TMEDA-Promoted Cross-Coupling Of N-Heteroaromatic Compounds With Grignard Reagents

N-heteroarenes, such as quinoline, isoquinoline, usually serve as critical cores of natural products and their derivatives are both biologically and pharmaceutically active. The most important method of synthesizing these heterocyclic compounds is aryl and N-heteroaryl cross-coupling reaction. It recently has got lots of successful developments. Expanding the range of substrates, economizing the costs and pursuing milder reactive condition, however, is still challenging.In our report, we used tetramethylethylenediamine (TMEDA) as a ligand or an additive and effectively improved the conversation of cross-coupling reaction between N-heterocyclic compounds and a number of aromatic Grignard reagents. Fortunately, most of our products were afforded in good to excellent yields. Except quinoline,3-bromoquinoline and quinoxaline, our reaction system directly obtained2-substituted quinoline derivatives or other N-heterocyclic compounds in high yield. It is also worth mentioning that, in comparison with previous reports, our reactive condition is mild (in50℃) and the scopes both of nucleophiles and electrophiles were largely developed. Finally, a tentative mechanism for the coupling reaction was showed:the extra Grignard reagent served as a mild oxidant and TMEDA was able to doubly metallate Grignard reagent or other magnesium salts in order to improve the conversation of this reaction. So we could get high yields of2-substituted quinoline derivatives or other compounds.In summary, we have developed an efficient C-C coupling method of N-heterocyclic aromatic compounds with aromatic Grignard reagents. The addition of TMEDA effectively improved the addition-oxidation process and no catalytic metal is needed. This process is mild, cost-effective, therefore it supply a new access to coupling of N-containing hetero-aromatic compounds with other aromatic compounds.