Palladium(II) catalyzed oxidative functionalization of c h bonds using alkyne as building block

List of Schemes Scheme 1.1 Traditional functional- group-based transformation vs transi-tion-metal -catalyzed C-H bond functionalization Scheme 1.2 C-H bond functionalization of azobe

PALLADIUM(II)-CATALYZED

OXIDATIVE FUNCTIONALIZATION OF C-H BONDS

USING ALKYNE AS BUILDING BLOCK

I

Declaration

I hereby declare that this thesis is my original work and it has been written by me in

its entirety, under the supervision of Dr Wang Jian, Chemistry Department, National

University of Singapore, between Aug 2010 and Aug 2014

I have duly acknowledged all the sources of information which have been used in the

thesis

This thesis has also not been submitted for any degree in any university previously

The content of the thesis has been published in:

1) S Y Peng, T Gao, S F Sun, Y H Peng, M H Wu, H B Guo, J Wang*, Adv

Synth Catal 2014, 356, 319

2) S Y Peng, L Wang, J Wang*, Chem Eur J 2013, 19, 13322

3) S Y Peng, L Wang, J Y Huang, S F Sun, H B Guo, J Wang*, Adv Synth

Acknowledgements

It is my great pleasure to take this opportunity to express my gratitude and thanks

to all the people who have helped and encouraged me during my Ph.D studies

Noth-ing in this thesis would have been possible without each and every one of you Thank

you!

First and foremost, I want to express my deepest respect and most sincere

grati-tude to my supervisor, Prof Dr Wang Jian, for offering me the great opportunity to

be his Ph.D student and guiding me to the intriguing and challenging field of

palla-dium chemistry Dr Wang is a great supervisor to me He has great passion and

en-thusiasm for chemistry, even when it did not want to cooperate I would like to thank

him for supporting me, teaching me and guiding me within the chemistry community,

and thanks for encouraging me in my ambitions His broad knowledge, enthusiasm,

inspiration and dedication to science will with no doubt benefit me through all my life

His believing in me as a chemist gives me the confidence to go forward to further

pursue my research career

Next, I wish to express my warm and sincere thanks to my senior, Dr Wang Lei,

who has helped me enormously with my research projects in National University of

Singapore Our extensive discussion has been very helpful for me to understand what

the problem was and how to solve it This thesis would be impossible without his

generous help Besides, I also want to give my great appreciation to another senior,

Miss Ren Qiao, for her valuable advice and friendly help, although we have focused

III

on different research fields

I would like to thank all my lab mates in Dr Wang’s lab, past and present, our

postdoctors: Dr Gao Yao-Jun, Dr Xue Fei and Dr Li Wen-Jun, our Masters: Huang

Yuan, Wang Peng-Cheng, Lu Xian, Xiao Dan and Xue Cheng-Wen, our lovely and

active Honours: N g Hui-Fen, Siaw Woon-Yew etc., whose effective collaboration,

helpful discussion and friendship have greatly helped me during my four years’ life

and studies

I also want to thank the research scholarship provided by National University of

Singapore In addition, I want to extend my gratitude to all the laboratory staff of our

chemistry department, particularly Madam Tan Geok-Kheng and Madam Hong

Yi-Mian for X-ray crystallography analysis, Madam Han Yan-Hui and Dr Wu Ji- En

for NMR training and testing, Madam Wong Lai-Kwai and Madam Liu Q i-Ping for

mass analysis Thanks also go to the administrative and technical staff, especially

Madam Suriawati Binte Sa’Ad in our department administrative office, Mr Lee

Yoon-Kuang, Mr Phua Wei-De Victor and Mr.Soffiyan Bin Hamzah in our lab supply

store

I would also like to express my sincere thanks to all my friends in Singapore for

their help during the past four years I will definitely miss and treasure their

friend-ships

Finally, my deepest gratitude goes to my family for their unflagging love and

support throughout my life THANK YOU!

Table of Contents

Declaration I

Acknowledge ments II

Table of Contents IV

Summary IX

List of Tables XI

List of Figures XIII

List of Schemes XIV

List of Abbreviations XIX

List of Publications XXIII

Chapter 1 Introduction 1

1.1 Transition-Metal-Catalyzed C-H Bond Functionalization 1

1.2 Traditional Pd(0)-Catalyzed Cross-Coupling Reactions 7

1.3 Modern Pd-Catalyzed C-H Functionalization Reactions 12

1.3.1 C-H Bond Functionalization via Pd(0)/Pd(II) Catalysis 13

1.3.2 C-H Bond Functionalization via Pd(II)/Pd(IV) Catalysis 15

1.3.3 C-H Bond Functionalization via Pd(0)/Pd(II)/Pd(IV) Catalysis 18

1.3.4 C-H Bond Functionalization via Pd(II)/Pd(0) Catalysis 20

1.4 Pd-Catalyzed Alkyne Transformation via C-H Functionalization 27

1.4.1 Pd-Catalyzed Alkynylation Reactions 28

1.4.2 Pd-Catalyzed Alkyne Cycloaromatization Reactions 39

1.5 Project Objectives 49

V

Chapter 2 Palladium-Catalyzed [2+2+1] Oxidative Annulation of

4-Hydroxycoumarins with Unactivated Internal Alkynes: Access to Spiro

Cyclopentadiene-chroman-2,4-dione Complexes 52

2.1 Introduction 53

2.2 Results and Discussion 54

2.3 Conclusion 60

2.4 Experimental Section 61

2.4.1 General Information 61

2.4.2 Preparation and Characterization of Compounds 2-3 62

2.4.3 Preparation and Characterization of Compounds 2-4 74

2.4.4 Preparation and Characterization of Compound 2-5 79

2.4.5 Preparation and Characterization of Compound 2-6 80

2.4.6 X-ray Crystallographic Analysis 80

Chapter 3 Palladium-Catalyzed Oxidative Annulation via C–H/N–H Functionalization: Access to Substituted Pyrroles 84

