Dearomative Selective Reduction of Structurally Diverse N-Heteroarenes Enabled by Titanium Catalysis

The reduction of aromatic compounds is a stalwart transformation in modern organic synthesis since it allows the generation of novel complex three-dimensional (3D) chemical entities from two-dimensional precursors (2D), linking readily available aro-matic feedstocks with unobtainable alicyclic structures. However, controlling the high level of selectivity of N-heteroarenes (quinolines and pyridines), particularly substituents positioned on the reducible quinoline ring, is both intriguing and challeng-ing, and methods for selective saturation of structurally complex derivatives (multiple aromatic rings) are rarely unaddressed and need some advances. Also, many approaches suffer from scalability problems as well as high cost and low availability of both catalysts and tailor-made ligands. To address this issue, we herein report the first example of commercially available ti-tanocene dichloride (Cp2TiCl2)-catalyzed dearomative selective reduction of structurally diverse nitrogen-based heteroarenes with ammonia borane as a reducing agent (>100 examples). The developed protocol features the advantage of chemoselectivity and wide functional group tolerance of quinolines. Meanwhile, the efficient reduction of challenging and unprotected functional-ized pyridines as well as pyrazines is also furnished with remarkable functional group preservation and also with an improved F(sp3) carbon fraction. Additionally, a few selected furans and benzofuran derivatives were also successfully demonstrated un-der synthetically relevant conditions, and gram-scale synthesis was effectively executed. The methodology can be extended to the saturation of complex N-heteroarenes with conserved selectivity. In addition, density functional theory (DFT) calculations were carried out to shed light on the mechanistic insights into the reduction of quinoline.