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 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.

Figure 1.

(a) Cu-catalyzed oxidation-induced formal N–N reductive elimination for the synthesis of pyrazoles from electron-poor enamines and nitriles. (b) Ni-mediated N–N bond reductive elimination. (c) Formal [2+2+1] multicomponent synthesis of pyrazoles via oxidation-induced N–N coupling, and a proposed catalytic cycle for pyrazoles compared to the previously reported [2+2+1] synthesis of pyrroles.

Figure 2.

Multicomponent coupling of p-tolunitrile, 3-hexyne, and azobenzene catalyzed by py₂TiCl₂(NPh).

Figure 3.

Computed cycle for pyrazole formation via direct N–N bond coupling (M06/6–311G(d,p)/SMD, 145 °C, C₆D₅Br) compared to C–N bond formation in the analogous multicomponent pyrrole synthesis (M06/6–311G(d,p)/SMD, 115 °C, PhCF3) by Ti imido catalysts. Pyrrole computations and intermediate labels are adapted from ref 37. All free energies are referenced to py3TiCl2(NPh) = 0.0 kcal/mol.

Figure 4.

Syntheses of diazatitanacyclohexadienes 5a, 7a, and 7b and ORTEP diagrams of 5a and 7a. Thermal ellipsoids are drawn at 50% probability and hydrogen atoms omitted for clarity. Full crystallographic data for 5a, 7a, and 7b is available in the Supporting Information.

Figure 5.

Reaction of 8a with a series of Ti complexes spanning Ti^II, Ti^III, and Ti^IV oxidation states.

Figure 6.

Oxidation of 9a to 10a by PhICl₂ followed by thermal elimination of Cp₂TiCl₂ to give 1a, and ORTEP diagrams of 9a and 10a. Thermal ellipsoids are drawn at 50% probability, and hydrogen atoms are omitted for clarity. One crystallographically independent molecule of 10a and a solvent Et₂O have also been omitted. Full crystallographic data is available in the Supporting Information, including CIF files.

Figure 7.

Cyclic voltammogram of 9a (DCM solvent, 3.5 mM 9a, 0.1 M NBu4BPh4) at scan rates 1–200 mV/s (red-blue). Inset displays i_pa/i_pc as a function of scan rate.

Figure 8.

Proposed mechanism for pyrazole formation from diazatitanacyclohexadienes.

Figure 9.

Analogy between electrocyclic N–N coupling and the electrocyclic Nazarov cyclization of dienones.