Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines - sequential versus multicomponent reaction approach

Barbara Palka; Angela Di Capua; Maurizio Anzini; Gyté Vilkauskaité; Algirdas Sačkus; Wolfgang Holzer

doi:10.3762/bjoc.10.183

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines - sequential versus multicomponent reaction approach

Beilstein J Org Chem. 2014 Jul 31:10:1759-64. doi: 10.3762/bjoc.10.183. eCollection 2014.

Authors

Barbara Palka¹, Angela Di Capua², Maurizio Anzini³, Gyté Vilkauskaité⁴, Algirdas Sačkus⁵, Wolfgang Holzer¹

Affiliations

¹ Division of Drug Synthesis, Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
² Division of Drug Synthesis, Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria ; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy.
³ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100, Siena, Italy.
⁴ Division of Drug Synthesis, Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria ; Institute of Synthetic Chemistry, Kaunas University of Technology, LT-50254 Kaunas, Lithuania.
⁵ Institute of Synthetic Chemistry, Kaunas University of Technology, LT-50254 Kaunas, Lithuania.

Abstract

A straightforward synthesis of 6-substituted 1-phenyl-3-trifluoromethyl-1H-pyrazolo[4,3-c]pyridines and the corresponding 5-oxides is presented. Hence, microwave-assisted treatment of 5-chloro-1-phenyl-3-trifluoromethylpyrazole-4-carbaldehyde with various terminal alkynes in the presence of tert-butylamine under Sonogashira-type cross-coupling conditions affords the former title compounds in a one-pot multicomponent procedure. Oximes derived from (intermediate) 5-alkynyl-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehydes were transformed into the corresponding 1H-pyrazolo[4,3-c]pyridine 5-oxides by silver triflate-catalyzed cyclization. Detailed NMR spectroscopic investigations ((1)H, (13)C, (15)N and (19)F) were undertaken with all obtained products.

Keywords: 13C; 15N; 19F); NMR (1H; Sonogashira coupling; microwave-assisted reactions; multicomponent reactions; trifluoromethylpyrazoles.