3.1 Introduction 85

3.2 Results and Discussion 87

3.3 Conclusion 93

3.4 Experimental Section 94

3.4.1 General Information 94

3.4.2 Preparation and Characterization of Compounds 3-3 95

3.4.3 Preparation and Characterization of Compound 3-4 110

3.4.4 Preparation and Characterization of Compound 3-5 110

3.4.5 X-ray Crystallographic Analysis 111

Chapter 4 Direct Access to Highly Substituted 1-Naphthols through Palladium-Catalyzed Oxidative Annulation of Benzoylacetates and Inte rnal Alkynes 115

4.1 Introduction 116

4.2 Results and Discussion 118

4.2.1 Reaction Optimization 118

4.2.2 Substrate Scope 119

4.2.3 Competition Experiments 122

4.2.4 Synthetic Transformations 123

4.2.5 Mechanistic Investigation 126

4.3 Conclusion 127

4.4 Experimental Section 128

4.4.1 General information 128

4.4.2 Preparation and Characterization of Compounds 4-3 129

4.4.3 Intermolecular Competition Experiments 148

4.4.4 Kinetic Study 150

4.4.5 Large Scale Application 151

4.4.6 Preparation and Characterization of Compound 4-4 152

4.4.7 Preparation and Characterization of Compound 4-5 153

4.4.8 Preparation and Characterization of Compound 4-6 154

VII

4.4.9 Preparation and Characterization of Compound 4-7 155

4.4.10 Preparation and Characterization of Compound 4-8 156

4.4.11 Preparation and Characterization of Compound 4-9 157

4.4.12 Preparation and Characterization of Compound 4-10 158

4.4.13 Preparation and Characterization of Compound 4-11 159

4.4.14 Preparation and Characterization of Compound 4-12 160

4.4.15 Preparation and Characterization of Compound 4-13 161

4.4.16 X-ray Crystallographic Analysis 162

Chapter 5 Iron-catalyze d Ene-type Propargylation of Diarylethylenes with Propargyl Alcohols 164

5.1 Introduction 165

5.2 Results and Discussion 166

5.3 Conclusion 172

5.4 Experimental Section 172

5.4.1 General Information 172

5.4.2 Preparation and Characterization of Compounds 5-3 173

5.4.3 X-ray Crystallographic Analysis 187

Chapter 6 Facile Synthesis of 4-Substituted 3,4-Dihydrocoumarins via an Organocatalytic Double Decarboxylation Process 189

6.1 Introduction 190

6.2 Results and Discussion 192

6.3 Conclusion 198

6.4 Experimental Section 198

6.4.1 General Information 198

6.4.2 Preparation and Characterization of Compounds 6-3 199

References 208

1 H NMR and 13 C NMR Spectra of Major Compounds……….228

IX

Summary

One of the over-arching goals of the research in Dr Wang’s lab is to develop

methodologies for the regioselective and diverse functionalization of C–H bonds The

Pd(II)-catalyzed C-H activation/functionalization organic transformations have

be-come a practical and powerful tool in organic chemistry This thesis describes my

ef-forts during my Ph.D research for Pd(II)-catalyzed C–H functionalization reactions

that result in the formation of many biologically and pharmaceutically important

molecules utilizing alkyne as a universal building block

Chapter 1 gave a brief introduction of transition metal catalysis, followed by a

general evaluation of the research progress of Pd-chemistry, particularly Pd- mediated

alkyne transformations, which were elucidated with selected examples

Chapter 2 described an efficient synthesis of an interesting spiro

cyclopentadi-ene-chroman-2,4-dione heterocycles The method employed a direct Pd(II)-catalyzed

oxidative [2+2+1] cycloaddition of readily available starting materials:

4-hydroxycoumarins and unactivated internal alkynes Various substituents were well

tolerated in the reaction, which led to a number of unique molecular structures

Chapter 3 developed an efficient synthesis of highly substituted pyrroles The

method utilized simple and readily available enamines and alkynes, and employed

direct Pd(II)-catalyzed oxidative annulation procedure A mechanistic investigation of

pyrrole- forming reaction established a viable catalytic cycle The mild nature of the

reaction and the significance of the pyrrole scaffold as structural element should

ren-der this method attractive for both synthetic and medicinal chemistry

Chapter 4 disclosed an efficient synthesis of highly substituted 1-naphthols The

method utilized simple and readily available benzoylacetates and unactivated internal

alkynes as starting materials, and employed a direct Pd(II)-catalyzed oxidative

annu-lation procedure involving C-H activation The mild nature of the reaction, functional

group compatibility and the significance of the 1-naphthol scaffold as structural

ele-ment should render this method attractive in different disciplines

The diarylalkenyl propargylic complex framework has been found in many

nat-ural products and medicinal regents In chapter 5, an unprecedented Fe-catalyzed

ene-type reaction of propargylic alcohols with 1,1-diaryl alkenes was developed,

which enabled us to furnish a diarylalkenyl propargylic complex in moderate to high

