VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY HUYNH VAN TIEN TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS Ph. THESIS HO CHI MINH CITY - 2023 VIETNAM NATIONAL UNIVERSITY HO CHI MINH CITY HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY HUYNH VAN TIEN TRANSITION METAL-FREE SYNTHESIS AND FUNCTIONALIZATION OF 5- AND 6-MEMBERED HETEROCYCLIC COMPOUNDS Major: Chemical engineering Code: 9520301 Independent examiner: Assoc. Pham Nguyen Kim Tuyen Independent examiner: Assoc. Tran Ngoc Quyen Examiner: Assoc.
Hoang Thi Kim Dung Examiner: Assoc. Nguyen Phuong Tung Examiner: Assoc. Le Thi Hong Nhan Supervisor: Prof. Phan Thanh Son Nam DECLARATION OF ORIGINALITY I understand the University’s policy.
I hereby declare that this thesis is my original research work and has not been submitted or considered for publication elsewhere. I have not sought or used the services of any professional agencies to produce this work. All sources used in this thesis are clearly and fully referenced in the text and references, following the referencing title indicated by the Department. Dissertation author Huynh Van Tien i ABSTRACT This thesis gave new methods to synthesize 4-phenylquinazolines, 2-arylquinoxalines, N-arylindoles, and thiocromenones.
The formation of 4-phenylquinazolines was performed through the oxidation protocol, in which the organic peroxide was used as an oxidant that could readily generate 4-phenylquinazolines from 2-aminobenzophenones without any additional catalyst. The reactions between o-phenylenediamines and phenylglyoxal derivatives in ethyl acetate to form 2-phenylquinoxalines gave excellent yields at room temperature without using the catalyst. N-arylindoles were easily obtained from indoles and nitrobenzene in the absence of transition metals, at room temperature, under simple base conditions. And thiocomenones were generated via a two-step one-pot protocol, in which the condensation of 2’-chloroacetophenones and aryl aldehydes formed 2’-chlorochalcone intermediates, which were then cyclized to thiocromenones by adding elemental sulfur.
The utilities of this thesis were (1) transition metal-free catalyst, (2) inexpensive and abundant additivities source, (3) different syntheses of heterocyclic compounds from commercially available starting materials. This thesis has contributed new methods in organic synthesis and could be applied to chemical and pharmaceutical industries. ii TÓM TẮT Luận án đưa ra các phương pháp mới để tổng hợp các dẫn xuất của 4-phenylquinazoline, 2-arylquinoxaline, N-arylindole và thiocromenone. Các dẫn xuất của 4-phenylquinazoline được tổng hợp thông qua quá trình oxy hóa, trong đó peroxide hữu cơ đóng vai trò là chất oxy hóa để dễ dàng chuyển hóa các dẫn xuất 2-aminobenzophenone thành các sản phẩm mong muốn mà không cần sử dụng xúc tác kim loại nào.
Trong luận án này, các dẫn xuất của 2-phenylquinoxaline được tổng hợp thông qua phản ứng ngưng tụ giữa các dẫn xuất của o-phenylenediamine và các dẫn xuất của phenylglyoxal trong dung môi ethyl acetate ở nhiệt độ phòng trong thời gian ngắn và đạt hiệu suất rất cao mà không cần thêm điều kiện nào khác. Luận án cũng đã đưa ra quy trình tổng hợp các dẫn xuất của N-arylindole từ các dẫn xuất của indole và nitrobenzene trong điều kiện nhiệt độ phòng, sử dụng bazơ đơn giản là NaOH và không sử dụng xúc tác. Đặc biệt, lần đầu tiên một quy trình hai bước, sử dụng trực tiếp lưu huỳnh nguyên tố để tổng hợp các dẫn xuất của thiocromenone đã được luận án đưa ra, trong đó bước đầu tiên là phản ứng ngưng tụ giữa các dẫn xuất của các dẫn xuất của 2’-chloroacetophenone với các dẫn xuất của benzaldehyde để hình thành sản phẩm trung gian là các dẫn xuất của 2’-chlorochalcone, các dẫn xuất này sau đó tiếp tục thực hiện quá trình oxy hóa đóng vòng thành thiocromenone khi thực hiện bước hai là thêm lưu huỳnh nguyên tố vào. Điểm nổi bật của luận án này là (1) không sử dụng xúc tác kim loại chuyển tiếp, (2) sử dụng nguồn xúc tác, phụ gia phong phú, rẻ tiền, (3) tổng hợp nhiều hợp chất dị vòng khác nhau từ các nguyên liệu ban đầu phổ biến trên thị trường.
