WO2011009934A1 - Tris(1,2,3-triazol-4-yl)methane organometallic compounds as catalysts and processes using them. - Google Patents

Abstract

Compounds of formula (I) or theirs salts, where Y is a (C₁-C₄)alkyl biradical and n is 1 or 0; M is Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, or Cr; R₁ is a known ring system with 1 -2 rings, isolated or fused; each ring having 5-6 members independently selected from C, N, O, S, CH, CH₂, and NH, the rings being saturated, partially unsaturated or aromatic, and optionally being substituted by at least one radical selected: halogen, nitro, cyano, (C₁-C₄)alkyl, halo-(C₁-C₄)alkyl, -O-(C₁-C₄)alkyl. -CO-(C₁-C₄)alkyl, - COO-(C₁-C₄)alkyl, -OC(O)-(C₁-C₄)alkyl, -C(O)NR₄R₅, -(C₁-C₄)alkyl-NR₄R₅, -S- (C₁-C₄)alkyl, -SO-(C₁-C₄)alkyl, -SO2-(C₁-C₄)alkyl, -NHSO₂-(C₁-C₄)alkyl, -SO₂- NR₄R₅, and -NR₄R₅; R₂ is -OR₃, wherein R₃ is selected from the group consisting of hydrogen, benzyl, and an hydroxyl protective group, or a polymeric support, optionally including a linker; and R₄ and R₅ are independently H, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, or (C₂-C₄)alkynyl, optionally substituted by at least one radical selected from halogen, nitro, cyano, and amino; are useful as catalyst, in particular, in a process for the preparation of substituted 1,2,3-triazoles.

Description

Trisd ,2,3-triazol-4-yl)nnethane orqanometallic compounds as catalysts and processes using them.

The present invention relates to new chemical catalysts. Particularly, the present invention refers to coordination complexes and organometallic compounds comprising triazole chelating ligands as catalysts. The invention further provides processes for the preparation thereof, as well as processes catalyzed by the catalysts of the invention. BACKGROUND ART

Interest for organometallic compounds has been increasing in organic synthesis due to the latest developments of novel synthetic strategies and the novel approaches to old synthetic strategies which have been revisited. Many of these recently developed strategies or approaches take benefit of the abilities of the organometallic compounds as catalysts.

Metal-reagent, metal-ligand and steric interactions occurring on

organometallic compounds makes them advantageous for regiospecific and stereospecific synthesis, and catalysis.

"Click" chemistry is a recent approach to several synthetic strategies which recently has been object of major investigation efforts worldwide. Click reactions are simple and efficient processes which allow benign reaction conditions and comprise simple workup and purification processes. Click reactions involve a number of reactive modular building blocks selectively leading to a wider range of potential products (cf. Sharpless et al., Angew. Chem. Int. Ed. 2001 , 40, pp. 2004-2021 ). Cycloaddition chemistry comprises a number of reactions that potentially meet the criteria of the click chemistry, e.g. hetero-Diels-Alder, and

1 ,3-dipolar cycloadditions. Dipolar cycloadditions are a group of reactions wherein two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity (cf. Muller, Pure Appl. Chem., 1994, vol. 66, No. 5, pp. 1077-1184).

In WO 2003/101972, Sharpless et al. discloses Cu catalyzed regiospecific 1 ,3-cycloaddition processes between azides and acetylenes. Therein, Cu (II) catalytic systems comprising ascorbate and water for the in situ preparation of the more active Cu (I) species were preferred rather than the direct use of Cu (I) salts or coordination compounds. Former Cu (I) systems were impaired by the low product yields obtained and the requirement of inert atmosphere and a less benign solvent system.

Sharpless et al; in Organic Letters, 2004, vol. 6, No. 17, pp. 2853-2855, disclosed 1 ,2,3-triazoles as co-catalysts for catalyzed regiospecific

1 ,3-cycloaddition processes between azides and acetylenes.

Tris(1 -benzyl-1 H-1 ,2,3-triazol-4-yl-methyl)ethan-1 -ol was tested as

co-catalyst in Cu (II) catalytic systems comprising ascorbate and water for the reaction of phenyl acetylene and benzyl azide. Yields of 29% were attained when using said compound in processes with a reaction time of 24h, showing poor co-catalyst abilities. The most suitable yields were obtained with reaction times of 24h and catalytic systems comprising mono, bis or tris(1 ,2,3-triazoles) compounds derived from the thmethylamine thradical as co-catalysts. Thus, although the presence of such co-catalysts improves the catalyst activity, the reaction times are still long. For example, Sharpless et al. provides TBTA compound with central nitrogen (Table 2 compound 4) which still requires long reaction times, although providing moderate yields, when used as co-catalyst for click cycloaddition reactions. Maisonial et al; in Eur. J.lnorg. Chem., 2008, pp.298-305 also refers to co-catalysts with central nitrogen atoms. More specifically, Maisonial et al. discloses TBTA in Figure 3, Compound (4) citing the above Sharpless et al, 2004, and its use in a range of click cycloadditions.

Other catalysts for carrying out 1 ,3-dipolar cycloadditions are known in the art. For instance, Vincent et al; in Chem. Commun., 2008, pp.741 -743, disclosed a catalyst for Huygens 1 ,3-dipolar cycloadditions comprising a Cu

(I) complex with a tetracoordinated (C18₆tren) ligand with a central N atom. Organic solvents are used to promote the selective precipitation of the products. It is also known the use of organocatalysts and metallic catalysts supported on polymers to improve the recycling and reuse of catalytic systems. For instance, WO 2008/022961 describes organocatalysts for asymmetric reactions that are immobilized on a proline based solid support. All the organocatalysts described are N-heterocycles supported on polymers through triazole or tetrazole linkers. There is also described their use together with organic solvents and water in asymmetric reactions.

From what is known in the art it is derived that there is still the need of finding highly selective catalysts which allow improving reaction times and yields of processes, for example those involving click reactions, in benign reaction conditions, without the need of using co-catalysts and/or reactants for in situ preparation of metals in unstable oxidation states.

SUMMARY OF THE INVENTION

The inventors have found new ths-triazole organometallic catalysts useful for carrying out click reactions, which overcome most of the drawbacks of the known catalysts. Surprisingly, the new tris-triazole organometallic catalysts allow to carry out click reactions with excellent yields and selectivity with short reaction times through the stabilization of metals in unstable oxidation states, and even in the presence of water and air. Furthermore, there is no need of any further co-catalyst or reactant.

The new tris-triazole organometallic catalysts are readily recycled and reused, and they remain stable in storage without specific air or moisture conditions.

Thus, according to a first aspect of the present invention, it is provided catalysts of formula (I) or their salts:

where, Y is a (Ci-C₄)alkyl biradical; n is selected from 0 and 1 ; M is a metal selected from Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr; R₁ is a known ring system with 1 -2 rings, isolated or fused; wherein each one of the rings has 5-6 members, each member independently selected from C, N, O, S, CH, CH₂, and NH, the rings being saturated, partially unsaturated or aromatic, and optionally being substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl, halo-(Ci-C₄)alkyl,

-O-(Ci-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(C_rC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl,

-SO₂-(CrC₄)alkyl, -NHSO₂-(C_rC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅; R₂ is -OR₃, where R₃ is selected from the group consisting of hydrogen, benzyl, an hydroxyl protective group, -P, and -L-P; wherein P is a polymeric support; and L is a biradical selected from the group consisting of (C-ι-C-ιo)alkyl biradicals and compounds of formula (IV)

(IV)

where the symbol ΛΛAΓ indistinctly indicates the positions through which L is attached to the oxygen atom of R₂ and to P; and R₄ and R₅ are independently selected from H, (Ci-C₄)alkyl, optionally substituted by at least one radical selected from halogen, nitro, cyano, and amino; (C₂-C₄)alkenyl, optionally substituted by at least one radical selected from halogen, nitro, cyano, amino; and (C₂-C₄)alkynyl, optionally substituted by at least one radical selected halogen, nitro, cyano, and amino.

As mentioned above, the catalysts of the present invention are useful for carrying out click reactions in benign reaction conditions. Thus, according to a second aspect of the invention, it is provided a process for the preparation of substituted 1 ,2,3-triazoles which comprises reacting an azide and a terminal alkyne in the presence of a catalytic amount of a compound of formula (I), as defined above. The process is advantageous since it progresses with excellent yields and selectivity. It is also advantageous because it allows to carry out a simple workup and purification steps.

