Thiophenecarboxylates

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). 

Thiophene-4-carboxylic acid, 3-bromo-debromination, 4, 78 Thiophenecarboxylic acids acidity, 4, 71... 

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)... 

It now seems definitely proved that the thiothiophthene (86) rearranged reversibly to a thiophene (87) under the influence of alkali and not to a thiepin derivative, The dimethyl ether of (87) has been oxidized to 4-methylsulfonyl-2-thiophenecarboxylic acid (88)... 

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 amount of 4-substitution is in certain cases even more strongly dependent upon the type of reaction. Thus the bromination of 2-thiophenealdehyde gives only 5-bromo-2-thiophenealdehyde. > The reason for this has been discussed. Also 2-thiophenecarboxylic acid gives the 5-isomer upon bromination and chlorination. Whereas a -j-M-substituent, as mentioned before, strongly activates... 

From resonance structure (12) it is obvious that a —I—M-substit-uent strongly deactivates the 2-position toward electrophilic substitution, and one would thus expect that monosubstitution occurs exclusively in the 5-position. This has also been found to be the case in the chlorination, bromination, and nitration of 3-thiophenecarboxylic acid. Upon chlorination and bromination a second halogen could be introduced in the 2-position, although further nitration of 5-nitro-3-thiopheneearboxylic acid could not be achieved. Similarly, 3-thiophene aldehyde has been nitrated to 5-nitro-3-thiophene aldehyde, and it is further claimed that 5-bromo-3-thiopheneboronic acid is obtained upon bromination of 3-thiopheneboronic acid. ... 

Additional examples of the reactivity of the 4-position in thiophenes with —I-j-M-substituent in the 3-position are provided by the bromination of 3-thiophenecarboxylic acid to 2,4,5-tribromothio-phenecarboxylic acid and the recent diacetylation of 2,5-dimethyl-thiophene by Goldfarb et who used the swamping catalyst... 

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). °... 

Carboxyl groups are easily removed during nitration especially at higher temperatures. A detailed study on the nitration of 5-bromo-2-thiophenecarboxylic acid showed that the proportion of 2,4-dinitro-5-bromothiophene increased with the concentration of sulfuric and nitric acid. The mechanism of this decarboxylative nitration... 

In the absence of oxygen, these thiolene-2-ones are rather stable and have been kept at 0°C for several months. 3-Hydroxythiophene, on the other hand, which has been prepared in low yield from 3-thio-phenemagnesium bromide in the same way as the 2-isomer, or through decarboxylation of 3-hydroxy-2-thiophenecarboxylic acid, "" is very unstable. Its IR spectrum indicates that it also exists as a tautomeric mixture largely in its enolic form. ... 

It has been shown that 2,3-thiophenedicarboxylic acid is preferentially esterified in the 2-position and the dimethyl ester is preferentially hydrolyzed in this position. The structure proof was difficult to achieve as rearrangements occurred. Thus both isomeric amides (195) and (196) were decarboxylized to the N-methylanilide of 3-thiophenecarboxylic acid (197). The same carbomethoxy benzoyl-thiophene, proved to be 2-carbomethoxy-3-benzoylthiophene (198),... 

Sodium thenoate is bromodecarboxylated in low yield, slower than sodium anisate, but more rapidly than sodium benzoate. However, the Hunsdiecker reaction with silver salts has been used preparatively for the synthesis of 2,3-dibromo-4-nitrothiophene from 3-bromo-4-nitro-2-thiophenecarboxylic acid. ... 

Fatty acids are prepared by acylating thiophene with acid chlorides and reducing the ketones (218) to alkylthiophenes according to Wolff-Kishner or Clemmensen. The latter are then acetylated and oxidized by hypochlorite to 5-alkyl-2-thiophenecarboxylic acids, > ... 

The antiadrenaline and antinoradrenaline activity of iV-benzyl-A -2 -halogenoethyl 2-thenylamines has been studied, " as has the radiation protective action of iV-phenylamidines of thiophenecarboxylic acid in white rats. ... 

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

CN 5-nitro-2-thiophenecarboxylic acid [3-(5-nitro-2-furanyl)-2-propylidenfc]hydrazide... 

C7H,j05S 97-05-2) see Domiodol 3-sulfo-2-thiophenecarboxylic acid (C5H4O5S2 59337-95-0) see Tenoxicam sulfuric acid zinc salt (1 1) heptahydrate (H 405SZn 7446-20-0) see Pyrithione zinc... 

C4H4S 110-02-1). see Clopidogrel hydrogensulfate Oxitefonium bromide Penthienate methobromide Suprofen 2-Thiophenecarboxylic acid Tiaprofenic acid Ticlopidine Tiemonium iodide Tienilic acid... 

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. 

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