Utilization of ketoxime esters as building blocks for the sythesis of b ketosulfones and furocoumarins

Novel pathway to β-ketosulfones through ketoxime esters under copper catalysis .... Synthesis of β-ketophosphonates through α-functionalization of ketoxime esters under copper catalysi

VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY

BACH KHOA UNIVERSITY

-

TO ANH TUONG

UTILIZATION OF KETOXIME ESTERS

AS BUILDING BLOCKS FOR THE SYNTHESIS

OF β-KETOSULFONES AND FUROCOUMARINS

Major: Chemical Engineering

Number: 60.52.75

MASTER THESIS

HO CHI MINH CITY, AUGUST 2018

CÔNG TRÌNH ĐƯỢC HOÀN THÀNH TẠI TRƯỜNG ĐẠI HỌC BÁCH KHOA –ĐHQG -HCM

Cán bộ hướng dẫn khoa học 1: GS TS Phan Thanh Sơn Nam

3 Phản biện 2: PGS TS Nguyễn Thị Phương Phong

4 Ủy viên: PGS TS Nguyễn Đình Thành

ĐẠI HỌC QUỐC GIA TP.HCM CỘNG HÒA XÃ HỘI CHỦ NGHĨA VIỆT NAM TRƯỜNG ĐẠI HỌC BÁCH KHOA Độc lập – Tự do – Hạnh phúc

NHIỆM VỤ LUẬN VĂN THẠC SĨ

Họ tên học viên: Tô Anh Tường MSHV: 1770013

Chuyên ngành: Kỹ thuật Hóa học Mã số: 60.52.75

I Tên đề tài

Utilization of ketoxime esters as building blocks for the synthesis of β-ketosulfones and furocoumarins (Sử dụng ketoxime ester làm nguyên liệu để tổng hợp các dẫn xuất β-

ketosulfone và furocoumarin)

Nhiệm vụ và nội dung:

1 Khảo sát hoạt tính xúc tác của MOF Cu2(OBA)2BPY cho phản ứng tổng hợp

các dẫn xuất β –ketosulfone từ các ketoxime ester

2 Phát triển phương pháp mới sử dụng ketoxime ester để tổng hợp khung furo[3,2,c]coumarin

II Ngày giao nhiệm vụ: 15/01/2018

III Ngày hoàn thành nhiệm vụ: 15/06/2018

IV Cán bộ hướng dẫn: GS.TS Phan Thanh Sơn Nam

TP.HCM, ngày 16 tháng 06 năm 2018

TRƯỞNG KHOA KỸ THUẬT HÓA HỌC

ACKNOWLEDMENTS

I would like to thank:

Nguyen Thai Anh Nguyen Thi Hong Ngoc Nguyen Huynh Thanh Hai

Duong Ngoc Tan Xuan Nguyen Dang Hieu

Le Van Thanh

And my family

ABSTRACT

In this master thesis, I would like to present two new protocols that exploited the potential of reactive ketoxime esters in organic synthesis Our studies also overcame some of the remaining limitations of this research field

In the first work, Cu2(OBA)2BPY MOF was successfully synthesized and employed to be an efficient heterogeneous catalyst for the oxidative coupling of ketoxime esters to form β-sulfonylvinylamines, which were then hydrolyzed to obtain

many times without a significant deterioration in the catalytic performance This work provided a typical example for the promising combination of copper-based MOFs as heterogeneous catalysts and reactive ketoxime esters

In the second study, a novel copper-catalyzed direct Cα-O bond formation of

ketoxime esters followed by cyclization to obtain furo[3,2,c]coumarins was explored

The new approach featured a facile synthesis of wide range of these bicyclic skeletons

in good yields form readily available materials and cheap CuBr2 catalyst, addressing the issues of previous methods

TABLE OF CONTENTS

ACKNOWLEDMENTS iv

ABSTRACT v

TABLE OF CONTENTS vi

LIST OF ABBREVIATIONS viii

LIST OF SCHEMES x

LIST OF FIGURES xiii

LIST OF TABLES xv

LIST OF PUBLICATIONS xvi

Chapter 1 - Ketoxime esters as versatile building blocks in organic synthesis 1

1 Introduction 1

2 Ketoxime esters under copper catalysis 2

Annulations of oxime esters under copper catalysis 3

α-functionalization of ketoxime esters under copper catalysis 8

Summary 10

3 Thesis objectives 11

Chapter 2 - An efficient access to β-ketosulfones via ketoxime esters 12

1 Literature review 12

Introduction 12

Previous approaches 13

Our approach and objectives 19

2 Experimental section 29

Materials and instrumentations 29

Preparation and characterization of Cu2(OBA)2BPY 30

Catalytic studies 30

3 Results and discussion 33

Preparation and characterization of Cu2(OBA)2BPY 33

Catalytic studies 34

4 Conclusion 52

Chapter 3 - A novel pathway to furo[3,2,c]coumarins via ketoxime esters 53

1 Literature review 53

Introduction 53

Previous approaches 54

Our approach and objectives 64

2 Experimental section 67

Materials and instrumentation 67

Catalytic studies 67

3 Results and discussion 69

Screening reaction conditions 70

Proposing the reaction mechanism 75

Expansion of the substrate scope 77

4 Conclusion 81

Chapter 4 - Conclusion 82

REFERENCES 83

APPENDICES 91

CAN Cerium (IV) ammonium nitrate

COF Covalent organic framework

CPO Coordination polymer of Oslo

EWG Electron withdrawing group

FID Flame ionization detector

FT-IR Fourier-transform infrared spectroscopy

GC Gas chromatography

GC-MS Gas chromatography coupled with mass spectrometry

HKUST (Hong-Kong University of Science and Technology

m-CPBA meta-Chloroperoxybenzoic acid

mesoMOF Mesoporous metal organic framework

MIL Mate´riauxs de l’Institut Lavoisier

MOCN Metal-organic coordination network

MOF Metal-organic framwork

MPF Metal peptide framework

RPF Rare-earth polymeric framework

SBU Secondary building unit

SC-XRD Single crystal X-ray diffraction

SEM Scaning electron microscope

TEM Transmission electron microscope

ZIF Zeolitic imidazolate framework

ZMOF Zeolite-like metal organic framework

LIST OF SCHEMES

Scheme 1.1 General pathways for N-O bond activation of oxime esters under

transition-metal catalysis 1

Scheme 1.2 Annulation of ketoxime esters and aldehydes to pyridines 3

Scheme 1.3 Modular pyridine synthesis from oximes and enals 3

Scheme 1.4 Three-component approach to poly-substituted pyridines 4

Scheme 1.5 Three-component approach to 2-aminopyridines 4

Scheme 1.6 Pathway from ketoxime esters to pyrazolines 4

Scheme 1.7 Three-component synthesis of pyrazoles 5

Scheme 1.8 Synthesis of benzo-fused pyrazoles from o-bromophenyl oxime esters and amines 5

