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novel methodology for the sulfenylation and sulfonylation of the c1 h bond in pyrrolo 1 2 a quinoxaline derivatives

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VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY

<b>HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY </b>



<b>LE THI MAI KHANH </b>

<b>NOVEL METHODOLOGY FOR THE SULFENYLATION AND SULFONYLATION </b>

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THIS THESIS IS COMPLETED AT

<b>HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY – VNU-HCM </b>

<b>Supervisor: Prof. Phan Thanh Son Nam </b>

<b> Dr. Nguyen Thanh Tung </b>

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 5<small>th</small>, 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).

<b>CHAIRMAN OF THESIS COMMITTEE </b>

<b>DEAN OF FACULTY OF CHEMICAL ENGINEERING </b>

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<small>VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY </small>

<b><small>HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY ─────────────────────────────── </small></b>

<b><small>SOCIALIST REPUBLIC OF VIETNAM </small></b>

<small>Independence – Freedom – Happiness </small>

<i><b>In English: Novel methodology for the sulfenylation and sulfonylation of the C1-H </b></i>

<i>bond in pyrrolo[1,2-a]quinoxaline derivatives </i>

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

<i>dẫn xuất pyrrolo[1,2-a]quinoxaline </i>

<b>2. Dissertation objectives: </b>

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

<i><b>coupling reaction between 4-arylpyrrolo[1,2-a]quinoxalines and aryl disulfides. </b></i>

<i>- 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 </i>

<b>arylsulfinates. </b>

<b>- 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. </b>

<b>3. Start date: 16</b><small>th</small><b> February, 2023 4. Finish date: 10</b><small>th</small><b> December, 2023 </b>

<b>5. Supervisor: Prof. Phan Thanh Son Nam; Dr. Nguyen Thanh Tung </b>

<i>Ho Chi Minh City, January 2024 </i>

<b>SUPERVISOR 1 SUPERVISOR 2 HEAD OF DEPARTMENT </b>

<b>DEAN OF FACULTY OF CHEMICAL ENGINEERING </b>

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<b>ACKNOWLEDGEMENT </b>

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.

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<b>ABSTRACT </b>

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

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,

<i>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] </i>

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.

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<b>TÓM TẮT </b>

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

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

<i>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 </i>

đã được hoạt hóa thành cơng, 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.

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<b>GUARANTEE </b>

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

<b>Author Le Thi Mai Khanh </b>

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<b>TABLE OF CONTENTS </b>

ACKNOWLEDGEMENT __________________________________________ iABSTRACT ___________________________________________________ iiTÓM TẮT _____________________________________________________ iiiGUARANTEE __________________________________________________ ivTABLE OF CONTENTS __________________________________________ vLIST OF FIGURE ______________________________________________ viiiLIST OF SCHEME ______________________________________________ ixLIST OF TABLE _______________________________________________ xiiiCHAPTER 1: LITERATURE REVIEW _____________________________ 11.1. <i>Introduction about the pyrrolo[1,2-a]quinoxaline scaffold ___________ 1</i>

1.2. The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines ________________ 21.3. <i>Direct C-H functionalization of pyrrolo[1,2-a]quinoxalines__________ 8</i>

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

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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

<i>3.1. The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines ________ 44</i>

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 _____________________________________________________ 56

3.1.4. 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 ____________________________________________ 79

3.2.4. Control experiments and proposed mechanism ___________________ 86CHAPTER 4: CONCLUSION ___________________________________ 91

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4.1. Conclusion remarks _________________________________________ 914.2. Suggestions for future works __________________________________ 91LIST OF PUBLICATION ________________________________________ 92REFERENCES ________________________________________________ 93APPENDIX __________________________________________________ 103SHORT RESUME _____________________________________________ 141

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<b>LIST OF FIGURE </b>

<b>Figure 1.1: Examples of biologically active dihydroquinoxalines and quinoxalines 1</b>

<b>Figure 1.2: Representative drugs featured by sulfides, sulfoxides, or sulfones ... 19</b>

<b>Figure 3.1: GC-MS result of the post-reaction mixture in the preliminary test ... 47</b>

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

<b>4-Figure 3.3: The effect of transition-metal source on the reaction yield ... 51</b>

