Substituted Thiophenes from 3-Bromothiophene

3-Bromothiophene is an important starting compound for the synthesis of other 3-substituted thiophenes. The very facile bromine-lithium exchange reaction proceeds almost qualitatively and the butyl bromide present in the solution does not interfere in subsequent reactions with reactive electrophilic reagents. The following procedures are examples of smooth reactions with the intermediary 3-lithiothiophene. 

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In addition, complexes of P(/-Bu)3 have been shown to catalyze the formation of diaryl heteroarylamines from bromothiophenes.224 Aminations of five-membered heterocyclic halides such as furans and thiophenes are limited because their electron-rich character makes oxidative addition of the heteroaryl halide and reductive elimination of amine slower than it is for simple aryl halides. Reactions of diarylamines with 3-bromothiophenes occurred in higher yields than did reactions of 2-bromothiophene, but reactions of substituted bromothiophenes occurred in more variable yields. The yields for reactions of these substrates in the presence of catalysts bearing P(/-Bu)3 as ligand were much higher than those in the presence of catalysts ligated by arylphosphines. 

Lithiothiophene is a key to the synthesis of many 3-substituted thiophenes. It is prepared from 3-bromothiophene, itself obtained from 2,3,4-tribromothiophene by selective Zn reduction (CHEC 3.14.3.8), or by rearrangement of 2-bromothiophene with NaNH2-NH3 (CHEC 3.15.9.6.3). 

A similar procedure yielded the manganese derivatives from 3-bromothiophene and 3,4-dibromothiophene <1997TL993, 1997JOC6921>. Starting from 3,4-dibromothiophene, unsymmetrically substituted thiophenes could be prepared through a stepwise process. 

The readily accessibile 3-bromothiophene (80 % overall yield from thiophene [142]) makes this exchange reaction an attractive route to 3-substituted thiophenes. 3-Bromofuran can be synthesized from furan, but a rather lengthy route must be followed (involving inter alia a Diels-Alder reaction with furan and cyclopentadiene... 

Halothiophenes, which are not activated through the presence of —I—M-substituents, undergo substitution smoothly under more forcing conditions with copper salts in pyridine or quinoline. Hence 3-cyanothiophene and 5-methyl-2-cyanothiophene have been obtained from the corresponding bromo compounds. 2-Bromothiophene reacts readily with aliphatic cuprous mercaptides in quinoline at 200°C to give thioethers in high yields. The use of the copper-catalyzed Williamson synthesis of alkoxythiophenes from iodo- or bromo-thiophenes and alcoholate has been mentioned before. The reaction of 2-bromothiophene with acetanilide in nitrobenzene in... 

Bromination. Another useful example of electrophilic substitution of thiophene and alkylthiophenes is that of bromination. Thus, thiophene itself undergoes electrophilic substitution in the presence of bromine. The reaction proceeds systematically from 2-bromothiophene, to 2,5-dibromothiophene, to 2,3,5-tribromothiophene and finally to tetrabromothiophene (29, 30). These brominated thiophenes exhibit sufficiently different physical properties to allow their ready purification. A more controlled method, especially for mono-... 

Aminations of five-membered heterocyclic halides, such as furans and thiophenes, are limited. These substrates are particularly electron-rich. As a result, oxidative addition of the heteroaryl halide and reductive elimination of the amine are slower than for simple aryl halides (see Sections 4.7.1 and 4.7.3). In addition, the amine products can be air-sensitive and require special conditions for their isolation. Nevertheless, Watanabe has reported examples of successful couplings between diarylamines and bromothiophenes [126]. Triaryl-amines are important for materials applications because of their redox properties, and these particular triarylamines should be especially susceptible to electrochemical oxidation. Chart 1 shows the products formed from the amination of bromothiophenes and the associated yields. As can be seen, 3-bromothiophene reacted in higher yields than 2-bromothiophene, but the yields were more variable with substituted bromothiophenes. In some cases, acceptable yields for double additions to dibromothiophenes were achieved. These reactions all employed a third-generation catalyst (vide infra), containing a combination of Pd(OAc)2 and P(tBu)3. The yields for reactions of these substrates were much higher in the presence of this catalyst than they were in the presence of arylphosphine ligands. 

Direct substitution in the 3-position of the thiophene ring is difficult and can be achieved only by activation of this reaction site. Thus the isomeric 3-thiophenethiol may be prepared by this general method starting from a 3-haIogenothiophene. For example, this thiol may be obtained from 3-bromothiophene in 63% yield.5... 

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