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 OF THE C1-H BOND IN PYRROLO[1,2-a]QUINOXALINE DERIVATIVES PHÁT TRIỂN PHƯƠNG PHÁP SULFENYL VÀ SULFONYL HÓA LIÊN KẾT C1-H CỦA DẪN XUẤT PYRROLO[1,2-a]QUINOXALINE Major: Chemical Engineering Major code: 8520301 MASTER’S THESIS HO CHI MINH CITY, January 2024 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. Tran Hoang Phuong Chairman 2. Phan Thi Hoang Anh Examiner 3.
Tran Phuoc Nhat Uyen Examiner 4. Nguyen Dang Khoa Secretary 5. Nguyen Thanh Tung 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 DEAN OF FACULTY OF THESIS COMMITTEE CHEMICAL ENGINEERING VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY SOCIALIST REPUBLIC OF VIETNAM HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY Independence – Freedom – Happiness ─────────────────────────────── ────────────────── 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. Start date: 16th February, 2023 4. Finish date: 10th December, 2023 5.
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 i 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. Le Thi Mai Khanh ii 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. iii 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.
iv 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 v TABLE OF CONTENTS ACKNOWLEDGEMENT __________________________________________ i ABSTRACT ___________________________________________________ ii TÓM TẮT _____________________________________________________ iii GUARANTEE __________________________________________________ iv TABLE OF CONTENTS __________________________________________ v LIST OF FIGURE ______________________________________________ viii LIST OF SCHEME ______________________________________________ ix LIST OF TABLE _______________________________________________ xiii CHAPTER 1: LITERATURE REVIEW _____________________________ 1 1. Introduction about the pyrrolo[1,2-a]quinoxaline scaffold ___________ 1 1. The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines ________________ 2 1.
Direct C-H functionalization of pyrrolo[1,2-a]quinoxalines__________ 8 1. Direct C1-H functionalization in pyrrolo[1,2-a]quinoxaline skeleton _ 9 1. Direct C-H functionalization at other positions in pyrrolo[1,2- a]quinoxaline skeleton ______________________________________________ 15 1. C-S coupling reactions of aromatic compounds __________________ 18 1.
The synthesis of sulfides via C-S bond construction _____________ 19 1. The synthesis of sulfones via C-S bond construction ____________ 24 1. Objectives of the work _____________________________________ 32 CHAPTER 2: EXPERIMENTAL SECTION ________________________ 34 2. Research methodology _______________________________________ 34 vi 2.
Materials and Instrumentations_________________________________ 34 2. The synthesis of 4-aryl pyrrolo[1,2-a]quinoxalines________________ 38 2. The synthesis of pyrrolo[1,2-a]quinoxalines _____________________ 40 2. The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines ______ 41 2.
The synthesis of sodium sulfinate derivatives ____________________ 42 2. The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines ___ 42 CHAPTER 3: RESULTS AND DISCUSSION _______________________ 44 3. The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines________ 44 3. Structure analysis of the product from the sulfenylation reaction _____ 47 3.
The investigation of the effect of reaction conditions on the reaction yield ________________________________________________________________ 49 3. Substrate scope of the sulfenylation between pyrrolo[1,2-a]quinoxalines and disulfides _____________________________________________________ 56 3. Control experiments and proposed mechanism ___________________ 63 3. The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines ____ 67 3.
Structure analysis of sulfonylated pyrrolo[1,2-a]quinoxalines _______ 69 3. The investigation of the effect of reaction conditions on the reaction yield ________________________________________________________________ 71 3. Substrate scope of the sulfonylation between pyrrolo[1,2-a]quinoxalines and sodium arylsulfinates ____________________________________________ 79 3. Control experiments and proposed mechanism ___________________ 86 CHAPTER 4: CONCLUSION ___________________________________ 91 vii 4.
