Unexpected Solvent Effects in Controlling Stereoselectivity and Product Distribution: Catalyst-free Reaction of Propranolol with (S)-2-acetoxy-succinic Acid Divinyl Ester

• 1、Department of chemistry, Zhejiang University, Hangzhou 310027

Abstract：The stereoselectivity and product distribution of catalyst-free reaction of propranolol with (S)-2-acetoxy-succinic acid divinyl ester are shown to be solvent-dependent. In moderate polar solvents, propranolol undergo regioselective acylation and (R)-propranolol vinyl ester spontaneously cyclize, so as to provide the remained (S)-propranolol vinyl ester with high 97% de value. The intramolecular hydrogen bond between the carbonyl group and the propranolol's hydroxy functionality affects the cyclization activity of (R)- or (S)-propranolol vinyl ester in different solvents. However, strong polar solvent are favorable for the cyclization of both (R)- and (S)-propranolol vinyl ester. Distribution of obtained six- or seven-membered morpholinone derivatives was dependent on the nature of the solvent. The best result was the selective formation of 3-morpholinone derivatives in 96% yields. A tandem process of transesterification and β-elimination/Michael addition is a tentative mechanism basing on some designed experiments.

keywords： Organic synthesis Propranolol Cyclization Stereoselectivity Solvent effect

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