Accepted Manuscript

Title: A reusable polystyrene-supported copper(II) catalyticsystem for N-arylation of indoles and Sonogashira couplingreactions in water

Author: Kodicherla Balaswamy Perumgani C. PullaiahMandapati Mohan Rao

PII: S0926-860X(14)00420-7DOI: http://dx.doi.org/doi:10.1016/j.apcata.2014.07.001Reference: APCATA 14894

To appear in: Applied Catalysis A: General

Received date: 1-5-2014Revised date: 28-6-2014Accepted date: 1-7-2014

Please cite this article as: K. Balaswamy, P.C. Pullaiah, M.M. Rao, A reusablepolystyrene-supported copper(II) catalytic system for N-arylation of indoles andSonogashira coupling reactions in water, Applied Catalysis A, General (2014),http://dx.doi.org/10.1016/j.apcata.2014.07.001

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A reusable polystyrene-supported copper(II) catalytic system for N-arylation of indoles and Sonogashira coupling reactions in water Kodicherla Balaswamy, Perumgani C. Pullaiah, Mandapati Mohan Rao*

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

*Corresponding author

Tel.: +91-40-27193181; fax: +91-40-27160921

E-mail: mandapati@iict.res.in

Research Highlights:

The synthesized polystyrene-supported copper complex was fully characterized.

This complex exhibited efficient catalytic activity in N-arylation and Sonogashira cross

coupling reactions.

The catalyst can be reused minimum 4 times with slight change in the activity.

Abstract

A polymer–anchored Cu(II) N,N-dimethylethylenediamine complex was prepared and

characterized by various techniques, including Fourier transform infrared spectroscopy

(FTIR), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX),

atomic absorption spectroscopy (AAS), and thermogravimetric analysis (TGA). This

heterogeneous Cu(II) catalyst, efficiently works for the N-arylation of indoles and

Sonogashira coupling of terminal alkynes with aryl iodides in aqueous medium. The effect of

solvent, and base for the C–N, and C–C coupling reactions were reported. Further, the

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catalyst can be easily recovered quantitatively by simple filtration and reused up to four times

without significant loss of its catalytic activity.

Keywords: polystyrene-supported Cu(II) catalyst, N-arylation, Sonogashira cross-coupling,

aryl iodide, aqueous solution

1. Introduction Transition metal-catalyzed aryl-nitrogen and aryl-carbon bond forming via cross-coupling

reactions represent a powerful means for the preparation of various compounds, which have

high utilities in biological, pharmaceutical, and material science [1–4]. Various strategies

were developed for the N-arylation of heterocycles. The Ullmann-type coupling of aryl

halides with nitrogen heterocycles represents a straightforward and inexpensive approach to

N-aryl nitrogen heterocycles [5–7]. The efficiency of copper-catalyzed Ullmann reactions

was improved by the correct choice of copper sources, bases, ligands, and other additives in

the past few years; several mild and efficient methods were reported for the N-arylation of

indoles [8–10]. Although this copper-catalyzed N-arylation of indoles or other heterocycles

are highly efficient, the problem with homogeneous catalysis is the difficulty to separate

catalyst from the reaction mixture. To overcome this, the development of a highly efficient

and recyclable heterogeneous catalyst, by immobilization of catalytically active species, i.e.,

organometallic complexes, onto a solid support is essential [11]. Till date, many

heterogeneous copper catalytic systems were developed for the cross-coupling reactions, such

as Merrifield resin supported phenanthroline copper(I) complex [12], immobilized copper in

organic-inorganic hybrid material [13], immobilized copper in MCM-41 [14], copper ferrite

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nanoparticles [15], [Cu30I16(mtpmt)12(µ10-S4)] [16], Al2O3-supported Cu(II) catalyst [17],

glycerol ingrained copper [18], nano copper oxide catalyst [19], and polymer supported

copper(II) catalyst [20].

The Sonogashira-type coupling between terminal alkynes with aryl halides is commonly

employed for the synthesis of molecules containing acetylenic moiety. Homogeneous copper

catalysis has been reported for cross-coupling reactions [21,22]. Generally, various ligands

are applied for effective coupling reactions. Recently, Bolm and co-workers have

demonstrated that the coupling of aryl iodides and terminal alkynes could readily be

performed by using a sub-loaded amount of [Cu(DMEDA)2]Cl2·H2O [23,24]. Thus,

compared to palladium-copper, the lone copper catalyst is more attractive and considered to

be a better choice for the coupling of aryl halides and terminal alkynes [25–27]. The copper

catalyst together with bis-nitrogen compounds such as 1,10-phenanthroline [28,29], and

ethylenediamine [30] are effective catalytic systems for alkynylation of aryl halides.

