第一部分. 分子內威悌反應策略進行多種雜環之多樣性導向合成及吡唑啉酮/噻唑酮衍生物之β-醯化反應 第二部份. 透過3-高醯基香豆素及不飽和吡唑啉酮經有機催化 (3+2) 環化反應進行螺環吡唑啉酮之不對稱合成
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2020
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第一部分:
本部分分為三個章節,以Wittig反應的發展與應用為主軸,內容涵蓋以分子內Wittig反應建構五、六、七員環分子之方法學開發,並且可以應用於多樣性導向合成。此外,完成以有機膦試劑催化反應於不飽和雙鍵系統β位置建構碳-碳單鍵之方法開發,此類直接在α或β位置直接建構碳–碳單鍵的反應為數不多,亦可以顯示有機膦試劑在合成上的廣用性。
第一章:
此章節以α-鹵代酮腙 (α-halohydrazone)、α-鹵代酮肟 (α-haloketoxime) 分別製備為有機鏻鹽,接續以分子內Wittig反應合成三取代吡唑、雙取代異噁唑衍生物之方法開發。此外,我們也將反應延伸應用至化學選擇性的Wittig反應,經反應條件優化後,可以溶劑調控其多樣性導向合成,分別製備經重排反應的異噁唑及4H-苯並吡喃衍生物,以延伸至多樣性導向合成之應用。
整體而言,可以一個共同的合成策略建構三種不同的雜環分子,並且以多種分析工具與控制實驗進行反應機制的探討與驗證。
關鍵詞:威悌反應、化學選擇性、多樣性導向
第二章:
本實驗室長期致力於開發以不飽和羰基化合物進行分子內Wittig反應建構雜環化合物的方法學開發,在反應中添加有機膦試劑以良好的區域選擇性做加成反應生成磷–兩性離子或有機鏻鹽,接續以分子內Wittig反應進行合環。而本章節延續本實驗室的研究主題,以α, β, γ, δ -不飽和吡唑 (α, β, γ, δ -Unsaturated Pyrazolones) 作為起始物進行多樣性導向合成螺環吡唑啉酮、1H-㗁呯[2,3-c]吡唑衍生物。
在此合成方法中,由有機膦試劑進行1,6加成反應得到七員環–betaine中間體,在調控反應條件後可以引導出不同的產物,一路徑會進行非預期的δ-碳-醯化/環化/分子內Wittig反應得到螺環吡唑啉酮衍生物,而在較大立體障礙的官能基條件下則會直接進行分子內Wittig反應得到七員環–1H-㗁呯[2,3-c]吡唑衍生物。
以控制實驗與實驗數據的對照可以證明不同位向betaine中間體在影響反應的選擇性扮演極重要的角色,由醯氯試劑所提供的立體效應與溶劑的優化,可以使反應經碳–氧鍵的斷鍵或是直接進行Wittig反應導向不同的兩種產物,進而增進對反應機制的了解。
關鍵詞:威悌反應、1,6-加成、δ位-碳醯化、多樣性導向
第三章:
本章節討論以有機膦試劑催化直接合成β-醯化吡唑啉酮和噻唑酮的合成方法開法,可以在溫和有效的條件下合成官能化的β-取代的吡唑啉酮和噻唑酮衍生物,且具有良好的官能基耐受性。我們的研究成果也顯示以帶有雜環的醯化試劑則會使產物吡唑啉酮和噻唑酮可使生成E / Z異構物。另外,也成功以克級反應製備吡唑啉酮和噻唑酮,以增進本方法之應用價值與廣用性。
關鍵詞:β-醯化反應、1,4-加成、有機膦、吡唑啉酮衍生物、噻唑酮衍生物
第二部分:
本部分以一個章節探討環化加成反應對於有機催化的重要性,特別是以1,3-偶極體進行環化加成反應建構含多個立體中心的複雜全碳環狀分子,可以突顯有機不對稱催化在合成上的應用價值。
第四章:
本章節顯示了以α, β-吡唑啉酮與3-高醯基香豆素進行麥可-麥可串聯反應,製備(3+2)環化加成反應之產物–一系列具有五個連續立體中心的香豆素/吡唑啉酮稠合的螺環戊烷化合物,可以有機鹼催化劑控制不對稱合成,具有優異的產率與鏡像選擇性,並且以單晶繞射對其絕對立體組態進行驗證。
關鍵詞:(3+2)環化加成反應、3-高醯基香豆素、1,3-偶極體、螺環戊烷、鏡像選擇性
PART-I This part is subdivided into three chapters which illustrates the brief history of Wittig reaction, its development throughout these years and its applications toward synthesis of heteroarenes/carbocyclic compounds via intermolecular, intramolecular and diversity-oriented manner. Also the brief introduction about some elegant synthetic methods of five, six and seven membered heteroarenes/carbocycles and its biological importance is discussed. Moreover, discussion about transformation of C–H bonds of electron deficient alkenes into C–C bonds using different protocols such as the MBH reaction and its importance in organic chemistry and also demonstrated few known methodologies for the direct C–C bond formation at and β-positions. CHAPTER-1: “An Intramolecular Wittig Approach toward Heteroarenes: Synthesis of Pyrazoles, Isoxazoles, and Chromenone-oximes.” In this section, we demonstrated efficient strategy for the synthesis of substituted pyrazoles and isoxazoles via a phosphine-mediated intramolecular Wittig reaction of α-halohydrazones or ketoximes under mild and metal-free conditions. In addition, we have explored the possibility of chemoselective intramolecular Wittig reaction that could result in rearranged isoxazoles and chromenone-oxime derivatives in a diversity-oriented manner. The rearranged isoxazole products have been determined on the basis of EI-MS. A wide range of substitution effects have been studied and several control experiments were also performed to prove the plausible reaction mechanism for the present protocol. Keywords: Wittig reaction, Chemoselective, Diversity-Oriented. CHAPTER-2: “Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and 1H-Oxepino[2,3-c]pyrazoles from Doubly Conjugated Pyrazolones