A new domino oxidation—rearrangement of 2,3-dihydrowogonin to negletein

Article abstract of DOI:10.1016/j.tetlet.2016.02.093

We report an expeditious, iodine-catalysed oxidation of 2,3-dihydrowogonin to negletein which comprises a Wessely–Moser rearrangement (WMR), associated not with an O-demethylation, as usual, but with an oxygen to oxygen methyl shift. In contrast, DDQ in 1

Full text of DOI:10.1016/j.tetlet.2016.02.093

Tetrahedron Letters 57 (2016) 1560–1562
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Tetrahedron Letters
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A new domino oxidation—rearrangement of 2,3-dihydrowogonin
to negletein
Cornelia Spoerlein-Guettler a, Wolfgang Milius b, Johannes Obenauf c, Rainer Schobert a,
⇑
a Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany
b Lehrstuhl fuer Anorganische Chemie I, University Bayreuth, 95440 Bayreuth, Germany
c Lehrstuhl fuer Anorganische Chemie II, University Bayreuth, 95440 Bayreuth, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an expeditious, iodine-catalysed oxidation of 2,3-dihydrowogonin to negletein which com-
prises a Wessely–Moser rearrangement (WMR), associated not with an O-demethylation, as usual, but
with an oxygen to oxygen methyl shift. In contrast, DDQ in 1,4-dioxane oxidised 2,3-dihydrowogonin
to wogonin without rearrangements.
Received 2 February 2016
Revised 24 February 2016
Accepted 25 February 2016
Available online 27 February 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Negletein
Iodine oxidation
Wessely–Moser rearrangement
Wogonin
Introduction
over 90% yield (Scheme 1). Figure 2 shows its molecular structure
as obtained from a single crystal X-ray diffraction analysis. Basic
Scutellaria baicalensis Georgi is a herb traditionally used in Chi-
nese folk medicine. The root extract was employed to treat hyper-
tension, atherosclerosis, infections and fever, among other
ailments.1,2 One of its major constituents is 5,7-dihydroxy-8-meth-
oxyflavone, a.k.a. wogonin (1), which is known to have anti-inflam-
matory, antioxidant, antiangiogenic3 and antitumour properties.4
Despite its simple structure, chemical syntheses are few and far
between.5–7 Huang et al.6 achieved the best yield with 20% over
three steps starting from 3,4,5-trimethoxyphenol and cinnamoyl
chloride which were submitted to a Friedel–Crafts acylation afford-
ing the corresponding chalcone. While they reported that its par-
tial demethylation and subsequent oxidative cyclisation left a
mixture of 1 (24%) and the regioisomeric oroxylin A (2; 46%)
(Fig. 1), we found a different outcome. Herein, we8 report a high-
yielding synthesis of negletein (3) via a domino oxidation–rear-
rangement of 2,3-dihydrowogonin.
hydrolysis of complex 4 left chalcone 5. While Huang et al. had
reported to have obtained the corresponding demethylated chal-
cone 6 upon refluxing of 5 for 2 h in a mixture of 47% HBr and gla-
cial acid, we isolated none of this but a separable mixture of 2,3-
dihydrowogonin (7) (61%) as colourless fibres and of 2,3-dihy-
drooroxylin A (8) (21%) as a brown solid under identical conditions.
Obviously, a twofold demethylation with subsequent ring-closing
Michael addition had taken place under the strongly acidic condi-
tions. Recently, Tietze et al. found that heating of 2,3,4-trimethoxy-
6-hydroxychalcones in glacial acid alone also led to the formation
of flavanones, albeit without demethylation.9 Next, we tried to oxi-
dise pure 2,3-dihydrowogonin (7) to give wogonin (1) with cat-
alytic amounts of iodine in DMSO, a protocol also used by the
Huang group to cyclise–oxidise chalcones with OH-groups on the
A-ring. However, this failed, too. Yet, when carried out under strict
exclusion of air10 this reaction yielded negletein (3) as the sole pro-
duct in over 70% yield. Its NMR data were in line with the litera-
ture11 and its melting point identical to that of an authentic
sample.
Results and discussion
At first glance the conversion of 7 to 3 resembles the Wessely–
Moser rearrangement (WMR) of 5,8-dimethoxy or 5,7,8-tri-
methoxy flavanones and flavones under demethylating acidic con-
ditions which proceeds by ring opening of the pyrone ring, rotation
about the phenylAC(@O) bond and ring closure to give isomeric
flav(an)ones.12–14 However, in the present case a flavanone is
oxidised and the methyl group is retained yet shifted to the oxygen
3,4,5-Trimethoxyphenol was acylated with cinnamoyl chloride
according to Huang et al. A careful hydrolytic workup afforded
the crystalline BF2 chelate complex 4 of the known chalcone 5 in
⇑
Corresponding author. Fax: +49 921 552671.
E-mail address: Rainer.Schobert@uni-bayreuth.de (R. Schobert).
http://dx.doi.org/10.1016/j.tetlet.2016.02.093
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

