Palladium catalysed arylation of 6,8-dimethoxybenzofuranone Abdelkarim Sani Souna Sido, Loı ¨c Boulenger and Laurent De ´saubry * UMR 7175-LC1, Department of Medicinal Chemistry, Faculte ´ de Pharmacie, 67401 Illkirch cedex, France Received 26 July 2005; revised 9 September 2005; accepted 12 September 2005 Available online 3 October 2005 Abstract—6,8-Dimethoxybenzofuranone was arylated in the presence of a palladacycle catalyst and p-methoxyphenol to afford pre- cursors of anti-cancer and anti-inflammatory drugs. Ó 2005 Elsevier Ltd. All rights reserved. Rocaglamide 2 and its related flavaglines isolated from plants of the Aglaia species exhibit potent cytostatic and proapoptotic activity in cancer cells, but are not toxic to the organism. 1–3 Recent findings have shown that these compounds also display potent anti-inflam- matory properties both in vitro and in vivo. 4,5 Their cel- lular target and mechanism of action are considered to be distinct from those of known anti-inflammatory and anti-cancer agents. The most straightforward syntheses of flavaglines start from 1 (Fig. 1). 6,7 However, these approaches suffer from the difficulty to prepare 2-arylbenzofuranones: the synthesis of these com- pounds by the Hoesch reaction is restricted to benzo- furanones substituted by electron-donating groups. 8 Moreover, this reaction displays a lack of reproducibil- ity as reported by Taylor and co-workers, and verified by us. 6 In the course of our research on the structure–activity relationship of rocaglamide, we needed to develop a concise and flexible synthesis of 2-arylbenzofuranones. The recent development of palladium-catalysed a-aryla- tion of ketones provides an opportunity to prepare these compounds. 9 To explore this reaction, we chose pallada- cycle 4 as a catalyst, due to its efficiency, stability and ease of preparation. 10 First, we examined the reaction of dimethoxybenzofura- none 3 with phenyl bromide in toluene under reflux. The use of K 3 PO 4 as a base led exclusively to the formation of tar (Table 1, entry 1). Switching to a stronger base, t-BuOK, afforded the expected adduct 5 in low yield as well as O-phenyl ether 6 and diadduct 7 (entry 2). Because the efficiency and the cleanliness of the reaction were poor, we examined whether the addition of p-meth- oxyphenol could improve this process as it has been ob- served by Buchwald with the arylation of enolates catalysed by Pd 2 (dba) 3 . 11 We were pleased to observe that this additive doubled the yield and suppressed totally the formation of diadduct 7 (entry 3). As far as we know, it is the first observation that a phenolate increases the efficiency of a palladacycle catalyst. Increasing the quantity of phenylbromide to 2 equiv increased the yield up to 48% (entry 4). Only 10% of the by-product 6 was formed. Lowering the amount of t-BuOK to 2.5 equiv or replacing toluene by DMF decreased both the yield of arylation (entries 5 and 6). As experience was gained with the previous example, we successfully applied the a-arylation reaction to several bromoarenes (Table 2). 12 Arylated benzofuranones were obtained in reasonable yields with a predominance of the desired adducts 8. 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.09.062 Keywords: Arylation; Benzofuranone; Palladacycle. * Corresponding author. Tel.: +33 390 244 220; fax: +33 390 244 310; e-mail: desaubry@pharma.u-strasbg.fr O O MeO OMe OMe O MeO MeO OMe HO Ph HO O NMe 2 2 1 Figure 1. Rocaglamide 2 and its synthetic precursor 1. Tetrahedron Letters 46 (2005) 8017–8018 Tetrahedron Letters