According to another aspect of the invention, it is provided a process for the preparation of the catalyst of formula (I) as defined above, comprising the step of reacting a compound of formula (II),

with a metal salt ,where R-i, R₂, Y, and n are as defined above for compound (I), and the metal is selected from Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr.

Intermediate compounds of formula (II) as defined above are new and also form part of the present invention.

Finally, another aspect of the present invention relates to the use of the compound of formula (I) as defined above as a catalyst, in particular for click reactions.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, an aspect of the present invention is the provision of compounds of formula (I) as defined above which are useful as catalyst.

Preferably, in compound (I) the metal is selected from Cu, Ag, Au, V, Ru, and Fe.

More preferably, the metal in compound of formula (I) is Cu (I). Cu (I) has been reported as a very effective catalyst for a number of processes, e.g. 1 ,3-cycloadditions between alkynes and azides, but due to its low redox stability it has been reported that it is not suitable for using in aqueous solvents and in air conditions. As an alternative complex catalytic systems for the in situ reduction of Cu (II) to Cu (I) have been used but they result in more complex catalytic processes because of the requirement of auxiliary reagents, specific solvents or reaction conditions (temperature, reaction time).

Compounds of formula (I) where M is Cu (I) have shown to be stable in water containing solvents and without specific atmosphere conditions, even when comprising metals in unstable oxidation states, without the need of co-catalysts or in situ redox processes. The stabilization effect of the compounds of formula (I) towards metals in unstable oxidation states has been shown both in the reaction mixture and when storing the catalyst in a solid form.

Thus, compounds of formula (I) have shown to provide excellent yields and specificity when acting as a catalyst, in particular for click reactions, providing an improved catalyst activity even in aqueous conditions and using metals in unstable oxidation states. There is no need of in situ redox processes or stabilizing ligands. From a practical point of view, the use of water as the solvent in chemical reactions is a very favourable characteristic providing environmental friendly and secure processes by reducing the need of organic solvents.

Without pretending to be bound by theory, it is believed that the excellent properties of the compound of the invention can be related with the specific structural geometry of the cavity wherein the metal is allocated. The specific geometry of the cavity is defined by the relative position of the nitrogen atoms on position 1 of each of the triazoles in respect of the central axis of the ligand. Said position depends on the selection on the distance between the central C atom of the ligand and the C atom in the position 5 of the triazole to which it is bounded, as well as the geometrical distortion due to the N-metal bonds. As it can be supposed from the experimental results of the use of the catalyst of the present invention, said specific structural features of the catalysts of formula (I) seems to improve the metal-ligand, metal-reagents, and steric interactions to provide excellent catalytic properties in addition to an additional stabilization effect.

In a preferred embodiment of the invention, n is 1 ; and the substituents of Ri are selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl, -O-(Ci-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl,

-SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅.

In a preferred embodiment of the invention, compounds of formula (I) are those where n is 1 and Y is CH₂. In a preferred embodiment of the invention, compounds of formula (I) are those where Ri is a known ring with 5 to 6 carbon atoms, the ring being saturated, partially unsaturated or aromatic, and optionally being substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, (d-C₄)alkyl, -O-(Ci-C₄)alkyl, -CO-(Ci-C₄)alkyl, -COO-(d-C₄)alkyl, -OC(O)-(Ci-C₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(Ci-C₄)alkyl, -SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅; More preferably, Ri is selected from naphthyl and phenyl, each optionally substituted by at least one of halogen, nitro, cyano, (Ci-C₄)alkyl, -O-(Ci-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl,

-SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅; and R₄ and R₅ are independently selected from H and (Ci-C₄)alkyl. Even more preferably, Ri is phenyl optionally substituted by the previous radicals.

In a further more preferred embodiment, compounds of formula (I) are those where Ri is unsubstituted phenyl. The most preferred compound of formula (I) is [Cu[tris(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)methanol]]CI (TTr-CuCI).

In a particular embodiment of the invention, R₃ is selected from H and benzyl.

In another preferred embodiment of the invention, compounds of formula (I) are those where R₃ is selected from -P and -L-P. In both cases, the

compounds of formula (I) are supported on a polymer, directly or through a suitable linker. The polymer may be, for instance, a polystyrene resin (PS), a polyacrylate, a polyacrylamide, a polyvinylpyrrolidinone, a polysiloxane, a polybutadiene, a polyisoprene, a polyalkane, a polyoxazoline, or a polyether. Particularly preferred is a polystyrene resin, and even more preferred are Merrifield resin, highly crosslinked polystyrene resins, for example ArgoPore resins, or PS-PEG resin. In a particular embodiment, the resin used is the Merrifield 1 % DVB or 2% DVB which is advantageous due to their high hydrophobicity. The term "polymeric support" is art-recognized and refers to a soluble or insoluble polymer onto which the active unit is anchored directly or through a linker. Many suitable polymeric supports are known, and include soluble polymers such as polyethylene glycols or polyvinyl alcohols, as well as insoluble polymers such as polystyrene resins. A polymeric support is termed "soluble" if the polymer, or the polymer-supported compound, is soluble under the conditions employed. However, in general, a soluble polymer can be rendered insoluble under defined conditions. Accordingly, a polymeric support may be soluble under certain conditions and insoluble under other conditions.

In a particular embodiment of the invention, compounds of formula (Ia) are those where R₃ is a hydroxyl protective group.

The term "protecting group" refers to a chemical moiety or group which protects or prevents an active moiety or group from participating with or interfering with one or more chemical synthetic steps and its removal restores the moiety to its original active state. The term protecting group as used herein refers to those groups intended to protect against undesirable reactions during synthetic procedures. Such protecting groups are well known to those skilled in the art. Examples of hydroxy protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry", Chapter 2 (Wiley, 3rd ed. 1999).

Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. Particularly preferred are methyl ether, methoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, benzyl ether, t-butylmethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetate, pivalic acid ester, benzoic acid ester and the like.

In a more preferred embodiment, the compounds of formula (I) are those which are supported directly to a polymeric support -P.

In a particular embodiment, the compounds of formula (I) are those which are supported to a polymeric support through a linker. Preferably, the linker L is a biradical selected from -CH₂- and:

Alternatively, suitable linkers also comprise triazole compounds of formula

wherein the symbol ^■—- indistinctly indicates the positions through which L is attached to the oxygen atom of R₂ and to P.

The term "linker" is art-recognized and refers to a molecule or group of molecules connecting a support, including a solid support or polymeric support, and the active unit. The linker may be comprised of a single linking molecule or may comprise a linking molecule and a spacer molecule, intended to separate the linking molecule and the active unit by a specific distance.

In a further embodiment of the invention, compounds of formula (I) are those wherein n is 0. All the preferred embodiments regarding the preferred values of R-I, R₂, M, P, and L described above for the compound where n=1 are also preferred embodiments for the compounds where n=0. Preferably the compound of formula (I) where n is 0 is [Cu[tris(1 -(4-methoxyphenyl)-1 H- 1 ,2,3-triazol-4-yl)methanol] ]CI .

The compounds of formula (I) are useful as catalysts. Thus, the use of compounds of formula (I) as catalyst is also part of the invention. In a preferred embodiment, the compounds of formula (I) are used as catalyst in a dipolar cycloaddition reaction.

According to another aspect, the invention provides a process for the preparation of substituted 1 ,2,3-triazoles which comprises reacting an azide and a terminal alkyne in the presence of a catalytic amount of the catalysts of the invention. As it is illustrated in the Examples, a large functional group tolerance has been observed. Amines, alcohols, ester derivatives of alkynes gave very good yields in short reaction times. Aliphatic acetylenes have given the desired product with a very good yield but with longer reaction time. Suitable organic azides for use in the process catalyzed by the catalyst of the invention include (C-ι-C-ιo)alkyl azides, (C₂-Ci₀)ether azides, (C₅-C₂o)aryl azides, and aralkyl azides, each may be substituted with one or more functional groups. The term "(C-ι-C-ιo)alkyl" as used herein refers to an optionally substituted saturated branched, linear or cyclic hydrocarbon chain with 1 to 10 carbon atoms. Preferably, the alkyl chain has one to four carbon atoms. Also preferably, the alkyl chain is substituted by a cyano group. The term "(C₂-C-ι₀)ether" as used herein refers to an optionally substituted branched, linear or cyclic ether chain with 2 to 10 carbon atoms. Preferably, the ether chain has 2 to 6 carbon atoms.

