Luận văn thạc sĩ Kỹ thuật hóa học: Novel methodology for the sulfenylation and sulfonylation of the C1-H bond in pyrrolo (1,2-a) quinoxaline derivatives

Dissertation objectives: - The synthesis of 4-aryl-1-phenylthiopyrrolo[1,2-a]quinoxalines through the C-S coupling reaction between 4-arylpyrrolo[1,2-a]quinoxalines and aryl disulfides

VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY



LE THI MAI KHANH

NOVEL METHODOLOGY FOR THE SULFENYLATION AND SULFONYLATION

THIS THESIS IS COMPLETED AT

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY – VNU-HCM

Supervisor: Prof Phan Thanh Son Nam

Dr Nguyen Thanh Tung

Examiner 1: Dr Phan Thi Hoang Anh

Examiner 2: Dr Tran Phuoc Nhat Uyen

This master’s thesis is defended at Ho Chi Minh City University of Technology, VNU-HCM on January 5th, 2024

Master’s Thesis Committee:

1 Assoc Prof Dr Tran Hoang Phuong

2 Dr Phan Thi Hoang Anh

3 Dr Tran Phuoc Nhat Uyen

4 Dr Nguyen Dang Khoa

5 Dr Nguyen Thanh Tung

Chairman Examiner Examiner Secretary Member

Approval of the Chairman of the Master’s Thesis Committee and Dean of Faculty

of Chemical Engineering after the thesis was corrected (If any)

CHAIRMAN OF

THESIS COMMITTEE

DEAN OF FACULTY OF CHEMICAL ENGINEERING

VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

───────────────────────────────

SOCIALIST REPUBLIC OF VIETNAM

Independence – Freedom – Happiness

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APPROVAL OF MASTER’S DISSERTATION

Full name: LE THI MAI KHANH Student ID: 2170977

Day of birth: 24/11/1999 Place of birth: Ho Chi Minh City Major: Chemical Engineering Major ID: 8520301

1 Name of dissertation

In English: Novel methodology for the sulfenylation and sulfonylation of the C1-H

bond in pyrrolo[1,2-a]quinoxaline derivatives

In Vietnamese: Phát triển phương pháp sulfenyl và sulfonyl hóa liên kết C1-H của

dẫn xuất pyrrolo[1,2-a]quinoxaline

2 Dissertation objectives:

- The synthesis of 4-aryl-1-(phenylthio)pyrrolo[1,2-a]quinoxalines through the C-S

coupling reaction between 4-arylpyrrolo[1,2-a]quinoxalines and aryl disulfides

- The synthesis of 4-aryl-1-(phenylsulfonyl)pyrrolo[1,2-a]quinoxalines through the C-S coupling reaction between 4-arylpyrrolo[1,2-a]quinoxalines and sodium

arylsulfinates

- The optimization of the conditions for both reactions

- The investigation of the substrate scope for both reactions

- The proposal of plausible mechanisms for both reactions

3 Start date: 16th February, 2023

4 Finish date: 10th December, 2023

5 Supervisor: Prof Phan Thanh Son Nam; Dr Nguyen Thanh Tung

Ho Chi Minh City, January 2024

SUPERVISOR 1 SUPERVISOR 2 HEAD OF DEPARTMENT

DEAN OF FACULTY OF CHEMICAL ENGINEERING

ACKNOWLEDGEMENT

My master’s thesis marks one of the most significant milestones in my academic journey, representing my endless effort in more than two years to achieve a fruitful outcome – a Master’s degree at HCMUT, VNU-HCM However, I could have not completed it without the support and care of my supervisors, mentors, teammates, and colleagues Therefore, I sincerely express my gratitude to those who have contributed to my current achievements

First of all, I would like to deliver many thanks to VNU-HCM Key Laboratory

of Materials Structure Analysis (MANAR), Ho Chi Minh City University of Technology, VNU-HCM for creating such precious opportunities for me to take my thesis project

Most importantly, I would like to express my sincerest gratitude to my supervisors, Dr Nguyen Thanh Tung and Prof Phan Thanh Son Nam, who always wholeheartedly supported me not only in terms of academic issues but also with thoughtful encouragement Moreover, I would also like to send my thankfulness to MSc Le Xuan Huy, a kind and passionate mentor, who is always ready to answer my chemistry questions More than knowledge, the “things” you lay in me were the positive change in awareness, skills as well as heartfelt appreciation

Although there were countless moments for me to feel grateful about during the thesis period, the occasion to know and work with my team was the most priceless Thanks to you all, Thien Son, Hoang Huy, Nhu Y, Thu Ha, Thai Quyen, Van Phu, and Thuy Ca, my journey was full of memorial stories Each member left in me deep impressions with a very special sensation

Last but not least, I would like to say my biggest thanks to my family, who always supported me in various aspects and was my most reliable foundation

ABSTRACT

The importance of pyrrolo[1,2-a]quinoxalines as a class of nitrogen-containing

heterocycles has drawn increased attention to the diversification of its framework due

to a wide variety of uses in various industries, particularly in pharmacy In this study,

regioselective sulfenylation and sulfonylation of 4-arylpyrrolo[1,2-a]quinoxalines were first disclosed It was shown that a wide range of 4-arylpyrrolo[1,2-a]

quinoxaline derivatives have been compatible with both protocols, resulting in the formation of the desired products in moderate to good yields The plausible mechanisms for both transformations were also proposed in this report

TÓM TẮT

Ngày nay, pyrrolo[1,2-a]quinoxaline được biết đến là một loại dị vòng chứa nitơ

có tiềm năng ứng dụng rộng rãi trong các ngành công nghiệp khác nhau đặc biệt là

công nghiệp dược phẩm Do đó, việc đa dạng hóa các cấu trúc từ khung chất này ngày

càng thu hút được nhiều sự chú ý Trong nghiên cứu này, phản ứng sulfenyl hóa và

sulfonyl hóa chọn lọc tại vị trí C1 trên khung pyrrolo[1,2-a]quinoxaline đã được công

bố Dưới điều kiện phản ứng tối ưu, nhiều dẫn xuất 4-aryl pyrrolo[1,2-a]quinoxaline

