Thiophene alcohols Friedel-Crafts reaction

Cope and Burrows414 have prepared a number of aminoalkylbenzo-[6]thiophenes with the general formula (195) by Friedel-Crafts reaction between benzo[6]thiophene and various amino tertiary alcohols. On treatment with formamide in formic acid, (3-benzo[6]-thienyl)acetone affords 3-(2-aminopropyl)benzo[6]thiophene [Eq. (11)].557 Recent patents535,570 describe how isocyanates with the... 

All lation. Thiophenes can be alkylated in the 2-position using alkyl halides, alcohols, and olefins. Choice of catalyst is important the weaker Friedel-Crafts catalysts, eg, ZnCl2 and SnCl, are preferred. It is often preferable to use the more readily accompHshed acylation reactions of thiophene to give the required alkyl derivatives on reduction. Alternatively, metalation or Grignard reactions, on halothiophenes or halomethylthiophenes, can be utilized. 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

Friedel-Crafts alkylation of benzo[6]thiophene has received little attention. The published results, which deserve reexamination, indicate that exclusive 3-substitution occurs in some cases, whereas in others, 2-substitution predominates. Benzo[6]thiophene is alkylated with isopropyl chloride, isopropanol, or propene in the presence of various acid catalysts under a variety of reaction conditions to give a mixture of 2- and 3-isopropylbenzo[6]thiophene in which the 2-isomer predominates (78-92%).358 410 In contrast, alkylation with isobutene in the presence of either 80% sulfuric acid415 or 100% phosphoric acid416 is said to afford exclusively 3-/er<-butylbenzo[6]thiophene in yields of 100 and 75%, respectively. In neither case was the structure of the product rigorously confirmed. Likewise, 3-Jeri-amylbenzo [63-thiophene is the exclusive product of alkylation with tert-amyl alcohol in the presence of stannic chloride414 alkylation with pent-l-ene, hex-l-ene, and a Ci8 propylene polymer is also claimed to give... 

Notably, this reaction shows a high tolerance towards a wide variety of functional groups, such as CHO, C02R, I, Br, Cl, F, OH and OMe, and also thiophene and furan derivatives, which is a rare feature in Friedel-Crafts-type chemistry. In the reaction with o-xylene, various alcohols were successfully used as benzylation agents, forming the corresponding products in high yield and selectivity (Table 6.1). 

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