Copper(II)-Promoted Alkyne Coupling Reactions and the Ruthenium-Catalyzed Cycloaddition of Cyanoalkynes

This dissertation describes the development of several Cu(II)-promoted coupling reactions involving alkynes, including Cu(II)-mediated cyanation of terminal alkynes using NaCN, and Cu(II)-catalyzed oxidative formation of alkynyltriazoles by intercepting alkyne homocoupling reaction using organic azide. 1-Cyanoalkynes, the products from the cyanation of terminal alkynes, are effective to deliver 4-cyano-1,2,3-triazoles regiospecifically via ruthenium-catalyzed cycloaddition with organic azides (RuAAC). Mechanistic experiments indicate a ruthenium catalytic cycle that is different from the reported RuAAC mechanisms. Also, the mechanism of Cu(II)-catalyzed oxidative formation of alkynyltriazoles was studied in detail by using N-heterocyclic carbene copper complexes and ESI-MS technique. Chapter 1 provides the background on Cu-promoted coupling reaction involving alkynes. Cu-catalyzed azide-alkyne cycloaddition and its applications are also summarized in that chapter. Chapter 2 presents the work on Cu(II)-mediated formation of 1-cyanoalkynes and their reactivity in Ru-catalyzed azide-alkyne cycloadditions. First, a facile method to synthesize 1-cyanoalkynes is introduced. This method uses a combination of Cu(II) perchlorate and sodium cyanide. DIPEA and 1-methylimidazole (or imidazole) are applied as the base and the supporting ligand, respectively. A series of 1-cyanoalkynes are synthesized and applied in ruthenium-catalyzed azide-alkyne cycloaddition. Experiments indicate that 1-cyanoalkyne reacts faster than terminal alkyne and other electro-poor internal alkynes. Supported by kinetic experiment and computational study, a catalytic cycle different from the reported RuAAC mechanism is proposed. The development of Cu(II)-catalyzed oxidative formation of alkynyltriazoles is described in Chapter 3. The reaction starts from terminal alkynes and organic azides with copper(II) acetate as the catalyst and the basic additive DBN. The method is evaluated in a broad scope of azides and alkynes. The reactivity rankings of azides and alkynes are concluded after the substrate scope expansion, and a systematic approach to optimizing yield is provided. Mechanistic experiments are applied regarding the dependence of each reaction component and the role of basic additive in the determination of oxidative products. Comparing to existing methods, this work provides the larges substrate scope and a detailed mechanistic study. Chapter 4 demonstrates the mechanistic study of Cu(II)-catalyzed oxidative formation of triazoles using air-stable copper(I) complexes of N-heterocyclic carbenes. The reactions are analyzed by NMR and ESI-MS technique. The effect of copper source and the additive, DBN or potassium carbonate, are studied using both analytical methods. DBN inhibits the cycloaddition step while potassium carbonate allows the cycloaddition to occur. ESI-MS is applied to detect potential reaction intermediates and to study the effect of additive on the formation of NHC-copper complexes. Base on the results from NMR and ESI-MS experiments, the effect of additive on the selectivity of oxidative products (alkynyltriazole and bistriazole) is illustrated. The supporting information file includes the 1H and 13C NMR spectra of 1-cyanoalkynes, 4-cyano-1,2,3-triazoles, and 5-alkynyl-1,2,3-triazoles synthesized in this dissertation. The images of isotopic patterns for the copper complexes identified from ESI-MS experiments are attached in the supporting information file. This file also includes X-ray crystallography data of some 4-cyano-1,2,3-triazoles.