An Ugi-Joullié Platform for Medicinally Relevant 1,4-Dihydrobenzothiazines

A concise and modular synthetic platform for the rapid assembly of functionalized 1,4-dihydrobenzothiazines is reported through an Ugi-Joullié two-component reaction of a preformed benzothiazine-derived imine with diverse isocyanides. The methodology proceeds under mild, operationally simple conditions and exhibits broad isocyanide scope, accommodating aryl, benzylic, aliphatic, and heterocyclic substituents to furnish a 19-member library of benzothiazines in 51%-96% yields. The reaction demonstrates high functional-group tolerance and scalability to the millimole level, enabling efficient access to structurally diverse benzothiazine derivatives relevant for medicinal chemistry exploration. Single-crystal X-ray diffraction analyses revealed characteristic conformational features of the scaffold, including a twisted-boat geometry and a Z-oriented arrangement of the two NH groups. In addition, late-stage oxidation of the sulfur atom to the corresponding sulfone was readily achieved in high yield, highlighting the versatility of the scaffold for post-assembly diversification. Preliminary antimicrobial evaluation against a panel of Gram-positive and Gram-negative bacterial strains revealed strain-dependent antibacterial activity for selected derivatives, supporting the suitability of the benzothiazine framework for further medicinal chemistry optimization.