Functionalization of primary C-H bonds in methylazaarenes with 3-substituted nitrobenzenes for the synthesis of 2-pyridylbenzothiazoles

Gần đây, các hợp chất hữu cơ có chứa nguyên tố lưu huỳnh đã được các nhà khoa học trên toàn thế giới chú ý đến do các đặc tính sinh học và hóa học quan trọng của chúng. Benzothiazole xuất hiện lần đầu tiên vào năm 1860 như một loại lưu huỳnh organosulfur đã trở nên phổ biến kể từ đó. Bộ xương dị vòng của nó mang một thiazole vòng 5 cạnh đã được các nhà khoa học quan sát là nguồn lý tưởng của khung lõi và các mảnh giới hạn cho việc thiết kế và tổng hợp các phân tử mục tiêu trên một quy mô thời gian hợp lý. Việc nghiên cứu các phân tử này cho phép nhà hóa dược học nhanh chóng phát hiện ra hợp chất hoạt tính sinh học trong nhiều lĩnh vực điều trị. Hơn nữa, các dị vòng chứa nitơ và lưu huỳnh cũng đóng một vai trò quan trọng trong nhiều lĩnh vực công nghiệp liên quan đến hóa học đặc biệt và tốt. Những ứng dụng này kích thích sự quan tâm đến việc phát triển nhiều phương pháp tổng hợp các hợp chất sử dụng khung chức năng benzothiazole.2pyridylbenzothiazole là một dẫn xuất của họ benzothiazoles, và cũng có rất nhiều ứng dụng trong lĩnh vực dược phẩm và lĩnh vực công nghiệp. Tuy nhiên, bên cạnh công dụng của nó trong nhiều lĩnh vực đời sống, benzothiazole dường như vẫn chưa nhận được sự quan tâm đúng mức mà nó đáng có. Không có quá nhiều phương pháp được phát triển để tổng hợp các hợp chất hữu ích này. Hai phương pháp truyền thống để tổng hợp benzothiazole từ aminothiophenol và thioamit có nhiều ưu điểm, tuy nhiên vẫn còn tồn tại nhiều hạn chế. Hầu hết các hạn chế đều liên quan đến hiệu suất nguyên tử, bước và oxy hóa khử của phản ứng. Vì vậy, để phát triển một kỹ thuật mới, đơn giản để điều chế và nâng cao tính đa dạng của ứng dụng từ 2pyridylbenzothiazole, đề tài “Chức năng hóa liên kết CH sơ cấp trong methylazaarenes với nitrobenzenes 3 thay thế để tổng hợp 2pyridylbenzothiazoles” đã được thực hiện. Trong công trình này, điều kiện tối ưu của phản ứng này và phạm vi của các dẫn xuất 2pyridylbenzothiazoles đã được nghiên cứu.

This thesis marks the final stage of my endeavor in conquering the Bachelordegree in Chemical Engineering at Ho Chi Minh city University of Technology, which

I have been desperately struggling for throughout my youth For the first chapter of mythesis, I would like to extend my deep gratitude to people who devoted themselves to acertain extent to help me complete my undergraduate thesis as well as myself

I would like to express my special gratitude to Prof Dr Phan Thanh Son Nam,who gave me a valuable chance to work in his laboratory, motivated me by his passionand wide knowledge and provided me vital facilities to accomplish my thesis

I would also like to express my gratitude to my supervisor, Dr Nguyen ThanhTung, for giving me a lot of crucial advices and important feedbacks to enhance myB.Eng thesis

I deeply thank to Mr Tran Minh Khoa, M Sc To Anh Tuong for teaching me alot about chemistry knowledge, and giving me a lot of advices during my thesis.Special thanks to my co-worker, Nguyen Le Hoang Kim and Ms Pham Thuy Hangand my colleagues in the laboratory for helping me complete this thesis

Finally, I would like to express my sincere gratitude to my family Theirunconditional love and encouragement have always been with me in everyachievement I get in my life

Ho Chi Minh City, July 2020

Do Quoc Duy

attention from scientist all over the world due to their important biological andchemical properties Benzothiazole appeared first time in 1860 as a class oforganosulfur has become popular since then Its heterocycle skeleton bearing a 5-membered ring thiazole has been observed by scientist to be an ideal source of corescaffolds and capping fragments for the design and synthesis of target molecules on areasonable time scale The investigation of these molecules enables the medicinalchemist to rapidly discover biologically active compound in many fields oftherapeutic Moreover, nitrogen- and sulfur- containing heterocycles also plays animportant role in many industrial fields related to special and fine chemistry Theseapplications ignite an interest in developing many methods for synthesizingcompounds that wield benzothiazole functional skeleton.

2-pyridylbenzothiazole is a derivative of benzothiazoles family, and also has a lot

of applications in pharmaceutical field and industrial field However, besides itsuseful in many fields of life, benzothiazole still seems not to receive enough attentionthat it deserves There are not so many methods developed for synthesizing thesehelpful compounds Two traditional methods to synthesis benzothiazole fromaminothiophenols and thioamides had many advantages, however a lot of drawbacksstill exists Most of the drawbacks were related to atom-, step- and redox efficiency ofthe reaction Thus, to develop a new, simple technique for preparing and enhancing thevariety of application from 2-pyridylbenzothiazole, the thesis “Functionalization ofprimary C-H bonds in methylazaarenes with 3-substituted nitrobenzenes for thesynthesis of 2-pyridylbenzothiazoles” was carried out In this work, the optimizedcondition of this reaction and the scope of 2-pyridylbenzothiazoles derivatives wereinvestigated

Synthesis of benzothiazoles often requires use of pre-functionalized and/or highmolecular weight starting materials, thus raising concerns from the viewpoints of atomefficiencies and practicability Herein, we report a method for preparation ofbenzothiazoles from 3-substituted nitroarenes, methylazaarenes and elemental sulfur.The transformation readily proceeded in the presence of 1,4-diazabicyclo[2,2,2]octane(DABCO) base without the need of any solvents Our work has attempted to study thescope and limitation of the reaction, including compatibility of substituents on bothnitroarenes compound and methylazaarenes Our method would offer prominentbenefits compared to conventional method since (1) stable, abundant 3-substitutednitroarenes is utilized as nitrogen source instead of thiophenol or thioamides; (2)simple, cheap elemental sulfur is used as redox moderator and building block agent;(3) the conditions do not involve the presence of any metals or solvents.

