Huisgen's Cycloaddition Reactions: A Full Perspective

Send Orders for Reprints to [email protected] Current Organic Chemistry, 2016, 20, 000-000

1

Huisgen’s Cycloaddition Reactions: A Full Perspective Majid M. Heravi*, Mehrnoush Tamimi, Hoda Yahyavi and Tayebeh Hosseinnejad

Department of Chemistry, Alzahra University, Vanak, Tehran, Iran Abstract: Huisgen cycloaddition reaction has been originally utilized for the synthesis of 1, 2, 3-triazoles regioisomers. In this review, its stereochemistry and also mechanistical features of Huisgen cycloaddition reaction based on the quantum chemistry are highlighted. Thermal and copper catalyzed approaches to the synthesis of 1,2,3triazoles will also be re-visited. Finally, the synthesis of alternative region-isomer, 1,5-disubstituted-1,2,3-triazoles under ruthenium catalysis and transition metal free conditions is described.

Keywords: Huisgen cycloaddition, 1,2,3-triazoles, quantum chemistry, copper, regioisomers, ruthenium.

1. INTRODUCTION Huisgen cycloaddition reaction that is basically a 1,3-dipolar cycloaddition reaction. It was discovered by Huisgen and his assistants in 1960 [1]. Cycloaddition reaction is a process in which two or more systems combine to form a stable cyclic molecule. In these reactions sigma bonds are formed between the termini of systems without elimination of any segment, and often but not always proceeded via a concerted mechanism. Notably, the Diels-Alder (D-A) reaction has always been considered as a model and symbol of cycloaddition reaction [2] (Scheme 1).

A

B

B C

A

C

+

1,3-Dipolar Cycloaddition 2

1

3

Diels-Alder Reaction

+ 4

2

aromatic heterocycle and their chemistry has been well known. Substituted 1,2,3-triazoles can be synthesized via the 1,3-dipolar cycloaddition reaction of an azide source and alkynes. This reaction basically should give two regioisomers. Huisgen cycloaddition reactions are simple but potent tool for the production of five membered systems such as 1,2,3 triazole, isoxazoles, isoxazolines, pyrazoles, pyrazolones, 1,2,4-oxadiazolines and etc [5-8]. Notably, it was Huisgen himself predicted the non-regioselectivity of 1,3cycloadditions [9]. However, a particular 1,3-dipolar cycloaddition reaction of an azide source and alkynes, currently, is known as a significant strategy for the regio and stereoselective synthesis of 1,2,3-triazoles and their ring-opened acyclic derivatives [10]. The premier example of a click reaction " was the cycloaddition of alkyne 6 with azide 7 to produce the triazole 8, 9 as a mixture of 1,4adduct and 1,5-adduct in which the formation of one regioisomer is predominant [5] (Scheme 2). heat

R

+ N 6

5

Majid M. Heravi

N

N

R'

7

N N

N

These reactions proved to be a powerful tool in the construction of differently sized cyclic systems, including heterocycles. The most familiar of these cycloadditions resulting in, particularly five membered heterocycles, is known as 1,3-dipolar cycloaddition. These particular reactions are also considered as classic reactions in the field of heterocyclic chemistry and especially used for construction of a wide variety of five member heterocycles [3]. An important point which arises for these kinds of reactions is their regioselectivity. The term, regioselectivity, when it is used in organic chemistry refers to the inclination and preference of one direction over all other achievable directions by either the formation or cleavage of chemical bonds. It can often apply to which of many possible positions a reagent may affect [4]. 1,2,3-Triazoles, with two carbon atoms and three adjacent nitrogen atoms are a basic

*Address correspondence to this author at the Department of Chemistry, Alzahra University, Vanak, Tehran, Iran; Tel: +98 21 88044051; Fax: +98 21 88041344; E-mail: [email protected] 1385-2728/16 $58.00+.00

N

+ N

R' N

R

R 8

Scheme 1.

R'

9

Scheme 2.

The regioselectivity of the 1,3-dipolar cycloaddition reaction chiefly is attributed to the electronic and steric effects. Moreover, the effects of metals such as Cu(I) presumably should be considered, significantly. The high regioselectivity of Cu(I)-catalyzed alkyne-azide, 1,3-dipolar cycloaddition (entitled as CuAAC reactions) has been broadly and widely studied during the past decade [11-17, 6]. These types of reactions have the same advantages of reactions that are modular, wide in scope, stereospecific and high yielding, generating only non-offensive by products giving the opportunity to have access to desired compounds. Moreover, they fulfill the concept of “Click Chemistry” [18]. We are interested in heterocyclic chemistry [19-29]. We have currently been engaged in the synthesis of 1,2,3-triazoles via click reaction [30-35]. We have also recently published a review article on Recent Applications of Click Reaction in the Synthesis of 1,2,3triazoles [36]. © 2016 Bentham Science Publishers

2

Current Organic Chemistry, 2016, Vol. 20, No. ??

Heravi et al.

In this chapter, we wish to describe the history, mechanisms, application of a particular and unique reaction called Huisgen cycloaddition reaction. The high regioselectivity of Huisgen cycloaddition reaction, considering orbital coefficients of HOMO-LUMO as well as issues concerning its stereochemistry and also mechanistical and thermodynamical features will also be discussed based on the quantum chemistry approaches. Moreover the recent developments in asymmetric Huisgen cycloaddition reactions will be outlined. Notably, in this chapter, we like to underscore, albeit, briefly, the role of computational studies on the regioselective nature of click reaction.

stereochemistry. The reacting components in the 1,3-dipolar cycloaddition are a three atom entity, a-b-c (1,3-dipole) 5 and a two atom entity, d-e (dipolarophile), which react in a [4s+2s]-fashion to form a five-membered ring 7. The reaction is mechanistically related to the Diels-Alder reaction, in which a four-atom, 4electron component (diene 5) and a 2-electron component (dienophile 8) also react in a [4s+2s] fashion to furnish six-membered compound 9 (Scheme 3) [37,39-41].

2. HUISGEN CYCLOADDITION REACTION: CONCEPT OF CLICK CHEMISTRY

R

A A'

A'

R'

heat

+

A''

The concept of 1,3-dipolar cycloaddition reactions which is known as Huisgen cycloaddition reactions (led to a new approach for synthesizing several heterocyclic compounds) was presented via the monumental and interesting work by Huisgen and his co-workers [37]. Rolf Huisgen born 13 June 1920 in Germany; at the age of 94, he remained dedicated to the University of Munich, where he joined in 1952 attaining emeritus status in 1988. Rolf Huisgen was the first expert who understood the scopes and limitations of 1,3-dipolar cycloaddition reactions [1]. The Huisgen reaction is undoubtedly of paramount significance to the synthesis of a variety of five membered heterocycles. However, due to breaking out of the second world war he had to slow down his research works and only extended them in post-war chemistry departments in Germany and Austria and did not to have the opportinity to circumvent the problem of regioselectivity in 1,3-dipolar reaction). In 2001, an American chemist, K. Barry Sharpless (Noble prize laureate in chemistry 2001) has referred to the cycloaddition of terminal acetylenes and an appropriate azide source as "the cream of the crop" of click chemistry and "the premier example of a click reaction was reported" [38, 18]. As a matter of fact, the click chemistry basically should not be a single specific reaction, but covers the formation of products, especially naturally occurring compounds in which substances are generated via grouping of small modular units. However, the term, Click Reaction, which has been coined by Karl Barry Sharpless, Hartmuth Kolb, and M.G. Finn in The Scripps Research Institute in 2001, is often referred to Cu(I) catalyzed Huisgen type cycloaddition, showing extraordinarily high regioselectivity and giving high yields [39,18]. In other words, it is reasonable to name a reaction, a click reaction which is wide in scope, having no by product or only one that can be removed without cost-effective chromatography, giving high yield, being physiologically stable, and having high atom economy. These reactions should be regio and stereospecific, stereoselective and being done under operationally simple and mild reaction conditions. Besides they could be conducted in easily removable and disposable or benign solvents [18]. After breakthrough of this reaction, much attention has been paid to this important strategy, due to the level of regio and stereoselectivity provided for the synthesized five-membered heterocycles, especially 1,2,3-triazoles and their ring-opened acyclic derivatives. The 1,3-dipolar cycloaddition reaction is a five-atom equivalent of the Diels-Alder reaction for the construction of fivemembered rings. As we mentioned earlier Diels-Alder reaction has always been considered as a model and symbol of cycloaddition reactions, proved as concerted cycloaddition, and hence being stereospecific, confirmed by observation of specific syn or anti-

A

A''

R''

R''

R'

R' A A' A'' R

A' heat

A

A''

+ R''

R''

R'

Scheme 3.

1,3-Dipolar cycloadditions are useful methods for the preparation of five-membered heterocycles. They enable access to polyfunctional compounds with multiple asymmetric centers including multiple stereogenic centers from simple starting materials with high level of stereocontrol. Commonly, 1,3-dipolar cycloadditions are considered as a key step in the total synthesis of many natural products and biologically active compounds [42-44]. The cycloaddition of a variety of 1,3-dipoles and dipolarophiles using different chiral catalysts and auxiliaries is actually a new area of research, while great advancements were achieved and novel strategies to obtain enantiomerically enriched heterocyclic systems have been presented. However, the endeavors for innovation of new synthetic tools, for discovery of unexplored aspects and issues regarding, 1,3dipolar cycloaddition reactions are still in much demand [45]. The 1,3-dipole is a three-atom, 4 -electron system in which 4 electrons are distributed in two filled -orbitals and there is one empty -orbital with a central heteroatoms, which are commonly, oxygen, nitrogen or sulphur. There are wide varieties of dipoles that include a combination of carbon, oxygen and nitrogen atoms within their structures. 1,3-Dipoles can be divided into two different types with the common structural feature that both have at minimum one zwitterionic resonance structure. In 1,3-dipoles of the propargyl anion type, one of the resonance structures has a double bond on the sextet atom and the other resonance structure has a triple bond on that atom. On the other hand,1,3-dipoles of the allyl anion type have the resonance structure containg a single bond on the sextet atom and the other structure has a double bond (Scheme 4) [10, 40,46]. The dipolarophile is a 2-electron that easily reacts with a 1,3dipole in 1,3-dipolar cycloaddition fashion. The more common, electron deficient alkenes, alkynes, carbonyls and nitriles are used as dipolarophiles. Azo, nitros and imines can also act as dipolarophiles. Various C-C dipolarophiles used in 1,3-dipolar cycloadditions, are illustrated in Scheme 5 [42,47]. 1,3-Dipoles can be produced via various methods. As shown in Scheme 6, one of the most common routes is the nitrogen extrusion from an appropriate precursor [48]. Generally, decomposition of an azide is thermody-

Huisgen’s Cycloaddition Reactions


a

b

a

a

Sextet structure

a

a

c

b

b

Octet structure

b

a

c

b

c

a

c

c

b

a

c

Octet Structures

a

Sextet Structures

a

3

b c b

c

b

b

c

a

c

a

b

c b c

Allyl Type

Propargyl-Allenyl Scheme 4. Propargyl Anion-Type Nitrile yides

C

N

cycloaddition was independently reported by the Sharpless and Meldal research groups [49-51].

C

C

N

C

N

N

Nitril Imines

C

N

N

C

Nitrile Oxides

C

N

O

C

N

O

3. MECHANISM OF HUISGEN CYCLOADDITION REACTIONS

Diazo alkanes

N

N

C

N

N

C

Azides

N

N

N

N

N

N

Nitrous Oxide

N

N

O

N

N

O

Azimine

N

N

N

N

N

N

Nitro compound

O

N

O

O

N

O

Allyl type Azomethine ylide

C

N

C

C

N

C

Azomethine imines

C

N

N

C

N

N

Nitrone

C

N

O

C

N

O

Carbonyl ylide Ozone Nitros imine Carbonyl imine

C

O

C

C

O

O O

O

O

O O

N O

N

N O

N

C

N

C

N

O

O

C

Scheme 5.

namically favorable. However, aliphatic azides are not reactive towards basic dipolarophiles, most probably due to their particular high kinetic stability. In this regard, Sharpless and his co-workers paid attention on Cu(I)-catalyzed, Huisgen type 1,3 cycloaddition reactions. Interestingly, after extensive investigations, in 2002, a fruitful, facile and regioselective, Cu(I)-catalyzed azide-alkyne

Fundamentally, there are two reasonable mechanisms that justify the formation of the 1,3-dipolar cycloaddition product (products) a) a concerted pericyclic cycloaddition mechanism, initially proposed by Rolf Huisgen; b) the stepwise mechanism involving the creation of a diradical intermediate, proposed firstly by Firestone (Scheme 7) [37, 52, 53]. Huisgen proposed a mechanism for the 1,3-dipolar cycloaddition which occurs between diazo compounds (1,3-dipolar) and various alkenes(dipolarophilic) [54, 55, 10]. The kinetic studies, solvent and substituent effects and observed stereochemistry, all support the concerted pericyclic mechanism, ruling out the possible stepwise reaction involving the generation of a diradical. The observed high degree of stereospecificity particularly, is a strong proof for the preferable concerted mechanism [10, 56]. Remarkably, the reaction rate is not highly affected by the dielectric constant of the solvent, at least in the majority of 1,3dipolar cycloadditions. The independence of the solvent polarity, the very negative entropy of activation, the stereospecificity and most importantly the observed regiospecificity confirms the formation of very highly ordered transition state [40, 57, 58]. Although this mechanism had been proven by evidence, Huisgen and Firestone have discussed this matter for years. Firestone’s suggestion favored the generation of a diradical intermediate in which the mechanism involves two stages. At first stage, diradical has been created, then electrostatic interactions between them become large enough to influence the formation of the second bond [52, 59]. A condition for such a reaction to take place is certainly dependent on the resemblance of the interacting HOMO and LUMO orbitals, which in turn related to relative orbital energies of both the dipolarophile and the dipole. During the interaction of the LUMO of the dipolarophile with the HOMO of the dipole which is normally increased by electron-withdrawing groups on the dipolarophile, a new bond is formed, whereas electron donating groups on the dipolarophile normally assist the inverse of this interaction [60, 61]. The extent of nucleophilicity and electrophilicity at each terminus can be evaluated using the frontier molecular orbitals, which can be obtained computationally. Generally, the atom that carries the largest orbital coefficient in the HOMO acts as the nucleophile, whereas that in the LUMO acts as the electrophile. The most nu-

4


Heravi et al.

cleophilic atom is usually, but not always, the most electron-rich atom [62, 63]. In the 1,3-dipolar cycloadditions, the identity of the dipole-dipolarophile pair determines whether either the HOMO or the LUMO character of the 1,3-dipole will govern. The practical attempts of several groups, involved in this dispute were more supportive to the concerted mechanism based on the stereospecificity of the reaction. However, the general agreement that, process is a [3+2] (3 atoms + 2 atoms resulting in a 5 atom product) cycloaddition reaction and in terms of orbital symmetry classification, it is classified as a [4+2] cycloaddition reaction analogous to that of Diels-Alder reaction. Ph Me

Me

Rh2(Pfm) 4

N O

Me N2

Ph

N CO2Me O

Me

11

10

REGIOSELECTIVITY:

The synchronicity and regiselectivity of 1,3-dipolar cycloaddition reactions have been rationalized through quantum chemistry calculations [65]. From the electronic viewpoint, in general the orbital coefficients of HOMO-LUMO interaction will specify the regioselectivity. The atoms with the largest coefficients on HOMO and LUMO will combine with each other preferentially and determine the regioselective behavior [66]. The concerted reaction results from overlap of orbitals of one molecule (dipolar) with orbitals of the other (dipolarophile). In the transition state; stabilization chiefly resulted from the overlap between HOMO of one reactant (dipole or dipolarophile) with LUMO of the other (dipolarophile or dipole) in bonding fashion. It should be emphasized that the high electronic interaction and high level of regio and stereospecificity are achieved via unification of HOMO and LUMO, thus regioselectivity is governed by the atoms that carry the largest orbital HOMO and LUMO coefficients [48, 64, 67]. Generally, for dipolarophiles with electron-withdrawing groups; the dipole-HOMO and dipolarophile-LUMO interaction ocuurred dominantly. The vice-versa occurred at dipolarophiles with electron-donating groups. With respect to the principle of maximum overlap, the preferred conformations of isomers can be predicted by unification of two sites of the reactants having the largest coefficient value [68]. Scheme 8 displays perturbation molecular orbital (PMO) diagram as the dipole and dipolarophile approach together en route to the transition state. PMO can help to rationalize more decisively the degree of synchrony of bond formation which may cause the transition state, in addition to creating a model that helps to predict regiochemistry. This PMO diagram can be a useful tool for determining

O

CO2Me O

4. STEREOCHEMISTRY AND QUANTUM CHEMISTRY STUDY

Scheme 6.

The role of solvents and substituents on the rate constants, activation parameters and orientation phenomena in mechanism of 1,3dipolar cycloadditions has been studied. The stereoselectivity was examined using cis or trans isomeric dipolarophiles and a high stereoselectivity observed for each isomer [10]. All experimental results are in agreement with concerted mechanism for 1,3- dipolar cycloaddition. This conclusion can also be supported in terms of molecular orbitals which show that the two new -bonds are formed simultaneously [37]. The FMO theory together with experimental results revealed the high observed stereospecificity for these cycloadditions [64]. In the next section, this issue will be discussed concisely from the computational chemistry points of view. B A B A

C

a C

+ B A b

Scheme 7.

Scheme 8.

CH2

B A

B C

A +

C



H3CO2C

CN S

NC R2C

S

13

CH2

5

CO2CH3

R2C H3CO2C NC

12

S

CH2

R 2C

CH2

+

CO2CH3 CN

NC H3CO2C

CO2CH3 CN

trans 15

cis 14 Scheme 9.

Ph

Ph

C

N

N

Ph

Ph

N

H Ph

Cis

H Ph

16 + Ph

N

18 Ph

Ph Trans

17

N

Ph

Ph

N

H H

Ph 19

Scheme10.

which of two possible HOMO-LUMO pairs is best matched in terms of energy and will consequently have the best overlap and produce the dominant interaction. It has been shown that HOMO-LUMO pair which is the best matched in terms of energy, leads to the greatest energy stabilization as the bonds begin to form. This energy is shown by E1 in Scheme 8 and corresponds to the formation of one of the two bonds. The second HOMO-LUMO pair, which is not as well matched, will provide less energy stabilization as the second bond begins to form. This energy is shown by E2 in Scheme 8. If E1 is equal to E2, then the reaction is synchronous. If E1 is greater than E2 (as shown), the reaction becomes asynchronous. The greater the E1 than E2, the more asynchronous the reaction becomes, with the C-E bond associated with E1 forming faster than the A-D bond associated with E2. Huisgen rationalized that zwitterion formation occurs when E2 is negligibly small and can no longer defray the "entropy price" of the transition state. Under concerted conditions, the summation of the stabilizing energy from bond formation (E1+E2) outweighs the unfavorable S of having both bonds form at once. In the zwitterionic case, the second HOMOLUMO interaction has been reduced and can be negligible. In this case, E1 + E2, no longer outweighs the unfavorable S of having both bonds form at the same time via a highly ordered transition state. It has been reported that by creating a large difference in elec-

tron demand among an electron-rich thiocarbonyl ylide dipole and electron-poor dicyano-substituted dipolarophile, products with mixed stereochemistry will be obtained. The E-alkene dipolarophile afforded both cis and trans products in 94% yield and the 48:52 ratio in which the stereochemistry is clearly scrambled [54,69]. Strictly speaking, there is a large difference in electron demand between thiocarbonyl ylide 12 as a 1,3-dipole added to dicyanosubstituted dipolarophile 13. Thus this cycloaddition can be considered, non-stereospecific (Scheme 9). In Scheme 10, the cycloaddition of cis and trans stilbenes to diphenyl nitrile imine 16 has been illustrated that generates two isomers of tetraphenyl pyrazines 18 and 19, respectively. In this reaction, regioselectivity can be interpreted in terms of HOMO-LUMO interaction between 1,3-dipole and dipolarophile. It should be stated that HOMO of 1,3-dipole with electron-releasing group interacts with LUMO of dipolarophile, predominantly. However, for dipolarophiles bearing electron-donating groups, a considerable reverse interaction occurs between HOMO of dipolarophiles and LUMO of 1,3-dipole. On the basis of principle of maximum HOMO-LUMO overlap, the major isomeric product of reaction can be determined through interaction of two sites of the reactants with the largest coefficient value. In this content, two regioisomers, pyrazoline-3-carboxylic ester 23 and pyrazoline-4-carboxylic ester 24 can be produced. However, the regioisomer 23 as the major product was observed (Scheme 11). Moreover, two substituents compete at withdrawing electrons from the dipolarophile (alkene), in methyl cinnamate. It has been shown that the carboxyl is a better electron-withdrawing group than phenyl. Hence, cycloaddition yields carboxyl group on C3 and phenyl group on C4, regioselectively [66, 70] (Scheme 12). In this light, reaction of a metal-azide PPh3AuN3 28 and a metal-acetylide PPh3AuC CPh 29 affords 4-phenyl-1,5-bis triphenylphosphine gold(I) 1,2,3-triazolate 30 regioselectively and in excellent yield through Huisgen 1,3-dipolar cycloaddition reaction (Scheme 13) [71]. It should be mentioned that these reactions have been well recognized and classified as inorganic click (iclick) reactions. Experimental characterizations such as multinuclear NMR spectroscopy and single crystal X-ray crystallography were conN

NH

N COOCH3

20

N

N +

Ph

C H

C H 21

Ph

COOCH3

H 22

N H3COOC Ph 24

Scheme 11.

23

N

X

H2C

N Ph COOCH3

6


H2C

N

Heravi et al.

H2C

N

N

H2C

N Ph

CO2Me

N

N

Ph

CO2Me

N

N

N

N

N

N

3

4 3

3 CO2Me

Ph

Ph 26

25

CO2Me 27

Scheme 12.

AuPPh3 Ph3PAu

N

AuPPh3

+ Ph

CDCl3

Ph3PAu

N N

N N 28

Ph 29

N

30 1,5 product

Scheme 13.

Fig. (1). HOMOs for 1,5-isomer (a) and 1,4-isomer (b).

firmed using density functional theory (DFT) computations [72,73]. It has been indicated computationally that 1,5-isomer is more stable than 1,4-isomer by 3.3 kcal.mol-1 and the energy difference is due to the broken electronic delocalization in 1,4-isomer. Precisely speaking, HOMO of the 1,5-isomer includes a -bonding orbital delocalized over the two rings (Fig.1a) while in 1,4-isomer, perpendicular rings localize HOMO -orbital on triazolate ring (Fig. 1b). The LUMO orbitals for both isomers embrace high lying * orbitals of the P-aryl species leading to a HOMO-LUMO gap of 2.98 eV and 3.38 eV for 1,5-isomer and 1,4-isomer, respectively. The structural elucidation, obtained from the single crystal X-ray diffraction experiment disclosed the more favorable formation of the 1,5-digold substituted product, over the corresponding 1,4-digold isomer. More importantly, all structural aspects were supported via spin restricted geometry optimization and DFT calculations, using the atomic coordination of the crystal structure as the initial input. In Fig. 2, B3LYP/6-31G** [74] optimized geometry of 1,5-regioisomer has been displayed. It should be noticed that the twist angle between the ring planes of the triazolate and 4-phenyl has been calculated 16º that is in a reliable agreement with the solid state characterization. Furthermore, geometry optimization of 1,4-regioisomer was also performed to assess the origin of regioselectivity (that was illustrated in Fig. 3). Structural analysis of 1,4-regioisomer revealed

Fig. (2). Optimized geometry of 1,5-regioisomer calculated at B3LYP/631G** level of theory.

that the calculated bond lengths confirm reliably crystallographical data of 1,5-regioisomer, but there is a considerable difference within the relative disposition of the triazolate and 4-phenyl ring, so that planes including non-H atoms bisect at 43º and two adjacent Au(I) ions inhibit coplanarity of the rings based on a steric origin.



7

Fig. (3). Optimized geometry of 1,4-regioisomer calculated at B3LYP/6-31G** level of theory.

The regioselectivity of the Huisgen 1,3-dipolar cycloaddition depends on electronic and steric effects. Steric effects can either cooperate with the electronic effects or be in against [67, 75, 76]. In this content, the click reaction between azides and alkynes, which is a remarkable reaction for the synthesis of 1,2,3-triazole proceeds regioselectively, resulting in the formation of the corresponding regioisomers (Scheme 14) [48]. Furthermore, copper-catalyzed azide-alkyne cycloaddition (CuAAC), is one of the best well defined click reactions to date, which has an enormous rate acceleration of 107 to 108 and also high regioselectivity compared to the catalyst-free 1,3-dipolar cycloadditions (Scheme 15). N N

N

Ph

PhO 1,4-triazole major 33

PhO +

N3

31

Ph N

32 Ph

N

N

PhO 1,5-triazole minor 34 Scheme 14.

CuSO4.5H2O R

N3

R'

+

Na ascorbate

R

N N

N

H2O/tBuOH, r.t 1

2

3

R'

Scheme 15.

It is important to state that although the thermal dipolar azidealkyne cycloaddition reaction occurs through a concerted mechanism, computational assessments on metal-acetylide complexes demonstrated that the concerted mechanism is strongly disfavored compared to a stepwise pathway. In this respect, many computational studies are devoted to approve the proposed regioselective mechanism of 1,3-dipolar cycloaddition reaction in the presence of an appropriate catalyst [77-86] through determining the activation energy parameters by the establishment of optimized transition state, calculation of intrinsic reaction coordinates (IRCs) [87] and activation of energies.

The un-catalyzed, 1,3-dipolar cycloaddition reaction between azidobenzene and phenylacetylene has been assessed via DFT calculations at B3LYP/6-311+G* level of theory [88]. Computational results proposed that the activation free energy of corresponding transition state for production of 1,5-disubstituted 1,2,3-triazole is 30.1 kcal mol-1 while the barrier for generation of 1,5-regioisomer is 27.8 kcal mol-1, which is only 2.3 kcal mol-1 lower compared to the generation of 1,4-disubstituted regioisomer and consequently confirms the low regioselectivity of the cycloaddition when is conducted under catalyst-free conditions. It should also be noticed that for presenting a better description for long-range interactions, dispersion contribution has been added into B3LYP functional. In this respect, an atom-atom additive damped empirical potential of the form -f(R)C6/R6, which denoted as B3LYP-D3BJ, was used to give more accurate informations in term of energy [89]. Polarized continuum model [90] was also applied being aware of the solvent effects by single point energy calculations at B3LYP-D3BJ/6311+G* level of theory on the gas phase stationary points. In (Fig. 4), the reaction Gibbs free energy profile is illustrated. As a result, the transition metal catalyzed 1,3-dipolar azide-alkyne cycloadditions, nowadays is well-established and recognized as a powerful methodology for the highly regioselective synthesis of 1,2,3triazoles that leads to improve the reactivity and control the regioselectivity [91-97]. It is worthy to mention that regioselective formation of either 1,4- or 1,5-disubstituted 1,2,3-triazoles through 1,3dipolar cycloaddition, is highly dependent on the kind of metal being used as a catalyst [48,49, 98,99] (Scheme 16). In the copper-catalyzed azide-alkyne cycloaddition reactions (CuAAC), DFT computational results have shown that coordination of Cu(I) to alkyne is more and less endothermic in MeCN but exothermic in water. Interestingly, the coordination of Cu to acetylene, has found no effect on 1,3-dipolar cycloaddition. The concluded rate at room temperature is also reasonable. Ring contraction to a triazolyl-copper derivative upon protonolysis leads to the triazole derivatives along with the termination catalytic cycle (Scheme 17) [77]. In this light, the cycloaddition reaction of O- and Npropargylated compounds with perfluorinated azides has been assessed via DFT approaches from both kinetical and thermodynamical points of view [79]. Furthermore, the observed behavior in [3+2] cycloaddition reaction between N- and O-propargylated thienopyrimidines and alkyl azides have also been construed based on DFT computations at B3LYP/6-31G* level of theory [77]. Based on the kinetical and thermodynamical calculated results, the experimental results in the formation of anti product have been

8


Heravi et al.

G(THF)B3LYP-D3BJ (G(gas)B3LYP kcal/mol N N

N

30.1 (35.0)

Ph

ts

Ph

ts

0.0 (0.0) Ph

-51.7 (-42.0)

Ph

N

ts

Ph

+ N

N N

N

N

27.8 (33.2)

ts

Ph

N

Ph

N

Ph

Ph

N

-49.9 (-38.4)

N N

N

Ph 1,5-disubstituted

1,4-disubstituted

Fig. (4). Free energy profiles for the uncatalytic cycloaddition of phenylacetylene and azidobenzene.

N

R

N

R

[Cu]

N

N

N

N

R

N

N

[Ru]

N

+ H

R'

R'

R'

H

H

1,5-product 1,4-product

4

3 Scheme 16.

R N

H

N

N R'

R'

CuLn-1

CuLn-1

R' N

N

N

R

CuLn R N

R'

N N R'

3

H

CuLn-2 N N

N R

R'

CuLn-2 N N

N

R

Scheme 17.

confirmed and being ascribed to the steric repulsions, arising from the bulky alkyl group attached to azide. Transition states were inquired to be saddle points by survey on one imaginary frequency and consequently, the intrinsic reaction coordinates (IRCs) were followed to accredit the corresponding reactants and products [100,101].

Moreover, the role of dinuclear copper(I) complexes in CuAAC reaction mechanism has been investigated computationally at B3LYP/LACV3P*+ level of theory [73] applying PBF solvent model [102] for water [103]. Accordingly, the energy barrier for a mononuclear route was calculated 17 kcal/mol while the energy of activation for the addition of azide to the dicopper chloride complex


R


N N

Cp* Ru

Cl

L

Cp*

N Cl

Ru

L

N

R

N

R'

N N N

carbon-nitrogen bond is constructed between the more electronegative carbon of the alkyne and the terminal nitrogen of azide. Electrophilic nitrogen of the azide is participating in the formation of the ruthenium-catalyzed azide-alkyne cycloaddition. This step is accompanied with the formation of the triazole via reductive elimination. DFT calculations support this mechanistic pathway and indicate that the reductive elimination step is actually ratedetermining step [78]. The stringent analysis of computational results revealed that the calculated activation energy is changed considerably in the un-catalyzed reaction (30.9 kcal/mol vs 13.1 kcal/mol) in comparison with that of the ruthenium- catalyzed reaction which resulted in the opsite regioisomer, the corresponding 1,5-triazoles, which is in agreemement with the observed increase in reaction rate [110]. It should be noted that all the possible reaction pathways, including intermediates and transition states have been optimized at B3LYP/6-31G* level of theory has discussed in terms of relative energies and in the case of ruthenium, LANL2DZ effective core potential (ECP) [111] has actually been applied. More recently, the regioselective synthesis of 5-sulfenyl triazoles has been reported via iridium catalyzed 1,3 dipolar cycloaddition of azides with internal thioalkynes [97]. This regioselective behavior was then assessed computationally by concentration on the role of catalyst ([(Ir(cod)Cl]2 , (cyclooctadiene denoted as cod) ) in the reaction pathway[112]. In this respect, DFT calculations were performed at M06 level of theory by applying ECP of Hay and Wadt with double- valence basis sets (LANL2DZ) for Ir [113] and 6-31G* basis set were employed for N, S, Cl, Br, O and also C atoms in the triple bonds of alkynes and double bonds of 1,5cyclooctadiene and the 6-31G basis set was used for all other atoms. The reaction pathway for azide-thioalkyne cycloaddition using [Ir(cod)Cl]2 as catalyst was modeled through the following steps: (i) formation of an active complex species in which azide and alkyne substrates are coordinated to the Ir(I) metal center (ii) oxidative coupling between the terminal nitrogen of azide and the methylsubstituted carbon of MeC CSMe 35 to generate the metallabicyclic Ir-carbene intermediate (iii) reductive elimination to give the intermediate, where the cycloaddition product acts as a ligand (iv) ligand substitution of alkyne species for triazole molecule 36 to reproduce the active species (Scheme 19). In (Fig. 5), the com-

R'

+

N R

R' 4 Cp* Cl

Ru

Cp* N

N N

Cl

R

Ru

R'

N

N

R

N

R'

Scheme 18.

was calculated to be 10.5 kcal/mol. In another attempt, the stepwise behavior of bond-forming between carbon and nitrogen has been investigated. The crossover successful experiments with an isotopically enriched exogenous copper source and also the equivalence of two copper atoms were performed within the cycloaddition steps and reported [104]. As a result, it can be deduced that in catalyzed CuAAC reaction, copper(I) acetylide species prefers to aggregate with at least two copper(I) centers [103-106]. On the other hand, it has been found that a ruthenium complex in azide-alkyne cycloaddition reactions (RuAAC) behave as an efficient alternative catalyst which interestingly provides a condition for the reaction to proceed with opposite regioselectivity, thus giving the 1,5-disubstituted triazoles as the corresponding regioisomer [107-109]. Based on DFT calculations, few mechanistic reaction models have convincingly been proposed, focused on the electronic features of the reaction mechanism in which the steric effect can be considered negligible [78,85,86]. In Scheme 18, catalytic cycle of the RuAAC reaction has been represented using CpRuClL2 as catalyst. In the first step, an oxidative coupling of the azide and the alkyne produces a six-membered ruthenacycle, in which the first new R2

S

R

R1

35 + N3

[Ir]

N N

R1

N

R2

S

N

[Ir]

N

R1

R (i)

N S

R

R2

36

R1 R1

R2

N N S

(iii) [Ir]

Scheme 19.

