Luận văn thạc sĩ Kỹ thuật hóa học: Transition metal-free synthesis and functionalization of 5-and 6-membered heterocyclic compounds

VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

HUYNH VAN TIEN

TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED

HETEROCYCLIC COMPOUNDS

Ph.D THESIS

HO CHI MINH CITY - 2023

VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

HUYNH VAN TIEN

TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED

Supervisor: Prof Dr Phan Thanh Son Nam

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DECLARATION OF ORIGINALITY

I understand the University’s policy I hereby declare that this thesis is my original research work and has not been submitted or considered for publication elsewhere I have not sought or used the services of any professional agencies to produce this work All sources used in this thesis are clearly and fully referenced in the text and references, following the referencing title indicated by the Department

Dissertation author

Huynh Van Tien

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ABSTRACT

This thesis gave new methods to synthesize 4-phenylquinazolines, 2-arylquinoxalines,

N-arylindoles, and thiocromenones The formation of 4-phenylquinazolines was performed

through the oxidation protocol, in which the organic peroxide was used as an oxidant that could readily generate 4-phenylquinazolines from 2-aminobenzophenones without any

additional catalyst The reactions between o-phenylenediamines and phenylglyoxal

derivatives in ethyl acetate to form 2-phenylquinoxalines gave excellent yields at room

temperature without using the catalyst N-arylindoles were easily obtained from indoles

and nitrobenzene in the absence of transition metals, at room temperature, under simple base conditions And thiocomenones were generated via a two-step one-pot protocol, in which the condensation of 2’-chloroacetophenones and aryl aldehydes formed 2’-chlorochalcone intermediates, which were then cyclized to thiocromenones by adding elemental sulfur The utilities of this thesis were (1) transition metal-free catalyst, (2) inexpensive and abundant additivities source, (3) different syntheses of heterocyclic compounds from commercially available starting materials This thesis has contributed new methods in organic synthesis and could be applied to chemical and pharmaceutical industries

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TÓM TẮT

Luận án đưa ra các phương pháp mới để tổng hợp các dẫn xuất của 4-phenylquinazoline,

2-arylquinoxaline, N-arylindole và thiocromenone Các dẫn xuất của 4-phenylquinazoline

được tổng hợp thông qua quá trình oxy hóa, trong đó peroxide hữu cơ đóng vai trò là chất oxy hóa để dễ dàng chuyển hóa các dẫn xuất 2-aminobenzophenone thành các sản phẩm mong muốn mà không cần sử dụng xúc tác kim loại nào Trong luận án này, các dẫn xuất của 2-phenylquinoxaline được tổng hợp thông qua phản ứng ngưng tụ giữa các dẫn xuất

của o-phenylenediamine và các dẫn xuất của phenylglyoxal trong dung môi ethyl acetate

ở nhiệt độ phòng trong thời gian ngắn và đạt hiệu suất rất cao mà không cần thêm điều kiện

nào khác Luận án cũng đã đưa ra quy trình tổng hợp các dẫn xuất của N-arylindole từ các

dẫn xuất của indole và nitrobenzene trong điều kiện nhiệt độ phòng, sử dụng bazơ đơn giản là NaOH và không sử dụng xúc tác Đặc biệt, lần đầu tiên một quy trình hai bước, sử dụng trực tiếp lưu huỳnh nguyên tố để tổng hợp các dẫn xuất của thiocromenone đã được luận án đưa ra, trong đó bước đầu tiên là phản ứng ngưng tụ giữa các dẫn xuất của các dẫn xuất của 2’-chloroacetophenone với các dẫn xuất của benzaldehyde để hình thành sản phẩm trung gian là các dẫn xuất của 2’-chlorochalcone, các dẫn xuất này sau đó tiếp tục thực hiện quá trình oxy hóa đóng vòng thành thiocromenone khi thực hiện bước hai là thêm lưu huỳnh nguyên tố vào Điểm nổi bật của luận án này là (1) không sử dụng xúc tác kim loại chuyển tiếp, (2) sử dụng nguồn xúc tác, phụ gia phong phú, rẻ tiền, (3) tổng hợp nhiều hợp chất dị vòng khác nhau từ các nguyên liệu ban đầu phổ biến trên thị trường Luận án đã đóng góp các phương pháp mới trong tổng hợp hữu cơ và có triển vọng ứng dụng trong lĩnh vực hóa học, dược phẩm

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ACKNOWLEDGMENT

I would like to express my gratitude to the lecturers of Ho Chi Minh City University of Technology, especially Prof Dr Phan Thanh Son Nam and Dr Nguyen Thanh Tung who guided me throughout the time of studying and writing my doctoral thesis I would like to thank all members of The Materials Structure Research Laboratory of Ho Chi Minh City University of Technology, who have supported me while I do the thesis Thanks to my lovely students of Department of Chemical Engineering of Ho Chi Minh City University of Technology and students from the Faculty of Chemical Technology of Ho Chi Minh City University of Food Industry for their full co-operation in my research

Thanks to the Board of Directors and my partners at Ho Chi Minh City University of Food Industry who have facilitated me during I complete my graduate studies Thanks so much to my family and friends who have shared and encouraged me to overcome all the disadvantages to complete my doctoral thesis

In the wealth of knowledge, I certainly will not completely satisfy all the readers I would like to receive the suggestions of readers to help me improve my knowledge

