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

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

1,2-Addition and cycloaddition reactions of niobium bis(imido) and oxo imido complexes

“…17,18 Since then, further work in investigating reactions across terminal imido groups in high-valent early transition metal complexes has led to the development of a number of catalytic processes involving nitrene transfers, 19-21, including imine and azide metatheses, [22][23][24][25] hydroaminations of alkenes and alkynes, [26][27][28][29][30][31] and carboaminations to give a,b-unsaturated imines. [32][33][34] In addition, Ti imido, [35][36][37] Zr imido, 38 and V bis(imido) complexes 14 have recently been shown to carry out multicomponent coupling to give carbodiimides, pyrroles, pyrazoles, and other nitrogen-containing heterocycles.…”

Pyrazole Scaffold Synthesis, Functionalization, and Applications in Alzheimer’s Disease and Parkinson’s Disease Treatment (2011–2020)

“…In each of the above-mentioned methodologies for pyrazole synthesis, all the [ NN ] fragments either came from hydrazine derivatives or from azo compounds. Pearce and co-workers recently reported a novel fragment combination mode [ NC ] + [ CC ] + [ N ] using a multicomponent oxidative coupling to make multi-substituted pyrazoles [ 38 ]. In these reactions, diazatitana-cyclohexadiene intermediates that were generated from alkynes, nitriles, and titanium imido complexes, could produce pyrazole derivatives after a 2-electron oxidation process triggered by oxidant TEMPO ( Scheme 33 ).…”

Synthesis, Structural and Physicochemical Characterization of a Titanium(IV) Compound with the Hydroxamate Ligand N,2-Dihydroxybenzamide

“…The design, synthesis, and physicochemical characterization of polyoxo-titanium clusters (PTCs) have been an active research area over the last decade, due to their interesting electronic properties for various applications in nanotechnology [ 1 , 2 , 3 , 4 , 5 , 6 ], photocatalytic hydrogen production [ 7 , 8 , 9 ], degradation of environmental pollutants [ 10 , 11 ], catalysis [ 12 , 13 , 14 , 15 , 16 , 17 ], solar energy conversion [ 18 , 19 ], and copolymerization of carbon dioxide [ 20 ]. At this point, it is worth noting that according to an excellent review, published very recently, the chemistry of group IV elements is underexplored [ 21 ].…”