chemical yields

3,4-Dihydrocoumarins have attracted considerable attention due to their various

biological activities In chapter 6, we have documented an efficient and convenient

double decarboxylation process for the synthesis of 4-substituted

3,4-dihydrocoumarins in moderate to excellent yields under metal- free reaction

con-ditions

XI

List of Tables

Table 1.1 Traditional Pd(0)-catalyzed cross-coupling reactions

Table 2.1 Optimization of reaction conditions

Table 2.2 Substrate scope of 4-hydroxycoumarins

Table 2.3 Substrate scope of alkynes

Table 2.4 Synthesis of furo[3,2-c]coumarins

Table 2.5 Crystal data and structure refinement for 2-3aa

Table 2.6 Crystal data and structure refinement for 2-4aa

Table 3.1 Optimization of reaction conditions

Table 3.2 Substrate scope of 4-aminocoumarins

Table 3.3 Substrate scope of symmetric alkynes

Table 3.4 Substrate scope of asymmetric alkynes

Table 3.5 Crystal data and structure refinement for 3-3da

Table 3.6 Crystal data and structure refinement for 3-5

Table 4.1 Optimization of the reaction conditions

Table 4.2 Substrate scope of β-ketoesters

Table 4.3 Substrate scope of internal alkynes

Table 4.4 Crystal data and structure refinement for 4-3oa

Table 5.1 Investigation of ene-type reactions

Table 5.2 Investigation of catalysts

Table 5.3 Optimization of other parameters

Table 5.4 Substrate scope of propargylic alcohols

Table 5.5 Substrate scope of diarylethylenes

Table 5.6 Crystal data and structure refinement for 5-3ap

Table 6.1 Investigation of catalysts

Table 6.2 Optimization of reaction conditions

Table 6.3 Substrate scope of coumarin-3-carboxylic acids

Table 6.4 Substrate scope of malonic acid half-thioesters

Table 6.5 Substrate scope of α-functionalized carboxylic acids

XIII

List of Figures

Figure 2.1 X-ray structure of 2-3aa

Figure 2.2 X-ray structure of 2-4aa

Figure 3.1 Examples of pyrrole pharmaceuticals

Figure 3.2 X-ray structure of 3-3da

Figure 3.3 X-ray structure of 3-5

Figure 4.1 Important examples of substituted 1-naphthols

Figure 4.2 X-ray structure of 4-3oa

Figure 5.1 X-ray structure of 5-3ap

Figure 6.1 Examples of 3,4-dihydrocoumarin based natural products

List of Schemes

Scheme 1.1 Traditional functional- group-based transformation vs

transi-tion-metal -catalyzed C-H bond functionalization

Scheme 1.2 C-H bond functionalization of azobenzene by stoichiometric

transi-tion metal complex Cp2Ni

Scheme 1.3 C-H bond functionalization by catalytic transition metal complexes

Scheme 1.4 ‘Inner-sphere’ mechanism of C-H activation

Scheme 1.5 ‘Outer-sphere’ mechanism of C-H activation

Scheme 1.6 Gaunt’s iterative Cu-catalyzed arylation methodology of anilines

Scheme 1.7 Yu’s end-on-template-directed meta-selective C-H functionalizaiton

Scheme 1.8 Mechanisms for Pd(0)-catalyzed cross-coupling reactions

Scheme 1.9 C-H bond cleavage of electron-rich heterocycles via Pd(0)/Pd(II)

catalysis

Scheme 1.10 C-H bond activation of non-heterocycles via Pd(0)/Pd(II) catalysis

Scheme 1.11 Pd(0)/Pd(II) catalytic cycle

Scheme 1.12 ortho-Methylation of anilide via Pd(II)/Pd(IV) catalytic cycle

Scheme 1.13 X-ray structures of Pd(IV) complexes

Scheme 1.14 Pd(II)/Pd(IV) catalytic cycle

Scheme 1.15 C-H bond arylation via Pd(II)/Pd(IV) catalytic cycle

Scheme 1.16 C-H bond activation via Pd(II)/Pd(IV) catalytic cycle by Sanford

Scheme 1.17 C-H bond arylation using ArI via Pd(II)/Pd(IV) catalytic cycle by

Daugulis

XV

Scheme 1.18 Catellani reaction: Pd(0)/Pd(II)/Pd(IV) catalysis

Scheme 1.19 Pd(0)/Pd(II)/Pd(IV) catalysis without norbornene by Dyker

Scheme 1.20 Three types of mechanisms of C-H bond activation via Pd(II)/Pd(0)

catalysis

Scheme 1.21 Initial report of oxidative olefination via Pd(II)/Pd(0) catalysis

Scheme 1.22 Directed ortho-olefination via Pd(II)/Pd(0) catalysis

Scheme 1.23 Selective olefination strategies via Pd(II)/Pd(0) catalysis

Scheme 1.24 meta-Olefination strategy via Pd(II)/Pd(0) catalysis

Scheme 1.25 Oxazoline-directed ortho-C-H activation via Pd(II)/Pd(0) catalysis

Scheme 1.26 Directed ortho-C-H activation via Pd(II)/Pd(0) catalysis

Scheme 1.27 C-H Activation of active olefins and (hetero)arenes via Pd(II)/Pd(0)

