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.

ACKNOWLEDGEMENT This thesis marks the final stage of my endeavor in conquering the Bachelor degree 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 my thesis, I would like to extend my deep gratitude to people who devoted themselves to a certain 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 passion and wide knowledge and provided me vital facilities to accomplish my thesis I would also like to express my gratitude to my supervisor, Dr Nguyen Thanh Tung, for giving me a lot of crucial advices and important feedbacks to enhance my B.Eng thesis I deeply thank to Mr Tran Minh Khoa, M Sc To Anh Tuong for teaching me a lot 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 Hang and my colleagues in the laboratory for helping me complete this thesis Finally, I would like to express my sincere gratitude to my family Their unconditional love and encouragement have always been with me in every achievement I get in my life Ho Chi Minh City, July 2020 Do Quoc Duy INTRODUCTION Recently, the organic compounds containing sulfur elements have caught some attention from scientist all over the world due to their important biological and chemical properties Benzothiazole appeared first time in 1860 as a class of organosulfur has become popular since then Its heterocycle skeleton bearing a 5membered ring thiazole has been observed by scientist to be an ideal source of core scaffolds and capping fragments for the design and synthesis of target molecules on a reasonable time scale The investigation of these molecules enables the medicinal chemist to rapidly discover biologically active compound in many fields of therapeutic Moreover, nitrogen- and sulfur- containing heterocycles also plays an important role in many industrial fields related to special and fine chemistry These applications ignite an interest in developing many methods for synthesizing compounds 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 its useful in many fields of life, benzothiazole still seems not to receive enough attention that it deserves There are not so many methods developed for synthesizing these helpful compounds Two traditional methods to synthesis benzothiazole from aminothiophenols and thioamides had many advantages, however a lot of drawbacks still exists Most of the drawbacks were related to atom-, step- and redox efficiency of the reaction Thus, to develop a new, simple technique for preparing and enhancing the variety of application from 2-pyridylbenzothiazole, the thesis “Functionalization of primary C-H bonds in methylazaarenes with 3-substituted nitrobenzenes for the synthesis of 2-pyridylbenzothiazoles” was carried out In this work, the optimized condition of this reaction and the scope of 2-pyridylbenzothiazoles derivatives were investigated ABSTRACT Synthesis of benzothiazoles often requires use of pre-functionalized and/or high molecular weight starting materials, thus raising concerns from the viewpoints of atom efficiencies and practicability Herein, we report a method for preparation of benzothiazoles 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 the scope and limitation of the reaction, including compatibility of substituents on both nitroarenes compound and methylazaarenes Our method would offer prominent benefits compared to conventional method since (1) stable, abundant 3-substituted nitroarenes 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 not involve the presence of any metals or solvents CONTENTS LIST OF SCHEMES Different factors that influence the synthesis from N,N-dimethyl-3-nitroaniline, 2picoline 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 LIST OF FIGURES LIST OF ABBREVIATIONS Ar Aromatics DABCO 1,4-Diazabicyclo[2.2.2]octane DME Dimethoxyethane DMF Dimethylformamide DMSO Dimethylsulfoxide DPE Diphenyl Ether FID Flame ionization detector GC Gas chromatography GC-MS Gas chromatography coupled with mass spectrometry LR Lawesson’s Reagent MBTU Methabenthiazuron MW Microwave NMR Nuclear magnetic resonance NMP N-Methyl-2-pyrrolidone TLC Thin layer chromatography TBAI Tetrabutylammonium iodide Literature review 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 fifth most common on Earth It was first discovered by Ancient Greeks and called sulfur theion, a word that persists in several sulfur-containing compounds Many of which begin with the prefix “thio-“, including the class of compounds called thiazol Sulfur can be found in all over the world Especially in native and volcanic deposits, where it is founded with abundant reserve Though sometimes found in native 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, which was the only commercialized industrial method of recovering elemental sulfur until the late 20th century Moreover, sulfur also appears as an undesirable compound for any processes related to fossil fuel due to hydrogen sulfide, which is produced during crude processing Sour crude oils which possess a high percentage of hydrogen sulfide are often required extra expenses for treating refinery [2] Today, sulfur obtained and recovered from refining industry accounts for 98% of world elemental sulfur production In history, sulfur has been used in production of black gunpowder, vulcanization of rubber, and other synthesis of sulfur-containing compounds Many years have passed, and we have come to better understand about this compound, also discover new properties of elemental sulfur, which can be efficient in application of organic synthesis 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 is cyclo-S8 The S8 molecule is the best well-known form, also being most interested in the field of research The pure sulfur is non-polar, so it is insoluble in water but dissolves well in variety of organic solvents When dissolved in polar solvents such as Literature review methanol or acetonitrile, even