One-Pot Cascade [3 + 2 + 1] Annulation: Synthesis and Mechanistic Insight of s-Triazines and Pyrimidines Using Azo-Supported Metalloradical Nickel Catalyst

Abstract

Highly efficient Ni-catalyzed C─N/C─C bond formation from amidines during the [3 + 2 + 1] annulation by primary alcohols alone or by primary alcohols with secondary alcohols/phenyl acetylenes has been successfully accomplished toward scaled synthesis of s-triazine and pyrimidines, respectively. A strongly π-acidic bis-azo NNN-pincer scaffold was successfully introduced for dual functionalization such as augmenting the sustainability of the molecular catalyst by enhancing the metal–ligand integrity and interposing a potent electron-sink chromophore. The high yield synthesis (up to 94%) of poly-azaheterocycles with merely 0.001 mol% catalyst loading demonstrates the potency of azo-anion radical assisted catalysis. A diverse range of primary and secondary alcohols are successfully used as substrates. Furthermore, use of methanol/ethanol as C1/C2 synthon (alkylating agents) enables the formation of challenging imine intermediates from amidines through dehydrogenation under mild conditions. This facilitates the synthesis of wide varieties of s-triazines, and pyrimidines driven by the auto-tandem catalyst. Mechanistic investigations reveal that the formation of C─C and C─N bonds proceed through a metalloradical catalysis (MRC) pathway instead of borrowing hydrogen (BH) method and thereby addresses the challenge of controlling stereoselection. This process is initiated by Ni-catalyzed acceptorless dehydrogenation (AD) of the alcohol substrate, followed by a series of sequential steps, including condensation, aza-Michael addition, cyclization, and subsequent dehydrogenation. The well-defined one-electron reductive response at −0.34 V (versus Fc⁺/Fc) is indicative of the involvement of azo anion radical during catalytic annulation. The formation of the ligand radical intermediate was further substantiated by an electron paramagnetic resonance (EPR) study conducted both in the presence and absence of radical scavengers, specifically 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and butylated hydroxytoluene (BHT).