Recently, we have reported homogeneous thiopseudourea Pd(II) complex as catalyst for the

cross-coupling reactions [31,32].

Polystyrene is also one of the most popular polymeric supports used in synthetic organic

chemistry because of its low cost, ready availability, chemical inertness, and facile

functionalization. In recent years, a variety of aqueous catalytic systems and polymer-

supported metal catalysts for the C–C coupling reactions were reported [33–35]. From the

standpoint of environmentally benign organic synthesis, the development of highly active and

easily reusable immobilized catalysts in aqueous media is of great interest to chemists.

However, to the best of our knowledge, no reports are available on N-arylation of indoles

and Sonogashira coupling reactions catalyzed by polystyrene-supported Cu(II) complex.

Herein, we report the synthesis and characterization of new polystyrene-supported copper

complex catalyst and its application to cross-coupling reactions in water.

2. Experimental All reagents and substrates were purchased from Aldrich. Chloromethylated polystyrene

(5.5mmol /g Cl loading, crosslinked with 5.5% DVB (divinylbenzene), particle size 16-50

mesh) was purchased from Aldrich Chemical Company. CuBr2 was procured from Merck

and used without further purification.

2.1. Preparation of Polymer-Bound N, N-dimethylethylenediamine 2

A polymeric ligand was prepared by the following procedure reported in the literature

[36]. A 250 mL round-bottom flask equipped with a magnetic stirrer was charged with

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CH3CN (100 mL). To this chloromethylated polystyrene (0.5g, 2.25 mmol/Cl), N,N-

dimethylethylenediamine (2.3 mL, 22.5 mmol) 1, and NaI (14.9 mg, 0.1 mmol) were added

and the mixture was refluxed for 48 h. The mixture was filtered and the residue was washed

sequentially with CH3CN (3×20 mL), 1:1 CH3OH-1 M aq K2CO3 (3×20 mL), 1:1 CH3OH-

H2O (3×20 mL), and Et2O (3×10 mL), and then dried in an oven.

2.2. Preparation of polystyrene-supported Cu(II) complex 3

To the polystyrene-supported ligand EtOH (100 mL) was added and kept for 30 min. A

solution of CuBr2 (0.5g) in EtOH (10 mL) was then added, and the mixture was kept at 50 °C

for 6 h. The brown coloured complex, impregnated with the metal, was filtered, washed

thoroughly with EtOH (3×30 mL), and finally dried in vacuum at 70 °C for 24 h.

2.3. General experimental procedure for N-arylation reaction

The catalyst 3 (30 mg, 0.03 mmol of Cu), indole (1.0 mmol), aryl halides (1.2 mmol),

K2CO3 (276 mg, 2 mmol), cetyltrimethylammonium bromide (36 mg, 0.1 mmol), and water

(3 mL) were added to a reaction vessel. The mixture was stirred at 110 oC for 10 h, then

cooled to room temperature and catalyst was filtered, the filtrate was extracted with ethyl

acetate (3×10 mL). The combined organic layers were extracted with water, saturated brine

solution, and dried over anhydrous Na2SO4. The organic layers were evaporated under

reduced pressure and the resulting crude product was purified by column chromatography by

using ethyl acetate/hexane (1:4) as eluent to give the corresponding N-substituted indoles.

2.4. General experimental procedure for Sonogashira cross-coupling reaction

In a typical reaction, a mixture of aryl halides (1.2 mmol), phenylacetylene (1.5 mmol),

K2CO3 (276 mg, 2 mmol), cetyltrimethylammonium bromide (36 mg, 0.1 mmol), H2O (3

mL) and catalyst 3 (30 mg, 0.03 mmol of Cu) was stirred at 110 oC for 10 h, then cooled to

room temperature, filtered and washed with ethyl acetate (3×10 mL). The combined organic

layers were extracted with water, saturated brine solution, and dried over anhydrous Na2SO4.

