Ruthenium‐Catalyzed Cycloadditions of 1‐Haloalkynes with Nitrile Oxides and Organic Azides: Synthesis of 4‐Haloisoxazoles and 5‐Halotriazoles

Abstract

(Cyclopentadienyl)(cyclooctadiene) ruthenium(II) chloride [CpRuCl(cod)] catalyzes the reaction between nitrile oxides and electronically deficient 1-choro-, 1-bromo- and 1-iodoalkynes leading to 4-haloisoxazoles. Organic azides are also suitable 1,3-dipoles, resulting in 5-halo-1,2,3-triazoles. These air tolerant reactions can be performed at room temperature with 1.25 equiv of the respective 1,3-dipole relative to the alkyne component. Reactive 1-haloalkynes include propiolic amides, esters, ketones and phosphonates. Post-functionalization of the halogenated azole products can be accomplished using palladium-catalyzed cross-coupling reactions as well as via manipulation of reactive amide groups. The lack of catalysis observed with Cp*RuCl(cod) is attributed to steric demands of the Cp* (η5-C5Me5) ligand in comparison to the parent Cp (η5-C5H5). This hypothesis is supported by the poor reactivity of (η5-C5Me4CF3)RuCl(cod), which serves as a an isosteric mimic of Cp* and as an isoelectronic analog of Cp.

Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends

“…Among all the Ru catalysts, the most investigated ones are the pentamethylcyclopentadienyl ruthenium chloride-based (noted [Cp*RuCl]) complexes), although Fokin's group also observed that the steric encumbrance imparted by the Cp* ligand is detrimental to the reaction [81]. These complexes catalyzed the regioselective RuAAC reaction of terminal alkynes forming, unlike CuAAC catalysts, 1,5-disubstituted 1,2,3-triazoles, and also unlike the CuAAC catalysts, they reacted with internal alkynes providing trisubstituted 1,2,3-triazoles [28,39,40,82].…”

“…These complexes catalyzed the regioselective RuAAC reaction of terminal alkynes forming, unlike CuAAC catalysts, 1,5-disubstituted 1,2,3-triazoles, and also unlike the CuAAC catalysts, they reacted with internal alkynes providing trisubstituted 1,2,3-triazoles [28,39,40,82]. The Cp*RuCl based catalysts provided multiple application that were recently developed (vide infra) [81,[83][84][85][86][87]. M a n u s c r i p t The first mechanistic investigation was proposed by Lin, Jia, Fokin and coworkers based on DFT calculations [39].…”

“…Recent applications of Cp*RuCl-based catalysts included the synthesis of 4-haloisoxazoles and 5-halotriazoles [81], thiolactoside glycoclusters [83], one-step synthesis of triazoles [84], palladium-based metallocene complexes [85], 1,2,3-triazole peptides [86], 5-TTF-1,2,3-triazoles [87], 1,5-substitued 1,2,3-triazole amino acids [182], 5-amino-1,2,3-triazole-4-carboxylic acid [183a], and fluorinated 1,4,5-substituted 1,2,3-triazoles [183b]. RuAAC reactions catalyzed by Ru(II) complexes and RuNPs were also reported.…”

A novel formulation of zolpidem for direct nose-to-brain delivery: synthesis, encapsulation and intranasal administration to mice

“…All reactions were carried out using freshly distilled and dry solvents. Parent N,N‐dipropylpropiolamide was prepared according to published procedures …”

Application of diethyl ethynephosphonate for the synthesis of 3-phosphonylated β-lactams via Kinugasa reaction

“…Compound 4 has however been used extensively in [3+2]-cycloadditions with organic azides. [17][18][19][20] …”