Microwave-assisted continuous flow organic synthesis

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The synthesis of new chemical entities is the backbone of discovery in the pharmaceutical, agrochemical, and materials sectors. In the business world, the race to be first to discover is essential in these societally-important areas; this will control the intellectual property (i.e., patent space) and the associated wealth from these efforts. As a result, chemists have strived to develop new reagents, catalysts, processes, and devices in order to make more compounds more quickly, and ideally more structurally diverse to feed into these important research areas. To meet this important demand, this proposal outlines the development of a conceptually new strategy for the simultaneous preparation of organic compounds both very rapidly, and in large numbers. Performing reactions in a flowed format, rather than statically in a conventional batch reaction set up allows for in-process alterations of reaction conditions, such as reaction optimization and in-line processing (analysis or purification) of the products. A potential drawback with flow is that reactions reside in the flow system for a shorter period of time than in a standard batch reactor. If a reaction is kinetically slow, the benefits of flow will be offset by the poor reaction conversion resulting in low yield and purification problems because the product mixture is contaminated with unreacted starting materials. Microwave irradiation is known to dramatically accelerate the rate of chemical transformations; combining microwave with flow will allow the realization of the full benefits of both techniques. Preliminary experiments have shown that reactions flowed through small diameter tubes (capillaries) while being irradiated actually show greater rate enhancement over larger diameter tubes and, we believe, offers the greatest hope for wide acceptance of flow synthesis. This proposal also proposes further advances by combing flow microwave with capillaries loaded with new supported reagents, catalysts, and scavengers through which the reactions flow to allow one-sequence synthesis and purification. Essentially, this amounts to the creation of an automated, multi-step chemical synthesis machine capable of running multiple reactions simultaneously through parallel capillaries.