Tolerance of Hydroxyl and Ortho-Substituted Groups in the Hayashi–Miyaura Reaction: A Study on Nitroolefin Substrates

This research investigates the underexplored potential of the palladium-catalyzed Hayashi–Miyaura reaction in asymmetric synthesis, focusing on the preparation of novel derivatives of 2,2-diaryl-1-nitroethanes. These compounds are of interest as potential building blocks in medicinal and materials chemistry, yet they remain largely unexamined in enantioselective transformations. The study specifically targets three challenging substrates: 1,3-dimethoxy-5-(2-nitro-1-(o-tolyl)ethyl)benzene, 2-(2-nitro-1-phenylethyl)phenol, and 4-(2-nitro-1-phenylethyl)phenol. These molecules were selected to probe the reaction’s tolerance toward ortho-substitution and free hydroxyl groups—features known to complicate catalytic processes.

Using the chiral catalytic system (S)-iPr-IsoQuinox/Pd(TFA)₂, six different combinations of nitrostyrenes and arylboronic acids were examined. The results revealed that while ortho-substitution on the boronic acid significantly decreased reactivity, similar substitution on the nitrostyrene was well tolerated. Moreover, the reaction demonstrated compatibility with free hydroxyl groups, thereby expanding its applicability to functionalized aromatic systems. Selected substrate combinations were further evaluated using an immobilized catalytic system, which delivered yields and enantioselectivities comparable to those of the homogeneous reaction, albeit with moderate reductions in some cases.

Overall, this work broadens the synthetic scope of the Hayashi–Miyaura reaction and demonstrates its utility in the development of enantioenriched nitroalkanes. It also contributes to the growing field of sustainable catalysis by evaluating recyclable catalyst systems for asymmetric transformations.