An Improved Synthesis of Imidazo[4,5‐b]pyridines and Imidazo[4,5‐b]pyrazines by Palladium Catalyzed Amidation using Xantphos in a 1,4‐Dioxane:tert‐Amyl Alcohol Solvent System

Abstract

b]pyrazines using a palladium-catalyzed amidation that utilizes Xantphos as an ancillary phosphine ligand is reported. The use of a binary solvent system comprised of 1,4-dioxane and tert-amyl alcohol was crucial in eliminating unwanted by-products.

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

“…The previous work of Rosenberg et al has certain limitations like the high cost of the biarylphosphine ligand, the ineffectiveness of electron-deficient benzyl moiety and incompatibility of unhindered chlorides [157]. Inspired from this Rosenberg et al have described a palladium-catalyzed amidation reaction using XantPhos as a ligand to synthesize imidazo[4,5- b ]pyridines (Scheme 89) [159].…”

Rapid Construction of an Imidazo[4,5-b]pyridine Skeleton from 2-Chloro-3-nitropyridine via Tandem Reaction in H2O-IPA Medium

“…8 The second method involves the N–C–N–C bond formation, which occurs via Pd- or Cu-catalyzed regiospecific cyclization of 2-halo-3-acylaminopyridines with amines, Pd-catalyzed amidation of 2-chloro-3-amino-substituted pyridines, and Cu- and Pd-catalyzed amidation reaction of 3-amino- N -Boc-4-chloropyridine using ligands (Scheme 1). 9…”

Synthesis ofN-Substituted 3-Amino-4-halopyridines: A Sequential Boc-Removal/Reductive Amination Mediated by Brønsted and Lewis Acids

“…Initially attempts were made to alkylate 3-amino-4-chloropyridine using reductive amination conditions that have provided high yields in similar pyridine systems (AcOH and NaBH(OAc) 3 are typically effective for 3-amino-2-chloropyridine, 5 for example), but these reactions showed poor conversion or failed completely. This lack of reactivity is attributed to the higher basicity of the 3-amino-4-chloropyridine (the pK a of 4-chloropyridinium has been reported as 3.83, 6 while 2-chloropyridinium has a pKa of 0.75 7 ), allowing it to act as a buffer, slowing imine formation or decelerating reduction of the imine by limiting protonation.…”

“…Reductive amination remains one of the simplest, mildest, and most economical methods for forming C–N bonds. 1a,5b,10 However, there are still limitations to this chemistry. Generally, less nucleophilic amines require stronger acids to facilitate the conversion to the imine/iminium.…”

“…Generally, less nucleophilic amines require stronger acids to facilitate the conversion to the imine/iminium. 5b,10a Selectivity between the reduction of the imine and carbonyl reactant decreases with increased acid strength, however, which may hinder product formation. 10b Despite this limitation, working in highly acidic media also presented an opportunity to facilitate Boc-removal in situ , so the reductive amination with stronger Brønsted acids was initially evaluated.…”