Utopia Point Bayesian Optimization Finds Condition-Dependent Selectivity for N-Methyl Pyrazole Condensation.

ABSTRACT

Utopia Point Bayesian Optimization (UPBO) was used to identify reaction conditions that are highly selective for the formation of N1 and N2-methyl-3-aryl pyrazole constitutional isomers. UPBO was used to explore a wide chemical space and identify basic reaction conditions for a typically acid-catalyzed Knorr pyrazole condensation. These studies revealed that selectivity in the reaction stems from a condition-dependent equilibrium of intermediates prior to dehydration. For the N2-methyl isomer reaction pathway, a hemiaminal intermediate was found to form reversibly under the reaction conditions, enabling a highly selective synthesis of the N2 isomer upon dehydrative workup. UPBO was able to successfully optimize conversion and selectivity simultaneously with search spaces of >1 million potential variable combinations without the need for high-performance computational resources.