S2 (578.66): C, 64.34; H, 3.83; N, 9.68; S, 11.08%. Found: C, 64.28; H, 3.76; N, 9.59; S, 11.00%.
(Z)-5-(2-(Benzothiazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-N-4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (32): Yield (77%), mp 210-212 °C; IR (KBr) vmax/cm–1: 3395 (NH), 1680, 1669 (CO), 1601 (C=N); 1H NMR (DMSO-d6) δ 6.80-8.15 (m, 19H, ArH), 10.60 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 104.21, 118.89, 119.91, 120.50, 120.94, 122.72, 122.94, 124.12, 124.23, 125.29, 128.36, 128.45, 128.62, 129.29, 129.20, 133.33, 138.27, 139.41, 142.16, 147.21, 155.05, 156.32, 162.67, 182.32; MS (m/z, %): 596 (M+, 100%); Anal. Calcd for C30H20N4O4S3 (596.70): C, 60.39; H, 3.38; N, 9.39; S, 16.12%. Found: C, 60.32; H, 3.30; N, 9.29; S, 16.04%.
(Z)-5-(2-(1-Methyl-1H-benzimidazol-2-yl)-2-oxo-1-(phenylsulfonyl)ethylidene)-N-4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (33): Yield (78%), mp 221-223 °C; IR (KBr) vmax/cm–1: 3393 (NH), 1677 (CO), 1665 (CO), 1600 (C=N); 1H NMR (DMSO-d6) δ 4.02 (s, 3H, NCH3), 6.80-7.89 (m, 19H, ArH), 10.60 (s, 1H, D2O-exchangeable, NH); 13C NMR (DMSO-d6) δ 32.23, 104.31, 114.68, 115.32, 120.96, 122.75, 122.93, 124.11, 124.30, 128.42, 128.61, 128.73, 129.29, 129.62, 133.68, 134.32, 137.69, 138.28, 141.18, 142.17, 147.09, 155.93, 162.71, 164.17, 182.35; MS (m/z, %): 593 (M+, 100%); Anal. Calcd for C31H23N5O4S2 (593.68): C, 62.72; H, 3.90; N, 11.80; S, 10.80%. Found: C, 62.65; H, 3.83; N, 11.70; S, 10.72%.

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