Synthetic Approaches to Benzo-fused Systems by Applications of the Baylis-Hillman Methodology

Abstract

본 논문에서는 DABCO 등의 3차 아민을 촉매로 하여 탄소-탄소간의 결합을 유도해내는 Baylis-Hillman 방법론의 적용을 통한 다양한 benzo-fused systems의 합성에 대해 고찰하였다. 본 논문은 총 4개의 장으로 구성되어 있다. 제 1장에서는 대표적으로 유명한 benzo-fused ring compounds에 대한 예와 Baylis-Hillman 반응에 대해 간략히 설명하였다. 또한 Baylis-Hillman 반응생성물을 이용하여 다양한 benzo-fused ring compounds를 합성한 본 연구실의 연구결과물들에 대해 서술하였고 마지막으로 신규 benzo-fused systems 에 대한 합성적 접근방법들을 소개하였다. 제 2장에서는 ortho-substituted benzaldehydes를 출발물질로 하여 새로운 benzo-fused heterocyclic compounds 합성에 대한 접근방식에 대해 소개하였다. 이 전략적 접근 하에 phenylethynyl-, 1-propynyl- 그리고ethynylmagnesium bromide 같은 Grignard reagents 들과 2-azidobenzaldehyde의 Baylis-Hillman acetates와의 반응을 통하여 5-carbomethoxy-4H-1,2,3-triazolo[1,5-a][1]benzazepine 유도체를 합성하였다. 용이하게 합성할 수 있는 2-azidobenzaldehyde의 BH-acetates는 이 신규고리화합물의 합성을 위한 출발물질로 사용되었고 이를 tetrahydrofuran 용매하에서 alkynide Grignard reagents와 7-24시간 반응시킨 후 2-4 시간의 환류반응을 통하여 [3+2]dipolar cycloaddition 메커니즘을 거쳐 목표화합물을 얻을 수 있었다. 제 3장에서는 α-vinylated products를 출발물질로 사용하여 pyranonaphthoquinone 유도체를 합성하는 합성 경로에 대해 설명하였다. BH 반응 조건하에서 α-vinylnaphthoquinones가 출발물질로 합성되었고 이를 여러 allyl alcohols 과 반응시켜 ring-closing metathesis 반응을 위한 전구체인 dienes를 합성하였다. Dichloromethane 용매하에 이 dienes에 Grubbs’ second generation catalyst를 첨가하여 환류반응 시킨 후 목표로 했던 pyranonaphthoquinones를 합성할 수 있었다. 마지막으로 제 4장에서는 5-membered ring 화합물로부터 유사 benzo-fused system에 대한 합성적 접근에 관하여 논하였다. 따라서 pyrrolo[2,1-b]thiazole 유도체를 합성하기 위한 목적으로 thiazole-2-carboxaldehyde의 BH-acetates의 thermal reactivity의 조사 연구가 수행되었다. 출발물질인Thiazole-2-carboxaldehyde의 BH adducts는 다양한 BH 반응조건에서 얻어졌고, 이를 acetylation 시킨 후 diphenyl ether 용매하에 환류반응을 시켜 thermal cyclization을 통하여 목표화합물인 pyrrolo[2,1-b]thiazoles를 얻을 수 있었다. 상기 명시된 화합물들의 구조는 1H NMR, 13C NMR, IR, GC/Mass 그리고 HRMS spectroscopic 자료들을 이용하여 규명하였다.; In this dissertation, three types of synthetic approaches to various benzo-fused systems by applications of the Baylis-Hillman (BH) methodology known for one of the Carbon-Carbon bond forming reactions were disclosed. This dissertation is consisted of four chapters. In chapter 1, some pharmaceutically or industrially used benzo-fused molecules were introduced and Baylis-Hillman chemistry were explained briefly. Then, our group’s former reports on the syntheses of several benzo-fused compounds using the BH reaction were described. Finally, synthetic strategies for the syntheses of benzo-fused systems were introduced concisely. Chapter 2 showed the strategy for the synthesis of a novel benzo-fused heterocyclic system from ortho-substituted benzaldehydes. Thus, 5-carbomethoxy-4H-1,2,3-triazolo[1,5-a][1]benzazepines from the reaction of several Baylis-Hillman acetates of 2-azidobenzaldehyedes with alkynide Grignard reagents such as phenylethynyl-, 1-propynyl- and ethynylmagnesium bromides were synthesized under this strategy. The readily available ortho-azido BH acetates provided a convenient starting point for the synthesis of this ring system. Treatment of the BH acetates with alkynide Grignard reagents in tetrahydrofuran for 7-24 hours and reflux 2-4 hours gave 5-carbomethoxy-4H-1,2,3-triazolo[1,5-a][1]benzazepine derivatives. In chapter 3, the synthesis of pyranonaphthoquinone derivatives by the application of α-vinylated products as another strategy was introduced. Accordingly, the α-vinylnaphthoquinones were first synthesized as the starting materials under BH reaction conditions. Then, treatment of α-vinyl products with several allyl alcohols afforded disubstituted naphthoquinones. With these diene precursors in hand, the targeted pyranonaphthoquinones were obtained via the ring closing metathesis reaction using Grubbs’ second generation catalyst in refluxing dichloromethane. Finally, chapter 4 described the other strategy for the synthesis of an analogous benzo-fused system from five membered ring molecules. Therefore, the thermal reactivity of the BH acetates of thiazole-2-carboxaldehyde was investigated with the aim of obtaining pyrrolo[2,1-b]thiazole derivatives. The BH adducts of thiazole-2-carboxaldehyde were synthesized as starting materials under various BH reaction conditions. Then, the BH acetates were produced by acetylating the corresponding BH adducts. The desired pyrrolo[2,1-b]thiazoles were obtained successfully from the thermal cyclization reaction in refluxing diphenyl ether. The structures of hitherto novel benzo-fused compounds were established on the basis of 1H NMR, 13C NMR, IR, GC/Mass and HRMS spectroscopic data.