We have developed the first example of a practical, regioselective, and enantioselective intermolecular Buchner ring expansion which is enabled by using continuous flow. Historically, the intermolecular Buchner reaction has been greatly underutilized in synthesis due to poor selectivity and limited substrate scope that arise from the exothermic nature of the reaction. We have demonstrated that the practicality and utility of the reaction are greatly improved under flow conditions due to improved heat transfer and mixing. Reactions of ethyl diazoacetate with a range of symmetric and nonsymmetric arenes afford cycloheptatrienes in good yield and excellent regioselectivity. We also demonstrate the first example of an asymmetric intermolecular Buchner reaction with disubstituted diazo esters in good to excellent enantioselectivity (up to 98% <i>ee</i>). The reaction proceeds with absolute regioselectivity affording cycloheptatrienes with an all carbon quaternary center. The novel highly oxidized seven membered rings are unique scaffolds that can be applied in numerous synthetic and medicinal chemistry programs. To fully leverage their potential, we have embarked on a search for selective reactions of the cycloheptatrienes under thermal, photochemical, oxidative, and reducing conditions.  These studies have led us to carry out a number of reaction screens to provide a knowledge base and toolbox of reactions for manipulating the reactivity the cycloheptatrienes and generating new and exciting molecular scaffolds, which will be tested for neurotrophic activity.

Using flow chemistry to enable the regio- and enantioselective intermolecular Buchner ring expansion

256th National Meeting (2018)

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