Luận án đã đóng góp các phương pháp mới trong tổng hợp hữu cơ và có triển vọng ứng dụng trong lĩnh vực hóa học, dược phẩm. iii ACKNOWLEDGMENT I would like to express my gratitude to the lecturers of Ho Chi Minh City University of Technology, especially Prof. Phan Thanh Son Nam and Dr. Nguyen Thanh Tung who guided me throughout the time of studying and writing my doctoral thesis.
I would like to thank all members of The Materials Structure Research Laboratory of Ho Chi Minh City University of Technology, who have supported me while I do the thesis. Thanks to my lovely students of Department of Chemical Engineering of Ho Chi Minh City University of Technology and students from the Faculty of Chemical Technology of Ho Chi Minh City University of Food Industry for their full co-operation in my research. Thanks to the Board of Directors and my partners at Ho Chi Minh City University of Food Industry who have facilitated me during I complete my graduate studies. Thanks so much to my family and friends who have shared and encouraged me to overcome all the disadvantages to complete my doctoral thesis.
In the wealth of knowledge, I certainly will not completely satisfy all the readers. I would like to receive the suggestions of readers to help me improve my knowledge. Sincerely, Huynh Van Tien iv TABLE OF CONTENTS TABLE OF CONTENTS. v LIST OF TABLES.
vii LIST OF SCHEMES. viii LIST OF FIGURES. xi LIST OF ABBREVIATIONS. 1 CHAPTER 1 LITERATURE OVERVIEWS .1 Introduction of quinazoline compounds .1 Biological activity of the quinazoline compounds.
Synthetic approaches to quinazoline derivatives .2 Introduction of quinoxaline compounds .1 Biological activity of quinoxaline compounds .2 Synthetic approaches to quinoxaline derivatives .3 Introduction of N-arylindole compounds .1 Biological activity of the N-arylindole compounds .2 Synthetic approaches to N-arylindole derivatives .4 Introduction of thiocromenone compounds .1 Biological activities of thiocromenone compounds .2 Synthetic approaches to thiocromenone derivatives. Aims of this work .1 Materials and Instruments .1 General procedure for the synthesis of 4-phenylquinazoline .2 General procedure for the synthesis of 2-phenylquinoxaline .3 General procedure for the synthesis of 1-(4-nitrophenyl)-1H-indole.4 General procedure for the synthesis of 2-phenyl-4H-thiochromen-4-one. 40 CHAPTER 3 RESULTS AND DISCUSSIONS .1 Synthesis of quinazoline derivatives via peroxide-mediated direct oxidative amination of C(sp3)-H bonds .2 Condensation of 1,2-phenylenediamines and dicarbonyl compounds in ethyl acetate toward quinoxalines .3 Oxidative nucleophilic functionalization of nitrobenzene with N-H bond to synthesize 1-(4-nitrophenyl)-1H-indoles .4 Elemental sulfur for the synthesis of 2-arylthiochromenones. 88 LIST OF PUBLICATIONS.
