molecules

Review Recent Progress of Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions (CuAAC) in Sustainable Solvents: Glycerol, Deep Eutectic Solvents, and Aqueous Media

Noel Nebra 1,* and Joaquín García-Álvarez 2,*

1 UPS, CNRS, LHFA UMR 5069, Université de Toulouse, 118 Route de Narbonne, 31062 Toulouse, France 2 Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica “Enrique Moles” (IUQOEM), Facultad de Química, Universidad de Oviedo, E-33071 Oviedo, Spain * Correspondence: [email protected] (N.N.); [email protected] (J.G.-Á.)



Academic Editor: Alejandro Baeza Carratalá
 Received: 7 April 2020; Accepted: 23 April 2020; Published: 26 April 2020

Abstract: This mini-review presents a general overview of the progress achieved during the last decade on the amalgamation of CuAAC processes (copper-catalyzed azide-alkyne cycloaddition) with the employment of sustainable solvents as reaction media. In most of the presented examples, the use of water, glycerol (Gly), or deep eutectic solvents (DESs) as non-conventional reaction media allowed not only to recycle the catalytic system (thus reducing the amount of the copper catalyst needed per mole of substrate), but also to achieve higher conversions and selectivities when compared with the reaction promoted in hazardous and volatile organic solvents (VOCs). Moreover, the use of the aforementioned green solvents also permits the improvement of the overall sustainability of the Cu-catalyzed 1,3-dipolar cycloaddition process, thus fulfilling several important principles of green chemistry.

Keywords: CuAAC; water; glycerol; deep eutectic solvents; cycloadditions; green chemistry; metal-catalysis

1. Introduction The employment of copper catalysts, as opposed to the use of stoichiometric amounts of other typical promoters (like Brønsted acids, bases, radicals, etc.), has permitted the discovery of a plethora of new synthetic protocols within the toolbox of organic chemists [1]. Thus, the introduction of these Cu-catalyzed methodologies in different fields (ranging from asymmetric synthesis [2] to cross-coupling processes [3]) paved the way for the convenient and successful synthesis of high value-added organic products (like for example agrochemical or pharmaceutical commodities). Moreover, Cu is usually considered as “the metal of choice” in organic transformations being catalyzed by coinage metals [4]. This is due to the following properties: (i) it is an earth-crust abundant first row transition metal, and thus cheaper than other second or third row precious metals (like for example, Pd, Pt, Rh, Ir, or Au); (ii) it presents a wide variety of oxidations states (Cu(0), Cu(I), Cu(II) or even Cu(III)) with different coordination environments (for example, linear, square planar or tetrahedral); (iii) it accommodates both hard or soft donor ligands in its coordination sphere, and forms σ- or/and π-interactions with unsaturated organic substrates (like alkenes or alkynes); (iv) it is an important metal in Biology (present in enzymes and proteins) [5], also being the less toxic first row metal (together with Fe); and (v) it is active under both homogenous or heterogeneous [6] conditions.

Molecules 2020, 25, 2015; doi:10.3390/molecules25092015 www.mdpi.com/journal/molecules Molecules 2020, 25, 2015 2 of 18

MoleculesMolecules 20 20,20 25, ,2 x5 ,FOR x FOR PEER PEER REVIEW REVIEW 2 of2 of18 18 These advantageous properties make copper catalysts suitable candidates to be used in organic These advantageous properties make copper catalysts suitable candidates to be used in organic synthesis,These thus advantageous being not surprising properties make to observe copper a catalysts positive suitable slope in candidates the tendency to be ofused the in number organic of synthesis, thus being not surprising to observe a positive slope in the tendency of the number of publicationssynthesis, onthus this being topic not since surp 2010rising (see to Figureobserve1). a positive slope in the tendency of the number of publicationspublications on on this this topic topic since since 2010 2010 (see (see Figure Figure 1). 1).

Figure 1. Articles related with the topic “Cu-catalyzed organic reactions” obtained from Web of Science. FigureFigure 1. 1.A rticlesArticles related related with with the the topic topic “ Cu“Cu-catalyzed-catalyzed organic organic reactions reactions” ” obtained obtained from from Web Web of of WithScience.Science. no doubt, one of the most prolific and successful applications of copper catalysts in organic synthesis are the so-called CuAAC reactions (Copper-catalyzed azide-alkyne cycloaddition) that belong With no doubt, one of the most prolific and successful applications of copper catalysts in to the familyWith no of “click doubt, chemistry” one of the procedures. most prolific First and coined successful by Sharpless application backs of in copper2001 [7 ], catalysts this concept in organic synthesis are the so-called CuAAC reactions (Copper-catalyzed azide-alkyne cycloaddition) appearedorganic tosynthesis design are thermodynamically the so-called CuAAC driven reactions chemical (Copper processes-catalyzed that azide allow-alkyne the direct cycloadd synthesisition) of that belong to the family of “click chemistry” procedures. First coined by Sharpless back in 2001 [7], highlythat belong complex to organicthe family architectures of “click chemistry by starting” procedures from simple. First and coined readily-available by Sharpless back organic in 2001 building [7], thisthis concept concept appeared appeared to to design design thermodynamically thermodynamically driven driven chemical chemical processes processes that that allow allow the the direct direct blocks. Moreover, to be considered “click”, these reactions should be in accordance with the following synthesissynthesis of of highly highly c omplexcomplex organic organic architectures architectures by by starting starting from from simple simple and and readily readily-available-available principles: (i) tolerance of moisture and oxygen (i.e., standard bench conditions); (ii) “solventless” organicorganic building building blocks. blocks. Moreover, Moreover, to to be be considered considered “click “click”, ”these, these reactions reactions should should be be in in accordance accordance conditions or using a benign solvent is required; (iii) the isolation of the final products must be withwith the the following following principles principles: i:) itolera) tolerancence of of moisture moisture and and oxygen oxygen (i.e., (i.e., standard standard bench bench conditions); conditions); straightforward (i.e., nearly quantitative and without tedious steps of purification); and (iv) should ii)ii “) solventless“solventless” ” conditions conditions or or using using a a benign benign solvent solvent is isrequired; required; iii) iii) the the isolation isolation of of the the final final occurproductsproducts with totalmust must regio- be be straightforward andstraightforward stereoselectivity. (i.e., (i.e., Innearly nearly this sense, quantitative quantitative the aforementioned and and without without CuAAC tedious tedious (independently steps steps of of reportedpurification)purification) by the; ;and and groups iv) iv) should ofshould Meldal occur occur [8 ]wit andwith h Sharpless total total regio regio [-9 ])-and and is considered stereo stereoselectivityselectivity as one. . In of In this the this sense,most sense, genuine the the examplesaforementionedaforementioned of this “clickCuAAC CuAAC chemistry” (independently (independently concept. reported reported This major by by the the discovery groups groups of isof Meldal basedMeldal [ on8 []8 and the] and previouslySharpless Sharpless [9reported []9) ]is) is Huisgenconsideredconsidered cycloaddition, as as one one of of the a the synthetic most most genuine genuine tool that examples examples proceeds of slowlyof this this “ click under“click chemistry thermal chemistry” conditions ”concept. concept. Thgiving This is major majorrise to a mixturediscoverydiscovery of is the isbased based corresponding on on the the previously previously 1,4- and reported reported 1,5-disubstituted Huisgen Huisgen cycloaddition, cycloaddition, 1,2,3-triazoles a synthetica (seesynthetic Scheme tool tool that1 a)that [proceeds10 proceeds]. Meldal andslowlyslowly Sharpless under under found thermal thermal that conditions justconditions by simple giv giving additioning rise rise ofto to a a copper a mixture mixture catalyst, of ofthe the this corresponding atom corresponding economic 1,4 1,41,3-dipolar- -and and cycloaddition1,51,5-disubstituted-disubstituted leads 1,2,3 1,2,3 to- thetriazoles-triazoles 1,4-triazole (see (see Scheme asScheme the 1a) only 1a) [1 product[10]0. ]Meldal. Meldal of and reaction, and Sharples Sharples thuss fs fulfillingound found that that now just just by the by simple principles simple ofaddition “clickadditionchemistry” of of a coppera copper (seecatalyst, catalyst, Scheme this this1 atomb). atom Although economic economic either 1,3 1,3-dipolar- metal-freedipolar cycloaddition cycloaddition [ 11] or Ag-[ leads leads12 ],to Ru-[to the the 131,4 1,4],-triazole Ir-[-triazole14] and Ni-catalyzedasas the the only only product [product15] cycloadditions of of reaction, reaction, thus ofthus azidesfulfilling fulfilling and now now alkynes the the principles haveprinciples been of of reported,“ click“click chemistry chemistry only Cu-catalysts” ”(see (see Scheme Scheme have found1b1).b ).Although aAlthough wide chemicaleither either metal metal application-free-free [1 [11]1 or] [ 16or Ag], Ag- like:[1-[21],2 ], (i)Ru Ru- drug[1-[31],3 ],Ir discovery -Ir[1-[41]4 and] and Ni and Ni-catalyzed- development;catalyzed [15 [15] cycloadditions] cycloadditions (ii) synthesis of of azides and alkynes have been reported, only Cu-catalysts have found a wide chemical application peptides,of azides carbohydrate-based and alkynes have been molecules reported, or only nucleosides Cu-catalyst/nucleotides;s have found (iii) a wide polymer chemical science; application and (iv) [16], like: i) drug discovery and development; ii) synthesis of peptides, carbohydrate-based macrocyclic[16], like: chemistry. i) drug discovery and development; ii) synthesis of peptides, carbohydrate-based moleculesmolecules or or nucleosides/nucleotides nucleosides/nucleotides; iii); iii) polymer polymer science; science; and and iv) iv) macrocyclic macrocyclic chemistry. chemistry.

