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
Trang 2THIS 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:
1 Chairman: Assoc Prof Dr Tran Hoang Phuong 2 Examiner 1: Dr Dang Bao Trung
3 Examiner 2: Dr Tran Phuoc Nhat Uyen 4 Secretary: Dr Nguyen Dang Khoa 5 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 CHEMICAL ENGINEERING DEAN OF FACULTY OF
Trang 3VIETNAM 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: Chemica l 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 SUPERVISORS: Dr Nguyen Thanh Tung
Prof Dr Phan Thanh Son Nam
Ho Chi Minh City, 12 June 2023
SUPERVISORS HEAD OF DEPARTMENT
Dr Nguyen Thanh Tung Prof Dr Phan Thanh Son Nam Dr Nguyen Thanh Tung
Trang 4ACKNOWLEDGEMENT
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
Trang 5ABSTRACT
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
Trang 6TÓM TẮT
Việc sử dụng các dẫn xuất o-nitrophenol thay thế cho dẫn xuất o-aminophenol
tương ứng trong các phản ứng đóng vịng đã thu hút sự chú ý trong hơn một thập kỉ qua, khi các phương pháp đóng vịng trực tiếp khơng 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 vịng với các dẫn xuất phenyl isothiocyanate để
Trang 7DECLARATION 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
Trang 8TABLE OF CONTENTS
CHAPTER 1 LITERATURE REVIEW 1
1.1 Elemental sulfur in the synthesis of heterocycles 1
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 2 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
Trang 92.4.2.2 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 3 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 4 CONCLUSION AND FUTURE REMARKS 54
4.1 Conclusion 54
4.2 Future remarks 54
LIST OF PUBLICATIONS 56
Trang 11LIST OF SCHEMES
Scheme 1.1 Synthesis of thiophenes from aryl acetaldehyde, 1,3-dicarbonyls, and S 2
Scheme 1.2 Michael-Gewald reaction to synthesize 2-aminothiophenes 2
Scheme 1.3 Modified Gewald reaction to synthesize 2-aminothiophenes 3
Scheme 1.4 One-pot four-component synthesis of 2-aminothiophenes 3
Scheme 1.5 Sulfurative denitration synthesis of benzothiophenes 3
Scheme 1.6 Copper-catalyzed tandem cyclization synthesis of benzo[4,5]thieno[3,2-d]thiazoles 4
Scheme 1.7 Metal-free tandem cyclization synthesis of benzo[4,5]thieno[3,2-d]thiazol-2-amines 5
Scheme 1.8 Copper-mediated synthesis of benzo[4,5]thieno[2,3-d]thiazoles 5
Scheme 1.9 Synthesis of thiazoles 6
Scheme 1.10 Synthetic pathways of benzothiazoles from o-iodoanilines 6
Scheme 1.11 Synthetic pathways of benzothiazoles from o-chloronitrobenzenes 7
Scheme 1.12 Synthesis of benzisothiazoles from o-chloroarylamidines 8
Scheme 1.13 Iodonium-mediated synthesis of 1,2,3-thiadiazoles 8
Scheme 1.14 Synthetic pathways of 1,2,4-thiadiazoles 9
Scheme 1.15 One-pot synthesis of 1,2,3,4-thiatriazoles 9
Scheme 1.16 Synthesis of sultams from o-nitrochalcones 9
Scheme 1.17 Willgerodt-Kindler-like synthesis of benzoxazoles 10
Scheme 1.18 Synthesis of quinoxaline-2-thiones from o-phenylenediamines 11
Scheme 1.19 Synthesis of dibenzo[d,f][1,3]diazepines from 2,2’-diaminobiaryls 11
Trang 12Scheme 1.21 Synthesis of 2-aminobenzoxazoles from o-aminophenols and aryl
isothiocyanates 12
Scheme 1.22 Sulfur as lone catalyst for reductive annulations of o-nitrophenols 13
Scheme 1.23 Synthetic pathways of benzazoles from o-hydroxy/amino/mercaptan nitrobenzenes 14
Scheme 1.24 Synthesis of 2-aminobenzoxazoles from phenolic thioureas 18
Scheme 1.25 Two-step synthesis of 2-aminobenzoxazoles from o-aminophenols 18
Scheme 1.26 Synthesis of 2-aminobenzoxazoles from thiourea, o-iodophenols, and aryl iodides 19
Scheme 1.27 Synthetic pathways for 2-arylamino benzazoles from o-hydroxy/mercaptan anilines 19
Scheme 1.28 Green synthetic pathways for 2-arylamino benzazoles from o-hydroxy/mercaptan anilines 20
Scheme 1.29 Research hypothesis 21
Scheme 2.1 Synthesis of 1f 26
Scheme 2.2 Synthesis of 1i 26
Scheme 2.3 Synthesis of 1k and 1l 27
Scheme 2.4 Synthesis of 1p 27
Scheme 2.5 Synthesis of 1j 27
Scheme 2.6 Synthesis of 1m 28
Scheme 2.7 Synthesis of 1q 28
