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Received: 19 May 2014 Revised: 11 June 2014 Accepted: 29 June 2014 Published online in Wiley Online Library

(wileyonlinelibrary.com) DOI 10.1002/aoc.3193

Polymer-anchored copper(II) complex: anefficient reusable catalyst for the synthesis ofpropargylaminesBalaswamy Kodicherla, Pullaiah C. Perumgani and Mohan Rao Mandapati*

A new, heterogeneous, polymer-supported copper(II) complex was prepared and characterized using various techniques,including Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, atomic

absorption spectroscopy and thermogravimetric analysis. This heterogeneous copper catalyst is efficient for the synthesis ofpropargylamines via a three-component coupling reaction of aldehydes, amines and alkynes. The effect of solvent on thecoupling reactions was investigated. Further, the catalyst can be easily recovered quantitatively by simple filtration and reusedfor a minimum number of cycles without significant loss of its catalytic activity. Copyright © 2014 John Wiley & Sons, Ltd.

Additional supporting information may be found in the online version of this article at the publisher’s web-site.

Keywords: polymer-anchored copper(II) catalyst; propargylamine; aldehyde; amine; alkyne

* Correspondence to: Mohan Rao Mandapati, Inorganic and Physical Chemistry,Indian Institute of Chemical Technology, India. E-mail: mandapati@iict.res.in

I&PC Division, Indian Institute of Chemical Technology, Hyderabad - 500 607,India

Introduction

Transition metal-catalysed three-component coupling of analdehyde, an amine and an alkyne, commonly known as A3

coupling, has been established as a convenient and generalapproach towards propargylamines.[1] The resultant propargy-lamines obtained from the A3 coupling reaction are versatile in-termediates for organic synthesis[2,3] and important structuralelements of natural products and drug molecules.[4–7]

Propargylamines are traditionally synthesized by the nucleo-philic attack of lithium acetylides or Grignard reagents on iminesor their derivatives.[8–10] However, these methods require theuse of stoichiometric amounts of organometallic reagents andharshly controlled reaction conditions which limit their use. So,further modifications have been made for the synthesis ofpropargylamines and their derivatives. Correspondingly, homoge-neous catalysts such as Cu(I)/Cu(II),[11–14] Ag,[15–17] Au,[18,19] Ir,[20,21]

Zn,[22–24] Ni,[25] Co[26] and Bi[27] have been applied for the A3

coupling reactions. However, using homogeneous catalysts bringsinherent complications in catalyst separation and reuse. In orderto overcome this drawback, heterogeneous catalysts due to theirthermal stability, reusability and high catalytic activities have beenwidely investigated for A3 coupling reactions.[28–35]

At present, chloromethylated polystyrene is one of themost popular polymeric supports used in the preparationof heterogeneous transition metal complexes because of itslow cost, ready availability, chemical inertness and facilefunctionalization. In recent years, a variety of polymer-supported metal catalytic systems for cross-coupling reac-tions were reported.[36–43]

Herein, we report a polymer-anchored copper(II) complex as anew heterogeneous catalyst for the synthesis of propargylamines.There is no report on the usage of this copper catalyst for thesynthesis of propargylamines by the A3 coupling reaction ofaldehydes, alkynes and amines. Here we report the synthesisand characterization of a polymer-anchored copper(II) N,N-

Appl. Organometal. Chem. (2014)

dimethylethylenediamine complex along with its catalytic activityfor the A3 coupling reaction to generate propargylamines.

Experimental

All reagents and substrates were purchased from Aldrich.Chloromethylated polystyrene (5.5mmolg�1 Cl loading, crosslinkedwith 5.5% divinylbenzene, particle size 16–50mesh) was purchasedfrom Aldrich Chemical Company. CuBr2 was procured from Merckand used without further purification.

