Electron-rich 2-bromothiophene

It was discovered, however, that the ligandless conditions were highly dependent on the heteroaryl halide substrate [84], For example, 5-acetyl-2-bromothiophene reacted with the thiophene in the presence of PdfOAcij to furnish the desired product in 84% yield, but efficient coupling with the more electron-rich 2-bromothiophene required the use of PdidppfjCIj. Other heterocyles were coupled to 23, but these also required the use of Pd(dppf)Cl2 as shown in the table below. 

Chelation assistance by a removable 8-aminoquinolinyl moiety also resulted in the formation of a Csp —Csp bond between aromatic amides and thiophenes under the action of the low-cost nickel(II) bromide catalyst system (2015OL5228). Specifically, electron-rich 2-bromothiophene derivatives converted easily to the coupled products and boronic acids, aldehydes, and esters were tolerated on the thiophene. N-Heteroarenes such as 2-bro-mopyridines, 5-bromoindoles, and 2-bromothiazoles were also coupled to aromatic amides under similar conditions. 

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. 

The first example was published by Watanabe and coworkers. They successfully aminated both a- and [l-halothiophenes [185]. In a strategy employing the sterically hindered, electron-rich phosphine ligand P(r-Bu)3, NaOz-Bu as the base, and PdlOAcJj as the catalyst, 2,5-dibromothiophene was bisaminated with diphenylamine to afford 2,5-bis(diphenylamino)-thiophene (285). This method is also apphcable to 3-bromothiophene (69% yield), whereas the monoamination of 3,4-dibromothiophene was... 

The scope of the reaction is broadened by the use of the tetrahydrophosphepine ligand. In addition to heterocycles that were reactive with PCy3 or cyclohexyl-phobane as ligands, 4,5-dimethylthiazole can be arylated. The scope with respect to the bromoarene partner is also broadened to include electron-rich bromoarenes and heteroaryl bromides such as 3-bromothiophene, 5-bromo-iV-methylindole, 5-bromobenzofuran, and 5-bromobenzothiophene. Functional groups including sulfoxides, chlorides, fluorides, ketones, esters, primary and secondary amides, phenols, anilines, and pyridines can be tolerated under these conditions. Sterically hindered and/or ortho substituted substrates are unreactive, but meta and para substituted substrates are well-tolerated. 

The last method, F, which uses NiCl2-2,2 -bipyridine complex, works well only for the most reactive aryl iodides [31]. It is mechanistically more complicated because here lead(II) bromide acts as the source of lead(0) which actually reduces Ni"(bpy)X2 back to the catalytically active Ni°(bpy). Since the 2,2 -bip)ridme 75 is somewhat more electron-rich ligand than simple 2,2 -bipyridine (5), the resulting nickel(II) complex employed in the related Chen s method is sUghtly more reactive with electron-poor aryl halides, e.g. bromides, but generally the method is appUcable only with aryl iodides [30]. For instance, both iodo- and bromobenzene gave biphenyl (8) in 98 and 88% yields, respectively, but 2-bromothiophene was coupled in only 22% yield [30], Scheme 8. Chromium(II) chloride in a catalytic amount was used as an intermediate reductant as it provides an effective redox system, Cr(II) / Cr(III) between Ni(0) / Ni(II) and metallic manganese as the ultimate reductant. 

The palladium-catalyzed Heck reactions of 3- and 2-bromothiophene 111 with the electron-rich olefins butyl vinyl ether 112 and allyl alcohol 114 proceed effectively in the ionic hquid l-butyl-3-methylimidazolium tetrafluoroborate (Scheme 47) [340], The special feature of this reaction is that only branched olefin products are formed using the imidazolium ionic hquid, whereas the utilization of normal solvents gives rise to a mixture of regioisomers. 

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