Methyl 2-Thiophenecarboxylate

Apparatus Chap. I, Fig. 1, contents 500 ml for the lithiation, 11 for the reaction with chloroformate. 

Comparative experiments with aryllithium compounds (phenyllithium and para-fluorophenyllithium), however, resulted in low yields of the methyl esters in spite of the fact that a 300 % excess of chloroformic ester had been used. Reactions of C1COOR with lithio derivatives of heterocycles containing an azomethine function (e.g. lithiated thiazole, imidazole, pyridine) cannot succeed, since the excess of chloroformate will react with the basic nitrogen atom. A comparable situation arises if the organolithium intermediate has been generated by means of LDA reaction of C1COOR with the diisopropylamine liberated in the metallation will provide HC1 which will of course inactivate the organolithio compound. 

The first distillation is carried out at low pressure to avoid strong heating, which might give rise to decomposition of the residue. 

The methyl ester of l-methylpyrrole-2-carboxylic acid can be prepared in a similar way from 2-lithio-l-methylpyrrole (prepared as described in Exp. 8) and CICOOCH3. The boiling point of the ester is ca. 50 °C/0.5 mm, n 2 1.5132, the yield is 65 %. 

23 iV9N-Dimethy]-2-Furancarboxamide and iV9iV-Dimethyl 2-Thiophenecarboxainide 

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In a recent paper by Salimbeni et al. [2], a novel series of such All antagonists has been presented on the basis of a comparative analysis of theoretical distributions of the electrostatic potential (inactive compounds and overlay studies, employing a computational model of an All active conformation, it was found that the compound named LR-B/081 [3, 4] (C3oH30N603S), i.e. 2-[(6-butyl-2-methyl-4-oxo-5- 4-[2-(lH-tetrazol-5-yl)phenyl] benzyl -3H-pyrimidin-3-yl)methyl]-3-thiophenecarboxylate (Scheme 1), was one of the most potent in the series, and was selected as a candidate for further studies. 

Carboxylation. The reagent has been used in a preparation of dimethyl 2,4-thiophenedicarboxylate (3) from methyl 3-thiophenecarboxylate (I). ... 

Methyl-A > ( 1 >testosterone, 239, 2-Methyl-3-thiazoline, 344 Methylthiomethyl esters, 84-85 Methyl 3-thiophenecarboxylate, 70 l-Methyl-3-p-tolylhydrazine, 345 Methyl p-tolyl sulfoxide, 466, 513... 

The dianions of methylated thiophenecarboxylic acids e.g. 155) are also readily generated by reaction with LDA they undergo preparatively useful reactions with a range of carbon electrophiles (80JOC4528). 

Similarly, methyl thiophenecarboxylate reacts at the C5 position with a series of substituted benzaldehydes and acetophenone in the presence of the SmI2/THF-HMPA system to give a samarium enediolate which can be trapped by a second electrophile [59] (Scheme 23). The samarium-bonded ketyl anion radical does not trap the hydrogen atom or undergo acyloin coupling, presumably due to the hindrance of the ligated HMPA molecules. 

Optical activity owing to restricted rotation (atropisomerism) has been demonstrated in two phenylthiophenes 2-(6-methyl-2-nitro-phenyI)-3-thiophenecarboxylic acid (41), which rapidly racemized in solution, and 2,5-dimethyl-4- (6 -methyl-2 -nitrophenyl) 3-thio-phenecarboxylic acid (42), which was optically stable (at room temperature). Recently the first bithienyl, 2,2 -dicarboxy-4,4 -dibromo-5,5 -dimethyl-3,3 -bithienyl (43), has been resolved into optical anti-podes which were optically stable. 

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. ... 

Halogenated- ,/S-unsaturated ketones or aldehydes are reacted with methyl thioglycolate and cyclized with alkali alcoholate/ Thus jS-bromobenzalacetone (75) gives methyl 3-methyl-5-phenyl-2-thio-phenecarboxylate (76) and from a-methyl-j5-chlorocrotonaldehyde (77), 4,5-dimethyl-2-thiophenecarboxylate (78) is obtained. 

Using a,jS-dihalogenonitriles instead of carbonyl derivatives in the reaction with methyl thioglycolate leads to methyl 3-amino-2-thio-phenecarboxylates. Thus, a, -dichlorobutyronitrile (79) gave methyl 3-amino-5-methyl-2-thiophenecarboxylate (80)... 

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... 

Finally, certain 3-substituted compounds can be prepared by utilizing the - meta) directing powet (cf. Section IV,B) of some groups in the 2-position which afterward can be removed. 3-Nitrothiophene is prepared by nitration of 2-thiophenesulfonyl chloride and by removal of the sulfonic acid group of the 4-nitro-2-sulfonyl chloride formed with superheated steam. Another approach to 3-nitrothio-phene is to nitrate 2-cyanothiophene, separate the 4-nitro-2-cyano-thiophene from the 5-isomer, hydrolyze, and decarboxylate. A final method of preparation of 3-nitrothiophene is by simultaneous de-bromination and decarboxylation of 5-bromo-4-nitro-2-thiophene-carboxylic acid obtained through the nitration of methyl 5-bromo-2-thiophenecarboxylate. 

