Formal radical cyclization onto benzene rings—a general method
proceeding via cross-conjugated dienones
Derrick L. J. Clive,* Stephen P. Fletcher and (in part) Mingzhao Zhu
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
E-mail: derrick.clive@ualberta.ca
Received (in Corvallis, OR, USA) 10th December 2002, Accepted 2nd January 2003
First published as an Advance Article on the web 20th January 2003
Cross-conjugated dienones of type 5 (X = I), which are
readily available from phenols, undergo radical cyclization
(5 ? 6 ? 7), and the products are easily aromatized (7 ? 8),
giving substances that are formally derived by radical
cyclization onto a benzene ring (cf. eqn. (1)).
PhI(OAc)2 (0.44 mmol), K2CO3 (0.87 mmol) and the alcohol (1
mL); the excess of alcohol is removed in vacuo and the products
are chromatographed using a small amount of Et3N in the
eluant. In the case of the transformation 13a ? 13b, the starting
phenol (13a) must contain a trace of EtOAc.11 In most cases
iodo alcohols can be used, but in order to make 11aA we had to
use an indirect method via the chloro alcohol, as the iodo
alcohol was not stable to PhI(OAc)2. Chloride 13a (as opposed
to the iodide) was used simply because it was an easily
accessible known8 starting material.
Cyclization of an alkyl radical onto a benzene ring in the sense
of eqn. (1) (x, y = linking chain) would offer a useful route to
benzo-fused compounds. Although examples related to eqn. (1)
are known,1,2 there is need for a mild general procedure that
In all cases the radical cyclization step proceeded without
incident,12 except for a homolog of 11aA with five carbons in the
halo alkoxy chain; this gave a complex mixture when heated
with Bu3SnH in the presence of AIBN. The cyclization
products, which were all single isomers, were aromatized by
acid treatment. In the case of 13c and 14c we were unable to
obtain the derived phenols but could easily make the corre-
sponding acetates by including Ac2O in the acid hydrolysis
medium.
(1)
operates under standard radical cyclization conditions.3,4 We
report an indirect method that satisfies this requirement. Our
approach (Scheme 1) involves converting the starting benze-
noid compound into a cross-conjugated dienone (3 ? 5); this
readily undergoes radical cyclization (5 ? 6 ? 7), affording a
product which is easily aromatized (7 ? 8).
Our method can be modified in a number of synthetically
useful ways, and three possibilities were examined. The first is
shown in Table 1, entry vi, and the others are summarized in
Scheme 2. Reduction (NaBH4, CeCl3·7H2O) of ketone 12c
(Scheme 2) gave a single alcohol 12e; on aromatization
(TsOH·H2O) a product (12f) was obtained (85%) lacking the
phenolic hydroxyl group, as expected. When dienone 12b was
cyclized in the presence of allyltributyltin (Scheme 2), the
intermediate radical was captured to afford 12g as a mixture of
isomers, and acid-catalyzed aromatization then gave 12h (72%
from 12b).
The cross-conjugated enones 5 are available by reaction of p-
methoxyphenols 3 with a,w-halo alcohols in the presence of
PhI(OAc)2 and K2CO3.5 We have examined halo alcohols 4
(Scheme 1, X = Cl, I); the reaction 3 ? 5 does not appear to
work with a,w-(phenylseleno) alcohols, at least as judged by
experiments with 4 (n = 1, 3, X = SePh). Compounds of type
5 can, of course, also be made from phenols already bearing a
halo alkoxy unit (see Table 1, entry iv, compound 12a and entry
v, compound 13a); in these cases, the oxidation with PhI(OAc)2
is done in the presence of MeOH. Enones 5 undergo radical
cyclization under standard conditions6 and, when the products 7
are exposed to the action of TsOH·H2O, they are converted into
Compounds 14b and 12e contained slight impurities (1H
NMR), but the derived aromatization products were obtained
pure (1H NMR) in the yields indicated.
We thank the Natural Sciences and Engineering Research
Council of Canada and Merck Frosst for financial support. SPF
holds an NSERC Postgraduate Scholarship.
8
the phenols 8. Table 1 lists our results. Phenols 3, 12a,7 13a
and 14 were converted into enones 9a, 10a, 11a (from 3), 12b
(from 12a), 13b (from 13a) and 14a 9 (from 14), by oxidation in
the presence of the indicated alcohols. Our optimized conditions
involve adding a solution of the starting phenol (0.40 mmol) in
the appropriate alcohol10 (2 mL) to a stirred mixture of
Scheme 1
Scheme 2
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CHEM. COMMUN., 2003, 526–527
This journal is © The Royal Society of Chemistry 2003