Baylis-Hillman 반응을 이용한 Benzo-fused 7-Membered Lactone의 합성

Abstract

Baylis-Hillman 반응은 탄소 탄소 결합 형성 반응의 하나로 합성적으로 매우 유용한 다양한 작용기를 지닌 분자를 제공함으로써 많은 화학자들의 관심의 대상이 되어 왔으며 최근에는 bezo-fused heterocycle들의 편리한 합성법으로 다양한 연구가 활발하게 진행되고 있다. 우리 그룹은 B-H 반응을 이용하여 생리활성을 가진 여러 헤테로고리 화합물을 합성하였고, 현재에도 연구하고 있다. 본인의 지난 2년간 연구 또한 B-H 생성물의 고리화 반응을 통해 다양한 헤테로고리 화합물을 합성하는 일이었고 그 결과는 다음과 같다. Salicyl aldehyde의 Baylis-Hillman 반응은 coumarin 이나 chromene 유도체가 생성되는 것으로 알려져 있어 반응성이 좋은 -OH 치환기를 benzyl group으로 protecting하고 metyl acrylate 3당량과 DABCO, triethanolamine을 촉매로 사용하여 Baylis-Hillman 생성물을 얻었다. 그 후, DMAP과 acetic anhydride를 이용하여B-H acetate를 85-98%의 수율로 얻었고, DMSO:H₂O (3:1)를 용매에서KCN을 이용하여 S_(N)2'type의 반응을 진행시켜 11a-f 생성물을 69-91%의 수율로 얻을 수 있었다. 모든 반응의 경우 100% E - form의 stereoselectivity를 가지는 것을 ¹H nmr 분석을 통하여 확인할 수 있었다. Debenzylation은 boron trifluoride etherate와 dimethyl sulfide, dichloromethane을 사용하여 12a-f를 65-84%의 수율로 얻을수 있었으며 toluene 용매와 para-toluenesulfonic acid 조건에서 0.5-8시간 동안 환류시켜 Pinner cyclization을 통하여 원하는 생성물인 7-membered lactone을 50-87%의 수율로 얻을 수 있었다. Electron-donating 또는 electron-withdrawing 치환기가 있는 salicyl aldehyde로 반응을 진행시켰지만 모두 비슷한 수율을 나타내어 치환기의 영향은 없는 것으로 판단되었다. 또한 sodium methoxide와 methanol을 용매로 사용한 base 조건에서는 3-cyanomethyl coumarin 16 생성물이 낮은 수율로 합성되었고 (36%), 출발물질인 12a가 25%의 수율로 회수 되었으며 예상했던 dihydrobenzofuran 17의 화합물은 생성되지 않았다.; As one of the carbon-carbon 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 Bayli-Hillman adducts in order to furnish the cyclized target molecules. These are the result of research. The Baylis-Hillman reactions of salicylaldehydes with acrylic acid esters are well known and to afford a mixture of coumarins and chromenes, directly. So, treatment of several known O-benzyl protected 2-hydroxybenzaldehydes 8a-f with 3 equivalents of methyl acrylate and triethanolamine in the presence of 1 equivalent of 1,4-diazabicyclo[2,2,0]octane (DABCO) without solvent at room temperature produced BH adducts, methyl 3-(2-benzyloxy)phenyl-3-hydroxy-2-methylenepropanoates 9a-f in 69-95% yields. The reaction of 9a-f with acetic anhydride in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) in dichloromethane at room temperature gave BH acetates 10a-f in 85-98% yields. The cyanation reaction of the acetates 10a-f with potassium cyanide in dimethyl sulfoxide-water (3:1) at room temperature occurred in an S_(N)2´ fashion to give methyl 3-(2-benzyloxy)phenyl-2-(cyanomethyl)-propenoates 11a-f (69-91%). In all cases, the stereoselectivity was found to be 100% E-selectivity, as determined by ¹H nmr analysis of alkene and methylene protons by comparison with literature values. Debenzylation of 11a-f using boron trifluoride etherate and dimethyl sulfide in dichloromethane gave the required key intermediate methyl 3-(2-hydroxyphenyl)-2-(cyanomethyl)propenoates 12a-f in 65-84% yields. We investigated intramolecular Pinner cyclization reaction using 12a-f with para-toluenesulfonic acid in toluene. After stirring the mixture at reflux temperature for 0.5-8 hours, the desired methyl 2-oxo-2,3-dihydrobenzo[b]oxepine-4-carboxylates 14a-f were obtained in 50-87% yields. Electron-donating or electron-withdrawing substituted compounds gave the corresponding benzoxepines in reasonable yields. Next we examined a reaction using 12a with sodium methoxide in methanol. After stirring the mixture at reflux temperature for 24 hours, the only product 3-cyanomethyl coumarin 16 was obtained in a disappointing yield (36%) along with the recovered starting compound 12a (25%). When using excess base the increase of yield was unsuccessful. Apparently under these reaction conditions, base-promoted E/Z isomerization took place preferentially to give 15, followed by subsequent formation of lactone to produce coumarin 16. The possible dihydrobenzofuran 17 was not obtained.