Regioselective Synthesis of 9- <i>O</i> -Arylboldine Derivatives Using the Copper-Catalyzed Chan–Lam Reaction†

High Resolution Image Download MS PowerPoint Slide While alkylated and acylated aporphine derivatives are well-represented in the literature, O -arylated analogues remain scarce. We report here a practical and regioselective methodology for the synthesis of 9- O -arylboldine derivatives. Our approach utilizes a copper-catalyzed Chan–Lam coupling reaction, enabling the efficient preparation of 30 novel 9- O -arylboldine derivatives. This operationally simple procedure proceeds at room temperature under ambient air conditions, employing readily available phenylboronic acids as coupling partners. Extensive one- and two-dimensional NMR studies unequivocally confirmed the desired 9- O -regioselectivity. Further demonstrating the scope of this method, we synthesized five new 3-bromo-9- O -arylboldine derivatives starting from 3-bromoboldine. Additionally, some 9- O -phenylboldine derivatives served as versatile intermediates, undergoing transformations to access N, N -dimethylammonium derivatives and enabling the conversion of 4′-formylphenyl derivative 6w into four aminoaporphine derivatives via reductive amination. This study confirms the usefulness of the Chan–Lam cross-coupling reaction as a powerful and flexible synthetic tool for the derivatization of natural products, particularly with the goal of expanding the chemical diversity of aporphine alkaloids.