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

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