đã được hoạt hóa thành công, tạo ra sản phẩm tương ứng với hiệu suất trung bình đến

tốt Thêm vào đó, cơ chế của cả hai phản ứng cũng được đề xuất trong báo cáo này

GUARANTEE

I hereby declare that I am the sole individual who was responsible for the workload in this thesis, under the supervision of Prof Phan Thanh Son Nam and Dr Nguyen Thanh Tung, at VNU-HCM Key Laboratory of Materials Structure Analysis (MANAR), Ho Chi Minh City University of Technology, VNU-HCM

The data and experimental results in this thesis were completely authentic and have not been published in any other dissertations of the same academic level

If the above declaration is not true, I will take full responsibility for my thesis

Ho Chi Minh City, January 2024

Author

Le Thi Mai Khanh

TABLE OF CONTENTS

ACKNOWLEDGEMENT iABSTRACT _ iiTÓM TẮT _ iiiGUARANTEE ivTABLE OF CONTENTS vLIST OF FIGURE viiiLIST OF SCHEME ixLIST OF TABLE _ xiiiCHAPTER 1: LITERATURE REVIEW _ 11.1 Introduction about the pyrrolo[1,2-a]quinoxaline scaffold _ 1

1.2 The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines 21.3 Direct C-H functionalization of pyrrolo[1,2-a]quinoxalines 8

1.3.1 Direct C1-H functionalization in pyrrolo[1,2-a]quinoxaline skeleton _ 91.3.2 Direct C-H functionalization at other positions in pyrrolo[1,2-a]quinoxaline skeleton 151.4 C-S coupling reactions of aromatic compounds 181.4.1 The synthesis of sulfides via C-S bond construction _ 191.4.2 The synthesis of sulfones via C-S bond construction 241.5 Objectives of the work _ 32CHAPTER 2: EXPERIMENTAL SECTION 342.1 Research contents _ 342.2 Research methodology _ 34

2.3 Materials and Instrumentations _ 342.3.1 Materials 342.3.2 Instrumentations 372.4 Experimental section 382.4.1 The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines 382.4.2 The synthesis of pyrrolo[1,2-a]quinoxalines _ 402.4.3 The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines 412.4.5 The synthesis of sodium sulfinate derivatives 422.4.4 The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines _ 42CHAPTER 3: RESULTS AND DISCUSSION _ 44

3.1 The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines 44

3.1.1 Structure analysis of the product from the sulfenylation reaction _ 473.1.2 The investigation of the effect of reaction conditions on the reaction yield 493.1.3 Substrate scope of the sulfenylation between pyrrolo[1,2-a]quinoxalines and disulfides _ 563.1.4 Control experiments and proposed mechanism _ 633.2 The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines 673.2.1 Structure analysis of sulfonylated pyrrolo[1,2-a]quinoxalines _ 693.2.2 The investigation of the effect of reaction conditions on the reaction yield 713.2.3 Substrate scope of the sulfonylation between pyrrolo[1,2-a]quinoxalines and sodium arylsulfinates 793.2.4 Control experiments and proposed mechanism _ 86CHAPTER 4: CONCLUSION _ 91

4.1 Conclusion remarks _ 914.2 Suggestions for future works 91LIST OF PUBLICATION 92REFERENCES 93APPENDIX 103SHORT RESUME _ 141

LIST OF FIGURE

Figure 1.1: Examples of biologically active dihydroquinoxalines and quinoxalines 1

Figure 1.2: Representative drugs featured by sulfides, sulfoxides, or sulfones 19

Figure 3.1: GC-MS result of the post-reaction mixture in the preliminary test 47

Figure 3.2: The coupling constant between pyrrolic protons of a) 4-phenylpyrrolo[1,2-a]quinoxaline, b) 4-phenyl-1(phenylthio)pyrrolo[1,2-a]quinoxaline, c) 1-chloro-4-phenylpyrrolo[1,2-4-phenyl-1(phenylthio)pyrrolo[1,2-a]quinoxaline, and d) 4-phenyl-1-(trifluororomethyl)pyrrolo[1,2-a]quinoxaline 49

Figure 3.3: The effect of transition-metal source on the reaction yield 51

Figure 3.4: The effect of catalyst loading on the reaction yield 52

Figure 3.5: The effect of iodine source on the reaction yield 53

Figure 3.6: The effect of solvent type on the reaction yield 55

Figure 3.7: GC-MS result of post-reaction mixture in the presence of radical quenchers 1,1-diphenylethylene 66

Figure 3.8: Several functionalized 4-phenylpyrrolo[1,2-a]quinoxaline structures and their coupling constant J 70

Figure 3.9: FT-IR spectrum of the sulfonylated pyrrolo[1,2-a]quinoxaline 71

Figure 3.10: Different examined ligands for the sulfonylation of pyrrolo[1,2-a]quinoxalines 73

Figure 3.11: The effect of ligands on the reaction yield 75

Figure 3.12: The effect of copper catalysts on the reaction yield 77

LIST OF SCHEME

Scheme 1.1: Synthesis of pyrrolo[1,2-a]quinoxalines via Pictet-Spengler reaction 2 Scheme 1.2: Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-

aminophenyl)-pyrrole and benzylamines 3

Scheme 1.3: Synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-aminoaryl)pyrrole

and aldehydes using oxygen as a sole oxidant 4

Scheme 1.4: Acid acetic-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)-pyrroles and aryl aldehydes 5

Scheme 1.5: Copper-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminoaryl)pyrroles and arylacetic acids 6

Scheme 1.6: Copper(II)-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)pyrroles and aldehydes 7

Scheme 1.7: Iron-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)pyrroles and inactivated methyl arenes 8

