Batch and Continuous-Flow Huisgen 1,3-Dipolar Cycloadditions with

Research Article pubs.acs.org/journal/ascecg

Cite This: ACS Sustainable Chem. Eng. 2017, 5, 10722-10734

Batch and Continuous-Flow Huisgen 1,3-Dipolar Cycloadditions with an Amphiphilic Resin-Supported Triazine-Based Polyethyleneamine Dendrimer Copper Catalyst Shiguang Pan,† Shuo Yan,†,‡ Takao Osako,†,‡ and Yasuhiro Uozumi*,†,‡ †

Institute for Molecular Science (IMS), JST-ACCEL, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan Department of Functional Molecular Science, School of Physical Sciences, SOKENDAI (The Graduate University for Advance Studies), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan

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‡

S Supporting Information *

ABSTRACT: A polystyrene−poly(ethylene glycol) (PS−PEG) resin-supported triazine-based polyethyleneamine dendrimer copper catalyst (PS−PEG-TD2−CuSO4) was prepared and characterized by means of CP-MAS NMR, UV−vis/NIR, FTIR, SEM-EDX, XPS, and ICP-AES analyses. PS−PEG-TD2−CuSO4 was highly active in the Huisgen 1,3-dipolar cycloaddition of various organic azides with alkynes in water as well as the three-component reaction of alkynes, alkyl bromides, and sodium azide under batch conditions to give the corresponding triazoles in excellent yields with high recyclability of the catalyst. TEM analysis suggested that the copper nanoparticles generated in situ through reduction of PS−PEG-TD2−CuSO4 with sodium ascorbate serve as the active catalytic species. The application of PS−PEG-TD2−CuSO4 catalyst in a continuous-flow Huisgen reaction for the synthesis of 1,2,3-triazoles was also examined. The cycloaddition of organic azides with alkynes was completed within 22 s in the continuous-flow system containing PS−PEG-TD2−CuSO4 to give the corresponding triazoles in up to 99% yield. Moreover, the continuous-flow system accomplished the long-term continuous-flow cycloaddition for 48 h producing 10 g of a triazole as well as the successive flow reaction producing various kinds of triazoles. KEYWORDS: Copper, Alkyne−azide cycloaddition, Aqueous reaction, Batch reaction, Continuous-flow reaction, Heterogeneous catalysis

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INTRODUCTION

contain cheaper, more-abundant, transition metals such as Cu or Fe. The replacement of noble metals with more-abundant transition metals with plentiful natural reserves is an important strategy for increasing sustainability.26 Therefore, the development of efficient organic transformations using immobilized abundant transition metal as catalysts becomes a new challenge toward achieving green, sustainable, catalytic organic transformations. On other hand, continuous-flow organic transformations have recently attracted much attention in synthetic organic chemistry as well as industrial processes.27−30 The continuous-

The development of green, sustainable, catalytic organic transformations is a major challenge in recent organic chemistry.1−9 In particular, heterogeneous switching of homogeneous transition-metal catalysis has been recognized as an important strategy for realizing green sustainable transformations10−17 and provides considerable advantages in terms of recycling of the catalysts and reduction of the contamination in the resulting products. As our contribution to this research field, we have previously developed various noblemetal catalysts (Pd, Pt, Rh, or Ru) immobilized on amphiphilic polystyrene−poly(ethylene glycol) (PS−PEG) resin, and have applied them in a wide variety of organic transformations in water.18−25 However, there are few examples of efficient organic transformations using immobilized catalysts that © 2017 American Chemical Society

Received: August 5, 2017 Revised: September 20, 2017 Published: September 22, 2017 10722

DOI: 10.1021/acssuschemeng.7b02646 ACS Sustainable Chem. Eng. 2017, 5, 10722−10734

Research Article

ACS Sustainable Chemistry & Engineering Scheme 1. Preparation of PS−PEG-TD2−CuSO4 Catalysta

a

Conditions: (a) cyanuric chloride (10 equiv based on NH2 groups), DIPEA (10 equiv based on NH2 groups), THF, r.t., 48 h; (b) diethylenetriamine (10 equiv based on NH2 groups), DIPEA (10 equiv based on Cl groups), DMF, 80 °C, 48 h; (a) cyanuric chloride (10 equiv based on NH2 groups), DIPEA (10 equiv based on NH2 groups), THF, r.t., 48 h; diethylenetriamine (10 equiv based on NH2 groups), DIPEA (10 equiv based on Cl groups), DMF, 80 °C, 48 h; (e) CuSO4·5H2O (1.0 mmol per gram of PS−PEG-TD2), MeOH, r.t., 6 h.

flow transformations show great advantages over conventional batch transformations in respect to safety, efficiency, productivity, reproducibility, and scale-up synthesis. Therefore, continuous-flow switching of the conventional flask reactions using heterogeneous transition-metal catalysis is also becoming a very powerful strategy for realizing green, sustainable, catalytic organic transformations. Copper-catalyzed azide−alkyne cycloaddition (CuAAC), the so-called Huisgen reaction, is the most convenient protocol for the synthesis of functional 1,2,3-triazoles31−37 in organic chemistry, supramolecular chemistry, biochemistry, and materials science.38−42 There has been a recent focus on switching from homogeneous to heterogeneous catalysts in CuAAC to realize this as a green sustainable organic transformation.43,44 Despite the numerous recent advances in heterogeneous CuAAC,45−80 effective heterogeneous copper catalysts in both batch and continuous-flow azide−alkyne cycloaddition are quite limited.81−85 Therefore, the development of effective supported copper catalysts for the alkyne−azide cycloaddition applicable to both batch and continuous-flow reactions is highly desired to realize further green sustainable organic transformations.