The term "(C₅-C₂o)aryr, as used herein, whether used alone or as part of another group, is defined as a radical derived from one of the known ring systems with 1 -3 rings, having from 5 to 20 carbon atoms wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from C, N, O, S, CH, CH₂, NH; is saturated, partially unsaturated or aromatic, and; is isolated or, partially or totally fused; being each ring forming part of the ring system optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, hydroxyl, cyano, (Ci-C₆)alkyl, (C₂-C₈)alkenyl, -O(C_rC₆)alkyl, -CO(C_rC₆)alkyl,

-COO(Ci-C₆)alkyl, and -OC(O)-(C_rC₆)alkyl. Preferably, the ring system is aromatic and each ring has 5-6 members, each member independently selected from C, CH, and CH₂.

The term "aralkyl", as used herein, whether used alone or as part of another group, is defined as an (C-ι-C-ιo)alkyl substituted by a (C₅-C₂₀)aryl group, both groups as defined herein. Preferably, aralkyl group comprises a ring system having 1 or 2 rings, each having 5-6 members independently selected from C, CH, and CH₂. More preferably, the ring system is selected from phenyl, biphenyl, benzyl, and naphtyl, optionally substituted by halogen, nitro, cyano, (CrC₄)alkyl and -O-(d-C₄)alkyl.

Preferred types of azides include aryl azides and aralkyl azides as defined herein. Mixtures of any two or more organic azides can be used, if desired. The use of mixtures of organic azides will yield a mixture of thazoles.

Suitable alkyl azides include, but are not limited to, methyl azide, ethyl azide, n-propyl azide, isopropyl azide, cyclopropyl azide, 3-cyanopropyl azide, n-butyl azide, sec-butyl azide, tert-butyl azide, cyclobutyl azide, 4-cyanobutyl azide, pentyl azide, 3-cyanopentyl azide, cyclopentyl azide,

2,2-dimethylpropyl azide, hexyl azide, cyclohexyl azide, 4-cyanocyclohexyl azide, methylcyclohexyl azide, heptyl azide, octyl azide, cyclooctyl azide, nonyl azide, and decyl azide. Preferred alkyl azides include methyl azide, 3-cyanopropyl azide, heptyl azide, and octyl azide. It is noted that methyl azide, ethyl azide, and n-propyl azide are quite explosive, and thus care should be exercised in their handling.

Examples of ether azides that can be used in the practice of this invention include 3,3-dimethoxypropyl azide, 3,3-diethoxypropyl azide, 4-butyloxybutyl azide, 4-propoxypentyl azide, 5-methoxyhexyl azide, 4-(2-tetrahydrofuranyl)- butyl azide, 2-[2-(1 ,3-dioxolanyl)]-ethyl azide, 2-[2-(1 ,3-dioxanyl)]-ethyl azide, 3-[2-(1 ,3-dioxolanyl)]-butyl azide, 4-[2-(1 ,3-dioxanyl)]-pentyl azide,

6-(2-tetrahydrofuranyl)-hexyl azide, 3,3-diethoxypropyl azide, 2-[2-(1 ,3- dioxolanyl)]-ethyl azide. Aryl azides that can be used in this invention include, but are not limited to, phenyl azide, 2-cyanophenyl azide, 4-cyanophenyl azide, 3-nitrophenyl azide, 4-nitrophenyl azide, tolyl azide, 2-methyl-4-nitrophenyl azide, 3-methyl-5- cyanophenyl azide, 2,5-dimethylphenyl azide, biphenyl azide, 3-nitro-biphenyl azide, 4'-cyanobiphenyl azide, naphthyl azide, 1 -(4-cyano)naphthyl azide, 2-(6-nitro)naphthyl azide, 1 -anthryl azide, 1 -(10-cyano)anthryl azide,

2-(6-nitro)anthryl azide, 2-phenanthryl azide, 1 -(6-cyano)phenanthryl azide, and 2-(9-nitro)-phenanthryl azide. Suitable aralkyl azides include benzyl azide, 4-tert-butylbenzyl azide,

4-nitrobenzyl azide, 4-methoxybenzyl azide, 2-chlorobenzyl azide,

3-nitrobenzyl azide, 4-methylbenzyl azide, 2-phenylethyl azide, 2-(3- cyanophenyl)ethyl azide, 2-(4-nitrophenyl)ethyl azide, 2-(2- methylphenyl)ethyl azide, 3-phenylbutyl azide, diphenylmethyl azide,

4-cyanobenzyl azide, 4-nitrobenzyl azide, 1 -naphthylmethyl azide, [1 -(6- cyano)-naphthyl]ethyl azide, 2-naphthylethyl azide,

[2-(4-nitro)-naphthyl]methyl azide. Preferred aralkyl azides include benzyl azide, 4-tert-butylbenzyl azide, 4-nitrobenzyl azide, 4-methoxybenzyl azide, 2-chlorobenzyl azide, 3-nitrobenzyl azide, 4-cyanophenyl azide, and

4-nitrophenyl azide.

Many of the organic azides that can be used in this invention are relatively stable, and thus can be purchased or prepared ahead of time and stored until needed. Some of the organic azides that can be used in the practice of this invention are not stable in the sense that they cannot be stored for later use. Therefore, it could be desirable to obtain the azides in situ, allowing to skip the isolation process of azides which could be sometimes dangerous and difficult. Azides can be obtained by reacting an organic halide and an alkali metal azide. Azides could be prepared in situ and reacted with alkynes under the same reaction conditions. As it is illustrated in the examples, mixing the benzyl bromide derivatives with sodium azide and alkyne in water at 40 ⁰C in the presence of 1 mol% of TTr-CuCI gives the corresponding triazoles in high yields after 8 hours. This reaction can also be performed in a microwaves reactor using a mixture of organic solvent (preferably acetonitrile, DMF,

DMSO, or acetone) and water. In this case the reaction temperature is 100⁰C, and the reaction time is 40 minutes.

The organic group of the organic halide can be, for example, alkyl, ether, aryl, or aralkyl as defined for organic azides above. Preferably, the halide is chloride, bromide, or iodide. Organic bromides and organic iodides are more preferred.

The alkali metal azide can be lithium azide, sodium azide, or potassium azide; preferably sodium azide. Normally, approximately equimolar amounts of the organic halide and the alkali metal azide are used; a slight excess of the alkali metal azide (e.g., about 1.01 to about 1.10 moles of alkali metal azide per mole of organic halide) is preferred. Suitable functional groups in terminal alkynes include, for instance, carbon-carbon double bonds, ether groups, ester groups, ketyl groups, hydroxyl groups, chlorine atoms, fluorine atoms, trihydrocarbylsilyl groups, nitrogen atoms (e.g., as amino groups).

According to the invention, terminal alkynes typically have three to twenty carbon atoms, and preferably five to twelve carbon atoms. When expressed as R₆C≡CH, groups R₆ may include alkyl groups (straight chain, cyclic, or, preferably, branched), alkenyl groups (straight chain, branched, or,

preferably, cyclic), aryl groups, and silyl groups.

The internal alkynes according to the invention typically have four to twenty carbon atoms, and preferably six to twelve carbon atoms. When expressed as R₇C≡CR₈, groups R₇ and R₈, which may be the same or different, include alkyl groups (straight chain, branched, or cyclic), alkenyl groups (straight chain, branched, or cyclic), and aryl groups. Mixtures of any two or more alkynes can be used, if desired. The use of mixtures of alkynes will yield a mixture of triazoles.

