Tetrahedron 72 (2016) 5257e5283 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron report 1120 Advances of azide-alkyne cycloaddition-click chemistry over the recent decade Maya Shankar Singh *, Sushobhan Chowdhury, Suvajit Koley Department of Chemistry (Centre of Advanced Study), Institute of Science, Banaras Hindu University, Varanasi 221005, India article info Article history: Received 5 September 2015 Available online 14 July 2016 Keywords: Azide-alkyne Click chemistry CuAAC 1,2,3-Triazoles Copper catalysis Organic synthesis Contents 1. Introduction . ................................................5257 2. Mechanistic overview . ............................................... 5258 3. Copper-catalyzed reactions . ............................................... 5258 3.1. Copper halide catalysis . ......................5259 3.2. Copper sulfate catalysis . ......................5264 3.3. Copper acetate catalysis . ......................5268 3.4. Copper triflate catalysis . ......................5270 3.5. Use of other copper catalysts . ......................5271 4. Use of other non-copper catalysts . ...........................................5274 5. Photoclick chemistry . ................................................5277 6. Advances of click methods in chemical biology . .................................. 5279 7. Summary and outlook . ............................................... 5280 Acknowledgements . ......................5280 References and notes . ......................5280 Biographical sketch . ......................5283 1. Introduction the tools of their arsenal to improve the ease and practicality of synthesis and related separation/purification processes. Huisgen During the past years, a variety of scientific and methodological 1,3-dipolar cycloaddition between organic azides and alkynes is developments have been achieved, which urge chemists to increase one among many synthetic tools that became quite well-known over the recent decade, mainly due to its key improvement in terms of rate and regioselectivity. The revolutionary idea was in- dependently introduced by Sharpless and Meldal groups in 2002 * Corresponding author. Fax: þ 91 542 236 8127; e-mail address: mayashankarbhu@ through the introduction of Cu(I) catalysis termed as ‛Click gmail.com (M.S. Singh). http://dx.doi.org/10.1016/j.tet.2016.07.044 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved. 5258 M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 Chemistry’.1 Copper-catalyzed azide-alkyne cycloaddition (CuAAC) undergoes ring contraction to give copper triazolyl derivative, is a type of Huisgen 1,3-dipolar cycloaddition based on the for- which upon protonolysis gives the desired 1,2,3-triazole product mation of 1,4-disubstituted 1,2,3-triazoles between a terminal al- (Fig. 1). kyne and an aliphatic azide in the presence of copper, and is classified as a ‛click reaction’. Click chemistry promotes the use of organic reactions that allow the connection of two molecular building blocks in a facile, selective, high-yielding reaction under mild reaction conditions with few or no byproducts. Furthermore, this chemistry has the capacity to promote bioconjugation and peptide ligation, stemming from the properties of the triazole linkage as a peptide mimetic. The tremendous synthetic potential of initial protocols for Huisgen 1,3-dipolar cycloaddition reaction between organic azides and alkynes was limited by the markable disadvantages like heat- ing requirement, prolonged reaction time and formation of struc- tural isomers due to the lack of selectivity. The wonderful Cu(I)- catalyzed modification introduced at the dawn of last decade, allowed the cycloaddition to occur at room temperature or with moderate heating leading to the exclusive formation of 1,4- disubstituted triazole with shortest workup and purification steps. In 2005, another analogous RuAAC was reported by Fokin group, which led to the selective formation of 1,5-disubstituted triazole.2 Therefore, these remarkable modifications turned azide- alkyne click method a practically quantitative, robust, insensitive Fig. 1. Proposed mechanism for copper-catalyzed azide-alkyne cycloaddition (CuAAC). and general orthogonal ligation reaction that is suitable in all as- pects of drug discovery, combinatorial chemistry, target-templated The analogous RuAAC does not involve a ruthenium acetylide in situ chemistry, material chemistry, proteomics and DNA research intermediate like copper, since it applies to both terminal as well as using bio-conjugation reactions.1 non-terminal alkynes. In the first step, the spectator ligands get Since the introduction of Cu(I) catalysis, azide-dipolarophile 1,3- displaced to form activated complex. This is followed by oxidative