Catalysis by high-valent metals such as titanium(IV) impacts our lives daily through reactions like olefin polymerization. In any catalysis, optimization involves a careful choice of not just the metal but also the ancillary ligands. Because these choices dramatically impact the electronic structure of the system and, in turn, catalyst performance, new tools for catalyst development are needed. Understanding ancillary ligand effects is arguably one of the most critical aspects of catalyst optimization and, while parameters for phosphines have been used for decades with low-valent systems, a comparable system does not exist for high-valent metals. A new electronic parameter for ligand donation, derived from experiments on a high-valent chromium species, is now available. Here, we show that the new parameters enable quantitative determination of ancillary ligand effects on catalysis rate and, in some cases, even provide mechanistic information. Analysing reactions in this way can be used to design better catalyst architectures and paves the way for the use of such parameters in a host of high-valent processes.

Nitrogen-based heterocycles are important frameworks for pharmaceuticals, natural products, organic dyes for solar cells, and many other applications. Catalysis for the formation of heterocyclic scaffolds, like many C-C and C-N bond-forming reactions, has focused on the use of rare, late transition metals like palladium and gold. Our group is interested in the use of Earth-abundant catalysts based on titanium to generate heterocycles using multicomponent coupling strategies, often in one-pot reactions. To be of maximal utility, the catalysts need to be easily prepared from inexpensive reagents, and that has been one guiding principle in the research. For this purpose, a series of easily prepared pyrrole-based ligands has been developed. Titanium imido complexes are known to catalyze the hydroamination of alkynes, and this reaction has been used to advantage in the production of α,β-unsaturated imines from 1,3-enynes and pyrroles from 1,4-diynes. Likewise, catalyst design can be used to find complexes applicable to hydrohydrazination, coupling of a hydrazine and alkyne, which is a method for the production of hydrazones. Many of the hydrazones synthesized are converted to indoles through Fischer cyclization by addition of a Lewis acid. However, more complex products are available in a single catalytic cycle through coupling of isonitriles, primary amines, and alkynes to give tautomers of 1,3-diimines, iminoamination (IA). The products of IA are useful intermediates for the one-pot synthesis of pyrazoles, pyrimidines, isoxazoles, quinolines, and 2-amino-3-cyanopyridines. The regioselectivity of the reactions is elucidated in some detail for some of these heterocycles. The 2-amino-3-cyanopyridines are synthesized through isolable intermediates, 1,2-dihydro-2-iminopyridines, which undergo Dimroth rearrangement driven by aromatization of the pyridine ring; the proposed mechanism of the reaction is discussed. The IA-based heterocyclic syntheses can be accomplished start to finish (catalyst generation to heterocyclic synthesis) in a single vessel. The catalyst can be formed in situ from commercially available Ti(NMe2)4 and the protonated form of the ligand. Then, the primary amine, alkyne, and isonitrile are added to the flask, and the IA product is synthesized. The volatiles are removed (if necessary), and the next reagent is added. A brief video showing the process for the simple heterocycle 4-phenylpyrazole from phenylacetylene, cyclohexylamine, tert-butylisonitrile, and hydrazine hydrate is included. Further development in this field will unlock new, efficient reactions for the production of carbon-carbon and carbon-nitrogen bonds. As an example of such a process recently discovered, a catalyst for the regioselective production of pyrazoles in a single step from terminal alkynes, hydrazines, and cyclohexylisonitrile is discussed. Using titanium catalysis, many heterocyclic cores can be accessed easily and efficiently. Further, the early metal chemistry described is often orthogonal to late metal-based reactions, whi...

Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4 μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.

The hafnium complex (N oct N dipp )Hf(Me) 3 (1, N oct N dipp = N-octyl-N′-(2,6-diisopropylphenyl)-1,4-diaza-2,3,3trimethyl-1-butene) contains a bidentate imino-anilido ligand. This complex undergoes protonolysis by the ammonium Brønsted acid [HN(Me)(C 18 H 37 ) 2 ][B(C 6 F 5 ) 4 ] to produce a competent alkene polymerization precatalyst, [(N oct N dipp )Hf(Me) 2 (N(Me)-(C 18 H 37 ) 2 )][B(C 6 F 5 ) 4 ] (2). Unlike most alkene polymerization precatalysts, 2 contains two Hf−Me groups, which have the potential to initiate and propagate two polymer chains simultaneously. Herein, we demonstrate that 2 does indeed grow two polymer chains at each hafnium center. Additional unusual characteristics for an early transition-metal catalyst include: (1) the numberaverage polymer molar mass (M n ) is independent of the concentration of monomer; (2) linear plots of monomer concentration as a function of time during polymerization indicate apparent zeroth-order dependence of rate on the monomer concentration; and (3) apparent first-order dependence of steady-state rate of polymerization on the initial concentration of monomer. While saturation behavior with respect to monomer concentration is common with late transition-metal-derived catalysts, propagation rate laws for early transition-metal complexes overwhelmingly are first-order in monomer concentration. Based on operando NMR kinetics, end group analysis, active site counting with chromophore quench labels, iodine quenching studies, and gel permeation chromatography, we propose a unified kinetic and mechanistic model for the polymerization of 1-octene with 2.

Review: 40 refs.