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Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids

Nature Protocols volume 9, pages 1183–1191 (2014)Cite this article

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Abstract

This protocol describes how to prepare 2-(2-formylalkyl)-arenecarboxylic acid derivatives, common building blocks for the synthesis of various valuable chemicals (e.g., anti-obesity and Alzheimer's disease treatment pharmaceuticals), by using the fully regioselective hydroformylation of vinyl arene derivatives. This catalytic reaction proceeds cleanly with 100% regioselectivity and chemoselectivity. The procedure is reliably scalable and can be efficiently conducted on a multigram scale. The analytically pure product is easily isolated with a nearly quantitative yield by using a simple acid-base extraction workup and avoids any tedious chromatography. This protocol details the synthesis of a bisphosphite ligand (L1) that is a pivotal element of the catalytic system used, Rh(acac)(CO)2 with ligand L1, starting from commercial building blocks. The protocol also describes a general procedure for the preparative hydroformylation of vinylarene-2-carboxylic acid derivatives to 2-formylalkylarene products, providing a representative example for the hydroformylation of 2-vinylbenzoic acid (1a) to 2-(3-oxopropane)-benzoic acid (2a). The synthesis of L1 (six chemical reactions) uses 2-nitrophenylhydrazine, 4-benzyloxybenzoylchloride and (S)-binol, and takes 5–7 working days. The actual hydroformylation reaction of each vinyl arene derivative takes ∼4 h of active effort over a period of 1–3 d.

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Figure 1: Examples of the hydroformylation of 2-vinylarenecarboxylic acids 1a–q to 2-(2-formylalkyl) arenecarboxylic acid derivatives 2a–q.
Figure 2: Synthesis of ligand L1 from commercial 2-nitrophenylhydrazine and (S)-binol.

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Acknowledgements

We acknowledge the Dutch National Research School Combination Catalysis Controlled by Chemical Design (NRSC-Catalysis) for financial support.

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  1. van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands

    Paweł Dydio & Joost N H Reek

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  1. Paweł Dydio
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P.D. designed and carried out the experiments, and wrote the paper. J.N.H.R. designed the experiments and wrote the paper.

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Correspondence to Joost N H Reek.

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Dydio, P., Reek, J. Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids. Nat Protoc 9, 1183–1191 (2014). https://doi.org/10.1038/nprot.2014.077

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