Scheme 2.8 Synthesis of 1r 29
Scheme 2.9 Model reaction to test hypothesis feasibility 29
Scheme 2.10 Optimization studies 30
Scheme 2.11 General procedure for substrate scope investigation 30
Trang 14LIST OF FIGURES
Figure 1.1 Structure of Fe/S cluster and its ability to accept and release electrons, from
[42] 15
Figure 1.2 General catalytic cycle of Fe/S cluster 16
Figure 1.3 Some biologically active compounds with 2-aminobenzoxazole core 17
Figure 3.1 Various Fe-based catalysts 33
Figure 3.2 Fe(acac)3 amount 34
Figure 3.3 Reaction temperature 35
Figure 3.4 Different molar ratios between 1a and 2a 36
Figure 3.5 Sulfur amount 37
Figure 3.6 Various bases 39
Figure 3.7 Base amount 40
Figure 3.8 Various solvents 41
Figure 3.9 Reaction duration 42
Figure 3.10 Possible mechanism 52
Trang 15LIST OF APPENDIX FIGURES
Figure Appendix A.1 Calibration curve of instrument 1 67
Figure Appendix A.2 Calibration curve of instrument 2 68
Figure Appendix B.1 Typical GC-MS chromatogram 69
Figure Appendix C.1 1H NMR spectrum of 3aa 71
Figure Appendix C.2 13C NMR spectrum of 3aa 71
Figure Appendix C.3 1H NMR spectrum of 3ab 73
Figure Appendix C.4 13C NMR spectrum of 3ab 73
Figure Appendix C.5 1H NMR spectrum of 3ac 75
Figure Appendix C.6 13C NMR spectrum of 3ac 75
Figure Appendix C.7 1H NMR spectrum of 3ad 77
Figure Appendix C.8 13C NMR spectrum of 3ad 77
Figure Appendix C.9 1H NMR spectrum of 3ae 79
Figure Appendix C.10 13C NMR spectrum of 3ae 79
Figure Appendix C.11 19F NMR spectrum of 3ae 80
Figure Appendix C.12 1H NMR spectrum of 3af 82
Figure Appendix C.13 13C NMR spectrum of 3af 82
Figure Appendix C.14 19F NMR spectrum of 3af 83
Figure Appendix C.15 1H NMR spectrum of 3ag 85
Figure Appendix C.16 13C NMR spectrum of 3ag 85
Figure Appendix C.17 19F NMR spectrum of 3ag 86
Figure Appendix C.18 1H NMR spectrum of 3ah 88
Figure Appendix C.19 13C NMR spectrum of 3ah 88
Trang 16Figure Appendix C.21 1H NMR spectrum of 3ai 91
Figure Appendix C.22 13C NMR spectrum of 3ai 91
Figure Appendix C.23 HRMS spectrum of 3ai 92
Figure Appendix C.24 1H NMR spectrum of 3ba 94
Figure Appendix C.25 13C NMR spectrum of 3ba 94
Figure Appendix C.26 1H NMR spectrum of 3ca 96
Figure Appendix C.27 13C NMR spectrum of 3ca 96
Figure Appendix C.28 1H NMR spectrum of 3da 98
Figure Appendix C.29 13C NMR spectrum of 3da 98
Figure Appendix C.30 19F NMR spectrum of 3da 99
Figure Appendix C.31 1H NMR spectrum of 3ea 101
Figure Appendix C.32 13C NMR spectrum of 3ea 101
Figure Appendix C.33 1H NMR spectrum of 3fa 103
Figure Appendix C.34 13C NMR spectrum of 3fa 103
Figure Appendix C.35 1H NMR spectrum of 3ga 105
Figure Appendix C.36 13C NMR spectrum of 3ga 105
Figure Appendix C.37 HRMS spectrum of 3ga 106
Figure Appendix C.38 1H NMR spectrum of 3ha 108
Figure Appendix C.39 13C NMR spectrum of 3ha 108
Figure Appendix C.40 HRMS spectrum of 3ha 109
Figure Appendix C.41 1H NMR spectrum of 3ia 111
Figure Appendix C.42 13C NMR spectrum of 3ia 111
Figure Appendix C.43 HRMS spectrum of 3ia 112
Figure Appendix C.44 1H NMR spectrum of 3ja 114
Trang 17Figure Appendix C.46 HRMS spectrum of 3ja 115
Figure Appendix C.47 1H NMR spectrum of 3ka 117
Figure Appendix C.48 13C NMR spectrum of 3ka 117
Figure Appendix C.49 HRMS spectrum of 3ka 118
Figure Appendix C.50 1H NMR spectrum of 3la 120
Figure Appendix C.51 13C NMR spectrum of 3la 120
Figure Appendix C.52 HRMS spectrum of 3la 121
Figure Appendix C.53 1H NMR spectrum of 3ma 123
Figure Appendix C.54 13C NMR spectrum of 3ma 123
Figure Appendix C.55 HRMS spectrum of 3ma 124
Figure Appendix C.56 1H NMR spectrum of 3na 126
Figure Appendix C.57 13C NMR spectrum of 3na 126
Figure Appendix C.58 HRMS spectrum of 3na 127
Figure Appendix C.59 1H NMR spectrum of 3oa 129
Trang 18LIST OF TABLES
Trang 19LIST OF APPENDIX TABLES
Trang 20LIST OF ABBREVIATIONS
1,1-DPE 1,1-Diphenylethylene acac Acetylacetonate ion CNS Central nervous system
Cy Cyclohexyl group
DABCO 1,4-Diazabicyclo[2.2.2]octane DiPEA Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO Dimethyl sulfoxide
