Pyrazolo isoquinolines

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Electrocyclization reactions are often used to synthesize fused thiophenes. Diazotization of an aminoisoquinoline gave a mixture of products including a 6-thiaellipticine and a pyrazolo[3,4-A]isoquinoline in 34% and 41% yields, respectively (Eq. 30) <96CC2711>. A diazotization... 

Cyano-4-hydroxypyridazino[l,6- ]quinolinium betaine 67 could be isolated from the reaction mixture of 1-amino-2-ethoxycarbonylquinolinium mesitylensulfonate and acrylonitrile in a few percent. Reaction of the 2-amino-1-ethoxycarbonylisoquinolinium salt with acrylonitrile afforded only a pyrazolo[5,l- ]isoquinoline derivative. 

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 diazopyrazole (93) with various phosphorus ylides afforded 3/7-pyrazolo[5,l-c]-1,2,4-triazoles (94) by elimination of triphenylphosphine (79TL1567). Reaction of 1-chloroisoquinoline with 5-phenyltetrazole gives 3-phenyl-1,2,4-triazolo[3,4-a]isoquinoline (96) via intermediate (95) (70CB1918) (cf conversion 86 — 87). 

The diazonium salt 453, derived from aminoisoquinoline 452, undergoes thermal cyclization to afford 6-thiaellip-ticine 454 and 37/-pyrazolo[3,4-, ]isoquinoline 455. Formation of 454 may involve the cyclization of an aryl radical intermediate (Scheme 74) <1996CC2711>. Isomerically pure 4,6-dimethyldibenzothiophene 457 <1996T3953> and benzothiophene 459 <2005T8711> can be synthesized from the diazonium salts 456 and 458, respectively. 

The Pschorr reaction has been employed successfully in the preparation of a pyrazolo[3,4-c]isoquinoline derivative (565) (78JHC1287). 

S. Li, Y. Luo, J. Wu, Org. Lett. 2011, 13, 4312 315. Three-component reaction of N -(2-alkynylbenzylidene)hydrazide, alkyne, with sulfonyl azide via a multicatalytic process a novel and concise approach to 2-amino-H-pyrazolo[5,l-a] isoquinolines. 

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. 

TMSK can also be used in [3+2] cycloadditions to generate pyrroloisoquinolines and pyrazolo[5,l-a]isoquinolines, from isoquinolinium methylides and A-tosyliminoisoquinolinium ylides, respectively (eqs 23 and 24). 

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). 

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