Sincerely,

Huynh Van Tien

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TABLE OF CONTENTS

TABLE OF CONTENTS v

LIST OF TABLES vii

LIST OF SCHEMES viii

LIST OF FIGURES xi

LIST OF ABBREVIATIONS xii

INTRODUCTION 1

CHAPTER 1 LITERATURE OVERVIEWS 3

1.1 Introduction of quinazoline compounds 3

1.1.1 Biological activity of the quinazoline compounds 3

1.1.2 Synthetic approaches to quinazoline derivatives 4

1.2 Introduction of quinoxaline compounds 9

1.2.1 Biological activity of quinoxaline compounds 9

1.2.2 Synthetic approaches to quinoxaline derivatives 9

1.3 Introduction of N-arylindole compounds 15

1.3.1 Biological activity of the N-arylindole compounds 15

1.3.2 Synthetic approaches to N-arylindole derivatives 16

1.4 Introduction of thiocromenone compounds 23

1.4.1 Biological activities of thiocromenone compounds 23

1.4.2 Synthetic approaches to thiocromenone derivatives 24

1.5 Aims of this work 31

2.2.1 General procedure for the synthesis of 4-phenylquinazoline 38

2.2.2 General procedure for the synthesis of 2-phenylquinoxaline 39

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2.2.3 General procedure for the synthesis of 1-(4-nitrophenyl)-1H-indole 39

2.2.4 General procedure for the synthesis of 2-phenyl-4H-thiochromen-4-one 40

CHAPTER 3 RESULTS AND DISCUSSIONS 42

3.1 Synthesis of quinazoline derivatives via peroxide-mediated direct oxidative amination of C(sp3)-H bonds 42

3.2 Condensation of 1,2-phenylenediamines and dicarbonyl compounds in ethyl acetate toward quinoxalines 58

3.3 Oxidative nucleophilic functionalization of nitrobenzene with N-H bond to synthesize 1-(4-nitrophenyl)-1H-indoles 63

3.4 Elemental sulfur for the synthesis of 2-arylthiochromenones 78

CONCLUSIONS 88

LIST OF PUBLICATIONS 91

REFERENCES 92

APPENDICES 106

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LIST OF TABLES

Table 2.1 List of chemicals and their manufacturers 34

Table 3.1 Effect of oxidizing agents on the synthesis of 4-phenylquinazoline 43

Table 3.2 Effect of oxidant amount on the synthesis of 4-phenylquinazoline 44

Table 3.3 Effect of nitrogen sources on the synthesis of 4-phenylquinazoline 45

Table 3.4 Effect of nitrogen source amount on the synthesis of 4-phenylquinazoline 47

Table 3.5 Effect of temperature on the synthesis of 4-phenylquinazoline 48

Table 3.6 Synthesis of 4-phenylquinazolines via the three-component coupling reaction utilizing different sp3 carbon sourcesa 53

Table 3.7 Screening reaction conditionsa of the condensation of 1,2-phenylenediamine and phenylglyoxal toward 2-phenylquinoxaline 58

Table 3.8 Effect of temperature on the synthesis of 1-(4-nitrophenyl)-1H-indole 64

Table 3.9 Effect of reactant mole proportion on the synthesis of indole 65

1-(4-nitrophenyl)-1H-Table 3.10 Effect of bases on the synthesis of 1-(4-nitrophenyl)-1H-indole 66

Table 3.11 Effect of base amount on the synthesis of 1-(4-nitrophenyl)-1H-indole 68

Table 3.12 Effect of solvents on the synthesis of 1-(4-nitrophenyl)-1H-indole 69

Table 3.13 Effect of concentration of starting materials on the synthesis of nitrophenyl)-1H-indole 70

1-(4-Table 3.14 Effect of reaction environments on the synthesis of indole 71

1-(4-nitrophenyl)-1H-Table 3.15 Effect of time on the synthesis of 1-(4-nitrophenyl)-1H-indole 72

Table 3.16 Expanding the scope of reaction of indole and nitrobenzene 74

Table 3.17 Effect of solvents on the synthesis of 2-arylthiocromenone 79

Table 3.18 Effect of water on the synthesis of 2-arylthiocromenone 81

Table 3.19 Effect of amount of DMF on the synthesis of 2-arylthiocromenone 82

Table 3.20 Effect of reaction time on the synthesis of 2-arylthiocromenone 83

Scheme 1.3 Synthesis of quinazoline derivatives catalyzed by Ni-catalyst 6

Scheme 1.4 Synthesis of quinazoline derivatives via sequential Ullmann-type coupling and aerobic oxidation 7

Scheme 1.5 Synthesis of quinazoline derivatives via I2/KI-promoted oxidative C(sp3C(sp2) bond formation 7

)-Scheme 1.6 Synthesis of 4-phenylquinazoline via direct sp3 C-H bond functionalization 8 Scheme 1.7 The common approaches for the synthesis of quinoxaline derivatives 10

Scheme 1.8 Synthesis of quinoxaline derivatives by using PEG solvent 11

Scheme 1.9 Synthesis of quinoxaline derivatives by using microwave 11

Scheme 1.10 Synthesis of quinoxalines from α-haloketones by using K10 clay catalyst 12 Scheme 1.11 Synthesis of quinoxaline derivatives from α-hydroxyketones 12

Scheme 1.12 Synthesis of quinoxaline derivatives from epoxides 13

Scheme 1.13 Synthesis of quinoxaline derivatives from epoxy ketones 13

Scheme 1.14 Synthesis of quinoxaline derivatives from alkenes 14

Scheme 1.15 Synthesis of quinoxaline derivatives from nitroolefins 14

Scheme 1.16 Nucleophilic substitution of p-Chloronitrobenzene 16

Scheme 1.17 A two-step synthesis of 2-nitrodiarylamines 17

Scheme 1.18 Formation of 2-nitrodiarylamines by the reaction of anilines and nitroarenes 18

Scheme 1.19 Direct methoxylation of nitroarenes 18

Scheme 1.20 Oxidative nucleophilic alkoxylation of nitrobenzenes 19

Scheme 1.21 Palladium-catalyzed coupling indoles and halogen-substituted arenes 20

