Synthesis of Imidazoles and Oxazoles via a Palladium-Catalyzed Decarboxylative Addition/Cyclization Reaction Sequence of Aromatic Carboxylic Acids with Functionalized Aliphatic Nitriles

Abstract

We herein report an efficient approach for the assembly of multiply substituted imidazoles and oxazoles in a singlestep manner. These transformations are based on a decarboxylation addition and annulation of readily accessible aromatic carboxylic acids and aliphatic nitriles and exhibit good functional group compatibility and a high step economy. The reaction is scalable, and asprepared products could be transformed into practical skeletons. Importantly, the late-stage derivatization of Momelotinib highlights the potential utility of this methodology.

An efficient and straightforward approach for accessing thionoesters via palladium-catalyzed C–N cleavage of thioamides

“…Based on the known palladium chemistry, 106–109 a plausible mechanism for the catalytic reaction was proposed (Scheme 7): (i) oxidative addition takes place at the C–N bond of thioamide 1a to give thio-acylpalladium( ii ) complex II ; (ii) following transmetalation, complex III is produced by the reaction of benzyl alcohol 2a ; and (iii) then, reductive elimination occurs to form thionoester product 3a and regenerates the Pd(0) species I .…”

The Renaissance of Organo Nitriles in Organic Synthesis

“…reported a Pd(II)‐catalyzed decarboxylative addition/cyclization of aromatic carboxylic acids ( 152 ) with functionalized aliphatic nitriles ( 150 and 151 ) to synthesize imidazoles ( 153 ) and oxazoles ( 154 ) in a single step (Scheme 61). [70] A wide range of aliphatic nitriles and benzoic acids as well as heterocyclic carboxylic acids are well tolerated in this protocol. Further, the synthetic utility of this transformation is demonstrated through a late‐stage modification to a drug molecule viz .…”

“…Initially, metathesis between the palladium catalyst and arylhydrazine forms a palladiaziridine intermediate (A), which is followed by coordination with the cyano group to afford intermediate (B 154) in a single step (Scheme 61). [70] A wide range of aliphatic nitriles and benzoic acids as well as heterocyclic carboxylic acids are well tolerated in this protocol. Further, the synthetic utility of this transformation is demonstrated through a late-stage modification to a drug molecule viz.…”

Heterocycle Synthesis via Decarboxylative Cyclization Methods

“…[6] A palladium-catalyzed decarboxylation addition and cyclization reaction of available aliphatic nitriles and carboxylic acids 141 was developed by Chen and Lv et al in 2021 (Scheme 20). [34] In the absence of silver oxidants, a wide range of functionalized aliphatic nitriles and various benzoic and heterocyclic carboxylic acids were efficiently introduced to produce a many different structural imidazole and oxazole skeletons 143 and 145 in good yields and exhibited good functional group compatibility. Notably, the gram-scale production and latestage modifications of momelotinib 147 and various derivatives of the final products further demonstrated the potential unity of the transformation.…”