Copper thiophene-2-carboxylic acid

The 2-indolinone system has been found in a large number of pharmaceutically active compounds. This framework could be constructed by a tandem Heck-Suzuki reaction sequence [137]. Intramolecular Heck reaction of 390 afforded a cyclized intermediate that, in situ, reacted with boronic acid 187 to produce 391 in a single pot sequence. The reaction made use of copper thiophene-2-carboxylic acid (CuTC) to generate base-free conditions for the Suzuki reaction. 

Pyrrole-2-carboxylic acid easily loses the carboxylic group thermally. Pyrrole-3-carboxylic acid and furan-2- and -3-carboxylic acids also readily decarboxylate on heating to about 200°C. Thiophene-carboxylic acids require higher temperatures or a copper-quinoline catalyst. In furans, 2-carboxylic acid groups are lost more readily than 3-carboxylic acid groups (Scheme 64). 

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... 

The 2-chloro(perfluoro)cycloalkenylzinc reagent (472) reacts with thiophene carboxylic acid chlorides in the presence of CuBr to form the ketones (473) in excellent yields. The reaction is probably mediated by the corresponding 2-chloro(perfluoro)cycloalkenyl copper <91JCS(P1)1601>. 

Rates of debromination of bromonitro-thiophenes and -selenophenes with sodium thio-phenoxide and sodium selenophenoxide have been studied. Selenophene compounds were about four times more reactive than the corresponding thiophene derivatives. The rate ratio was not significantly different whether attack was occurring at the a- or /3-position. As in benzenoid chemistry, numerous nucleophilic displacement reactions are found to be copper catalyzed. Illustrative of these reactions is the displacement of bromide from 3-bromothiophene-2-carboxylic acid and 3-bromothiophene-4-carboxylic acid by active methylene compounds (e.g. AcCH2C02Et) in the presence of copper and sodium ethoxide (Scheme 77) (75JCS(P1)1390). 

Later Gronowitz and Maltesson reported the extension of this method to the preparation of thieno[2,3-6]thiophene (1) derivatives. A mixture of 3-(3-thienyl)acrylic acid, thionyl chloride, and pyridine was heated for 24 hours. 2-Chloro-3-(3-thienyl)-acrylic acid (4.5%), 3,5-dichlorothieno[2,3-6]thiophene-2-carbonyl chloride (99) (9.5%), 3-chlorothieno[2,3-Z)]thiophene-2-carbonyl chloride (100) (79.1%), and other compounds were detected by GLC among the reaction products [Eq. (31)]. Hydrolysis of the reaction mixture gave 3-chlorothieno[2,3-Z>]thiophene-2-carboxylic acid in 63% yield dechlorination of the latter by copper in propionic acid converted it into thieno[2,3-6]thiophene-2-carboxylic acid. 

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). 

Dibromobenzo[6]thiophene and its 6-carboxylic acid undergo bisdehalogenation on treatment with sodium hydrazide and hydrazine 515 and on catalytic reduction in alkaline solution,77 respectively. Bromonitrobenzo[6]thiophenes readily undergo debromination on treatment with copper and quinoline,412 copper bronze and benzoic acid,84 or tin and hydrochloric acid.516... 

Benzo[c]thiophene may be prepared by low-pressure (20 mm) vapor-phase catalytic dehydrogenation of l,3-dihydrobenzo[c]thio-phene (Section III,A) at 330° under nitrogen,5,8 by decarboxylation of benzo[c]thiophene-1 -carboxylic acid (Section III,C) with copper in quinoline16,38 or by dehydration of l,3-dihydrobenzo[c]thiophene 2-oxide (Section VI,A) in acetic anhydride or over aluminum oxide at 20 mm Hg and 100°-125° in a sublimation tube.52 A trace of water appears to be beneficial to the first reaction, and it has been suggested53... 

Decarboxylation of 5,7-dimethyl-8-oxo-6-aza-8//-indeno[2,1 - ]thiophene-4-carboxylic acid could be effected by heating an admixture of it and copper powder <87H(26)1535). Direct sublimation in vacuo afforded the desired product (58%). 9-Chloro-2- and 3-methyltriazolo[4,5-/]quinoline-7-carboxylic acids are decarboxylated under similar conditions <93H(36)259>. The cyano group of 8-cyano-7-oxo-4,5,6,7-tetrahydrothiazolo[4,5-/]quinolines can be converted into an amino group by cone. HC1 mediated hydrolysis to the amide, followed by Hofmann rearrangement <89H(29)I517>. 

CnTC = thiophene-2-carboxylic acid copper(I) salt [C5H3Cn02S]... 

The preparation of thieno[3,2-fc]thiophene was reported by Iddon and co-workers [76, 77] and it is readily prepared in four steps from commercially available 3-bromothiophene (Scheme 17.1). Thus 3-bromo-thiophene can be lithiated in the 2-position with a bulky non-nucleophilic base such as lithium diisopropylamine. Quenching of the resulting thiophene anion with dimethylfonnamide or tV-formylpiperidine afforded the thiophene aldehyde. Treatment of this o-bromoaldehyde with ethyl 2-sulfanylacetate in the presence of base afforded thieno[3,2-fc]thiophene carboxylate ester in good yield. Hydrolysis of the ester group, followed by thermal decarboxylation of the resulting acid with quinoline in the presence of copper, afforded the unsubstituted thieno[3,2-f>]thiophene in overall yields of approximately 60 % over the four steps. 

Alternatively, 3-vinylthiophenes 13 can be prepared through regioselective oxidative coupling of thiophene-2-carboxylic acid derivatives 11 with different alkenes 12 in the presence of a rhodium catalyst ([Cp RhCl2]2) and copper (II) acetate monohydrate as oxidant (Scheme 7) [32]. Thereby, the carboxylic group facilitates ort/io-olefination and is subsequently removed by decarboxylation in a one-pot sequence. Additionally, benzo[Z>]thiophenes can equally be coupled effectively with butyl acrylate giving rise to the vinylated product in a yield of 70%. 

In 1967, Wynberg et al. reported the first synthesis of air-sensitive thieno[3,4-b] thiophene [51]. The sulfoxide (131) was converted into anhydride 133 in refluxing acetic anhydride (132). Hydrolysis to form thieno[3,4-Z>]thiophene-2-carboxylic acid (134) then copper/quinoline decarboxylation gave 2, isolated initially as a picrate (Scheme 29). 

Thasana and coworkers reported the preparation of the coumestan derivative 95 through the intramolecular lac-tonization, mediated by copper(I) thiophene-2-carboxylate under MW irradiation, of 2-(2-bromophenyl)-6-methoxy-benzofuran-3-carboxylic acid 94 (Scheme 42) [141]. The same reaction took place employing substoichiometric Cul (0.5 equivalent), albeit in a remarkably lower yield (31%). 

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