The Mitsunobu reaction has been widely employed to activate alcohols for bimolecular substitution with a wide range of pronucleophiles (pKa &lt; 11) using stoichiometric amounts of diethyl azodicarboxylate (DEAD) and triphenylphosphine (TPP.) In 2019, a redox-neutral Mitsunobu protocol was reported, in which a novel 2-hydroxybenzylphosphine oxide (2-HOBPO) organocatalyst activated alcohols for an SN2 reaction without any stoichiometric additives like DEAD or TPP, and produced water as the sole byproduct. However, this redox-neutral protocol required highly acidic pronucleophiles (pKa &lt; 3.5) severely limiting the scope compared to the classical Mitsunobu reaction. Herein we present a facile modular synthesis to prepare novel 2-HOBPO analogs capable of facilitating the redox-neutral Mitsunobu coupling. A systematically varied library of 2-HOBPO catalyst analogs with modifications that influence the steric bulk and electronics of the organocatalyst will elucidate the structure-activity relationship and promote the rational design of organocatalysts to expand the scope of the redox-neutral Mitsunobu reaction.

Understanding structure-activity relationships to improve alcohol activation

ACS Spring 2022

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