Scheme 1.8: NCS-promoted thiocyanation of pyrrolo[1,2-a]quinoxalines using

NH4SCN and KSCN as the thiocyanate source 9

Scheme 1.9: NCS-promoted selenocyanation of pyrrolo[1,2-a]quinoxalines using

KSeCN as the selenocyanate source 10

Scheme 1.10: Selective chlorination of the C1-H bond in

4-arylpyrrolo[1,2-a]quinoxalines utilizing NCS and DMSO 11

Scheme 1.11: Cu-catalyzed direct C1-H difluoromethylation of

pyrrolo[1,2-a]quinoxalines using CuCl, 2,2’-bipyridine, and B2Pin2 12

Scheme 1.12: Copper-catalyzed direct C1-H trifluoromethylation of

pyrrolo[1,2-a]quinoxalines with CF3SOONa 13

Scheme 1.13: Direct Pd-catalyzed C-H arylation of pyrrolo[1,2-a]quinoxalines using

Pd(OAc)2 and X-Phos 15

Scheme 1.14: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines utilizing TBAI

and TsNHNH2 16

Scheme 1.15: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using I2 and PTSA.H2O 17

Scheme 1.16: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using NIS 18 Scheme 1.17: Disulfenylation of imidazo[1,2-a]pyridine derivatives employing

elemental sulfur and arylhalides 20

cheme 1.18: Dehydrogenative aryl C-S coupling from thiols using iodine(III)

reagent PhI(OAc)2 21

Scheme 1.19: Copper-catalyzed C5-sulfenylation of N-alkyl-8-aminoquinoline

utilizing sulfonyl hydrazides 22

Scheme 1.20: A combination of catalytic AgOAc and DABCO direct sulfenylation

of pyrazolones with diaryl disulfides 23

Scheme 1.21: A copper-catalyzed ortho-selective direct C-H sulfenylation of

N-aryl-azaindoles with disulfides as the sulfur source using Cu(OAc)2 and PhCOOH in mesitylene 24

Scheme 1.22: Copper-catalyzed, visible-light-promoted sulfonylation of aryl halides

with sodium arylsulfinates 25

Scheme 1.23: Copper-catalyzed cyclization between N-propargylamines and sodium

sulfinates to obtain 3-sulfonylated quinolines 26

Scheme 1.24: Selective MOF-derived cobalt-catalyzed C-H oxidative sulfonylation

of tetrahydroquinoxalines 27

Scheme 1.25: Non-directed copper-promoted site-selective C-H sulfonylation of

phenothiazines 28

Scheme 1.26: Sulfonylation of aryl iodides and bromides using arylsulfonyl

hydrazides, copper catalyst, and PEG-400 30

Scheme 1.27: Copper-catalyzed synthesis of sulfonylation isoquinolin-1(2H)-ones

employing sulfonylacetonitriles and DMEDA ligand 31

Scheme 1.28: Sulfenylation (top) and sulfonylation (bottom) of

pyrrolo[1,2-a]quinoxalines 33

Scheme 2.1: The general synthesis of 4-arylpyrrolo[1,2-a]quinoxalines from

arylaldehydes 38

Scheme 2.2: The general synthesis of 4-arylpyrrolo[1,2-a]quinoxalines from

arylacetic acid 40

Scheme 2.3: The synthesis of pyrrolo[1,2-a]quinoxalines 40

Scheme 2.4: The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines 41

Scheme 2.5: The synthesis of sodium sulfinate derivatives 42

Scheme 2.6: The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines 43

Scheme 3.1: The synthesis of 4-phenyl-1(phenylthio)pyrrolo[1,2-a]quinoxaline 47

Scheme 3.2: The investigation of the effect of transition-metal source 50

Scheme 3.3: The investigation of the effect of catalyst loading 51

Scheme 3.4: The investigation of the effect of the iodine source 53

Scheme 3.5: The investigation of the effect of solvent type at 120 ℃ 54

Scheme 3.6: The investigation of the effect of solvent type at 80 ℃ 54

Scheme 3.7: The investigation of the effect of the atmospheric environment 55

Scheme 3.8: The investigation on the scope of pyrrolo[1,2-a]quinoxalines 56

Scheme 3.9: The investigation of the scope of disulfides 62

Scheme 3.10: The reaction in the absence of disulfides 64

Scheme 3.11: The idoination of 4-phenylpyrrolo[1,2-a]quinoxaline 65

Scheme 3.12: The synthesis of 4-phenyl-1-(phenylthio)pyrrolo[1,2-a]quinoxaline in the presence of radical quencher 1,1-diphenylethylene 65

Scheme 3.13: Proposed mechanism for the sulfenylation reaction 67

Scheme 3.14: The synthesis of 4-phenyl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxaline 68

Scheme 3.15: The investigation on the effect of temperature on the reaction yield 72 Scheme 3.16: The investigation on the effect of type of ligands on the reaction yield 74

Scheme 3.17: The investigation on the effect of copper catalyst on the reaction yield 76

Scheme 3.18: The investigation on the effect of reactant ratio on the reaction yield 78

Scheme 3.19: The investigation on the scope of pyrrolo[1,2-a]quinoxalines 79

Scheme 3.20: The investigation on the scope of sodium arylsulfinates 84 Scheme 3.21: The first step of the sulfonylation reaction of pyrrolo[1,2-

a]quinoxalines 87

Scheme 3.22: The sulfonylation of pyrrolo[1,2-a]quinoxalines in the presence of a

radical quencher 1,1’-diphenylethylene 88

Scheme 3.23: Proposed mechanism for the sulfonylation of

pyrrolo[1,2-a]quinoxalines 89

LIST OF TABLE

Table 2-1: List of chemicals purchased and used in the study 35

Table 3-1: The effect of the atmospheric environment on the reaction yield 56

Table 3-2: Scope of pyrrolo[1,2-a]quinoxalines 57

Table 3-3: Scope of disulfides 62

Table 3-4: The effect of reaction temperature on the reaction yield 73

Table 3-5: The effect of sodium benzenesulfinate loadings on the reaction yield 79