via Intramolecular Wittig Reaction” Our group has long been devoted toward the in situ generation of phosphorus zwitterions or phosphonium salts by the addition of phosphine to conjugated carbonyl compounds at different positions for their subsequent Wittig reaction. In continuation of the legacy of our research, we were interested in the development of new methods for the diversity-oriented synthesis of privileged heterocycle scaffolds. Thus, inhere we have developed a novel method for the diversity-oriented synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles. The methodology attributes O-acylation of phosphorus zwitterion which was formed by an initial tandem phospha-1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, will form seven-membered betaine intermediate, that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner via a δ-C-acylation/ cyclization/Wittig reaction sequence or the intramolecular Wittig reaction. To investigate the mechanism, we have performed several control experiments and we found that the betaine intermediates plays a pivotal role for the formation of cyclic products via the C-O bond cleavage for δ-C-acylation or the direct Wittig reaction, depending on the nature of the solvent and the steric hindrance of acyl chlorides. Keywords: Wittig reaction, 1,6-addition, δ-C-acylation, Diversity-Oriented. CHAPTER-3: “Organophosphane-Catalyzed Direct β-Acylation of 4-Arylidene-Pyrazolones and 5-Arylidene-Thiazolones with Acyl Chlorides” This section discusses an efficient synthesis of direct β-acylated pyrazolones and thiazolones using acyl chlorides as trapping reagents in presence of the base catalyzed by organophosphanes. The substrate scope is wide which allows synthesis of functionalized β-substituted pyrazolone and thiazolone derivatives at mild and efficient conditions. Our studies also revealed that the pyrazolones and thiazolones bearing heterocycles at olefinic position allows the product to generate E/Z-isomers. To demonstrate the synthetic utility of our protocol we have performed gram scale reactions of three different substrates in each case, and the efficiency of the reaction shown very promising results. Keywords: Direct β-acylation, 1,4-addition, Organophosphane, Functionalized Pyrazolones and Thiazolones. ABSTRACT PART-II This part contains one chapter, which illustrates the importance of cycloaddition reactions and organocatalysis. In particular, it describes about 1,3-dipole precursor and their reactions, to construct complex structures with all carbon rings via cycloaddition reactions. CHAPTER-4: “Asymmetric Synthesis of Spiro-pyrazolones via Organocatalytic (3+2) Cycloaddition Reaction between 3-Homoacylcoumarin and Unsaturated Pyrazolone Derivatives” This chapter demonstrates a double Michael cascade reaction between α,β-unsaturated pyrazolone and 3-homoacylcoumarin derivatives to give (3+2) cycloaddition product. A series of coumarin/pyrazolone fused spirocyclopentane bearing five contiguous stereocenters, catalyzed by organo base with excellent yields and enantioselectivity’s. We have successfully devised a new method for the synthesis of spiro-pyrazolones derivatives in upto 98% yield and upto 99% ee with single diastereomer. The absolute configurations of products have been confirmed by X-ray diffraction analysis. Keywords: (3+2)Cycloaddition, 3-homoacylcoumarin, 1,3-dipole, Spirocyclopentane, Enantioselective reaction.