SchemeSchemeScheme 1. 1. Cu-catalyzed 1.Cu Cu-catalyzed-catalyzed cycloaddition cycloaddition cycloadditionof of azides of azides azides and and terminal and terminal terminal alkynes alkynes alkynes (CuAAC; (CuAAC (CuAAC (b)); vs.;b ) b thermo-)vs vs. . dynamicallythermodynamicallythermodynamically driven driven Huisgen driven Huisgen Huisgen cycloaddition cycloaddition cycloaddition (a). (a )(.a ).

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In accordance with the originally coined definition of “click chemistry” and the requirements for a chemical process to be considered “click” [7], the desired transformation should take place under solventless reaction conditions. However, it is now well-established that solvents usually present a concomitant positive effect in the overall synthetic process, the so-called “solvent effect” [17]. This unquestionable positive solvent effect is generally associated with the capability of solvents to: (i) stabilize both metallic catalysts and transient intermediates; (ii) reduce unwanted side reactions; and (iii) help in the control of the heat flow. Thus, in most cases, the best option to work under strict “click” conditions is to replace traditional and hazardous volatile organic solvents (VOCs) with an environmentally friendly reaction media. In theory, these solvents to be considered green should be [18]: (i) biorenewable and biodegradable; (ii) cheap and easily available; (iii) non-toxic for both the environment and the human beings; (iv) safe (non-flammable, low vapor pressure); and (v) capable of dissolving a wide range of chemicals. With these strict requirements in mind, it is not surprising to find that the pool of available green and sustainable solvents is quite narrow, being the most typical examples: (i) water [19]; (ii) biomass derived solvents (like glycerol [20], γ-valerolactone [21], 2-methyl-THF [22] or lactic acid [23]); or (iii) Deep Eutectic Solvents (DESs)[24]. Thus, this mini-review focuses on the recent progress achieved on 1,3-dipolar cycloadditions of azides and alkynes mainly using molecular Cu-catalysts (CuAAC) that take place in glycerol (Gly), Deep Eutectic Solvents (DESs), or water as sustainable reaction media.

2. Cu-Catalyzed 1,3-Dipolar Cycloaddition of Azides and Alkynes (CuAAC) in Glycerol (Gly) As previously commented, the use of green solvents is mandatory for the development of CuAAC processes under “click” conditions [7]. In this regard, biomass derived solvents are playing a pivotal role in the substitution of traditional volatile and hazardous organic solvents (VOCs) by greener, safer and sustainable reaction media [25]. Among all biomass-derived solvents, glycerol (Gly, which is obtained as a major by-product from the biodiesel industry [26] or from the conversion of lignocellulose or cellulose into other chemical compounds [27]), has received great attention from the synthetic community as a plausible candidate for the replacement of VOC solvents in organic synthesis [20]. Moreover, due to its: (i) inherent physicochemical properties (low toxicity, non-flammability, high polarity, and boiling point); (ii) capability to dissolve both inorganic and organic compounds; (iii) easily separation of organic products and catalysts from the reaction media (that allows catalyst recycling); and (iv) previously reported competence to enhance both selectivity and productivity of given chemical reactions [28], glycerol is considered one of the archetypical prototypes of green and sustainable solvents. In this sense, García-Álvarez and co-workers [29] paved the way to follow in the CuAAC reaction using CuI/glycerol as catalytic system. This unprecedented combination promoted the Huisgen cycloaddition of organic azides with either terminal or internal 1-iodoalkynes at room temperature using low catalyst loadings (1 mol% in Cu), in the presence of air and in the absence of any external base (Scheme2a). In this work, the authors were able to recycle the aforementioned catalytic system up to six consecutives cycles and avoid the use of VOC solvents, as straightforward isolation of the desired triazoles was accomplished by simple filtration of the reaction crude. For comparison, the catalytic activity of CuI in a conventional and hazardous volatile organic solvent (i.e., CH2Cl2) was also evaluated and longer reaction times (24 h) were needed to achieve quantitative conversions (99%). This example supports clearly our previous affirmation which assessed the importance of green solvents in the design of a synthetic chemical process, thus disclosing a new example of an accelerated organic reaction in environmentally friendly reaction media. More recently, Schoffstall and co-workers have employed the same catalytic system (CuI/glycerol) for the synthesis of 1,2,3-triazoles containing fluorinated groups (Scheme2b) [ 30]. In the same year (2019), Bez et al. proved the beneficial effect of L-proline as a ligand to improve the catalytic activity of CuI in CuAAC cycloadditions using glycerol as solvent [31]. This methodology was successfully applied to the synthesis of possible pharmacologically active heterocyclic compounds like, for example, those derived from propargylated dihydroartemisinin (Scheme2c). Molecules 2020, 25, 2015 4 of 18 Molecules 2020, 25, x FOR PEER REVIEW 4 of 18

SchemeScheme 2.2.Cycloaddition Cycloaddition of of azides azides and and alkynes alkynes (CuAAC) (CuAAC) in purein pure glycerol glycerol as solvent as solvent catalyzed catalyzed by CuI by (aCuI,b) ( ora and the mixtureb) or the CuI mixture/L-proline CuI/L (c-).proline (c).

ContemporaneouslyContemporaneously toto andand independent independent ofof thethe pioneeringpioneering workwork byby GarcGarcíaía--ÁÁlvarez lvarez etet al., al., GGómezómez etet al.al.demonstrated demonstrated that that glycerol glycerol by by itself itself (without (without the the help help of of any any transition transition metal metal catalysts) catalysts) is ableis able to promote to promote the Huisgenthe Huisgen reaction reaction of internal of internal alkynes alkynes and organic and organic azides azides when when employing employing both microwaveboth microwave irradiation irradiation and thermal and thermal treatment treatment (warming (warming up to 100 up◦ C)to [10032,33 °C]) (Scheme [32,33] 3(a).Scheme For the 3a) case. For ofthe unsymmetrically case of unsymmetrically substituted substituted alkynes, the alkynes authors, the observed authors theobserved formation the offormation an almost of equimolar an almost mixtureequimolar of bothmixture regioisomers. of both regioisomers. After this seminal work, the same authors reported the possibility to use Cu(I)-based-nanoparticles as highly efficient catalyst for the cycloaddition of organic azides and terminal alkynes [34]. In this work, Gómez, Pericàs and co-workers studied deeply the role of different aliphatic and aromatic amines as co-catalysts for CuAAC reactions finding that an excess of oleylamine (5 mol%) favors the in-situ generation of Cu-nanoparticles when using CuI (1 mol%) as pre-catalyst (see Scheme3b). Remarkably, the formation of these Cu(I)-nanoparticles was also observed in other highly polar solvents like water or dioxane. More recently, the Gómez group has also reported the three-component version of AAC cycloadditions (by using the mixture NaN3/PhCH2Br as a source of benzyl azide) in pure glycerol (at 80 ◦C) by employing small and well-dispersed zerovalent PdCu bimetallic nanoparticles (PdCuNPs, mean diameter, ca. 3 4 nm) stabilized by polyvinylpyrrolidone (PVP) as catalysts (see Scheme3c) [ 35]. − Apart from glycerol, other biosourced alcohol-type solvents like polyethylene glycol (PEG) have been employed in CuAAC reactions [36–43]. In this sense, PEG-400 has been used as environmentally friendly and inexpensive solvent thanks to its: (i) low toxicity; (ii) non-volatility; (iii) recyclability and biodegradability; (iv) thermal stability; and (v) commercial availability [44]. Thus, the first work in this field was reported back in 2006 by Sreedhar and co-workers who describe an efficient and reliable CuI-catalyzed three-component reaction that employs terminal alkynes, NaN3 and Baylis-Hillman acetates as starting materials for the high-yielding synthesis of 1,4-disubtitutes triazoles in PEG at room temperature (see Scheme4)[ 36]. At this point it is important to note that better yields of the desired triazoles were obtained when hazardous and volatile organic solvents (like THF, CH CN or DMSO) were replaced by PEG. After this pioneering 3 work, the aforementioned CuI/PEG catalytic system was applied for the synthesis of: (i) β-hydroxy

