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.
The continuous flow alcoholysis of dialkyl H-phosphonates by aliphatic alcohols in the absence of a catalyst was elaborated using a microwave (MW) reactor equipped with a flow cell. By the precise control of the reaction conditions, the synthesis could be fine-tuned towards dialkyl H-phosphonates with two different and with two identical alkyl groups. In contrast to the “traditional” batch alcoholysis, flow approaches required shorter reaction times, and the products became available at a larger scale.
The synthesis of α-aryl-α-aminophosphonates was performed by the three-component Kabachnik-Fields reaction of primary amines, benzaldehyde derivatives and dialkyl phosphites in a continuous flow microwave reactor. The target compounds could be obtained in high (~90%) yields without any catalyst in simple alcohols as the solvent. The flow process elaborated required shorter reaction times and lower excess of the reagent, as compared to the “traditional” batch reactions, and allowed the synthesis of the α-aminophosphonates on a somewhat larger scale.
The synthesis of dialkyl H-phosphonates and α-aminophosphonates was studied in a continuous flow microwave reactor. Depending on the conditions, the alcoholysis of dialkyl H-phosphonates could be fine-tuned towards the mixed and the fully transesterified products. The continuous flow synthesis of α-aryl-α-aminophosphonates was elaborated utilizing the aza-Pudovik reaction of imines and dialkyl H-phosphonates, as well as the by the Kabachnik-Fields condensation of primary amines, benzaldehyde and >P(O)H reagents.
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