New synthetic approach to pyrazolopyrazine derivatives from 2,2‐dichlorovinylacetophenones

• Published in: Journal of heterocyclic chemistry 2023-10, Vol.60 (10), p.1714-1726
• Main Authors: Guirado, Antonio, Vera, María, Martiz, Bruno, Ródenas, Francisco, Bautista, Delia, Gálvez, Jesús
• Format: Article
• Language: English
• Subjects: Ammonium hydroxide; Aromatic compounds; Crystallography; Hydrochlorides; Molecular structure; Pyrazines; Reaction mechanisms; Sodium hydroxide
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4712

New efficient synthetic methods in pyrazoline and pyrazolopyrazine chemistry have been developed starting from 2,2‐dichlorovinylacetophenones 1, which were sequentially transformed into 3‐aryl‐5‐dichloromethyl‐1‐(2‐hydroxiethyl)‐2‐pyrazolines 2, 3‐aryl‐5‐dichloromethyl‐1‐(2‐O‐tosylhydroxyethyl)‐2‐pyrazolines 3, 3‐aryl‐5‐dichloromethyl‐1‐(2‐azidoethyl)‐2‐pyrazolines 4, and 3‐aryl‐5‐dichloromethyl‐1‐(2‐aminoethyl)‐2‐pyrazoline hydrochlorides 5, by reaction with 2‐hydroxyethylhydrazine, O‐tosylation, azidation, and catalytic hydrogenation, respectively. Compounds 5 were treated with aqueous sodium hydroxide to provide 2‐aryl‐4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyrazines 6 in one‐step conversions involving cyclization and aromatization. A reaction mechanism has been proposed with the aid of DFT theoretical calculations. Compounds 6 could also be obtained directly in one‐pot reactions of tosylates 3 with ammonium hydroxide followed by the addition of sodium hydroxide. The molecular structure of 2‐(4‐chlorophenyl)‐4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyrazine 6c was determined by X‐ray crystallography. Simplicity, good overall yields and inexpensive starting materials are advantageous features of the improved synthetic procedures reported herein.