Batch and Continuous-Flow Huisgen 1,3-Dipolar ... - ACS Publications

Subscriber access provided by University of Sussex Library

Article

Batch and Continuous-Flow Huisgen 1,3-Dipolar Cycloadditions with An Amphiphilic Resin-Supported TriazineBased Polyethyleneamine Dendrimer Copper Catalyst Shiguang Pan, Shuo Yan, Takao Osako, and Yasuhiro Uozumi ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.7b02646 • Publication Date (Web): 22 Sep 2017 Downloaded from http://pubs.acs.org on September 24, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Sustainable Chemistry & Engineering is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Sustainable Chemistry & Engineering

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,†,‡ 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. E-mail: [email protected] KEYWORDS: Copper; Alkyne-Azide Cycloaddition; Aqueous Reaction; Batch Reaction; Continuous-Flow Reaction; Heterogeneous Catalysis. ABSTRACT: A polystyrene-poly(ethylene glycol) (PS–PEG) resin-supported triazine-based polyethyleneamine dendrimer copper catalyst (PS–PEG-TD2–CuSO 4) was prepared and characterized by means of CP-MAS NMR, UV-vis/NIR, FTIR, SEM-EDX, XPS, and ICP-AES analyses. PS–PEG-TD2–CuSO 4 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–CuSO 4 with sodium ascorbate serve as the active catalytic species. The application of PS–PEG-TD2–CuSO 4 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 seconds in the continuous-flow system containing PS–PEG-TD2– CuSO 4 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 ten grams of a triazole as well as the successive flow reaction producing various kinds of triazoles.

INTRODUCTION The development of green, sustainable, catalytic organic transformations is a major challenge in recent organic chemistry.1-9 In particular, heterogeneous switching of homogeneous transitionmetal 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 noble-metal 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 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-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

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 three-component 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–CuSO 4) for the Huisgen reaction under batch and continuous-flow conditions.94 Under batch condi-

Page 2 of 31

tions, the PS–PEG-supported copper catalyst efficiently promoted the Huisgen 1,3-dipolar cycloaddition of organic azides with terminal alkynes in the 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 continuousflow system containing PS–PEG-TD2–CuSO 4 has been successfully developed. In the continuous-flow system, the cycloaddition of alkynes and organic azides was completed within 22 seconds, giving the corresponding 1,2,3-triazoles in up to 99% yield. The flow system containing PS–PEG-TD2–CuSO 4 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.

H 2N NH 2 N

Cl 100 µm

a)

H N

PS PEG

N

PEG

N

N

H N

PS

b)

N

N

Cl O

O

PS

n

NH 2

NH 2

PS-PEG-CC1

PS-PEG-NH 2 (NH 2: 0.27 mmol/g)

H 2N

Cl

N

NH

N PS

d)

N N

NH

PS

N N

N

H 2N

N N

H 2N

e)

NH 2 100 µm

H N

N N

NH

N NH 2

N

PS-PEG-TD2-CuSO 4 (Cu loading: 0.793 mmol/g)

N

N N

Cl

PS-PEG-CC2

NH 2

N N

N

NH 2

N

N

N H

Cl N

N

N

N

Cl

N

NH

NH 2

H N

N

N

H N

PEG

N

Cl

N

NH 2

N N

N

N

Cl

N

N H

H 2N

N

N

N

H N

PEG

N

Cl

NH 2

H 2N

N N

H 2N PS-PEG-TD1

NH 2

Cl N

c)

N N

H 2N

NH 2

NH 2 PS-PEG-TD2

Scheme 1. Preparation of PS–PEG-TD2–CuSO 4 catalyst. Conditions: (a) cyanuric chloride (10 equiv based on NH 2 groups), DIPEA (10 equiv based on NH 2 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 NH 2 groups), THF, r.t., 48 h; diethylenetriamine (10 equiv based on NH 2 groups), DIPEA (10 equiv based on Cl groups), DMF, 80 °C, 48 h; (e) CuSO 4⋅5H 2O (1.0 mmol per gram of PS–PEG-TD2), MeOH, r.t., 6 h.


Page 3 of 31

a)

1660 cm-1 1563 cm-1 (N-H bend) (C=N) 4000

2000 Wavenumber (cm-1)

3000

1000

Figure 1. FT-IR spectra of (a) PS–PEG-NH2, (b) PS–PEG-TD2, and (c) PS–PEG-TD2–CuSO 4. 100 a)

Reflectance (%)

90 b) 80

70

790 nm

Field-emission scanning electron microscopy (FE-SEM) analyses of PS–PEG-NH 2, PS–PEG-TD2, and PS–PEG-TD2–CuSO 4 were conducted (Figures 3a–c). The resins PS–PEG-TD2 and PS–PEG-TD2–CuSO 4 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. Energydispersive X-ray (EDX) analysis of PS–PEG-TD2 and PS–PEGTD2–CuSO 4 (Figures 4a and 4b, respectively) showed the presence of copper and sulfur in PS–PEG-TD2–CuSO 4 (Figure 4b), clearly confirming that complexation of PS–PEG-TD2 with CuSO 4 had occurred. An ICP-AES analysis of PS–PEG-TD2– CuSO 4 provided further confirmation of successful complexation,

c)

407 nm

The resulting resin and the supported PS–PEG-TD2–CuSO 4 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–PEG-TD2–CuSO 4 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 CuSO 4, the sharp peak of 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 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 CuSO 4, 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 charge-transfer (LMCT) and d–d transitions, respectively (Figure 2b).

b)

312 nm

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).11e Treatment of amino-functionalized PS–PEG (PS– PEG-NH 2, 0.27 mmol/g NH 2) with excess cyanuric chloride (10 equiv based on NH 2 groups) in the presence of excess N,Ndiisopropylethylamine (DIPEA, 10 equiv based on NH 2 groups) in THF at room temperature for 48 hours gave PS–PEG-supported cyanuric chloride (PS–PEG-CC1). This was treated with excess diethylenetriamine (10 equiv based on Cl groups) to afford a firstgeneration triazine-based 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 CuSO 4 was carried out by mixing the resin (1.0 g) with CuSO 4·5H 2O (1.0 mmol) in MeOH at room temperature for 6 hours to give green polymer beads of PS– PEG-TD2–CuSO 4.

