Merging inline crystallization and pulsed flow operation to enable enantiospecific solid state photodecarbonylation

Abstract

The enantioselective formation of C–C bonds is arguably one of the most important reactions in organic chemistry. While elegant solutions have been devised for the total synthesis of several natural products, active pharmaceutical ingredients (API), and related scaffolds, efficient methods that strive towards the principles of green chemistry remain highly desirable additions to the synthetic organic toolbox. Additionally, modern strategies become increasingly challenging when the desired structures are highly strained, sterically encumbered, or contain adjacent quaternary chiral centers. In this research, the hexasubstituted ketone d,l-2,4-dimethyl-3-oxo-2,4-diphenylpentanedinitrile was chosen as a highly strained and chiral proof-of-concept substrate to evaluate the scalability of solid state photoelimination chemistry. Performing the photodecarbonylation of easily accessible alpha-chiral ketones in the solid state physically restricts the mobility of the generated radical intermediates, resulting in high regio- and enantiospecificity. Additionally, aqueous suspensions can be used, resulting in a simple filtration as the only purification step. The continuous flow HANU™ 2X 15 photoreactor, preceded by a custom inline crystallization setup, were shown to be key enabling technologies to achieve the previously problematic continuous operation and scale-up of these reactions. A solid-to-solid photochemical process was successfully optimised, resulting in a STY of 3.6 kg h⁻¹ m⁻³.