Synthesis of a γ-keto amide derived from thiophene using a carboxyl ester as precursor

Abstract

The aim of this work is the synthesis of a gama-keto amide derived from thiophene, using several simple experimental techniques and cheap and commercially available reagents. The students will have contact with several classical reactions in organic chemistry such as alkaline hydrolysis of a y-keto ester (saponification), nucleophilic substitution (conversion of a carboxylic acid to amide) using two different synthetic methodologies: i) mixed anhydride and ii) direct amidation of a carboxylic acid in the presence of DCC/OHBt coupling agents. The preparation of 1-(piperidin-1-yl)-4-(thiophen-2-yl)butane-1,4-dione through two different methods will allow the analysis of the efficiency of the two experimental procedures as well as the study of the two reaction mechanisms. Several experimental techniques are considered such as heating at reflux, liquid-liquid extraction, recrystallization, thin layer chromatograpy (TLC), gravity filtration, column chromatography on silica gel and melting point. The determination of the structure of all synthesized compounds are also performed through 1H NMR, 13C NMR and IR spectroscopic techniques. The duration of the experiment are 5 sessions: session 1: preparation of 4-oxo-4-(thiophen-2-yl)butanoic acid; session 2: preparation of 1-(piperidin-1-yl)-4-(thiophen-2-yl)butane-1,4-dione (method A: mixed anhydride), session 3: purification of the 1-(piperidin-1-yl)-4-(thiophen-2-yl)butane-1,4-dione using column chromatography on silica gel; session 4: preparation of 1-(piperidin-1-yl)-4-(thiophen-2-yl)butane-1,4-dione (method B: direct amidation in the presence of DCC/OHBt coupling agents), session 5: purification of the 1-(piperidin-1-yl)-4-(thiophen-2-yl)butane-1,4-dione through extraction followed by crystallization. The difficulty level of this experiment is high and the level of study is intermediate.