Dendrimers have been recognized as attractive materials in synthetic chemistry and material science, and they show some specific characteristics, such as highly branched three-dimensional structures and strong encapsulation of transition metals.86−90 The use of dendrimers immobilized on support materials in heterogeneous transition-metal catalysis has been investigated.60,91−93 One successful example is the threecomponent cycloaddition of alkynes, alkyl halides, and sodium azide in aqueous ethanol (H2O−EtOH = 2:1), which was achieved by using a silica-supported triazine−dendrimer copper catalyst.60 However, the range of substrates was limited to alkyl azides generated from alkyl halides and sodium azide. Furthermore, the continuous-flow CuAAC reaction has yet to be investigated. An improvement in this catalytic system is required to realize an effective, green, sustainable, coppercatalyzed Huisgen reaction. Here, we describe the development of an amphiphilic polystyrene−poly(ethylene glycol) (PS− PEG) resin-supported triazine-based polyethyleneamine dendrimer−copper catalyst (PS−PEG-TD2−CuSO4) for the Huisgen reaction under batch and continuous-flow conditions.94 Under batch conditions, the PS−PEG-supported copper catalyst efficiently promoted the Huisgen 1,3-dipolar cycloaddition of organic azides with terminal alkynes in the 10723


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ACS Sustainable Chemistry & Engineering

primary NH vibration at 1660 cm−1 was broadened and overlapped with the CN stretch. These results indicated that the dendrimer units including triazines and diethylenetriamines were successfully immobilized onto the PS−PEG resin. In the UV−vis spectrum of PS−PEG-TD2 (Figure 2a), the absorption

presence of sodium ascorbate in water to give the corresponding 1,2,3-triazoles in good-to-excellent yields with high catalyst recyclability. The catalytic system was also applied to the three-component reaction of alkynes, alkyl bromides, and sodium azide in water. Furthermore, the continuous-flow system containing PS−PEG-TD2−CuSO4 has been successfully developed. In the continuous-flow system, the cycloaddition of alkynes and organic azides was completed within 22 s, giving the corresponding 1,2,3-triazoles in up to 99% yield. The flow system containing PS−PEG-TD2−CuSO4 accomplished the long-term continuous-flow cycloaddition for 48 h producing ten grams of a triazole from as well as successive flow reaction of a wide variety of starting materials producing various kinds of triazoles.

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RESULTS AND DISCUSSION A second-generation triazine-based dendrimer immobilized on PS−PEG resin (PS−PEG-TD2) was prepared by a procedure similar to that used for the synthesis of silica-supported dendrimer (Scheme 1).60 Treatment of amino-functionalized PS−PEG (PS−PEG-NH2, 0.27 mmol/g NH2) with excess cyanuric chloride (10 equiv based on NH2 groups) in the presence of excess N,N-diisopropylethylamine (DIPEA, 10 equiv based on NH2 groups) in THF at room temperature for 48 h gave PS−PEG-supported cyanuric chloride (PS−PEGCC1). This was treated with excess diethylenetriamine (10 equiv based on Cl groups) to afford a first-generation triazinebased dendrimer (PS−PEG-TD1). This was then converted into the corresponding second-generation dendrimer (PS− PEG-TD2) by a similar stepwise procedure. Complexation of PS−PEG-TD2 with CuSO4 was carried out by mixing the resin (1.0 g) with CuSO4·5H2O (1.0 mmol) in MeOH at room temperature for 6 h to give green polymer beads of PS−PEGTD2−CuSO4. The resulting resin and the supported PS−PEG-TD2− CuSO4 copper catalyst were characterized by means of spectroscopic analyses [CP-MAS 13C NMR, diffuse reflectance (DR) UV−vis, and FTIR]. In the CP-MAS 13C NMR spectrum of PS−PEG-TD2, the characteristic peaks derived from triazine and diethylenetriamine (Figure S1 in Supporting Information) were observed. FTIR study for PS−PEG-TD2 and PS−PEGTD2−CuSO4 showed the characteristic peaks associated with the CN stretch of triazine at 1563 cm−1 (Figure 1). After coordination of PS−PEG-TD2 with CuSO4, the sharp peak of

Figure 2. UV−vis/NIR spectra of (a) PS−PEG-TD2 and (b) PS− PEG-TD2−CuSO4.

peaks at about 229 and 278 nm were attributed to n−π* and π−π* electron transfers for the aromatic ring and amine groups. After complexation of the polymer with CuSO4, these absorption peaks were red-shifted to 247 and 312 nm, respectively, and new peaks appeared near 407 and 790 nm; these new absorptions were assigned to ligand-to-metal chargetransfer (LMCT) and d−d transitions, respectively (Figure 2b). Field-emission scanning electron microscopy (FE-SEM) analyses of PS−PEG-NH2, PS−PEG-TD2, and PS−PEGTD2−CuSO4 were conducted (Figures 3a−c). The resins PS−PEG-TD2 and PS−PEG-TD2−CuSO4 showed a spherical structure. The morphology of the surface of the resin slightly changed on immobilization of the dendrimer unit and loading of the copper species. Energy-dispersive X-ray (EDX) analysis of PS−PEG-TD2 and PS−PEG-TD2−CuSO4 (Figures 4a and 4b, respectively) showed the presence of copper and sulfur in PS−PEG-TD2−CuSO4 (Figure 4b), clearly confirming that complexation of PS−PEG-TD2 with CuSO4 had occurred. An ICP-AES analysis of PS−PEG-TD2−CuSO4 provided further confirmation of successful complexation, and showed that the copper loading of PS−PEG-TD2−CuSO4 was 0.793 mmol/g. To optimize the conditions for the catalytic Huisgen reaction in water under batch conditions, we selected the reaction of ethynylbenzene (1a) with benzyl azide (2A) as a model reaction (Table 1). When the model reaction was carried out in the absence of the catalyst in water at 25 °C for 12 h, none of the desired triazole 3aA was formed (Table 1, entry 1). When the reaction was carried out in the presence of PS−PEG-TD2− CuSO4 (0.5 mol % Cu), the desired product 3aA was obtained in 29% GC yield (entry 2). The addition of a phase-transfer reagent such as tetrabutylammonium bromide (TBAB) or cetyl(trimethyl)ammonium bromide (CTAB) (entries 3 and 4, respectively) produced no significant improvement in the Huisgen reaction in water. Increasing the amount of the PS− PEG-TD2−CuSO4 catalyst improved the yield of 3aA (entries 5 and 6), and the reaction in the presence of PS−PEG-TD2− CuSO4 (5 mol % Cu) afforded a quantitative yield of 3aA (entry 6).95 We also submitted PS−PEG-TD2−CuI, which was prepared by treatment of PS−PEG-TD2 with CuI under inert

Figure 1. FT-IR spectra of (a) PS−PEG-NH2, (b) PS−PEG-TD2, and (c) PS−PEG-TD2−CuSO4. 10724