Examples of terminal alkynes that can be used in the practice of this invention include, but are not limited to, 1 -propyne, cyclopropylacetylene, 1 -butyne, 1 -pentyne, 3,3-dimethyl-1 -butyne, 1 -hexyne, cyclohexylacetylene, 1 -heptyne, 3-cyclopentyl-1 -propyne, 1 -octyne, 1 -nonyne, 1 -decyne, 2-methyl-1 -buten-3- yne, 3-penten-1 -yne, 3-hexen-1 -yne, 2-ethynylcyclopentene,

1 -ethynylcyclohexene, 3-ethyl-3-penten-1 -yne, 5-decen-1 -yne,

phenylacetylene, 3-tert-butylphenylacetylene, 1 -ethyl-4-ethynylbenzene, 4-phenyl-1 -butyne, 4-methoxyphenylacetylene, 1 -ethynyl-3,5- dimethoxybenzene, 1 -ethynyl-4-phenoxybenzene, 3-chloropropyne (propargyl chloride), 4-chlorobutyne, 3-chloro-3-methyl-1 -butyne, 5-chloropentyne,

4-chlorohexyne, 6-chlorohexyne, 7-chloro-3-heptyne,

2-fluorophenylacetylene, 3-fluorophenylacetylene, 4-fluorophenylacetylene, 2-methyl-3-fluorophenylacetylene, 4-ethynylbiphenyl, 1 -ethynylnaphthalene, 2-ethynylnaphthalene, 2-ethynyl-6-methoxynaphthalene,

1 -ethynylanthracene, 2-ethynyl-6-methoxyanthracene, 9- ethynylphenanthrene, 2-ethynyl-6-fluorophenanthrene, 2-propyn-1 -ol

(propargyl alcohol), 3-butyn-1 -ol, 2-methyl-3-butyn-2-ol, 1 -pentyn-4-ol, 1 -hexyn-3-ol, 1 -hexyn-5-ol, 1 -ethynyl-1 -cyclohexanol, 1 -octyn-3-ol, hydroxyphenylacetylene, 3-hydroxy-3-phenyl-1 -propyne, 2-phenyl-3-butyn-2- ol, 3-methoxypropyne, 3-propoxypropyne, 3-tert-butoxy-1 -butyne, methyl propiolate, ethylpropiolate, 3-butyn-2-one, 1 -pentyn-3-one, 4-methyl-1 - pentyn-3-one, 2-pentyn-4-one, 1 -hexyn-3-one, 3-hexyn-2-one, 2-hexyn-4- one, 3-heptyn-2-one, (trimethylsilyl)acetylene, (triethylsilyl)acetylene, (triisopropylsilyl)acetylene, (dimethylphenylsilyl)acetylene,

(methyldiphenylsilyl)acetylene, (triphenylsilyl)acetylene,

3-(dimethylannino)propyne, 3-(dipropylamino)propyne, 4-(diethylamino)-2- butyne, 5-(dimethylamino)-3-pentyne, 5-(diethylamino)-3-pentyne,

2-ethynylpyridine, 3-ethynylpyridine, and 4-ethynylpyridine.

The catalysts of the invention can also be useful for a number of processes comprising functionalization of C-H bonds by the insertion of carbene or nitrene, cyclopropanation of alkenes, aziridination of alkenes, oxidation of alkanes to alcohols by insertion of oxygen into C-H bonds, and cycloaddition reactions. More particularly, the catalysts have shown to be useful in click reactions, particularly in the formation of triazoles via the cycloaddition of azide and acetylene.

In a prefered embodiment of the invention, the catalysts in general or for each of the processes above are those of formula (I) where n is 1 , and the substituents of Ri are selected from the group consisting of: halogen, nitro, cyano, (d-C₄)alkyl, -O-(C_rC₄)alkyl, -CO-(Ci-C₄)alkyl, -COO-(d-C₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl, -SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅.

Compounds of formula (I) may be prepared by a process comprising the step of reacting a compound of formula (II),

where R-i, R₂, Y, and n are as defined above for compound (I); with a metal salt wherein the metal is selected from Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr. These metal salts are soluble in the reaction solvent and contains the metal in the desired oxidation state. In a preferred embodiment, the metal salt is (M^a+)_b(X^b")_a wherein M is a metal selected from the group consisting of Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr; X is an anion selected from the group consisting of halogen, BF₄ ^", PF₆ ^", OTf, acetate, and acetylacetonate; a is the number of total positive charges of the metal ion; and b is the number of total negative charges of the anion. Preferably, the metal is Cu (I).

Preferably, the reaction is carried out in water, or mixtures of an organic solvent and water. Appropriate organic solvents include (Ci-C₄)alcohols such as n- and t-butanol, ethanol or methanol, (C₂-C₅)-ethers such as

tetrahydrofuran; acetonitrile or dimethylformamide.

Compounds of formula (II) are new and also form part of the invention.

Preferred compounds of formula (II) are those yielding to the preferred compounds of formula (I) mentioned above. The most preferred compounds of formula (II) are those where, n is 1 , and the substituents of Ri are selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl,

-O-(Ci-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl,

-SO₂-(C_rC₄)alkyl, -NHSO₂-(C_rC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅.

These compounds may be prepared by the process below.

In a first step, tris(trimethylsilylethynyl)methanol (Ilia) can be prepared by reacting thmethylsilylethylene with a strong base such as n-butyl lithium at a temperature comprised between 0-5 ⁰C, followed by reacting the compound obtained with chloroethylformate at a temperature about -78 ⁰C for 3 h (Step A).

Alternatively, the known 3 steps synthesis of

tris(trimethylsilylethynyl)methanol using ethylformate described by Lickiss et a!.. J. Orqanomet. Chem., 1986, vol. 308, p. 261 , can be used.

The first process using ethylchloroformate is considered advantageous since it is a single step synthesis.

In a second step, step B, the process comprises a first desilylation of a compound (Ilia) by a base such as K₂CO₃ in an appropriate solvent such as methanol to yield the corresponding desilylated compound of (Ilia), and the subsequent 1 ,3-dipolar cycloaddition reaction using a CuSO₄/ascorbate catalytic system according to Sharpless et al, Organic Letters, 2004, Vol. 6, No. 17, pgs. 2853-2855, rendering the compounds of formula (Ma) of the invention.

Preferably, the reaction of the azido moiety with the alkyl moiety takes place under 1 ,3-dipolar cycloaddition conditions. Alternatively to the known

CuSO₄/ascorbate reaction above, the reaction can be catalyzed by a catalytic amount of the catalyst of formula (I). When using the catalyst of the invention, the 1 ,3-dipolar cycloaddition reaction in Step B is performed in the presence of a catalytic amount of a compound of formula (I) such as TTr-CuCI.

For example, compounds of formula (II) are obtained by the reaction of the desilylated reaction mixture with a solution of the corresponding azide in a suitable solvent such as water. A catalyst of formula (I) such as TTr-CuCI is added and the reaction mixture is stirred, for example for 6 h, and the compounds of formula (II) are then recovered by filtration.

The use of the catalyst of the invention in its own preparation process allows improving its preparation by the lower reaction times, high yields and the use of water based solvents without using complex catalytic systems and in situ redox processes.

Scheme I illustrates a particular embodiment of the process: Scheme I

TMS

(Ilia)

1. K₂CO₃₁ MeOH

Step (B) 2. R_r(Y)_n-azide,

CuSO₄-5H₂O,

sodium ascorbate,

MeOH

(Ma)

Scheme Il illustrates a particular embodiment of the process, where Step B is catalyzed by the catalyst of the invention:

Scheme Il

Compounds of formula (Ma) can be further benzylated by a first treatment with a base, e.g. an hydride, in a suitable organic solvent and a subsequent reaction with L-Benzyl, being L a leaving group, e.g. an halogen. Compounds of formula (Ma) can be further hydroxyl -protected with the introduction of suitable protecting groups by the general methods known in the art, as disclosed in, for example, Green et al., "Protective Groups in Organic Chemistry", Chapter 2 (Wiley, 3rd ed. 1999). Alternatively, compounds of formula (Ma) can also be further propargylated in order to prepare a supported catalyst of formula (I) wherein R₂ is -OR₃ and R₃ is -P, or -L-P, wherein P is a polymeric support; and L is a biradical of formula (IV)

(IV) wherein the symbol ^ΛΛT indistinctly indicates the positions through which L is attached to the oxygen atom of R₂ and to P.

The propargylation substitution reaction of compounds of formula (Ma) can be carried out through a first reaction with a hydride base and the subsequent addition of the propargyl moiety to the activated oxygen atom.

