Copper(II)-Mediated Aerobic Oxidation of Benzylimidates: Synthesis of Primary α-Ketoamides

Abstract

A simple and straightforward method for the synthesis of primary α-ketoamides has been discovered. The reaction represents the first example of benzylimidates directly converting to primary α-ketoamides by using sustainable molecular oxygen as an oxidant. This reaction proceeds in the presence of copper(II) salt via cleavage of benzylic C-H and C-O bonds of the benzylimidates with liberation of alcohols as the only byproduct. A wide substrate scope, operationally mild conditions, the use of single substrates, and a reaction scaled up to grams make this strategy very attractive and practical. Furthermore, mechanistic studies illustrate that the imidate group adjacent to the benzylic position plays crucial role in facilitating this chemical process.

Diverse Oxidative C(sp2)–N Bond Cleavages of Aromatic Fused Imidazoles for Synthesis of α-Ketoamides and N-(pyridin-2-yl)arylamides

“…The imidazo­[1,2- a ]­pyridine substrate 1a could be oxidized by Cu­(II) to give the radical anion intermediate VI and then be deprotonated under a base to afford the amine radical VII . Amine radical VII could be oxidized by air to afford the intermediate VIII with the assistance of the Cu­(II) catalyst. ,, Intramolecular cyclization of complex VIII gives intermediate IX and releases the Cu­(II) catalyst for an additional catalytic oxidative process. , Intramolecular rearrangement of intermediate IX leads to the di-ketone intermediate X , ,, which could be fragmented into the amide radical XI and isocyanate intermediate XII . Aerobic oxidation of the amide radical XI gives the product 3a . , Hydrolysis of the isocyanate intermediate XII leads to various by-products such as the primary amines and urea, as detected by HR-MS.…”

Copper-Promoted Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems to Organometallic Transformations

“…Using a similar approach, Kumar reported the synthesis of primary α -ketoamides by copper-mediated aerobic oxidation of benzylimidates (Figure 117). 375 The substrates were converted to the corresponding oxygenation products using stoichiometric amounts of Cu(OAc) 2 (2 equiv) and O 2 in DMF (80 °C, 6 h). For most of the substrates, yields higher than 50% were observed (Figure 117, ii).…”

Microwave-assisted synthesis of new 2-aryl and 2-alkylimidazolones and evaluation of their in vitro anticancer activity and their in vivo toxicity on zebrafish embryos

“…The target temperature was reached within the required time and the chosen microwave maximal power was set to 100 W. The reaction temperature is monitored using calibrated infrared sensor and the reaction time. The imidates salts 1a (Kumar et al 2016), 1b (Yadav and Babu 2005), 1c (Yadav and Babu 2005) and 1d (Shi et al 2018) were prepared as previously described.…”