INTRODUCTION II ABSTRACT III LIST OF SCHEMES VII LIST OF FIGURES X LIST OF TABLES X LIST OF ABBREVIATIONS XI

CHAPTER 1: LITERATURE REVIEW 1

1.1 ELEMENTAL SULFUR IN ORGANIC SYNTHESIS 1

1.1.1 General introduction 1

1.1.2 Elemental sulfur in organic synthesis 2

1.2 SYNTHESIS OF BENZOTHIAZOLE 10

1.2.1 Introduction 10

1.2.2 Conventional methods 17

1.2.3 Reaction between Nitroarenes and Sulfur - Recent approaches 23

1.3 Thesis approach 31

CHAPTER 2: EXPERIMENTAL 34

2.1 MATERIALS AND INSTRUMENTATION 34

2.1.1 Materials 34

2.1.2 Instrumentation 35

2.2 EXPERIMENTAL PROCEDURE OF THE N,N-DIMETHYL-2-(PYRIDINE-2-YL)BENZO[D]THIAZOL-5-AMINE SYNTHESIS 36

2.2.1 General procedure 36

CHAPTER 3: RESULTS AND DISCUSSION 40

3.1 OPTIMIZING THE REACTION CONDITIONS 40

3.1.1 Effect of temperature 41

3.1.2 Effect of amount of DABCO 43

3.1.3 Effect of solvents 44

3.1.4 Effect of molar ratios 47

3.1.5 Effect of amount of sulfur 48

3.1.6 Effect of reaction times 50

3.1.7 Summary of condition screening 51

3.1.8 Characterization of N,N-dimethyl-2-(pyridine-2-yl)benzo[d]thiazol-5-amine (3aa) 52

3.2 SUBSTRATE SCOPE 54

3.2.1 Characterization of N,N-Dimethyl-2-(3-methylpyridin-2-yl)benzo[d]thiazol –5-amine (3ab)……… 54

3.2.2 Characterization of N,N-Dimethyl-2-(6-methylpyridin-2-yl)benzo[d]thiazol -5-amine (3ac)………55

3.2.3 Characterization of N,N-Dimethyl-2-(3-methylpyridin-4-yl)benzo[d]thiazol -5-amine (3ad) ……… 56

3.2.4 Characterization of N,N-Dimethyl-2-(quinolin-2-yl)benzo[d]thiazol-5-amine (3ae) 57

3.2.5 Characterization of 2-(6-Aminopyridin-2-yl)-N,N-dimethylbenzo[d]thiazol-5-amine (3af) ……….58

3.2.6 Characterization of 5-(4-Methylpiperazin-1-yl)-2-(quinolin-2-yl) benzo[d]thiazole (3be) ……… 59

3.2.7 Summary of substrate scope 60

APPENDIX A: CALIBRATION CURVE 72 APPENDIX B: GC RESULTS 74 APPENDIX C: CHARACTERIZATION DATA 77

Scheme 1.1: Oxidative condensation-cyclization of aryl-2-pyridylmethylamines and

aldehydes using elemental sulfur as an oxidant 2

Scheme 1.2: Reaction between Anthrone and Sulfur 2

Scheme 1.3: Synthesis benzimidazole from tri-n-propylamine and sulfur 3

Scheme 1.4: 2,4-diarylpyrroles can be formed using elemental sulfur as a reduction 3

Scheme 1.5: Proposed mechanism for 2,4-diarylpyrroles synthesis 3

Scheme 1.6: Some selected example products synthesized by this method 4

Scheme 1.7: Using sulfur to reduce nitroarenes to the corresponding anilines 4

Scheme 1.8: Synthesis of dihydrooxazole using sulfur as a catalyst 4

Scheme 1.9: Some selected example products synthesized by this method 4

Scheme 1.10: Synthesis quinolines using sulfur catalyst 5

Scheme 1.11: Proposed mechanism for quinoline synthesis 5

Scheme 1.12: Some selected example products synthesized by this method 5

Scheme 1.13: Synthesis N.N’-diarylureas, using sulfur catalyst 5

Scheme 1.14: Synthesis of thienoanthraquinone using catalyst as the building block 6

Scheme 1.15: Applied in the reaction of the chlorinated derivatives 23’ 6

Scheme 1.16: Synthesis of benzothophenes using sulfur as the building block 6

Scheme 1.17: Some selected example products synthesized by this method 7

Scheme 1.18: Synthesis of N-arylphenothiazines using sulfur as the building block 7

Scheme 1.19: Synthesis of 1,2-Dithiole by using sulfur 7

Scheme 1.20: Some selected example products synthesized by this method 7

Scheme 1.21: Synthesis of 1,2,3-Thiadiazole motifs by using sulfur 8

Scheme 1.22: Transformation of benzylamines into thiobenzamides 8

Scheme 1.23: Synthesis of thioamide by using elemental sulfur 9

acids using polyphosphoric acid as solvent 18

Scheme 1.26: Preparation of Lawesson's reagent and its benzothiazoles synthesis

bromide substitution 23

Scheme 1.32: Synthesis of 2-hetarylbenzothiazole from 2-halonitroarene,

methylhetarene and elemental sulfur 24

Scheme 1.33: Synthesis of 2-arylbenzothiazoles from o-halonitrobenzenes and

benzylamine 25

Scheme 1.34: Synthesis of 2-(3-pyridyl)benzothiazole in two studies [59, 60] 26 Scheme 1.35: Synthesis of 2-aroylbenzothiazoles from o-halonitrobenzenes,

acetophenones, and elemental sulfur 27

Scheme 1.36: Decarboxylative redox cyclization for the synthesis of 2-substituted

benzothiazoles 29

Scheme 1.37: Synthesis of 2-aroylbenzothiazoles from o-halonitrobenzenes,

benzaldehydes, and elemental sulfur 29

Scheme 1.38: The propose mechanism of the multicomponent redox condensation 30 Scheme 1.39: Synthesis of 2-aroylbenzothiazoles from anilines, acetophenones, and