The resulting propargylated compound of formula (Ma) can be further reacted with an azide-functionalized polymeric support to link the ligand to the polymeric support through a 1 ,2,3,-triazole linker. Preferably, the linker is obtained by a 1 ,3-dipolar cycloaddition reaction catalyzed by the compound of formula (I). The resulting supported ligand can be reacted with a metal salt to obtain the supported catalyst of the invention. Scheme III illustrates a particular embodiment of the process. Scheme

Compounds of formula (Ma) can also be further treated in order to prepare a supported catalyst of formula (I) which is directly attached to the polymeric support -P, thus R₂ being -OR₃ and R₃ is -P, wherein P is a polymeric support. The preparation of such directly supported catalysts can comprise the reaction between a functional ized polymeric support P-L, where L is a leaving group, e.g. an halide, and compounds of formula (Ma) in the presence of a base, e.g. an hydride, and a suitable organic solvent to obtain a supported catalyst of formula (I) which is directly attached to the polymeric support -P. The resulting supported ligand can be reacted with a metal salt to obtain the supported catalyst of the invention. Scheme IV illustrates a particular embodiment of the process.

L =

(Md) Alternatively, compounds of formula (Ma) can also be further treated in order to prepare a supported catalyst of formula (I) wherein R₂ is -OR₃ and R₃ is -L-P, wherein P is a polymeric support; and L is a (C-ι-C-ιo)alkyl biradical. The catalysts of the present invention which are linked to a polymeric support through a (C-ι-C-ιo)alkyl linker can be prepared by the alkylation of a

functionalized resin, for example by carboxylating and subsequently reducing the carboxylic acid group to a halo-alkyl moiety, and further attaching the compounds of formula (II) to the alkylated resin. The resulting supported ligand can be reacted with a metal salt to obtain the supported catalyst of the invention. Scheme V illustrates a particular embodiment of the process.

Scheme V

In a further embodiment of the invention, compounds of formula (Ma) can also be linked to the polymeric resin through a carbamate moiety acting as a linker. Such supported ligands can be prepared by the oxidation of a cyanate functionalized resin to obtain a carbamate functionalized resin, which is finally reacted with the compounds of formula (Ma). The resulting supported ligand can be reacted with a metal salt to obtain the supported catalyst of the invention. Scheme Vl illustrates a particular embodiment of the process. Scheme Vl

Alternatively, the linker moiety can be a (C-ι-C-ιo)polyether, which can be obtained by the reaction of compounds of formula (Ma) and a functional ized 5 resin. The functionalized resin can be prepared by the repeated substitution of the resin by the same or different desired diols. Then, when the desired polyether linker has been formed on the resin, the polyether functionalized resin can be reacted with the compound of formula (Ma). The resulting supported ligand can be reacted with a metal salt to obtain the supported O catalyst of the invention. Scheme VII illustrates a particular embodiment of the process.

Scheme VII

^X HO(CH₂)_nOH _p^O(CH₂)_nOH SOCI₂ ^ ^₀(CH₂)_nCI

5 NaH₁ DMF Pyridine ^P *^"

X = CI, Br

Other suitable processes for the immobilization of the ligands on polymeric supports for the preparation of supported catalysts may be used, for example, c.f. Pericas et al., J. Orq. Chem. 2007, vol. 72, pg. 2460 and WO

0 2008/022961 .

In a preferred embodiment of the invention compounds of formula (Ma) are those where n is 1 , and the substituents of Ri are selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl, -O-(Ci-C₄)alkyl,

5 .CO-(CrC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅,

-(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl, -SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅.

Throughout the description and claims the word "comprise" and variations of 0 the word, such as "comprising", is not intended to exclude other technical features, additives, components, or steps.

Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. EXAMPLES

Example 1 : Preparation of tris(trimethylsilylethvnyl)methanol

(Ilia)

To a solution of thmethylsilylethylene (3.0 ml_, 21.2 mmol) in dry THF (30 ml_), a solution of n-BuLi in hexane (2.5 M, 9.0 ml_, 22.5 mol) was added dropwise at 0 ⁰C and the solution was stirred for 2 h before it was cooled to - 80 ⁰C. Ethyl chloroformate (0.67 ml_, 7.06 mmol) was added and the solution left warming to room temperature under stirring for 3 h. During the warming, the colour of the solution turned into dark red. The reaction was quenched with saturated NH₄CI solution and extracted with Et₂O (4 x 40 ml_). The combined organic phase was dried over MgSO₄ and the solvent was removed under reduced pressure to give crude tris(trimethylsilylethynyl)methanol as a solid. It was purified using flash column chromatography, using hexane as only eluent and recrystallized in hexane to get analytically pure product (1.61 g, 72%).

¹H-NMR (400 MHz, CDCI₃): δ 0.17 (s, 27 H), 2.95 (s, 1 H) ppm; ¹³C-NMR (100 MHz, CDCI₃): δ 0.3 (CH₃), 57.0 (C), 88.2 (C), 101.8 (C) ppm. Example 2: Preparation of tris(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)methanol using CuSO₄/ascorbate catalyst system.

(Ilia)

Tris(trimethylsilylethynyl)methanol (1.00 g, 3.13 mmol) was stirred in methanol (10 ml_) in the presence of K₂CO₃ (4.20 g, 37.5 mmol) at room temperature for 4 h. The reaction was monitored by TLC (eluenthexane) and after disappearance of starting material, the solution was filtered to remove excess K₂CO₃ and added to a solution of benzyl azide (1.25 g, 9.40 mmol) in methanol (10 ml_). CuSO₄-5H₂O (38.9 mg, 0.156 mmol) and sodium ascorbate (93.0 mg, 0.468 mmol) was added as solids and the solution was left stirring overnight. Solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml_) and extracted with saturated Na₂CO₃ solution (5 x 30 ml_) till the obtention of a colourless aqueous phase. The organic phase was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to afford crude product as a solid. The purification of tristriazole was performed by flash column chromatography, using

ethylacetate as only eluent (0.866 g, 55%).

Example 3: Preparation of tris(1 -benzyl-1 /-/-1 ,2,3-triazol-4-yl)methanol using TTr-CuCI complex as catalyst.

Tris(trimethylsilylethynyl)methanol (1.00 g, 3.13 mmol) was stirred in methanol (10 ml_) in the presence of K₂CO₃ (4.20 g, 37.5 mmol) at room temperature for 4 h. The reaction was monitored by TLC (eluenthexane) and after disappearance of starting material, the solution was filtered to remove excess K₂CO₃ and added to a solution of benzyl azide (1.25 g, 9.40 mmol) with water. TTr-CuCI (9.4 mg, 0.0156 mmol) was added as a solid and the suspension was left stirring for 6 h. During the reaction, the precipitation of the solid product could be seen. After the completion, water was added to the reaction mixture and the solid product was obtained by simple filtration in very good yield. Recrystallization in ethylacetate/hexane gave analytically pure tris(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)methanol (1.35 g, 86%).

¹H-NMR (400 MHz, CDCI₃): δ 4.58 (s, 1 H), 5.46 (s, 6H), 7.23-7.38 (m, 15H), 7.58 (s, 3H) ppm; ¹³C-NMR (100 MHz, CDCI₃): δ (CH₃), (C), (C), (C) ppm. HRMS (TOF ES+): Found = 504.2250; Calculated for C₂₈H₂₆N₉O (M+H⁺) = 504.2260

Example 4: Preparation of CuCI[I -benzyl-1 H-1 , 2,3-triazole-4-yl)-methanol1 (TTr-CuCI: compound of formula (I) with Ri = phenyl, and M = Cu(I))

To the solution of tris(1 -benzyl-1 H-1 , 2,3-triazol-4-yl)methanol (503 mg, 1.00 mmol) in dioxane (10 ml_), CuCI (98 mg, 1.00 mmol) was added as a solid and the reaction mixture was heated up to 60 ⁰C for 6 h. Then, the solvent was removed under reduced pressure and the residue was dissolved in 2-3 ml_ dichloromethane and added dropwise to 20 ml_ of hexane. The precipitation Of TTr-CuCI could be seen. After filtration, the green-blue coloured TTr-CuCI was obtained (565 mg, 95%).

The complex was air and moisture stable. No special storage was necessary.

¹H-NMR (400 MHz, CDCI₃): δ 5.29 (br s, 1 H), 5.49 (s, 6H), 7.23-7.36 (m, 15H), 7.79 (br s, 3H) ppm; HRMS (MALDI+): Found: 566.1536, calculated for C₂₈H₂₅CuN₉O: 566.1473.

