Wheel-shaped copper containing polyoxotungstate as an efficient catalyst in the three-component synthesis of 1,2,3-triazoles

Abstract

Wheel-shaped polyoxotungstate [Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]²⁵⁻ (Cu₂₀ POM) was used as an efficient catalyst for the preparation of triazoles from the corresponding alkyl halides, sodium azide, and alkynes. In this click reaction, the three-component synthesis of 1,2,3-triazoles was performed under mild reaction conditions at room temperature and high to excellent yields were obtained. The isolation and purification processing of organic azides were avoided in this procedure, as they were prepared in situ.

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1. Introduction

“Click Chemistry”, which was first proposed in 2001, relates to reactions that exhibit high yields, high regio- and stereo-specificity, and create only by-products that can be removed simply.¹ 1,3-Dipolar cycloadditions, nucleophilic ring opening reactions of epoxides and aziridines, non-aldol type carbonyl reactions such as formation of hydrazones and heterocycles, additions to carbon–carbon multiple bonds such as oxidative formation of epoxides and Michael additions are examples of click reactions.^2,3 Huisgen 1,3-dipolar cycloaddition is an interesting reaction, used in the preparation of 1,2,3-triazoles. Unfortunately, the non-catalyzed Huisgen 1,3-dipolar cycloaddition of alkynes to azides requires elevated temperatures⁴ and by using asymmetric alkynes, a mixture of two regioisomers are also produced.⁵

Copper(I) catalyzed triazole formation from azides and alkynes is an extraordinarily robust reaction which can be performed under different conditions.^4,6 In this regard, copper-catalyzed azide–alkyne Huisgen cycloaddition (CuAAC) is one of the most powerful chemical reactions within the field of click chemistry. CuAAC as a prototype click reaction has emerged as a green methodology to connect diverse building blocks in chemical synthesis, functionalization of proteins and nucleic acids, biological chemistry, materials science and drug discovery.^7–9 Different copper(I) catalysts such as CuI, CuOTf·C₆H₆ and [Cu(CH₃CN)₄]PF₆ have been employed in the CuAAC reaction.^10,11 The 1,3-dipolar cycloaddition of organic azides to alkynes using a dicopper-substituted silicotungstate has also been reported. In this work, the authors showed that the reduced dicopper core plays an important role in the CuAAC reaction.¹²

In most of the reports, organic azides and alkynes are two main components in the synthesis of 1,2,3-triazoles.¹³ Although organic azides are generally stable and safe, small organic azides could be especially dangerous and difficult to handle.¹⁴ In order to avoid the isolation and purification processing of organic azides in these types of cycloaddition reactions, different methodologies have been delivered in the literature. One-pot syntheses of triazoles from aromatic halides,¹⁵ amines,¹⁴ boronic acids¹⁶ or alkyl/allyl halides¹⁷ were performed by the in situ preparation of azides.

Polyoxometalates (POMs) are a distinctive class of well-known metal oxide inorganic molecular clusters. Because of their widespread applications in various fields such as chemical, biological and materials sciences, catalysis and magnetism, they have attracted extensive interest.^18–20 In the last 20 years, POM chemistry has completely changed, and nowadays it could be regarded as a new type of nanochemistry or nanomaterials science.²¹

The discovery of [Mo₁₅₄(NO)₁₄O₄₄₈H₁₄(H₂O)₇₀]²⁸⁻ (Mo₁₅₄), which is one of the first structures based on non-classical POM units, was a turning point in the field of giant POMs.^22,23 Wheel-shaped polyoxotungstate [Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]²⁵⁻ (Cu₂₀ POM) is the first transition-metal substituted derivative of [H₇P₈W₄₈O₁₈₄]³³⁻ (P₈W₄₈), obtained in a direct reaction using copper(II) ions.²⁴ The P₈W₄₈ compound is a stable wheel-shaped precursor which is made by fusing four Dawson-type P₂W₁₂ fragments.²⁵ The Cu₂₀ POM cluster is the smallest type of macro-ion showing unique blackberry self-assembly behavior.

Herein, for the first time, the one-pot synthesis of 1,2,3-triazoles from alkyl halides, sodium azide and alkynes in the presence of Cu₂₀ POM as a highly efficient catalyst is reported (Scheme 1).