Preparation of Polymer-BoundN,N-dimethylethylenediamine (2)

The polymer-supported ligand was prepared following a proce-dure reported in the literature.[44] A 250ml round-bottom flaskequipped with a magnetic stirrer was charged with CH3CN(100ml). To this were added chloromethylated polystyrene(0.5 g, 2.25mmol/Cl), N,N-dimethylethylenediamine (1; 2.3ml,22.5mmol) and NaI (14.9mg, 0.1mmol) and the mixture wasrefluxed for 48 h. The mixture was filtered and the residue waswashed sequentially with CH3CN (3 × 20ml), 1:1 CH3OH–1M aq.K2CO3 (3 × 20ml), 1:1 CH3OH–H2O (3 × 20ml) and Et2O(3 × 10ml). It was then dried in an oven.

Preparation of Polystyrene-Supported Metal Complex (3)

To the polystyrene-supported ligand, EtOH (100ml) was addedand kept for 30min. A solution of CuBr2 (0.5 g) in EtOH (10ml)

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Scheme 1. Preparation of polystyrene-supported copper complex 3.

K. Balaswamy et al.

was then added, and the mixture was kept at 50°C for 6 h. Thebrown-coloured complex 3 impregnated with the metal wasfiltered, washed thoroughly with EtOH (3 × 30ml) and finallydried in vacuum at 70°C for 24 h.

General Experimental Procedure for A3 Coupling Reaction

To a mixture of aromatic aldehyde (1.0mmol), amine (1.1mmol) andphenylacetylene (1.1mmol) in toluene (5ml) was added the catalyst3 (30mg, 0.03mmol of Cu) and the solution was stirred at 110°C for6h. After the completion of reaction (as monitored using TLC), thetoluene was removed under reduced pressure. The crude mixturewas purified by column chromatography (EtOAc–petroleum ether,1:4) to afford the pure product. The known products were confirmedfrom 1H NMR, 13C NMR and mass spectra.

Analytical Data of New Compounds

3-(1-Morpholino-3-phenylprop-2-ynyl)benzonitrile (Table 2, entry 16)

Orange oily liquid. IR (KBr, cm�1): 2958, 2856, 2230, 2106, 1719,1601, 1449, 1264, 1114, 1003, 758, 690. 1H NMR (300MHz, CDCl3,Me4Si, δ, ppm): 7.98 (s, 1H, C2―H), 7.92 (d, J= 7.9 Hz, 1H, C4―H),7.60 (d, J= 7.6 Hz, 1H, C6―H), 7.53–7.46 (m, 3H, C5―H, C2′―Hand C6′―H), 7.36–7.34 (m, 3H, C3′―H, C4′―H and C5′―H), 4.83 (s,1H, ―CH―N), 3.78–3.72 (m, 4H, ―CH2OCH2―), 2.67–2.60 (m, 4H,―CH2NCH2―). 13C NMR (75MHz, CDCl3, δ, ppm): 139.5 (C3), 132.7(C4), 131.9 (C2), 131.6 (C2′ and C6′), 131.3 (C6), 128.9 (C5), 128.5(C4′), 128.2 (C3′ and C5′), 122.1 (C1′), 118.7 (C�N), 112.2 (C1),89.5 (―C�C―Ph), 83.0 (―C�C―Ph), 66.8 (―CH2OCH2―),61.0 (―C―N―), 49.5 (―CH2NCH2―). ESI-MS (m/z): (M +H)+ =303. Anal. Calcd for C20H18N2O (%): C, 79.44; H, 6.00; N, 9.26.Found (%): C, 78.97; H, 6.12; N, 9.38.

4-(1-Morpholino-3-phenylprop-2-ynyl)benzonitrile (Table 2, entry 17)