at room temperature, S is partially transformed to S6 and S7 and attains an equilibrium in which about 1% of the sulfur is present as the smaller rings [3] When we heat the elemental sulfur, an S-S bond homolytic scission phenomenon occurs, which results in sulfur being melted into an amber yellow, mobile liquid Eventually, this occurs at 120oC Moreover, 95% of sulfur in liquid sulfur is in the S8 form As such, chemical reactions occur from over 120 oC 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 those are 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 of benzaldehydes 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 a variety of Imidazo [1,5-] pyridines in high yields (Scheme 1.1) Scheme 1.1: Oxidative condensation-cyclization of aryl-2-pyridylmethylamines and aldehydes using elemental sulfur as an oxidant Loskutov reported that at room temperature, anthrone and sulfur reacted smoothly, with the presence of nitrogen nucleophiles such as aniline and hydrazine derivatives, which results in 10-iminoanthraquinones and anthraquinones [5] (Scheme 1.2) Literature review 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) 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] (Scheme 1.4) 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 suggested with the reduction of the nitro group of the starting butyrophenone by sulfur into hydrazone via aci-nitro tautomer (Scheme 1.5) Literature review Scheme 1.5: Proposed mechanism for 2,4-diarylpyrroles synthesis The next steps could be transamination starting with ammonia (in the ammonium acetate 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 NaHCO 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 Scheme 1.7: Using sulfur to reduce nitroarenes to the corresponding anilines 1.2.2.3 Sulfur as catalyst Sulfur in stoichiometric amounts was found to catalyze the reaction between an aromatic nitrile ArCN and ethanolamine to provide the corresponding dihydrooxazoles in good yield [9] (Scheme 1.8) Scheme 1.8: Synthesis of dihydrooxazole using sulfur as a catalyst 10 Appendices APPENDIX A: CALIBRATION CURVE Calibration curve was established by using GC analytical samples containing product (N-dimethyl-2-(pyridine-2-yl)benzo[d]thiazol-5-amine) and internal standard (diphenyl ether) with the respective ratio (Product/DPE) in turn: 1:1; 3:4 (0.75); 1:2 (0.50); 1:4 (0.25); 1:20 (0.05) The ratios of the peak area of the product (P) to the peak area of the internal standard (IS) was calculated as follows: Where Sproduct and Sinternal standard are respectively the peak areas of N-dimethyl-2(pyridine-2-yl)benzo[d]thiazol-5-amine and diphenyl ether measured on the GC chromatogram The experimental data to prepare the calibration curve is shown in the table below Table AA.1: Peak area and mol number of product and internal standard Peak area ratio Molar ratio P IS P/IS P IS P/IS 9068.2 347705.4 0.026080 15.3 84.7 0.045481 54373.8 289563.4 0.187779 85.6 85.6 0.251782 112468.3 271246.7 0.414635 170.2 86.6 0.494842 181753.9 258116.5 0.704155 255.9 84 0.767036 263981.1 278193.4 0.948912 342.4 87.6 0.984135 The calibration curve for GC analysis of the product is shown in Figure Figure AA.1: Calibration curve for GC analysis of the product GC yield of the reaction was calculated as follows: Appendices Where: nProduct (mol): mole of the product obtained; noProduct (mol): calculated mole of the product when reaction yield equals 100%; ninternal standard (mol): mole of diphenyl ether in the sample; SProduct: Peak area of product was displayed on GC (desired product); SInternal Standard: Peak area of diphenyl ether Appendices APPENDIX B: GC RESULTS Figure AB.1: GC result of benzothiazoles 3aa Figure AB.2: GC result of benzothiazoles 3ab Appendices Figure AB.3: GC result of benzothiazoles 3ac Figure AB.4: GC result of benzothiazoles 3ad Appendices Figure AB.5: GC result of benzothiazoles 3ae Figure AB.6: GC result of benzothiazoles 3af Appendices APPENDIX C: CHARACTERIZATION DATA N,N-dimethyl-2-(pyridine-2-yl)benzo[d]thiazol-5-amine (3aa) Figure AC.1: 1H NMR spectrum of benzothiazole 3aa Appendices Figure AC.2: 13C NMR spectrum of benzothiazole 3aa N,N-Dimethyl-2-(3-methylpyridin-2-yl)benzo[d]thiazol-5-amine (3ab) Figure AC.3: 1H NMR spectrum of benzothiazole 3ab Appendices Figure AC.4: 13C NMR spectrum of benzothiazole 3ab Appendices N,N-Dimethyl-2-(6-methylpyridin-2-yl)benzo[d]thiazol-5-amine (3ac) Figure AC.5: 1H NMR spectrum of benzothiazole 3ac Appendices Figure AC.6: 13C NMR spectrum of benzothiazole 3ac N,N-Dimethyl-2-(3-methylpyridin-4-yl)benzo[d]thiazol-5-amine (3ad) Appendices Figure AC.7: 1H NMR spectrum of benzothiazole 3ad Figure AC.8: 13C NMR spectrum of benzothiazole 3ad N,N-Dimethyl-2-(quinolin-2-yl)benzo[d]thiazol-5-amine (3ae) Appendices Figure AC.9: 1H NMR spectrum of benzothiazole 3ae Figure AC.10: 13C NMR spectrum of benzothiazole 3ae Appendices 2-(6-Aminopyridin-2-yl)-N,N-dimethylbenzo[d]thiazol-5-amine (3af) Figure AC.7: 1H NMR spectrum of benzothiazole 3af Appendices Figure AC.8: 13C NMR spectrum of benzothiazole 3af 5-(4-Methylpiperazin-1-yl)-2-(quinolin-2-yl)benzo[d]thiazole (3be) Figure AC.9: 1H NMR spectrum of benzothiazole 3be Appendices Figure AC.10: 13C NMR spectrum of benzothiazole 3be ... 2-pyridylbenzothiazole, the thesis ? ?Functionalization of primary C-H bonds in methylazaarenes with 3-substituted nitrobenzenes for the synthesis of 2-pyridylbenzothiazoles? ?? was carried out In this work, the optimized... Diphenyl ether (DPE) 2,3-Lutidine (2,3-dimethylpyridine) 2,6-Lutidine (2,6-dimethylpyridine) 3,4-Lutidine (3,4-dimethylpyridine) Quinaldine (2-Methylquinoline) 2-Amino-6-picoline 6-nitroquinoline 1-Methyl-4-(3-nitrophenyl)... to form benzothiazole Initially, the experiment was conducted successfully with DABCO acted as bases Therefore, I continued investigated the amount of DABCO for proceeding the reaction with the