Scheme 1.9 Pyrazolo[1,5-a]indoles synthesis from ketoxime esters 5

Scheme 1.10 Homo-coupling of ketoxime esters to symmetrical pyrroles 6

Scheme 1.11 Synthesis of asymmetrically substituted pyrroles from ketoximes 6

Scheme 1.12 Synthesis of 2-aminothiazoles from ketoxime esters 7

Scheme 1.13 Synthesis of 2-alkoxythiazoles from ketoxime esters 7

Scheme 1.14 A straightforward way from pyridines to imidazo[1,2-a]pyridines 7

Scheme 1.15 Cyclization of o-haloaryloxime acetates to construct nitrogen-containing heterocycles 8

Scheme 1.16 Novel pathway to β-ketosulfones through ketoxime esters under copper catalysis 8

Scheme 1.17 Synthesis of β-ketophosphonates through α-functionalization of ketoxime esters under copper catalysis 9

Scheme 1.18 Synthesis of enaminones via C-C cross-coupling α-functionalization of ketoxime esters 9

Scheme 2.1 β-ketosulfones as vital intermediates in organic transformation 12

Scheme 2.2 The summary of common pathways to prepare β-ketosulfones 13

Scheme 2.3 α-acylation of alkylsulfones 13

Scheme 2.4 Sulfonylation of silyl enol ethers 14

Scheme 2.5 Sulfonylation of α-haloketones by sodium arene sulfinates via nucleophilic

Scheme 2.6 Oxidation of β-ketosulfides 15

Scheme 2.7 The oxidative coupling of alkynes and sulfinic acids 15

Scheme 2.8 The oxidative coupling of alkynes and sulfinates in aqueous media 16

Scheme 2.9 The oxidative coupling of alkenes and sulfinates in aqueous media 16

Scheme 2.10 The oxidative coupling of alkenes and sulfinic acids 16

Scheme 2.11 The oxidative coupling of arylketones and sulfinic sodium sulfinates to prepare β-ketosulfones 17

Scheme 2.12 The addition of arylboronics acids to (arylsulfonyl)acetonitriles followed by the hydrolysis to prepare β-ketosulfones 17

Scheme 2.13 The two-step synthesis of (arylsulfonyl)acetonitriles 17

Scheme 2.14 The sulfonylation of oxime acetate followed by the hydrolysis to prepare β-ketosulfones 18

Scheme 2.15 The preparation of oxime acetates 18

Scheme 2.16 The general strategy of the solvothermal synthesis 22

Scheme 2.17 Synthetic pathway to ketoxime esters 31

Scheme 2.18 Reaction to synthesize sodium sulfinates 31

Scheme 2.19 The model reaction for optimization 35

Scheme 2.20 The optimal reaction conditions 42

Scheme 2.21 Proposed reaction mechanism 45

Scheme 2.22 Expansion of the substrate scope 49

Scheme 3.1 A possible synthetic pathway of 4-hydroxycoumarins from available compounds 54

Scheme 3.2 Conventional synthesis of furo[3,2-c]coumarins from 4-hydroxycoumarins and α-haloketones 54

Scheme 3.3 Synthesis of α-tosyloxyketones from hypervalent iodine followed by cyclization of 4-hydroxycoumarins 55

Scheme 3.4 Aldehydes as C-3 sources for construction of furo[3,2-c]coumarins 55

Scheme 3.5 Isocyanides as ring-closure partners 56

Scheme 3.6 Furo[3,2-c]coumarin synthesis via phosphine zwitterions 57

Scheme 3.7 Unexpected exploration from dicoumarol synthesis 57

Scheme 3.8 One-pot pseudo three-component synthesis of furo[3,2-c]coumarins 57

Scheme 3.9 One-pot synthesis of furo[3,2-c]coumarins under CuBr2/O2 catalytic

system 58

Scheme 3.10 Cyclization of 4-hydroxycoumarins and nitroallylic acetates with the presence of base 58

Scheme 3.11 Cyclization of 4-hydroxycoumarins and β-nitrostyrenes under microwave irradiation 59

Scheme 3.12 Selective synthesis of furo[3,2-c]coumarins by reaction of 4-hydroxycoumarins and nitroallylic alcohols 59

Scheme 3.13 Four-component reaction producing furo[3,2-c]coumarins 60

Scheme 3.14 Oxidative addition of 4-hydroxycoumarins to electron-rich alkenes promoted by metal oxidants 60

Scheme 3.15 Aerobic oxidative cyclization of 4-hydroxycoumarins and alkenes 61

Scheme 3.16 Cyclization of 3-diazo-4-hydroxycoumarins and terminal alkynes catalyzed by rhodium (II) 61

Scheme 3.17 Two-step synthesis of furo[3,2-c]coumarins catalyzed by palladium 62

Scheme 3.18 Sequential Pd/Cu-catalyzed alkynylation and intramolecular hydroalkoxylation 62

Scheme 3.19 Visible-light-promoted iridium-catalyzed alkyne insertion with 3-bromo-4-hydroxycoumarins followed by annulation 63

Scheme 3.20 Aerobic oxidative annulation of un-activated 4-hydroxycoumarins and terminal alkynes catalyzed by FeCl3/ZnI2 63

Scheme 3.21 The observation from our previous study 65

Scheme 3.22 Synthetic pathway to ketoxime esters 68

Scheme 3.23 Model reaction and starting conditions 69

Scheme 3.24 The optimal reaction conditions 74

Scheme 3.25 Control experiments 75

Scheme 3.26 Plausible reaction mechanism 76

Scheme 3.27 Expansion of the substrate scope 77

LIST OF FIGURES

Figure 2.1 (a) The components of MOF-5: the Zn4O(−CO2)6 SBU as an octahedron,

the ditopic terephthalate linker as a rod and their assembly into the crystalline net 20

