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공학석사학위논문

Microwave-Assisted C-C Coupling Reaction

using Polymer-supported Electron-Rich

Oxime Palladacycles in Aqueous Condition

전자가 풍부한 옥심 팔라다싸이클 수지를 이용한 수용액상의

마이크로파 탄소-탄소 짝지음 반응

2014년 2월

서울대학교 대학원

화학생물공학부

박 성 준

전자가 풍부한 옥심 팔라다싸이클 수지를 이용한 수용액상의

마이크로파 탄소-탄소 짝지음 반응

Microwave-Assisted C-C Coupling Reaction using

Polymer-supported Electron-Rich Oxime Palladacycles

in Aqueous Condition

지도교수 이 윤 식

이 논문을 공학 석사 학위논문으로 제출함

2014년 2월

서울대학교 대학원

화학생물공학부

박 성 준

박성준의 석사 학위논문을 인준함

2014 년 2 월

위 원 장 김영규 (인)

부 위 원 장 이윤식 (인)

위 원 이종찬 (인)

i

Abstract

Microwave-Assisted C-C Coupling Reaction

using Polymer-supported Electron-Rich

Oxime Palladacycles in Aqueous Condition

Sung Jun Park

Chemical and Biological Engineering

The Graduate School

Seoul National University

Oxime palladacycles are highly active palladium catalysts for C-C

coupling reactions, and possess advantages such as easy preparation,

and air, moisture stability. Previously, electron-rich oxime

palladacycle on polymer support has been prepared to provide

efficient C-C coupling activity and reusability of the catalyst for green

purposes. For water-based Suzuki coupling reaction, microwave

chemistry was applied to polymer-supported oxime palladacycle

system. Suzuki reaction of aryl halide and heterocyclic halide with

phenylboronic acid was successfully performed using polymer-

supported electron-rich oxime palladacyles under the microwave

system to acquire reaction products in water medium.

Keywords : Oxime palladacycle, Microwave, Suzuki-Miyaura

Reaction

Student number : 2012-20944

ii

TABLE OF CONTENTS

Abstract ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• i

List of Abbreviations ••••••••••••••••••••••••••••••••••••••••••••••••••••••••• v

List of Figures ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• vi

List of Tables •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• vii

List of Schemes •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• vii

1. Introduction ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 1

1.1. Electron-rich Oxime Palladacycle •••••••••••••••••••••••••••••••••••••••••••• 1

1.2. Microwave Application for Efficient Catalysis ••••••••••••••••••••••• 4

1.3. C-C Coupling Reactions in Water using Electron-rich Oxime

Palladacycle ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7

1.4. Research Objectives ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 8

2. Experimental Section •••••••••••••••••••••••••••••••••••••••••••••••••••• 9

2.1. General ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9

2.1.1. Materials •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9

2.1.2. Instrument ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9

2.2. Preparation of Electron-Rich Oxime Palladacycle Resins

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 11

2.2.1. Immobilization of 4′-Hydroxy-3, 5-Dimethoxyacetophenone

iii

Derivatives on CM PS •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 11

2.2.2. Preparation of Oxime Resins••••••••••••••••••••••••••••••••••••••••••••••••••••• 11

2.2.3. Preparation of Palladium Loaded Oxime Resins••••••••••••••••••• 12

2.3. Suzuki Coupling Reactions Catalyzed by Electron-Rich

Oxime Palladacycle Resins •••••••••••••••••••••••••••••••••••••••••••••••••• 13

2.3.1. Optimization of Suzuki Coupling Reactions ••••••••••••••••••••••••• 13

2.3.2. General Experimental Procedure for Suzuki Coupling Reac-

tion of Aryl Halides with Phenylboronic Acid•••••••••••••••••••••• 13

2.3.3. Reaction Profile of Suzuki Coupling Reaction using the

Microwave and Oil Bath••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 14

2.3.4. Reusability Test of Electron-Rich Oxime Palladacycle Resins

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 15

3. Results and Discussion •••••••••••••••••••••••••••••••••••••••••••••••• 16

3.1. Preparation and Characterization of Electron-Rich Oxime

Palladacycle Resins •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 16

3.1.1. Preparation of Oxime Resins ••••••••••••••••••••••••••••••••••••••••••••••••••••• 16

3.1.2. Characterization of Electron-Rich Oxime Palladacycle Resin

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 19

3.2. Suzuki Coupling Reaction Catalyzed by Electron-Rich Oxime

Palladacycle Resins•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 21

3.2.1. Effectes of Solvents and Bases in Suzuki Coupling Reaction

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 21

iv

3.2.2. Reaction Profile Comparison of Suzuki Coupling Reaction

by Microwave Heating and Conventional Heating ••••••••••••• 26

3.2.3. Suzuki Coupling Reaction of Various Aryl Halides with

Phenylboronic Acid ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 28

3.2.4. Suzuki Coupling Reaction of Various Aryl Halides with

Phenylboronic Acid in Water ••••••••••••••••••••••••••••••••••••••••••••••••••••• 31

