Nucleophilic and acid catalysis in phosphoramidite alcoholysis

Abstract

Numerous triflates, mesylates, chlorides, trifluoroacetates and tetrazolides of trialkylammonium, pyridinium and azolium ions have been studied as activators for the reaction of N,N,O,O′-tetraisopropylphosphoramidite with propan-2-ol in acetonitrile. The progress of the reactions was followed by ³¹P NMR spectroscopy, and the pK_a values of the activators were determined by a ¹³C NMR spectroscopic method based on competing simultaneous protonation of two bases. The salts promoted the reaction both as acids and nucleophiles, the acidity playing a more important role than the nucleophilicity. The Brønsted α value for the general acid catalysis was observed to range from 0.6 to 0.9 and the β_nucl value to be 0.2 (pK_a of the conjugate acid used as the measure of nucleophilicity). Mixtures of neutral azoles or pyridines and weakly acidic ammonium salts were also shown to be useful activators that allow the acidity and nucleophilicity to be tuned independently of each other.