Example 5: Preparation of substituted 1 ,2,3- triazoles by dipolar cvcloaddition reaction between a benzyl azide and several alkynes catalyzed by TTr-CuCI

Ph^^lvT ^_N

R

(V)

Preparation of the compound of formula (V) with R = phenyl.

To a mixture of phenyl acetylene (102 mg, 1.00 mmol), benzyl azide (133 mg, 1.00 mmol) in water (1 ml_), TTr-CuCI (for 0.5 mol%; 3.0 mg) was added and mixture was left stirring at room temperature for 4 h. The product was filtered and washed with water. The crude product was purified by flash column chromatography using hexane:EtOAc (85:15) mixture as eluent to give the compound in 94% yield.

The compounds of the following list were prepared according to the previous process using the corresponding alkyne derivatives. Compound of formula (V) with R = -CH₂-CH₂-CH₂-CH₃

Reaction time: 16 h

Temperature: 40 ⁰C

Amount of catalyst: 0.25 mol%

Yield: 98 %

Compound of formula (V) with R = -CH₂-CH₂-CH₂-CH₂-CH₂-CH₃

Reaction time: 16 h

Temperature: 40 ⁰C

Amount of catalyst: 0.25 mol%

Yield: 98 %

Compound of formula (V) with R = -COOEt

Reaction time: 12 h

Temperature: r.t.

Amount of catalyst: 0.5 mol%

Yield: 96 %

Compound of formula (V) with R = -p-(C₆H₄)-CH₂OH

Reaction time: 2 h

Temperature: r.t.

Amount of catalyst: 0.5 mol%

Yield: 92 %

Compound of formula (V) with R = -CH₂-OH

Reaction time: 6 h

Temperature: r.t.

Amount of catalyst: 0.5 mol%

Yield: 84 % Compound of formula (V) with R = -CH₂-N(CH₃)₂

Reaction time: 4 h

Temperature: r.t.

Amount of catalyst: 0.5 mol%

Yield: 97 %

Example 6: Preparation of (1 -benzyl-1 H-1 ,2,3-triazol-4-yl)methanamine by TTr-CuCI catalyzed dipolar cvcloaddition between benzylazide and prop-2- yn-1 -amine

To a mixture of prop-2-yn-1 -amine (1.00 mmol), benzyl azide (133 mg, 1.00 mmol) in a 2:1 mixture of n-butanol and water (1 ml_), TTr-CuCI (1 mol %; 6.0 mg) was added and mixture was left stirring at room temperature for 5 h. The product was filtered and washed with water. The crude product was purified by flash column chromatography using hexane:EtOAc (85:15) mixture as eluent to give the compound in 47 % yield.

Example 7: Preparation of 1 -benzyl-4-phenyl-1 ,2,3-triazole by TTr-CuCI catalyzed dipolar cvcloaddition reaction in different reaction conditions

The reaction was carried out using different solvents, catalyst mol %, reaction time, and temperature Table 1 illustrates the reaction conditions used. Table 1

En tr TTr-CuCl

Solvent T (⁰C) Time (h) Yk ϊld (%) y mol (%)

isxsssssssssssssssssssssssssss røssssssssssss ςsxsssssssssssssssssssssssssssss

1 H₂O 0.5 r.t. 4 94

2 H₂O 1 r.t. 4 97

3 H₂O 0.25 40 4 95

MeOH:H₂O

4 0.5 r.t. 4 88

(1 :1 )

5 EtOHiH₂O (1 :1 ) 0.5 r.t. 4 80

6 THF: H₂O (1 :1 ) 0.5 r.t. 18 93

7 THF: DMF (1 :1 ) 0.5 r.t. 18 90

Example 8: Preparation of substituted 1 ,2 ,3- triazoles bv TTr-CuCI catalyzed dipolar cvcloaddition reaction usinq benzvl bromide derivatives for in situ preparation of azides

Azides could be also prepared in situ and reacted with alkynes under the same reaction conditions. This allows skipping the isolation process of azides which could be sometimes dangerous and difficult.

(Vl)

Preparation of compound of formula (Vl) with R=H and R'=Ph

To a mixture of phenyl acetylene (102 mg, 1.00 mmol), benzyl bromide (171 mg, 1.00 mmol) and sodium azide (71 mg, 1.10 mmol) in water (1 ml_),

TTr-CuCI (0.01 mmol, 6.0 mg) was added and mixture was left stirring for 8 h at 40 ⁰C. The product was filtered and washed with water. The crude product was purified by flash column chromatography using hexane:EtOAc mixture as eluent. Yield 99%. The compounds of the following list were prepared according the previous process using the corresponding alkyne derivatives.

Compound of formula (Vl) with R = -f-butyl in para position, R' = Ph.

Yield: 98 %

Compound of formula (Vl) with R = -NO₂ in para position, R' = Ph.

Yield: 98 % Compound of formula (Vl) with R = MeO- in para position, R' = Ph.

Yield: 93 %

Compound of formula (Vl) with R = -Cl in ortho position, R' = Ph.

Yield: 80 %

Compound of formula (Vl) with R = -NO₂ in meta position, R' = Ph.

Yield: 88 %

Compound of formula (Vl) with R = -NO₂ in para position, R'=

-p-(C₆H₄)-CH₂-OH Yield: 90 %

Example 9: Preparation of N-aryl tristriazolylmethanol ligands (compounds of Formula II, n=0) Process A:

In a round bottom flask, tris(methylsilylethynyl)methanol (1 equiv.) in methanol (1.5 ml) was stirred in the presence of K₂CO₃ (12 eq.) at room temperature for 4 h. The reaction was monitored by TLC (hexane:ethyl acetate 90:10 as eluent). After disappearance of the starting material, the solution was filtered through silica gel to remove excess of K₂CO₃, using methanol as eluting solvent, and then it was concentrated by rotavapor (200 mbar) to less than half of the original volume. Then, water (12 ml), the organic azide (4 equiv.) and TTrCuCI catalyst (0.01 eq.) of Example 4 were added successively. The mixture was stirred for 24 h at 3O⁰C. During the reaction, the product precipitated. After filtration, the solid was washed with

dichloromethane and dried. Process B:

As process A, but the mixture was stirred overnight at room temperature. During the reaction, the product precipitated. After filtration, the solid was washed with dichloromethane and dried.

Process C:

As process A, but after concentration under reduced pressure, a solution of the organic azide (4 eq.) in methanol, CuSO₄.5H₂O (0.1 equiv.), and sodium ascorbate (0.3 eq.) were added, and the mixture was stirred overnight.

Solvent was removed under reduced pressure, and the crude product was washed with methanol and dichloromethane, filtered, and dried. The following compounds of formula Il with n=0 were obtained by the processes above.

Tris(1 -(3,4-dichlorophenyl)-1 H-1 ,2,3-triazol-4-yl)methanol_(HOTTrPh₄CI₂): Organic azide: 4-azido-1 ,2-dichlorobenzene

Process: A

Yield: 43%

Structural data: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.87 (s, 1 H), 8.32 (d, J = 2.5

Hz, 1 H), 8.03 (dd, J = 8.8, 2.5 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H) ppm.

Elemental analysis: C 58.62, H 4.78, N 21.56.

Tris(1 -(4-methylphenyl)-1 H-1 ,2,3-triazol-4-yl)methanol (HOTTrPh₄Me): Organic azide: 1 -azido-4-methyl benzene

Process: B

Yield: 37%

Structural data: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.68 (s, 1 H), 7.83 (d, J = 8.3

Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 2.38 (s, 4H) ppm. Elemental analysis: C

66.64, H 4.99, N 24.56.

Tris(1 -(4-methoxyphenyl)-1 H-1 ,2,3-triazol-4-yl)methanol (HOTTrPh4OMe):

Organic azide: 1 -azido-4-methoxybenzene

Process: B

Yield: 31 %

Structural data: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.63 (s, 1 H), 7.86 (d, J = 9.0

Hz, 2H), 7.13 (d, J = 9.0 Hz, 2H), 3.85 (d, J = 11.6 Hz, 4H) ppm. Elemental analysis: C 58.25, H 4.49, N 21.12.

Tris(1 -(4-bromophenyl)-1 H-1 ,2,3-triazol-4-yl)methanol (HOTTrPh₄Br):

Organic azide: 1 -azido-4-bromobenzene Process: B

Yield: 32%

Structural data: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.80 (s, 1 H), 7.95 (d, J = 8.8

Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H) ppm.