3.2.5. Reusability Test of Electron-Rich Oxime Palladacycle Resins

for Suzuki Coupling Reaction •••••••••••••••••••••••••••••••••••••••••••••••••••• 35

4. Conclusion •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 37

References •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 38

Abstract in Korean •••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 42

v

List of Abbreviations

CMPS Chloromethyl Polystyrene

DVB Divinylbenzene

DMF N,N -dimethylformamide

EtOH Ethyl Alcohol

EA Elemental Analysis

EDX Energy Dispersive X-ray Spectrometer

FE-SEM Field Emission Scanning Electron Microscopy

FT-IR Fourier Transform-Infrared Spectroscopy

GC-MS Gas Chromatography/Mass Spectroscopy

ICP-AES Inductively Coupled Plasma-Atomic

Emission Spectroscopy

MeOH Methyl Alcohol

NHC N-Heterocyclie Carbene

Pd Palladium

PTC Phase Transfer Catalysis

PVP Polyvinylpyrrolidone

RT Room Temperature

TBAB Tetra-N-Butyl Ammonium Bromide

TEA Triethylamine

THF Tetrahydrofuran

XPS X-ray Photoelectron Spectroscopy

vi

List of Figures

Figure 1. Palladium catalysts on various supports •••••••••••••••••••••••••••••••• 3

Figure 2. Mechanisms and Thermal Gradient of Microwave Heating

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 6

Figure 3. FT-IR spectra of ketone resins and oxime resins (Ketone

group: 1679 cm-1, Hydroxyl group: 3374 cm-1) ••••••••••••••••• 18

Figure 4. FE-SEM Image of CMPS Resins (a) and Oxime

Palladacycle Resins (b) ••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 20

Figure 5. Analysis of Chloro-Bridged, Divalent Palladium on Oxime

Palladacycle Resin by EDX (a) and XPS Analysis (b).

Binding Energy (eV) is shown in (c) •••••••••••••••••••••••••••••••••• 20

Figure 6. Reaction Profile Comparison of the Suzuki Coupling

Reaction of 4-Bromoanisole with Phenylboronic Acid using

the Microwave and Oil Bath ••••••••••••••••••••••••••••••••••••••••••••••••• 27

vii

List of Tables

Table 1. Effect of Solvent Conditions in Suzuki Coupling Reaction of

4-Bromoanisole with Phenylboronic Acid •••••••••••••••••••••••••••• 24

Table 2. Effect of Various Bases in Suzuki Coupling Reaction of 4-

Bromoanisole with Phenylboronic Acid ••••••••••••••••••••••••••••• 25

Table 3. Suzuki Coupling Reaction of various Aryl Halides with

Phenylboronic Acid ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 30

Table 4. Effect of Bases in Suzuki Coupling Reaction of 4-

Bromoanisole with Phenylboronic Acid in Water •••••••••••••• 33

Table 5. Suzuki Coupling Reaction of various Aryl Halides with

Phenylboronic Acid in Water •••••••••••••••••••••••••••••••••••••••••••••••• 34

Table 6. Reusability Test of Electron-Rich Oxime Palladacycle

Resins••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 36

viii

List of Schemes

Scheme 1. Overall Synthesis of Electron-Rich Oxime Palladacycle

Resins •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 17

Scheme 2. Suzuki Coupling Reaction of 4-Bromoanisole and

Phenylboronic Acid in Various Solvent Conditions

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 21

Scheme 3. Suzuki Coupling Reaction of 4-Bromoanisole and

Phenylboronic Acid using Various Bases•••••••••••••••••••••••••• 23

Scheme 4. Suzuki Coupling Reaction of 4-Bromoanisole and

Phenylboronic Acid by Microwave Heating (60W) and Oil

Bath Heating •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 26

Scheme 5. Coupling Reaction of Aryl Halides with Phenylboronic

Acid ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 29

Scheme 6. Effect of Bases in Suzuki Coupling Reaction of 4-

Bromoanisole and Phenylboronic Acid in Water ••••••••••••• 32

Scheme 7. Suzuki Coupling Reaction of Various Aryl Halides and

Phenylboronic Acid in Water, using TBAB (1 mmol)

