Benzo thiophene-2-carboxylic acid

The reaction of butadiene with the sulfone of 3-benzo[6]thiophene-carboxylic acid under Diels-Alder conditions gives the adduct (32). Catalytic reduction over platinum oxide removes the 2,3-double bond. 

Thiophene- and benzo[6]thiophene-carboxylic acids undergo all the normal reactions of an aromatic carboxylic acid (63AHC(1)1, 70AHC(11)177). They can be converted to acid chlorides, amides and esters the esters can be used to make hydrazides. Benzo[6]thiophene-2-carboxylic acid chloride has been converted to the methyl ketone with dimethylcadmium and to the diazoketone with diazomethane. Bromodecarboxylation of the silver salts (Hunsdiecker reaction) has been used to prepare the dibromo compounds (340) and (341). 

A chloroacetylbenzo[6]thiophene is readily converted into the corresponding benzo[6]thiophene carboxylic acid by alkaline hydrolysis of its pyridinium salt.132 464... 

Esters, amides, and primary alcohols are obtained from benzo[6]-thiophene carboxylic acids by standard procedures.337 481,585 692 093,695 Acid chlorides undergo the Arndt-Eistert reaction,337,568,689 react with diethyl ethoxymagnesium malonate to give the corresponding methyl ketone,144 557 and are reduced to the aldehyde with 1 ithium tri-ferf-butoxy aluminohydride.33 7... 

Benzo[6]thiophene carboxylic acids have been decarboxylated byT heating them with oxalic acid,254 by heating the ester with IN NaOH in dioxane,441 by heating the barium salt with barium hydroxide in vacuo,162, by heating them in quinoline with copper chromite347, 352.353 or> preferably, with copper,109 185 189,298 315 343 344 351 412 422, 638 an(j py heating them alone in quinoline54 or pyridine.114... 

In 1967, two reactions that proceeded by the intramolecular cyclization mechanism and led to fluorinated benzo[Z>]thiophenes were carried out. The first is based on the reaction of the lithium salt of pentafluorothiophenol and diethyl acetylenedicarboxylic ether (67JCS(C)1225) (Scheme 148). Here the intermediate species is a carbanion. In the second process, the starting compound is a benzylidene rhodanine derivative, giving benzo[Z>]thiophene carboxylic acid 157 in alkaline media. This reaction occurs via the intermediate S-nucleophile (Scheme 149). 

Benzo[b]thiophene-2-carboxylic acid, 3-acetamino-ethyl ester synthesis, 4, 875... 

Benzo[b]thiophene-2-carboxylic acids synthesis, 4, 893-894, 921 Benzo[b]thiophene-3-carboxylic acids synthesis, 4, 922... 

In the context of preparing benzothienyloxy phenylpropanamines as inhibitors of serotonin and norepinephrine uptake, a group from Eli Lilly and Company has developed a two-step synthesis of benzo[fo]thiophenes (Scheme 6.193) [354]. Thus, a 2-mercapto-3-phenylpropenoic acid derivative was cyclized with iodine in 1,2-dimethoxyethane at 120 °C to give 5-fluoro-4-methoxybenzothiophene-2-carboxylic acid in 67% yield. Decarboxylation under strongly basic conditions involving 1,8-di-azabicyclo[5.4.0]undec-7-ene (DBU) as base in N,N-dimethylacetamide (DMA) as... 

Unsubstituted thieno[3,4-6]thiophene (3) (see Litvinov and Fraenkel ), was prepared by Cava and Pollack s method for benzo[c]-thiophene i.e., thermal decomposition of H, 3 -benzo[c]thiophene sulfoxide. By refluxing 4/f,6/f-thieno[3,4-ft]thiophene-2-carboxylic acid 5-oxide (91) with acetic anhydride (the synthesis of dihydrothieno-thiophenes will be described below), Wynberg et a/." obtained the mixed anhydride 92 in 95% yield. Hydrolysis gave thieno[3,4-6]-thiophene-2-carboxylic acid (93) (88%). Decarboxylation of the acid (93) gave thienothiophene 3, unstable at room temperature [Eq. (29)]. 

Electron-withdrawing substituents seem to stabilize the benzo[cjfuran system as they do in the analogous benzo[c]thiophene and benzo [c]indole series. l-Cyano-3-phenylbenzo[c]furan (128) was obtained from the aldehyde 127 as stable yellow needles hydrolysis with base yields the carboxylic acid (129). Catalyzed hydrogenation of these cornpounds leads to 1,3-dihydrobenzo[c]furans (130, R = CH2NH2, COOH = Ph). Increased... 

