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.

Chemodivergent Nickel(0)-Catalyzed Arene C–F Activation with Alkynes: Unprecedented C–F/C–H Double Insertion

“…In sharp contrast, in the presence of PivOH, product 2aa was not observed, while up to 46% of the linear alkenylation product 4aa was obtained (Figure 2a), providing a new strategy towards molecular complexity by C-F activation. (19), Ni-C2 2.1060 (17), Ni-C3 1.8946 (16), Ni-N1 1.9209 (16), Ni-N2 1.9011(16) (orange: first inserted alkyne in E conformation; magenta: second inserted alkyne in Z conformation; green: nickel(II) center). c) Competition experiment with equimolar amounts of 1a and the analogous non-fluorinated substrate, obtaining 2aa and 3aa products mainly from C-F activation (1a, full conversion).…”

“…Transition metal-catalysed Ar-F functionalization is considerably more challenging than classical Ar-H or Ar-Hal (Hal = I, Br, Cl) activation, generally showing low selectivities and requiring electronically biased polyfluorinated substrates. [5][6][7] In particular, C-C formation reaction via C-F cleavage of fluoroarenes using nickel catalyst has been reported for Kumada-Corriu, [8][9][10][11][12][13][14][15][16] Suzuki-Miyaura [17][18][19][20][21][22] and Negishi 23 cross-coupling reactions. However, all these methods use activated aryl nucleophiles, such as highly reactive Grignard reagents, zincates and boronic acids as the coupling partner for C-C formation via transmetallation (Scheme 1a).…”