One‐Pot Synthesis of Quinazolin‐4(3H)‐ones through Anodic Oxidation and the Related Mechanistic Studies

Abstract

A metal-free and oxidant-free method for the one-pot preparation of quinazolin-4(3H)-ones enabled by electrochemical oxidation is described. Together with 2-aminobenzamides, a variety of aldehydes were successfully applied to an acid-catalyzed annulation and direct anodic oxidation cascade, affording structurally diverse quinazoline-4(3H)-ones in good to excellent yields. Additionally, certain alcohols can be directly applied instead of the corresponding aldehydes to achieve the same final products with the assistance of an electrolysis mediator (TEMPO). The reaction mechanism was carefully examined and the results strongly suggest that the direct and indirect oxidation go through different pathways. As an efficient and environmentally friendly access to a broad range of quinazolin-4(3H)-ones, the synthetic utility of this method was demonstrated by gram-scale operation, as well as the preparation of bioactive mackinazolinone and truncated erlotinib.

Mn‐Catalyzed Electrochemical Synthesis of Quinazolinones from Primary Alcohols/Benzyl Ethers and o‐Aminobenzamides

“…We are interested in taking this chemistry further and we questioned whether the tandem electrochemical alcohol‐to‐quinazolinone process could be achieved by a redox‐active metal (Scheme ). Herein, we describe the first Mn catalyzed cascade cyclization reaction to afford quinazolinones from 2‐aminobenzamides and alcohols under electrochemical conditions in an undivided cell . Noteworthy, benzyl methyl ethers could also participate in this reactions to afford quinazolinones in good yields.…”

“…Herein, we describe the first Mn catalyzed cascade cyclization reaction to afford quinazolinones from 2-aminobenzamides and alcohols under electrochemical conditions in an undivided cell. [9] Noteworthy, benzyl methyl ethers could also participate in this reactions to afford quinazolinones in good yields.…”

“…The reaction was performed under a constant current electrolysis in an undivided cell using LiClO 4 as the electrolyte, CH 3 CN as the solvent, CF 3 COOH (TFA) as an additive, and Pt foils as electrodes. After the electrolysis was carried out at room temperature for 4 hours, the desired product 3 a was obtained in a yield of 11 % ( [6][7][8][9]. It was interesting that water had a significant influence on this reaction (Table 1, entries 10-12).…”

Metal‐ and Catalyst‐Free Electrochemical Synthesis of Quinazolinones from Alkenes and 2‐Aminobenzamides

“…The condensation of 4 c with 1 a affords imine B and releases H 2 O, and the subsequent intramolecular cyclization forms C . Finally, the rapid anodic oxy‐dehydrogenation of C yields the desired product, quinazolinone 3 c . On the cathode, protons are reduced to hydrogen to complete the electrochemical cycle.…”

“…On the basis of the above results and previous reports, a plausible reaction mechanism of this metal-and catalyst-free electrochemical synthesis of quinazolinones was proposed as shown in Scheme 5. First, phenylethylene 2 c is anodically oxidized into the corresponding radical cation A [31] that undergoes the 1, 2-addition reaction with methanol to afford 1-(1,2dimethoxyethyl)-4-methoxybenzene 6 c. [32] The anodic reoxidation and CÀ C bond cleavage of 6 c yield 1-(dimethoxymethyl)-4methoxybenzene 5 c [33] that is hydrolyzed by the trace amount of water in solvent to 4-methoxybenzaldehyde 4 c. [34] The condensation of 4 c with 1 a affords imine B and releases H 2 O, and the subsequent intramolecular cyclization forms C. [35] Finally, the rapid anodic oxy-dehydrogenation of C yields the desired product, quinazolinone 3 c. [30,36] On the cathode, protons are reduced to hydrogen to complete the electrochemical cycle.…”