<b>Figure 3.4: The effect of catalyst loading on the reaction yield ... 52</b>

<b>Figure 3.5: The effect of iodine source on the reaction yield ... 53</b>

<b>Figure 3.6: The effect of solvent type on the reaction yield... 55</b>

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

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

<b>Figure 3.9: FT-IR spectrum of the sulfonylated pyrrolo[1,2-a]quinoxaline ... 71</b>

<b>Figure 3.10: Different examined ligands for the sulfonylation of </b>a]quinoxalines ... 73

<b>pyrrolo[1,2-Figure 3.11: The effect of ligands on the reaction yield ... 75</b>

<b>Figure 3.12: The effect of copper catalysts on the reaction yield ... 77</b>

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<b>LIST OF SCHEME </b>

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

aminophenyl)-pyrrole and benzylamines ...3

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

and aldehydes using oxygen as a sole oxidant...4

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

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

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

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

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

1-(2-aminophenyl)pyrroles and aldehydes ...7

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

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

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

NH<small>4</small>SCN and KSCN as the thiocyanate source ...9

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

KSeCN as the selenocyanate source ... 10

<b>Scheme 1.10: Selective chlorination of the C1-H bond in </b>

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

<b>Scheme 1.11: Cu-catalyzed direct C1-H difluoromethylation of </b>

pyrrolo[1,2-a]quinoxalines using CuCl, 2,2’-bipyridine, and B<small>2</small>Pin<small>2</small> ... 12

<b>Scheme 1.12: Copper-catalyzed direct C1-H trifluoromethylation of </b>

pyrrolo[1,2-a]quinoxalines with CF<small>3</small>SOONa ... 13

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

Pd(OAc)<small>2</small> and X-Phos ... 15

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

and TsNHNH<small>2</small>... 16

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<b>Scheme 1.15: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using I2</b> and PTSA.H<small>2</small>O... 17

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

elemental sulfur and arylhalides... 20

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

reagent PhI(OAc)<small>2</small> ... 21

<b>Scheme 1.19: Copper-catalyzed C5-sulfenylation of N-alkyl-8-aminoquinoline </b>

utilizing sulfonyl hydrazides... 22

<b>Scheme 1.20: A combination of catalytic AgOAc and DABCO direct sulfenylation </b>

of pyrazolones with diaryl disulfides ... 23

<b>Scheme 1.21: A copper-catalyzed ortho-selective direct C-H sulfenylation of </b>

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

<b>Scheme 1.22: Copper-catalyzed, visible-light-promoted sulfonylation of aryl halides </b>

with sodium arylsulfinates ... 25

<b>Scheme 1.23: Copper-catalyzed cyclization between N-propargylamines and sodium </b>

sulfinates to obtain 3-sulfonylated quinolines ... 26

<b>Scheme 1.24: Selective MOF-derived cobalt-catalyzed C-H oxidative sulfonylation </b>

of tetrahydroquinoxalines ... 27

<b>Scheme 1.25: Non-directed copper-promoted site-selective C-H sulfonylation of </b>

phenothiazines ... 28

<b>Scheme 1.26: Sulfonylation of aryl iodides and bromides using arylsulfonyl </b>

hydrazides, copper catalyst, and PEG-400 ... 30

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

employing sulfonylacetonitriles and DMEDA ligand ... 31

<b>Scheme 1.28: Sulfenylation (top) and sulfonylation (bottom) of </b>

pyrrolo[1,2-a]quinoxalines ... 33

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

arylaldehydes... 38

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

arylacetic acid... 40

<b>Scheme 2.3: The synthesis of pyrrolo[1,2-a]quinoxalines ... 40</b>

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

<b>Scheme 2.5: The synthesis of sodium sulfinate derivatives ... 42</b>

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

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

<b>Scheme 3.2: The investigation of the effect of transition-metal source ... 50</b>

<b>Scheme 3.3: The investigation of the effect of catalyst loading ... 51</b>

<b>Scheme 3.4: The investigation of the effect of the iodine source ... 53</b>

<b>Scheme 3.5: The investigation of the effect of solvent type at 120 ℃ ... 54</b>