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 32

Scheme 8. Suzuki Coupling Reaction of 4-Bromoanisole and

Phenylboronic Acid for Reusability Test using Oxime

Palladacycle Resins •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 35

１

1. Introduction

1.1. Developments of Supported Oxime Palladacycle

Catalysts

Oxime palladacycle has been proved to be highly active palladium

catalysts for various coupling reactions such as Mizoroki-Heck,

Suzuki-Miyaura, Stille, Sonogashira, and Ullmann-type reactions by

the pioneering works of the Najera group.1-3 The remarkable features

of ketoxime-derived palladacycles such as stability against heat, air,

and moisture,4-6 led the Najera group to investigate their catalytic

activity in C-C coupling reactions (Figure 1a).7

Nevertheless these highly effective homogeneous catalysts needed

feasible means of easy separation and recycling. For greener chemistry,

the developments of heterogeneous catalytic systems for palladium

have been robustly studied.8-10 Leyva group covalently anchored

oxime-carbapalladacycle on silica supports to create the

heterogeneous catalytic system (Figure 1b).11 Najera group used

polymer support to prepare Kaiser oxime resin, which showed

efficient catalytic activity in Suzuki and Heck reactions (Figure 1c).12-

２

14 These solid-supported oxime palladacycles showed not only

outstanding catalytic activities in coupling reactions, but also low

leaching of palladium in reusability tests. A different approach such as

using PVP for oxime palladacycle support was also demonstrated by

Kirschning group (Figure 1d), which suggested a well suited catalyst

for C-C coupling reactions in continuous flow reactors.15

As mentioned above, various oxime palladacycle catalysts were

designed and developed in order to meet the major concerns in

practicability, which include easy scale-up, work up, recyclability, and

low palladium leaching. With the same concerns, electron-rich oxime

palladacycles were developed by modifying the oxime ligands in our

previous work.16 Considering the fact that catalytic activities could be

controlled by varying the substituents of the oxime containing

aromatic ring,17 alterations in the number of the methoxy groups were

made to adjust the electron-richness of the oxime ligands (Figure 1e).

As a result, oxime palladacycle with dimethoxy substituents showed

highly active catalytic performance in Suzuki reaction.

３

(a) Oxime palladacycle complex used in various C-C coupling reactions

(b) SiO2-OC-Pd Catalyst

(c) Kaiser oxime palladacycle on PS support (d) Oxime palladacycle on PVP support

O

R1

R2

PdN

Cl

OHa: R1=H, R2=Hb: R1=H, R2=OCH3

c: R1=OCH3, R2=OCH3

a-c

(e) Oxime palladacycles with different methoxy substituents

Fig. 1 Palladium catalysts on various supports.

４

1.2. Microwave Application for Efficient Catalysis

Electron-rich oxime palladacycle with dimethoxy-substituted

ligands showed best performance in the C-C coupling reactions.14 For

the purpose of easy separation and recycling, the electron-rich oxime

palladacycle was anchored to chloromethyl polystyrene (CMPS) resin.

To develop full activity of the catalyst, induction time should be

concerned. The induction time of a catalyst refers to the time needed

for reaching a steady state catalytic activity.18 For the Suzuki reaction,

palladium catalysts also require induction time, during which the

palladium precursor complex is converted into the active catalytic

form.19 There are numerous factors that could affect the induction time

of a catalytic system, but in simplicity, the most probable factor that

would be directly influenced is temperature. Microwave is a widely

used tool in organic reactions because of its highly effective heating

ability. Microwave is capable of simultaneous, bulk heating of

dielectric molecules, through the mechanism of the dipolar

polarization and ionic conduction processes (Figure 2a).20

Microwave’s electromagnetic radiation produces an oscillating field,

where the dipoles or ions continuously attempt to realign themselves.

５

Within this electric field, rotation of polar molecules lags behind the

oscillations, producing resistive heating in the medium. In case of ions,

the charged particles oscillate back and forth, collide with neighboring

molecules and produce heat.21 Owing to this phenomenon, microwave

heating shows evident difference with conventional oil bath heating.

While the oil bath heating gradient makes its way from the outside of

the reactor to the inside, microwave heating initiates from within the

medium (Figure 2b).22 By using the microwave, various advantages

are provided, such as increased reaction rates, excellent control of

reaction parameters, selective heating, and higher yields.23-24 Of

course, there exist limitations such as difficulties in scale-up, in situ

monitoring, and high costs,20 but utilizing the robust heating capability

was inevitable.

６

(a) Dipolar Polarization (top), and Ionic Conduction (bottom)

(b) Microwave heating vs. Conventional heating

Fig. 2 Mechanisms and Thermal Gradient of Microwave Heating.

