Utilization of elemental sulfur in the synthesis of 2 aminobenzoxazoles

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 Dr 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: Chairman: Assoc Prof Dr Tran Hoang Phuong Examiner 1: Dr Dang Bao Trung Examiner 2: Dr Tran Phuoc Nhat Uyen Secretary: Dr Nguyen Dang Khoa Member: Dr 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 THESIS COMMITTEE Assoc Prof Dr Tran Hoang Phuong 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 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 tổng hợp dẫn xuất dị vòng 2aminobenzoxazole 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 SUPERVISORS: Dr Nguyen Thanh Tung Prof Dr Phan Thanh Son Nam Ho Chi Minh City, 12 June 2023 SUPERVISORS Dr Nguyen Thanh Tung Prof Dr Phan Thanh Son Nam HEAD OF DEPARTMENT 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 Dr 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 onitrophenols 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 dẫn xuất o-nitrophenol thay cho dẫn xuất o-aminophenol tương ứng phản ứng đóng vòng thu hút ý thập kỉ qua, phương pháp đóng vịng trực tiếp không thông qua phản ứng khử riêng biệt phát triển rộng rãi Nhiều nghiên cứu tổng hợp thành cơng benzoxazole vị trí C2 phương pháp nói trên, nhiên họ trọng vào nhóm gốc carbon Do đó, phản ứng tổng hợp 2-aminobenzoxazole, nhánh quan trọng benzoxazole vị trí C2, dựa vào dẫn xuất o-aminophenol làm khung sườn sản phẩm Luận văn khắc phục nhược điểm báo cáo hướng sử dụng dẫn xuất o-nitrophenol phản ứng đóng vịng với dẫn xuất phenyl isothiocyanate để tổng hợp khung sản phẩm 2-aminobenzoxazole Phản ứng xảy điều kiện sử dụng sắt(III) acetylacetonate làm xúc tác, lưu huỳnh nguyên tố, NaOH làm base DMSO làm dung môi Nhiều dẫn xuất 2-arylaminobenzoxazole gắn nhóm nitro, trifluoromethyl, cyano, acetyl, sulfonyl, amine bậc hai, pyrrolyl, hay dị vòng thơm tổng hợp thành công với hiệu suất từ trung bình đến tốt Trong đó, số dẫn xuất công bố lần đầu tiên, cho thấy phạm vi ứng dụng rộng phương pháp Phản ứng cho qua chế xúc tác cụm nguyên tử Fe/S, lưu huỳnh nguyên tố tham gia với hai vai trò: vừa thành phần tạo nên cụm nguyên tử Fe/S trên, vừa 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 Dr 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 LITERATURE REVIEW .1 1.1 Elemental sulfur in the synthesis of heterocycles 1.1.1 Elemental sulfur acting as a building block for heterocycles .1 1.1.2 Elemental sulfur acting as an oxidant 10 1.1.3 Elemental sulfur acting as a catalyst for non-redox reactions 12 1.1.4 Elemental sulfur acting as a catalyst for redox condensations 13 1.1.4.1 Elemental sulfur as lone catalyst 13 1.1.4.2 Elemental sulfur and a Fe source as co-catalysts 13 1.2 Synthesis of the 2-aminobenzoxazole scaffold 16 1.2.1 Introduction to 2-aminobenzoxazoles .16 1.2.2 Reported pathways for the synthesis of 2-aminobenzoxazoles 17 1.3 Research hypothesis 21 1.4 Aims of research 21 CHAPTER EXPERIMENTAL 22 2.1 Research objectives 22 2.2 Methodology 22 2.3 Materials and Instrumentation 22 2.3.1 Materials .22 2.3.2 Instrumentation 25 2.4 Experimental procedure .26 2.4.1 Synthesis of various o-nitrophenols 26 2.4.2 Optimization studies 29 2.4.2.1 Model reaction .29 v 2.4.2.2 