EI Electron ionization
ESI Electrospray ionization
GC Gas chromatography
GC-MS Gas chromatography – Mass spectrometry HRMS High-resolution mass spectrometry
LC-MS Liquid chromatography – Mass spectrometry
m.p Melting point
NMM N-methylmorpholine
NMP N-methylpiperidine
NMR Nuclear magnetic resonance
rr Regioisomeric ratio
r.t Room temperature
SNAr Aromatic nucleophilic substitution
TBAB tert-Butylammonium bromide
TBAI tert-Butylammonium iodide
TBHP tert-Butyl hydroperoxide
TLC Thin-layer chromatography
TMS Tetramethylsilane
Trang 21NMR splitting patterns s singlet d doublet t triplet q quartet dd doublet of doublets td triplet of doublets dt doublet of triplets tt triplet of triplets
ddd doublet of doublets of doublets tdd triplet of doublets of doublets
Trang 22CHAPTER 1 LITERATURE REVIEW 1.1 Elemental sulfur in the synthesis of heterocycles
Elemental sulfur is one of the most important materials in organic chemistry recently Although the element itself only constitutes 0.052 wt.% of the Earth’s crust, sulfur in its elemental form is a readily available material with a production rate of more than 70 million tons per year, as it is a by-product of modern oil and gas refineries [1, 2] Elemental sulfur exists as a stable, non-volatile, non-hygroscopic, free-flowing yellow solid; therefore, it is generally safe to work with sulfur [1] These properties, along with its cheapness and abundance, have made elemental sulfur a promising reactant for organic chemists to explore [1]
Regarding reactivity, although elemental sulfur is not very reactive under ambient conditions, its reactivity can be largely modified upon heating and/or addition of a base or a transition metal ion [2] Moreover, since sulfur shows a wide range of covalency from two, four, to six, it can comfortably participate in cyclic structures As a result, elemental sulfur has been incorporated into a variety of organic reactions, especially in the syntheses of heterocycles
1.1.1 Elemental sulfur acting as a building block for heterocycles
As previously mentioned, the ability to form cyclic structures is an interesting reactivity of elemental sulfur Because of this, numerous sulfur-containing heterocycles have been synthesized
Trang 23Scheme 1.1 Synthesis of thiophenes from aryl acetaldehyde, 1,3-dicarbonyls, and S 2-Aminothiophene, a scaffold present in various pharmaceutical agents, was successfully generated in Gewald reaction and its modifications [2] In one example, the Michael-Gewald modification used a Michael addition between indoles or pyrrole and acroleins to generate the carbonyl component, which was subsequently consumed in a Gewald-like reaction with acetonitriles and elemental sulfur to produce highly substituted 2-aminothiophenes (Scheme 1.2) [4]
Scheme 1.2 Michael-Gewald reaction to synthesize 2-aminothiophenes
Trang 24four-component version of this transformation, using L-proline as the catalyst (Scheme 1.4) It was also noted that both versions of this transformation comfortably progressed at room temperature [5]
Scheme 1.3 Modified Gewald reaction to synthesize 2-aminothiophenes
Scheme 1.4 One-pot four-component synthesis of 2-aminothiophenes
Benzo-fused thiophenes were another important structure of sulfur-containing
heterocycles Nguyen et al reported a sulfurative denitration and cyclization of
o-nitrochalcones to produce the benzothiophene structure (Scheme 1.5) [6] This
transformation tolerated many functional groups but required an ortho nitro group to
proceed Mechanistic studies revealed that elemental sulfur was activated by strong bases, such as DiPEA or other tertiary amines, to serve as an active reactant
Trang 25More complicated benzothiophene structures were also synthesized Huang et al
reported a bis-heteroannulation reaction to generate the benzo[4,5]thieno[3,2-d]thiazole
structure from acetophenone oximes, aryl aldehydes, and elemental sulfur in the presence of copper(I) salt (Scheme 1.6) [7]
Scheme 1.6 Copper-catalyzed tandem cyclization synthesis of