Scheme 1.41: Reaction scope with respect to nitroarenes 33 Scheme 1.42: Thioamidation/cyclization of nitroarene 33 Scheme 3.1: Different factors that influence the synthesis from N,N-dimethyl-3-

nitroaniline, 2-picoline and sulfur to 2-pyridylbenzothiazole……… ….41

Scheme 3.2: DMSO used as solvent in benzothiazole synthesis reaction………45 Scheme 3.3: Acetonitrile used as solvent in 2-arylbenzimidazoles synthesis

reaction……….45

Scheme 3.4: 1,4-dioxane used as solvent in bezothiazoles synthesis reaction via an

intramolecular C-S bond formation……… 46

Scheme 3.5: The final condition of reaction……….51

Figure 1.2: Marketed drugs containing benzothiazole moiety 11

Figure 1.3: Anticancer activity of benzothiazole derivatives 12

Figure 1.4: Antimicrobial activity of benzothiazole derivatives 13

Figure 1.5: anticonvulsant activity of benzothiazole derivatives 14

Figure 1.6: Antimalarial activity of benzothiazole derivatives 15

Figure 1.7: Anti-inflammatory activity of benzothiazole derivatives 16

Figure 1.8: Typical examples of benzothiazolium compounds which can be used in combination with mercury salts in film materials 16

Figure 1.9: Benzothiazole derivatives' industrial applications 17

Figure 3.1: Effect of temperatures on the reaction yield 42

Figure 3.2: Effect of DABCO amounts on the reaction yield 44

Figure 3.3: Effect of solvents on the reaction yield……….46

Figure 3.4: Effect of reactant molar ratios on the reaction yield……… 47

Figure 3.5: Effect of sulfur amounts on the reaction yield……… 49

Figure 3.6: Effect of reaction times on reaction yield 50

Figure 3.7: 1H NMR spectrum of benzothiazole 3aa……… 52

Figure 3.8: 13C NMR spectrum of benzothiazole 3aa ………52

LIST OF TABLES Table 1.1: Aromatic aldehydes and corresponding 2-substituted benzothiazoles 20

Table 2.1: The list of chemicals used in researching process 34

Table 3.1: Scope of the reaction 60

CHAPTER 1: LITERATURE REVIEW 1.1 ELEMENTAL SULFUR IN ORGANIC SYNTHESIS

1.1.1 General introduction

Sulfur is the tenth most common element by mass in the universe, and the fifthmost common on Earth It was first discovered by Ancient Greeks and called sulfurtheion, a word that persists in several sulfur-containing compounds Many of whichbegin with the prefix “thio-“, including the class of compounds called thiazol

Sulfur can be found in all over the world Especially in native and volcanicdeposits, where it is founded with abundant reserve Though sometimes found innative and pure form, sulfur on Earth usually occurs as sulfide and sulfate minerals [1].Those native sulfur from underground can be extracted using Frasch process, whichwas the only commercialized industrial method of recovering elemental sulfur until thelate 20th century Moreover, sulfur also appears as an undesirable compound for anyprocesses related to fossil fuel due to hydrogen sulfide, which is produced duringcrude processing Sour crude oils which possess a high percentage of hydrogen sulfideare often required extra expenses for treating refinery [2] Today, sulfur obtained andrecovered from refining industry accounts for 98% of world elemental sulfurproduction

In history, sulfur has been used in production of black gunpowder, vulcanization

of rubber, and other synthesis of sulfur-containing compounds Many years havepassed, and we have come to better understand about this compound, also discovernew properties of elemental sulfur, which can be efficient in application of organicsynthesis In addition, sulfur in elemental form is not expensive and readily material,which make sulfur becoming one of the good choices for synthetic organic chemistry.Sulfur forms a number of polyatomic molecules, which the most popular iscyclo-S8 The S8 molecule is the best well-known form, also being most interested inthe field of research The pure sulfur is non-polar, so it is insoluble in water but

methanol or acetonitrile, even at room temperature, S8 is partially transformed to S6

and S7 and attains an equilibrium in which about 1% of the sulfur is present as thesmaller rings [3] When we heat the elemental sulfur, an S-S bond homolytic scissionphenomenon occurs, which results in sulfur being melted into an amber yellow, mobileliquid Eventually, this occurs at 120oC Moreover, 95% of sulfur in liquid sulfur is inthe S8 form As such, chemical reactions occur from over 120oC to 160oC on basis of

S8 molecules

1.1.2 Elemental sulfur in organic synthesis

In this part, we will go through the chemical properties of Sulfur, especially thoseare applied in organic chemistry

1.1.2.1 Sulfur as oxidant agent

Elemental sulfur has been used as an oxidant in various reactions In 2009,Shihabara et al successfully conducted an oxidative condensation-cyclization ofbenzaldehydes and aryl-2-pyridylmethylamines with the presence of elemental sulfur

as a mild oxidant [4] The reaction did not use any kind of catalyst and resulted in avariety of Imidazo [1,5-α] pyridines in high yields (Scheme 1.1).

O

Y

H2N +

S8

80oC, DMSO X

N N

Y

Scheme 1.1: Oxidative condensation-cyclization of aryl-2-pyridylmethylamines and

aldehydes using elemental sulfur as an oxidantLoskutov reported that at room temperature, anthrone and sulfur reactedsmoothly, with the presence of nitrogen nucleophiles such as aniline and hydrazine

derivatives, which results in 10-iminoanthraquinones and anthraquinones [5] (Scheme

1.2).

O O O

S8DMF, r.t., 24h

N

+

O R

Scheme 1.2: Reaction between Anthrone and Sulfur

Reaction to form benzimidazole, starting with sulfuration of tri-n-propylamine into thioamide, which lately reacted subsequently with o-phenylenediamine resulted in

the desire product [6] (Scheme 1.3).