Figure 2.2 The most commonly used methods for MOF preparation 21

Figure 2.3 Development of MOF catalysts in comparison to the MOF in the recent years 22

Figure 2.4 Link between Cu(II) ions and ligands in MOF Cu2(OBA)2BPY 24

Figure 2.5 The coordination modes of OBA2- anions with metal: (I) bis(chelating bidentate), (II) bis(bridging-bidentate), (III) both bis(chelating bidentate) and bis(bridging-bidentate) 24

Figure 2.6 The eight-membered ring chain 25

Figure 2.7 Structure 2D helical layers 25

Figure 2.8 The 3D pillared-layer structure of MOF Cu2(OBA)2BPY 25

Figure 2.9 (a) The 3D network with helical channels by BPY bridges in Cu2(OBA)2BPY viewed along the c-axis, all OBA2- anions are omitted for clarity (b) Spacefilling diagram of the helical chains in the 2D helical layer (c) The 3D network of Cu2(OBA)2BPY viewed along the c-axis 26

Figure 2.10 Reaction of benzothiazole with iodobenzene using Cu2(OBA)2BPY catalyst 27

Figure 2.11 Our approach to β-ketosulfones synthesis 28

Figure 2.12 Synthesis of Cu2(OBA)2BPY 33

Figure 2.13 Powder X-ray diffraction patterns of Cu2(OBA)2BPY a) The activated Cu2(OBA)2BPY; b) The simulated Cu2(OBA)2BPY 34

Figure 2.14 Effect of temperatures on the reaction yield 35

Figure 2.15 Effect of reactant molar ratio on the reaction yield 37

Figure 2.16 Effect of different solvents on the reaction yield 38

Figure 2.17 Effect of reactant concentrations on the reaction yield 39

Figure 2.18 Effect of catalyst amount on the reaction yield 40

Figure 2.19 Effect of reaction times on the reaction yield 41 Figure 2.20 Comparison of catalytic activity of Cu2(OBA)2BPY to other copper-based

Figure 2.21 Comparison of catalytic activity of Cu2(OBA)2BPY to other copper-based

homogeneous catalysts 44

Figure 2.22 Leaching test results compared to optimal condition 46

Figure 2.23 The reutilization of the catalyst 47

Figure 2.24 FT-IR analyses of the new (a) and recovered (b) catalyst 48

Figure 2.25 XRD determination of the new (a) and recovered (b) catalyst 48

Figure 3.1 Structures of some synthetic furanocoumarins 53

Figure 3.2 Effect of catalysts on the reaction yield 70

Figure 3.3 Effect of solvents on the reaction yield 71

Figure 3.4 Effect of reaction molar ratios on the reaction yield 72

Figure 3.5 Effect of temperatures on the reaction yield 73

Figure 3.6 Effect of catalyst amounts on the reaction yield 74

LIST OF TABLES

Table 2.1 Synthesis of β-ketosulfones via Cu2(OBA)2BPY-catalyzed direct C-S coupling reaction followed by hydrolysis step 49

Table 3.1 Synthesis of substituted furo[3,2,c]coumarins via copper-catalyzed

4-hydroxycoumarins with ketoximes 77

LIST OF PUBLICATIONS

Related publications:

1 Tuong A To, Chau B Tran, Ngoc T H Nguyen, Hai H T Nguyen, Anh T

Nguyen, Anh N Q Phan and Nam T S Phan An efficient access to ketosulfones via β-sulfonylvinylamines: metal–organic framework catalysis for

β-the direct C–S coupling of sodium sulfinates with oxime acetates RSC

Advances, 2018, 8, 17477-17485 (See published paper at the end of this thesis)

2 Tuong A To, Yen H Vo, Anh T Nguyen, Anh N Q Phan, Thanh Truong and

Nam T S Phan A new route to substituted furocoumarins via copper-catalyzed

cyclization between 4-hydroxycoumarins and ketoximes, Organic and

Biomolecular Chemistry, 2018,16, 5086-5089 (See published paper at the end of

this thesis)

Other publications:

1 Yen H Vo, Thanh V Le, Hieu D Nguyen, Tuong A To, Hiep Q Ha, Anh T

Nguyen, Anh N.Q Phan and Nam T.S Phan Synthesis of quinazolinones and benzazoles utilizing recyclable sulfated metal-organic framework-808 catalyst in

glycerol as green solvent, Journal of Industrial and Engineering Chemistry, 2018,

64, 107-115

2 Thanh T Hoang, Tuong A To, Vi T.T Cao, Anh T Nguyen, Tung T Nguyen,

Nam T.S Phan Direct oxidative CH amination of quinoxalinones under

copper-organic framework catalysis, Catalysis Communications, 2017, 101, 20-25

3 Yen H Vo, Tuong A To, Hue T T Nguyen, Phuong T M Ha, Son H Doan,

Tan H L Doan, Ha V Le, Thach N Tu, Nam T S Phan Iron-catalyzed one-pot sequential transformations: Synthesis of quinazolinones via oxidative Csp3-H bond activation using a new metal-organic framework as catalyst, submitting

Chapter 1 - Ketoxime esters as versatile building blocks in organic synthesis

1 Introduction

The early application of oximes started 19th century, which are well-known for the Beckmann rearrangement, the Semmler–Wolff reaction as well as for reagents in organic synthesis and applications in industry [1, 2] In the last decade, oxime derivatives, especially O-acyl oximes, have gained a lot of attention and have been applied as versatile building blocks under many kinds of transition-metal catalysis, such

as Pd, Cu, Rh, Ru, etc., especially for the construction of nitrogen containing heterocycles as well as nitrogen containing functional groups In terms of reaction mechanism, highly active imino radicals are generated via single-electron-transfer

oxidation of a transition metal with the N–O σ bond (Scheme 1.1a) Oxidative addition

of a low-valance metal to the N–O σ bond forming imino-metal complexes is also a

proposed pathway to activation of ketoxime esters (Scheme 1.1b) [3] These resulting

reactive intermediates could be further utilized to synthesize variety of valuable products

