Diverse Applications of Flow Technology in Discovery Chemistry

Abstract

The research presented herein describes the development of methods and applications of flow technology in discovery chemistry. The first two chapters highlight the use of several beneficial features offered by flow technology to increase the throughput, safety, and convenience of organic synthesis. The last two chapters describe the use of microfluidic technology as a platform for rapid reaction discovery. Working with researchers at Abbott Laboratories, a droplet-based library method was developed. This approach allowed for the preparation of a theoretically unlimited number of compounds in a single run using minimal amounts of material. The universal nature of this approach was subsequently demonstrated in the preparation of two 20-membered libraries based around thiazole and pyrazole cores. A second methodology study, also completed with researchers at Abbott Laboratories, took advantage of the intrinsic closed environment of flow systems which enabled the creation, reaction, and removal of noxious chemicals in situ. Using these features an in situ synthesis of isocyanides, reagents notorious for their unpleasant smell, was developed. Coupling this method to the Ugi four-component reaction, a series of medicinally relevant amides was synthesized. Reactions performed in the flow system experienced an overall reduction in transformation time from two-days to two-hours and gave yields that were generally higher than those for the same reactions performed on the benchtop or in the microwave. Expanding the application of this technology toward the discovery and development of new synthetic methodologies we partnered with the laboratory of Dr. John A. Porco, Jr. at Boston University to explore transformations of multifunctional substrates. Given the variant nature of these reactions, both a simple iminium ether and a densely functionalized iminium ether derived from a bicyclo[3.2.1]octanoid scaffold were explored. Multidimensional reaction screening on an automated microfluidic platform was employed to facilitate the simultaneous investigation of multiple reaction variables. While the majority of products obtained from the study resulted from expected modes of O- and N- alkylation, several interesting transformations were uncovered. These included the pseudo-dimerization of homophthalic anhydride, an unusual integration of the van Leusen sulfone, and an unexpected carbon-carbon bond forming event of ethyl diazoacetate and acetonitrile. Finally, in a follow-up study, collaboration with Boston University was continued to explore additional reactivity of the bicyclo[3.2.1]octanoid scaffold. Preliminary reaction screens uncovered the synthesis of a series of densely functionalized donor-acceptor cyclopropanes which resulted from the photochemical rearrangement of the bicyclic scaffolds. Expansion of the photochemical screening to a polycyclic iminium ether led to the first example of an aza-di-pi reaction of a charged iminium species. Subjection of the new cyclopropane scaffolds to a variety of reaction conditions led to the discovery of additional rearrangement reactions affording several structurally diverse chemotypes including a fused dihydropyran, a fused pyrrole, a bicyclic imide, and a complex cyclic imine.