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 similar to 4 h of active effort over a period of 1-3 d

Chirality: a key parameter in chemical probes

Many small molecule bioactive and marketed drugs are chiral. They are often synthesised from commercially available chiral building blocks. However, chirality is sometimes incorrectly assigned by manufacturers with consequences for the end user ranging from: experimental irreproducibility, wasted time on synthesising the wrong product and reanalysis, to the added cost of purchasing the precursor and resynthesis of the correct stereoisomer. Further on, this could lead to loss of reputation, loss of funding, to safety and ethical concerns due to potential in vivo administration of the wrong form of a drug. It is our firm belief that more stringent control of chirality be provided by the supplier and, if needed, requested by the end user, to minimise the potential issues mentioned above. Certification of chirality would bring much needed confidence in chemical structure assignment and could be provided by a variety of techniques, from polarimetry, chiral HPLC, using known chiral standards, vibrational circular dichroism, and x-ray crystallography. A few case studies of our brushes with wrong chirality assignment are shown as well as some examples of what we believe to be good practice.</p

Phenylene- and biphenylene-bridged bis-imidazolylidenes of palladium. Influence of the presence of pyrene tags on the catalytic activity of the complexes

A series of dimetallic complexes with N-heterocyclic carbene ligands with formally identical stereoelectronic properties have been obtained and fully characterized. The dimetallic complexes were bridged by bis-imidazolylidenes, with different spacers (phenylene and biphenylene). The N substituents were methyl or methylpyrene groups. The related monometallic complexes were also obtained. The catalytic properties of the complexes were tested in the acylation of aryl halides with hydrocinnamaldehyde and in the Suzuki−Miyaura coupling between aryl halides and arylboronic acids. In general, the dimetallic complexes display better activities than the monometallic analogues. The results also indicate that those complexes with pyrene groups at the N substituents display better catalytic activities than those with N-methyl groups. These observations are interpreted as a consequence of the π stacking interaction between the substrates and the pyrene groups in the pyrene-containing catalysts, which may provide some beneficial catalytic properties. The addition of a catalytic amount of pyrene to the Suzuki−Miyaura coupling reactions results in a partial inhibition of the activities of the complexes with the pyrene substituents, while the activity of the complexes with the N-methyl groups is not affected