７

1.3. C-C Coupling Reactions in Water using Electron-rich Oxime Palladacycle Catalyst and Microwave Heating

Water is at the very forefront of the solvent replacement research

following the green chemistry principles.25 The focus of using water

as solvent comes from its nontoxic, readily available, nonflammable,

and environmentally friendly characteristics. However, low solubility

of organic substrates in water needs to be overcome for efficient

reactions. Several variations are used to overcome this, which include

organic cosolvents, ionic derivatization, surfactants, or hydrophilic

auxiliaries.26-31 Among the auxiliary reagents, tetrabutylammonium

bromide (TBAB) is one of the most widely used phase transfer

catalyst (PTC) in Suzuki reactions. PTCs are defined as reagents that

facilitate the migration of a reactant in a heterogeneous system from

one phase to another, where the reaction could take place.32 TBAB is a

representative quaternary ammonium salt in PTC, and has shown

excellent catalytic activity in various organic reactions such as Heck,

Suzuki, and Hiyama reactions in neat water.1-3

８

1.4. Research Objectives

In this study, we present the Suzuki coupling reactions of

phenylboronic acid and various aryl halides using the polymer-

supported electron-rich oxime palladacycle catalyst and the

microwave heating. The microwave heating is expected to provide a

shorter induction time for the catalyst, owing to its highly efficient

heating capability. In addition, considering the fact that dipolar

molecules are effectively heated under microwave irradiation,

effective Suzuki reactions in water is also anticipated.

９

2. Experimental Section

2.1. General

2.1.1. Materials

Unless otherwise noted, all solvents and reagents were obtained

from commercial suppliers and used without further purification. CM

PS resin (1% DVB-PS, 100-200 mesh) was obtained from BeadTech,

Inc. (Korea).

2.1.2. Instruments

The CMPS resins were characterized by FT-IR (Bomem,

FTLA2000) and elemental analysis (EA, Leco, CHNS-932). The

morphologies of the resin were investigated by field emission scanning

electron microscopy (FE-SEM, Jeol Inc. JSM-6700F). The loading of

palladium on the resin was detected by energy dispersive X-ray

spectrometer (EDX, Jeol Inc. JSM-6700F) and quantified by

inductively coupled plasma atomic emission spectroscopy (ICP-AES,

１０

SHIMADZU, ICPS-1000 IV). Palladium 3d binding energy was

investigated by X-ray photoelectron spectroscopy (XPS, ThermoVG,

SIGMA PROBE). Suzuki reactions were performed under microwave

irradiation with CEM Discover Synthesis Unit (CEM Corp., Matthews,

NC) in sealed glass vessels (10 mL) under magnetic stirring. The

temperature was controlled by a calibrated infrared temperature control

under the reaction vessel. The crude product yield of Suzuki reactions

was measured by gas chromatography/mass spectroscopy (GC-MS,

Hewlett Packard).

１１

2.2. Preparation of Electron-Rich Oxime Palladacycle Resins

2.2.1. Immobilization of 4′-Hydroxy-3, 5-Dimethoxyacetophenone

Derivatives on CM PS

CM PS resin (1 g, 2.19 mmol/g) was pre-swollen in DMF (100 mL)

and 4′-hydroxy-3, 5-dimethoxyacetophenone (0.86 g, 4.38 mmol),

sodium methoxide (0.35 g, 6.57 mmol), and potassium iodide (1.09 g,

6.57 mmol) were added to the resin. The mixture was stirred by

overhead stirrer at 70 °C for 12 h. After cooling to room temperature,

the resulting keto resin was washed with H2O, 1N HCl, DMF, CH2Cl2,

and MeOH (×3) and dried in vacuo.

2.2.2. Preparation of Oxime Resins

Excess amount of hydroxylamine hydrochloride (1.14 g, 16.40

mmol) and pyridine (1.30 mL, 16.40 mmol) were added to the keto

resins which were preswollen in absolute EtOH. The mixture was

heated at reflux with stirring for 24 h. After cooling to room

temperature, the resins were washed with EtOH, DMF, CH2Cl2, and

MeOH (×3) and dried in vacuo. The loading level of oxime was

１２

determined by elemental analysis (% N, 0.96 mmol/g).

2.2.3. Preparation of Palladium Loaded Oxime Resins

To a suspension of oxime resin (1 g) in dry THF, Li2PdCl4 (78.63

mg, 0.30 mmol) and NaOAc (24.61 mg, 0.30 mmol) and dissolved in

THF were added. The mixture was stirred at room temperature for 12 h.

After the reaction, the resin was washed with THF in a Soxhlet

apparatus and dried in vacuo. The palladium content on palladated

oxime resin was determined by ICP-AES.

For ICP-AES analysis, the resin was treated with HNO3 at 100 °C

for 4 h. After filtration and washing the resin with distilled water, the

filtrate was diluted to 25 mL with distilled water and analyzed by ICP-

AES.

