Metal-Free Phosphination and Continued Functionalization of Pyridine: A Theoretical Study

Abstract

This study investigates the mechanism of metal-free pyridine phosphination with P(OEt)3, PPh3, and PAr2CF3 using density functional theory calculations. The results show that the reaction mechanism and rate-determining step vary depending on the phosphine and additive used. For example, phosphination of pyridine with P(OEt)3 occurs in five stages, and ethyl abstraction is the rate-determining step. Meanwhile, 2-Ph-pyridine phosphination with PPh3 is a four-step reaction with proton abstraction as the rate-limiting step. Energy decomposition analysis of the transition states reveals that steric hindrance in the phosphine molecule plays a key role in the site-selective formation of the phosphonium salt. The mechanism of 2-Ph-pyridine phosphination with PAr2CF3 is similar to that with PPh3, and analyses of the effects of substituents show that electron-withdrawing groups decreased the nucleophilicity of the phosphine, whereas aryl electron-donating groups increased it. Finally, TfO− plays an important role in the C–H fluoroalkylation of pyridine, as it brings weak interactions.

First total synthesis of caerulomycin K: a case study on selective, multiple C–H functionalizations of pyridines

“…Notably, the Ph 3 P addition occurs almost exclusively at the para-position (due to stereoelectronic reasons), thus no regioselectivity problems are encountered during this reaction. 28 This was also conrmed by 31 P NMR, with only a sharp singlet observed at 23.01 ppm. Repeating the procedure using now 2 as the starting material, the reaction crude revealed two new signals of similar intensity at 23.55 ppm and 15.37 ppm.…”

Late‐Stage Functionalisation of Pyridine‐Containing Bioactive Molecules: Recent Strategies and Perspectives

“…the additional use of transition metals or designed phosphines such as 154 ) [85] . As for the N ‐aminopyridinium salts, the para ‐selectivity (determined in the first step of the reaction) is attributed to the steric congestion around the ortho ‐position [86] . Notably, tuning of the reaction conditions (e.g.…”

“…[85] As for the N-aminopyridinium salts, the para-selectivity (determined in the first step of the reaction) is attributed to the steric congestion around the ortho-position. [86] Notably, tuning of the reaction conditions (e.g. reagents addition) allows also chemoselective para-functionalisations of complex substrates containing multiple pyridine rings.…”