Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane

Abstract

Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, convenient, green, and highly efficient regioselective ring opening reactions of sterically hindered (2 R ,3 S )-3-( N -Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involve the reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41–98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR experiments suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first-time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving an equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent, and simple workup procedures.

Metal‐Free Ring‐Opening of Epoxides

“… Microwave assisted ring opening reactions of sterically hindered epoxide with deactivated anilines in nitromethane solvent [93] …”

“…In 2020 Poonam et al [93] explored a greener approach for the ring opening reactions of sterically hindered epoxide(196) with deactivated anilines (15) as nucleophile in nitromethane solvent under microwave irradiation. The corresponding βamino alcohol (197) are obtained moderate to good yields 41-98 % and high regioselectivity.…”

“…In 2020 Poonam et al [93] . explored a greener approach for the ring opening reactions of sterically hindered epoxide( 196 ) with deactivated anilines( 15 ) as nucleophile in nitromethane solvent under microwave irradiation.…”

A potent candidate against Zika virus infection: Synthesis, bioactivity, radiolabeling and biodistribution studies

“…In this work, we have improved the ring-opening reaction conditions i.e., faster, convenient, small to large scale (1-2 g) synthesis, and easy work-up procedures. 34 The modified reaction conditions include the usage of ethanol as a safe and economic solvent with a reduced reaction time, 30 minutes, as shown in Scheme 1. Aminemediated ring-opening of epoxide abides a regioselective attack on the less hindered carbon through the SN2 reaction mechanism.…”

Solvent-free mechanochemical grinding facilitates clean synthesis of N-substituted amines

“…Other types of equip-ment like shakers, 8 planetary mills, 9 automated grinders, 10 and twin screw extruders 11 are also used in research. [12][13][14][15][16][17][18] Particularly, for the preparation of active pharmaceutical ingredients (APIs) and natural products, mechanochemical molecular rearrangements have become an even more desirable and sustainable synthetic technique. 19 Rearrangements induced by mechanochemistry are still in their infancy, but they represent a promising way for chemists to combine molecular variety and greener approaches to develop more selective and efficient synthesis with less environmental footprints.…”