Ethyl 2-thiophenecarboxylate

A solution of 16 g. (0.125 mole) of 2-thiophenecarboxylic acid (p. 282) and 150 ml. of ethanol is treated with a stream of dry hydrogen chloride for 2 hours. The ethanol is removed by distillation on a water bath, and the residue is subjected to steam distillation. The yellow oily ester is removed from the distillate by extraction with ether. The ethereal solution is dried and distilled to give 14 g. (72%) of ethyl 2-thiophenecarboxylate boiling at 96°/18 mm. 

Marvel, Johnston, Meier, Mastin, Whitson, and Himel, J. Am. Chem. Soc., 66, 916 (1944) Marvel, Whitson, and Johnston, ibid., 66, 415 (1944). 

A 200-ml. Soxhlet extractor is mounted between a one-neck flask and a reflux condenser, the condenser carrying a calcium chloride drying tube at the top. Calcium carbide is placed in the extractor thimble, and a mixture of 175 g. (1.29 moles) of o-toluic acid [Org. Syntheses Coll. Vol. 2, 588 (1943)], 1.2 1. of absolute ethanol, and 4 ml. of concentrated sulfuric acid is placed in the flask. The mixture is heated to reflux for 24 hours, after which the excess ethanol is recovered by distillation. The residual material is washed with 10% aqueous sodium hydroxide, and the mixture is extracted with benzene if necessary to obtain clean separation of the layers. The organic layer is distilled to give 155 g. (76%) of ester, b.p. 88-92°/5 mm. 

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A soln. of ethyl 2-thiophenecarboxylate in dimethyl sulfoxide added during 10 min. under Ng to a stirred soln. of 4 moles methylenetriphenylphosphorane in the same solvent, stirring continued 1 hr. at room temp, and 1 hr. at 50 , poured onto crushed ice-pentane, and stirred overnight at room temp. -> 2-iso-propenylthiophene. Y 71%. F. e. and limitations s. A. P. Uijttewaal, F. L. Jon-kers, and A. van der Gen, Tetrah. Let. 1975, 1439. 

The mercaptals obtained by the acid catalyzed reaction of J3-ketoesters, e.g., ethyl acetoacetate, with methyl thioglycolate (73) undergo the Dieckmann cyclization with alcoholic potassium hydroxide at lower temperatures to give ethyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (74) in 75% yield. ° Besides ethyl acetoacetate, ethyl a-ethylacetoacetate, ethyl benzoyl acetate, and ethyl cyclopentanonecarboxylate were also used in this reaction/ It is claimed that /8-diketones, hydroxy- or alkoxy-methyleneketones, or /8-ketoaldehyde acetals also can be used in this reaction. From acetylacetone and thioglycolic acid, 3,5-dimethyl-2-thiophenecarboxyl-ic acid is obtained. ... 

The usefulness of the Grignard reagent of 3-bromothiophene is somewhat limited as it can only be prepared by the entrainment method. The simultaneous formation of Grignard reagents from 3-bromothiophene and a fivefold molar excess of ethyl bromide gave, however, a 55% yield of 3-thiophenecarboxylic acid upon carbona-tion. With acetaldehyde, a 55% yield of methyl 3-thienyl carbinol... 

Archer, owing to very unfortunate coincidences, had mistaken acid potassium tartrate for the acetylamino acid. Goldfarb et al. prepared authentic 5-acetylamino-2-thiophenecarboxylic acid, mp 230 232°C (methyl ester, mp 171-171.5°C ethyl ester, mp 161°C), through reduction of 5-nitro-2-thiophenecarboxylic acid with Raney nickel in acetic anhydride and proved the structure by Raney nickel desulfurization to 8-aminovaleric acid. They also confirmed that the acid mp 272-273°C (methyl ester, mp 135-136°C ethyl ester, mp 116-117°C) is 4-acetylamino-2-thiophenecar boxy lie acid as originally stated by Steinkopf and Miiller. The statement of Tirouflet and Chane that the acid obtained upon reduction and acetylation of 5-nitro-2-thiophenecarboxylic acid melts at 272°C must result from some mistake as they give the correct melting point for the methyl ester. 