Scheme 1.1 General pathways for N-O bond activation of oxime esters under

hydroxylamine derivatives are generally more favored than other bonds so this cleavage usually is utilized to initiate further transformation for construction of a broad kinds of functionalized compounds [5]

Among various transition metals employed for this transformation of oxime esters, copper is the most common catalyst which was reported in many publications throughout the literature The usage of oxime esters under copper catalysis will be reviewed in the next part

2 Ketoxime esters under copper catalysis

Transition-metal-catalyzed selective functionalization of the C–H bond to direct oxidative coupling forming C–C or C-heteroatom bonds has gained great interest in terms of short step and high atom economy [6-11] However, they also face some challenges: the late transition metal catalysts are expensive and toxic, and stoichiometric amounts of oxidants are needed To address problems cause by using stoichiometric oxidants, they are replaced by green oxidants such as O2 [12-14] or an internal oxidant [5, 15-17]

As aforementioned in Scheme 1.1, the activation of N-O bond of oxime esters

are generally along with oxidation of transition metals There is consequently an ingenious synthetic strategy that designs hydroxylamine derivatives as both reactants and oxidants towards transition metal-catalyzed oxidative C–H functionalization [5] Among the various metals employed, copper has gained significant attention thanks to its availability, low cost, low toxicity as well as ease of use [18-23] The combination of copper salts with these oxime derivatives has emerged as a promising strategy in green chemistry to construct carbon-carbon or carbon-heteroatom bonds [24-29]

The reactions of oxime esters with copper catalysis have been described and they are divided into two main categories: Annulations of oxime esters and α-functionalization of ketoxime esters [3, 5] These two classifications will be reviewed

in followed subparts

Annulations of oxime esters under copper catalysis

2.1.1 Poly-substituted pyridine synthesis

One of the most classical reactions of oxime esters with copper catalysis was the publication of Guan and co-workers in 2011 In this report, the annulation of two ketoxime ester molecules and an arylaldehyde under copper salt/NaHSO3 catalytic

system generated multi-substituted pyridines (Scheme 1.2) [30] This method addressed

the current desire of the construction of pyridine rings which are compatible with various functional groups and using readily available starting materials Furthermore, this also marked the first step of the combination of oxime esters and copper catalyst

Scheme 1.2 Annulation of ketoxime esters and aldehydes to pyridines [30]

Another approach to poly-substituted pyridine using ketoxime esters was of Yoshikai and co-worker A new catalytic system, copper salt-iminium, was employed

to catalyze a cascade reaction for modular pyridine synthesis from oximes and enals

(Scheme 1.3) [31] After optimization study, the authors defined the methods using

pyrrolidinium salt or i-Pr2NH This method showed its efficiency for a wide range of ketoxime esters such as aryl, heteroaryl, alkenyl, alkyl and even cyclic ketones

Scheme 1.3 Modular pyridine synthesis from oximes and enals [31]

Followed the same synthetic strategy, Jiang and co-workers developed their own method from oxime esters to poly-substituted pyridines The Michael receptors, enals,

in the previous report were replaced by in-situ enones generated via Knoevenagel reaction between aldehydes and activated methylene compounds under catalysis of base

(Scheme 1.4) [27]

Scheme 1.4 Three-component approach to poly-substituted pyridines [27]

Another report with the same strategy was reported by Cui and co-workers in

2014 The condensation of malonitrile and aldehydes catalyzed by piperidine generated

the Michael receptors for the annulation with ketoxime esters (Scheme 1.5) [26] The

remarkable point of this report was the production of 2-aminopyridine products which were vital compounds to construct N-heterocycles

Scheme 1.5 Three-component approach to 2-aminopyridines [26]

2.1.2 Pyrazole synthesis

In the previously mentioned publication, Cui and co-workers also reported a pathway from ketoxime esters to pyrazolines N-sulfonylimines were coupling partners

of ketoxime esters to perform cyclization reaction producing pyrazolines (Scheme 1.6)

[26] This was the first time pyrazoline skeletons to be synthesized by ketoxime esters under copper catalysis

Scheme 1.6 Pathway from ketoxime esters to pyrazolines [26]

In 2014, copper-catalyzed cascade reactions of oxime acetates, amines and aldehydes for the preparation of 1,3- and 1,3,4-substituted pyrazoles was reported by Jiang and co-workers The present relay oxidative process involved copper-promoted N–O bond cleavage and C–C/C–N/N–N bond formations to produce pyrazolines Different to the last report, in-situ generated pyrazolines were gone through dehydrogenative aromatization under Cu/O2 system to afford pyrazoles (Scheme 1.7)

good functional group tolerance Especially, the combination of oxime esters and O2

made this transformation into a totally redox neutral process

Scheme 1.7 Three-component synthesis of pyrazoles [25]

In the same year, Jiang’s group continued to report another synthetic pathway to pyrazole heterocyles from o-bromophenyl oxime esters and amines The domino reactions of Ullmann-type N-arylation followed by N-N bond formation under copper catalysis and support of base yielded a wide range of benzo-fused pyrazole derivatives

concise synthesis of pyrazolo[1,5-a]indole derivatives (Scheme 1.9) [33] High atom-

and step-economy were notable features provided by this transformation Mechanistic studies indicated that the reaction proceeds through a radical procedure Oximes as an internal oxidant were demonstrated to be a driver to initiate aerobic oxidation

Scheme 1.9 Pyrazolo[1,5-a]indoles synthesis from ketoxime esters [33]

2.1.3 Poly-substituted pyrrole synthesis

In 2014, Guan’s group utilized in the same CuBr/NaHSO3 catalytic system of their previous report in 2011 [30] to develop an efficient synthetic pathway for symmetrical pyrroles from aryl alkyl ketoxime acetates in the absence of aldehydes

(Scheme 1.10) [34] This transformation required high reaction temperature (140 oC) Furthermore, limitation of substrate scope was also a drawback when ethyl ketoxime acetates show very low reactivity For example, acetophenone oxime ester affords 2,5-diphenylpyrrole only in 10% yield

Scheme 1.10 Homo-coupling of ketoxime esters to symmetrical pyrroles [34]