Orange solid; m.p. 78–80°C. IR (KBr, cm�1): 2967, 2859, 2221,2109, 1717, 1607, 1446, 1271, 1117, 1003, 762, 694. 1H NMR(300MHz, CDCl3, Me4Si, δ, ppm): 7.80 (d, J=8.0 Hz, 2H, C2―Hand C6―H), 7.67 (d, J=8.3 Hz, 2H, C2′―H and C6′―H), 7.52–7.51(m, 2H, C3′―H and C5′―H), 7.36–7.34 (m, 3H, C3―H, C5―H andC4′―H), 4.84 (s, 1H, ―CH―N), 3.77–3.72 (m, 4H, ―CH2OCH2―),2.66–2.60 (m, 4H, ―CH2NCH2―). 13C NMR (75MHz, CDCl3,δ, ppm): 143.4 (C4), 132.0 (C2 and C6), 131.7 (C2′ and C6′), 129.1(C3 and C5), 128.6 (C4′), 128.3 (C3′ and C5′), 122.3 (C1′), 118.7(C�N), 111.6 (C1), 89.6 (―C�C―Ph), 83.2 (―C�C―Ph), 66.9(―CH2OCH2―), 61.6 (―C―N―), 49.7 (―CH2NCH2―). ESI-MS(m/z): (M+H)+ = 303. Anal. Calcd for C20H18N2O (%): C, 79.44; H,6.00; N, 9.26. Found (%): C, 79.52; H, 5.89; N, 9.16.

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Results and Discussion

Catalyst Characterization

Polystyrene-bound ligand 2 was prepared by treating chloro-methylated polystyrene with 1 under acetonitrile reflux for 48 h.The product 2 was characterized using FT-IR spectroscopy. Then,the ligand-functionalized polystyrene-supported copper(II) com-plex 3 was prepared by reacting a suspension of 2 in a solutionof CuBr2 in EtOH at 50°C for 6 h (Scheme 1). The catalyst 3 wascharacterized using FT-IR spectroscopy, scanning electron micros-copy (SEM) coupled with energy dispersive X-ray spectroscopy(EDX) and atomic absorption spectroscopy (AAS). The amount ofcopper incorporated into the polymer was determined usingAAS, which showed a value of 6.22% (0.98mmol g�1).

In the FT-IR spectrum (Fig. S1a, supporting information) ofchloromethylated polystyrene, a sharp C―Cl peak (correspondingto ―CH2Cl groups) at 670 cm

�1 and a peak at 1263 cm�1 (corre-sponding to H―C―Cl wagging modes in the starting polymer)are observed. The absence of these peaks in the spectrum of2 (Fig. S1b) indicates the bonding of polymer to ligand. In theFT-IR spectrum of catalyst 3, a slight shift of peaks towards higherwavenumber is observed, indicating metal complex formationon the surface of the polymer (Fig. S1c). The SEM images of 2and 3 clearly show the morphological difference betweenligand and complex. The existence of the copper metal is fur-ther proved using EDX analysis (Fig. 1). The thermal stabilityof the complex was investigated using thermogravimetricanalysis (TGA). The negligible weight loss below 200°C isdue to the physically adsorbed solvent molecules. TGA showsthe stability of the complex 3 up to 350°C and further weightloss at a higher temperature (above 350°C) is attributed to thedecomposition of the complex (Fig. S2, supporting information).The activity of the copper complex 3 was tested for A3

coupling reactions.

Catalytic A3 Coupling Reaction

After the successful preparation and characterization of complex3, we examined its catalytic activity for the multicomponentcoupling of aldehydes, amines and alkynes. In order to establishthe optimum conditions, the catalytic activity of complex 3 wasexamined in a model reaction using benzaldehyde, piperidineand phenylacetylene under solvent reflux conditions (Table 1).Complex 3 is found to be the most effective catalyst in terms ofreaction rate and isolated yield of the corresponding product intoluene at 110°C for 6 h (Table 1, entry 1). When the A3 couplingreaction is carried out in other solvents, such as DMF, DMSO,acetonitrile, THF or dichloroethane (DCE), a significant decreasein yield is noticed. When polar protic solvents are applied, only

ohn Wiley & Sons, Ltd. Appl. Organometal. Chem. (2014)

10 µm

10 µmkeV

keV

C)

A) B)

D)

Figure 1. SEM-EDX analysis of (A, B) polystyrene-supported N,N-dimethylethylenediamine ligand 2 and (C, D) polystyrene-supported copper complex 3.

