VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY NGUYEN DUC THANH UTILIZATION OF ELEMENTAL SULFUR IN THE SYNTHESIS OF 2-AMINOBENZOXAZOLES Major : Chemical Engineering Major Code : 8520301 MASTER’S THESIS HO CHI MINH CITY, July 2023 THIS THESIS IS COMPLETED AT HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY – VNU-HCM Supervisors: Dr. Nguyen Thanh Tung Prof. Phan Thanh Son Nam Examiner 1: Dr. Dang Bao Trung Examiner 2: Dr.
Tran Phuoc Nhat Uyen This master’s thesis was defended at Ho Chi Minh City University of Technology – VNU-HCM on 3rd July 2023. Master’s Thesis Committee: 1. Tran Hoang Phuong 2. Dang Bao Trung 3.
Tran Phuoc Nhat Uyen 4. Nguyen Dang Khoa 5. Nguyen Thanh Tung Approval of the Chairman of Master’s Thesis Committee and Dean of Faculty of Chemical Engineering after the thesis being corrected (if any). CHAIRMAN OF DEAN OF FACULTY OF THESIS COMMITTEE CHEMICAL ENGINEERING Assoc.
Tran Hoang Phuong VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY SOCIALIST REPUBLIC OF VIETNAM HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY Independence – Freedom – Happiness THE TASK SHEET OF MASTER’S THESIS Full name: NGUYEN DUC THANH Student ID: 2070486 Date of birth: 16/08/1998 Place of birth: Hanoi Major: Chemical Engineering Major ID: 8520301 I. THESIS TITLE: In English: Utilization of elemental sulfur in the synthesis of 2-aminobenzoxazoles In Vietnamese: Sử dụng lưu huỳnh nguyên tố trong tổng hợp các dẫn xuất dị vòng 2- aminobenzoxazole II. TASKS AND CONTENTS: - Investigate novel transformation using o-nitrophenol, phenyl isothiocyanate, iron salt, and elemental sulfur to synthesize the 2-aminobenzoxazole scaffold - Optimize reaction conditions - Study substrate scope and perform scale-up synthesis - Study and propose reaction mechanisms III. THESIS START DATE: 14/02/2022 IV.
THESIS COMPLETION DATE: 01/05/2023 V. Nguyen Thanh Tung Prof. Phan Thanh Son Nam Ho Chi Minh City, 12 June 2023 SUPERVISORS HEAD OF DEPARTMENT Dr. Nguyen Thanh Tung Prof.
Phan Thanh Son Nam Dr. Nguyen Thanh Tung DEAN OF FACULTY OF CHEMICAL ENGINEERING ACKNOWLEDGEMENT This thesis marks the final stage of my master’s program at the University of Technology – VNU-HCM (HCMUT). Upon this moment, I have received considerable guidance and assistance from various people and institutions. Therefore, I would like to take this chance to express my gratitude to all the help during my study.
Firstly, I would like to thank HCMUT for providing me with time and facilities to conduct my research and finish my degree. I would like to thank Dr. Nguyen Thanh Tung and Prof. Phan Thanh Son Nam, my supervisors, for their invaluable instructions and guidance when writing this thesis and the research manuscript.
I would also thank lecturers of Faculty of Chemical Engineering, who have provided me with precious knowledge from their respective fields and area of chemical engineering. I would also like to acknowledge the help of my colleagues Huynh Nhat Tan, Tran The Danh, and Ly Minh Thang. They have worked closely with me both in and out of the lab and helped me speed up this project. I would also like to express my thankfulness to Vingroup Innovation Foundation (VinIF) for funding my study through a generous scholarship.
The scholarship has helped cover my tuition fee and other research-related expenses, which significantly eased my mind and helped me focus on completing my study. Finally, my sincere gratitude goes to my family and my girlfriend for understanding and supporting me in pursuing postgraduate studies. Their unconditional love and constant encouragement have always been my motivation through every problem in my life. Ho Chi Minh City, June 2023 Nguyen Duc Thanh i ABSTRACT Utilization of o-nitrophenols to replace o-aminophenols in annulation reactions has witnessed prominent attention over the last decade, as direct methods without a separate reduction step were developed.
These developments have been applied to synthesize various 2-substituted benzoxazoles, yet they have been exorbitantly focused on syntheses of carbon-substituted derivatives. Syntheses of 2-aminobenzoxazoles, an important branch of 2-substituted benzoxazoles, still rely on o-aminophenols as the building block. This research has filled this gap as I report direct annulations of o- nitrophenols with aryl isothiocyanates to furnish 2-aminobenzoxazoles. Reactions proceeded in the presence of iron(III) acetylacetonate catalyst, elemental sulfur, NaOH as a base, and DMSO as a solvent.
