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Palladium-Catalyzed Oxidant Dependent Switchable Aza-Wacker Cyclization and Oxidative Dimerization of Benzimidates

Rodney A. Fernandes* and Ashvin J. Gangani

*Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, Maharashtra, India, Email: rfernandchem.iitb.ac.in

R. A. Fernandes, A. J. Gangani, Org. Lett., 2022, 24, 7400-7404.

DOI: 10.1021/acs.orglett.2c02942



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Abstract

Whereas the reaction of O-homoallyl benzimidates with Cu(OAc)2 as oxidant involved an aza-Wacker-type intramolecular cyclization under Pd-catalysis to deliver 4-methylene-1,3-oxazines, K2S2O8 as oxidant promotes a dimerization of O-homoallyl benzimidates to yield benzohydrazonates (azines).

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Details

The document discusses a study on the palladium-catalyzed synthesis of 1,3-oxazines and benzohydrazonates (azines) from O-homoallyl benzimidates, highlighting an oxidant-dependent switchable reaction. Using Cu(OAc)2 as the oxidant under Pd-catalysis, the reaction yields 4-methylene-1,3-oxazines through an intramolecular aza-Wacker-type cyclization. Conversely, employing K2S2O8 as the oxidant results in the oxidative dimerization of O-homoallyl benzimidates to form benzohydrazonates. The study emphasizes the atom economy and operational simplicity of the procedure, which allows for the divergent synthesis of significant molecular scaffolds. The synthesized oxazines exhibit various bioactivities, including sedative, anticoagulant, and antimalarial properties, and are present in anti-HIV drugs like Bictegravir and Dolutegravir. The research also explores the scope of the reaction with different benzimidates, achieving good yields with various substituents. Additionally, the study investigates the synthetic utility of the products through further functionalization, such as Sonogashira coupling and haloalkoxylation. Control experiments suggest that the aza-Wacker reaction proceeds without radical involvement, while the dimerization process is radical-initiated. The findings contribute to the understanding of palladium-catalyzed oxidative amination and dimerization, offering new pathways for synthesizing valuable chemical compounds.


Key Words

N-heterocycles, O-heterocycles, Copper(II)


ID: J54-Y2022