Multicomponent Pyrazole Synthesis from Alkynes, Nitriles, and Titanium Imido Complexes via Oxidatively Induced N-N Bond Coupling

Adam J. Pearce, Robin P. Harkins, Benjamin R. Reiner, Alexander C. Wotal, Rachel J. Dunscomb, Ian A. Tonks

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Pyrazoles are an important class of heterocycles found in a wide range of bioactive compounds and pharmaceuticals. Pyrazole synthesis often requires hydrazine or related reagents where an intact N-N bond is conservatively installed into a pyrazole precursor fragment. Herein, we report the multicomponent oxidative coupling of alkynes, nitriles, and Ti imido complexes for the synthesis of multisubstituted pyrazoles. This modular method avoids potentially hazardous reagents like hydrazine, instead forming the N-N bond in the final step via oxidation-induced coupling on Ti. The mechanism of this transformation has been studied in-depth through stoichiometric reactions of the key diazatitanacyclohexadiene intermediate, which can be accessed via multicomponent coupling of Ti imidos with nitriles and alkynes, ring opening of 2-imino-2H-azirines, or direct metalation of 4-azadiene-1-amine derivatives. The critical transformation in this reaction is the 2-electron oxidation-induced N-N coupling on Ti. This is a rare example of formal N-N coupling on a metal center, which likely occurs through an electrocyclic mechanism analogous to a Nazarov cyclization. Conveniently, these 2-electron-oxidized diazatitanacyclohexadiene intermediates can be accessed via disproportionation of the 1-electron-oxidized species, which allows utilization of weak oxidants such as TEMPO

Original languageEnglish (US)
Pages (from-to)4390-4399
Number of pages10
JournalJournal of the American Chemical Society
Volume142
Issue number9
DOIs
StatePublished - Mar 4 2020

Bibliographical note

Funding Information:
Financial support was provided by the National Institutes of Health (1R35GM119457) and the Alfred P. Sloan Foundation (I.A.T. is a 2017 Sloan Fellow). Instrumentation for the University of Minnesota Chemistry NMR facility was supported through a grant through the National Institutes of Health (S10OD011952). X-ray diffraction experiments were performed with a diffractometer purchased through a grant from NSF/MRI (1229400) and the University of Minnesota.

Publisher Copyright:
© 2020 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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