Organocatalytic Triazole Formation, Followed by Oxidative Aromatization: Regioselective Metal‐Free Synthesis of Benzotriazoles

Abstract

Herein we report on our studies on the sequential one-pot combinations of amine-catalyzed multicomponent reactions (MCRs). We have developed the copper-free synthesis of functionalized bicyclic N-aryl-1,2,3-triazole and N-arylbenzotriazole products 4 and 5 from the simple unmodified starting materials through [3+2]-cycloaddition ([3+2]-CA) and oxidative aromatization reactions in one pot under amine catalysis. The sequential one-pot reaction proceeds in good yields with high selectivity by using pyrrolidine as the catalyst from the simple unmodified substrates of enones, aryl azides, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Furthermore, we have demonstrated the medicinal applications of products 4 and 5 through simple organic reactions.

New click-chemistry methods for 1,2,3-triazoles synthesis: recent advances and applications

“…The regioselective synthesis of N-arylbenzotriazoles was successfully achieved using a cyclic enone and an arylazide under pyrrolidine catalysis at room temperature. 19 Further aromatization by DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) allowed access to fused heterocyclic scaffolds. A tandem one-pot Knoevenagel/azide-alkyne cycloaddition reaction between indole, pyrazole or aryl containing aldehydes and phenylazide were successfully conducted in the presence of piperidinium acetate in methanol (scheme 2).…”

Lewis Base Catalyzed Aerobic Oxidative Intermolecular Azide–Zwitterion Cycloaddition

“…More recently, organocatalytic triazole formation has been used as a powerful, albeit less developed, alternative to metal‐catalyzed AAC reactions. The groups of Ramachary16a,h and Bressy,16c as well as our group,16b,d,f,g,j independently reported the organocatalytic regioselective synthesis of substituted 1,2,3‐triazoles through enamine intermediates formed in situ. This method attracted much attention because of the common green features of organocatalysis 17.…”

The Rich Chemistry Resulting from the 1,3‐Dipolar Cycloaddition Reactions of Enamines and Azides

“…In recent years, advancement in enamine mediated organocatalysis has had a significant impact in the field of 1,2,3‐triazole synthesis 8a], [8b] This reaction generally involves the catalytic formation of an enamine intermediate through the reaction of a carbonyl compound 31 and an amine catalyst, followed by its cycloaddition reaction with an organic azide.…”

“…An organocatalytic approach was first used by Ramachary et al for the synthesis of fused NH ‐1,2,3‐triazoles by the reaction of Hagemann's esters with tosyl azide in the presence of 20 mol‐% of proline as organocatalyst and DMSO as the solvent . After this seminal report, many enamine mediated triazole forming reactions were published, which utilize secondary amines such as proline, pyrrolidine, or diethylamine as the catalysts of choice . In general terms, the enolizable carbonyl compounds used in these reactions could be classified into three different categories according to the acidity of α‐H atoms: (1) activated saturated ketones 32a and 32b , (2) activated unsaturated carbonyl compounds, which include α,β‐unsaturated aldehydes 33 and Hagemann's esters 34 and (3) non‐activated ketones, for example, cyclic and acyclic ketones 35 (Scheme ).…”