Tetrahedron Letters
Dearomatising cyclisation of lithiated allyl phenyl ethers: the role
of an oxazoline substituent
⇑
Rebecca A. Harvey, Ol’ga Karlubíková, Sean Parris, Jonathan Clayden
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 3-allyloxyphenyl oxazolines with organolithium bases leads to allyllithiums which undergo
dearomatising cyclisation. The resulting dearomatised anions may be quenched with electrophiles to
form partially saturated benzopyran derivatives.
Received 22 April 2013
Revised 16 May 2013
Accepted 22 May 2013
Available online 31 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Dearomatisation
Allyllithium
Oxazoline
Cyclisation
Recent years have seen significant progress in the use of dearo-
matisation as an efficient synthetic method for the construction of
synthetically versatile partially saturated carbocyclic and hetero-
cyclic systems.1–3 Oxidation of phenols, in particular, has shown
particular utility, with the resulting radical cations being trapped
by intramolecular nucleophiles to provide spirocyclic products
bearing further valuable functionality.2 Similarly, nucleophilic
trapping of pyridinium cations gives spiroheterocyclic systems.3
Anionic dearomatisation chemistry1 relies on the presence of
electron-withdrawing substituents to stabilise a forming anion,
and seems at first therefore incompatible with phenolic derivatives
such as phenyl ethers. However, we reasoned that by combining a
nucleophile tethered to a phenyl ether with a second electron
withdrawing group, valuable conceptually and practically simple
dearomatisations might become possible. The oxazoline group
has a successful track-record in the promotion of dearomatisa-
tion.4–6 Meyers used it in conjunction with organometallic nucleo-
philes to dearomatise pyridyl or phenyl rings, and we showed that
under certain conditions and with certain substitution patterns,
phenyl oxazolines more generally succumb to dearomatising at-
tack by organolithiums.5 Alternatively, complexation to stoichiom-
etric Cr has been used to facilitate these reactions.6
Treatment of 2a with tert-BuLi at À78 °C in THF, followed by
quench with methyl iodide, gave mixtures of products 4a and 4b
arising simply from metallation of the allyl group (Scheme 2).
However, above À40 °C, dearomatised products were identifiable
in the crude reaction mixture, and on warming to 0 °C, a 4:1 mix-
ture of the diastereoisomers of 3a was isolated in 62% yield. NOE
studies identified the relative configuration of the two diastereoi-
somers. The major product arises from the adoption of the exo po-
sition by the oxazoline substituent, as noted previously in
oxazoline-directed cyclisations.5
Under similar conditions, 2b and 2c also cyclised, but in low yield,
and the cyclisations resulted in inseparable complex mixtures of
diastereoisomers. Protonation or oxidation of the intermediate
dearomatised anion returned rearomatised benzodihydropyrans 5
in low yield (Scheme 3).
To explore the possibility of the anionic dearomatisation of phe-
nyl ethers, 3-hydroxyphenyloxazoline 1 was derivatised as the al-
lyl ethers 2a–d with the aim of forming allyl anions capable of
undergoing dearomatising cyclisation (Scheme 1).
⇑
Corresponding author. Fax: +44 (161) 2754939.
Scheme 1. Synthesis of the allyl phenyl ethers 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.