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Tandem Transformations of Nitriles to the N-heterocyclic Compounds via the Blaise Reaction

Title
Tandem Transformations of Nitriles to the N-heterocyclic Compounds via the Blaise Reaction
Authors
XUAN ZI
Issue Date
2017
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Doctor
Advisors
이상기
Abstract
졸업논문의 연구목적은 Blaise중간체를 이용하여 다양한 N-heterocyclic 화합물을 다단계 촉매반응으로 합성하는 방법을 개발하는 것이다. Blaise중간체는 특별한 화학반응 성질을 가지고 있으며, 즉 enamine의 nucleophilic 한 carbon과 nitrogen, 그리고 electrophilic 한 ester 를 갖추는 것이다. 그러므로 여러 가지의 electrophile, nucleophile 또한 전이 금속과 cross coupling 반응에도 적용할 수 있다. Chapter 1: Simple 한 nitriles 로부터 두 가지 N-heterocyclic 화합물을 합성하였다 (Primidin-2,4-dione 과 Pyridine). Primidin-2,4-dione는Blaise중간체와 isocyanate에 C/N 선택적으로 반응한 다음 분자내 cyclization 일어나여 합성할 수 있다. Pyridine 는Blaise중간체와 α,β-unsaturated ketone과 반응하여, Michel addition, cyclization, oxidative aromatization 통해 연속적반응으로 합성할 수 있다. Chapter 2: Blaise 중간체 와 전이금속촉매와의 반응을 몇 가지 연구하였다. 첫 번째 반응은Blaise/Ullmann Coupling 이다. 이 반응에서 Blaise 중간체를 합성중에 남은 zinc또는 DMF가 염기 와 고열 하에서 분해된 dimethylamine 영향에 Pd(0)를 환원할 수 있었다. 두 번째 반응은 Pd(0)촉매하에서 2-Bromoaryl nitriles에 시작되어 연속적인Blaise/Aminocarbonylation반응을 통해 (Z)-3-Methyleneisoindolin-one을 합성하였다. Bisphosphine리간드의 선택이 효율적인 반응에 아주 큰 영향을 미치는 것으로 보인다. 세 번째 연구는 Blaise중간체가 산화반응으로 통해서 두 가지 치환체 위치가 다른 Pyrrole를 합성하는 것이다. Solvent의polarity가 반응의 생산물의 선택성에 큰 영향을 끼친다고 볼 수 있다.;The Ph.D. thesis was divided into two sections: 1. Using ambivalent -C/-N nucleophilicity of Blaise reaction intermediate to synthesize N-heterocyclic compounds (pyrimidin-2, 4-diones and highly substituted pyridines); 2. Combination of Blaise reaction with palladium chemistry (Blaise/Ullmann coupling, Pd-catalyzed aminocarbonylation, oxidative cross coupling reaction of BRIs). Chapter I. A.Tandem Synthesis of Pyrimidin-2,4-diones Divergent tandem synthesis of pyrimidin-2,4-diones have been well developed. The chemoselectivity of Blaise reaction intermediate towards isocyanate was largely determined by α-substituent. α-Substituted BRIs act as the N-nucleophile (path a),whereas α-Unsubstituted BRIs was observed propensity to be a C-nucleophile (path b and path c), which allowed us to install different functional groups at C-5 position such as alkyne, NBS and isocyanate via sequential tandem one-pot manner. B. Tandem Synthesis of Highly substituted Pyridines The α-unsubstituted Blaise reaction intermediate act as C-nucleophile towards α,β-unsaturated ketones to undergo Michael addition/cyclization/oxidative aromatization procedures, providing highly substituted pyridines with flexible control over the substitution patterns around the pyridine rings. Chapter II. A.Tandem Blaise/Ullmann Coupling Reaction Tandem Blaise / Ullmann coupling reactions from 2-bromoaryl substituted BRIs under Pd(PPh3)4 with t-BuOK under DMF was developed. The regeneration of Pd(0) active species result in the actions of left over zinc in the reaction mixture and/or the decomposition of DMF under base, releasing with carbon monoxide and dimethylamine. The potential use of this 2,2’substituted enamine moieties as the coupling products could be easily transform to seven-membered N-heterocyclics under acidic conditions. B. Tandem Pd-catalyzed Aminocarbonylation A novel route to stereocontrolled (Z)-3-methyleneisoindolin-1-ones was achieved starting from 2-bromoarylnitriles via tandem sequential reaction with Blaise reaction/Pd-catalyzed intramolecular aminocarbonylation using carbon monoxide at one atmosphere pressure. It has been found that the conformational flexibility of bisphosphine ligand is of great importance to the success of this tandem aminocarbonylation reaction. C. Tandem Oxidative Coupling of BRIs Approach to Pyrroles Enamine moiety, is widely utilized as the key subunit of pyrroles. Based on the previous work, the potential application part of Blaise/Ullmann coupling reaction, we envisioned α-unsubstituted Blaise reaction intermediate may undergo oxidative homocoupling at α-carbon position by a proper oxidant, followed by protonation/conjugate addition/deamination process, providing symmetric substituted pyrroles (pyrrole A). While, the position of substituents on pyrroles largely depends on the choice of solvent polarity, also it involves palladium chemistry (pyrrole B).
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