Synthesis of novel pyrazolo[3,4-b]quinolinebisphosphonic acids and an unexpected intramolecular cyclization and phosphonylation reaction.

Novel pyrazolo[3,4-b]quinoline -ketophosphonic and hydroxymethylenebisphosphonic acid compounds were synthesized using different methodologies, starting from 2-chloro-3-formylquinoline 1. New phosphonic acid compounds were obtained as N-1 derivatives with a side chain with 1 or 3 (n=1 or 3) methylene groups. All phosphonic acid compounds and their corresponding ester and carboxylic acid precursors were fully characterized, and their structures elucidated by spectroscopic data, using NMR techniques, infrared and high-resolution mass spectra. During the process to obtain the N-1 substituted derivative with two methylene groups (n=2) in the side chain, an unexpected addition-cyclization cascade reaction was observed, involving the phosphonylation of an aromatic ring and the formation of a new six member lactam ring to afford a tetracyclic ring system. This was an unexpected result since other pyrazolo[3,4-b]quinoline derivatives and all corresponding pyrazolo[3,4-b]pyridine already prepared, under similar experimental conditions, did not undergo this reaction. This domino reaction occurs with different phosphite reagents but only to afford the six-member ring. The spectroscopic data allowed the identification of the new tetracyclic synthesized compounds and the X-ray diffraction data of compound 11 enabled the confirmation of the proposed structures.