Table 3-6: Scope of pyrrol[1,2-a]quinoxalines 80

Table 3-7: Scope of sodium benzenesulfinates 85

CHAPTER 1: LITERATURE REVIEW

1.1 Introduction about the pyrrolo[1,2-a]quinoxaline scaffold

Over the past few decades, nitrogen-containing heterocycles have been broadly utilized as valuable scaffolds in developing products of natural compounds, pharmaceuticals, and agrochemicals thanks to their resemblance to various natural and synthesized molecules with discovered biological features Therefore, nitrogen-containing cyclic structures, namely pyrroles, pyridines, indoles, and imidazoles, have become attractive classes in organic synthesis Among these, pyrrolo[1,2-

a]quinoxaline with the structure of a quinoxaline skeleton combined with a

five-membered heterocycle forming the so-called fused-quinoxaline scaffold, has been considered as a privileged structure in the drug industry [1], [2] In particular,

pyrrolo[1,2-a]quinoxaline derivatives with a substituent at the C-4 position exhibit

many valuable biological activities such as antileishmanial, antiproliferative, anticancer, and anti-HIV,…[3]–[6] Some of them have also been found to be essential

inhibitors and receptors in the human body [7]–[9] (Figure 1.1) Additionally, several

pyrrolo[1,2-a]quinoxaline derivatives have shown promise in applications for

electrical and optical devices due to their excellent fluorescence and photophysical properties [10]–[12]

Figure 1.1: Examples of biologically active dihydroquinoxalines and quinoxalines

1.2 The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines

In general, the synthesis process of the pyrrolo[1,2-a]quinoxalines scaffold

requires an intermediate with the pyrrole ring along with a functional group at the

ortho-position acting as a nitrogen synthon for the cyclization of the desired product

Due to numerous applications of pyrrlo[1,2-a]quinoxalines, tremendous efforts have

been put into developing novel methodologies and transformations for them To date,

the synthesis of pyrrolo[1,2-a]quinoxalines has been accomplished in a variety of

ways, in which the Pictet-Spengler reaction has been considered the most popular protocol This synthesis approach involves the condensation between 1-(2-aminoaryl)pyrroles and aldehydes, leading to the formation of an imine intermediate, followed by the intramolecular annulation and oxidation stages to afford the

corresponding 4-substituted pyrrolo[1,2-a]quinoxalines (Scheme 1.1) [13]

Scheme 1.1: Synthesis of pyrrolo[1,2-a]quinoxalines via Pictet-Spengler reaction

Due to its widespread use, diversified coupling reactants have recently been developed, allowing for simple and practical annulation For example, in 2015, Wang

et al developed an efficient iodine-catalyzed protocol to synthesize

pyrrolo[1,2-a]quinoxalines from 1-(2-aminophenyl)pyrroles and benzylamines in the presence of

iodine as an economical and effective catalyst (Scheme 1.2) In particular, o-xylene

was chosen as the solvent, and the reaction proceeded under the oxygen atmosphere Subsequently, the scope of this transformation was explored Notably, different benzylamine derivatives and various substituted 1-(2-aminophenyl)pyrroles

furnished corresponding pyrrolo[1,2-a]quinoxalines in excellent yields Based on the

results, it could be inferred that the reaction showed no dependence on the nature of the substituents In conclusion, this method's advantages include a low-cost, non-toxic catalyst, efficient procedure, and a wide range of substrate tolerance [14]

Scheme 1.2: Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)-pyrrole and benzylamines

Another work is from the research group of Wang with a viable and ecologically

friendly protocol for the synthesis of pyrrolo[1,2-a]quinoxalines This synthetic

method was conducted at 140 ℃, involving the cyclization between aminoaryl)pyrroles and aldehydes under an oxygen atmosphere as a sole oxidant

1-(2-(Scheme 1.3) It was found that both aromatic and aliphatic aldehydes were well

tolerated with this reaction, resulting in good to excellent yields of the desired

products It was noteworthy that para-substituted aldehydes afforded the

corresponding products in good yields while aliphatic aldehydes showed marginally lower yields In addition, heterocyclic aldehydes were also well tolerated under the reaction conditions It was inferred that the influence of the substituents had a negligible impact on the transformation This approach provided a simple and

environmentally friendly way to obtain pyrrolo[1,2-a]quinoxalines under additive-

and metal-free conditions

Scheme 1.3: Synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-aminoaryl)pyrrole

and aldehydes using oxygen as a sole oxidant

According to Allan et al., a novel approach to synthesize

pyrrolo[1,2-a]quinoxalines through the Pictet-Spengler reaction was devised [15] Under an

oxygen environment along with the presence of a catalytic amount of acetic acid, the

reaction produced the highest yield of the cyclized compounds (Scheme 1.3) The

exploration of the substrate scope revealed that the use of electron-rich benzaldehyde derivatives provided the desired products in good yields Regarding benzaldehydes

bearing electron-withdrawing substituents, while ortho- and para-substituted benzaldehydes produced the corresponding products in good yields, meta-isomers

deterred the aromaticity, resulting in inseparable mixtures of desired products and their 4,5-dihydro derivatives The investigations of substituted anilines indicated that the position of the electron-withdrawing groups on 1-(2-aminophenyl)-pyrroles had

a significant influence on the formation of desired products, which was probably because of the conjugation with the lone pair of electrons belonging to the pyrrolic nitrogen atom With the advantages of using readily available starting materials under

mild conditions, this approach has been used as a synthesis procedure for various biologically active chemicals

Scheme 1.4: Acid acetic-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)-pyrroles and aryl aldehydes

