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C at eg or y Synthesis of Heterocycles Y. L U , D . - H . WA N G , K . M . E N G L E , J . - Q . YU * ( T H E S C R I P P S R E S E A R C H I N S T I T U T E , LA JOLLA, USA) Pd(II)-Catalyzed Hydroxyl-Directed C–H Olefination Enabled by Monoprotected Amino Acid Ligands J. Am. Chem. Soc. 2010, 132, 5916-5921. K ey wo rd s isochromans C–H olefination Synthesis of Isochromans by PalladiumCatalyzed C–H Olefination palladium 5 R3 + R1 H Pd(OAc)2 (10 mol%) (+)-menthyl(O2C)-Leu-OH (20 mol%) R4 1 R2 R3 O 7 Li2CO3, AgOAc, C6F6, 80 °C, 48 h OH 6 R1 8 R4 3 30–98% yield 18 examples 2 R2 R1 R3 OH R4 4 R1 = H, 5-Me, 6-Me, 7-Me, 6,8-Me2, 6-MeO, 7-MeO, 6,7-(MeO)2, 6,8-(MeO)2, 7-F, 5-Cl, 7-Cl, 7-Br, 7-F3C R2, R3 = Me, n-Pr, i-Bu; R4 = CO2Et, COMe, P(O)(OEt)2 MeO MeO O O CO2Et 5 43% yield O MeO CO2Et 6 63% yield Significance: The synthesis of isochromans 3 from tertiary alcohols 1 and alkenes 2 via a palladium-catalyzed hydroxyl-directed C–H olefination– intramolecular oxidative cyclization sequence is described. Optimization of the reaction conditions showed that the amino acid ligand shown is critical for high conversion. Instructively, hexafluorobenzene is preferred to toluene to avoid competing olefination of the solvent. In general, yields were higher with electron-rich arenes (R1 = Me, OMe) compared to electron-poor ones (R1 = Hal, CF3). The EWG on the alkene is required since only the uncyclized olefins 4 were isolated with electron-neutral alkenes (R4 = alkyl, aryl). The methodology was extended to secondary and primary alcohols (5–8), although the yields were somewhat low due to competing decomposition of the starting materials. CO2Et 7 60% yield 2010 © THIEME STUTTGART • NEW YORK CO2Et 8 28% yield Comment: Compounds containing the isochroman nucleus are found in many natural and synthetic products. Examples include the synthetic musk galaxolide and the NSAID etodolac (E. L. Larghi, T. S. Kaufman Synthesis 2006 , 187). Classical methods for their synthesis include the cyclization of phenylethanols (see Book below) and the oxa-Pictet–Spengler reaction (see Reference above). The current method exhibits high functional group tolerance and uses readily available starting materials, although the catalyst loadings are somewhat high. Book: K. Ding, Z. Wang, In Science of Synthesis, Vol. 37; C. J. Forsyth, Ed.; Georg Thieme Verlag: Stuttgart, New York, 2008 , 514-517. SYNFACTS Contributors: Victor Snieckus, Timothy Hurst Synfacts 2010, 7, 0754-0754Publishedonli e: x .x .201 Published online: 22.06.2010 DOI: 10.1055/s-0029-1220134; Reg-No.: V06410SF © Georg Thieme Verlag Stuttgart · New York 754 O This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R2