4-substituted 3-bromothiophenes

The same strategy was applied to 4-substituted 3-bromothiophenes to make unsymmetrical 3,4-disubstituted thiophenes. As shown in Table 8.19, crosscoupling products were obtained in moderate yields (36-66%) under mild conditions. Oxidative additions of Mn to the 4-substituted bromothiophenes were performed at rt in 5 h, and the successive coupling reactions of thienylmanganese bromides with benzoyl chlorides afforded unsymmetrical 3,4-disubstituted thiophenes at rt in 30 min without a catalyst (Table 8.19, entries 1 and 2). 

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. 

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. 

In closely related conditions 2-bromothiophene leads to the migration of the bromine atom onto the 3-position (ref. 86) while KNH2 gives an amination on this site (refs. 87, 88). A similar reaction-type is also obtained with substituted bromothiophenes a transhalogenation mechanism has been proposed (ref. 89) (Fig. 14). 

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... 

A similar substituted furan synthesis was realized via a Pd-catalyzed tandem carbonylation-arylation using an a,p-acetylenic ketone, carbon monoxide, and bromothiophene [104],... 

Carbon-heteroatom bond forming reactions are also efficient in introducing amines onto other five membered heterocycles. 2-, and 3-bromothiophene were both coupled with diphenylamine using the highly active palladium-PlBih catalyst system. The reactions furnished the desired products in both cases, although the yield varied significantly with the substitution pattern (6.75.),106... 

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). 

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-... 

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