PAPER 2281 E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans by Reaction of Silyl Enol Ethers with Phthaloyl Dichloride E/Z-Selective Synthesis of Alkylidene-3-oxo-3H-isobenzofurans Satenik Mkrtchyan, a Zorik Chilingaryan, a,b Gagik Ghazaryan, a,b Rüdiger Dede, a Nasir Rasool, a,c Muhammad A. Rashid, a Alexander Villinger, a Helmar Görls, d Gnuni Karapetyan, a Tariel V. Ghochikyan, b Ashot Saghiyan, b,e Peter Langer* a,f a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany b Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia c Government College University, Faisalabad, Punjab, Pakistan d Institut für Anorganische und Analytische Chemie, Universität Jena, August-Bebel-Str. 2, 07740 Jena, Germany e CJSC Scientific Research Institute of Biotechnology, Gyurjyan Str. 14, 0056, Yerevan, Armenia f Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de Received 22 March 2011; revised 6 May 2011 SYNTHESIS 2011, No. 14, pp 2281–2290xx.xx.2011 Advanced online publication: 15.06.2011 DOI: 10.1055/s-0030-1260071; Art ID: N32011SS © Georg Thieme Verlag Stuttgart · New York Abstract: The reaction of silyl enol ethers with phthaloyl dichlo- ride afforded alkylidene-3-oxo-3H-isobenzofurans with very good E/Z-selectivity. Key Words: cyclizations, O-heterocycles, phthalic acid deriva- tives, silyl enol ethers g-Alkylidenebutenolides are present in a number of natu- ral products. 1 They are synthetically available by lacton- ization of 2-en-4-ynoic acids 2 or by stereospecific b- eliminations 3 and other methods. Highly unsaturated de- rivatives, such as the natural products lissoclinolide or di- hydroxerulin, have been prepared by Wittig reaction of g- (3-phosphaprop-2-enylidene)butenolides with aldehydes or by the reaction of g-(3-oxaprop-2-enylidene)buteno- lides with phosphoranes. 4 Simple g-alkylidenebutenolides can be synthesized by Wittig reaction of maleic anhy- drides with stabilized phosphorus ylides. 5 Recently, we have reported the preparation of g-(2,4-dioxobut-1- ylidene)butenolides by Wittig reaction of (2,4-dioxobu- tylidene)triphenylphosphanes. 6 Some years ago, we have developed an alternative approach to g-alkylidenebuteno- lides based on the cyclization of 1,3-bis(silyl enol ethers) 7 with oxalyl chloride. 8 3-Alkylidene-3H-isobenzofuran-1-ones can be regarded as benzoannulated g-alkylidenebutenolides. Naturally oc- curring derivatives include (racemic) senkyunolide E, 9 thunberginol F, 10 and dactylicapnosine (Figure 1). 11 3- Alkylidene-3H-isobenzofuran-1-ones have been prepared mainly by condensation of 1,3-dicarbonyl compounds with phthaloyl dichloride, 12 Wittig reactions of phthalic anhydride, 13 and palladium-catalyzed cyclizations. 14 Re- cently, we have reported the synthesis of 3-(2,4-dioxobut- 1-ylidene)-3H-isobenzofuran-1-ones based on the reac- tion of 1,3-bis(silyloxy)buta-1,3-dienes with phthaloyl dichloride. 6 Herein, we report what are, to the best of our knowledge, the first reactions of 3-silyloxy-2-en-1-ones with phthaloyl dichloride. These reactions provide a con- venient approach to alkylidene-3-oxo-3H-isobenzo- furans. Figure 1 Structure of naturally occurring 3-alkylidene-3H-isoben- zofuran-1-ones The reaction of phthaloyl dichloride (1) with 1,3-bis(silyl- oxy)buta-1,3-diene 2, derived from ethyl acetoacetate, has been reported 6 to result in the formation of ethyl (Z)-3- oxo-4-[1-oxoisobenzofuran-3(1H)-ylidene]butanoate (3) (Scheme 1). The best yields were obtained when the reac- tion was carried out in the absence of any Lewis acid. The reaction of 1 with 3-silyloxy-2-en-1-one 4a, available from methyl acetoacetate in one step, resulted under iden- tical conditions in the formation of a complex mixture. The use of Me 3 SiOTf (0.3 equiv) also gave unsatisfactory results. After some experimentation, the desired product, 3-alkylidene-3H-isobenzofuran-1-one 5a, was formed in up to 48% yield when 1.0 equivalent of TiCl 4 was em- ployed and when the reaction was carried out in the pres- O OH O senkynolide E OH O O OH OH thunberginol F O O O O OMe OMe N O Me N O O O MeO MeO Me H H dactylicapnosine