A pyridine core is a ubiquitous structural motif found in many biologically active natural products and pharmaceuticals. The regioselective functionalization of pyridines, [1] such as the C2selective addition of highly reactive nucleophiles and C2selective deprotonation with a strong base followed by reactions with electrophiles, [2] has long been investigated by many researchers. Catalytic CÀH bond functionalization of pyridines provides atom- [3] and step-economical [4] methods for accessing various functionalized pyridines, and thus has attracted recent interest. [5][6][7][8][9][10][11][12][13][14][15][16] In many reports, a Lewis basic sp 2 nitrogen atom in the pyridine ring was utilized as the directing group, and CÀH bond activation by transition-metal catalysts occurred selectively at the C2 position. [5,7] In contrast, reports on the C3-or C4-selective catalytic CÀH bond functionalization of pyridines without an additional directing group are limited. [8][9][10][11] Thus, further studies into the development of new catalysts for C3-or C4-selective direct functionalization of pyridines are highly desirable. In 2010, Nakao, Hiyama, and co-workers, [10a] and Ong et al. [10b] independently reported the first C4-selective direct functionalization of pyridines through an oxidative addition/insertion/ reductive elimination sequence catalyzed by Ni 0 and bulky Lewis acids. There remains room for improvement in the C4selective direct functionalization of pyridines, however, especially in terms of catalyst loading.To realize the C4-selective alkylation of pyridines, we searched for a new catalyst system based on a different strategy, catalytic nucleophilic addition/rearomatization. [14][15][16] Our working hypothesis is shown in Scheme 1. Hydrometalation of alkenes with a metal hydride catalyst (I) would afford an alkyl-metal species (II). If the alkyl-metal species (II) has sufficient nucleophilicity, its addition to pyridine may afford a dihydropyridine intermediate (III). To realize an atom-economical catalytic process, rearomatization of pyridine without any oxidants and regeneration of the metalhydride catalyst (I) are required.We first screened various metal salts and hydride sources that fulfilled the requirements for Scheme 1. Selected results from the optimization studies are summarized in Table 1.

A Lewis acid catalyzed benzylic C-H bond functionalization of alkyl-substituted azaarenes is described. Sc(OTf)(3) and Y(OTf)(3) promoted the direct addition of alkyl-substituted azaarenes and benzoxazole to enones and an α,β-unsaturated N-acylpyrrole. Products were obtained in 60-96% yield.

Pyridine mit Anhang: Ein neuer Katalysator für die atomökonomische C4‐selektive direkte Alkylierung von Pyridinen wird beschrieben. Eine Kombination aus CoBr2 und LiBEt3H katalysiert die Reaktion von Pyridinen mit 1‐Alkenen bei 70 °C und ergibt die Alkylierungsprodukte mit C4/C2‐Verhältnissen von >20:1. Substrat/Katalysator‐Verhältnisse bis zu 4000 und eine Umsatzzahl von 3440 wurden erreicht.

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