catalysis

Scheme 1.28 Oxidative homocoupling of thiophenes via Pd(II)/Pd(0) catalysis

Scheme 1.29 Oxidative arene-arene cross-coupling via Pd(II)/Pd(0) catalysis

Scheme 1.30 Pd-Catalyzed symmetrical 1,3-diyne formation

Scheme 1.31 Pd-Catalyzed unsymmetrical 1,3-diyne formation

Scheme 1.32 Pd-Catalyzed 1,3-enyne formation via Sonogashira reaction

Scheme 1.33 Pd-Catalyzed 1,3-enyne formation via alkyne dimerization

Scheme 1.34 Pd-Catalyzed 1,3-enyne formation via oxidative coupling of alkynes

and alkenes

Scheme 1.35 Pd-Catalyzed 1,3-enyne formation via other strategies

Scheme 1.36 Pd-Catalyzed direct alkynylation of heteroaromatic compounds

Scheme 1.37 Pd-Catalyzed oxidative alkynylation of heterocycles

Scheme 1.38 Pd-Catalyzed direct alkynylation of arenes

Scheme 1.39 Pd-Catalyzed oxidative alkynylation of arenes

Scheme 1.40 Pd-Catalyzed alkynylation of alkanes

Scheme 1.41 Naphthalene and phenanthrene formation via Pd(0)-catalyzed cyclo-

aromatization of alkynes and iodobenzenes

Scheme 1.42 Phenanthrene formation via Pd(0)-catalyzed cycloaromatization of

alkynes

Scheme 1.43 Benz[a]anthracene formation via Pd(0)-catalyzed

cycloaromatiza-tion of alkynes

Scheme 1.44 Benzene formation via Pd(II)-catalyzed oxidative

cycloaromatiza-tion of alkynes and alkenes

Scheme 1.45 Naphthalene formation via Pd(II)-catalyzed oxidative

cycloaromati-zation of alkynes

Scheme 1.46 PAHs via Pd(II)-catalyzed oxidative cycloaromatization of alkynes

Scheme 1.47 Traditional Pd(0)-catalyzed heterocarbocycle formation

Scheme 1.48 Indole synthesis via Pd(II)-catalyzed oxidative cycloaromatization

of alkynes

Scheme 1.49 Indole- fused carbocycles via Pd(II)-catalyzed oxidative

cycloaroma-tization of alkynes by Jiao

Scheme 1.50 Carbazole formation via Pd(II)-catalyzed oxidative

cycloaromatiza-tion of alkynes by Miura

XVII

Scheme 1.51 Heteroaromatic hydrocarbon formation via Pd(II)-catalyzed

oxida-tive cycloaromatization of alkynes

Scheme 1.52 Polyarylated (hetero)aromatic compounds formation via

Pd(II)-catalyzed oxidative annulation of alkynes

Scheme 1.53 Initial try for Fe-catalyzed and metal-free reactions

Scheme 2.1 Pd-catalyzed cascade reactions of 4-hydroxycoumarins with internal

alkynes

Scheme 2.2 Cyclic ketone as substrate

Scheme 2.3 Plausible mechanism

Scheme 2.4 Plausible mechanism

Scheme 2.5 Transformations of compound 2-4aa

Scheme 3.1 Transition- metal-catalyzed pyrrole synthesis

Scheme 3.2 Initial try

Scheme 3.3 Substrate scope of N-protected 4-aminocoumarin and β-enaminones

Scheme 3.4 Synthetic transformations of compound 3-3aa

Scheme 3.5 Plausible mechanism

Scheme 4.1 Challenges in the synthesis of 1-naphthols

Scheme 4.2 Competition experiments

Scheme 4.3 Synthetic transformations of compound 4-3aa

Scheme 4.4 Synthetic transformations of compound 4-4

Scheme 4.5 Gram-scale synthesis of 4-3aa

Scheme 4.6 Kinetic study

Scheme 4.7 Plausible mechanism

Scheme 5.1 Propargylation methods

Scheme 5.2 Proposed catalytic cycle

Scheme 6.1 Approaches to 3,4-dihydrocoumarins

Scheme 6.2 Control experiments

TBAB Tetra-n-butylammonium bromide

XXIII

List of Publications

1 “Palladium-Catalyzed [2+2+1] Oxidative Dearomatizative Annulation of

Ani-soles with Unactivated Internal Alkynes”, S Y Peng, L Wang, J Wang*,

Man-uscript in preparation

2 “Palladium-Catalyzed [2+2+1] Decarboxylative Annulation of Cinnamic acids

with Unactivated Internal Alkynes: Access to Pentafulvene Derivatives”, S Y

Peng, L Wang, J Wang*, Manuscript in preparation

3 “Palladium-Catalyzed [2+2+1] Oxidative Annulation of 4-Hydroxycoumarins

with Unactivated Internal Alkynes: Access to Spiro

Cyclopentadi-ene-Chroman-2,4-dione Complexes”, S Y Peng, T Gao, S F Sun, Y H Peng,

M H Wu, H B Guo, J Wang*, Adv Synth Catal 2014, 356, 319

4 “Direct Access to Highly Substituted 1-Naphthols through Palladium-Catalyzed

Oxidative Annulation of Benzoylacetates and Internal Alkynes”, S Y Peng, L

Wang, J Wang*, Chem Eur J 2013, 19, 13322

5 “Palladium-Catalyzed O xidative Annulation via C-H/N-H Functionalization:

Access to Substituted Pyrroles”, S Y Peng, L Wang, J Y Huang, S F Sun, H

B Guo, J Wang*, Adv Synth Catal 2013, 355, 2550

6 “Facile Synthesis of 4-Substituted 3,4-Dihydrocoumarins via an Organocatalytic

Double Decarboxylation Process”, S Y Peng, L Wang, H B Guo, S, F Sun, J

Wang*, Org Biomol Chem 2012, 10, 2537

7 “Iron-Catalyzed Ene-type Propargylation of Diarylethylenes with Propargyl

Al-cohols”, S Y Peng, L Wang, J Wang*, Org Biomol Chem 2012, 10, 225

8 “Palladium-Catalyzed Cascade Reactions of Coumarins with Alkynes: Synthesis

of Highly Substituted Cyclopentadiene Fused Chromones”, L Wang, S Y Peng,

J Wang*, Chem Commun 2011, 47, 5422 (Back Cover)

9 “Amine-Catalyzed [3+2] Huisgen Cycloaddition Strategy for the Efficient

As-sembly of Highly Substituted 1,2,3-Triazoles”, L Wang, S Y Peng, J T Lee

Danence, Y J Gao, J Wang*, Chem Eur J 2012, 18, 6088 (Highlight in

SYNFACT)

10 “Palladium-Catalyzed O xidative Cycloaddition through C-H/N-H Activation:

Access to Benzazepines”, L Wang, J Y Huang, S Y Peng, H Liu, X F Jiang*,

J Wang*, Angew Chem Int Ed 2013, 52, 1768

1

Chapter 1 Introduction

1.1 Transition-Metal-Catalyzed C-H Bond Functionalization

Most scientists describe a ‘transition metal’ as any element in the d-block of the

periodic table, which includes groups 3 to 12 on the periodic table.[1] The transition

metals and their compounds are known for their homogeneous and heterogeneous

catalytic activity, which is ascribed to their ability to adopt multiple oxidation states

and to form complexes They could lower the activation energy and allow some

tradi-tionally impossible reactions to occur Transition- metal-catalyzed C-H bond

function-alization chemistry complements traditional functional-group-based chemistry and

significantly broadens the scope of organic chemistry

The traditional functional-group-based manipulation (Scheme 1.1a), that is

ex-changing one functional group for another, requires the starting material

pre-functionalized, which decreases both efficiency and atom economy, because FG1

must be first installed and then lost as a byproduct in the installation of FG2.[2] In

con-trast, transition-metal-catalyzed C-H bond functionalization would allow for the

for-mation of FG2 in one step with no byproduct but one H, which increases efficiency

and atom economy (Scheme 1.1b).[3]

Scheme 1.1 Traditional functional-group-based transformation vs transition metal

catalyzed C-H bond functionalization

stoichiometric transition metal complex Cp2Ni (Scheme 1.2).[4] Although the reaction

mechanism for this metalation reaction has not been elucidated, the ortho-C-H bond

was apparently cleaved After this pioneering study, many research groups have

re-ported about the cleavage of C-H bonds via the use of stoichiometric amount of

tran-sition metal complex.[5] The reaction mechanism of such C-H bond cleavage reactions

has been elucidated by a large number of review articles.[5,6]

Scheme 1.2 C-H bond functionalization of azobenzene by stoichiometric transition

metal complex Cp2Ni

N N

NiCp H

Transition- metal-catalyzed functionalization of C-H bonds appeared in the early

1990s (Scheme 1.3).[7-9] In 1989, Jordan reported the Zr-catalyzed addition of a C-H

bond of α-picoline to an olefin (Scheme 1.3a).[7]

After this discovery, in 1992, Moore

found that the Ru-catalyzed three-component coupling of pyridine, CO and olefins

provided the corresponding α-acylpyridines (Scheme 1.3b).[8]

Subsequently, in 1993,

Murai reported the highly efficient, selective functionalization of C-H bonds in

aro-matic ketones with olefins in the presence of a Ru-catalyst (Scheme 1.3c).[9] Since

these discoveries, the chemistry of transition- metal-catalyzed functionalization of C-H

bonds in organic synthesis has rapidly expanded

Scheme 1.3 C-H bond functionalization by catalytic transition metal complexes

Me a)

H Me

O

O R

Ru3(CO)12H

c)

R Toluene, 135oC

[RuH 2 (CO)(PPh 3 ) 3 ]

Although all of these transition metal catalysts promote the same general

trans-formations (C-H bonds to C-C/C-heteroatom bonds), they could proceed within two

different mechanistic manifolds: ‘inner-sphere’ and ‘outer-sphere’, which were named

by Sanford.[10] The key distinguishing feature of the ‘inner-sphere’ mechanism is the

formation of a discrete organometallic intermediate containing an M-C σ-bond (M is

transition metal) by the direct contact of metal ion and C-H bond.The cleavage of

C-H bond could proceed via oxidative addition or electrophilic substitution (Scheme

1.4) The oxidative addition is direct insertion of the metal into the C-H bond,

there-fore the oxidation state of the metal increases by two (Scheme 1.4a) Metals that

acti-vate C-H bonds by oxidative addition include Zr(II), Ru(0), Rh(I), Ir(I) and Pt(IV).[13]

There is no oxidation state change in electrophilic substitution, because a ligand is

replaced by a covalently bound carbon (Scheme 1.4b).Transition metals that are

known to promote electrophilic C-H activation include Pd(II), Pt(II) and Rh(III).[13]