The organic layers were evaporated under reduced pressure and the resulting crude product

was purified by column chromatography by using ethyl acetate/hexane (1:9) as eluent to give

the corresponding product. All the products were confirmed by 1H, 13C NMR, and mass

spectroscopic analysis. See the Supporting Information for full details.

3. Results and discussion 3.1. Catalyst characterization

Due to insolubilities of the polymeric Cu(II) catalyst in all common organic solvents, its

structural investigation was limited to its physicochemical properties, FTIR, SEM, EDX,

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TGA and AAS spectroscopic data. Polymeric ligand 2 was prepared by treating

chloromethylated polystyrene with N,N-dimethylethylenediamine 1 in refluxing acetonitrile

for 48 h. The product 2 was characterized by FTIR. Then, the ligand-functionalized

polystyrene-supported Cu(II) complex 3 was prepared by a suspension of 2 in a ethanolic

solution of CuBr2 at 50 oC for 6 h (Scheme 1). The catalyst 3 was characterized by FT-IR,

SEM-EDX, and AAS. The amount of copper incorporated into the polymer was determined

by atomic absorption spectroscopy (AAS), which showed a value of 6.22% (0.98 mmol/g).

(Scheme 1)

In the IR spectrum (Fig. S1a, supporting information) of chloromethylated polystyrene a

sharp C–Cl peak (corresponding to –CH2Cl groups) at 670 cm–1 and a peak at 1263 cm–1

(corresponding to H–C–Cl wagging modes in the starting polymer) were observed. The

absence of above peaks in the polymer-bound N,N-dimethylethylenediamine (Fig. S1b)

indicates the bonding of polymer to the ligand. In the IR spectrum of catalyst 3, a slight shift

of peaks toward higher wave number was observed, indicating the metal complex formation

on the surface of the polymer (Fig. S1c).

Morphological features of the polymeric ligand and Cu(II) complex were investigated by

making use of scanning electron microscopy. SEM-EDX of the polymeric ligand and its

Cu(II) complex are given in Fig. 1. The scanning electron micrographs (Fig. 1, A&C) of the

polymer supported ligand and Cu(II) catalyst clearly show the morphological change which

occurred on the surface of polystyrene after loading of metal on it. The voids/channels

present in the polymeric ligand might be due to the swelling of polymer or the reactivity of

active sites buried in the polymer matrix. The presence of white flakes on the surface

indicates the formation of polymer supported Cu(II) complex (Fig. 1C). Energy dispersive X-

ray spectroscopy (EDX) analysis data for the polymer anchored ligand and copper catalyst

are given in Fig. 1 (B&D). The EDX spectrum shows the presence of copper in the complex.

Thermal stability of the complex was investigated by TGA. The negligible weight loss

below 200 ºC is due to the physically adsorbed solvent molecules. Thermogravimetric

analysis shows stability of the complex 3 up to 350 ºC and further weight loss at a higher

temperature (above 350 ºC) was attributed to the decomposition of complex Fig. S2

(supporting information). Activity of the Cu(II) complex 3 was tested for N-arylation, and

Sonogashira coupling reactions.

(Fig. 1)

3.2. Catalytic N-arylation and Sonogashira reactions

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Initial studies were performed upon the N-arylation reaction of iodobenzene with indole

and phenylacetylene with iodobenzene (Sonogashira coupling) as a model reactions using 3

(30 mg, 0.03 mmol of Cu) as the catalyst in water at 110 oC for 10 h (Table 1). From the

results shown in the table, we derive that among the bases, additives and different water

miscible solvents employed the K2CO3, CTAB and water system is optimum for C–N and C–

C coupling reactions (Table 1, entry 1). When the reactions were done without catalyst, the

reaction did not proceed (Table 1, entry 11). The reactions of N-arylation of indole and

Sonogashira coupling of phenylacetylene with bromobenzene were carried out at optimised

conditions to give the corresponding products in 30% and 38% yield, respectively (Table 1,

entry 12). It should be noted that the coupling reactions of the chlorobenzene also took place

under similar conditions (Table 1, entry 13), though the reactivity was much lower than their

iodo and bromo counterparts.