Scheme 1.22 Copper-catalyzed coupling indoles and halogen-substituted arenes 20

Scheme 1.23 N-Arylation of indoles and N-(naphthalene-1-yl)picolinamide 21

Scheme 1.39 Synthesis of quinoxaline from o-phenylenediamine and phenylglyoxal in

ethyl acetate 33

Scheme 1.40 N-Arylation of indole and nitrobenzene 33

Scheme 1.41 Using elemental sulfur for the synthesis of 1-thioflavone 33 Scheme 3.1 Screening of reaction conditions of synthesis of 4-phenylquinazoline via peroxide-mediated direct oxidative amination of C(sp3)-H bonds 42 Scheme 3.2 Control experiments for the synthesis of 4-phenylquinazolinevia peroxide-mediated direct oxidative amination of C(sp3)-H bonds 49

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Scheme 3.3 Proposed reaction mechanism for the synthesis of 4-phenylquinazolinevia

peroxide-mediated direct oxidative amination of C(sp3)-H bonds 51

Scheme 3.4 Proposed reaction mechanism for the synthesis of 2-phenylquinoxalines via condensation of 1,2-phenylenediamines and dicarbonyl compounds 60

Scheme 3.5 Synthesis of 2‑phenylquinoxalinesa 61

Scheme 3.6 Investigating the effect of diverse parameters on the synthesis of nitrophenyl)-1H-indole 63

1-(4-Scheme 3.7 Possible mechanism for oxidative amination of nitrobenzene with heterocycles 73

N-Scheme 3.8 Synthesis N-arylindole derivatives 74

Scheme 3.9 Investigating the effect of diverse parameters on the synthesis of

2-arylthiocromenone 79

Scheme 3.10 Plausible mechanism for the synthesis of 2-arylthiocromenone 84

Scheme 3.11 Synthesis of thiocromenone derivatives 85

Scheme 3.12 Synthesis of 2-(hetero)aryl thiochromenones from trans-chalcones 86

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LIST OF FIGURES

Figure 1.1 Pharmacological significance of quinazolines 3

Figure 1.2 Several commercially quinoxaline derivatives 9

Figure 1.3 N-arylindoles and its applications 15

Figure 1.4 Structures of flavone, 1-thioflavone, and its oxidized derivatives 24

Figure 2.1 Experimental procedure diagram for the synthesis of 4-phenylquinazoline 38

Figure 2.2 Experimental procedure diagram for the synthesis of 2-phenylquinoxaline 39

Figure 2.3 Experimental procedure diagram for the synthesis of indole 40

1-(4-nitrophenyl)-1H-Figure 2.4 Experimental procedure diagram for the synthesis of thiochromen-4-one 41

2-phenyl-4H-xii

LIST OF ABBREVIATIONS

DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

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INTRODUCTION

Heterocyclic compounds were important compounds that exhibit an extensive range of physical, chemical, and biological properties [1] Heterocyclic compounds had been presented in numerous pharmacological areas, such as anti-cancer, antibiotics, anti-inflammatory, anti-inflammatory and depression, anti-malarial, anti-HIV, antibacterial, antifungal, antiviral, antidiabetic, herbicides, fungicides, and insecticides In addition, they were considered in pharmaceutical chemistry and agriculture [2] Heterocycles were also applied in material science such as dyes, fluorescence sensors, brighteners, information storage, plastics, and analytical reagents [3] Moreover, heterocyclic compounds could be used as synthetic intermediates, protective groups, asymmetric auxiliary groups, catalytic asymmetric…in organic synthesis In fact, heterocyclic frameworks such as quinazolines,

quinoxalines, thiocromenones, and N-aryl-indoles have become an interesting topic in

organic synthesis

Due to a wide range of applications of heterocyclic compounds in pharmaceutical, cosmetic, and agrochemical industries, developing effective processes to synthesize 5- and 6-membered heterocyclic compounds such as quinazoline, quinoxaline, thiocromenone,

and N-arylindole derivatives have been highly demanding However, the currently

available reactions often require transition metal catalysts under extreme conditions Therefore, proposing new methods for the synthesis of heterocyclic compounds without the use of any transition metal catalyst would be considered

In the progression of studying documents, and investigating many reactions to create heterocyclic compounds, the possible protocols for the synthesis of 4-phenylquinazoline,

2-phenylquinoxaline, 2-arylthiocromenone, and N-arylindole derivatives without using

transition metal catalysts were detected On that basis, the reaction conditions for each reaction were screened to maximize yield, conducted survey products to develop plausible reaction mechanisms, and extended the application scope of each protocol As a result, the thesis provided effective procedures to synthesize 4-phehylquinazolines,

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2-phenylquinoxalines, N-arylindoles, and 2-arylthiocromenones, these methods did not

overlap with previous publications

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1.1 Introduction of quinazoline compounds

1.1.1 Biological activity of the quinazoline compounds

Quinazoline derivatives are organic compounds, based on the quinazoline framework, which is an aromatic heterocyclic structure containing nitrogen They were commonly present in nature and also could be synthesized [4] Most of the quinazoline derivatives were yellow solids and poorly soluble in water As most of them demonstrated a wide range of biological activities, quinazoline derivatives have attracted more and more attention from researchers

The pharmacological studies of quinazoline compounds date back to the 1940s Researchers have identified many biological activities, including anti-cancer, anti-viral, anti-convulsant, anti-inflammatory, analgesic, and anti-oxidation Several applications of quinazoline derivatives showed in Figure 1.1 [5]

Figure 1.1 Pharmacological significance of quinazolines

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Scientists have synthesized various quinazoline compounds with different biological activities by combining other activity groups to the starting quinazoline compound structure using modern synthesis approaches In biology, pesticide, and medicine, production many quinazoline derivatives have also been investigated and developed into commercially available drugs, such as bactericidal fluquinconazole, insecticide fenazaquin, and Iressa anti-cancer [6]