9

N N N

N

[Ir]

R

R

S R2

(ii)

10


Heravi et al.

N L

N N

Ir

N

L

N

L

L Ir

N S

S

Cl Cl B2

B1

6.6 (-7.3)

8.3 (-5.3)

L

L

L Cl

L Cl

Ir

S

Ir S

N N

N

N

N N

B3

B4

8.9 (-5.2)

7.9 (-6.1)

Fig. (5). The four structural isomers of the active species [Ir(cod)Cl(MeCCSMe)(N3Me)]. G(THF)B3LYP-D3BJ phase)B3LYP

(G(gas

Ph

kcal/mol

N

N

N

ts

22.6 (33.0)

ts

Zn

Ph

N

30.6 (32.9)

Ph

N

Ph Zn

ts

Et

N Et

ts 11.0 (7.8) Ph 0.0 (0.0)

N N N Ph

4.5 (7.3)

Zn Et Ph

Ph N N N

N

Et

Et

+ N

Zn

Ph Zn N Ph

N N -45.3 (-31.7)

Ph

N Zn

Ph

Et

1,4-disubstituted

Ph

N N Ph

-39.2 (-26.7)

N Zn

Et

1,5-disubstituted

Fig. (6). Free energy profiles for the cycloaddition of ethyl- (phenylethynyl)zinc and azidobenzene.

plexation of [Ir(cod)Cl(MeC CSMe)] with N3Me molecule has been depicted which has produced the 18-electron [Ir(cod)Cl(MeC CSMe)(N3Me)] species with four possible structural isomers. Based on the above-mentioned mechanism, the potential energy profiles have been calculated and it was deduced that alkyl and arylthio substituent can stabilize the metallabicyclic Ir-carbene intermediate, generated in Ir-mediated azide-alkyne oxidative coupling step in which azide terminal nitrogen attacks to -alkyne carbon and consequently facilitate the reductive elimination to produce 5-sulfenyltriazole as sole regioisomer [112]. In another recent research, zinc catalyzed 1,3-dipolar azidealkyne cycloaddition reaction has been reported. In this work, 1,5-

substituted 1,2,3-triazole was synthesized regioselectively at room temperature under mild reaction condition [114]. The mechanistical features of this regioselective synthesis were investigated via DFT computations. It should be mentioned that the intrinsic reaction coordinates (IRCs) calculations have been performed for zinc mediated dipolar cycloaddition to determine the reaction pathway at B3LYP/6-311+G* level of theory. In (Fig. 6), the computed reaction energy profile for 1,3-dipolar cycloaddition of ethyl (phenylethynyl)zinc and azidobenzene has been shown. It should be noted that ethyl(phenylethynyl)zinc is easily produced from phenylacetylene and diethylzinc. In the first step, ethyl(phenylethynyl)zinc species coordinated to the neutral



11

Fig. (7). B3LYP optimized geometries of transition structures TS-1 and TS-2. The calculated bond lengths have been reported in Å.

The optimized geometry of the corresponding transition states for 1,4 and 1,5-regioisomer (denoted as TS-1 and TS-2) is depicted in (Fig. 7). In TS-1, two carbon-nitrogen bond lengths are 1.96 Å and 2.35 Å, respectively and the calculated distance between nitrogen and zinc is 2.90 Å while in TS-2, nitrogen-zinc bond length calculated was 2.22 Å. This comparison demonstrates that during the formation of neutral nitrogen-carbon bond, the nucleophilic nitrogen still coordinates with zinc. In overall, the calculated results for the reaction pathway between azidobenzene and ethyl(phenylethynyl)zinc demonstrated that the formation of 1,5-diphenyl 1,2,3triazole is faster than 1,4-regioisomer due to a lower activation energy barrier. In order to investigate the interaction between ethyl(phenylethynyl)zinc 38 and azidobenzene 37 more concisely, FMO computations have been performed [115,116]. The molecular orbitals and orbital energies of azidobenzene and ethyl(phenylethynyl)zinc have been illustrated in Fig. 8). The energy levels of HOMO and LUMO for the ground state of azidobenzene were calculated -14.5 eV and 1.4 eV, respectively at B3LYP/6-311+G* level of theory. The calculated energy gap between HOMO of phenylethynylzinc and LUMO of azidobenzene have been obtained 7.3 eV lower than those of between HOMO of azidobenzene and LUMO of phenylethynylzinc. Therefore, in the transition state of dipolar cycloaddition between ethyl (phenylethynyl) zinc and azidobenzene, the reactivity and regioselectivity are majorly depending on orbital interaction between HOMO of azidobenzene and LUMO of phenylethynylzinc.

Energy Level(eV)

2.2eV LUMO -1.4eV LUMO

-6.4eV HOMO -14.5eV HOMO

5. SYNTHESIS OF FIVE MEMBERED HETEROCYCLES 5.1. 1,2,3-Triazoles

Zn 37

N N N

Et

38

Fig. (8). Calculated frontier molecular orbitals for ethyl(phenylethynyl)zinc and azidobenzene molecules. The orbital energies have been obtained in eV.

nitrogen of azidobenzene that was found being endothermic with 4.5 kcal.mol-1. In the next step, 1,5-diphenyl-4-(ethyl)zinc-1,2,3triazole was produced via a concerted way with an overall activation free energy of 26.6 kcal mol-1. In the other pathway, coordination of the nucleophilic nitrogen atom of azidobenzene and ethyl(phenylethynyl)zinc was assessed computationally and it was found that this step is endothermic with 11.0 kcal.mol-1. In the next step, the subsequent cycloaddition generates 1,4-regioisomer with an overall barrier of 30.6 kcal.mol-1.

In general, the synthesis of 1,2,3-triazole based on Huisgen cycloaddition reaction usually occurs via one of the three approaches as depicted in Scheme 20. 5.1.1. Thermal Reactions The importance of Huisgen 1,3 dipolar cycloaddition reactions in the synthesis of 1,2,3-triazole is undeniable [9,10]. In 1883, Michael successfully performed the thermal reaction of dimethyl acetylenedicarboxylate (DMAD) with phenyl azide. It is the first example of cycloaddition reaction between azide and an alkyne [117]. Using such conditions Dimroth and Fester attempted to carry out the direct construction of unsubstituted NH-1,2,3-triazole ring via the reaction between hydrazoic acid 40 (HN3) and acetylene 39 under prolonged heating under pressure in a sealed tube [118]. 1,3Dipolar cycloaddition between hydrazoic acid 40 and a series of acetylene 42 containing alkyl group was conducted in refluxing benzene [119] (Scheme 21). In 2005, Krivopalov and Shkurko pre-

12


Heravi et al.

R1 N3

Thermal

R2

+

N

R2

heat R3

R1 N3

CuAAc

Cu(I) +

R1

N

R2

R2

N

+

N R3

N

R3

N

N R1

R2

N N R1

R1 N3

RuAAc

N

Ru(I) R2

+

N N R1

R2 Scheme 20. Synthesis of 1,2,3-triazole via three different approaches

Me2O , EtOH CH

CH

HN3

+

39

N N

70h

41

40

HN3, benzene 90-135°C, 29-48 h R1

C

N

100 °C

CH

R1 N

14-72%

H

N N H

42

43

R1 = H, Me, Et, Pr, Bu, C5H11, i-C5H11, n-C6H13, n-C7H15, n-C8H17, n-C9H19, n-C10H21 Scheme 21.

HN3

COOH

59

HOOC

N

NH

N

44

NH N

N

In this section, we mentioned significantly to recent Huisgen 1,3 dipolar cycloaddition reactions. Alkynes containing electron withdrawing group(s) generally undergoes cycloaddition with azides 59 to afford 1,2,3-triazole 46 with better yields [121] (Scheme 22). Hydrazoic acid in reaction with 4-(trimethylsilyl)but-3-yn-2one 47 also gives unsubstituted NH-1,2,3-triazole 48 [122] (Scheme 23).Hydrazoic acid is an unstable and explosive compound. Thus, organic azides (trimethylsilyl, alkyl, allyl, aryl) and metal azides are frequently used as alternatives, in the Huisgen 1,3 dipolar cycloaddition reactions. Birkofer and Wegner first reported the reaction of trimethylsilyl azide as the safe synthetic equivalent of the highly explosive hydrazoic acid /sodium azide with acetylenes to obtain 2trimethylsilyl-1,2,3-triazoles 51 followed by hydrolyzing the adduct under mild conditions, to provide alkyl 1,2,3-triazoles 52 in excellent yields [123] (Scheme 24). In 1992, Jenkins disclosed an efficient and facile synthesis of azabicyclic triazole 54 from the reaction of trimethyl silyl azide with the corresponding acetylene 53 [124] (Scheme 25).

46

45

H

N N Me

Scheme 22.

(H3C)3Si

O Si(CH3)3

+

COR

N H

53

sented a review highlighting different routes for the formation of 1,2,3 triazole ring mostly achivead under thermal conditions [120].

R2

49

Consequently, the reaction conditions were changed to improve the yield of products. Cycloaddition reaction between phenylacetylene 55 and dimethylammonium azide 56 gave a mixture of 4phenyltriazole 57 and 5-phenyltetrazole 58 as by-product [125]

R2

N

(CH3)3SiN3 50

54

Scheme 25.

Scheme 23.

R2

N

48

R=H, C2H5, C(CH3)3, C6H5, CH3, CH(CH3)2

R1

2) CH2N2

N N

47

1) TMS-N3 N

HN3

R

N

R2

N R1

N

H2O

N NSi(CH3)3

R1

N

N N

R1

N H

Si(CH3)3 51 R1, R2= CN, COOH, COOR, H Scheme 24.

52



Me2NH2N3 56

Ph

Ph

Ph N

N

DMF 55

13

NH

+

N

N

120°C,10h

N

HN

57

58

Scheme 26. Table 1.

R2 R1–N3

+

R2

N

N N

+

N

N R2

R1

N R1

3

4

R1

R2

Yield3 (%)

Yield4 (%)

Refs.

Ph

Ph

43

52

[141]

Ph

CO2Me

88

12

[142]

Benzyl

CONHBn

65

22

[143]

CF2CFHCF3

Butyl

37

58

[144]

CH2PO(OEt)2

CH2OH

30

69

[145]

4-Tol

Bz

60

11

[146]

CH2CH 2COOEt

COPh

62

38

[147]

Benzotriazolylmethyl

Ph

40

60

[148]

Table 2. R2

R2

R1 DMSO/CH3CN/H2O

R3

NC

R1

R1 NaN3

R3

N

N NH

R2

N

90-120°C, 1.5h

50°C, 24-72h

R3

R4

R4

R4

60

59

61 R1

R2

R3

R4

Time(h)

Yield 61(%)

1

H

H

H

H

48

58

2

H

H

OCH3

H

24

85

3

OCH3

OCH3

H

H

24

80

4

H

OCH3

OCH3

H

24

70

5

H

OCH3

OCH3

OCH3

24

75

(Scheme 26). Remarkably, thermal cycloaddition of azides and alkynes even at elevated temperature proceeds sluggishly, requiring long reaction times (80-120 °C for 12-24 h). Besides, thermal conversion of unsymmetrically substituted alkynes resulted in a mixtures of both 1,4- and 1,5-regioisomers. In fact, by using thermal conditions, the kinetics is relatively low and the regioselectivity is unpredictable. The ratio of the two products depends on the structure of the monosubstituted alkyne (Table 1). Electronic effects of the substituents on the alkynes in the efficiency and facility of these

cycloaddition reactions have been studied. As it can be observed the presence of multi electron –donating substituents on alkyne for the synthesis of 4-aryl-5-cyano-2H-1,2,3- triazoles 61 makes the reaction proceed slower and requiring higher temperature for completion of the reaction [126] (Table 2). The thermally induced reaction of azides (1,3-dipole) with alkynes (dipolarophile) was investigated by introduction of divers substituents including alkyl [120], aryl [127-131], heterocyclic [132-135], carboxyl, formyl, cyano, nitro, benzoyl [136-141,126] substituent on alkynes (Scheme 27).

14


Heravi et al.

R1

R2

NaN3 R1

R2

N

Solvent, heat

63

62 R1:H,

N N H

Ph

R2: CN, NO2, CHO, COOH, COPh Solvent: DMA, DMSO

CN

R

NaN3, DMF,170°C

CN

6h, inert atmosphere

N

N

64

N H

R=H, CN

65

Scheme 27.

X R2 R1

X R1

TMSN3 or HN3 or RN3

R2

N

heat

N N R

X= C, N R1= H, CH3, COCH3, Ph R2= H, NO2, Cl, Br, F, CH3, NHCOCH3 R= H, -CH2CH2COOH, CH2CH2COOCH3 Scheme 28.

O

O N

N O

N

N

N

RCH2N3 37%-64%

66

O

N

N

N

N

N N

CH2R

67

R= CH2OH, HOCH 2CH(OH), HOCH 2(CHOH)CH(OH), CO 2Me, Ph Scheme 29.

Alkynes containing heterocyclic fragments can be used as dipolarophiles in the successful Huisgen cycloaddition reactions [133,134] (Scheme 28). Pyrimidopurine derivatives bearing acetylenic group reacted with organic azides to afford corresponding triazole 67 in moderate yield [149] (Scheme 29). Huisgen cycloaddition reaction between substituted pyrimidine and pyridine containing acetylenic moiety with sodium azide has been conducted, giving the corresponding desired products 69 [132] (Scheme 30). Steel et al. successfully accomplished the synthesis of 4,5-di(2pyridyl)-1,2,3-triazole 71 from the reaction of di(2-pyridyl)acetylene 70 and trimethylsilyl azide [150] (Scheme 31). Synthesis of 4-carbaldehyde-1,2,3-triazole via 1,3-DC between azides and acetylenic aldehydes has been fruitfully accomplished, giving the corresponding triazoles in satisfactory yields [151-153, 122]. Addition of

tropylium azide 72 to propargyl aldehyde 73 in CCl4 under thermal conditions on a steam bath afforded 4-formy1-1,2,3-triazole 74 in 67% yield (Scheme 32). 1,2,3-Triazole bearing formyl group, susceptible for further reaction, synthesized under mild and safe conditions, in virtually quantitative yield upon the reaction of sodium azide with , acetylenic aldehydes 98 in DMSO at room temperature. In this way, the generation of hazardous and explosive HN3 in basic medium during the reaction can be avoided [137, 154] (Scheme 33). Thermal reaction of several internal alkyne 77 with sodium azide was elaborated by Hou and Hung group to produce the corresponding 4,5-disubstituted-1,2,3 triazole 78 [131] (Scheme 34). Some internal and inactive alkynes (for example p-flurophenyl-pyridyl acety-



15

F F N N

NaN3

NH

DMA, 100°C 68

X

N

X

N

R

X=N,C

69

R

R=H,Cl Scheme 30.

TMS-N3 N

N N

N N

N

70

N H 71

Scheme 31.

CHO N

N

N

N

CHO

N CCl4

+

N

steam bath H 72

73 74

Scheme 32.

H O

1) 1equiv nBuLi; THF; -40°C R

1)1.1 equiv NaN3; DMSO; r.t

R

O

R 2) 2equiv DMF; -40°C to r.t; 0.5h 3) Reverse 10% aq. KH2PO4(4equiv) MTBE; 5°C

H 75

2) CH3CN/H2O/0.1% H3PO4

N

N N H 76

entry

R

a

Ph

b

TBSO(CH2)3

c

THPO(CH2)2

d

THPOCH2

e

TBSOCH2

f

n-C4H9

g

4-ClC6H4

h

4-MeOC6H4

i

4-FC6H4

Yield %

>98%

41-61%

Scheme 33.

lene 79) underwent cycloaddition reaction with trimethylsilyl azide under high pressure at elevated temperature [134, 135, 149]

(Scheme 35). 4-Dodecyl-1,2,3-triazole 83 was obtained through thermal and high pressure induced cycloaddition reaction of tet-

16


Heravi et al.

N N

R1

R2

NH

NaN3 Cl

Cl R2

DMF, 170°C, 3-4h, 75-88%

R1

Cl

Cl 78

77 R1=R2=Cl R1=R2=H R1=R2=H Scheme 34.

radecyne with trimethylsilyl azide according to the method as stated previously by Birkofer[155] (Scheme 36). 1-(4-Fluorophenyl)-5(2H-1,2,3-triazol-4-yl)-1H indole 85 also was produced under high pressure and thermal conditions.(Scheme 37). In 2006, Blass et al. reported the synthesis of 2,4-substituted-1,2,3-triazoles 87 from benzoyl acetylene 86 via [2+3] cycloaddition with TMSN3 in DMA as solvent at 110°C [138] (Scheme 38). Insertion of azide anion in the presence of palladium to aryl/benzyl halide produced the corresponding aryl/ benzyl azide 88 which then underwent 1,3-dipolar cycloaddition with alkynoic acid/DMAD 89 under refluxing benzene [156, 157] (Scheme 39). N N N

Me3SiN3, autoclave

NH N

130°C, 48h, 81%

F 80

F 79 Scheme 35.

O

O N

TMSN3, DMA

R

110°C

N

86

87

Scheme 38.

A triple bond conjugated with a Fischer carbene complex undergoes [3+2] cycloaddition reaction with various organic azides regioselectively, leading to triazolyl Fischer carbene complexes. This highly activated triple bond is responsible for accelerating of Huisgen reaction in the absence of catalyst at ambient temperature [158] (Scheme 40). Alkynes containing electron-withdrawing groups undergo cycloaddition to azide in short reaction time. Alkoxycarbonyl, carboxyl, acyl, cyano, aryl, haloalkyl, trimethylsilyl, phenylsulfonyl or phosphonate were found to activate alkynes. Thus such alkynes requiring low temperature when are subjected to Huisgen cycloaddition with azides. Table 3 shows the effects of different EWG on the yield of Huisgen cycloaddition [159]. The effect of carboxylic acid, acyl and amido groups on reactivity of alkynes in cycloaddition reaction is exhibited in Table 4. Acetylene dicarboxylic amide is less reactive compared to acetylene dicarboxylate. Thus, for completing the reaction high temperature is required. For improving the reaction conditions, katritzky et al. employed microwave irradiation in the reaction of acetylene dicarboxylic amide with benzyl azide at 85°C in DMF. The reaction (CH2)11Me

Me(H2C)11

+

TMSN3

autoclave, 135-150°C, 28h

N

N N

50%

H

82

81

83

Scheme 36.

N HN N N

Me3SiN3, sealed tube, 170°C, 24h

N

F 84 Scheme 37.

NH

R

85

F



(OC)5W

OEt

17

OEt Ar +

R'

Ar

n

(CO)5W

neat

N3

R' N

40°C 3-7h

93

92

N N 94

67-89%

n=0,1

Ar=Ph Ar=4-Me-C6H4 Scheme 40. Table 3.

N

Conditions

O +

R

N

R'

N

N

R' N3

N

N

+

OMe 95

R

96

R'

R 3

4

R

R'

Conditions

Yield (%)

CO2Me

p-OMePh

dioxane, 20°C, 10day

94%(3+4)

CHO

p-OMePh

20°C, 30day

95%(3+4)

H

CH(Ph)CH(I)tBu

25°C

90% (3)

CH2OH

Ar

Toluene, 55°C, 7day

49%(3)

CH2OH

p-OMePh

Toluene, 20°C, 60day

90%(3+4)

Ph

Me

benzene, 60°C, 8day

100%(3)

Table 4. N

O R1

N

Conditions

N

R

R-N3 R2

R1

O R2

97

98

R1

R2

R

Conditions

Yield (%)

COOH

OH

Et

reflux, ether, 15min

66%

COOH

OH

p-OMeC6H4CH2

reflux, acetone,36h

84%

COOPh

Ph

CH2CH 2Cl

reflux, Et2O

86%

H

Ph

4-NO2C6H4

reflux, ether

43%

CONH2

NH2

PhCH2

i)DMF, 110°C, 2h or ii)DMF, 85°C MW,30min

time was reduced drastically to give C-carbamoyl-1,2,3- triazole. This reaction was the first example of Huisgen 1,3-dipolar cycloadditions being done under un-conventional heating [160,161,144] (Scheme 41,42). Huisgen 1,3-dipolar cycloaddition reaction can occur between different substituted alkynes and, azidophosphonates 106 for the synthesis of triazoles containing phosphonate functional group 107a and 107 b. In this case alkynyl phosphonate also can be used in reaction with azide ion [146, 162] (Scheme 43). The phosphonate substituent is an activating group but to overwhelmed the steric hindrance due to this group, a higher reaction temperature is mandatory for 1,3- dipolar cycloaddition reaction [145] (Scheme 44).

73% 65%

Phosphorous containing azide such as diethyl -azido-aminophosphonic acid underwent cycloaddition reaction with alkynes to produce a mixture of 1,4 and 1,5-triazoles.When monosubstituted acetylene(R1=H, R2= Bu, CH2Cl, CH2Br) was reacted with azide,the amount of 1,5 regioisomer in the mixture was increased. On the contrary and interestingly by using other groups on acetylene 1,4 /1,5 regioisomer was obtained in 98:2 ratio [163] (Scheme 45). Arylacetylene 111 in the presence of triphenyl phosphine in basic medium produced arylethynyltriphenylphosphonium salts 112 which subsequently underwent cycloaddition with azide ion. The corresponding ylide easily hydrolyzed in aqueous basic solution to furnish the respective l,2,3-triazole. In addition,

18


Heravi et al.

N N3

100 or 101

N R2

N

R

N3

100 or 101

R1

99 100 or 101

O 100) H N H 55°C,120W, 30min

N3 Ph

O

O 101) H

N 85°C,170W, 30min

Scheme 41.

O

O

RHN

103

OEt N

N H

MW,120W, 100°C,1h

R

N

R

O

O

H N

102

OEt

O

O H N

EtO

R

N N

Ph

104

Ph

103

OEt

N

105 O

H N

N

N

O

O

O

O

102 EtO

reflux, acetone 4h

N N

Ph

N3

O

H N

OEt

R= Tolylene-2,4, 57% R=n-C6H12, 40% R=4,4'-C6H4CH2C6H4

R=Ph, 76% R=p-tolyl, 64%

Scheme 42.

(EtO)2OP

(EtO)2OP N

(EtO)2OP

N3

+

R1

R2

N N

N

N

A/ B/C/D 106

R1

R2 107a

R1=PO(OEt)2 R2= Me

R1=

107a:107b

A= neat ,100°C, 60h

93%

75:25

B= LiClO4, Et2O, 168h

12%

93:7

C= MW, neat, 20min

78%

66:34

86%

25:75

85%

44:56

83%

50:50

R 2=

H, COOMe R1= Me, R2= COOMe R1=Ph, R2= COOEt

N

+

D= toluene, reflux, 30-40h

R1 107b

R2

Scheme 43.

triazolyl ylides 114 can be subjected into wittig reaction as well as nucleophilic substitution [140] (Scheme 46). Phosphinylated alkynes underwent 1,3-dipolar cycloadditions with organic azides. The cycloaddition reaction of aryl azides to propynylphosphonates and propynylphosphine oxides was performed regioselectivly in a way that phosphinyl group occupied the 4-position of triazole product [164, 165] (Scheme 47). Heterocyclic -aminophosphonic acids were synthesized via 1,3-dipolar cycloaddition reaction of azides with alkynes. The generated acetylenic Schiff base reacted with different azides to give the products in moderate to good yields. The two possible regioisomers were separated by column chromatography on silica gel. In the cases, where R=Ph, p-H3CC6H4, p-O2N-C6H4 and p-CH3O-C6H4, the cycloaddition reaction

resulted in one regioisomer exclusively [166] (Scheme 48). Electron-deficient alkynes can be added to azides to afford the corresponding 1,2,3-triazoles. Thus, when ethylazidoalkyl-carboxylates reacted with DMAD in THF under reflux, 1 –ethoxycarbonylalkyl- 1,2,3-triazole was provide in satisfactory yield. In a similar way, the cycloaddition reaction of azides 123 with acetylenecarboxylates 124 such as ethyl propiolate, ethyl phenylpropiolate, reacted with acetylenephosphonate and propargyl bromide afforded substituted triazoles 125a and 125b as regioisomers [167] (Scheme 49). Reaction of bis-substituted (diphenyphosinoyl or diphenythiophosinoyl or diphenyselenophosinoyl) alkyne 126 with sodium azide was elaborated by Trofimenko group. Initially the sodium salt of 1,2,3-triazolide 155 upon acidic hydrolysis gave the desired 1,2,3



(EtO)2OP EtO2C

N3

+

R1

THF or toluene

R2

N

N

110°C, 96h

PO(OEt)2

(EtO)2OP

CO2Et

N

R1

+

N R2 109a

CO2Et N R2

N

:

R1 109b

R1=H, R2=Me 75% R1=Me, R2=Me 70%

30 : 70 50 : 50

108

19

Scheme 44.

O

RHN O

O RHN

RHN

P(OEt)2

R1

P(OEt)2

R2

R1

r.t Neat or benzene,reflux 18-312h

N3 R=PhCO, CCl3CH2O2C, PhCH2, CF3CO, PhCH2O2C

P(OEt)2

N N

R2

N

R1

N

+

N

N

R2

O

RHN

P(OEt)2

110a

110b

R1= H, COOMe, Ph R2= Ph, COOMe, COOEt, CH2Br, CH2Cl, CH3(CH2)3, C3H7CHOH Scheme 45.

OH, OX ArC

ArC

CH

(C6H5)3P

CX

ArC

X=Br, Cl

CP(C6H5)3X

ether, 25°C

112

111 YC6H4 ArC

CP(C6H5)3X

+

NaN3

Ar

P(C6H5)3

DMF

H2O, OH

N

N N

N

NaX

N H

113

N

+ (C6H5)3PO

114

Y=H, 4-Cl Scheme 46.

EtO O RO

P

X R1

OR 117 R1=

N3 118

O R1

P EtO

N

N N 119

X

Me, Cl, NEt2, P(O)(OEt)2

Scheme 47.

triazole derivarives 128. Due to less electron-withdrawing nature of PPh2=Se substituents, the reactivity of triple bond in this reaction diminishes in this order: –PPh2=O>–PPh2=S>–PPh2=Se. Consequently, the requisite to heating and reaction time should be vice versa [168-170] (Scheme 50). Acetylenic silyl ketone 129 simply reacted with both aromatic and aliphatic azides to produce acylsilane triazoles 130a, 130b in good yield. Desilylation ocurred in the presence of alkaline ethanol solution to afford formyl triazole 131 [171] (Scheme 51). 1,3-

Dipolar cycloadditions of acetylenic sulfones 132 or 133 proceeded smoothly, both in solution and on polymer supports. The majority of the products were obtained in high regioselectivity and often in satisfactory yield. The regiochemistry and yields of these processes on liquid and solid phases are basically similar. Noticeably, the reactions performed on polymer supports frequently needing longer reaction times [172] (Scheme 52). ,’-Difluoroazides 136 upon treatment with terminal acetylene [3+2] cycloaddition reaction afforded 1,4 and 1,5-disubstituted isomer of triazole 137a and 137b

20


Br

O

Ph N

Heravi et al.

H2 C P(OEt)2

H C

N PTC

Ph

Ph

N

RN3

P(OEt)2

Ph

H2C

120

O

Ph

O

Ph

H C

P(OEt)2

121

Ph

N

R

N i) benzene, reflux, 2-10h

P(OEt)2

H2C

N R

N

H C

N

+

H2C

i)

O

Ph

122a

N N

122b

R=CH2Ph, Ph, p-NO2-C6H4 CH2CO2Et, p-CH3C6H4, p-CH3OC6H4 Scheme 48.

R1

R1 R1

THF R2

+ EtOOC

EtOOC

R3

N3

N

N

+

N

N

EtOOC

reflux R2

T=66°C

36h

R3

125b

125a R1=H R2=R3=COOMe

N

R2

R3

124

123

N

80%

T=66°C 50h 75:25 R1=H R2=H R3=COOEt R1=H R2=Ph R3=COOEt T=110°C 72h 50:50 R1=H R2=Me R3=(EtO)2PO T=110°C 96h 30:70

85% 88% 75%

Scheme 49.

X Ph

P

X C

C

Ph

P

X

X Ph Ph P Ph

+ NaN3

P

Ph Ph

X

X Ph Ph P

DMF

P

Ph Ph

H2O , H N

Ph

Na

126

N N

N

76 -83%

N N

127

128

H

X=O ,S ,Se Scheme 50.

O

O O

reflux toluene +

SiPh3

Ph3Si

RN3

+

SiPh3

N

N N

129

N

N N

R

130b

130a O

R

CHO

Ph3Si

NaOH N

N N

N R

EtOH

N N

R

131 Scheme 51.

[145] (Scheme 53). Reaction between sulfonyl azides 139 and sodium phenylacetylide 138 produced adduct 140. The linear adduct 140 underwent ring-closure isomerization to afford sodium salt of 1-tosyl-5-phenyltriazole 141 followed by hydrolysis afforded the desirable 1,2,3-triazole 142 was obtained [173] (Scheme 54). Hanamoto and co-workers used tributyl(3,3,3-trifluoro-1propynyl)stannane 143 as a dipolarophile in the Huisgen cycloaddition reaction with phenyl azide to provide trifluoromethylated triazole 144 [174] (Scheme 55). Pentafluorosulfanyl groups substituted on alkyne compared with CF3 group have higher dielectric constant and a greater electron withdrawing ability. Hence, the use of SF5

substituent as an alternative for the CF3 was investigated. Reaction of phenyl azide with 1-pentafluorosulfanyl acetylene 148 in the presence or without catalyst led to the desired 1-phenyl-4pentafluorosulfanyl-1,2,3-triazole 149 in good yield [175]. Noticeably, this report is the first Cu-catalyzed “click reaction” employing gaseous alkynes (Scheme 56). Using chiral organoazides 150 in Huisgen cycloaddition reaction with diethyl acetylene dicarboxylate 151 provided chiral triazole 152 [176] (Scheme 57). Reaction of meso dimethyl-,’-dibromoadipate 153 with an equimolar quantity of sodium azide led to monosubstituted product (-azido-’bromoadipate 154), followed by conducting the Huisgen cycloaddi-



R O Me

S

R

+

Bn-N3

O

O S

CO2CH2

N

reflux LiOH, THF for cleavage of polymer

134

132

N

ArO2S

ArO2S

N

R

N

N

+

Bn

Bn

135a

135b

R=Bu Ar=4-MePh 3day 57% 28% R=Bu Ar=X 7day 55% 29% R=Ph Ar=X 4day 40% 46%

R

O X

N

Toluene

21

133

Scheme 52.

R F R

F

F3C

+

N3 F

N

6h, 50-95%

R

F

90-130°C

CF3

N

+

N

FF

FF 137a

137b

R=Ph

1:2

R=Bu

2:3

R=COOCH3

4:1

R=SiMe3

CF3

N N

N

136

F

137a

Scheme 53.

Na

Tos

+

139

138

N

Tos

Na

140

H3O

N

N

N

H

Na Tos

N

N3

Tos

N

N

N N

141

142

Scheme 54.

CF3

i) 2eq .LDEA F3C

Br ii)Bu3SnCl ether, -78 CH(OMe)3 143 +

Ph

N

N

143 57% F3C

Ph N

N 80 - 85oC

SnBu3

N SnBu3

N 144

I2 THF

F3C

Ph N N

I

N 145

Scheme 55.

tion reaction with an acetylenic compound provided the 1,4- and 1,5-regioisomers of bromoadipate 155 which was used for the synthesis of pipecolic acid 156 or proline derivatives 157 [177, 178] (Scheme 58). Huisgen [3 + 2] cycloadditions of chiral ynamides 158 with BnN3 were established by Hsung and coworker in 2006.

The result indicated only 1,4-cycloadduct 159 was obtained regioselectively in good yield [179] (Scheme 59). In 1983, Trybulski et al. reported a facile synthesis of 1,2,3-triazole fused benzazepine 160 via reaction of acetylenic benzophenones 161 with sodium azide in warm DMSO/HOAc. While cycloaddition product was

22


Heravi et al.