Transmittance

RESULTS AND DISCUSSION

278 nm 247 nm 229 nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


60

50 190

290

390

490 590 Wavelength (nm)

690

790

Figure 2. UV-vis/NIR spectra of (a) PS–PEG-TD2 and (b) PS– PEG-TD2–CuSO 4.

a)

b)

c)

Figure 3. SEM images of (a) PS–PEG-NH2, (b) PS–PEG-TD2, and (c) PS–PEG-TD2–CuSO 4.


ACS Sustainable Chemistry & Engineering 180

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

160

cps/eV

1

(a)

Page 4 of 31

Table 1. Optimization of Reaction Conditionsa

140 120

PS-PEG-TD2-CuSO 4

100

Ph + N 3

80

Ph

60

(Cu: x mol%) sodium ascarbate (10 mol%) additive

1a

40

2A

C C N N O O

Ph N N N

H 2O (1.0 mL), N 2, rt, 12 h

Ph

3aA

20

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

0 0.5 0.5

1.0 1.0

1.5 1.5

2.0 2.0

2.5 2.5 keV keV

cps/eV 120

3.0 3.0

3.5 3.5

4.0 4.0

4.5 4.5

5.0 5.0

1

(b)

100 80

60

40

20

S C C N O O S

Cu Cu

SS

Cu Cu

Cu

Cat. Loading [mol%] 0 0.5 0.5 0.5 1.0 5.0 5.0 5.0 0 5.0

Additive

Yield/%b

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

0 29 34 30 65 100 99 21 0 95

a

0 0.5 0.5

1.0 1.0

1.5 1.5

2.0 2.0

2.5 2.5 keV keV

3.0 3.0

3.5 3.5

4.0 4.0

4.5 4.5

5.0 5.0

Figure 4. EDX spectra of (a) PS-PEG-TD2 and (b) PS-PEG-TD2CuSO 4.

and showed that the copper loading of PS–PEG-TD2–CuSO 4 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 hours, 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–CuSO 4 (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–PEGTD2–CuSO 4 catalyst improved the yield of 3aA (entries 5 and 6), and the reaction in the presence of PS–PEG-TD2–CuSO 4 (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 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–PEG-TD2–CuSO 4, 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–CuSO 4 and 10 mol% of sodium ascorbate in water at room temperature are the optimal conditions for this transformation.98

Reaction conditions: ethynylbenzene (1a, 0.5 mmol), PhCH2N 3 (2A, 0.5 mmol), PS–PEG-TD2–CuSO 4, sodium ascorbate (10 mol%), H2O (1.0 mL), N 2, 25 °C, 12 h. b Determinined by GC ananlysis with a biphenyl as internal standard. c The reaction was carried out using PS–PEG-TD2–CuI instead of PS–PEG-TD2–CuSO 4 in the absence of sodium ascorbate. d No sodium ascorbate. e The reduced copper catalyst prepared by treatment of PS–PEG-TD2–CuSO 4 with sodium ascorbate was used without further addition of sodium ascorbate.

The Huisgen reaction of ethynylbenzene (1a) with benzyl azide (2A) proceeded efficiently in the presence of PS–PEGTD2–CuSO 4 with sodium ascorbate, suggesting that the catalytically active copper species is generated in situ by the reaction of PS–PEG-TD2–CuSO 4 with sodium ascorbate. To identify the active species, we performed a TEM analysis of the copper catalyst obtained by treatment of PS–PEG-TD2–CuSO 4 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 counter anion SO 42– 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.


Page 5 of 31

ACS Sustainable Chemistry & Engineering 3aA–eA in 93–99% isolated 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).

a)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

b)

Table 2. Cycloaddition of Terminal Alkynes and Various Organic Azides Using PS–PEG-TD2–CuSO 4a PS-PEG-TD2-CuSO 4

R

+ R'

N3

R'

(Cu: 5 mol%) sodium ascarbate (10 mol%) H 2O (1.0 mL), N 2, rt, 12 h

1

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. a)

3

Y

X H OCH3 CH3 F CF3

Cu2p3/2

1i

Y

950 940

b)

930 920

910

1k

1g

900

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

Cu2p3/2 Cu2p1/2

980 c)

80

970

960

950 940

930 920

910

900

cps/eV

1

70 60 50 40 30

20 O SS CC NN O

SS

Cu Cu

Cu

10

Cu Cu

0 0.5 0.5

1.0 1.0

1.5 1.5

2.0 2.0

2.5 2.5 keV keV

3.0 3.0

3.5 3.5

4.0 4.0

4.5 4.5

5.0 5.0

Figure 6. XPS spectra of (a) PS–PEG-TD2–CuSO 4 and (b) after treatment with sodium ascorbate, and (c) EDX spectra of the reduced copper catalyst.

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 electron-donating or electron-withdrawing substituents at the para position reacted with benzyl azide (2A) to give the corresponding 1,2,3-triazoles

N3

1m

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

a

2G

N3

1j

1l

960

2A: Y = H 2B: Y = CH3 2C: Y = CF3

S

CH3

H 3C

970

CH 2N 3

1h 1a: X = 1b: X = 1c: X = 1d: X = 1e: X =

1f

980

R

N

Cu(II) satellite Cu2p1/2

2

N N N

2D: Y = H (CH 2) 4CH3 2E: Y = CH3 2F: Y = Cl

CH3(CH 2) 7 N 3 2H

O C 2H 5OCCH 2 N 3 2I

CH 2OH COOCH3

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

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

Yield/%b 97 99 99 93 98 97 98 97 91 88 95 93 99 95 93 99 95 96 92 85 99

Reaction conditions: alkyne (1, 0.5 mmol), organic azide (2, 0.5 mmol), PS–PEG-TD2–CuSO 4 (Cu loading: 5.0 mol%), sodium ascorbate (10 mol%), H2O (1.0 mL), N 2, 25 °C, 12 h. b Isolated yield.