1.1.2 Synthetic approaches to quinazoline derivatives

Since the 1940s, several studies have reported on the synthesis of quinazoline derivatives Among them, the ‘’green’’ methods have been favorably applied to manufacture drug substances and chemical precursors All of these methods provided instant access to the new quinazoline compounds, thus efficiently increasing the structural diversity starting from simple substrates

In 2010, Zhang and co-workers successfully developed a mild and efficient method for the synthesis of 2-phenylquinazolines which used the substituted 2-aminobenzophenones and benzylamines via a tandem reaction following sp3 C-H functionalization [7] The reactions of 2-aminobenzophenones (1eq.) with 2 eq of benzylic amines (2eq.) occurred at 90 °C for 12 h in the presence of 0.1 eq of molecular iodine as the catalyst and 2 eq of TBHP as an oxidant in acetonitrile The desired products were obtained in good yields (Scheme 1.1)

Scheme 1.1 Synthesis of 2-phenylquinazolines via a tandem reaction following sp3 C-H functionalization

In 2018 D.S.Deshmukh and B.M.Bhanage described a green synthesis of quinazolines protocol under solvent-free conditions [8] Preliminary, they had synthesized 6-chloro-2-phenylquinazoline from 2-amino-5-chlorobenzaldehyde and benzylamine in the presence of molecular iodine (20 mol%) in DMSO at 80 °C for 24 h under an oxygen

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balloon, the desired product was obtained in 84% yield Interestingly, the solvent had no significant impact on the reaction, as when the reaction occurred at 130 °C within only 3 h under solvent-free conditions, the desired product reached 82% of yield The reaction between 2-amino-5-chlorobenzophenone and benzylamine was also performed, which yielded 81% of the desired product Under the optimized reaction conditions, a series of 2-arylquinazolines were obtained with good to excellent yields Furthermore, 2-aminobenzaldehydes could also be replaced by 2-aminobenzyl alcohols to provide corresponding derivatives of quinazoline In addition, quinazoline derivatives could be achieved via acceptor-less dehydrogenative coupling of 2-aminobenzylalcohols with benzonitriles (Scheme 1.2) Using oxygen as a green oxidant in combination with the molecular iodine under solvent-free conditions helped this method to become more economical and greener

Scheme 1.2 Synthesis of 2-arylquinazolines via benzylic sp3 C–H bond amination catalyzed by molecular iodine

In another approach, in 2018, S Parua and co-workers developed an alternative method for the synthesis of quinazolines via acceptorless dehydrogenative coupling reactions catalyzed by an inexpensive, earth-abundant, and easy to prepare

Ni(II)-catalyst (Scheme 1.3) [9] In the presence of [Ni(MeTAA)] catalyst, t-BuOK in

xylene solvent for 24 h, both dehydrogenative coupling of 2-aminobenzylamine with benzyl alcohol at 140 °C and dehydrogenative coupling of 2-aminobenzylalcohol with benzonitrile at 100 °C produced 85% yield of 2-phenylquinazoline A series of substituted

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quinazolines were achieved from low-cost and available starting precursors in moderate to high yields Generally, this synthesis approach was a simple and straightforward operation, high atom economy, and did not require expensive metals such as ruthenium or iridium

Scheme 1.3 Synthesis of quinazoline derivatives catalyzed by Ni-catalyst

Due to the advantages of time-saving and atom-economy, the transition-metal-catalyzed oxidative aminations of sp3 C-H bond have emerged as important methods for the C-N bond formation Nevertheless, the methods were limited to the range of suitable substrates and the availability of the starting materials Especially, for the substrates bearing the electron-withdrawal groups, the reactions hardly occurred and usually resulted in low yields Moreover, as homogeneous transition metal catalysts could cause contamination due to metal stains, the approaches might not be used in the pharmaceutical industry

Recently, copper-catalyzed N-arylation-cyclization has also been used to synthesize

quinazoline derivatives Scientists had developed a simple and efficient copper-catalyzed method for the synthesis of quinazolines via Ullmann-type coupling reactions In 2010, C Wang and co-workers described a novel method for the synthesis of quinazoline derivatives via copper-catalyzed coupling The protocol used readily available substituted (2-bromophenyl)-methylamines and aromatic amides as starting materials The cascade reactions were carried out under air without any ligand addition via sequential Ullmann-type coupling and aerobic oxidation (Scheme 1.4) [10] This approach complemented a simple and practical strategy for the synthesis of quinazoline derivatives

required quinazoline compounds were produced from amidine substrates in the presence of I2/KI as the catalyst, and K2CO3 as the base in DMSO at 100 °C Most amidine substrates were easily transformed into the desired products in the medium in good yields under appropriate conditions Thus, this realistic and environmental approach implemented a practical strategy for the synthesis of quinazolines from amidine substrates

Scheme 1.5 Synthesis of quinazoline derivatives via I2/KI-promoted oxidative C(sp3)-C(sp2) bond formation

Direct C-H bond functionalization has emerged as a powerful and environmentally benign approach in the synthesis of complex structures, constituting a perfect synthetic scheme concerning atom economy and waste minimization [12-14] As no pi-bonding functionality exists in saturated carbons, the possibility to functionalize them via classical reactions was significantly problematical, and the activation of C(sp3)-H bonds would offer an opportunity for new transformations [15] Direct oxidative amination reactions have been highly attractive methods, leading to C-N bond formation in which most of the procedures

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relied on transition metal catalysts or iodine-based catalysts [16-18] Recently, numerous reagents have been utilized as C1 synthons for the synthesis of nitrogen-containing

compounds in the presence of a catalyst, including N,N-dimethylformamide [19], dimethyl

sulfoxide [20-23], methanol [24, 25], carbon dioxide [26, 27], carbon monoxide [28],

tertiary aliphatic amine [29], dimethyl carbonate [30], dimethylaniline [31] and

N,N-dimethylethanolamine [32] Additionally, the utilization of abundant and inexpensive ammonia and ammonium salts as an ideal nitrogen source for the synthesis of nitrogen-containing organic molecules has recently attracted significant interest [33-37] In 2013,