[180] (Scheme 60). The thermal-assisted conditions can be also employed for the cycloaddition of azide 164 to trimethylsilylsubstituted alkynes giving spiroacetal-triazoles 165 in satisfactory yield. This reaction needs, being performed under pressure in prolonged heating, thus should be performed in a sealed tube [181] (Scheme 61). In 2011, kloss et al. described the synthesis of 1,5 disubstitued triazole in metal free conditions. In this method, reaction of aromatic azides and TMS-acetylene 166 mediated by water provided the corresponding 1,4 cycloadduct 167 with high selectivity [182] (Scheme 62). In 2008, Jarowski et al. represented Huisgen cycloaddition reaction of 4-azido- N,N-dimethylaniline 168 with some terminal acetylene such as 1-propynaldehyde mediated by methyl ethyl ketone in 30 minute [139] (Scheme 63). An un-catalyzed, one-pot synthesis of 1,2,3-triazole derivatives from the reaction of benzyl and alkyl halides, NaN3 and alkynes has been reported. The reaction of terminal aryl alkynes and (NaN3)

N H TMSN3

N

CF3

+ 146

R'

N R'

SF5

+

CF3

147 Cu(I)

N3

N

N

148

N SF5

149

R' =H ,Ph ,allyl Scheme 56.

exposed to methyl amine for removing of phthaloyl group, ring closure was occured spontaneously. The result indicated when X=Cl in the absence of acetic acid compound 163 was produced

CONH2

CO2C2H5

N

EtOH , reflux ,12 h 150

Ph

+

N

N CO2C2H5

90% CO2C2H5 151

C2H5O2C 152 CONH2

R

N3 150:(s)-11-a-K Scheme 57.

R1 N N3 MeOOC Br

NaN3

COOMe H

H 153

Br

N

O

O

acetone, r.t.

N

N COOH

HOOC

or

N N

N

N H

O O O

toluene

N

N

N +

N Bn

Br 155

O

N N

140°C, 14h Ph

N R

R

Bn

159 R= n-hex 58% R=Ph 53% R=TIPS 90%

Scheme 59.

O O

O

Scheme 58.

158

R1

N

N

156

N

155

O HOOC

N H 157

Ph

Br R2

R2

R1

N

O

O 100%

R1=R2=COOMe

COOH

O

O

Br 154

N

acetylene

O O

R2

N



H N

Phth

N

Phth N

N N

NaN3

O

X

R

DMSO 50 °C for 48h

Y

23

O

X

N

+ Cl

Y

HOAc

O 161 X=H,Cl Y=H,Cl N

rt H 2 h, eN 12 M OH Et

H N

163

162 a R=Phth b R=NH2

N

N

X

Y

160

Scheme 60.

TBDPSO TBDPSO heating or Cu(I) +

O

R1

O

R2

R1 O

O

N3

N N

R2 N

165

164

R1=H R2=TMS 64%(+36%164) 1 R =COOEt R2=TMS 84% Scheme 61.

Me3Si R2

H2O, 85-120°C

R1 N3

SiMe3

R2

N 5-46h

166

N

N

R1

167 high selectivity

R2= aryl, C6F5 R1= H, aryl,n-Bu,C6F5, COOEt Scheme 62.

N

N3

O

N

168 H

N

O Methyl ethyl ketone, 60°C, 30min

N

H

N 169

Scheme 63.

afforded 1,2,3-triazoles (171a) and (171b) in excellent yields. It has been found that, for aliphatic bromides (170) the ratio of 1,4- and 1,5-isomers depends on the length of the carbon chain [183] (Scheme 64). The silylated dipolarophile (trimethylsilyl) acetylene reacted with differently para-substituted phenyl azides, 2azidobenzo[b] thiophene (2- BTA) and 3-azidobenzo[b] thiophene (3-BTA) to give the triazole derivatives. Aryl azides, 2-BTA and 3-

BTA showed similar 1,3-dipolar cycloadditions with (trimethylsilyl)acetylene 173 to afford 1-aryl(or heteroaryl)-4-trimethylsilyl1,2,3-triazoles 174 in virtually quantitative yields [184] (Scheme 65). Terminal and internal alkynes was reacted with -azido amino esters 175 through 1,3- dipolar cycloaddition under reflux in benzene to afford a mixture of regioisomers 176a and 176b [185] (Scheme 66).

24


Heravi et al.

Ph N

N NaN3

Ph R

N

N

+

H2O, 100°C

R

R

170

:

171a R=Bu R=-(CH2)7-Me R=-(CH2)9-Me R=-(CH2)15-Me

Ph

N

N

Br

171b

62% (57:43) 92% (73:27) 78%(100:0) 75%(100:0)

Scheme 64.

Me3Si

25 °C 9-40day ArN3

SiMe3

+

172

neat

N

N

173

N

Ar

174 Ar=p-X-C6H5, 2-or-3-benzo[b]thienyl Scheme 65.

O

RHN O RHN

R1

R2

R1

N

R2

N

OCH3 N

OCH3 N3

R2

N

R1

N

OCH3 N

+

176b

176a

175

O

RHN

Scheme 66.

R2

R1

O

OEt

H2O, rt, 6-12h R1

R2

+

N3

OEt 178

177 R1 = H, R2= COOEt R1=

COOEt

,R2

R1=

H2C

O

N

N

O

N 179

82%

=CH3 O S

67-94%

94% OEt

R2=H

67%

O R1= COOEt ,R2 =COOEt 81% Scheme 67.

Strong electron-withdrawing substituents on alkyne and ring strains can activate the alkyne to undergo Huisgen cycloadditions without using any catalyst at room temperature [186,187]. Cycloaddition reaction bering done under metal free- catalyst conditions, so-called Cu-free click reaction, plays an important role in living cell systems. In 2009, Jewett and Bertozzi documented Cufree click cycloaddition reactions in chemical biology [188]. Electronic and steric effects are important in Huisgen cycloaddition reaction being occurred under mild reaction conditions [39,18]. For example, electron-deficient alkynes successfully underwent Huisgen cycloaddition reaction in the absence of any catalyst at room temperature. Reaction of ethyl 5-azidovalerate 178 with electrondeficient alkynes 177 afforded 1,4-disubstituted [1,2,3]-triazole 179, when Cu(I) catalyst was utilized, the reaction was completed in 1h with high yield [187] (Scheme 67). Arylacetylenes reacted

with an azide in boiling water to afford 1,4-disubstituted 1,2,3triazoles in satisfactory yields. Interestingly, similar interaction between a terminal aliphatic alkyne and azides gave a mixture of regioisomers. Treatment of m-nitroazidobenzene with either aryl alkynes or aliphatic alkynes, gave 1,4-disubstituted 177 derivatives as sole products [189] (Scheme 68). Reaction of cyclooctyne and phenylazide occurs rapidly under un-catalyzed reaction conditions at room temperature [190,191]. The bond angle of the sp-hybridized carbons in cyclooctynes is 160° which is overcome by the activation barrier of distorting the alkyne’s bond angle much easier compared to linear alkynes with bond angle of 120° (Scheme 69). An intramolecular Huisgen cycloaddition reaction was carried out in azidoalkyne 182 to afford a triazole 183 analogue of potent antitumor dehydropyrrolizidine alkaloid [192] (Scheme 70). The 1,3-dipolar cycloaddition reactions



Ar

R

N3

Ar

R'

Ar

N

N

N

H2O, 85 or 120°C

N

N N

+ R'

R

R

R' 180b

180a Ar=Ph Ar=4-OMePh Ar=4-ClPh Ar=4-NO2Ph Ar=Tol Ar=Ph Ar=4-OMePh Ar=4-ClPh Ar=4-OMePh

25

R=H R'=Tol 81% a R=H R'=Ph 97% a R=H R'=Ph 86% a R=H R'=CO2Et 95% a R=H R'=Ph 85% a R=H R'=CH2OAc 63%(15:1)a:b R=H R'=CH2OAc 58%(7.3:1)a:b R=H R'=CH2OAc 93%(2.5:1) a:b R=Ph R'=Ph 36% a

Scheme 68.

of 1,3-bis (2,6-diisopropylphenyl)imidazol-2-ylidene dihydridoboron azide 184 proceeded smoothly with alkynes and nitriles, bearing electron-withdrawing groups under thermal conditions. Novel, and relatively stable NHC-boryl-substituted triazoles 185, tetrazoles 186 were provided in satisfactory yields [193] (Scheme 71). N

R'N3 R

N

R

N R'

R

180°

R 120° N

N

N

R'N3 120°

160° Scheme 69.

A microwave-promoted intramolecular Huisgen cycloaddition has been performed in the synthesis of 1,2,3-triazole fused diben-

zoazocine. For this goal, biaryl-azidoalkyne was prepared by sequential Suzuki coupling/ propargylation, and further reacted intramoleculary to obtain dibenzotriazolo [1,5] azocine 189. When R2= OAc lesser rigidity led to the high yield of the corresponding product [194] (Scheme 72). Rapid intramolecular cyclization of 2-azidoacetamides 190 derived from -chiral propargylic amines using the microwave enhanced Huisgen cycloaddition reaction provided 1,2,3- triazoles 191 fused with dihydropyrazinone in good yield [195] (Scheme 73). We also considered some valuable books covering the synthesis of 1,2,3 triazoles via 1,3-dipolar cycloaddition reactions [196-198]. Owing to some limitation of the early Huisgen cycloaddition, need of strong electron-withdrawing substituent on alkyne, prolonged heating reaction time and difficulties encountered in separation of mixture of regioisomers, the synthesis of 1,2,3- triazoles has always been considered for being developed. The use of transitionmetal catalysts has overcome to some of the above drawbacks. Among the catalysts, examined, the Copper(I) species has been identified as the best candidate for acceleration of Huisgen 1,3 dipolar cycloaddition. Copper catalyzed Huisgen 1,3- dipolar cyTBSO

OH

OTBS

HO N3

N3

181

N

HO

Toluene

N

N

reflux. 24h,59% 183

182

Scheme 70.

R'

N BH2N3 N dipp 184 dipp=diisopropylphenyl

Scheme 71.

NHCBH2

O

dipp

R

N

N

NHCBH2

N +

R'

O

N

O

N N R'

R

R

185a

185b

R'=H R=OMe,Me 80°C 3.5-4h a: 91%,94% R'=CO2Me R=Me 80°C 5h a: 96% R'=CO2Et R=Et 110°C 3h a: 92% R'=CH3 R=CO2Et 180°C 3h a:55% b:23% a/b:80/20 R'=Ph R=OMe 110°C, 7d a:54% b:27% R'=Ph R=Me 180°C 2h a:47% b:39%

26


Heravi et al.

Br

O

R1

Ph

Ph

OTBDMS +

R1

MeO

A/B

R2

N

N3

B(OH)2 186

R2

OMe 187

MeO

MeO 188

N N

OMe

189

OMe

R1=R2=O

A: o-dichlorobenzene, 210°C, 15 min, microwave, 43%

R1=OAc, R2=H

B: DMF, 120°C, 15 min, microwave, 76%

Scheme 72.

O N3

HN

N

N

R

N CH3CN/ H2O : 4/ 1

R' R

microwave , 160 oC ,1h

O

N H

R'

191

190 Scheme 73.

R1 N

N

N

A.CuSO4 .5H2O , 0.25 -2 mol% sodium ascorbate, 5 - 10mol% H2O/ BuOH ,2:1 ,rt , 6 - 12 h

R

N N

N R2

or H

R1

B.Copper metal H2O/BuOH , 2:1, rt ,12 - 24h

Scheme 74.

cloaddition process has emerged as first example of click reaction, a term coined in 2001 by Sharpless and his co-workers resulted in rapid and efficient Huisegn cycloaddition reaction under mild reaction conditions obtaing the desired products regioselectively and in virtually quantitative yields [18, 50]. 5.1.2. Copper(I)-catalyzed synthesis of 1,2,3-triazoles Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) proved to be an important milestone for regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles. Some properties involving enormous rate accelerating (107 to 108 comparing to the un-catalyzed process reactions), compatibility with most functional groups, solvents, and additives and stability to aqueous and oxic conditions make this reaction well-documentd and special [6,77]. Interestingly, Sharpless and Meldal reported Huisgen cycloaddition reaction under copper catalysis independently in the same year (Scheme 74). Meldal et al. achieved and reported a regiospecific Cu(I)catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides under solvent-free condtions. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were employed and fruitfully transformed, via Cu(I)-catalyzed cycloaddition reaction, providing diversely 1,4-substituted [1,2,3]-triazoles in peptide scaffold or side chains [50] (Scheme 75). The sources of active Cu(I) could be achieved directly from Cu(I) salts (iodide, bromide, chloride, acetate) and coordinated complexes such as [Cu(CH3CN)4]PF6 and [Cu(CH3CN)4]OTf [199,200] or Cu(II) salt together with an in situ reducing agent (so-

dium ascorbate) [49] or from in situ oxidation of Cu(0) metal(copper nanoparticles, nanoclusters or copper wire). It is worthy to mention that the so-called CuAAC reaction was comprehensively reviewed, considering several Cu(I) species provided from different sources, under divers conditions [201-203]. Table 5 indicates some diffferent copper source catalyzed two-component reaction between pre-synthesized azides and alkynes. Cu(I) is often the first choice for [3+2] cycloaddition reactions. Most of these catalytic systems are also at work in homogeneous catalysis processes, due to many attempts which have been made to improve reaction conditions and achieving high efficiencies, in recent years. Copper pollution and toxicities, difficulty of separating the catalyst from reaction mixture, the requirement for employing reducing agents and stabilizing ligands are the drawbacks of the homogeneous catalysis in CuAAC reactions. In certain cases, using the heterogeneous catalytic system in click chemistry is preferred being due to the facile isolation and recycling of the catalyst as well as the reaction is being conducted under environmental friendly conditions. Immobilization of the catalytic system on solid supports led to the removal of the catalyst easily from the reaction system, when the reaction is completed. The solid support based on polymer such as Amberlyst 21, natural biopolymer, chitosan, inorganic solid such as silica, clay, alumina and carbon support such as charcoal, carbon nanotube can be selected and used. In addition Cu(0) metal such as copper nanoparticles, nanoclusters or copper wire can be also utilized as a heterogeneous catalyst [203,204]. Immobilized Cu(I) catalysts suffer from oxidation to Cu(II) and/or disproportionation to



O FmocHN

27

O Copper(I) catalysis

FGFG

H2N

FGFG

OH

i.ii,iii R

192

N

193 N

= HMBA-PEGA800

N

FGFG=Phe-Gly-Phe-Gly OAc OAc Me

R=

FmocHN

O

Me AcO

HO2C

H

H2N Bn SPh

i)R-N3, DIPEA, CuI ii)20%piperidine/DMF iii)0.1M NaOH(aq) Scheme 75.

N NBu N N

BuN N N

194

In 2007, Rodionov et al. found and reported the key role of amine ligands, particularly heterocyclic ones (polytriazole and benzimidazole) in accelerating of the rate of Huisgen cycloaddition reaction [209,210].

Bu N N N

Dı´ez-Gonza´lez also focused on using of ligated copper for stabilizing the oxidation state of copper and increase its reactivity in the click azide–alkyne cycloaddition reactions [211]. In addition to ligand and copper(I) stabilizer, organic co-solvent also enhanced the catalytic activity of copper(I), decreased reaction times and improved efficiency of the reaction [212].

Fig. (8). TBTA structure.

Cu(0) and Cu(II). Recent studies revealed that supported Cu(II) catalysts were reduced to Cu(I) species by alkyne via homocoupling reaction [205,206]. Organic solvents, inert atmosphere and prolonged reaction times are vital requirement for these protocols, mentioned in most related articles. However, Fokin et al. utilized polytriazolylamines as copper (I) stabilizing ligands without the requirement for any inert atmosphere and reducing agents. The catalytic activity of copper (I) drastically increased by using TBTA in click reaction [207,208] (Fig. 8).

In recent years, nano particles catalyzed reactions have been developed as a sustainable alternative to conventional catalysis. The high activity and selectivity of these catalysts are the result of high surface-to-volume ratio, another aspect which should be considered is the immobilization of copper(I) salt nanoparticles on highsurface-area supports which permits a higher stability and dispersity of the particles which results in the superior activity and recycling

N

N

N

N N3

N

N

Ph

MeO

MeO

MeO

h, MeOH

CuSO4, NaAsc,DMF

MeO

MW, 110°C, 30min

N 195

MeO

1h

N 196

O

N N

PhN3 CuSO4, NaAsc,DMF

MeO

MW, 150°C, 30min MeO

N H 198

Scheme 76.

O

N H 197

O

N

MeO

MeO

MeO 199

N H

O

O

28


Heravi et al.

N O CuI/Et3N/DMF r.t. ultrasonic

N3 N

n

R

N

O

N N

n

R

O

O 201

200 n=1-4 Scheme 77.

Cl

R

N

N3

Cl R1

[Bmim]BF4 2-7hours 34-70%

202 R=Cl,F R1=Ph, alkyl R2=H, I

Cl

R

R R1

R2

R2 N

N N

R1

+

N

N N

N

203a

203b

major

minor

R2 N

Scheme 78.

properties of the catalyst. Various copper nanoparticles were applied in CuAAC reactions which enlisted in Tables 5 and 6. Microwave irradiation resulting in the enhancement of reaction temperatures not only leads to speed up the reaction rate but also provides cleaner reaction and preventing the sensitive groups and reagents from polymerizations and decomposition [213-215]. See Table 5 entry 1,5,6,8,9,10, 29, 38, 39, 58, 61, 66, 75 and Table 6 entry 1, 26, 29, 33, 34, 37. The fluorescent properties of some 3- and 4-triazolyl-2(1H)quinolones 196, 199 were studied and encouraged Glasnov and Kappe research groups to synthesize these compounds under microwave-irradiation, catalyzed by CuAAC [216] (Scheme 76). Ultrasonic energy and also microwave irradiation have been frequently utilized in the synthjesis of heterocyclic chemistry [216]. Cu(I) catalyzed Huisgen cycloaddition reaction has been observed being accelerated under ultrasonic irradiation in compared with other reaction conditions [217]. See Table 5 entry 39, 54, 55, 56, 63, 80 and Table 6 entry 30. A series of 1,2,3-triazoles 201 were prepared from the reaction of N-phthalimidoalkyl-azides 200 and alkynes catalyzed by CuI in the presence of Et3N under ultrasound irradiation in DMF as solvent [218] (Scheme 77). CuAAC reactions frequently perform in water as a ‘‘green’’ solvent. Ionic liquids (ILs) can also be employed as the alternative environmentally benign solvents in organic synthesis, particularly, when the complete solubility of reactant is required for the reaction to proceed. Zhong and Guo introduced the first ionic liquid mediated Huisgen [2+3] cycloaddition. Reaction between various aromatic azides 202 and alkyne afforded a mixture of isomers 203a and 203b in good yields [219] (Scheme 78). Many other conditions have been used by application of various catalysts which are presented in tabular format in Table 5. Copper-catalyzed azide-alkyne (CuAAC) Huisgen-type 1,3cycloadditions are used in the synthesis of macromolecules, includ-

ing polymer, Peptide, carbohydrate, oligonucleotides, therapeutics, bioconjugates, biomaterials [301-305]. Covalent immobilization of homogeneous catalysts were also one of applications of CuAAC reactions [306]. Organic azides were found to be difficult to handle due to low molecular weight and unstability [307], Thus in situ generation of organic azide via a three-component, one-pot click reaction minimizes the hazards caused by their isolation and handling. In fact, displacement of azide with the corresponding aryl halide is a modified Ullmann-type reaction and nucleophilic substitution in the aromatic ring (SNAr) which has been first demonstrated by Fokin and co-workers. The first in situ organic azides have been generated when reagents upon prolong heating conditions were resulted in a mixture of both regioisomers in the Huisgen cycloaddition reaction [308]. The copper (I)-catalyzed Huisgen cycloaddition reaction has been generally used in multi-component reactions (MCRs) to prepare 1,2,3-triazoles bearing various functional groups. Fokin and co-workers reported a successful approach towards a one-pot synthesis of 1,4-disubstituted-1,2,3-triazole derivatives from the reactions of halides, sodium azide and alkynes under Cu(I) catalysis. Cu(I) was generated in situ in the presence of copper(II) sulfate and sodium ascorbate in mixed solvent of water and tertbutyl alcohol as co solvent. Variously substituted including primary, secondary, tertiary alcohols, ester, carboxylic acid, amide, primary, secondary and tertiary amine, adamantly, sulfonamide and tetrazole on azides or acetylenes were all tolerated against any transformation [49]. In 2004, Fokin et al. presented a convenient procedure for a one pot synthesis of 1,4-disubstituted-1,2,3-triazole 206 with trapping azide, generated from treating of inorganic azide with aromatic and aliphatic halides 204. The substitution is exclusively simplistic when activated halides, such as allylic, propargylic, and benzylic, are used [309] (Scheme 79).



Table 5.

R2 R1

R2

+

R3 N3

N

Conditions R1

N N R3

R1

R2

R3

H

Ph

Methyl dihidropyrimidinone

Conditions

Yields(%)

Refs.

73

[220]

30-90

[221]

83-96

[222]

80-99

[223]

40-84

[224]

92-99

[225]

59-80

[226]

91-98

[227]

75-94

[228]

CuSO4, Na ascorbate, DMF 1

MW, 80°C, 1min

Ph, alkyl, ester, amide

CH2CF3, CH2 CF2 CF2 ,

CuI, Et3N

CH2CF3(CF2)5

CH3CN, H2O, 25°C; 20 h

2

H

3

H

4

H

Ar, alkyl alcohol

Ph, Bn

5

H

Pyrazinone-O-CH2

Ph, Bn

Ph, Bn, alkyl Aryl amine, alkyl alcohol, ester

Aliphatic, Bn, Ar

Nanosized Cu(0),H2O/t BuOH r.t, 2 h Cu nanoclusters, H2O/t-BuOH (2: 1), 25°C; 18 h. Cu wire, CuSO4 .5H2O, MW, H2 O/tBuOH 2.5-15min

6

H

Ar, Alk, alkyl alcohol

7

Et

Et

Bn, phenethyl,

Cu/C, Dioxane, 60°C

1-adamantyl

10-12min, MW,150°C,3min N,N’-bis(2,4,6-trimethylphenyl)-4,5-

Bn

dihydro-imidazol-2-ylidene- CuBr Neat, 48h, 70°C CuI, DIPEA

8

H

Ph, Bn, alkyl Amine, alkyl alcohol, ester

Nucleoside

silica gel MW(95-115°C) 1.5-3min

9

H

CH(Ph)NHCOMe

Ph, Bn

10

H

Alk, Ar

carbanucleosides

11

H

12

H

13

H

Ar, Alk, alkyl alcohol, ester, ketone, amide (CH2)n COOH, N=0-5

Bn, Ar

Bn

CuSO4. 5H2O, NaAsc, t-BuOH/H2O, MW , 125°C, 10min Cu(I) H2O/t-BuOH, MW CuI-USY, toluene, 15 h, rt Cu(OAc)2, Na ascorbate, tBuOH/H2O, rt

>90

[229, 230]

52-78

[231]

90-95

[232]

82-98

[233]

82-97

[234]

57-99

[235]

63-92

[236]

(Cu/AlO(OH)

Ar, Alk, CO 2Et n-Octyl, Bn, Ar Cyclohexenyl, ether, alkyne

n-hexane, r.t 1-24h SiO2–NHC–Cu(I)

14

H

Ar, COOEt, CH2OH

Bn,Ar, aliphatic

Neat, inert atmosphere r.t.0.5–3 h

15

H

16

H

Ph, CO2Me, CH 2OPh,

Bn,CH2 CO2Et,

Cu(I)-Wyoming’s

Alkyne

(CH2)3NHTFA

montmorillonite,CH2Cl 2, r.t.18h

CH(NHR)CF3

Benzyl, benzoyl, alkyl alcohol,

R=Bn, p-methoxy phenyl

alkyl ester

CuI, CH3 CN, rt

29

30


Heravi et al.

Table 5. contd….

R1

R2

R3

Conditions

Yields(%)

Refs.

A:CuSO4/sodium ascorbate, tBuOH17

H

Ph, alkyl, alkyl alcohol, amine

(CH2)nPO(OEt)2 n=1-5

H2O, r.t, 4-6h B: CuI, tBuOH-H2O , 69-91

80-90°C, 8h C: CuI, THF, DIPEA (N,N-

[237, 238]

diisopropylethylamine), 6-7h 18

H

19

H

20

H

TMS Ar,CH2OH,CH2 CH2OH CH2OPh, CH2CH 2CH 2OH,

aryl

Ar, Alk

-Keggin silicotungstate TBA4 a, CH3 CN

4-CH3Bn

1.5-18h

Bn, PMB,

PSCUb

HO(CH2)3OPh

H2O/t-BuOH (1: 4), 25°C3-24h

Ar, Cyclohexyl,

Bn, Ar, cyclohexyl, Allyl ben-

22

H

cyclohexenyl Alkyl

zene

24

H

25

H

Coumarine, Ar

Cyclopropyl, CH2OH, Ar, COOEt, COOMe

Ar, alkyl alcohol, steroid

DMF r.t. 15-45min

1-C8H17

Ph, CH2OPh, CH 2Phth

H

PVP-protected CuNPs

Bn, adamantyl,

H

23

MeOH, H2O

Bn, Ar

21

CH2OH

K2CO3 ,CuSO4 , Na ascorbate,

CuNPs Et3N, THF, 65 °C

CH2CO 2Et Bn, adamantyl, alkyl alcohol.phenethyl

[239]

91-97

[240]

80-99

[241]

82-99

[242]

88-97

[243]

99

[244]

75-89

[245]

>90

[246]

89-95

[247]

72-99

[248]

50-95

[249]

83-100

[250]

72-91

[251]

92-99

[252]

44-87

[253]

92-99

[254]

45-99

[255]

chitosan schiff base-copper(I) triflate complexes, EtOH/H2O (75:25) 25°C, 14h CuII–HTc, CH 3CN. r.t.

Bn, ph

6-12h homogeneous copper–

Ar, Bn, adamantyl, monosacharide, nucleoside

41-85

phenanthroline EtOH or H2O,70°C, 12h copper nanoparticles in

26

H

Ph, (CH2)2OH, CH 2OPh

Ph, Bn

Bmim.BF4/water r.t.10-50min

27

H

28

H

CH2OPh, CH2OH, CO 2Me, Ph,

Bn, (CH2)3OH, CH2CO 2Et,

A21•CuI d

TMS, (CH2)3N

(CH2)3NHTFA

Neat

CH2OH, Ar, Alk, CH2N(CH 3)2

2-Picolyl, methylquinolyl

Cu(OAc)2,tBuOH, rt, 60-120s e

29

30

H

H

CH2OH, pyridyl, CH2NHBoc, CO2Et

Ar, amide, amine, ether

+

+

Si-Lm •Cu /Fe3O 4@Si-Lm•Cu /DwCH2Ph, CH2 CH2OH, adamantyl

BPMA•Cu+ t.BuOH:H2O or neat or MW

Bn, CH2 CH2 CH2OH, t-

CH2OO Bu

Cu3N/Fe3N@SiO 2 Et3N, CH 3CN, rt 12h-5day

Bn, Benzoyl, CH2 COOEt, 31

H

Phenyl, CO2Et,

CH2CN, Ph,

CuSO4. 5H2O, NaAsc, PhCOOH, t-

CH2=CHCH 3

cyclohexyl,

BuOH/H2O (1:2), r.t.3-120min

n-hexyl 33

H,

Ph, CO2Et, CO 2Me, CH2OPh,

COOMe

CH2OAc

34

H

35

H

Ph, CH2OH, CH 2Br, CH2OCOCH=CH2 Ar, Alk, HOC(CH 2)2

Bn, n-C9H17

Bn

Bn, Ar, aliphatic

Polymer-Supported terpyridine Copper Complex, H2O, 50°C h, CuCl2, PMDETAf rt, DMSO120-600min Cu(PPh3)2NO3, r.t. Neat 24-72h



31

Table 5. contd….

R1

R2

R3

Conditions

Yields(%)

Refs.

36

H

Ph

Ar, Alk

Zn/C, DMF, 50°C, 15h

64-95

[256]

37

H

Ph, Phenethyl, Alk, cycloalkene,

Ar, Alk, allyl cycloalkane,

cycloalkane, alkyl alcohol

cycloalkene, CH2CO 2Me

80-97

[257]

50-98

[258-260]

80-86

[261]

86-96

[262]

68-93

[263]

Unsupported CuNPs Et3N/THF, 65 °C. 10-120min A: NEt3, CuBr, DMF, 100°C, 2h

38

TMS

Ph, Ar, Bu

Ar, TMS, COOMe, COOEt, Bu,

B: KOtBu, DMF, 25°C, 24h

Bn

C:MeOH, 120°C, MW, 20min. TBAF/CuI/DIPEA or CuF2 Cu(0) turning, dioxane/H2O 8:2,

39

H

Ph

CH3(CH2) 16

70°C, Oil bath 6h /MW 3h /US 2h/US-MW 2h CS-Cu g, H2O:dioxane 8:2,

CH2CH 2OH 40

Bn, Alk

H Ar, CHOHCH 3

70 °C, 30 min

BTSO2CHF

AgBF4,Cu(MeCN)PF6 TMS

41

Ar, Alk CH2Cl 2, MeOH, 25°C

42

H

Ar, ROCH 2

CH2Ar

43

H

Ar, Alk, CO 2Et

CH2R, Alk

[CuCCPh2]n, H2O, microwave, 100°C, 10min

[264] 66-98

[CuBr(PPh3)], H2O 53-99

[265]

90-98

[266]

68-96

[267]

69-96

[268]

80-99

[269]

76-98

[270]

Or neat, 25°C H 44

Ar, Alk, CO 2Et

Bn, Ar

45

H

-L-Si(OEt)3

Ar, Alk

46

Ag(R1=H)

Ar, Alk

CH2Ar, Alk

47

H

Ar, Alk, CO 2Me

Bn

48

H

Ar, Alk

CH2Ar, CH2Alk

CuI, DIPEA, HOAC, CH 2Cl 2, 25°C CuBr(PPh)3, THF, Et3N, Microwave, 100°C, 5min [Cu(MeCN)4]PF6, 1,10phenanthroline, pyridine CuCl(TPh), Neat, 25°C Cu(I)Isonitrile Complex H2O, 25°C

49 50

H H (R1=Br in product)

CO2H (R2=H in product)

Ar

CuI, Na ascorbate, DBU, DMF

50–94

[271]

Ar

Suger

CuBr, DIPEA, NCS, THF, 25°C

46–81

[272]

45–96

[273]

Cu(OAc)2,H2O, 2-

51

H

Ar, Alk

CO2Me, RSO2

52

H

Ph, CH2OAr

Bn, Alk

Cul, NaOH,MeOH, 25°C

43–94

[274]

53

H

Ar, CO2 R

CH2Ar, Alk

Cu2O, TFA, H2O, 25°C

88–98

[275]

54

TMS

1,3-Dioxin-4-one

Ar, Alk

70–85

[276]

55

H

CH2OH

Ar, Bn

50–90

[277]

56

TMS

5-Pyrimidinone

Ar, Alk

79–88

[278]

57

H

55-98

[279]

86-99

[280]

Ph, alkyl alcohol, Alk cycloalkyl, CO2Me, CO2Et

Bn, n-Octyl

aminophenol,MeCN,25°C

Cul, TBAF, THF, 25°C, sonication, R1 becomes H Cul, PMDTA, THF, ultrasound, 25°C Cul, TBAF, THF, sonication, 25°C R1 becomes H CuHAPh, H 2O, 50-70°C, 8h nano-FGTi-Cu

58

H

Ar

Bn

MW, 120 °C 8-12min

32


Heravi et al.

Table 5. contd….

59

R1

R2

R3

H

Ph, Alk, CH 2CH2 CH2OH

Bn, Alk, cycloalkyl

Conditions Cu@FeNPs H2O, r.t, 12 h

Yields(%)

Refs.

