Thermal and Photoinduced Copper-Promoted C–Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis

2-Alkyl-1,2-benzisoselenazol-3(2 H )-ones, represented by ebselen ( 1a ), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N -substituted ortho -halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2 H )-ones containing a C–Se–N bond. The copper ligand (1,10-phenanthroline) facilitates C–Se bond formation during heating via a mechanism that likely involves atom transfer (AT), whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of 15 2-alkyl-1,2-benzisoselenazol-3(2 H )-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide–alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis ( Mtb ) growth and Mtb Antigen 85C ( Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 μg/mL and an Mtb Ag85C apparent IC 50 of 8.8 μM.