benzo[4,5]thieno[3,2-d]thiazoles
In another publication, these authors also reported a metal-free approach to synthesize the same structure, albeit with an arylamino substituent instead of aryl group (Scheme 1.7) [8] Mechanistically, it was suggested that 3-aminobenzothiophene could
be the intermediate, which underwent an sulfuration upon heating to produce the
o-aminothiophenol-like structure and then reacted with the C1-synthon with the aid of elemental sulfur to furnish the desired structure [7, 8] In both examples, elemental sulfur was activated either by a transition metal ion or by a base Since both methods
involved formation of a C-S bond adjacent to the original oxime group,
Trang 26Scheme 1.7 Metal-free tandem cyclization synthesis of
benzo[4,5]thieno[3,2-d]thiazol-2-amines
Another benzo-fused structure, benzo[4,5]thieno[2,3-d]thiazole, was also
achieved using elemental sulfur, as reported by Zhang et al., where the use of arylacetonitrile instead of acetophenone oxime resulted in an inverted position of the thiazole ring with respect to the benzothieno moiety (Scheme 1.8) In terms of mechanism, a similar pathway as acetophenone oximes was proposed, where
2-aminobenzothiophene would be generated and further sulfurated to obtain the
o-aminothiophenol-like structure, before capturing an aldehyde molecule to complete the final structure [9] Although this was a copper(I)-mediated coupling reaction, the mechanism showed that elemental sulfur was first activated by a base before participating in the catalytic cycle Moreover, this transformation did not exhibit
regioselectivity issue, since the arylacetonitriles had an o-Br group to direct sulfuration
Scheme 1.8 Copper-mediated synthesis of benzo[4,5]thieno[2,3-d]thiazoles
Thiazoles were another heterocyclic structure that could be furnished using elemental sulfur Wang et al reported a copper(II)-catalyzed synthesis of thiazoles from
Trang 27an enamine intermediate, which was subsequently sulfurated, oxidized, and cyclized to generate the thiazole ring (Scheme 1.9) [10]
Scheme 1.9 Synthesis of thiazoles
Scheme 1.10 Synthetic pathways of benzothiazoles from o-iodoanilines
Compared to thiazoles, benzothiazoles were more significant toward pharmaceutical applications; therefore, more approaches to synthesize this structure were published, and elemental sulfur proved to be the simplest external sulfur source
Various authors reported the synthesis of benzothiazoles from reactions of
o-iodoanilines, elemental sulfur, and a C1-synthon, assisted by different forms of copper-based catalysts One equivalent of elemental sulfur could act as the sulfide source to first
Trang 28reacted with the C1-synthon with the aid of more elemental sulfur to furnish the benzothiazole ring Various C1-synthons were reported such as arylaldehydes [11], benzyl chlorides [12], benzylamines [13], and arylacetic acids [14] Each reaction tolerated a wide range of functionalities (Scheme 1.10)
Benzothiazoles could also be obtained from o-chloronitrobenzenes, elemental
sulfur, and a C1-synthon Several types of C1-synthons were reported for this type of transformation such as benzylamines [15], acetophenones [16], benzaldehydes [17], and
4-picolines [18] (Scheme 1.11) Since o-chloronitrobenzenes required 8 electrons per
molecule while these C1-reagents could only supply a maximum of 6 electrons per molecule, additional electrons should be supplied by elemental sulfur to complete the redox equations As a result, sulfur acted both as a sulfide source and an external complementary reducing agent in these reactions [2]
Scheme 1.11 Synthetic pathways of benzothiazoles from o-chloronitrobenzenes
Benzisothiazoles, isomers of benzothiazoles, could be achieved from reactions
between o-chloroarylamidines and elemental sulfur, albeit with a prolonged heating
Trang 29Scheme 1.12 Synthesis of benzisothiazoles from o-chloroarylamidines