49-93

[281]

38-96

[282]

70-100

[283]

100

[283]

CuFe2O4NPs 60

H

Ar

Ar, CH2 COOEt

2,2'-bipyridine, Et3N, rt-40°C,24-72h CuO NPs/ acetylene black(AB),H2O,

61

H

Ph, Bn

MW

Ph, Bn, CH2OPh, TMS, CO 2Et

10min 62

H

Ph

Bn

63

H

Ph

Bn

CO2Et ,CH2PO(OEt)2 64

COOEt,H

CH2-heteroarylAlk,

Bn, suger

CH2-nucleoide 65

TMS, TIPS

Ph, Bn

Bn

66

H

Ph

Bn

CuO NPs, H2O, 100°C, 10min C:ZnO-CuO hybrid NPs, Ultrasonic, H2O:t-BuOH (2:1) r.t.10min Nanocrystalline CuO Dioxane, 90 °C, 3 h. CuI, NEt3, THF, AgF rt, 5h

[283] 100

62-78

[284]

65-86

[285]

99

[286]

12-99

[287]

82-90

[288]

80-91

[289]

79-90

[290]

92

[291]

69-94

[292]

80-98

[293]

55-91

[294]

54-98

[295]

90-94

[296]

78-99

[297]

Cu/porous glass, Na ascorbate,H2O, MW 100-120°C 67

H

Ph, pyridine-2-yl, Bu

Bn, allyl

Chitj-CuSO4,H 2O,rt, 4-12 h

68

H

Benzoyl

Alk, Ar

[Cu(Im12)2]kCuCl2

[bmim]BF4, 25°C, 10-15 min 69

H

Ph,COOEt, CH2OBn, CH2CH 2OBn

Cu/aminoclay

Bn, Ph

H2O, 60 ºC,1-2 h (polystyrene-1,5,7- triazabicyclo[4,4,0]dec-5-ene/Cu

70

H

RCH2OH

Bn

polystyrene-2-iodoxybenzamide) rt, DMF,12-24h

71

H

CH(OH)COOEt

72

H

Ph, alkyl alcohol, ether

CH2CF3

CuSO4. 5H2O , NaAsc, H 2O, 30 ºC, 2h

Bn, Ph, CH2CONHCH

Cu2O/C,iPrOH:H2O(1:1),

(CH3)CH2Ph

Et3N, 80°C, 2h

Bn, Alk, Ar, 73

H

Ph, TMS, Alk, cycloalkyl, amine,

alkyl halide, CO2Et, alkyl alcohol, amine,

Fe3O4/Si

[CuI] or [CuI(IAd)]lH2O, r.t-40 ºC,18h

cyclohexenyl 74

75

Ar H,CO2Me, TMS

BF3K

Ar, Alk

Alk, Ar, alkyl alcohol, Ar, CO2Me

Bn, n-decyl

Hydroxy propyl, acetoxy propyl

76

H

Ph

77

H

Ph, CH2OH, COOMe, Bu

Bn,1-adamantyl, Alk, benzoyl, cyclohexyl

CuI, H2O 60°C Cu/porous,glass, H2O, MW, 10 min, 80°C CuI /CuNPs /copper turnings, PEG2000, 70 °C PS-C22-CuIm, H2O, r.t.



33

Table 5. contd…. R1

R2

R3

Ph, Cy, alkyl, alkyl alcohol,

78

H

79

H

Ph, Bn

Bn

80

H

Ph

quinolyl

Conditions copper(I)oxide nanoparti-

Bn

amine

cles(Cu2ONP) glycerol, 100°C,2h Cu/APSiO2 n, THF, RT CuSO4. 5H2O, NaAsc, [bmim][BF4], Sonication, 1.5h

Yields(%)

Refs.

91-97

[298]

99

[299]

94

[300]

a

[-H2SiW10O36 Cu2(μ-1,1-N3)2Ar b Ionic polystyrene-Supported Copper c copper–aluminum hydrotalcite Amberlyst supported CuI e Lm=2-picolylamine(PMA), histamine (His), bispicolylamine(BPMA), bispyridylamine(BPA), , g N,N,N,N,N-pentamethyldiethylenetriamine, h crosslinked chitosan Cu(I), hHydroxyapatite-supported copper(II) ,I ferrite-glutathione , j chitosan ,k IM= imidazol l(IAd = 1,3-di(adamantyl)imidazol-2-ylidene), mPolystyrene resinsupported CuI-cryptand 22, n Aminopropyl-silica-supported Cu nanoparticles d

R1 X

CuSO4.5H2O NaN3

+

+

R2

204a-d

206a-d

sodium ascorbate DMF/H2O(4:1)

205

Br

Cl R1 X :

Cl Cl

204a N Ph

I

Cl

N

Br

204c

204b

Br

N

204d

N

N N Ph

Product:

N

N

N

N

N

N

Ph

N Ph

N

N

S

N

N

N

N N

206b

206c

206a

N N

Ph

N Ph

N N 206d

N Ph

Scheme 79. N X

Fe

N N

NaN3, [bmim][BF4]/H2O Fe CuI, Na2CO3

207

208 X=Cl, Br

209

N I

N

NaN3, [bmim][BF4]/H2O

Fe

N

Fe 210

L-Proline, CuI, Na2CO3 211

212

Scheme 80.

Another copper(I) salts such as CuI, CuOTf.C6H6 and [Cu(NCCH3)4][PF6] can also catalyze the cycloaddition reactions, while these Cu(I) salts frequently require a nitrogen base/ligand or co- solvent to prevent Cu(I) from oxidation or disproportionation [310]. Díez-González categorized the ligands used in CuAAc reactions, into 4 groups. Nitrogen-based ligands, phosphorus-based ligands, carbon-based ligands and sulfur-based ligands. Et3N, DIPEA and polytriazole are the most common base/ligands, applicable in CuAAC reactions [311]. Cu(I) can be generated in situ from Cu(0) in the presence of Cu(II) as an oxidant and reaction took place under assisted microwave irradiation [312].

In 2006, Liang proposed a three component reaction of sodium azide, various halide 208 and terminal alkynes 207 in [bmim][BF4]/H2O inthe presence of copper(I). Alkyl, benzyl and phenyl halides were easily produced the corresponding triazoles 209, nevertheless phenyl iodide 210 needed the addition of 20% Lproline 211 at 65 °C to afford the desirable triazoles 212 [313] (Scheme 80). Several methods have been developed for in situ generation of the organic azides via three-component reaction of appropriate halide, azide and alkyne, as summarized in Table 6. 2-Pyrrolecarbaldiminato–Cu(II) 215 complex not only acts as an efficient catalyst for the synthesis of 1,4-disubstituted-1,2,3-

34


Heravi et al.

Table 6.

R2 N

Conditions R1 X

+

R2

R3

+ NaN3

R3

N N R1

R1

1

Bn, Methyl, Phenethyl

R2

R3

X

Ar

H

Cl, Br, I

Conditions

Yield (%)

Refs.

84-93

[312]

52-98

[313]

43-98

[314]

40-92

[315]

85-96

[316]

80-91

[317]

70

[318]

71-91

[319]

72-81

[256]

28-98

[320]

76-99

[321]

21-97

[255]

48–71

[322]

65-85

[323]

75–84

[324]

61–100

[325]

9–63

[326]

Cu(0),CuSO4,MW H2O-tBuOH, 10-15min CuSO4.5H2O, NaAs,L-

2

Ar, Vinyl

Aliphatic, aromatic

H

Cl,Br, I

Proline, Na2CO3, DMSO:H2O 9:1, 60°C

3

Ar

Ar,CH2OH, TMS, CH2CH 2CH 2CN, CH 2TMS

CuI, Na ascorbate H

Br,I

DMSO:H2O 5:1 CHDAa25°C or 70°C,1.5-16h

4

Alk, allyl

Ar, Allyl

H

Cl, Br,I

Cu–Al2O3 NPs, r.t, H2O

5

Bn

Ar, -CH2OH

H

Cl

H2O, 55-100°C

CuX(Cl, Br)

10-12h 6

-CH2COOEt

Aryl, Sulfonamide

H

Br

7

Ar

Bu

H

I

Bn,Alk,vinyl,

Ar, Alk, Alkyl alcohol, aza-

8

Ether, azacrown ether,

crown ether, methoxy an-

H

Br, Cl, I

Phenethyl

thra-9,10-quinone

Bn, 2-ClBn

Ph

CuSO4, Na ascorbate, H2OtBuOH CuI, DMEDA DMF,22°C, 2h, R-I Cu/C, H 2O,100°C 0.5-20h Zn/C, DMF, 50°C

9

H

Br, Cl 15h

10

Bn, allyl,Alk, adamantly, ester,benzoyl

Br, I,

Cu-USY, water, inert atmos-

Cl,OTs, OTf

phere, 90°C, 15h

H

Cl, Br, I

Cu NPs /C, H 2O,70°C,3-10h

Ar, Alk,alkyl alcohol

H

Ph, TMS,CH 2Phth, CH2 OPh

Bn, benzoyl, Allyl, Alk 11

methylacetate, 3-ethyl1H-indole

12

Bn, Ar, Alk

Ar

H

Br

13

2-Thiazolyl

Ar

H

Br

14

-CH(Me)COPh,

Ph

H

Br, OTs

Ar, ArCONHR

H

OH

-CH2COPh, -CH(Et)COPh

Cu(PPh3)2NO3, H2O, PTC,r.t-60°C 14h CuI, DMDAb,DMF CuI, H2O or H2Oacetone(1:1), 8-12h, r.t. Tslmc ,TBAId

15

PhSCF2 CH2

Et3N, DMF, 100°C CuSO4.5H2O 16

Ar

Ph, Alk

CO2H

I

sodium ascorbate tBuOH,H2O, 65°C CuSO4

17

Ph(CH2)2

Hydroxypiperidine

H

Br

sodium ascorbate CHCl3



35

Table 6. contd…

R1

R2

R3

X

Conditions

Yield (%)

Refs.

18

Bn

Ar

H

Br, Cl

Cu-CPSILe, H2 O, r.t

80-98

[327]

19

Bn

Ar

H

Br, Cl

Cu-PSILf, H2O, r.t

92-98

[327]

20

Bn

Ar

H

Br, Cl

CuO/SiO2, H2O, r.t

52-98

[327]

21

ArBF3K

Ar, Alk

H

Br, I

65–98

[328]

61–88

[329]

76-99

[330]

70-95

[331]

82-91

[332,333]

89-96

[334]

83-96

[335]

45-99

[297]

88-98

[336]

80

[337]

89-92

[338]

71-91

[34]

48

[295]

CuBr DMDA, Cs2 CO3 DMSO, 90°C CuSO4.5H2O

22

Ar

Ph, Ar, Alk

H

N2X

sodium ascorbate t-BuOH, H2O, 25°C CuNps/C, H 2O or

23

Bn, Ar, Alk vinyl, benzoyl, , cyclhexyl

Aliphatic, aromatic, TMS

H

Br,Cl, I

H2O-EtOH (1:1), 70-100°C, 3-8h

CH2-O-Steroide CH2-O-Cyclohexyl CuNps/C,

CH2OCH(CH3) 24

H

Bn

Br

COOMe,

H2O, 70°C 8-16h

CH2ONH(Ph) COMe CH2-COPh, CH2 COR 25

CH2-CO-NR2 CH2-COOR

Ph, amine, Alk alcohol

H

Br

H

Br, Cl

P4VPy-CuI, water, reflux. 2570min

R=Alk Ph, CH2OH, CH 2OPh, 26

Alk, Bn

CH2morpholine,

MNPs–CuBr

4-CH2OH-C6H4 COOCH2

H2O/PEG, 80°C, MW, 1528min

Alk,Ar,CH2OPh 27

Bn, methyl acetate

CH2SPh,Heteroaryl

H

Br

H

Cl, Br, I

H

Br

Cellulose-CuINPs, H2O,70°C

CH2-Phth 28

29

Bn, Alk 1-adamantyl, benzoyl, Cy

Alk, Bn

Ph, CH2OH, COOMe, Bu

Ar, CH2OH, Phenoxy methyl

Bn, Allyl, Alk cyclohexyl

Bu, Phenoxy methyl, methyl

H2O, r.t. 15-21h CuBr on graphene oxide/Fe3O4, 80°C, H2O,MW,525min DHMCh/ Cu(OAc)2. H2O

Ar,CH2OH, CHOH(CH 3)2, 30

PS-C22-CuIg

H, Ph

Br, Cl, I

benzoyloxy

a: r.t/sonication b: reflux,0.25-15h CuOCeO2-Amberlite-

31

Bn, benzoyl, methyl acetate

Ar

H

Br

supported azide EtOH, reflux 45-120min CuI-NPs-modified

32

Bn, benzoyl, CH2OCO 2Me

poly(styrenecoAr, CH2OH, COH(CH3)2

H

Cl, Br,I

maleic anhydride) H2O, reflux 20-145 min Cu/porous glass

33

Bn

Ar

H

Cl

H2O, MW, 100 °C, 10min

36


Heravi et al.

Table 6. contd…

R1

R2

R3

X

Bn

alkyl alcohol, cyclohexenyl,

H

Br, Cl

Aromatic, Aliphatic

H

Br, Cl

Ph, Bu, Hex

H

Conditions

Ar, Alk, 34

36

Bn, Heterobenzyl

alkylhalide, CH2CO2Et

37

38

39

Bn, allyl, Et, Bu,4OMeBn

Cl, Br

Ph, CH2OH

H

Br, I

H

Br

Ph,CH2OH,

CH2Ph, CH2 COPh

C(CH3)2OH

[340]

48-98

[341]

83-98

[342]

91-97

[343]

83-93

[344]

CuNPs@agarose H2O, 40°C, 8h

F4 H

81-96

100°C, 3.5-10h

B(OH)2N2+B

Alk, Aromatic

[339]

Cu(II-PBS HPMO)j H2O,

-

Bn, Alk

52-95

10min

Br, Cl,

Bn, Alk, Phenethyl,

Refs.

Cu/SiO2, H2O, 70°C, MW,

cycloalkyl alcohol, COOEt 35

Yield (%)

OSPs-CuBri H2O, MW, 70°C, 15min SiO2–Cu2O, H 2O, rt, 2-8h Nano Fe3O4@TiO2/Cu2O H2O, reflux, 15-25min

a 1,2-cyclohexyldimethyl amine bN, N’-dimethylethylenediamine, c N-(p-toluenesulfonyl)imidazole, d tetrabutylammoniumiodide , ecross-linked polymeric ionic liquid materialsupported copper, f imidazolium-loaded Merrifield resin supported copper, g Polystyrene resin-supported CuI-cryptand 22, h 7,8-dihydroxy-4-methylcoumarin, i oyster shell powders (OSPs)-supported CuBr catalyst, j Cu(II) porphyrin bridged silsesquioxane bridged hybrid periodic mesoporous organosilica

Cu(II)-complex (CH2Br)n

+

NaN3

215

Ph

+

N N

H2O, 24h, 60°C 214

213

N Ph n

216

n=2,3 Scheme 81.

triazole but also accelerated the formation of di/tri-triazoles 216 in water at room temperature [345] (Scheme 81). The first one-pot transformation of inactivated olefins into 1,2,3-triazoles was reported by Alonso and co-workers. In this approach , two sequential reactions, including the ring-opening of in situ generated episulfonium ions by the azide anion and the reaction of the in situ generated azides with alkynes catalyzed by CuNPs/C were observed [346] (Scheme 82). R1

1)CuNPs/C Me2SSMeBF4 NaN3, MeCN, r.t, 1h

R2

2) R3C

217

CH, 70°C

16-24h

R1

SCH3

R2

N N

R3 N

218 19-91%

Scheme 82.

In 2004, Ramachary et al introduced regiospecific organo/CuI catalyst for one-pot synthesis of 1,4-disubstituted 1,2,3-triazoles through Wittig/Knoevenagel/Diels–Alder/Huisgen cycloaddition reaction Sequences. In this procedure, dispiro[5.2.5.2] hexadecane was formed in situ during reaction of phosphorane 219, benzaldehyde 220 , spirolactone 221 under proline catalysis followed by Cu catalyzed further reaction of dispiro intermediate 222 with benzyl azide to provide predictable spirotrione-1,2,3-triazole 223 in 90% yield [347] (Scheme 83)

Afterwards, Ramachary et al. in continuation of their work elaborated a one-pot synthesis of polysubstituted triazoles 228 through Friedel–Crafts alkylation/Huisgen cycloaddition reactions of 2-naphthol 224, 1-prop-2-ynyl-1H-indole-2,3-dione 225 and bisazido benzenes 226 under dimethylamino-ethanol 227/CuI organocatalyst [348] (Scheme 84). Terminal alkynes similar to organic azides can be prepared in situ. This corresponding alkyne can be generated in situ from deboronation of the potassium trifluoroborat-alkyne [294](Table 5 entry 74), desilylation of TMS-alkynes [258-260] (Table 5 entry 38), decarboxylation of alkynoic acids [325] (Table 5 entry 16) and Seyferth–Gilbert homologation reaction. In situ generated terminal alkyne, coupled with CuAAC gives 1,2,3-triazole from various aldehyde as precursor in a one-pot fashion [349] (Scheme 85). One pot reaction of vinyl halide 233a with organic azide 234 in basic condition led to access to terminal alkynes intermediate which afforded 1,5-disubstituted-1,2,3 triazoles 235. Aryl vinyl halides 223b were reacted with aryl azides more conveniently in comparison with alkyl vinyl halide [350] (Scheme 86). Reaction of an o-(trimethylsilylaryl) triflate 226 with either CsF or KF/18-Crown-6 was achieved via benzyne intermediate 227 which underwent cycloaddition with azides at room temperature in 18h [351] or 0.25-0.50h [352] (Scheme 87). Microwave assisted one-pot reaction of O-(trimethylsilylaryl) triflate 226, primary halide 229 and azide has been reported. In this



N

O

N

O N

R O

Ph P 219

O O

L-Proline EtOH 65°C, 3-12h

ArCHO

Ph Ph

O O

R-N3

O

O

+

O O

O ArCHO

CuSO4, Cu rt, 15-48h

O

220

O

O

O O

N

O

221

O

N N

223

222

R=Bn 90% R=CH2COOEt 80% R=1-Adamantyl 90% Scheme 83.

HO

1) O

N 227

OH

CH2Cl2 O

HO HO

O

O

25°C

N 2)

225

224

OH OH

N3

N

N

EtOH CuSO4, Cu 25°C, 2-3h

N

N

N 226

228

Scheme 84.

O

O + R2

H

K2CO3 MeOH/THF

O P

OMe OMe

Me

N

R1

R1 N3

58-92%

or

R1=Bn, amino acid, nucleoside, glycoside R2= aryl, aryl boronate

R1

NH2 +

O N N

S

HCl

N3

O Scheme 85.

KOtBu

Br R1 R1=alkyl R2 =aryl

Scheme 86.

+

R2 N

R2 N3 224

223b

R2= aryl

N N

DMF or THF

223a

N

N

CuI

N2

N N

N

N3

R1 225 30-96%

R2

R

37

38


Heravi et al.

Z TMS

N

BnN3, CsF

N

Z

Z

N

MeCN, rt, 18h

OTf

Bn

228

228a 228b 228c 228d

4,5-Me2 4,5(OMe)2 4,5-F2 3-OMe

71% 71% 56% 78%

226 BnN3

F

Z 227 Scheme 87.

CsF, MeCN MW, 20min, 125°C

TMS R

X

+

NaN3

N N

Z

+ Z OTf

N

or KF/18-crown-6, MeCN MW, 20min,125°C

230

226

229

R

63-88% Z= H, 4,5-F2, 3-OMe R=Bn Scheme 88.

N

NH2

N

1) t-BuONO 232, TMSN3 MeCN, rt, 1h

N NH2

OMe

2) t-BuONO, MeCN MW 150°C, 15min reflux 15h

233 COOH

231

234 or

TMS

CsF, rt, 15h OTf

OMe

reflux: 75% MW: 86% r.t: 67%

Scheme 89.

reaction, both organic azide and triple bond generated in situ, which produced corresponding benzotriazole 230 [353] (Scheme 88). Moses et al. reported in situ generation of benzyne from o(trimethylsilyl)aryl triflates which reacted with anthranilic acid 233. In addition, organic azide also generated in situ from transformation of amino compounds 231 in reaction which reacted with diazo transfer reagent 232. Ligation of azide to benzyne occurred under microwave irradiation to give 234 but in shorter reaction times [354] (Scheme 89). 5-Cu(I)-1,2,3-triazole 240 was introduced as the intermediate of CuAAC reaction. Several efforts have been made to trap the latter by an exogenous electrophile (E+) to generate 1,4,5-trisubstituted 1,2,3-triazoles [355] [92]. Synthesis of 1,4,5-trisubstituted 5-halo1,2,3-triazoles 237 through Huisgen azide-alkyne cycloaddition reaction has been developed. 5-Halo-1,4-disubstituted-1,2,3-triazole is an attractive intermediate for further transformation into a range of functional groups. Wu group proposed an interesting approach to regiospecific synthesis of 1,4,5-trisubstituted 5-iodo-1,2,3-triazole

in the presence of iodine monochloride. In this protocol cuprate– triazole intermediate 238 was generated and trapped by iodonium ion to accsess the corresponding trisubstituted triazole [356]. The proposed mechanism was shown in figure 9. Other methods to produce 1,4,5-trisubstituted 5-iodo-1,2,3-triazole including reaction of 1-halo alkyne 235 with azide 236 was carried out in the presence of various catalyst were depicted in Table 7. A new cascade reaction of 1-copper(I) alkynes 239 with azides (cycloaddition) followed by NCS electrophilic substitution was accomplished as a facile and effective method for the preparation of 1,4,5-trisubstituted 5-chloro-1,2,3-triazoles 241 [366] (Scheme 90). However, in the similar conditions, when NBS or NIS was used, the click reaction failed. Copper-catalyzed chemo and regioselective cycloaddition of organic azides 242 to aluminum acetylides 243 produces aluminotriazoles 244. The carbon-aluminum bond amenable being occupied by various electrophiles and easily generates 1,4,5trisubstituted triazoles 245 [82] (Scheme 91).



39

Table 7. N

catalyst R1

X

R2

+

N R2

N

N3 R1

235

a;

Y

236

237

X

Catalyst

Refs.

H

CuI-ICl Y=I

[356]

I

CuI-NBS

[357]

I

CuI-DMAP

[358]

I

CuI/TTTAa or TBTA

[359,360]

I

Cu(ClO4)2·6H2O-NaI

[361]

I

Cu(ClO4)2·6H2O-TBTA-alkali iodide

[362]

b

I

PTA -iminophosphorane Cu(I)

[363]

H

Cu (CH3CN)PF6, DIEA, NMO

[364]

Br

CuBr, Cu(OAc)2

[365]

H

CuBr-NCS

[272]

TTTA: Tris((1-tertbutyl-1H-1,2,3-triazolyl)methyl)amine PTA : 1,3,5-triaza-7-phosphaadamantane

b:

R1

In addition, by employing an aerobic oxidative coupling protocol, Cu/triazole complex was promisingly trapped by Hphosphonates as nucleophile scavenger in a controlled fashion to create various 1,2,3-triazolyl-5-phosphonates 249. It is a good example of the direct buildup of a Csp2-P bond at ambient temperature via aerobic oxidative coupling processes. This CuAA[P]C approach shows several advantages, such as a high regioselectivity and effectiveness, mild reaction conditions, and tolerance to a broad range of substrates carrying delicate functional groups. The CuAA[P]C via direct incorporation, dedicates P as an associate to convey a “Click Reaction” to proceed more smoothly, readily and cleanly via direct incorporation of as a “click reaction” to afford structurally stylish phosphorus compounds [367] (Scheme 92). A rapid and regioselective synthesis of 1,2,3-triazoles at low temperature has been reported. Reaction of organic azides and propargyl cations 251 created in situ by acids, afforded fully substituted 1H-1,2,3-triazole 254 at ambient temperature but also at -90 °C. Both terminal and internal alkynes, as well as sterically bulky substituents can successfully be used in this reaction leading to the desired products in good yields. Different kinds of three-

I 1

R1

I (LnCu)++

N

N N

R2 R2

R1

I

N

CuLn

N

N

1

R2

N

N

R1

X N

LnCu

LnCu R1

N

N

N

R2 X 238

Fig. (9). Mechanism reaction of 1-halo alkyne with azide.

N PhC

N

BnN3

CCu

N

Bn

Cu Cu

Ph

N

NCS

N

Bn

Cl

Ph

Cu(I)

239

N

241

240

Scheme 90. R2 R1 N3

242

+

R2

AlMe2 243

CuI PMDTA toluene RT, 48 h

R2 [E+] AlMe2

N N

N R1

RT

244

R1:alkyl, aryl R2: alkyl, aryl , E: DCl , D2O ,NBS ,NIS , ClCO2 AlK , X: D , Cl, Br ,I,CO2 AlK

Scheme 91.

X

N N

N 245

R1

40


Heravi et al.

R2 R1 N3

R2

+

246

+

OEt

P

CuCl, TEA, rt

(ETO)2P(O)H

N

OEt N

N

248

247

O

R1 249

Scheme 92.

BF3.OEt2 or TMSOTf BnN3

Ph Ph

N

Bn

CH2Cl2, -60°C,5min

nBu

HO

N N Ph Ph

Nucleophile, -60°C to 0°C, 30min

250

nBu OH

254

BF3.OEt2 or TMSOTf CH2Cl2, -60°C,5min

BnN3

Ph

N N

Ph

N

Bn

nBu

Ph Ph

251

N

Nu

nBu Ph

Bn

N

N

nBu

OH

252

Ph 253

Scheme 93. Table 8. R1

R2 R1 B(OH)2

N

256 + NaN3

N Condition

255

257

R1

R2

Conditions

Refs.

1

Ar, vinyl

Hex, Ar

CuSO4,MeOH r.t., air, 12-20min

[369]

2

Ar, Phenoxy

Ar

A21-CuI, MeOH, rt, 6-24h

[370]

Ar

Ph, Alk alcohol, amine

1.Cu2–-CDa, NaN3(3eq), H2O, rt, 2-6h

4-MeOPh,

COOH

2. rt, 4h

3

4

Phenol

Ar, Alk

amine

Cyclohexyl

4-PhOPh

5

6

Aryl 1-pentenyl

Ar

[371]

Method A:Clay-Cu(II)

Ar, Bn

a

N

R2

H2O: ACN (1:1)or H2O, rt, 3-8h Method B:CuSO4/NaN3

[372]

H2O: ACN (1:1) or H2O, rt, 2.5-6h 1. Cu/Al2O3

Ar

K2CO3 , 600 rpm,6 ball,1 h

[373]

2. 600 rpm, 1 h Ar

CuFe2O4, H2O, r.t., 12h (Boronic acid or boronate)

[374]

Copper-Beta-cyclodextrine complex

component reactions were examined in the presence of allenylaminodiazonium 252 which was detected as an intermediate [368] (Scheme 93). A new and convenient approach for three-component synthesis of 1,2,3-triazoles via generation of azides from boronic acids via the Huisgen cycloaddition reaction has been successfully achieved. Noticeably, the transformation of the boronic acids to azide is faster than that of the halides.

In 2007, Liu et al. firstly reported the synthesis of 1-aryl- and 1vinyl-1,2,3-triazoles from boronic acid in mild reaction conditions in the presence of different Cu salts, including Cu(OAc)2, CuSO4, CuI, and CuCl. Good results were gained by replacing boronic acid as advantageous alternative substrates to aryl halides. It is worthy to mention that by conducting the reaction via this approach there is no need to isolate the unstable aryl azides [369]. Some 1,2,3triazoles, starting from boronic acids were enlisted in Table 8.



41

Table 9.

R1 NH2

conditions

N

R2

N R

259

N R2

260

R1

R2

Conditions

Refs.

alkyl

Alkyl, aryl

tBuONO, TMSN3, Cu(I)

[354]

Bn, amine, ester

Ph

Bn, Phenethyl, alkyl

Alkyl, aryl, alcohol

TfN3, CuSO4 , NaHCO 3 CH2Cl 2/MeOH/H2 O, rt, 30min, then Na ascorbate, TBTA,MW 80°C, 10-30min

[380]

TfN3, Cu/C, Ba(OH)2, DMC [381] then Cu/C, TEA DMC, r.t-40°C, 18-48 min Aryl

Ph, alkyl, cycloalkyl

Ph, amine

Ph, p-Tol, alkyl

CuNps/C, tBuONO, 70°C, H2O, 3-8h

[330]

TfN3 or NfN3 or imidazole-1-sulphonyl azide hydrochloride, [375,382] CuSO4.5H2O, Na ascorbate, NaHCO 3, Et2O, MeOH , H2O, r.t, 6h

Table 10. R N

conditions R

N2X

+

R2

N N

R3 R2

261 R

262

263

R2

R3

x

H, TMS

Ph, Pyridyl, Bu

Cl-, ZnCl 4-, HSO4-

Fast Red RC, Fast Blue B, Fast Corinth V,

R3 Conditions

Refs

NaN3, K2 CO3 , CuSO 4, Na ascorbate, tBuOH:H2O r.t., 24h

Variamine Blue B

[329]

Ar

H

Ph, TMS

BF4-

CuNps/C, NaN 3, 70°C, H2 O,

[330]

Ar

H

Ph

N2OSO3-SiO 2

NaN3,CuSO4 , Na ascorbate, H2O, rt

[383]

Transformation of amino compounds to azide is the convenient method to generate in situ organic azide for [3+2] cycloaddition reaction with alkynes. Amino compounds 259 as a masked azide can be readily transformed into their corresponding azides in the presence of tertbutyl nitrite (t-BuONO) along with azidotrimethylsilane (TMSN3) or trifyl azide (TfN3) [375]. Noticeably, the use of tert-butyl nitrite (t-BuONO) together with NaN3 and TfN3 in the synthesis of aromatic azides has been reported previously [376,377]. Barral et al. have described an efficient procedure for tandem diazo transfer/click reactions. This methodology allowed access to 1,2,3-triazoles 260 without the requirement of isolation of the corresponding aromatic azide. This pathway is particularly useful when unstable low molecular weight and polyvalent aromatic azides are in demand [378]. Furthermore, this approach was developed by using microwave irradiation which led to the considerable increase in the rate of reaction, leading to 1,4-disubstituted triazoles [379] (Table 9). A wide variety of aromatic diazonium salts 261 as an azide precursor were employed in two- and three-steps, one pot tandem click reactions to produce the desirable 1,2,3-triazoles 263 (Table 10). Ring opening of epoxide by sodium azide was explored as an efficient route to generate organic azides in situ in a one pot fashion. A one-pot synthesis of -hydroxy-1,2,3-triazoles proceeded via

ring cleavage of epoxide under SN2 mechanism by sodium azide. Steric and electronic factors affect the direction of nucleophilic attack in this protocol. Azidolysis of epoxides 264 and 1,3-dipolar cycloaddition with alkynes 265 in the presence of different catalyst indicated that, aryl-substituted oxiranes lead to primary -hydroxytriazoles 266b and alkyl-substituted oxiranes gives rise to secondary -hydroxy-triazoles 266a as major product (Table 11). Liang and co-workers reported a copper-catalyzed preparation of (1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines 270 starting from different amines 267, propargyl halides 268 and azides 269 in water at ambient temperature [394] (Scheme 94). Selenium triazoles 273, 277 were efficiently synthesized from the reaction of azido arylselenides 272 with various terminal alkynes in the presence of copper(II)/Na ascorbate as a catalyst in an appropriate solvent. Azido arylselenides were generated in situ using primary amines 271 via Cu(II)-catalyzed diazo transfer reaction [395] (Scheme 95). Under the similar reaction conditions diphenyl diselenide 274 was reacted with NaBH4/EtOH and methylene chloride under reflux followed by addition of NaN3 [396,397] (Scheme 96). Tellurium triazole 279 also was produced under similar conditions through a copper catalyzed Huisgen cycloaddition reaction [290] (Scheme 97).

42


Heravi et al.

Table 11. OH O

NaN3

R2

+ R1

N

R1

N

different catalysts

N

R1

N

N N

R2

265

264

+

OH

266b

266a

R2

R1=alkyl R1=aryl R1

R2

Catalyst

Product

Refs.

Me, Bu

Ph

CuSO4/ Sodium ascorbate

87-92%(9:1)a:b

[384]

CH2OAr

Ph

CuI in PEG-400

85-91% a

[385]

Ph

Ph, alkyl alcohol

Cu(OAc)2.H2O

76-98% b

[386]

Cu –zeolites

84-94% b

[387]

T (o-Cl)PPCua, ascorbic acid

78-93% b

[388]

T (o-Cl)PPCu-AMWCNTb , ascorbic acid

84-95% b

[389]

Cu(bhppda)cH2O, ascorbic acid

78-90% b

[389]

88-90% a

[390]

Ph

Ph Ph, -CH2OAr,

Ph

CH2OH, Bu Ph, -CH2OAr,

Ph

CH2OH, Bu Ph, -CH2OAr,

Ph

a: b: c:

I

CH2OH, Bu

Alkyl

Ph

CuNPs/C

Aryl, alkyl

Ph

Cu(I)@phosphorated SiO2

Aryl, alkyl

Ph

(Cu@PMO NCs), MW, US

Ar: 93-95 b

[391]

Alk: 83-88%a Alk: 74-86% a

[392,393]

Ar: 98-99% b

meso-tetra(2-chlorophenyl)porphyrin-Cu meso-tetra(2-chlorophenyl)porphyrin-Cu on multi-walled carbon nano tube N2,N6-bis(2-hydroxyphenyl)pyridine-2,6-dicarboxamidato

N R1

X

NH

R

+

+

R2 267

n

N3

70-98%

269

N

n

R

R1 N

H2O, rt, 7-24min

268

R1, R 2 = alkyl, Ph

10mol%CuI, Et3N

N

R2

270

n=0,1,2

X= Br, Cl

amine= morpholine, piperidine, pipirazine Scheme 94.

X

Ar

X

Ar

TMSN3, iBuCH2ONO NH2

THF, air, r.t. 272

X

R2

Cu(OAc)2.H2O sodium ascorbate H2O/THF(1:1), r.t 12h

N3

271

R1

N

N N

R2

R1

273

75-99%

X=S, Se

Ar

75-97% Scheme 95.

Cu(OAc)2.H2O(5%) sodium ascorbate(10%) ArSeSeAr 274 Ar: Ph, 4-Me-C6H4, 4-Cl-C6H4 Scheme 96.