106 vi LIST OF TABLES Table 2.1 List of chemicals and their manufacturers .1 Effect of oxidizing agents on the synthesis of 4-phenylquinazoline .2 Effect of oxidant amount on the synthesis of 4-phenylquinazoline .3 Effect of nitrogen sources on the synthesis of 4-phenylquinazoline .4 Effect of nitrogen source amount on the synthesis of 4-phenylquinazoline .5 Effect of temperature on the synthesis of 4-phenylquinazoline .6 Synthesis of 4-phenylquinazolines via the three-component coupling reaction utilizing different sp3 carbon sourcesa.7 Screening reaction conditionsa of the condensation of 1,2-phenylenediamine and phenylglyoxal toward 2-phenylquinoxaline .8 Effect of temperature on the synthesis of 1-(4-nitrophenyl)-1H-indole .9 Effect of reactant mole proportion on the synthesis of 1-(4-nitrophenyl)-1H- indole .10 Effect of bases on the synthesis of 1-(4-nitrophenyl)-1H-indole .11 Effect of base amount on the synthesis of 1-(4-nitrophenyl)-1H-indole .12 Effect of solvents on the synthesis of 1-(4-nitrophenyl)-1H-indole .13 Effect of concentration of starting materials on the synthesis of 1-(4- nitrophenyl)-1H-indole .14 Effect of reaction environments on the synthesis of 1-(4-nitrophenyl)-1H- indole .15 Effect of time on the synthesis of 1-(4-nitrophenyl)-1H-indole .16 Expanding the scope of reaction of indole and nitrobenzene.17 Effect of solvents on the synthesis of 2-arylthiocromenone .18 Effect of water on the synthesis of 2-arylthiocromenone .19 Effect of amount of DMF on the synthesis of 2-arylthiocromenone .20 Effect of reaction time on the synthesis of 2-arylthiocromenone. 83 vii LIST OF SCHEMES Scheme 1.1 Synthesis of 2-phenylquinazolines via a tandem reaction following sp3 C-H functionalization .2 Synthesis of 2-arylquinazolines via benzylic sp3 C–H bond amination catalyzed by molecular iodine .3 Synthesis of quinazoline derivatives catalyzed by Ni-catalyst .4 Synthesis of quinazoline derivatives via sequential Ullmann-type coupling and aerobic oxidation .5 Synthesis of quinazoline derivatives via I2/KI-promoted oxidative C(sp3)- C(sp2) bond formation .6 Synthesis of 4-phenylquinazoline via direct sp3 C-H bond functionalization .7 The common approaches for the synthesis of quinoxaline derivatives .8 Synthesis of quinoxaline derivatives by using PEG solvent .9 Synthesis of quinoxaline derivatives by using microwave .10 Synthesis of quinoxalines from α-haloketones by using K10 clay catalyst 12 Scheme 1.11 Synthesis of quinoxaline derivatives from α-hydroxyketones .12 Synthesis of quinoxaline derivatives from epoxides .13 Synthesis of quinoxaline derivatives from epoxy ketones .14 Synthesis of quinoxaline derivatives from alkenes .15 Synthesis of quinoxaline derivatives from nitroolefins .16 Nucleophilic substitution of p-Chloronitrobenzene.17 A two-step synthesis of 2-nitrodiarylamines .18 Formation of 2-nitrodiarylamines by the reaction of anilines and nitroarenes .19 Direct methoxylation of nitroarenes .20 Oxidative nucleophilic alkoxylation of nitrobenzenes .21 Palladium-catalyzed coupling indoles and halogen-substituted arenes .22 Copper-catalyzed coupling indoles and halogen-substituted arenes .23 N-Arylation of indoles and N-(naphthalene-1-yl)picolinamide .24 N-arylation of indole using a benzyne intermediate .25 N-arylation of indoles by SNAr of aryl fluorides .26 A pathway to thioflavone scaffold via nucleophilic attack and cyclization by Truce and Goldhamer .27 Approach to thiochromen-4-ones by condensation of thiophenol derivatives with β–ketoesters .28 Synthesis of 2-substituted thiochromen-4-ones using Wittig reagent .29 Lee’s