DESINGN AND SYNTHESIS OF NEW STRATEGIES FOR FUSED & SPIRO O, N-HETEROCYCLIC MOIETIES THROUGH MCRs

Abstract

접합된 또는 스파이로 N,O-헤테로고리 화합물들을 MCR 반응으로 만드는 새로운 합성법의 설계 및 합성 연구"라는 제목의 논문은 8개의 장으로 구성되어 있으며, 본 논문은 산소 및 질소를 포함하는 fused-spiro bicyclic framework의 합성을 위한 새로운 다성분 일단계 반응의 전략을 다룹니다. 일련의 O-접합된 헤테로사이클릭 스캐폴드는 Paal-Knorr 분자내 고리화 반응과 Knoevenagel, Michael 첨가반응을 통하여 위치 화학 및 이종 선택적 반응을 이용하여 우수한 수율로 합 성되었다. 또한, 생물학적으로 중요한 분자 코어의 다양한 배열에 쉽게 액세스할 수 있는 여러 흥미로운 새로운 합성방법론이 개발되었다. 이 방법론적 변형은 다양한 기능성에 대하여 이용할 수 있으므로 광범위한 기질 범위에 대하여 사용할 수 있다. 1장 디히드로푸로푸란과 기능화된 푸란의 캐스케이드 합성을 위한 일당계 링-클로저 및 링-오픈 시퀀스를 다룬다. 2장 1,2-디케톤 및 1-시아노케톤으로 Spiro Indoline-Pyran 및 Fused Epoxyetheno Indeno-Furan을 만드는 확산 고리첨가반응을 설명한다. 3장 α-Cyanoketones 및 cyclic α-Diketones으로 새로운 Heterocyclic [4.3.3] Propellanes을 DBU 촉진 합성법에 대하여 묘사한다. 4장 메틸 4-(4-클로로페닐)-5,7-디옥소-1-페닐-1,4,5,6,7,8-헥사히드 로피라졸로[4', 3': 5,6]피라노[2,3-d]피리미딘-3-카르복실레이트의 4성분 일단계 합성법을 설명한다; 친환경 합성법. 5장 무용매 조건에서 2-아미노-4-페닐벤조[4,5]이미다조[1,2-a]피리미딘-3-카보니트릴을 트리에틸아민 촉매를 사용하여 만드는 전례없는 합성법을 다룬다. 6장 무촉매 조건에서 1,3-옥사지노 퀴놀린 및 크로메노 1,3-옥사진 유도체를 PEG의 도움에 의한 일단계 3성분 합성에 대 한 우리의 접근 방식을 설명한다. 7장 물 용매에서 연속적인 C–C 및 C–N 결합 형성을 통한 3-((benzo[d]thiazol-2-ylamino)(phenyl) methyl)-4-hydroxy-1-methylquinolin-2(1H)-one의 새로운 합성법을 다룬다. 8장 Sequential Annulation Strategy를 통한 새로운 Penta cyclic Indolo-furo[3,2-c]quinoline 및 Dihydrochromeno-furo[2,3-b]indol의 입체선택적으로 형성하는 방법을 설명한다.