Molecules 2020, 25, x FOR PEER REVIEW 4 of 18

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MoleculesScheme2020, 253., 2015Cycloaddition of azides and alkynes (AAC) in pure glycerol as solvent reported by the5 of 18 groups of Gómez and Pericàs which employed microwaves (a), CuI/oleylamine (b) or Cu/Pd metallic nanoparticles (c) as promoters. or N-tosylamino 1,2,3-triazole scaffolds [37]; (ii) biologically active bis(indolyl)methane derivatized 1,4-disubstitutedScheme 2. Cycloaddition 1,2,3-bistriazoles of azides [38]; and (iii) alkynes 1,4-diaryl-1 (CuAHAC)-1,2,3-triazoles in pure glycerol by reactionas solvent of catalyzed diaryliodonium by After this seminal work, the same authors reported the possibility to use salts,CuI NaN (a andand b terminal) or the mixture alkynes CuI/L [39];-proline and (iv) (c 4-substituted-1,2,3-triazole). analogues of azole antifungal Cu(I)-based3 -nanoparticles as highly efficient catalyst for the cycloaddition of organic azides and agents [40]. Not only CuI, but also the archetypical catalytic mixture CuSO 5H O/ascorbic acid has terminalContemporaneously alkynes [34]. In to this and work, independent Gómez, Pericàs of the andpioneering co-workers work studied by4· García2 deeply-Á lvarez the roleet al. of, been fruitfully applied in CuAAC processes devoted to the synthesis of 1,2,3-triazole tethered differentGómez et aliphatic al. demonstrated and aromatic that glycerolamines asby co itself-catalysts (without for theCuAAC help ofreactions any transition finding metal that ancatalysts) excess benzimidazo[1,2-a]quinolines [41] or 1H-1,2,3-triazole tethered pyrazolo[3,4-b]pyridin-6(7H)-ones [42] ofis oleylamine able to promote (5 mol%) the Hufavorsisgen the reaction in-situ generatio of internaln of alkynes Cu-nanoparticles and organic when azides using when CuI employing (1 mol%) by employing PEG as sustainable solvent at high temperatures (100–120 C). Finally, Astruc and asboth pre microwave-catalyst (see irradiation Scheme and 3b). thermal Remarkably treatment, the formation(warming ofup theseto 100 Cu(I) °C)◦ -[nanoparticles32,33] (Scheme was 3a) .also For co-workers nicely described the use of PEG as stabilizer for copper nanoparticles (CuNP) which are observedthe case of in unsymmetricallyother highly polar substituted solvents like alkynes water, theor dioxane.authors Moreobserved recently, the formation the Gómez of groupan almost has catalytically active in CuAAC processes in a mixture water/tBuOH and in the presence of air [43]. alsoequimolar reported mixture the of three both- componentregioisomers. version of AAC cycloadditions (by using the mixture NaN3/PhCH2Br as a source of benzyl azide) in pure glycerol (at 80 °C) by employing small and well-dispersed zerovalent PdCu bimetallic nanoparticles (PdCuNPs, mean diameter, ca. 3−4 nm) stabilized by polyvinylpyrrolidone (PVP) as catalysts (see Scheme 3c) [35]. Apart from glycerol, other biosourced alcohol-type solvents like polyethylene glycol (PEG) have been employed in CuAAC reactions [36–43]. In this sense, PEG-400 has been used as environmentally friendly and inexpensive solvent thanks to its: i) low toxicity; ii) non-volatility; iii) recyclability and biodegradability; iv) thermal stability; and v) commercial availability [44]. Thus, the first work in this field was reported back in 2006 by Sreedhar and co-workers who describe an efficient and reliable CuI-catalyzed three-component reaction that employs terminal alkynes, NaN3 and Baylis-Hillman acetates as starting materials for the high-yielding synthesis of 1,4-disubtitutes triazoles in PEG at room temperature (see Scheme 4) [36]. At this point it is important to note that better yields of the desired triazoles were obtained when hazardous and volatile organic solvents (like THF, CH3CN or DMSO) were replaced by PEG. After this pioneering work, the aforementioned CuI/PEG catalytic system was applied for the synthesis of: i) β-hydroxy or N-tosylamino 1,2,3-triazole scaffolds [37]; ii) biologically active bis(indolyl)methane derivatized 1,4-disubstituted 1,2,3-bistriazoles [38]; iii) 1,4-diaryl-1H-1,2,3-triazoles by reaction of diaryliodonium salts, NaN3 and terminal alkynes [39]; and iv) 4-substituted-1,2,3-triazole analogues of azole antifungal agents [40]. Not only CuI, but also the archetypical catalytic mixture CuSO4·5H2O/ascorbic acid has been fruitfully applied in CuAAC processes devoted to the synthesis of 1,2,3-triazole tethered benzimidazo[1,2-a]quinolines [41] or 1H-1,2,3-triazole tethered

pyrazolo[3,4-b]pyridin-6(7H)-ones [42] by employing PEG as sustainable solvent at high temperaturesScheme 3. (100Cycloaddition–120 °C). of Finally, azides andAstruc alkynes and (AAC) co-workers in pure nicely glycerol described as solvent the reported use ofby thePEG as stabilizergroups for of copper Gómez andnanoparticles Pericàs which (CuNP) employed which microwaves are catalytically (a), CuI/oleylamine active in (bCuAAC) or Cu/Pd processes metallic in a nanoparticles (c) as promoters. mixture water/tBuOH and in the presence of air [43].

Scheme 4. CuI-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles starting from Baylis–Hillman Scheme 4. CuI-catalyzed synthesis of 1,4-disubstituted 1,2,3-triazoles starting from Baylis–Hillman acetates, terminal alkynes and sodium azide using PEG as sustainable solvent. acetates, terminal alkynes and sodium azide using PEG as sustainable solvent. 3. Cu-Catalyzed 1,3-Dipolar Cycloaddition of Azides and Alkynes (CuAAC) in Deep Eutectic Solvents3. Cu-Catalyzed(DESs) 1,3-Dipolar Cycloaddition of Azides and Alkynes (CuAAC) in Deep Eutectic Solvents (DESs) Deep Eutectic Solvents (DESs)[24] are defined as the result of the combination of two (or even three)Deep chemical Eutectic substances Solvents which(DESs) are[24] able are defined to form as a newthe result eutectic of the mixture combination (with aof melting two (or pointeven belowthree) thatchemical of its substancesindividual components) which are able through to form the a formation new eutectic of a tridimensionalmixture (with ahydrogen-bond melting point networkbelow that [45 of]. Oneits individual of the most components) commonly usedthrough components the formation in the of synthesis a tridimen of thesesional eutectic hydrogen mixtures-bond isne thetwork biorenewable [45]. One of and the biodegradable most commonly ammonium used components salt choline in chloride the synthesis (ChCl, of vitamin these B4) eutectic [46].