These transformations often proceed with high selectivity for the less sterically

hin-dered C-H bond of a molecule, since the C-H bond reacts directly with the metal

b) Electrophilic Substitution

- HL

H

The key distinguishing feature of ‘outer-sphere’ mechanism is that the substrate

does not interact directly with the transition metal, but instead reacts with an active

coordinated ligand of the transition metal ([M]=X, M is transition metal, X is

lig-and).[10] The ligand is typically an oxo-, imido- or carbene species (Scheme 1.5) The

cleavage of C-H bond could proceed by either direct insertion (Scheme 1.5a) or

H-atom abstraction/radical rebound process (Scheme 1.5b).[13] Transition metals that

are known to catalyze through these indirect C-H functionalization reactions include

Fe(III), Mn(III), Ru(IV) and Rh(II).[13] These transformations typically show high

se-lectivity for weaker C-H bonds, such as benzylic, allylic and adjacent to a heteroatom,

because of the radical and/or cationic intermediate

Scheme 1.5 ‘Outer-sphere’ mechanism of C-H activation

b)

H-Atom Extraction Radical Rebound

a) Direct Insertion

[M] =X [M] =X

R [M]-X

H X

R

H

-

[M]

It should be noted that there are other different classifications of

transi-tion- metal-catalyzed C-H activation mechanisms Shul’pin divided all the C-H bond

splitting reactions which are promoted by metal complexes into three groups based on

their mechanisms.[11] Crabtree labeled the mechanisms as ‘organometallic’ and

‘coor-5

dination’, which was similar with Sanford’s ‘inner-sphere’ and ‘outer-sphere’

classifi-cation method mentioned above.[12] Bercaw gave a more detailed classification:

‘oxi-dative addition’, ‘σ-bond metathesis’, ‘metalloradical activation’, ‘1,2-addition’ and

‘electrophilic activation’.[13] Another thing to be noted is that the different

classifica-tion methods are all rather approximate division of all the known reacclassifica-tions in

accord-ance with their mechanisms Nevertheless, the unambiguous assignment of a process

to a particular type requires a detailed knowledge of the reaction mechanism

Unfor-tunately, many processes’ mechanisms have not yet been elucidated even broadly

The biggest challenge of transition-metal-catalyzed C-H bond functionalization

should be regioselectivity because most organic molecules contain many different

types of C-H bonds Therefore, developing transformations that regioselectively

func-tionalize a single C-H bond within a complex structure remains a long-standing

criti-cal challenge in this field Until now, a number of approaches have been used to

ad-dress this problem The popular ones include: (i) the use of substrates containing

weaker or activated C–H bonds, such as benzylic, allylic and adjacent to a

heteroa-tom,[14] (ii) the use of σ-chelating directing groups, which lead to ortho-selectivity

through the formation of a conformationally rigid five-, six- or seven- membered

cy-clic pre-transition state,[15] (iii) the use of transition metal catalysts/ligands to control

regioselectivity.[16] Recently, Gaunt reported an elegant Cu-catalyzed arylation

meth-odology to functionalize all three positions of anilines with exquisite selectivity

(Scheme 1.6).[17] Yu reported another Pd-catalyzed method to activate meta-C-H

bonds via an end-on template strategy (Scheme 1.7).[18] This method overrides

or-tho-directing effects as well as electronic and steric biases on the appended arene

One thing to be mentioned is that there are a number of non-transition metal

cat-alyzed C-H bond functionalization reactions, including electrophilic aromatic

substi-tutions (such as the well-known Friedel–Crafts reactions), directed

reac-tions.[21] They are widely used in synthetic organic chemistry and often exhibit

com-7

plementary levels of reactivity, functional group tolerance and selectivity to the

tran-sition-metal-catalyzed reactions

One of the over-arching goals of the research in Dr Wang’s lab is to pursue

methodologies that employ unactivated internal alkynes as building blocks to

synthe-size biologically and pharmaceutically important molecules via Pd-catalyzed C-H

functionalization strategies So, the next section will give a brief summary of

Pd-chemistry, including traditional Pd-catalyzed crossing-coupling reactions and

modern Pd-catalyzed C-H functionalization/C-C coupling reactions, and then put an

emphasis on recent Pd-catalyzed alkyne chemistry

1.2 Traditional Pd(0)-Catalyzed Cross-Coupling Reactions

Traditional Pd(0)-catalyzed cross-coupling reactions have found widespread

popularity in synthetic chemistry and the common ones are listed in Table 1.1.[22]

These reactions involve developing methods for C-C and C-heteroatom bonds

for-mation under mild reaction conditions and with high degrees of selectivity All of the

traditional Pd(0)-catalyzed cross-coupling reactions continue to enjoy avid attention

from the academic and industrial communities Substantial growth in this area has

taken place during the last decade in terms of publications and patents, with the

Suzu-ki-Miyaura, Heck and Sonogashira cross-coupling reactions proving by far the most

popular ones.[22]

Table 1.1 Traditional Pd(0)-catalyzed cross-coupling reactions

1[23] Heck Reaction

I

PdCl2(1.0 mol%) KOAc, MeOH, 120oC 74% yield Mizoroki 1971

Heck 1972

I Pd(OAc) 2 (1.0 mol%)

n-Bu3N, 100oC 75% yield

2[24,25]

Corriu-Kumada Reaction

[Pd(PPh 3 ) 4 ] (0.029 mol%) Benzene, R.T , 3h99% yield Murahashi 1975

Heck 1975 Br

88% yield

[Pd(OAc) 2 (PPh 3 ) 2 ] (2 mol%)

