Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C–H bond functionalization

Abstract

A novel protocol for nickel-catalyzed direct sp(2) C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach provides new access to a variety of alkylated N-aromatic heterocycles which are potentially of great importance in medicinal chemistry.

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…(1)]. [126] Theu se of Ni(dppp)Cl 2 and 1,2-dichloroethane as catalyst and oxidant, smoothly promotes the transformation with simple primary and secondary alkyl Grignard reagents at room temperature [Scheme 39, Eq. [126] Theu se of Ni(dppp)Cl 2 and 1,2-dichloroethane as catalyst and oxidant, smoothly promotes the transformation with simple primary and secondary alkyl Grignard reagents at room temperature [Scheme 39, Eq.…”

Beyond Friedel and Crafts: Innate Alkylation of C−H Bonds in Arenes

“…(1)] . Finally, the alkylation of benzimidazole derivatives, as well as of some purines, could also be performed with alkyl Grignard reagents under nickel catalysis, as described by Qu and Guo . The use of Ni(dppp)Cl 2 and 1,2‐dichloroethane as catalyst and oxidant, smoothly promotes the transformation with simple primary and secondary alkyl Grignard reagents at room temperature [Scheme , Eq.…”

Nickel‐Catalyzed Coupling of Thiomethyl‐Substituted 1,3‐Benzothiazoles with Secondary Alkyl Grignard Reagents

“…However, in the synthetic application of this reaction, difficulties would arise from low stability of some of the metalated 1,3‐azoles7 and/or the limited compatibilities of functional groups under the strong basic conditions. More recently, the insertion of olefins into C2H bonds (Scheme , path C)8 and oxidative coupling at the C2 position with alkyl Grignard reagents (Scheme , path D)9 or with N ‐tosylhydrazones as the carbene source (Scheme , path E)10 have been reported. Although these reactions can be useful for introducing primary alkyl groups, except when hydrazones are used in the reaction,10 examples of the introduction of secondary alkyl groups are limited to allylic,4f isopropyl,5b benzylic,8c cyclo‐alkyl9 groups.…”

“…More recently, the insertion of olefins into C2H bonds (Scheme , path C)8 and oxidative coupling at the C2 position with alkyl Grignard reagents (Scheme , path D)9 or with N ‐tosylhydrazones as the carbene source (Scheme , path E)10 have been reported. Although these reactions can be useful for introducing primary alkyl groups, except when hydrazones are used in the reaction,10 examples of the introduction of secondary alkyl groups are limited to allylic,4f isopropyl,5b benzylic,8c cyclo‐alkyl9 groups. This can be attributed to the low reactivities of secondary alkyl groups due to steric hindrance and/or to the ease of β‐hydrogen elimination from secondary alkyl–metal intermediates.…”