Utilization of elemental sulfur in the synthesis of 2 aminobenzoxazoles

TASKS AND CONTENTS: - Investigate novel transformation using o-nitrophenol, phenyl isothiocyanate, iron salt, and elemental sulfur to synthesize the 2-aminobenzoxazole scaffold - Optim

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:

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

Assoc Prof Dr 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: 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 aminobenzoxazole

2-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

Dr Nguyen Thanh Tung Prof Dr 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 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

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

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

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

TABLE 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

2.4.2.1 Model reaction 29

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 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

REFERENCES 57

APPENDIX A CALIBRATION CURVE 66

APPENDIX B GC-MS CHROMATOGRAM OF REACTION MIXTURE 69 APPENDIX C SPECTRAL DATA 70

LIST 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

Scheme 1.20 Synthesis of benzazoles from o-hydroxy/amino anilines and trihaloamides 12

Scheme 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

Scheme 2.12 1-mmol synthesis of 3aa 31

Scheme 3.1 Optimal set of conditions 42Scheme 3.2 Control experiments 50

LIST 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

Figure 3.11 Possible pathway from II to III 53

LIST 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

Figure Appendix C.20 19F NMR spectrum of 3ah 89

Figure 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

Figure Appendix C.45 13C NMR spectrum of 3ja 114

Figure 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

Figure Appendix C.60 13C NMR spectrum of 3oa 129

LIST OF TABLES

Table 2.1 List of chemicals and their manufacturers 23Table 3.1 Substrate scope 43

LIST OF APPENDIX TABLES

Table Appendix A.1 Data for constructing calibration curves 66

LIST OF ABBREVIATIONS

1,1-DPE 1,1-Diphenylethylene

acac Acetylacetonate ion

CNS Central nervous system

SNAr Aromatic nucleophilic substitution

TBAI tert-Butylammonium iodide

CHAPTER 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

Thiophenes might be the most important sulfur-containing heterocycles Substituted thiophenes could be achieved from a reaction mixture of aryl acetaldehydes, elemental sulfur, and 1,3-dicarbonyls, following a [2+2+1] cyclization (Scheme 1.1) [3] Various functionalities were compatible with this transformation Notably, the reaction showed regioselectivity toward the less hindered carbonyl group when asymmetric 1,3-dicarbonyls were employed

Scheme 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

The use of Michael addition reactions prior to forming 2-aminothiophenes could serve to diversify the molecular complexity of such valuable biologically active scaffold However, this method suffered an unexpected side reaction when malononitrile was used as the acetonitrile derivative A different approach to diversify the scope of Gewald-like reactions was reported by Kavitha et al., where the carbonyl component was replaced by a benzylidenemalononitrile, a condensation product of an aldehyde and malononitrile (Scheme 1.3) More interestingly, the authors also reported a direct four-

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

Scheme 1.5 Sulfurative denitration synthesis of benzothiophenes

More 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,

meta-substituents on the oxime ring would inevitably produce pairs of isomers, of which the 5-substituted products were more favorable

Scheme 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

aryl acetaldehydes, primary amines, and elemental sulfur The reaction progressed via

an 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 based catalysts One equivalent of elemental sulfur could act as the sulfide source to first

copper-convert o-iodoaniline to o-aminothiophenol-like structures These structures then

reacted 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

(Scheme 1.12) However, this transformation only tolerated substituents that are not sensitive to such a strong base as K3PO4 [19]

Scheme 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)

Synthetic methods for 5-aryl-1,2,3,4-thiatriazoles using elemental sulfur were also developed In the first step, reactions between aromatic nitriles, elemental sulfur, and hydrazine under microwave produced the respective thiohydrazides, which were one nitrogen atom short of the desired products Subsequent diazotization of the terminal

NH2 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

with all atoms conserved in the sultam products This type of reactions utilized a base

as 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

pathway was observed for reaction with acetophenones and elemental sulfur Instead of following the Willgerodt-Kindler-like pathway, this transformation first progressed

through 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 phenylenediamine and o-aminophenol could be attributed to the presence of an

o-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

than o-diaminoarenes and the chloro-substituted Cα was a better electrophilic site than a saturated carbon, hence it was easier for sulfur to oxidize Therefore, facile oxidation of this Cα by elemental sulfur with the aid of base produced the thioamide intermediate, before subsequent attack of the remaining amino group furnished the seven-membered heterocyclic structure of diazepine It should be noted that, although the mechanism involved a thioamide intermediate, this was not the Willgerodt-Kindler-type mechanism since no rearrangement occurred

1.1.3 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 phenylenediamines, o-aminophenols, and o-aminothiophenols on trihaloacetamides to

o-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]

Scheme 1.21 Synthesis of 2-aminobenzoxazoles from o-aminophenols and aryl

isothiocyanates

1.1.4 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 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

2-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

Although elemental sulfur alone was able to catalyze C-N bond formation from nitro group, it was the other reagent being initially oxidized to a more reactive form by elemental sulfur that facilitated reactions with the nitro substituent In other cases where

Combination 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

It was noted that all these C1-synthons should be oxidized to achieve the +3 oxidation state in 2-aryl benzazoles In this method, direct electron flow from the C1-synthon to the nitro compound was reported, which eliminated the use of an external oxidant in traditional methods [1]

It 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]

Although most reports depicted the Fe/S cluster as having a cubic lattice, its exact structure was not known However, it was known that the cluster comprised many iron atoms capable of existing in a wide range of easily interchangeable oxidation states [38], which enabled the whole electronic flexibility of the cluster Sulfur atoms provided the cluster with stabilization in the forms of sulfur bridges and external sulfide ligands [38] Figure 1.2 illustrated a general catalytic cycle for this method, as reported in various publications [37-41] In this graphical mechanism, the Fe/S cluster was drawn

in a simplified form, which omitted the charges on Fe atoms for clarity purposes The cluster was also assumed a cubic structure, but only one face was shown to allow for clear visualization of the mechanistic pathway

Figure 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

Benzoxazoles belong to the family of benzo-fused 1,3-azoles along with benzimidazoles and benzothiazoles, a family which has shown broad biological activity properties such as anti-proliferative, anti-cancer, anti-HIV, anti-microbial, anti-viral, herbicidal, and anti-fungal [43-49] Most of these biologically active compounds

possess 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

Because of their importance in medicinal and pharmaceutical fields, many attempts were made to synthesize 2-aminobenzoxazoles Retro-synthetically, there were some different ways to split the 2-aminobenzoxazole structures into its precursors

The 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,

o-iodophenols, and iodobenzenes (Scheme 1.26) [62] Despite a wide scope, this method was also not attractive because of its multistep nature

Scheme 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

to complete the 2-arylaminobenzoxazole structure through tandem formation of a C-O