LETTER 998 ▌ 998 letter Regiospecific Synthesis of Novel Furo[4,5-c]coumarins in a One-Pot Reaction Furo[4,5-c]coumarins Bahador Karami,* Saeed Khodabakhshi, Khalil Eskandari Department of Chemistry, Yasouj University, Yasouj, 75918-74831, Iran Fax +98(74)12242167; E-mail: karami@mail.yu.ac.ir Received: 01.01.2013; Accepted after revision: 17.03.2013 Abstract: A new and expedient assembly of an interesting class of amido-substituted furo[4,5-c]coumarins has been successfully achieved through a one-pot sequential coupling and cyclization strategy starting from 4-hydroxycoumarin, aryl glyoxals and benz- amide. All the reactions showed selectivity towards furo[4,5-c]cou- marin, instead of the corresponding isoxazolo-substituted coumarins. Key words: library construction, coumarins, glyoxals, benzamide Furocoumarins have attracted interest due to their estro- genic activity and their presence in foodstuffs such as soy- beans. 1,2 Several synthetic strategies have been reported for coumestan derivatives (such as coumestrol) that com- bine benzofuran and coumarin scaffolds. 3–6 Our continued interest in synthesizing a coumarin-based combinatorial 7–9 library led us to develop an efficient pathway for the preparation of new classes of furocouma- rin molecules. In recent years, several research groups have focused on the synthesis of furo[3,2-c]coumarins as potent biologically active compounds. 10–14 Nair and co- workers have also reported a three-component reaction in- volving [4+1] cycloaddition, leading to amino-substituted furo[3,2-c]coumarin derivatives. 15 This method was im- proved by Wu, who developed a microwave-assisted pro- tocol. 16 As part of an ongoing program for the construction of het- erocyclic compounds, 17–20 we present herein an expedient pathway for the preparation of novel amido-substituted furo[4,5-c]coumarins 4, variously substituted on the five- membered ring, starting from 4-hydroxycoumarin 1 and aryl glyoxals 2 (obtained by selenium dioxide mediated oxidation of the corresponding phenyl ketones 21 ) and benzamide 3 (Scheme 1). Although this reaction could provide two structural isomers, the isoxazolo-substituted coumarins 5 are not observed. Our initial study was performed with 1, phenyl glyoxal 2a and 3 in acetic acid. To prevent the formation of side prod- ucts, such as bis-aroylcoumarins, we first treated benz- amide with phenyl glyoxal 2a to form the imine, followed by addition of 4-hydroxycoumarin 1. 22 Gratifyingly, we observed formation of the desired product 4a. After con- firming the regiospecificity of the reaction by NMR spec- troscopic analysis, we extended our studies to various aryl glyoxals (Table 1) and were pleased to find that the reac- tion led regiospecifically to the desired products. Mechanistically, the following scheme may be invoked to explain the formation of product 4. The reaction is thought to take a place in three steps. It is reasonable to assume that the initial event involves the generation of intermedi- ate A through condensation of benzamide and the aryl glyoxal. In the next step, intramolecular cyclization of in- termediate B gives intermediate C followed by final dehy- dration to form 4 (Scheme 2). In conclusion, we have demonstrated that amido-substi- tuted furo[4,5-c]coumarins can be produced from 4-hy- droxycoumarin, aryl glyoxals and benzamide. Scheme 1 O O OH Ar O HO OH H O NH 2 O O OH O N Ar O O Ar HN O O + 1 2 3 4 5 70–90% 0% + SYNLETT 2013, 24, 0998–1000 Advanced online publication: 09.04.20130936-52141437-2096 DOI: 10.1055/s-0032-1316895; Art ID: ST-2013-D0002-L © Georg Thieme Verlag Stuttgart · New York Downloaded by: CSIC - Centro Nacional de Quimica Organica. Copyrighted material.