Thiophene alcohols acylation

Sulfonated styrene—divinylbensene cross-linked polymers have been appHed in many of the previously mentioned reactions and also in the acylation of thiophene with acetic anhydride and acetyl chloride (209). Resins of this type (Dowex 50, Amherljte IR-112, and Permutit Q) are particularly effective catalysts in the alkylation of phenols with olefins (such as propylene, isobutylene, diisobutylene), alkyl haUdes, and alcohols (210) (see Ion exchange). Superacids. 

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 . 

Alkylation of thiophene by alkenes, catalyzed by H2SO4, is not as efficient a reaction as acylation polymerization often occurs, resulting in lower yields of desired products. Moreover, the reagent is not selective, since mixtures of 2- and 3-alkylthiophenes result (63AHC(l)l). Various alcohols have been used as the carbenium ion source, in the presence of SnCl4. Thus 7-butanol gives 2,5-di-f-butylthiophene. 

The 3-acylbenzo[6]thiophenes, separated from the mixture obtained on acylation of benzo[6]thiophene (Section 3.14.2.4), are readily reduced to 3-alkylbenzo[6]thiophenes. 3-Benzo[6 ]thienyllithium can be prepared from 3-bromobenzo[6]thiophene at -70 °C (68JCS2733) and this may serve as a source of 3-acylbenzo[Z>]thiophenes. In certain instances, Friedel-Crafts alkylation gives the 3-substituted benzo[6]thiophenes nearly exclusively. For example, 3-t-amylbenzo[6]thiophene was the exclusive product of alkylation of benzo[6 Jthiophene with t-amyl alcohol in the presence of tin(IV) chloride <70AHC(11)177). 

Lithiation of the methyl of (methylthio)benzene followed by acylation with an acyl chloride and acidification to pH 4-5 yields benzothiophene in good yields, but when aroyl chlorides are used, the mixture has to be heated in benzene. An attempted dehydration of the secondary alcohol (87.4) with hydrobromic acid led to S-demethylation and cyclization. Similar treatment of the isomeric 2-(2-methy thio-4-nitrophenyl)-l-phenylethanol gave a high yield of 6-nitro-2-phenyl-2,3-dihydrobenzo[fi]thiophene [2653]. 

Numerous hydrolaseotalyzed KRs of various secondary alcohols were performed in continuous-flow mode (Figure 9.8 and Table 9.6). The bioimprinting effect in sol-gel immobilization of various lipases (Lipase AK, Lipase PS, CaLB, and CrL) was studied (116]. The performance of the immobilized biocatalysts were characterized by enantiomer selective acylation of various racemic secondary alcohols in two different multisubstrate systems (mix A rac-23a,c-e and mix B rac-23b and roc-23i) in batch and continuous-flow mode. The synthetic usefiilness of the best biocatalysts was demonstrated by the KR of racemic l-(thiophen-2-yl)ethanol (rac-23j) in batch and continuous-flow systems [116]. 

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