One‐Pot and Two‐Chamber Methodologies for Using Acetylene Surrogates in the Synthesis of Pyridazines and Their D‐Labeled Derivatives

• Published in: Chemistry, an Asian journal an Asian journal, 2021-08, Vol.16 (16), p.2286-2297
• Main Authors: Ledovskaya, Maria S., Polynski, Mikhail V., Ananikov, Valentine P.
• Format: Article
• Language: English
• Subjects: Acetylene; Chambers; Chemistry; Cycloaddition; Deuteration; deuterium; Installation procedures; labeling; Organic chemistry; pyridazine; Pyridazines; Quantum chemistry; Vinyl ethers
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.202100562

Acetylene surrogates are efficient tools in modern organic chemistry with largely unexplored potential in the construction of heterocyclic cores. Two novel synthetic paths to 3,6‐disubstituted pyridazines were proposed using readily available acetylene surrogates through flexible C2 unit installation procedures in a common reaction space mode (one‐pot) and distributed reaction space mode (two‐chamber): (1) an interaction of 1,2,4,5‐tetrazine and its acceptor‐functionalized derivatives with a CaC2−H2O mixture performed in a two‐chamber reactor led to the corresponding pyridazines in quantitative yields; (2) [4+2] cycloaddition of 1,2,4,5‐tetrazines to benzyl vinyl ether can be considered a universal synthetic path to a wide range of pyridazines. Replacing water with D2O and vinyl ether with its trideuterated analog in the developed procedures, a range of 4,5‐dideuteropyridazines of 95–99% deuteration degree was synthesized for the first time. Quantum chemical modeling allowed to quantify the substituent effect in both synthetic pathways. Two novel synthetic paths to 3,6‐disubstituted pyridazines and 4,5‐dideuteropyridazines from 1,2,4,5‐tetrazines and acetylene surrogates were proposed. CaC2 demonstrated excellent results in reactions with 1,2,4,5‐tetrazine and acceptor‐substituted derivatives, and benzyl (D3‐)vinyl ether was found to be a better choice for reactions with donor‐substituted tetrazines. Competitive experiments and quantum chemical calculations were performed for mechanistic study.