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Figure 3. SEM images of (a) PS−PEG-NH2, (b) PS−PEG-TD2, and (c) PS−PEG-TD2−CuSO4.

atomosphere,96 to this reaction, giving triazole 3aA in 99% GC yield in the absence of sodium ascorbate (entry 7). The Huisgen reaction of 1a with 2A in the presence of PS−PEGTD2−CuSO4, but in the absence of sodium ascorbate, gave 3aA in 21% GC yield (entry 8).97 As a control experiment, the reaction in the presence of the polymer ligand PS−PEG-TD2 alone gave none of the desired product 3aA (entry 9), indicating that the copper species is essential for this transformation. We conclude therefore that a 5.0 mol % Cu loading in the form of PS−PEG-TD2−CuSO4 and 10 mol % of sodium ascorbate in water at room temperature are the optimal conditions for this transformation.98 The Huisgen reaction of ethynylbenzene (1a) with benzyl azide (2A) proceeded efficiently in the presence of PS−PEGTD2−CuSO4 with sodium ascorbate, suggesting that the catalytically active copper species is generated in situ by the reaction of PS−PEG-TD2−CuSO4 with sodium ascorbate. To identify the active species, we performed a TEM analysis of the copper catalyst obtained by treatment of PS−PEG-TD2− CuSO4 with sodium ascorbate (2.0 equiv) in water at room temperature for 10 min. The TEM image revealed that copper nanoparticles were generated and dispersed inside the polymer matrix. The size of the particles was distributed in the range 1.0−14 nm (average 6.8 nm; Figure 5). An XPS analysis

showed that the characteristic copper(II) satellite peaks at 944 and 964 eV, respectively, disappeared on treatment with sodium ascorbate (Figure 6). This result suggested that sodium ascorbate reduced the copper(II) species on the polymer to copper(I) or copper(0) species.99−102 To further confirm the oxidation of copper species, EDX analysis of the reduced copper catalyst was performed (Figure 6c). The characteristic peak derived from the sulfur atom of the counteranion SO42− was still observed in the EDX spectrum. These results indicated that reduction of the copper(II) species with sodium ascorbate would generate copper(I) nanoparticles in the polymer matrix. The catalytic activity of the reduced copper catalyst and PS− PEG-TD2−CuI was examined. The reduced copper containing copper nanoparticles afforded the triazole 3aA in 95% GC yield (entry 10, Table 1), while PS−PEG-TD2−CuI gave the corresponding triazole 3aA in 99% GC yield (Table 1, entry 7). These results suggested that copper(I) nanoparticles are the catalytically active species in this transformation. Having determined the optimal reaction conditions, we next examined the substrate scope for the azide−alkyne cycloaddition in water (Table 2). Arylalkynes 1a−g bearing electrondonating or electron-withdrawing substituents at the para position reacted with benzyl azide (2A) to give the corresponding 1,2,3-triazoles 3aA−eA in 93−99% isolated 10725


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yield (Table 2, entries 2−5). Meta and ortho methyl substituents on the ethynylbenzene (1f and 1g) were also tolerated, and the corresponding products 3fA and 3gA were obtained in 98 and 97% yield, respectively (entries 6 and 7). Alkynes bearing pyridyl or thienyl groups (1h and 1i) also participated in the catalytic reaction to provide the desired products 3hA and 3iA in 97 and 91% yield, respectively (entries 8 and 9). The supported copper catalyst was also effective for the reaction of aliphatic alkynes 1j−m, giving the corresponding 1,2,3-triazoles 3jA−mA in 88−99% yield (entries 10−13). Various benzyl, phenyl, or alkyl azides 2B−I reacted with ethynylbenzene (1a) under the optimized conditions to give the corresponding 1,2,3-triazoles 3aB−aI in 85−99% yield (entries 14−21). To demonstrate an application of our method, we synthesized rufinamide (Banzel; 3nJ), an antiepileptic drug developed by Novartis (Scheme 2).103−105 The cycloaddition reaction of enamide 1n and azide 2J in the presence of PS− PEG-TD2−CuSO4 in water under the optimized catalytic conditions proceed smoothly to give 3nJ in 85% yield. Next, the three-component reaction of alkynes, sodium azide, and alkyl bromides in water was examined under the optimized conditions (Table 3). Under these conditions, the alkyl bromide reacted with sodium azide; to form an alkyl azide in situ; this then underwent a Huisgen reaction with the alkyne. The three-component reaction of ethynylbenzene (1a), sodium azide, and benzyl bromide (4) proceeded efficiently to afford triazole 3aA in 98% yield (Table 3, entry 1). Ethynylbenzenes bearing electron-donating (4-OMe, 1b) or electron-withdrawing groups (4-CF3, 1e) also underwent three-component reactions with sodium azide and benzyl bromide (4) to give the corresponding triazoles 3bA and 3eA in excellent yields (entries 2 and 3). A variety of substituted benzyl bromides 5−8 were also converted into the corresponding triazoles 3aB, and 3aK−aM in 90−99% yield (entries 4−7). Ethyl bromoacetate (9) reacted with 1a to provide triazole 3aI in 99% yield. Recycling of catalysts is important in relation to both industrial applications and green sustainable molecular transformations. A recycling experiment with the supported copper catalyst was performed in the reaction of ethynylbenzene (1a) with ethyl azidoacetate (2I). When the reaction as complete, the catalyst was separated from the reaction mixture by simple filtration, washed with ethyl acetate and water, and dried carefully under a vacuum, before being reused in subsequent runs. ICP analyses of the solution from the first reaction cycle showed that 0.69% of copper species leached from the catalyst. As shown in Figure 7, the catalyst was reused seven times without significant loss of its catalytic activity. In addition, the filtration test was conducted to prove that the supported copper catalyst served as a heterogeneous catalyst. After the reaction of ethynylbenzene (1a) with ethyl azidoacetate (2I) was carried out under the standard catalytic conditions for 30 min, the supported copper catalyst and the product 3aI (22% GC yield) were removed by simple filtration. Further reaction of the resulting filtrate containing the substrates 1a and 2I did not produce the product 3aI. This result clearly demonstrated that the supported copper catalyst heterogeneously promotes the Huisgen 1,3-dipolar cycloaddition under batch conditions. With the successful results for the heterogeneous CuAAC under batch conditions, PS−PEG-TD2−CuSO4 catalyst was next applied to the continuous-flow reaction. The continuous flow cycloaddition was performed with a flow reactor (X-Cube

Figure 4. EDX spectra of (a) PS−PEG-TD2 and (b) PS−PEG-TD2− CuSO4.