Scheme 1 One-pot synthesis of 1,2,3-triazoles in the presence of Cu₂₀ POM.

2. Results and discussion

In this work, the catalytic role of several copper containing POMs in the CuAAC reaction for the one-pot synthesis of 1,2,3-triazoles from alkyl halides, sodium azide and alkynes is investigated. Different Cu containing POMs were synthesized and characterized according to the literature^26–30 and used in this cycloaddition reaction. As the starting point of our exploration, the reaction between benzyl bromide and phenylacetylene was chosen as a model reaction. In Table 1, the catalytic effects of different copper containing POMs and CuI, as a simple copper(I) salt, in the synthesis of 1,2,3-triazoles are shown. As can be seen in Table 1, among the different Cu substituted POMs, Cu₂₀ POM is the most effective catalyst (Table 1, entry 6). From these results, Cu₂₀ POM was selected as the best catalyst in this system. Using various amounts of Cu₂₀ POM catalyst was also investigated, and 10 μmol was chosen as the optimal amount.

Table 1 The catalytic effect of different Cu containing POMs in the synthesis of 1,2,3-triazoles^a

Entry	Catalyst	Time (h)	Yields^b (%)
a Reaction conditions: benzyl bromide (0.5 mmol), phenylacetylene (0.5 mmol), sodium azide (0.5 mmol), sodium ascorbate (10 mol%) and catalyst (10 μmol), in water/t-BuOH (2 : 1; 3 mL) at room temperature.b Isolated yields.c Reaction in the absence of sodium ascorbate.
1	[γ-H2SiW10O36Cu2(μ-1,1-N3)2]^4−	4	55
2	[SiW9O37{Cu(H2O)}3]^10−	2	60
3	[K3Cu3(NO3)(PW9O34)2]^9−	2	65
4	[Cu4(PW9O34)2]^10−	2	80
5^c	[Cu20Cl(OH)24(H2O)12(P8W48O184)]^25−	4	<1
6	[Cu20Cl(OH)24(H2O)12(P8W48O184)]^25−	1.5	>98
7	[H7P8W48O184]^33−	2	<1
8	CuI	2	25
9	Without catalyst	2	<1

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In the presence of CuI under the same reaction conditions, only yields of 25% for the corresponding 1,2,3-triazoles were observed (Table 1, entry 8). The cycloaddition reaction in the absence of a catalyst did not proceed, thus the presence of catalyst is crucial (Table 1, entry 9). The same result was also obtained for [H₇P₈W₄₈O₁₈₄]³³⁻, the precursor of the [Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]²⁵⁻ catalyst, which indicated the catalytic effect of the substituted coppers in the reaction. In the presence of Cu(II) containing POM, or in other words, the absence of sodium ascorbate, the cycloaddition reaction rarely proceeded (Table 1, entry 5). As mentioned above, it was reported that CuAAC reactions are catalyzed by copper(I) catalysts.¹² So, copper(II) atoms in Cu₂₀ POM and/or other POMs should be reduced to copper(I). In the presence of Cu(II) containing POMs and sodium ascorbate (10 mol%) as a reducing agent, the Cu(I) catalysts were prepared and used in a one-pot cycloaddition of benzyl bromide, phenylacetylene and sodium azide. By using sodium ascorbate as a reducing agent, the CuAAC reaction was efficiently performed at room temperature to give the corresponding product in 98% yield.

By the addition of sodium ascorbate to the catalytic system, the color of the Cu₂₀ POM solution has been changed from blue to colorless (Fig. 1) and the catalytic reaction was initiated after the formation of copper(I) containing POMs. This proposal could be supported by the fact that the absorption band at 700 nm, which is assignable to the d–d transition of the copper(II) atoms in Cu₂₀ POM, disappears¹² (Fig. 1). The results also indicated that almost all copper(II) atoms in the POM catalyst might be reduced to copper(I) species.

Fig. 1 UV-vis spectra of the Cu₂₀ POM solutions before (a) and after (b) addition of sodium ascorbate.

