Heteroaryl bromides with heterocycles

Hence, microwave irradiation in DMA for 12 min at 120 °C or 30 min at 140 °C, depending on the substrate, resulted in 20 or 21 in 90-96% yields, compared to yields around 50% and a 24 h reaction time for conventional heating. As can be seen in Eq. 2 in Fig. 5, two possibilities exist to connect the heteroaryl bromide part with the five-membered heterocycle (indicated by a and fi. Table 2) that results in a six-membered 2-pyridone ring. Still, a very high selectivity was obtained yielding the 2-pyridones 21, in which the new bond had been introduced at Ca. It should be noted that the obtained structures 20 and 21 represent heterocyclic derivatives of 2-quinolones rather than true 2-quinolones. 

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

Catalysts generated from A-heterocyclic carbenes 23-25 (Figure 7) have been shown to efficiently catalyze the coupling of aryl and heteroaryl halides with indoles. Reactions conducted with the terf-butoxide base, which is typically used for the C—N coupling, did not occur, but reactions with NaOH as base occurred to high conversion85. Although 4-bromotoluene and bromobenzene reacted with numerous substituted indoles under these conditions, electron-rich and orf/zo-substituted aryl bromides reacted slowly and in low or moderate yields. 

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. 

Zinc Reagents. Coupling of heteroaryl iodides or bromides with ethynylzinc halides yields alkynylated heterocycles (Scheme 31). The ethynylzinc reagent can be prepared in situ by addition of a zinc halide to the ethynylmagnesium halide, which is either... 

The use of transition-metal catalysts in the substitution of aryl halides by amines has been reviewed. There has also been a summary of the use of palladium catalysts in the reaction of aryl and heteroaryl halides with primary and secondary amines. It has been shown that the amination of aryl sulfamates by aliphatic amines may be achieved using a nickel catalyst with an A-heterocyclic carbene ligand. Suitable ligands for nickel and palladium in the catalysed amination reactions of aryl sulfamates and imidazolylsulfonates have been identified. " The palladium-catalysed reaction of aryl nonafluorobutanesulfonates with primary sulfonamides may yield substituted products such as (22). Kinetic data suggest that reductive elimination from the palladium intermediate is likely to be rate limiting. A-Arylmethanesulfonamides may also be formed from aryl bromides and chlorides using a palladium catalyst... 

Reaction of phenacyldimethylsulfonium bromides 114 with diazotized heterocyclic amine 99a yielded 7V-heteroaryl-2-oxo-2-arylethanehydrazo-noyl bromides 5e (87JHC1341). 

For Suzuki reactions using haloboronic acids and another halide, the obviously best course is to have a more reactive halide in the substrate than in the boronate, so there are quite a few examples of chloro-heteroaryl-boronic acids coupling efficiently with aryl bromides. This difference is clearly shown by the coupling reactions of 2-chloro- and 2-bromopyridine-5-boronic acids with bromo-heterocycles. ... 

Direct Carbonylative Coupling. Unsymmetrical diaryl ketones were synthesized via the direct carbonylative coupling of aryl iodides and heteroarenes in the presence of catalytic [PdCl(cinnamyl)]2, l,3-bis(diphenylphosphino)propane (dppp) as the ligand, and stoichiometric Cul. Thus, heterocycles such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, and imidazoles reacted, with 4-iodoanisole in 56-75% yields (eq 1). Aryl iodides containing a variety of electron-donating or electron-withdrawing substitutents were tolerated in the reaction (eq 2) however, aryl bromides provided only traces of products. The role of the stoichiometric copper salt was to form a heteroaryl-Cu species, which could easily transmetallate to Pd. No reaction was observed in the absence of the Cul additive. 

Scheme 9 Copper bromide/L23-catalyzed reactions of alkyl amines and N-heterocycles with aryl or heteroaryl iodides...

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