An Auxiliary Ligand-Free Iron Carbonyl Catalyzed Transfer Hydrogenation for N-Heterocycle Synthesis = 보조 리간드 비의존적 철-카보닐 촉매를 사용한 수소 이동화 반응 및 N-헤테로고리 화합물 합성

국문 초록 (Abstract)

수소 이동화 (TH) 반응은 직접적인 수소화 반응의 대체제로써 수소 기체 대신 다루기 쉬운 수소 공여체를 수소의 공급원으로 사용하는 과정이다. TH 반응에 사용되는 촉매 중 리간드-금속 이중작용성 수소 이동화 촉매는 다양한 전이 금속을 중심으로 하여 리간드와 금속이 동시에 반응에 참여하는 형태로, 안정적인 반응 조건과 높은 수소이동화 활성으로 인해 많은 연구가 진행되었다. 그 중 Shvo 촉매를 바탕으로 설계된 사이클로펜타다이엔온 철 카보닐 복합체 (CIC)는 철 원소의 풍부함과 낮은 독성을 갖는 이점이 존재한다. 이를 토대로 CIC 복합체를 사용하여 C-N 결합을 형성하고 N-헤테로고리 화합물을 합성하는 전략이 대두되었다. N-헤테로고리 화합물은 약물 개발에 있어 중요한 핵심 구조이며, 미국 FDA에 의하면 약 59%의 약물 구조가 N-헤테로고리 중심 구조를 가지고 있다.
본 연구에서는 CIC 복합체의 전구체인 철 카보닐 촉매를 사용하여 알코올과 니트로아렌 사이의 수소 이동화 반응을 발견하고 다양한 N-헤테로고리 합성에 응용하였다. 수소 이동화 반응에서 알코올은 수소 공여체의 역할을 수행하며 니트로아렌은 수소 수용체의 역할을 할 수 있다. 따라서 수소 이동화를 통해 알코올은 카보닐로, 니트로아렌은 아닐린으로 산화환원되며 순차적인 축합 반응과 고리화 반응을 통해 최종적으로 N-헤테로고리 화합물을 형성할 수 있다.
본 연구에서는 상술한 반응 과정을 거쳐 N-헤테로고리 화합물 중에서 quinazolinone, benzoxazole, pyrrolo[1,2-α]quinoxaline 유도체를 합성하였다. 이러한 방법론은 실험 과정이 간단하고 경제적으로 안정적이며, 추가적인 리간드의 도입이 필요하지 않아 N-헤테로고리 화합물 합성의 지속 가능한 대안을 제시하였다. 또한 대조 실험을 통해 알코올의 산화 반응 과정 중에서 수소 분자가 생성되어 니트로 작용기가 아민으로 환원되는 과정에 관여한다는 것을 입증하였다. 밀도범함수 이론 계산을 실행한 결과 철 트라이카보닐 중간체가 알코올의 산화과정에서 수소 분자를 형성하는 것을 촉진하고, 알코올과 나이트로기 사이의 수소 이동화 반응을 매개하는 것을 확인하였다.

다국어 초록 (Multilingual Abstract)

Transfer hydrogenation (TH) reaction has emerged as an alternative route to direct hydrogenation reactions, in which a simple hydrogen donor is employed as the hydrogen source instead of molecular hydrogen. In this context, ligand-metal bifunctional catalysts involve both the metal center and the ligand participate in hydrogen transfer. They have been extensively studied due to their mild reaction conditions and high efficacy in TH. In particular, the cyclopentadienone iron carbonyl (CIC) complex, an iron-based analogue of the Shvo-catalyst, offers advantages arising from the natural abundance and low toxicity of iron. On this basis, synthetic strategies employing CIC complexes, for the construction of C-N bond and N-heterocycles by TH process have recently attracted considerable attention. Indeed, N-heterocycles are key structural motifs in drug discovery and development, and approximately 59% of small molecule drugs contain N-heterocycle scaffolds.
In this thesis, we report an iron carbonyl-catalyzed TH process between alcohols and nitroarenes, and its subsequent application to the synthesis of diverse N-heterocycles. In the TH process, alcohols act as hydrogen donors, while nitroarenes serve as hydrogen acceptors. Through TH process, alcohols are oxidized to aldehydes, and nitroarenes are reduced to anilines. The in situ generated aldehyde and aniline intermediates then undergo sequential condensation and annulation process. After the final oxidation, the corresponding N-heterocycle structure could be obtained.
Using this transfer hydrogenation strategy, a variety of N-heterocycle compounds were successfully synthesized. With the nitroarene substrates bearing additional nucleophilic functional group, quinazolinone, benzoxazole, and pyrrolo[1,2-α]quinoxaline derivatives were obtained in high yields. This methodology does not require any additional auxiliary ligands, rendering the process operationally simple, economically favorable, and environmentally friendly. Various scopes of iron carbonyl-catalyzed TH indicate that iron carbonyl complexes demonstrate high potential for the replacement of CIC complex for TH-utilized N-heterocycle synthesis. Control experiments confirmed the generation of molecular hydrogen during alcohol oxidation, which is involved in the reduction of nitroarenes to the corresponding amines. Density functional theory (DFT) calculations further support that an in situ generated iron tricarbonyl intermediate mediates facilitates generation of molecular hydrogen from alcohol oxidation, and mediates hydrogen transfer between alcohols and nitro group.