Section 3.2.3.4 gives the pATa values of thiophenecarboxylic acids. Using crm and crp values derived from benzene chemistry, p-values for basic hydrolysis of 5-X thiophene-2-carboxylic acid ethyl esters and for ionization of 4- and 5-X-thiophene-2-carboxylic acids... 

Reaction of thienyllithium with C02 leads to thiophenecarboxylic acid. Other electrophiles which provide derivatives of carboxylic acids include ethyl chloroformate and phenyl isocyanate (Scheme 176) <790R(26)1>. 

Preparation of ethyl 2-(2-methylpropyl)amino-5-(l-naphthalenylmethyl)-3-thiophenecarboxylate... 

In ethyl 2-amino-4-phenylthiophene-3-carboxylate 28, steric repulsion between the ethoxy group and the phenyl ring is reduced by the phenyl ring being twisted out of the plane by an angle of 70.2°. Determination of the molecular structure of 2-thiophenecarboxylic acid shows the dihedral angle between thiophene and the carboxyl group to be 1.49°. 

Mono- and disubstituted-3,4-dihydroxythiophenes can potentially exist in four tautomeric forms, 237-240 (Scheme 18). For unsubstituted and for most disubstituted derivatives, the hydroxyketo form 238 or 239 is observed. In monosubstituted products (R H, R = H), 238 is the only one observed <1971T3839>. However 3,4-dihydroxy-2-thiophenecarboxylic acid ethyl ester existed as the dihydroxy tautomer 241. 

Procedure. The sodium amalgam is prepared as described above (see Preparation of Sodium Amalgam Sand of 2-thiophenccarboxylic acid), blanketed with 200 ml. of ether, and the 3-methylthiophene is added. Ethyl chloride is condensed from a cylinder into a tared flask cooled in an ice bath, poured into 4(X) ml. of ice cold ether, and added rapidly to the reaction flask maintained at 10-20°. The mixture is stirred for two hours at room temperature. Carbonation is then carried out as described above under 2-thiophenecarboxylic acid and the product is purified in the same manner (one-half the amount of water and acid being required). The white crystalline needles melt at 119-121°. 

The action of potassium thiocyanate on 101 gave the corresponding derivative 110 (67BRP1057612). The 3-ethoxycarbonylmethyl derivative 110 (R = CH2COOC2H5) was obtained by the action of ethyl glycinate on methyl 3-isothiocyanato-2-thiophenecarboxylate 111 (80EUP43054). 

The Hiyama couplings of heterocycles are still being developed to their full potential. Nevertheless, several heteroaryl halides have been cross-coupled with aryl or heteroaryl silicon reagents [52]. For example, in the presence of catalytic tt-allylpalladium chloride dimer and two equivalents of KF, the cross-coupling of ethyl(2-thienyl)difluorosilane (53) and methyl 3-iodo-2-thiophenecarboxylate led to bis-thiophene 54 under relatively forcing conditions [53]. 

The adducts of heteroaromatic / -enamino esters with dimethyl acetyl-enedicarboxylates 266 are cyclized in a base-catalyzed reaction to yield 4-oxo-l,4-dihydro-2,3-pyridinedicarboxylic derivatives 267147 (Scheme 71). Ethyl 2-amino-3-thiophenecarboxylate (26)21 also gives, with dimethyl acetylenedicarboxylate, a wide variety of cyclization products (268-271, E = C02Me)148 (Scheme 72). 

A multistep preparation of a thieno[3,2-e]-l,4-diazepin-2(3//)-one (285) has been accomplished, starting from the thienooxazinone 284 obtained from methyl 3-acetylaminothiophene-3-carboxylate (283) and phosphorus pentachloride.154 Similarly, 3-methylthieno[2,3-d]pyrimidin-4-(3//)-ones (288) were obtained in an exothermic reaction by heating methyl 2-acylamino-3-thiophenecarboxylates (286) with N,AT-dimethylphosphordiamidate (287) up to 250°C155 (Scheme 78). Ethyl 2-acylamino-3-pyridinecarboxylate (289) gave, on heating with excess amine hydrochloride and phosphorus pentoxide/iV,AP-dimethylcyclohexylamine, a series of pyrido[2,3-d]pyrim-idine-4(3if)-ones (290).156... 

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