The reactions of organic azides and alkynes catalysed by copper species represent the prototypical examples of click chemistry. The so-called CuAAC reaction (copper-catalysed azide-alkyne cycloaddition), discovered in 2002, has been expanded since then to become an excellent tool in organic synthesis. In this contribution the recent results described in the literature since 2010 are reviewed, classified according to the nature of the catalyst precursor: copper(I) or copper(II) salts or complexes, metallic or nano-particulated copper and several solid-supported copper systems.

Well-defined copper(I) complexes of composition [Tpm*(,Br) Cu(NCMe)]BF4 (Tpm*(,Br) =tris(3,5-dimethyl-4-bromo-pyrazolyl)methane) or [Tpa(*) Cu]PF6 (Tpa(*) =tris(3,5-dimethyl-pyrazolylmethyl)amine) catalyze the formation of 2,5-disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5-isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper-acyl nitrene species, in contrast to the well-known mechanism for the copper-catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper-acetylide complex.

Three novel Cu(I) complexes bearing tris(pyrazolyl)methane ligands, Tpm(x), have been prepared from reactions of equimolar amounts of CuI and the ligands Tpm, (HC(pz)(3)), Tpm*, (HC(3,5-Me(2)-pz)(3)), and Tpm(Ms), (HC(3-Ms-pz)(3)). X-ray diffraction studies have shown that the Tpm and Tpm(Ms) derivatives exhibit a 2:1 Cu:ligand ratio, whereas the Tpm* complex is a mononuclear species in nature. The latter has been employed as a precatalyst in the arylation of amides and aromatic thiols with good activity. The synthesis of a Tpm*Cu(I)-phthalimidate, a feasible intermediate in this catalytic process, has also been performed. Low temperature (1)H NMR studies in CDCl(3) have indicated that this complex exists in solution as a mixture of two, neutral and ionic forms. Conductivity measurements have reinforced this proposal, the ionic form predominating in a very polar solvent such as DMSO. The reaction of Tpm*Cu(I)-phthalimidate with iodobenzene afforded the expected C-N coupling product in 76% yield accounting for its role as an intermediate in this transformation.

The use of structurally well-characterized copper(I) species as precatalysts in C−N and C−S bond forming reactions is described. Two new dinuclear Cu(I) complexes containing two isomeric ligands of bis(7-azaindolyl)methane have been synthesized and fully characterized by NMR and X-ray diffraction studies. Both copper(I) species exhibit a 1:1 Cu/L ratio and have been used as precatalysts in the N-arylation of 2-pyrrolidinone and S-arylation of thiols with aryl iodides. The complexes efficiently catalyze these cross-coupling reactions, affording high yields of products under mild conditions.

Novel tris(pyrazolylmethyl)amine ligands Tpa(Me3), Tpa*(,Br), and Tpa(Br3) have been synthesized and structurally characterized. The coordination chemistries of these three new tetradentate tripodal ligands and the already known Tpa and Tpa* have been explored using different copper(I) salts as starting materials. Cationic copper(I) complexes [Tpa(x)Cu]PF6 (1-4) have been isolated from the reaction of [Cu(NCMe)4]PF6 and 1 equiv of the ligand. Complexes 2 (Tpa(x) = Tpa*) and 3 (Tpa(x) = Tpa(Me3)) have been characterized by X-ray studies. The former is a 1D helical coordination polymer, and the latter is a tetranuclear helicate. In both structures, the Tpa(x) ligand adopts a μ(2):κ(2):κ(1)-coordination mode. However, in solution, all of the four complexes form fluxional species. When CuI is used as the copper(I) source, neutral compounds 5-8 have been obtained. Complexes 6-8 exhibit a 1:1 metal-to-ligand ratio, whereas 5 presents 2:1 stoichiometry. Its solid-state structure has been determined by X-ray diffraction, revealing its 3D polymeric nature. The polymer is composed by the assembly of [Tpa2Cu4I4] units, in which Cu4I4 presents a step-stair structure. The Tpa ligands bridge the Cu4I4 clusters, adopting also a μ(2):κ(2):κ(1)-coordination mode. As observed for the cationic derivatives, the NMR spectra of 5-8 show the equivalence of the three pyrazolyl arms of the ligands in these complexes. The reactivities of cationic copper(I) derivatives 1-4 with PPh3 and CO have been explored. In all cases, 1:1 adducts [Tpa(x)CuL]PF6 [L = PPh3 (9-11), CO (12-15)] have been isolated. The crystal structure of [Tpa*Cu(PPh3)]PF6 (9) has been obtained, showing that the coordination geometry around copper(I) is trigonal-pyramidal with the apical position occupied by the tertiary amine N atom. The Tpa* ligand binds the Cu center to three of its four N atoms, with one pyrazolyl arm remaining uncoordinated. In solution, the carbonyl adducts 13-15 exist as a mixture of two isomers; the four- and five-coordinate species can be distinguished by means of their IR νCO stretching bands. Finally, the catalytic activities of complexes 1-4 have been demonstrated in carbene- and nitrene-transfer reactions.

