Benzothiophene nitration

Indole, like benzothiophene, reacts with electrophiles to give preferentially -substituted products. Bromination241-243 in dioxane or pyridine, nitration by ethyl nitrate,244 chlorination by sulfuryl chloride,245 iodination in aqueous solution,246, 247 Vilsmeier and Reimer-Tiemann formylations,248-261 diazo coupling,252 thio-cyanation,263 and nitrosation254 all give the 3-substituted indoles, practically free from other isomers. 

Benzothiophene, like thiophene, is a n-electron rich heterocycle. Unlike thiophene, electrophilic attack occurs selectively at the P-position (or 3-position) [10a, Ila] however, substitution at the a-center (2-position) can also be achieved [11b]. The order of positional reactivity, based on nitration, is 3 > 2 > 6 > 5 > 4 > 7 [1 la, 12a]. Also, halogenation under acidic conditions affords the 3-halobenzothiophene [11c, 13a]. In terms of metalation chemistiy, deprotonation occurs preferentially at the 2-position (a) [lid, 13b] metal-halogen exchange is also favored at the a-center over the P-center [12b]. 

When 5-methylene-2,3,4,5-tetrahydro-1 -benzothiepine (111) was subjected to ring expansion reaction conditions (treatment with silver nitrate in the presence of iodine in methanol), intramolecular attack by sulfur at the initially formed halomethyl group led to the bicyclo[3.2. Ijoctane intermediate (112), which yielded the benzothiophene derivative (113) without formation of any ring expansion products (Scheme 15) <89TL4279>. 

The electrophilic substitution of these systems is much less regioselective than that of indole (effectively complete selectivity for attack at C-3), even to the extent that the hetero-ring positions are only a little more reactive than some of the benzene ring positions. For example, nitration of benzothiophene gives a mixture in which, although more than half the product is the 3-nitro-derivative, 2-nitro-, 4-nitro-, 6-nitro- and 7-nitrobenzothiophenes are also all produced, each representing about 10% of the product mixture. Measurements of detritiation of... 

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