A new parallel, rapid, and green Knoevenagel condensation catalyzed by in-situ generated carbonic acid (CO2 (g) in water): Application to intermediate of AMG 837

This work demonstrates the first-ever use of carbonic acid from sparkling water and the one generated in-situ from dry ice for efficient Knoevenagel condensation. Various aldehydes reacted well with active methylenes in a shorter reaction time in environmentally-friendly ethanol: water (1:1) mixture as solvent at room temperature with workup by filtration or extraction. Carbonic acid is a non-toxic and inexpensive green catalyst. Carbonic acid offers easy availability and leaves no traces of catalyst in the product. The current protocol was also extended to intermediates of AMG 837, a novel GPR40 agonist. A novel post-synthesis analysis tool was used to evaluate the quality of the organic preparation based on yield, cost, safety, conditions, and ease of workup/ purification, which are atom economy (AE) of 89.47%, reaction mass efficiency (RME) is 86.31%, E-factors value of 0.16 and the eco-scale score for the method is 80.0 for model reaction. The overall atom economy (AE) of 91.73%, reaction mass efficiency (RME) is 80.95%, E-factors value of 0.25, and the eco-scale score for the method is 73.95.

Automated summary

This work demonstrates the use of carbonic acid from sparkling water and dry ice for efficient Knoevenagel condensation. The reaction showed good results with shorter reaction time using environmentally-friendly ethanol: water mixture as solvent. Carbonic acid is a non-toxic and inexpensive catalyst that is readily available and leaves no traces in the product. The method was also successfully applied to intermediates of a novel GPR40 agonist.