development of a process that operates under the standard
mild conditions for radical cyclization (Bu3SnH, catalytic
AIBN, refluxing PhH) would undoubtedly be useful. Recent
publications7,8 from this laboratory have described an indirect
method for effecting such reactions, where the ring being
formed contains oxygen7 or nitrogen8 (eq 1, X ) O or
NCOOPh). A key step in the approach for oxygen-containing
heterocycles (Scheme 1) is oxidative conversion of the
several appropriately substituted para-alkyl phenols, we
found that yields are poor (<50%) for MeOH,12 t-BuOOH,13
or water11 as the external nucleophile.14 Consequently, we
considered alternative key intermediates that conform to the
general structure 9, where Y is a group that can be removed
in the final process of rearomatization, and we eventually
selected Y ) CO2Bu-t as a suitable candidate. This choice
was guided in part by the fact that preparation of the
corresponding methyl esters had already been described (Y
) CO2Me in 9),15 and we expected that the same procedure,
using tert-butyl esters, would be applicable to the problem
at hand.
Scheme 1. Formal Cyclization onto an Aromatic Ring
By analogy with the methyl ester route,15 t-butyl benzoate16
was subjected to Birch reduction (Scheme 2), and the
Scheme 2. Formal Cyclization onto a Benzene Ring
benzenoid substrate into a cross-conjugated ketone (3 f 4);
this undergoes radical cyclization (4 f 5), and then acid-
catalyzed rearomatization (5 f 6) generates the product of
formal closure onto the benzene ring (cf. eq 1). The
corresponding process for benzo-fused nitrogen heterocycles8
is similar, except that a different method is used to prepare
the key cross-conjugated ketone.
A useful feature of the route is that after the radical
cyclization an additional substituent can be introduced (cf.
5 f 6, R ) alkyl or aryl). We have now modified our
approach so that it can be applied to the case of benzo-fused
carbocycles (cf. eq 1, X ) carbon).
Although direct extension of Scheme 1, along the lines
summarized in eq 2, would seem an obvious first step,9 it is
intermediate anion was trapped by alkylation with 1,3-
dibromopropane. Oxidation of the resulting diene, using CrO3
in Ac2O-AcOH,17 served to produce the desired cross-
known that oxidation of para-alkyl phenols rarely affords
good yields,10,11 and in test experiments of our own, with
(12) Cf.: Pelter, A.; Ward, R. S.; Abd-El-Ghani, A. J. Chem. Soc., Perkin
Trans. 1 1992, 2249-2251.
(13) We examined t-BuOOH because a few examples of phenol oxidation
in acceptable yield had been reported: (a) Murahashi, S.-I.; Naota, T.;
Miyaguchi, N.; Noda, S. J. Am. Chem. Soc. 1996, 118, 2509-2510. (b)
Ochiai, M.; Nakanishi, A.; Yamada, A. Tetrahedron Lett. 1997, 38, 3927-
2930.
(7) Clive, D. L. J.; Fletcher, S. P.; Liu, D. J. Org. Chem. 2004, 69, 3282-
3293.
(8) Fletcher, S. P.; Clive, D. L. J.; Peng, J.; Wingert, D. A. Org. Lett.
2005, 7, 23-26.
(9) For a related approach to cyclization onto a cross-conjugated ketone,
see: Villar, F.; Kolly-Kovac, T.; Equey, O.; Renaud, P. Chem.-Eur. J.
2003, 9, 1566-1577.
(10) For example: (a) Camps, P.; Gonza´lez, A.; Mun˜oz-Torrero, D.;
Simon, M.; Zu´n˜iga, A.; Martins, M. A.; Font-Bardia, M.; Solan, X.
Tetrahedron 2000, 56, 8141-8151. (b) Liu, Q.; Rovis, T. J. Am. Chem.
Soc. 2006, 128, 2552-2553. (c) Oxidation of trimethylsilyl ethers of para-
aryl phenols is more efficient and gives yields in the range 66-82%: Felpin,
F.-X. Tetrahedron Lett. 2007, 48, 409-412. In our hands, the triisopropyl
ether of para-propylphenol (cf. ref 11) did not react with PhI(OAc)2.
(11) Cf.: McKillop, A.; McLaren, L.; Taylor, R. J. K. J. Chem. Soc.,
Perkin Trans. 1 1994, 2047-2048.
(14) We did not try the recently reported use of oxone (it does not appear
to give high yields in cases where the alkyl group on the phenol is larger
than methyl): Carren˜o, M. C.; Gonza´lez-Lo´pez, M.; Urbano, A. Angew.
Chem., Int. Ed. 2006, 45, 2737-2741.
(15) Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem. Soc. 1986, 108,
5893-5901.
(16) Wright, S. W.; Hageman, D. L.; Wright, A. S.; McClure, L.
Tetrahedron Lett. 1997, 38, 7345-7348.
(17) Schultz, A. G.; Lavieri, F. P.; Macielag, M.; Plummer, M. J. Am.
Chem. Soc. 1987, 109, 3991-4000.
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