Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids.
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.
van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Paweł
P
Dydio
van 't Hoff Institute for Molecular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Joost N H
JN
Reek
D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D002384:Catalysis; D005561:Formates / Q000737:chemistry; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D015394:Molecular Structure; D009284:Naphthols; D010659:Phenylhydrazines; D014753:Vinyl Compounds / Q000737:chemistry*
C406944:BINOL, naphthol; D002264:Carboxylic Acids; D005561:Formates; D006841:Hydrocarbons, Aromatic; D009284:Naphthols; D010659:Phenylhydrazines; D014753:Vinyl Compounds; C106724:oxomethylium; C060574:2-nitrophenylhydrazine