Tris(1 -(4-trifluoromethylphenyl)-1 H-1 ,2,3-triazol-4-yl)methanol

(HOTTrPh4CF₃):

Organic azide: 1 -azido-4-(trifluoromethyl)benzene

Process: C

Yield: 75%

Structural data: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.96 (s, 1 H), 8.25 (d, J = 8.5

Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H) ppm. ¹³C NMR (100 MHz, DMSO-d⁶) δ 67.4

(C), 120.5 (CH), 121.9 (C), 122.5 (C), 125 (CH), 128 (C), 139.5 (C), 152.8 (C) ppm. Elemental analysis: C 46.38, H 2.61 , N 15.70.

Example 10: Preparation of substituted 1 ,2,3- triazoles by dipolar

cvcloaddition reaction between a benzyl azide and an alkyne catalyzed by catalysts of formula (I) with M= Cu and n=0.

In a vial fitted with a screw cap, catalyst (0.5 mol%; 3.0 mg) was added to a mixture of phenylacetylene (1.05 mmol) and benzylazide (1.00 mmol) in water (1 ml_); mixture was stirred at room temperature for 24 h. Whenever the product precipitated, it was simply filtered and washed with water. Otherwise, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and solvent was removed in vacuo. When required, the product was purified by flash column chromatography.

Electron rich aryl rings born by the ligand enable to access higher

conversions and cleaner reactions. Specifically, HOTTrPh4OMe-CuCI provided the substituted triazole yielding 100%, thus not requiring any purification step.

Example 11 : Preparation of Benzylated TTr (TTrOBn)

Into a flame dried flask with a suspension of NaH (8 mg, 60% in oil, 0.28 mmol) in DMF (1 ml_), a solution of TTr (100 mg, 0.2 mmol) in DMF (1 ml_) was added dropwise at -20 ⁰C under nitrogen. After stirring for 2 h at room temperature, the suspension became a clean solution and was cooled to 0 0C, and (0.047 ml_, 0.4 mmol) was added dropwise. The reaction mixture was let to warm to room temperature and further stirred for 14 h. Water was added to the reaction mixture which was extracted with dichloromethane (3 x 10 ml_). The combined organic phase was dried over MgSO4, filtered and solvent was removed under reduced pressure. In order to get rid of DMF, the crude product was dissolved in ethyl acetate: hexane (4:1 ) mixture and washed with water (3 x 20 ml_). Organic phase was dried over MgSO4, filtered and solvent was removed under reduced pressure to get a crude solid product which was further purified by flash column chromatography using ethylacetate as eluent (0.089 g, 82%).

¹H NMR (400 MHZ, CDCI₃): δ = 7.87 (s, 3H, H^trιazolΘ), 7.35-7.17 (s, 2OH, H^Ph), 5.49 (s, 6H, PhCH₂), 4.45 (s, 2H, PhCH₂ ^0Bn).

¹³C NMR ((CDg)₂SO): 5 = 149.2, 138.3, 134.4, 129.1 , 128.7, 128.2, 128.1 , 127.9, 72.9, 66.7, 54.2.

HRMS calculated for C₃₅H₃₂N₉O: 594.2730. Found: 594.2724 ([M+H]⁺).

Example 12: Preparation of TTrOBn-CuCI

TTrOBn-CuCI

To the solution of TTrOBn (100 mg, 0.2 mmol) in dioxane (3 ml_), CuCI (19.6 mg, 0.2 mmol) was added as a solid and the reaction mixture was heated up to 60 ⁰C for 6 h. Then, the solvent was removed under reduced pressure and the residue was dissolved in 1 -2 ml_ dichloromethane and added dropwise to 20 ml_ of hexane. The precipitation of TTrOBn-CuCI could be seen. After filtration, the green-blue colored TTrOBn-CuCI was obtained (113 mg, 95%).

Example 13: Preparation of 1 -benzyl-4-phenyl-1 ,2,3-triazole by dipolar cvcloaddition reaction catalyzed by TTrOBn-CuCI catalyst.

4h, r t

0 5 mol%

To a mixture of phenyl acetylene (107 mg, 1.05 mmol), benzyl azide (133 mg, 1.00 mmol) in water (1 ml_), TTrOBn-CuCI (for 0.5 mol%; 3.4 mg) was added and mixture was stirred at room temperature for 4h. The product was filtered and washed with water. The crude product was purified by flash column chromatography using hexane:EtOAc (80:20) mixture as eluent (233 mg, 99%). Example 14: Preparation of 3-[tris(1 -benzyl-1 /-/-1 ,2,3-triazol-4-yl)methoxy1 propyne

To the suspension of NaH (80 mg, 60% in oil, 2.0 mmol) in DMF (2 ml_), a solution of the compound obtained in Example 2 (503 mg, 1.0 mmol) in DMF (2 ml_) was added dropwise at 0 ⁰C. After stirring for 2 h at room temperature, the clean solution was cooled to 0 ⁰C, and a commercial solution of propargyl bromide in toluene (0.220 ml_, 80% solution in toluene, 2.0 mmol) was added dropwise. The reaction mixture was let to warm to room temperature and further stirred for 14 h. Water was added to the reaction mixture which was extracted with dichloromethane (3 x 10 ml_). The combined organic phase was dried over MgSO₄, filtered and solvent was removed under reduced pressure. In order to get rid of DMF, the crude product was dissolved in ethyl acetate: hexane (4:1 ) mixture and washed with water (3 x 20 ml_). Organic phase was dried over MgSO₄, filtered and solvent was removed under reduced pressure to get crude solid product which was further purified by flash column chromatography using ethylacetate as eluent (0.444 g, 82%).

¹H-NMR (400 MHz, CDCI₃): δ 2.05 (t, J=2.4 Hz, 1 H), 4.11 (d, J=2.4 Hz, 2H), 5.49 (s, 6H), 7.27-7.35 (m, 15H), 7.85 (s, 3H) ppm.

HRMS (ES+): Calculated for C₃IH₂₇N₉ONa: 564.2236, found: 564.2253. Example 15: Preparation of polymer supported TTr ligand with a triazole linker (poly-Tr-TTr) using TTr-CuCI as catalyst.

The azide functionalized Merrifield resin (100 mg, f = 0.94 mmol/g) was added to the solution of 3-[tris(1 -benzyl-1 H-1 ,2,3-triazol-4-yl)methoxy] propyne (510 mg, 0.94 mmol) in 1 :1 mixture of DMF:THF (5 ml_). TTr-CuCI (5.6 mg, 0.0094 mmol) was added to the mixture and shacked for 48 h at 40 ⁰C. The reaction was monitored by IR spectroscopy and stopped after the disappearance of azide peak around 220 cm^"1. The resin was washed with water, THF and methanol respectively and then dried at 50 ⁰C overnight. The functionalization was calculated by elemental analysis to give f = 0.56 mmol/g. Elemental Analysis: 80.87% C, 6.67% H, 9.37% N

Example 16: Preparation of polymer supported TTr-CuCI with a triazole linker (pol V-Tr-TTr-CuCI)

CuCI (5 mg, 0.05 mmol) was mixed and shacked at room temperature with the resin obtained in Example 15 (50 mg) in THF (2 ml_) until the disappearance of solid CuCI. The colour of the resin turned into green after the completion of complexation. The resin was washed with THF and then dried at 50 ⁰C overnight. Example 17: Preparation of 1 -benzyl-4-phenyl-1 ,2,3-triazole by dipolar cvcloaddition reaction catalyzed by polymer supported poly-Tr-TTr-CuCI.

To a mixture of phenyl acetylene (102 mg, 1.00 mmol), benzylazide (133 mg, 1.00 mmol) in water (2 ml_), Poly-Tr-TTr-CuCI (11 mg, 0.01 mmol Cu) was added and shacked for 3 h at 40 ⁰C. When the reaction was complete, water0 was removed by filtration and then click product was dissolved in EtOAc and the resin was filtered. Organic solvent was removed under reduced pressure to get the desired product (220 mg, 94%). The resin was dried with a flow of nitrogen for 1 h and then treated with CuCI (1 mg, 0.01 mmol) in THF (2ml_) for 15 h. Then, it was filtered and washed with THF and dried with a flow of5 nitrogen for 1 h and used for the subsequent dipolar cycloaddition catalyzed by Cu.

