Efficient Palladium-Catalyzed Synthesis of 2-Aryl Propionic Acids.

Helfried Neumann,Matthias Beller,Alexey G Sergeev,Anke Spannenberg

doi:10.3390/molecules25153421

Helfried Neumann, Matthias Beller + Show 2 more

Open Access

https://doi.org/10.3390/molecules25153421

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Abstract

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps.

Highlights

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen
2-Aryl propionic acids, such as ibuprofen, ketoprofen, naproxen, and flurbiprofen, belong to an important class of non-steroidal anti-inflammatory drugs (NSAIDs) which are extensively used in the treatment of inflammatory diseases and for the relief of pain [1]
Notable progress has been reported in the enantioselective hydroxycarbonylation of styrenes [5,6,7], still, the racemic hydroxy/alkoxy-carbonylation continues to be attractive for the scientific community, too

Summary

Introduction

2-Aryl propionic acids, such as ibuprofen, ketoprofen, naproxen, and flurbiprofen, belong to an important class of non-steroidal anti-inflammatory drugs (NSAIDs) which are extensively used in the treatment of inflammatory diseases and for the relief of pain [1]. Palladium complexes in the presence of acid represent state-of-the-art catalyst systems for the synthesis of 2-aryl propionic acid. Our group reported a two-step protocol for the synthesis of ketoprofen and suprofen. These two drugs were synthesized following a tandem carbonylative Suzuki coupling and subsequent hydroxycarbonylation [14]. Inspired by this previous work and our interest in carbonylation reactions [15], here we describe a more flexible two-step, one-pot procedure for the synthesis of diverse. We utilized the palladium-catalyzed Heck reaction with aryl bromides and ethylene to give the corresponding styrene derivatives [16,17] which are directly hydroxycarbonylated to the desired 2-aryl propionic acids without changing the palladium catalyst

Results and Discussion

Results and Discussion to yield

Discussion to yieldand

Palladium-catalyzed two-step synthesis for 2-aryl propionic acid