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

Abstract

A palladium-mediated one-pot synthesis of amidines from aromatic carboxylic acids and carbodiimides (RNCNR) is reported as an isoelectronic adaption of CO 2 ExIn (ExIn = Extrusion−Insertion) reactions developed for the synthesis of thioamides from carboxylic acids and isothiocyanates (RNCS). Multistage mass spectrometry (MS n ) experiments for model systems established "proof of concept", demonstrating decarboxylation of [(L)Pd(O 2 CAr)] + (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 2,4,6trimethoxybenzoic acid into amidines in solution was probed by 1 H NMR spectroscopy as was the use of stoichiometric amounts of PdX 2 salts (X = O 2 CCH 3 and O 2 CCF 3 ) and three different carbodiimides, RNCNR (R = i Pr, c Hex, 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′-R 2 -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.

Palladium-Mediated CO2 Extrusion Followed by Insertion of Isocyanates for the Synthesis of Benzamides: Translating Fundamental Mechanistic Studies To Develop a Catalytic Protocol

“… a X = OH, Y = S, see ref ; X = OH, Y = NR, see ref ; X = NHR, Y = O, see ref ; X = OH, Y = O, this work. …”

Organometallic Gas‐phase Ion Chemistry and Catalysis: Insights Into the Use of Metal Catalysts to Promote Selectivity in the Reactions of Carboxylic Acids and Their Derivatives

“…Due to the high stability of CO2, the overall reaction shown in eq. 38 is exothermic for the preparation of amides , thioamides (Noor et al, 2017) and amidines (Yang et al, 2019). In our studies of ExIn reactions, we showed that gas-phase (Scheme 26A) and solutionphase (Scheme 26B) mechanistic work on ligated palladium complexes can guide the development of one-pot synthetic methods for the palladium mediated ExIn synthesis of amides, thioamides and amidines (Scheme 26C).…”

“…These reactions involve organometallic intermediates rather than radicals, which tend to be unreactive in the key C-C bond-forming step unless they are nucleophilic radicals (Weragoda et al, 2018). Due to the high stability of CO 2 , the overall reaction shown in Equation 38 is exothermic for the preparation of amides , thioamides (Noor et al, 2017), and amidines (Yang et al, 2019).…”

“…In our studies of ExIn reactions, we showed that gasphase (Scheme 26A) and solution-phase (Scheme 26B) mechanistic work on ligated palladium complexes can guide the development of one-pot synthetic methods for the palladium mediated ExIn synthesis of amides, thioamides, and amidines (Scheme 26C). In the case of thioamides (Noor et al, 2017) and amidines (Yang et al, 2019), the inserted product remains strongly bound to the metal, which is why their synthesis requires stoichiometric amounts of palladium. In contrast, for amides the inserted metal is readily displaced from the metal center, which allowed the development of a rapid microwave protocol that was catalytic in palladium .…”

Gas-Phase Synthesis and Reactivity of Ligated Group 10 Ions in the Formal +1 Oxidation State

“…Thus, we were interested in developing a gasphase synthesis of ligated group 10 cations in the formal oxidation state of +1. We chose the [(phen)M(O2CCH3)] + complexes as suitable precursors since: the 1,10-phenanthroline (phen) ligand has been widely used in condensed phase synthetic and catalytic studies [28]; our previous work has shown that these complexes are readily generated via ESI-MS and readily fragment via decarboxylation [29] to generate organometallic cations, [(phen)M(CH3)] + , which undergo a number of interesting reactions of relevance to catalysis [30][31][32][33][34][35]; CID of related cations suggest that bond homolysis should occur [36]. Here we examine the use of bond homolysis reactions of [(phen)M(CH3)] + to generate the cations [(phen)M] +• for subsequent ion-molecule reaction studies with background water, O2 and N2 and the reagents acetone and allyl iodide.…”