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. 

The position of substitution in disubstituted thiophenes can, in most cases, easily be deduced from the directing effect of each substituent. Thus with a - -M-substituent in the 2-position and a —M-substituent in the 5-position, both substituents direct the entering group to the 3-position as is exemplified by the nitration of methyl 2-bromo-5-thiophenecarboxylate to methyl 2-bromo-3-nitro-5-thio-phenecarboxylate (109) or in the chlororaethylation of methyl 2-methyl-5-thiophenecarboxylate to methyl 2-methyl-3-chloromethyl-5-thiophenecarboxylate (110). °... 

CN 4-methyl-3-[[l-oxo-2-(propylamino)propyl]amino]-2-thiophenecarboxylic acid methyl ester monohydrochloride... 

The beneficial effect of added phosphine on the chemo- and stereoselectivity of the Sn2 substitution of propargyl oxiranes is demonstrated in the reaction of substrate 27 with lithium dimethylcyanocuprate in diethyl ether (Scheme 2.9). In the absence of the phosphine ligand, reduction of the substrate prevailed and attempts to shift the product ratio in favor of 29 by addition of methyl iodide (which should alkylate the presumable intermediate 24 [8k]) had almost no effect. In contrast, the desired substitution product 29 was formed with good chemo- and anti-stereoselectivity when tri-n-butylphosphine was present in the reaction mixture [25, 31]. Interestingly, this effect is strongly solvent dependent, since a complex product mixture was formed when THF was used instead of diethyl ether. With sulfur-containing copper sources such as copper bromide-dimethyl sulfide complex or copper 2-thiophenecarboxylate, however, addition of the phosphine caused the opposite effect, i.e. exclusive formation of the reduced allene 28. Hence the course and outcome of the SN2 substitution show a rather complex dependence on the reaction partners and conditions, which needs to be further elucidated. 

Reaction of pyrocatechol dichloromethylene acetaP (133) with dibenzothiophene in the presence of titanium tetrachloride yields o-hydroxjrphenyl-2-dibenzothiophenecarboxylate (134) (100%). This reaction is closely related to the Rieche formylation of dibenzothiophene (Section VI,F, 1) in which a mixture of 2- and 4-dibenzothiophene-carboxaldehyde was obtained. The complete absence of the 4-isomer in this reaction may be due to steric effects at the 4-position between the sulfur atom and the bulky reagent. Hydrolysis of 134 yields 2-dibenzo-thiophenecarboxylic acid (70%). 4-Methyl-3-dibenzothiophenecar-... 

Hi) Carboxylic acids and derivatives. The haloform reaction on thienyl methyl ketones leads to thiophenecarboxylic acids, which can be treated with Raney nickel to produce the open-chain acids. This method has been used for the five-carbon homologation of carboxylic acids and to produce dicarboxylic acids (Scheme 51). Long-chain carboxylic acids may also be prepared by using dicarboxylic acid derivatives for the acylation of thiophenes (Scheme 52). In the synthesis of Queen substance, the precursor (213) has been generated by Raney nickel desulfurization of the appropriate thiophene-2-acetic acid derivative (79T329). 

A solution of 80 pi apiece 0.2 M l-methyl-2-pyrrolidinone 2-thiophenecarboxylic acid (Step 5 Acid), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexaflu-orophosphate, 1-hydroxybenzotriazole, 30 pi 0.2 M l-methyl-2-pyrrolidinone, and 0.5 M apiece diisopropylethylamine and pyridine were stirred 30 minutes, then treated with 75 pi 0.2 M l-methyl-2-pyrrolidinone containing the Step 4 product. The mixture was stirred overnight at ambient temperature, then concentrated, and diluted with 1000 pi CH2C12. The solution was washed with 800 pi apiece saturated NaHC03 solution and 1.81% HC1 and then brine. The organic layer was reconcentrated and the product isolated in 51 % yield. 

The H NMR spectra of methyl 3-, 4-, and 5-substituted 2-thiophenecarboxylates 62-64 have been obtained to compare with those of 2- and 3-substituted thiophenes 65 and 66 < 1983BCJ2463>. 

The electrochemical reduction of thiophene and 5-methyl-2-thiophenecarboxylic acid has been reported but would appear not to be of preparative interest. Thus, thiophene affords a mixture of 2,5-dihy-drothiophene (56%) and tetrahydrothiophene (44%) in 55% yield upon electrolysis in aqueous DMF. ... 

Scope of the Reaction. This method has been successfully applied to the preparation of 5-methyl-, tert-hvkty -, toZ-amyl-, tert octy -, and 5-(l-phenylethyl)-2-thiophenecarboxylic acids in yields ranging from 46-85% of theory. 

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