K3PO4–Mediated Synthesis of Chromeno–[3,4‐c]isoxazole from 3–Nitro–2H–chromene and α–Chloro Aldehyde via Michael Addition/C−Cl Bond Cleavage/Deformylation as Key Fragmentation Sequences

Abstract

AbstractHere we report a transition metal– and oxidant–free annulation cascade method for the synthesis of chromeno–isoxazoles. The annulation reaction involves easily accessible starting materials, 3‐nitro‐2H‐chromene and α‐chloro aldehyde, yielding the structurally intriguing framework, chromeno[3,4‐c]isoxazoles employed by tripotassium phosphate as a base. The isoxazole ring construction over the 2H–chromene unit is believed to occur via a series of multiple reaction sequences. Here, the enolate generation/Michael addition/C−Cl bond cleavage/oxy–anionic addition to reactive tethered‐aldehyde/deformylation via retro–C−C and N−O bond cleavages are the most possible sequences which furnish the desired end–product in good chemical yields. The multiple reaction sequences occur in one‐pot at mild conditions, supported by experimental results and a few control experiments including DFT studies. This process exhibits a broad substrates scope illustrating good functional group compatibility towards both the nitrochromenes and aldehydes, and thus prove to be a general and efficient protocol for the synthesis of chromeno[3,4–c]isoxazoles. Overall, the use of nitrochromene as the limiting reagent, noteworthy functional group tolerance, scalability including great applications like chiral pool strategy towards the synthesis of enantioenriched chromeno‐isoxazole are the additional features.