Late-Stage Intermolecular Allylic C-H Amination

Abstract

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [Mn^III(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [Mn^III(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

Scheme 1.

Approaches for Allylic C—H Amination

Scheme 2.

Late-Stage Allylic C–H Amination on Five Classes of Olefin-containing Natural Products^a

Scheme 3.

Mechanistic Insights Probing Reaction Pathway (a), and Reactivity Properties (b, c, d)^a