Development of a continuous process for α-thio-β-chloroacrylamide synthesis with enhanced control of a cascade transformation

Abstract

A continuous process strategy has been developed for the preparation of α-thio-β-chloroacrylamides, a class of highly versatile synthetic intermediates. Flow platforms to generate the α-chloroamide and α-thioamide precursors were successfully adopted, progressing from the previously employed batch chemistry, and in both instances afford a readily scalable methodology. The implementation of the key α-thio-β-chloroacrylamide casade as a continuous flow reaction on a multi-gram scale is described, while the tuneable nature of the cascade, facilitated by continuous processing, is highlighted by selective generation of established intermediates and byproducts.

Regioselective Thermal [3+2]‐Dipolar Cycloadditions of α‐Diazoacetates with α‐Sulfenyl/Sulfinyl/Sulfonyl‐β‐Chloroacrylamide Derivatives to Form Densely Functionalised Pyrazoles

“…While previously described α‐thioamides were generated using either thiophenol, benzyl mercaptan or 1‐butanethiol in the presence of freshly prepared sodium ethoxide, each of the novel α‐thioamides 7d, 7e, 7l, 7m were generated using aqueous sodium hydroxide as base, obviating the requirement for chromatographic purification. While the generation of α ‐thio‐ β ‐chloroacrylamides in continuous flow is amenable to scale up, all substrates used in this study were formed using optimised batch conditions described previously . The novel α ‐thio‐ β ‐chloroacrylamides 8d, 8e, 8l, 8m are fully characterised in this work.…”

Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide

“…Recent work has assessed the challenges associated with scaling-up this three-step process, successfully enabling samples of up to 25 g of the α-thioamide 2 to be prepared (Scheme ). , However, scale-up of the final cascade step has posed more serious practical considerations with regard to achieving the hot plunge effect in batch. Heat transfer through larger volumes results in a delay reaching the desired temperature in the bulk of the reaction medium.…”

“…This approach enabled the production of more material than would be possible in batch, through scaling-out the process and therefore removing the any potential problems associated with heat and mass transfer in scale-up. Significant difficulties still remained in achieving a complete process operable on the desired scale, including management of the various impurities generated in the cascade process, removal of the poorly soluble succinimide byproduct, and isolation of batches of solid Z -3 in acceptable yield and purity. , …”

“…This difficulty had been addressed by replacing toluene with acetonitrile as the reaction solvent, as succinimide is highly soluble in acetonitrile, enabling the reaction to be implemented in a continuous flow process (Scheme ). Removal of the succinimide byproduct subsequently required employment of a static batch-type workup, in which acetonitrile was evaporated under vacuum and the residue was then dissolved in toluene and cooled on ice, enabling separation of the precipitated succinimide by filtration. Toluene was then removed from the filtrate, and the product mixture was purified by recrystallization from an ethyl acetate/heptane mixture (Scheme ).…”

“…Toluene was then removed from the filtrate, and the product mixture was purified by recrystallization from an ethyl acetate/heptane mixture (Scheme ). A fully operational flow process would require that the succinimide byproduct removal also be carried out in flow. Herein, we describe the development of a fully operational flow process for this step, including reaction and inline workup before product isolation as a batch crystallization process.…”