Synthesis of Coumarin Derivatives using o-Hydroxybenzophenones with Phenylacetic Acid and Acetic Anhydride

Abstract

The coumarin subunit has been interested because it is found in many natural products displaying diverse biological activities. The range of compounds includes antifungals, anticoagulants, compounds active against psoriaris, and carcinogen. So, many studies have been performed for the efficient syntheses of coumarin derivatives. There have been many synthetic routes to the coumarins, including the Perkin, Knoevenagel, and Pechmann reactions. In the present study, coumarin derivatives which contain two phenyl groups were prepared by Ac_(2)O and phenylacetic acid from o-hydroxybenzophenones in the presence of TEA in acetone at 55℃. In the Sham and Ray method, the yields of coumarin derivatives were lower than ours due to Ac_(2)O as solvent. Our results showed higher yields of coumarin derivatives than the Shama and Ray's method in the previous papers. A new intermediate form was proposed to our mechanism on these reactions. The key role of this intermediate was the ring conformation toward final coumarin products. This ring conformation in stable intermediate did not convert to coumarin easily. The effect of solvent, base, and temperature was studied to get optimal conditions of reactions. In the last of this paper, reactivity of o-hydroxybenzophenone derivatives was discussed as two factors of inductive effects on the two benzene ring with substituents. First, electron-donating group in benzene rings enhanced the reactivity of 2-hydroxy group in 0-hydroxybenzophenone as nucleophile. Second, electron-withdrawing group in benzene rings enhanced the reactivity of carbonyl carbon in 2-hydroxybenzophenone as nucleophilic center. Finally, the results of these two inductive effects of substituents on the benzene ring showed a variable yields due to the compensation of two factors in 2-hydroybenzophenone derivatives.;약학적으로 유용성이 큰 coumarin과 chromone은 독성이나 돌연변이성이 없어 오래전부터 많은 연구가 있었다. 이에 본 연구에서는 coumarin의 합성 방법들을 살펴보고, 몇 가지 유도체들을 합성하는 실험을 시도하였다. 실험 방법은 Ac_(2)O/Et_(3)N(TEA) induced condensation을 이용하여 ο-hydroxybenzophenone 유도체 (2-hydroxybenzophenone, 2,2'-dihydroxybenzophenone, 2,4-dihydroxybenzophenone, 2-hydroxy-5-methylbenzophenone, 5-chloro-2-hydroxy-4-methylbenzophenone 및 2,4-dihydroxybenzophenone에 alkylation시킨 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-ethoxybenzophenone 그리고, 2,4,4'-trihydroxybenzophenone에 methylation시킨 2-hydroxy-4,4'-dimethoxybenzophenone)들을 출발물질로 하여 coumarin 유도체들을 합성하였다. 염기로는 triethylamine, pyridine, DMAP등 아민류를 사용하였고, 용매는 아세톤과 CH_(2)Cl_(2), acetic anhydride 등을 사용하여 효과를 비교해 보았다. 그리고, 2,4-Dihydroxybenzophenone에서 2-Hydroxy-4-methoxy, 2-Hydroxy-4-ethoxybenzophenone을 합성할 때 촉매효과를 보인 DMAP와 선행연구에서 효과가 있다고 보고한 phenol의 촉매 효과를 비교하였다. 합성한 coumarin 유도체들은 3,4-diphenylcoumarin, 7-methoxy-3,4-diphenylcoumarin, 7-ethoxy-3,4-diphenylcoumarin, 6-methy-3,4-diphenylcoumarin, 7-methoxy-4-(4'-methoxyphenyl)-3-phenylcoumarin, 4-(2'-acetoxy-phenyl)-3-phenylcoumarin, 7-acetoxy-3,4-diphenylcoumarin, 6-chloro-7-methyl-3,4-diphenylcoumarin 등 coumarin 유도체들과 coumarin 합성의 출발물질이 된 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-ehtoxybenzophenone들이다. 반응결과는 ο-hydroxybenzophenone을 같은 몰량의 phenylacetic acid를 사용하여 염기인 triethylamine(TEA)와 acetic anhydride를 ο-hydroxybenzophenone에 대해 1:8의 비율로 acetone에서 reflux온도로 반응시켜 coumarin 유도체들을 합성한 경우가 가장 수득율이 좋았다. 이것은 용매로 Ac_(2)O를 사용한 선행연구보다 좋은 결과였다. 치환체에 따른 반응성 비교 실험을 하였는데, 2-hydroxy기의 nucleophilicity를 증가시켜 반응성을 높이는 역할과 carbonyl carbon의 극성화된 양전하를 증가시켜 반응성을 높이는 역할로서의 치환기의 영향을 살펴보았다.