<b>Scheme 3.6: The investigation of the effect of solvent type at 80 ℃... 54</b>

<b>Scheme 3.7: The investigation of the effect of the atmospheric environment ... 55</b>

<b>Scheme 3.8: The investigation on the scope of pyrrolo[1,2-a]quinoxalines ... 56</b>

<b>Scheme 3.9: The investigation of the scope of disulfides ... 62</b>

<b>Scheme 3.10: The reaction in the absence of disulfides ... 64</b>

<b>Scheme 3.11: The idoination of 4-phenylpyrrolo[1,2-a]quinoxaline ... 65</b>

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

<b>Scheme 3.13: Proposed mechanism for the sulfenylation reaction ... 67</b>

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

<b>Scheme 3.15: The investigation on the effect of temperature on the reaction yield 72Scheme 3.16: The investigation on the effect of type of ligands on the reaction yield</b> ... 74

<b>Scheme 3.17: The investigation on the effect of copper catalyst on the reaction yield</b> ... 76

<b>Scheme 3.18: The investigation on the effect of reactant ratio on the reaction yield</b> ... 78

<b>Scheme 3.19: The investigation on the scope of pyrrolo[1,2-a]quinoxalines ... 79</b>

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

a]quinoxalines ... 87

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

radical quencher 1,1’-diphenylethylene ... 88

<b>Scheme 3.23: Proposed mechanism for the sulfonylation of </b>

pyrrolo[1,2-a]quinoxalines ... 89

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<b>LIST OF TABLE </b>

<b>Table 2-1: List of chemicals purchased and used in the study... 35</b>

<b>Table 3-1: The effect of the atmospheric environment on the reaction yield ... 56</b>

<b>Table 3-2: Scope of pyrrolo[1,2-a]quinoxalines ... 57</b>

<b>Table 3-3: Scope of disulfides ... 62</b>

<b>Table 3-4: The effect of reaction temperature on the reaction yield ... 73</b>

<b>Table 3-5: The effect of sodium benzenesulfinate loadings on the reaction yield ... 79</b>

<b>Table 3-6: Scope of pyrrol[1,2-a]quinoxalines ... 80</b>

<b>Table 3-7: Scope of sodium benzenesulfinates ... 85</b>

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<b>CHAPTER 1: LITERATURE REVIEW </b>

<i><b>1.1. Introduction about the pyrrolo[1,2-a]quinoxaline scaffold </b></i>

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-

<i>a]quinoxaline with the structure of a quinoxaline skeleton combined with a </i>

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,

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

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

<b>inhibitors and receptors in the human body [7]–[9] (Figure 1.1). Additionally, several </b>

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

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

<i><b>Figure 1.1: Examples of biologically active dihydroquinoxalines and quinoxalines </b></i>

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<b>1.2. The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines </b>

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

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

<i>ortho-position acting as a nitrogen synthon for the cyclization of the desired product. </i>

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

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

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

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

<i><b>corresponding 4-substituted pyrrolo[1,2-a]quinoxalines (Scheme 1.1) [13]. </b></i>

<i><b>Scheme 1.1: Synthesis of pyrrolo[1,2-a]quinoxalines via Pictet-Spengler reaction </b></i>

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

<i>et. al. developed an efficient iodine-catalyzed protocol to synthesize </i>

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

<i><b>iodine as an economical and effective catalyst (Scheme 1.2). In particular, o-xylene </b></i>

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

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<i>furnished corresponding pyrrolo[1,2-a]quinoxalines in excellent yields. Based on the </i>

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].

<i><b>Scheme 1.2: Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from </b></i>

<i>1-(2-aminophenyl)-pyrrole and benzylamines </i>

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

<i>friendly protocol for the synthesis of pyrrolo[1,2-a]quinoxalines. This synthetic </i>

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

<b>1-(2-(Scheme 1.3). It was found that both aromatic and aliphatic aldehydes were well </b>

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

<i>products. It was noteworthy that para-substituted aldehydes afforded the </i>

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

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

and metal-free conditions.

