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  • br Chemistry The methylsulfanyl dihydro H thieno g isothiadi

    2021-10-13


    Chemistry The 8-methylsulfanyl-4,5-dihydro-1H-thieno[3,4-g]isothiadizaole scaffold was synthesized from commercially available 1,3-dioxolane-2,1′-cyclohexane-4-one 17 (Scheme 1). The isothiadizaole ring was formed with SOCl2 from N-carboxamide hydrazine imine 19, which was prepared from 17 and hydrazinecarboxamide 18. Aldol reaction AS1842856 australia of 20 with carbon disulfide and the subsequent methylation with MeI afforded the precursor 21 of the desired tricyclic scaffold. Thiophene ring formation was successfully achieved by the treatment of 21 with ethyl 2-mercaptacetate under basic conditions. Transformation of ethyl ester 22 to carboxamide 24 was conducted by hydrolysis with aqueous NaOH, followed by condensation with NH4Cl and HATU. The synthetic procedure for the preparation of the 8-methylsulfanyl-4,5-dihydro-1H-thieno[3,4-g] isothiazole scaffold is shown in Scheme 2. Vilsmeier–Haack reaction of commercially available 25 with PBr3 and DMF gave formyl derivative 26 in 39% yields. Isothiazole ring formation of 26 with sodium thiocyanate afforded the desired tricyclic derivative 27. Transformation of ethyl ester 27 to carboxamide 29a was conducted by hydrolysis with aqueous NaOH, followed by condensation with aqueous ammonia via AS1842856 australia chloride formation with oxalyl chloride. Dehydration of the carboxyl group of 29a with POCl3 provided nitrile derivative 30. N-Substituted carboxamide derivatives 29b–h were synthesized by two methods (Scheme 3). The direct condensation of carboxylic acid 28 using HATU in the presence of NMM provided 29b–d, f in 36–76% yields. Stepwise amidation via acid chloride 31, obtained from 28 by treatment with SOCl2, afforded 29e, g, h in 13–28% overall yield in two steps. The synthesis of various 8-substituted-4,5-dihydro-1H-thieno[3,4-g]isothiazole derivatives is shown in Scheme 4. Sulfoxide 32 and sulfone 33 were synthesized separately by oxidation of sulfide 29a with the appropriate number of equivalents of mCPBA. For preparation of the final 8-aryloxy-4,5-dihydro-1H-thieno[3,4-g]isothiazole derivatives, SNAr reaction of sulfone 33 with phenol in the presence of Cs2CO3 afforded desired product 34b in only 10% yield. On the other hand, it was previously reported that the SNAr reaction of bicyclic 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo[c]thiophene derivative 35 successfully provided aryl ether derivatives.2(a), 2(b) In fact, nucleophilic addition was successfully employed to prepare 34b by treatment of 35 with phenol in the presence of K2CO3 in 88% yield. The reason for this substantial improvement in yield is likely due to the improved electrophilicity of the bicyclic 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo[c]thiophene intermediate relative to the tricyclic 4,5-dihydro-1H-thieno[3,4-g]isothiazole intermediate. These findings led us to the facile preparation of a wide variety of 8-aryloxy-4,5-dihydro-1H-thieno[3,4-g]isothiazole derivatives 34a–i. Introduction of the isothiazole ring into 36a–h, followed by transformation of the ethyl ester group to a carboxamide group was accomplished using the same method shown in Scheme 2 to afford derivatives 34a–h. Oxidation of 34e with mCPBA gave N-oxypyridine analog 34i in good yield. The synthesis of various 8-(pyridin-2-yloxy)-4,5-dihydro-1H-thieno[3,4-g]isothiazole derivatives was accomplished by Pd-catalyzed coupling as the key reaction (Scheme 5). Bromo analogs 44, 45 and 47 as key intermediates were synthesized in a similar manner to that shown in Scheme 4. A carbon monoxide-free, Pd-catalyzed Heck aminocarbonylation reaction of 47 employing the Herrmann-Beller palladacycle catalyst in conjunction with Mo(CO)6 as a solid CO source in the presence of DBU successfully provided a variety of N-substituted-6-carboxamide-3-oxy-pyridine derivatives 52e–f. The Pd-catalyzed Heck carbonylation of 47 with Pd(OAc)2 and dppf catalyst in the presence of MeOH under CO atmosphere gave methyl ester intermediate 52l in 64% yield. The transformation of methyl ester 52l to primary amide 52d was conducted by hydrolysis with aqueous NaOH, followed by the condensation with HOBt·NH3 and WSC.