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–CuSO 4 in water under the optimized catalytic conditions proceed smoothly to give 3nJ in 85% yield. CONH 2 1n

(Cu: 5.0 mol%)

+

F

F

PS-PEG-TD2-CuSO 4 sodium ascarbate (10 mol%)

N3

F

H 2O (1.0 mL), N 2, rt, 12 h

N N N

CONH 2

85% yield

F

(Rufinamide, 3nJ)

2J

Scheme 2. Application of PS–PEG-TD2–CuSO 4 to the synthesis of rufinamide (3nJ) from the cycloaddition reaction of 1n with 2J. Table 3. Three-Component Reaction of Alkynes, Sodium Azide, and Alkyl Bromides Using PS–PEG-TD2–CuSO 4a R'

PS-PEG-TD2-CuSO 4 (Cu: 5 mol%)

R + NaN 3 + R"CH 2 Br sodium ascarbate (10 mol%) H 2O (1.0 mL), N 2, rt, 12 h 1

4-9

Y

CH 2Br 4: 5: 6: 7: 8:

Entry 1 2 3 4 5 6 7 8

N N N

Y= Y= Y= Y= Y=

H CH3 Cl Br NO 2

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

R

3

Y

CH 2N 3 2A: Y = 2B: Y = 2K: Y = 2L: Y = 2M: Y =

H CH3 Cl Br NO 2

Alkyl bromide 4 4 4 5 6 7 8 9

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.

O C 2H 5OCCH 2Br 9(

100

2I)

100

100

100

100

1

2

3

4

100

100

100

98

6

7

8

80

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

Yield/%b 98 99 99 99 98 90 94 99

GC yield of 3aI (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 31

60

40

20

0

Cycles

5

Figure 7. Results of recycling experiments for the reaction of 1a with 2I using PS–PEG-TD2–CuSO 4.

a

Reaction conditions: alkyne (1, 0.5 mmol), alkyl bromide (4-9, 0.55 mmol), NaN 3 (0.5 mmol), PS–PEG-TD2–CuSO 4 (Cu loading: 5.0 mol%), sodium ascorbate (10 mol%), H2O (1.0 mL), N 2, 25 °C, 12 h. b Isolated 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 threecomponent 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 electrondonating (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–

With the successful results for the heterogeneous CuAAC under batch conditions, PS–PEG-TD2–CuSO 4 catalyst was next applied to the continuous-flow reaction. The continuous flow cycloaddition was performed with a flow reactor (X-CubeTM ThalesNano Nanotechnology, Inc.) containing a catalyst cartridge (internal dimensions: 70 mm x 4 mm) of PS–PEG-TD2–CuSO 4 (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


Page 7 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


rate of 1 mL/min at 25 °C, affording a moderate yield of 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 sec 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).

lent yields. These results suggested that the continuous-flow system of PS–PEG-TD2–CuSO 4 would be very useful for a combinatorial approach in the drug discovery where the synthesis of many types of triazoles is required. Table 5. Continuous-Flow Cycloaddition of Terminal Alkyne with Various Organic Azides Cycloaddition Using PS–PEG-TD2– CuSO 4a R 1 (12.5 or 25 mM) +

R'

PS-PEG-TD2-CuSO 4 (300mg, 0.238 mmol Cu)

2 (12.5 or 25 mM) + sodium ascorbate (1.25 or 2.5 mM)

H 2O/EtOH (1:3), 75 oC 1.0 mL/min (contact time 22 sec)

N

Ph 1a

PS-PEG-TD2-CuSO 4

+

(300mg, 0.238 mmol Cu)

PhCH 2 N 3 2A

H 2O/EtOH (1:3)

+ sodium ascorbate

flow rate, T (X-Cube TM reactor)

H OCH3 CH3 F CF3

Ph

1i

Ph

1f

1l

3aA

3 4

1c 2 3 4 5 6 7

N3

1k

H 3C

Entry 1 2

Conc. of 1a /mM 10 10 25 25 25 25 50

2A: Y = H 2B: Y = CH3 2C: Y = CF3

CH3

1g

Entry

S

CH 2N 3

1j

N N N

T/°C

Yield/%b

25 25 25 50 75 100 75

82 100 50 86 100 100 -d

5 6 7 8 9 10 11 12 13 14 15 16 17 18

a

Reaction conditions: the flow cycloaddition was performed with an X-CubeTM flow reactor containing a catalyst cartridge of PS-PEGTD2-CuSO 4 (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. b Determined by GC analysis with an internal standard. c Without addition of sodium ascorbate (10 mol%). d The product participated in the pipeline.

To further demonstrate the practical utility of our continuousflow system for CuAAC, the successive synthesis of a variety of triazoles was carried out using the flow reactor containing of PS– PEG-TD2–CuSO 4 (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 excel-

1m

Alkyneb 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)

a

R

3

Y

1h 1a: X = 1b: X = 1c: X = 1d: X = 1e: X =

N N N

(Continuous-flow reactor)

X

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

R'

N3

2D

(CH 2) 4CH3 CH 2OH COOCH3

CH3(CH 2) 7 N 3 2H


Azide 2A 2A

Triazole 3aA 3bA

Yield/%c 99 99

2A 2A

3cA 3dA

96 99

2A 2A 2A 2A

3eA 3fA 3gA 3hA

99 96 91 99

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

3iA 3jA 3kA 3lA 3mA 3aB 3aC 3aD 3aH 3aI

93 93 92 91 98 96 99 96 89 99

Reaction conditions: the flow cycloaddition was performed with an X-CubeTM flow reactor containing a catalyst cartridge of PS–PEGTD2–CuSO 4 (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. b Concentration was shown in the parentheses. c Purification by recrystallization from hexane-EtOAc.


ACS Sustainable Chemistry & Engineering Ph

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

PS-PEG-TD2-CuSO 4

1a (25 mM) O +

N N N

EtOCCH 2 N 3 2I (25 mM)

H 2O/EtOH (1:3) , 75 °C

+ sodium ascorbate (2.5 mM)

CONCLUSION

CO2Et

(300mg, 0.238 mmol Cu)

Ph

3aI

1.0 mL/min (contact time: 22 s)

14.4 g (87%)

(X-Cube TM reactor)

Scheme 3. Long-term continuous-flow cycloaddition of 1a with 2I. Table 6. Successive Continuous-Flow Alkyne-Azide Cycloaddition Using The X-Cube Reactora R PS-PEG-TD2-CuSO 4

1 (12.5 or 25 mM) +

R'

(300mg, 0.238 mmol Cu)


H 2O/EtOH (1:3), 75 oC

1a: X = 1c: X = 1e X = 1o: X =

N N N

1.0 mL/min (contact time 22 sec)

R

CH 2N 3 2A: Y = H 2N: Y = CH 2OH

O C 2H 5OCCH 2 N 3

COOCH3

1m

Alkyneb 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)

EXPERIMENTAL SECTION

Y

H CH3 CF3 (CH 2) 4CH3

2I

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

In conclusion, an amphiphilic polystyrene-poly(ethylene glycol) (PS–PEG) resin-supported triazine-based polyethyleneamine dendrimer–copper sulfate complex (PS–PEG-TD2–CuSO 4) was developed and used as an efficient catalyst for the Huisgen 1,3dipolar 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–CuSO 4 with sodium ascorbate, act as the active catalytic species. Under continuous-flow conditions, various triazoles were obtained in a short process time. The longterm flow cycloaddition reaction provided more than ten grams of the triazole for 48 h. Further investigations on the application of PS–PEG-TD2–Cu(II) catalysts in other organic transformations are currently ongoing in our laboratory.

