om8b00776_si_001.pdf (4.85 MB)
Download file

Synthesis of Amidines by Palladium-Mediated CO2 Extrusion Followed by Insertion of Carbodiimides: Translating Mechanistic Studies to Develop a One-Pot Method

Download (4.85 MB)
journal contribution
posted on 17.12.2018, 12:21 authored by Yang Yang, Asif Noor, Allan J. Canty, Alireza Ariafard, Paul S. Donnelly, Richard A. J. O’Hair
A palladium-mediated one-pot synthesis of amidines from aromatic carboxylic acids and carbodiimides (RNCNR) is reported as an isoelectronic adaption of CO2ExIn (ExIn = Extrusion–Insertion) reactions developed for the synthesis of thioamides from carboxylic acids and isothiocyanates (RNCS). Multistage mass spectrometry (MSn) experiments for model systems established “proof of concept”, demonstrating decarboxylation of [(L)­Pd­(O2CAr)]+ (L = 1,10-phenanthroline or py), to give [(L)­PdAr]+, followed by reaction with a carbodiimide, RNCNR, to yield [(L)­Pd­(NRC­(NR)­Ar)]+ (R = isopropyl). DFT calculations predicted these reactions as highly exothermic and occurring via carbodiimide insertion into the Pd–Ph bond. 2,6-Dimethoxy and 2,4,6-trimethoxy substitution for the Pd–Ar moiety results in slower reactions with minor changes in mechanism. The individual reaction steps associated with the conversion of 2,6-dimethoxybenzoic acid and 2,4,6-trimethoxybenzoic acid into amidines in solution was probed by 1H NMR spectroscopy as was the use of stoichiometric amounts of PdX2 salts (X = O2CCH3 and O2CCF3) and three different carbodiimides, RNCNR (R = iPr, cHex, and Ph). Use of palladium trifluoroacetate gives less of the undesired protodecarboxylation product formed by protonation of the Pd–Ar bond to release ArH. DFT studies for solution phase one-pot reactions provide support for the mechanism and explain competitive factors contributing to the desired insertion step or the alternative protonation step to release ArH. An understanding of mechanism obtained from the model studies encouraged development of a solution-phase one-pot synthesis of N,N′-diisopropyl-2,6-dimethoxybenzamidine using stoichiometric amounts of palladium carboxylates. Reaction conditions, product isolation and characterization, yields, and the scope of the one-pot synthesis of N,N′-R2-2,6-dimethoxybenzamidine were established, in which borohydride is added in workup as a hydrogen source. Attempts to make the chemistry catalytic in palladium are described.