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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
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R2