(Table 1)

Using the optimized reaction conditions, we explored the general applicability of catalyst

3 with indoles and aryl iodides containing electron withdrawing or donating substituents, and

the results were summarized in Table 2. We were pleased to find out that all reactions

afforded the desired coupling products in excellent yields within 10 h, and the substituent,

either an electron-donating group such as methoxy group (Table 2, entry 6) or an electron

withdrawing group such as Cl, NO2, or COCH3 (Table 2, entries 5, 7 and 8) on the para

position of phenyl ring had almost no significant effect on these reactions.

(Table 2)

Furthermore, under the aforementioned optimized condition, we investigated the

usefulness of catalyst 3 for the Sonogashira cross-coupling reaction. When the reaction of

phenylacetylene with iodobenzene was performed 85% yield of the product was obtained

(Table 3, entry 1). We explored the scope of the catalyst for phenylacetylene with aryl

iodides containing electron withdrawing or donating substituents. Iodobenzene having

electron deficient groups (p-Cl, CF3, NO2, COCH3, and o-CHO) underwent the Sonogashira

coupling with phenylacetylene under similar conditions to afford the corresponding

biarylacetylenes in 83%, 84%, 80%, 78%, and 66% yield, respectively (Table 3, entries 2–5,

and 9). The Sonogashira coupling of iodobenzene bearing electron donating groups (p-CH3,

OCH3, m-CH3, and o-CH3) also gave the corresponding biarylacetylenes in 82%, 76%, 78%

and 75% yield, respectively (Table 3, entries 6–8 and 10).

(Table 3)

3.3. Recyclability test

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The reusability of the catalyst is a very important theme, especially for commercial

applications. Therefore, the recovery and reusability studies of the catalyst were done by

conducting the reaction of iodobenzene with indole (N-arylation), and iodobenzene with

phenylacetylene (Sonogashira reaction). Not much decrease in the activity of catalyst was

observed even after 4 cycles (Fig. 2).

(Fig. 2)

To determine the degree of leaching of the copper from the heterogeneous catalyst, the

catalyst was removed by filtration and the copper content of the filtrate was determined by

AAS. During the course of N-arylation and Sonogashira coupling reactions, 0.2% and 0.4%

of copper was lost into solution after the first run respectively. After four recycles loss of 5%

(N-arylation), and 7% (Sonogashira reaction) were observed.

3.4. Heterogeneity test

To determine whether the catalyst is actually functioning in a heterogeneous manner, a

hot-filtration test was performed in the N-arylation reaction of indole with iodobenzene, the

solid catalyst was filtered out after the reaction proceeded for 6 h. The liquid phase of the

reaction mixture was collected at the reaction temperature. After the workup with

ethylacetate, the obtained aqueous solution was reused for fresh reaction, stirred under the

same reaction conditions. After 10 h, the reaction mixture was cooled and extracted with

ethylacetate. No product formation was observed (monitored by thin layer chromatography).

This shows that the reaction was caused by the heterogeneous catalyst only.

4. Conclusion We developed a clean and safe protocol for the N-arylation and Sonogashira reactions

catalyzed by the 3 complex. The present system is highly air and moisture stable and the

catalyst can be synthesized readily from inexpensive and commercially available starting

materials. Moreover, the catalyst could be reused for four consecutive cycles without a

noticeable loss of its catalytic activity. These advantages make the process highly valuable

from the synthetic and environmental points of view.

Acknowledgement

KB acknowledges CSIR, New Delhi, for providing his senior research fellowship. PCP

acknowledges CSIR-UGC, New Delhi, for his junior research fellowship.

Appendix A. Supplementary data

Supplementary data to this article can be found online at doi:

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Scheme Captions:

Scheme 1. Preparation of polystyrene-supported Cu(II) complex 3.

Figure Captions:

Figure 1. SEM-EDX of polystyrene-supported N,N-dimethylethylenediamine ligand (A&B)

and polystyrene-supported Cu(II) complex 3 (C&D).

Figure 2. Catalyst recyclability test Table Captions:

Table 1

Screening reaction conditions for N-arylation and Sonogashira cross-coupling.

Table 2

N-arylation of indoles with different aryl iodides catalyzed by polystyrene-supported Cu(II)

complex 3.

Table 3

Sonogashira coupling reactions of phenylacetylene with different aryl iodides catalyzed by

polystyrene-supported Cu(II) complex 3.

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N NH2

Cl

N NH

CuBr2EtOH50 oC, 6 h

NaI, CH3CN, Reflux, 48 h

N

Cu

NH

BrBr

1 2

3

Scheme 1. Preparation of polystyrene-supported Cu(II) complex 3.