Wang and co-workers previously reported an iodine-catalyzed oxidative amination of

N-alkylamides with 2-carbonyl anilines and ammonia to form 4-substituted quinazolines in the presence of peroxide as the oxidant (Scheme 1.6a) [38] In 2015, Liu and co-workers synthesized 4-substituted quinazolines by using the iodine-catalyzed three-component reaction between 2-carbonyl anilines, ammonium chloride, and tertiary amines under oxygen atmosphere (Scheme 1.6b) [39] In 2016, Ma and co-workers demonstrated a copper-catalyzed reaction between 2-carbonyl anilines, ammonium acetate,

and N-alkylamides or DMSO, with molecular oxygen used as an oxidant (Scheme 1.6c)

[40]

Scheme 1.6 Synthesis of 4-phenylquinazoline via direct sp3 C-H bond functionalization The fascinating biological and pharmacological properties of nitrogen-containing molecules have forced the construction of the C-N bond of extreme importance [41, 42] Therefore, the synthesis of quinazoline compounds has been considered an attractive research topic

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1.2 Introduction of quinoxaline compounds

1.2.1 Biological activity of quinoxaline compounds

Among many nitrogen heterocycles, quinoxaline compounds were well-recognized as

essential substances, possessing a wide range of applications in pharmaceutical,

agricultural, and material industries Over the last two decades, quinoxalines have been known to play an important role in medicinal science [43] Quinoxaline derivatives showed highly significant biological activities such as anti-cancer, anti-HIV, antimicrobial, anti-inflammatory, anti-tumor, anti-tuberculosis, antioxidant, and anti-Alzheimer's [44] In addition, they were also used as reagents in organic synthesis and applied in the photovoltaic industry [45]

Figure 1.2 Several commercially quinoxaline derivatives

1.2.2 Synthetic approaches to quinoxaline derivatives

The synthesis of quinoxaline derivatives has been developed for a long time, the most

common approach was the condensation reactions of o-phenylenediamine with different carbonyls such as α-diketone, α-hydroxyl ketone, α-haloketone to form quinoxaline

derivatives In 2003, Carta and co-workers synthesized 2,3-bis(bromomethyl)quinoxaline derivatives by refluxing the mixture of 1,2-diaminobenzenes with 1,4-dibromo-2,3-

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butanediones in ethanol in 10 minutes The desired products were obtained in 73-92% yields (Scheme 1.7a) [46] Similarly, in 2006, Wang's group refluxed for 20 hours a mixture of nitrobenzene-1,2-diamine and furil in ethanol to obtain quinoxaline derivatives in 72% yield (Scheme 1.7b) [47] Five years later, in 2011, Tingoli et al., used acid acetic as a catalyst for the synthesis of quinoxaline derivatives via the condensation reactions of

o-phenylenediamines with 1,2-diketones in ethanol, at 60 °C for 2 hours, the results have

shown that the predicted products achieved good to excellent yields (Scheme 1.7c) [48]

Scheme 1.7 The common approaches for the synthesis of quinoxaline derivatives With an attempt to develop facile, efficient, more sustainable, and environmental-friendly protocols for the synthesis of quinoxalines, the imine formation-water release pathways have remained interesting [49] Recently, scientists have focused on reusable catalysts, microwave assistances, and green solvents to develop more effective methods A wide range of catalysts have been used for the synthesis of quinoxaline, including gallium(III) triflate [50], iodine [51], [52], graphite [53], nano-TiO2 [54], nano nickel [55], Bronsted acid ionic liquid [(CH2)4SO3HMIM][HSO4] [56], lithium bromide [57], ammonium bifluoride NH4HF2 [58] , nano copper [59], sulfamic acid/MeOH [60]

In 2013, a non-catalyst protocol for the synthesis of quinoxalines was published by Huang's

group Briefly, the condensation reaction of α-dicarbonyl and 1,2-diaminobenzene in

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polyethylene glycol (PEG) was demonstrated A wide range of quinoxaline derivatives was achieved in high yields in the absence of metal catalysts In addition, PEG could be easily recovered and reused while maintaining its effectiveness (Scheme 1.8) [61]

Scheme 1.8 Synthesis of quinoxaline derivatives by using PEG solvent

Another sustainable approach was proposed by Zhou and co-workers in 2009 using the microwave oven to synthesize quinoxalines without adding any catalysts and solvents The

condensation reactions of aromatic dicarbonyls with o-phenylenediamines to achieve

quinoxaline derivatives were carried out in a microwave oven for short time The desired products were obtained in good to excellent yields A large number of substitutes were used to synthesize the corresponding quinoxaline compounds (Scheme 1.9) [62]

Scheme 1.9 Synthesis of quinoxaline derivatives by using microwave

Besides α-dicarbonyls, α-haloketones were also considered as potential substrates for the synthesis of a wide range of quinoxalines However, the reactions between α-haloketones

with 1,2-diamines normally required the presence of oxidants at high temperatures [49] In 2014, Jeganathan and co-workers previously proposed an efficient method along with the reaction mechanism for the synthesis of 2-phenylquinoxaline derivatives using heterogeneous K10-montmorillonite (K10 clay) catalyst at 50 °C in acetonitrile solvent In addition, the catalyst remained stable for reused up to six times (Scheme 1.10) [63]

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Scheme 1.10 Synthesis of quinoxalines from α-haloketones by using K10 clay catalyst

Similar to the starting substrates, in 2015, Lu's group synthesized 2-phenylquinoxaline

derivatives from 1,2-diaminoarenes and α-halomethyl aryl ketones in DMSO, under the

air, in the presence of NaHCO3 [64] Similarly, in the same year, the green method was reported by Kumar’s group, by which the oxidative cyclization reaction between 1,2-diaminobenzenes with phenacyl bromides to achieve quinoxalines was carried out under air, at 80 °C, in water [65]