Suggestions for future works __________________________________ 91 LIST OF PUBLICATION ________________________________________ 92 REFERENCES ________________________________________________ 93 APPENDIX __________________________________________________ 103 SHORT RESUME _____________________________________________ 141 viii 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 .1: GC-MS result of the post-reaction mixture in the preliminary test .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-a]quinoxaline, and d) 4-phenyl-1- (trifluororomethyl)pyrrolo[1,2-a]quinoxaline .3: The effect of transition-metal source on the reaction yield .4: The effect of catalyst loading on the reaction yield .5: The effect of iodine source on the reaction yield .6: The effect of solvent type on the reaction yield.7: GC-MS result of post-reaction mixture in the presence of radical quenchers 1,1-diphenylethylene.8: Several functionalized 4-phenylpyrrolo[1,2-a]quinoxaline structures and their coupling constant J.9: FT-IR spectrum of the sulfonylated pyrrolo[1,2-a]quinoxaline .10: Different examined ligands for the sulfonylation of pyrrolo[1,2- a]quinoxalines .11: The effect of ligands on the reaction yield .12: The effect of copper catalysts on the reaction yield. 77 ix LIST OF SCHEME Scheme 1.1: Synthesis of pyrrolo[1,2-a]quinoxalines via Pictet-Spengler reaction .2: Iodine-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2- aminophenyl)-pyrrole and benzylamines .3: Synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2-aminoaryl)pyrrole and aldehydes using oxygen as a sole oxidant.4: Acid acetic-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1- (2-aminophenyl)-pyrroles and aryl aldehydes .5: Copper-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2- aminoaryl)pyrroles and arylacetic acids .6: Copper(II)-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1- (2-aminophenyl)pyrroles and aldehydes .7: Iron-catalyzed synthesis of pyrrolo[1,2-a]quinoxalines from 1-(2- aminophenyl)pyrroles and inactivated methyl arenes .8: NCS-promoted thiocyanation of pyrrolo[1,2-a]quinoxalines using NH4SCN and KSCN as the thiocyanate source .9: NCS-promoted selenocyanation of pyrrolo[1,2-a]quinoxalines using KSeCN as the selenocyanate source .10: Selective chlorination of the C1-H bond in 4-arylpyrrolo[1,2- a]quinoxalines utilizing NCS and DMSO .11: Cu-catalyzed direct C1-H difluoromethylation of pyrrolo[1,2- a]quinoxalines using CuCl, 2,2’-bipyridine, and B2Pin2 .12: Copper-catalyzed direct C1-H trifluoromethylation of pyrrolo[1,2- a]quinoxalines with CF3SOONa .13: Direct Pd-catalyzed C-H arylation of pyrrolo[1,2-a]quinoxalines using Pd(OAc)2 and X-Phos .14: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines utilizing TBAI and TsNHNH2.15: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using I2 and PTSA.16: Direct C3-H iodination of pyrrolo[1,2-a]quinoxalines using NIS .17: Disulfenylation of imidazo[1,2-a]pyridine derivatives employing elemental sulfur and arylhalides.18: Dehydrogenative aryl C-S coupling from thiols using iodine(III) reagent PhI(OAc)2 .19: Copper-catalyzed C5-sulfenylation of N-alkyl-8-aminoquinoline utilizing sulfonyl hydrazides.20: A combination of catalytic AgOAc and DABCO direct sulfenylation of pyrazolones with diaryl disulfides.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 .22: Copper-catalyzed, visible-light-promoted sulfonylation of aryl halides with sodium arylsulfinates.23: Copper-catalyzed cyclization between N-propargylamines and sodium sulfinates to obtain 3-sulfonylated quinolines .24: Selective MOF-derived cobalt-catalyzed C-H oxidative sulfonylation of tetrahydroquinoxalines .25: Non-directed copper-promoted site-selective C-H sulfonylation of phenothiazines .26: Sulfonylation of aryl iodides and bromides using arylsulfonyl hydrazides, copper catalyst, and PEG-400 .27: Copper-catalyzed synthesis of sulfonylation isoquinolin-1(2H)-ones employing sulfonylacetonitriles and DMEDA ligand .1: The general synthesis of 4-arylpyrrolo[1,2-a]quinoxalines from arylaldehydes.2: The general synthesis of 4-arylpyrrolo[1,2-a]quinoxalines from arylacetic acid.3: The synthesis of pyrrolo[1,2-a]quinoxalines .4: The synthesis of 4-aryl-1-(arylthio)pyrrolo[1,2-a]quinoxalines .5: The synthesis of sodium sulfinate derivatives .6: The synthesis of 4-aryl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxalines .1: The synthesis of 4-phenyl-1(phenylthio)pyrrolo[1,2-a]quinoxaline .2: The investigation of the effect of transition-metal source .3: The investigation of the effect of catalyst loading .4: The investigation of the effect of the iodine source .5: The investigation of the effect of solvent type at 120 ℃.6: The investigation of the effect of solvent type at 80 ℃.7: The investigation of the effect of the atmospheric environment .8: The investigation on the scope of pyrrolo[1,2-a]quinoxalines .9: The investigation of the scope of disulfides .10: The reaction in the absence of disulfides .11: The idoination of 4-phenylpyrrolo[1,2-a]quinoxaline .12: The synthesis of 4-phenyl-1-(phenylthio)pyrrolo[1,2-a]quinoxaline in the presence of radical quencher 1,1-diphenylethylene.13: Proposed mechanism for the sulfenylation reaction .14: The synthesis of 4-phenyl-1-(arylsulfonyl)pyrrolo[1,2-a]quinoxaline .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 .17: The investigation on the effect of copper catalyst on the reaction yield .18: The investigation on the effect of reactant ratio on the reaction yield .19: The investigation on the scope of pyrrolo[1,2-a]quinoxalines .20: The investigation on the scope of sodium arylsulfinates .