<i><b>Scheme 1.3: Synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-aminoaryl)pyrrole </b></i>

<i>and aldehydes using oxygen as a sole oxidant </i>

<i>According to Allan et. al., a novel approach to synthesize </i>

<i>pyrrolo[1,2-a]quinoxalines through the Pictet-Spengler reaction was devised [15]. Under an </i>

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

<b>reaction produced the highest yield of the cyclized compounds (Scheme 1.3). The </b>

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

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

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

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

<i><b>Scheme 1.4: Acid acetic-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from </b></i>

<i>1-(2-aminophenyl)-pyrroles and aryl aldehydes </i>

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

<i>et. al. reported a copper-catalyzed C-H activation reaction of arylacetic acids, </i>

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

<b>1-(2-aminophenyl)pyrrole (Scheme 1.5) [16]. In this protocol, CuSO</b><small>4</small> as a catalyst and 2,2’-bipyridyl as a ligand were employed to transform aryl acetic acids into benzaldehydes, under the O<small>2</small> atmosphere. To broaden the scope of this study, different arylacetic acids were first screened, indicating that various arylacetic acids were well

<i>tolerated and gave the corresponding pyrrolo[1,2-a]quinoxalines in good yields. </i>

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,

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

<i><b>Scheme 1.5: Copper-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from </b></i>

<i>1-(2-aminoaryl)pyrroles and arylacetic acids </i>

Also utilizing a copper-based catalyst, which was Cu(OTf)<small>2</small><i>, Krishna et. al. </i>

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

<i>pyrrolo[1,2-a]quinoxalines [17]. This reaction started with the formation of imines </i>

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

<b>a solvent (Scheme 1.6). Through the screening process, Cu(OTf)</b><small>2</small> 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,

<i>heteroaromatic aldehydes, and (R)-O-isopropylidene glyceraldehyde could smoothly </i>

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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.

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

<i>1-(2-aminophenyl)pyrroles and aldehydes </i>

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-

<i>co-a]quinoxalines [18]. Under the air environment at 120 ℃, methyl arenes were directly </i>

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

<b>iron catalyst (Scheme 1.7). In general, methyl arenes bearing electron-donating </b>

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,

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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.

<i><b>Scheme 1.7: Iron-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from </b></i>

<i>1-(2-aminophenyl)pyrroles and inactivated methyl arenes </i>

<i><b>1.3. Direct C-H functionalization of pyrrolo[1,2-a]quinoxalines </b></i>

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

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

<i>diversity of this N-containing heterocycles class. In fact, the </i>

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

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.

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<i><b>1.3.1. Direct C1-H functionalization in pyrrolo[1,2-a]quinoxaline skeleton </b></i>

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

<i>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 </i>

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

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

MeCN solvent using NCS as a promoter and sole oxidant, with either NH<small>4</small>SCN or

<b>KSCN as thiocyanate sources, particularly (Scheme 1.8) [19]. The range of </b>

<i>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 </i>

NH<small>4</small>SCN, generating desired products with good yields.

<i><b>Scheme 1.8: NCS-promoted thiocyanation of pyrrolo[1,2-a]quinoxalines </b></i>

<i>using NH<small>4</small>SCN and KSCN as the thiocyanate source </i>

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

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

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<i>the functionalized structures. Pyrrolo[1,2-a]quinoxaline was processed with </i>

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

<b>was a slight modification in the used solvent changing to ethyl acetate (Scheme 1.9). </b>

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

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

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

<i>a]quinoxaline. The mechanism of this transformation was proposed, in which the </i>

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.

<i><b>Scheme 1.9: NCS-promoted selenocyanation of pyrrolo[1,2-a]quinoxalines </b></i>

<i>using KSeCN as the selenocyanate source </i>

In 2021, our research group demonstrated the selective chlorination and

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

[20]. Initially, a variety of chlorinating sources was screened to maximize the chlorination yields, including Bu<small>4</small><i>NCl, 1-Trifluoromethyl-1,2-benziodoxol-3(1H)-</i>

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<i>one (Togni’s reagent), N-chlorosuccinimide (NCS), Trichloroisocyanuric acid </i>

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

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

presence of dimethyl sulfoxide (DMSO) as a catalyst in CHCl<small>3</small> solvent for 24 h at

<b>room temperature (Scheme 1.10). To further extend the substrate scope, the </b>

<i>chlorination of pyrrolo[1,2-a]quinoxaline derivatives was examined. The obtained </i>

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

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

were also well-tolerated with the reaction conditions.