Alternatively, α-hydroxyketones have also been the precursors for the synthesis of

quinoxalines In 2009, Chan and Wen demonstrated a copper-catalyzed reaction between

α-hydroxyketones and o-phenylenediamines to form quinoxalines in toluene solvent, at

100 °C, in the presence of oxygen as an oxidant (Scheme 1.11a) [66] Recently, Paul S and B Basu synthesized quinoxalines by using KF-alumina (ratio 2:3) as a catalyst for

oxidation-condensation reactions of α-hydroxyketones with o-phenylenediamines at 80 °C

for 5 h under solvent-free (Scheme 1.11b) [67]

Scheme 1.11 Synthesis of quinoxaline derivatives from α-hydroxyketones

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In addition, a large number of approaches for the synthesis of quinoxalines from

α-haloketones or α-hydroxyketones with 1,2-diamines were proposed by using metal

catalysts such as MnO2 [68], RuCl2(PPh3)3/diglyme [69], CuCl2 [70], FeCl3/morpholine [71], Pd [72], and MnO2 [73] In most cases of transition metal catalysts, the protocols offered a broad scope of the substrates at high efficiency

Otherwise, quinoxaline derivatives could be synthesized from epoxide derivatives and

o-phenylenediamines In 2002, Antoniotti and Dunach synthesized quinoxalines via the

Bi-catalyzed condensation of epoxides and o-phenylenediamines in the presence of

copper triflate in DMSO under oxygen atmosphere (Scheme 1.12) [74] The corresponding products achieved a moderate yield (53-70%)

Scheme 1.12 Synthesis of quinoxaline derivatives from epoxides

In 2007, a significant series of quinoxalines were synthesized by Nasar and co-workers

The acid-catalyzed reactions between epoxy ketones and o-phenylenediamines in

ethanol-reflux were investigated The products were obtained in moderate yields (55-61%) A plausible mechanism was also proposed (Scheme 1.13) [75]

Scheme 1.13 Synthesis of quinoxaline derivatives from epoxy ketones

Unlike traditional methods, in 2010, Kumar and co-workers developed a novel approach to synthesizing quinoxalines by using alkenes as the starting substrates Under air, in the presence of a mixture of CuCl2 and PdCl2 catalysts in solvent-friendly PEG-400/water

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(ratio 8:2) alkenes were oxidized to α-diketones Quinoxalines were further obtained via

the condensation reactions of α-diketones with o-phenylenediamines (Scheme 1.14) [76]

Scheme 1.14 Synthesis of quinoxaline derivatives from alkenes

Nitroolefins were also used to synthesize quinoxalines In 2013, Chen and co-workers

demonstrated a copper-catalyzed reaction between nitroolefin with o-phenylenediamine at

110 °C in ethanol to form quinoxaline A series of substituted quinoxalines were obtained from the starting precursors in moderate to high yields (Scheme 1.15) [77]

Scheme 1.15 Synthesis of quinoxaline derivatives from nitroolefins

In addition to o-phenylenediamines, a few substrates were also used to synthesize

quinoxalines, including o-nitroanilines [78, 79], N-arylenamines [80], and

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o-diisocyanoarenes [81, 82] Moreover, as all of these approaches used transition metal

catalysts, and toxic solvents and were carried out under extreme conditions, they might not be probably applied in the pharmaceutical industry Because of the importance of quinoxaline compounds, studies on finding efficient methods to synthesize them would be always an interesting topic, especially finding high-performance methods based on available materials, transition metal-free catalysts, and performing in friendly solvents

1.3 Introduction of N-arylindole compounds

1.3.1 Biological activity of the N-arylindole compounds

N-arylindole is a basic structure found in many biological and pharmaceutical compounds

It was also present in chemical materials and fundamental ligands used in chemical

processes [83-85] N-arylindoles display a lot of valuable activities such as

anti-inflammatory, anti-cancer, anti-viral, anti-convulsant, and treatment of schizophrenia [86-90]

Figure 1.3 N-arylindoles and its applications

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1.3.2 Synthetic approaches to N-arylindole derivatives

1.3.2.1 Overview of the nucleophilic substitution reaction of nitrobenzenes

Nitroarenes have played an important role as precursors for the synthesis of aniline derivatives in organic synthesis Recently, many studies have shown that nitroarenes could be used to directly replace anilines for coupling reactions that form new C−N bonds [91] The conversion ability of the -NO2 functional group in the nitrobenzene and its homologous was shown to be relatively flexible Meanwhile, the conversion of C−H bonds into nitroarenes often encountered many obstacles While some electrophilic substitution reactions to nitroarenes did not occur (such as the Friedel-Crafts reactions) due to the strong electron attraction of the -NO2 group, the halogenation, sulfonation, or nitrification

reactions only selectively target the meta C−H bond The development of the general

methods that allow the flexible transformation of other C−H sites on nitroarenes has been of great interest to many researchers

Scheme 1.16 Nucleophilic substitution of p-Chloronitrobenzene

Since the 1960s, the nucleophilic aromatic substitution of halogen or pseudohalogen groups in aromatic rings, especially haloaromatics was an important process in organic synthesis and the chemical industry [92-94] In general, due to the electron-withdrawing

17

effect of -NO2, the addition of nucleophiles into nitroarenes could proceed at ortho and

para positions to the nitro group, whether they contained nucleofugal groups or hydrogen

(Scheme 1.16)

The most common property of the nucleophilic substitution reaction of nitroarenes was C bond formation using an external oxidizing agent to modify the C-H bond of the nucleophiles [95-97] Besides following C-C bonds, the nucleophilic substitution reactions from nitroarenes to form C-N, and C-O bonds have also been of great interest In 2010, Wróbel and co-workers successfully performed a nucleophilic substitution reaction