NH2

NH 2

N

H N Et

S8

Scheme 1.3: Synthesis benzimidazole from tri-n-propylamine and sulfur

1.2.2.2 Sulfur as reductant agent

2,4-Diarylpyrroles can be synthesized in excellent yields by heating a mixture of

a 4-nitro-1,3-diarylbutan-1-one, ammonium acetate and sulfur in morpholine [7]

S8

O NH

N H

Ar Ar

80oC, 30 min

Scheme 1.4: 2,4-diarylpyrroles can be formed using elemental sulfur as a reduction

A plausible mechanistic explanation for the formation of pyrrole was suggestedwith the reduction of the nitro group of the starting butyrophenone by sulfur into

hydrazone via aci-nitro tautomer (Scheme 1.5).

The next steps could be transamination starting with ammonia (in the ammoniumacetate form) with hydroxylamine as leaving nucleophile and simultaneous cyclization

to afford the expected pyrrole Figure below illustrates some selected example

products synthesized by this method (Scheme 1.6).

Scheme 1.6: Some selected example products synthesized by this method

With the presence of a weak inorganic base NaHCO3 in DMF, sulfur may be

used to reduce selectively nitroarenes to the corresponding anilines [8] (Scheme 1.7).

Nitrile, chloro and ester groups were not affected

NO2R

NH2R

S8NaHCO3DMF, 130oC

Scheme 1.7: Using sulfur to reduce nitroarenes to the corresponding anilines

N

N O

S

Scheme 1.9: Some selected example products synthesized by this method

With the presence of CO (high pressure) and H2O, sulfur acts as the catalyst forreduction reaction of β-(2-nitrophenyl)-α,β-unsaturated ketones to form corresponding

quinolines [7] (Scheme 1.10).

R' O

Scheme 1.10: Synthesis quinolines using sulfur catalyst

The active reducing agent we used here was hydrogen sulfide, which is generatedfrom the hydrolysis of carbonyl sulfide At high temperature, carbonyl sulfide isreadily available by the addition of sulfur to carbon monoxide The nitro substrate wasreduced into aniline, which underwent subsequently a cyclization-dehydration

sequence to reach quinoline product (Scheme 1.11).

R' O

NO2

R

R' O

Scheme 1.12: Some selected example products synthesized by this method

A catalytic system consists of sulfur elemental, Net3 in the ionic liquid Bmin-BF4

was developed for reductive reaction of Nitrobenzene, ArNO2 and its correspondinganiline ArNH2 The reaction occurs under high pressure of carbon monoxideconditions, which provide symmetrical N,N’-diarylureas in high yield (up to 96%) [8]

(Scheme 1.13).

S8 NEt3BmimBF4

Scheme 1.13: Synthesis N.N’-diarylureas, using sulfur catalyst

1.2.2.4 Sulfur as building block – sulfuration reaction

a) Reaction with formation of heterocycles:

When heating at 78oC the mixture of anthraquinones and elemental sulfur in anethanolic alkaline solution, we can achieve the corresponding thienoanthraquinone

adducts, which also in the high yields [10] (Scheme 1.14).

O

O R

S 8 + NaOH, 78oC EtOH

O

O

S R

Scheme 1.14: Synthesis of thienoanthraquinone using catalyst as the building block

Scheme 1.15: Applied in the reaction of the chlorinated derivatives 23’.

2– Substituted benzothophenes could be prepared in moderate yields, withstarting materials is α-substituted 2-bromo-β-methoxystyrenes This is a two-stepreaction The first step consisted in a sulfur incorporation by treatment of lithiatedderivatives with elemental sulfur The second one is the cyclization sequence of theresulting methoxy-2-sulfanylstyrenes, which was conducted at room temperature with

concentrated HI in acetonitrile [11] (Scheme 1.16).

Scheme 1.17: Some selected example products synthesized by this method

With the presence of atmospheric O2/KI/DMSO system, N-arylphenothiazines

were achieved through reactions between anilines and cyclohexanone [12] (Scheme

1.18).

O

R

N S

Scheme 1.18: Synthesis of N-arylphenothiazines using sulfur as the building block

There is also report about synthesis 1,2-Dithiole The 1,2-Dithiole wassynthesized by the reaction of acetodithioacetates at 90oC, under the presence ofelement Sulfur and InCl3 However, it is not clear how many sulfur atoms from

elemental sulfur were incorporated into products [13] (Scheme 1.19) Figure illustrates

some selected example products synthesized by this method

S R

Scheme 1.20: Some selected example products synthesized by this method

1,2,3-Thiadiazole motifs can be synthesized from N-tosylhydrazones and sulfur

via the TBAI-catalyzed reaction Products of this reaction are intermediates of

synthetic processes [14] (Scheme 1.21).

N NHTs

S

N N TBAI (20% mol)

K2S2O8

100oC, 2h + S8

Scheme 1.21: Synthesis of 1,2,3-Thiadiazole motifs by using sulfur

b) Reactions without formation of sulfa-heterocycles

In the presence of elemental sulfur, benzylamine can be able to react to form

N-benzylthiobenzamide via 2 intermediate reactions: oxidation into imine NH’ –

transimination to imine even at 1000C The process of the transformation ofbenzylamines into thiobenzamides proceeded faster under microwave conditions

(Scheme 1.22)

S N

N H NH

N H

NH S

MW

170oC, 15mins

S8

Scheme 1.23: Synthesis of thioamide by using elemental sulfur

Primaryalkil halides (1a-c) (and sulfonates 35d) were rapidly converted to theircorresponding dialkyl disulfides 36a-d This reaction occurs under solvent-freeconditions with the presence of sulfur, NaBH4 as a reducing agent and neutral alumina

as a solid support [15] (Scheme 1.24) We obtained an excellent yield at 35a.

