3-Hydroxythiophene-2-carboxylates

Rotational equilibria of 2-carbonyl substituted thiophene and furan derivatives were calculated and show that the 2-substituent favors the anti-isomer in thiophene <96MI199>. NMR shifts of 35 alkyl 3-hydroxythiophene-2-carboxylates and 3-alkylamino-l-(3-thienyloxy)-2-propanols have been compiled and analyzed <96HC17>. 

The alkylation of 5-(4-hydroxyphenoxy)-l/f-l,2,3-triazoles (147) under alkaline conditions exclusively yields the isomeric N(2) and N(3) alkylation products (148) and (149) (Equation (9)). For R = PhCH2, the N(2) and N(3) isomers are obtained in almost equal amounts, but for R = PhjC, only 1% of the N(3) isomer is formed because of steric hindrance. No N(l) alkylation is observed. Acylation and sulfonation of (147) under similar conditions results in attack at the phenolic oxygen <82JHCl 147>. Reaction of benzotriazole with 2-chlorothiophen-3-ones (150) in acetic acid gives 5-(benzotriazol-l-yl)-3-hydroxythiophene-2-carboxylates (151) (Equation (10)) <87JHC1301>. 

Chlorination of methyl 3-hydroxythiophene-2-carboxylate by sulfuryl chloride gives the 2-chloro-thiophen-3-one (250). This reacts with a series of nucleophiles at position 5 by an addition-elimination process, giving 5-substituted-3-hydroxythiophene-2-carboxylates <86JCR(S)168, 87JHC1301,90JHC315>. 

Methyl 3-hydroxythieno[2,3-Zr)thiophene-2-carboxylates were also synthesized by cyclization of substituted methyl 3-hydroxythiophene-2-carboxylates (91MI1). 

The reaction of 3-hydroxythiophen-2-carboxylates with P4S10 leads to thieno[3,2-c]l,2-dithiolan-3-thione (138) and the phosphorus-containing... 

Potassium hydroxide alcohol 3-Hydroxythiophene-2-carboxylic acid esters from y ketocarboxylic acid esters s. 12, 943... 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity. The synthesis of this compound starts by a multi-step conversion of hydroxythiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycine ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 ( shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22],... 

The presence of alkyl, or other groups, both stabilise the oxy compounds and the double bond to which they are attached. In these more stable compounds alternative tautomers are found, thus 5-methyl-2-hydroxythiophene exists as a mixture (actually separable by fractional distillation ) of the two enone tautomers and ethyl 5-hydroxythiophene-2-carboxylate is in the hydroxy-form to the extent of 85%. ... 

Carboxylic acids can be attached to these linkers using methods of ester bond formation such as carbodiimide/DMAP [23] and acid chloride/base. For the loading of N-protected-a-amino acids in particular, an array of different methods has been developed to minimize enantiomerizahon and dipeptide formation during the esterification reaction. These include the use of MSNT/N-methylimidazole [24], mixed anhydrides generated with 2,6-dichlorobenzoyl chloride [25], esters of 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene [26] and acid fluorides [27]. Phenols and N-protected hydroxylamines have been immobilized using the Mitsunobu reaction [28, 29], The latter are particularly useful for the preparation of hydroxamates [29, 30],... 

Compounds such as (246) having a carbonyl substituent at position 3 and a hydroxyl at 2 exist exclusively in the enol form. On the other hand, if the ester is located at position 5, then about 15% of the keto form is seen at equilibrium along with 85% of the enol. 3-Hydroxythiophene-4-carboxylic acid esters seem to exist as a mixture of both tautomers <86HC(44/3)l>. 

Hydroxythiophenes from a-mercapto-carboxylic acid esters. 4-Methylpenta-2,3-dienenitrile added dropwise with stirring during 5 min. to a suspension of methyl sodium sulfidoacetate (prepared from mercaptoacetate and Na-ethoxide in abs. ethanol) in anhydrous ether, and stirred 1 hr. at room temp, after the mildly exothermic reaction has ceased -> 4-hydroxy-2-isopropylthiophene-3-carbonitrile. 

The prior to imiversal synthesis to this kind of product was reported in 1910 by Senary [27] as the multi step reaction of ethyl 4-chloro-2-( ano-3-oxobutanoate (1). After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino-4-hydroxythiophene-3-carboxylate (4) in equilibrium with its cyclic tautomer - the appropriate imine 3 (Scheme 1). 

Synthesis of Thiophens by Ring-closure Reactions.— The Hinsberg reaction between a-diketones and dialkyl thiodiacetate has been used for the synthesis of a series of 3,4-disubstituted thiophen-2-carboxylates and -2,5-dicarboxylates. The corresponding condensation of ethyl phenyl glyox-ylate and methyl pyruvate with dialkyl thiodiacetate, which yields 3-phenyl-and 3-methyl-4-hydroxythiophen-2,5-dicarboxylates, proceeds through a... 

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