3- Aminothiophene-2-carboxylic acid derivatives

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

The Gewald synthesis of 2-aminothiophen-3-carboxylic acid derivatives has been extended to cyanoacetic acid hydrazides. In the base-catalysed reaction with cyclohexanone and sulphur, the hydrazides yielded the thienopyrimidone derivative (24), which could be hydrolysed to the 2-aminothiophen-3-carboxylic acid hydrazide (24a). A series of substituted 2-aminothiophen-3-carboxylic esters have been prepared by a... 

Liebscher J, Feist K (1985) Formylation products of thioamides Part 11. A novel route to substituted 2-aminothiophenes by the reaction of S-alkylated thioamides with carboxylic acid derivatives. Synthesis 1985 412-414... 

Scheme 12. Microwave-assisted synthesis of 2-aminothiophene-3-carboxylic acid derivatives [24],...

The reaction of 2-aminothiophene-3-carboxylic acids (55) or 2-aminotet-rahydrobenzo(b)thiophene-3-carboxylic acid [55, R = R1 = —(CH2)4—] and EMME by heating at 110-120°C for 1-2 hr gave a mixture of 3-carboxylic acids (56) and decarboxylated derivatives (57) (75GEP2435025). 

Diaminothiophene has been prepared and isolated as the hydrobromide. The free base is not stable <85JCR(S)296>. The t-butoxycarbonyl derivative of 3-aminothiophene was carboxylated at position 2 by lithiation (Bu"Li) followed by reaction with CO2. Reaction of this carboxylic acid (504) with diphenyl phosphorazidate in t-butanol gave the bis-carbamate (505). Removal of the protecting groups by HBr gave the hydrobromide salt of 2,3-diaminothiophene. 2,3-Diamino-benzo[Z>]thiophene was made by a similar procedure. 

Sodium 3-aminothiophene-2-carboxylates were reacted with EMME in boiling toluene in the presence of acetic acid for 4-6 hr to give 3-thienylaminomethylenemalonates (58) in moderate yields (87T3295 88EUP269295). The 5-bromo derivative of compound 58 (R = Br) was prepared in the reaction of 3-amino-5-bromothiophene and EMME, but 2-amino-5-nitrothiophene failed to react (87T3295). 

The key intermediate for the synthesis of penthiopyrad, l-methyl-3-trifluoro-methylpyrazole-4-carboxylate 29, is prepared as shown in Scheme 11.8 by treatment of ethyl trifluoroacetate with ethyl cyanoacetate in the presence of a base such as sodium methoxide to give butenoate 27 followed by treatment of methyUiydrazine sulfate in the presence of trifluoroacetic acid. The deamination of 28 by diazotization-deazotization gives the key intermediate 29. The final steps to penthiopyrad involve amination of ester 29 with the appropriate 2-alkenyl-3-aminothiophene derivative followed by hydrogenation using a noble metal catalyst. ... 

An elegant method for the utility of unstable 3-unsubsti-tuted 2-aminothiophene derivatives 385 in the Yonemitsu-type reaction has been elaborated by Krayushkin et al. (Scheme 13.81) [153]. Starting from stable 4,5-disubstituted ethyl 2-aminothiophene-3-carboxylates 383, the ester functionality is hydrolyzed to yield the corresponding alkali metal carboxylates 384. These are directly subjected to the three-component Yonemitsu-type reaction in acetic acid as the reaction medium. Protonation of the carboxylate followed by decarboxylation generates the 2-aminothiophene derivatives 385 that directly undergo Yonemitsu reaction without the need of isolation of those intermediates. This method has been applied to methyl 2,4-diaminothiazole-5-carboxylates 388 [154], ethyl 5-aminopyrazole -carboxylates 389 [155], dimethyl 3-aminopyrrol-2,4-dicarboxylates 390 [156], 4,5-disubstituted methyl 3-aminothiophene-2-carboxylates 391 [157], dimethyl 3-amino-4-phenylthiophene-2,5-dicarboxylate 392 [156], and ethyl 5-amin(Mmidazol-4-carboxylates 393 [158]. 

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