Catalytic enantioselective synthesis of small-molecule building blocks with allylic stereogenic centers is an important objective in organic synthesis, but preparing this motif wherein the adjacent olefin is 1,2-disubstituted in a single step is a tremendous challenge. Late-transition-metal-catalyzed intermolecular couplings of nucleophiles and 1,3-dienes in hydrofunctionalization reactions have quickly emerged as a compelling approach to these and related compounds. In this Perspective, we illustrate how these intermolecular diene hydrofunctionalizations have provided an avenue to complex, highly desirable chemical space that is not readily accessed by other technologies. We also aim to provide some insight into the varying mechanistic pathways and nuances of these myriad reactions to help inform future reaction and catalyst design.

We report a method for the catalytic, enantioselective intermolecular addition of aliphatic amines to acyclic 1,3-dienes. In most cases, reactions proceed efficiently at or below room temperature in the presence of 5 mol % of a Pd catalyst bearing a PHOX ligand, generating allylic amines in up to 97:3 er. The presence of an electron-deficient phosphine within the ligand not only leads to a more active catalyst but also is critical for achieving high site selectivity in the transformation.

We report a highly enantioselective Pd-PHOX-catalyzed intermolecular hydroalkylation of acyclic 1,3-dienes. Meldrum's acid derivatives and other activated C-pronucleophiles, such as β-diketones and malononitriles, react with a variety of aryl- and alkyl-substituted dienes in ≤20 h at room temperature. The coupled products, obtained in up to 96% yield and 97.5:2.5 er, are easily transformed into useful chemical building blocks for downstream synthesis.

In this study, we establish that conjugated enynes undergo selective 1,4-hydroamination under Pd catalysis to deliver chiral allenes with pendant allylic amines. Several primary and secondary aliphatic and aryl-substituted amines couple with a wide range of mono-and disubstituted enynes in a nonenantioselective reaction where DPEphos serves as the ligand for Pd. Benzophenone imine acts as an ammonia surrogate to afford primary amines in a two-step/one-pot process. Examination of chiral catalysts revealed a high degree of reversibility in the C-N bond formation that negatively impacted enantioselectivity. Consequently, an electron-poor ferrocenyl-PHOX ligand was developed to enable efficient and enantioselective enyne hydroamination.

We describe the development of Pd–PHOX-catalysed enantioselective couplings of internal dienes with malononitrile and other activated C-pronucleophiles.