Because of its inexpensive cost, abundance, and high catalytic efficiency, copper has been used as an alternative for precious metal catalysts in organic synthesis Lade

et al reported a copper-catalyzed C-H activation reaction of arylacetic acids,

providing an efficient method to synthesize pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)pyrrole (Scheme 1.5) [16] In this protocol, CuSO4 as a catalyst and 2,2’-bipyridyl as a ligand were employed to transform aryl acetic acids into benzaldehydes, under the O2 atmosphere To broaden the scope of this study, different arylacetic acids were first screened, indicating that various arylacetic acids were well

tolerated and gave the corresponding pyrrolo[1,2-a]quinoxalines in good yields

Furthermore, several heteroarylacetic acids also reacted smoothly, providing the desired product with good to excellent yields In addition, good yields of the products were afforded when utilizing substituted 1-(2-aminophenyl)pyrroles with various arylacetic acids Based on the results, it could be inferred that the electron density of substituents may have insignificant effects on the transformation In summary,

effective procedure, numerous functional groups tolerance, and commercially available starting materials were key advantages of this method

Scheme 1.5: Copper-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminoaryl)pyrroles and arylacetic acids

Also utilizing a copper-based catalyst, which was Cu(OTf)2, Krishna et al

established a simple, copper-catalyzed Pictet-Spengler reaction to synthesize

pyrrolo[1,2-a]quinoxalines [17] This reaction started with the formation of imines

from 1-(2-aminophenyl)-pyrroles and aldehydes, followed by the intramolecular cyclization, and oxidation catalyzed by copper(II) triflate as a catalyst, in ethanol as

a solvent (Scheme 1.6) Through the screening process, Cu(OTf)2 was confirmed to

be superior for this conversion, affording the desired product with the highest yield

of 96% after an hour of reaction at room temperature Notably, 4,5-dihydro derivatives could be afforded when decreasing the reaction temperature to 0-10 ℃ The results showed that benzaldehydes with various electron-donating or electron-withdrawing groups at different positions were compatible with this protocol A noteworthy point of this procedure is that hydroxylated benzaldehydes,

heteroaromatic aldehydes, and (R)-O-isopropylidene glyceraldehyde could smoothly

proceed with this reaction, giving corresponding products in good yields To sum up, this method offered several benefits, including a straightforward reaction mechanism, easily accessible starting materials, minimal catalyst loading, facile product isolation,

a wide range of substrates, good functional group tolerance, and gram-scale synthesis

Scheme 1.6: Copper(II)-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)pyrroles and aldehydes

In 2021, by using 1-(2-aminophenyl)pyrroles and methyl arenes, Ahn and workers reported a simple and effective technique to produce pyrrolo[1,2-

co-a]quinoxalines [18] Under the air environment at 120 ℃, methyl arenes were directly

converted to benzaldehydes by di-tert-butyl peroxide (DTBP) in the presence of an

iron catalyst (Scheme 1.7) In general, methyl arenes bearing electron-donating

groups, such as methyl groups, performed better yields than those with withdrawing groups This was explained by the stabilization of the electron-donating group on the benzyl cation charge that was produced during benzylic carbon activation Electron-withdrawing substituents could lower the efficiency of the annulation, affording the corresponding products in moderate yields Additionally, the position of the substituent significantly affected the electron density of 2-aminophenyl pyrroles, causing an impact on the entire reaction process Moreover,

electron-the scope reaction was also extended to 1-(2-aminophenyl)indoles, which was considerably influenced by the substituent position on the indole moiety In conclusion, this methodology was well-tolerated with diverse functional groups and allowed for additional functionalization, making a high possibility for industrial applications

Scheme 1.7: Iron-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from

1-(2-aminophenyl)pyrroles and inactivated methyl arenes

1.3 Direct C-H functionalization of pyrrolo[1,2-a]quinoxalines

Despite the fact that the synthesis of substituted pyrrolo[1,2-a]quinoxalines had

received a lot of attention, most of the prior studies primarily only focused on the synthesis of C4-substituted pyrrolo[1,2-a]quinoxalines, which severely limit the

diversity of this N-containing heterocycles class In fact, the

pyrrolo[1,2-a]quinoxalines scaffold possesses multiple reactive sites on its structure, which allow

them to participate in the direct functionalization of C−H bonds, which is a promising and powerful approach for the preparation of complex structures with a good-atom-economy manner

1.3.1 Direct C1-H functionalization in pyrrolo[1,2-a]quinoxaline skeleton

According to the literature, there is an increasing number of publications about

C-H functionalizing pyrrolo[1,2-a]quinoxaline and its derivatives at the C1 position

In 2020, a novel approach to thiocyanate pyrrolo[1,2-a]quinoxalines piqued the

interest of the synthetic chemistry community Herein, Yang and co-workers reported

the selective formation of C1-thiocyanated pyrrolo[1,2-a]quinoxaline scaffold in

MeCN solvent using NCS as a promoter and sole oxidant, with either NH4SCN or

KSCN as thiocyanate sources, particularly (Scheme 1.8) [19] The range of

substituted pyrrolo[1,2-a]quinoxaline was also investigated and it turned out that both pyrrolo[1,2-a]quinoxalines with various functional groups on the quinoxaline skeleton and 4-arylpyrrolo[1,2-a]quinoxalines substrates tolerantly reacted with

NH4SCN, generating desired products with good yields

Scheme 1.8: NCS-promoted thiocyanation of pyrrolo[1,2-a]quinoxalines

using NH 4 SCN and KSCN as the thiocyanate source

Based on the previous condition for the thiocyanation, the investigation on the

selenocyanation of pyrrolo[1,2-a]quinoxaline derivatives was carried out to broaden

the functionalized structures Pyrrolo[1,2-a]quinoxaline was processed with

potassium selenocyanate (KSeCN) under optimal reaction conditions; however; there

was a slight modification in the used solvent changing to ethyl acetate (Scheme 1.9)

The scope for selenocyanation was carried out with the obtained condition Most of

the 4-aryl pyrrolo[1,2-a]quinoxalines proceeded smoothly, and yields of 40–68%

were achieved However, it was difficult to selenocyanate substrates bearing strong electron-withdrawing substituents, for example, 4-(4-nitrophenyl)pyrrolo[1,2-

a]quinoxaline The mechanism of this transformation was proposed, in which the

reaction started with an electrophilic addition with thiocyanate cation to form an intermediate, followed by hydrogen abstraction to give the corresponding thiocyanated products Overall, this method has benign reaction conditions, and a wide range of potential substrates, and could be applied for gram-scale synthesis