The thesis entitled “Design and Synthesis of New Strategies for Fused and Spiro O, N-Heterocyclic Moieties through MCRs” is divided into eight chapters. In this context, the present thesis deals with the construction of new multicomponent strategies for the synthesis of oxygen and nitrogen fusedspiro bicyclic frameworks. A series of O-fused heterocyclic scaffolds were synthesized in moderate to excellent yields by using regio- chemo- and distereoselective reaction via Knoevenagel, Michael adduct, through PaalKnorr intramolecular cyclization reaction. Moreover, a number of exciting novel methodologies has been developed to readily access to diverse array of biologically relevant molecule cores. This methodological transformation are tolerated of a variety of functionalities, thus giving broad substrate scope. Chapter 1: We have developed a simple novel ring-closure, ring-opening pathways using the organo-base system for the synthesis of the highly substituted dihydrofurofuran and furan framework by the triethylaminecatalyzed one pot three-component reaction. The protocol involved a Knoevenagel and Michael adduct via Paal-Knorr cyclization with aromatic/aliphatic glyoxal and 2-cyanoacetophenone under mild and heating conditions with excellent yields through a simple filtration method. The merits of this methodology was easily available feedstocks, inexpensive catalyst, gram scale synthesis, wide functional group tolerance, open-air reaction setup and no workup and column-chromatography make the developed methodology a practical way to access dihydrofurofuran and Functionalized furans. Chapter 2: A simple and efficient method for the construction of spiro indoline-pyran and fused epoxyetheno indeno [1,2-b] furan compounds from 1-cyanoketones and 1,2-diketone has been developed. The synthesis proceeded through the Knoevenagel, Michael adduct via intramolecular/PaalKnorr cyclization under similar reaction condition. The less commonly used 1-cyanoketones and active carbonyl compounds served as the indole containing pyran and bicyclic furan source for the preparation of a new series of heterocyclic compounds. This heterocyclic structure allows one and more than one tetra-substituted carbon center and sequential hexa and penta-cyclic core under very mild conditions and shows excellent chemo and regioselectivity. In addition, the synthesis of spiro indoline-3,4’-Pyran and epoxyetheno indeno [1,2-b] furan was demonstrated in a gram scale. Scheme 2. A operationally simple one-step method developed for the spiro indoline-3, 4’-pyran and fused epoxyetheno indeno [1, 2-b]furan derivatives from 1‑cyanoketones and cyclic 1,2-diketon. Chapter 3: An effective base-catalyzed Knoevenagel, Michael and intramolecular/Paal-Knorr cyclization strategy for the construction of heterocyclic [4.3.3] tetrahydro epoxyetheno benzo-furan propellanes (TEBFs) from cyclic α-diketones and α‑cyanoketones is reported through single-step reaction. The reaction proceeds under mild reaction conditions and shows excellent chemo and distereoselectivity in the absence of any external transition metal and ligands. The one-pot two-component procedure also shows the merits of straightforward reaction conditions, simple operation, using available feedstock, wide substrate scope, and high atom and step economy. This reaction provides facile access to highly substituted fused tetrahydro furo-furan propellanes, which can be used in the field of chemical and pharmaceutical research. Chapter 4: A simple and efficient synthetic protocol for the synthesis of methyl 4-(4-chlorophenyl)-5,7-dioxo-1-phenyl-1,4,5,6,7,8-hexahydropyrazolo [4',3':5,6] pyrano[2,3-d] pyrimidine -3- carboxylate derivatives via a one pot four-component reaction catalyzed by L-Proline has been successfully developed. This new protocol produces pyrano pyrimidine carboxylate derivatives in good to excellent yields, with operational simplicity. The remarkable features of this methodology are high yields, metal-free catalyst, easy work-up procedure, and a greener method that avoids toxic catalyst and hazardous solvents. Chapter 5: An efficient and experimentally straightforward method for the synthesis of 2-amino-4-phenylbenzo [4,5] imidazo [1,2-a] pyrimidine-3-carbonitrile derivatives has been developed via one pot three-component reaction of 2-aminobenzimidazole, cyanoacetamide and aromatic aldehydes in the presence of triethylamine under solvent free reaction condition. This green procedure offers several advantages such as high atom economy, short reaction time, metal free and solvent free reaction conditions, easy work up and column chromatography-free method with a wide range of functional group tolerance. This has made the protocol sustainable and economical. Chapter 6: A straightforward and greener PEG-assisted protocol has been disclosed for the cascade synthesis of [1, 3] Oxazino quinoline, and chromeno [1, 3] oxazin derivatives via three component reaction of multifarious aromatic amines with formaldehyde and 4-hydroxyquinoline-2(1H)-one or 4-methylumbelliferone by using very convenient reaction conditions. This methodology represents a sustainable approach for rapid access to a library of diversity oriented highly pure [1, 3] oxazino scaffolds with broad substrate scope. Scheme 6. Synthesis of [1, 3] Oxazino quinoline (4) and chromeno 1,3-oxazin (6) derivatives. Chapter 7: A simple, efficient, and eco-friendly protocol has been developed for the synthesis of novel 3-((benzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl)-4-hydroxy-1-methylquinolin-2(1H)-one derivatives using a one-pot C−C and C−N bond forming strategy from the reaction of 4-hydroxy-1-methylquinolin-2(1H)-one, 2-aminobenzothiazole and aromatic aldehydes in aqueous solvent without using any metal catalyst. Several advantages of this protocol include its operational simplicity, short reaction time, mild reaction condition, efficient utilization of all the reactants, wide functional group tolerance, using water as an environmentally friendly solvent and non-chromatographic purification procedure. Chapter 8: An efficient, rapid and green synthesis of indolo-furo-quinoline and chromeno-furo-indoles has been developed by one-pot reaction of 2,4-quinolinediol or 4-hydroxycoumarin, phenylglyoxal and aromatic amine in the presence of acetic acid as an reaction medium cum promoter at room temperature. This scalable tandem reaction affords a series of novel dihydroindolo-furo-quinoline and dihydro-chromeno-furo-indole derivatives with two adjacent stereogenic centers in good to excellent yields and with high regioselectivity and stereoselectivity. Moreover, this cascade reaction provides a distinct Knoevenagel, Michael and through intramolecular cyclization in sequential manner under mild reaction conditions to access the diversely decorated indolo-furo-quinoline and chromeno-furo-indoles of considerable importance to natural product synthesis and medicinal chemistry.