Flash chemistry enables high productivity metalation-substitution of 5-alkyltetrazoles |
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Authors: | Jeff Y F Wong Christopher G Thomson Filipe Vilela Graeme Barker |
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Institution: | Institute of Chemical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS UK.; Continuum Flow Lab, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS UK |
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Abstract: | Tetrazoles play a prominent role in medicinal chemistry due to their role as carboxylate bioisosteres but have largely been overlooked as C–H functionalisation substrates. We herein report the development of a high-yielding and general procedure for the heterobenzylic C–H functionalisation of 5-alkyltetrazoles in up to 97% yield under batch conditions using a metalation/electrophilic trapping strategy. Through the use of thermal imaging to identify potentially unsafe exotherms, a continuous flow procedure using a flash chemistry strategy has also been developed, allowing products to be accessed in up to 95% yield. This enabled an extremely high productivity rate of 141 g h−1 to be achieved on an entry-level flow system.We report a α-metalation-substitution of readily deprotected 5-alkyltetrazoles under batch and continuous flow conditions. In flow, thermal imaging enabled identification of an unsafe exotherm and optimisation of a productivity rate of 141 g h−1. |
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