Ruthenium-Catalyzed Azide−Alkyne Cycloaddition: Scope and Mechanism

Abstract

The catalytic activity of a series of ruthenium(II) complexes in azide-alkyne cycloadditions has been evaluated. The [Cp*RuCl] complexes, such as Cp*RuCl(PPh 3) 2, Cp*RuCl(COD), and Cp*RuCl(NBD), were among the most effective catalysts. In the presence of catalytic Cp*RuCl(PPh 3) 2 or Cp*RuCl(COD), primary and secondary azides react with a broad range of terminal alkynes containing a range of functionalities selectively producing 1,5-disubstituted 1,2,3-triazoles; tertiary azides were significantly less reactive. Both complexes also promote the cycloaddition reactions of organic azides with internal alkynes, providing access to fully-substituted 1,2,3-triazoles. The ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) appears to proceed via oxidative coupling of the azide and alkyne reactants to give a six-membered ruthenacycle intermediate, in which the first new carbon-nitrogen bond is formed between the more electronegative carbon of the alkyne and the terminal, electrophilic nitrogen of the azide. This step is followed by reductive elimination, which forms the triazole product. DFT calculations support this mechanistic proposal and indicate that the reductive elimination step is rate-determining.

Surface Doping Quantum Dots with Chemically Active Native Ligands: Controlling Valence without Ligand Exchange

“…Nevertheless, we found that we can completely avoid this problem by using a much more robust, ligated ruthenium click catalyst, Cp*Ru(COD)Cl, which was recently reported in the literature (Scheme 4). 81 …”

Copper-Catalysed Multicomponent Click Synthesis of 5-Alkynyl 1,2,3-Triazoles under Ambient Conditions

“…This powerful, highly reliable, and selective reaction is the paradigm of a click reaction, as it meets the set of stringent criteria required in click chemistry as defined by Sharpless et al 4 Consequently, this protocol has found increasing application in a variety of disciplines such as organic chemistry, drug discovery and medicinal chemistry, polymer and materials science, or bioconjugation. 5 The copper-catalysed azide-alkyne cycloaddition (Cu-AAC) provides a direct entry into 1,4-disubstituted 1,2,3-triazoles, whereas the formation of the 1,4,5-trisubstituted derivatives relies on the use of ruthenium catalysts 6 or modification of preformed 1,2,3-triazoles. 7 In the latter context, three different approaches have been devised for the introduction of substituents at the 5-position of the triazole unit, namely: (a) the interception of stoichiometrically functionalised 5-cuprated-1,2,3-triazoles, (b) the use of stoichiometrically functionalised terminal alkynes, and (c) the catalytic direct functionalisation of C-H bonds.…”

Ruthenium‐Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

“…Unfortunately, when we tested the reaction of the thioalkyne 2 a with the fluorogenic anthracenyl‐azide probe 1 a ,19 the yield of the corresponding adducts ( 3 aa / 3 aa′ ) was modest (Table 1, entry 1) 20. Remarkably, when using Cp*Ru(cod)Cl as a catalyst,15a we observed, after 24 hours, a substantial formation of the desired cycloadducts with excellent regioselectivity ( 3 aa / 3 aa′ =19:1, 58 % combined yield, entry 2). This good result, together with the previously demonstrated biocompatibility of this type of ruthenium complex,21 prompted us to further explore the process.…”