１３

2.3. Suzuki Coupling Reaction Catalyzed by Electron-Rich Oxime Palladacycle Resins

2.3.1. Optimization of Suzuki Coupling Reaction

Suzuki coupling reaction of 4-bromoanisole (1 mmol) with

phenylboronic acid (1.2 mmol) was carried out using oxime

palladacycle resin (1 mol% Pd) and K2CO3 (1.5 mmol) as a base in

various solvent systems to investigate the optimal condition. The

following solvent systems (3 mL) were examined; H2O, DMF,

H2O/DMF (1:1), H2O/DMF (2:1), H2O/DMF (1:2), H2O/DMF (2:3),

H2O/DMF (3:2), H2O/DMF (3:1), and H2O/DMF (1:3). The reaction

mixture was microwave-heated under 40W at 50 °C for 15 minutes in a

sealed vessel (10 mL). To identify the effects of bases, Na2CO3, K2CO3,

Cs2CO3, TEA, CH3COONa, KOH, NaOH, K3PO4·H2O, and

Na3PO4·H2O were tested in the H2O/DMF (2:1) system.

2.3.2. General Experimental Procedure for Suzuki Coupling

Reaction of Aryl Halides with Phenylboronic Acid

Aryl halide (1 mmol), phenylboronic acid (1.2 mmol, 1.2 equiv),

and a base (1.5 mmol, 1.5 equiv) dissolved in distilled water and DMF

(3/1, v/v, 3 mL) were added to palladated oxime resins (1 mol% Pd: 16

１４

mg). The mixture was microwave-heated under 60W at various

temperatures (50~100 °C) for 30 minutes in a sealed vessel (10 mL).

After filtration and washing the resins with distilled water (1 mL × 5)

and diethyl ether (1 mL × 5), the filtrate was poured into diethyl ether.

The organic layer was washed with water and dried over MgSO4 and

the solvent was evaporated under reduced pressure. The crude product

was identified by gas chromatography/mass spectroscopy (GC-MS).

Suzuki coupling reactions in water was also performed in the same

manner. In this case only water (3 mL) was used in the presence of the

phase transfer catalyst, TBAB.

2.3.3. Reaction Profile of Suzuki Coupling Reaction using the

Microwave and Oil Bath

4-Bromoanisole (31.30 μL, 1 mmol), phenylboronic acid (36.58

mg, 1.2 mmol), and K2CO3 (51.83 mg, 1.5 mmol) dissolved in distilled

water and DMF (3/1, v/v, 3 mL) were added to palladated oxime resins

(1 mol% Pd: 16 mg). The mixture was either microwave-heated

under 60W at 50 °C or heated in an oil bath at 50 °C for a period of 3, 5,

10, 15, 20, 30, 45, 60 minutes in a sealed vessel (10 mL, microwave) or

１５

a glass vial (10 mL, oil bath). Each reaction mixture was filtered and

washed with distilled water (1 mL × 5) and diethyl ether (1 mL × 5),

and the filtrate was poured into diethyl ether. The organic layer was

washed with water and dried over MgSO4 and the solvent was

evaporated under reduced pressure. The crude product was identified

by GC-MS.

2.3.4 Reusability Test of Electron-Rich Oxime Palladacycle Resins

4-Bromoanisole (31.30 μL, 1 mmol), phenylboronic acid (36.58

mg, 1.2 mmol), and K2CO3 (51.83 mg, 1.5 mmol) dissolved in distilled

water and DMF (3/1, v/v, 3 mL) were added to palladated oxime resins

(1 mol% Pd: 16 mg). The mixture was microwave-heated under 60W at

50 °C for 30 minutes in a sealed vessel (10 mL). After filtration and

washing the resins with distilled water (1 mL × 5) and diethyl ether (1

mL × 5), the filtrate was poured into diethyl ether. The organic layer

was washed with water and dried over MgSO4 and the solvent was

evaporated under reduced pressure. The crude product was identified

by GC-MS. The filtered resins were reused 5 times for the same

reaction.

１６

3. Results and Discussion

3.1. Preparation and Characterization of Electron-Rich Oxime Palladacycle Resins

3.1.1. Preparation of Oxime Resins

First, to prepare oxime ligands on polymer support, dimethoxy

substituted hydroxyacetophenone as oxime precursor was chosen. As

shown in Scheme 1, 4’-hydroxy-3, 5-dimethoxyacetophenone was

immobilized on CM PS in the presence of NaOCH3 and KI. The keto

group was converted to oxime group by reacting with excess

hydroxylamine hydrochloride and pyridine. Loading level of oxime

group, determined by nitrogen analysis was 0.96 mmol/g. The chemical

conversions from CMPS to oxime resin were verified by FT- IR

analysis (Figure 3). As shown in the last step of Scheme 1, the oxime

resins were treated with palladium precursor (Li2PdCl4) in dry THF and

were shaken at RT for 6 h. As demonstrated in previous work,

dimethoxy group-attached oxime ligand was able to catch and stabilize

palladium source efficiently due to the good σ-donor electron-rich

ligand.