However, the reaction is incompatible with reducible substituents such as nitro 35b ornitrile 35c

NaBH 4 / alumina r.t., grinding, 5-15mins

1/2/2

1/3/2

t (min) 5

15

<5

3

Yield (%) 94

20

48

84

S SR

Benzothiazole is the name of a fused membered rings, which contain heterocyclesbearing thiazole The presence of sulfur and nitrogen atoms are constituted the corestructure of thiazole and many pharmacologically and biologically active compounds[16] Benzothiazole consists of a 5-membered 1,3-thiazole ring, attached to a benzenering All nine atoms of the bicycle and the attached substituents are coplanar [17]

(Figure 1.1)

N

S

N S

Figure 1.1: Thiazole (I) and benzothiazole (II)

In 1887, 2-substituted benzothiazole was first synthesized by A W Hofmann[18] In the mid-19th century, 2-aminobenzothiazoles were studied as central musclerelaxants Since then, medicinal chemists have lost interest in this chemical family notuntil Riluzole was discovered [19] Riluzole (6-trifluromethoxy-2-benzothiazloamine)was discovered for experiments purpose It has an ability to interfere with glutamateneurotransmission in biochemical, electrophysiological biphasic and behavioralexperiments Since then, benzothiazoles and its derivatives have gained popularityagain in pharmaceutical fields Although benzothiazoles have been successfullyapplied in a short interval of time, the range of their application is very broad.

1.2.1.1 Biological applications of benzothiazole derivatives

A review of recent literature revealed that a heterocyclic moiety was appeared inthe structure of many antimicrobial agents [20], in particular, benzothiazole derivativeshas received special attention since they belong to a medicinal chemical family withproven utility Because of its valuable scaffold, benzothiazole possesses diversebiological activities, such as anticancer [21], antimicrobial [22], anticonvulsant [23],anti-inflammatory [24], antiviral [25] and antimalarial [26] effects In thepharmaceutical market nowadays, benzothiazole also appeared as core nucleus invarious drugs, all due to their diverse biological activities, e.g viozan (dual D2dopamine receptor, β2-adrenoceptor agonist), probenazole (herbicide), riluzole,

ethoxazolamide (carbonic anhydrase inhibitor, etc) (Figure 1.2)

O O

O Probenazole

2-((5-substituted-derivatives 1 and evaluated their anticancer activity against A549, C6, MCF-7 and

HT-29 cells [27] Novel benzothiazole-based non-sulfamide NAE (NEDD8 activating

enzyme) inhibitors 2a-c, which were discovered by Zhuang et al in 2017, also proved

that their potential in antitumor activity with IC50 values in nanomolar range [28].Berberine-benzothiazole conjugates synthesized by Mistry et al also proved theirabilities in fighting against HeLa, CaSki (cervical cancer) and SK-OV-3 (ovarian

cancer) 3a-b (Figure 1.3).

S

N NH

O

CF3

H N O S HO

2a

S

N NH

O

CF3

H N O S

2b

S

N NH

O

CF3

H N O S

2c H2N

O

-O OCH3

H N N

H N N

S NC

3b

Figure 1.3: Anticancer activity of benzothiazole derivatives

b) Antimicrobial activity

In 2018, Haroun et al successfully synthesized

2-(6-methoxybenzo[d]thiazole-2-ylimino)-5-benzyliden-thiazolidin-4-one derivatives 4, which were then evaluated for

antimicrobial activity The results found that almost all compounds exhibited about

2-17 better than the reference drugs ampicillin [29] Quinoline-based

benzothiazolyl-1,2,4-triazole 5a-b are synthesized and screened for antimicrobial activity by Peter and Park [30] Compound 5a exhibited potent activity against Gram-positive bacteria Staphylococcus aureus while compound 5b was effective against Gram positive

bacteria B cereus (Figure 1.4)

S

O

N HN S

O 4

N N

N N S HN

S N

Br

O

N N

N N S HN

S N

2-[(6-substituted-derivatives as anticonvulsant agents In those 2-[(6-substituted-derivatives, two compound 6a and 6b

exhibited as most active compounds in comparison with the standard drug: phenytoinand carbamazepine [31] Another study of benzothiazoles about anticonvulsant was

studied by Liu et al in 2016 [32] Among the benzothiazole derivatives, compound 7

was found to be most effective comparing to standard drugs (carbamazepine) inanticonvulsant assay Liu et al also reported the synthesis of a new anticonvulsant

series of 7-alkoxy[1,2,4]triazolo[3,4-b]benzothiazole-3(2H)-ones [33] Among those derivatives, two derivatives 7-propoxy[1,2,4]triazolo[3,4-b]benzothiazole-3(2H)-one

8a and 7-butoxy[1,2,4]triazolo[3,4-b]benzothiazole-3(2H)-one 8b showed highest

activity against maximal electroshock-induced toxic extensions, in comparison to

carbamazepine (Figure 1.5).

N S NH

N H

O

S

N S NH

N H

O

S N

S

N

N NH O

N

N NH O

O

Figure 1.5: anticonvulsant activity of benzothiazole derivatives

d) Antimalarial activity

Thakkar et al have successfully synthesized a novel series of benzothiazole

analogues, and compounds 9a and 9b were found to be most active in antimalarial

activity test [34] While Sharma et al synthesized a new series of benzo[d]thiazole-2-yl)-2-substituted phenyl-1H-benz[d]imidazole-1-carbothioamide

N-(6-metho-derivatives The compound substituted with (3,4,5-trimethoxy) 10a and with

(3,4-dinitro) 10b shows high inhibition against P.falciparum when compare to reference

drug chloroquine [35] A series of amodiaquine analogues of benzothiazole 11a-c were

synthesized by Ongarora et al These compounds could block the formation of toxicquinone imine and aldehyde metabolites without affecting antiplasmodial activity

(Figure 1.6).

N Cl

11a

N

S

NH N HN

N Cl

11b

N

S

NH N HN

N Cl

-activity According to result, compounds 12 was found to be most active when

compare to reference drug diclofenac sodium After that, Tariq et al continuedinvestigated further and synthesized N-(benzothiazole-2-yl)-2-[(5-(phenoxymethyl)-4-

aryl-4H-1,2,4-triazol-3-yl)thio]acetamide derivatives [37] Among all derivatives,

compound 13 exhibited to be the most active compound in anti-inflammatory activity (Figure 1.7).

