Baylis-Hillman 반응을 이용한 Thiochromenes의 합성

Abstract

Thiobenzopyran 유도체와 thiochromene은 anti-inflammation,^(1) anti-HIV,^(2) anti-bacteria,^(3) anti-hyperplasia,^(4) anti-psychiatric^(5) 와 anti-cancer^(6)에 생리 약리활성 효과를 가지고 있어 최근 다양한 연구가 진행되고 있다. 이러한 생리 약리활성이 있는 thiochromene을 보다 효과적으로 합성할 수 있는 방법이 중요하게 대두되고 있다. 본 연구는 이미 발표된 thiochromene의 합성 방법들의 단점을 보완하며, 경제적이고 효과적인 방법으로 thiochromene 합성을 시도하였다. ortho 위치에 leaving group (halogen, nitro) 을 포함한 benzaldehydes를 starting물질로 사용하여 Baylis-Hillman acetate를 합성한 후 thioacetic acid를 이용하여 thioester 그룹을 도입했다. Thioester 그룹을 hydrolysis하여 분자 내 SNAr반응(intramolecular nucleophilic aromatic substitution) 으로 thiochromene의 합성을 시도하였으나 기대했던 thiochromene은 합성되지 않고 autooxidation^(7)에 의해 symmertrical diallyl disulfide가 합성 되었고 disulfide bond를 끊어 thiochromene의 합성을 시도해보았지만 원하는 물질을 얻을 수 없었다. 적절한 nucleophile을 찾던 중 bis-nucleophile 인 sodium sulfide를 생각하게 되었고 BH acetate에서 one-pot으로 sodium sulfide를 aqueous dimethyl sulfoxide (DMSO) 용매 하에서 분자 내 SNAr반응으로 새로운 방법으로 thiochromene을 합성할 수 있었다. Thiochromene 합성과정 중 중간체를 거치는 것이 관찰되었고 반응시간 (5분) 으로 조절하여 중간체를 분리하여 spectra data를 비교해본 결과 symmetric diallyl disulfide가 중간체임을 확인한 결과로 가능성 있는 mechanism을 제시할 수 있었다. BH chemistry를 이용하여 새롭게 효과적으로 thiochromene을 합성하는 방법을 제시했다.; Recently, several studies have examined thiochromene units, sulfurcontaining analogues of benzopyran, because they demonstrate a wide range of biological activities. For instance, thiochromenes exhibit antiinflammation, ^(1) anti-HIV,^(2) anti-bacteria,^(3) anti-hyperplasia,^(4) antipsychiatric^(5) and anti-cancer^(6) activities. Therefore, it is important to develop new and more efficient synthetic pathways to achieve a diverse array of thiochromene pharmacophores. In principle, compounds having the thiol group at the allylic position of 3-arylpropenoates after hydrolysis of the thiolester group might be extended further to build thiochromene derivatives via an intramolecular nucleophilic aromatic substitution reaction (SNAr). However, after a hydrolysis reaction of 2- acetylthiomethylpropenoates, no traces of the intended allyl thiols were produced. Instead, symmetrical diallyl disulfides were produced via autooxidation of thiols^(7) At this stage, a one-pot procedure might be used to obtain 3-carbomethoxy-2H-thiochromenes using bis-nucleophile sodium sulfide. Sodium sulfide (3 mmoles) was added to a stirred solution of BH acetate (2 mmoles) in aqueous dimethyl sulfoxide (7.7 ml, v/v= 10/1) at 40 °C. After stirring for 10 minutes to 36 hours, the reaction mixture was diluted with water (20 ml) and extracted with diethyl ether (3 × 50 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The resulting mixture was chromatographed on silica gel and eluted with hexane/ethyl acetate (10:1) to produce thiochromenes as an oil or solid. we developed a new strategy for the synthesis of 3-carbomethoxy-2H-thiochromenes from easily accessible BH acetates and sodium sulfide. Although satisfactory results in product yields were not obtained, the efficacy of BH chemistry in heterocycle synthesis was demonstrated.