ArSe

275

N3

+

R

R

SeAr

H 276

THF/H2O(1:1) 8h, r.t. air

R: Ph, alk, alkyl alcohol, alkyl ester, allyl

N

N N 277



43

1)TMSN3, iBuCH2ONO THF, air, r.t. Te Te Te Te

N

N

Cu(OAc)2.H2O sodium ascorbate H2O/THF(1:1), r.t 12h

278

N

N

Ph

2)

NH2

NH2

N

N Ph

Ph

279 50%

Scheme 97.

R

N3

281 Cu(OAc)2.H2O Na ascorbate

RSe

R1 H RSe

n N

n 280

CH2Cl2/H2O(1:1) 12h, r.t. air R= aryl, Heteroaryl 1 R = H, Me, OMe, Cl, CF3 n=0,1,2,3

N N 282 74-96%

Scheme 98.

Alves et al. achieved and reported the synthesis of organoselenium-functionalized triazoles 282 by reaction between alkynylselenium 280 and benzyl azides 281 in the presence of copper(II) acetate and sodium ascorbate [398] (Scheme 98). 1,4,5-Trisubstituted 5-(2-alkoxy-1,2-dioxoethyl)-1,2,3-triazoles 285 were appropriately synthesized in a one-pot three component reaction in which 5-Cu(I)-1,2,3-triazole intermediate was produced from Cu-alkyne 283 and organic azide 284 reactions. The generated intermediate selectively trapped by alkoxalyl chloride to afford the corresponding triazoles in 70-92% [399] (Scheme 99). N R1

() n X

N

R2 + NaN3

326

conditions

( ) R1 n

327

n=0,1 X=Br, Cl or I R1, R2= aryl, alkyl, alkyl amine

conditions

N

R2

i) 18-97% ii)50-88%

i)DMA, MW, 80°C,10min, then [RuClCp*(PPh3)2], MW, 100°C,, 30min or ii)RuH2(CO)(PPh3)3, BuNI, H2O,80°C, 2h

Scheme 99.

4,5-Disubstituted-1,2,3-(NH)-triazoles 288 were synthesized in a one pot sequential protocol including palladium catalyzed Sonogashiro coupling of acid chlorides and terminal acetylenes 286 followed by cycloaddition reaction with azide. Ultrasonic irradiation accelerated the reaction rate to obtain the target product in excellent yield [400] (Scheme 100) The sustainability of trapping of the vinyl copper intermediate created in situ from azide-[3+2] cycloadditions. Allyl iodide 290 was found to be important in this reaction. This confirmed that the intermediate can play a crucial role as an electrophile required for the trapping to afford the corresponding 1,2,3-triazole 291 [401] (Scheme 101). 4-Vinyl-1,2,3-triazole 296, as a monomer in polymerization reaction, was produced directly from the Huisgen cycloaddition reaction of alkynes bearing a hydroxy groups [402] For example propargylic alcohol 292 can undergo the CuAAC reaction, followed by elimination of a hydroxyl group to afford 4-vinyl-1,2,3-triazole [402-404]. Hydroxyl group in click product can be transformed in to a phosphine-ylide reagent, followed by Wittig coupling with formaldehyde to afford the desired product [405] (Scheme 102). In this line, N-vinyl triazoles 298 can be generated via the CuAAC reaction of 2-azidoethyl 4-methylbenzenesulfonate 297 with alkynes, followed by removal of a tosyl group [406] (Scheme 103). O

a) PdCl2(PPh3)2, CuI Et3N, ultrasonic, 1h

O R1 286

+

R2

Cl 287

b)NaN3, DMSO, 1h-3h

R2

R1 N

N N H 288

R1= Ar, Alk R2= Ar, cyclohex-1-en Scheme 100.

88-99%

44


Heravi et al.

O

N

N BnN3, allyl-I 290

O

CuBr 2,6-lutidine, CH3CN, rt, 2d

O

O

Bn N

N

N Ph

allyl Ph

291

289 Scheme 101.

OH

OH

292 a) R-N3, CuAAC b) Wittig strategy

293

R1, R2, R3= H

a) R-N3, CuAAC b) Elimination of H2O

R1

R1 R3

OH

Me

R2

a) Deprotonation N

b) R-N3, CuAAC

N

b) Elimination of H2O

N

TMS 294

Me

a) R-N3, CuAAC

295 296 R1,R2= H R3= Me

R1= H, amine R2, R3= H

Scheme 102.

R N3

OTs

a) CuAAC, R

N

b) elimination of TsOH 297

N

N 298

taining TMS group were deprotected using AgBF4 which then undewent copper catalyzed Huisgen cycloaddition reaction in the presence of Cu(CH3CN)4PF6 , with subsequent olefination reaction of 300 with various carbonyl compounds 301 leading to the formation of the desired N-substituted vinyl and fluorovinyl triazoles 302 in moderate to high yields [263] (Scheme 104).

Scheme 103.

5.1.3. Ruthenium Catalyzed Synthesis of 1,2,3-triazole

In 2011, Kumar et al. used a combination of click and JuliaKocienski reactions to produce 4-vinyl- and 4-fluorovinyl-1,2,3triazoles 302a and 302b. In this protocol, an appropriate propargyl and fluoropropargyl substituted benzothiazolyl sulfones 299 con-

1,5-Disubstituted 1,2,3-triazole can be generated through thermal Huisgen 1,3- dipolar cycloaddition together with 1,4 – substituted isomer in low regioselectivity under tedious procedure and challenging method [407]. Accessing to 1,5-disubstituted tria-

X BT

R-N3 AgBF4 (20 mol%) Cu(CH3CN4PF6 (20 mol %)

BT

DCM / MeOH, rt

O

X

S O

S O

TMS 299

R

N 300

aldehyde 301 [(CH3)3Si]2NLi DMF / DMPU -78 °C

N BT=

N

68-93%

R= p-MeO-C6H4-, Ph(CH2)-, CH3(CH2)9

X= H or F

N O

S X R1 N R2

N

N

R

302 302a x= H: 31-85%: 302b X= F: 47-90% R = p-MeO-C6H4-: Ph(CH2)3 Scheme 104.



X

R'

+

N

R

Ru or R4NOH, DMSO

RN3

303

45

N

N

R'

X 304

X=H, R''

N

R

N

N

H+ R R'

M

RN3

+

305

N N R'

R' 308

N M

306 M=Li, Na, Mg, Zn, Si, Ge, Sn

R

E+

N N R'

N E+

307 Scheme 105. Synthesis of 1,5-disubstituted 1,2,3-triazoles. Table 12.

10 mol % Cp*RuCl(PPh3)2 R1

R2 + 309

R3 N

N

R3

R1

R2

N

N

+

N PhH , 80 oC

310

2.5-4h

R2

R3 N N

N

R1

N 311b

311a

R1

R2

R3

311a:311b

Ph, Bu, Et

CO2Et, CO2Me

CH2Ph

100:0

Ph

CH2OH, CMe2OH, CH 2NEt2

CH2Ph

0:100

Me

t-Bu

CH2Ph

0:100

Ph

Me

1-adamantyl

0:100

Ph

CH(OEt)2

CH2Ph

50:50

Ph

Pr

CH2Ph

13:87

zole, regioselectively was conveniently achieved by ruthenium catalyzed azide-alkyne cycloaddition reaction(RuAAC). Other protocols to synthesize this regioisomer are cycloaddition reaction transition metal- free conditions [191,188,408,215], using KOtBu and NMe4OH as well as strong alkali medium [409]. Investigation on the reactions of sodium, lithium, magnesium, zinc [410-414, 114,173] tin, germanium, and silicon [415] acetylides with organic azides were also indicated that 1,5-disubstituted 1,2,3-triazoles are the main products obtained via cycloaddition reactions (Scheme 105). In 2004, Fokin et al. introduced cycloaddition of terminal alkynes and organic azides catalyzed by ruthenium complexes. Screening efficiency of ruthenium complexes in cycloaddition reaction resulted in Cp*RuCl(PPh3)2 which be led to complete conversion of reactant to 1,5-disubstituted 1,2,3-triazole [98]. In 2006, Majireck et al. reported the cycloadditions of azides with unsymmetrical internal alkynes in the presence of Cp*RuCl(PPh3)2 catalyst in refluxing benzene. In some cases, using alkyl phenyl and dialkyl acetylenes, a mixture of both 1,4 and 1,5-disubstituted 1,2,3-triazoles were achieved [416] (Table 12). [Cp*RuCl]4 as cocatalyst in DMF under microwave irradiation has conducted the

CuAAC reaction considerably better than Cp*RuCl(PPh3)2 in most other solvents [417]. Table 13 shows the pathway for the synthesis of some 1,5-disubstituted 1,2,3-triazole in different conditions in the presence of ruthenium catalyst. In 2007, Imperio et al. by using the appropriate reagents in click reaction successfully obtaine triazole as intermediate 314, 318 which can be used for the synthesis of analouge of natural lignans [421] (Scheme 106). Evaluation of catalytic activity of 13 kinds of ruthenium(II) complexes in cycloaddition reaction, of primary and secondary azide and terminal/internal alkyne in refluxing THF displayed that Cp*RuCl(PPh3)2,Cp*RuCl(COD), Cp*RuCl(NBD) and [Cp* RuCl]4 are the most effective catalysts to produce 1,5- disubstituted-1,2,3-triazole, regioselectively. In certain condtions, RuCl2 (PPh3)3, RuHCl(CO)(PPh3)3, RuH2(CO)(PPh3)3, and Ru(OAc)2 (PPh3)2 afforded 1,4-substituted triazole regioisomer in low yield [78]. Galli et al. attempted to obtain 1,5-disubtituted triazoles under ruthenium catalysis. However, they obtained an inseparable mixture of 1,5 and 1,4-disubstituted triazoles 322 in very low yields [422] (Scheme 107). This reaction under Sharpless conditions afforded 1,4-disubstituted triazole in excellent yield.

46


Heravi et al.

Table 13. R3 R1

R2

+

R1

conditions

R3-N3

N N N

R2 R1

R2

R3

Conditions

Refs.

H, Ph

Cp*RuCl(PPh3)2, benzene 80°C/dioxane 60°C, 2-12h

[416]

Ph

[Cp*RuCl]4, DMF, MW,110°C, 20min

[417]

Bn, Octyl

[Cp*RuCl]n, THF, Reflux

[418]

Ar, alkyl,

Bn, alkyl alcohol, phenethyl

alcohol

alkyl, hetaryl

H

CF3

R4=Ph, Cy, allylbenzene

R4R5CH(OH)

R5= Ph, Cy PhSO2NH2

H

Suger

[Cp*RuCl(cod)], toluene ,N2, 100 °C, 18h

[419]

Ar, Ferrocenyl

H

Ar, alkyl, Phenethyl, Bn, Cy

RuH2CO(PPh3)3, Bu4NBr , H 2O ,80°C ,2h

[420]

CH2CH 2OMs

H

Octyl, Bn, Cy

Cp*RuCl(PPh3)2, Dioxane

[403]

H

Bn, n-heptyl, Ph

Ar, alkyl alcohol, alkyl amine, TMS, Cy, Cy-OH

Cp*Ru(L)X, DCM,rt,40°C, 20-80min

[86]

X = Cl or OCH2 CF3, L= PPr3, PCy,NHC carben ligand

N N

O

N

O

N

O

N3

O Cp*Ru(PPh3)2Cl

+

O

N

N

H3CO

OCH3

H3CO

benzene, reflux H3CO

OCH3 312

O

OCH3

H3CO

OCH3

313

315

314

or

OCH3

N O N3

N

O

N

Cp*Ru(PPh3)2Cl

N

O

O

N

N

O

+ benzene, reflux

O H3CO 316

H3CO

OCH3

H3CO

OCH3

OCH3

H3CO

OCH3

317

OCH3 319

318

Scheme 106. N N3 O

Cp*RuCl(PPh3)2

320

R1(H)

N

N +

N

O

H(R1)

N

R1 benzene, reflux 321

3day-1week

322

Scheme 107.

Noticeably, Cp*RuCl(PPh3)2 can be empolyed for the synthesis of 4,5-diaryl-N1-substituted-1,2,3 triazoles 325 [131] (Scheme 108). In situ generation of organic azides was carried out via sequential reactions of various primary halides 326 and sodium azide fol-

lowed by addition of alkyne 327 in the presence of ruthenium complexes as catalysts. These reactions were applied in Microwave or thermal conditons to furnish 1,5-regioisomer 328 in good to excellent yields [420,423] (Scheme 109).



N Cl

Cl

N

323

47

CH2COR N

RuCpCl(PPh)3

+

benzene, reflux, 75-80% Cl

325

N3CH2COR

Cl

R=OnBu R=N(CH2)5

324 Scheme 108..

N R1

() n X

+ NaN3

N

R2

conditions

326

The proposed mechanism for the synthesis of 1,5-disubstituted1,2,3-triazoles 341 from lithium or magnesium acetylides 338 with organic azides 337 [410] was depicted in figure 9.

N

R2

( ) R1 n

327

n=0,1 X=Br, Cl or I R1, R2= aryl, alkyl, alkyl amine

i) 18-97% ii)50-88%

R1

R1

i)DMA, MW, 80°C,10min, then [RuClCp*(PPh3)2], MW, 100°C,, 30min

conditions

I 1

I

N

N N

(LnCu)++ R2

or

R1

I

ii)RuH2(CO)(PPh3)3, BuNI, H2O,80°C, 2h

R2 N

CuLn

Scheme 109.

N

N

1

5.1.4. Transition metal-free Synthesis of 1,5-disubstituted 1,2,3triazole In 2011, Meza-Aviña et al., reported the regioselective synthesis of 1,5-substituted sulfonyl triazoles 331 using the Huisgen cycloaddition reaction between terminal alkynes 329 and sulfonyl azides 330 in the presence of n-BuLi. Electron-poor (nitro group) and sterically hinderered arenes(o-anisole) had low efficiency in this reaction in terms of yields and reaction times [424] (Scheme 110). ArO2S

N N

N

R 2) ArSO2N3 25-45min

R 14-87%

R=Ph, 4-OMeC6H4, 2-OMeC6H4, 4-CF3C6H4, TMS, t-Bu N.R

Scheme 110.

Liu et al. synthesized the triazole-based monophosphine 336 (ClickPhos) ligand for being used in Suzuki-Miyaura coupling reaction based on azidation of magnesium acetylides 333 in the presence of ammonium chloride and phosphorous nucleophile [425] (Scheme 111).

Ar Ph

N N

N

N

LnCu

MgBr

Ph

LnCu

R1

N

N N

R2

X 238

Synthesis of 1,5 disubstituted triazole was carried out via AAC reaction in the presence of zinc reagents. Formation of zinc acetylides intermediate followed by trapping with different electrophiles led to regioselective production of 1,4,5-trisubstituted 1,2,3triazoles 342 [114] (Scheme 112). In 1976, Himbert et al. elaborated the synthesis of 1,5disubstituted triazole using Sn,Ge or Si acetylides 345 in cycloaddition reaction with organic azides 346 [415] (Scheme 113). In 1994, Hlasta' and Ackerman reported the synthesis of a novel series of 1,2,3-triazoles 349 via cycloaddition reaction of N(azidomethy1)benzisothiazolone 347 with various electrondeficient acetylenes 348 [426] (Scheme 114). The results indicated that TMS substitution on alkyne led to the generation of just one isomer of triazole; however, in the Huisgen cycloaddition reaction, unsymmetrical alkyne afforded a mixture of

Ph

N N

N

NH4Cl

N N

N

N Ar

MgBr

Ar

H

1.LDA 2.R2PCl R=Ph, Cy, t-Bu

Scheme 111.

R1

X

N

Fig. (9).

1) n-BuLi, THF, -78 °C 15min

R=NO2

R2

Ph

N N

N

Ar

PR2 75-93%

48


Heravi et al.

NC

N3 ZnEt2 THF, rt, 18h

H

N

Ph

N

N

+

N

N Ph

CN then NH4Cl Scheme 112.

Li

R3M

MR3 O2N

N

N

1R2RN

R3MX

+ R1

N

N3

R2

R1

N

N

R2

R1,R2= Aryl, alkyl M=Sn, Ge, Si Scheme 113.

N

O

O N3 X

N S O

N

Y

R5

N

benzene, reflux

O

O X=CO2Me,H,Ph X=TMS

R4

N

Y=CO2Me,CO2Et Y= CO2 Me

S

O 1,4 and 1,5 isomer 68% Only 1,5 isomer

Scheme 114.

R

R'

N

N

R' N R

SiMe3

R

+

SiMe3

N

N N SiMe3

100% regioselectivity

Scheme 115.

Me3Si R1

N3

+

TMS

R2

R2

R2

H2O, 80-120°C

+ N

N N

R1=p-Tolyl, R2=meseityl >99% a R1=1-adamantyl, R2=meseityl >99% a

a

R1

SiMe3

N

N N

R1

b

Scheme 116.

regioisomers of triazoles in which the electron-withdrawing group located at the 4-position and the electron-donating group located at the 5-position. In fact, electronic and steric factors of trimethylsilyl(TMS)group on acetylenes are responsible for electrophilicity of the -carbon of alkynes and generated 4-TMS-triazoles, regioselectively. Hlasta and co-workers in continuation of their work observed complete regioselectivity of trimethylsilyl substitute in the Huisgen cycloaddition reaction [427]. Reaction of TMS-acetylenes 350 with different azides 351 resulted in the formation of 1,5triazoles 352a in good yields and excellent regioselectivities. The results indicated that the level 1,5 regioselectivity depends on electronic effect of the TMS moiety, and independent of steric bulkiness effect of substituents [182] (Scheme 115, 116).

Cyclodextrin (CD) attached to acetylene 353 in the form of the amide in the reaction with azide 354 produced 1,5-disubstituted1,2,3-triazoles 355 as a major product. The host–guest complexes formation between azide and cyclodextrin not only brought about the 1,5 isomer more regioselectively but also accelerated cycloaddition reaction rate [428] (Scheme 117). In recent years, Hong et al. discovered that rare earth metal can efficiently catalyze the Huisgen cycloaddition reaction resulted in the synthesis of 1,5-disubstituted triazole 358. Indeed, organo samarium-catalyzed cycloaddition of alkynes 356 with azides 357 based on activation of terminal alkyne C–H bond giving the desired product in satisfactory yield [429] (Scheme 118).



49

O H N O H N H2O or DMF R

N

+

N

N

Heat

Major product

RN3 R=4-tBuPh, Ph, 4-tBuPhCH2 Scheme 117.

Ph

Bn

N3

Sm[N(SiMe3)2]3 Toluene, 50°C 24h

Bn

N N

Ph

N Sm

MeI, DMF 80°C, 24h

Bn

N N

Ph

N Me

23% Scheme 118.

6. CONCLUSION

[11]

In summary, the Huisgen cycloaddition reaction is a key approach for the synthesis of 1,2,3-triazoles. In thermal conditons, 1,4 and 1,5-disubstituted isomers were generated with no regioselectivity. CuAAC and RuAAC-catalyzed reactions are established as valuable examples of click chemistry. Under copper(I) catalysis the 1,4-disubstituted isomer is obtained as sole product whereas. 1,5disubstituted-1,2,3-triazole were synthesized under ruthenium catalysis or transition metal- free catalyst.

[12] [13]

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

[14] [15]

[16] [17] [18]

[19]

ACKNOWLEDGEMENTS

[20]

The authors gratefully acknowledge the partial financial support received from the research council of Alzahra University.

[21] [22]

REFERENCES [1] [2] [3]

[4]

[5] [6]

[7]

[8] [9] [10]

Huisgen, R. Centenary lecture - 1,3-dipolar cycloadditions. Proceed. Chem. Soc. London., 1961, 357. Diels, O.; Alder, K. Synthesen in der hydroaromatischen Reihe. Justus Liebigs Annalen der Chemie, 1928, 460(1), 98-122. Huisgen, R.; Szeimies, G.; Möbius, L., 1.3Dipolare Cycloadditionen, XXXII. Kinetik der Additionen organischer Azide an CCMehrfachbindungen. Chem. Ber., 1967, 100(8), 2494-2507. Andersh, B.; Kilby, K.N.; Turnis, M.E.; Murphy, D.L. Regioselectivity in organic synthesis: Preparation of the bromohydrin of alpha-methylstyrene. J. Chem. Educ., 2008, 85(1), 102-110. Kolb, H.C.; Sharpless, K.B. The growing impact of click chemistry on drug discovery. Drug. Discov. Today. 2003, 8(24), 1128-1137. Bock, V.D.; Hiemstra, H.; Van Maarseveen, J.H. CuIcatalyzed alkyne–azide “click” cycloadditions from a mechanistic and synthetic perspective. Eur. J. Org. Chem., 2006, 2006(1), 51-68. Binder, W.H.; Kluger, C. Azide/alkyne-“click” reactions: Applications in material science and organic synthesis. Curr. Org. Chem., 2006, 10(14), 1791-1815. Binder, W.H.; Sachsenhofer, R. ‘Click’chemistry in polymer and materials science. Macromol. Rapid. Commun., 2007, 28(1), 15-54. Huisgen, R. Kinetics and mechanism of 1, 3dipolar cycloadditions. Chem. Int. Ed. Engl., 1963, 2(11), 633-645. Huisgen, R. 1, 3dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl., 1963, 2(10), 565-598.

[23]

[24]

[25]

[26]

[27]

[28]

[29]

Moses, J.E.; Moorhouse, A.D. The growing applications of click chemistry. Chem. Soc. Rev., 2007, 36(8) 1249-1262. Santoyo, G.F.; Hernandez, M.F. Top. Heterocycl. Chem., 2007, 7, 133-140. Tron, G.C.; Pirali, T.; Billington, R.A.; Canonico, P.L.; Sorba, G.; Genazzani, A.A. Click chemistry reactions in medicinal chemistry: Applications of the 1, 3dipolar cycloaddition between azides and alkynes. Med. Res. Rev., 2008, 28(2), 278-308. Moorhouse, A.E.D.; Moses, J.E.E. Click chemistry and medicinal chemistry: A case of “cycloaddiction”. Chem. Med. Chem., 2008, 3(5), 715-723. Holub, J.M.; Kirshenbaum, K. Tricks with clicks: Modification of peptidomimetic oligomers via copper- catalyzed azide-alkyne [3+ 2] cycloaddition. Chem. Soc. Rev., 2010, 39(4), 1325-1337. Pedersen, D.S.; Abell, A. 1, 2, 3triazoles in peptidomimetic chemistry. Eur. J. Org. Chem., 2011, 2011(13), 2399-2411. Svobodová, H.; Noponen, V.; Kolehmainen, E.; Sievänen, E. Recent advances in steroidal supramolecular gels. RSC Adv., 2012, 2(12), 4985-5007. Kolb, H.C.; Finn, M.; Sharpless, K.B. Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem. Int. Ed., 2001, 40(11) 2004-2021. Heravi, M.M.; Alishiri, T. Dimethyl acetylenedicarboxylate. Adv. Heterocycl. Chem., 2014, 113, 1. Heravi, M.M.; Talaei, B. Ketenes as privileged synthons in the synthesis of heterocyclic compounds, part 1: Three-and four-membered heterocycles. Adv. Heterocycl. Chem., 2014, 113, 143-244. Heravi, M.M.; Khaghaninejad, S. Paal-Knorr reaction in the synthesis of heterocyclic compounds. Adv. Heterocycl. Chem., 2014, 111, 95-146. Heravi, M.M.; Khaghaninejad, S.; Mostofi, M. Pechmann reaction in the synthesis of coumarin derivatives. Adv. Heterocycl.Chem., 2015, 112, 1. Heravi, M.M.; Khaghaninejad, S.; Nazari, N. Bischler–Napieralski reaction in the synthesis of isoquinolines. Adv. Heterocycl. Chem., 2015, 112, 183226. Heravi, M.M.; Talaei, B. Ketenes as privileged synthons in the synthesis of heterocyclic compounds part 2: Five-membered heterocycles. Adv. Heterocycl.Chem., 2015, 114, 147-225. Heravi, M.M.; Vavsari, V.F. Recent advances in application of amino acids: Key building blocks in design and synthesis of heterocyclic compounds. Adv. Heterocycl. Chem., 2015, 114, 77-145. Heravi, M.M.; Sadjadi, S.; Oskooie, H.A.; Shoar, R.H.; Bamoharram, F.F. Heteropolyacids as heterogeneous and recyclable catalysts for the synthesis of benzimidazoles. Catal. Commun., 2008, 9(4), 504-507. Heravi, M.M.; Khorasani, M.; Derikvand, F.; Oskooie, H.A.; Bamoharram, F.F. Highly efficient synthesis of coumarin derivatives in the presence of H 14 [NaP 5 W 30 O 110] as a green and reusable catalyst. Catal. Commun., 2007, 8(12), 1886-1890. Heravi, M.M.; Hashemi, E.; Beheshtiha, Y.S.; Kamjou, K.; Toolabi, M.; Hosseintash, N. Solvent-free multicomponent reactions using the novel Nsulfonic acid modified poly (styrene-maleic anhydride) as a solid acid catalyst. J. Mol. Catal. A: Chem., 2014, 392, 173-180. Heravi, M.M.; Mousavizadeh, F.; Ghobadi, N.; Tajbakhsh, M. A green and convenient protocol for the synthesis of novel pyrazolopyranopyrimidines via a one-pot, four-component reaction in water. Tetrahedron Lett., 2014, 55(6), 1226-1228.

50 [30]

[31]

[32]

[33] [34]

[35]

[36]

[37] [38]

[39]

[39]

[40] [41]

[42]

[43] [44] [45] [46] [47] [48] [49]

[50]

[51]

[52] [53]

[54]

[55]

[56]

Current Organic Chemistry, 2016, Vol. 20, No. ?? Fazeli, A.; A Oskooie, H.; S Beheshtiha, Y.; Heravi, M.M.; Valizadeh, H. Green and facile synthesis of 1, 4-disubstituted 1, 2, 3-triazoles via a click reaction of -bromo ketones, [bmim] n3 and terminal acetylenes. Lett. Org. Chem., 2013, 10(10), 738-743. Fazeli, A.; Oskooie, H.A.; Beheshtiha, Y.S.; Heravi, M.M.; Moghaddam, F.M.; Foroushani, B.K. Synthesis of 1, 4-disubstituted 1, 2, 3-triazoles from aromatic a-bromoketones, sodium azide and terminal acetylenes via cu/cu(otf)2-catalyzed click reaction under microwave irradiation. Z. Naturforsch. B., 2013, 68(4), 391-396. Fazeli, A.; Oskooie, H.A.; Beheshtiha, Y.S.; Heravi, M.M.; Valizadeh, H.; Bamoharram, F.F. Heteropolyacid catalyzed click synthesis of 5-substituted 1H-tetrazoles from [bmim] N3 and nitriles under solvent-free conditions. Monatsh. Chem. Chem. Mon., 2013, 144(9) 1407-1410. Heravi, M.M.; Asadi, S.; Lashkariani, B.M. Recent progress in asymmetric Biginelli reaction. Mole. Divers., 2013, 17(2), 389-407. Hashemi, E.; Beheshtiha, Y.S.; Ahmadi, S.; Heravi, M.M. In situ prepared CuI nanoparticles on modified poly (styrene-co-maleic anhydride): An efficient and recyclable catalyst for the azide–alkyne click reaction in water. Transit. Metal. Chem., 2014, 39(5), 593-601. Mirsafaei, R.; Heravi, M.M.; Ahmadi, S.; Moslemin, M.H.; Hosseinnejad, T. In situ prepared copper nanoparticles on modified KIT-5 as an efficient recyclable catalyst and its applications in click reactions in water. J. Mole. Catal. A: Chem., 2015, 402, 100-108. Heravi, M.M.; Hamidi, H.; Zadsirjan, V. Recent applications of click reaction in the synthesis of 1, 2, 3-triazoles. Curr. Org. Synth., 2014, 11(5), 647675. Huisgen, R. In: 1,3- Dipolar Cycloadditional Chemistry, Padwa, A. Ed.; Wiley: New York, 1984; pp. 1-176. Evans, R.A. The rise of azide–alkyne 1, 3-dipolar'click'cycloaddition and its application to polymer science and surface modification. Aust. J. Chem., 2007, 60(6), 384-395. Padwa, A.; Smolanoff, J.; Tremper, A. Photochemical transformations of small ring heterocyclic systems. LXV. Intramolecular cycloaddition reactions of vinyl-substituted 2H-azirines. J. Am. Chem. Soc., 1975, 97(16), 4682-4691. Kolb, H.C.; Finn, M.; Sharpless, K.B. Clickchemie: Diverse chemische Funktionalität mit einer Handvoll guter Reaktionen. Angew. Chem., 2001, 113(11) 2056-2075. Padwa, A.; Hornbuckle, S.F. Ylide formation from the reaction of carbenes and carbenoids with heteroatom lone pairs. Chem. Rev., 1991, 91(3) 263-309. Evans, D.A.; Ripin, D.H.; Halstead, D.P.; Campos, K.R. Synthesis and absolute stereochemical assignment of (+)-miyakolide. J. Am. Chem. Soc., 1999, 121(29), 6816-6826. Padwa, A.; Pearson, W.H. Synthetic applications of 1, 3-dipolar cycloaddition chemistry toward heterocycles and natural products. John Wiley & Sons: 2002; Vol. 59, pp. 170-199. Chiu, P. Application of the carbene cyclization-cycloaddition cascade in total synthesis. Pure. Appl. Chem., 2005, 77(7) 1183-1189. Gothelf, K.V.; Jørgensen, K.A. Asymmetric 1, 3-dipolar cycloaddition reactions. Chem. Rev., 1998, 98(2) 863-910. Pellissier, H. Asymmetric 1, 3-dipolar cycloadditions. Tetrahedron, 2007, 63(16), 3235-3285. Cox, A.P.; Thomas, L.F.; Sheridan, J. Microwave spectra of diazomethane and its deutero derivatives. 1958. Nature, 181, 1000-1001. Dahmen, A.; Hamberger, H.R. Huisgen, and V. Markowski. Chem. Commun., 1971, 1192. Padwa, A.; Prein, M. Acyclic stereocontrol in [3+ 2]-cycloadditions of amino acid-derived isomünchnone dipoles. Tetrahedron, 1998, 54(25), 6957-6976. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process: Copper (I)catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem., 2002, 114(14) 2708-2711. Tornøe, C.W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase:[1, 2, 3]-triazoles by regiospecific copper (I)-catalyzed 1, 3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem., 2002, 67(9) 30573064. Storr, T.E.; Baumann, C.G.; Thatcher, R.J.; De Ornellas, S.; Whitwood, A.C.; Fairlamb, I.J. Pd (0)/Cu (I)-mediated direct arylation of 2deoxyadenosines: Mechanistic role of Cu (I) and reactivity comparisons with related purine nucleosides. J. Org. Chem., 2009, 74(16) 5810-5821. Firestone, R.A. Mechanism of 1, 3-dipolar cycloadditions. J. Org. Chem., 1968, 33(6). 2285-2290. Blanco-Ania, D.; Valderas-Cortina, C.; Hermkens, P.H.; Sliedregt, L.A.; Scheeren, H.W.; Rutjes, F.P. Synthesis of dihydrouracils spiro-fused to pyrrolidines: Drug like molecules based on the 2-arylethyl amine scaffold. Molecules, 2010, 15(4), 2269-2301. Huisgen, R. 1, 3-dipolar cycloadditions. 76. Concerted nature of 1, 3-dipolar cycloadditions and the question of diradical intermediates. J. Org. Chem., 1976, 41(3), 403-419. Huisgen, R.; Mloston, G.; Langhals, E. The first two-step 1, 3-dipolar cycloadditions: non-stereospecificity. J. Am. Chem. Soc., 1986, 108(20) 64016402. Bihlmaier, W.; Geittner, J.; Huisgen, R.; Reissig, H. Stereospecificity of diazomethane cycloadditions.. Heterocycles, 1978, 10, 147-152.

