Synthesis of 4-amino-5-(3-chlorobenzo[ b ]thien-2-yl)-3-mercapto- 1,2,4-triazolo[3,4-b ][1,3,4]thiadiazoles and triazolo[3,4, b ][1,3,4]thiadiazines under classical and microwave conditions

Conventional heating and microwave (MW) irradiation of 3-chloro-2-chlorocarbonylbenzo[ b ]thiophene ( 1 ) with hydrazine hydrate afforded the corresponding hydrazide 2 . Potassium dithiocarbazate 3 was cyclized with hydrazine to afford 4-amino-5-(3-chlorobenzo[ b ]thien-2-yl)-3-mercapto-1,2,4-triazole ( 4 ). Treatment of 4 with formic acid afforded the N-formyl derivative 5 and not the cyclized product 6 , but with acetic anhydride afforded the triazolothiadiazole 8 . Reaction of 4 with carbon disulfide in pyridine afforded 3-(3-chlorobenzo[ b ]thien-2-yl)-1,2,4-triazolo[3,4-b ][1,3,4]thiadiazol-6(5 H )thione ( 9 ) which was alternatively obtained by fusion of 4 with thiourea. Fusion of 4 with urea gave 6-amino-3-(3-chlorobenzo[ b ]thien-2-yl)-1,2,4-triazolo [3,4-b ][1,3,4]thiadiazol-6(5 H )one ( 11 ). The 3-(3-chlorobenzo[ b ]thien-2-yl)-5 H -1,2,4-triazolo[3,4-b ][1,3,4]thiadiazino[5,6-b ]quinoxaline ( 12 ) was synthesized by reaction of 4 with 2,3-dichloroquinoxaline. Simultaneous deamination and dethiolation of 4 gave 14 . Carboxymethylation of 4 afforded 15 and not the cyclized compound 16 . Carbethoxymethylation of 4 in presence of triethylamine afforded the thioalkylated product 17 and in presence of sodium ethoxide gave two 1,2,4-triazolo[1,3,4]thiadiazine derivatives 16 and 18 . Better yields and shorter reaction times were achieved using MW.


Introduction
Compounds bearing the 1,2,4-triazole ring are well known as powerful antimicrobial, 1 anticonvulsant, 2 antidepressant, 3 antihypertensive, 4 antitumorial 5 and analgesic 6 agents.[9][10][11] On the other hand, benzo [b]thiophene are of current interest due to their wide spectrum of pharmacological properties as antiallergic, 12 antiinflammatory, analgesic 13,14 and ocular hypotensive activities. 15A drug based on the benzo[b]thiophene ring is Raloxifene, approved by the U. S. Food and Drug Administration for the prevention and treatment of osteoporosis associated with woman postmenopansal. 16ontinuing our efforts directed toward the synthesis of new heterocyclic compounds with anticipated biological activities, we have investigated a green chemistry approach for the synthesis of heterocycles combining the benzothiophene and triazolothiadiazole or triazolothiadiazine rings.Much attention has been recently directed in our laboratory to use microwave (MW) in organic synthesis, [17][18][19][20][21][22][23][24][25][26][27] as a result of its extensive popularity as a powerful tool for rapid and efficient synthesis of a variety of organic compounds.It has not only been used to dramatically accelerate organic reactions, but also to improve both the yields and selectivity 28- 30 .

Results and Discussion
Microwave irradiations were done on reaction mixtures, placed in a closed Teflon vessel, by using a domestic microwave.Thus 3-chloro-2-chlorocarbonylbenzo[b]thiophene (1) was mixed with hydrazine hydrate and then were irradiated for 1.5 min to give 3-chloro-2hydrazinocarbonylbenzo[b]thiophene (2) in 98% yield; conventional heating required 1 h to give 2 in 80% yield. 31Condensation of 2 with carbon disulfide in ethanol containing potassium hydroxide required 4 min, under MW, to give the corresponding potassium dithiocarbazate 3, whereas the conventional method required 16 h.Ring closure of 3 with an excess of hydrazine hydrate afforded 4-amino-5-(3-chlorobenzo[b]thien-2-yl)-3-mercapto-1,2,4-triazole (4) in 72 % yield upon heating for 4 h, while the reaction time was reduced to 2 min with an improvement of the isolated yield (86%) upon irradiation with MW (Scheme 1).Its 1 H NMR spectrum showed the two characteristic singlets of the NH 2 and SH protons at δ 5.84 and 14.20, respectively.