１７

Scheme 1 Synthesis of Electron-Rich Oxime Palladacycle Resins.

１８

Fig 3. FT-IR spectra of keto resins and oxime resins (keto group: 1710 cm-1, oxime

group 1614 cm-1, hydroxyl group: 3349 cm-1).

１９

3.1.2. Characterization of Electron-Rich Oxime Palladacycle Resins

The resulting palladated oxime resins were analyzed by FE-SEM

to identify any external morphology changes during the reaction. The

FE-SEM images exhibited the same surface morphology without any

physical damages during the reactions (Figure 4). The existence of Pd

on the resin was verified by EDX analysis. From the existence of Cl

and Pd atoms in EDX spectra (Figure 5a), it was indirectly concluded

that the oxime ligands formed a palladium complex via the chloro

bridge form.7 To support this result, the oxidation state of Pd on the

resins was determined by XPS, and Pd peak (Pd 3d5/2) was found in

337.77 eV which corresponds to Pd (II) (Figure 5c).33 Therefore, it is

demonstrated that Pd atom was immobilized on the oxime palladacycle

resin as a chloro-bridge complex in the divalent state. The amount of

immobilized Pd on the resins was quantified by ICP-AES. The loading

level of Pd was 0.16 mmol/g.

２０

(a) (b)

Fig 4. FE-SEM Image of CMPS Resins (a) and oxime palladacycle resins (b).

(a) (b)

(c)

Fig. 5. Analysis of chloro-bridged, divalent palladium on oxime palladacycle resin

by EDX (a) and XPS analysis (b). Binding energy (eV) is shown in (c).

２１

3.2. Suzuki Coupling Reaction Catalyzed by Electron-Rich Oxime Palladacycle Resins

3.2.1. Effects of Solvents and Bases on Suzuki Coupling Reaction

A model reaction of 4-bromoanisole with phenylboronic acid was

carried out to optimize the reaction condition using the Pd catalysts. In

our previous work, H2O/DMF (1:1) was the optimum solvent system

for the reaction, but considering the heating mechanism of the

microwave, solvent ratios with higher water proportion were examined.

First, Suzuki coupling reactions were carried out using Cs2CO3 (1.5

mmol) as a base in the following solvent conditions; H2O, DMF,

H2O/DMF (1:1), H2O/DMF (2:1), H2O/DMF (1:2), H2O/DMF (2:3),

H2O/DMF (3:2), H2O/DMF (3:1), and H2O/DMF (1:3), using the Pd

catalysts (1 mol%), (Scheme 2).

Scheme 2. Suzuki coupling reaction of 4-bromoanisole and phenylboronic acid in

various solvent conditions.

２２

As expected, solvent conditions with higher water proportion were

more effective to perform the reaction. While H2O/DMF (2:1) system

showed the best result (entry 5 in Table 1), slightly decreased yield

was observed in the H2O/DMF (3:1) condition (entry 8 in Table 1).

This is probably due to the delicate solvent balance required for

Suzuki coupling reaction when inorganic base is used, because

heterogeneous reaction requires both the compatibility of solid support

and the solubility of organic, or inorganic reagents. The heating

mechanism of the microwave would surely be more effective when

there is more water in the solvent system, but the decrease in the

organic solvent could become a drawback for the solubility of organic

substrates.

Base screening test was also performed, applying the new solvent

system (Scheme 3). Inorganic bases generally exhibited moderate

performance except for CH3COONa, and organic base such as TEA

was not suitable, as previously observed. The results with K2CO3,

Cs2CO3 and KOH were analogous, and K2CO3 which showed the best

yield (entry 2 in Table 2) was used in the following Suzuki coupling

reactions.

２３

Scheme 3. Suzuki coupling reaction of 4-bromoanisole and phenylboronic acid

using various bases.

２４

Table 1. Effect of Solvent Conditions in Suzuki Coupling Reaction of 4-

Bromoanisole with Phenylboronic Acida

Entry Solvent Yield (%)b

1 H2O 2

2 DMF 1

3 H2O/DMF (1:1) 80

4 H2O /DMF (1:2) 20

5 H2O /DMF (2:1) 88

6 H2O /DMF (2:3) 10

7 H2O /DMF (3:2) 74

8 H2O /DMF (3:1) 84

9 H2O /DMF (1:3) 8

aConditions: 4-Bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), Cs2CO3 (1.5 mmol) in various solvent systems (v/v, 3

mL) at 40W and 50ºC for 15 minutes. bGC yields.