C. Spoerlein-Guettler et al. / Tetrahedron Letters 57 (2016) 1560–1562
1561
OMe
8
HO
O
1
Ph
HO
O
O
Ph
7
2
3
6
4
MeO
5
OH
O
OH
wogonin (1)
oroxylin A (2)
MeO
O
O
Ph
HO
negletein (3)
OH
Figure 2. Molecular structures of chalcone BF2 complex 4 (left; CCDC 1429261) and
of negletein (3; right; CCDC 1429260), obtained via the route outlined in Scheme 3,
both as thermal ellipsoid representations at 50% probability level (H-atoms
omitted).
Figure 1. Structures of wogonin (1), oroxylin A (2), and negletein (3).
atom of a neighbouring OH-group. Additional experiments showed
that neither wogonin (1), nor oroxylin A (2) reacted with catalytic
amounts of iodine in DMSO under an atmosphere of argon or with
solutions containing HI which is likely to develop in the course of
the conversion of 7 to 3. This means that neither wogonin nor
oroxylin A is an intermediate en route this reaction. While the sto-
ichiometric iodination of flavanones under basic15 or strongly
acid16 conditions was reported to afford 3-iodoflavones via the
enolate or enol, respectively, we propose a different mechanism
for the conversion of 7 to 3 which is only catalytic in iodine
(Scheme 2). First, 2,3-dihydrowogonin may get iodinated, i.e., oxi-
Me
H
OMe
OMe
O
I
I
HO
O
O
Ph
DMSO
HO
O
O
Ph
+ HI
O
O
Ph
Ph
I2
H
- HI
I
OH
OH
OH
OH
O
7
9
- HI
OH
I
I
I
MeO
OH Ph
I
MeO
HO
OH Ph
I
MeO
O
O
+ HI
dised, in benzylic position to give a-iodoether 9 with concomitant
formation of HI. The latter induces a methyl shift from 8-O to 7-O
by protonating the most basic 8-O-atom and by abstracting the
most acidic H-atom from 7-O. The resulting para-hydroquinone
OH
O
OH
O
OH
11β
11α
10
- HI
10 is ring-opened by HI-induced cleavage of its
diiodide 11 . Its rotamer 11b can re-cyclise more effectively to
afford 12, a regioisomer of -iodoether 9, via displacement of an
a-iodoether to give
I
a
Re-oxidation of HI:
2 HI I2
MeO
HO
O
O
Ph
- HI
MeO
HO
O
O
Ph
a
iodide by the less hindered and more strong nucleophilic OH-group
of the para-hydroquinone. The final step in the conversion of 7 to 3
is the b-elimination of a second equivalent of HI. The HI gets
OH
12
OH
3
DMSO Me2S + H2O
Scheme 2. Tentative mechanistic proposal for the oxidation of 2,3-dihydrowogonin
(7) to negletein (3) by catalytic iodine/DMSO.
re-oxidised to iodine by the solvent DMSO for which there is liter-
ature precedent.17
Mixtures of azobisisobutyronitrile (AIBN) and N-bromo-succin-
18
imide (NBS) in CCl4 also oxidised 2,3-dihydrowogonin to negle-
tein. Even the bisacetylated 2,3-dihydrowogonin 1319 furnished
bisacetylated negletein 1420 when oxidised with NBS/AIBN in
CCl4 (Scheme 3). The formal retention of the acetyl groups during
this rearrangement was surprising yet may be rationalised by their
known migratory propensity21 and by assuming a mechanism sim-
ilar to the one shown in Scheme 2. HBr rather than HI would initi-
ate the methyl shift by cleavage of the neighbouring acetate,
followed by acetyl migrations and the WMR. Deprotection of 14
required refluxing with 3 N hydrochloric acid in acetone for 16 h
since the more common basic protocols led to decomposition. An
X-ray diffraction analysis of suitable crystals of the product negle-
tein confirmed its identity (Fig. 2).
OMe
AcO
O
Ph
MeO
RO
O
O
Ph
(i)
OAc O
OR
13
14: R = Ac
3: R = H
(ii)
Scheme 1. Reagents and conditions: (i) cinnamoyl chloride, BF3 Â Et2O, 30 min,
reflux, 91%; (ii) AcOEt, NaHCO3, 30 min, rt, 83%; (iii) HBr, AcOH, 2 h, reflux, 61% 7,
21% 8; (iv) argon atmosphere, iodine, DMSO, 2 h, reflux, 72%.
Scheme 3. Reagents and conditions: (i) CCl4, NBS, AIBN, 2 h, reflux, 49%; (ii)
acetone, 3 N HCl, 16 h, reflux, 100%.

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C. Spoerlein-Guettler et al. / Tetrahedron Letters 57 (2016) 1560–1562
OMe
OMe
Supplementary data
HO
O
O
Ph
HO
O
O
Ph
(i)
Supplementary data (experimental procedures, compound
characterisation, and copies of 1H and 13C NMR spectra) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2016.02.093.
OH
OH
7
1
Scheme 4. Reagents and conditions: (i) DDQ, 1,4-dioxane, 16 h, reflux, 36%.
References and notes
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Finally, we found that our initial intention, the oxidation of 2,3-
dihydrowogonin (7) to wogonin (1), was possible in a moderate
36% yield by means of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in 1,4-dioxane according to a general protocol by Kim et al.22
(Scheme 4). Unlike oxidations with I2/DMSO or NBS, such with
DDQ do not imply free hydrohalic acids which are apparently
required for the induction of the observed methyl shifts and WMR.
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Conclusion
Contrary to previous reports, we found that 2,3-dihydro-wogo-
nin cannot be oxidised to wogonin by halo oxidants such as I2/
DMSO or NBS. Instead, negletein was formed as the sole product
of a domino sequence comprised of a methyl shift, a Wessely–
Moser rearrangement, and the formation of a 2-alkene. Flavones
such as wogonin and oroxylin A did not react under these condi-
tions. In principle, other flavanones with aptly positioned hydroxy
and methoxy groups should also be amenable to this reaction.
Work is in progress to clarify this point.
18. Patil, A. D.; Deshpande, V. H. Indian J. Chem. 1983, 22B, 109–113.
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Acknowledgements
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2530.
Dedicated to Professor Steven Victor Ley (University of Cam-
bridge) on the occasion of his 70th birthday. We thank the Phyto-
Lab GmbH & Co. KG, Vestenbergsgreuth, Germany, for a gift of pure
oroxylin A and wogonin.