Typical optimization experiments .30 2.4.3 General procedure for the syntheses of 2-aminobenzoxazoles 30 2.4.4 Scale-up synthesis of N-phenylbenzo[d]oxazol-2-amine (3aa) 31 CHAPTER RESULTS AND DISCUSSION 32 3.1 Optimization studies 32 3.1.1 Model reaction 32 3.1.2 Effect of various Fe-based catalysts 32 3.1.3 Effect of catalyst amount 33 3.1.4 Effect of reaction temperature 34 3.1.5 Effect of reactants molar ratio 35 3.1.6 Effect of sulfur amount .37 3.1.7 Effect of various bases 38 3.1.8 Effect of base amount 39 3.1.9 Effect of various solvents 40 3.1.10 Effect of reaction duration 41 3.2 Substrate scope and limitation 42 3.3 Mechanistic studies 50 3.3.1 Control experiments 50 3.3.2 Proposed mechanism 51 CHAPTER CONCLUSION AND FUTURE REMARKS 54 4.1 Conclusion 54 4.2 Future remarks 54 LIST OF PUBLICATIONS .56 REFERENCES 57 APPENDIX A CALIBRATION CURVE 66 vi APPENDIX B GC-MS CHROMATOGRAM OF REACTION MIXTURE 69 APPENDIX C SPECTRAL DATA 70 vii 6-morpholino-N-phenylbenzo[d]oxazol-2-amine (3ka) Prepared from 5-morpholino-2-nitrophenol (1k) and phenyl isothiocyanate (2a) under air as described in Chapter and purified by column chromatography on silica gel (230 – 400 mesh or 37 – 63 µm, hexane/ethyl acetate = 3:1 (v/v), TLC silica gel 60 F254, Rf = 0.17) as a white solid (16.5 mg, 56%), m.p 181 – 183 oC H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.74 (dd, J = 8.7, 1.1 Hz, 2H), 7.37 – 7.33 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.00 (tt, J = 7.3, 1.1 Hz, 1H), 6.85 (dd, J = 8.6, 2.3 Hz, 1H), 3.78 – 3.73 (m, 4H), 3.11 – 3.07 (m, 4H) 13 C NMR (151 MHz, DMSO-d6) δ 156.99, 147.98, 147.51, 138.92, 135.26, 128.87, 121.68, 117.20, 116.27, 112.24, 97.42, 66.14, 49.84 HRMS (ESI) m/z: [M+H+], calcd for C17H18N3O2+ = 296.1394, found 296.1396 116 Figure Appendix C.47 1H NMR spectrum of 3ka Figure Appendix C.48 13C NMR spectrum of 3ka 117 Figure Appendix C.49 HRMS spectrum of 3ka 118 6-(4-methylpiperazin-1-yl)-N-phenylbenzo[d]oxazol-2-amine (3la) Prepared from 5-(4-methylpiperazin-1-yl)-2-nitrophenol (1l) and phenyl isothiocyanate (2a) under air as described in Chapter and purified by column chromatography on silica gel (230 – 400 mesh or 37 – 63 µm, ethyl acetate/methanol = 4:1 (v/v), TLC silica gel 60 F254, Rf = 0.23) as a dark-brown solid (18.6 mg, 60%), m.p 173 – 175 oC H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.76 – 7.71 (m, 2H), 7.38 – 7.32 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.00 (tt, J = 7.3, 1.2 Hz, 1H), 6.84 (dd, J = 8.6, 2.4 Hz, 1H), 3.14 – 3.10 (m, 4H), 2.52 – 2.49 (m, 4H, overlapped), 2.25 (s, 3H) One four-proton signal overlapped with residual solvent signal 13 C NMR (151 MHz, DMSO-d6) δ 156.90, 147.95, 147.43, 138.94, 134.99, 128.85, 121.63, 117.16, 116.21, 112.52, 97.60, 54.60, 49.36, 45.55 HRMS (ESI) m/z: [M+H+], calcd for C18H21N4O+ = 309.1710, found 309.1716 119 Figure Appendix C.50 1H NMR spectrum of 3la Figure Appendix C.51 13C NMR spectrum of 3la 120 Figure Appendix C.52 HRMS spectrum of 3la 121 N-phenyl-6-(1H-pyrrol-1-yl)benzo[d]oxazol-2-amine (3ma) Prepared from 2-nitro-5-(1H-pyrrol-1-yl)phenol (1m) and phenyl isothiocyanate (2a) under air as described in Chapter and purified by column chromatography on silica gel (230 – 400 mesh or 37 – 63 µm, hexane/ethyl acetate = 5:1 (v/v), TLC silica gel 60 F254, Rf = 0.42) as a pale-yellow solid (14.0 mg, 51%), m.p 201 – 203 oC H NMR (600 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.4, 1.