The catalyst could be recycled and reused 5 times without any loss of activity after reconditioning with copper(l) chloride solution (Table 2). To the best of o our knowledge, this is the best reusable catalyst for dipolar cycloaddition catalyzed by Cu in terms of catalyst amount, reaction time and conditions.

Table 2

Recycling supported p poollyy--TTrr--TTlTr-CuCI in dipolar c

5

# of cycle Yield (%)

1 94

2 92

3 94

0 4 94

5 93 5 Example 18: Preparation of polymer supported TTr ligand with a methylene linker (poly-Me-TTr)

Into a flame dried flask with a suspension of NaH (16.8 mg, 60% in oil, 0.7 mmol) in DMF (2 ml_), a solution of TTr (252 mg, 0.5 mmol) in DMF (2 ml_) was added dropwise at 0 ⁰C under nitrogen. After stirring for 2 h at room temperature, the clean solution was cooled to 0 ⁰C, and a solution of commercial Merhfield resin PS-crossl inked 1 % with DVB (1.1 mmol/g functionality, 0.327 g, 0.36 mmol) in DMF (3 ml_) was added via cannula. The reaction mixture was let to warm to room temperature and was further heated to 50 ⁰C and shacked for 68 h. After the reaction mixture cooled down to room temperature, it was filtered and washed with excess DMF, H₂O, THF, THF- MeOH (1 :1 ), MeOH, THF; respectively. The resulting polymer was dried in a vacuum drying oven at 50 ⁰C for overnight.

Elemental analysis (%) = N 4.25, C 86.25, H 7.38.

f_max= 0.86 mmol/g.

f = 0.34 mmol/g.

Example 19: Preparation of polymer supported TTr-CuCI with a methylene linker (polv-Me-TTr-CuCI)

CuCI (16 mg, 0.16 mmol, 2 eq.) was mixed and shacked at room temperature with poly-Me-TTr (262 mg) in THF (10 ml_) until the colour of the resin turned into green with the completion of complexation. The resin was washed with excess THF, H₂O and THF, and was finally dried under vacuum overnight.

Example 20: Preparation of 1 -benzyl-4-phenyl-1 ,2,3-triazole by dipolar cvcloaddition reaction catalyzed by polv-Me-TTr-CuCI.

4h, 40 °C

1 mol%

Into a vial containing a mixture of phenyl acetylene (107 mg, 1.05 mmol), benzylazide (133 mg, 1.00 mmol) in water (2 ml_), PoIy-Me-TTr-CuCI (30.4 mg, 0.01 mmol Cu) was added and mixture was shacked for 4 h at 40 ⁰C. When the reaction was complete, water was removed by filtration and then click product was dissolved in EtOAc and the resin was filtered. Organic solvent was eliminated under reduced pressure to get the desired product (214 mg, 91 %). The resin was dried under vacuum overnight. Then, it was used for the subsequent CuAAC reaction. The first reuse gave 85% yield at 40 ⁰C after 4h. A further reuse decreased the yield even more, to 15%.

However, reconditioning of the resin with CuCI in the conditions described in Example 17 regenerated its catalytic activity. Afterward, other solvents were tested to improve the stability of the resin and minimize copper leaching. It was found that a 1 :1 MeOH/water mixture increased the stability up to four cycles, with triazole yields between 95-99%:

a conversion by ¹H-MNR.

b Copper reconditioning overnight before a click

Compounds on Table 3 were prepared according the previous process using the following reagents and reaction conditions:

Table 3

(continued)

Claims

1. A compound of formula (I) or a salt thereof:

(I)

wherein,

Y is a (Ci-C₄)alkyl biradical; n is an integer from 0 to 1 ;

M is a metal selected from the group consisting of Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr;

Ri is a known ring system with 1 -2 rings, isolated or fused; wherein each one of the rings has 5-6 members, each member independently selected from C, N, O, S, CH, CH₂, and NH, the rings being saturated, partially unsaturated or aromatic, and optionally being substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl,

halo-(Ci-C₄)alkyl, -O-(d-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(Ci-C₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(Ci-C₄)alkyl, -SO₂-(C_rC₄)alkyl, -NHSO₂-(C_rC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅; and

R₂ is -OR₃, wherein R₃ is selected from the group consisting of hydrogen, benzyl, a hydroxyl protective group, -P, and -L-P; wherein P is a polymeric support; and

L is a biradical selected from the group consisting of (C-ι-C-ιo)alkyl biradicals and compounds of formula (IV)

(IV)

wherein the symbol

indistinctly indicates the positions through which L is attached to the oxygen atom of R₂ and to P; and

R₄ and R₅ are independently selected from the group consisting of H, (Ci-C₄)alkyl, optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, and amino; (C₂-C₄)alkenyl, optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, amino; and (C₂-C₄)alkynyl, optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, and amino.

2. The compound according to claim 1 , wherein; n is 1 ; and ; the substituents of Ri are selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl, -O-(C_rC₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl,

-OC(O)-(Ci-C₄)alkyl, -C(O)NR₄R₅, -(C_rC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(Ci-C₄)alkyl, -SO₂-(Ci-C₄)alkyl, -NHSO₂-(Ci-C₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅;

3. The compound according to claim 2, wherein M is Cu (I).

4. The compound according to any of the claims 2-3, wherein R₁ is a known ring with 5 to 6 carbon atoms, the ring being saturated, partially unsaturated or aromatic, and optionally being substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, (Ci-C₄)alkyl,

-O-(CrC₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(C_rC₄)alkyl, -OC(O)-(C_rC₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R₅, -S-(C_rC₄)alkyl, -SO-(C_rC₄)alkyl,

-SO₂-(Ci-C₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅

5. The compound according to any of the claims 2-4, wherein R₁ is phenyl, optionally substituted by at least one of halogen, nitro, cyano, (Ci-C₄)alkyl, -O-(Ci-C₄)alkyl, -CO-(C_rC₄)alkyl, -COO-(Ci-C₄)alkyl, -OC(O)-(Ci-C₄)alkyl, -C(O)NR₄R₅, -(CrC₄)alkyl-NR₄R_5j -S-(CrC₄)alkyl, -SO-(CrC₄)alkyl,

-SO₂-(CrC₄)alkyl, -NHSO₂-(CrC₄)alkyl, -SO₂-NR₄R₅, and -NR₄R₅; and R₄ and R₅ are independently selected from H and (Ci-C₄)alkyl.

6. The compound according to claim 5, which is [Cu[tris(1 -benzyl-1 H-1 ,2,3- thazol-4-yl)methanol)]]CI.

7. The compound according to any of the claims 2-5, wherein R₃ is -P.

8. The compound according to any of the claims 2-5, wherein R₃ is -L-P and L is a biradical selected from the group consisting Of -CH₂- and

9. The compound according to claim 1 , wherein n is 0

10. The compound according to claim 9, which is [Cu[tris(1 -(4- methoxyphenyl)-1 H-1 ,2,3-triazol-4-yl)methanol)]]CI.

11. A process for the preparation of substituted 1 ,2,3-triazoles which comprises reacting an azide and a terminal alkyne in the presence of a catalytic amount of a compound of formula (I) as defined in any of the claims 1 -10.

12. A process for the preparation of a compound of formula (I) as defined in any of the claims 1 -10 comprising the step of reacting a compound of formula (II),

(H) wherein R₁, R₂, Y and n are as defined in claim 1 ; with a metal salt wherein the metal is selected from the group consisting of Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr.

13. The process according to claim 12, wherein the metal salt is (M^a+)_b(X^b")_a wherein M is a metal selected from the group consisting of Cu, Ag, Au, V, Fe, Zn, Ni, Co, Mn, Ru, and Cr; X is an anion selected from the group consisting of halogen, BF₄ ^", PF₆ ^", OTf, acetate, and acetylacetonate; a is the number of positive charges of the metal ion; and b is the number of negative charges of the anion.

14. A compound of formula (II)

wherein R₁, R₂, Y and n are as defined in any of the claims 1 -5 or 7-9.

15. The compound according to claim 14, wherein n and ; the substituents of R-i are as defined in claim 2

16. Use of compound of formula (I) as defined in any of the claims 1 -10, as a catalyst.

17. Use according to claim 16 as a catalyst in a 1 ,3-dipolar cycloaddition reaction.