Molecules 2020, 25, x FOR PEER REVIEW 6 of 18 Molecules 2020, 25, 2015 6 of 18 mixtures is the biorenewable and biodegradable ammonium salt choline chloride (ChCl, vitamin B4) [In46 combination]. In combinationwithdi withfferent different hydrogen hydrogen bond donors bond like: donors (i) naturally like: i) naturally occurring occurring polyols (glycerol, polyols (glycerol,ethylene glycolethylene or carbohydrates)glycol or carbohydrates) [47], (ii) biorenewable [47], ii) biorenewable organic acidsorganic [48 acids], or (iii) [48] urea, or iii) [49 urea]; choline [49]; cholinechloride chloride (ChCl) is ( ableChCl to) is form able sustainable to form sustainable and liquid and eutectic liquid mixtures eutectic which mixtures have which found have application found applicationin a plethora in of a diplethorafferent chemicalof different fields chemical [50–52]. fields As expected, [50–52]. As and expected, when the and concept when of the Deep concept Eutectic of DSolventseep Eutectic crossed Solvents the field crossed of traditional the field organic of traditional synthesis, organic CuAAC synthesis, was also assayedCuAAC in was these also sustainable assayed inreaction these sustainable media. In thisreaction sense, media. König In etthis al. sense, were König the real et pioneersal. were the in thisreal fieldpioneers back in in this 2009 fiel byd backreporting in 2009 the by CuI-catalyzed reporting the cycloaddition CuI-catalyzed of cycloaddition phenylacetylene of phenylacetylene with benzyl azide with for benzyl the synthesis azide for of the archetypicalsynthesis of 1,4-disubstituted the archetypical 1,2,3-triazoles 1,4-disubstituted [53]. However, 1,2,3-triazole it shoulds [53]. be However, mentioned it that: should (i) quite be mentioned that: i) quite drastic conditions (85 °C, 5 mol% of CuI and 5 h of reaction) were needed to drastic conditions (85 ◦C, 5 mol% of CuI and 5 h of reaction) were needed to obtain the desired triazole obtainin high the yield desired (93%, triazole see Scheme in high5a), andyield (ii) (93%, no recycling see Scheme studies 5a) of, and the catalyticii) no recycling system studies in DESs ofwere the catalytic system in DESs were reported. In contrast, employing a catalytic system based on the reported. In contrast, employing a catalytic system based on the combination of CuSO4 with sodium combinationascorbate as reducing of CuSO agent4 with (typically sodium usedascorbate in other as CuAACreducing reactions), agent (typically the yield used of the in desiredother CuAAC triazole reactions), the yield of the desired triazole only reached 84%. The use of the ternary eutectic mixture only reached 84%. The use of the ternary eutectic mixture D-sorbitol/urea/NH4Cl, as sustainable D-sorbitol/urea/NH4Cl, as sustainable solvent, also allowed the in-situ synthesis of the benzyl azide solvent, also allowed the in-situ synthesis of the benzyl azide (starting from PhCH2Br and NaN3) in (startingthe corresponding from PhCH three-component2Br and NaN3) versionin the corresponding of the CuAAC process.three-component Interestingly, version the aforementionedof the CuAAC process.CuAAC processInterestingly, proceeded the slightly aforementioned better when CuAAC the L-carnitine-based process proceeded eutectic slightly mixture betterL-carnitine when/Urea the wasL-carnitine used as-based sustainable eutectic solvent mixture (see L- Schemecarnitine/Urea5b). This was experimental used as sustainable observation solvent was attributed(see Scheme to 5theb). formation This experimental of a coordination observation complex was betweenattributed CuI to and theL -carnitineformation that of preventeda coordination the unwanted complex betweenoxidation CuI of Cu(I) and L into-carnitine Cu(II). that Lately, prevented García-Alvarez the unwant anded co-workers oxidation demonstrated of Cu(I) into thatCu(II). the Lately, use of Garcíathe eutectic-Alvarez mixture and co formed-workers by cholinedemonstrated chloride that and the glycerol use of the (1ChCl eutectic/2Gly )mix allowedture formed the use by of choline milder chloridereaction conditionsand glycerol (room (1ChCl temperature/2Gly) allowed and 1the mol% use ofof CuI)milder although reaction longer conditions reaction (room times temperature (14 h) were andneeded 1 mol to% reach of CuI) quantitative although yieldslonger (97%, reaction Scheme times5c) (14 [ 29 h)]. were At this needed point, to it reach is important quantitative to note yields that, (97%, Scheme 5c) [29]. At this point, it is important to note that, when the eutectic mixture when the eutectic mixture 1ChCl/2Gly was replaced by volatile and hazardous CH2Cl2, under the same 1catalyticChCl/2Gly conditions, was replaced a longer by volatile reaction and time hazardous (24 h) was CH needed2Cl2, tounder achieve the quantitativesame catalytic conversion. conditions, a longer reaction time (24 h) was needed to achieve quantitative conversion.

Scheme 5. DESs Scheme 5. CuICuI-catalyzed-catalyzed cycloaddition of of azides azides and and alkynes alkynes in in the Deep Eutectic Mixtures ( DESs)):: D-Sorbitol/Urea/NH4Cl (a); L-carnitine/Urea (b); or Choline Chloride/Glycerol (c). D-Sorbitol/Urea/NH4Cl (a); L-carnitine/Urea (b); or Choline Chloride/Glycerol (c). More recently, and bearing in mind the positive effect observed in CuAAC when: (i) the eutectic More recently, and bearing in mind the positive effect observed in CuAAC when: i) the mixture 1ChCl/2Gly was employed as sustainable solvent, and (ii) nitrogenated ligands (amines) are eutectic mixture 1ChCl/2Gly was employed as sustainable solvent, and ii) nitrogenated ligands added as co-catalyst to the reaction media; Handy et al. reported the CuI-catalyzed cycloaddition (amines) are added as co-catalyst to the reaction media; Handy et al. reported the CuI-catalyzed of in-situ generated aryl azides with terminal alkynes by employing the aforementioned 1ChCl/2Gly cycloaddition of in-situ generated aryl azides with terminal alkynes by employing the eutectic mixture as sustainable solvent in the presence of N,N-dimethylethylenediamine (DMEAD, aforementioned 1ChCl/2Gly eutectic mixture as sustainable solvent in the presence of

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Molecules 2020, 25, x FOR PEER REVIEW 7 of 18 20 mol%) as co-catalyst. Although the catalytic system was recycled up to 4 consecutive cycles, N,N-dimethylethylenediamine (DMEAD, 20 mol%) as co-catalyst. Although the catalytic system quite drastic reaction conditions (75 ◦C, 10 mol% of CuI and 5–10 h, see Scheme6) were still needed to achievewas recycled moderate up to to 4 good consecutive yields (40–88%) cycles, quite [54,55 ].drastic reaction conditions (75 °C, 10 mol% of CuI and 5–10 h, see Scheme 6) were still needed to achieve moderate to good yields (40–88%) [54,55].

Scheme 6.6.CuI-catalyzed CuI-catalyzed three-component three-component cycloaddition cycloaddition of in-situ of in generated-situ generated aryl azides aryl andazides terminal and alkynesterminal in alkynes the eutectic in the mixture eutectic 1 mixtureChCl/2Gly 1ChCl. /2Gly.

