Thieno-thiophenes chlorination

Starting from 2-thienylacrylic acid (244), thionyl chloride and pyridine, the chlorinated thieno[3,2-6]thiophene derivative (245) was formed along with the more highly chlorinated product (246), which was isolated as its methyl ester (247 Scheme 83). In refluxing toluene or chlorobenzene, product (245) was not observed and only the ring-chlorinated acid chloride (246) was isolated in 13% yield. A number of analogs were prepared via this reaction <76AHC(19)123). 

A similar type of reaction, with bond formation between a chlorine substituted thiophene moiety and a phenyl ring connected to the thiophene via an amide bond, was used in the synthesis of 12-carbomethoxy-2-chloronaphtho[2",r, 2,3,-/ ]thieno[4,5, 2,3]-... 

This series was confirmed experimentally. For example, the following series of reactivities of different positions in these compounds was obtained in studies of acetylation, formylation and chlorination of thiophene (140), thieno[2,3-fe]thiophene (142) and thieno[3,2-Z>]thiophene (145) C(2) (145)>C(2) (142)>C(2) (140)>C(3) (142)>C(3) (145)>C(3) (140) (72CS137). In formylation, position 4 in thieno[3,4-f ]thiophene (148) was found (70RTC77) to be more readily subjected to the attack of an electrophilic species compared to position 6. 

When thieno[2,3- ]pyrazine was chlorinated, the reaction resembled the corresponding pyridine and pyrimidine (152) analogues in that 13-substitution in the thiophene ring was observed (80JHC1019). 

This order of reactivity was observ for add dedeuteration, but for acetylation, formylation, and chlorination it was slightly different thieno[3,2-h]thiophene (2) > thieno[2,3-h]thiophene (1) > thiophene thieno[3,4-6]thiophene (3) was not studied. A substantially greater discrepancy between theoretical and experimental data was observed for nucleophilic substitution from the data on base dedeuteration and competitive metalation reactions/ the order of decreasing reactivity was as follows thieno[2,3-h]thiophene (1) > thieno[3,2-h]thiophene (2) > thiophene. To a certain extent this may be explained by differences in the mechanism of metalation and deuterium exchange with a base. A discrepancy between calculation and experiment was also found for free-radical substitution. ... 

Since bromination and chlorination result in a greater variety of di-substituted products of thieno[2,3-Zi]thiophene 1 than of thieno[3,2-6]-thiophene 2, the conclusion has been drawn that a halogen in position 2 in thienothiophene 1 deactivates position S to a lesser extent than in thienothiophene 2 and that the halogen deactivating effect in 1 is similar to that in thiophene. 

Studies on the Chemistry of Thienoannulated 0,N- and S,N-Containing Heterocycles. 1. Nucleophilic Substitution Reactions on Chlorinated Thiophene Derivatives as a Basis for the Synthesis of Thienoannulated 0,N- and S,N-Heterocycles, Puschmann, I. Erker, T. Heterocycles 1993,36,1323. See also Studies on the Chemistry of Thienoanellated 0,N- and S,N-Containing Heterocycles. II. Synthesis on Thieno-Dilthiazem Analogs, Puschmann, 1. Erker, T. Heterocycles 1995, 41, 709. 

No ring or side chain chlorination was detected when ethyl 3-thienylacrylate (248) was reacted with thionyl chloride, the sole product isolated being 2-chlorocarbonyl thieno[2,3-6]thiophene (249 Scheme 84). Ethyl 2-furylacrylate (250) did not give an analogous product (251) upon reaction with thionyl chloride (Scheme 85) (75BSF2575). 

A quantitative study of acetylation, chlorination, and formylation of thieno[3,2-b]thiophene (8.185, X, Y = S), selenolo[3,2-6]thiophene (8.185, X = S, Y = Se), and selenolo[3,2-6]selenophene (8.185, X, Y = Se) gave the rates relative to thiophene given in Table 8.21 [80CS( 15)206]. Only a-substitution was observed (due to the high selectivity of the reactions), and the results clearly show that replacement of S by Se increases the reactivity (cf. the reactivity of selenophene and thiophene, Chapter 6). 

Methyl 4,5,6,7-tetrafiuorobenzo[h](hiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfbne reaction with chlorine or sulfuryl chloride produces a 2,3-dichIoride derivative <94JFCS1>. HOF MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to 3,5-dioxides <94CC1959>. Bromination of thieno[c]fused l,S-n hthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHCS21>. 

The comparative reactivities in electrophilic substitution of selenolo[3,2-Z ]thio-phene (143) and -selenophene (144) with respect to thieno[3,2-Z ]thiophene (142) were studied by the method of competitive reactions (80CS206). The reactivity was found to change in the following order 144 >143 >142. This series agrees well with a higher substitution rate in selenophene compared to thiophene in acetylation, formylation and chlorination reactions. 

Synthesis.—The reactions of thiophen-2- and 3-acrylic acid with thionyl chloride in the presence of pyridine yield a mixture of chlorinated derivatives of thieno[3,2-b]thiophen-2-carboxylic acid and thieno[2,3-b]-thiophen-2-acrylic acid. From thiophen-2,5-diacrylic acid, (241) was obtained. Aromatization of (66) gives thieno[2,3-b]thiophens. Reaction of (242) with methyl thioglycolate yielded (243)." Ethylthiophen was... 

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