For preparation of asymmetrically substituted pyrroles, Jiang and co-workers employed a CuCl/Na2SO3 catalytic system, catalyzed the oxidative [3+2] cycloaddition

of ketoximes and electron-deficient alkynes (Scheme 1.11) [35] Generally, the reaction

of oxime acetates with dimethyl acetylenedicarboxylate smoothly gave the desired products in moderate to good yields Unlike the previous approach, methyl, non-methyl

as well as dialkyl ketoximes provided same high reactivities

Scheme 1.11 Synthesis of asymmetrically substituted pyrroles from ketoximes [35] 2.1.4 Thiazole synthesis

Ketoxime esters under copper catalysis was also an efficient tool to construct sulfur-containing heterocycles The first report to synthesize thiazoles involving oximes and copper catalyst was published in 2016 by Jiang’s group The cyclization of ketoxime esters and isothiocyanates was performed under CuI/Cs2CO3 catalytic system,

generating 2-aminothiazoles with up to 90% yields (Scheme 1.12) [29]

Scheme 1.12 Synthesis of 2-aminothiazoles from ketoxime esters [29]

In 2018, Jiang’s group expanded the application of ketoxime esters in thiazole synthesis to 2-alkoxythiazole derivatives Another sulfur source, xanthates, was

employed instead of isothiocyanates to obtain 2-alkoxythiazoles (Scheme 1.13) [36]

Scheme 1.13 Synthesis of 2-alkoxythiazoles from ketoxime esters [36]

2.1.5 Other nitrogen-containing heterocycles

Beside pyridines, pyrazoles, pyrroles or thiazoles, the role of ketoxime esters as flexible reagents was also proved by the synthesis of other more complex nitrogen-containing heterocycles such as imidazo[1,2-a]pyridines, quinolines, quinazolines and

so on In 2013, Jiang and co-workers were successful to directly functionalize pyridines with ketoxime esters under copper catalysis and oxygen atmosphere () [37] This report provided a straightforward way from pyridines to this scaffold, avoiding the current intensive usage of 2-aminopyridines, which were traditionally derived from pyridines

Scheme 1.14 A straightforward way from pyridines to imidazo[1,2-a]pyridines [37]

In 2016, based on the previous report in 2014 [32] (Scheme 1.8), which was the

arylation of nucleophiles with o-haloaryl oxime acetates followed by annulation to construct nitrogen-containing rings, Jiang’s group developed a novel method to prepare isoquinolines and indolo[1,2-a]quinazolines Indole derivatives were employed as reactants in Ullmann-type N-arylation with o-haloaryl oxime acetates prior to C-N bond

formation to generate indolo-fused quinazolines (Scheme 1.15a) Similarly,

isoquinolines were also produced with the same approach by reaction of o-haloaryl

oxime acetates with activated methylene compounds (Scheme 1.15 b and c) [38]

Scheme 1.15 Cyclization of o-haloaryloxime acetates to construct nitrogen-containing

heterocycles [38]

α-functionalization of ketoxime esters under copper catalysis

Along with being the powerful synthetic pathways to nitrogen-containing heterocycles, ketoxime esters under copper catalysis was also used as an efficient strategy to directly α–functionalize ketones or enamines One of the most classical methods in this category was reported by Jiang’s group in 2013 Alkyl aryl oxime esters were employed in direct oxidative C–S bond formation with sodium sulfinates as the

coupling partners, providing a novel access to sulfonylvinylamines Because ketosulfones are an important class of organic synthesis intermediates, β-

β-sulfonylvinylamines were further hydrolyzed to obtain these valuable compounds

(Scheme 1.16) [24] A wide substrate scope, available starting materials and avoiding

the usage of additives were strong points of this pathway in comparison of the

conventional methods to β-ketosulfones

Scheme 1.16 Novel pathway to β-ketosulfones through ketoxime esters under copper

catalysis [24]

Because phosphorus-containing compounds had wide applications in many fields,

a great challenge in oxidative Csp3-H/P-H cross-coupling, especially the direct ketone

α-Csp3-H/P-H coupling In this scenery, Lei and co-workers presented a solution for this current problem by employment of ketoxime esters and copper catalyst in 2015 In details, oxidative Csp3-H/P-H cross-coupling reaction of ketoxime esters and phosphine oxides were performed under CuCl/PCy3 catalytic system to produce α-phosphorylketimines Anhydride acetic was added into the reaction to convert ketimines

to enamides, shifting the equilibrium of the first reaction toward the ketimines After

that, reaction mixture was treated with aqueous HCl to obtain β-ketophosphonates

(Scheme 1.17) [39]

Scheme 1.17 Synthesis of β-ketophosphonates through α-functionalization of

ketoxime esters under copper catalysis [39]

Copper catalyst also worked for the case of C-C cross-coupling functionalization of ketoxime esters Oxidative functionalization of aromatic oxime

α-acetates with α-keto acids was reported by Deng, Jiang and co-workers in 2017 (Scheme 1.18) [40] This process involved N–O/C–C bond cleavages and C–C bond formations

to produce enaminones under redox-neutral conditions

Scheme 1.18 Synthesis of enaminones via C-C cross-coupling α-functionalization of

ketoxime esters [40]

Summary

In the last decade, a variety of oxidative C–H activation methods with the utilization of stoichiometric strong oxidants have been developed Transition-metal-catalyzed C–H functionalization involving the usage of internal oxidant was one of the most powerful methods which could address this remaining issue In this scenery, ketoxime esters, which can be easily prepared from readily available reagents, have emerged as promising internal oxidants Because of the weakness of N-O bond in oxime group, highly active imino radicals are simply produced via single-electron-transferoxidation of a transition metal with the N–O σ bond Oxidative addition of a low-valance metal to the N–O σ bond forming imino-metal complexes is also a starting point of catalytic cycles of transition-metal catalysts These radicals, high-valance metals and high-valance metal complexes could be versatile materials for construction of numerous valuable products

With the current trend of replacing noble transition metals with first-row transition metals in catalysis field, copper has gained significant attention due to its abundance, low cost and low toxicity The combination of ketoxime esters and copper catalysis was demonstrated to be significantly efficient through many reports Those transformations give convenient routes to a wide range of N-heterocycles such as pyridines, pyrazoles, pyrroles, thiazoles as well as pyridine-fused polycyclic products, and so forth Copper catalysis was also effective for the α-functionalization of ketoxime esters, generating precious α-functionalized enamines and ketones These present methodologies are meaningful and attractive for the fact that N-heterocycles as well as α-functionalized enamines or ketones have wide applications in the many fields