In the next step, the effect of different solvents in the cycloaddition reaction between benzyl bromide and phenylacetylene in the presence of Cu₂₀ POM as a catalyst at room temperature was studied. From the results in Table 2, among different solvents, a mixture of water and t-BuOH was found to be the best (Table 2, entry 10) and the cycloaddition reaction in other solvents was performed in moderate to good yields. A key aspect of this solvent mixture was that both the Cu(I) POM catalyst and substrates were highly soluble in it, and so the reaction rate was increased.

Table 2 Catalytic synthesis of 1,2,3-triazoles in different solvents^a

Entry	Solvent	Yields (%)
a Reaction conditions: benzyl bromide (0.5 mmol), phenylacetylene (0.5 mmol), sodium azide (0.5 mmol), sodium ascorbate (10 mol%), catalyst (10 μmol), and solvent (3 mL) at room temperature in 2 h.
1	MeCN	65
2	Me2SO	50
3	H2O	70
4	EtOH	60
5	i-PrOH	57
6	t-BuOH	<20
7	H2O/EtOH (2 : 1)	73
8	H2O/MeCN (2 : 1)	68
9	H2O/Me2SO (2 : 1)	80
10	H2O/t-BuOH (2 : 1)	>98

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With the optimal reaction conditions in hand, phenylacetylene, benzyl bromide, sodium azide, Cu₂₀ POM catalyst and sodium ascorbate were suspended in a 2 : 1 mixture of water and t-BuOH and after completion of the reaction, 1-benzyl-4-phenyl-1H-1,2,3-triazole was obtained in 98% yield (Table 3, entry 1). The reaction scope was explored by testing other benzyl halides with different substituents, as shown in Table 3. In this catalytic system, different benzyl halides were converted to the corresponding 1,2,3-triazole in excellent yields. The reaction of benzyl chloride was completed within 2 h to give the desired product in 97% yield (Table 3, entry 2). Due to the presence of the strongly electron withdrawing nitro-group on the phenyl ring, p-nitro benzyl bromide (Table 3, entry 4) was shown to be less reactive than the other benzyl halides. In this catalytic cycloaddition reaction, the preparation of triazoles with aliphatic alkynes as well as aromatic terminal ones was also performed (Table 3, entry 7–10).

Table 3 One-pot synthesis of 1,2,3-triazoles from benzyl halides, sodium azide, and alkynes in the presence of Cu₂₀ POM as a catalyst^a

Entry	Benzyl halide	Alkyne	Time (h)	Yields^b (%)
a Reaction conditions: benzyl halide (0.5 mmol), alkyne (0.5 mmol), sodium azide (0.5 mmol), sodium ascorbate (10 mol%), Cu20 POM catalyst (10 μmol) in water/t-BuOH (2 : 1) at room temperature.b Isolated yields.c Excess amount of 1-pentyne was used.d Data from recovered catalyst after run three.
1		Phenylacetylene	1.5	>98
2		Phenylacetylene	2	97
3		Phenylacetylene	1.45	98
4		Phenylacetylene	3	90
5		Phenylacetylene	2	96
6		Phenylacetylene	2	94
7		1-Octyne	4	98
8		1-Octyne	4	96
9^c		1-Pentyne	4	93
10^c		1-Pentyne	4	90
11^d		Phenylacetylene	1.5	95

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Ultimately, the recovered catalyst was reused under the same reaction conditions three times and any significant loss of catalytic activity was not observed (Table 3, entry 11). The XRD pattern of the recovered catalyst after the third run revealed that the structure of the catalyst was preserved (Fig. S1†).

Based on previous discussions³¹ and the above mentioned results, a mechanistic pathway for the CuAAC reaction was proposed (Fig. 2). As above, it could be seen that the presence of sodium ascorbate is crucial, because it reduces Cu(II) to Cu(I) in Cu₂₀ POM. Also, in this catalytic system the alkyne oxidative homocoupling products were not detected. So, it might be deduced that the Cu(I) species reacts with alkynes to give copper acetylide. The 1,3-dipolar cyclization of the resulting Cu acetylide and an in situ prepared organic azide followed by protonation, produces the triazole product and regenerates the Cu(I) catalyst.

