A metal–organic framework as a highly efficient and reusable catalyst for the solvent-free 1,3-dipolar cycloaddition of organic azides to alkynes

Abstract

A new highly efficient and reusable Cu-MOF has been developed for the regioselective synthesis of 1,2,3-triazoles via the 1,3-dipolar cycloaddition of organic azides to terminal alkynes under solvent-free conditions. This protocol has the advantages of excellent product yields and a low catalyst loading. Moreover, the catalyst may be recovered and reused efficiently up to 5 cycles without major loss of reactivity.

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1,2,3-Triazoles are ubiquitous structural motifs found in a wide range of biologically active natural products and have various applications in pharmaceuticals, agrochemicals, biochemicals and materials science.¹ Huisgen 1,3-dipolar cycloaddition of organic azides to terminal alkynes is one of the most important synthetic routes to triazole derivatives. The traditional Huisgen uncatalyzed thermal approaches results in the formation of a 1 : 1 mixture of 1,4- and 1,5-regioisomers.² In 2002, the groups of Sharpless³ and Meldal⁴ have independently discovered the highly regioselective Huisgen 1,3-dipolar cycloaddition of azides and alkynes catalyzed by Cu(I) species under mild conditions to afford 1,4-disubstituted 1,2,3-triazoles. This copper(I)-catalyzed azide–alkyne-cycloaddition (CuAAC) is now also known as the click reaction, which has found a myriad of applications in modern synthesis.⁵

It is well known that a Cu(I) species is required for the catalyzed Huisgen 1,3-dipolar cycloadditions.^5–7 The Cu(I) species are generally prepared by the in situ reduction of Cu(II) salts, such as using CuSO₄ and sodium ascorbate as the precatalysts,⁶ by the in situ oxidation of Cu(0) metals,⁷ or by a Cu(II)/Cu(0) comproportionation.⁸ Later, it was found that Cu(I) species stabilized by various ligands such as nitrogen-⁹ and sulphur-containing compounds,¹⁰ N-heterocyclic carbenes (NHC),¹¹ and polydentate ligands¹² not only accelerate the catalytic process but also allow the direct use of Cu(I) salts as catalysts for this 1,3-dipolar cycloaddition. Most of the reported copper-catalyzed azide–alkyne cycloaddition reactions are homogeneous¹³ and have serious drawbacks such as the difficulty in separation and subsequent reuse of the expensive catalysts and the indispensability of additives such as stabilizing ligands and bases.

The development of robust, easily recoverable, and recyclable heterogeneous catalysts can potentially solve these problems, which has received particular research interest in the recent years.¹⁴ Indeed, the versatility of the click chemistry has driven the development of a large number of protocols in which various recoverable and reusable catalysts were employed, such as Cu-zeolites,^14a–c Cu on charcoal,^14d,e polymer-supported copper catalyst,^14f,g Cu(0)/Al₂O₃,^14h Cu(II)-hydrotalcite,¹⁴ⁱ Cu(0) nanocluster,^14j CuBr on graphene oxide/Fe₃O₄,^14k Cu/SiO₂,^14l Cu on nanosilica triazine dendrimer,^14m Cu on resin,¹⁴ⁿ and Cu₂O nanocrystals.^14o

Unlike immobilized metal complexes, metal–organic frameworks (MOFs) are easily synthesized under mild reaction conditions and the pore volumes and/or surface area in MOFs and their functionalized organic linkers may be rationally designed and altered by introducing suitable metal ions and organic linkers. Heterogeneous catalysis is one of the most important applications of MOFs, mainly because the coordinatively unsaturated metal centers in MOFs may exhibit increased activity for catalysis and MOFs can maintain sufficient structural integrity for liquid phase reactions.¹⁵ Nevertheless, despite the progress made in the MOF-catalyzed organic reactions,¹⁶ MOFs have been rarely used as catalysts in the click chemistry.¹⁷ Herein, we describe the synthesis, characterization of a new Cu-MOF and its application for the azide–alkyne cycloaddition reaction under solvent-free conditions.

