1,6-Aza-Michael addition of para-quinone methides with N-heterocycles catalyzed by Zn(OTf)2: A regioselective approach to N-diarylmethyl-substituted heterocycles

• Published in: Tetrahedron 2020-07, Vol.76 (28-29), p.131338, Article 131338
• Main Authors: Guin, Soumitra, Saha, Hemonta K., Patel, Ashvani K., Gudimella, Santosh K., Biswas, Subhankar, Samanta, Sampak
• Format: Article
• Language: English
• Subjects: 1,6-aza-Michael; N-heterocycles; Para-quinone methides; Regioselectivities; Zn(OTf)2-catalyzed
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2020.131338

An efficient Zn(OTf)2-catalyzed regioselective C–N bond making reaction between a bunch of aryl/heteroaryl-substituted para-quinone methides as ideal 1,6-acceptors and various aromatic/non-aromatic aza-heterocycles bearing N–H moiety namely carbazoles, pyrazoles, indazole, benzotriazole and saccharin is reported. This 1,6-aza-Michael technique delivers predominantly N1-diarylmethyl-substituted heterocyclic scaffolds bearing a valuable phenolic moiety in good to high yields with an excellent regioselectivity. Furthermore, this LUMO lowering catalytic system allows different kinds of useful functionalities and excels with broad substrates under mild conditions. Importantly, our control experiments suggested that N2-adducts of indazole, benzotriazole and 3-methyl pyrazole as minor isomers were progressively converted into N1-adducts during the reaction via a retro-aza-Michael reaction triggered by Zn(OTf)2, offering excellent regioselectivities of the products. [Display omitted] •Zn(OTf)2-catalyzed 1,6-aza-Michael reaction of NH-heterocycles to para-quinone methides was developed.•Excellent regioselective access to N-alkylated heterocycles with a valuable phenolic moiety.•The regioisomeric ratio is highly dependent on the solvent used for this reaction.•Applicable to large-scale synthesis under mild conditions.