Lewis Acid Promoted Benzylic Cross‐Couplings of Pyridines with Aryl Bromides

Non-directed allylic C–H acetoxylation in the presence of Lewis basic heterocycles

“…While Lewis basic functionalities have been employed for directed C–H activation, 8,11 they generally impede alternate non-directed C–H functionalization reactivity (Figure 1). 27–35 These issues have been addressed in the context of transition metal-catalyzed olefin metathesis, 36 but they have yet to be investigated within the framework of C–H activation. Herein, we describe two strategies to block the Lewis basic sites that would otherwise have a deleterious effect on the desired C–H activation process.…”

Chemoselective palladium-catalyzed deprotonative arylation/[1,2]-Wittig rearrangement of pyridylmethyl ethers

“…12 Difficulties in the direct benzylic arylation of 2-substituted pyridines, however, have been encountered and are attributed to the ability of pyridyl nitrogens to act as ligands. 12j, 13 Successful strategies to circumvent this potential problem include addition of Lewis acids to bind the pyridyl nitrogen and increase the reactivity of the benzylic C–H’s. 12j Notably, acceleration of palladium catalyzed reactions of pyridine derivatives by addition of Lewis acids has been described by Nolan, 14 Hartwig, 15 and Trost.…”

“…12j, 13 Successful strategies to circumvent this potential problem include addition of Lewis acids to bind the pyridyl nitrogen and increase the reactivity of the benzylic C–H’s. 12j Notably, acceleration of palladium catalyzed reactions of pyridine derivatives by addition of Lewis acids has been described by Nolan, 14 Hartwig, 15 and Trost. 16 Other workarounds include use of substrates with directing groups, such as 2-(2-pyridyl)acetic acids, 12h 2-(2-pyridyl)ethanols, 12b pyridine N -oxides, 12d, 12f and N -iminopyridines.…”

“…12j Notably, acceleration of palladium catalyzed reactions of pyridine derivatives by addition of Lewis acids has been described by Nolan, 14 Hartwig, 15 and Trost. 16 Other workarounds include use of substrates with directing groups, such as 2-(2-pyridyl)acetic acids, 12h 2-(2-pyridyl)ethanols, 12b pyridine N -oxides, 12d, 12f and N -iminopyridines. 12e We previously used 2-benzyl pyridine (p K a = 28.3–28.7 in THF), where the benzylic hydrogens are estimated to about 6 orders of magnitude more acidic than those in 2-picoline (p K a = 34 in THF).…”

Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

“…A highly regioselective zincation of various lutidines can be achieved under mild conditions using TMPZnCl·LiCl (62) [52 -56]. Thus, 2,3-dimethylpyridine (63) direct zincation of 2,4-dimethylpyridine (67) using TMPZnCl·LiCl (62) produces a mixture of regioisomers, the addition of BF 3 ·OEt 2 considerably improves the regioselectivity of the metalation and leads only to the 4-benzylated pyridine 68 in 82 % yield after Pdcatalyzed cross coupling (Scheme 16) [56].…”