Abstract
A mild and efficient nickel-catalyzed method for the coupling of unactivated primary and secondary alkyl chlorides with the C-H bond of indoles and pyrroles is described which demonstrates a high level of chemo and regioselectivity. The reaction tolerates numerous functionalities, such as halide, alkenyl, alkynyl, ether, thioether, furanyl, pyrrolyl, indolyl and carbazolyl groups including acyclic and cyclic alkyls under the reaction conditions. Mechanistic investigation highlights that the alkylation proceeds through a single-electron transfer (SET) process with Ni(i)-species being the active catalyst. Overall, the alkylation follows a Ni(i)/Ni(iii) pathway involving the rate-influencing two-step single-electron oxidative addition of alkyl chlorides.
Highlights
Functionalized heterocycles are core structures that are found in many natural products, vital drug candidates, and other compounds with signi cant biological activity.[1]
To make the Ni-catalyzed C–H functionalization more general and practical, the major challenge is to perform the reaction under mild conditions employing a wide variety of inexpensive and high-demand unactivated chloro-electrophiles
To achieve this target for alkylation, we screened the coupling of alkyl chlorides with indoles in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) at 60 C
Summary
Functionalized heterocycles are core structures that are found in many natural products, vital drug candidates, and other compounds with signi cant biological activity.[1]. Upon achieving the C-2 alkylation of indoles using an inexpensive (thf)2NiBr2/bpy catalyst under mild conditions, we explored the scope of the reaction with a variety of simple and functionalized alkyl chlorides (Scheme 1). Reaction conditions: indole 1 (0.20 mmol), alkyl halide 2 (0.40 mmol), LiHMDS (0.067 g, 0.40 mmol), (thf)2NiBr2 (0.0037 g, 0.01 mmol), bpy (0.0016 g, 0.01 mmol), and toluene (1.0 mL).
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