臺灣博碩士論文加值系統

含有雜原子的化合物是大量銷售的市售藥物中最突出的實體。在含雜原子的分子子集中，苯並咪唑，苯並硒唑，吲哚和吡咯被認為是藥物和藥物發現的特權核心。特別地，這些與其他生物學重要雜環稠合/連接的雜環部分被認為是藥物和藥物發現研究中的著名支架。因此，必須關注融合和連接的雜環分子的合成。本論文涉及生物學上有趣的稠合和連接的雜環的設計和合成。論文分為五章，以方便和更好地理解。
第一章報導催化劑控制的化學反應環化策略，以便從易得的鄰吲哚苯胺與重氮酯作為偶聯配偶體的反應中獲得二氮雜[1,7-a]吲哚和吲哚並[1,2-a]喹喔啉。在Rh（III）催化劑下，反應通過游離胺輔助的C2-H活化進行，然後酰胺化，以高選擇性方式得到二氮雜[1,7-a]吲哚。在Ru（II）催化劑的作用下，反應包括形成Ru-卡賓配合物，然後通過金屬烯反應，β-氫化物消除進行-NH2基團插入和級聯環化，得到吲哚並[1,2-a]喹喔啉。主導產品。這種新開發的催化劑控制策略廣泛適用於一系列indolo-fused diazepine / quinoxaline以及吡咯並稠合的二氮雜卓/喹喔啉支架的構建，產率極高。我們相信這種方法可以開闢催化和有機合成領域的新途徑。
第二章通過Ru（II）催化的[4 + 2] 2-芳基苯並咪唑和苯乙烯的環化反應，簡便合成了苯並咪唑並[2,1-a]異喹啉。暫定的機理研究意味著當前的反應涉及通過2-芳基苯並咪唑的鄰位C-H活化然後C-N還原消除形成順序的C-C / C-N鍵。這種新開發的策略可廣泛應用並且耐受各種2-芳基苯並咪唑和乙烯基衍生物，並且允許具有吸引力的載體以良好的產率直接構建多種C6-取代的苯並咪唑並喹啉支架。
在第三章中，描述了新的角型異香豆素硒的合成，其涉及2-氨基苯並硒唑的構建，區域選擇性C2 N-烷基化和炔烴插入。通過3-氨基-4-氟苯甲酸甲酯和異硒酸酯的反應，實現了快速且無金屬的2-氨基苯並鍺的合成。 2-氨基苯並噻唑的進一步N-烷基化導致形成兩種對炔插入具有不同反應性的區域異構體。通過釕（II）催化的氧化環化實現了苯並[1,3-d]硒唑骨架上α-吡喃酮環的區域選擇性構建。很明顯，硒唑氮在觀察到的選擇性中起重要作用。
第四章描述了2-氨基苯並咪唑與異硫氰酸酯和二鹵代甲烷的選擇性合成苯並咪唑硫雜環丁烷和苯並咪唑硫噻嗪的發散反應。在氫化鈉存在下，2-氨基苯並咪唑的一鍋反應得到苯並咪唑硫雜環丁烷，而三乙胺通過順序逐步方式促進苯並咪唑並二噻嗪的形成。反應順序包括硫脲的初始形成，隨後是區域選擇性親核加成和用二鹵代親電試劑進行分子內閉環。觀察到的該反應的區域選擇性取決於鹼的性質和反應順序。
最後一章討論了在微波輻射下可溶性聚合物載體上新型苯並咪唑連接的烷氧基吡咯並[1,2-a]喹喔啉酮的有效級聯合成。通過控制微波能量，已經開發了兩種專用協議用於部分和全部還原環化。從相同底物開始，通過部分還原環化（60℃，7分鐘）得到鄰硝基吡咯羧酸鹽，N-羥基吡咯喹喔啉酮，並通過完全還原環化（85℃，12分鐘）完成吡咯並喹喔啉酮的合成。 。該方法代表使用Pd / C和甲酸銨作為還原劑首次合成N-羥基吡咯並喹喔啉酮。進一步使用各種烷基溴，將獲得的吡咯並喹喔啉酮轉化為相應的O-和N-烷基化類似物，以提供多種新的分子實體。

