Chiral acid-catalysed enantioselective C−H functionalization of toluene and its derivatives driven by visible light

Abstract

Toluene and its derivatives are petroleum-derived raw materials produced from gasoline by catalytic reformation. These abundant chemical feedstocks are commonly used as solvents in organic synthesis. The C(sp 3 )−H functionalization of these unactivated substrates has been widely used to directly introduce benzylic motifs into diverse molecules to furnish important compounds. Despite these advances, progress in asymmetric catalysis remains underdeveloped. Here, we report photoinduced radical-based enantioselective C(sp 3 )−C(sp 3 ) coupling reactions of activated ketones with toluene and its derivatives by means of chiral acid catalysis. With a La(OTf) 3 /pybox complex catalyst, a variety of chiral 3-hydroxy-3-benzyl-substituted 2-oxindoles, including many conventionally difficult-to-access variants, are obtained directly from isatins in high yields with good to excellent enantioselectivities. Acenaphthoquinone is also compatible with the use of a chiral phosphoric acid (CPA) catalyst, leading to another series of important enantioenriched tertiary alcohols.

Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates

“…A noteworthy feature for the reactions discussed above is the difficulty in controlling the stereochemistry on the C-H-derived alkyl radical carbons, when an amine or Lewis acid catalyst is not directly bound to these radicals. Thus, poor to moderate diastereoselectivity is usually obtained [48][49][50][51]53,55,57,58 .…”

“…In addition to these chiral-at-metal Lewis acids, other catalysts of Ni ( 11 ) 56 , Cu ( 12 ) 57 , and La ( 13 ) 58 (Fig. 5e ) with various chiral ligands have recently been discovered to promote C( sp 3 )–H functionalization via enantioselective radical coupling.…”

“…Thus, α-C( sp 3 )–H bonds of cyclic ketones are directly oxidized with high enantioselectivity. In addition, CPA has been also briefly explored by Jiang’s group for the enantioselective coupling of C–H-derived free benzylic radicals with ketyl radicals 58 . A noteworthy feature for the reactions discussed above is the difficulty in controlling the stereochemistry on the C–H-derived alkyl radical carbons, when an amine or Lewis acid catalyst is not directly bound to these radicals.…”

Visible Light‐Driven Cooperative DPZ and Chiral Hydrogen‐Bonding Catalysis

“…Notably, these conditions are not required since the enantioselective coupling of benzyl radicals with push−pull‐type ketone‐substituted α‐oxo radicals could also provide products with satisfactory results when using CPA as the H‐bonding catalyst (Scheme 13D). [ 41 ]…”

Tyrosine and Drug-like Late-stage Benzylic Functionalization via Photoredox Catalysis

“…1, a). 16 A commonly used approach in photoredox C-H functionalization relies on hydrogen atom transfer (HAT), [17][18][19][20][21][22][23][24][25] in which a photocatalytically generated radical species is able to abstract a hydrogen atom from the substrate. However, C-H bond discrimination issues often lead to a poor site-selectivity for benzylic positions.…”