Thieno thiophene-2-carboxylic acid

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

Earlier, cyclization of a-mercaptoacrylic acids in the presence of iodine was shown to yield fused thiophenes, which was utilized by Schneller and Petru [12] to synthesize thieno[23-h] thiophene carboxylic acid, which on decarboxylation yielded T23bT, an overall 60% yield (Scheme 11.3). 

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)]. 

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. 

Similarly, acetylation of thieno[3,2-6]thiophene (2) afforded 2-acetyl-thieno[3,2-6]thiophene, which was converted into methyl n-hexyl ketone by desulfurization with Raney nickel. Oxidation of 2-acetylthieno-[3,2-i]thiophene followed by nitration gave 5-nitrothieno[3,2-6]-thiophene-2-carboxylic acid. Decarboxylation of the latter furnished 2-nitrothieno[3,2-ft]thiophene identical with the compound obtained by direct nitration of thienothiophene 2 [Eq. (60)]. 

Unsubstituted thienothiophenes 1 and 2 are smoothly formylated in the 2-positions by DMF-phosphorus oxychloride in dchloro-ethane. The site of substitution in thienothiophene 2 was confirmed by preparing the corresponding formyl derivative from 2-lithiothieno-[3,2-6]thiophene and DMF, and in the case of 1, by oxidizing the formyl derivative to thieno[2,3-h]thiophene-2-carboxylic acid, as well as the NMR spectra [Eqs. (66) and (67)]. 

Wynberg and Feijen studied thieno[3,4-6]thiophene (3) formylation and found that both positions 4 and 6 are attacked. This is in accordance with theoretical predictions. The reaction produces a mixture (7 3) of 4-formyl- (194) and 6-formylthieno[3,4-6]thiophene (195) in 56% total yield after separation and purification. The formyl derivatives obtained were oxidized to the corresponding carboxylic acids 196 and 197, which were converted into 3-ethylpentanoic 198 and 4-methylhexanoic (199) acids by desulfurization with Raney nickel [Scheme 15]. 

Bugge brominated thienothiophenes 1 and 2 with IV-bromo-succinimide in glacial acetic acid to 2-bromothieno[2,3-6]thiophene (66%) and 2-bromothieno[3,2-6]thiophene (55%). The structure of 2-bromothieno[2,3-6]thiophene was confirmed by the replacement of bromine by lithium at —70° followed by carbonation to thieno[2,3-6j-thiophene-2-carboxylic acid 2-bromothieno[3,2-fe]thiophene was independently prepared by the treatment of 2-lithiothieno[3,2-6]thiophene with one equivient of bromine at —70°. The 2-bromo derivatives of thienothiophenes 1 and 2 decompose within several hours at 20°, but remain uncWged for weeks at —15°. 

Oxidation of acetyl- and acetylnitro-substituted thienothiophenes 1 and 2 with ferricyanide or hypoiodite to the corresponding acids was used primarily to confirm the site of electrophilic substitution at position 2 in the thienothiophenes. " Permanganate degrades the thieno[3,2-A]-thiophene (2) ring system, while potassium hypobromite produced bromo derivatives of thieno[2,3-6]thiophene-2-carboxylic acid. ... 

Incorporating an electron-donor alkyl group into position 2 of 2 was shown by foe present authors to facilitate S-oxidation thus, 2-efoyl-thieno[3,2-6]thiophene-l,1-dioxide (214) was prepared at40°-45° from 2-ethylthieno[3,2-6]thiophene, hydrogen peroxide and acetic acid. The thieno[3,2-6]thiophene system undergoes oxidation even if foe second a-position is carboxy-substituted oxidation of 5-efoylthieno[3,2-6]-thiophene-2-carboxylic acid furnished foe 4,4-dioxide (215) subsequently decarboxylated to sulfone (214) [Eq. (70)]. The [2,3-6] isomers, 20 and 55, with foe sulfur atoms bound to foe same carbon atom, do not form sulfones under similar conditions. 

Wynberg and Feijen prepared d-methylhexanoic acid (236) by desulfurization of thieno[3,4-6]thiophene-2-carboxylic (93) and 6-carboxylic (197) acids [Eq. (80)]. The analogous reaction with thieno-[3,4-A]thiophene-4-carboxylic acid (196) produce 3-ethylpentanoic acid (237) [Eq. (81)]. 

It is not necessary for the carbonyl functionality on the thiophene ring to be an ester. The carboxylic acid 399, shown in Scheme 32, is converted by reaction with a variety of acid chlorides (or acid anhydrides) into thieno-oxazinones 400. Reaction of 400 with dry ammonia generates 401 in average yields <2002JCM5>. 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

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). 

Reaction of thieno[3,4-6]thiophene (8) with DMF/POCl3 gave a 7 3 mixture of C-4 and C-6 formyl derivatives (58) and (59), respectively (76AHC(19)123). The substitution pattern was ascertained by oxidation to the carboxylic acids (60) and (61) and subsequent reductive desulfurization. The C-4 substituted isomer (60) yielded 3-ethylpentanoic acid (62) while the C-6 isomer led to 4-methylhexanoic acid (63 Scheme 14). 

Thienothiophenes 1 and 2 with ethylmagnesium bromide afford organometallic derivatives that can be carbonated to form the 2-carboxylic acids identical with those prepared by oxidation of the 2-acetyl derivatives.19-21,26,218 Thieno[3,2-i]thiophene-2,5-dicarboxylic acid was obtained analogously in the reaction of thienothiophene 2, using an excess of ethylmagnesium bromide.218... 

The construction of the pyranooxepin system shown in equation (52) proceeds by way of a dibenzox-epinone acetic acid, followed by intramolecular enol ester formation.67 The regioselective cyclization of 4-(2-naphthyloxy)butanoyl chloride proceeds as expected (equation 53) using tin(lV) chloride as the catalyst, but a mixture of products was obtained when the related carboxylic acid was treated with poly-phosphoric acid.68 The preparation of a thieno[fr]suberanone in 40% yield has been achieved by the interaction of tin(IV) chloride with 5-(2-thienyl)valeryl chloride.69 Once again, the expected increase in yield is obtained when cyclization occurs to the 2-position in thiophene. The product shown in equation (54) was isolated in 81 % yield.70 Other intramolecular reactions involving thiophenes have been reported.71... 

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