Green aza-Michael reactions under ambient conditions

Abstract

The purpose of this study was to screen various catalysts, solvents and reaction conditions for the aza-Michael addition of l-pentylamine to dimethyl maleate to determine which would be the most green and efficient for this reaction and to investigate whether they could be extended to other classes of amines and other common Michael acceptors. Potassium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), Amberlyst resins, alumina and a binary mixture of DBU and acetic acid were tested as catalysts, using THF and acetonitrile as solvents, for the reaction between 1-pentylamine and dimethyl maleate. It was found that none of these catalysts and solvents improved the yield and reaction time with respect to the neat reaction, without catalyst under ambient conditions which gave a yield of 96% of the product, dimethyl 2-(pentylamino )succinate, after 4 hours of reaction. The addition of various amines onto dimethyl maleate was carried out in the absence of solvent and catalyst under ambient conditions. It was found that the linear aliphatic primary amines resulted in yields of 85-96% in 4-5 hours of mono-adduct, while the branched and cyclic aliphatic primary and secondary amines tested resulted in yields of 51-85% and reaction times of 5-7 hours. These adducts have not previously been reported in the literature and are therefore thought to be novel compounds. No reaction was observed for the aromatic amines tested (aniline, p-ethylaniline and N-methylaniline ). When methyl acrylate and acrylonitrile were used as acceptors with 1-hexylamine the mono-adduct was obtained in high yield (70- 80%) after 20 hours, but some bis-adduct (8-12%) was also obtained due to lack of selectivity. When trans-methyl crotonate was used, the yield of mono-adduct was 60%, after 96 hours of reaction. 1-Hexylamine did not react with trans-4 phenyl-buten-2-one, trans-2-hexenal, 2-cyclopentenone and 2-cyclohexenone under these conditions. Sodium hydride and potassium tert-butoxide were tested as basic catalysts in a variety of solvents to elicit the Dieckmann cyclisation of methyl 3-[hexyl(3-methoxy-3 oxopropyl)amino ]propanoate. However, in all cases the reaction was unsuccessful due to degradation of products. An intramolecular amide synthesis was attempted on dimethyl 2 (hexylamino )succinate by gradually warming it to 180 °C. However this led to the breakdown of the compound.