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.2 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.36 (t, J = 2.2 Hz, 2H), 7.05 (tt, J = 7.4, 1.2 Hz, 1H), 6.26 (t, J = 2.2 Hz, 2H) 13 C NMR (126 MHz, DMSO-d6) δ 158.31, 147.53, 139.99, 138.56, 135.01, 128.97, 122.19, 119.51, 117.57, 116.67, 115.86, 110.11, 101.56 HRMS (ESI) m/z: [M+H+], calcd for C17H14N3O+ = 276.1132, found 276.1134 122 Figure Appendix C.53 1H NMR spectrum of 3ma Figure Appendix C.54 13C NMR spectrum of 3ma 123 Figure Appendix C.55 HRMS spectrum of 3ma 124 1-(5-methyl-2-(phenylamino)benzo[d]oxazol-7-yl)ethan-1-one (3na) Prepared from 2’-hydroxy-5’-methyl-3’-nitroacetophenone (1n) and phenyl isothiocyanate (2a) under air as described in Chapter and purified by column chromatography on silica gel (230 – 400 mesh or 37 – 63 µm, hexane/ethyl acetate = 3:1 (v/v), TLC silica gel 60 F254, Rf = 0.38) as a pale-yellow solid (5.6 mg, 21%), m.p 212 – 214 oC H NMR (600 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.78 (dd, J = 8.7, 1.1 Hz, 2H), 7.51 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.40 – 7.37 (m, 2H), 7.05 (tt, J = 7.3, 1.1 Hz, 1H), 2.72 (s, 3H), 2.42 (s, 3H) 13 C NMR (151 MHz, DMSO-d6) δ 194.90, 158.54, 144.12, 144.04, 138.49, 133.22, 128.94, 122.27, 121.92, 121.62, 119.59, 117.65, 29.46, 20.82 HRMS (ESI) m/z: [M+H+], calcd for C16H15N2O2+ = 267.1128, found 267.1130 125 Figure Appendix C.56 1H NMR spectrum of 3na Figure Appendix C.57 13C NMR spectrum of 3na 126 Figure Appendix C.58 HRMS spectrum of 3na 127 N-phenyloxazolo[4,5-c]pyridin-2-amine (3oa) Prepared from 3-nitropyridin-4-ol (1o) and phenyl isothiocyanate (2a) under air as described in Chapter and purified by column chromatography on silica gel (230 – 400 mesh or 37 – 63 µm, hexane/ethyl acetate = 1:2 (v/v), TLC silica gel 60 F254, Rf = 0.46) as a pale-orange solid (13.9 mg, 66%) A 10 mol% of unknown impurities was also obtained H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.72 (s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 5.3 Hz, 1H), 7.48 – 7.36 (m, 2H), 7.08 (tt, J = 7.2, 1.2 Hz, 1H) 13 C NMR (151 MHz, DMSO-d6) δ 158.17, 152.45, 142.89, 140.17, 138.19, 138.01, 129.04, 122.70, 117.93, 105.22 Data obtained are in agreement with published data [33] 128 Figure Appendix C.59 1H NMR spectrum of 3oa Figure Appendix C.60 13C NMR spectrum of 3oa 129 PERSONAL DETAILS Full name: NGUYEN DUC THANH Date of birth: 16/08/1998 Place of birth: Hanoi, Vietnam Address: 13.7 block B, My Phuoc Apartment, 280/29 Bui Huu Nghia Street, Ward 2, Binh Thanh District, Ho Chi Minh City, Vietnam EDUCATION Undergraduate Ho Chi Minh City University of Technology – VNU-HCM Bachelor of Engineering (Honored) | 2016 – 2020 Major: Chemical Engineering Graduated Excellent, University Silver Medal Postgraduate Ho Chi Minh City University of Technology – VNU-HCM Master of Science | 2021 – 2023 Major: Chemical Engineering Thesis title: Utilization of elemental sulfur in the synthesis of 2-aminobenzoxazoles PROFESSIONAL EXPERIENCE No record