method for the synthesis of 2-aryl-thiochromen-4-ones .30 ICl-induced cyclization of alkynones furnishing 3-iodo(thio)chromen-4-ones .31 The approach to 2,3-disubstituted thiochromen-4-ones from alkynes and thioisatins .32 Dehydrogenation of thiochroman-4-ones .33 Synthesis of thiochromanones by direct condensation of 2'- mercaptoacetophenones with benzaldehyde.34 Synthesis of 2-arylthiochroman-4-ones through 2’halochalcones .35 Xanthate as the sulfur precursor for the preparation of 2-substituted thiochromen-4-ones .36 Using NaSH for the synthesis of 2-substituted thiochromen-4-ones .37 Pd-catalyzed approach to 2-substituted thiochromen-4-ones uses conjugate addition tandem reaction in CO atmosphere .38 Metal-free synthesis of 4-phenylquinazoline .39 Synthesis of quinoxaline from o-phenylenediamine and phenylglyoxal in ethyl acetate .40 N-Arylation of indole and nitrobenzene .41 Using elemental sulfur for the synthesis of 1-thioflavone .1 Screening of reaction conditions of synthesis of 4-phenylquinazoline via peroxide-mediated direct oxidative amination of C(sp3)-H bonds .2 Control experiments for the synthesis of 4-phenylquinazoline via peroxide- mediated direct oxidative amination of C(sp3)-H bonds .3 Proposed reaction mechanism for the synthesis of 4-phenylquinazoline via peroxide-mediated direct oxidative amination of C(sp3)-H bonds .4 Proposed reaction mechanism for the synthesis of 2-phenylquinoxalines via condensation of 1,2-phenylenediamines and dicarbonyl compounds .5 Synthesis of 2‑phenylquinoxalinesa .6 Investigating the effect of diverse parameters on the synthesis of 1-(4- nitrophenyl)-1H-indole .7 Possible mechanism for oxidative amination of nitrobenzene with N- heterocycles .8 Synthesis N-arylindole derivatives .9 Investigating the effect of diverse parameters on the synthesis of 2- arylthiocromenone .10 Plausible mechanism for the synthesis of 2-arylthiocromenone .11 Synthesis of thiocromenone derivatives .12 Synthesis of 2-(hetero)aryl thiochromenones from trans-chalcones. 86 x LIST OF FIGURES Figure 1.1 Pharmacological significance of quinazolines .2 Several commercially quinoxaline derivatives.3 N-arylindoles and its applications .4 Structures of flavone, 1-thioflavone, and its oxidized derivatives .1 Experimental procedure diagram for the synthesis of 4-phenylquinazoline .2 Experimental procedure diagram for the synthesis of 2-phenylquinoxaline .3 Experimental procedure diagram for the synthesis of 1-(4-nitrophenyl)-1H- indole .4 Experimental procedure diagram for the synthesis of 2-phenyl-4H- thiochromen-4-one. 41 xi LIST OF ABBREVIATIONS DABCO 1,4-diazabicyclo[2.2]octane DBU 1,8-Diazabicyclo[5.0]undec-7-ene DCB 1,2-dichlorobenzene DCE 1,2-dichloroethane DEG Diethylene glycol DMA N,N-dimethylaniline DMAc N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide Eq.
Equivalent i Pr Isopropyl GC Gas Chromatography GC-MS Gas Chromatography-Mass Spectrometry HRMS High-resolution mass spectrometry NMP N-methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PPh3 Triphenylphosphine rt Room temperature TBAI Tetrabutylammonium iodide TBHP Tert-butyl hydroperoxide TMEDA N,N,N',N'-tetramethylethylenediamine xii INTRODUCTION Heterocyclic compounds were important compounds that exhibit an extensive range of physical, chemical, and biological properties [1]. Heterocyclic compounds had been presented in numerous pharmacological areas, such as anti-cancer, antibiotics, anti- inflammatory, anti-inflammatory and depression, anti-malarial, anti-HIV, antibacterial, antifungal, antiviral, antidiabetic, herbicides, fungicides, and insecticides.