3


X

Run No. 1 2 3 4 5 6 7 8 9 10 11

R'

N3

Page 8 of 31

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

Yield/%c 99 99 96 99 99 97 99 97 98 96 98

a

Reaction conditions: the flow cycloaddition was performed with an X-CubeTM flow reactor containing a catalyst cartridge of PS–PEGTD2–CuSO 4 (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. b Concentration was shown in the parentheses. c Purification by recrystallization from hexane-EtOAc.

Long-term continuous flow cycloaddition of ethynylbenzene (1a) and ethyl azidoacetate (2I) was carried out using the flow reactor containing of PS–PEG-TD2–CuSO 4 (Scheme 3). Before the flow cycloaddition was started, PS–PEG-TD2–CuSO 4 was pretreated with an aqueous solution of sodium 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) in a mixture of H 2O 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 hour, producing 14.4 gram of triazole 3aI (87% yield).

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 UV-3600 spectrophotometer. The FESEM 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 LABS Profile plasma spectrometer. The continuous-flow reaction was performed in an X-Cube 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–PEGCC1) 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, and the mixture was shaken at 80 °C for 48 h. The resulting PS–PEG-TD1 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 (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–PG-TD2 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 x 10 mL), and dried in vacuo overnight to provide the PS–PEG-TD2–CuSO4 catalyst. UV-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.


Page 9 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 above, 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 pre-treated 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 XCubeTM 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 4ethynyltoluene (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. Followed the similar operation, total 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.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website.

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

AUTHOR INFORMATION Corresponding Author * 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.

ACKNOWLEDGMENT 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).

REFERENCES (1) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (2) Sheldon, R. A.; Arends, I. W. C. E.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim, 2007. (3) Sheldon, R. A. Green Solvents for Sustainable Organic Synthesis: State and the Art. Green Chem. 2005, 7, 267-278. DOI: 10.1039/B418069K. (4) Clark, J. H. Green Chemistry: Today (and Tomorrow). Green Chem. 2006, 8, 17-21. DOI: 10.1039/B516637N. (5) Li, C.-J.; Trost, B. M. Green Chemistry for Chemical Synthesis. Proc. Natl. Acad. Sci. USA 2008, 105 (36), 13197-13202. DOI: 10.1073/pnas.0804348105. (6) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice. Chem. Soc. Rev. 2010, 39, 301-312. DOI: 10.1039/B918763B. (7) Jessop, P. G. Searching for Green Solvents. Green Chem. 2011, 13, 1391-1398. DOI: 10.1039/C0GC00797H. (8) Simon, M.-O.; Li, C.-J. Green Chemistry Oriented Organic Synthesis in Water. Chem. Soc. Rev. 2012, 41, 1415-1427. DOI: 10.1039/C1CS15222J. (9) Sheldon, R. A. Fundamentals of Green Chemistry: Efficiency in Reaction Design. Chem. Soc. Rev. 2012, 41, 1437-1451. DOI: 10.1039/C1CS15219J. (10) Sheldon, R. A.; van Bekkum, H. Fine Chemical Through Heterogeneous Catalysis; Wiley-VCH, Weinheim, 2001. (11) Barbaro, P.; Liguori, F. Heterogenized Homogeneous Catalysts for Fine Chemical Production: Catalysis by Metal Complexes; Vol. 33, Springer, Dordrechet, 2010. (12) Kirschning, A.; Monenschein, H.; Wittenberg, R. Functionalized Polymers-Emerging Versatile Tools for Solution-Phase Chemistry and Automated Parallel Synthesis. Angew. Chem., Int. Ed. 2001, 40 (4), 650679. DOI: 10.1002/1521-3773(20010216)40:43.0CO;2-C.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(13) Leadbeater, N. E.; Marco, M. Preparation of Polymer-Supported Ligands and Metal Complexes for Use in Catalysis. Chem. Rev. 2002, 102 (10), 3217-3274. DOI: 10.1021/cr010361c. (14) McNamara, C. A.; Dixon, M. J.; Bradley, M. Recoverable Catalysts and Reagents Using Recyclable Polystyrene-Based Supports. Chem. Rev. 2002, 102 (10), 3275-3300. DOI: 10.1021/cr0103571. (15) Kaneda, K.; Ebitani, K.; Mizugaki, T.; Mori, K. Design of HighPerformance Heterogeneous Metal Catalysts for Green and Sustainable Chemistry. Bull. Chem. Soc. Jpn. 2006, 79 (7), 981-1016. DOI: 10.1246/bcsj.79.981. (16) Lu, J.; Toy, P. H. Organic Polymer Supports for Synthesis and for Reagent and Catalyst Immobilization. Chem. Rev. 2009, 109 (2), 815838. DOI: 10.1021/cr8004444. (17) Kann, N. Recent Applications of Polymer Supported Organometallic Catalysis in Organic Synthesis. Molecules 2010, 15 (9), 6306-6331. DOI: 10.3390/molecules15096306. (18) Uozumi, Y.; Shibatomi, K. Catalytic Asymmetric Allylic Alkylation in Water with a Recyclable Amphiphilic Resin-Supported P,NChelating Palladium Complex. J. Am. Chem. Soc. 2001, 123 (12), 29192920. DOI: 10.1021/ja005866j. (19) Uozumi, Y.; Nakazono, M. Amphiphilic Resin-Supported Rhodium-Phosphine Catalysts for C-C Bond Forming Reaction in Water. Adv. Synth. Catal. 2002, 344, 274-277. DOI: 10.1002/16154169(200206)344:3/43.0CO;2-S. (20) Uozumi, Y.; Nakao, R. Catalytic Oxidation of Alcohols in Water under Atmospheric Oxygen by Use of an Amphiphilic Resin-Dispersion of a Nanopalladium Catalyst. Angew. Chem., Int. Ed. 2003, 42 (2), 194197. DOI: 10.1002/anie.200390076. (21) Yamada, Y. M. A.; Arakawa, T.; Hocke, H.; Uozumi, Y. A Nanoplatinum Catalyst for Aerobic Oxidation of Alcohols in Water. Angew. Chem., Int. Ed. 2007, 46 (5), 704-706. DOI: 10.1002/anie.200603900. (22) Oe, Y.; Uozumi, Y. Highly Efficient Heterogeneous Aqueous Kharasch Reaction with an Amphiphilic Resin-Supported Ruthenium Catalyst. Adv. Synth. Catal. 2008, 350, 1771-1775. DOI: 10.1002/adsc.200800359. (23) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada, Y. M. A. Asymmetric Suzuki-Miyaura Coupling in Water with a Chiral Palladium Catalyst supported on an Amphiphilic Resin. Angew. Chem., Int. Ed. 2009, 48 (15), 2708-2710. DOI: 10.1002/anie.200900469. (24) Hudson, R.; Hamasaka, G.; Osako, T.; Yamada, Y. M. A.; Li, C.J.; Uozumi, Y.; Moores, A. Highly Efficient Iron(0) NanoparticleCatalyzed Hydrogenation in Water in Flow. Green Chem. 2013, 15, 21412148. DOI: 10.1039/C3GC40789F. (25) Osako, T.; Torii, K.; Uozumi, Y. Aerobic Flow Oxidation of Alcohols in Water Catalyzed by Platinum Nanoparticles Dispersed in an Amphiphilic Polymer. RSC Adv. 2015, 5, 2647-2654. DOI: 10.1039/C4RA14947E. (26) Greenwood, N. N.; Earnshaw, A. Chemistry of the Elements, 2n d ed.; Elsevier, Oxford, 2012. (27) Pastre, J. C.; Browne, D. L.; Ley, S. V. Flow Chemistry Synthesis of Natural Products. Chem. Soc. Rev. 2013, 42 (23), 8849-8869. DOI: 10.1039/C3CS60246J. (28) McQuade, D. T.; Seeberger, P. H. Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis. J. Org. Chem. 2013, 78 (13), 6384-6389. DOI: 10.1021/jo400583m. (29) Ricciaedi, R.; Huskens, J.; Verboom, W. Nanocatalysis in Flow. ChemSus Chem. 2015, 8 (16), 2586-2605. DOI: 10.1002/cssc.201500514. (30) Kobayashi, S. Flow “Fine” Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods. Chem. Asian J. 2016, 11 (4), 425436. DOI: 10.1002/asia.201500916. (31) Meldal, M.; Tornoe, C. W.; Christensen, C. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-

