Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis

Abstract

Direct C-4-selective addition of pyridine across alkenes and alkynes is achieved for the first time by nickel/Lewis acid cooperative catalysis with an N-heterocyclic carbene ligand. A variety of substituents on both alkenes and pyridine are tolerated to give linear 4-alkylpyridines in modest to good yields. The addition across styrene, on the other hand, gives branched 4-alkylpyridines. A single example of C-4-selective alkenylation is also described.

Cobalt‐Catalyzed C4‐Selective Direct Alkylation of Pyridines

“…In contrast, under the Ni 0 /Al system, which proceeds by oxidative addition, H/D scrambling occurred at both the C2 and C3 positions. [10,27] Altogether, these contrasting observations suggest that the present cobalt-catalyzed C4-selective alkylation of pyridines would proceed through a pathway that does not involve oxidative addition. In summary, we have developed a new catalyst for the atom-economical C4-selective direct alkylation of pyridines.…”

“…[26] 2) The C3-alkylation adduct was not detected at all under the present conditions. C3 functionalization was, however, the major side reaction in the Ni 0 /Al system used by the groups of Nakao/Hiyama and Ong, [10] which proceeds through oxidative addition. 3) Profiles of H/D scrambling when using [D 5 ]pyridine as a substrate under the present cobalt-catalyzed conditions and the Ni 0 /Al system were markedly different.…”

CH Bond Alkylation (Including Hydroarylation of Alkenes)

“…In addition to iridium and cobalt catalysis, and following the work initiated by Cavell et al [138] on the alkylation of azolium salts, nickel-catalyzed alkylations of various heteroarenes (i.e., indoles [139], benzimidazoles [139], benzothiazoles [139], benzoxazoles [139] In addition, the selective C-4 alkylation of pyridines could be achieved through the use of sterically hindered NHC ligands and cooperative Lewis acids (Scheme 19.99) [142,143]. The best yields were obtained with the very bulky (2,6-t-Bu 2 -4-Me-C 6 H 2 O) 2 AlMe (MAD) aluminum reagent.…”

Transition-Metal-Catalyzed Functionalization of Pyridines

“…(mono 45%, di: 31%) R = CH 2 SiMe 3 : (mono: 40%) 48% (39) 2010 年 Nakao 和 Hiyama 等 [50] 报道了 Ni(cod) 2 催化 的吡啶对位烷基化, 主要生成直链烷基化产物, 只有吡 啶和苯乙烯反应主要生成支链烷基化产物(Eq. 40).…”