C-between nitroarenes and anilines in the presence of t-BuOK in DMF, at -60 °C, resulting in the formation of N-aryl-2-nitroso anilines [98] Then, in 2016, they also successfully

carried out a two-step reaction to form 2-nitrodiarylamines by maintaining the first step, developing different oxidation conditions, and using NaBO3.4H2O in acetic acid or 2-iodoxybenzoic acid (Scheme 1.17) [99]

Scheme 1.17 A two-step synthesis of 2-nitrodiarylamines

A rather similar method was also developed by Beier et al., [100] In the first step of the

synthesis of N-aryl-2-nitrosoanilines, the base n-BuLi was used in the THF to deprotonate

the N−H of aniline Then, the nitroarenes were added to the mixture at -110 ℃ and -120 ℃ The selective oxidation of nitroso to nitro was carried out under KMnO4 in NH3liquid at -110 ℃ The developed method has shown high compatibility with many aniline derivatives (Scheme 1.18) Meanwhile, most of the nitroarenes with good yields had strong electron-absorbing groups such as SF5 or CF3

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Scheme 1.18 Formation of 2-nitrodiarylamines by the reaction of anilines and nitroarenes Several methods of using oxygen-containing nucleophilic agents for the formation of C-O bonds have also been reported previously One of the earliest reports was published by Suzuki and co-workers [101] The methoxylation of C(sp2)-H bonds of 1,3-dinitrobenzene and 5-substituted derivatives were performed in 1,3-dimethylimidazolidin-2-one (DMI) with the methoxy source MeOK at room temperature, affording 2,4-dinitroanisole and its 6-substituted derivatives in low to moderate yields (Scheme 1.19) Extensions to mono, dinitronaphthalene, and

nitroquinoline also gave methoxy derivatives in the ortho or para positions at moderate

yields

Scheme 1.19 Direct methoxylation of nitroarenes

Recently, in 2011, a more general method, which allowed alkoxylation of C(sp2)−H bonds of nitrobenzene derivatives has been developed by Beier’s group [102] The nucleophilic

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substitution reaction of nitroarenes with the base t-BuOK for the formation of aromatic

ethers was carried out at a low temperature, in the presence of AcOH and the oxidizing agent O2 in THF (Scheme 1.20) Some other alcohols could also be used as alkoxylation sources by pre-reacting with KH at room temperature to give the alkoxyl anion On this basis, the coupling reaction between the C(sp2)-H bond of 1-nitro-4-pentafluorosulfanyl benzene with alcohols such as methanol, n-butanol, iso-propanol, and cyclohexanol all proceeded well

Scheme 1.20 Oxidative nucleophilic alkoxylation of nitrobenzenes

1.3.2.2 Synthesis of N-arylindole derivatives via C-N coupling reactions

Among the methods of the synthesis of N-arylindoles, the Fisher indole synthesis method

was the most widely used [84] The Ullmann-type coupling of aryl halides with indoles

showed a facile, and inexpensive approach to N-arylindoles [103-105] Normally, the

copper-catalyzed Ullman coupling reactions required high temperatures Palladium was an alternative transition metal for copper which addresses the problems of extreme reaction

temperatures In early 2000, Buchwald’s group demonstrated an approach to N-arylate

indoles via a coupling reaction between indoles with halobenzenes using phosphines as a supporting ligand in combination with a Palladium catalyst Various aryl of chlorides, bromides, iodides, and triflates were used and the side products were minimized by using relevant ligands (Scheme 1.21) [106] Although the temperature was reduced, the reaction efficiency was not increased and the side products remained

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Scheme 1.21 Palladium-catalyzed coupling indoles and halogen-substituted arenes

A wide range of applications of Pd-catalyzed reactions for the synthesis of N-arylindoles

has been reported [107] One of the drawbacks of utilizing palladium as a catalyst was its high cost The straightforward solution was to use the copper catalysts derived from copper iodide and simple diamine ligand Which could efficiently catalyze the coupling of aryl halides with amides (Goldberg coupling) and N-H heterocycles with excellent yields

under relatively mild conditions and with low quantities of copper [108] The N-arylation

of indoles reported by Buchwald and co-workers was a typical example The coupling could be achieved using 0.2 mol% of CuI and 1 mol% of chelating substance, providing a 98% yield of desired products [109] On the other hand, some limitations in the method were found when easily ionizable functional groups such as phenols or benzoic acids were present as the substituents on the arene This could be explained by the fact that the coordination of the synthesized phenolate or aryl carboxylate to copper resulted in the inactivation of catalytic species The second explanation could be that the phenolate or aryl carboxylate would limit solubility in the nonpolar solvents (Scheme 1.22) [110]

Scheme 1.22 Copper-catalyzed coupling indoles and halogen-substituted arenes

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The cross-dehydrogenative couplings (CDC) functionalized C-H bonds of substrates to

form C-N bonds for the synthesis of N-arylindoles have been investigated over the past few

decades These methods have gained a lot of attention as they allowed useful and unprecedented reactions which did not require preactivation and/or preoxidation of either coupling partner, and they were also more atom-economical [111-116]

On the basics of the copper-catalyzed cross dehydrogenative coupling reaction, in 2016, Punniyamurthy and co-workers introduced a novel method for regioselective

N-arylation of azoles via dehydrogenative coupling with N-(quinolin-8-yl)benzamides

[117] Moreover, N-(quinolin-8-yl)thiophene-2-carboxamide could also cross-couple with

azoles (Scheme 1.23) [118, 119] This protocol showed highly practical and functional group tolerance, specifically, a large alkyl substituent at the 3-position, which could be used for product modifications

Scheme 1.23 N-Arylation of indoles and N-(naphthalene-1-yl)picolinamide

The direct transitional-metal-free cross-coupling afforded an efficient synthetic tool for the selective carbon−carbon and carbon−heteroatom bond formations from simple substrates Among them, the C-N bond formation has gained a lot of attention, as this motif, in

particular, N-arylated indoles were present in myriad compounds that were important in

biological, medical, and material sciences [83-89]