Table 1. Optimization of Reaction Conditionsa

Entry

Cat. Loading (mol %)

Additive

Yield (%)b

1 2 3 4 5 6 7c 8d 9 10e

0 0.5 0.5 0.5 1.0 5.0 5.0 5.0 0 5.0

− − TBAB (10 mol %) CTAB (10 mol %) − − − − PS−PEG-TD2 (30 mg) −

0 29 34 30 65 100 99 21 0 95

a

Reaction conditions: ethynylbenzene (1a, 0.5 mmol), PhCH2N3 (2A, 0.5 mmol), PS−PEG-TD2−CuSO4, sodium ascorbate (10 mol %), H2O (1.0 mL), N2, 25 °C, 12 h. bDeterminined by GC ananlysis with a biphenyl as internal standard. cThe reaction was carried out using PS−PEG-TD2−CuI instead of PS−PEG-TD2−CuSO4 in the absence of sodium ascorbate. dNo sodium ascorbate. eThe reduced copper catalyst prepared by treatment of PS−PEG-TD2−CuSO4 with sodium ascorbate was used without further addition of sodium ascorbate.

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Figure 5. (a) TEM image of copper nanoparticles generated in situ in the PS−PEG resin and (b) the size distribution of the copper nanoparticles.

3aA (entry 3). Increasing the reaction temperature to 75 or 100 °C completed the reaction, giving 3aA in a quantitative yield (entries 5 and 6). However, introduction of a 50 mM solution to the flow reactor resulted in blockage of the flow stream due to the poor solubility of the product (entry 7).107 To demonstrate the substrate tolerance in the flow system, the substrate scope was investigated (Table 5). Various aromatic and aliphatic acetylenes bearing a wide range of electronic properties and functionalities (1a−m) underwent the cycloaddition with benzyl azide (2A) within 22 s to provide the desired triazoles (3aA−3mA) in excellent yields (91−99%) (entries 1−13). Various benzyl, aromatic, and aliphatic azides were also applicable to the reaction of ethynylbenzene (1a), afforded the corresponding triazoles (3aB−aD, 3aH, and 3aI) in 89−99% yields (entries 14−18).

ThalesNano Nanotechnology, Inc.) containing a catalyst cartridge (internal dimensions: 70 mm × 4 mm) of PS− PEG-TD2−CuSO4 (300 mg, 0. 238 mmol Cu). After treatment of the packed catalytic beads with an aqueous solution of sodium ascorbate (25 mM at a flow rate of 1.0 mL min−1, an aqueous ethanol solution (H2O/EtOH = 3:1 (v/v)) of ethynylbenzene (1a, 10 mM) and benzyl azide (2A, 1.0 equiv) was introduced into the reactor at 25 °C at a flow rate of 1.0 mL min−1 to give the desired triazole 3aA in 82% GC yield (Table 4, entry 1), where the total contact time between the solution and catalyst was 22 s.106 When the solution of the substrates containing sodium ascorbate (10 mol %) was used as a mobile phase, the yield of 3aA was improved to a quantitative GC yield (entry 2). In order to increase the production, a 25 mM solution of the substrate was introduced to the reactor at a flow rate of 1 mL/min at 25 °C, affording a moderate yield of 10727


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Table 2. Cycloaddition of Terminal Alkynes and Various Organic Azides Using PS−PEG-TD2−CuSO4a

Figure 6. XPS spectra of (a) PS−PEG-TD2−CuSO4 and (b) after treatment with sodium ascorbate, and (c) EDX spectra of the reduced copper catalyst.

Entry

Alkyne

Azide

Triazole

Yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1a 1a 1a 1a 1a 1a 1a 1a

2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2B 2C 2D 2E 2F 2G 2H 2I

3aA 3bA 3cA 3dA 3eA 3fA 3gA 3hA 3iA 3jA 3kA 3lA 3mA 3aB 3aC 3aD 3aE 3aF 3aG 3aH 3aI

97 99 99 93 98 97 98 97 91 88 95 93 99 95 93 99 95 96 92 85 99

a Reaction conditions: alkyne (1, 0.5 mmol), organic azide (2, 0.5 mmol), PS−PEG-TD2−CuSO4 (Cu loading: 5.0 mol %), sodium ascorbate (10 mol %), H2O (1.0 mL), N2, 25 °C, 12 h. bIsolated yield.

To further demonstrate the practical utility of our continuous-flow system for CuAAC, the successive synthesis of a variety of triazoles was carried out using the flow reactor containing of PS−PEG-TD2−CuSO4 (Table 6). Different kinds of substrate solutions were successively introduced to the flow reactor containing the cartridge (without the need for changing new catalyst). As shown in Table 6, the 11 successive reactions gave 11 triazoles in excellent yields. These results suggested that the continuous-flow system of PS−PEG-TD2− CuSO4 would be very useful for a combinatorial approach in the drug discovery where the synthesis of many types of triazoles is required. Long-term continuous flow cycloaddition of ethynylbenzene (1a) and ethyl azidoacetate (2I) was carried out using the flow reactor containing of PS−PEG-TD2−CuSO4 (Scheme 3). Before the flow cycloaddition was started, PS−PEG-TD2− CuSO4 was pretreated with an aqueous solution of sodium

Scheme 2. Application of PS−PEG-TD2−CuSO4 to the Synthesis of Rufinamide (3nJ) from the Cycloaddition Reaction of 1n with 2J

ascorbate (25 mM) at a flow rate of 1.0 mL min−1 for 20 min. A 2880 mL solution of ethynylbenzene (1a, c = 25 mM), ethyl azidoacetate (2I, 1.0 equiv), and sodium ascorbate (0.1 equiv) 10728


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ACS Sustainable Chemistry & Engineering Table 3. Three-Component Reaction of Alkynes, Sodium Azide, and Alkyl Bromides Using PS−PEG-TD2−CuSO4a

Entry

Alkyne

Alkyl bromide

Triazole

Yield (%)b

1 2 3 4 5 6 7 8

1a 1b 1e 1a 1a 1a 1a 1a

4 4 4 5 6 7 8 9

3aA 3bA 3eA 3aB 3aK 3aL 3aM 3aI

98 99 99 99 98 90 94 99

Table 4. Optimization of the Continuous-Flow Alkyne-Azide Cycloaddition Using PS−PEG-TD2-CuSO4a

a

Reaction conditions: alkyne (1, 0.5 mmol), alkyl bromide (4-9, 0.55 mmol), NaN3 (0.5 mmol), PS−PEG-TD2−CuSO4 (Cu loading: 5.0 mol %), sodium ascorbate (10 mol %), H2O (1.0 mL), N2, 25 °C, 12 h. bIsolated yield.