N

S

NH N

N NH

N ClCl

Figure 1.7: Anti-inflammatory activity of benzothiazole derivatives

1.2.1.2. Industrial applications of benzothiazole derivatives

Being heterocyclic compounds, Benzothiazole derivatives are also famous forvarious fields of chemical research, for instance, industrial applications Some areknown as intermediates for dies [38], plant protectants [39], and photographicsensitizers

Benzothiazole salts have been applied in photographic for a long time Since

1989, C R Messing has invented a new way to stabilize photographic recordingmaterial with respect to reducing or to eliminating chemical fog formation during filmstorage [40] He employed a combination of mercury compound and benzothiazolium

in the film materials (Figure 1.8).

N+CH S

Cl

Cl

-N+C

H2C

F 3 C

Cl

CH3CO2

-Figure 1.8: Typical examples of benzothiazolium compounds which can be used in

combination with mercury salts in film materials2-substituted benzothiazoles are also contributes to plant protectants industry.Benzothiazole itself is a fungicide [41] Methabenthiazuron (MBTU) is used asherbicide in winter corn crops, slimicides in the paper and pulp industry [42] On theother hand, 2-aminobenzothiazole is used in disperse azo dye manufacture

O CH 3 H Benzothiazole 2-Amino Benzothiazole

methods: condensation reaction of 2-aminothiophenols and Jacobson’s cyclization ofthiobenzanilides.

1.2.2.1 Condensation reaction of 2-Aminothiophenols

The pioneer method was condensation of aminothiophenol with the substitutednitriles, aldehydes, carboxylic acids, acyl chloride or esters 2-aminothiophenol is anoxygen sensitive compound, so it easily forms derivatives such as acid salts, alkalinesalts or disulfides, which results in allowing them to react with a number of reagents[44] Early examples of 2-arylbenzothiazole syntheses that are still valuable todayinvolve the condensation of 2-aminothiophenol with a benzoic acid or relatedderivatives by heating in a high boiling solvent such as polyphosphoric acid [45-49]

(Scheme 1.25).

NH2SH

HO O

R

+ polyphosphoric acid

Scheme 1.25: Synthesis 2-arylbenzothiazoles from 2-aminothiophenol and benzoic

acids using polyphosphoric acid as solventThere is another green way accessing to benzothiazole by condensation reactionbetween thiophenols and carboxylic acids without using solvent In 2006, Seijas et al.reported that Lawesson’s reagent can be used effectively as a promoter under thesolvent-free, microwave-assisted condition, to achieving both benzoxazoles andbenzothiazoles [50] Lawesson’s reagent was first made in 1956 and is commerciallyavailable on the market today It can also be easily prepared in the laboratory byheating anisole with diphosphoruspentasulfide until the mixture of both becomes clearand no more hydrogen sulfide is formed, the recrystallized from toluene or xylene

(Scheme 1.26) Much of the chemistry of Lawesson’s reagent is from its central

phosphorus/sulfur four-membered ring, which will break two reactive dithiophosphinewhen it is heated So that, it has been used in this way to form with carboxylic acids amixed anhydride, which activate carboxylic acids towards peptide bond formation [51,

benzothiazoles from benzoic acide and o-aminothiophenol afforded poor to moderate

yields (12% for 2-phenylbenzothiazole) [53] However, with the presence ofLawesson’s reagent, the yield highly improved (91% for 2-phenylbenzothiazole)

NH2HS

+ R COOH

LR

N R

Scheme 1.26: Preparation of Lawesson's reagent and its benzothiazoles synthesis

applicationHowever, there are several drawbacks of Lawesson’s reagent, i.e it isappropriate only for small-scale reaction due to its relatively high molecular weight Inaddition, Lawesson’s reagent is hazardous, and smelling, required proper care andhandling [54, 55]

Replace acid carboxylic with aldehydes can also be resulted in benzothiazolewith high yield A series of benzothiazole compounds with a variety of differentsubstituents were successfully synthesized by Guo and co-workers He used theoriginal condensation reaction between 2-aminothiophenol and aldehydes, with thepresence of a mixture of H2O2/HCl as a catalyst in ethanol at room temperature for 1

hour [56] (Scheme 1.27) After investigated, both aldehydes bearing electron-donating

substituents and electron-withdrawing substituents could be used to obtain thecorresponding benzothiazoles in high yields Also, short reaction time, easy and quickisolation of the products and excellent yields are advantages of this method

NH2HS

30% H2O2/ 37% HCl (6:3)

N R

85 - 94%

Scheme 1.27: Condensation of 2-aminothiophenol and aldehydes at room temperature

Entry Aldehydes Time (min) Yield (%)

Table 1.1: Aromatic aldehydes and corresponding 2-substituted benzothiazoles

There are numerous ways to converge 2-aminothiophenol into 2-substitutedbenzothiazole Below are some examples of condensation reaction between 2-aminothiophenol with ketones, and Acyl Chloride

In 2010, Racane and colleagues have suggested an efficient synthesis of amidino benzothiazoles by a condensation reaction between 2-aminothiophenol with4-nitrobenzoylchloride, which is available commercially, under reflux conditions in

nitro-acid acetic for 4 hours (Scheme 1.28)

NH2HS

+

S N

R2

Scheme 1.28: Condensation of nitro-substituted 2-aminobenzothiole with

4-nitrobenzoylchlorideDeng et al reported an efficient benzothiazole formation from 2-aminobenzenethiols and aryl ketones, with the presence of molecular oxygen as anoxidant [57] The reaction is metal-free and iodine-free reaction Solvent used in this

reaction is chlorobenzene/DMSO system (Scheme 1.29) In addition, this reaction was

suitable for methyl, methoxy, fluorine, chlorine, bromine and nitro-substituted rawmaterials, which can be successfully transformed intro corresponding substituentbenzothiazoles

NH2HS

+

S

N Ar R

Scheme 1.29: Condensation of 2-aminobenzenethiols and aryl ketones

In conclusion, synthesizing benzothiazole from 2-aminothiophenol has manyadvantages, i.e short reaction time, high yield, wide range of substrate scope, etc.However, this method suffers from limitations, such as atom-, step-, and redoxefficiency Also, the difficulties encountered in the preparation of oxidizable 2-aminothiophenols bearing substituents are considered More steps of preparation ofstarting materials are required

1.2.2.1 Using Thioamide cyclisation:

Among the traditional methods, the Jacobsen cyclisation was one of the mostcommonly used one, which was first reported in 1886 by Jacobson and Frankenbacher[58] The reaction involved using thiobenzanilide with different reagents and catalysts,via intramolecular C-S bond form/ C-H functionalization

In this way, Jacobsen cyclisation reaction of thiobenzanilide was used underbasic conditions Thiobenzanilide (which is prepared from the corresponding amide bysulfurisation), is oxidized in basic medium by potassium ferricyanide to the

corresponding 2-substituted benzothiazole [45] (Scheme 1.30).

