Study on the Microwave-Assisted Batch and Continuous Flow Synthesis of N-Alkyl-Isoindolin-1-One-3-Phosphonates by a Special Kabachnik–Fields Condensation

Abstract

A simple and efficient microwave (MW)-assisted method was elaborated for the catalyst-free synthesis of isoindolin-1-one-3-phosphonates by the three-component condensation of 2-formylbenzoic acid, aliphatic primary amines and various dialkyl phosphites. The batch and the continuous flow reactions were optimized in respect of the temperature, the reaction time and the molar ratio of the starting materials. To evaluate the potential of MW irradiation, comparative thermal experiments were also carried out. In order to obtain “real time” information about the condensation, the special Kabachnik–Fields reaction of 2-formylbenzoic acid, butylamine and diethyl phosphite was monitored by in situ FT-IR spectroscopy. The novel title compounds could be prepared in high yields at low temperature under a short reaction time. A suitable method could also be developed for the preparation of the isoindolin-1-one-3-phosphonates at a “few g” scale by using a continuous flow MW reactor.

Three-component synthesis, utilization and biological activity of phosphinoyl-functionalized isoindolinones

“…The condensations were performed at 25 °C, for 10 or 20 min without any catalyst in acetonitrile, according to the method described above. Altogether eight 3-oxoisoindolin-1ylphosphine oxides (12)(13)(14)(15)(16)(17)(18)(19) having different substituents on the phosphorus atom were synthesized in excellent yields (94-98%). Due to the P-stereogenic centre in the P-functionality, all products (12)(13)(14)(15)(16)(17)(18)(19) were formed as a mixture of two diastereomers, and both diastereomers were racemates.…”

“…Altogether eight 3-oxoisoindolin-1ylphosphine oxides (12)(13)(14)(15)(16)(17)(18)(19) having different substituents on the phosphorus atom were synthesized in excellent yields (94-98%). Due to the P-stereogenic centre in the P-functionality, all products (12)(13)(14)(15)(16)(17)(18)(19) were formed as a mixture of two diastereomers, and both diastereomers were racemates. Therefore, two signals were observed in the 31 P NMR spectra, and two signals were Scheme 4.…”

“…Others reported syntheses in the presence of a special catalyst or additive, such as NaH [16], T3P ® [17] or OSU-6 [18] in MeOH, EtOAc or EtOH, respectively. In our previous study, we have described an efficient catalyst-free method for the batch and continuous flow synthesis of 3oxoisoindolin-1-ylphosphonates (1) containing alkyl substituents on the nitrogen atom by the three-component reaction of 2formylbenzoic acid, aliphatic primary amines and dialkyl phosphites or ethyl phenyl-H-phosphinate [19] (Scheme 1).…”

Synthesis of α-Aminophosphonates and Related Derivatives; The Last Decade of the Kabachnik–Fields Reaction

“…In a somewhat analogous reaction, Bálint et al reacted 2-formylbenzoic acid, primary amines, and dialkyl phosphites to afford, eventually, after an intramolecular cyclization, isoindolin-1-one-3-phosphonates [ 66 ].…”

Microwave-Assisted Multicomponent Syntheses of Heterocyclic Phosphonates

“…As the first part of our project, a number of isoindolin-1-one-3-phosphonates (1) could be prepared by the catalyst-and solvent-free three-component condensation of 2-formylbenzoic acid, aliphatic primary amines and various dialkyl phosphites under MW conditions (Figure 1.) [14]. The reaction was optimized in detail on a selected model of 2-formylbenzoic acid, butyl amine and diethyl phosphite.…”