The Cu-MOF was readily synthesized from hydrothermal reactions from copper acetate, organic linkers 2,4,6-tri(4-pyridyl)-1,3,5-triazine (PTZ) and sodium 2,6-naphthalene disulfonate (NSA) in high yield (see the ESI†). Single-crystal structure of Cu-MOF indicates that it can be formulated as Cu(PTZ)(NSA)_0.5·H₂O. The purity of the phase was confirmed by powder XRD (Fig. S1†). The thermo gravimetric analysis (TGA) shows a clear loss of lattice water (obsd: 3.30 wt%; calcd: 3.36 wt%) from 100 °C to 170 °C and the de-solvated Cu-MOF can be stable up to 440 °C before decomposition (Fig. S2†). As shown in the crystallographic structure in Fig. 1a, each Cu ion is coordinated by three nitrogen atoms from three PTZ ligands and one oxygen atom from a sulfonate ligand in a tetrahedral coordination geometry. The ratio between the Cu ions and sulfonate ligands is 2 : 1. The oxidation state of Cu in the MOF was confirmed by X-ray photoelectron spectroscopy (Fig. S3†). The peak of binding energy of Cu2p at 932.50 eV, which was corrected with reference to C1 s (284.6 eV), is in good agreement with the data observed in Cu₂O, indicating that Cu is +1.¹⁸ Due to the weak interactions between the sulfonate ligand and the Cu(I) ion [Cu–O distance is 2.370(2) Å], the Cu(I) site is readily accessible as a Lewis acid for potential heterogeneous catalysis. The packing diagram of Cu-MOF shows that the disulfonate serves as an anionic template bonding to the cationic layers (Fig. 1b).

Fig. 1 (a) Coordination environment of Cu in Cu-MOF; (b) packing diagram of Cu-MOF along a-axis.

To test the catalytic activity of this novel MOF, we investigated the cycloaddition reaction between phenylacetylene (1a) and benzylazide (2a) using 5 mol% of Cu-MOF as the catalyst. The reaction was initially carried out at room temperature in CH₂Cl₂ as a solvent. As the results in Table 1 show, after 7 h, the desired 4-phenyltriazole (3a) was formed in an excellent yield (94%) and in a highly regioselective fashion (Table 1, entry 1). No formation of the regioisomer 5-phenyltrazole (4a) was observed in this reaction. The catalytic activity of the Cu-MOF in this reaction was unequivocally established by conducting a control experiment without the MOF catalyst: no formation of 3a was observed in the absence of the catalyst under otherwise identical reaction conditions (Table 1, entry 2). A screen of the catalyst loading (entries 3–6) revealed that the reaction proceeded well even with a catalyst loading of only 0.25 mol%, although the reaction took slightly longer time to complete (entry 6). A higher yield (92%) and shorter reaction time may be achieved at this loading by conducting the reaction under reflux conditions (entry 7). To our pleasure, the reaction also proceeded well with this low catalyst loading (0.25 mol%) under solvent-free conditions at rt (entry 8). At 50 °C, the reaction time was dramatically shortened to 2.5 h and a high yield of 3a (94%) was obtained (entry 9). Under these new conditions, we found that the reduction of the catalyst loading to 0.10 and 0.010 mol% resulted in longer reactions times and lower product yields (entries 10 and 11). Most importantly, these lower loadings led to the formation of a mixture of two regioisomeric products 3a and 4a, in ratios of 83 : 17 and 61 : 39, respectively (entries 10 and 11). A control experiment under these conditions without the MOF catalyst showed that the lower regioselectivities observed were most likely due to the contribution of the background reaction, which in 24 h gave a mixture of products 3a and 4a in a ratio of 51 : 49, with yields of 40% and 39%, respectively (entry 12).

Table 1 Optimization of the reaction conditions for the synthesis of 3a^a

Entry	Loading (mol%)	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Unless otherwise indicated, all reactions were conducted with 1a (1.0 mmol), 2a (1.0 mmol) in the indicated solvent (1.0 mL). b Yield of the isolated product. The number in the parentheses is the yield of the isolated 4a. c The ratio of 3a : 4a was 83 : 17 according to the crude NMR. d The ratio of 3a : 4a was 61 : 39 according to the crude NMR. e The ratio of 3a : 4a was 51 : 49 according to the crude NMR.
1	5.0	CH2Cl2	rt	7	94
2	No catalyst	CH2Cl2	rt	7	0
3	2.5	CH2Cl2	rt	7	93
4	1.0	CH2Cl2	rt	14	92
5	0.5	CH2Cl2	rt	24	92
6	0.25	CH2Cl2	rt	32	87
7	0.25	CH2Cl2	Reflux	12	92
8	0.25	Neat	rt	8	92
9	0.25	Neat	50	2.5	94
10	0.10	Neat	50	8	78 (12)^c
11	0.010	Neat	50	20	55 (34)^d
12	No catalyst	Neat	50	24	40 (39)^e