Et3N, 100oC, .5 h Br

Me

MeMe

Me Me Me

[Pd(PPh 3 ) 4 ] (0.5mol%)

CuI(1mol%)

Et2NH, R.T , 3h90% yield

I Sonogashira 1975

4[27] Negishi Reaction

[PdCl 2 (PPh 3 ) 2 ] (5 mol%)

i-Bn2AlH(10mol%)

THF, R.T , 2h74% yield Negishi 1977

Jutand 1977 I

47% yield

ZnCl

[Pd(PPh 3 ) 4 ] (0.5 mol%) DMM/HMPA, reflux, 6 h

96% yield

[Pd(PPh 3 ) 4 ] (1 mol%) benzene, 100oC, 20 h

[PhCH 2 Pd(PPh 3 ) 2 Cl]

(0.05mol%) HMPA, 65oC, 10 min 89% yield

Still 1978 O

Cl Me

4 Sn

O Me SnBu3

B O O

98% yield

9

7[30] Hiyama Reaction

I

[Pd(allyl)Cl] 2 (2.5 mol%) TASF, HMPA, 50oC 89% yield Hiyama 1988

Denmark 1999

2 ] (5 mol%) TBAF(3.0 equiv.THF, R.T , 10min 91% yield

Buchwald 1995

Br PdCl2[P(o

tolyl) 3 ] 2

(2 mol%) NaOtBu, Toluene, 100 o C 86% yield

H

O H

N

N O

9[32] Tsuji-Trost Reaction

CO 2 Et

CO 2 Et

Na DMSO/EtOH, R.T.

CO 2 Et

CO 2 Et

CO 2 Et

CO 2 Et 41% yield 43% yield

DTPF(9mol%) KN(TMS) 2 (2.2 equiv.)THF, reflux, 45 min 79% yield Hartwig 1997

Buchwald 1997 Br

91% yield

Pd 2 (dba) 3 (1.5 mol%)

BINAP (3.6 mol%) NaOtBu, THF, 70 o C

I

Me O

O Me

O

O Me MeO

OMe

The generally accepted mechanisms for these Pd(0)-catalyzed cross-coupling

re-actions are depicted as four types based on different coupling partners (Scheme 1.8):

(i) The coupling partner is an alkene (Scheme 1.8a, Table 1.1, entry 1) The oxidative

addition of the aryl halide (pseudohalide) to the catalytically active Pd(0) species

ini-tiates the catalytic cycle The reaction progresses by co-ordination of an alkene to the

Pd(II) species, followed by its syn- migratory insertion The newly generated

organo-palladium species then undergoes syn- β-hydride elimination to form the alkene

prod-uct Subsequently, base-assisted elimination of HX from [HPdX] occurs to regenerate

the Pd(0) catalyst (ii) The coupling partner is an organometalic R-M species (Scheme

1.8b, Table 1.1, entries 2-8) The first step is also the oxidative addition of the aryl

halide (pseudohalide) to the catalytically active Pd(0) species to initiate the catalytic

cycle The oxidative addition is followed by transmetalation of an organometallic

species to generate a Pd(II) intermediate bearing the two organic coupling partner

fragments Subsequent reductive elimination results in C-C bond formation with the

regeneration of Pd(0) species to re-enter into the catalytic cycle One thing to be noted

is that the organometallic R-M species could be generated in situ from a carboxylic

acid, by, for example, the action of an additional metal or an additive, such as

TBAC.[34] (iii) The Tsuji–Trost reaction is conceptually a Pd(0)- mediated coupling

reaction, but is mechanistically different from the conventional cross-coupling

pro-cesses mentioned above and achieves an allylic substitution via an intermediate

π-allyl-Pd complex (Scheme 1.8c, Table 1.1, entry 9) First, the Pd(0) coordinates to

the alkene, forming a η2

which the leaving group is expelled and a η3

then adds to the allyl group regenerating the η2

comple-tion of the reaccomple-tion, the Pd(0) detaches from the alkene and starts again in the catalytic

cycle (iv) The end result of an α-arylation reaction is a formal C(sp2

)-C(sp3) coupling

of aryl halides (pseudohalides) with enolates generated in situ from various carbonyl

compounds such as ketones, amides, esters and aldehydes (Scheme 1.8d, Table 1.1,

entry 10) The first step is the oxidative addition of the aryl halides (pseudohalides) to

the catalytically active Pd(0) species Next is transmetalation of an intermediate

eno-late formed in situ to allow the final reductive elimination to achieve the C-C coupling

The mechanism of the α-arylation reaction follows the conventional cross-coupling

LG R

LG R

However, despite the many significant discoveries and developments in

tradi-tional Pd(0)-catalyzed cross-coupling reactions, there still remain some major

un-solved problems: (i) From the view points of efficiency and atom economy, the

prep-aration of pre- functional partners remains a challenge in academic and industrial

lev-els The installation of these pre-functional groups involves extra synthetic steps The

generation of waste after C-C bond formationis also not atom economic (ii) Only

partial success in C(sp2)-C(sp3) and C(sp3)-C(sp3) cross-coupling reactions involving

alkyl halides has been achieved (iii) The reaction mechanism is not clear Although

the steric and electronic effects of ligands involved in various steps of the catalytic

cycle are now reasonably rationalized, there remains, in many cases, a lack of

under-standing about the mechanism of the active Pd(0) catalytic species formation from the

preformed Pd(II) complexes (iv) In the area of asymmetric catalysis, simple methods

using chiral ligands to form enantioenriched products need to be developed, and

fur-ther to achieve practical and hence widely applications

In order to improve the efficiency and atom economy, Pd-catalyzed C-H bond

fuctionalization is developed for the direct conversion of C-H bonds into C-C and

