Free radical reactions represent an important and versatile class of chemical transformations. Nitrogen-centered radical applications remain underexplored due to the lack of convenient methods for their generation. Recent advances have improved access to nitrogen-centered radicals. Guided by this approach, we hypothesized that alcohols and amines could anchor sulfamate ester and sulfamide directing groups, which could support nitrogen-centered radicals, and thereby guide C–H functionalization reactions. The featured directed technology has been inspired by one of the most reliable and powerful known reactions to guide C–H functionalization reactions: the Hofmann–Löffler–Freytag (HLF) reaction. Like many of the most robust radical-mediated technologies, the HLF reaction is typically guided through 1,5-hydrogen-atom transfer (HAT) processes, which proceeds through a kinetically-favorable six-membered ring transition state. By contrast, few reports describe 1,6-HAT with a traceless linker, such as a sulfamate ester or a sulfamide, and there are no general strategies to enable alcohols or amines to serve as anchors to direct functionalization of aliphatic gamma-C(sp3)–H centers. This talk will outline this novel strategy to harness alcohols and amines to replace C–H bonds at gamma-C(sp3)–H centers, which are not generally accessible to directed functionalization. We will demonstrate that C–H abstraction can be robustly coupled with varied functionalization reactions. This talk will highlight the first generalizable synthetic strategy to functionalize gamma-C(sp3)–H bonds based on masked alcohols or amines, to push the boundaries of organic chemistry at a fundamental level and benefits drug discovery.

Alcohol and amine derivatives guide position-selective C–H functionalization reactions

2019 Fall National Meeting

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