<i><b>Scheme 1.10: Selective chlorination of the C1-H bond in </b></i>

<i>4-arylpyrrolo[1,2-a]quinoxalines utilizing NCS and DMSO </i>

<i>In the same year, Yang et. al. reported the difluoromethylation of </i>

<i>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 </i>

promoted in the presence of a base (NaHCO<small>3</small>) and a ligand (2,2’-bipyridine) in the CH<small>3</small><b>CN (Scheme 1.11). The examination of different substituted pyrrolo[1,2-</b>

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<i>a]quinoxalines was also explored and it turned out that the effect of different </i>

<i>substituents on the para-position of the benzene ring in 4-aryl </i>

<i>pyrrolo[1,2-a]quinoxalines was negligible, forming an excellent functional group tolerance. In </i>

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

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.

<i><b>Scheme 1.11: Cu-catalyzed direct C1-H difluoromethylation of </b></i>

<i>pyrrolo[1,2-a]quinoxalines using CuCl, 2,2’-bipyridine, and B<small>2</small>Pin<small>2 </small></i>

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

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

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

<i>of 1-(trifluoromethyl)pyrrolo[1,2-a]quinoxaline was obtained with CF</i><small>3</small>SO<small>2</small>Na as a trifluoromethylation reagent in the presence of K<small>2</small>S<small>2</small>O<small>8</small> as an oxidant, CuSO<small>4</small>.5H<small>2</small>O

<b>as a catalyst, and dimethyl sulfoxide (DMSO) as a solvent at 80 ℃ for 12 h (Scheme 1.12). </b>

<i><b>Scheme 1.12: Copper-catalyzed direct C1-H trifluoromethylation of </b></i>

<i>pyrrolo[1,2-a]quinoxalines with CF<small>3</small>SOONa </i>

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

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

<i>or C8 positions. Additionally, 3-aryl substituted pyrrolo[1,2-a]quinoxalines were also </i>

competent towards this transformation. In conclusion, a novel methodology was

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

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

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

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

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

palladium salts and ligands. In the exploration of the Pd source, Pd(OAc)<small>2</small> was clearly superior to other popular Pd catalysts, including Pd(PPh<small>3</small>)<small>4</small>, PdCl<small>2</small>(PPh<small>3</small>)<small>2</small>, and PdCl<small>2</small>(MeCN)<small>2, </small>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 PCy<small>3</small> and S-Phos. The results also revealed the inefficiency in the utilization of PPh<small>3</small> and P(Furan-2-yl)<small>3</small>, 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 Cs<small>2</small>CO<small>3</small> rarely showed their support except for Ag<small>2</small>CO<small>3</small>, for which this compound was

<b>chosen for this conversion (Scheme 1.13). </b>

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.

<i>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 </i>

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

<i>complex was created and underwent the oxidative addition with p-methyl </i>

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.

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<i><b>Scheme 1.13: Direct Pd-catalyzed C-H arylation of pyrrolo[1,2-a]quinoxalines </b></i>

<i>using Pd(OAc)<small>2</small> and X-Phos </i>

<i><b>1.3.2. Direct C-H functionalization at other positions in pyrrolo[1,2-a]quinoxaline skeleton </b></i>

Despite remarkable advancements made in the C-H functionalization of

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

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

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

(TBAI) as an iodine source in the presence of 4-methylbenzenesulfonohydrazine (TsNHNH<small>2</small><i><b>), tert-butyl hydroperoxide (TBHP) in the 1,4-dioxane solvent (Scheme </b></i>

<b>1.14) [24]. With the optimal conditions in hand, the scope of this transformation was </b>

<i>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 </i>

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

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<i><b>Scheme 1.14: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines </b></i>

<i>utilizing TBAI and TsNHNH<small>2</small></i>

It is notable that the use of TBAI with TsNHNH<small>2</small><i> formed p-toluenesulfonic acid </i>

(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 I<small>2</small> with a catalytic amount of PTSA.H<small>2</small><b>O in DMSO at 100 °C (Scheme </b>

<i><b>1.15). Different pyrrolo[1,2-a]quinoxalines were investigated to widen the scope of </b></i>

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

<i>iodination of pyrrolo[1,2-a]quinoxalines with various substituent tolerance, </i>

gram-scale synthesis, and potential synthetic applications.

