A versatile synthesis of pyrazolo 3,4-c isoquinoline derivatives by reaction of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes: the effect of the heterocycle on the reaction pathways

Bogza, S.L.; Kobrakov, K.I.; Malienko, A.A.; Perepichka, I.F.; Sujkov, S.Y.; Bryce, M.R.; Lyubchik, S.B.; Batsanov, A.S.; Bogdan, N.M.

Abstract

The reaction of 4-(3,4-dimethoxyphenyl)-5-aminopyrazoles 7A-D with aromatic and heterocyclic aldehydes in strong acidic media (trifluoroacetic or formic acid) has been studied. The initial azomethine derivatives 8 undergo cyclization similar to the Pictet-Spengler condensation to form the intermediate 4,5-dihydroisoquinolines 9 which readily dehydrogenate giving 5-aryl(heteroaryl)-pyrazolo[3,4-c]isoquinoline derivatives 10 as the final products. Whereas for benzaldehyde and its derivatives this one-pot synthesis presents a convenient general route to 5-aryl-pyrazolo[3,4-c]isoquinolines 10, in the case of heterocyclic aldehydes the product structure varies markedly with the structure of the aldehyde used: (i) 3-pyridyl-, 3-quinolyl-, 3-thienyl-, and 1,2,3-thiadiazolyl-5carboxaldehydes give 5-heteroarylpyrazolo[3,4-c]isoquinolines; (ii) 1-methylbenzimidazolyl-2-carboxaldehyde gives only intermediate azomethine 8Dh, which does not cyclize; (iii) 1-R-3-indolylcarboxaldehydes(R = H, CH3, CH2Ph) eliminate the heteroaryl fragment resulting in 5-unsubstituted pyrazolo [ 3,4- c] isoquinolines 11. Thienyl-2carboxaldehyde reacts by both pathways ( i) and ( iii) depending on the reaction conditions. The single crystal X-ray structures for 10Dj, 10Cd and 11D provide confirmation of the different types of products formed in these reactions. Mechanisms which explain these transformations are presented.

• Journal Article Type: Article
• Publication Date: 2005
• Journal: Organic and Biomolecular Chemistry
• Print ISSN: 1477-0520
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 5
• Pages: 932-940
• Public URL: https://durham-repository.worktribe.com/output/1603511