Nickel-Catalyzed Chemoselective Arylation of Amino Alcohols

A systematic evaluation of competitive bisphosphine/Ni-catalyzed C-N versus C-O cross-couplings involving model compounds enabled development of hitherto unknown chemoselective O- and N-arylation of amino alcohols with (hetero)aryl chloride electrophiles, without recourse to protection group chemistry. Use of the CyPAd-DalPhos pre-catalyst C2 enabled particularly challenging O-arylation chemoselectivity in amino alcohols featuring branched primary and secondary alkylamine groups, while selective N-arylation was observed in substrates featuring less-hindered linear alkylamine and aniline reacting groups. Useful reaction scope in the (hetero)aryl chloride was achieved throughout, and the ability to conduct such transformations using benchtop handling of materials is demonstrated.

Automated summary

A systematic evaluation of competitive bisphosphine/Ni-catalyzed C-N versus C-O cross-couplings involving model compounds enabled the development of selective O- and N-arylation of amino alcohols with (hetero)aryl chloride electrophiles, without the need for protection group chemistry. The use of the CyPAd-DalPhos pre-catalyst C2 allowed for challenging O-arylation in amino alcohols with branched alkylamine groups, while selective N-arylation was observed in substrates with less hindered linear alkylamine and aniline groups. The reaction scope in (hetero)aryl chloride was broad, and the transformations could be conducted using benchtop handling of materials.