H N S

R

S

K3Fe(CN)6NaOH (aq), 90oC

Scheme 1.30: The thioamide cyclisation route to 2-arylbenzothiazole

As mentioned above, there is a variety of other reaction conditions forthiobenzanilide cyclisation under basic/oxidizing conditions have been studied, i.e.sodium hydrine/iodine [59], 2,6-dichloro-3,5-dicyano-1,4-benzoquinone[60, 61],

hypervalent ioding reagents (Dess-Martin periodinane) [62], caesiumcarbonate/CuI/1,10-phenanthroline [63, 64], and hydroxide [65] There was also studyreported using microwave irradiation to facilitate the oxidative cyclisation, usingmanganese triacetate as oxidizing agent [66]

Nevertheless, with some specific thiobenzanilide substitution pattern, theJacobsen cyclisation can lead to mixtures of regioisomeric corresponding 2-arylbenzothiazole products This is one limitation of Jacobsen cyclisation reaction.This issue was illustrated for the cyclisation of the thiobenzanilide derived from 3,4-difluoroaniline, where the cyclisation leaded to a mixture of the 5,6-difluoro- and 6,7-difluoro-2-arylbenzothiazole isomeric products [67] However, we can avoid theregioselectivity issue and access to pure product regioisomers by the presence of an

ortho-bromine atom, that was subject to nucleophilic substitution in the key cyclisation

step, controlling the regioselectivity of cyclisation towards the desire

5,6-difluorobenzothiazole [58, 68] (Scheme 1.31).

H N S

NO2Me F

F

S

N F

F

NO2Me

S

N

NO2Me

F F

H N S

NO2Me F

N F

F

NO2Me

K3Fe(CN)6, NaOH EtOH/H2O

still remarkable disadvantages of these pathways such as the limitation of scaling upexperiment, the employment of reagents or catalysts in large amounts, harsh reactionconditions, etc And the most important drawback is the starting materials of bothaminothiophenol and thioamide are not readily available More steps of preparation ofstarting materials are required Therefore, there should be a demand for novelapproaches in which the synthesis of benzothiazoles would be further improved Theserecent advances in preparation of benzothiazole will be summarized in the nextsubpart.

1.2.3 Reaction between Nitroarenes and Sulfur - Recent approaches

With the aim of overcoming aforementioned drawbacks of traditional methods,

an ongoing search for new methods has been carried out to find atom-, step-, redox-,economically and conveniently operated processes, which could employ readilyavailable materials with greener conditions Moreover, the reaction must provide awide range of substrates scope that are generally incompatible with Lawesson’sreagents Meanwhile, nitrobenzene derivatives have been seen as a potential buildingblock for azoles compounds However, using redox reaction of nitroarene derivatives

to form benzothiazole was still remained unfamiliar with the world

In 2013, Nguyen et al first developed a simplest, straightforward and atomeconomic approach to 2-hetarylbenzothiazole from 2-halonitroarene, methyl hetareneand elemental sulfur under mild conditions [69] This method is believed to resolve allaforementioned drawbacks, also develop greener and sustainable process This method

is attracted the interests by the direct redox nitro-methyl reaction, so that the

carbon-nitrogen bond was formed without added oxidizing or reducing agent (Scheme 1.32).

Based on the same atom- and step-economic principle [70], in this cascade reaction,methyl group in carbon synthon donated up to 6 electrons to a nitro group in nitrogensynthon Therefore, added oxidizing or reducing agent would be unnecessary Sulfurelement is acted as the electron moderator of the reaction Plus, the appearance of a

halogen atom at the o-position of the nitroarenes would promote the nucleophilic

introduction of a sulfur atom It is due to the strong electron-withdrawing effect of the

nitro group that even metallic catalyst is not added, nitroarenes still have the ability toperform the nucleophilic reaction with elemental sulfur The scope of the reaction wasinvestigated with a variety of functional groups For instance, methyl, chloride,methoxy, trifluoromethyl and nitro functionalities are all suitable to this conversion.For methyl hetarene, a variety of substituted groups have been investigated Most ofthe cases resulted in moderate yields, expect of the case of 3-picoline Furtherinvestigation explained that because of the regioselectivity in methyl group at C-4position when 3,4-lutidine was employed.

NO2X

Scheme 1.32: Synthesis of 2-hetarylbenzothiazole from 2-halonitroarene,

methylhetarene and elemental sulfur

In 2014, Nguyen continued previous studies about the role of elemental sulfur

in benzothiazole synthesis redox condensation reaction In this study, he investigateddisproportionation behavior of elemental sulfur without catalyst, thereby filling theelectron gap for the unbalanced electron transfer process Different to previous study,methylhetarene was replaced by benzylamine, which was more basic, so thisfunctional group replacement can occur and even increase the activation of elementalsulfur However, benzylamine had only four electrons transferred from the carbonsynthon, which was not equal to the number of electrons required for the reduction ofnitro synthon So, two more electrons need to be donated from sulfur element in order

to form the 2-arylbenzothiazole [71] (Scheme 1.33) This is the reason of

disproportionation of elemental sulfur

X = F, Cl, Br, I

+ S8 +

R1

S N

as an aromatic amino group were tested and formed the corresponding benzothiazoles

in moderate to good yields In contrast to the previous study, o-fluoronitrobenzene resulted in a low yield (25%) along with a significant quantity of by product N-benzyl- o-nitroaniline ( ≈ 50 %¿ The driving force for this reaction is assumed to be thepropensity of the fluoride group, which acts as a better leaving group instead of being

a part in nucleophilic substitution Additionally, replaced benzylic amine with aliphaticamines, such as octylamine, failed to provide the corresponding benzothiazole Thiscase proved that the necessary of benzyl amine in the succeed of reaction Noteworthy,this method could successfully obtain 2-(3-pyridyl) benzothiazole, which could not besynthesized by previously study approach starting from 3-picoline [59](Scheme 1.34).

