Computational Exploration of Anomalous Regioselectivities in Cycloadditions of Ketenes to Oxazolines

Thermal (2 + 2) cycloadditions of several N-carboalkoxy (R)-2-tert-butyldihydrooxazoles with ketenes have been studied experimentally by the Ghosez group. Contrary to results from Seebach and co-workers that the electrophilic addition of acylating agents occurs beta to dihydrooxazole nitrogen, Ghosez found major cycloadducts resulting from an attack of ketene carbonyl carbon beta to oxygen. We investigate the potential energy surface for the cycloaddition of diphenyl- and phenylchloroketenes to two (R)-2-tert-butyldihydrooxazoles with omega B97X-D and mPW1PW91 density functional theory and DLPNO-CCSD(T) wave function theory. These (2 + 2) cycloadditions are concerted but highly asynchronous, and the selectivity trends in ketene addition cases are in good agreement with the experiment. We propose a model based on the buildup of charge in oxazoline to reconcile the regiochemical differences between Ghosez and Seebach's observations.

Automated summary

In this study, the thermal (2 + 2) cycloadditions of N-carboalkoxy (R)-2-tert-butyldihydrooxazoles with ketenes were experimentally investigated. The major cycloadducts were found to result from the attack of ketene carbonyl carbon beta to oxygen, contrary to previous results. Computational analysis using density functional theory and wave function theory supported the experimental findings and proposed a model based on charge accumulation in oxazoline to explain the regiochemical differences between Ghosez and Seebach's observations.