dipolar cycloaddition has been advanced remarkably over the last coupling between terminal nitrogen of azide and more electro- decade, and now has engulfed almost every section of chemistry negative less sterically demanding carbon of the alkyne to form and applied sciences. Realizing the importance and practical ap- a Ruthenacycle. The Ruthenacycle then undergoes reductive elim- plicability of the method, a number of reviews describing its vari- ination to release 1,2,3-triazole compound regenerating the active ous aspects in different scientific fields like carbohydrate chemistry, complex for the next cycle (Fig. 2).6 polymer, drug discovery, materials etc. are already reported and emerging frequently in the literature.3 However, no well-directed database describing the azide-dipolarophile cycloaddition meth- odologies developed over the recent years is yet reported. There- fore, this is a significant topic for all the sectors of chemistry and applied sciences. To fulfill the demand and in continuation of our previous report on 1,3-dipolar cycloaddition chemistry,4 herein we present an overview of the open literature focussed on the de- velopment of azide-dipolarophile 1,3-dipolar cycloaddition chem- istry over the recent years (2006 onwards). Starting with a preliminary discussion on the mechanistic aspects, the report is categorized based on different dipolarophiles to couple with azide dipole leading to the formation of diverse 1,2,3-triazoles and re- lated systems. The azide-alkyne cycloaddition section is further sub-categorized based on the use of different copper catalysts (i.e., click chemistry) as well as non-copper catalysts. Additionally, a sub-section based upon the short discussion on photoclick chemistry under click methods on chemical biology has also been included. In this review, we use the terms CuAAC and click chem- Fig. 2. Proposed mechanism for ruthenium catalyzed azide-alkyne cycloaddition istry interchangeably. (RuAAC). 2. Mechanistic overview The classical Huisgen 1,3-dipolar cycloaddition of organic azide 3. Copper-catalyzed reactions with dipolarophiles is a one-step process,4 whereas its copper(I)- catalyzed variant is considered to be a step-wise process in- The copper either as metal or in salt form (ionic or complex) has volving copper in the intermediate steps.5 In the initial step, copper been employed as a most effective catalyst to promote the 1,3- forms acetylide via coordination with alkyne. In the next step, azide dipolar addition reaction-click chemistry. In this section, the click binds to the copper followed by the formation of an unconventional reactions, which are catalyzed by different copper catalysts, are copper(III)metallacycle. The energy calculation showed a consider- highlighted. This section has been further sub-divided into five able low energy barrier for the step justifying the higher rate of the classes depending on the type of copper catalysts used either in reaction than its uncatalyzed version. The intermediate then zero, mono or divalent form. M.S. Singh et al. / Tetrahedron 72 (2016) 5257e5283 5259 3.1. Copper halide catalysis protonation.57 Trialkylsilyl-protected alkynes such as 2-silylalkynyl substituted benzofuran 19 and indole 20 have been utilized as Among copper halide catalysts, copper iodide is being fre- a source of alkyne for click method to access benzofuran- and quently used in various transformations. Few reports of copper indole-substituted 1,2,3-triazoles 22 and 23, respectively (Scheme bromide catalysis are also available. Cu(I) combined with Cu(II) 3).10 Here, in situ deprotection of silyl group followed by final cy- salts, other metal complexes or ionic liquids are also used as ef- clization involving click approach afforded the desired triazoles. fective catalytic systems. Most of the reactions proceed smoothly at Aryl iodides 24 are transformed into 4-aryl-1,2,3-triazoles 27 via room temperature. However, there are many reports, which require palladium-catalyzed Sonogashira coupling followed by copper- traditional heating and some are facile upon application of un- catalyzed click reaction using trimethylsilyl acetylene 25 as acety- conventional energy sources like microwave (MW) irradiation and lene surrogate.11 In the first step, there occurs the formation of ultrasound/sonication conditions. Use of co-solvent systems also TMS-protected phenyl acetylenes 26 through Sonogashira reaction. promotes the reactions efficiently. In this part, we categorized the The fact was also confirmed by the isolation of TMS-protected features as systematically as possible so that it would help the phenyl acetylenes in presence of electron-donating functional reader to find the required portion at one stroke. groups such as amino and