Heteroatom containing compounds are most prominent entities in large number of selling marketed drugs. In the subset of heteroatom-containing molecules, the benzimidazole, benzoselenazole, indole, and pyrrole were recognized as the privileged core in the medicinal and drug discovery. Especially, these heterocyclic moieties fused/linked with other biological important heterocycles are considered to be prestigious scaffolds in the medicinal and drugs discovery research. Hence, it is imperative to focus on the synthesis of fused and linked heterocyclic molecules. The present thesis deals with the design and synthesis of biologically interesting fused and linked heterocycles. The thesis is divided into five chapters for the sake of convenience and better understanding.
The first chapter reports a catalyst-controlled chemodivergent annulation strategy to access diazepino [1,7-a]indole and indolo [1,2-a]quinoxaline from reaction of readily available o-indolo anilines with diazo esters as a coupling partner. Under the Rh(III) catalyst, reaction proceeded through the free amine assisted C2-H activation followed by amidation leading to the diazepino[1,7-a]indole in highly selective manner. While with Ru(II) catalyst, reaction involves formation of Ru-carbene complex followed by –NH2 group insertion and cascade cyclization via metallo-ene type reaction, β-Hydride elimination to furnish the indolo[1,2-a]quinoxaline as the predominant product. This newly developed catalyst controlled strategy is widely applicable to the construction of a series of indolo-fused diazepine/quinoxaline as well as pyrrolo-fused diazepine/quinoxaline scaffolds in excellent yields. We believe that this method may open new avenues in catalysis and organic synthesis field.
The second chapter deals with a facile and straightforward synthesis of benzoimidazo[2,1-a]isoquinolines through Ru(II)-catalyzed [4+2] annulation reaction of 2-aryl benzimidazole and styrene. Tentative mechanistic studies imply the current reaction involves sequential C-C/C-N bond formation through the ortho C-H activation of 2-aryl benzimidazole followed by C-N reductive elimination. This newly developed strategy is widely applicable and tolerates various 2-arylbenzimidazole and vinyl derivatives, and allows the attractive vehicle for direct construction of diverse C6-substituated benzoimidazoisoquinoline scaffold in good yields.
In the third chapter, synthesis of new angular isocoumarinoselenazoles is described which involves the construction of 2-amino benzoselenazoles, regioselective C2 N-alkylation and alkyne insertion. An expeditious and metal-free synthesis of 2-aminobenzoselenazoles by the reaction of methyl 3-amino-4-fluorobenzoate and isoselenocyanates was achieved. Further N-alkylation of 2-aminobenzoselenazoles resulted in the formation of two regioisomers with differential reactivity towards alkyne insertion. The regioselective construction of α-pyrone ring on the benzo[1,3-d]selenazole skeleton was achieved via ruthenium (II)-catalyzed oxidative annulation. It is clear that the selenazole nitrogen plays an important role in the observed selectivity.
The fourth chapter describes a divergent reaction of 2-aminobenzimidazole with isothiocyanates and dihalomethanes for the selective synthesis of benzoimidazothiazetidine and benzoimidazothiadiazine. A one-pot reaction of 2-aminobenzimidazole in the presence of sodium hydride delivers benzoimidazothiazetidine, whereas triethylamine promotes the formation of benzoimidazothiadiazine via a sequential stepwise fashion. The reaction sequence involves the initial formation of thiourea followed by regioselective nucleophilic addition and intramolecular ring-closing with dihalo electrophiles. The observed regioselectivity of this reaction is governed by the nature of bases and the reaction sequence.
The final chapter deals with an efficient cascade synthesis of novel benzimidazole linked alkyloxypyrrolo[1,2-a] quinoxalinones on soluble polymer support under microwave irradiation. Two exclusive protocols have been developed for the partial and full reductive cyclization by controlling the microwave energy. Commencing from the same substrate, ortho-nitro pyrrole carboxylates, N-hydroxy pyrroloquinoxalinones were obtained by partial reductive cyclization (60 °C, 7 min), and the synthesis of pyrroloquinoxalinones was accomplished by full reductive cyclization (85 °C, 12 min). This method represents the first synthesis of N-hydroxy pyrroloquinoxalinones using Pd/C and ammonium formate as reducing agents. Further employing a variety of alkyl bromides, the obtained pyrroloquinoxalinones were transformed to the corresponding O- and N-alkylated analogues to deliver the diverse novel molecular entities.

TABLE OF CONTENTS

Contents Page

Acknowledgement I
Abstract III
List of Schemes VII
List of Tables XI
List of Figures XIII
Acronyms XVI
List of Publications XVIII
Chapter 1: Catalyst-Controlled Chemodivergent Annulation to Indolo/Pyrrolo- Fused Diazepine and Quinoxaline

Introduction 2
Present Strategy 10
Result and discussion 10
Conclusion 27
Experimental Section 28
Characterization Data 32
X-ray Data 49
References 67
Spectral Data 70
Chapter 2: Direct Access To Dihydrobenzoimidazo[2,1-a]isoquinolines through Ruthenium-Catalyzed Formal [4+2] Annulation
Introduction 167
Present Strategy 172
Results and Discussion 173
Conclusion 188
Experimental Section 188
Characterization Data 190
X-ray Data 204
References 223
Spectral Data 226
Chapter 3: Regioselective Synthesis of Angular Isocoumarinoselenazoles: A Benzoselenazole-directed, Site Specific, Ruthenium-catalyzed C(sp2)-H Activation
Introduction 300
Proposed Strategy 301
Results and Discussion 305
Conclusion 328
Experimental Section 329
Characterization Data 332
X-ray Data 357
References 420
Spectral Data 423
Chapter 4: Three Component Divergent Reactions: Base Controlled Amphiphilic Synthesis of Benzimidazole Linked Thiazetidines and Fused Thiadiazines
Introduction 613
Present work 618
Results and discussion 619
Conclusions 629
Experimental Section 629
Characterization Data 631
X-ray Data 643
References 671
Spectral Data 673
Chapter 5: Microwave Controlled Reductive Cyclization: A Selective Synthesis of Novel Benzimidazole-alkyloxypyrrolo [1,2-a]quinoxalinones
Introduction 741
Present Strategy 746
Results and Discussion 746
Conclusion 752
Experimental Section 753
Characterization Data 756
X-ray Data 764
References 771
Spectral Data 774

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Chapter-2
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