Reduction of Resource Use & Waste Generation in Nucleophilic Substitutions: “Low Waste” Alkyl Halide Synthesis

Nucleophilic substitution reactions are among the most commonly executed reactions employed in the synthesis of pharmaceutical compounds. Alkyl halides or pseudohalides are typically employed as the electrophilic reagents in these reactions, but both the reactions in which these electrophilic species are formed and the processes used to generate the precursors required for these reactions are highly resource intensive and result in very significant waste generation. Herein, we report on the development of methodology in which the resource- and waste-intensity of nucleophilic substitution reactions can be drastically reduced. This involves facile generation of alkylating agents from alcohols by treatment with a single bench-stable reagent that is commercially available and cheap, and which is itself available through a “low waste” synthetic route – diphenyl H-phosphonate. The alkyl phenyl H-phosphonate alkylating agents formed undergo nucleophilic substitution by iodide and bromide salts (in one-pot processes), enabling production of alkyl iodides and bromides in yields of 60–99% in most cases, with lower yields being observed only for certain challenging substrates. Low process mass intensity (PMI) values were demonstrated for alkyl halide-forming reactions conducted using this methodology (along with other very favorable green chemistry metrics), indicating that these reactions result in low waste generation, while the use of reagents that are formed through “low waste” upstream processes means that waste generation associated with the overall process of alkyl halide formation is also very low. The methodology is applicable to primary, secondary, tertiary and benzylic alcohols, is tolerant of a wide variety of functional groups, and has been shown to be effective in the synthesis of several representative pharmaceutical compounds.