Aryl chlorides are numerous in a wide variety of small molecules, especially prevalent in pharmaceuticals as synthetic handles for late-stage functionalization and for improvement in bioavailability. As such, there is a comprehensive library of methodologies to access aryl chlorides, with electrophilic aromatic substitution (SEAr) in the forefront. However, one of the main shortcomings of SEAr is the innate electronic properties of the substrate leading to a mixture of undesired regioisomers. Therefore, it becomes a synthetic challenge to access the less favored regioisomers when the substrate has a strong activating electronic preference. In 2015, we disclosed that sulfur-derived Lewis bases such as triphenylphosphine sulfide can catalyze the chlorination of arenes and heterocycles under mild conditions through activation of N-chlorosuccinimide. One of the shortcomings was that it did not address the issue of regioselectivity. Hence in 2016, we developed a regiocontrolled EAS chlorination and bromination of phenols, which highlighted various Lewis Base catalysts that could reverse or enhance the innate regioselective nature of the phenol. Despite these results, we found limitations in reactivity and substrate scope for less electron-rich heteroarenes. To solve these problems, we embarked on mechanistic studies to better understand how our Lewis base catalysts function. Our initial in silico findings predicted our catalyst can interact with the chlorine atom through a halenium adduct, implying that catalyst structure can control regioselectivity. Additionally, monitoring reactions via nuclear magnetic resonance (NMR) spectroscopy and 1H kinetic experiments revealed the formation of unique catalytic byproducts for both triphenylphosphine and Nagasawa’s bis-thiourea in the presence of N-chlorosuccinimide, which can heavily impact the rate and regioselectivity of SEAr halogenation. Based on these results, we then developed new selenium Lewis base catalysts derived from 1-indanol that could enhance the initial rate of reaction while imparting comparable regioselective control on phenol without degradation over time.

Mechanistic insights and kinetic studies of Lewis base chlorination of arenes and heterocycles

2019 Fall National Meeting

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