PART-I This part is subdivided into three chapters which illustrates the brief history of Wittig reaction, its development throughout these years and its applications toward synthesis of heteroarenes/carbocyclic compounds via intermolecular, intramolecular and diversity-oriented manner. Also the brief introduction about some elegant synthetic methods of five, six and seven membered heteroarenes/carbocycles and its biological importance is discussed. Moreover, discussion about transformation of C–H bonds of electron deficient alkenes into C–C bonds using different protocols such as the MBH reaction and its importance in organic chemistry and also demonstrated few known methodologies for the direct C–C bond formation at and β-positions. CHAPTER-1: “An Intramolecular Wittig Approach toward Heteroarenes: Synthesis of Pyrazoles, Isoxazoles, and Chromenone-oximes.” In this section, we demonstrated efficient strategy for the synthesis of substituted pyrazoles and isoxazoles via a phosphine-mediated intramolecular Wittig reaction of α-halohydrazones or ketoximes under mild and metal-free conditions. In addition, we have explored the possibility of chemoselective intramolecular Wittig reaction that could result in rearranged isoxazoles and chromenone-oxime derivatives in a diversity-oriented manner. The rearranged isoxazole products have been determined on the basis of EI-MS. A wide range of substitution effects have been studied and several control experiments were also performed to prove the plausible reaction mechanism for the present protocol. Keywords: Wittig reaction, Chemoselective, Diversity-Oriented. CHAPTER-2: “Diversity-Oriented Synthesis of Spiropentadiene Pyrazolones and 1H-Oxepino[2,3-c]pyrazoles from Doubly Conjugated Pyrazolones via Intramolecular Wittig Reaction” Our group has long been devoted toward the in situ generation of phosphorus zwitterions or phosphonium salts by the addition of phosphine to conjugated carbonyl compounds at different positions for their subsequent Wittig reaction. In continuation of the legacy of our research, we were interested in the development of new methods for the diversity-oriented synthesis of privileged heterocycle scaffolds. Thus, inhere we have developed a novel method for the diversity-oriented synthesis of spiropentadiene pyrazolones and 1H-oxepino[2,3-c]pyrazoles. The methodology attributes O-acylation of phosphorus zwitterion which was formed by an initial tandem phospha-1,6-addition of PBu3 to α,β,γ,δ-unsaturated pyrazolones, will form seven-membered betaine intermediate, that preferentially resulted in the aforementioned cyclic products in a diversity-oriented manner via a δ-C-acylation/ cyclization/Wittig reaction sequence or the intramolecular Wittig reaction. To investigate the mechanism, we have performed several control experiments and we found that the betaine intermediates plays a pivotal role for the formation of cyclic products via the C-O bond cleavage for δ-C-acylation or the direct Wittig reaction, depending on the nature of the solvent and the steric hindrance of acyl chlorides. Keywords: Wittig reaction, 1,6-addition, δ-C-acylation, Diversity-Oriented. CHAPTER-3: “Organophosphane-Catalyzed Direct β-Acylation of 4-Arylidene-Pyrazolones and 5-Arylidene-Thiazolones with Acyl Chlorides” This section discusses an efficient synthesis of direct β-acylated pyrazolones and thiazolones using acyl chlorides as trapping reagents in presence of the base catalyzed by organophosphanes. The substrate scope is wide which allows synthesis of functionalized β-substituted pyrazolone and thiazolone derivatives at mild and efficient conditions. Our studies also revealed that the pyrazolones and thiazolones bearing heterocycles at olefinic position allows the product to generate E/Z-isomers. To demonstrate the synthetic utility of our protocol we have performed gram scale reactions of three different substrates in each case, and the efficiency of the reaction shown very promising results. Keywords: Direct β-acylation, 1,4-addition, Organophosphane, Functionalized Pyrazolones and Thiazolones. ABSTRACT PART-II This part contains one chapter, which illustrates the importance of cycloaddition reactions and organocatalysis. In particular, it describes about 1,3-dipole precursor and their reactions, to construct complex structures with all carbon rings via cycloaddition reactions. CHAPTER-4: “Asymmetric Synthesis of Spiro-pyrazolones via Organocatalytic (3+2) Cycloaddition Reaction between 3-Homoacylcoumarin and Unsaturated Pyrazolone Derivatives” This chapter demonstrates a double Michael cascade reaction between α,β-unsaturated pyrazolone and 3-homoacylcoumarin derivatives to give (3+2) cycloaddition product. A series of coumarin/pyrazolone fused spirocyclopentane bearing five contiguous stereocenters, catalyzed by organo base with excellent yields and enantioselectivity’s. We have successfully devised a new method for the synthesis of spiro-pyrazolones derivatives in upto 98% yield and upto 99% ee with single diastereomer. The absolute configurations of products have been confirmed by X-ray diffraction analysis. Keywords: (3+2)Cycloaddition, 3-homoacylcoumarin, 1,3-dipole, Spirocyclopentane, Enantioselective reaction.
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Keywords
威悌反應, 化學選擇性, 多樣性導向, 1,3-偶極體, 1,6-加成, δ位-碳醯化, 鏡像選擇性, β-醯化反應, 1,4-加成, 有機膦, 吡唑啉酮衍生物, 噻唑酮衍生物, (3+2)環化加成反應, 3-高醯基香豆素, 螺環戊烷, Wittig reaction., Chemoselective, Diversity-Oriented, Enantioselective reaction, 1,6-addition, δ-C-acylation, (3+2) Cycloaddition, Direct β-acylation, 1,4-addition, Organophosphane, Functionalized Pyrazolones and Thiazolones, 3-homoacylcoumarin, 1,3-dipole, Spirocyclopentane