Scheme 1.9: NCS-promoted selenocyanation of pyrrolo[1,2-a]quinoxalines

using KSeCN as the selenocyanate source

In 2021, our research group demonstrated the selective chlorination and

bromination of 4-arylpyrrolo[1,2-a]quinoxalines via direct C1-H bond activation

[20] Initially, a variety of chlorinating sources was screened to maximize the chlorination yields, including Bu4NCl, 1-Trifluoromethyl-1,2-benziodoxol-3(1H)-

one (Togni’s reagent), N-chlorosuccinimide (NCS), Trichloroisocyanuric acid

(TCICA), and Trimethylsilyl chloride (TMSCl) Consequently, the highest yield of

1-chloro-4-aryl pyrrolo[1,2-a]quinoxaline was obtained when employing NCS in the

presence of dimethyl sulfoxide (DMSO) as a catalyst in CHCl3 solvent for 24 h at

room temperature (Scheme 1.10) To further extend the substrate scope, the

chlorination of pyrrolo[1,2-a]quinoxaline derivatives was examined The obtained

results indicated that the reaction conditions were compatible with various functional groups on benzene rings, although 4-nitro-substituted substrates showed lower yields

Moreover, pyrrolo[1,2-a]quinoxalines containing heterocycles at the C4 position

were also well-tolerated with the reaction conditions

Scheme 1.10: Selective chlorination of the C1-H bond in

4-arylpyrrolo[1,2-a]quinoxalines utilizing NCS and DMSO

In the same year, Yang et al reported the difluoromethylation of

pyrrolo[1,2-a]quinoxalines with ethyl 2-bromo-2,2-difluoroacetate or 2-bromo-2,2-difluoro-N, N-diethylacetamide employing a copper catalyst [21] The transformation was

promoted in the presence of a base (NaHCO3) and a ligand (2,2’-bipyridine) in the

CH3CN (Scheme 1.11) The examination of different substituted

pyrrolo[1,2-a]quinoxalines was also explored and it turned out that the effect of different

substituents on the para-position of the benzene ring in 4-aryl

pyrrolo[1,2-a]quinoxalines was negligible, forming an excellent functional group tolerance In

addition, 3-iodopyrrolo[1,2-a]quinoxaline was favorable for this coupling, which

enhanced the possibility of further derivatization of these skeletons In addition, gram-scale synthesis of this structure and several difluoroalkylated reagents were conducted, giving the desired product in 51% yield

Scheme 1.11: Cu-catalyzed direct C1-H difluoromethylation of

pyrrolo[1,2-a]quinoxalines using CuCl, 2,2’-bipyridine, and B 2 Pin 2

A plausible mechanism was also proposed, starting with the generation of L-CuI-Bpin species under a basic environment, followed by the single-electron transfer with 2-bromo-2,2-difluoroacetate to produce a free radical ethyl difluoroacetate for the radical addition, after base-promoting the intermediate to remove an HBr molecule

In summary, this method has a wide spectrum of substrate applications and potent substituent compatibility

After one year, Li and co-workers developed a Cu(II)-catalyzed direct C1-H

trifluoromethylation of pyrrolo[1,2-a]quinoxalines due to the widely used of

trifluoromethyl compounds [22] After screening the reaction conditions, 53% yield

of 1-(trifluoromethyl)pyrrolo[1,2-a]quinoxaline was obtained with CF3SO2Na as a trifluoromethylation reagent in the presence of K2S2O8 as an oxidant, CuSO4.5H2O

as a catalyst, and dimethyl sulfoxide (DMSO) as a solvent at 80 ℃ for 12 h (Scheme 1.12)

Scheme 1.12: Copper-catalyzed direct C1-H trifluoromethylation of

pyrrolo[1,2-a]quinoxalines with CF 3 SOONa

Subsequently, the substrate scope of 4-arylpyrrolo[1,2-a]quinoxalines was

investigated The obtained results indicated the good tolerance of the standard reaction conditions with substrates bearing either electron-donating groups or electron-withdrawing groups on the phenyl rings, as well as functional groups at C7

or C8 positions Additionally, 3-aryl substituted pyrrolo[1,2-a]quinoxalines were also

competent towards this transformation In conclusion, a novel methodology was

constructed for the selective trifluoromethylation of pyrrolo[1,2-a]quinoxalines via

direct C1-H bond with a broad substrate scope and a feasible gram-scale synthesis Based on successful C-C bond formation in previous works, Yang and colleagues

reported a direct synthetic route for the diarylation of pyrrolo[1,2-a]quinoxalines

using aryl iodides with the support of a palladium catalyst in 2021 [23] The arylation

of pyrrolo[1,2-a]quinoxalines was investigated under various conditions using

palladium salts and ligands In the exploration of the Pd source, Pd(OAc)2 was clearly superior to other popular Pd catalysts, including Pd(PPh3)4, PdCl2(PPh3)2, and PdCl2(MeCN)2, with 46% yield of target products Next, a wide range of ligands were brought to investigation, and the utilization of X-Phos improved the yield to 63%, compared to around 54% for PCy3 and S-Phos The results also revealed the inefficiency in the utilization of PPh3 and P(Furan-2-yl)3, affording the desired product with a low yield of 32% and 25%, respectively The yield of the arylation process was significantly reduced in the absence of external ligands, marking the important role of it in this Pd-mediated arylation Toluene was considered as the most suitable solvent for this protocol while other organic solvents suppressed the formation of desired products Other additives including AgOAc, AgOTf, and

Cs2CO3 rarely showed their support except for Ag2CO3, for which this compound was

chosen for this conversion (Scheme 1.13)

Based on the acquired optimal conditions, the substrate scope for this methodology was next examined It was shown that 4-substituted aryl iodides bearing various functional groups such as -F, -Cl, -Br, -OMe, and -OEt are well tolerated