3 Thesis objectives

Ketoxime esters under copper catalysts have been proved to be an efficient tool

in organic synthesis through numerous reports Along with aforementioned great achievements reviewed in the previous part, there was still some limitations in ketoxime ester chemistry

First, the used copper-based catalysts were generally copper salts which are homogeneous catalysts The number of research using heterogeneous catalysts in this field is modest Nowadays, green chemistry have gained significant attention from chemists for an environmentally benign chemistry Under viewpoints of green chemistry, there was a reasonable demand for developing new methods which utilize heterogeneous catalysts featuring reusability, recyclability as well as minimizing wastes of whole processes

There are two main trends of publications in this field which are annulation for heterocycle formation and α-functionalization of ketoxime esters In the first sector, most of the synthesized heterocycles are nitrogen-containing but oxygen-containing rings are still rare The C-O bond formation for α-functionalization of ketoxime esters are also scarce

To address the two remaining issues of ketoxime esters under copper catalysis, there were two aims of this master thesis:

1 Improving a known method by applying a copper-based heterogeneous catalyst

2 Developing a novel protocol involving α-functionalized C-O bond formation

of ketoxime esters and/or construction of oxygen-containing heterocycles

Chapter 2 - An efficient access to

β-ketosulfones via ketoxime esters

1 Literature review

Introduction

β-ketosulfones is a vital class of compounds in organic synthesis These

compound have been widely used in the synthesis of many products, such as olefins [41], disubstituted acetylenes [41], trisubstituted allenes [42], lycopodine alkaloids [43],

polyfunctionalized 4H-pyrans [44, 45], quinolines [46], vinyl sulfones [47], and others Furthermore, facile reductive elimination of β-ketosulfones leads to the formation of

ketones [48] They can be easily transformed into the corresponding alkynes [49], epoxy

sulfones [50] and β-hydoxysulfones [51-53] (Scheme 2.1) They are also used in

antifungal [54] and antibacterial drugs, and are potential nonnucleoside inhibitors [24]

Scheme 2.1 β-ketosulfones as vital intermediates in organic transformation

Because of their broad applications, numerous synthetic routes of them have been reported These methods will be presented in sequence

Previous approaches

1.2.1 Conventional approaches

Owing to their good reactivity and applications, numerous methods have been

reported for the preparation of β-ketosufones and were summarized in Scheme 2.2

Scheme 2.2 The summary of common pathways to prepare β-ketosulfones

α-Acylation of alkylsulfones was the most classical way to synthesize

β-ketosulfones In this method, alkylsulfone derivatives were deprotonated at α-position

by being treated with strong bases such as NaH, n-BuLi, t-BuOK or Grignards reagents The carbanions subsequently underwent nucleophilic substitution with carbonyl

chlorides or esters to obtain β-ketosulfone products (Scheme 2.3) [55-63] The usage of

such bases, which are very sensitive to the moisture leading to harsh reaction condition, was a remarkable drawback of this pathway

Scheme 2.3 α-acylation of alkylsulfones [55-63]

Sulfonylation of silyl enol ethers was an alternative method to obtain

β-ketosulfones Sulfonyl chlorides was used as sulfonylating agents that react with silyl

enol ethers to produce β-ketosulfones under catalysis of ruthenium(II) phosphine

there was a noteworthy drawback that silyl enol ethers are not commercially available and their preparation requires 48 hours to complete Moreover, sulfonyl chlorides are moisture-sensitive compounds that can react violently with water to form hydrogen chloride, a corrosive toxic gas [65]

Scheme 2.4 Sulfonylation of silyl enol ethers [64]

Another common way to prepare β-ketosulfones was sulfonylation of

α-haloketones by sodium arenesulfinates via nucleophilic substitution reaction (Scheme 2.5) [66-70] However, this pathway still had drawbacks, which were prolonged reaction

times, the use of expensive reagents and the limitation of commercial α-haloketones

Some reports employed special solvents like ionic liquids to dissolve sulfinate salts and

to facilitate nucleophilic substitution reaction Some further problems of this method were the limitations of the reaction substrates and halide derivatives are hazardous compounds

Scheme 2.5 Sulfonylation of α-haloketones by sodium arene sulfinates via

nucleophilic substitution reaction [66-70]

If metallic sulfinates were not available, thiols could be alternative nucleophiles

which reacted with α-haloketones to form β-ketosulfides These products were then

treated with oxidants to generate respective β-ketosulfones (Scheme 2.6) [71-73]

Despite the popularity of thiol derivatives as starting materials, this method required stoichiometric strong oxidants and utilization of toxic halides

Scheme 2.6 Oxidation of β-ketosulfides [71-73]

In conclusion, these traditional approaches had same drawbacks, such as multiple syntheses, unavailable reagents, the requirement of pre-activated reagents, the use of strong additives, the disadvantage of using homogeneous catalyst and specially the limitations of the reaction substrates Therefore, it is meaningful and challenging to develop new methods that use new reagents and go through a new mechanism to obtain

β-ketosulfones Such methods will be presented in the next section

1.2.2 Recent approaches

Over the past years, oxidative coupling has emerged as an attractive and challenging as well as an eco-friendly and green method to construct carbon–carbon and carbon–heteroatom bonds [74] These reactions have many advantages, such as decreasing number of reaction steps, reducing waste and maximizing atom efficiency However, they also face some challenges, one of which was utilization of stoichiometric amounts of oxidants To remedy the problems cause by using stoichiometric oxidants, they are replaced by green oxidants such as O2 [12-14]

Leading this trend in β-ketosulfones synthesis, in 2013, Lei and co-workers firstly reported that alkynes could be coupling partners to obtain β-ketosulfones through this

approach Oxidative coupling reaction of alkynes and sulfinic acids with the presence

of oxygen could produce β-ketosulfones (Scheme 2.7) [75] Although this approach

could be carried out under a mild, metal-free and redox neutral condition, it still had drawbacks Limitation of substrate scope was one of them because this transformation seemed to be unsuitable for internal alkynes The production of pyridinium sulfonates

as by-products was also a noteworthy disadvantage

Scheme 2.7 The oxidative coupling of alkynes and sulfinic acids [75]

