Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic π-Facial Discrimination

Abstract

Chiral iridium complexes modified by SEGPHOS catalyze the 2-propanol mediated reductive coupling of branched allylic acetates 1a–1o with formaldehyde to form primary homoallylic alcohols 2a–2o with excellent control of regio- and enantioselectivity. These processes, which rely on enantiotopic π-facial discrimination of σ-allyliridium intermediates, represent the first examples of enantioselective formaldehyde C-C coupling beyond aldol addition.

Enantioselective Formation of All-Carbon Quaternary Centers via C–H Functionalization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethylation

“…Furthermore, enantiotopic π-facial discrimination for the reactive allyliridium isomer is efficient, resulting in high levels of enantioselectivity. 8 Thus, by inverting the canonical behavior of methanol in its reaction with unsaturates (etherification), enantioselective C–H functionalization of methanol is achieved for the first time (Scheme 1). …”

Recent Developments in C–C Bond Formation Using Catalytic Reductive Coupling Strategies

“…86 More recently, it has been shown that SEGPHOSmodified chiral iridium complex 131 can catalyze regioand enantioselective reductive coupling of allylic acetates 129 with formaldehyde to form primary homoallylic alcohols 130 using 2-propanol as a reductant (Scheme 25). 87 Iridium-catalyzed allylation of aldehyde or alcohol proelectrophiles with allene gas as the pronucleophile has also been reported (Scheme 26). 88 An inversion of enantioselectivity is observed for allene versus allyl acetate pronucleophiles using the same catalyst and ligand combination.…”

Experimental and density functional theory studies on hydroxymethylation of phenylboronic acids with paraformaldehyde over a RhPPh3 catalyst

“…As well known, the hydroxymethylation is an important reaction for introduction of a hydroxymethyl group into a molecular. [15][16][17][18][19][20][21][22] It has been reported that BAs could be synthesized via hydroxymethylation of aryl halides and triflates [23] ; however, the catalyst was rather complicated and high loadings (the combination of 5 mol % Pd (dba) 2 , 12 mol% Ru-phos, and 1.5 equiv. Na 2 CO 3 ), and the reactants were expensive resulting in a high-cost route.…”