More sophisticated sulfur-containing heterocycles were also achieved using elemental sulfur as one of the building blocks 1,2,3-Thiadiazoles were synthesized from the corresponding acetophenone tosylhydrazones and elemental sulfur under various oxidative conditions All these conditions made use of iodonium ion in various forms such as combinations of ammonium iodide and an oxidant [20, 21] or I2/DMSO [22] (Scheme 1.13) Iodonium ions would play the role of an initial oxidant to functionalize the terminal methyl group, which facilitated the introduction of sulfur chain to the carbon skeleton Subsequent shortening of sulfur chain and elimination of tolylsulfinic acid furnished the desired ring
Scheme 1.13 Iodonium-mediated synthesis of 1,2,3-thiadiazoles
When benzamidines were used instead of acetophenone tosylhydrazones, along with a C1-synthon, 1,2,4-thiadiazoles were obtained Various C1-synthons for this reaction were reported, ranging from 2-methylquinolines or benzaldehydes [23], acetophenones [24] to benzyl halides [25, 26] In all transformations, a base was required to activate elemental sulfur, and the reaction temperatures were somewhat high (Scheme 1.14)
Trang 30NH2 group with NaNO2/HCl introduced the needed nitrogen atom, then cyclization to 1,2,3,4-thiatriazoles followed (Scheme 1.15) [27]
Scheme 1.14 Synthetic pathways of 1,2,4-thiadiazoles
Scheme 1.15 One-pot synthesis of 1,2,3,4-thiatriazoles
Scheme 1.16 Synthesis of sultams from o-nitrochalcones
Heterocycles with a higher covalency of sulfur, sultams, were also achieved using elemental sulfur as the building blocks, as reported by Nguyen et al (Scheme 1.16) [28]
It was noted that, reactions between o-nitrochalcones and elemental sulfur progressed
Trang 31as the catalyst on o-nitrochalcones to promote Cα-S bond formation, rather than as an activator for elemental sulfur An interesting part in the mechanism of this transformation was the migration of two oxygen atoms from the nitro group to sulfur, instead of a sulfurative denitration as discussed above [6] This might be due to the role of different bases in the mechanisms
1.1.2 Elemental sulfur acting as an oxidant
Besides acting as building blocks, elemental sulfur could play the role of an oxidant in the synthesis of other heterocycles, since it can be reduced to sulfide One interesting pathway of this type of reactions was the base-promoted Willgerodt-Kindler-like rearrangement, where aryl methyl ketones underwent oxidative rearrangement to generate a thioamide [1], which would undergo further coupling and cyclization to generate heterocycles One example of this was reported by Nguyen et al., where the
elemental sulfur-promoted oxidative rearranging coupling of o-aminophenols with
acetophenones furnished the 2-benzylbenzoxazole structure Since the authors used a tertiary base, a thioamide intermediate was not observed, as it would be unstable However, when a primary base, cyclohexylamine, was used in one control experiment, a thioamide derivative was detected, alongside the desired product These results confirmed the Willgerodt-Kindler-like pathway (Scheme 1.17) [29]
Scheme 1.17 Willgerodt-Kindler-like synthesis of benzoxazoles
When o-phenylenediamines were used instead of o-aminophenols, a different
Trang 32through condensation of one amino group with acetophenone, which resulted in an enamine intermediate This enamine was then oxidized by elemental sulfur at Cα and underwent intramolecular cyclization and aromatization to complete the
quinoxaline-2-thione structure (Scheme 1.18) [30] The difference in reactivity between o-phenylenediamine and o-aminophenol could be attributed to the presence of an
additional highly nucleophilic amino group
Scheme 1.18 Synthesis of quinoxaline-2-thiones from o-phenylenediamines
Besides oxidizing acetophenone, elemental sulfur could also oxidize similar structures, such as α-chloroamides, as reported in a publication by Tikhonova and co-workers [31] In this publication, 2,2’-diaminobiaryls were allowed to react with α-chloroamides in the presence of elemental sulfur and a base, generating 2-amido
