Unstable diazo compounds for cross-coupling in continuous flow

    Angewandte Cover

    An outstanding paper by Andreas Greb et al. from the laboratory of Professor Steven Ley at the University of Cambridge has demonstrated how a little-used photochemical method of generating diazo compounds can be used in continuous flow with the Vapourtec UV-150 photoreactor to produce highly versatile, but previously challenging to produce and handle, non-stabilised diazo species.1

    Diazo compounds are useful for a wide range of transformations in chemical synthesis, and are very versatile reagents, but there can be concerns of safety for their synthesis and handling. Some of the smaller and less stable diazo compounds, especially those without proximal electron-withdrawing groups or pi-orbital systems can be alarmingly difficult to handle, often explosive. Despite their challenging characteristics, non-stabilised diazo compounds would greatly expand the reactivity available to the organic chemist, and when combined with a suitable boronic acid, can enable metal-free C(sp2)-C(sp3) coupling.2

    Using a Vapourtec E-Series equipped with a UV-150 photoreactor, the Ley group have used a photochemical method, first reported in 1989 but little used,3 in continuous flow to produce a wide range of diazo compounds from a fairly easily obtained oxadiazoline species. Continuous flow photochemical excitation of the oxadiazoline in the UV-150 photoreactor at 310 nm generates the non-stabilised diazo compound, ready to be cross-coupled with a suitable boronic acid. Conveniently, the group found that the oxadiazolines showed good stability and could be stored for a reasonable duration. Using inline IR analysis, the group were able to monitor the generation of the diazo product in real time, and reliably produce the required species when necessary.

    Having developed an effective method for continuous flow photochemical diazo compound synthesis, the group used commonly available boronic acids or boroxines to explore the functional group compatibility of the newly generated diazo species. Excitingly, Greb et al. were able to achieve high isolated yields from the C(sp2)-C(sp3) coupling with a wide range of functionalities present in the oxadiazoline,1 even including an epoxide and an alkyl bromide. Functional groups were also well tolerated on the boronic acid, where a range of electron withdrawing and electron rich groups were assessed. By using different work-up strategies, it was also possible to obtain oxidised cross-coupled products with a similar tolerance of functional groups. The work of the group culminated in an impressive multi-step synthesis using the continuous flow photochemical formation and cross-coupling of a cyclobutyl diazo compound in the UV-150 photoreactor to create a valuable cyclobutyl boronic pinacol ester, which was then reacted further with a variety of different furan and isoquinoline substrates. Finally, the strategy was applied to a three-step synthesis of the drug baclofen in a very effective demonstration of how this continuous flow photochemical approach to diazo compound synthesis can be applied to a complete synthesis.

    “Alkyl diazo compounds are potentially very powerful synthetic reagents, but are often considered too hazardous to generate and handle” says Dr Ryan Skilton, research scientist at Vapourtec, “by generating these species in continuous flow photochemically, in-situ and in small quantities as required, Dr Greb and Professor Ley’s group have overcome many of the handling issues associated with these unstable reagents, and been able to synthesise a wide range of products containing different functionalities and in high yields”. At Vapourtec, we believe this is an excellent example of continuous flow photochemistry being used to overcome the hazards associated with an otherwise very useful class of compounds.

    References

    1.       Greb, A., Poh, J.S., Greed, S., Battilocchio, C., Pasau, P., Blakemore, D. C., Ley, S. V., Angew. Chem. Int. Ed., Accepted Author Manuscript. doi:10.1002/anie.201710445

    2.       D. N. Tran, C. Battilocchio, S.-B. Lou, J. M. Hawkins, S. V. Ley, Chem. Sci. 2015, 6, 1120-1125.

    3.       M. W. Majchrzak, M. Bekhazi, I. Tse-Sheepy, J. Warkentin, J. Org. Chem. 1989, 54, 1842-1845.

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