Page 10 of 31

Dipolar Cycloaddition of Terminal Alkynes to Azides. J. Org. Chem. 2002, 67 (9), 3057-3064. DOI: 10.1021/jo011148j. (32) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes. Angew. Chem., Int. Ed. 2002, 41 (14), 2596-2599. DOI: 10.1002/15213773(20020715)41:143.0.CO;2-4. (33) Bock, V. C.; Hiemstra, H.; van Maarseveen, J. H. CuI -Catalyzed Alkyne-Azide “Click” Cycloaddition from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem. 2006, 51-68. DOI: 10.1002/ejoc.200500483. (34) Gil, M. V.; Arevalo, M. J.; Lopez, O. Click Chemistry-What’s in a Name? Triazole Synthesis and Beyond. Synthesis 2007, 1589-1620. DOI: 10.1055/s-2007-966071. (35) Meldal, M.; Tornre, C. W.; Cu-Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108 (8), 2952-3015. DOI: 10.1021/cr0783479. (36) Hein, J. E.; Fokin, V. V. Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAc) and Beyond: New Reactivity of Copper(I) Acetylides. Chem. Soc. Rev. 2010, 39, 1302-1315. DOI: 10.1039/B904091A. (37) Diez-Gonzalez, S. Well-Defined Copper(I) Complexes for Click Azide-Alkyne Cycloaddition Reactions: One Click Beyond. Catal. Sci. Technol. 2011, 1, 166-178. DOI: 10.1039/C0CY00064G. (38) Iha, R. K.; Wooley, K. L.; Nystrom, A. M.; Burke, D. J.; Kade, M. J.; Hawker, C. J. Applications of Orthogonal “Click” Chemistries in the Synthesis of Functional Soft Materials. Chem. Rev. 2009, 109 (11), 5620-5686. DOI: 10.1021/cr900138t. (39) Hua, Y.; Flood, A. H. Click Reaction Generates Privileged CH Hydrogen-Bonding Triazoles: the Latest Addition to Anion Supramolecular Chemistry. Chem. Soc. Rev. 2010, 39, 1262-1271. DOI: 10.1039/B818033B. (40) El-Sagheer, A. H.; Brown, T. Click Chemistry with DNA. Chem. Soc. Rev. 2010, 39, 1388-1405. DOI: 10.1039/B901971P. (41) Qin, J.; Lam, J. W. Y.; Tang, B. Z. Click Polymerization. Chem. Soc. Rev. 2010, 39, 2522-2544. DOI: 10.1039/B909064A. (42) Kempe, K.; Krieg, A.; Becer, C. R.; Schubert, U. S. “Click” on/with Polymers: A Rapidly Expanding Field for the Straightforward Preparation of Novel Macromolecular Architectures. Chem. Soc. Rev. 2012, 41, 176-191. DOI: 10.1039/C1CS15107J. (43) Dervaux, B.; Prez, F. E. D. Heterogeneous Azide-Alkyne Click Chemistry: Towards Metal-Free and Products. Chem. Sci. 2012, 3, 959966. DOI: 10.1039/C2SC00848C. (44) Gawande, M. B.; Goswami, A.; Felpin, F.-X.; Asefa, T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S.; Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis. Chem. Rev. 2016, 116 (6), 3722-3811. DOI: 10.1021/acs.chemrev.5b00482. (45) Lipshutz, B. H.; Taft, B. R. Heterogeneous Copper-in-CharcoalCatalyzed Click Chemistry. Angew. Chem. Int. Ed. 2006, 45 (48), 82358238. DOI: 10.1002/anie.200603726. (46) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.; Herscovici, J. Resuable Polymer-Supported Catalyst for the [3+2] Huisgen Cycloaddition in Automation Protocols. Org. Lett. 2006, 8 (8), 16891692. DOI: 10.1021/ol060283I. (47) Chan, T. R.; Fokin, V. V. Polymer-Supported Copper(I) Catalyzed for the Experimentally Simplified Azide-Alkyne Cycloaddition. QSAR Comb. Sci. 2007, 26, 1274-1279. DOI: 10.1002/qsar.200740131. (48) Chassaning, S.; Sido, A. S. S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. “Click Chemistry” in Zeolites: Copper(I) Zeolites as New Heterogeneous and Ligand-Free Catalysts for the Huisgen [3+2] Cycloaddition. Chem. Eur. J. 2008, 14 (22), 6713-6721. DOI: 10.1002/chem.200800479. (49) Park, I. S.; Kwon, M. S.; Kim, Y.; Lee, J. S.; Park, J. Heterogeneous Copper Catalyst for the Cycloaddition of Azides and Alkynes without Additives under Ambient Conditions. Org. Lett. 2008, 10 (3), 497500. DOI: 10.1021/ol702790w.