dibenzo[d,f][1,3]diazepines (Scheme 1.19)
Scheme 1.19 Synthesis of dibenzo[d,f][1,3]diazepines from 2,2’-diaminobiaryls
The amide group remained intact during the transformation instead of condensing with amine groups, which might be attributed to the fact that aryl amines were weaker
Trang 331.1.3 Elemental sulfur acting as a catalyst for non-redox reactions
Elemental sulfur could also act as a catalyst for non-redox cyclization reactions to
furnish heterocycles Deng et al reported a sulfur-promoted triple substitution of o-phenylenediamines, o-aminophenols, and o-aminothiophenols on trihaloacetamides to
furnish families of 2-amido benzazoles, which was of biological importance (Scheme 1.20) [32] This seemed to be a simple cycloaddition as the saturated carbon of trihaloacetamides was already at its required +3 oxidation state However, the transformation failed to progress in the absence of elemental sulfur It was later shown that sulfur bonded to the XH moiety and promoted the displacement of two halogen
atoms by the o-amino group Subsequent elimination of the sulfur chain produced anion
X-, which displaced the remaining halogen atom and generated the desired heterocycles The catalytic cycle then continued with the liberated sulfur chain
Scheme 1.20 Synthesis of benzazoles from o-hydroxy/amino anilines and
trihaloamides
A previous publication by our group discussed elemental sulfur-promoted
annulation reactions between o-aminophenols and aryl isothiocyanates to generate
2-aminobenzoxazoles, another scaffold present in various biologically active compounds
Notably, o-aminothiophenol could also tolerate this reaction (Scheme 1.21) This also
seemed like a simple cycloaddition reaction; however, only 8% yield of the desired product was obtained in the absence of elemental sulfur [33]
Trang 341.1.4 Elemental sulfur acting as a catalyst for redox condensations
Elemental sulfur could also act as a catalyst for redox annulations, since it could tolerate a wide range of oxidation states from -2 to +6 The most popular substrates of these transformations might be aromatic nitro compounds, as these were known to be a readily available nitrogen atom supply to heterocyclic structures Direct utilization of these substrates with the aid of elemental sulfur could help avoid doing separate reduction step to anilines [2]
1.1.4.1 Elemental sulfur as lone catalyst
Gan et al and Dang et al reported, in three separate publications, elemental
sulfur-catalyzed reductive annulations of o-nitrophenols or o-nitroanilines with arylmethyl
chlorides [34], arylacetic acids [35], or benzaldehydes [36] to generate 2-arylbenzoxazoles or 2-arylbenzimidazoles (Scheme 1.22) In all cases, sulfur oxidatively activated the C1-synthons beforehand to enhance the reaction rates of these reagents with electron-poor aromatic nitro compounds
Scheme 1.22 Sulfur as lone catalyst for reductive annulations of o-nitrophenols
1.1.4.2 Elemental sulfur and a Fe source as co-catalysts
Trang 35Combination of elemental sulfur with a Fe source, either metallic Fe or Fe salts, was shown to have comfortably overcome such difficulties A wide range of C1-synthons such as arylacetonitriles [37], acetophenones or methylquinolines [38], dibenzyl disulfides or arylmethyl mercaptans [39], methyl hetarenes [40], and arylacetic acids
[41] successfully cyclized with o-nitrophenols, o-nitroanilines, or even bis(o-nitroaryl) disulfides, stable forms of corresponding o-nitrothiophenols, as were reported in
multiple publications from Nguyen’s and Gan’s groups (Scheme 1.23)
Scheme 1.23 Synthetic pathways of benzazoles from o-hydroxy/amino/mercaptan
nitrobenzenes
Trang 36It was interesting that the use of arylacetic acids as the coupling partner was also reported, since elemental sulfur alone was able to catalyze reaction of these substrates
with o-nitrophenols as discussed above However, addition of 5 mol% FeCl2.4H2O significantly reduced the amount of sulfur needed from 3 equivalents to 40 mol% [41] Therefore, a combination of Fe salt and elemental sulfur proved to be more effective than elemental sulfur alone