목차 (Table of Contents)

• ABSTRACT i
• TABLE OF CONTENTS iii
• LIST OF FIGURES viii
• LIST OF TABLES ix
• LIST OF SCHEMES x
• INTRODUCTION 1
• 1. Transfer Hydrogenation (TH) 1
• 1.1. Comparison with classical hydrogenation 1
• 1.2. History of catalytic transfer hydrogenation 3
• 2. Metal catalysts used in transfer hydrogenation 9
• 2.1. Ligand-metal bifunctional catalyst 9
• 2.1.1. Previous ligand-metal bifunctional catalyst 9
• 2.1.2. Shvo-type ligand-metal bifunctional catalyst 12
• 2.2. Cyclopentadienone iron carbonyl (CIC) complexes 15
• 2.2.1. Basic concept and mechanism of CIC complex 15
• 2.2.2. Derivation of CIC complex 18
• 3. N-Heterocycles: Quinazolinones, benzoxazoles, and pyrrolo-quinoxalines 23
• 3.1. Outline of N-heterocycles 23
• 3.2. Synthetic approaches for N-heterocycle formation 25
• 3.2.1. Transfer hydrogenative C-N coupling 25
• 3.2.2. N-heterocycle synthesis using CIC complexes 27
• 3.3. Our synthetic strategies for N-heterocycles 31
• RESULTS AND DISCUSSION 33
• 1. Evaluation of iron carbonyl-catalyzed TH 33
• 2. Synthesis of quinazolinones using iron carbonyl-catalyzed TH 36
• 2.1. Optimization of reaction conditions 36
• 2.2. Scope of alcohol and nitroarene substrates 39
• 2.3. Scope of 2-nitrobenzonitrile substrates 44
• 2.4. Derivation using the synthesized quinazolinones 47
• 3. Synthesis of benzoxazoles using iron carbonyl-catalyzed TH 49
• 3.1. Optimization of reaction conditions 49
• 3.2. Scope of alcohol and nitroarene substrates 51
• 4. Synthesis of pyrrolo[1,2-α]quinoxalines using iron carbonyl-catalyzed TH 52
• 4.1. Optimization of reaction conditions 52
• 4.2. Scope of alcohol and nitroarene substrates 54
• 5. Mechanistic studies 55
• 5.1. Control experiments of iron carbonyl-catalyzed TH 55
• 5.2. Experimental evidence for a radical mechanism 59
• 5.3. Stepwise verification experiment 60
• 5.4. Reaction progress depending on time 61
• 5.5. DFT calculation 63
• 5.5.1. Energy diagram of alcohol oxidation 63
• 5.5.2. Energy diagram of nitro reduction 66
• CONCLUSION 68
• EXPERIMENTAL SECTION 69
• 1. General information 69
• 2. Synthetic procedures for substrates 70
• 3. Synthesis of quinazolinones 82
• 3.1. General procedure A using N-substituted 2-nitrobenzamide 82
• 3.2. General procedure B using 2-nitrobenzonitriles 112
• 3.3. Procedure for the synthesis of 9 (Bouchardatine) 118
• 3.4. Procedure for the synthesis of compound 11 120
• 3.5. Procedure for the synthesis of compound 12 122
• 4. Synthesis of benzoxazoles 125
• 5. Synthesis of pyrrolo[1,2-α]quinoxalines 130
• 6. Mechanistic study 135
• 6.1. Control study 135
• 6.2. Radical clock experiment 137
• 6.3. Stepwise confirmation experiment 139
• 7. DFT calculations 140
• 7.1. Computational details 140
• 7.2. Energy Correlation 140
• 7.3. Cartesian coordinates of computed structures 141
• REFERENCES 153
• APPENDIX 162
• 국문초록 250