4.4. Cu Cu-Catalyzed-Catalyzed 1,3 1,3-Dipolar-Dipolar Cycloaddition of Azides and Alkynes (CuAAC) inin Water In opposite to thethe moremore traditionaltraditional VOCs, the use of water as a reaction media ooffersffers multiplemultiple advantages suchsuch as: as: (i) i) its non-toxicitynon-toxicity and and non-flammability; non-flammability; (ii) ii) elevated boiling boiling point; point; (iii) iii) highhigh availability and and low low price; price and; and (iv) iv)non-miscibility non-miscibility with with organic organic compounds compounds that enables that enables easy product easy separationproduct separation and catalyst and catalyst recycling recycling upon decantation. upon decantation Taken. Taken together, together, and inand agreement in agreement with with the principlesthe principles of green of green chemistry, chemistry water, water [19] [19] emerges emerges as oneas one of theof the most most attractive attractive solvents solvents in termsin terms of sustainabilityof sustainability and and often often represents represents the solventthe solvent of choice of choice when when dealing dealing with CuAAC with CuAAC processes. processesThis is. inThis part is duein part to the due pioneering to the pioneering work reported work reported by Sharpless by Sharpless and Fokin and in Fokin 2002 occurring in 2002 occurring in aqueous in t solutionsaqueous solutions (2:1 mixture (2:1 of mixture water ofand waterBuOH) and [9tBuOH)] that inspired [9] that ainspired plethora a ofplethora international of international research groupsresearch worldwide groups worldwide to study CuAACto study reactionsCuAAC reactions in this environmentally in this environmentally friendly solvent. friendly On solvent. the other On hand,the otherand hand, keeping andin k mindeeping that in mind the state that of the the state art forof the the art CuAAC for the processes CuAAC hasprocesses been reviewed has been recentlyreviewed [56 recently–62], this [5 section6–62], t focuseshis section on mostfocuses representative on most representative examples appeared examples since appear 2015 merginged since the2015 use merging of molecular the use copper of molecular catalysts copper and pure catalysts aqueous and media.pure aqueous media. In spite spite of of the the well well documented documented viability viability of ofCuAAC CuAAC reactions reactions in pure in pure water water under under ligand ligand-- and andadditive additive-free-free conditions conditions [63] [, 63the], the finding finding of of highly highly efficient efficient CuAAC CuAAC procedures procedures catalyzed catalyzed by commercially available available Cu Cu salts salts is isan an active active research research area. area. In this In sense, this sense, impressive impressive substrate substrate scope scopewas reached was reached recently recently by Jiang by Jiang and Xu and using Xu usingCu(II) Cu(II) catalysts catalysts in very in very low metallic low metallic charges charges (see (see Scheme7a,b) [ 64,65]. Both Cu(II) catalysts (CuSO 5H O[64] or Cu(acac) [65]) required harsh Scheme 7a,b) [64,65]. Both Cu(II) catalysts (CuSO4·5H4· 2O2 [64] or Cu(acac)2 2[65]) required harsh conditions.conditions. In contrast, they proved eefficientfficient for thethe three-componentthree-component synthesissynthesis ofof 1,4-disubstituted1,4-disubstituted 1,2,3-triazoles starting from terminal alkynes, NaN and organic halides (R-X). 1,2,3-triazoles starting from terminal alkynes, NaN33 and organic halides (R-X). Milder conditions were required using CuCl2 as catalyst in combination with an organic photosensitizer (eosin Y disodium salt (EY)) and green LED irradiation (Scheme7c) [ 66]. The CuCl2/EY photocatalytic system enabled the isolation of a broad family of 1,4-disubstituted 1,2,3-triazoles in moderate to excellent yields (49–100%) and the aforementioned catalytic system was recycled up to three consecutive runs [66]. An additional example of ligand-free CuAAC protocols in neat water includes the use of ultrasound irradiation [67] to enhance the activity of a Cu(I) salt (i.e., CuCl) as catalyst (Scheme8). In this sense, Chen, Qu and co-workers used CuCl (10 mol%) to build 1,4-disubstituted 1,2,3-triazoles at room temperature upon ultrasound irradiation (150 W), including a family of triazoles generated from coumarine-derived alkynes or azides thereby granting access to highly functionalized heterocycles that were isolated in ca. 90% yield (see Scheme8a,b) [ 67]. Remarkably, lower yields were reached in the absence of ultrasonic power, even in the presence of trimethylamine as co-catalyst, or when using t mixtures H2O/VOCs or pure organic solvents (DMSO, DMF, toluene or BuOH) instead of neat water as a reaction medium.

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N,N-dimethylethylenediamine (DMEAD, 20 mol%) as co-catalyst. Although the catalytic system was recycled up to 4 consecutive cycles, quite drastic reaction conditions (75 °C, 10 mol% of CuI and 5–10 h, see Scheme 6) were still needed to achieve moderate to good yields (40–88%) [54,55].

Scheme 6. CuI-catalyzed three-component cycloaddition of in-situ generated aryl azides and terminal alkynes in the eutectic mixture 1ChCl/2Gly.

4. Cu-Catalyzed 1,3-Dipolar Cycloaddition of Azides and Alkynes (CuAAC) in Water In opposite to the more traditional VOCs, the use of water as a reaction media offers multiple advantages such as: i) its non-toxicity and non-flammability; ii) elevated boiling point; iii) high availability and low price; and iv) non-miscibility with organic compounds that enables easy product separation and catalyst recycling upon decantation. Taken together, and in agreement with the principles of green chemistry, water [19] emerges as one of the most attractive solvents in terms of sustainability and often represents the solvent of choice when dealing with CuAAC processes. This is in part due to the pioneering work reported by Sharpless and Fokin in 2002 occurring in aqueous solutions (2:1 mixture of water and tBuOH) [9] that inspired a plethora of international research groups worldwide to study CuAAC reactions in this environmentally friendly solvent. On the other hand, and keeping in mind that the state of the art for the CuAAC processes has been reviewed recently [56–62], this section focuses on most representative examples appeared since 2015 merging the use of molecular copper catalysts and pure aqueous media. In spite of the well documented viability of CuAAC reactions in pure water under ligand- and additive-free conditions [63], the finding of highly efficient CuAAC procedures catalyzed by commercially available Cu salts is an active research area. In this sense, impressive substrate scope was reached recently by Jiang and Xu using Cu(II) catalysts in very low metallic charges (see Scheme 7a,b) [64,65]. Both Cu(II) catalysts (CuSO4·5H2O [64] or Cu(acac)2 [65]) required harsh Molecules 2020, 25, 2015 8 of 18 conditions. In contrast, they proved efficient for the three-component synthesis of 1,4-disubstituted 1,2,3-triazoles starting from terminal alkynes, NaN3 and organic halides (R-X).

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Scheme 7. Ligand-free Cu(II)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes (CuAAC) in pure water enabled by thermal treatment (equations a and b) or green LED irradiation (equation c).

Milder conditions were required using CuCl2 as catalyst in combination with an organic photosensitizer (eosin Y disodium salt (EY)) and green LED irradiation (Scheme 7c) [66]. The CuCl2/EY photocatalytic system enabled the isolation of a broad family of 1,4-disubstituted 1,2,3-triazoles in moderate to excellent yields (49–100%) and the aforementioned catalytic system was recycled up to three consecutive runs [66]. An additional example of ligand-free CuAAC protocols in neat water includes the use of ultrasound irradiation [67] to enhance the activity of a Cu(I) salt (i.e., CuCl) as catalyst (Scheme 8). In this sense, Chen, Qu and co-workers used CuCl (10 mol%) to build 1,4-disubstituted 1,2,3-triazoles at room temperature upon ultrasound irradiation (150 W), including a family of triazoles generated from coumarine-derived alkynes or azides thereby granting access to highly functionalized heterocycles that were isolated in ca. 90% yield (see Scheme 8a,b) [67]. Remarkably, lower yields were reached in the absence of ultrasonic power, even in the presence of Scheme 7. Ligand-free Cu(II)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes (CuAAC) in trimethylamine as co-catalyst, or when using mixtures H2O/VOCs or pure organic solvents (DMSO, pure water enabled by thermal treatment (equations (a,b)) or green LED irradiation (equation (c)). DMF, toluene or tBuOH) instead of neat water as a reaction medium.

Scheme 8. Ligand-free CuCl-catalyzed 1,3-dipolar cycloaddition of terminal alkynes (CuAAC) with Scheme 8. Ligand-free CuCl-catalyzed 1,3-dipolar cycloaddition of terminal alkynes (CuAAC) with common organic azides (a) or coumarine-derived azides (b) in water. common organic azides (a) or coumarine-derived azides (b) in water. The efficiency of the CuAAC reactions in aqueous media can be improved using heteroatom-based The efficiency of the CuAAC reactions in aqueous media can be improved using donor ligands that enhance the solubility and stability of the Cu catalyst. Classical examples of this heteroatom-based donor ligands that enhance the solubility and stability of the Cu catalyst. strategy combined CuX species (X = I, Br) and NEt3 [68], N-alkylimidazoles [69] or thioethers [70,71]. Classical examples of this strategy combined CuX species (X = I, Br) and NEt3 [68], In 2014, Sarma and colleagues carried out the cycloaddition of organic azides with terminal alkynes in N-alkylimidazoles [69] or thioethers [70,71]. In 2014, Sarma and colleagues carried out the excellent yields (82–92%) catalyzed by CuI (0.5 mol%) and the hydroquinidine-1,4-phthalazinediyl cycloaddition of organic azides with terminal alkynes in excellent yields (82–92%) catalyzed by CuI ligand ((DHQD)2PHAL; 1 mol%) in pure water (see Scheme9a) [ 72]. The efficiency of the CuI/ (0.5 mol%) and the hydroquinidine-1,4-phthalazinediyl ligand ((DHQD)2PHAL; 1 mol%) in pure (DHQD)2PHAL catalytic system in the 1,3-dipolar cycloaddition of phenylacetylene and benzyl azide water (see Scheme 9a) [72]. The efficiency of the CuI/(DHQD)2PHAL catalytic system in the was completely inhibited in absence of ligand, and the beneficial effect of water was demonstrated 1,3-dipolar cycloaddition of phenylacetylene and benzyl azide was completely inhibited in absence by the lower activity of the aforementioned catalytic system when using volatile organic solvents of ligand, and the beneficial effect of water was demonstrated by tthe lower activity of the such as THF, CH2Cl2, DMSO, DMF, acetone, toluene, or mixtures H2O/ BuOH [72]. Cu(OAc)2 and aforementioned catalytic system when using volatile organic solvents such as THF, CH2Cl2, DMSO, hydrazine monohydrate (NH2NH2 H2O) was used by Xu and co-workers to prepare a family of DMF, acetone, toluene, or mixtures· H2O/tBuOH [72]. Cu(OAc)2 and hydrazine monohydrate 1,4-disubstituted 1,2,3-triazoles in neat water (see Scheme9b) [ 73]. In this case, the hydrazine behaves (NH2NH2·H2O) was used by Xu and co-workers to prepare a family of 1,4-disubstituted 1,2,3-triazoles in neat water (see Scheme 9b) [73]. In this case, the hydrazine behaves as stoichiometric reducing agent to generate Cu(OAc) species in-situ that underwent spontaneous decomposition in aqueous media to produce spherical Cu2O-NPs with size distribution ranging from 400 to 500 nm (characterized by powder XRD, SEM and TEM). It should be noted that the excellent catalytic activity and robustness of discrete Cu2O species in AAC reactions occurring in neat water at room temperature and in absence of additives was noticed back in 2011 by Bi and

