Heavy-oxygen water is a chemical substance. It is a colorless, odorless and tasteless liquid. Some physical properties are slightly different from those of ordinary water. It is mainly used as a tracer in scientific research fields such as chemistry, biology, medicine, agriculture, and geology.
By designing a multifunctional supported single-atom cobalt catalyst, a four-component reductive coupling reaction of nitroaromatics, aldehydes, acetylenic esters and water was developed, and the direct, diversified and single diastereoselective synthesis of α-hydroxy-γ-lactam compounds was achieved. This catalytic synthesis method has the characteristics of wide substrate and functional group compatibility, simple operation, high atomic and step economy, and excellent catalyst reusability. The mechanism mechanism was studied experimentally using heavy oxygen water.
γ-Lactams are widely present in bioactive natural products, synthetic drugs, agricultural chemicals and functional materials. γ-Lactam compounds have been used as β-lactamase I, plant growth regulator II, and drugs for the treatment of hypertension, pain, nervous system disorders and related diseases. At present, although there are many methods available for the synthesis of γ-lactams, the direct, selective and diversified synthesis of α-hydroxy-γ-lactams using simple and readily available raw materials is an unsolved synthetic problem.
Nitroaromatics are a class of bulk chemicals, and their reduction process produces a variety of reactive intermediates. Some researchers designed and prepared multifunctional nitrogen and titanium dioxide co-doped carbon-supported single-atom cobalt catalyst CoSA-N/NC-TiO2, which was directly, diversifiedly and single diastereoselectively constructed from nitroaromatics, aldehydes, acetylenic esters and water through reduction coupling reactions. This catalytic synthesis method has the characteristics of simple operation, wide compatibility of substrates and functional groups, high step/atom economy, good chemical selectivity, and reusable catalysts.
The CoSA-N/NC-TiO2 catalyst was characterized by scanning transmission electron microscopy (STEM), spherical aberration electron microscopy (AC-HAADF-STEM), etc. The results showed that the CoSA-N/NC-TiO2 catalyst was mainly composed of atomically dispersed cobalt species supported by TiO2/N co-doped carbon. Synchrotron radiation X-ray absorption spectroscopy (XAS) data showed that each Co single atom was coordinated with four N atoms on average and anchored on the carbon support.
After fully characterizing the structure and composition of CoSA-N/NC-TiO2, the Researchers first applied it to catalyze the reductive coupling reaction of nitroaromatics, diethyl but-2-ynoate, formaldehyde and water. Various halogen, heteroatom, and unsaturated group-substituted nitro (hetero)aromatics can produce the target product α-hydroxy-γ-lactam with single diastereoselectivity (d.r. > 20: 1). The electronic effect and steric hindrance of the substituent have a certain influence on the reaction yield. Generally, electron-rich nitroaromatics have a higher yield than electron-poor nitroaromatics, which can be attributed to the key nucleophilic addition step with electron-rich intermediates. Among them, the structure of product 1 was confirmed by X-ray crystal diffraction, and the α-hydroxyl group and the β-ester group were on the same side. Except for but-2-ynoic acid diester, several other commercially available acetylenic esters can be effectively converted into the corresponding lactam products.
To further explore the universality of this catalytic reaction system, the Researchers studied the multicomponent reactions of different aliphatic aldehydes and aromatic aldehydes with nitrobenzene, but-2-ynoic acid diethyl ester and water. All reactions can produce the target product with a single diastereoselectivity.
To clarify the reaction path, the Researchers conducted an in-depth study of the mechanism. Control experiments showed that N-arylhydroxylamine was the key intermediate of the reaction. Deuteration experiments and heavy-oxygen water experiments proved that the γ-carbon of the product originated from the substrate aldehyde and the α-hydroxyl group originated from H2O. In addition, the Researchers also conducted various control experiments to prove that int-4 is the key intermediate of the reaction. Model reaction interruption experiments demonstrated that hydroxylamine int-1, hydroxyimide salt int-2, nitrosoalkenyl ester int-3', allylamine int-3 and amino acid ester int-4 were all reaction intermediates. Catalyst poisoning experiments and acid etching experiments showed that atomically dispersed CoN4 species were active sites for catalytic reduction.