Many derivatives of 2-aminobenzoxazoles bearing nitro, trifluoromethyl, cyano, acetyl, sulfonyl, secondary amines, pyrrolyl, and heteroaryl groups were obtained in moderate to good yields. Some of them were firstly reported, which confirmed the wide applicability of this method. The mechanism was shown to involve Fe/S cluster catalytic cycle, where elemental sulfur played both as a component of the cluster and as an external reductant. ii TÓM TẮT Việc sử dụng các dẫn xuất o-nitrophenol thay thế cho dẫn xuất o-aminophenol tương ứng trong các phản ứng đóng vòng đã thu hút sự chú ý trong hơn một thập kỉ qua, khi các phương pháp đóng vòng trực tiếp không thông qua phản ứng khử riêng biệt được phát triển rộng rãi.
Nhiều nghiên cứu đã tổng hợp thành công benzoxazole thế vị trí C2 bằng phương pháp mới nói trên, tuy nhiên họ quá chú trọng vào những nhóm thế gốc carbon. Do đó, các phản ứng tổng hợp 2-aminobenzoxazole, một nhánh quan trọng của benzoxazole thế vị trí C2, vẫn dựa vào các dẫn xuất o-aminophenol làm khung sườn sản phẩm. Luận văn này đã khắc phục nhược điểm trên khi báo cáo hướng sử dụng các dẫn xuất o-nitrophenol trong phản ứng đóng vòng với các dẫn xuất phenyl isothiocyanate để tổng hợp khung sản phẩm 2-aminobenzoxazole. Phản ứng xảy ra trong điều kiện sử dụng sắt(III) acetylacetonate làm xúc tác, lưu huỳnh nguyên tố, NaOH làm base và DMSO làm dung môi.
Nhiều dẫn xuất 2-arylaminobenzoxazole gắn những nhóm thế như nitro, trifluoromethyl, cyano, acetyl, sulfonyl, amine bậc hai, pyrrolyl, hay dị vòng thơm đều đã được tổng hợp thành công với hiệu suất từ trung bình đến tốt. Trong đó, một số dẫn xuất được công bố lần đầu tiên, cho thấy phạm vi ứng dụng rộng của phương pháp. Phản ứng được cho là đi qua cơ chế xúc tác của cụm nguyên tử Fe/S, trong đó lưu huỳnh nguyên tố tham gia với hai vai trò: vừa là thành phần tạo nên cụm nguyên tử Fe/S trên, vừa là chất khử bổ sung cho phản ứng. iii DECLARATION OF AUTHORSHIP I hereby declare that this thesis has been composed solely by myself, under supervision of Dr.
Nguyen Thanh Tung and Prof. Phan Thanh Son Nam, at University of Technology – VNU-HCM. To the best of my knowledge, this thesis contains no material previously published by any other person except where due reference has been made. This thesis contains no material which has been accepted as part of the requirements of any other academic degree or non-degree program, in English or in any other language.
This is a true copy of the thesis, including final revisions. Nguyen Duc Thanh iv TABLE OF CONTENTS CHAPTER 1. Elemental sulfur in the synthesis of heterocycles. Elemental sulfur acting as a building block for heterocycles.
Elemental sulfur acting as an oxidant. Elemental sulfur acting as a catalyst for non-redox reactions. Elemental sulfur acting as a catalyst for redox condensations. Elemental sulfur as lone catalyst.
Elemental sulfur and a Fe source as co-catalysts. Synthesis of the 2-aminobenzoxazole scaffold. Introduction to 2-aminobenzoxazoles. Reported pathways for the synthesis of 2-aminobenzoxazoles.
Aims of research. Materials and Instrumentation. Synthesis of various o-nitrophenols. Typical optimization experiments.
General procedure for the syntheses of 2-aminobenzoxazoles. Scale-up synthesis of N-phenylbenzo[d]oxazol-2-amine (3aa). RESULTS AND DISCUSSION. Effect of various Fe-based catalysts.
Effect of catalyst amount. Effect of reaction temperature. Effect of reactants molar ratio. Effect of sulfur amount.
Effect of various bases. Effect of base amount. Effect of various solvents. Effect of reaction duration.
Substrate scope and limitation. CONCLUSION AND FUTURE REMARKS .54 LIST OF PUBLICATIONS. GC-MS CHROMATOGRAM OF REACTION MIXTURE .70 vii LIST OF SCHEMES Scheme 1. Synthesis of thiophenes from aryl acetaldehyde, 1,3-dicarbonyls, and S.
Michael-Gewald reaction to synthesize 2-aminothiophenes. Modified Gewald reaction to synthesize 2-aminothiophenes. One-pot four-component synthesis of 2-aminothiophenes. Sulfurative denitration synthesis of benzothiophenes.