Lei’s work opened the new pathway for other groups to developed further methods using oxidative coupling strategy In 2014, Yadav and colleagues modified Lei’s report by sulfinate salts as sulfonyl sources The catalytic system of FeCl3, K2S2O8

and oxygen was employed to create β-ketosulfones (Scheme 2.8) [76] Using water as

a green reaction media and avoiding the production of sulfonate by-products were valuable improvements in comparison of the previous work Nevertheless, this work employed FeCl3/K2S2O8 as a homogeneous catalyst system, which was not reusable

Scheme 2.8 The oxidative coupling of alkynes and sulfinates in aqueous media [76]

In the same year, Yadav’s group aslo slightly modified their own method by replacing alkynes with alkenes AgNO3 was also used as a homogeneous catalyst instead

of FeCl3 (Scheme 2.9) [77] The disadvantages remaining on their previous work were

still unsolved

Scheme 2.9 The oxidative coupling of alkenes and sulfinates in aqueous media [77]

Another approach with the same strategy was of Wang and co-workers

β-ketosulfones were obtained in good yields by reaction of arylalkenes with sulfinic acids under FeCl2.4H2O catalysis and oxygen atmosphere (Scheme 2.10) [78]

Scheme 2.10 The oxidative coupling of alkenes and sulfinic acids [78]

These oxidative coupling of alkynes or alkenes with sodium sulfinates or sulfinic acids were generally suitable for terminal alkynes and alkenes, which means only non-

α-substituted β-ketosulfone derivatives were synthesized To overcome this difficulty,

arylketones reacted with sodium sulfinates catalyzed by CuBr2 with the presence of base

and ligand to produce β-ketosulfones (Scheme 2.11) [79] In contrast of aforementioned

reports, this method had good yield in the case of α-substituted β-ketosulfones but significantly low in the case of non-α-substituted β-ketosulfones In addition, the

ketones whose R1 groups (in Scheme 2.11) were electron donating groups required

prolonged reaction time and the use of ligand to reach the desirable yield

Scheme 2.11 The oxidative coupling of arylketones and sulfinic sodium sulfinates to

prepare β-ketosulfones [79]

Another strategy to prepare ketosulfones was the synthesis of

β-sulfonylvinylamines followed by the hydrolysis of them Lautens’ method was one of them The addition of arylboronic acids to (arylsulfonyl)acetonitriles was firstly

performed follow by the hydrolysis of the product in the acidic media (Scheme 2.12)

[80] Despite having very good yield among the large scope of both two reagents, this approach was still a multiple synthesis This is because (arylsulfonyl)acetonitriles were not available in market and could be prepared by a two-step procedure consuming from

17 to 24 hours (Scheme 2.13)

Scheme 2.12 The addition of arylboronics acids to (arylsulfonyl)acetonitriles

followed by the hydrolysis to prepare β-ketosulfones [80]

Scheme 2.13 The two-step synthesis of (arylsulfonyl)acetonitriles [80]

As aforementioned trend of oxidative cross-coupling reaction, besides employing

recent disadvantage of using stoichiometric oxidants [5, 15-17] Oxime esters were such kind of internal oxidants, participating as both oxidant and building blocks in the

reaction [3] In 2014, Jiang and co-workers applied ketoxime esters to synthesize

β-ketosulfones In details, ketoxime esters reacted with sodium sulfinates under copper

salt catalysis to generate β-sulfonylvinylamines β-ketosulfones were later obtained via

hydrolysis similar to Lautens’ pathway (Scheme 2.14) [24] In comparison to the recent

researches, having large substrate scope with high yield was a notable feature of this approach Although oxime acetates were not available in market, they could be synthesized with quantitative yields by a facile two-step procedure consuming totally only 2 hours of reaction time, using commercial cheap reagents such as

hydroxylammonium chloride and acetic anhydride (Scheme 2.15) [81] Furthermore,

additives such as oxidant and base were not employed so that the products were easier

to be worked-up, separated and purified

Scheme 2.14 The sulfonylation of oxime acetate followed by the hydrolysis to

prepare β-ketosulfones [24]

Scheme 2.15 The preparation of oxime acetates [81]

However, this method still suffers the drawbacks of using homogeneous catalyst such as the lacking of reusability, recyclability and metal trace in the product Nowadays, the green chemistry has been increasingly interested for the more environmental purposes so that there is a need of finding alternative heterogeneous catalysts to resolve these problems And recently, metal-organic frameworks, a new class of material, have been more and more attracted because of their potential catalytic features, with the high promise to be an excellent heterogeneous catalyst for this reaction

Our approach and objectives

1.3.1 Metal-organic frameworks

Metal-organic frameworks (MOFs) are extended metal–ligand networks with metal nodes and bridging organic ligands, also known as coordination polymers or metal-organic coordination networks (MOCNs) [82-84] For a solid to be labeled as MOF, it should meet these following conditions: strong bonding providing robustness, linking units that are available for modification by organic synthesis, and a geometrically well-defined structure [85] Because of their special structures, MOFs have many noteworthy properties compared with other conventional porous materials The most important characteristics of MOFs are enormous surface areas, ultrahigh porosity, tunable pore size, sustainable frameworks and predetermined structures [86]

MOFs are constructed by joining secondary building units (SBUs) with organic linkers, using strong bonds to create open crystalline frameworks with permanent

porosity (Figure 2.1) [87] The great diversity of metal SBUs and organic linkers has

led to thousands of MOFs being synthesized and studied Thesemetal-containing SBUs are essential to the design of directionality for the construction of MOFs and to the achievement of robust frameworks [88] The organic units are ditopic or polytopic organic carboxylates (and other similar negatively charged molecules) Longer organic linkers provide larger storage space and a greater number of adsorption sites within a given material However, the large space within the crystal framework makes it prone

to form interpenetrating structures (two or more frameworks grow and mutually intertwine together) [89]