Table 1. Screening of reaction conditions for A3 couplinga

Entry Solvent Yield (%)b

1 Toluene 85

2 Water Trace

3 DMF 48

4 DMSO 50

5 Acetonitrile 36

6 THF 22

7 Ethanol Trace

8 Methanol Trace

9 DCE 46

10 Toluene 85c

11 Toluene 65d

aReaction conditions: benzaldehyde (1mmol), piperidine(1.1mmol), phenylacetylene (1.1mmol), complex 3 (30mg,0.03mmol), reflux, 6 h.

bIsolated yield.cComplex 3: 40mg, 0.04mmol of Cu.dComplex 3: 10mg, 0.01mmol of Cu.

Polymer–copper(II) complex-catalysed A3 coupling reactions

Appl. Organometal. Chem. (2014) Copyright © 2014 John W

a trace amount of product is observed (Table 1, entries 2, 7 and8). We also studied the effect of catalyst 3 loading (Table 1,entries 10, 11). Thus, the optimized reaction conditions for theA3 coupling reaction are: 0.03mmol catalyst based on copper,toluene solvent and a temperature of 110°C.

The applicability of catalyst 3 was tested for the A3 couplingreaction of secondary amines and aldehydes. The results aresummarized in Table 2. It can be seen from these results thataromatic aldehydes with an electron-withdrawing group (Table 2,entries 4–8, 13 and 16–18) afford high yields compared toelectron-donating groups (Table 2, entries 2, 3, 9–11, 14 and15). The coupling reaction proceeds readily and smoothly to pro-vide the corresponding propargylamines in good to excellentyields using various amines. Among the various amines studied,piperidine gives superior yields compared with morpholine.

Recyclability Test

The reusability of the catalyst is a very important issue, especially forcommercial applications. Therefore, recovery and reusability studiesof the catalyst were done by conducting the reaction of benzalde-hyde, piperidine and phenylacetylene. Not much decrease in theactivity of the catalyst is observed even after five cycles (Fig. 2).

To determine the degree of leaching of the copper from theheterogeneous catalyst, the catalyst was removed by filtrationand the copper content of the filtrate was determined usingAAS. During the course of A3 coupling reactions, 0.3% of copperis lost into solution after the first run. After five recycles, a lossof 6% is observed.

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Figure 2. Catalyst recyclability test.

Table 2. Synthesis of propargylamines via A3 coupling reactionsa

Entry R Amine Yield (%)b

1 C6H5 Piperidine 85

2 3-CH3C6H5 Piperidine 70

3 4-CH3C6H5 Piperidine 78

4 4-ClC6H5 Piperidine 82

5 2-FC6H5 Piperidine 82

6 4-FC6H5 Piperidine 95

7 2-BrC6H5 Piperidine 81

8 4-BrC6H5 Piperidine 82

9 2-OCH3C6H5 Piperidine 68

10 4-OCH3C6H5 Piperidine 65

11 4-CF3C6H5 Piperidine 64

12 C6H5 Morpholine 82

13 4-FC6H5 Morpholine 90

14 4-CH3C6H5 Morpholine 78

15 4-OCH3C6H5 Morpholine 66

16 3-CNC6H5 Morpholine 78

17 4-CNC6H5 Morpholine 80

18 2-BrC6H5 Morpholine 81

aReaction conditions: aldehyde (1.0mmol), phenylacetylene (1.1mmol),amine (1.1mmol), complex 3 (30mg, 0.03mmol of Cu), toluene(5ml) at 110°C, 6h.

bIsolated yield.

K. Balaswamy et al.

Conclusions

We developed a highly efficient copper complex-catalysed three-component coupling of aldehyde, alkyne and amine via C―Hactivation. The process is simple and generates a diverse rangeof propargylamines in good yields. Moreover, the catalyst canbe reused for a minimum number of consecutive cycles withouta noticeable loss of its catalytic activity. These advantages makethe process highly valuable from synthetic and environmentalpoints of view.

Acknowledgements

KB acknowledges CSIR, New Delhi, for providing a senior researchfellowship. PCP acknowledges CSIR-UGC, New Delhi, for a juniorresearch fellowship.

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Supporting Information

Additional supporting information may be found in the onlineversion of this article at the publisher’s web-site.

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