Halides, aryl, arylation coupling with heterocycles

The cross-coupling of aromatic and heteroaromatic rings has been carried out extensively[555]. Tin compounds of heterocycles such as oxazo-lines[556,557], thiophene[558,559], furans[558], pyridines[558], and seleno-phenes [560] can be coupled with aryl halides. The syntheses of the phenylo.xazoline 691[552], dithiophenopyridine 692[56l] and 3-(2-pyridyl)qui-noline 693[562] are typical examples. 

Yields versus aryl halides are moderate to good. Other nitrogen heterocycles such as 2-chloro-5-trifluoromethylpyridine or 2-chloropyrimidine were also coupled with p-MeOCgHjZnBr in 33% and 54% yields, respectively. Under the same conditions, no coupling product was observed with 3-chloropyridine. This specific behavior of 2-chloropyridine as compared to aryl halides can be explained by the presence of the nitrogen atom close to the carbon—halogen bond. 

Various aryl, alkenyl and even alkylborane reagents of different reactivity can be used for coupling with aryl, alkenyl, alkynyl and some alkyl halides, offering very useful synthetic methods. The cross-coupling of aryl and heteroarylboronic acids with aryl and heterocyclic halides and triflates provide useful synthetic routes to various aromatic and heteroaromatic derivatives. Sometimes, the reaction proceeds in the... 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many amines couple with a variety of aryl halides and sulfonates to produce high yields of mixed arylamines with at least one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, pyrazoles, and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction con-... 

The Hiyama couplings of heterocycles are still being developed to their full potential. Nevertheless, several heteroaryl halides have been cross-coupled with aryl or heteroaryl silicon reagents [52]. For example, in the presence of catalytic tt-allylpalladium chloride dimer and two equivalents of KF, the cross-coupling of ethyl(2-thienyl)difluorosilane (53) and methyl 3-iodo-2-thiophenecarboxylate led to bis-thiophene 54 under relatively forcing conditions [53]. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

Aryl chlorides are more reluctant to undergo amination than most other aryl halides/pseudohalides. To address this problem, Caddick and coworkers investigated the outcome of palladium-N-heterocyclic carbenes as catalysts in rapid microwave promoted reactions [121]. para-Tolyl and para-anisyl chloride were coupled with aromatic and aliphatic amines in generally good yields within 6 min at 160 °C. Reactions between tolyl/anisyl/phenyl chlorides and aliphatic amines have also been reported by Maes et al. using a more classic reaction system with a phosphine ligand and a strong base the reaction afforded the desired products after 10 min irradiation at 110-200 °C [122]. 

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