Figure 2.1 (a) The components of MOF-5: the Zn4O(−CO2)6 SBU as an octahedron, the ditopic terephthalate linker as a rod and their assembly into the crystalline net (b) The components of HKUST-1: Cu2(−CO2)4 paddle wheel abstracted as a square, the tritopic linker as a triangle and their combination to form the crystalline net [90] During the development of MOFs, the lack of a generally unified definition leads

to several nomenclatures for MOFs [91] There are mainly three ways to name an MOF structure The first way is indicating the type of components of the material, like in the series MOF-n [92] (metal organic framework), COF-n [93] (covalent organic framework), RPF-n [94] (rare-earth polymeric framework), or MPF-n [95] (metal peptide framework) The second way is indicating the type of structure, such as ZMOF-

n [96] (zeolite-like metal organic framework), ZIF-n [97] (zeolitic imidazolate framework) and mesoMOF-n [98] (mesoporous metal organic framework) And the last method is indicating the laboratory in which the material was prepared, like in the series MIL-n [99] (mate´riauxs de l’Institut Lavoisier), HKUST-n [100] (Hong-Kong University of Science and Technology), and CPO-n [101] (coordination polymer of

A great number of MOF preparation methods have been found and researched: solvothermal/hydrothermal, microwave-assisted, sonochemical, electrochemical, mechanochemical, ionothermal, drygel conversion, microfluidic synthesis methods

[102, 103] (Figure 2.2) The most common method generating MOFs is solvothermal synthesis (Scheme 2.16) by heating the mixture of metal salt and organic ligand in a

solvent system at certain temperature [103, 104] The advantage of this method is the ability of obtaining MOFs crystals with quality high enough for their structure determination by Single Crystal X-Ray Diffraction (SC-XRD) However, this method exhibits some drawbacks such as long reaction time, difficulty in large-scale synthesis and many trials and errors are needed in order to gain crystals [102, 103, 105] Nevertheless, other methods could also be used to overcome those obstacles such as microwave-assisted synthesis protocol [106, 107], sonochemical method [108, 109], electrochemical [102, 110, 111], mechanochemical synthesis [112, 113] Yet, these MOF preparations cannot yield the crystals of sufficient quality for their structure determination by SC-XRD as solvothermal method

Figure 2.2 The most commonly used methods for MOF preparation [114]

Scheme 2.16 The general strategy of the solvothermal synthesis [103]

Thanks to the special structure with high porosity and surface area, MOFs have

a broad applications such as gas storage and separation [115, 116], drug delivery [117], biomedicine [118] and catalyst [119, 120] Recently, MOFs application in catalysis is immensely increasing, especially in heterogeneous catalysis since they can be easily separated and recycled from the reaction systems [121] Moreover, having open metal sites along with high metal content could assure its highly catalytic activity [104] Compared with conventional inorganic homogeneous catalysts, MOFs are not only higher effective, but also more environmental – friendly [122] As a result, the number

of researches related to MOFs as catalyst have significantly increased in recent years

(Figure 2.3) [123]

Figure 2.3 Development of MOF catalysts in comparison to the MOF in the recent

In conclusion, MOF are the attractive materials with promising applications, especially in heterogeneous catalysis due to their unique feature including large internal surface areas, uniform pore and cavity sizes, and the structure containing highly open metal sites and metal content In the next section, Cu2(OBA)2BPY, a typical copper MOF, will be reviewed

1.3.2 Cu 2 (OBA) 2 BPY metal-organic framework

a) Structure and properties

The as-synthesized porous frameworks can be divided into three groups, including multidimensional channels, pillared-layer architectures, and 3D nanotubular structures Among them, pillared layer architectures have been proven to be an effective and controllable route to design 3D frameworks with large channels [124-128] Besides, helical structures have received much attention in coordination chemistry and materials chemistry, that mainly because helicity is an essence of life and is also important in advanced materials, such as optical devices, enantiomer separation, chiral synthesis, ligand exchange, biological systems and, selective catalysis [129-135] The occurrence

of pillared-layer complexes with helical character is particularly rare, if any, this structure was expected to create an efficient catalyst because of its large surface area and good stabilities [136] MOF Cu2(OBA)2BPY is one of the catalyst having this complicated form, becoming a potential candidate for catalytic area MOF

Cu2(OBA)2BPY was synthesized from Cu(NO3)2.3H2O, 4,4’-oxybis(benzoic acid) (H2OBA) and 4,4’- bipyridine (BPY)

4,4’-oxybis(benzoic acid) (H2OBA) is a typical example of long V-shaped ligands It has been proven to be able to bridge two or more different metal centers and produce neutral architectures because of its two oxo carboxylate groups [137-140] 4,4’-bipyridine (BPY) is an excellent candidate for rigid rodlike organic building unit and shows many interesting supramolecular architectures [141, 142] Hence, metal–organic coordination polymers constructed by mixing ligands of pyridyl groups and carboxylate groups not only incorporate interesting properties of different functional group [143], but also are more adjustive through changing one of the two organic ligands [144-147]

The coordination environment of the Cu(II) ions in Cu2(OBA)2BPY is shown in

Figure 2.4 The Cu(II) ions have a trigonal bipyramid geometry formed by four

in the range 1.952(2)–2.172(2) Å and the Cu–N bond distance has a value of 1.999(2) Å The O/N–Cu–O/N bond angles are in the range 85.86(9)–172.03(10) Å [136]

Figure 2.4 Link between Cu(II) ions and ligands in MOF Cu2(OBA)2BPY [136]

In this MOF’s structure, each OBA ligand links four Cu(II) ions and adopts a

bis(bridging-bidentate) mode (Figure 2.5) The carboxylate groups of OBA ligands

have connectivity with the Cu(II) cations forming an eight-membered ring chains, as

shown in Figure 2.6, in which the adjacent Cu-Cu distances are alternately 3.0195 Å

and 4.414 Å The connectivity between the corner-shared eight-membered ring chains is

further bridged by the bent OBA ligands to produce 2D helical layers (Figure 2.7)

These adjacent helical layers are connected by BPY linkers as molecular pillars to form

a novel 3D framework (Figure 2.8) [136]

Figure 2.5 The coordination modes of OBA2- anions with metal: (I) bis(chelating bidentate), (II) bis(bridging-bidentate), (III) both bis(chelating bidentate) and

bis(bridging-bidentate) [136]