In 2018, Chang’s group developed a method for the synthesis of N-arylindoles using

benzynes In this protocol, the reaction between indole with 2-bromoacetophenone

occurred in the 1,4-dioxane solvent, in the presence of t-BuOK at 140 ºC for 16 h The

desired product was obtained at 66% yield The underlying mechanism indicated that in

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the presence of t-BuOK, 2-bromoacetophenone was enolated and then form the

intermediate benzyne, which performed nucleophilic substitution on the N-H bond (Scheme 1.24) [120] Although the reported scope of the reaction was limited, the synthesis

of N-arylindoles by this protocol has been considered

Scheme 1.24 N-arylation of indole using a benzyne intermediate

Similar to the transition metal-free pathway, Diness and co-workers proposed two

approaches for the synthesis of N-arylindoles via the coupling reactions between aryl

fluorides and indoles (Scheme 1.25) In the first approach, the reaction of pentafluorobenzene with indole was carried out in DMA solvent, at room temperature, in

the presence of t-BuONa, for 1 h afforded N-arylindoles in high yields This protocol could

be used for a broad range of pentasubstitute benzenes In the second approach, a similar reaction with 1-bromo-4-flourobenzene was conducted under extreme reaction conditions, giving a relatively high yield of products in high However, the scope of the reaction could not extend to more than 3 examples In addition, based on the transition metal-free arylation of indoles by nucleophilic aromatic substitution, a lot of protocols have been proposed, most of which proceeded under extreme conditions and limited scope of application [121] [122]

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Scheme 1.25 N-arylation of indoles by SNAr of aryl fluorides

Given their importance, N-arylindole derivatives have been attracting high attention and

numerous strategies were reported in the construction of functionalized indoles

Nevertheless, access to N-arylated indoles has remained extremely limited and highly

desirable

1.4 Introduction of thiocromenone compounds

1.4.1 Biological activities of thiocromenone compounds

Flavones belong to the class of flavonoids, which can be found widespread in nature The substitution of an oxygen atom at the number 1- position of a flavone by a sulfur atom in the scaffold leads to the formation of analogs called thiocromenones (thioflavones) In comparison with flavones, 1-thioflavones have been less exploited due to their absence in nature Nevertheless, 1-thioflavone and its derivatives have been widely investigated as a potential drug candidate for diverse pharmacological activities such as anti-bacterial, anti-fungal, anti-carcinogenic, and anticancer [123-126]

Furthermore, it was noticeable that 1-thioflavone scaffold could also act as the potential building block for the preparation of a variety of biologically active molecules One

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example was the oxidation of a sulfur atom whose oxidation number was -2, to higher oxidation states, yielding the sulfoxide and sulfone structures (Figure 1.4) [127, 128] Of particular note was that compounds possessing vinyl sulfone moiety have been reported in a broad range of biological activities, such as neuroprotective activity, anti-parasite activity, and inhibition of HIV-1 integrase enzyme [129-132]

As a result, much progress has been made to develop a highly efficient route to 1-thioflavones over the past decades The synthetic methods have focused on producing a diversely functionalized library of 1-thioflavone derivatives, while also paying attention to high yield, safe and simple operation Various protocols for the synthesis of 1-thioflavones and other 2-substituted thiochromen-4-ones have been developed Normally, they could be separated into multi-step and one-step procedures

Figure 1.4 Structures of flavone, 1-thioflavone, and its oxidized derivatives

1.4.2 Synthetic approaches to thiocromenone derivatives

By using sulfur-containing reactants as precursors, the initial strategy to synthesize thiochromen-4-ones involved the use of sulfur-containing structural motifs as the key reactants One early approach to thiochromen-4-one compounds was conducted by Truce and Goldhamer in 1959 [133] Firstly, both cis- and trans--p-tolyl-mercaptocinnamic acid

25

isomers were synthesized via nucleophilic addition of thiolate anion to propiolate (ester or salt), then were treated with different acidic conditions for cyclization Interestingly, both isomers were observed to yield the same 6- methylthioflavone product, which is opposed to the prediction that the trans isomer would form an indenone derivative (Scheme 1.26) In 1980, Wadsworth and Detty expanded the substrate scope to various thioflavones and selenoflavones using a more recent Friedel-Crafts-type cyclization modification [134] However, it also encountered a problem in which the competitive cyclization into the strongly activated groups could lead to the formation of indenones This drawback, along with the multi-step process resulted in a poor yield of target compounds with poor tolerance, although cyclizing step showed excellent reaction yields

Scheme 1.26 A pathway to thioflavone scaffold via nucleophilic attack and cyclization by Truce and Goldhamer

Another early method to achieve thiochromen-4-ones within one step was reported by Bossert (Scheme 1.27) [135] This method employed hot polyphosphoric acid as a catalyst for the direct condensation of thiophenol derivatives with β–ketoesters, which were

obtained by the reaction of benzoic acids and N, N-carbonyldiimidazole Despite being

used as a convenient method to produce the target product, the drawback included low yields and a limited scope of application [136, 137]

Scheme 1.28 Synthesis of 2-substituted thiochromen-4-ones using Wittig reagent Another approach using thiosalicylic acid as the starting material to afford 1- thioflavones was reported by Lee in 2009 (Scheme 1.29) [139] The strategy proceeded through the

formation of 2’-mercaptoacetophenone 1 from thiosalicylic acid, where compound 1 would be aroylated at the α-methyl position to furnish compound 2 Subsequently, compound 2

was cyclodehydrated in the presence of sulfuric acid and acetonitrile in a short reaction time to form 2-aryl-thiochromen-4-ones in good yields Various substituted aroylation agents were compatible with this protocol