Another reaction of such azides attached to the benzene part of benzo[7>]thiophene is the formation of benzoxazoles when heated in a mixture of carboxylic acid and PPA. The mechanism has been discussed in detail (79AG(E)900) and involves insertion of the singlet nitrene into the anhydride, followed by migration of the acyloxy group to the ortho position, and cyclization. The 5- and 6-azides thus given angularly fused benzoxazoles (Scheme 147). 

A concerted elimination-cyclization mechansim, involving a sulfenyl halide in a 1,3-butadiene-1-thio system, is the most probable mechanism for the formation of benzo[6 Jthiophenes from cinnamic acids or 4-aryl-2-butanones by treatment with thionyl chloride. The reactions shown in Scheme 5 have been carefully worked out, and the intermediates isolated (75JOC3037). The unique aspect of this synthesis is the reduction of the sulfinyl chloride (a) by thionyl chloride to form the sulfenyl chloride (b). The intermediate (b) was isolated and converted in pyridine to the 3-chlorobenzo[6]thiophene-2-carbonyl chloride in 36% yield (73TL125). The reaction is probably initiated by a sulfenyl ion attack on the aromatic ring, since it is promoted by electron-releasing groups para to the site of ring closure. For example, when X in (36) was N02, a 23% yield of (37), a mixture of 5-and 7-nitro derivatives, was obtained, but when X in (36) was OMe, a 54% yield of (37) was obtained, contaminated with some 3,4-dichloro-5-methoxybenzo[6]thiophene-2-carboxylic acid. 

Ring-closure techniques are more commonly used to obtain 3-alkylbenzo[6]thiophenes. Thus, acid-catalyzed cyclization of arylthio methyl ketones gives the 3-alkylbenzo[6]thio-phenes in good yield, with little rearrangement (equation 3). Formation of the 3-aryl-benzo[6]thiophenes by this approach is complicated, however, by rearrangement to the 2-isomer (Section 3.15.2.3.2). 3-Methylbenzo[f> Jthiophene is also obtained by decarboxylation of the corresponding 2-carboxylic acid (equation 4), readily available from ar-mer-captocinnamic acids (Section 3.15.2.1.1). 

The most direct synthesis of 2-acylbenzo[6]thiophenes involves reaction of the readily available 2-lithio derivative with acylating agents, such as nitriles, acid anhydrides, etc. (equation 19). Benzo[f>]thiophene-2-carboxylic acids are available by a variety of cyclization reactions (Section 3.15.9.2.4) and the acid chlorides or esters can be used to synthesize 2-acyl derivatives by conventional means. 

Synthesis of carboxylic acids, esters, amides and nitriles of thiophenes and benzo [b "[thiophenes... 

Mononitration of benzo[6]thiophene gives a complex mixture in which the 3-isomer predominates (73% in acetic anhydride at 25 °C) and can be separated from other isomers, which may include 4-, 5-, 6- and 7-nitro derivatives. However, benzo[6]thiophenes with electron-donating groups at the 3-position, e.g. 3-methyl-, 3-acetamido- or 3-bromo-benzo[6]thiophene, are nitrated almost exclusively in the 2-position. 2-Nitro-benzo[6] thiophene may be prepared by debromination of 3-bromo-2-nitro-benzo[6 ]thiophene, or by decarboxylation of 2-nitrobenzo[6]thiophene-3-carboxylic acid (70AHC(11)177). 

Benzo[6 jthiophenes with nitro groups at the 4-, 5-, 6- or 7-positions may be synthesized by ring closure reactions of appropriately substituted benzene derivatives. Nitration of 5-acetaminobenzo[6]thiophene gives the 4-nitro derivative, which can be hydrolyzed and deaminated to yield 4-nitrobenzo[6]thiophene (equation 44). 5-Nitrobenzo[6]thiophene is conveniently available by decarboxylation of 5-nitrobenzo[6]thiophene-2-carboxylic acid, which in turn is available by a Perkin reaction of 4-nitro-2-formylphenylthioglycoIic ester (equation 45 Section 3.15.2.3). The 7-nitro isomer may be obtained similarly. 

Another interesting derivative of benzo[c]thiophene which may be useful for preparative purposes has been described by Castro and coworkers. Strictly analogous to a synthetic sequence outlined in Section 3.17.2.1.1, 3-iodothiophene-4-carboxylic acid reacts with a copper(I) acetylide in DMF at 125 °C to give a l//-thieno[3,4-c]pyran-2-one (equation 53) (68JHC227). 

In a closely related reaction, heating the trimethylamine salt of the condensation product of dihydroresorcinol and 5-ethoxymethylene-3-methylrhodanine with aqueous alkali affords 4,5,6,7-tetrahydro-benzo[6]thiophen-4-one-2-carboxylic acid (92), via the intermediate (91).846... 

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