Molecules 2020, 25, 2015 9 of 18 as stoichiometric reducing agent to generate Cu(OAc) species in-situ that underwent spontaneous decomposition in aqueous media to produce spherical Cu2O-NPs with size distribution ranging from 400 to 500 nm (characterized by powder XRD, SEM and TEM). It should be noted that the Moleculesexcellent 2020 catalytic, 25, x FOR activity PEER REVIEW and robustness of discrete Cu2O species in AAC reactions occurring9 of 18 in neat water at room temperature and in absence of additives was noticed back in 2011 by Bi and ZhangZhang [ [6363],], also also pointing pointing to to the the key key role role of of water water since since only only traces traces (DMSO, (DMSO, THF THF,, and MeOH) or or very low low conversions conversions (< (< 20%;20%; CHCl CHCl3) 3we) werere reached reached using using volatile volatile organic organic solvents. solvents. Interestingly, Interestingly, the Cu(OAc)the Cu(OAc)2 to 2Cuto2O Cu-NPs2O-NPs conversion conversion co-produced co-produced HOAc HOAc as asby by-product,-product, that that suggested suggested the the beneficial beneficial rolerole of of acidic media for the CuAAC reaction to proceed [[73]73].. Built Built on on these observations, the the same same groupgroup developed developed the the fast fast and and high-yielding high-yielding 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition of organic of organic azides with azides terminal with terminalalkynes catalyzedalkynes catalyzed by Cu2O by (0.5 Cu mol%)2O (0.5 in mol%) neat water in neat using water carboxymethylpullulans using carboxymethylpullulans (CMP; 5 ( mol%)CMP; 5as mol%) a mild as source a mild of protons source of (see protons Scheme (see9c) Scheme [ 74]. Remarkably, 9c) [74]. Remarkably, the Cu2O/CMP the catalyticCu2O/CMP system catalytic was systemefficiently was recycled efficiently up recycled to 6 consecutives up to 6 consecutives runs, and might runs, be and recycled might sixbe recycled additional six runs additional upon acidic runs upontreatment acidic that treatment reactivates that thereactivates CMP co-catalyst. the CMP Jointco-catalyst work. performedJoint work byperformed the groups by ofthe Peric groupsàs and of PericGómezàs and proved Gómez the pivotalproved role the ofpivotal long chainrole of alkyl long amines chain inalkyl CuAAC amines reactions in CuAAC taking reactions place in taking polar placesolvents in polar such as solvents alcohols, such dioxane as alcohols and pure, dioxane water and [34 ]. pure For water the case [34]. of For water, the the case authors of water, clearly the authorsillustrated clearly the need illustrat of HN(octyl)ed the need2 or of oleylamine HN(octyl) in2 o catalyticr oleylamine amounts in catalytic to reach amounts nearly quantitative to reach nearly yield quantitativeof 1-benzyl-4-phenyl-1 yield ofH 1-1,2,3-triazole,-benzyl-4-phenyl whereas-1H-1,2,3 negligible-triazole, amounts whereas of the negligible cycloaddition amounts product of where the cycloadditionisolated in presence product of where NEt3 (5 isolated mol%) orin presence in the absence of NEt of3 any(5 mol additive%) or in (13%; the absence see Scheme of any9d) additive [34]. (13%; see Scheme 9d) [34].

SchemeScheme 9 9.. CuCuAACAAC reactions reactions in in pure pure water water enabled enabled by by commercially commercially available available Cu Cu-salts-salts and and nitrogen nitrogen compoundscompounds ( (aa,, bb, dand) or d proton) or proton sources sources (CMP; (CMP (c)).; c).

Copper acetylides are commonly invoked as catalytic intermediates in CuAAC reactions, which makes the synthesis of functionalized 1,2,3-triazoles from internal alkynes typically unreachable. This limitation is frequently circumvented using internal iodoalkynes [75], thus allowing for further modification of the triazole skeleton. An elegant approach to 5-iodo-1,2,3-triazoles taking place in water via three-component reaction between terminal alkynes, organic azides and NaI was discovered recently by Li, Cui and Zhang (see Scheme 10) [76]. After careful optimization of the reaction conditions (10 mol% of CuI along with equimolar amounts of NaI, DIPEA (diisopropylethylamine), TBACl (tetrabutylammonium chloride), Selectfluor (1.2 equiv

Molecules 2020, 25, 2015 10 of 18

Copper acetylides are commonly invoked as catalytic intermediates in CuAAC reactions, which makes the synthesis of functionalized 1,2,3-triazoles from internal alkynes typically unreachable. This limitation is frequently circumvented using internal iodoalkynes [75], thus allowing for further modification of the triazole skeleton. An elegant approach to 5-iodo-1,2,3-triazoles taking place in water via three-component reaction between terminal alkynes, organic azides and NaI was discovered recently by Li, Cui and Zhang (see Scheme 10)[76]. After careful optimization of the reaction conditions Molecules(10 mol% 2020 of, 25 CuI, x FOR along PEER with REVIEW equimolar amounts of NaI, DIPEA (diisopropylethylamine), TBACl10 of 18 (tetrabutylammonium chloride), Selectfluor (1.2 equiv of each), and mild heating), the authors isolated ofa number each), and of 5-iodo-1,2,3-triazoles mild heating), the authors in yields isolated ranging a number from 72 of to 91%.5-iodo By-1,2,3 applying-triazoles this in catalytic yields ranging cocktail, frombroad 72 substrate% to 91%. scope By applying and functional this catalytic group tolerancecocktail, broad was reached, substrate including scope and the functional incorporation group of tolerancerelevant motifs was reached, such as sugars,including fluorophore the incorporation groups, or of peptides. relevant motifs such as sugars, fluorophore groups, or peptides.

Scheme 10.10. SynthesisSynthesis ofof 5-iodo-1,2,3-triazoles 5-iodo-1,2,3-triazoles mediated mediated by by CuI, CuI DIPEA, DIPEA and and TBACl TBACl in pure in pure water water upon uponoxidizing oxidizing conditions. conditions.

