2The challenges of the 21 st century demand scientific and technological achievements which must be developed under sustainable and environmentally benign practices. In this vein, Click Chemistry and Green Chemistry walk hand in hand on a pathway of rigorous principles which help to safeguard the health of our planet against negligent and uncontrolled production. The copper-catalyzed azide-alkyne cycloaddition (CuAAC), the paradigm of a click reaction, is one of the most reliable and widespread synthetic transformations in organic chemistry, with multidisciplinary applications. Nanocatalysis is a Green Chemistry tool which can increase the inherent effectiveness of the CuAAC because of the enhanced catalytic activity of nanostructured metals and their plausible reutilization capability as heterogeneous catalysts.In this account, our contribution to Click Chemistry is described using unsupported and supported copper nanoparticles (CuNPs) as catalysts prepared by chemical reduction. Cu(0)NPs (3.0 ± 1.5 nm) in tetrahydrofuran were found to catalyze the reaction of terminal alkynes and organic azides, in the presence of triethylamine, at rates comparable to those achieved under microwave heating (10-30 min in most cases). Unfortunately, the CuNPs underwent dissolution under the reaction conditions and, consequently, could not be recovered. Compelling experimental evidence on the in-situ generation of highly reactive copper(I) chloride and the participation of copper(I) acetylides was provided.The supported CuNPs were found to be more robust and efficient catalyst than the unsupported counterpart in the following terms: (a) the multicomponent variant of the CuAAC could be applied, (b) with substantial decrease in the metal loading, (c) reactions could be conducted in neat water, and (d) with easy recovery and reutilization of the catalyst. In particular, the catalyst composed of oxidized CuNPs/C (Cu 2 O/CuO, 6.0 ± 2.0 nm) was shown to be highly versatile and 3 very effective in the multicomponent and regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles in water from organic halides as azido precursors; magnetically recoverable CuNPs (3.0 ± 0.8 nm)/MagSilica could be alternatively used for the same purpose under similar conditions. Incorporation of an aromatic substituent at the position 1 of the triazole could be accomplished using the same CuNPs/C catalytic system, but starting from aryl diazonium salts or anilines as azido precursors. CuNPs/C in water also catalyzed the regioselective double-click synthesis ofhydroxy-1,2,3-triazoles from epoxides. Furthermore, alkenes could be also used as azido precursors through a one-pot CuNPs/C-catalyzed azidosulfenylation-CuAAC sequential protocol, providing -methylsulfanyl-1,2,3-triazoles in a stereo-and regioselective manner. In all the types of reaction studied, CuNPs/C exhibited better behavior than some commercial copper catalysts as regards the metal loading, reaction time, yield and recyclability. Therefore, the results of this study also highlight the utility ...

Abstract:Copper nanoparticles on activated carbon have been found to effectively catalyse the multicomponent synthesis of 1,2,3-triazoles from different azide precursors, such as organic halides, diazonium salts, anilines and epoxides in water. The first one-pot transformation of an olefin into a triazole is also described. The catalyst is easy to prepare, very versatile and reusable at a low copper loading.

The Huisgen 1,3-dipolar cycloaddition of azides and alkynes 1 has become a synthetic cornerstone since the paramount discovery by the groups of Meldal 2 and Sharpless 3 of its copper(I)catalyzed version (CuAAC). 4 The superb reliability of the CuAAC reaction has increasingly attracted the attention from a diverse range of the areas of chemistry. 5 As a result, a plethora of methods have been developed around this reaction with the aim to increase efficiency. Among them, we consider of special interest those which combine three important aspects in modern synthetic organic chemistry, namely, (a) multicomponent synthesis; 6 the in situ generation of organic azides in the presence of the alkyne (three-component alkyneÀazide cycloaddition) minimizes hazards derived from the isolation and handling of the former, avoiding the time-consuming and waste generation of an additional synthetic step; (b) heterogeneous catalysis, 7 especially involving metal nanoparticles, 8 which offers several advantages over the homogeneous counterpart, such as easy recovery, easy recycling, and enhanced stability of the catalyst; and (c) reactions in water, 9 the solvent used by nature for biological chemistry which can make synthetic processes cheaper, safer, and greener. In this regard, some reports on the copper-catalyzed multicomponent synthesis of triazoles from organic halides in water, using heterogeneous catalysts, have appeared in the literature. 10 The azidolysis of epoxides 11 and the CuAAC have in common some inherent attributes which perfectly fit the set of stringent criteria required for click chemistry, in the terms coined by Sharpless et al. 12 Therefore, it is not surprising that, in recent years, an increasing interest emerged on the multicomponent synthesis of 1,2,3-triazoles through the in situ generation of azidoalcohols and further cycloaddition with alkynes. 13,14 The resulting products possess a 1-(hydroxyethyl)-1H-1,2,3-triazole 52 moiety which is also present in peptide surrogates of HIV-1 53 protease inhibitors. 15 The pioneering work in this field involved 54 homogeneous catalysis with CuSO 4 3 5H 2 O (10 mol %)/sodium 55 ascorbate (20 mol %)/H 2 O, 13a CuI (5 mol %)/PEG-400, 13b and 56 Cu(OAc) 2 3 H 2 O (10 mol %)/H 2 O. 13c Although the reactions 57 were carried out in one pot, the whole process was sequential; 58 therefore, the formation of the azidoalcohol needed monitoring 59 before the addition of the alkyne. It is worthy to note the one-pot 60 enantioselective biocatalytic azidolysis of aromatic epoxides, 61 linked to the dipolar cycloaddition with alkynes, reported by 62 the group of Feringa. 16 Some heterogeneous catalytic systems 63 have been developed recently, including porphyrinatocopper 64 nanoparticles on activated multiwalled carbon nanotubes 65 (5 mol %)/H 2 O, 14a Cu[N 2 ,N 6-bis(2-hydroxyphenyl)pyridine-2,-66 6-dicarboxamidate]H 2 O (5 mol %)/ascorbic acid (20 mol %)/ 67 H 2 O, 14b and copper(I)-modified zeolites (8 mol %)/H 2 O. 14c In 68 these cases, the catalyst could be easily recovered e...