Synthesis of substituted pyrido-oxazepine-3-ols and benzo-oxazin-2-yl methanol via tandem epoxide opening and SNAr reaction

A general and catalyst-free protocol for the synthesis of pyrido-oxazepine-3-ols and benzo-oxazin-2-yl methanol via tandem epoxide opening followed by SNAr reactions is reported. Oxirane derived from tribromopyridine undergoes epoxide opening followed by the SNAr reaction, yielding seven-membered pyrido-oxazepine-3-ols. Predominantly 2-cyclized pyrido-oxazepine-3-ols observed in this reaction. Oxirane derived from tribromonitrobenzene undergoes epoxide opening followed by SNAr reaction to produce six-membered benzo-oxazin-2-yl methanol. When oxirane treated with primary amine, mainly 2-cyclized benzo-oxazin-2-yl methanol is formed. furthermore, treatment of oxirane with secondary amine result in regio-selective 4-cyclized benzo-oxazin-2-yl methanol, accompanied by de-alkylation. A plausible reaction mechanism is proposed for the synthesis of benzo-oxazin-2-yl methanol, which proceeds via epoxide opening followed by a Smiles rearrangement.

Automated summary

A general and catalyst-free method for synthesizing pyrido-oxazepine-3-ols and benzo-oxazin-2-yl methanol is described, involving tandem epoxide opening and SNAr reactions. The reaction of oxiranes derived from tribromopyridine yields seven-membered pyrido-oxazepine-3-ols, predominantly in the 2-cyclized form. On the other hand, oxiranes derived from tribromonitrobenzene produce six-membered benzo-oxazin-2-yl methanol, with primary amines favoring 2-cyclization and secondary amines leading to regioselective 4-cyclization.