Regioselective Synthesis of 9‑O‑Arylboldine Derivatives Using the Copper-Catalyzed Chan-Lam Reaction†.

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.