Palladium Catalyst Recycling for Heck‐Cassar‐Sonogashira Cross‐Coupling Reactions in Green Solvent/Base Blend

Abstract

The identification of a green, versatile, user‐friendly, and efficient methodology is necessary to facilitate the use of Heck‐Cassar‐Sonogashira (HCS) cross‐coupling reaction in drug discovery and industrial production in the pharmaceutical segment. The Heck‐Cassar and Sonogashira protocols, using N‐hydroxyethylpyrrolidone (HEP)/water/N,N,N′,N′‐tetramethyl guanidine (TMG) as green solvent/base mixture and sulfonated phosphine ligands, allowed to recycle the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, and triflates. No catalyst leakage or metal contamination of the final product were observed during the HCS recycling. To our knowledge, a turnover number (TON) up to 2375, a turnover frequency (TOF) of 158 h−1, and a process mass intensity (PMI) around 7 that decreased around 3 after solvent, base, and palladium recovery, represent one of the best results to date using a sustainable protocol. The Heck‐Cassar protocol using sSPhos was successfully applied to the telescoped synthesis of Erlotinib (TON: 1380; TOF: 46 h−1).

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges

“…69 b After NBP was validated in full SPPS processes, the class of N -alkyl pyrrolidones was further explored by Tolomelli and Cabri 29 a,b after having tested their promising results in green cross-coupling reactions. 70 While retaining the main characteristics of the parent compound, NMP, they displayed a completely different metabolic profile in an in vitro metabolic investigation, being nontoxic and not reprotoxic. The high boiling and flash points of the above solvents represent industrially relevant features for recovery by distillation.…”

Fast MacMillan’s Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds

“…Under these conditions, product 4 was isolated in 82% yield after 16 h, providing a scaffold with three functionalizable branches bearing two orthogonal ester groups. On the same substrate, the Heck–Cassar–Sonogashira reaction (HCS) 30 performed using Heck–Cassar conditions with a small excess of phenylacetylene afforded compound 5 in 71% yield. For the more stable N -tertbutyl–substituted isooxazoline 3d , the Sonogashira protocol with trimethylsilylacetylene, including CuI as a cocatalyst, afforded compound 6 in 94% yield in 1 h at room temperature.…”

Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes†

“…The green solvent/base mixture of N ‐hydroxyethylpyrrolidone (HEP)/water/ N,N,N’,N’ ‐tetramethyl guanidine (TMG) was used in Sonogashira coupling reaction of aryl iodides, bromides and triflates. [ 63 ] In the presence of Pd(CH 3 CN) 2 Cl 2 and sSPhos , the Tyrosine kinase inhibitor Erlotinib was synthesized in high yield via a three‐step process including the Sonogashira coupling.…”