Pyrazole Pyrazolo isoquinolines

Besides uracil-6-iminophosphorane, the iminophosphorane component was extended to pyrazole 3 and pyrazolon-4-iminophosphoranes 363 (94JOC3985). In its electron distribution, 363 can be compared with uracil 346. With arylisocyanates, pyridine, or y-picoline, zwitterionic pyrazolo [3, 4 4,5]pyrido[6,l-a]pyrimidines (364) are obtained and with isoquinoline, 365 is formed (Scheme 131). Again, both systems show a typical negative solvatochromism (94JOC3985). 

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

The copper-catalyzed C—H activation reactions of 2-alkynylbromobenzene with pyrazoles, to afford pyrazolo[5,l-fl]isoquinolines, have been reported by Wu and coworkers as part of their efforts to synthesize drug-like small moleculesd Several ligands were screened under different base/solvent combinations. The reaction was found to proceed well with 10 mol% of ligand A, in the presence of 10 mol% 2,6-diethylaniline, whose role in the catalytic cycle remains unclear (Scheme 7.6). The reader is referred to the reference for a discussion of the mechanistic cycle for this tandem copper-catalyzed hydroamination and C—H activation reaction. 

Both LiCl and pivalic acid were required to maximize product yield and to suppress the formation of the heterodimer, albeit excess LiCl retarded the reaction. Other additives, such as Ag2C03 and AgOAc, were inferior however, AcOH was comparable to PivOH (67% vs. 75%). The chloro analog could be cyclized without LiCl in good yield (55%). A wide range of pyrazolo[5,l-a]isoindoles was accessible. Electron-deficient and electron-rich aryl bromides were compatible. Steric hindrance did not negatively impede the reaction. Other heteroarenes, such as naphthyl, thienyl, and pyridyl moieties, were viable substrates, albeit afforded lower yields of the product (50-55%). In addition, 2-bromo-phenethyl-pyrazole could be cyclized to generate 5,6-dihydropyrazolo[5,l-a]isoquinoline (eq 23). 

Furthermore, the pyrazole formation reaction was also combined with a palladium-catalyzed Sonogashira coupling with a terminal alkyne and subsequent intramolecular 6-endo alkyne hydroamination to provide an alternative approach to the facile synthesis of pyrazolo[5,l-a]isoquinoline 36 (Scheme 7.19) [72]. 

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