Rapid and Selective Syntheses of Trisubstituted -1,2,3-Triazoles Through Copper Mediated Azide Alkyne Cycloaddition

This dissertation describes the development of alternative products from the copper-catalyzed azide-alkyne cycloaddition (CuAAC). The first chapter provides an introduction to the CuAAC through the historic timeline of the development of reaction conditions. Finally the current mechanistic understanding and three applications of the commonly used reaction are described. The second chapter describes a method for the preparation of 5-iodo-1,2,3-triazoles directly from organic azides and terminal alkynes. The reaction is mediated by in-situ generated copper(I) catalyst and iodinating agents. The method described is a follow-up of the protocol developed by Dr. Brotherton in 2012. The methodological enhancements of the procedure described in Chapter 2 provides high conversion as well as high iodo/protio selectivity through the reduction in equivalents of alkyne, and employment of [Tri(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA). Through these improvements the method became more synthetically practical and increased the reaction substrate scope to include unreactive azides and alkynes. Chapter three describes the synthesis of 5,5’-bis(1,2,3-triazole)s (bistriazoles). These compounds have been proposed to be employed as chiral ligands in enantioselective synthesis. Previously reported methods for the synthesis of bistriazoles mainly require decreased reaction temperatures (0-35 oC) and long reaction times (20-48 hours) while applying a limited substrate scope. The method described in Chapter 3 is a simple and rapid process for the synthesis of bistriazoles from organic azides and terminal alkynes under oxidative conditions ( oxygen atmosphere) with a broad substrate scope. The reactions are mediated by copper(II) acetate, and completed within 3 hours, with ≥ 50% isolated yields. TBTA has been employed in the CuAAC to accelerate the formation of 1,2,3-triazoles, in addition TBTA accelerates the formation of bistriazoles. Employing K2CO3 as a basic additive in MeOH or EtOH as the solvent promotes the oxidative reaction that produces the bistriazole at the expense of the 1,2,3-triazole. In Chapter 4 the initial development of 5-alkynyl-1,2,3-triazoles is reported. The previously reported methods require extended reaction times with varying temperature (rt-60 oC) with a limited substrate scope. The method described in Chapter 4 is a simple and rapid process for the synthesis of 5-alkyny-1,2,3-triazoels from organic azides and terminal alkynes under oxidative conditions (oxygen atmosphere) with a developing substrate scope. The reactions are mediated by copper(II) acetate, completed within 3-5 hours, and produce ≥ 50% isolated yields. Employing 1,5-diazolbicyclo[4.3.0]non-5-ene (DBN) as the basic additive in MeOH or EtOH as the solvent promotes the oxidative reaction that produces the 5-alkynyl-1,2,3-triazoles at the expense of the 1,2,3-triazole and 5,5’-bis-(1,2,3-triazole)s. Chapter 5 summarizes the work conducted on modifying the conditions applied to the copper catalyzed azide alkyne cycloaddition (CuAAC). Modifications to enhance the synthesis of the 5-iodo-1,2,3-triazoles via CuAAC are the first addressed Which was followed by the unsuccessful application of the Ullmann reaction for the synthesis of 5,5’-bis(1,2,3-triazole)s. The subsequent employment of potassium carbonate in the CuAAC, afforded the desired bistriazoles with moderate to high selectivity over 1,4-disubstituted-1,2,3-triazoles. In addition, changing the base from potassium carbonate to DBN allowed for the 5-alkynyl-1,2,3-triazole to be produced as the major product while diminishing the bistriazole and protiotriazole.