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<i><b>Scheme 1.15: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines </b></i>

<i>using I<small>2</small> and PTSA.H<small>2</small>O </i>

<i>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) </i>

followed a solvent-mediated manner [25]. By employing CHCl<small>3</small> and DMF as

<i>solvents, 1-iodopyrrolo[1,2-a]quinoxaline and 3-iodopyrrolo[1,2-a]quinoxaline </i>

could be produced selectively. To investigate the conditions for the selective

<i>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 </i>

selective C1-iodination reaction could proceed smoothly in CHCl<small>3</small>, 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 I<small>2</small> 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.

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<i><b>Scheme 1.16: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using NIS </b></i>

<b>1.4. C-S coupling reactions of aromatic compounds </b>

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

<b>different biological activity were presented in Figure 1.2. </b>

Among various methodologies to attach the desired sulfur-containing

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

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

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

<i><b>Figure 1.2: Representative drugs featured by sulfides, sulfoxides, or sulfones 1.4.1. The synthesis of sulfides via C-S bond construction </b></i>

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

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

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

<i>mixed solvent medium of acetic acid and N, N’-dimethylformamide (DMF) </i>

<i><b>employing CuI as a catalyst and KOt-Bu as a base at 130 ℃ (Scheme 1.17). The </b></i>

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

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on, were compatible with this transformation while the strong electron-deficient NO<small>2</small>substituted derivative proceeded with a lower yield. Moreover, 6-halogenated

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

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.

<i><b>Scheme 1.17: Disulfenylation of imidazo[1,2-a]pyridine derivatives </b></i>

<i>employing elemental sulfur and arylhalides </i>

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

<i>attention as a sulfenylation source. In the same year, Mal et. al. proposed the direct </i>

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

<b>1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent (cheme 1.18) [34]. To broaden </b>

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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)<small>2</small> was utilized, while the major products were diaryl sulfoxides when the 3.0 equivalents of PhI(OAc)<small>2</small> 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.

<i><b>cheme 1.18: Dehydrogenative aryl C-S coupling from thiols </b></i>

<i>using iodine(III) reagent PhI(OAc)<small>2 </small></i>

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-NHNH<small>2</small>) in the presence of CuI as a catalyst, and Na<small>2</small>CO<small>3</small>

<i><b>as a base in p-xylene at 120 ℃ (Scheme 1.19). To further increase the scope of this </b></i>

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

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<i>8-the electron-withdrawing one. Thanks to 8-the less severe steric hindrance, </i>

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

<i>yields than those of ortho-substituted substrates. In brief, this method not only was </i>

the ideal regioselectivity scheme for C5-H sulfenylation but also provided free NH<small>2</small>functionalized quinolines for further work.

<i><b>-Scheme 1.19: Copper-catalyzed C5-sulfenylation of N-alkyl-8-aminoquinoline </b></i>

<i>utilizing sulfonyl hydrazides </i>

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

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<b>(Scheme 1.20). The results of substrate scope indicated that R</b><small>1</small> 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 R<small>2</small> and R<small>3</small> 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.

<i><b>electron-Scheme 1.20: A combination of catalytic AgOAc and DABCO direct sulfenylation </b></i>

<i>of pyrazolones with diaryl disulfides </i>

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

<i>ortho-position of N-aryl-7-azaindole to form </i>

<i>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 </i>

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

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<i><b>products (Scheme 1.21). Subsequently, various N-aryl-7-azaindoles and diaryl </b></i>

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

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

<i>meta-positions and substituted diaryl disulfides with ortho-position provided the </i>

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)<small>2</small> catalyst.

<i><b>Scheme 1.21: A copper-catalyzed ortho-selective direct C-H sulfenylation </b></i>

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

<i><b>1.4.2. The synthesis of sulfones via C-S bond construction </b></i>

Traditional methods for making sulfonyl compounds include the oxidization of

<i>corresponding sulfides or arene sulfonylation via the Friedel-Crafts method using </i>

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

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