Fig. 2 A plausible pathway for the one-pot synthesis of 1,2,3-triazoles using Cu₂₀ POM as a catalyst.

3. Experimental

3.1. Materials and methods

All chemicals were analytical grade, commercially available and used without further purification. Different POMs were prepared according to the literature and were used in the catalytic reactions.^24–30 Infrared spectra (KBr pellets) were recorded on a FTIR Bruker Vector 22 instrument. UV-vis spectra were recorded on a Cary 100 UV-vis spectrophotometer (190–2700 nm). The elemental analyses were performed on a Leco, CHNS-932 and a Perkin-Elmer 7300 DV elemental analyzer. ¹HNMR spectra were obtained in CDCl₃ on a Bruker (400 MHz; 296 K) and referenced to TMS (0.0 ppm) as an external standard. X-ray diffraction data (XRD) were obtained on a D8 Advanced Bruker using Cu Kα radiation (2θ = 10–80°).

3.2. Synthesis of Cu₂₀ POM

K₁₂Li₁₃[Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]·22H₂O was prepared according to the literature:²⁴ a sample of CuCl₂·2H₂O (0.60 mmol) was dissolved in a 1 M LiCH₃COO buffer solution (20 mL) at pH 6.0, then K₂₈Li₅[H₇P₈W₄₈O₁₈₄]·92H₂O (0.025 mmol) (synthesized according to the literature)²⁸ was added. This solution was heated to 80 °C for 1 h and after cooling to room temperature it was filtered. The filtrate was allowed to evaporate at room temperature. After 1–2 days a blue crystalline product started to appear. Evaporation was allowed to continue until the solution level had approached the solid product, which was then collected by filtration and air-dried. Yield: 30%. IR: [small nu, Greek, macron] = 1136(sh), 1121(s), 1080(s), 1017(m), 979(sh), 950(sh), 932(s), 913(sh), 830(sh), 753(s), 683(s), 570(sh), 525(w) cm⁻¹. Elemental analysis data for K₁₂Li₁₃[Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]: calcd: K: 3.2, Li: 0.6, W: 59.2, Cu: 8.5, P: 1.7; found: K: 3.35, Li: 0.71, W: 60.1, Cu: 8.3, P: 1.6 (Fig. S1–S5†).

3.3. General procedure for the three-component synthesis of 1,2,3-triazoles

A 10 mL glass vessel was charged with Cu₂₀POM catalyst (10 μmol), sodium ascorbate (10 mol%), an alkyne (0.5 mmol), sodium azide (0.5 mmol), and an alkyl halide (0.5 mmol) in a mixture of water and tert-butyl alcohol (2 : 1; 3 mL). The reaction vessel was stirred at room temperature for 2–4 h and the color of the reaction mixture changed from blue to yellow during the progress of the reaction. After completion of the reaction, the colorless triazole product was precipitated (Fig. S6–S12†). The products were quantitatively recovered by simple extraction with ethyl acetate (3 × 2 mL). The organic layer was separated, dried over MgSO₄ and concentrated under reduced pressure to give the corresponding 1,2,3-triazole. Purification of the obtained triazoles was accomplished using a recrystallization process (EtOAc:n-hexane). All of the products were known and characterized by comparing their spectral data with authentic samples.

4. Conclusion

In this catalytic system a wheel-shaped Cu₂₀ POM, [Cu₂₀Cl(OH)₂₄(H₂O)₁₂(P₈W₄₈O₁₈₄)]²⁵⁻, was first reduced and used for the one-pot synthesis of 1,2,3-triazoles in a CuAAC reaction. After optimization of the reaction conditions, the one-pot syntheses of different 1,2,3-triazoles from alkynes and in situ prepared organic azides exhibited high to excellent yields under mild reaction conditions. Moreover, this catalytic method avoids the isolation and handling of potentially unstable low molecular weight organic azides, and provides 1,2,3-triazole products in their pure form. Additionally, the triazole products could be easily separated from the reaction mixture.

Acknowledgements

Support for this research by the University of Isfahan is acknowledged.

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Footnote

† Electronic supplementary information (ESI) available: Synthesis and characterization of the catalysts and spectral data for the products are shown. See DOI: 10.1039/c5ra25116h

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