Furthermore, bulky derivatives namely 3-(thiophen-2-yl)pyrrolo[1,2-a]quinoxaline and 3-(naphthalen-2-yl)pyrrolo[1,2-a]quinoxaline were also compatible Extensive

testing of the approach was conducted for 4-aryl substrates and found that the steric hindrance of substituents on the benzene ring led to the regioselective formation of C-1 arylated products with no significant impact on the reaction yield A plausible mechanism was outlined for the Pd/Ag-mediated functionalization Firstly, Pd(0)-the

complex was created and underwent the oxidative addition with p-methyl

iodobenzene to obtain the Pd(II) complex, followed by transmetalation with the arylsilver intermediate and reductive elimination to create the 1-arylated product The afforded monoarylated product continued the described catalytic cycle to produce the diarylated product In conclusion, this technique offered a gram-level synthesis, a wide array of functional group tolerance, as well as a diverse substrate range

Scheme 1.13: Direct Pd-catalyzed C-H arylation of pyrrolo[1,2-a]quinoxalines

using Pd(OAc) 2 and X-Phos

1.3.2 Direct C-H functionalization at other positions in pyrrolo[1,2-a]quinoxaline

skeleton

Despite remarkable advancements made in the C-H functionalization of

pyrrolo[1,2-a]quinoxaline at the C1 position, there has been a rising interest in the

diversification of the C3 position In 2021, Liu and her co-workers proposed C3-H

direct iodination of pyrrolo[1,2-a]quinoxalines with tetra-n-butylammonium iodide

(TBAI) as an iodine source in the presence of 4-methylbenzenesulfonohydrazine (TsNHNH2), tert-butyl hydroperoxide (TBHP) in the 1,4-dioxane solvent (Scheme

1.14) [24] With the optimal conditions in hand, the scope of this transformation was

examined with different pyrrolo[1,2-a]quinoxalines The results disclosed that arylpyrrolo[1,2-a]quinoxalines with electron-deficient groups at the para-positions

4-of the benzene ring provided the target iodinated products with higher yields than substrates with electron-rich groups

Scheme 1.14: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines

utilizing TBAI and TsNHNH 2

It is notable that the use of TBAI with TsNHNH2 formed p-toluenesulfonic acid

(PTSA) during the redox process, which had a significant impact on promoting the iodination Therefore, an 86% yield of C3-iodinated product was obtained when employing I2 with a catalytic amount of PTSA.H2O in DMSO at 100 °C (Scheme

1.15) Different pyrrolo[1,2-a]quinoxalines were investigated to widen the scope of

this reaction, resulting in moderate to excellent yields with good functional group tolerance and the electronic effect of the substituents on aryl rings had little influence

In brief, the two approaches are novel methodologies for regioselective C3–H

iodination of pyrrolo[1,2-a]quinoxalines with various substituent tolerance,

gram-scale synthesis, and potential synthetic applications

Scheme 1.15: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines

using I 2 and PTSA.H 2 O

Another C3-iodination was reported by Liu et al in the same year In this protocol, pyrrolo[1,2-a]quinoxalines were treated with N-iodo-succininide (NIS)

followed a solvent-mediated manner [25] By employing CHCl3 and DMF as

solvents, 1-iodopyrrolo[1,2-a]quinoxaline and 3-iodopyrrolo[1,2-a]quinoxaline

could be produced selectively To investigate the conditions for the selective

iodination of pyrrolo[1,2-a]quinoxalines, initial attempts to perform the iodination between pyrrolo[1,2-a]quinoxalines and NIS were carried out Surprisingly, the

selective C1-iodination reaction could proceed smoothly in CHCl3, generating the target product with 81% yield The reaction yield was slightly lowered when the reaction time was cut down to 12 h Changes from NIS to I2 or TBAI had a negative impact on the reaction yield It was interesting to note that when the reaction solvent was a polar solvent such as DMF, DMSO, MeCN, EtOH, and MeOH, selective C3-

H iodinated product was produced Among these solvents, DMF served as the ideal solvent, yielding the product in 72% yield

Scheme 1.16: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using NIS

1.4 C-S coupling reactions of aromatic compounds

The introduction of a sulfur group in a molecular structure, whether in the form

of a sulfanyl, sulfinyl, or sulfonyl, has provided variation to its chemical structures and improved the biological activities of initial compounds Organosulfur compounds, such as sulfides, sulfoxides, and sulfones, represent an important family

of chemical substances due to the diversity of uses for which they are applied [26] Additionally, they have played a significant role in bioactive natural products, pharmaceuticals, insecticides, and materials [27]–[32] Therefore, the integration of sulfur-containing groups into other organic compounds has been gaining tremendous interest among researchers Several sulfur-containing substances such as sulfoxides, sulfides, and sulfones, which made up a significant fraction of medicinal drugs with

different biological activity were presented in Figure 1.2

Among various methodologies to attach the desired sulfur-containing

substituents onto other skeletons, pyrrolo[1,2-a]quinoxaline, for example, C-S

coupling reaction is considered as one of the most studied ones because of its high atom economy and direct pathway, which can cut down the number of used chemicals and waste Therefore, a more in-depth review of state-of-the-art C-S coupling

reactions will be presented in the following sections, targeting the sulfenylated- and sulfonylated products

Figure 1.2: Representative drugs featured by sulfides, sulfoxides, or sulfones 1.4.1 The synthesis of sulfides via C-S bond construction

In general, the coupling reaction of aryl halides with elemental sulfur, disulfides, thiols, or other sulfur-containing reagents was used in the traditional production of diaryl sulfides or aryl alkyl sulfides through a so-called sulfenylation reaction Until now, some of these transformations still necessitated the employment of transition-metal catalysts and ligands in the presence of a base to obtain the desired products For example, in 2018, Semwal and colleagues developed the disulfenylation of

imidazo[1,2-a]pyridines via Cu-catalyzed multicomponent reactions of heteroarene,

elemental sulfur, and aryl iodide [33] In specific, the reaction was performed in a

mixed solvent medium of acetic acid and N, N’-dimethylformamide (DMF)

employing CuI as a catalyst and KOt-Bu as a base at 130 ℃ (Scheme 1.17) The

investigations of substrate scope with various substituted haloarenes revealed that a wide range of functional groups including halogen, methoxyl, boronic acid, and so

on, were compatible with this transformation while the strong electron-deficient NO2substituted derivative proceeded with a lower yield Moreover, 6-halogenated

