N-Methylpyrazoles are found in many biologically active molecules and the control of N1 versus N2-methyl regioselectivity in the formation of N-methylpyrazoles is a longstanding challenge in organic synthesis. Therefore, the development of general methodologies that access either the N1-methyl or N2-methyl regioisomer via cyclization of vinylogous amides and methylhydrazine would be beneficial to the synthetic community. A traditional reaction optimization approach did not initially yield satisfactory results in terms of control of regioselectivity or product conversion. The initial reaction dataset was then used to do an iterative Bayesian optimization. Several algorithms were employed which led to improvements in regioselectivity and product conversion for both the N1 and N2-methylpyrazole isomers with simple vinylogous amide substrates. Additionally, preliminary mechanistic investigations of the N1 and N2 pathways will be discussed.

Development of regioselective N-methylpyrazole cyclizations using bayesian optimization

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