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.
