COMMUNICATION
A radical-based approach to hydroxytetralones from
unprotected phenolswz
Laurent Petit and Samir Z. Zard*
Received 30th March 2010, Accepted 2nd June 2010
First published as an Advance Article on the web 16th June 2010
DOI: 10.1039/c0cc00680g
Xanthates derived from unprotected 2-hydroxyacetophenones
undergo smooth intermolecular addition to unactivated alkenes
and subsequent cyclisation to give hydroxytetralones in
good yield.
with the more polar solvent. In our case, the stronger
intramolecular hydrogen bond would hopefully eliminate
any danger of complications arising from unwanted and
uncontrolled hydrogen abstractions.
In the event, we were greatly relieved to find that both the
intermolecular addition to acrolein acetal 4 and the ring
closure were quite efficient and furnished the desired
a-tetralone 11 in good overall yield (Scheme 3). The generality
of the sequence was tested with three other olefins, vinyl
acetate, 12 and 15, which afforded the corresponding tetra-
lones 110, 14 and 17. In the case of 14, the intermolecular
adduct 13 was not isolated; the reaction mixture from the first
step was simply diluted and treated with a stoichiometric
amount of peroxide.
As part of an ongoing synthetic project, we examined a
potentially short approach to pseudopteroxazole 1 proceeding
by way of a-tetralone 2 (Scheme 1).1 This key intermediate
appeared to be easily accessible by a general route to
a-tetralones we reported a few years ago.2,3 In the present
case, this would involve the radical addition of phenacyl
xanthate 3 to commercially available diethyl acetal 4 of
acrolein followed by cyclisation to the aromatic ring.
The synthesis of the xanthate component 3 was trivial and
the first intermolecular radical addition to alkene 4 took place
smoothly to give the expected adduct 5 in 77% yield
(Scheme 2). We were, however, disappointed to find that, in
contrast to the many previous cases we had studied, the
ring-closure could not be accomplished despite all our efforts.
The only product that could be isolated in poor yield was the
reduced starting material 6.4
A major hurdle on the route to pseudopteroxazole 1 and
substances with related structures has thus been removed. The
synthetic utility of this approach can be gauged by the two
transformations in Scheme 4. In the first, addition of xanthate
9 to vinyl acetate followed by cyclisation and saponification of
the ester group in 19 furnished racemic shinanolone 20, a
natural product isolated from various plant sources.7 The
second example testifies to the mildness of the reaction
conditions since the addition to alkene 21 derived from
citronellene and cyclisation could be accomplished without
harm to the epoxide group. An elaborate structure 23 could
hence be assembled in only two steps. It is worth noting that
tetralone 23 is closely related to the naturally occurring
seco-pseudopteroxazole and erogorgiaene, the biosynthetic
precursor of pseudopterosins and seco-pseudopterosins.8
A final interesting aspect is the flexibility inherent to this
chemistry. Variations can be introduced through both
partners in the process. The examples displayed in Scheme 5
illustrate some modifications in the xanthate component. For
instance, addition of xanthate 24 to vinyl pivalate and cyclisa-
tion provides compound 26, an advanced intermediate in the
synthesis of 10-Norparvulenone 27, which we recently
described.9 Eliminating the need to protect the phenolic group
therefore shortens the synthesis by two steps and increases
significantly the overall yield. The last example involving
xanthate 28 and leading to tetralone 30, albeit in modest yield,
One possible explanation is that the dipole–dipole repulsion
between the carbonyl and methoxy group forces the
intermediate radical into adopting conformation 7b that is
unfavourable for cyclisation. The ring closure is perhaps also
being hindered to a certain extent by the steric bulk of the
acetal group.
In order to overcome this repulsion and encourage the
radical to adopt
a more propitious conformation, we
considered the possibility of exploiting the intramolecular
hydrogen bond that is bound to exist with the naked phenol.
As indicated in structure 8, such a relatively strong hydrogen
bond would freeze the molecule in the desired conformation.
Another, perhaps less obvious advantage, is that the hydrogen
bond will slow down hydrogen abstraction from the phenol.
Indeed, phenols are extensively used as stabilisers and
inhibitors of radical chain reactions,5 but a study by Ingold
and co-workers revealed that hydrogen abstraction from
phenols could be slowed 200-fold on going from CCl4 to
t-butanol as solvent.6 This remarkable decrease in rate of
hydrogen abstraction was attributed to hydrogen bonding
`
´
Laboratoire de Synthese Organique associe au C.N.R.S.,
De´partement de Chimie, Ecole Polytechnique, F-91128 Palaiseau,
France. E-mail: zard@poly.polytechnique.fr; Fax: +33 169333851;
Tel: +33 169334872
w This paper is dedicated with affection to Prof. Anthony G. M. Barrett.
z Electronic supplementary information (ESI) available: Experimental
details, spectroscopic data and NMR spectra. See DOI: 10.1039/
c0cc00680g
Scheme 1
ꢀc
This journal is The Royal Society of Chemistry 2010
5148 | Chem. Commun., 2010, 46, 5148–5150
Petit, Laurent
