UC Santa Barbara

I. Nickel Catalyzed Reductions of gem-Dibromocyclopropanes to Cyclopropanes in WaterII. α-Arylations of (Hetero)Aryl Ketones in Aqueous Micellar Media III. Palladium Catalyzed Dehydration of Primary Amides to Nitriles in Water IV. Solid Handling Equipment Advancements for Nanoparticle Catalyzed Flow Chemistry in Aqueous Micellar Media

I. New techniques to access cyclopropanes are of great importance to the fine chemical industry. One route to this valuable moiety is through the synthesis of gem-dibromocyclopropanes followed by the reduction of the halides to access the saturated cyclopropane. However, contemporary reduction methods are plagued with selectivity and safety issues, as well as environmentally deleterious solvents and reagents. Herein are described both mild mono- and di-hydrodehalogenative reductions of gem-dibromocyclopropanes enabled by aqueous micellar media, providing an environmentally responsible alternative. The chemistry is performed using a ligated 0.5-5.0 mol % nickel catalyst activated by sodium borohydride in situ and boasts a wide substrate scope including pharmaceutically relevant compounds.

II. α-Arylation chemistry is traditionally limited to organic solvents due to the high pKa of the ketone alpha proton, especially with respect to the relative acidity of water. However, the introduction of a micellar array to an aqueous media creates a hydrophobic environment suitable to facilitate deprotonation of the ketone followed by coupling with an aryl halide. This is provided that the correct lipophilic base, which can gain access into the micelle inner core, is chosen to effect enolization. Under such conditions, using a Pd(I) bromide dimer pre-catalyst, α-arylation of aryl and heteroaryl ketones can be performed in recyclable water using as low as 2500 ppm of the transition metal under near ambient conditions.

III. Conventional methods to dehydrate primary amides to nitriles require the use of highly toxic, reactive, and moisture sensitive reagents, and are oftentimes performed at high temperatures (ca. >80 °C) in rigorously dry organic solvents. Recent mild techniques have been developed using palladium salts and a “sacrificial” nitrile, resulting in a water-shifting reaction to form the desired nitrile and a cheap amide byproduct. However, this chemistry is performed in mixtures of acetonitrile/water, obviating the overall “greenness” of the technology. This chapter discusses the development of ppm Pd-catalyzed dehydration chemistry in aqueous micellar media, removing the need for excess acetonitrile as co-solvent. This method uses highly reactive water-acceptor nitriles, methoxyacetonitrile or fluoroacetonitrile, tuned specifically for their respective amide reagents in aqueous micelles.

IV. Flow chemistry has evolved to be a disruptive technology in the field, resulting in novel techniques which have revolutionized the chemical industry. However, issues with solids, which can result in clogging of lines and equipment, have remained an unsolved problem. Herein, aqueous micellar nanoparticle-catalyzed Suzuki-Miyaura couplings are utilized as a method to probe novel solids handling equipment for plug flow and continuously-stirred tank reactor systems.