Heravi et al. [57]

[58] [59]

[60]

[61]

[62] [63]

[64]

[65]

[66] [67]

[68] [69]

[70]

[71]

[72] [73]

[74]

[75]

[76] [77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

Huisgen, R.; Reissig, H.U.; Huber, H.; Voss, S. -diazocarbonyl compounds and enamines-a dichotomy of reaction paths. Tetrahedron Lett., 1979, 20(32), 2987-2990. Williamson, D.; Cvetanovic, R. Rates of ozone-olefin reactions in carbon tetrachloride solutions. J. Am. Chem. Soc., 1968, 90(14), 3668-3672. Firestone, R. Orientation in 1, 3-dipolar cycloadditions according to the diradical mechanism. Partial formal charges in the linnett structures of the diradical intermediate. J. Org. Chem., 1972, 37, 2181-2191. Houk, K.; Sims, J.; Duke, R.; Strozier, R.; George, J.K. Frontier molecular orbitals of 1, 3 dipoles and dipolarophiles. J. Am. Chem. Soc., 1973, 95(22), 7287-7301. Geittner, J.; Huisgen, R.; Sustmann, R. Kinetics of 1, 3-dipolar cycloaddition reactions of diazomethane; A correlation with homo-lumo energies. Tetrahedron Lett., 1977, 18(10), 881-884. Berner, D.; McGarrity, J.F. Direct observation of the methyldiazonium ion in fluorosulfuric acid. J. Am. Chem. Soc., 1979, 101(11), 3135-3136. Müller, E.; Rundel, W. Untersuchungen an diazomethanen, VI. Mitteil.: Umsetzung von diazoäthanmit methyllithium. Chem. Ber., 1956, 89(4), 1065-1071. Caramella, P.; Gandour, R.W.; Hall, J.A.; Deville, C.G.; Houk, K. A derivation of the shapes and energies of the molecular orbitals of 1, 3-dipoles. Geometry optimizations of these species by MINDO/2 and MINDO/3. J. Am. Chem. Soc., 1977, 99(2), 385-392. Hosseinnejad, T.; Fattahi, B.; Heravi, M.M. Computational studies on the regioselectivity of metal-catalyzed synthesis of 1,2,3 triazoles via click reaction: A review. J. Mol.Model., 2015, doi: 10.1007/s00894-015-2810-2. Houk, K.N. Frontier molecular orbital theory of cycloaddition reactions. Acc. Chem. Res., 1975, 8(11), 361-369. Caramella, P.; Houk, K. Geometries of nitrilium betaines. The clarification of apparently anomalous reactions of 1, 3-dipoles. J. Am. Chem. Soc., 1976, 98(20), 6397-6399. Sustmann, R. Orbital energy control of cycloaddition reactivity. Pure Appl. Chem., 1974, 40(4), 569-593. Geittner, J.; Huisgen, R.; Reissig, H. Solvent dependence of cyclo-addition rate of phenyldiazomethane and activation parameters. Heterocycles, 1978, 11, 109-112. Houk, K.; Rondan, N.G.; Santiago, C.; Gallo, C.J.; Gandour, R.W.; Griffin, G.W. Theoretical studies of the structures and reactions of substituted carbonyl ylides. J. Am. Chem. Soc., 1980, 102(5), 1504-1512. Del Castillo, T.J.; Sarkar, S.; Abboud, K.A.; Veige, A.S. 1, 3-Dipolar cycloaddition between a metal-azide (Ph3PAuN3) and a metal-acetylide (Ph3PAuCCPh): An inorganic version of a click reaction. Dalton. Trans., 2011, 40(32), 8140-8148. Becke, A.D. A new mixing of Hartree–Fock and local densityfunctional theories. J. Chem. Phys., 1993, 98(2), 1372-1377. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlationenergy formula into a functional of the electron density. Phys. Rev., 1988, 37(2), 785-792. Mishra, J.K.; Rao, J.S.; Sastry, G.N.; Panda, G. Regioselective aminoethylation of 1, 4-benzodiazepin-2-one under conventional heating and microwave irradiation. Tetrahedron. Lett., 2006, 47(20), 3357-3360. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry. General Heterocyclic Chemistry Series 1. United States of America: Wiley-Interscience, 1983; pp. 141–145. Houk, K.N.;Yamaguchi, K. In: 1,3-dipolar Cycloaddition Chemistry, Padwa, A., Ed., Wiley: New York, 1984, Vol. 2, pp. 407. Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.V.; Noodleman, L.; Sharpless, K.B.; Fokin, V.V. Copper (I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc., 2005, 127(1) 210-216. Boren, B.C.; Narayan, S.; Rasmussen, L.K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V.V. Ruthenium-catalyzed azide alkyne cycloaddition: Scope and mechanism. J. Am. Chem. Soc., 2008, 130(28), 8923-8930. Sirisha, B.; Narsaiah, B.; Yakaiah, T.; Gayatri, G.; Sastry, G.N.; Prasad, M.R.; Rao, A.R. Synthesis and theoretical studies on energetics of novel Nand O-perfluoroalkyl triazole tagged thienopyrimidines–Their potential as adenosine receptor ligands. Eur. J. Med. Chem., 2010, 45(5), 1739-1745. DíezGonzález, S.; Correa, A.; Cavallo, L.; Nolan, S.P. (NHC) copper (I)catalyzed [3+ 2] cycloaddition of azides and monoor disubstituted alkynes. Chem. Eur. J., 2006, 12(29), 7558-7564. Buckley, B.R.; Dann, S.E.; Heaney, H. Experimental evidence for the involvement of dinuclear alkynylcopper (I) complexes in alkyne–azide chemistry. Chem. Eur. J., 2010, 16(21), 6278-6284. Zhou, Y.; Lecourt, T.; Micouin, L. Direct synthesis of 1, 4disubstituted5alumino1, 2, 3triazoles: Coppercatalyzed cycloaddition of organic azides and mixed aluminum acetylides. Angew. Chem. Int. Ed., 2010, 122(14), 2607-2610. Berg, R.; Straub, B.F. Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition. Beilstein. J. Org. Chem., 2013, 9(1) 2715-2750. Hein, J.E.; Fokin, V.V. Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: New reactivity of copper (I) acetylides. Chem. Soc. Rev., 2010, 39(4), 1302-1315.

Huisgen’s Cycloaddition Reactions [85]

[86]

[87] [88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100] [101] [102] [103] [104]

[105] [106]

[107] [108] [109] [110]

[111]

[112]

[113]

[114]

Hou, D.R.; Kuan, T.C.; Li, Y.K.; Lee, R.; Huang, K.W. Electronic effects of ruthenium-catalyzed [3+ 2]-cycloaddition of alkynes and azides. Tetrahedron, 2010, 66(48), 9415-9420. Lamberti, M.; Fortman, G.C.; Poater, A.; Broggi, J.; Slawin, A.M.; Cavallo, L.; Nolan, S.P. Coordinatively unsaturated ruthenium complexes as efficient alkyne–azide cycloaddition catalysts. Organometallics, 2012, 31(2), 756767. Gonzales, C.; Schlegel, H. Improved algorithms for reaction path following: Higher order implicit algorithms. J. Chem. Phys., 1991, 95, 5853-5860. Yingzi, L.; Qi, X.; Lei, Y.; Lan, Y. Mechanism and selectivity for zincmediated cycloaddition of azides with alkynes: A computational study. RSC Adv., 2015, 5, 49802-40808. Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem., 2011, 32(7), 1456-1465. Barone, V.; Cossi, M. Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J. Phys. Chem. A, 1998, 102(11), 1995-2001. Girard, C.; Önen, E.; Aufort, M.; Beauvière, S.; Samson, E.; Herscovici, J. Reusable polymer-supported catalyst for the [3+ 2] Huisgen cycloaddition in automation protocols. Org. Lett., 2006, 8(8), 1689-1692. Rodionov, V.O.; Fokin, V.V.; Finn, M. Mechanism of the ligandfree CuIcatalyzed azide–alkyne cycloaddition reaction. Angew. Chem. Int. Ed., 2005, 44(15), 2210-2215. Hu, M.; Li, J.; Q. Yao, S. In situ “click” assembly of small molecule matrix metalloprotease inhibitors containing zinc-chelating groups. Org. Lett., 2008, 10(24), 5529-5531. Chowdhury, C.; Sasmal, A.K.; Dutta, P.K. Efficient synthesis of [1, 2, 3] triazolo [5, 1-c][1, 4] benzoxazines through palladium–copper catalysis. Tetrahedron Lett., 2009, 50(22), 2678-2681. Fletcher, J.T.; Walz, S.E.; Keeney, M.E. Monosubstituted 1, 2, 3-triazoles from two-step one-pot deprotection/click additions of trimethylsilylacetylene. Tetrahedron Lett., 2008, 49(49), 7030-7032. Zhong, P.; Guo, S.R. Novel synthesis of 1, 2, 3triazoles via 1, 3dipolar cycloadditions of alkynes to azides in ionic liquid. Chin. J. Chem., 2004, 22(10), 1183-1186. Luo, Q.; Jia, G.; Sun, J.; Lin, Z., Theoretical studies on the regioselectivity of iridium-catalyzed 1, 3-dipolar azide–alkyne cycloaddition reactions. J. Org. Chem.., 2014, 79(24), 11970-11980. Zhang, L.; Chen, X.; Xue, P.; Sun, H.H.; Williams, I.D.; Sharpless, K.B.; Fokin, V.V.; Jia, G. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc., 2005, 127(46), 15998-15999. Li, L.J.; Zhang, Y.Q.; Zhang, Y.; Zhu, A.L.; Zhang, G.S., Synthesis of 5functionalized-1, 2, 3-triazoles via a one-pot aerobic oxidative coupling reaction of alkynes and azides. Chin. Chem. Lett., 2014, 25(8), 1161-1164. Gonzalez, C.; Schlegel, H.B. Reaction path following in mass-weighted internal coordinates. J. Phys. Chem., 1990, 94(14), 5523-5527. Gonzalez, C.; Schlegel, H.B. An improved algorithm for reaction path following. J. Chem. Phys., 1989, 90(4), 2154-2161. Roux, B.; Simonson, T. Implicit solvent models. Biophys. Chem., 1999, 78(1), 1-20. Ahlquist, M.; Fokin, V.V. Enhanced reactivity of dinuclear copper (I) acetylides in dipolar cycloadditions. Organometallics, 2007, 26(18), 4389-4391. Worrell, B.; Malik, J.; Fokin, V. Direct evidence of a dinuclear copper intermediate in Cu (I)-catalyzed azide-alkyne cycloadditions. Science, 2013, 340(6131), 457-460. Straub, B.F. -acetylide and -alkenylidene ligands in “click” triazole synthesis. Chem. Commun., 2007, (37), 3868-3870. Cantillo, D.; Ávalos, M.; Babiano, R.; Cintas, P.; Jiménez, J.L.; Palacios, J.C. Assessing the whole range of CuAAC mechanisms by DFT calculations—on the intermediacy of copper acetylides. Org. Biomole. Chem., 2011, 9(8), 2952-2958. Naota, T.; Takaya, H.; Murahashi, S.I. Ruthenium-catalyzed reactions for organic synthesis. Chem. Rev., 1998, 98(7), 2599-2660. Bruneau, C.; Dixneuf, P.H., Metal vinylidenes in catalysis. Acc. Chem. Res., 1999, 32(4), 311-323. Trost, B.M.; Toste, F.D.; Pinkerton, A.B. Non-metathesis rutheniumcatalyzed CC bond formation. Chem. Rev., 2001, 101(7), 2067-2096. Boz, E.; Tüzün, N.. Reaction mechanism of ruthenium-catalyzed azide– alkyne cycloaddition reaction: A DFT study. J. Organomet. Chem., 2013, 724, 167-176. Hay, P.J.; Wadt, W.R. Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals. J. Chem. Phys., 1985, 82(1), 299-310. Ding, S.; Jia, G.; Sun, J. Iridiumcatalyzed intermolecular azide–alkyne cycloaddition of internal thioalkynes under mild conditions. Angew. Chem. Int. Ed., 2014, 53(7), 1877-1880. Wadt, W.R.; Hay, P.J. Ab initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi. J. Chem. Phys., 1985, 82(1), 284-298. Smith, C.D.; Greaney, M.F. Zinc mediated azide–alkyne ligation to 1, 5-and 1, 4, 5-substituted 1, 2, 3-triazoles. Org. Lett., 2013, 15(18), 4826-4829.

Current Organic Chemistry, 2016, Vol. 20, No. ?? [115]

[116]

[117] [118] [119] [120]

[121] [122] [123] [124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

[136] [137]

[138]

[139]

[140]

[141]

51

Ess, D.H.; Houk, K. Theory of 1, 3-dipolar cycloadditions: Distortion/interaction and frontier molecular orbital models. J. Am. Chem. Soc., 2008, 130(31), 10187-10198. Lan, Y.; Wheeler, S.E.; Houk, K. Extraordinary difference in reactivity of ozone (OOO) and sulfur dioxide (OSO): A theoretical study. J. Chem. Theory. Comput., 2011, 7(7), 2104-2111. Michael, A. J. Prakt. Chem., 1883, 48, 94-99. Dimtoth, O.; Fester. G. Ber. Dtsch. Chem. Ges., 1910, 43, 2219-2223. Hartzel, L.W.; Benson, F.R. Synthesis of 4-alkyl-V-triazoles from acetylenic compounds and hydrogen azide1. J. Am. Chem. Soc., 1954, 76(3), 667-670. Krivopalov, V.P.; Shkurko, O.P. 1,2,3-triazole and its derivatives: Development of methods for the formation of the triazole ring. Russ. Chem. Rev., 2005, 74(4), 339. Birkofer, L.; Wegner, P. Isomere Nacetyl1.2. 3triazole. Chem. Ber., 1967, 100(11), 3485-3494. Birkofer, L.; Richtzenhain, K. Silylderivate von pyrazol, isoxazol und 1, 2, 3triazol. Chem. Ber., 1979, 112(8), 2829-2836. Birkofer, L.; Wegner, P. 1.3cycloadditionen mit trimethylsilylazid; über isomere Nacetyl1.2. 3triazole. Chem. Ber., 1966, 99(8), 2512-2517. Jenkins, S.M.; Wadsworth, H.J.; Bromidge, S.; Orlek, B.S.; Wyman, P.A.; Riley, G.J.; Hawkins, J. Substituent variation in azabicyclic triazole-and tetrazole-based muscarinic receptor ligands. J. Med. Chem., 1992, 35(13), 2392-2406. Trifonov, R.E.; Ostrovskii, V.A. An unusual formation of 5-phenyltetrazole in reaction of phenylacetylene with dimethylammonium azide, Croat. Chem., 1999, 72(4), 953-955. Cheng, Z.Y.; Li, W.J.; He, F.; Zhou, J.M.; Zhu, X.F. Synthesis and biological evaluation of 4-aryl-5-cyano-2H-1, 2, 3-triazoles as inhibitor of HER2 tyrosine kinase. Bioorg. Med. Chem., 2007, 15(3), 1533-1538. Buckler, R.T.; Hartzler, H.E.; Kurchacova, E.; Nichols, G.; Phillips, B.M. Synthesis and antiinflammatory activity of some 1, 2, 3-and 1, 2, 4triazolepropionic acids. J. Med. Chem., 1978, 21(12), 1254-1260. Livi, O.; Biagi, G.; Ferretti, M.; Lucacchini, A.; Barili, P. Synthesis and in vitro antiinflammatory activity of 4-phenyl-1, 2, 3-triazole derivatives. Eur. J. Med. Chem., 1983, 18(5), 471-475. Trybulski, E.; Benjamin, L.; Vitone, S.; Walser, A.; Fryer, R. 2benzazepines.[1, 2, 3] triazolo [4, 5-d][2] benzazepines and dibenzo [c, f][1, 2, 3] triazolo [3, 4-a] azepines. Synthesis and evaluation as central nervous system agents. J. Med. Chem., 1983, 26(3), 367-372. Calderone, V.; Giorgi, I.; Livi, O.; Martinotti, E.; Martelli, A.; Nardi, A. 1, 4and 2, 4-substituted-1, 2, 3-triazoles as potential potassium channel activators. VII. Il Farmaco, 2005, 60(5), 367-375. Hou, D.R.; Alam, S.; Kuan, T.C.; Ramanathan, M.; Lin, T.P.; Hung, M.S. 1, 2, 3-triazole derivatives as new cannabinoid CB1 receptor antagonists. Bioorg. Med. Chem. Lett., 2009, 19(3), 1022-1025. Tullis, J.S.; VanRens, J.C.; Natchus, M.G.; Clark, M.P.; De, B.; Hsieh, L.C.; Janusz, M.J. The development of new triazole based inhibitors of tumor necrosis factor- (TNF-) production. Bioorg. Med. Chem. Lett., 2003, 13(10), 1665-1668. Sobenina, L.N.; Tomilin, D.N.; Ushakov, I.A.; Mikhaleva, A.I.; Ma, J.S.; Yang, G.; Trofimov, B.A. Click chemistry with 2-ethynyl-4, 5, 6, 7tetrahydroindoles: Towards functionalized tetrahydroindole-triazole ensembles. Synthesis, 2013, 45(05), 678-682. Revesz, L.; Di Padova, F.E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.; Manning, U.; Wolf, R.; Zimmerlin, A.G. SAR of 2, 6-diamino-3, 5difluoropyridinyl substituted heterocycles as novel p38MAP kinase inhibitors. Bioorg. Med. Chem. Lett., 2002, 12(16), 2109-2112. Balle, T.; Perregaard, J.; Ramirez, M.T.; Larsen, A.K.; Søby, K.K.; Liljefors, T.; Andersen, K. Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective 1 adrenoceptor antagonists. J. Med. Chem., 2003, 46(2), 265-283. Sheehan, J.C.; Robinson, C.A. The synthesis of triazole analogs of histamine and related compounds. J. Am. Chem. Soc., 1949, 71(4), 1436-1440. Journet, M.; Cai, D.; Kowal, J.J.; Larsen, R.D. Highly efficient and mild synthesis of variously 5-substituted-4-carbaldehyde-1, 2, 3-triazole derivatives. Tetrahedron Lett., 2001, 42(52), 9117-9118. Blass, B.E.; Coburn, K.; Lee, W.; Fairweather, N.; Fluxe, A.; Wu, S.; Janusz, J.M.; Murawsky, M.; Fadayel, G.M.; Fang, B. Synthesis and evaluation of (2-phenethyl-2H-1, 2, 3-triazol-4-yl)(phenyl) methanones as Kv1. 5 channel blockers for the treatment of atrial fibrillation. Bioorg. Med. Chem. Lett., 2006, 16(17), 4629-4632. Jarowski, P.D.; Wu, Y.L.; Schweizer, W.B.; Diederich, F.O. 1, 2, 3-triazoles as conjugative -linkers in push pull chromophores: Importance of substituent positioning on intramolecular charge-transfer. Org. Lett., 2008, 10(15), 3347-3350. Tanaka, Y.; Miller, S.I. Synthesis and nucleophilic properties of 4-aryl-5triphenylphosphonium-1, 2, 3-triazole ylides or 4-aryl-1, 2, 3-triazol-5yltriphenylphosphoranes. J. Org. Chem., 1973, 38(15), 2708-2712. Caliendo, G.; Fiorino, F.; Grieco, P.; Perissutti, E.; Santagada, V.; Meli, R.; Raso, G.M.; Zanesco, A.; De Nucci, G. Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives. Eur. J. Med. Chem., 1999, 34(12), 1043-1051.

52 [142] [143]

[144]

[145] [146]

[147]

[148]

[149]

[150]

[151]

[152]

[153] [154]

[155]

[156]

[157]

[158]

[159]

[160] [161]

[162]

[163]

[164] [165] [166]

[167]

[168]

[169]

[170]

Current Organic Chemistry, 2016, Vol. 20, No. ?? Kirmse, W.; Horner, L. Umsetzung von phenylacetylen mit aziden und diazoverbindungen. Justus Liebigs Annalen der Chemie, 1958, 614(1), 1-3. Crandall, J.K.; Crawley, L.C.; Komin, J.B. Reaction of Nisopropylallenimine with organic azides. J. Org. Chem., 1975, 40(14), 20452047. Katritzky, A.R.; Singh, S.K. Synthesis of C-carbamoyl-1, 2, 3-triazoles by microwave-induced 1, 3-dipolar cycloaddition of organic azides to acetylenic amides. J. Org. Chem., 2002, 67(25), 9077-9079. Lermontov, S.; Shkavrov, S.; Pushin, A. The reaction of , -difluoroazides with acetylenic compounds. J. Fluorine Chem., 2000, 105(1), 141-147. Louërat, F.; Bougrin, K.; Loupy, A.; De Retana, A.M.O.; Pagalday, J.; Palacios, F. Cycloaddition reactions of azidomethyl phosphonate with acetylenes and enamines. Synthesis of triazoles. Heterocycles, 1998, 1(48), 161-170. Biagi, G.; Giorgi, I.; Livi, O.; Lucacchini, A.; Martini, C.; Scartoni, V. Studies on specific inhibition of benzodiazepine receptor binding by some Cbenzoyl1, 2, 3triazole derivatives. J. Pharm. Sci., 1993, 82(9), 893-896. Katritzky, A.R.; Fali, C.N.; Shcherbakova, I.V.; Verin, S.V. 1(Azidomethyl)benzotriazole and -5-phenyl-1,2,3,4-tetrazole as 1, 3-dipolar cycloaddition components. J. Heterocycl. Chem., 1996, 33(2), 335-339. Simo, O.; Rybár, A.; Alföldi, J. 2-triazolylpyrimido[1,2,3-cd]purine-8,10diones via 1,3-dipolar cycloadditions to 2-ethynylpyrimido[1,2,3-cd]purine8,10-dione. J. Heterocycl. Chem., 2000, 37(5), 1033-1039. Richardson, C.; Fitchett, C.M.; Keene, F.R.; Steel, P.J. 4, 5-Di (2-pyridyl)-1, 2, 3-triazolate: The elusive member of a family of bridging ligands that facilitate strong metal–metal interactions. Dalton Trans., 2008, 19, 2534-2537. Looker, J. Preparation of 1, 2, 3-triazoles from 7-azido-1, 3, 5cycloheptatriene. A displacement from nitrogen. J. Org. Chem., 1965, 30(2), 638-639. Hüttel, R. Über einige aldehyde der pyrazolund der 1.2.3triazolreihe. Berichte der deutschen chemischen Gesellschaft (A and B Series), 1941, 74(10), 1680-1687. Sheehan, J.C.; Robinson, C.A. The synthesis of phenyl-substituted triazole analogs of histamine. J. Am. Chem. Soc., 1951, 73(3), 1207-1210. Zheng, W.; Degterev, A.; Hsu, E.; Yuan, J.; Yuan, C. Structure–activity relationship study of a novel necroptosis inhibitor, necrostatin-7. Bioorg. Med. Chem. Lett., 2008, 18(18), 4932-4935. White, A.D.; Purchase, C.F.; Picard, J.A.; Anderson, M.K.; Mueller, B.S.; Bocan, T.M.; Bousley, R.F.; Hamelehle, K.L.; Krause, B.R.; Lee, P. Heterocyclic amides: Inhibitors of acyl-CoA: Cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit. J. Med. Chem., 1996, 39(20), 3908-3919. Gardiner, M.; Grigg, R.; Kordes, M.; Sridharan, V.; Vicker, N. One-pot sequential and cascade formation of triazoles via palladium catalysed azide capture-1, 3-dipolar cycloaddition. Tetrahedron, 2001, 57(36), 7729-7735. Gardiner, M.; Grigg, R.; Sridharan, V.; Vicker, N. Cascade and sequential palladium catalysed cyclisation-azide capture-1, 3-dipolar cycloaddition route to complex triazoles. Tetrahedron Lett., 1998, 39(5), 435-438. Chakraborty, A.; Dey, S.; Sawoo, S.; Adarsh, N.; Sarkar, A. Regioselective 1, 3-dipolar cycloaddition reaction of azides with alkoxy alkynyl fischer carbene complexes. Organometallics, 2010, 29(23), 6619-6622. Katritzky, A.R.; Zhang, Y.; Singh, S.K. 1, 2, 3-triazole formation under mild conditions via 1, 3-dipolar cycloaddition of acetylenes with azides. Heterocycles, 2003, 60(5), 1225-1239. Katritzky, A.R.; Singh, S.K. Microwave-assisted heterocyclic synthesis. Arkivoc, 2003, 13, 68-86. Katritzky, A.R.; Zhang, Y.; Singh, S.K.; Steelb, P.J. 1, 3-dipolar cycloadditions of organic azides to ester or benzotriazolylcarbonyl activated acetylenic amides. Arkivoc, 2003, 15, 47-64. Palacios, F.; Ochoa de Retana, A.; Pagalday, J. Synthesis of diethyl 1, 2, 3triazolealkyl-phosphonates through 1, 3-dipolar cycloaddition of azides with acetylenes. Heterocycles, 1994, 38(1), 95-102. Elachqar, A.; Hallaouiq, A.E.; Roumestant, M.; Viallefont, P. Synthesis of heterocyclic -aminophosphonic acids. Synth. Commun., 1994, 24(9), 12791286. Khusainova, N.G.; Pudovik, A.N. Organophosphorus compounds in 1, 3dipolar cycloaddition. Russ. Chem. Rev., 1978, 47(9), 803. Savignac, P.; and Iorga, B. Modern phosphonate chemistry, CRC Press, 2004, 19-47. Khalabi, R.E.; Hallaoui, A.E.; Ouazzani, F.; Elachqar, A.; Hajji, S.E.; Atmani, A.; Roumestanf, M.; Viallefont, P.; Martinez, J. New approach to the synthesis of heterocyclic -aminophosphonic acids. Phosphorus, Sulfur Silicon Relat. Elem., 1999, 149(1), 85-94. Palacios, F.; Ochoa de Retana, A.; Pagalday, J.; Sanchez, J. Cycloadditions of azidoalkylcarboxylates to acetylenes and enamines. Regioselective synthesis of substituted triazoles. Org. Prep. Proced. Int., 1995, 27(6), 603612. Rheingold, A.L.; LiableSands, L.M.; Trofimenko, S. 4, 5bis (diphenylphosphinoyl)1, 2, 3triazole: A powerful new ligand that uses two different modes of chelation. Angew. Chem., 2000, 112(18), 3459-3462. Rheingold, A.L.; Liable-Sands, L.M.; Trofimenko, S. 4, 5-bis (diphenylthiophosphinoyl)-1, 2, 3-triazole, L T-S2: A new varidentate ligand containing diphenylthiophosphinoyl moieties. Inorg. Chim. Acta, 2002, 330(1), 38-43. Trofimenko, S.; Rheingold, A.L.; Incarvito, C.D. 4, 5bis (diphenylphosphanyl)1, 2, 3triazole and Its conversion to 1, 1, 3, 3,tetraphenyl1,

Heravi et al.

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178]

[179]

[180]

[181]

[182]

[183]

[184]

[185]

[186]

[187]

[188] [189]

[190] [191]

[192]

[193]

[194]

[195]

[196] [197]

3diphospha2, 4, 5, 6tetraazapentalene. Angew. Chem. Int. Ed., 2003, 42(30), 3506-3509. Degl'Innoicnti, A.; Scafato, P.; Capperucci, A.; Bartoletti, L.; Mordini, A.; Reginato, G. Azide cyclizations with acetylenic silyl ketone: A general access to functionalized-1, 2, 3-triazolylacylsilanes and aldehydes. Tetrahedron Lett., 1995, 36(49), 9031-9034. Gao, D.; Zhai, H.; Parvez, M.; Back, T.G. 1, 3-dipolar cycloadditions of acetylenic sulfones in solution and on solid supports. J. Org. Chem., 2008, 73(20), 8057-8068. Boyer, J.; Mack, C.; Goebel, N.; Morgan, J.L. Notes-reactions of sodium phenylacetylide and sodium alkoxide with tosyl and mesyl azides. J. Org. Chem., 1958, 23(7), 1051-1053. Hanamoto, T.; Hakoshima, Y.; Egashira, M. Tributyl (3, 3, 3-trifluoro-1propynyl) stannane as an efficient reagent for the preparation of various trifluoromethylated heterocyclic compounds. Tetrahedron Lett., 2004, 45(41), 7573-7576. Ye, C.; Gard, G.L.; Winter, R.W.; Syvret, R.G.; Twamley, B.; Shreeve, J.N.M. Synthesis of pentafluorosulfanylpyrazole and pentafluorosulfanyl-1, 2, 3-triazole and their derivatives as energetic materials by click chemistry. Org. Lett., 2007, 9(19), 3841-3844. Ma, D.Y.; Wang, D.X.; Zheng, Q.Y.; Wang, M.X. Nitrile biotransformations for the practical synthesis of highly enantiopure azido carboxylic acids and amides,‘click’to functionalized chiral triazoles and chiral -amino acids. Tetrahedron: Asymmetry, 2006, 17(16), 2366-2376. Lenda, F.; Guenoun, F.; Tazi, B.; Martinez, J.; Lamaty, F. Synthesis of new triazole substituted pyroaminoadipic and pipecolic acid derivatives. Tetrahedron Lett., 2004, 45(48), 8905-8907. Lenda, F.; Guenoun, F.; Martinez, J.; Lamaty, F. Synthesis of new tetrazole and triazole substituted pyroglutamic acid and proline derivatives. Tetrahedron Lett., 2007, 48(5), 805-808. Zhang, X.; Hsung, R.P.; You, L. Tandem azidination–and hydroazidination– Huisgen [3+ 2]cycloadditions of ynamides. Synthesis of chiral amidesubstituted triazoles. Org. Biomole. Chem., 2006, 4(14), 2679-2682. Trybulski, E.; Benjamin, L.; Vitone, S.; Walser, A.; Fryer, R. 2benzazepines.[1, 2, 3] triazolo [4, 5-d][2] benzazepines and dibenzo [c, f][1, 2, 3] triazolo [3, 4-a] azepines. Synthesis and evaluation as central nervous system agents. J. Med. Chem., 1983, 26(3), 367-372. Choi, K.W.; Brimble, M.A. Synthesis of spiroacetal-triazoles as privileged natural product-like scaffolds using “click chemistry”. Org. Biomole. Chem., 2008, 6(19), 3518-3526. Kloss, F.; Köhn, U.; Jahn, B.O.; Hager, M.D.; Görls, H.; Schubert, U.S. Metalfree 1, 5regioselective azide–alkyne [3+ 2]cycloaddition. Chem. Asian. J., 2011, 6(10), 2816. Li, P.; Wang, L. One-pot synthesis of 1, 2, 3-triazoles from benzyl and alkyl halides, sodium azide and alkynes in water under transition-metal-catalyst free reaction conditions. Lett. Org. Chem., 2007, 4(1), 23-26. Zanirato, P. Reactivity of aryl and heteroaryl azides with vinylsilane and alkynylsilane. Formation of C-silylated 1, 2, 3-triazolines and 1, 2, 3triazoles. J. Chem. Soc. Perkin Trans. 1, 1991, (11), 2789-2796. Achamlal, S.; Elachgar, A.; El Hallaoui, A.; El Hajji, S.; Roumestant, M.; Viallefont, P. Synthesis of-triazolyl-amino acid derivatives. Amino Acids, 1997, 12(3), 257-263. Agard, N.J.; Prescher, J.A.; Bertozzi, C.R. A strain-promoted [3+ 2] azidealkyne cycloaddition for covalent modification of biomolecules in living systems. J. Am. Chem. Soc., 2004, 126(46), 15046-15047. Li, Z.; Seo, T.S.; Ju, J. 1, 3-Dipolar cycloaddition of azides with electrondeficient alkynes under mild condition in water. Tetrahedron Lett., 2004, 45(15), 3143-3146. Jewett, J.C.; Bertozzi, C.R. Cu-free click cycloaddition reactions in chemical biology. Chem. Soc. Rev., 2010, 39(4), 1272-1279. Wang, Z.X.; Qin, H.L. Regioselective synthesis of 1, 2, 3-triazole derivatives via 1, 3-dipolar cycloaddition reactions in water. Chem. Commun., 2003, (19), 2450-2451. Lutz, J.F. Copperfree azide–alkyne cycloadditions: New insights and perspectives. Angew. Chem. Int. Ed., 2008, 47(12), 2182-2184. Becer, C.R.; Hoogenboom, R.; Schubert, U.S. Click chemistry beyond metalcatalyzed cycloaddition. Angew. Chem. Int. Ed., 2009, 48(27), 49004908. Pearson, W.H.; Bergmeier, S.C.; Chytra, J.A. The synthesis of triazole analogues of antitumor dehydropyrrolizidine alkaloids. Synthesis, 1990, (2), 156-159. Merling, E.; Lamm, V.; Geib, S.J.; Lacôte, E.; Curran, D.P. [3+ 2]-dipolar cycloaddition reactions of an N-heterocyclic carbene boryl azide. Org. Lett., 2012, 14(11), 2690-2693. Beryozkina, T.; Appukkuttan, P.; Mont, N.; Van der Eycken, E. Microwaveenhanced synthesis of new (-)-steganacin and (-)-steganone aza analogues. Org. Lett., 2006, 8(3), 487-490. Xia, Y.; Chen, L.Y.; Lv, S.; Sun, Z.; Wang, B. Microwave-assisted or Cu– NHC-catalyzed cycloaddition of azido-disubstituted alkynes: Bifurcation of reaction pathways. J. Org. Chem., 2014, 79(20), 9818-9825. Finley, T.; Montgomery, J.A. The Chemistry of Heterocyclic Compounds, Triazoles 1, 2, 3. John Wiley & Sons: 1981; Vol. 39. Belskaya, N.; Subbotina, J.; Lesogorova, S. Synthesis of 2H-1, 2, 3-triazoles. In: Chemistry of 1, 2, 3-triazoles, Springer, 2015; pp. 51-116.

