Associate Professor Saint Louis University St. Louis, Missouri, United States
Objective : Exploration of an unusual beta-elimination reaction while resolving the low yielding synthesis of an acetamido phthalide derivative, which was identified as a hit for developing small molecule complement component C3b modulator using a virtual screening strategy.
Methods: Several nucleophilic and non-nucleophilic bases were explored to improve the synthesis of the hit compound from either the activated ester or the acid chloride. In most of the cases the reaction yielded with higher conversion to an undesired cinnamamide product. Further exploration of the undesired product opened a new avenue for the synthesis of a different class of biologically important cinnamamides. Whereas, complete elimination of the bases resulted in higher yield of the hit phthalide.
Results: Exploration of the beta-elimination, led a pathway to not only resolve the issue related to the synthesis of phthalide derivatives but also established an effective way of synthesizing cinnamamides with dissimilar substitutions.
Conclusions: In this present endeavor we found an efficient one-pot synthesis of preparing both the acetamido phthalides (2) and the (E) cinnamamide derivatives (3) from a common intermediate 2-(3-oxo-1,3-dihydroisobenzofuranone-1yl)acetylchloride (4) (Figure 1), just by including or eliminating the addition of non-nucleophilic amines to the corresponding acid chloride.
