A reaction with potential: an electrosynthesis of 1,3,4-oxadiazoles from n-acyl hydrazones Luke Chen 1,2 , James Thompson 1 , Craig Jamieson 2 1 GSK Medicines Research Centre, Stevenage, UK, 2 Department of Pure Applied Chemistry, Glasgow, UK This work has established the electrochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from N -acyl hydrazones. The 1,3,4-oxadiazole is a valuable heterocycle with useful medicinal properties. As a stable bioisostere of esters and amides, ubiquitous functional groups in many drugs and bioactive molecules, incorporating the underutilised oxadiazole enables the expansion and exploration of greater chemical space. [1] To highlight this, it is an important component of raltegravir, a top selling anti-HIV drug in 2020. [2] Consequently, more efficient methods to access these heterocycles are required. Common syntheses of 1,3,4-oxadiazole analogues in the literature involve oxidative or dehydrative cyclisation reactions. [3,4] These methods are, however, often limited by poor atom economy and the need for highly reactive, toxic, or corrosive reagents. Herein is described an electrochemical oxidation which offers a green and attractive alternative. Stoichiometric use of conventional chemical oxidants, and their associated hazards, have been avoided to convert inexpensive and readily available starting materials into valuable products.
Taking an indirect electrolysis approach, this strategy offers advantages to established protocols in that milder conditions can be employed to improve functional group compatibility. Extensive screening efforts have identified hydrogen atom transfer (HAT) mediators, such as DABCO, as the optimum redox catalysts for the reaction. The rapid reaction optimisation was accomplished using the IKA ElectraSyn 2.0, enabling greater accessibility of electrochemistry for synthetic, organic chemists. The operationally simple methodology is also amenable to a one- pot procedure from hydrazone precursors, further simplifying the process. Tolerance for a broad range of relevant functional groups has been demonstrated, with moderate to good yields obtained. This has enabled access to a wide array of medicinally privileged structures which would be valuable additions to a screening collection or as a tool for medicinal chemists, such as for determining structure-activity relationships. Work is ongoing to further explore the substrate scope, harnessing the reactivity to functionalise a wider range of hydrazones. References 1. J. Boström, A. Hogner, A. Llinàs, E. Wellner, and A. T. Plowright, J. Med. Chem. , 2012, 55 , 1817–1830. 2. F. Caputo, S. Corbetta, O. Piccolo, and D. Vigo, Org. Process Res. Dev. , 2020, 24 , 1149–1156. 3. K. D. Patel, S. M. Prajapati, S. N. Panchal, and H. D. Patel, Synth. Commun. , 2014, 44 , 1859– 1875. 4. L. Green, K. Livingstone, S. Bertrand, S. Peace, and C. Jamieson, Chem. Eur. J. , 2020, 26 , 14866–14870.
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