Thienothiophenes synthesis

According to the available literature, two main routes to the synthesis of isomeric thienothiophenes have been studied cyclization of various aliphatic substances, and cyclization of derivatives of the thiophene series. 

When studying the carcinogenic activity of polycyclic hydrocarbons and their antdogs containing thiophene rings (cf. Tilak "), Tilak et al synthesized both thienothiophene 1 and its isomer 2 in low yield from 2-thienyl dimethoxyethyl sulfide (23) and 3-thienyl diethoxyethyl sulfide (24), respectively, by the method developed for synthesis of thiophenes and thiopyrans - [Eqs. (10) and (11)]. The compounds 23 and 24 were prepared from 2- and 3-mercaptothiophenes. ... 

The synthesis of alkylated thieno[3,2-h]thiophenes (2) via a similar procedure was also studied. As stated above, existing methods for the preparation of a-alkyl-substituted thienothiophene 2 derivatives and thienothiophene 2 itself are inefficient. The reduction of 4-bromo-2-acetothienone (56) (prepared by bromination of 2-acetothienone )... 

Ortho-bi functional thiophenes provide the most convenient route to unsubstituted thieno[2,3-6]thiophene (1). 3-Bromothiophene yielded 3-thiophenealdehyde. The corresponding diethyl acetal, using the procedure for thienothiophene 2, led to thieno[2,3-6]thiophene (l) in about 40% yield based on 3-bromothiophene [Eq. (24)]. This method was also used by Gronowitz and Persson for the synthesis of thienothiophene 1. 

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)]. 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

In 1973 Cava et al. reported the synthesis of 4,6-dimethyl-l/f,3if-thieno[3,4-c]thiophene (142) and l,3,4,6-tetraphenylthieno[3,4-cl-thiophene (149) ° as well as data on some chemicaJ conversions of the latter and the dehydration of 4,6-dimethoxycarbonyl-l/f,3H-thieno-[3,4-c]thiophene sulfoxide. Thienothiophene (149) was also obtained (42%) by Potts and McKeough by condensation of anhydro-4-hydroxy-2,3,5-triphenylthiazolium hydroxide with dibenzoylacetylene followed by reaction of the product with P S,. 

The steam-volatility of isomeric thienothiophenes allows separation from the resinous products formed during their synthesis from citric acid or acetylene. Selenophenoselenophenes are also steam-volatile. It is, however, very difficult to separate the isomeric thienothiophenes from each other and from benzo[b]thiophene with which they are also... 

Bromination of the isomeric thienothiophenes (7) and (3) has been studied in more detail than chlorination or iodination. Although polybrominated derivatives of (7) and (3) were reported by early investigators, attempts to make monobromo derivatives using Br2-HOAc were reported to give polymeric products. The first successful synthesis of monobromo derivatives (82) and (83) was achieved by the use of one equivalent of NBS in glacial acetic acid. The presence of aa -dibromo derivatives (84) and (85) in the crude reaction product was inferred by a quantitative IR analysis. 

The assignment of the orientation in the bromo derivative (82) was confirmed by transformation via halogen-lithium exchange and carbonation to the known acid (55 Scheme 25). The orientation of bromine in (83) was proved by an independent synthesis via direct metalation of thienothiophene (3) followed by treatment with bromine (Scheme 26). Both bromo derivatives (82) and (83) were stable at -15°C or in acetone solution for several days whereas at 20 °C they decomposed within a few hours. 

A more general and straightforward method for the synthesis of the three classical thienothiophenes (la)-(lc) involves the condensation of an aldehyde function with an appropriate thioacetic acid substituent, in an ortho bifunctional thiophene derivative. 

In 1935 Challenger became interested in thienothiophenes because of their supposed presence in bituminous oils,18 and he investigated methods of synthesis of the isomeric compounds. Using the reaction between acetylene and sulfur,9-10 his group isolated both thieno[2,3-il-thiophene (1) and thieno[3,2-A]thiophene (2) from the products, but again in very low yields.18-21 From the by-products of the reaction, a mixture of isomeric dithienyls was isolated.22 They also predicted the presence of the third isomer, thieno[3,4-A]thiophene (3), in the reaction products,18,19 but failed to isolate it, probably owing to its instability.23,24... 

As stated above, one of the routes to thienothiophene 2 is cyclization of (3-thienylthio)acetic acid in the presence of concentrated sulfuric acid followed by action of the 2,3-dihydrothieno[3,2-i]thiophen-3-one (22, R = H) formed with lithium aluminum hydride.26,28 Attempts by the present authors41,33 as well as those of Gronowitz and Moses47 to obtain thienothiophene 1 by cyclizing (2-thienylthio)acetic acid or its chloride by various catalysts (stannic chloride, aluminum chloride or bromide, polyphosphoric acid or anhydrous HF) were unsuccessful. Synthesis of 2-ethyl-3-hydroxythieno[2,3-A]thiophene33 by procedures commonly used for the preparation of 3-hydroxybenzo[A]thiophene72-74 also failed. 

The above method was used for preparation of a new class of cofacially oriented neutral donor-acceptor thienothiophenes, namely 3-(4-methoxyphenyl)-4-(3-pyri-dyl) thicnol2,3-/ ]thiophene 199 and its ionic analog 200 (Scheme 37). The synthesis of 199 and 200 has been described to probe the presence of through-space charge transfer interactions [49],... 

Synthesis of thienothiophenes with the participation of thiyl radicals 91PS(58)151. 

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