Thorpe–Ingold Effect in Branch‐Selective Alkylation of Unactivated Aryl Fluorides

Abstract

Presented herein is a general protocol for the alkylation of simple aryl fluorides with unbiased secondary Grignard reagents by means of nickel catalysis. This study revealed a general Thorpe-Ingold effect in the ligand backbone which confers a high degree of selectivity for the secondary carbon center in the C-C coupling event. This protocol is characterized by mild reaction conditions, robustness, and simplicity. Both electron-rich and electron-deficient aryl fluorides are suitable candidates in this transformation. Equally amenable are a variety of heterocycles, permitting the coupling without over alkylation at the electrophilic sites.

A Concise and Efficient Approach to 2,6-Disubstituted 4-Fluoro­pyrimidines from α-CF3 Aryl Ketones

“…For instance, azidopyrimidines could be obtained by treating 4-fluoropyrimidines with sodium azide 13 (Figure 2, a). Meanwhile, 4-fluoropyrimidines reacted with Grignard reagents to afford alkylated pyrimidines 14 (Figure 2, b), and if reacted with amines, aminopyrimidines 15 would be obtained (Figure 2, c). Additionally, pyrimidone could be constructed by nucleophilic substitution from 4fluoropyrimidine followed by oxidation processes 16 ( Figure 2, d), and diaryl compounds could also be obtained via a nucleophilic substitution reaction 17 (Figure 2, e).…”

Recent Advances in Transition‐metal‐catalyzed C−C Bond Formation via C(sp2)−F Bond Cleavage

“…In 2018, Cornella and co‐workers developed the first general protocol for the nickel‐catalyzed alkylation of unactivated aryl fluorides with secondary Grignard reagents at room temperature (Scheme 22). [31] This procedure was characterized by minimal isomerization, mild reaction conditions, and tolerance of various functional groups and heterocycles. The employment of gem ‐dialkylated bisphosphine ligands resulted in a strong chelation of the nickel catalyst and induced a geometrically constrained environment that inhibited the isomerization of the alkyl moiety.…”

Transition-Metal-Catalyzed Cross-Coupling Reactions of Grignard Reagents

“…In 2018 Cornella and co-workers reported the robust, simple and highly selective nickel-catalyzed alkylation of unactivated aryl fluorides with secondary Grignard reagents under mild reaction conditions, shown in Scheme 13 for the reaction of 1-fluoro-4-methoxybenzene (26) with sec-butylmagnesium chloride (27) to give 1-sec-butyl-4methoxybenzene (28). 41 The reaction shows a wide functional group tolerance. In 2019, Tang and co-workers prepared tert-butylarenes 31 in moderate to good yields, but with an excellent t Bu/ i Bu ratio, via a ligand-free nickel-catalyzed Kumada-Tamao-Corriu cross-coupling of aryl bromides 30Br with tertbutylmagnesium chloride (14b) (Scheme 14).…”