Thieno thiophene-2-carboxamides

Diazotization followed by cyclization has been used to prepare fused thiophene derivatives. Thus diazotization of 3-aminothiophene-2-carboxamides in cone. HC1 leads to thieno-1,2,3-triazines (Scheme 122) (75CRV241). A similar reaction was also observed with the 4-carboxamide derivatives. With 2,4-dicarboxamides as substrates the 3-diazo group preferred to cyclize with the 2-carboxamide group. 

There is considerable interest in the chemistry of triazines as some of these compounds show pronounced antimalarial, antimicrobial and antiviral activity (76JCS(Pl)252l). Therefore two types of thiophenes annelated with a triazine ring will be mentioned. Thieno[2,3-d]-1,2,3-triazines were synthesized by cyclization of diazotized 2-aminothiophene-3-carboxamides (equation 55) (73M1586). Treatment of 3-alkylthio-6-styryl-5-oxo-2,5-dihydro-l,2,4-triazines with phosphorus pentasulfide in pyridine yields thieno[2,3-e]-l,2,4-triazines (equation 56) (78CI(L)585). Probably a thiation with subsequent cycloaddition and elimination of a hydride ion is involved. 

Trioxopyrido[3,2, 4,5]thieno[3,2-<7]pyrimidin-4(3//)-ones were synthesized by the reactions of 3-amino-2-ethoxycarbonylthieno[2,3-Z>]pyridines with isothiocyanates (1997JHC937) or by the reactions of 3-amino-2-cyano(carbamoyl)thieno[2,3-Z>]pyridines with carbon disulfide (1998M523). An analogous reaction of 2-amino-thiophene-3-carboxamide with carbon disulfide yielded thioxopyrimidinone 10 (1990PS181, 1993MI1). 

Ethoxalyl chloride (Et02C—COC1) in pyridine converted 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide to the 2-ethoxalylamino analog, which was heated at 260°C to give ethyl 5,6,7,8-tetrahydro-4-oxobenzo-thieno[2,3-d]pyrimidine-2-carboxylate (142) (moderate yield).215... 

Thiourea has been used similarly to prepare, at 175°C (3 hr) up to 205°C (20 min), good yields of annelated 2-thioxopyrimidin-4-ones such as 8-methyl-2-thioxo-8-azapurin-6-one (156) from 4-amino-1,2,3-triazole-5-car-boxamides (see 20),254 as well as pyrazolo[4,3-d]- and pyrazolo[3,4-d]pyri-midinediones from the appropriate aminopyrazolecarboxamides (see 15) 24,221 and thieno[2,3-d]pyrimidine-2,4-diones (see 12) from 2-amino-thiophene-3-carboxamide.25 5... 

Thieno[3,2-Z)]thiophene-2-carboxamides 317, which were prepared as mixtures of diastereomers and separated by high-performance liquid chromatography, were patented as cysteine protease inhibitors (98PCT9822494, 2001PCT0134153, 2001PCT0134154, 2001PCT0134159, 200IPCTO134565). 

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