Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4,3-c]quinolines and -isoquinolines from 4-and 5-aryl-substituted 1-benzyloxypyrazoles

1-Hydroxypyrazolo [3,4-c]quinoline (22), 1-hydroxypyrazolo [4,3-c] quinolin e (21), 1-hydroxypyrazolo[3,4-c] isoquinoline (20), and 1-hydroxypyrazolo [ 4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establi shing the pyridine B-ring in the terminal step. The pyridine ring of pyrazo loquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1 -benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent a t C-4 or C-5 with an iminophosphorane group installed at C-5 dr C-4 of 1-be nzyloxypyrazole by lithiation followed by reaction with tosyl azide: and th en with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The a-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazol ylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodo aniline or 2-bromobenzaldehyde. The order of reactions and use of protectin g groups in the individual sequences have been optimized. The 1-benzyloxy-s ubstituted pyrazoloquinolines and isoquinolines thus obtained were debenzyl ated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquin olines and isoquinolines 19-22.