Scheme 1
The functionalities in 4-amino-3-mecapto-5-substituted-1,2,4-triazoles made them valuable key precursors for the formation of fused heterocyclic compounds containing 1,2,4-triazolo [3,4b][1,3,4]thiadiazoles and [1,3,4]thiadiazines. [32][33][34] Thus, treatment of 4 with formic acid under reflux for 20 h afforded the N-formyl derivative 5 in 83% yield (Scheme 2).The same product 5 was also obtained in 92% yield, by subjecting the reaction mixture to MW for 3 min; the cyclized product 6 could not be detected.The IR spectrum of 4 showed absorption band at 1690 cm -1 for the carbonyl amide group.Its 1 H NMR spectrum in DMSO-d 6 solution showed a characteristic signal for the SH-proton at δ H 14.58 of one proton intensity indicating the preference of the thiol over the thione form.It showed the presence of two pairs of singlets for H-CONH protons at δ 8.33 and 8.38 in a ratio (1:6), and at δ 11.09 and 11.79, with the same ratio (1:6).This pairing of signals might be attributed to the different steric arrangement of amidic functionality in the geometric forms (A) and (B) with a predominance of the isomer (A) due to the possibility of hydrogen bonding between N-H and thiophene sulfur atom which could be more stronger than that in B. Attempted cyclization of 5 with H 2 SO 4 to the respective triazolothiadiazole 6 using a reported procedure 35 was unsuccessful under both conventional and MW conditions.Reaction of 4 with boiling acetic anhydride for 18 h caused a ring closure to form the thiadiazole ring of 8 in 80% yield, whereas 8 was obtained in 91% within 3 min under MW, via the possible formation of intermediate 7 which could be isolated in other analogues. 36he IR and 1 H NMR spectra of 8 confirmed the success of the cyclization by the disappearance of the signals corresponding to the SH and NH 2 protons and appearance of a singlet at δ 2.78 assigned to the methyl protons.
Heating compound 4 under reflux for 8 h with carbon disulfide in pyridine furnished 3- 9) in 70% yield (Scheme 2); 4 minutes were required under MW to afford 9 in 81% yield.Alternatively, compound 9 was obtained in moderate yield when a homogenous mixture of 4 and thiourea was fused for 3 h at 180-190 ºC.Its 1 H NMR spectrum showed a singlet at δ H 9.40 due to the NH group.
Fusion of 4 with urea gave 3- 3,4]thiadiazol-6(5H)one (10) .(13).This result indicated the generality of this reaction, which we have recently reported. 24he structure of 14 was confirmed from its 1 H NMR spectrum, which showed a singlet at δ H 8.69 for the triazole H-3 in addition to the singlet at δ H 13.94 ppm for the NH proton of the triazole ring.
Carboxymethylation of 4 with chloroacetic acid in H 2 O in presence of KOH as basic catalyst under conventional heating for 6 hr or MW for 2.5 min afforded 4-amino-5-(3chlorobenzo[b]thien-2-yl)-3-mercaptoacetic acid-1,2,4-triazole (15) in 80% and 90%, respectively (Scheme 3).The structures of the products resulting from the carboxymethylation of 4-amino-5-mercapto-1,2,4-triazoles were found in literature 37,38 to be either from uncyclized such as 15 or cyclized such as 16.The uncyclized nature of 15 was confirmed from its elemental analysis which was consistent with the molecular formula C 12 H 9 ClN 4 O 2 S 2 , and the existence of two singlets in the 1 H NMR spectrum at δ H 6.23 and 12.38 for the NH 2 and COOH protons, respectively which ruled out the existence of the cyclized compound 16.
On the other hand, carbethoxymethylation of 4 with ethyl chloroacetate in presence of triethylamine as catalyst in ethanol either under conventional heating for 2 h or under MW for 1.5 min resulted in the S-alkylation affording the uncyclized product 17 rather than 16 or 18.However, using aqueous potassium hydroxide in stead of triethylamine caused the elimination of a molecule of ethanol whereby the cyclized product 1,2,4-triazolo [1,3,4]thiadiazine derivative 16 was obtained.Its IR spectrum showed the absence of ester carbonyl absorption at 1724 cm -1 , characteristic for 17, and showed instead amidic carbonyl absorption at 1670 cm -1 .The 1 H NMR spectrum of 16 revealed the amidic proton of CONH at δ H 8.90, whereas the NH 2 protons in 17 appeared at δ H 5.24.
When the above reaction was carried out using sodium ethoxide as catalyst either by conventional heating or MW, the two 1,2,4-triazolo [1,3,4]thiadiazine derivatives 16 and 18 were obtained as a result of elimination of a molecule of water or ethanol, respectively.

