Since ortho-quinodimethane was first proposed in 1957, it has remained an elusive yet valuable molecule for the creation of complex compounds found in natural products and medicines. But two chemists from Japan have now found a simpler way to make this reactive intermediate from readily available chemicals.

The Diels–Alder reaction uses reactive dienes and a dienophile, like an alkene, to form six-membered rings and ortho-quinodimethane is a unique, highly reactive diene. ‘This property makes them particularly suitable for constructing benzo-fused systems, commonly found in bioactive compounds,’ says Junichiro Yamaguchi at Waseda University in Tokyo.

However, for 70 years researchers struggled to find an efficient way to produce ortho-quinodimethane. This is because of its exceptional reactivity in one of the few pathways available to make these polycyclic structures – the Diels–Alder reaction. ‘Conventional methods for generating [ortho-quinodimethane] require multi-step synthesis of precursors and, in some cases, harsh conditions to release it from these precursors.’

The reliance on harsh conditions and specific precursors restricts the practicality of ortho-quinodimethane and limits the diversity of obtainable structures. Ortho-quinodimethane must be generated in situ because it is highly unstable and has a lifespan of milliseconds.

While studying dearomatisation of benzyl-palladium species, Yamaguchi and his collaborator, Kei Muto, also at Waseda, saw a potential pathway for improved ortho-quinodimethane generation.

Their method uses a palladium-catalysed multi-component reaction, which starts with the catalyst forming a reactive intermediate from 2-vinylbromoarene and a diazo compound, in this case TMS-diazomethane. ‘A carbon nucleophile then attacks releasing [ortho- quinodimethane],’ says Muto. Furthermore, they found that building a dienophile into the nucleophile immediately induces the Diels-Alder in the same reaction vessel.

Yamaguchi and Muto demonstrated its utility by creating a range of products, including equilenin, a steroid hormone analogue used to build pharmaceuticals. ‘By varying the vinylbromoarene, diazo compound and nucleophile, we can generate a wide array of products with different ring systems and functional groups,’ explains Yamaguchi.

The two researchers believe this method is scalable because it uses mild conditions and common, stable reagents and can easily generate chemical libraries to screen for pharmaceuticals or functional materials.

Jin-Quan Yu, a chemist at The Scripps Research Institute, US, agrees that the starting materials are easy to use and that these materials, ‘can provide great diversity’.

Jared Shaw, at the University of California, Davis, noted that, while the conditions are milder, one compound used, TMS-diazomethane, is toxic and possibly difficult to handle at scale. ‘That said, this reaction produces few byproducts and scaling up would only be limited by the safe handling of the diazomethane.’

Shaw is intrigued by the reaction as it is one of the only multi-component reactions reported that proceeds via ortho-quinodimethane generation.

A key factor is the dual function of palladium. ‘This reaction uses palladium in two roles, ie the generation of [ortho-quinodimethane] followed by a subsequent alkylation reaction that sets up the intramolecular Diels-Alder reaction,’ says Shaw, ‘thus enabling a [multi-component reaction].’

Muto and Yamaguchi are now working on designing ligands and other catalyst systems to achieve asymmetric variants, specifically enantioselective reactions.