Regioselective Ortho‐Arylation of Polyhalo‐Substituted (Hetero)Aryl Tosylates Using an Integrated Continuous Flow/Batch Protocol

Abstract

The regioselective ortho arylation of polyhalo‐substituted (hetero)aryl tosylates has been investigated employing an integrated continuous flow/batch protocol. The regioselective ortho metalation of (hetero)aryl tosylates using n‐BuLi and ZnCl2 was effectively achieved using continuous flow chemistry in a short residence time of 10.92 s, without removal of the tosyloxy group. The Pd‐catalyzed Negishi coupling reactions of various (hetero)aryl iodides with the resulting arylzinc species proceeded readily at room temperature in 31% to 98% yields. Finally, the method was applied to the synthesis of perampanel in four linear steps, with an overall yield of 43%.

Integrated continuous‐flow/batch protocol for ortho‐selective alkynylation of (hetero)aryl tosylates

“…They achieved a linear alkyne synthesis without regioselectivities at elevated temperatures (Scheme 1b). 3f Recently, we reported a new and efficient platform for the ortho ‐selective arylation of polyhalo‐substituted (hetero)aryl tosylates 7 . The tosyloxy group was employed as a transformable directing group for the continuous‐flow regioselective zincation without the formation of (hetero)arynes.…”

“…We began our studies with (iodoethynyl)benzene 1a and 2,4‐dibromophenyl 4‐methylbenzenesulfonate 2a as test substrates containing two competitive bromines (Table 1). Initially, ortho ‐selective zincation was performed by modifying the previously reported flow conditions 7 . Subsequent alkynylation was then attempted under various reaction conditions to obtain ortho ‐alkynylated phenyl tosylate 3a .…”

“…Initially, ortho-selective zincation was performed by modifying the previously reported flow conditions. 7 Subsequent alkynylation was then attempted under various reaction conditions to obtain ortho-alkynylated phenyl tosylate 3a. The optimized conditions consisted of 2a (1.69 equiv), n-BuLi (1.70 equiv), zinc chloride (1.35 equiv), and Pd(dppf)Cl 2 (5 mol%) at room temperature (Entry 1).…”