ISSN 1424-6376
Page 124 Nucleophilic attack of hydrazine on the carbonyl-ester of 17 has been carried out by using MW for 2 min to afford the corresponding acid hydrazide 19 in 92% yield; conventional heating required 6 h to give 81%.
No reaction was observed under several attempts to react compound 4 with benzoin or dimedone in presence of different bases such as NaOH, NaOEt, NaOAc or NaH either under conventional heating or MW.Surprisingly, when the reactions were carried out in presence of NaH in DMF either by heating or under MW, an unexpected product was obtained which was found to be identical to that obtained from boiling 4 in DMF only.The 1 H NMR of this unexpected product confirmed the structure to be 3-

Scheme 4
In conclusion 4-Amino-5-(3-chlorobenzo[b]thien-2-yl)-3-mercapto-1,2,4-triazole (4) has proved to be a versatile precursor for the synthesis of various heterocyclic compounds possessing the benzothienyl ring linked to fused or functionalized triazole rings.The microwave technique has continued to add further improvements on the performance of reactions to provide products more efficiently in higher yields and in less reaction times (Table 1).

Experimental Section
General Procedures.Melting points were determined with a Melt-temp apparatus and are uncorrected.Irradiation was done in a domestic microwave oven EM-230M (1200 Watt output power under defrost temperature).The reactions were carried out in a closed Teflon vessel which was placed, for irradiation, at the center of the oven.IR spectra were recorded with Perkin-Elmer 1430 spectrometer 1 H NMR spectra were recorded on Jeol spectrometer (500 MHz).Chemical shifts (δ) are given in ppm relative to the signal for TMS as internal standard.Elemental analyses were performed in the unit of Microanalyses at Faculty of Science, Cairo University.

2-Carbonyl-potassium-dithiocarbazinate 3-chlorobenzo[b]thiophene (3). Method A.
Carbon disulfide (15 mmol) was added dropwise to a solution of 2 (10 mmol) in absolute ethanol (50 ml) containing potassium hydroxide (15 mmol) at 0 ºC.The reaction was stirred at room temperature for 16 h, and then cooled and diluted with diethyl ether.The precipitate was filtered, washed with diethyl ether and dried.The potassium dithiocarbazinate 3 was obtained in nearly quantitative yield and used without further purification as it was moisture sensitive.Method B. A mixture of compound 2 (1 mmol), KOH (1.5 mmol) and ethanol (5 ml) was treated with carbon disulphide (1.5 mmol) at 0 ºC.The reaction mixture was placed in closed Teflon vessel and irradiated by MW for 4 min.The reaction mixture was processed as described above (Table 1).

4-Amino-5-(3-chlorobenzo[b]thien-2-yl)-3-mercapto-1,2,4-triazole (4). Method A.
Hydrazine hydrate (95 %, 20 mmol) was added to a suspension of the potassium salt 3 (10 mmol) in water (10 ml) and the mixture was refluxed with stirring for 4 h.After cooling, it was diluted with water then acidified with aqueous hydrochloric acid.1).Method C. A mixture of 4 (10 mmol) and carbon disulphide (1 ml) in pyridine (25 ml) was refluxed for 8 h, then left to cool and poured on ice-cold water.The solid obtained was filtered, washed with water, dried and recrystallized from ethanol to give yellow plates identical with the product obtained above.