Baylis-Hillman 반응을 이용한 2-(9-Fluorenyl)acrylic Acid, 2-Amino-3H-1-benzazepine, 2,3-Dihydro-1H-indole 유도체의 합성

Abstract

Carbon-carbon bond formation is the most important and fundamental research area in organic chemistry as one of the challenging areas. There are numerous reported C-C bond formation reactions such as aldol, Reformatsky reaction, Claisen rearrangement, Diels-Alder, Wittig, Heck, Suzuki, Grubb's ring closing metathesis, and so forth. As one of the C-C bond formation reaction, Baylis-Hillman reaction has attracted the attention of a number of chemists in recent years as providing synthetically useful multifunctional molecule, which has grown from obscure level to the level of high synthetic popularity. As a part of group work, the key idea of my research was focused on Baylis- Hillman reaction followed by manipulation of BH adducts in order to furnish the cyclized target molecules. The results of researches were expressed in both chapter 1 and 2. In Chap 1, treatment of propiolic acid esters or N,N-dimethylpropynamide and various 2-biphenylcarboxaldehydes with Bu4NI/ZrCl₄, TiCl₄/Me₂S, or TiBr₄/Me₂S combination or treatment of methyl acrylate and 2-biphenylcarboxaldehydes with 1,4-diazabicyclo[2,2,2]octane (DABCO) and triethanolamine induce aldol-type reaction to furnish α-halo-α-(hydroxymethyl)acrylates or α-(hydroxymethyl)acrylates, respectively. These can be used for the preparation of 2-(9-fluorenyl)acrylic acid derivatives by intramolecular Friedel-Crafts reaction with sulfuric acid in tetrachloromethane. These fluorene containing acrylic acid derivatives will be able to dedicate to various research areas. In Chap 2, starting materials, [2-formamido, 2-acetamido, 2-propanoylamido, 2-benzoylamido]benzaldehydes, were prepared from [2-amino, 2-amino-5-chloro, 2-amino-methyl]benzyl alcohols, following the known procedure: N-protection and PCC oxidation of primary alcohol. Next, 3-[2-formamido-, 2-acetamido-, or 2-(propanoylamino)phenyl]-substituted methyl 2-(cyano-methyl)propenates were obtained from Morita-Baylis-Hillman reation of N-protected o-aminobenzaldehydes with methyl acrylate followed by acetylation and cyanation. Subsequently, 2-amino-3H-1-benzazepine-4-carboxylates or 2-(cyano-methyl)-2,3-dihydro-1H-indole-2-carboxylates were prepared from the reaction of 3-[2-formamido-, 2-acetamido-, or 2-(propanoylamino)phenyl]-substituted methyl 2-(cyanomethyl)propenates with sodium methoxide in methanol, respectively.; 탄소 탄소 결합은 유기화학의 가장 중요하고 기초적인 연구분야로 서 여전히 많은 연구가 지속되고 있는 반응의 하나이다. 그 예로 aldol reaction, Reformatsky reaction, Claisen rearrangement, Diels-Alder, Witting, Heck, Suzuki, Grubb’s ring closing methathesis 등의 반응들이 있다. Baylis-Hillman (B-H) 반응은 탄소 탄소 결합 형성 반응의 하나로 합 성적으로 매우 유용한 다양한 작용기를 지닌 분자를 제공함으로써 많은 화학자들의 관심의 대상이 되어 왔다. 본인의 지난 2 년간 연구는 Baylis-Hillman 생성물의 화학적 변환과 고리화 반응을 통해 원하고자 하는 다양한 화합물들을 합성하는 일 이었고 그 결과는 다음과 같다. Chapter 1. 목적 화합물 합성에 필요한 중간체 화합물 합성을 위해 propiolic acid esters 또는 N,N-dimethylpropynamide 와 다양한 종류의 2-biphenylcarboxaldehydes 를 Bu4NI/ZrCl₄, TiCl₄/Me₂S 또는 TiBr₄/Me₂S 조건 하에서 반응시켜 β-halo-α-(hydroxymethyl)acrylates 를 얻어낼 수 있었다. 다른 방법으로는 methyl acrylate 와 2-biphenyl-carboxaldehydes 를 1,4-diazabicyclo[2,2,2]octane (DABCO), triethanolamine 촉매하에서 반응시켜 aldol 타입의 반응을 통해 α-(hydroxylmethyl)-acrylates 를 얻 어낼 수 있었다. 이렇게 준비된 다양한 중간체 화합물들을 사염화 탄소를 용매로 하여 황산을 가해주었을 때 분자 내 Friedel-Crafts 반 응을 통해 2-(9-fluorenyl)acrylic acid derivatives 가 생성되는 것을 확 인할 수 있었다. 이렇게 새로운 방법으로 합성된 acrylic acid derivative 를 함유한 fluorene 화합물은 다양한 연구 분야에 기여할 수 있을 것이다. Chap 2. 출발 화합물인 [2-formamido, 2-acetamido, 2-propanoylamido, 2- benzoylamido]benzaldehydes 는 [2-amino, 2-amino-5-chloro, 2-amino-5- methyl]benzyl alcohols 로부터 알려진 방법에 따라 amine group 의 pretection 과 1 차 알코올의 PCC oxidation 을 통해 준비하였다. 다음 으로는 N-protected 2-aminobenzaldehydes 와 methyl acrylate 로부터 얻 어진 Baylis-Hillman 생성물을 시작으로 연속적으로 acetylation, cyanation 반응을 하여 중간체 화합물들을 얻어내었다. 준비된 중간 체 화합물 3-[2-formamido-, 2-acetamido-, or 2-(propanoylamino)-phenyl]- substituted methyl 2-(cyanomethyl)propenates 에 methanol 을 용매로 sodium methoxide 를 가하였을 때 2-Amino-3H-1-benzazepine-4- carboxylates 와 2-(cyanomethyl)-2,3-dihydro-1H-indole-2-carboxylate 가 합성되었다.