C-heteroatom bonds, a route which is highly efficient and atom economic by avoiding

the use of aryl halides (pseudohalides) and/or organometallic reagents and leaving H

as byproduct This methodology is rapidly developed in the past decades, widely used

in synthetic organic chemistry and exhibits complementary levels of reactivity,

func-tional group tolerance and selectivity to the tradifunc-tional Pd(0)-catalyzed cross-coupling

reactions So, in next section, I will give a general introduction about the recent

de-velopment of modern Pd-catalyzed C-H activation/functionalization reactions

1.3 Modern Pd-Catalyzed C-H Functionalization Reactions

In the past decades, Pd-catalyzed C-H functionalization reactions have emerged

as promising new catalytic transformations, although development in this field is still

at an early stage compared to the traditional Pd(0)-catalyzed cross-coupling reactions

This section includes a brief introduction of four extensively investigated modes of

catalysis for C-H bond functionalization: Pd(0)/Pd(II), Pd(II)/Pd(IV),

Pd(0)/Pd(II)/Pd(IV) and Pd(II)/Pd(0) catalysis Then emphasis is directed towards the

13

recent development of Pd-catalyzed alkyne chemistry involving C-H

functionaliza-tion

1.3.1 C-H Bond Functionalization via Pd(0)/Pd(II) Catalysis

The Pd(0)/Pd(II) C-H bond activation mode has been developed extensively in

the past three decades The initial proof ofconcept was established using electron-rich,

hence more reactive, heterocycles as substrates by Sakai and Ohta in 1982 (Scheme

1.9).[35] After these pioneering studies, many research groups have reported about C-H

bond cleavage of electron-rich heterocycles via the Pd(0)/Pd(II) catalysis.[36] The

sub-tle effects of the choice of catalysts, aryl halides and N-protecting groups on both

re-activity and selectivity have been observed.[36d-e]

Scheme 1.9 C-H bond cleavage of electron-rich heterocycles via Pd(0)/Pd(II)

cataly-sis

O

N Me

H

TsO

Pd/C(10mol%) NaHCO3, HMPT

100oC, 44% yield O

N Me

Ph TsO

N H

H

N

Cl Me

[Pd(PPh 3 ) 4 ] (4 mol%) KOAc(1.0 equiv.)DMA, reflux, 12 h 54% yield

N H

N N Me

Me

a)

b)

I

In 1997, Rawal discovered an intramolecular non- heterocyclic arene bond

aryla-tion, that phenolic OH group promotes ortho-arylation from an ether tethered aryl

bromide (Scheme 1.10a).[37] This reaction appears to be the first example of the

aryla-tion of non-heterocyclic arenes Within the same year, intermolecular arylaaryla-tion of

2-phenylphenol was demonstrated by Miura, making intermolecular arylation

reac-tions with non-heterocyclic arenes via Pd(0)/Pd(II) catalysis possible (Scheme

1.10b).[38] The arylation of C(sp3)-H bonds is also demonstrated, but much limited to

intramolecular reactions, among which a recent elegant example by Fagnou was to

develop a general method for the preparation of dihydrobenzofurans (Scheme

Css2COO3(1..1e uivv..)

PivvOOH(0..3e uivv..)M

A general mechanism for this mode of Pd(0)/Pd(II) catalysis is depicted in

Scheme 1.11, which is similar with the traditional Pd(0)-catalyzed cross-coupling

re-action mechanism (Scheme 1.8b), except that the second step is C-H activation, not

transmetalation This mode of Pd(0)/Pd(II) catalysis is the closest to the conventional

cross-coupling reactions A major challenge that still remains for this mode of

cataly-sis is to address its relatively limited substrate scope and versatility

Scheme 1.11 Pd(0)/Pd(II) catalytic cycle

15

Pd0 R-X

Oxidative Addition

Pd II

R X

R 1 H

C-H Activation

Pd II

R

R1

R-R1Reductive Elimination

1.3.2 C-H Bond Functionalization via Pd(II)/Pd(IV) Catalysis

Traditionally, Pd-catalyzed processes involve Pd(0)/Pd(II) complexes as

inter-mediates In recent times, the involvement of Pd(IV) complexes have been implicated

in many new synthetic methodologies, for which important advances have been made

in the last decades.[40] The first case that involved the Pd(IV) complex as intermediate

was reported by Tremont and Rhaman.[41] They described the first intriguing

methyla-tion of the ortho-C-H bond in anilides (Scheme 1.12) In this work, the reactivity of

the cyclopalladated intermediate with MeI was established and a plausible Pd(IV)

in-termediate was proposed

Scheme 1.12 ortho-Methylation of anilide via Pd(II)/Pd(IV) catalytic cycle

HN O

H MeI

Pd(OAc) 2

AgOAc TFA, 100oC, h

HN O Me

Pd IV I OAc Me

proposed Pd(IV) intermediate

The proposed oxidation of Pd(II) to Pd(IV) by MeI was unambiguously

sup-ported by X-ray crystallography The first crystal structure was obtained by Canty in