The use of well well-defined-defined Cu complexes as catalysts for the CuAAC CuAACss in aqueous media has been extensively studiedstudied usingusing phosphorus-donorphosphorus-donor ligands ligands [77 [7,787,7],8],N -HeterocyclicN-Heterocyclic Carbenes Carbenes (NHC) (NHC) [79 –[7981–], 81or], PTA-derived or PTA-derived iminophosphoranes iminophosphoranes (PTA (PTA= 1,3,5-Triaza-7-phosphaadamantane) = 1,3,5-Triaza-7-phosphaadamantane) [82,83 [8].2, To83]. the To bestthe bestof our of our knowledge, knowledge, the t firsthe first isolated isolated and and fully fully characterized characterized copper copper species species bearingbearing anan N--donordonor ligand that proved efficient efficient in CuAAC reactioreactionsns us usinging pure water as solvent was reported by Pericàs back in 2009 using a 1:1 1:1 complex complex of of CuC CuCll and and the the tris(1 tris(1-benzyl-1-benzyl-1HH--1,2,3-triazol-4-yl)methanol1,2,3-triazol-4-yl)methanol ligand [ [8844].]. Pursuing Pursuing th thisis approach, approach, Peric Pericàs àands and co- co-workersworkers prepared prepared a family a family of Cu of-complexes Cu-complexes (1a– f(1a) bearing–f) bearing tris(triazolyl)methane tris(triazolyl)methane ligands ligands that that catalyzed catalyzed the the cycload cycloadditiondition of of b benzylenzyl azide azide with phenylacetylene at at room room temperature temperatu inre neat in waterneat water as a solvent as a (see solvent Scheme (see 11 Schemea) [85]. A11 comparativea) [85]. A comparativestudy using study the simplest using the and simplest hydrophilic and hydrophilic Cu species Cu1b species(R = H; 1b R’ (R= = Ph),H; R’ which = Ph), behavedwhich behaved as the asmost the e mostfficient efficient catalyst catalyst for the modelfor the reactionmodel reaction between between phenylacetylene phenylacetylene and benzyl and azide, benzyl has azide, revealed has revealedthe positive the positive impact ofimpact water of (vs.water hexanes, (vs. hexanes, toluene, toluene, CH 2CHCl22,Cl THF2, THF or or CH CH3CN)3CN) on on thethe catalytic activity of of 1b1b [8 [855].] .The The (2- (2-pyrrolecarbaldiminato)-Cu(II)pyrrolecarbaldiminato)-Cu(II) catalyst catalyst 2 allowed2 allowed the three the three-component-component and highand- high-yieldingyielding synthesis synthesis of 1,4 of-disubstituted 1,4-disubstituted 1,2,3 1,2,3-triazoles-triazoles (see (seeScheme Scheme 11b) 11[8b)6]. [86Interestingly,]. Interestingly, the scopethe scope is restrictedis restricted to the to the use use of ofbenzyl benzyl halides halides which which leaves leaves the the inert inert aryl aryl-Cl-Cl and and/or/or aryl aryl-Br-Br bonds intact for further functionalization [ 86]].. T Thehe group groupss of of Mahmudov Mahmudov and and Pombeiro carried out the thrthree-componentee-component coupling of phenyl phenylacetylene,acetylene, benzyl bromide and NaN3 inin nea neatt water water catalyzed catalyzed by by . the Cu(II) Cu(II)-catalyst-catalyst 3.2H2H22OO (3 (3 mol%) mol%) upon upon microwave microwave irradiation irradiation (10 (10 W) W) and and strong strong heating heating (125 (125 °◦C;C; see Scheme 1111c) [8787]. Nevertheless, the the harsh conditions only only permitted the isolation of the model 1-benzyl-4-phenyl-11-benzyl-4-phenyl-1HH--1,2,3-triazole1,2,3-triazole in in 74% 74% yield. yield. A A last last example example of of AAC enabled by well-definedwell-defined [(NHC)CuCl] speciesspecies4 4was was given given by the by groupthe group of Szadkowska of Szadkowska [88]. In [8 order8]. In to order enhance to the enhan solubilityce the solubilityof 4 in aqueous of 4 in media, aqueous the media, authors the used authors a hydrophilic used a NHChydrophilic ligand NHC containing ligand the containing theophylline the theophyllinebackbone and backbone an ammonium and an moiety. ammonium This ligand moiety design. This strategyligand design proved strategy right and proved was keyright to and enhance was keythe catalyticto enhance activity the catalytic of 4 in neatactivity water of that4 in surpassedneat water the that one surpassed found in the non-polar one found organic in non solvents-polar t organic(toluene solventsor ethers), (toluene alcohols or (glycerol ethers), or alcohols MeOH), CH (glycerol2Cl2, DMSO or MeOH), or mixtures CH2Cl H2,O DMSO/ BuOH. or In mixtures addition, Hthe2O/ three-componenttBuOH. In additionsynthesis, the of functionalized three-component triazoles synthesis was accomplished of functionalized using low coppertriazoles loadings was accomplished(1 mol% of 4) andusing mild low conditions copper loading (rooms temperature;(1 mol% of 4) see and Scheme mild conditions 11d) [88]. (room temperature; see Scheme 11d) [88].

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Scheme 11. CuAAC reactions in neat water catalyzed by Cu-complexes containing tris(triazolyl)- Scheme 11. CuAAC reactions in neat water catalyzed by Cu-complexes containing methane (a), 2-pyrrolecarbaldiminato (b), arylhydrazone (c) or hydrophilic NHC (d) ligands. tris(triazolyl)methane (a), 2-pyrrolecarbaldiminato (b), arylhydrazone (c) or hydrophilic NHC (d) ligandsIn 2014,. Astruc and colleagues performed the 1,3-dipolar cycloaddition of terminal alkynes and organic azides enabled by either [Cu(hexabenzyltren)Br] (tren = triaminoethylamine; complex In 2014, Astruc and colleagues performed the 1,3-dipolar cycloaddition of terminal alkynes and 5 in Scheme 12) or the Sharpless-Fokin catalyst [CuSO4 5H2O and sodium ascorbate (NaAsc) in organic azides enabled by either [Cu(hexabenzyltren)Br] ·(tren = triaminoethylamine; complex 5 in Scheme 12] using micellar catalysis at nearly room temperature [89]. To meet success, the amphiphilic Scheme 12) or the Sharpless-Fokin catalyst [CuSO4·5H2O and sodium ascorbate (NaAsc) in Scheme dendrimer 6 that bears 27 triethylene glycol (TEG) units and nine intradentritic triazoles was used in 12] using micellar catalysis at nearly room temperature [89]. To meet success, the amphiphilic catalytic amounts allowing the encapsulation of the Cu(I) active sites (Scheme 12)[89]. The resulting dendrimer 6 that bears 27 triethylene glycol (TEG) units and nine intradentritic triazoles was used in Cu(I)-containing nanoreactor permitted the isolation of several 1,4-disubstituted 1,2,3-triazoles in catalytic amounts allowing the encapsulation of the Cu(I) active sites (Scheme 12) [89]. The resulting excellent yields and with excellent TON values (up to 510000). Moreover, at this point it is important to Cu(I)-containing nanoreactor permitted the isolation of several 1,4-disubstituted 1,2,3-triazoles in note that the authors reported the recycling (up to 10 consecutive runs) of the amphiphilic dendrimer 6 excellent yields and with excellent TON values (up to 510000). Moreover, at this point it is important using the Cu(I)-catalyst 5. to note that the authors reported the recycling (up to 10 consecutive runs) of the amphiphilic A year later, a similar approach was employed by Shin and Lim to isolate a family of glycidyl dendrimer 6 using the Cu(I)-catalyst 5. triazolyl polymers via CuAACs using CuSO 5H O (5 mol%), sodium ascorbate (NaAsc, 15 mol%) 4· 2 and β-cyclodextrin (β-CD; 2.5 mol%) using neat water as solvent (see Scheme 13)[90]. The replacement of β-CD by the zwitterionic surfactant Betaine permitted the groups of Lee and Lim to achieve the quantitative cycloaddition of phenylacetylene and benzyl azide combining CuSO 5H O (25 ppb), 4· 2 sodium ascorbate (15 mol%) and Betaine (5 mol%; see Scheme 14)[91]. Upon these conditions, 1 very impressive TON and TOF values (32,000,000 and 1,333,333 h− , respectively) were accomplished at nearly room temperature, and the micellar aqueous medium was reused up to three cycles [although higher copper charges (200 ppm) and longer reaction times were required to reach completion].