２５

Table 2. Effect of Various Bases in Suzuki Coupling Reaction of 4-Bromoanisole

with Phenylboronic Acid a

Entry Solvent Temp (°C) Yield (%)b

1 Cs2CO3 50 88

2 K2CO3 50 93

3 Na2CO3 50 69

4 K3PO4 50 74

5 Na3PO4 50 83

6 KOH 50 91

7 NaOH 50 84

8 CH3CHOONa 50 3

9 TEA 50 31

aConditions: 4-Bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), various bases (1.5 mmol) in H2O/DMF (v/v, 2:1, 3 mL),

at 40W and 50ºC for 15 minutes. bGC yields.

２６

3.2.2. Comparison of Suzuki Coupling Reaction by Microwave

Heating and Conventional Heating

To compare the effect of conventional heating and microwave

heating on reaction profile of the Suzuki reaction of 4-bromoanisole

with phenylboronic acid, reactions were performed in 3, 5, 10, 15, 20,

30, 45, and 60 minute time intervals (Scheme 5). As expected, the

reaction performed with microwave heating required far less induction

time for the conversion to the product (Figure 6). While the oil bath

heating consumed about 20 minutes for the oxime palladacycle

catalyst to reach its steady catalytic state, microwave heating reduced

the induction period down to 5 minutes and the reaction plateau was

reached in 20 minutes. This result clearly showed that the

instantaneous microwave heating effectively reduced the induction

time of the catalyst, allowing efficient catalytic activity.

Scheme 4. Suzuki coupling reaction of 4-bromoanisole and phenylboronic acid by

microwave heating (60W) and oil bath heating.

２７

Fig. 6. Reaction profiles of the Suzuki coupling reaction of 4-bromoanisole with

phenylboronic acid using the microwave and oil bath.

２８

3.2.3. Suzuki Coupling Reaction of Various Aryl Halides with

Phenylboronic Acid

Suzuki coupling reaction of various aryl halides with

phenylboronic acid was performed under microwave irradiation in

sealed vessels (Scheme 6). Deactivated aryl bromides as well as aryl

chlorides were converted to the corresponding biaryl compounds. Aryl

bromides were converted to the bromides in excellent yields under mild

conditions. Even at higher temperatures, Suzuki reaction of aryl

chlorides gave not so good yield except for the 4-chloroacetophenone

(entry 10 in Table 3). Further optimization of the reaction condition

will allow improvements in the coupling performance of aryl chlorides.

To extend the substrate variations, Suzuki reaction of heterocyclic aryl

halides with phenylboronic acids was performed. The production of

unsymmetrical biaryl compounds is useful for industrial applications.34-

36 We tested our oxime palladacycle catalysts in the coupling reactions

of 2-bromothiopene, 2-bromopyridine, and 2-bromonaphtalene with

phenylboronic acid, and the biaryls were successfully produced.

２９

X BHO

HO Pd catalyst (1 mol%)30 min, 40W

R

1.2 eqX= Br, Cl

1.0 eq

Base (1.5 eq)H2O/DMF (2:1)

R

Scheme 5. Suzuki coupling reaction of aryl halides with phenylboronic acid.

３０

Table 3. Suzuki Coupling Reaction of Various Aryl Halides with Phenylboronic

Acid a

Entry Substrate Temp (oC) Yield (%)b

1

50 99

2

50 97

3

50 97

4

50 90

5

50 93

6

70 68

7

70 58

8

100 97

9

100 15

10

100 26

11

100 69

12

100 33

13

100 95

aConditions: 4-Bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), K2CO3 (1.5 mmol) in H2O/DMF (v/v, 2:1, 3 mL) at

60W for 30 minutes. bGC yields.

BrN

Br

BrO

S Br

N Br

Br

３１

3.2.4. Suzuki Coupling Reaction of Various Aryl Halides with

Phenylboronic Acid in Water

Suzuki coupling reaction of aryl halides with phenylboronic acid

was performed in water, using TBAB (1 mmol) as an additive under

microwave irradiation. To find out the optimum reaction condition,

effects of bases were tested (Scheme 7). As expected, the high yields

with Cs2CO3 and K2CO3 was noticeable compared to other bases (entry

1, 2 in Table 4). Once again, K2CO3 which showed slightly higher yield

was chosen for further study. Unlike the Suzuki coupling reaction using

DMF as the co-solvent, the reaction did not occur at 50ºC, but at 70ºC.

Using this optimized condition, Suzuki coupling reactions of various

aryl halides with phenylboronic acid were performed (Scheme 8).

Unfortunately, the reactions of aryl chlorides with phenylboronic acid

were not satisfactory. Only 4-chloroacetophenone and 4-

chlorobenzonitrile were able to produce biaryl compounds, while the

others only showed side reactions. One of the reason for this result

could be that quaternary ammonium salts have limitations in their

usage at elevated temperatures (120~150 ºC), where decomposition

could occur.36 Also, the reactivity of aryl chlorides might be too slow

３２

for the coupling reaction. Further studies with other phase transfer

catalysts would be necessary.