-imidazo[1,2-a]pyridine was employed to react with different substituted aryl iodides

bearing either electron-withdrawing or electron-donating groups, furnishing the corresponding products in moderate to good yields In summary, this study featured

a gram-scale synthesis, a one-pot disulfenylated reaction utilizing elemental sulfur and haloarenes by double C−S−C bond formations

Scheme 1.17: Disulfenylation of imidazo[1,2-a]pyridine derivatives

employing elemental sulfur and arylhalides

Besides elemental sulfur, organosulfur compounds have also received a lot of

attention as a sulfenylation source In the same year, Mal et al proposed the direct

C-S coupling reaction of aryl thiols and benzenes bearing multiple methyl and/or methoxyl groups in the presence of phenyliodine diacetate (PIDA) as an oxidant and

1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent (cheme 1.18) [34] To broaden

the substrate scope, various aryl thiols and arenes were investigated As a result, thiols containing electron-deficient and electron-rich groups at different positions were well-tolerated with this protocol Interestingly, diaryl sulfides were primarily generated when 1.0 equivalent of PhI(OAc)2 was utilized, while the major products were diaryl sulfoxides when the 3.0 equivalents of PhI(OAc)2 were employed In conclusion, a novel dehydrogenative aryl C-S coupling had several key advantages including a mild reaction condition, metal-free, one-pot, and gram-scale synthesis

cheme 1.18: Dehydrogenative aryl C-S coupling from thiols

using iodine(III) reagent PhI(OAc) 2

In recent years, there have been more and more reports about the successful coupling between non-halide substrates and different sulfenylation sources For example, in 2018, a novel methodology for C5−H sulfenylation of unprotected 8- aminoquinolines by utilizing sulfonyl hydrazides as the sulfenylating reagent was presented by Yu and co-workers [35] In particular, 8-aminoquinoline was treated with tosyl hydrazide (Ts-NHNH2) in the presence of CuI as a catalyst, and Na2CO3

as a base in p-xylene at 120 ℃ (Scheme 1.19) To further increase the scope of this

method, various aryl-substituted sulfonyl hydrazides reacted with different aminoquinoline derivatives Notably, a wide range of functional groups was compatible under standard conditions However, electron-donating-group-substituted phenyl sulfonyl hydrazides produced corresponding products with better yields than

8-the electron-withdrawing one Thanks to 8-the less severe steric hindrance,

para-substitution of phenyl sulfonyl hydrazides afforded the target products with higher

yields than those of ortho-substituted substrates In brief, this method not only was

the ideal regioselectivity scheme for C5-H sulfenylation but also provided free NH2functionalized quinolines for further work

-Scheme 1.19: Copper-catalyzed C5-sulfenylation of N-alkyl-8-aminoquinoline

utilizing sulfonyl hydrazides

Heteroaryl sulfide scaffolds are a crucial class in organic synthesis that has a wide range of uses in the pharmaceutical industry and materials science [36] In 2018, the research group of Yotphan reported the direct C–H bond sulfenylation using aryl and heteroaryl disulfides as the sulfenylation source In particular, the reaction readily proceeded in the presence of a combination of catalytic 1,4-diazabicyclo[2.2.2]octane (DABCO) and AgOAc in methanol at ambient temperature under an air atmosphere

(Scheme 1.20) The results of substrate scope indicated that R1 containing rich-group-substituted phenyl ring was more favorable for this transformation than electron-deficient ones Nonetheless, lower yields of corresponding products were obtained when pyrazolones bear bulky R2 and R3 groups because of steric hindrance Furthermore, various aryl disulfides bearing different functional groups and heteroaryl disulfides were well-tolerated with this reaction condition, and good to excellent yields of target products were achieved In summary, facile procedure, mild reaction conditions, wide substituent tolerance, and reliable scalability were the key features of this methodology

electron-Scheme 1.20: A combination of catalytic AgOAc and DABCO direct sulfenylation

of pyrazolones with diaryl disulfides

In 2021, the Ru-Jian group discovered a selective C-H chalcogenation at the

ortho-position of N-aryl-7-azaindole to form

1-(2-(phenylthio)phenyl)-1H-pyrrolo[2,3-b]pyridine, which is an essential scaffold in many bioactive compounds with antibacterial and anticancer characteristics [37] This transformation occurred in

the presence of Cu(OAc)2 as the main catalyst along with PhCOOH as an additive in mesitylene at 140 ℃ under an air atmosphere, furnishing the corresponding thiolated

products (Scheme 1.21) Subsequently, various N-aryl-7-azaindoles and diaryl

disulfides were screened to extend the scope of this research As a result, both of them

bearing either electron-withdrawing or electron-donating groups at para-positions were well-tolerated with this protocol, while substituted N-aryl-7-azaindoles with

meta-positions and substituted diaryl disulfides with ortho-position provided the

lower yields In summary, this method possessed a number of considerable advantages such as facile procedure, mild reaction conditions, and the use of the inexpensive Cu(OAc)2 catalyst

Scheme 1.21: A copper-catalyzed ortho-selective direct C-H sulfenylation

of N-aryl-azaindoles with disulfides as the sulfur source using Cu(OAc) 2 and PhCOOH in mesitylene

1.4.2 The synthesis of sulfones via C-S bond construction

Traditional methods for making sulfonyl compounds include the oxidization of

corresponding sulfides or arene sulfonylation via the Friedel-Crafts method using

sulfonyl halides or sulfonic acids or their salt forms Let’s take sodium sulfinates as