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Once the reaction conditions were optimized, the scope of this cycloaddition reaction was investigated. The results are summarized in Table 2. As is evident from the results, besides phenylacetylene (entry 1), phenylacetylenes bearing electron-donating groups, such as 4-methyl (entry 2), 3-methyl (entry 3), or 4-methoxy (entry 4) groups, and electron-withdrawing groups, such as 4-bromo (entry 5), 2-bromo (entry 6), 3,5-difluoro (entry 7), and 2-trifluoromethyl (entry 8) groups, all underwent smooth reactions with benzylazide to yield the expected triazole 3 regioselectively in high yields (84–93%). 1-Ethynylnaphthalene also gave similar results to those of phenylacetylenes (entry 9). Alkyl-substituted acetylenes are also good substrates for this reaction. For example, phenylethyl-, 3-hydroxypropyl- and 1-hydroxycyclohexyl-substituted acetylenes all generated the desired products in high yields (entries 10–12). It is also worth noting that other functional groups, such as hydroxy (entries 11 and 12) and TMS (entry 13) groups, are tolerated in this reaction. In addition, the reaction of 4-methoxy-substituted benzylazide with phenylacetylene produced the expected product in 84% yield (entry 14). It needs to be pointed out that the Cu-MOF is a condensed structure, and there is no accessible channel, so the catalytic reactions take place on the surfaces of Cu-MOF. Because of this, the size effect of substrate does not determine the yield or reaction rate, while the electronic effect plays a major role, leading to the difference between entry 9 and 7.

Table 2 Synthesis of 1,2,3-triazoles catalyzed by Cu-MOF^a

Entry	R^1	R^2	Time (h)	Yield^b (%)
a All reactions were conducted with acetylene 1 (1.0 mmol), benzylazide 2 (1.0 mmol), and Cu-MOF (0.25 mol%) at 50 °C for the indicated reaction times. b Yield of the isolated product.
1	Ph	Ph	2.5	94
2	4-MeC6H4	Ph	2.5	93
3	3-MeC6H4	Ph	2.8	92
4	4-MeOC6H4	Ph	2.5	92
5	4-BrC6H4	Ph	2.5	89
6	2-BrC6H4	Ph	2.5	87
7	3,5-F2C6H3	Ph	2	84
8	2-CF3C6H4	Ph	2.5	85
9	1-Naphthyl	Ph	2	88
10	PhC2H4	Ph	2.5	89
11	OH(CH2)3	Ph	2.5	86
12	1-Hydroxycyclohexyl	Ph	2.5	87
13	TMS	Ph	2.5	86
14	Ph	4-MeOC6H4	3	84

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The main advantage of MOF catalysts lies in the fact that they can be easily recovered after the reaction due to their heterogeneity. Indeed, the Cu-MOF catalyst may be easily recovered using a centrifuge and washed with CH₂Cl₂ (5 mL) to remove traces of the previous reaction mixture and dried at 50 °C under vacuum for 2 h before using it for the next catalytic cycle. The PXRD pattern indicates the crystal structures of Cu-MOFs maintained after the catalytic reactions (Fig. S1†). Using 1a and 2a as the substrates, the reusability of the Cu-MOF catalyst was examined. As shown by the results in Table 3, the Cu-MOF catalyst may be recovered and reused for 5 cycles without any significant loss in catalytic activity. The main purpose of the recyclability study is to prove that Cu-MOF is still catalytically active after 5 recycles, though the time required in cycles 4 and 5 for complete conversion is slightly longer than those in the previous cycles.

Table 3 Recyclability studies^a

Entry	Reuse	Time (h)	Yield^b (%)
a All reactions were conducted with 1a, 2a, and Cu-MOF (0.25 mol%) at 50 °C for the indicated reaction times. b Yield of the isolated product 3a. c The reaction was carried out on a 3.0 mmol scale. d The reaction was carried out on a 2.0 mmol scale. e The reaction was carried out on a 1.0 mmol scale. f The reaction was carried out on a 0.50 mmol scale. g The reaction was carried out on a 0.40 mmol scale.
1	Cycle I	2.5	94^c
2	Cycle II	2.5	92^d
3	Cycle III	3	90^e
4	Cycle IV	3	87^f
5	Cycle V	3.5	87^g

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In conclusion, we have developed a new highly efficient Cu-MOF that catalyzes the high regioselective 1,3-dipolar cycloaddition of terminal alkynes to organic azides under solvent-free conditions. The desired triazoles were obtained in good to excellent yields in short reaction times. Many different functional groups are tolerated in this reaction. Moreover, the catalysts can be easily recovered and reused in this reaction without loss of the catalytic activity for at least five cycles.

Acknowledgements

J. Z. thanks the generous financial support for this research from the Welch Foundation (grant no. AX-1593) and the NIH-NIGMS (grant no. SC1GM082718); B.C. thanks the financial support for this research from the Welch Foundation (grant no. AX-1730).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Crystal structure and PXRD of the Cu-MOF, detailed experimental procedures, and characterization data for a new product. CCDC 1013552. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qi00148f

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