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In addition, the catalytic system was applied to the isolation of 1-benzyl-4-phenyl-1H-1,2,3-triazole in a gram scale using 2.5 ppm of Cu-catalyst (95% yield), and the scope of the reaction was extended to a family of aryl, alkyl, and ferrocenyl acetylenes, furnishing the corresponding triazoles in 76–98% yield uponMolecules very 2020 mild, 25, x conditionsFOR PEER REVIEW (copper loadings of 25–200 ppm and heating at 30 ◦C). 12 of 18

Scheme 12. CuAAC using [Cu(hexabenzyltren)Br] (5) or CuSO4/sodium ascorbate (NaAsc) catalytic Scheme 12. CuAAC using [Cu(hexabenzyltren)Br] (5) or CuSO4/sodium ascorbate (NaAsc) catalytic systems and enabled by the amphiphilic dendrimer (6). systems and enabled by the amphiphilic dendrimer (6). Last but not least, the group of Scarso proved that micellar catalysis can be applied to A year later, a similar approach was employed by Shin and Lim to isolate a family of glycidyl the CuAAC reaction in its three-component version. Thus, the selective coupling of terminal triazolyl polymers via CuAACs using CuSO4·5H2O (5 mol%), sodium ascorbate (NaAsc, 15 mol%) alkynes, organic bromides and NaN efficiently proceeds using the lipophilic catalyst [Cu(IMes)Cl] and β-cyclodextrin (β-CD; 2.5 mol%)3 using neat water as solvent (see Scheme 13) [90]. The (1 mol% Cu; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)) and the commercially available replacement of β-CD by the zwitterionic surfactant Betaine permitted the groups of Lee and Lim to surfactants named sodium lauryl sulfosuccinate (SLS) or DL-α-tocopherol methoxypolyethylene achieve the quantitative cycloaddition of phenylacetylene and benzyl azide combining CuSO4·5H2O glycol succinate (TPGS-750-M) giving access to the corresponding triazoles in variable yields (51–98%; (25 ppb), sodium ascorbate (15 mol%) and Betaine (5 mol%; see Scheme 14) [91]. Upon these see Scheme 15)[92]. It is important to note that the efficiency of [Cu(IMes)Cl] upon micellar conditions conditions, very impressive TON and TOF values (32,000,000 and 1,333,333 h−1, respectively) were to achieve the 1,3-dipolar cycloaddition between 1-octyne and benzyl azide notably outperforms its accomplished at nearly room temperature, and the micellar aqueous medium was reused up to three catalytic activity using volatile organic solvents such as CH Cl or MeOH, that only produced the cycles [although higher copper charges (200 ppm) and longer2 reaction2 times were required to reach desired triazole in ca. 5%. Unfortunately, attempts to make possible the recycling of the micellar completion]. In addition, the catalytic system was applied to the isolation of catalytic system proved unfruitful and the model triazole was isolated in only 27% yield. 1-benzyl-4-phenyl-1H-1,2,3-triazole in a gram scale using 2.5 ppm of Cu-catalyst (95% yield), and the scope of the reaction was extended to a family of aryl, alkyl, and ferrocenyl acetylenes, furnishing the corresponding triazoles in 76%–98% yield upon very mild conditions (copper loadings of 25–200 ppm and heating at 30 °C).

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Molecules 2020, 25, x FOR PEER REVIEW 13 of 18 Molecules 2020, 25, 2015 13 of 18 Molecules 2020, 25, x FOR PEER REVIEW 13 of 18

Scheme 13. CuAAC in micellar medium using the Sharpless-Fokin catalyst and β-cyclodextrin (β-CD).

Scheme 14. CuAAC mediated by the Sharpless-Fokin catalyst and Betaine in pure water.

Last but not least, the group of Scarso proved that micellar catalysis can be applied to the CuAAC reaction in its three-component version. Thus, the selective coupling of terminal alkynes, organicScheme bromides 13. CuAAC and NaN in 3 micellar efficiently medium proceeds using using the Sharplessthe lipophili-Fokinc catalyst catalyst [ andCu(IMes)Cl β-cyclodextrin] (1 mol% (β-CD). Cu; Scheme IMesScheme = 13. 1 1,33CuAAC. -CuAACbis(2,4,6 in micellarin-trimethylphenyl)imidazol micellar medium medium using using the Sharpless-Fokin the-2 -ylidene)) Sharpless- Fokin catalyst and catalyst the and β commercially-cyclodextrin and β-cyclodextrin ( β-CD available). surfactants(β-CD). named sodium lauryl sulfosuccinate (SLS) or DL-α-tocopherol methoxypolyethylene glycol succinate (TPGS-750-M) giving access to the corresponding triazoles in variable yields (51– 98%; see Scheme 15) [92]. It is important to note that the efficiency of [Cu(IMes)Cl] upon micellar conditions to achieve the 1,3-dipolar cycloaddition between 1-octyne and benzyl azide notably outperforms its catalytic activity using volatile organic solvents such as CH2Cl2 or MeOH, that only produced the desired triazole in ca. 5%. Unfortunately, attempts to make possible the recycling of the micellarScheme catalytic 1 14.4. CuAACCuAAC system mediated mediated proved by unfruitful the Sharpless Sharpless-Fokin and- Fokin the model catalyst triazole and Betaine was in isolated pure water. in only 27% yield. Scheme 14. CuAAC mediated by the Sharpless-Fokin catalyst and Betaine in pure water. Last but not least, the group of Scarso proved that micellar catalysis can be applied to the CuAAC reaction in its three-component version. Thus, the selective coupling of terminal alkynes, Last but not least, the group of Scarso proved that micellar catalysis can be applied to the organic bromides and NaN3 efficiently proceeds using the lipophilic catalyst [Cu(IMes)Cl] (1 mol% CuAAC reaction in its three-component version. Thus, the selective coupling of terminal alkynes, Cu; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)) and the commercially available organic bromides and NaN3 efficiently proceeds using the lipophilic catalyst [Cu(IMes)Cl] (1 mol% surfactants named sodium lauryl sulfosuccinate (SLS) or DL-α-tocopherol methoxypolyethylene Cu; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)) and the commercially available glycol succinate (TPGS-750-M) giving access to the corresponding triazoles in variable yields (51– surfactants named sodium lauryl sulfosuccinate (SLS) or DL-α-tocopherol methoxypolyethylene 98%; see Scheme 15) [92]. It is important to note that the efficiency of [Cu(IMes)Cl] upon micellar glycol succinate (TPGS-750-M) giving access to the corresponding triazoles in variable yields (51– conditions to achieve the 1,3-dipolar cycloaddition between 1-octyne and benzyl azide notably 98%; see Scheme 15) [92]. It is important to note that the efficiency of [Cu(IMes)Cl] upon micellar outperforms its catalytic activity using volatile organic solvents such as CH2Cl2 or MeOH, that only conditions to achieve the 1,3-dipolar cycloaddition between 1-octyne and benzyl azide notably produced the desired triazole in ca. 5%. Unfortunately, attempts to make possible the recycling of outperforms its catalytic activity using volatile organic solvents such as CH2Cl2 or MeOH, that only the micellar catalytic system proved unfruitful and the model triazole was isolated in only 27% produced the desired triazole in ca. 5%. Unfortunately, attempts to make possible the recycling of yield. the micellar catalytic system proved unfruitful and the model triazole was isolated in only 27% yield. Scheme 15. Three-component synthesis of 1,4-disubstitued 1,2,3-triazoles mediated by [Cu(IMes)Cl] and commercially available surfactants (TPGS-750-M or SLS) in aqueous media.

5. Conclusions “Click” criteria has been designed in order to reduce chemical waste production and favor the easy manipulation and isolation of the targeted high-value commodities. Amongst all metal-catalyzed transformations coming into existence upon strict “click” criteria, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) occupies a preferential place, and represents one of the most reliable synthetic tools in organic chemistry, leading to functionalized triazoles in a one-pot manner. This mini review collects remarkable contributions to the CuAAC reaction obeying the “click” criteria and occurring in environmentally friendly solvents namely: glycerol (Gly), Polyethylene glycol (PEG), Deep Eutectic mixtures (DESs) or water. As a general trend, CuAAC reactions can be achieved

Molecules 2020, 25, 2015 14 of 18 using either commercially available Cu-salts or in-house made Cu complexes containing an ancillary ligand, usually under mild reaction conditions. Although less common, different ways to enhance the catalytic activity of simple CuX and CuX2 salts in AACs include: (i) the combination of an organic photosensitizer and green LED irradiation; (ii) the controlled protonation of the Cu2O-catalyst using mild proton sources; (iii) the design of micellar aqueous solutions; and (iv) the use of sonication power or MW irradiation. By using these approaches, more efficient procedures were developed allowing to: (i) decrease the catalyst loadings up to ppb levels providing excellent TON and TOF values (32,000,000 1 and 1,333,333 h− , respectively); (ii) improve the substrate scope; and (iii) achieve the recovery of the Cu-catalyst and perform recycling experiments. In spite of growing interest in the field of CuAAC reactions using novel environmentally-friendly solvents, considerable room is still available for the improvement of this technology using the emerging “green solvents” named glycerol (Gly) and deep eutectic mixtures (DESs) as only a handful of examples have been reported in the literature.

Funding: J.G.-Á. thanks: PhosAgro/UNESCO/IUPAC for the award of a Green Chemistry for Life Grant; and Spanish MINECO (Projects CTQ2016-81797-REDC and CTQ2016-75986-P). Acknowledgments: N.N. acknowledges the CNRS and UPS for continuous support and the Institut de Chimie de Toulouse for the attribution of the ICT Young Investigator Award 2020. Conflicts of Interest: The authors declare no conflict of interest.

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