Selective reduction of carboxylic esters enabled by a coaxial double-tube continuous-flow reactor with on-the-fly H2 degassing

Abstract

The selective reduction of carboxylic esters bearing multiple readily reducible functionalities to primary alcohols with borohydrides represents a highly useful synthetic transformation. However, the need to use metal salts as additives to modulate selectivity and the safety issues associated with the exotherm and hydrogen gas evolution limit its wider applications in modern synthetic processes. Herein, we report on the development of a coaxial double-tube continuous-flow reactor which allows on-the-fly removal of the generated hydrogen gas from the reaction solution, eliminating the need for a downstream degassing procedure and enabling fully continuous processing of the hydridic type of reduction in a highly controlled and safe manner. This approach provides synthetically useful selective reduction of carboxylic esters with multiple readily reducible functionalities to primary alcohols, without the need to use metallic salts as additives. Taking advantage of the developed prototype, a diverse set of aliphatic unsaturated and polysubstituted aromatic esters, as well as chiral (4S,5R)-hemiesters, were reduced to the corresponding primary alcohols in only 1.25–2.5 min residence times in high yields. The synthetic utility of this flow protocol was corroborated by a multi-step synthesis of (3aS,6aR)-lactone, a key intermediate for preparing (+)-biotin. The multistep reactions were further integrated with microfluidic liquid–liquid extraction and membrane separation units, leading to outstanding productivity and minimized solvent/energy consumption and waste output. The integrated continuous-flow process produced (3aS,6aR)-lactone in an isolated yield of 94.5% and a space time yield of 44.0 g L⁻¹ h⁻¹ (i.e., 1.06 kg L⁻¹ day ⁻¹) after 24 h of continuous operation. A low value of process mass intensity of 16.62 was achieved.