Page 11 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(50) Coelho, A.; Diz, P.; Caamano, O.; Sotelo, E. Polymer-Supported 1,5,7-Triazabicyclo[4.4.0]dec-5-ene as Polyvalent Ligands in the CopperCatalyzed Huisgen 1,3-Dipolar Cycloaddition. Adv. Synth. Catal. 2010, 352 (7), 1179-1192. DOI: 10.1002/adsc.200900680. (51) Veerakumar, P.; Velayudham, M.; Lu, K.-L.; Rajagopal, S. Highly Dispersed Silica-Supported Nanocopper Heterogeneous Catalyst: Application in the synthesis of 1,2,3-triazoles and Thioethers. Catal. Sci. Technol. 2011, 1, 1512-1525. DOI: 10.1039/c1cy00300c. (52) Kumar, A.; Aerry, S.; Saxena, S.; de, A.; Mozumdar, S. Copper Nanoparticles in Guar-Gun: A Recyclable Catalytic System for the Huisgen [3+2]-Cycloaddition of Azides and Alkynes Without Additives under Ambient Conditions. Green Chem. 2012, 14, 1298-1301. DOI: 10.1039/C2GC35070J. (53) Kovács, S.; Zih-Perényi, K.; Révész, Á.; Novák, Z. Copper on Iron: Catalyst and Scavenger for Azide-Alkyne Cycloaddition. Synthesis 2012, 44, 3722-3730. DOI: 10.1055/s-0032-1317697. (54) Islam, R. U.; Taher, A.; Choudhary, M.; Siwal, S.; Mallick, K. Polymer Immobilized Cu(I) Formation and Azide-Alkyne Cycloaddition: A One Pot Reaction. Sci. Rep. 2015, 5, 9632-9639. DOI: 10.1038/srep09632. (55) Liu, X. Novoa, N.; Manzur, C.; Carrillo, D.; Hamon, J.-R. New Organometallic Schiff-Base Copper Complexes as Efeicient “Click” Reaction Precatalysts. New J. Chem. 2016, 40, 3308-3313. DOI: 10.1039/C5NJ02681D. (56) Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y. Amphiphilic SelfAssembled Polymeric Copper Catalyst to Parts per Million Levels: Click Chemistry. J. Am. Chem. Soc. 2012, 134 (22), 9285-9290. DOI: 10.1021/ja3036543. (58) Presolski, S. I.; Mamiduala, S. K.; Manzenrieder, F.; Finn, M. G. Resin-Supported Catalysts for CuAAC Click Reactions in Aqueous or Organic Solvents. ACS Comb. Sci. 2012, 14 (10), 527-530. DOI: 10.1021/co300076k. (59) Xiong, X.; Cai, L. Application of Magnetic NanoparticleSupported CuBr: A Highly Efficiently and Reusable Catalyst for the OnePot and Scale-Up Synthesis of 1,2,3-Trizoles under Microwave-Assisted Conditions. Catal. Sci. Technol. 2013, 3, 1301-1307. DOI: 10.1039/C3CY20680G. (60) Nasr-Esfahani, M.; Mohammadpoor-Baltork, I.; Khosropour, A. R.; Mirkhani, V.; Tangestaninejad, S.; Rudbari, H. A. Copper Immobilized on Nanosilica Triazine Dendrimer (Cu(II)-TD@nSiO2)-Catalyzed Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles and Bis- and Tris-Triazoles via A One-Pot Multicomponent Click Reaction. J. Org. Chem. 2014, 79 (3), 1437-1443. DOI: 10.1021/jo402170n. (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. DOI: 10.1039/C5NJ03219A. (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. DOI: 10.1021/acssuschemeng.5b01432. (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. DOI: 10.3987/COM-09-11872. (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. DOI: 10.1002/adsc.201000868. (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. DOI: 10.1039/C1GC16021D.