In all cases, the active catalyst was reported to be an Fe/S cluster, which formed from a Fe source and elemental sulfur In nature, Fe/S cluster is present in the active sites of many enzymes, enabling electron transfer in processes such as photosynthesis thanks to its flexibility in accepting and releasing electrons, which resembled the function of a capacitor in an electrical circuit [1, 42] Figure 1.1, adapted from [42], showed the structure of Fe/S cluster and its ability to tolerate many different oxidation states This interesting property of Fe/S cluster was utilized in organic synthesis to facilitate direct electron flow between two reactants, as described above
Figure 1.1 Structure of Fe/S cluster and its ability to accept and release electrons, from [42]
Trang 37Figure 1.2 General catalytic cycle of Fe/S cluster
After the Fe/S cluster was formed, two reactants complexed to it, and then redox reactions commenced It was noted that the structure ArCH2Y of those C1-synthons comfortably provided the site for initial oxidation to create the crucial C=N bond Then, an external reductant could either continue reducing the nitroso group or reduce the liberating nitrone intermediate, generating the benzazole structure Notably, reactions
between o-nitroanilines and acetophenones produced quinoxalines instead of
benzimidazoles [38] The authors, however, did not reason this behavior
1.2 Synthesis of the 2-aminobenzoxazole scaffold
1.2.1 Introduction to 2-aminobenzoxazoles
Trang 38possess a substituent at C2 position, and amino groups are among the most important types of substituents at this position [50-52]
Figure 1.3 Some biologically active compounds with 2-aminobenzoxazole core Specifically, the 2-aminobenzoxazole scaffold is present in many therapeutic agents for the treatment of CNS disorder, insomnia, or Alzheimer's disease [53] Besides, other compounds with this scaffold exhibit anti-inflammatory, anti-microbial, anti-tumor, neuroprotective, and anti-convulsant activities [54] Recently, an array of 2-aminobenzoxazoles as anti-fungal agents against phytopathogenic fungi were synthesized [55], while another array of 2-aminobenzoxazoles were proved as effective ChemR23 inhibitors [56] 2-aminobenzoxazoles were also proved to be effective VEGFR-2 inhibitors toward treatment of cancers [57] Some biologically active compounds with the 2-aminobenzoxazole core were present in Figure 1.3
1.2.2 Reported pathways for the synthesis of 2-aminobenzoxazoles
Trang 39The first pathway involved the use of asymmetric phenolic thioureas, which were only one C-O bond short of the complete structure, and this bond could be achieved by using visible light with a photocatalyst, a TBAI/H2O2 system, an organobismuth catalyst, or an alkaline solution of KIO4 (Scheme 1.24 and Scheme 1.25) [58-61] It was noted that in the latter two examples (Scheme 1.25), the thioureas were first synthesized
from o-aminophenols and aryl isothiocyanates, therefore, the limited set of available
thioureas in the former two examples could be easily overcome Although it was easy to achieve a wide scope of phenolic thioureas, the following intramolecular cycloaddition utilized either strong oxidants or sophisticated, well-tailored catalysts, which held this method back from being useful and convenient
Scheme 1.24 Synthesis of 2-aminobenzoxazoles from phenolic thioureas
Scheme 1.25 Two-step synthesis of 2-aminobenzoxazoles from o-aminophenols
Murthy Boddapati et al reported the similar two-step approach where the
2-arylaminobenzoxazole structure was built from three precursors: thiourea,
Trang 40Scheme 1.26 Synthesis of 2-aminobenzoxazoles from thiourea, o-iodophenols, and
aryl iodides
Scheme 1.27 Synthetic pathways for 2-arylamino benzazoles from
o-hydroxy/mercaptan anilines
Another pathway was direct coupling of o-aminophenols with a C1-N-Ar synthon