User‐Friendly [(Diglyme)NiBr₂]‐Catalyzed Direct Alkylations of Heteroarenes with Unactivated Alkyl Halides through CH Bond Cleavages

Abstract

A nitrogen and phosphorus ligand-free catalytic system derived from inexpensive [(di-A C H T U N G T R E N N U N G glyme)NiBr 2 ] allowed for efficient direct C À H bond alkylations of heteroarenes with unactivated b-hydrogen-containing alkyl halides under basic reaction conditions. Keywords: alkylation; azoles; C À H activation; heterocycles; mechanism; nickel Substituted heteroarenes are indispensable substructures of, among others, biologically active compounds and functional materials. [1][2][3] In particular, strategies relying on direct C À H bond functionalizations arguably constitute the most ecologically benign and economically attractive methods for their preparation. [4] In recent years, various transition metal catalysts were devised for versatile direct arylations, alkenylations or alkynylations of heteroarenes by cleavages of unreactive C À H bonds.[5] In contrast, direct alkylations of (hetero)arenes with unactivated alkyl halides under basic reaction conditions continue to be difficult, predominantly because these challenging electrophiles lead to undesired b-eliminations.[6] Remarkable recent progress was represented by efficient ruthenium [7] and palladium catalyzed [8] direct alkylations of (hetero)arenes.[6] On the contrary, direct alkylations with less expensive nickel catalysts [9] are scarce, and were thus far solely achieved with nickel complexes derived from tridentate nitrogen ligands. [8g,10-12] Thus, Hu and co-workers elegantly devised the nickel complex [( Me NN 2 )NiCl] bearing a tridentate pincer N 2 Nligand for direct functionalizations of heteroarenes with alkyl halides.[10] Unfortunately, the synthesis of this catalyst involves several reaction steps, which can limit its broader applications.[13] Moreover, four direct alkylations of benzothiazole were recently achieved with a nickel complex derived from the tridentate nitrogen ligand terpyridine.[8g] Within our research program directed towards the development of userfriendly and sustainable C À H bond functionalizations, [14] we developed a cost-effective nitrogen-and phosphorus ligand-free [15] free nickel catalyst for direct alkylations of heteroarenes, on which we wish to report herein.At the outset of our studies, we tested a diverse array of commercially available nickel precursors for the direct C À H bond functionalization of benzoxazole (1a) with alkyl iodide 2a as the electrophile, 2,2'-bipyridine (bpy, 4) as the ligand, and CuI [10] as cocatalyst (Table 1). Among different nickel sources, [(di- Table 1. Nickel precursors for the direct C À H bond alkyla-A C H T U N G T R E N N U N G tion.[a] Entry[Ni] 3aaA C H T U N G T R E N N U N G [(diglyme)NiBr 2 ] 61%[a] Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), [Ni] (5.0 mol%), CuI (7.5 mol%), 4 (6.0 mol%), t-BuOLi (2.0 mmol), 1,4-dioxane (3.0 mL), 140 8C, 16 h; isolated yields.

CH Bond Alkylation (Including Hydroarylation of Alkenes)

“…Experiments were run to understand the mechanism of this alkylation and suggested that an alkyl radical intermediate arising from the alkyl halide is produced during the reaction by single-electron transfer from a heteroarylnickelate intermediate (Scheme 19.33). These results were extended shortly thereafter by Ackermann et al [53], who described the alkylation of …”

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

“…(2)]. [121] More recently,t he Punji group reported the synthesis and use of quinoline-based NNNpincer nickel(II) complexes for the direct alkylation of Scheme 34. Nickel/copper-and copper-catalyzed alkylation of azoles with primary and secondary alkyl halides.…”

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

“…This last strategy was later on fully exploited by Ackermann for the nickel/copper co‐catalyzed direct alkylation of benzoxazoles and benzothiazoles with primary alkyl halides through the generation of alkyl radicals upon reaction with an azole–nickel(I) intermediate [Scheme , Eq. (2)] . More recently, the Punji group reported the synthesis and use of quinoline‐based NNN‐pincer nickel(II) complexes for the direct alkylation of benzothiazoles and 5‐aryloxazole derivatives with primary alkyl halides …”