Baylis-Hillman 반응을 이용한 Indenothiophenyl Acrylic Acid 유도체의 합성

Abstract

Baylis-Hillman 반응은 다양한 organic transformation에 적용 되는 치환기를 가지는 구조를 만들 수 있고, atom economical한 반응으로 탄소-탄소 결합을 형성하는 효과적인 방법이다. Friedel-Crafts반응은 기본적인 탄소-탄소 결합 반응 중의 하나로 우리 그룹에서는 intramolecular Friedel-Crafts 반응을 이용하여 2-biphenylcarboxaldehydes 의 Baylis-Hillman adducts로부터 2-(9-fluorenyl)acrylic acid 유도체를 합성하여 발표하였다. Baylis-Hillman 반응에 관한 지속적인 연구를 통해서 이와 같은 방법을 thiophene 과 furan substituted benzaldehydes 에 적용하면 indenothiophenes과 indenofurans 유도체를 합성할 수 있을 것이라는 생각 하에 연구를 진행하게 되었다. Indenothiophene 유도체들은 olefin 계열의 고분자 중합의 촉매로 사용 되고, 키나아제의 병리학적 활성을 막아주거나, 신경계전달물질의 생성에 관여하는 것으로 알려져 있다. 이러한 다양한 활성을 가지고 있는 indenothiophene은 일반적으로 indenothiophenone의 reduction을 통해서 합성된다. Indenothiophenone의 합성법은 크게 Friedel?Crafts 고리화반응, Palladium 촉매를 이용한 고리화반응과, Li을 이용한 metalation 반응 등이 알려져 있다 Heterocyclic substituted benzaldehydes 의 합성은 기존의 문헌에 알려진 방법인 Suzuki cross-coupling반응을 이용하여 합성하였다. β-iodo-Baylis-Hillman adducts는 methyl propiolate, tetrabutylammonium iodide, zirconium (IV) chloride와 heterocyclic substituted benzaldehydes 를 사용하여 합성하였고, 일반적인 Baylis-Hillman adducts는 methyl acrylate, 1,4-diazabicyclo[2,2,2]octane (DABCO), triethanolamine 과 heterocyclic substituted benzaldehydes 를 사용하여 합성하였다. Friedel-Crafts 고리화 반응을 통해 상온에서 Baylis-Hillman adducts에 95% 황산을 가하여 4H-indeno[1,2-b]thiophenes, 8H-Indeno[2,1-b]thiophenes, 8H-Indeno[2,1-b]furans를 합성하였다. 이와 같은 실험을 다른 헤테로 고리 화합물에 적용하려는 시도를 하였으나 2-(pyridin-4-yl)benzaldehyde의 경우에는 β위치에 I를 함유하고 있는 Baylis-Hillman adducts를 얻을 수 없었고, 일반적인 Baylis-Hillman adducts만을 얻을 수 있었으며, methyl 2-[1-hydroxy-1-{2-(pyridin-4-yl)phenyl}methyl] propenoate (2g)를 이용하여 산 조건에서 Friedel-Crafts 고리화 반응을 통해서 methyl 2-(9H-indeno[2,1-c]pyridin-9-yl)acrylate의 합성을 시도하였으나 원하는 화합물을 얻을 수 없었다. 결론적으로 우리 그룹에서는 산 조건하에서 Friedel-Crafts 고리화 반응을 통해서 indenothiophenes 과 indenofurans 유도체를 합성하는 새로운 방법을 증명하였다.; The Baylis-Hillman (BH) reaction has become a powerful tool for construction of carbon-carbon bonds in organic chemistry because it is completely atom economical and provides densely functionalized structural units, which have been successfully employed in a variety of interesting organic transformations. The Friedel-Crafts reaction is one of the most fundamental carbon-carbon bond forming reaction in organic synthesis. Recently, we reported the synthesis of 2-(9-fluorenyl)acrylic acid derivatives from BH adducts of 2-biphenylcarboxaldehydes by an intramolecular Friedel-Crafts reaction. During continued efforts to develop BH chemistry, we subsequently envisioned that application of this protocol to BH adducts of several thiophene- or furan-substituted benzaldehydes might lead to indenothiophenes or indenofurans having acrylic acid unit. Indenothiophene derivatives have received considerable attention in the field of organometallic chemistry because their transition metal complexes have been found to be promising catalysts for olefin polymerization. Indenothiophene is the core structure of potent molecules such as inhibitors of 1kk-β phosphorylation of 1kB and neurotransmitter release enhancers useful in the treatment of cognitive disorders. A general method for the synthesis of indenothiophenes is reduction of corresponding indenothiophenones. The most useful syntheses of indenothiophenones include Friedel-Crafts ring closures of 2-thienylbenzoic acids and derivatives, cycloaromatization of non-conjugated thienyl tetraynes, palladium-catalyzed cyclocarbonylation of o-haloheteroaryls, and direct double metalation of the appropriate 3-phenylhetarene with butyllithium followed by treatment of the resulting dilithium compound with ethyl N,N-dimethylcarbamate. However, far less attention has been devoted to indenofurans synthesis in the literature to date. The required β-iodo-BH adducts were prepared by the reaction of methyl propiolate with tetrabutylammonium iodide, followed by an aldol process with aldehydes in the presence of zirconium (IV) chloride in 62-68% yields. The typical BH reaction of starting material with methyl acrylate, 1,4-diazabicyclo[2,2,2]octane (DABCO), and triethanolamine without solvent gave BH adducts in 61-75% yields. On Friedel-Crafts cyclization of BH adducts with 95% sulfuric acid in tetrachloromethane at room temperature for 2-5 hours, 4H-indeno[1,2-b]thiophenes , 8H-Indeno[2,1-b]thiophenes or 8H-Indeno[2,1-b]furans were produced in 38-71% yields, respectively, presumably through the resonance-stabilized, more stable benzylic carbocation. The structures of 4H-indeno[1,2-b]thiophenes , 8H-Indeno[2,1-b]thiophenes, 8H-Indeno[2,1-b]furans were elucidated by 1H and 13C NMR and elemental analyses. In order to extend the scope of this methodology we have also examined 2-(pyridin-4-yl)benzaldehyde as an aldehyde in this study. The corresponding β-iodo-BH adduct was not produced by the reaction of methyl propiolate with tetrabutylammonium iodide and zirconium (IV) chloride, presumably due to basic nature of the pyridine. When using excess zirconium (IV) chloride and tetrabutylammonium iodide the reaction was unsuccessful. On the other hand, the typical BH reaction of 2-(pyridin-4-yl)benzaldehyde with methyl acrylate, DABCO, and triethanolamine without solvent gave methyl 2-[1-hydroxy-1-{2-(pyridin-4-yl)phenyl}methyl]propenoate in 78% yield. However, on Friedel-Crafts cyclization of methyl 2-[1-hydroxy-1-{2-(pyridin-4-yl)phenyl}methyl] propenoate with sulfuric acid or p-toluenesulfonic acid in tetrachloromethane or tetrahydrofuran at room or reflux temperature the desired methyl 2-(9H-indeno[2,1-c]pyridin-9-yl)propenoate was not produced, instead only decomposition was observed. In conclusion, we have demonstrated a new synthetic method for the preparation of indenothiophenes and indenofurans having acrylic acid unit by Friedel-Crafts cyclization of Baylis-Hillman adducts of hetarenobenzaldehydes. There is some limitation as regards the reactivity of Baylis-Hillman adduct having pyridine ring with sulfuric acid.