Titanium-Catalyzed Multicomponent Couplings: Efficient One-Pot Syntheses of Nitrogen Heterocycles

Abstract

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...

Substituted quinolines as noncovalent proteasome inhibitors

“…40–42 The titanium chemistry effectively adds an iminyl and amine group across the triple bond of an alkyne, iminoamination, to form unsymmetrical derivatives of 1,3-diimines. The 1,3-diimines, generated in situ, can then be applied to many different heterocyclic syntheses.…”

“…The 1,3-diimines, generated in situ, can then be applied to many different heterocyclic syntheses. 40 The quinolines were prepared from the 3-component coupling products using a modified Combes synthesis catalyzed by acetic acid, which rendered highly substituted frameworks in a one-pot procedure (Fig. 2).…”

“…44–46 The catalysts for this study were isolated as pure compounds before use; however, it is possible to generate the catalysts in situ from the protio-ligand and commercially available Ti(NMe 2 ) 4 as well. 40 The applications of these two catalysts in iminoamination have been discussed elsewhere in detail. 40 In short, more reactive Ti(dpm)(NMe 2 ) 2 is often used for more difficult internal alkyne substrates, while milder Ti(dpma)(NMe 2 ) 2 is often used with sensitive terminal alkynes to avoid potential side reactions.…”

“…40 The applications of these two catalysts in iminoamination have been discussed elsewhere in detail. 40 In short, more reactive Ti(dpm)(NMe 2 ) 2 is often used for more difficult internal alkyne substrates, while milder Ti(dpma)(NMe 2 ) 2 is often used with sensitive terminal alkynes to avoid potential side reactions. In addition, the two catalysts can direct regioselectivity for the substrates, which broadens the structural diversity.…”

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

“…Even though MCRs normally run without catalysts, there are special applications for both various transition metal catalysts [79,118,[139][140][141][142][143][144][145][146] and organic catalysts [79,[147][148][149][150].…”