Synthesis of 2H-1, 4-benzoxazine compounds

Optically pure 3,4-dihydro-2H-1,4-benzoxazines are important structural units widely found in natural products and pharmaceutically active molecules, such as the well-known broad-spectrum antibiotic levofloxacin. The asymmetric synthesis of such compounds has attracted considerable attention from chemists. Over the past decades, numerous synthetic approaches have been developed, including multi-step synthesis and kinetic resolution. However, strategies for the direct construction of 3,4-dihydro-2H-1,4-benzoxazines via asymmetric catalysis remain relatively limited.

In our work, we employed bifunctional quaternary phosphonium salt catalysts to stereoselectively control the capture of α-haloketones (as C1 synthons) by o-aminophenols and aldehydes, which in situ generate 1,5-bifunctional active intermediates. Through an asymmetric three-component [5 + 1] cycloaddition reaction, we achieved the efficient and highly selective synthesis of 3,4-dihydro-2H-1,4-benzoxazine derivatives, offering a novel strategy for the construction of these heterocyclic compounds.

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