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X . WA N G , Y. L U , H . - X . D A I , 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 , L A J O L L A ,
USA)
Synthesis of
Heterocycles
Pd(II)-Catalyzed Hydroxyl-Directed C–H Activation/C–O Cyclization: Expedient Construction of
Dihydrobenzofurans
J. Am. Chem. Soc. 2010, 132, 12203-12205.
K e y w ord s
Palladium(II)-Catalyzed Heteroannulation
Route to Dihydrobenzofurans
3
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.5 equiv)
R
R1
H
OH
Li2CO3, C6F6, 100 °C, 36 h
1
dihydrobenzofurans
C–H activation
palladium
4
5
R1
6
R2
O
R3
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R2
C a te go r y
2
42–91% yield
22 examples
R1 = H, 4-Me, 5-Me, 6-Me, 5-OMe, 6-OMe, 6-F, 4-Cl, 5-Cl, 6-Cl, 4-Br, 6-Br, 6-CF3, 6-CO2Me, 5,6-(OMe)2
R2 = Me, Et, n-Pr
R3 = H, Me, n-Pr, i-Bu, Bn, Ph, CO2Et
Significance: Reported is the synthesis of di-
hydrobenzofurans 2 from homobenzylic alcohols
1 via an intramolecular palladium-catalyzed C–H
activation/C–O cyclization sequence. Both EDGs
and EWGs are tolerated at various positions
around the ring. Yields are excellent (>75%) in almost all cases, except for R3 = CO2Et (50%) and
R3 = H (42%). The stability of halogen substituents
(R1 = Cl, Br) to the reaction conditions, providing a
handle for further functionalization, is worthy of
note. Two examples of spirocyclic dihydrobenzofurans (a model system for the core structure of
the natural product stachybotrylactam) were also
prepared in high yield.
Comment: The dihydrobenzofuran ring system is
common in many natural products (e.g. stachybotrylactam, rocaglamide) and pharmaceuticals
(e.g. oxycontin). Although amine-directed C–H
activation for the formation of azacycles has been
previously developed, the use of a hydroxyl group
for such a process is less common. The current
method provides a convenient entry into dihydrobenzofurans in excellent yield and with high
functional group tolerance. The scope of this
methodology is limited, however, by the need for
a 2,2-dialkyl moiety to achieve the best yields.
Victor Snieckus, Timothy Hurst
Synfacts 2010, 11, 1223-1223 Publishedonli e:x .x .201 Published online: 21.10.2010
DOI: 10.1055/s-0030-1258837; Reg-No.: V13310SF © Georg Thieme Verlag Stuttgart · New York
SYNFACTS Contributors:
2010 © THIEME STUTTGART • NEW YORK
1223