Huisgen’s Cycloaddition Reactions [198]

[199]

[200]

[201] [202]

[203] [204] [205]

[206]

[207] [208]

[209]

[210]

[211]

[212] [213] [214]

[215] [216] [217] [218]

[219]

[220]

[221]

[222]

[223]

[224]

[225] [226]

Yet, L. FiveMembered Heterocycles with Three Heteroatoms: Triazoles. Modern Heterocyclic Chemistry; Builla, J.A.; Vaguero. J.; Barluenga, J. Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2011, Vol 4, pp. 989-1045. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V.V.; Sharpless, K.B.; Finn, M. Bioconjugation by copper (I)-catalyzed azide-alkyne [3+ 2] cycloaddition. J. Am. Chem. Soc., 2003, 125(11), 3192-3193. Gupta, S.S.; Kuzelka, J.; Singh, P.; Lewis, W.G.; Manchester, M.; Finn, M. Accelerated bioorthogonal conjugation: A practical method for the ligation of diverse functional molecules to a polyvalent virus scaffold. Bioconjugate Chem., 2005, 16(6), 1572-1579. Meldal, M.; Tornøe, C.W. Cu-catalyzed azide alkyne cycloaddition. Chem. Rev., 2008, 108(8), 2952-3015. Haldón, E.; Nicasio, M.C.; Pérez, P.J. Copper-catalysed azide–alkyne cycloadditions (CuAAC): An update. Org. Biomole. Chem., 2015, 13(37), 9528-9550. Alonso, F.; Moglie, Y.; Radivoy, G. Copper nanoparticles in click chemistry. Acc. Chem. Res., 2015, 48(9), 2516-2528. Dervaux, B.; Du Prez, F.E. Heterogeneous azide–alkyne click chemistry: Towards metal-free end products. Chem. Sci., 2012, 3(4), 959-966. Kamata, K.; Yamaguchi, S.; Kotani, M.; Yamaguchi, K.; Mizuno, N. Efficient oxidative alkyne homocoupling catalyzed by a monomeric dicoppersubstituted silicotungstate. Angew. Chem. Int. Ed., 2008, 47(13), 2407-2410. Kamata, K.; Yamaguchi, S.; Kotani, M.; Yamaguchi, K.; Mizuno, N. Efficient oxidative alkyne homocoupling catalyzed by a monomeric dicoppersubstituted silicotungstate. Angew. Chem., 2008, 120(13), 2441-2444. Chan, T.R.; Hilgraf, R.; Sharpless, K.B.; Fokin, V.V. Polytriazoles as copper(I)-stabilizing ligands in catalysis. Org. Lett., 2004, 6(17), 2853-2855. Rodionov, V.O.; Presolski, S.I.; Díaz, D.; Fokin, V.V.; Finn, M. Ligandaccelerated Cu-catalyzed azide-alkyne cycloaddition: A mechanistic report. J. Am. Chem. Soc., 2007, 129(42), 12705-12712. Rodionov, V.O.; Presolski, S.I.; Gardinier, S.; Lim, Y.H.; Finn, M. Benzimidazole and related ligands for Cu-catalyzed azide-alkyne cycloaddition. J. Am. Chem. Soc., 2007, 129(42), 12696-12704. Lee, B.Y.; Park, S.R.; Jeon, H.B.; Kim, K.S. A new solvent system for efficient synthesis of 1,2,3-triazoles. Tetrahedron Lett., 2006, 47(29), 51055109. Díez-González, S. Well-defined copper (I) complexes for click azide–alkyne cycloaddition reactions: One click beyond. Catal. Sci. Technol., 2011, 1(2), 166-178. Appukkuttan, P.; Mehta, V.P.; Van der Eycken, E.V. Microwave-assisted cycloaddition reactions. Chem. Soc. Rev., 2010, 39(5), 1467-1477. Bougrin, K.; Benhida, R. MicrowaveAssisted Cycloaddition Reactions. Microwaves in Organic Synthesis, 3rd ed, 2012; Vol.1, pp. 737-809. Barge, A.; Tagliapietra, S.; Binello, A.; Cravotto, G. Click chemistry under microwave or ultrasound irradiation. Curr. Org. Chem., 2011, 15(2), 189203. Kappe, C.O.; Van der Eycken, E. Click chemistry under non-classical reaction conditions. Chem. Soc. Rev., 2010, 39(4), 1280-1290. Cella, R.; Stefani, H.A. Ultrasound in heterocycles chemistry. Tetrahedron, 2009, 65(13), 2619-2641. Sreedhar, B.; Reddy, S.P. Sonochemical synthesis of 1, 4disubstituted 1, 2, 3triazoles in aqueous medium. Synth. Commun., 2007, 37(5), 805-812. Silva, M.T.D.; Oliveira, R.N.D.; Valença, W.O.; Barbosa, F.C.; Silva, M.G.D.; Camara, C.A. Synthesis of N-substituted phthalimidoalkyl 1H-1, 2, 3-triazoles: A molecular diversity combining click chemistry and ultrasound irradiation. J. Braz. Chem. Soc., 2012, 23(10), 1839-1843. Zhong, P.; Guo, S.R. Novel synthesis of 1, 2, 3triazoles via 1, 3dipolar cycloadditions of alkynes to azides in ionic liquid. Chin. J. Chem., 2004, 22(10), 1183-1186. Khanetskyy, B.; Dallinger, D.; Kappe, C.O. Combining biginelli multicomponent and click chemistry: Generation of 6-(1, 2, 3-triazol-1-yl)dihydropyrimidone libraries. J. Comb. Chem., 2004, 6(6), 884-892. Wu, Y.M.; Deng, J.; Fang, X.; Chen, Q.Y. Regioselective synthesis of fluoroalkylated [1,2,3]-triazoles by Huisgen cycloaddition. J. Fluorine Chem., 2004, 125(10), 1415-1423. Orgueira, H.A.; Fokas, D.; Isome, Y.; Chan, P.C.M.; Baldino, C.M. Regioselective synthesis of [1, 2, 3]-triazoles catalyzed by Cu (I) generated in situ from Cu (0) nanosize activated powder and amine hydrochloride salts. Tetrahedron Lett., 2005, 46(16), 2911-2914. Pachón, L.D.; Van Maarseveen, J.H.; Rothenberg, G. Click chemistry: Copper clusters catalyse the cycloaddition of azides with terminal alkynes. Adv. Synth. Catal., 2005, 347(6), 811-815. Kaval, N.; Ermolat'ev, D.; Appukkuttan, P.; Dehaen, W.; Kappe, C.O.; Van der Eycken, E. The application of “click chemistry” for the decoration of 2 (1 H)-pyrazinone scaffold: Generation of templates. J. Comb. Chem., 2005, 7(3), 490-502. Lipshutz, B.H.; Taft, B.R. Heterogeneous copperincharcoalcatalyzed click chemistry. Angew. Chem., 2006, 118(48), 8415-8418. DíezGonzález, S.; Correa, A.; Cavallo, L.; Nolan, S.P. (NHC) copper (I)catalyzed [3+ 2] cycloaddition of azides and monoor disubstituted alkynes. Chem. Eur. J., 2006, 12(29), 7558-7564.


[228]

[229]

[230]

[231]

[232]

[233]

[234]

[235]

[236] [237]

[238]

[239]

[240]

[241]

[242]

[243]

[244]

[245]

[246]

[247]

[248]

[249]

[250]

[251]

53

Guezguez, R.; Bougrin, K.; El Akri, K.; Benhida, R. A highly efficient microwave-assisted solvent-free synthesis of -and -2-deoxy-1, 2, 3triazolyl-nucleosides. Tetrahedron Lett., 2006, 47(28), 4807-4811. Castagnolo, D.; Dessì, F.; Radi, M.; Botta, M. Synthesis of enantiomerically pure -[4-(1-substituted)-1, 2, 3-triazol-4-yl]-benzylacetamides via microwave-assisted click chemistry: Towards new potential antimicrobial agents. Tetrahedron: Asymmetry, 2007, 18(11), 1345-1350. Broggi, J.; Joubert, N.; Aucagne, V.; Berteina-Raboin, S.; Diez-Gonzalez, S.; Nolan, S.; Topalis, D.; Deville-Bonne, D.; Balzarini, J.; Neyts, J. Alkyneazide click chemistry mediated carbanucleosides synthesis. Nucleos. Nucleot. Nucl., 2007, 26(10-12), 1391-1394. Broggi, J.; Joubert, N.; Aucagne, V.; Zevaco, T.; Berteina-Raboin, S.; Nolan, S.P.; Agrofoglio, L.A. Study of different copper (I) catalysts for the “Click Chemistry” approach to carbanucleosides. Nucleos. Nucleot. Nucl., 2007, 26(6-7), 779-783. Chassaing, S.; Kumarraja, M.; Sani Souna Sido, A.; Pale, P.; Sommer, J. Click chemistry in CuI-zeolites: The huisgen [3+ 2]-cycloaddition. Org. Lett., 2007, 9(5), 883-886. Mindt, T.L.; Schibli, R. Cu (I)-catalyzed intramolecular cyclization of alkynoic acids in aqueous media: A “Click Side reaction”. J. Org. Chem., 2007, 72(26), 10247-10250. Li, P.; Wang, L.; Zhang, Y. SiO 2–NHC–Cu (I): An efficient and reusable catalyst for [3+ 2] cycloaddition of organic azides and terminal alkynes under solvent-free reaction conditions at room temperature. Tetrahedron, 2008, 64(48), 10825-10830. Park, I.S.; Kwon, M.S.; Kim, Y.; Lee, J.S.; Park, J. Heterogeneous copper catalyst for the cycloaddition of azides and alkynes without additives under ambient conditions. Org. Lett., 2008, 10(3), 497-500. Jlalia, I.; Elamari, H.; Meganem, F.; Herscovici, J.; Girard, C. Copper (I)doped Wyoming’s montmorillonite for the synthesis of disubstituted 1, 2, 3triazoles. Tetrahedron Lett., 2008, 49(48), 6756-6758. Martinelli, M.; Milcent, T.; Ongeri, S.; Crousse, B. Synthesis of new triazole-based trifluoromethyl scaffolds. Beilstein. J. Org. Chem., 2008, 4(1), 19. Artyushin, O.I.; Vorob'eva, D.V.; Vasil'eva, T.P.; Osipov, S.N.; Röschenthaler, G.V.; Odinets, I.L. Facile synthesis of phosphorylated azides in ionic liquids and their use in the preparation of 1, 2, 3triazoles. Heteroat. Chem., 2008, 19(3), 293-300. Delain-Bioton, L.; Villemin, D.; Lohier, J.F.; Sopkova, J.; Jaffres, P.A. Synthesis of triazolyl-alkylphosphonate starting from azidoalkylphosphonates or -alkynylphosphonates. Tetrahedron, 2007, 63(39), 9677-9684. Fletcher, J.T.; Walz, S.E.; Keeney, M.E. Monosubstituted 1, 2, 3-triazoles from two-step one-pot deprotection/click additions of trimethylsilylacetylene. Tetrahedron Lett., 2008, 49(49), 7030-7032. Sarkar, A.; Mukherjee, T.; Kapoor, S. PVP-stabilized copper nanoparticles: A reusable catalyst for “click” reaction between terminal alkynes and azides in nonaqueous solvents. J. Phys. Chem., 2008, 112(9), 3334-3340. Kamata, K.; Nakagawa, Y.; Yamaguchi, K.; Mizuno, N. 1, 3-dipolar cycloaddition of organic azides to alkynes by a dicopper-substituted silicotungstate. J. Am. Chem. Soc., 2008, 130(46), 15304-15310. Sirion, U.; Bae, Y.J.; Lee, B.S.; Chi, D.Y. Ionic polymer supported copper(I): A reusable catalyst for huisgen’s 1,3-dipolar cycloaddition. Synlett, 2008, 2008(15), 2326-2330. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Copper nanoparticles in click chemistry: An alternative catalytic system for the cycloaddition of terminal alkynes and azides. Tetrahedron Lett., 2009, 50(20), 2358-2362. Chtchigrovsky, M.; Primo, A.; Gonzalez, P.; Molvinger, K.; Robitzer, M.; Quignard, F.; Taran, F. Functionalized chitosan as a green, recyclable, biopolymersupported catalyst for the [3+ 2] huisgen cycloaddition. Angew. Chem., 2009, 121(32), 6030-6034. Namitharan, K.; Kumarraja, M.; Pitchumani, K. CuII–hydrotalcite as an efficient heterogeneous catalyst for huisgen [3+2] cycloaddition. Chem. Eur. J., 2009, 15(12), 2755-2758. Chtchigrovsky, M.; Primo, A.; Gonzalez, P.; Molvinger, K.; Robitzer, M.; Quignard, F.; Taran, F. Functionalized chitosan as a green, recyclable, biopolymer-supported catalyst for the [3+2] huisgen cycloaddition. Angew. Chem. Int. Ed., 2009, 48(32), 5916-5920. Raut, D.; Wankhede, K.; Vaidya, V.; Bhilare, S.; Darwatkar, N.; Deorukhkar, A.; Trivedi, G.; Salunkhe, M. Copper nanoparticles in ionic liquids: Recyclable and efficient catalytic system for 1, 3-dipolar cycloaddition reaction. Catal. Commun., 2009, 10(8), 1240-1243. Jlalia, I.; Meganem, F.; Herscovici, J.; Girard, C. “Flash” solvent-free synthesis of triazoles using a supported catalyst. Molecules, 2009, 14(1), 528539. Brotherton, W.S.; Michaels, H.A.; Simmons, J.T.; Clark, R.J.; Dalal, N.S.; Zhu, L. Apparent copper (II)-accelerated azide alkyne cycloaddition. Org. Lett., 2009, 11(21), 4954-4957. MegiaFernandez, A.; OrtegaMunoz, M.; LopezJaramillo, J.; HernandezMateo, F.; SantoyoGonzalez, F. Nonmagnetic and magnetic supported copper (I) chelating adsorbents as efficient heterogeneous catalysts and copper scavengers for click chemistry. Adv. Synth. Catal., 2010, 352(18), 33063320. Lee, B.S.; Yi, M.; Chu, S.Y.; Lee, J.Y.; Kwon, H.R.; Lee, K.R.; Kang, D.; Kim, W.S.; Lim, H.B.; Lee, J.; Youn, H.J.; Chi, D.Y.; Hur, N.H. Copper ni-

54

[252]

[253]

[254] [255]

[256] [257]

[258]

[259]

[260]

[261]

[262]

[263]

[264]

[265]

[266]

[267]

[268]

[269]

[270]

[271]

[272]

[273]

[274]

[275]

[276]

Current Organic Chemistry, 2016, Vol. 20, No. ?? tride nanoparticles supported on a superparamagnetic mesoporous microsphere for toxic-free click chemistry. Chem. Commun., 2010, 46(22), 39353937. Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y. Carboxylic acidpromoted copper (I)-catalyzed azide alkyne cycloaddition. J. Org. Chem., 2010, 75(20), 7002-7005. Suzuka, T.; Ooshiro, K.; Kina, K.Y. Reusable polymer-supported terpyridine copper complex for [3+ 2] Huisgen cycloaddition in water. Heterocycles, 2010, 81(3), 601-610. Tasdelen, M.A.; Yagci, Y. Light-induced copper (I)-catalyzed click chemistry. Tetrahedron Lett., 2010, 51(52), 6945-6947. Wang, D.; Li, N.; Zhao, M.; Shi, W.; Ma, C.; Chen, B. Solvent-free synthesis of 1, 4-disubstituted 1, 2, 3-triazoles using a low amount of Cu (PPh 3) 2 NO 3 complex. Green. Chem., 2010, 12(12), 2120-2123. Meng, X.; Xu, X.; Gao, T.; Chen, B. Zn/Ccatalyzed cycloaddition of azides and aryl alkynes. Eur. J. Org. Chem., 2010, 2010(28), 5409-5414. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Unsupported copper nanoparticles in the 1, 3dipolar cycloaddition of terminal alkynes and azides. Eur. J. Org. Chem., 2010, 2010(10), 1875-1884. Wu, L.; Chen, Y.; Tang, M.; Song, X.; Chen, G.; Song, X.; Lin, Q. Potassium tert-butoxide promoted cycloaddition reaction for the synthesis of 1, 5disubstituted 1, 2, 3-triazoles from aromatic azides and trimethylsilylprotected alkynes. Synlett, 2012, 23(10), 1529-1533. Cuevas, F.; Oliva, A.I.; Pericàs, M.A. Direct copper (I)-catalyzed cycloaddition of organic azides with TMS-protected alkynes. Synlett, 2010, 12, 18731877. Friscourt, F.; Boons, G.J. One-pot three-step synthesis of 1, 2, 3-triazoles by copper-catalyzed cycloaddition of azides with alkynes formed by a Sonogashira cross-coupling and desilylation. Org. Lett., 2010, 12(21), 4936-4939. Cintas, P.; Barge, A.; Tagliapietra, S.; Boffa, L.; Cravotto, G. Alkyne–azide click reaction catalyzed by metallic copper under ultrasound. Nat. Protocols, 2010, 5(3), 607-616. Martina, K.; Leonhardt, S.E.; Ondruschka, B.; Curini, M.; Binello, A.; Cravotto, G. In situ cross-linked chitosan Cu (I) or Pd (II) complexes as a versatile, eco-friendly recyclable solid catalyst. J. Mol. Catal. A: Chem., 2011, 334(1), 60-64. Kumar, R.; Pradhan, P.; Zajc, B. Facile synthesis of 4-vinyl-and 4fluorovinyl-1, 2, 3-triazoles via bifunctional “click-olefination” reagents. Chem. Commun., 2011, 47(13), 3891-3893. Buckley, B.R.; Dann, S.E.; Heaney, H.; Stubbs, E.C. Heterogeneous catalytic reactions “on water” by using stable polymeric alkynylcopper (I) precatalysts: Alkyne/azide cycloaddition reactions. Eur. J. Org. Chem., 2011, 2011(4), 770-776. Lal, S.; Díez-González, S. [CuBr (PPh3) 3] for azide alkyne cycloaddition reactions under strict click conditions. J. Org. Chem., 2011, 76(7), 23672373. Shao, C.; Wang, X.; Zhang, Q.; Luo, S.; Zhao, J.; Hu, Y. Acid–base jointly promoted copper (I)-catalyzed azide–alkyne cycloaddition. J. Org. Chem., 2011, 76(16), 6832-6836. Bü rglová, K.N.; Moitra, N.; Hoda ová, J.; Cattoën, X.; Man, W.C.M. Click approaches to functional water-sensitive organotriethoxysilanes. J. Org. Chem., 2011, 76(18), 7326-7333. Silvestri, I.P.; Andemarian, F.; Khairallah, G.N.; Yap, S.W.; Quach, T.; Tsegay, S.; Williams, C.M.; Richard, A.; Donnelly, P.S.; Williams, S.J. Copper (i)-catalyzed cycloaddition of silver acetylides and azides: Incorporation of volatile acetylenes into the triazole core. Org. Biomole. Chem., 2011, 9(17), 6082-6088. Nakamura, T.; Terashima, T.; Ogata, K.; Fukuzawa, S.I. Copper (I) 1, 2, 3triazol-5-ylidene complexes as efficient catalysts for click reactions of azides with alkynes. Org. Lett., 2011, 13(4), 620-623. Liu, M.; Reiser, O. A copper (I) isonitrile complex as a heterogeneous catalyst for azide alkyne cycloaddition in water. Org. Lett., 2011, 13(5), 11021105. Xu, M.; Kuang, C.; Wang, Z.; Yang, Q.; Jiang, Y. A novel approach to 1monosubstituted1, 2, 3-triazoles by a click cycloaddition/decarboxylation process. Synthesis, 2011, 2011(02), 223-228. Li, L.; Li, R.; Zhu, A.; Zhang, G.; Zhang, L. CuBrNCS-mediated multicomponent azide-alkyne cycloaddition: Mild and efficient synthesis of 5bromo-1, 4-disubstituted-1, 2, 3-triazoles. Synlett, 2011, (6), 874-878. Liu, Y.; Wang, X.; Xu, J.; Zhang, Q.; Zhao, Y.; Hu, Y. Highly controlling selectivity of copper (I)-catalyzed azide/alkyne cycloaddition (CuAAC) between sulfonyl azides and normal alkynes or propynoates. Tetrahedron, 2011, 67(34), 6294-6299. González, J.; Pérez, V.M.; Jiménez, D.O.; Lopez-Valdez, G.; Corona, D.; Cuevas-Yañez, E. Effect of temperature on triazole and bistriazole formation through copper-catalyzed alkyne–azide cycloaddition. Tetrahedron Lett., 2011, 52(27), 3514-3517. Shao, C.; Zhu, R.; Luo, S.; Zhang, Q.; Wang, X.; Hu, Y. Copper (I) oxide and benzoic acid ‘on water’: A highly practical and efficient catalytic system for copper (I)-catalyzed azide–alkyne cycloaddition. Tetrahedron Lett., 2011, 52(29), 3782-3785. Stefani, H.A.; Vieira, A.S.; Amaral, M.F.; Cooper, L. Synthesis of 5-alkynyl2, 2, 6-trimethyl-1, 3-dioxin-4-ones and 1, 4-disubstituted-1, 2, 3-triazoles. Tetrahedron Lett., 2011, 52(33), 4256-4261.

Heravi et al. [277]

[278]

[279]

[280]

[281]

[282]

[283]

[284] [285]

[286]

[287]

[288]

[289]

[290]

[291]

[292]

[293]

[294]

[295] [296]

[297]

[298]

[299]

[300]

[301]

[302]

Stefani, H.A.; Canduzini, H.A.; Manarin, F. Modular synthesis of mono, di, and tri-1, 4-disubstituted-1, 2, 3-triazoles through copper-mediated alkyne– azide cycloaddition. Tetrahedron Lett., 2011, 52(46), 6086-6090. Stefani, H.A.; Amaral, M.F.; Manarin, F.; Ando, R.A.; Silva, N.C.; Juaristi, E. Functionalization of 2-(S)-isopropyl-5-iodo-pyrimidin-4-ones through Cu (I)-mediated 1, 3-dipolar azide–alkyne cycloadditions. Tetrahedron Lett., 2011, 52(51), 6883-6886. Masuyama, Y.; Yoshikawa, K.; Suzuki, N.; Hara, K.; Fukuoka, A. Hydroxyapatite-supported copper (II)-catalyzed azide–alkyne [3+ 2] cycloaddition with neither reducing agents nor bases in water. Tetrahedron Lett., 2011, 52(51), 6916-6918. Baig, N.R.B.; Varma, R.S. A highly active magnetically recoverable nano ferrite-glutathione-copper (nano-FGT-Cu) catalyst for Huisgen 1,3-dipolar cycloadditions. Green. Chem., 2012, 14(3), 625-632. Hudson, R.; Li, C.J.; Moores, A. Magnetic copper–iron nanoparticles as simple heterogeneous catalysts for the azide–alkyne click reaction in water. Green. Chem., 2012, 14(3), 622-624. Ishikawa, S.; Hudson, R.; Moores, A.; Li, C.J. Ligand modified CuFe2O4 nanoparticles as magnetically recoverable and reusable catalyst for azidealkyne click condensation. Heterocycles, 2012, (86), 1023-1030. Woo, H.; Kang, H.; Kim, A.; Jang, S.; Park, J.C.; Park, S.; Kim, B.S.; Song, H.; Park, K.H. Azide-alkyne huisgen [3+ 2] cycloaddition using CuO nanoparticles. Molecules, 2012, 17(11), 13235-13252. Elayadi, H. Arkivoc, 2012, 8, 76-89. Hwang, S.; Bae, H.; Kim, S.; Kim, S. An efficient and high-yielding one-pot synthesis of 4-acyl-1, 2, 3-triazoles via triisopropylsilyl-protected ynones. Tetrahedron, 2012, 68(5), 1460-1465. Jacob, K.; Stolle, A.; Ondruschka, B.; Jandt, K.D.; Keller, T.F. Cu on porous glass: An easily recyclable catalyst for the microwave-assisted azide–alkyne cycloaddition in water. Appl. Catal. A. Gen., 2013, 451, 94-100. Baig, R.N.; Varma, R.S. Copper on chitosan: A recyclable heterogeneous catalyst for azide–alkyne cycloaddition reactions in water. Green. Chem., 2013, 15(7), 1839-1843. Ahmady, A.Z.; Heidarizadeh, F.; Keshavarz, M. Ionic liquid containing copper (I): A new, green, homogeneous, and reusable catalyst for click cyclization. Synth. Commun., 2013, 43(15), 2100-2109. Kumar, A.S.; Datta, K.; Rao, T.S.; Raghavan, K.; Eswaramoorthy, M.; Reddy, B. Aminoclay-supported copper nanoparticles for 1, 3-dipolar cycloaddition of azides with alkynes via click chemistry. J. Nanosci. Nanotechnol., 2013, 13(4), 3136-3141. Diz, P.M.; Coelho, A.; El Maatougui, A.; Azuaje, J.; Caamano, O.; Gil, A.; Sotelo, E. Copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions: Polymer-assisted assembly of 4-acyl-1-substituted-1,2,3triazoles. J. Org. Chem., 2013, 78(13), 6540-6549. Su, N.N.; Li, Y.; Yu, S.J.; Zhang, X.; Liu, X.H.; Zhao, W.G. Microwaveassisted synthesis of some novel 1, 2, 3-triazoles by click chemistry, and their biological activity. Res. Chem. Intermed., 2013, 39(2), 759-766. López-Ruiz, H.; De la Cerda-Pedro, J.E.; Rojas-Lima, S.; Pérez-Pérez, I.; Rodríguez-Sánchez, B.V.; Santillan, R.; Coreño, O. Cuprous oxide on charcoal-catalyzed ligand-free synthesis of 1, 4-disubstituted 1, 2, 3-triazoles via click chemistry. Arkivoc, 2013, 3, 139-164. Collinson, J.M.; Wilton-Ely, J.D.; Díez-González, S. Reusable and highly active supported copper (I)–NHC catalysts for Click chemistry. Chem. Commun., 2013, 49(97), 11358-11360. Song, J.H.; Choi, P.; Lee, S.E.; Jeong, K.H.; Kim, T.; Kang, K.S.; Choi, Y.S.; Ham, J. Efficient and rapid regioselective onepot synthesis of 1, 4disubstituted 1, 2, 3triazoles from in situ generated potassium arylethynyltrifluoroborates through sonogashira reaction. Eur. J. Org. Chem., 2013, 2013(28), 6249-6253. Jacob, K.; Stolle, A. Microwave-assisted azide-alkyne cycloaddition in water using a heterogeneous Cu-catalyst. Synth. Commun., 2014, 44(9), 1251-1257. Billault, I.; Pessel, F.; Petit, A.; Turgis, R.; Scherrmann, M.C. Investigation of the copper(i) catalysed azide-alkyne cycloaddition reactions (CuAAC) in molten PEG2000. New J. Chem., 2015, 39(3), 1986-1995. Movassagh, B.; Rezaei, N. Polystyrene resin-supported CuI-cryptand 22 complex: A highly efficient and reusable catalyst for three-component synthesis of 1, 4-disubstituted 1, 2, 3-triazoles under aerobic conditions in water. Tetrahedron, 2014, 70(46), 8885-8892. Chahdoura, F.; Pradel, C.; Gómez, M. Copper (I) oxide nanoparticles in glycerol: A convenient catalyst for crosscoupling and azide–alkyne cycloaddition processes. ChemCatChem, 2014, 6(10), 2929-2936. Jumde, R.P.; Evangelisti, C.; Mandoli, A.; Scotti, N.; Psaro, R. Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for continuousflow Huisgen azide-alkyne cycloaddition (CuAAC). J. Catal., 2015, 324, 2531. Marullo, S.; D’Anna, F.; Rizzo, C.; Noto, R. The ultrasounds–ionic liquids synergy on the copper catalyzed azide–alkyne cycloaddition between phenylacetylene and 4-azidoquinoline. Ultrason. Sonochem., 2015, 23, 317-323. Liang, L.; Astruc, D. The copper (I)-catalyzed alkyne-azide cycloaddition (CuAAC)“click” reaction and its applications. An overview. Coord. Chem. Rev., 2011, 255(23), 2933-2945. Kempe, K.; Krieg, A.; Becer, C.R.; Schubert, U.S. “Clicking” on/with polymers: A rapidly expanding field for the straightforward preparation of novel macromolecular architectures. Chem. Soc. Rev., 2012, 41(1), 176-191

Huisgen’s Cycloaddition Reactions [303] [304]

[305]

[306]

[307] [308]

[309]

[310]

[311]

[312]

[313]

[314]

[315]

[316]

[317]

[318]

[319]

[320]

[321]

[322]

[323]

[324]

[325]

[326]

[327]

[328]

Yang, M.; Li, J.; Chen, P.R. Transition metal-mediated bioorthogonal protein chemistry in living cells. Chem. Soc. Rev., 2014, 43(18), 6511-6526. Amblard, F.; Cho, J.H.; Schinazi, R.F. Cu (I)-catalyzed Huisgen azide alkyne 1, 3-dipolar cycloaddition reaction in nucleoside, nucleotide, and oligonucleotide chemistry. Chem. Rev., 2009, 109(9), 4207-4220 Lutz, J.F.; Zarafshani, Z. Efficient construction of therapeutics, bioconjugates, biomaterials and bioactive surfaces using azide–alkyne “click” chemistry. Adv. Drug. Deliv. Rev., 2008, 60(9), 958-970. Fernandes, A.E.; Jonas, A.M.; Riant, O. Application of CuAAC for the covalent immobilization of homogeneous catalysts. Tetrahedron, 2014, 70(9), 1709-1731. Scriven, E.F.; Turnbull, K. Azides: Their preparation and synthetic uses. Chem. Rev., 1988, 88(2), 297-368. Maksikova, A.; Serebryakova, E.; Tikhonova, L.; Vereshchagin, L. Synthesis of 1-alkyl-4 (5)-hydroxymethyl-1, 2, 3-triazoles. Chem. Heterocycl. Compd., 1980, 16(12), 1284-1285. Feldman, A.K.; Colasson, B.; Fokin, V.V. One-pot synthesis of 1, 4disubstituted 1, 2, 3-triazoles from in situ generated azides. Org. Lett., 2004, 6(22), 3897-3899. Kolthoff, I.; Coetzee, J. Polarography in acetonitrile. II. Metal ions which have significantly different polarographic properties in acetonitrile and in water. Anodic waves. Voltammetry at rotated platinum electrode. J. Am. Chem. Soc., 1957, 79(8), 1852-1858. Diez-Gonzalez, S. The use of ligands in copper-catalyzed [3+ 2] azidealkyne cycloaddition: Clicker than Click chemistry? Curr. Org. Chem., 2011, 15(16), 2830-2845. Appukkuttan, P.; Dehaen, W.; Fokin, V.V.; Van der Eycken, E. A microwave-assisted click chemistry synthesis of 1, 4-disubstituted 1, 2, 3-triazoles via a copper (I)-catalyzed three-component reaction. Org. Lett., 2004, 6(23), 4223-4225. Zhao, Y.B.; Yan, Z.Y.; Liang, Y.M. Efficient synthesis of 1,4-disubstituted 1,2,3-triazoles in ionic liquid/water system. Tetrahedron Lett., 2006, 47(10), 1545-1549. Andersen, J.; Bolvig, S.; Liang, X. Efficient one-pot synthesis of 1-aryl 1,2,3-triazoles from aryl haldides and terminal alkynes in the presence of sodium azide. Synlett, 2005, (19), 2941-2947. Kantam, M.L.; Jaya, V.S.; Sreedhar, B.; Rao, M.M.; Choudary, B.M. Preparation of alumina supported copper nanoparticles and their application in the synthesis of 1,2,3-triazoles. J. Mol. Catal. A: Chem., 2006, 256(1-2), 273277. Wang, Z.X.; Zhao, Z.G. Synthesis of 1,4-disubstituted 1,2,3-triazoles via a three-component reaction in water in the presence of cux (X = Cl, I). J. Heterocycl. Chem., 2007, 44(1), 89-92. Odlo, K.; Høydahl, E.A.; Hansen, T.V. One-pot synthesis of 1, 4disubstituted 1, 2, 3-triazoles from terminal acetylenes and in situ generated azides. Tetrahedron Lett., 2007, 48(12), 2097-2099. Ackermann, L.; Potukuchi, H.K.; Landsberg, D.; Vicente, R. Coppercatalyzed “click” reaction/direct arylation sequence: Modular synthesis of 1, 2, 3-triazoles. Org. Lett., 2008, 10(14), 3081-3084. Sharghi, H.; Khalifeh, R.; Doroodmand, M.M. Copper nanoparticles on charcoal for multicomponent catalytic synthesis of 1,2,3-triazole derivatives from benzyl halides or alkyl halides, terminal alkynes and sodium azide in water as a “green” solvent. Adv. Synth. Catal., 2009, 351(1-2), 207-218. Bénéteau, V.; Olmos, A.; Boningari, T.; Sommer, J.; Pale, P. Zeo-click synthesis: Cu I-zeolite-catalyzed one-pot two-step synthesis of triazoles from halides and related compounds. Tetrahedron Lett., 2010, 51(28), 3673-3677. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Multicomponent synthesis of 1, 2, 3triazoles in water catalyzed by copper nanoparticles on activated carbon. Adv. Synth. Catal., 2010, 352(18), 3208-3214. Li, W.T.; Wu, W.H.; Tang, C.H.; Tai, R.; Chen, S.T. One-pot tandem copper-catalyzed library synthesis of 1-thiazolyl-1, 2, 3-triazoles as anticancer agents. ACS. Comb. Sci., 2010, 13(1), 72-78. Vantikommu, J.; Palle, S.; Reddy, P.S.; Ramanatham, V.; Khagga, M.; Pallapothula, V.R. Synthesis and cytotoxicity evaluation of novel 1, 4disubstituted 1, 2, 3-triazoles via CuI catalysed 1, 3-dipolar cycloaddition. Eur. J. Med. Chem., 2010, 45(11), 5044-5050. Zhang, J.; Wu, J.; Shen, L.; Jin, G.; Cao, S. Novel synthesis of difluoromethylcontaining 1, 4disubstituted 1, 2, 3triazoles via a click– multicomponent reaction and desulfanylation strategy. Adv. Synth. Catal., 2011, 353(4), 580-584. Kolarovic, A.; Schnü rch, M.; Mihovilovic, M.D. Tandem catalysis: From alkynoic acids and aryl iodides to 1, 2, 3-triazoles in one pot. J. Org. Chem., 2011, 76(8), 2613-2618. Harmsen, R.A.G.; Sydnes, L.K.; Törnroos, K.W.; Haug, B.E. Synthesis of trans-4-triazolyl-substituted 3-hydroxypiperidines. Synthesis, 2011, 2011(05), 749-754. Wang, Y.; Liu, J.; Xia, C. Insights into supported copper (II)catalyzed azidealkyne cycloaddition in water. Adv. Synth. Catal., 2011, 353(9), 15341542. Bolla, K.; Kim, T.; Song, J.H.; Lee, S.; Ham, J. Efficient and rapid synthesis of regioselective functionalized potassium 1, 2, 3-triazoletrifluoroborates via 1, 3-dipolar cycloaddition. Tetrahedron, 2011, 67(31), 5556-5563.


