2-Alkynylbenzaldehydes의 Baylis-Hillman 생성물로부터 Dipolar 경로를 통한 Naphtho[2,1-c]isoxazoles의 합성

Abstract

Carbon-Carbon bond를 이끌어 내는 반응으로 최근에 organic trans-formations에 자주 쓰이고 있는 Baylis-Hillman 반응이 많은 주목을 받고 있다. 최근 들어 Baylis-Hillman adducts를 이용하여 benz-annulated system 또는 여러 heterocyclic system 에 대한 편리한 합성 방법을 다양하게 제시하고 있다. 여기에는 indolizines, quinolines, chromenes, thiochromenes, indenes, pyridopyrimidones, 1,4-oxazepin-7-ones and coumarins 등의 합성이 알려져 있다. 우리그룹은 새로운 기능성이나 새로운 생리활성을 줄 수 있는 후보물질의 발견은 새로운 화학을 이용할 때 가능성이 가장 크다는 생각 하에 그 동안 생리활성이 기대되는 물질 탐색, 합성 및 새로운 방법론을 개발하는 연구를 수행하였다. 우리그룹은 4-5년 동안 Baylis-Hillman reaction과 헤테로고리 화합물에 관한 다양한 지식을 축적하였고, 본 연구를 계속 발전시켜 Baylis-Hillman reaction을 통해 천연물의 기본적인 단위를 합성하는데 관심을 가지게 되었다. 그래서 우리는 nitrile oxide와 alkyne 과의 intramolecular 1,3-dipolar cycloaddition 을 통해 cyclization을 시켜 다양한 생물학적 특성과 의학적 용도, 산업적 용도를 가진 isoxazole 의 편리한 합성을 성공적으로 수행하였다.; Baylis-Hillman reaction is an emerging carbon-carbon bond forming reaction. It involves the coupling of the 6-position of activated alkenes with carbon electrophiles under the influence of a tertiary amine or Lewis base. Although it has long reaction time, it possesses the two most important requirements, atom economy and generation of functional groups. So it qualifies to be in the list of efficient synthetic reactions. And it continues to stimulate research due to its immense synthetic potential among them. We synthesize 4-carbomethoxynaphtho[2,1-c]isoxazoles via the treatment of the acetates of Baylis-Hillman adduct of 2-alkylnylbenzaldehydes with nitrite anion and subsequent in situ generation of nitrile oxides by the dehydration of 2-nitromethylcinnamates with phenyl isocyanate-triethylamine. Treatment of Baylis- Hillman acetates 2a-d with sodium nitrite in DMF at room temperature for 1.5-10 hours afforded o-acetylenic 2-nitromethylcinnamic acid methyl esters in 3a-d 20- 70% yields. A better result was obtained when Methyl 3-(2-Ethynylphenyl)-2- 45 nitromethyl-2-propanoate 2a in dichloromethane was treated with sodium nitrite in the presence of tetrabutylammonium fluoride hydrate at room temperature for 6 days, thus providing 3a in 53% yield. The (E)-sterochemistry of the products was established by comparing 1H nmr values of olefinic and methylene protons with literature values. In situ generation of nitrile oxides by the dehydration of 2- nitromethylcinnamic acid methyl esters 3a-d with phenyl isocyanate in the presence of catalytic amounts of triethylamine, and subsequent intramolecular 1,3-dipolar cycloaddition reation of nitrile oxides to triple bonds in refluxing toluene produced in moderate yields of the corresponding 4-carbomethoxynaphtho[2,1-c]isoxazoles.