Entry

Conc. of 1a (mM)

T (°C)

Yield (%)b

1c 2 3 4 5 6 7

10 10 25 25 25 25 50

25 25 25 50 75 100 75

82 100 50 86 100 100 −d

Reaction conditions: the flow cycloaddition was performed with an X-Cube flow reactor containing a catalyst cartridge of PS−PEG-TD2CuSO4 (300 mg, 0.238 mmol Cu). After introduction of an aqueous solution of sodium ascorbate (25 mM) at a flow rate of 1.0 mL, a solution of ethynylbenzene (1a, 0.5 mmol), benzyl azide (2A, 0.5 mmol), and sodium ascorbate (0.05 mmol) in a mixture of H2O and EtOH (v/v = 1:3) was introduced into the reactor. bDetermined by GC analysis with an internal standard. cWithout addition of sodium ascorbate (10 mol %). dThe product participated in the pipeline. a

investigations on the application of PS−PEG-TD2−Cu(II) catalysts in other organic transformations are currently ongoing in our laboratory.

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Figure 7. Results of recycling experiments for the reaction of 1a with 2I using PS−PEG-TD2−CuSO4.

EXPERIMENTAL SECTION

General. All chemicals were commercially available and were used without further purification. Organic azides (except for 2A and 2I), which were prepared according to known procedures.108,109 Water was deionized with a Millipore system to Milli-Q grade. 1H and 13C{1H} NMR spectra were recorded on a JEOL-ECS400. GC analysis was carried out on a Hewlett-Packard 4890 system. IR spectra were recorded on a JASCO FT/IR 460 Plus spectrometer in the ART mode. DR UV−vis/NIR spectra were recorded with a Shimadzu UV3600 spectrophotometer. The FE-SEM images were recorded with a Hitachi SU6600 microscope. TEM analysis was carried out with a JEOL JEM-2100F transmission electron microscope. ICP analysis was performed in a LEEMAN LABORATORIES Profile plasma spectrometer. The continuous-flow reaction was performed in an XCube reactor (ThalesNano Nanotechnology Inc., Budapest) with no gas mode. Preparation of PS−PEG-TD2. A mixture of PS−PEG-NH2 resin (2.1 g, -NH2: 0.27 mmol/g), cyanuric chloride (CC) (5.7 mmol) and DIPEA (5.7 mmol) in THF (30 mL) was shaken at room temperature for 48 h. The mixture was filtered and the resulting resin beads (PS− PEG-CC1) were washed with CH2Cl2 (10 × 30 mL) and dried in vacuo overnight. The PS−PEG-CC1 was dissolved in DMF (30 mL), diethylenetriamine (11.4 mmol) and DIPEA (11.4 mmol) were added,

in a mixture of H2O and EtOH (v/v = 1:3) was continuously introduced to the flow system at 75 °C at a flow rate of 1.0 mL/ min for 48 h, producing 14.4 g of triazole 3aI (87% yield).

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CONCLUSION In conclusion, an amphiphilic polystyrene−poly(ethylene glycol) (PS−PEG) resin-supported triazine-based polyethyleneamine dendrimer−copper sulfate complex (PS−PEG-TD2− CuSO4) was developed and used as an efficient catalyst for the Huisgen 1,3-dipolar cycloaddition of organic azides with alkynes in water to give the corresponding triazoles in up to 99% isolated yield, with high catalyst recyclability under batch conditions. TEM analysis suggested that copper nanoparticles, generated in situ through reduction of PS−PEG-TD2−CuSO4 with sodium ascorbate, act as the active catalytic species. Under continuous-flow conditions, various triazoles were obtained in a short process time. The long-term flow cycloaddition reaction provided more than ten grams of the triazole for 48 h. Further 10729


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ACS Sustainable Chemistry & Engineering Table 5. Continuous-Flow Cycloaddition of Terminal Alkyne with Various Organic Azides Cycloaddition Using PS−PEG-TD2−CuSO4a

Entry

Alkyneb

Azide

Triazole

Yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

1a (25 mM) 1b (12.5 mM) 1c (12.5 mM) 1d (12.5 mM) 1e (12.5 mM) 1f (12.5 mM) 1g (12.5 mM) 1h (12.5 mM) 1i (25 mM) 1j (25 mM) 1k (25 mM) 1l (25 mM) 1m (25 mM) 1a (12.5 mM) 1a (12.5 mM) 1a (12.5 mM) 1a (25 mM) 1a (25 mM)

2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2A 2B 2C 2D 2H 2I

3aA 3bA 3cA 3dA 3eA 3fA 3gA 3hA 3iA 3jA 3kA 3lA 3mA 3aB 3aC 3aD 3aH 3aI

99 99 96 99 99 96 91 99 93 93 92 91 98 96 99 96 89 99

Table 6. Successive Continuous-Flow Alkyne−Azide Cycloaddition Using the X-Cube Reactora

Run No.