In conclusion, the method was appealing at it was successfully applied tosynthesize different benzothiazoles, even those with interesting biological activities,i.e fluorinated benzothiazole (PMX 610) and aminobenzothiazole

S

NO2Cl

To study about the disproportionation of elemental sulfur, the investigation wasstarted with determination of an equimolar combination of the three starting materials.Theoretically, the result of reaction is the desired 2-phenylbenzothiazole, along with

NH4Cl and 2 O equivalents On the investigation for the reducing agent accompaninedwith two oxygen equivalents, PhCH2NHSO3H.N2NCH2Ph and NH4CL appeared as themain by-product, along with the benzothiazole Only traces of N-benzylthiobenzamide(dimerizing sulfuration of benzylamine) and of o-chloroaniline (reduction of the nitrogroup of o-chloronitrobenzene) were observed With the formation of this sulfamate,elemental sulfur is confirmed to be responsible for electronic compensation, as it haddivided into two different oxidation states including S2- in benzothiazole and S6+ insulfamate, which donated four addition electrons for the aforementioned redoxprocess

Comparing to the reaction of methylhetarenes, the use of benzylamine required

an external electron donating source and a redox moderator, which was completelysatisfied by sulfur elements In this reaction, elemental sulfur acted as both oxidizing(converted into benzothiazole) and reducing (oxidized into sulfamate) agent, thusproviding the deficient electrons of the global transformation Based on theobservation and previously reported mechanisms [59, 72], the first step of the reactionwas considered to be the activation of elemental sulfur by benzylamine for thesubstitution of o-halo group Following was the intramolecular redox process,including N-O reductive cleavage and sulfur atom insertion which finally ended withthe disproportionation process of elemental sulfur to form PhCH2NHSO3H.N2NCH2Phand benzothiazole The byproduct N-benzylthiobenzamide can be formed by anindependent reaction between benzylamine and sulfur or between N-benzylbenzadimine and sulfur In conclusion, this reaction has proved the flexibleability to transfer to different oxidation states of elemental sulfur in the sulfur cycle

In 2015, Nguyen et al developed another report about the synthesis of

2-aroylbenzothiaozles The redox condensation reaction between o-halonitrobenzenes,

acetophenones and elemental sulfur occurred [73] (Scheme 1.35) Herein,

handling and available in great structural diversity material Base on the ability tofurnish 6 electrons required by the nitro groups, acetophenone was used as promisingreducing coupling partners, thus avoiding the redox redundant transformation andproviding a very direct approach to 2-aroylbenzothiazoles The scope of this reaction

is quite broad Under the optimized conditions, a variety of substituents on bothreactants were successfully applied, i.e methyl, fluoro, chloro, bromo, methoxy andtrifluoromethyl substituents Applying methyl, methoxy, phenoxyl, acetamido orchloride substituent on acetophenones scaffold were also resulted in satisfactory yields

of corresponding 2-aroylbenzothiazoles Interestingly, when trichloronitrobenzene was employed, the corresponding benzothiazole was still

2,3,4-obtained in good yield, despite of both o- and p-chloro groups are both strongly

activated by the nitro group

S

N

NO2Cl

Scheme 1.35: Synthesis of 2-aroylbenzothiazoles from o-halonitrobenzenes,

acetophenones, and elemental sulfurThe use of an additional base was required due to the result of a removal of onehydrogen chloride molecule In this case, N-methylmorpholine gave the best yieldamong all According to the propose mechanism by Nguyen and co-workers, N-methylmorpholine was accounted for the initiation of the reaction It reacted withsulfur element to generate ammonium polysulfide zwitterion Subsequently, the

zwitterion performed the nucleophilic reaction with o-halonitrobenzenes, before

reacted with acetophenones to form corresponding 2-aroylbenzothiazones In the end,elemental sulfur was regenerated partially, accompanied with the formation ofoxygenated sulfur compounds (“SO”) and N-methylmorphilinium hydrochloride.Moreover, the appearance of N-methylmorphilinium hydrochloride could alsoaccelerate the tautomerization of acetophenones, thus facilitating the reduction ofnitrone intermediate with the ammonium polysulfide zwitterion In conclusion, this

method is appealing because of atom-, step- and re-dox economical requirements wereall satisfied.

In the same year, Singh et al also develop a decarboxylative redox cyclizationstrategy for the synthesis of 2-substituted benzothiazoles This method was anothermodification of Nguyen previous reports, as arylacetic acids was used as carbon

synthon [74] (Scheme 1.36) Carboxylic acids were potential carbon synthon since

they were common, inexpensive, and readily available in great structural diversity Avariety of substituents on both arylacetic acids and o-chloronitroarenes such as fluoro,chloro, bromo, methyl, methoxy, phenyl, hydroxyl and nitro at different positions wereapplied successfully, resulted in the desired products in reasonably good yield.Notably, Ortho-substituted arylacetic acids gave lower yields than para- or meta-substituted reactants, due to steric hindrance Bicyclic acids, i.e 2-naphthylacetic acidand heteroaromatic acids were also suitable to the reaction conditions, with moderateyield of corresponding benzothiazole However, aliphatic acids such as valeric,heptanoic, and 3-(3,4-dimethoxyphenyl) -propanoic acids failed to go through thereaction under present optimized condition The reaction mechanism proposed bySingh was suggested to involve the radical pathway because of the successivedecarboxylation and sulfur extrusion to generate the benzyl radical Subsequently,benzyl radical reacted with NO2 group of the substrate followed by dehydration andeventually underwent cyclization reduction to provide the desired product Inconclusion, this method was an efficient sulfur mediated decarboxylative redoxcyclization approach for the synthesis of 2-substituted benzothiazoles as the reaction ismetal-free, solvent-free and did not use external oxidant

S

N

NO2Cl + S 8 +

R1

HO O