[330]

[331]

[332]

[333]

[334]

[335]

[336]

[337]

[338]

[339]

[340]

[341]

[342]

[343]

[344]

[345]

[346]

[347]

[348]

[349]

[350]

[351]

55

Fletcher, J.T.; Reilly, J.E. Fast dye salts provide fast access to azidoarene synthons in multi-step one-pot tandem click transformations. Tetrahedron Lett., 2011, 52(42), 5512-5515. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Click chemistry from organic halides, diazonium salts and anilines in water catalysed by copper nanoparticles on activated carbon. Org. Biomole. Chem., 2011, 9(18), 6385-6395. Alonso Valdés, F.; Moglie, Y.; Radivoy, G.; Astiz, Y.M. Multicomponent click synthesis of potentially biologically active triazoles catalysed by copper nanoparticles on activated carbon in water. Heterocycles, 2011, 84(2), 10331044. Albadi, J.; Keshavarz, M.; Abedini, M.; Vafaie-Nezhad, M. Copper iodide nanoparticles on poly (4-vinyl pyridine) as new and green catalyst for multicomponent click synthesis of 1, 4-disubstituted-1, 2, 3-triazoles in water. Chin. Chem. Lett., 2012, 23(7), 797-800. Albadi, J.; Keshavarz, M.; Shirini, F.; Vafaie-nezhad, M. Copper iodide nanoparticles on poly(4-vinyl pyridine): A new and efficient catalyst for multicomponent click synthesis of 1,4-disubstituted-1,2,3-triazoles in water. Catal. Commun., 2012, 27, 17-20. Xiong, X.; Cai, L. Application of magnetic nanoparticle-supported CuBr: A highly efficient and reusable catalyst for the one-pot and scale-up synthesis of 1, 2, 3-triazoles under microwave-assisted conditions. Catal. Sci. Technol., 2013, 3(5), 1301-1307. Chavan, P.V.; Pandit, K.S.; Desai, U.V.; Kulkarni, M.A.; Wadgaonkar, P.P. Cellulose supported cuprous iodide nanoparticles (Cell-CuI NPs): A new heterogeneous and recyclable catalyst for the one pot synthesis of 1, 4disubstituted–1, 2, 3-triazoles in water. RSC Adv., 2014, 4(79), 42137-42146. Xiong, X.; Chen, H.; Tang, Z.; Jiang, Y. Supported CuBr on graphene oxide/Fe 3 O 4: A highly efficient, magnetically separable catalyst for the multi-gram scale synthesis of 1, 2, 3-triazoles. RSC Adv., 2014, 4(19), 98309837. Sharghi, H.; Shiri, P.; Aberi, M. An efficient catalytic system based on 7,8dihydroxy-4-methylcoumarin and copper(II) for the click synthesis of diverse 1,4-disubstituted-1,2,3-triazoles under green conditions. Mol. Divers, 2014, 18(3), 559-575. Albadi, J.; Shiran, J.A.; Mansournezhad, A. Click synthesis of 1, 4disubstituted-1, 2, 3-triazoles catalysed by CuO–CeO2 nanocomposite in the presence of amberlite-supported azide. J. Chem. Sci., 2014, 126(1), 147-150. Radatz, C.S.; Do Amaral Soares, L.; Vieira, E.R.; Alves, D.; Russowsky, D.; Schneider, P.H. Recoverable Cu/SiO 2 composite-catalysed click synthesis of 1, 2, 3-triazoles in water media. New J. Chem., 2014, 38(4), 1410-1417. Prasad, A.N.; Reddy, B.M.; Jeong, E.Y.; Park, S.E. Cu (ii) PBS-bridged PMOs catalyzed one-pot synthesis of 1, 4-disubstituted 1, 2, 3-triazoles in water through click chemistry. RSC Adv., 2014, 4(56), 29772-29781. Gholinejad, M.; Jeddi, N. Copper nanoparticles supported on agarose as a bioorganic and degradable polymer for multicomponent click synthesis of 1, 2, 3-triazoles under low copper loading in water. ACS. Sustain. Chem. Eng., 2014, 2(12), 2658-2665. Xiong, X.; Cai, L.; Jiang, Y.; Han, Q. Eco-efficient, green, and scalable synthesis of 1, 2, 3-triazoles catalyzed by Cu (I) catalyst on waste oyster shell powders. ACS. Sustain. Chem. Eng., 2014, 2(4), 765-771. Gupta, M.; Gupta, M.; Paul, S.; Kant, R.; Gupta, V. One-pot synthesis of 1,4disubstituted 1,2,3-triazoles via Huisgen 1,3-dipolar cycloaddition catalysed by SiO2–Cu(I) oxide and single crystal X-ray analysis of 1-benzyl-4-phenyl1H-1,2,3-triazole. Monatsh. Chem. Chem. Mon., 2015, 146(1), 143-148. Nemati, F.; Heravi, M.M.; Elhampour, A. Magnetic nanoFe3O4@TiO2/Cu2O core-shell composite: An efficient novel catalyst for the regioselective synthesis of 1,2,3-triazoles using a click reaction. RSC Adv., 2015, 5(57), 45775-45784. Zhou, C.; Zhang, J.; Liu, P.; Xie, J.; Dai, B. 2-pyrrolecarbaldiminato-Cu(ii) complex catalyzed three-component 1,3-dipolar cycloaddition for 1,4disubstituted 1,2,3-triazoles synthesis in water at room temperature. RSC Adv., 2015, 5(9), 6661-6665. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Alkenes as azido precursors for the one-pot synthesis of 1,2,3-triazoles catalyzed by copper nanoparticles on activated carbon. J. Org. Chem., 2013, 78(10), 5031-5037. Ramachary, D.B.; Barbas, C.F. Towards organoclick chemistry: Development of organocatalytic multicomponent reactions through combinations of aldol, wittig, knoevenagel, michael, Diels–Alder and Huisgen cycloaddition reactions. Chem. Eur. J., 2004, 10(21), 5323-5331. Ramachary, D.B.; Reddy, G.B.; Mondal, R. A new organocatalyst for Friedel–Crafts alkylation of 2-naphthols with isatins: Application of an organo-click strategy for the cascade synthesis of highly functionalized molecules. Tetrahedron Lett., 2007, 48(43), 7618-7623. Luvino, D.; Amalric, C.; Smietana, M.; Vasseur, J.J. Sequential seyferthgilbert/CuAAC reactions: Application to the one-pot synthesis of triazoles from aldehydes. Synlett, 2007, (19), 3037-3041. Wu, L.; Chen, Y.; Luo, J.; Sun, Q.; Peng, M.; Lin, Q. Base-mediated reaction of vinyl bromides with aryl azides: one-pot synthesis of 1, 5-disubstituted 1, 2, 3-triazoles. Tetrahedron Lett., 2014, 55(29), 3847-3850. Campbell-Verduyn, L.; Elsinga, P.H.; Mirfeizi, L.; Dierckx, R.A.; Feringa, B.L. Copper-free ‘click’: 1, 3-dipolar cycloaddition of azides and arynes. Org. Biomol. Chem., 2008, 6(19), 3461-3463.

56 [352]

[353]

[354] [355]

[356]

[357]

[358]

[359]

[360]

[361]

[362]

[363]

[364]

[365]

[366]

[367]

[368]

[369]

[370]

[371]

[372]

[373]

[374]

[375]

[376]

Current Organic Chemistry, 2016, Vol. 20, No. ?? Shi, F.; Waldo, J.P.; Chen, Y.; Larock, R.C. Benzyne click chemistry: Synthesis of benzotriazoles from benzynes and azides. Org. Lett., 2008, 10(12), 2409-2412. Ankati, H.; Biehl, E. Microwave-assisted benzyne-click chemistry: Preparation of 1H-benzo [d][1, 2, 3] triazoles. Tetrahedron Lett., 2009, 50(32), 4677-4682. Zhang, F.; Moses, J.E. Benzyne click chemistry with in situ generated aromatic azides. Org. Lett., 2009, 11(7), 1587-1590. Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed., 2002, 41(14), 25962599. Wu, Y.M.; Deng, J.; Li, Y.; Chen, Q.Y. Regiospecific synthesis of 1, 4, 5trisubstituted-1, 2, 3-triazole via one-pot reaction promoted by copper (I) salt. Synthesis, 2005, (8), 1314-1318. Li, L.; Zhang, G.; Zhu, A.; Zhang, L. A convenient preparation of 5-iodo-1, 4-disubstituted-1, 2, 3-triazole: Multicomponent one-pot Reaction of azide and alkyne mediated by CuI NBS. J. Org. Chem., 2008, 73(9), 3630-3633. Smith, N.W.; Polenz, B.P.; Johnson, S.B.; Dzyuba, S.V. Base and concentration effects on the product distribution in copper-promoted alkyne–azide cycloaddition: Additive-free route to 5-iodo-triazoles. Tetrahedron Lett., 2010, 51(3), 550-553. Hein, J.E.; Tripp, J.C.; Krasnova, L.B.; Sharpless, K.B.; Fokin, V.V. Copper (I)catalyzed cycloaddition of organic azides and 1iodoalkynes. Angew. Chem., 2009, 121(43), 8162-8165. Spiteri, C.; Moses, J.E. Coppercatalyzed azide–alkyne cycloaddition: Regioselective synthesis of 1, 4, 5trisubstituted 1, 2, 3triazoles. Angew. Chem. Int. Ed., 2010, 49(1), 31-33. Brotherton, W.S.; Clark, R.J.; Zhu, L. Synthesis of 5-iodo-1, 4-disubstituted1, 2, 3-triazoles mediated by in situ generated copper (I) catalyst and electrophilic triiodide ion. J. Org. Chem., 2012, 77(15), 6443-6455. Zhu, L.; Barsoum, D.N.; Brassard, C.J.; Deeb, J.H.; Okashah, N.; Sreenath, K.; Simmons, J.T. Synthesis of 5-iodo-1, 2, 3-triazoles from organic azides and terminal alkynes: Ligand acceleration effect, substrate scope, and mechanistic insights. Synthesis, 2013, 45(17), 2372. García-Álvarez, J.; Díez, J.; Gimeno, J. A highly efficient copper (I) catalyst for the 1, 3-dipolar cycloaddition of azides with terminal and 1-iodoalkynes in water: Regioselective synthesis of 1, 4-disubstituted and 1, 4, 5trisubstituted 1, 2, 3-triazoles. Green. Chem., 2010, 12(12), 2127-2130. Gerard, B.; Ryan, J.; Beeler, A.B.; Porco, J.A. Synthesis of 1, 4, 5trisubstituted-1, 2, 3-triazoles by copper-catalyzed cycloaddition-coupling of azides and terminal alkynes. Tetrahedron, 2006, 62(26), 6405-6411. Kuijpers, B.H.; Dijkmans, G.C.; Groothuys, S.; Quaedflieg, P.J.; Blaauw, R.H.; Van Delft, F.L.; Rutjes, F.P. Copper (I)-mediated synthesis of trisubstituted 1, 2, 3-triazoles. Synlett, 2005, (20), 3059-3062. Wang, B.; Zhang, J.; Wang, X.; Liu, N.; Chen, W.; Hu, Y. Tandem Reaction of 1-copper (I) alkynes for the synthesis of 1, 4, 5-trisubstituted 5-chloro-1, 2, 3-triazoles. J. Org. Chem., 2013, 78(20), 10519-10523. Li, L.; Hao, G.; Zhu, A.; Fan, X.; Zhang, G.; Zhang, L. A copper (I)catalyzed threecomponent domino process: Assembly of complex 1, 2, 3triazolyl5phosphonates from azides, alkynes, and Hphosphates. Chem. Eur. J., 2013, 19(43), 14403-14406. Zhang, H.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.; Kakiuchi, K. Regioselective rapid synthesis of fully substituted 1, 2, 3-triazoles mediated by propargyl cations. Org. Lett., 2013, 15(20), 5222-5225. Tao, C.Z.; Cui, X.; Li, J.; Liu, A.X.; Liu, L.; Guo, Q.X. Copper-catalyzed synthesis of aryl azides and 1-aryl-1, 2, 3-triazoles from boronic acids. Tetrahedron Lett., 2007, 48(20), 3525-3529. Wang, L.; Cai, C. Reusable polymer-supported copper catalyst for one-pot synthesis of 1-alkyl-and 1-aryl-1, 2, 3-triazoles: green, simple, and effective. Green. Chem. Lett. Rev., 2010, 3(2), 121-125. Kaboudin, B.; Abedi, Y.; Yokomatsu, T. One-pot synthesis of 1, 2, 3triazoles from boronic acids in water using Cu (II)–-cyclodextrin complex as a nanocatalyst. Org. Biomol. Chem., 2012, 10(23), 4543-4548. Mohammed, S.; Padala, A.K.; Dar, B.A.; Singh, B.; Sreedhar, B.; Vishwakarma, R.A.; Bharate, S.B. Recyclable clay supported Cu (II) catalyzed tandem one-pot synthesis of 1-aryl-1, 2, 3-triazoles. Tetrahedron, 2012, 68(39), 8156-8162. Mukherjee, N.; Ahammed, S.; Bhadra, S.; Ranu, B.C. Solvent-free one-pot synthesis of 1, 2, 3-triazole derivatives by the ‘Click’reaction of alkyl halides or aryl boronic acids, sodium azide and terminal alkynes over a Cu/Al 2 O 3 surface under ball-milling. Green Chemistry, 2013, 15(2), 389-397. Kumar, A.S.; Reddy, M.A.; Knorn, M.; Reiser, O.; Sreedhar, B. Magnetically recoverable CuFe2O4 nanoparticles: Catalyzed synthesis of aryl azides and 1, 4diaryl1, 2, 3triazoles from boronic acids in water. Eur. J. Org. Chem., 2013, 2013(21), 4674-4680. Smith, N.M.; Greaves, M.J.; Jewell, R.; Perry, M.W.; Stocks, M.J.; Stonehouse, J.P. One-pot, three-component copper-catalysed ‘click’triazolesynthesis utilising the inexpensive, shelf-stable diazotransfer reagent imidazole-1-sulfonyl azide hydrochloride. Synlett, 2009, 2009(09), 1391-1394. Liu, Q.; Tor, Y. Simple conversion of aromatic amines into azides. Org. Lett., 2003, 5(14), 2571-2572.

Heravi et al. [377]

[378]

[379] [380]

[381]

[382]

[383]

[384]

[385]

[386]

[387]

[388]

[389]

[390]

[391]

[392]

[393]

[394]

[395]

[396]

[397]

[398]

[399]

Das, J.; Patil, S.N.; Awasthi, R.; Narasimhulu, P.C.; Trehan, S. An easy access to aryl azides from aryl amines under neutral conditions. Synthesis, 2005, (11), 1801-1806. Barral, K.; Moorhouse, A.D.; Moses, J.E. Efficient conversion of aromatic amines into azides: A one-pot synthesis of triazole linkages. Org. Lett., 2007, 9(9), 1809-1811. Moorhouse, A.D.; Moses, J.E. Microwave enhancement of a one-pot tandem azidation 'click' cycloaddition of anilines. Synlett, 2008, (14), 2089-2092. Beckmann, H.S.; Wittmann, V. One-pot procedure for diazo transfer and azide-alkyne cycloaddition: Triazole linkages from amines. Org. Lett., 2007, 9(1), 1-4. Lee, C.T.; Huang, S.; Lipshutz, B.H. Copperincharcoalcatalyzed, tandem onepot diazo transferclick reactions. Adv. Synth. Catal., 2009, 351(18), 3139-3142. Suárez, J.R.; Trastoy, B.; PérezOjeda, M.E.; MarínBarrios, R.; Chiara, J.L. Nonafluorobutanesulfonyl azide: A shelfstable diazo transfer reagent for the synthesis of azides from primary amines. Adv. Synth. Catal., 2010, 352(1415), 2515-2520. Zarei, A. One-pot, efficient, and regioselective synthesis of 1, 4-disubstituted 1, 2, 3-triazoles using aryldiazonium silica sulfates in water. Tetrahedron Lett., 2012, 53(38), 5176-5179. Yadav, J.; Reddy, B.S.; Reddy, G.M.; Chary, D.N. Three component, regioselective, one-pot synthesis of -hydroxytriazoles from epoxides via ‘click reactions’. Tetrahedron Lett., 2007, 48(49), 8773-8776. Kumaraswamy, G.; Ankamma, K.; Pitchaiah, A. Tandem epoxide or aziridine ring opening by azide/copper catalyzed [3+ 2] cycloaddition: Efficient synthesis of 1, 2, 3-triazolo -hydroxy or -tosylamino functionality motif. J. Org. Chem, 2007, 72(25), 9822-9825. Reddy, K.R.; Maheswari, C.U.; Rajgopal, K.; Kantam, M.L. One-pot sequential synthesis of -hydroxy-1,4-disubstituted-1,2,3-triazoles from in-situ generated -azido alcohol by click chemistry. Synth. Commun., 2008, 38(13), 2158-2167. Boningari, T.; Olmos, A.; Reddy, B.M.; Sommer, J.; Pale, P. Zeoclick chemistry: Copper (I)–zeolitecatalyzed cascade reaction; onepot epoxide ringopening and cycloaddition. Eur. J. Org. Chem., 2010, 2010(33), 63386347. Sharghi, H.; Beyzavi, M.H.; Safavi, A.; Doroodmand, M.M.; Khalifeh, R. Immobilization of porphyrinatocopper nanoparticles onto activated multiwalled carbon nanotubes and a study of its catalytic activity as an efficient heterogeneous catalyst for a click approach to the threecomponent synthesis of 1,2,3triazoles in water. Adv. Synth. Catal., 2009, 351(1415), 23912410. Sharghi, H.; HosseiniSarvari, M.; Moeini, F.; Khalifeh, R.; Beni, A.S. Onepot, threecomponent synthesis of 1(2hydroxyethyl)1H1,2,3triazole derivatives by coppercatalyzed 1,3dipolar cycloaddition of 2azido alcohols and terminal alkynes under mild conditions in water. Helv. Chim. Acta, 2010, 93(3), 435-449. Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Multicomponent click synthesis of 1, 2, 3-triazoles from epoxides in water catalyzed by copper nanoparticles on activated carbon. J. Org. Chem., 2011, 76(20), 8394-8405. Naeimi, H.; Nejadshafiee, V. Efficient one-pot click synthesis of -hydroxy1, 2, 3-triazoles catalyzed by copper (i)@ phosphorated SiO 2 via multicomponent reaction in aqueous media. New J. Chem., 2014, 38(11), 5429-5435. Naeimi, H.; Nejadshafiee, V.; Masoum, S. Highly efficient copper-imprinted functionalized mesoporous organosilica nanocomposites as a recyclable catalyst for click synthesis of 1, 2, 3-triazole derivatives under ultrasound irradiation: Multivariate study by factorial design of experiments. RSC Adv., 2015, 5(20), 15006-15016. Naeimi, H.; Nejadshafiee, V.; Masoum, S. Copper@ PMO nanocomposites as a novel reusable heterogeneous catalyst for microwaveassisted green synthesis of hydroxy1, 2, 3triazoles through experimental design protocol. Appl. Organomet. Chem., 2015, 29(5), 314-321. Yan, Z.Y.; Zhao, Y.B.; Fan, M.J.; Liu, W.M.; Liang, Y.M. General synthesis of (1-substituted-1H-1,2,3-triazol-4-ylmethyl)-dialkylamines via a copper(I)catalyzed three-component reaction in water. Tetrahedron, 2005, 61(39), 9331-9337. Braga, A.; Alves, D.; Deobald, A.; Camargo, L.; Hörner, M.; Rodrigues, O. Synthesis of arylseleno-1,2,3-triazoles via copper-catalyzed 1,3-dipolar cycloaddition of azido arylselenides with alkynes. Synthesis, 2011, 2011(15), 2397-2406. Huang, X.; Duan, D.H., A novel synthetic approach to -arylselenenyl tertiary alcohols by the one-pot reaction of chloromethyl selenides and ketones promoted by samarium diiodide. Synlett, 1998, 1998(11), 1191-1192. Seus, N.; Saraiva, M.T.; Alberto, E.E.; Savegnago, L.; Alves, D. Selenium compounds in Click chemistry: Copper catalyzed 1, 3-dipolar cycloaddition of azidomethyl arylselenides and alkynes. Tetrahedron, 2012, 68(51), 1041910425. Saraiva, M.T.; Seus, N.; De Souza, D.; Rodrigues, O.E.; Paixao, M.W.; Jacob, R.G.; Lenardao, E.J.; Perin, G.; Alves, D. Paper synthesis of [(arylselanyl) alkyl]-1,2,3-triazoles by copper-catalyzed 1,3-dipolar cycloaddition of (arylselanyl) alkynes with benzyl azides. Synthesis, 2012, 44, 1997-2004. Wang, B.; Ahmed, M.N.; Zhang, J.; Chen, W.; Wang, X.; Hu, Y. Easy preparation of 1, 4, 5-trisubstituted 5-(2-alkoxy-1, 2-dioxoethyl)-1, 2, 3-triazoles


[400]

[401]

[402]

[403]

[404]

[405]

[406]

[407]

[408]

[409]

[410] [411] [412] [413]

[414]


by chemoselective trapping of copper (I)–carbon bond with alkoxalyl chloride. Tetrahedron Lett., 2013, 54(45), 6097-6100. Li, J.; Wang, D.; Zhang, Y.; Li, J.; Chen, B. Facile one-pot synthesis of 4, 5disubstituted 1, 2, 3-(NH)-triazoles through sonogashira coupling/1, 3dipolar cycloaddition of acid chlorides, terminal acetylenes, and sodium azide. Org. Lett., 2009, 11(14), 3024-3027. Zhang, X.; Hsung, R.P.; Li, H. A triazole-templated ring-closing metathesis for constructing novel fused and bridged triazoles. Chem. Commun., 2007, (23), 2420-2422. Thibault, R.J.; Takizawa, K.; Lowenheilm, P.; Helms, B.; Mynar, J.L.; Fréchet, J.M.; Hawker, C. J. A versatile new monomer family: Functionalized 4vinyl-1, 2, 3-triazoles via click chemistry. J. Am. Chem. Soc., 2006, 128(37), 12084-12085. Nulwala, H.; Takizawa, K.; Odukale, A.; Khan, A.; Thibault, R.J.; Taft, B.R.; Lipshutz, B.H.; Hawker, C.J. Synthesis and characterization of isomeric vinyl-1, 2, 3-triazole materials by azide-alkyne click chemistry. Macromolecules, 2009, 42(16), 6068-6074. Reck, F.; Zhou, F.; Girardot, M.; Kern, G.; Eyermann, C.J.; Hales, N.J.; Ramsay, R.R.; Gravestock, M.B. Identification of 4-substituted 1, 2, 3triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A. J. Med. Chem., 2005, 48(2), 499-506. Takizawa, K.; Nulwala, H.; Thibault, R.J.; Lowenhielm, P.; Yoshinaga, K.; Wooley, K.L.; Hawker, C.J. Facile synthesis of 4vinyl1, 2, 3triazole monomers by click azide/acetylene coupling. J. Polym. Sci. Part A: Polym. Chem., 2008, 46(9), 2897-2912. Nulwala, H.; Burke, D.J.; Khan, A.; Serrano, A.; Hawker, C.J. Nvinyltriazoles: A new functional monomer family through click chemistry. Macromolecules, 2010, 43(12), 5474-5477. Landge, K.P.; Seo, Y.W.; Kwak, J.; Park, W.K.; Gong, J.Y.; Lee, H.Y.; Koh, H.Y. Versatile synthesis of disubstituted triazole library for dopamine and serotonin receptor ligands. Korean Chem. Soc., 2011, 32(8), 3101-3105. Debets, M.F.; Van der Doelen, C.W.; Rutjes, F.P.; Van Delft, F.L. Azide: A unique dipole for metalfree bioorthogonal ligations. ChemBioChem, 2010, 11(9), 1168-1184. Kwok, S.W.; Fotsing, J.R.; Fraser, R.J.; Rodionov, V.O.; Fokin, V.V. Transition-metal-free catalytic synthesis of 1, 5-diaryl-1, 2, 3-triazoles. Org. Lett., 2010, 12(19), 4217-4219. Akimova, G.S.; Chistokletov, V.N.; Petrov, A.A. Zh. Org. Khim., 1967, 3, 2241-2246. Akimova, G.S.; Chistokletov, V.N.; Petrov, A.A. Zh. Org. Khim., 1967, 3, 968-974. Akimova G.S., Chistokletov, V.N., Petrov, A.A. Zh. Org. Khim., 1968, 4, 389-393. Krasinski, A.; Fokin, V.V.; Sharpless, K.B. Direct synthesis of 1, 5disubstituted-4-magnesio-1, 2, 3-triazoles, revisited. Org. Lett., 2004, 6(8), 1237-1240. Fridman S.G.; Lisovska, N.M.; Zap. Inst. Khim., Akad. Nauk. U.R.S.R., Inst. Khim. 1940, 6, 353-360.

Received: September 01, 2015

[415]

[416]

[417] [418]

[419]

[420]

[421]

[422]

[423]

[424]

[425]

[426]

[427]

[428]

[429]

57

Himbert, G.; Frank, D.; Regit, M. Untersuchungen an diazoverbindungen und aziden, XXV1) azidadditionen an (silyäthinyl),(germyläthinyl)und (stannyläthinyl) amine. Chem. Ber., 1976, 109(1), 370-394. Majireck, M.M.; Weinreb, S.M. A study of the scope and regioselectivity of the ruthenium-catalyzed [3+ 2]-cycloaddition of azides with internal alkynes. J. Org. Chem., 2006, 71(22), 8680-8683. Rasmussen, L.K.; Boren, B.C.; Fokin, V.V. Ruthenium-catalyzed cycloaddition of aryl azides and alkynes. Org. Lett., 2007, 9(26), 5337-5339. Zhang, C.T.; Zhang, X.; Qing, F.L. Ruthenium-catalyzed 1, 3-dipolar cycloaddition of trifluoromethylated propargylic alcohols with azides. Tetrahedron Lett., 2008, 49(24), 3927-3930. Salmon, A.J.; Williams, M.L.; Maresca, A.; Supuran, C.T.; Poulsen, S.A. Synthesis of glycoconjugate carbonic anhydrase inhibitors by rutheniumcatalysed azide-alkyne 1, 3-dipolar cycloaddition. Bioorg. Med. Chem. Lett., 2011, 21(20), 6058-6061. Siyang, H.X.; Liu, H.L.; Wu, X.Y.; Liu, P.N. Highly efficient click reaction on water catalyzed by a ruthenium complex. RSC Adv., 2015, 5(6), 46934697. Imperio, D.; Pirali, T.; Galli, U.; Pagliai, F.; Cafici, L.; Canonico, P.L.; Sorba, G.; Genazzani, A.A.; Tron, G.C. Replacement of the lactone moiety on podophyllotoxin and steganacin analogues with a 1, 5-disubstituted 1, 2, 3-triazole via ruthenium-catalyzed click chemistry. Bioorg. Med. Chem., 2007, 15(21), 6748-6757. Galli, U.; Ercolano, E.; Carraro, L.; Blasi Roman, C.R.; Sorba, G.; Canonico, P.L.; Genazzani, A.A.; Tron, G.C.; Billington, R.A. Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage. ChemMedChem, 2008, 3(5), 771-779. Johansson, J.R.; Lincoln, P.; Nordén, B.; Kann, N. Sequential one-pot ruthenium-catalyzed azide-alkyne cycloaddition from primary alkyl halides and sodium azide. J. Org. Chem., 2011, 76(7), 2355-2359. Meza-Aviña, M.E.; Patel, M.K.; Lee, C.B.; Dietz, T.J.; Croatt, M.P. Selective formation of 1, 5-substituted sulfonyl triazoles using acetylides and sulfonyl azides. Org. Lett., 2011, 13(12), 2984-2987. Liu, D.; Gao, W.; Dai, Q.; Zhang, X. Triazole-based monophosphines for Suzuki-Miyaura coupling and amination reactions of aryl chlorides. Org. Lett., 2005, 7(22), 4907-4910. Hlasta, D.J.; Ackerman, J.H. Steric effects on the regioselectivity of an azide-alkyne dipolar cycloaddition reaction: The synthesis of human leukocyte elastase inhibitors. J. Org. Chem., 1994, 59(21), 6184-6189. Coats, S.J.; Link, J.S.; Gauthier, D.; Hlasta, D.J. Trimethylsilyl-directed 1, 3dipolar cycloaddition reactions in the solid-phase synthesis of 1, 2, 3triazoles. Org. Lett., 2005, 7(8), 1469-1472. Barr, L.; Lincoln, S.F.; Easton, C.J. A cyclodextrin molecular reactor for the regioselective synthesis of 1, 5-disubstituted-1, 2, 3-triazoles. Supramol. Chem., 2005, 17(7), 547-555. Hong, L.; Lin, W.; Zhang, F.; Liu, R.; Zhou, X. Ln [N (SiMe 3) 2] 3catalyzed cycloaddition of terminal alkynes to azides leading to 1, 5disubstituted 1, 2, 3-triazoles: New mechanistic features. Chem. Commun., 2013, 49(49), 5589-5591.

Revised: December 09, 2016

Accepted: December 13, 2016

Huisgen's Cycloaddition Reactions: A Full Perspective

Huisgen's Cycloaddition Reactions: A Full Perspective

Suggest Documents

Huisgen's Cycloaddition Reactions: A Full Perspective

Cycloaddition reactions of unsaturated sulfones - Semantic Scholar

Porphyrins in 1,3-Dipolar Cycloaddition Reactions

cycloaddition reactions of 2 - Scholars Research Library

cycloaddition reactions be explained using singlet ...

coumarins: Cycloaddition Reactions between ... - Wiley Online Library

Kinetics and Mechanism of Chloroprene Cycloaddition Reactions

Convenient synthesis and cycloaddition reactions of 2

Cycloaddition Reactions of 1,5,6 ... - ACS Publications

Dipolar Cycloaddition Reactions of Enamines and ...

cycloaddition reactions of 2 - Scholars Research Library

Dipolar cycloaddition reactions of diazoindene and

Addition and Cycloaddition Reactions of Phosphinyl

cycloaddition

Kinetic aspects of [3+2] cycloaddition reactions between (E)-3,3,3 ...

Catalytic [2 + 2] and [3 + 2] cycloaddition reactions

Aryl nitrile oxide cycloaddition reactions in the ... - Semantic Scholar

Cycloaddition reactions of thioisatin with thiazolidine-2 ... - Springer Link

Covalent functionalization by cycloaddition reactions of pristine, defect ...

Studies in the cycloproparene series: cycloaddition reactions ... - Arkivoc

Highly diastereoselective 1,3-dipolar cycloaddition reactions of trans-2 ...

Versatile cycloaddition reactions of 1-alkyl-1,2 ...

Cycloaddition Reactions of (C6F5)2BN3 with ... - Semantic Scholar

Cycloaddition Reactions of C, N-Diphenylnitrone to Methylene-Î³ ...