Br

BHO

HO Pd catalyst (1 mol%)

15 min, 100oC, 40W

O

1.2 eq1.0 eq

O

Base (1.5 mmol), TBAB (1 mmol), H2O

Scheme 6. Effect of bases in Suzuki coupling reaction of 4-bromoanisole and

phenylboronic acid in water.

Scheme 7. Suzuki coupling reaction of various aryl halides and phenylboronic acid in

water, using TBAB (1 mmol).

３３

Table 4. Effect of Bases in Suzuki Coupling Reaction of 4-Bromoanisole with

Phenylboronic Acid in Water a

Entry Base Yield (%)b

1 Cs2CO

3 89

2 K2CO

3 91

3 Na2CO

3 73

4 K3PO

4 69

5 Na3PO

4 44

6 KOH 71

7 NaOH 52

8 CH3CHOONa 67

9 TEA 49

aConditions: 4-Bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), and base (1.5 mmol) in H2O (3 mL) at 40W and 100ºC

for 15 minutes. bGC yields.

３４

Table 5. Suzuki Coupling Reaction of Various Aryl Halides with Phenylboronic

Acid in Water a

Entry Substrate Temp (ºC) Yield (%)b

1

70 92

2

70 95

3

70 97

4

70 95

5

70 96

6

100 62c

7

120 88

aConditions: Aryl halides (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), and K2CO3 (1.5 mmol) in H2O (3 mL) at 60W for 30

minutes. bGC yields. cCs2CO3 was used as a base.

Br

O

BrN

Br

BrO

ClO

３５

3.2.5. Reusability Test of Electron-Rich Oxime Palladacycle Resins

for Suzuki Coupling Reaction

One of the major advantages of heterogeneous catalyst is that the

catalyst can be easily isolated and reused. To evaluate the reusability of

electron-rich oxime palladacycle resins, recycling test was carried out

by using the recovered catalysts in Suzuki coupling reaction of 4-

bromoanisole with phenylboronic acid (Scheme 9). The retrieved

electron-rich oxime palladacycle resins consistently gave the product 4-

bromo-1, 1’-biphenyl in high yield until the fifth cycle, maintaining

good catalytic activity.

Scheme 8. Suzuki coupling reaction of 4-bromoanisole and phenylboronic acid for

reusability test using oxime palladacycle resins.

３６

Table 6. Reusability Test of Electron-Rich Oxime Palladacycle Resinsa

Yield (%)b

1st Cycle 2nd Cycle 3rd Cycle 4th Cycle 5th Cycle

94 96 95 95 95

aConditions: 4-Bromoanisole (1 mmol), phenylboronic acid (1.2 mmol), oxime

palladacycle resins (1 mol%), and K2CO3 (1.5 mmol) in H2O/DMF (v/v, 2:1, 3 mL) at

60W and 50ºC for 30 minutes. bGC yields.

３７

4. Conclusion

In this study, polymer-supported electron-rich oxime palladacycle

was used as a heterogeneous catalyst for Suzuki coupling reaction

using the microwave heating. The microwave heating allowed

significant reduction in the induction time of the catalyst. The reaction

time of the Suzuki coupling of aryl halides and phenylboronic acid

was effectively decreased, while maintaining high production yields.

To explore further the advantage of our oxime palladacycle catalyst,

Suzuki coupling reaction in water was also attempted. Most of the

reactions were performed well affording excellent yields (92~97%),

except for aryl chloride substrates. In this case, rather harsh reaction

conditions were tried, but failed, probably because the phase transfer

catalyst could not bear the extreme temperature. Finally, our oxime

palladacycle catalysts could be successfully reused up to 5 cycles

without losing its catalytic activity.

３８

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４２

초 록

옥심 팔라다싸이클은 탄소-탄소 짝지음 반응에 있어서 매우

강력한 팔라듐 촉매이며 쉽게 만들 수 있다는 점과 공기, 수

분에 대해 안정하다는 장점을 지닌다. 이전에, 환경친화적인

화학을 위해서 전자가 풍부한 옥심 팔라다싸이클을 고분자

지지대에 고정시켜서 효과적인 탄소-탄소 짝지음 반응과 재

사용에 대한 성능을 실험했다. 본 연구에서는 물에서의 스즈

키 반응을 위해서 고분자에 고정된 옥심 팔라다싸이클 시스

템에 마이크로파 화학을 적용시켰다. 그 결과, 고분자에 고정

된 전자가 풍부한 옥심 팔라다싸이클과 마이크로파 시스템을

이용하여 할로젠화 벤젠, 헤테로고리 벤젠과 페닐기 붕소산과

의 스즈키 반응을 성공적으로 수분 매체에서 실행할 수 있었

다.

주요어: 옥심 팔라다싸이클, 마이크로파, 스즈키-미야우라 반응

학 번: 2012-20944