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Fast Heck-Cassar-Sonogashira (HCS) Reactions in Green Solvents.

ABSTRACT: The replacement of toxic solvents with greener alternatives in Heck-Cassar-Sonogashira (HCS) cross-couplings was investigated. The fine-tuning of the HCS protocol allowed to achieve complete conversions and high speed under mild conditions. N-Hydroxyethylpyrrolidone (HEP) gave the best results. Moreover, the methodology was successfully applied to the synthesis of an intermediate of the anticancer drug Erlotinib, demonstrating the versatility of the new green protocol.

SUBMITTER: Ferrazzano L

PROVIDER: S-EPMC8007125 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Fast Heck-Cassar-Sonogashira (HCS) Reactions in Green Solvents.

Ferrazzano L L Martelli G G Fantoni T T Daka A A Corbisiero D D Viola A A Ricci A A Cabri W W Tolomelli A A

Organic letters 20200428 10

The replacement of toxic solvents with greener alternatives in Heck-Cassar-Sonogashira (HCS) cross-couplings was investigated. The fine-tuning of the HCS protocol allowed to achieve complete conversions and high speed under mild conditions. <i>N</i>-Hydroxyethylpyrrolidone (HEP) gave the best results. Moreover, the methodology was successfully applied to the synthesis of an intermediate of the anticancer drug Erlotinib, demonstrating the versatility of the new green protocol. ...[more]

PMID: 32342693

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

Project description: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 ).

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