Alkyneb

Azide

Triazole

Yield (%)c

1 2 3 4 5 6 7 8 9 10 11

1a (25 mM) 1c (12.5 mM) 1o (12.5 mM) 1e (12.5 mM) 1m (25 mM) 1a (25 mM) 1c (12.5 mM) 1o (12.5 mM) 1e (12.5 mM) 1a (25 mM) 1m (25 mM)

2A 2A 2A 2A 2A 2I 2I 2I 2I 2N 2N

3aA 3cA 3oA 3eA 3mA 3aI 3cI 3oI 3eI 3aN 3mN

99 99 96 99 99 97 99 97 98 96 98

Reaction conditions: the flow cycloaddition was performed with an X-Cube flow reactor containing a catalyst cartridge of PS−PEG-TD2− CuSO4 (300 mg, 0.238 mmol Cu). After introduction of an aqueous solution of sodium ascorbate (25 mM) at a flow rate of 1.0 mL, a solution of alkyne (1, 1.0 mmol), azide (2, 1.0 mmol), and sodium ascorbate (0.1 mmol) in a mixture of H2O and EtOH (v/v = 1:3, 40, or 80 mL) was introduced into the reactor at 75 °C at a flow rate of 1.0 mL min−1. bConcentration was shown in the parentheses. c Purification by recrystallization from hexane-EtOAc. a

Scheme 3. Long-Term Continuous-Flow Cycloaddition of 1a with 2I

a Reaction conditions: the flow cycloaddition was performed with an X-Cube flow reactor containing a catalyst cartridge of PS−PEG-TD2− CuSO4 (300 mg, 0.238 mmol Cu). After introduction of an aqueous solution of sodium ascorbate (25 mM) at a flow rate of 1.0 mL, a solution of alkyne (1, 1.0 mmol), azide (2, 1.0 mmol), and sodium ascorbate (0.1 mmol) in a mixture of H2O and EtOH (v/v = 1:3, 40, or 80 mL) was introduced into the reactor at 75 °C at a flow rate of 1.0 mL min−1. bConcentration was shown in the parentheses. c Purification by recrystallization from hexane−EtOAc.

(30 mL) was treated with diethylenetriamine (20.9 mmol) and DIPEA (20.9 mmol), and the resulting mixture was shaken at 80 °C for 48 h. The PS−PEG-TD2 resin beads were collected by filtration and washed with CH2Cl2 (10 × 30 mL) and dried in vacuo overnight (1.2 g). 13C NMR (CP-MAS) (ppm): 167.0, 146.9, 128.5, 100.0, 71.5, 47.1, 40.4. UV−vis (nm): 229, 278. IR (neat, cm−1): 3432 (br), 2908, 2868, 1660, 1563, 1103, 699. Preparation of PS−PEG-TD2−CuSO4. A mixture of PS−PGTD2 resin (1.0 g) and CuSO4·5H2O (250 mg) in MeOH (10 mL) was shaken at room temperature for 6 h. The resulting resin beads were collected by filtration, washed with MeOH (10 × 10 mL), and dried in vacuo overnight to provide the PS−PEG-TD2−CuSO4 catalyst. UV−

and the mixture was shaken at 80 °C for 48 h. The resulting PS−PEGTD1 resin beads were washed with CH2Cl2 (10 × 30 mL), and dried in vacuo overnight (2.3 g). Triazine-based polyethyleneamine dendrimer TD2 (generation 2.0) supported on PS−PEG resin was prepared by following a similar procedure to that used for the preparation of PS−PEG-TD1. A mixture of PS−PEG-TD1 resin (1.0 g), cyanuric chloride (CC) (10.4 mmol), and DIPEA (10.4 mmol) in THF (30 mL) was shaken at room temperature for 48 h. The mixture was filtered, and the resulting PS−PEG-CC2 resin beads were washed with CH2Cl2 (10 × 30 mL) and dried in vacuo overnight. A mixture of PS−PEG-CC2 and DMF 10730


Research Article

ACS Sustainable Chemistry & Engineering vis (nm): 247, 312, 407, 790. IR (neat, cm−1): 3425 (br), 2911, 2864, 1563(br), 1112, 699. ICP analysis: 0.793 mmol/g of Cu. General Procedure for Cycloaddition of Alkynes with Organic Azides. A mixture of catalyst PS−PEG-TD2−CuSO4 (Cu loading: 0.025 mmol, 5 mol %), alkyne 1 (0.5 mmol), and azide 2 (0.5 mmol) in water (1.0 mL) was stirred at 25 °C under N2 for 12 h. When the reaction was complete, EtOAc (3.0 mL) was added and the mixture was stirred for 5 min. The resulting mixture was filtered and the recovered supported catalyst was washed by EtOAc (2 × 3.0 mL). The organic phases were combined, dried (Na2SO4), and concentrated, and the residue was purified by column chromatography to give the 1,2,3-triazole 3. Recycling Experiment for the Huisgen Reaction of Alkynes with Organic Azide. After the Huisgen reaction discussed previously, the supported catalyst was recovered by simple filtration under an inert atmosphere and washed twice with EtOAc and water. The recovered catalyst was dried in vacuo and reused in a subsequent reaction without an additional charge of copper. General Procedure for Three-Component Reaction of Alkynes, Alkyl Bromides, with Sodium Azides. A mixture of catalyst PS−PEG-TD2−CuSO4 (Cu loading: 0.025 mmol, 5 mol %), alkyne 1 (0.5 mmol), alkyl bromide 4−9 (0.55 mmol), and sodium azide (0.55 mmol) in water (1.0 mL) was stirred at 25 °C under nitrogen for 12 h. When the reaction was complete, EtOAc (3.0 mL) was added and the mixture was stirred for 5 min. The resulting mixture was filtered, and the recovered resin beads were washed with EtOAc (2 × 3.0 mL). The organic phases were combined, dried (Na2SO4) and concentrated, and the residue was purified by column chromatography to give the 1,2,3-triazole 3. General Procedure for Continuous-Flow Cycloaddition of Alkynes with Organic Azides. A solution of alkyne (1.0 mmol), azide (1.0 mmol), and sodium ascorbate (0.1 mmol) in a 1:3 (v/v) mixture of H2O and EtOH (40 or 80 mL) was introduced at a flow rate of 1.0 mL/min into an X-Cube reactor system (ThalesNano Nanotechnology Inc., Budapest) fitted with a catalyst cartridge containing PS−PEG-TD2−CuSO4 (300 mg, 0.238 mmol Cu), which pretreated with an aqueous solution of sodium ascorbate (25 mM) at a flow rate of 1.0 mL min−1. The flow reaction was conducted at 75 °C. When the reaction was complete, the flow system was washed through with a 1:3 (v/v) mixture of H2O and EtOH (10 mL) to ensure that all the product was collected. The resulting solution was extracted with EtOAc, and the extracts were concentrated by evaporation. The desired product was purified by crystallization from hexane−EtOAc. General Procedure for Successive Continuous-Flow Cycloaddition. The successive continuous-flow cycloaddition was performed with an X-Cube reactor containing a catalyst cartridge of PS−PEG-TD2−CuSO4 (300 mg, 0.238 mmol Cu). After introduction of an aqueous solution of sodium ascorbate (25 mM) at a flow rate of 1.0 mL min−1, a solution of ethynylbenezne (1a, 1.0 mmol), benzyl azide (2A, 1.0 mmol), and sodium ascorbate (0.1 mmol) in a mixture of H2O and EtOH (1:3 (v/v), 40 mL) was introduced at a flow rate of 1.0 mL/min into the reactor. The flow reaction was conducted at 75 °C. After introduction of the substrate solution, a mixture of H2O and EtOH (1:3 (v/v), 10 mL) was introduced into the flow system at a flow rate of 1.0 mL/min. Then, a solution of 4-ethynyltoluene (1c, 1.0 mmol), benzyl azide (2A, 1.0 mmol), and sodium ascorbate (0.1 mmol) in a mixture of H2O and EtOH (1:3 (v/v), 80 mL) was introduced at a flow rate of 1.0 mL/min into the reactor. Following the similar operation, a total of 11 kinds of substrate solutions were introduced into the reactor successively without changing the catalyst. In all cases, the resulting solution was extracted with EtOAc, and the extracts were concentrated by evaporation. The desired product was purified by crystallization from hexane−EtOAc.

