O-H hydrogen bonding promotes H-atom transfer from α C-H bonds for C-alkylation of alcohols

Abstract

The efficiency and selectivity of hydrogen atom transfer from organic molecules are often difficult to control in the presence of multiple potential hydrogen atom donors and acceptors. Here, we describe the mechanistic evaluation of a mode of catalytic activation that accomplishes the highly selective photoredox α-alkylation/lactonization of alcohols with methyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a particular role of tetra-n-butylammonium phosphate in enhancing the selectivity for α C-H bonds in alcohols in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds.

Fig. 1. Proposed hydrogen bond–assisted C–H activation of alcohols

BDE values are available in (–15).

Fig. 2. Reaction development

(A) H-bond–assisted C–H activation of alcohols. Shown is a proposed mechanistic pathway for the C-alkylation of alcohols with Michael acceptors. SET, single-electron transfer. (B) Evaluation of hydrogen-bonding catalysts. Yield determined by means of ¹H NMR, using an internal standard. (C) Selected scope of simple alcohol addition to methyl acrylate. Only products are shown; experimental conditions are as in (B). Isolated yields are reported.

Fig. 3. Selected alcohol scope for H-bond–assisted C–H activation

Additions to methyl acrylate were carried out at 27°C for 24 hours, unless otherwise noted. Isolated yields are reported. Detailed experimental procedures and full scope of alcohols/Michael acceptors are provided in the supplementary materials. Dagger symbol indicates 40 hours reaction time; double-dagger symbol indicates 48 hours reaction time; and asterisk indicates 1:1 mixture of E/Z isomers. No alkylation of positions marked with blue circles was observed in any case.

Fig. 4. Mechanistic studies

(A) H-bond–dependent selectivity of α-oxy C–H alkylation. (B) Kinetic isotope effect determined from two parallel kinetic analyses. (C) Kinetic isotope effect determined from intramolecular competition experiment. (D) Kinetic isotope effect determined from intermolecular competition experiment. (E) Evaluation of the enantiomeric excess of unreacted alcohol under standard C-alkylation conditions. (F) Effect of TBAP on the rate of C–H abstraction from 35.