Copper-catalyzed tandem cyclization synthesis of benzo[4,5]thieno[3,2- d]thiazoles. Metal-free tandem cyclization synthesis of benzo[4,5]thieno[3,2-d]thiazol- 2-amines. Copper-mediated synthesis of benzo[4,5]thieno[2,3-d]thiazoles. Synthesis of thiazoles.
Synthetic pathways of benzothiazoles from o-iodoanilines. Synthetic pathways of benzothiazoles from o-chloronitrobenzenes. Synthesis of benzisothiazoles from o-chloroarylamidines. Iodonium-mediated synthesis of 1,2,3-thiadiazoles.
Synthetic pathways of 1,2,4-thiadiazoles. One-pot synthesis of 1,2,3,4-thiatriazoles. Synthesis of sultams from o-nitrochalcones. Willgerodt-Kindler-like synthesis of benzoxazoles.
Synthesis of quinoxaline-2-thiones from o-phenylenediamines. Synthesis of dibenzo[d,f][1,3]diazepines from 2,2’-diaminobiaryls. Synthesis of benzazoles from o-hydroxy/amino anilines and trihaloamides. Synthesis of 2-aminobenzoxazoles from o-aminophenols and aryl isothiocyanates.
Sulfur as lone catalyst for reductive annulations of o-nitrophenols. Synthetic pathways of benzazoles from o-hydroxy/amino/mercaptan nitrobenzenes. Synthesis of 2-aminobenzoxazoles from phenolic thioureas. Two-step synthesis of 2-aminobenzoxazoles from o-aminophenols.
Synthesis of 2-aminobenzoxazoles from thiourea, o-iodophenols, and aryl iodides. Synthetic pathways for 2-arylamino benzazoles from o- hydroxy/mercaptan anilines. Green synthetic pathways for 2-arylamino benzazoles from o- hydroxy/mercaptan anilines. Synthesis of 1k and 1l.
Model reaction to test hypothesis feasibility. General procedure for substrate scope investigation. 1-mmol synthesis of 3aa. Optimal set of conditions .50 x LIST OF FIGURES Figure 1.
Structure of Fe/S cluster and its ability to accept and release electrons, from [42]. General catalytic cycle of Fe/S cluster. Some biologically active compounds with 2-aminobenzoxazole core. Various Fe-based catalysts.
Different molar ratios between 1a and 2a. Possible pathway from II to III .53 xi LIST OF APPENDIX FIGURES Figure Appendix A. Calibration curve of instrument 1. Calibration curve of instrument 2.
Typical GC-MS chromatogram. 1H NMR spectrum of 3aa. 13C NMR spectrum of 3aa. 1H NMR spectrum of 3ab.
13C NMR spectrum of 3ab. 1H NMR spectrum of 3ac. 13C NMR spectrum of 3ac. 1H NMR spectrum of 3ad.
13C NMR spectrum of 3ad. 1H NMR spectrum of 3ae. 13C NMR spectrum of 3ae. 19F NMR spectrum of 3ae.
1H NMR spectrum of 3af. 13C NMR spectrum of 3af. 19F NMR spectrum of 3af. 1H NMR spectrum of 3ag.
13C NMR spectrum of 3ag. 19F NMR spectrum of 3ag. 1H NMR spectrum of 3ah. 13C NMR spectrum of 3ah.
19F NMR spectrum of 3ah .89 xii Figure Appendix C. 1H NMR spectrum of 3ai. 13C NMR spectrum of 3ai. HRMS spectrum of 3ai.
1H NMR spectrum of 3ba. 13C NMR spectrum of 3ba. 1H NMR spectrum of 3ca. 13C NMR spectrum of 3ca.
1H NMR spectrum of 3da. 13C NMR spectrum of 3da. 19F NMR spectrum of 3da. 1H NMR spectrum of 3ea.
13C NMR spectrum of 3ea. 1H NMR spectrum of 3fa. 13C NMR spectrum of 3fa. 1H NMR spectrum of 3ga.
13C NMR spectrum of 3ga. HRMS spectrum of 3ga. 1H NMR spectrum of 3ha. 13C NMR spectrum of 3ha.
HRMS spectrum of 3ha. 1H NMR spectrum of 3ia. 13C NMR spectrum of 3ia. HRMS spectrum of 3ia.
1H NMR spectrum of 3ja. 13C NMR spectrum of 3ja. 114 xiii Figure Appendix C. HRMS spectrum of 3ja.
1H NMR spectrum of 3ka. 13C NMR spectrum of 3ka. HRMS spectrum of 3ka. 1H NMR spectrum of 3la.
13C NMR spectrum of 3la. HRMS spectrum of 3la. 1H NMR spectrum of 3ma. 13C NMR spectrum of 3ma.
HRMS spectrum of 3ma. 1H NMR spectrum of 3na. 13C NMR spectrum of 3na. HRMS spectrum of 3na.
1H NMR spectrum of 3oa. 13C NMR spectrum of 3oa .