A New Strategy for the Synthesis of Tertiary Amides via a Copper-Catalyzed Decyanation Reaction of N,N-Disubstituted 2-Aminomalononitriles

Abstract

The development of new synthetic methodology and reagent is always a hot topic in organic synthesis community. Among the strategies used, chemical property investigation of synthetic intermediates with multifunctional groups represents a direct and efficient way. In this paper, as a systematic continuation of α-aminomalononitrile based synthetic application studies, α-aminomalononitrile has been developed for the first time as a surrogate for carbamoyl anions and applied to the synthesis of tertiary amides via a copper-catalyzed decyanation reaction. This strategy features simple reaction conditions, scalability, and wide substrate scope. This work not only further enriches the reaction model of aminonitrile compounds, but also provides an alternative synthetic strategy for the synthesis of substituted amides from simple formamides. In this process, the substrates could be readily synthesized through the nucleophilic addition or substitution reaction of α-aminomalononitriles, and they would be converted to corresponding tertiary amide in the presence of CuF 2 in DMSO. As an example, the formal hydrocarbamoylation reaction of unsaturated bonds could be achieved. A general procedure for the strategy is as follows: α-aminomalononitrile derived from formamide is used to undergo nucleophilic addition or substitution reaction with electrophilic reagents. Next, the two cyano groups of the synthesized substrates could be removed under the catalysis of CuF 2 to form a C＝O double bond in situ, thereby achieving the synthesis of corresponding tertiary amide. During the reaction, the α-aminomalononitrile substrate (0.4 mmol), CuF 2 (5 mol%), DMSO (3 mL) were placed in a sealed reaction tube at 100 ℃ at an argon atmosphere for about 32 hours. Then, the reaction system was washed out with ethyl acetate, and the organic phase was washed with water to remove DMSO. Next, the aqueous phase was extracted with ethyl acetate. Finally all organic phases were combined, washed once with saturated brine. After drying the organic phase over anhydrous sodium sulfate, it was concentrated by a vacuum pump. Finally, the residue was purified by flash column chromatography to give amide product.

Synthesis of Benzylidene Analogs of Oleanolic Acid as Potential α-Glucosidase and α-Amylase Inhibitors

“…It is conservatively estimated that T2DM will affect approximately 500 million people worldwide by 2030, and the mortality rate for the disease and its associated complications is one death every 6 s as of now ( Kumar et al, 2021 ). The effective way to reduce blood glucose levels in the treatment and prevention of T2DM and its complications is the clinical use of oral hypoglycemic agents such as sulfonylureas ( Liang et al, 2020 ; Ling et al, 2021 ), biguanides ( Zheng T.-L. et al, 2021 ; Kathuria et al, 2021 ), thiazolidinedione-derived drugs ( Long et al, 2021 ; Liu et al, 2021 ), dipeptidyl-peptidase IV inhibitors ( Carullo et al, 2021 ; Cheng et al, 2022 ), α -glucosidase inhibitors ( Hossain et al, 2020 ), sodium-glucose cotransporter-2 inhibitors ( Provenzano et al, 2021 ), and glucagon-like peptide-1 (GLP-1) receptor agonists ( Furer et al, 2021 ; Saxena et al, 2021 ). Among these, α -glucosidase inhibitors are widely used as clinical drugs including acarbose, voglibose, miglitol, and emiglitate, and there are reports on α -amylase inhibitors derived from the natural product.…”

Copper-Catalyzed Asymmetric Ring-Opening Reaction of Cyclic Diaryliodonium Salts with Imides

“…Nevertheless, these strategies were not efficient enough for the preparation of a primary amine type product; either the steps were relatively long or the yield was low. , Therefore, it is of great significance to further explore an alternative method for obtaining axially chiral two-substituted biaryls, which could be readily derivatized to various types of aromatic amines. In connection with our interests in copper catalysis and asymmetric catalysis, we envisioned that it might be feasible for a copper-catalyzed asymmetric ring-opening imidation of diaryliodonium salts to stereoselectively afford chiral biaryl imides from simple and readily available imides . Because imides are convenient precursors for the divergent synthesis of different types of amines or amide derivatives, such a strategy might offer a new opportunity for preparing synthetically important axially chiral 2-aminobiaryls.…”