(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. DOI: 10.1039/C2GC16421C. (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. DOI: 10.1039/C2GC16301B. (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. DOI: 10.1039/C3CC44371J. (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. DOI: 10.1039/C3RA00038A. (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. DOI: 10.1016/j.apcata.2013.01.023. (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. Asia J. 2013, 8 (11), 2822-2827. DOI: 10.1002/asia.201300690. (72) Chavan, P. V.; Pandit, K. S.; Desai, U. V.; Kulkarni, M. A.; Wadgaonkar, P. P. Cellulose Supported Cuprous Iodide Nanoparticles (CellCuI 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. DOI: 10.1039/C4RA05080K. (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 2014, 386, 78-85. DOI: 10.1016/j.molcata.2014.01.027. (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), 40474054. DOI: 10.1002/chem.201304536. (75) Movassagh, B.; Rezaei, N. Polystyrene Resin-Supported CuICryptand 22 Complex: A highly Efficient and Reusable Catalyst for ThreeComponent Synthesis of 1,4-Disubstituted 1,2,3-Triazoles Under Aerobic Conditions in Water. Tetrahedron 2014, 70 (46), 8885-8892. DOI: 10.1016/j.tet.2014.09.092. (76) Tajbakhsh, M.; Farhang, M.; Baghbanian, S. M.; Hosseinzadeh, R.; Tajbakhsh, M. Nano Magnetite Supported Metal Ions as Robust, Efficient and Recyclable Catalysts for Green Synthesis of Propargylamines and 1,4-Disubstituted 1,2,3-Triazoles in Water. New J. Chem. 2015, 39, 1827-1839. DOI: 10.1039/C4NJ01866D. (77) Islam, R. U; Taher, A.; Choudhary, M.; Witcomb, M. J.; Mallick, K. A polymer Supported Cu(I) Catalysts for the ‘Click Reaction’ in Aqueous Media. Dalton Trans. 2015, 44, 1341-1349. DOI: 10.1039/C4DT02962C. (78) Reddy, V. H.; Reddy, Y. V. R.; Sridhar, B.; Reddy, B. V. S.; Green Catalytic Process for Click Synthesis Promoted by Copper Oxide Nanocomposite Supported on Graphene Oxide. Adv. Synth. Catal. 2016, 358 (7), 1088-1092. DOI: 10.1002/adsc.201501072. (79) Jahanshahi, R.; Akhlaghinia, B. CuII Immobilized on Guanidinated Epibromohydrin Functionalized γ-Fe2O3@TiO2 (γ-Fe2O3@TiO2-EGCuII ): A Novel Magnetically Recyclable Heterogeneous Nanocatalyst for the Green One-Pot Synthesis of 1,4-Disubstituted 1,2,3-Triazoles Through Alkyne-Azide Cycloaddition in Water. RSC Adv. 2016, 6, 29210-29219. DOI: 10.1039/C6RA05468D. (80) Ghodsinia, S. S. E.; Akhlaghinia, B.; Jahanshahi, R. Direct Access to Stabilized CuI Using Cuttlebone as Natural-Reducing Support for



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Efficient CuAAC Click Reactions in Water. RSC Adv. 2016, 6, 6361363623. DOI: 10.1039/C6RA13314B. (81) A minireview for continuous-flow synthesis of triazoles, see: Ötvös, S. B.; Fülöp, F. Flow Chemistry as a Versatile Tool for the Synthesis of Triazoles. Catal. Sci. Technol. 2015, 5, 4926-4941. DOI: 10.1039/C5CY00523J. (82) Bogdan, A. R.; Sach, N. W. The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4-Disubstituted 1,2,3Triazoles. Adv. Synth. Catal. 2009, 351 (6), 849-854. DOI: 10.1002/adsc.200800758. (83) Bogdan, A. R.; James, K. Synthesisi of 5-Iodo-1,2,3-TriazoleContaining Macrocycles Using Copper Flow Reactor Technology. Org. Lett. 2011, 13 (15), 4060-4063. DOI: 10.1021/ol201567s. (84) Ötvös, S. B.; Má ndity, I. M.; Kiss, L.; Fülöp, F. Alkyne-Azide Cycloadditions with Copper Power in a High-Pressure-Continuous-Flow Reactor: High-Temperature Conditions Versus the Role of Additives. Chem. Asian J. 2013, 8 (4), 800-808. DOI: 10.1002/asia.201201125. (85) Jumde, R. P.; Evangelisti, C.; Mandoli, A.; Scotti, N.; Psaro, R. Aminopropyl-Silica-Supported Cu Nanoparticles: An Efficient Catalyst for Continuous-Flow Huisgen Azide-Alkyen Cycloaddition (CAAC). J. Catal. 2015, 324, 25-31. DOI: 10.1016/j.jcat.2015.01.014. (86) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. About Dendrimers: Structure, Physical Properties, and Applications. Chem. Rev. 1999, 99 (7), 1665-1688. DOI: 10.1021/cr970069y. (87) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.; Yeung, L. K. Dendrimer-Encapsulated Metal Nanoparticles: Synthesis, Characterization, and Applications to Catalysis. Acc. Chem. Res. 2001, 34 (3), 181-190. DOI: 10.1021/ar000110a. (88) Grayson, S. M.; Fréchet, J. M. Convergent Dendrons and Dendrimers: From Synthesis to Applications. Chem. Rev. 2001, 101 (12), 3819-3868. DOI: 10.1021/cr990116h. (89) Gebbink, R. J. M. K.; Kruithof, C. A.; van Klink, G. P. M.; Koten, G. V. Dendritic Supports in Organic Synthesis. Rev. Mol. Biotechnol. 2002, 90, 183-193. DOI: 10.1016/S1389-0352(01)00060-5. (90) Astruc, D.; Boisselier, E.; Ornelas, C. Dendrimers Designed for Functions: From Physical, Photophysical, and Supramolecular Properties to Applications in Sensing, Catalysis, Molecular Electronics, Photonics, and Nanomedicine. Chem. Rev. 2010, 110 (4), 1857-1959. DOI: 10.1021/cr900327d. (91) Reynhardt, J. P.; Yang, Y.; Sayari, A. H. Alper, Periodic Mesoporous Silica-Supported Recyclable Rhodium-Complexed Dendrimer Catalysts. Chem. Mater. 2004, 16 (21), 4095-4102. DOI: 10.1021/cm0493142. (92) Biradar, A. V.; Biradar, A. A.; Asefa, T. Silica-Dendrimer CoreShell Microspheres with Encapsulated Ultrasmall Palladium Nanoparticles: Efficient ad Easily Recyclable Heterogeneous Nanocatalysts. Langmuir 2011, 27 (23), 14408-14418. DOI: 10.1021/la203066d. (93) Isfahani, A. L.; Mohammadpoor-Baltork, I.; Mirkhani, V.; Khosropour, A. R.; Moghadam, M.; Tangestaninejad, S.; Kia, R. Palladium Nanoparticles Immobilized on Nano-Silica Triazine Dendritic Polymer (Pdnp-nSTDP): An Efficient and Reusable Catalyst for Suzuki-Miyaura Cross-Coupling and Heck Reactions. Adv. Synth. Catal. 2013, 355 (5), 957-972. DOI: 10.1002/adsc.201200707. (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. DOI: 10.1055/s-0035-1561361. 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.

