Abstract
Alkoxy radicals have long been recognized as powerful synthetic intermediates with well-established reactivity patterns. Due to the high bond dissociation free energy of aliphatic alcohol O-H bonds, these radicals are difficult to access through direct homolysis, and conventional methods have instead relied on activation of O-functionalized precursors. Over the past decade, however, numerous catalytic methods for the direct generation of alkoxy radicals from simple alcohol starting materials have emerged and created opportunities for the development of new transformations. This minireview discusses recent advances in catalytic alkoxy radical generation, with particular emphasis on progress toward the direct activation of unfunctionalized alcohols enabled by transition metal and photoredox catalysis.
Highlights
In 1911, Heinrich Wieland published one of the earliest reports that implicated the intermediacy of alkoxy radicals in an organic reaction, suggesting that alkoxy radicals were necessary in the formation of tetraphenyldiphenoxyethane from bis(triphenylmethyl)peroxide.[1]
Due to the high bond dissociation free energy of aliphatic alcohol O–H bonds, these radicals are difficult to access through direct homolysis, and conventional methods have instead relied on activation of O-functionalized precursors
Numerous catalytic methods for the direct generation of alkoxy radicals from simple alcohol starting materials have emerged and created opportunities for the development of new transformations. This minireview discusses recent advances in catalytic alkoxy radical generation, with particular emphasis on progress toward the direct activation of unfunctionalized alcohols enabled by transition metal and photoredox catalysis
Summary
In 1911, Heinrich Wieland published one of the earliest reports that implicated the intermediacy of alkoxy radicals in an organic reaction, suggesting that alkoxy radicals were necessary in the formation of tetraphenyldiphenoxyethane from bis(triphenylmethyl)peroxide.[1]. Spectroscopic, mechanistic, and synthetic studies over the years have probed the reactivity of O-radicals,2c,3 nding that alkoxy radicals generally participate in one of three elementary reactions: (1) hydrogen atom transfer,[4,5] (2) b-scission,[6,7] and (3) alkene addition (Scheme 1).[8,9] Of these three reaction classes, perhaps the most common application of alkoxy radicals is hydrogen atom transfer (HAT).[10,11] Due to the propensity of O-centered radicals to form strong bonds to hydrogen atoms (O–H BDFE z 105 kcal molÀ1), hydrogen atom abstraction from comparatively weaker aliphatic C–H bonds (BDFE z 98–102 kcal molÀ1) is frequently observed.[12,13] In particular, intramolecular 1,5-HAT allows for the direct abstraction of d-C–H bonds and enables selective C–H functionalization, a synthetic strategy that has been exploited since the development of the Barton nitrite ester reaction[14] and continues to be explored in modern catalytic methods.2e,2f
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