Despite the 1,2,3-triazole ring does not occur in nature, synthetic molecules that contain this heterocyclic unit show diverse biological activities.1 The Huisgen thermal 1,3-dipolar cycloaddition reaction 2 of alkynes and organic azides is the most straightforward route for the synthesis of this interesting and notable stable five-membered heterocycle. However, the selectivity of the process is low, yielding mixtures of 1,4-and 1,5-disubstituted regioisomers. A major development in the field was made, independently, in 2002 by the groups of Meldal 3 and Sharpless: 4 the copper-catalyzed version of the Huisgen reaction, which remarkably improved the reaction rate and the selectivity, since it provided exclusively 1,4-disubstituted 1,2,3-triazoles in very high yields, overcoming the drawbacks of the original Huisgen procedure. Since then, the copper-catalyzed azidealkyne cycloaddition (CuAAC) 5 (Scheme 1a) has found tremendous applications in several disciplines 5-8 due to its versatility, in terms of both reaction conditions and functional group compatibility. However, electron deficient azides are challenging substrates since they do not very frequently provide the corresponding 1,2,3-triazoles. Thus, N-sulfonyl or N-phosphoryl azides usually react with alkynes, in the presence of the corresponding catalyst, rendering products derived from the reaction of ketenimine species, formed upon ring-opening of the triazole-cuprate intermediates, with nucleophiles. 9 Scarcely, a few systems have been described in which the presence of certain ligands 10a or the use of copper(I) complexes 10b,c allowed the formation of the 1,2,3-triazoles, particularly when N-sulfonyl azides are applied (Scheme 1b). 10 A few years ago, we found that the complex Br Cu(NCMe)]BF 4 (Tpm* ,Br = tris(3,5-dimethyl-4-bromopyrazolyl)methane) also promoted the exclusive formation of N-sulfonyl-1,2,3-triazoles in the cycloaddition reaction of N-sulfonyl azides with terminal alkynes. 11 Shortly after we found that when N-carbonyl azides were applied under the same catalytic conditions, 1,5-disubstituted oxazoles were isolated as products 12a (Scheme 1c) instead of the expected 1,2,3-N-carbonyl triazoles. To date, and to the best of our knowledge, the direct formation of N-carbonyl-1,2,3-triazoles by CuAAC using N-carbonyl azides as substrates (Scheme 1d) remains undescribed. Herein, we report the synthesis of 1,4-disubstituted N-carbamoyl 1,2,3-triazoles from the cycloaddition reaction of N-carbamoyl azides and alkynes catalyzed by [Tpa*Cu]PF 6 , (Tpa* = tris(3,5-dimethyl-pyrazolylmethyl)amine), which can be considered the first example of the formation of N-carbonyl 1,2,3,-triazole derivatives from a CuAAC reaction of a N-carbonyl azide. It is worth mentioning that the products prepared by this methodology have been described to be potent inhibitors of serine hydrolases. 13Scheme 1 Synthesis of 1,2,3-triazoles and oxazoles via CuAAC.

Intermediates. -Two copper complexes for the regioselective formation of 2,5-disubstituted oxazoles from carbonyl azides and terminal alkynes are developed. The reaction mechanism is investigated. An unprecedented reaction pathway involving the initial formation of an acyl-nitrene-copper species and not a copper-acetylide is proposed. This method represents a novel procedure for the synthesis of oxazoles from readily available starting materials. -(HALDON, E.; BESORA, M.; CANO, I.; CAMBEIRO, X. C.; PERICAS, M. A.; MASERAS, F.; NICASIO, M. C.; PEREZ*, P. J.; Chem. -Eur.

Pyrrole derivatives R 0120 Dinuclear Copper(I) Complexes as Precatalysts in Ullmann andGoldberg Coupling Reactions. -The new dinuclear Cu(I) complexes (I) and (II) containing two isomeric ligands of bis(7-azaindolyl)methane are used as efficient precatalysts in the N-arylation of 2-pyrrolidinone and the S-arylation of thiols with various aryl iodides. -(HALDON, E.; ALVAREZ, E.; NICASIO*, M. C.; PEREZ, P.