Acetate Assistance in Regioselective Hydroamination of Allenamides: A Combined Experimental and Density Functional Theory Study

Abstract

A key factor in the development of selective nucleophilic addition to allenamides is controlling the reactivity of electrophilic intermediates, which is generally achieved using an electrophilic activator via conjugated iminium intermediates. In this combined experimental and computational study, we show that a general and highly chemoselective hydroamination of allenamides can be accomplished using a combination of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and NaOAc. Experimental mechanistic studies revealed that HFIP mediates proton transfer to activate the allenamide, while the acetate additive significantly contributes to N-selective interception. This strategy enables a general hydroamination of allenamides without the use of metals. We demonstrated that various functionalized 1,3-diamines could be readily synthesized and diversified into value-added structural motifs. Detailed mechanistic investigations using the density functional theory revealed the role of NaOAc in the formation of reactive electrophilic intermediates, which ultimately governed the selective formation of 1,3-diamine products. Critically, calculations of the potential energy surface around the proton-transfer transition state revealed that two different reactive electrophilic intermediates were formed when NaOAc was added.

Difluoroenoxysilane: Expanding Allenamide Hydrodifluoroalkylation for Diverse Carbon Frameworks

“…Recently, both our research group and others have made significant progress in achieving the regioselective interception of various C and heteroatom nucleophiles with allenamides. − Most of these have been accomplished by generating conjugated iminium species, which are proposed to form via H + activation (for representative examples, see Scheme C). Therefore, we envisioned that if the corresponding HDFA were feasible, it would result in fluorine-containing molecular frameworks with enamide and carbonyl functionalities.…”