Page 12 of 31

(96) Preparation of PS–PEG-TD2–CuI: in glove box, 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 x 10 mL), and dried in glove box 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. DOI: 10.1021/ja410756b. (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. DOI: 10.1021/jp077603i. (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. DOI: 10.1039/C0GC00772B. (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, 82998303. DOI: 10.1039/C5NR01484K. (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. DOI: 10.1039/C5RA25317A. (103) Sobera, L. A.; Leeson, P. A.; Rabasseda, X.; Castañer, J. Rufinamide. Antiepileptic, treatment of Neurogenic Pain. L.A. Drugs Future 2000, 25 (11), 1145-1149. DOI: 10.1358/dof.2000.025.11.599595. (104) Rogawski, M. A. Diverse Mechanisms of Antiepileptic Drugs in the Development Pipeline. Epilepsy Res. 2006, 69 (3), 273-294. DOI: 10.1016/j.eplepsyres.2006.02.004. (105) Stafstrom, C. E. Update on the Management pf Lennox-Gastaut Syndrome with a Focus on Refinamide. Neuropsychiatr. Dis. Treat. 2009, 5, 547-551. DOI: 10.2147/NDT.S5300. (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 seconds. contact time (sec) =

reaction volume (mL) x 60 flow rate (mL/min)

(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, 413-414. DOI: 10.1055/s-19971206. (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, 1441-1448. DOI: 10.1055/s-0029-1218683.


Page 13 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


For Table of Contents Use Only

Synopsis Efficient and green-sustainable batch and continuous-flow systems for aqueous azide-alkyne cycloaddition with a PS-PEG supported dendrimer copper catalyst have been developed.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 31

Scheme 1

H 2N NH 2 N

Cl 100 µm

a)

H N

PS PEG

N

PEG

N

N

H N

PS

b)

N

N

Cl O

O

PS

n

NH 2

NH 2

PS-PEG-CC1

PS-PEG-NH 2 (NH 2: 0.27 mmol/g)

H 2N

Cl

N

NH

N PS

d)

N N

NH

PS

N N

N

H 2N

N N

H 2N

e)

NH 2 100 µm

H N

N N

NH

N NH 2

N N

N N

Cl

PS-PEG-CC2

NH 2

N N

N

NH 2

N

N

N H

Cl N

N

N

N

Cl

N

NH

NH 2

H N

N

N

H N

PEG

N

Cl

N

NH 2

N N

N

N

Cl

N

N H

H 2N

N

N

N

H N

PEG

N

Cl

NH 2

H 2N

N N

H 2N PS-PEG-TD1

NH 2

Cl N

c)

N N

H 2N NH 2 PS-PEG-TD2


NH 2

PS-PEG-TD2-CuSO 4 (Cu loading: 0.793 mmol/g)

Page 15 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 2

CONH 2

F

1n

PS-PEG-TD2-CuSO 4

+

(Cu: 5.0 mol%) sodium ascarbate (10 mol%)

N3 F

H 2O (1.0 mL), N 2, rt, 12 h

F N N N F

CONH 2

85% yield (Rufinamide, 3nJ)

2J



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 3

Ph 1a (25 mM) O +


EtOCCH 2 N 3 2I (25 mM) + sodium ascorbate (2.5 mM)

H 2O/EtOH (1:3) , 75 °C 1.0 mL/min (contact time: 22 s) (X-Cube TM reactor)

CO2Et N N N

Ph

3aI 14.4 g (87%)


Page 16 of 31

Page 17 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 2


Page 18 of 31

Page 19 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 4


Page 20 of 31

Page 21 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 6


Page 22 of 31

Page 23 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 7



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Artworks for Table 1

PS-PEG-TD2-CuSO 4

Ph + N 3

Ph

(Cu: x mol%) sodium ascarbate (10 mol%) additive

1a

2A

H 2O (1.0 mL), N 2, rt, 12 h

Ph N N N 3aA


Ph

Page 24 of 31

Page 25 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



PS-PEG-TD2-CuSO 4

R

+ R'

N3

R'

(Cu: 5 mol%) sodium ascarbate (10 mol%) H 2O (1.0 mL), N 2, rt, 12 h

1

2

N N N

R

3

N Y

X

CH 2N 3

N3

1h 1a: X = 1b: X = 1c: X = 1d: X = 1e: X =

H OCH3 CH3 F CF3

1i

CH3

2A: Y = H 2B: Y = CH3 2C: Y = CF3

S Y

N3

1j 2D: Y = H

1f

H 3C

1k 1l

1g

1m

2G

(CH 2) 4CH3 2E: Y = CH3

CH3(CH 2) 7 N 3 2H

O C 2H 5OCCH 2 N 3

2F: Y = Cl

CH 2OH COOCH3


2I


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 31


R'



N N N

4-9

Y

CH 2Br 4: 5: 6: 7: 8:

Y= Y= Y= Y= Y=

H CH3 Cl Br NO 2

3

Y

CH 2N 3 2A: Y = 2B: Y = 2K: Y = 2L: Y = 2M: Y =

H CH3 Cl Br NO 2

O C 2H 5OCCH 2Br 9(

2I)


R

Page 27 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



R'



N N N

4-9

Y

CH 2Br 4: 5: 6: 7: 8:

Y= Y= Y= Y= Y=

H CH3 Cl Br NO 2

3

Y

CH 2N 3 2A: Y = 2B: Y = 2K: Y = 2L: Y = 2M: Y =

H CH3 Cl Br NO 2

O C 2H 5OCCH 2Br 9(

2I)


R


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Page 28 of 31

Page 29 of 31


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


R 1 (12.5 or 25 mM) +

R'




N

1f

H 3C

1i

CH3

S

CH 2N 3 2A: Y = H 2B: Y = CH3 2C: Y = CF3

N3 1j 1k 1l

1g

R

3

Y

1h H OCH3 CH3 F CF3

N N N


X 1a: X = 1b: X = 1c: X = 1d: X = 1e: X =

R'

N3

1m

2D

(CH 2) 4CH3 CH 2OH COOCH3

CH3(CH 2) 7 N 3 2H



Page 30 of 31

Page 31 of 31

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



R PS-PEG-TD2-CuSO 4

1 (12.5 or 25 mM) +

R'

(300mg, 0.238 mmol Cu)

R'

N3



H CH3 CF3 (CH 2) 4CH3

COOCH3

1m

3


X 1a: X = 1c: X = 1e X = 1o: X =

N N N

Y

CH 2N 3 2A: Y = H 2N: Y = CH 2OH



R

Batch and Continuous-Flow Huisgen 1,3-Dipolar ... - ACS Publications

Recommend Documents