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CP-MAS NMR 13C spectrum of PS−PEG-TD2 (Figure S1), FTIR spectra of PS−PEG-NH2/CC1/TD1/CC2/ TD2 resins (Figure S2), and spectral assignment and 1H and 13C NMR spectra for the products (PDF)

AUTHOR INFORMATION

Corresponding Author

*Y. Uozumi. E-mail: [email protected]. ORCID

Takao Osako: 0000-0003-0621-4272 Yasuhiro Uozumi: 0000-0001-6805-3422 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the JST-ACCEL program (JPMJAC1401). We are also grateful for funding from the JSPS KAKENHI [Grand-in-Aid for Challenging Exploratory Research (No. 26620090), for Young Scientists (No. 26810099), for Scientific Research (C) (No. 16K05876), and for JSPS Fellows (No. 15F15039)]. S.P. acknowledges financial support from the Japan Society for Promotion of Sciences (JSPS; Postdoctoral Fellowship for Overseas Researchers).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b02646. 10731


Research Article

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(59) Xiong, X.; Cai, L. Application of Magnetic NanoparticleSupported CuBr: A Highly Efficiently and Reusable Catalyst for the One-Pot and Scale-Up Synthesis of 1,2,3-Trizoles under MicrowaveAssisted Conditions. Catal. Sci. Technol. 2013, 3, 1301−1307. (60) Nasr-Esfahani, M.; Mohammadpoor-Baltork, I.; Khosropour, A. R.; Mirkhani, V.; Tangestaninejad, S.; Rudbari, H. A.; Moghadam, M. Copper Immobilized on Nanosilica Triazine Dendrimer (Cu(II)-TD@ nSiO2)-Catalyzed Regioselective Synthesis of 1,4-Disubstituted 1,2,3Triazoles and Bis- and Tris-Triazoles via A One-Pot Multicomponent Click Reaction. J. Org. Chem. 2014, 79 (3), 1437−1443. (61) Bahrami, K.; Arabi, M. Copper Immobilized Ferromagnetic Nanoparticle Triazine Dendrimer (FMNP@TD-Cu(II))-Catalyzed Regioselective Synthesis of 1,4-Disustituted 1,2,3-Triazoles. New J. Chem. 2016, 40, 3447−3455. (62) Tavassoli, M.; Landarani-Isfahani, A.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Mohammadpoor-Baltork, I. Copper Dithiol Complex Supported on Silica Nanoparticles: A Sustainable, Efficient, and Eco-Friendly Catalyst for Multicomponent Click Reaction. ACS Sustainable Chem. Eng. 2016, 4 (3), 1454−1462. (63) Suzuka, T.; Ooshiro, K.; Kina, K. Reusable Polymer-Supported Terpyridine Copper Complex for [3 + 2] Huisgen Cycloaddition in Water. Heterocycles 2010, 81 (3), 601−610. (64) Wang, Y.; Liu, J.; Xia, C. Insights into Supported Copper(II)Catalyzed Azide-Alkyne Cycloaddition in Water. Adv. Synth. Catal. 2011, 353 (9), 1534−1542. (65) Borah, B. J.; Dutta, D.; Saikia, P. P.; Barua, N. C.; Dutta, D. K. Stabilization of Cu(0)-Nanoparticles into the Nanopores of Modified Montmorillonite: An Implication on the Catalytic Approach for “Click” Reaction Between Azides and Terminal Alkynes. Green Chem. 2011, 13, 3453−3460. (66) Hudson, R.; Li, C.-J.; Moores, A. Magnetic Copper-Iron Nanoparticles as Simple Heterogeneous Catalysts for the Azide-Alkyne Click Reaction in Water. Green Chem. 2012, 14, 622−624. (67) Baig, R. B. N.; Varma, R. S. A Highly Active Magnetically Recoverable Nano Ferrite-Glutathione-Copper (Nano-FGT-Cu) Catalyst for Huisgen 1,3-Dipolar Cycloadditions. Green Chem. 2012, 14, 625−632. (68) Collinson, J.-M.; Wilton-Ely, J. D. E. T.; Díez-González, S. Reusable and Highly Active Supported Copper(I)-NHC Catalysts for Click Chemistry. Chem. Commun. 2013, 49, 11358−11360. (69) Kale, S. R.; Kahandal, S. S.; Gawande, M. B.; Jayaram, R. V. Magnetically Recyclable γ-Fe2O3-HAP Nanoparticles for the Cycloaddition Reaction of Alkynes, Halides and Azides in Aqueous Media. RSC Adv. 2013, 3, 8184−8192. (70) Nador, F.; Volpe, M. A.; Alonso, F.; Feldhoff, A.; Kirschning, A.; Radivoy, G. Copper Nanoparticles Supported on Silica Coacted Maghemite as Versatile, Magnetically Recoverable and Reusable Catalyst for Alkyne Coupling and Cycloaddition Reactions. Appl. Catal., A 2013, 455, 39−45. (71) Sun, Q.; Lv, Z.; Du, Y.; Wu, Q.; Wang, L.; Zhu, L.; Meng, X.; Chen, W.; Xiao, F.-S. Recyclable Porous Polymer-Supported Copper Catalysts for Glaser and Huisgen 1,3-Dipolar Cycloaddition Reactions. Chem. - Asian J. 2013, 8 (11), 2822−2827. (72) Chavan, P. V.; Pandit, K. S.; Desai, U. V.; Kulkarni, M. A.; Wadgaonkar, P. P. Cellulose Supported Cuprous Iodide Nanoparticles (Cell-CuI NPs): A New Heterogeneous and Recyclable Catalyst for the One Pot Synthesis of 1,4-Disubstituted-1,2,3-Triazoles in Water. RSC Adv. 2014, 4, 42137−42146. (73) Roy, S.; Chatterjee, T.; Pramanik, M.; Roy, A. S.; Bhaumik, A.; Islam, Sk. M. Cu(II)-Anchored Functionalized Mesoporous SBA-15: An Efficient and Recyclable Catalyst for the One-Pot Click Reaction in Water. J. Mol. Catal. A: Chem. 2014, 386, 78−85. (74) Wang, D.; Etienne, L.; Echeverria, M.; Moya, S.; Astruc, D. A highly Active and Magnetically Recoverable Tris(triazolyl)-CuI Catalyst for Alkyne-Azide Cycloaddition Reactions. Chem. - Eur. J. 2014, 20 (14), 4047−4054. (75) Movassagh, B.; Rezaei, N. Polystyrene Resin-Supported CuICryptand 22 Complex: A highly Efficient and Reusable Catalyst for Three-Component Synthesis of 1,4-Disubstituted 1,2,3-Triazoles 10733