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Fig. 1. SEM-EDX of polystyrene-supported N, N-dimethylethylenediamine ligand (A&B)

and polystyrene-supported Cu(II) complex 3 (C&D). Table 1 Screening reaction conditions for N-arylation and Sonogashira cross-coupling.

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N

catalyst 3

base, solvent, additive110 oC, 10 h

Entry SolventBaseYield (%)a

1 H2OK2CO3

AdditiveeCTAB 82

2 K2CO3 H2O fTBAB 78

3 K2CO3 H2O gTBAI 68

4 K2CO3 H2O hPEG-400 66

5

6

7

8

9

10

K2CO3

K2CO3

K2CO3

K2CO3

H2O+ DMSO (1:1)

H2O+ DMF(1:1)

H2O+ CH3CN(1:1)

H2O+ THF (1:1)

CTAB

CTAB

CTAB

CTAB

76

74

68

trace

Na2CO3

KOAc

CTAB

CTAB

75

56

Reaction conditions: iodobenzene (1.2 mmol), indole (1 mmol), phenylacetylene (1.5 mmol), base (2 mmol), solvent (3 mL), catalyst 3 (30 mg, 0.03 mmol/Cu), additive (0.1 mmol) 110 oC, 10 h. a Isolated yield. b Without catalyst. c Reaction was done by bromobenzene (1.2 mmol), 110 oC, 10 h.d Reaction was done by chlorobenzene (1.2 mmol), 110 oC, 24 h.eCTAB= Cetyltrimethylammonium bromide. fTBAB= Tetrabutylammonium bromide.gTBAI= Tetrabutylammonium iodide. hPEG-400= Polyethylene glycol 400.

H2O

H2O

A

B

NH

A B

85

80

72

68

78

75

70

trace

76

60

11b K2CO3 H2O CTAB _ _

12c K2CO3 H2O CTAB 30 38

13d K2CO3 CTAB _H2O _

Table 2 N-arylation of indoles with different aryl iodides catalyzed by polystyrene-supported Cu(II) complex 3.

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NH

NAr

R2 R2

catalyst 3

K2CO3, CTAB, H2O

110 oC, 10 h

Entry R1 Yield (%)aArI

ArI

1 H I 82

2 H

3 H

4 H

5 H

6 H

7 H

8 H

I

I

I

I

I

I

I

H3C

CH3

CH3

Cl

OCH3

NO2

COCH3

I

I

I

I

I

R1R1

H

H

H

H

H

H

H

H

R2

9 2-CH3

10 H

11 H

12 H

13 3-CH3

H

5-NO2

5-CH3

5-OCH3

H

66

77

75

83

81

82

82

71

74

73

75

73

Reaction conditions: indoles (1 mmol), aryl iodides (1.2 mmol), catalyst 3 (30 mg, 0.03 mmol), K2CO3 (2 mmol), CTAB (0.1 mmol), water (3 mL), 110 oC, 10 h.aIsolated Yield.

Table 3 Sonogashira coupling reactions of phenylacetylene with different aryl iodides catalyzed by polystyrene-supported Cu(II) complex 3.

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CF3

COCH3

CH3

OCH3

NO2

CH3

H3CO

OHC

Icatalyst 3

K2CO3, CTAB, H2O110 oC, 10 h

R3R3

Entry R3 Product Yield (%)a

1 H

2 4-Cl Cl

3

4

5

6

7

8

9

10

4-CF3

4-NO2

4-COCH3

4-CH3

4-OCH3

3-CH3

2-CHO

2-OCH3

85

83

84

80

78

82

76

78

66

75

Reaction conditions: phenylacetylene (1.5 mmol), aryl iodides (1.2 mmol), catalyst 3 (30 mg, 0.03 mmol), K2CO3 (2 mmol), CTAB (0.1mmol), water (3 mL), 110 oC, 10 h.aIsolated yield.

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Fig. 2. Catalyst recyclability test

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A reusable polystyrene-supported copper(II) catalytic system for

N-arylation of indoles and Sonogashira coupling reactions in water

Kodicherla Balaswamy, Perumgani C. Pullaiah, Mandapati Mohan Rao*

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

e-mail:mandapati@iict.res.in