Enabling the use of unstable, hazardous reagents with continuous flow synthesis

Abstract

[chemical formula] Highly functionalized 2-arylindoles were synthesized from 2-alkenylarylisocyanides and arylboronic acids using a simple, inexpensive copper catalyst. The reaction exhibits excellent functional group tolerance for both the arylisocyanide and boronic acid coupling partners. To avoid the direct handling of the pungent arylisocyanide starting materials, continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ dehydration and cyclization of easy-to-handle 2-alkenyl-N-formylanilines. Laurel M. Heckman and Dr. Zhi He contributed equally to initial reaction investigation. Z.H. carried out the arylboronic acid scope. L. M. H. carried out reaction optimization, isocyanide scope and reactions in continuous flow. [chemical formula] Despite its utility, monochloramine (NH₂Cl) has not achieved widespread use as a nitrogen transfer reagent due to its unstable and hazardous nature. We developed a continuous flow platform for the safe, reliable, and inexpensive on-demand synthesis of NH₂Cl. Additionally we demonstrate the synthetic utility of NH2Cl by converting it to valuable NH aziridne and nitrile products in good to excellent yield in exceedingly short reaction times. Dr. Evan Styduhar developed continuous flow synthesis of NH₂Cl. E.S. also developed the reaction of NH2 Cl to form aziridines and nitriles in batch and continuous flow. Laurel M. Heckman helped optimize the continuous flow setup, performed the reaction scope in continuous flow, and explored additional substrates in batch. [chemical formula] A rapid, operationally simple synthesis of 6-TAMRA, an important probe for labeling biomolecules, from 2-carboxycarbonylterephthalic acid and 3-dimethylaminophenol is described herein. The intermediate ketoacid was synthesized in a single step from commercially available dimethylacetophenone. Additionally, progress was made towards a facile scalable synthesis in continuous flow. Dr. Justin A. M. Lummiss carried out the oxidation batch synthesis. Laurel M. Heckman carried out reaction screening and optimization of step 2 of the batch synthesis. L.M.H and J.A.M.L contributed equally to the experiments in continuous flow. Dale Thomas (graduate student, Jensen Research Group, MIT Department of Chemical Engineering) developed the fully automated platform. Bruce Adams (Staff, DCIF of MIT Department of Chemistry) helped with low temperature and 2-D NMR experiments. Peter MUller (Director, Diffraction Facility of MIT Department of Chemistry) carried out the single-crystal X-ray diffraction experiments.