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ACS Sustainable Chemistry & Engineering for Suzuki-Miyaura Cross-Coupling and Heck Reactions. Adv. Synth. Catal. 2013, 355 (5), 957−972. (94) We previously reported a polystyrene-supported copperdiethylentriamine catalyst. See: Yan, S.; Pan, S.; Osako, T.; Uozumi, Y. Recyclable Polystyrene-Supported Copper Catalysts for the Aerobic Oxidation Homocoupling of Terminal Alkynes. Synlett 2016, 27, 1232−1236 However, this catalyst was not suitable for the organic reactions in water because heavy leaching of the copper species to the reaction solution was observed.. (95) The reaction could be performed under air, giving the desired triazole 3aA in 94% GC yield. However, ICP analysis showed that 4.9% of copper species was leached to the solution, while only 0.69% of copper species was leached when the reaction performed under N2. (96) Preparation of PS−PEG-TD2−CuI: in glovebox, a mixture of PS−PEG-TD2 (1.0 g) and CuI (1.0 mmol) in MeCN (10 mL) was shaken at room temperature for 24 h. The resulting resin beads were collected by filtration, washed with MeCN (20 × 10 mL), and dried in glovebox to provide the PS−PEG-TD2−CuI. ICP analysis showed the copper loading of PS−PEG-TD2−CuI was 0.75 mmol/g. (97) The Cu(II) complex would be reduced to the active Cu(I) species by terminal alkyne, see: Zhang, G.; Yi, H.; Zhang, G.; Deng, Y.; Bai, R.; Zhang, H.; Miller, J. T.; Kropf, A. J.; Bunel, E. E.; Lei, A. Direct Observation of Reduction of Cu(II) to Cu(I) by Terminal Alkynes. J. Am. Chem. Soc. 2014, 136 (3), 924−926. (98) Although the reaction using PS−PEG-TD2−CuI proceeded well, PS−PEG-TD2−CuI must be stored and handled under inert atmosphere. Considering the practical operation and further application to the flow system, the combination of PS−PEG-TD2− CuSO4 and sodium ascorbate was selected as the optimized conditions for further investigation. (99) Sarkar, A.; Mukherjee, T.; Kapoor, S. PVP-Stabilized Copper Nanoparticles: A Reusable Catalyst for “Click” Reaction Between Terminal Alkynes and Azides in Nonaqueous Solvents. J. Phys. Chem. C 2008, 112 (9), 3334−3340. (100) Xiong, J.; Wang, Y.; Xue, Q.; Wu, X. Synthesis of Highly Stable Dispersions of Nanosized Copper Particles Using L-Ascorbic Acid. Green Chem. 2011, 13, 900−904. (101) Jiang, J.; Kim, S.-H.; Piao, L. The Facile Synthesis of Cu@SiO2 Yolk-Shell Nanoparticles via a Disproportion Reaction of SilicaEncapsulated Cu2O Nanoparticle Aggregates. Nanoscale 2015, 7, 8299−8303. (102) Dabiri, M.; Kasmaei, M.; Salari, P.; Movahed, S. K. Copper Nanoparticles Decorated Three Dimensional Graphene with High Catalytic Activity for Huisgen 1.3-Dipolar Cycloaddition. RSC Adv. 2016, 6, 57019−57023. (103) Sorbera, L. A.; Leeson, P. A.; Rabasseda, X.; Castañer, J. Rufinamide. Antiepileptic, treatment of Neurogenic Pain. L.A. Drugs Future 2000, 25 (11), 1145−1149. (104) Rogawski, M. A. Diverse Mechanisms of Antiepileptic Drugs in the Development Pipeline. Epilepsy Res. 2006, 69 (3), 273−294. (105) Stafstrom, C. E. Update on the Management pf LennoxGastaut Syndrome with a Focus on Refinamide. Neuropsychiatr. Dis. Treat. 2009, 5, 547−551. (106) The reaction volume was determined from the weight between the dry and the wet cartridges. The reaction volume was 0.36 mL. According the following equation, when the flow rate was set as 1.0 mL/min, the contact time was 22 s. (107) A quantitative GC yield was obtained using a mixture of H2O and DMF (v/v = 1:3) as solvent. (108) Alvarez, S. G.; Alvarez, M. T. A Practical Procedure for the Synthesis of Alkyl Azides at Ambient Temperature in Dimethyl Sulfoxide in High Purity and Yield. Synthesis 1997, 1997, 413−414. (109) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Copper(II)-Catalyzed Conversion of Aryl/Heteroaryl Boronic Acids, Boronates, and Trifluoroborates into the Corresponding Azides: Substrate Scope and Limitations. Synthesis 2010, 2010, 1441−1448.

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Batch and Continuous-Flow Huisgen 1,3-Dipolar Cycloadditions with

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