A new and efficient Baeyer-Villiger rearrangement of flavanone derivatives by the methyltrioxorhenium/H2O2 catalytic system

Article abstract of DOI:10.1016/S0040-4039(01)01005-X

The catalytic Baeyer-Villiger rearrangement of flavanones is described by the use of the homogeneous methyltrioxorhenium (MTO)/H₂O₂ system. In these experimental conditions 3,4-dihydro-4-phenyl-1,5-benzodioxepin-2-ones and previously

Full text of DOI:10.1016/S0040-4039(01)01005-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5401–5404
A new and efficient Baeyer–Villiger rearrangement of flavanone
derivatives by the methyltrioxorhenium/H O catalytic system
2
2
a,
a
a
b
b
Roberta Bernini, * Enrico Mincione, Manuela Cortese, Giovanni Aliotta, Anna Oliva and
a,
Raffaele Saladino *
a
Dipartimento A.B.A.C., Universit a` della Tuscia, Via S. Camillo de Lellis, 01100 Viterbo, Italy
b
a
Dipartimento di Scienze della Vita, II Universit a` di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
Received 10 May 2001; accepted 6 June 2001
Abstract—The catalytic Baeyer–Villiger rearrangement of flavanones is described by the use of the homogeneous methyltrioxo-
rhenium (MTO)/H O system. In these experimental conditions 3,4-dihydro-4-phenyl-1,5-benzodioxepin-2-ones and previously
2
2
not reported para-quinone derivatives have been obtained in mild experimental conditions from acceptable to good yields. © 2001
Elsevier Science Ltd. All rights reserved.
Flavonoids are polyphenolic compounds ubiquitous in
plants foods (fruits, vegetables) and they are important
components of the human diet. In particular,
dicted as a target for a large scale industrial preparation
12
of biologically important benzodiazepine analogues.
1
13
Methyltrioxorhenium (MTO) is a useful catalyst for
14 15
flavanones (2,3-dihydro-2-phenyl-4H-1-benzopyran-4-
one derivatives) are prominent components of Citrus
fruits and they are present in solid wastes and residues
both electrophilic and nucleophilic oxidations with
H O , including the oxidation of natural products such
2
2
16
as nucleic acid and cardanol derivatives. Herein we
report the first described catalytic Baeyer–Villiger rear-
rangement of flavanones. The oxidizing system used
was H O in the presence of catalytic amounts of MTO.
2
obtained during their industrial processing. These
compounds have been long recognized to possess
hypolipidemic, antihypertensive, diuretic and anti-
2
2
3
4
inflammatory activities, as well as antioxidant, anti-
The benzodioxepin-2-one derivatives obtained were
also tested for the inhibition of radish and wheat
germination. Flavanone derivatives 1–5 (1 mmol) were
allowed to react with H O (2.0–6.0 mmol; 35% aq.
5
6
tumoral, and antiproliferative properties. Oxidative
transformations of flavanones have been reported in the
literature to synthesize new derivatives with high bio-
logical activity and low toxicity. Among them, much
attention has been focused on the chemistry of the
C-ring, including the conversion of flavanones into
2
2
solution) in acetic acid/methanol (ratio 9:1; 5 ml) in the
presence of catalytic amounts of MTO (2 mol%) at
17
2
5–80°C. In the absence of MTO less than 2% conver-
7
8
flavones, and isoflavanone derivatives. On the other
hand, only few data are reported about methods of
expanding the C-ring, with the exception of the synthe-
sion of substrates takes place under otherwise identical
conditions. Treatment of flavanone 1, 5–methoxyfla-
vanone 2, and 7-methoxyflavanone 3, afforded the cor-
responding 1,5-benzodioxepin-2-ones 6–8 in high yields
and conversions (Scheme 1, Table 1).
sis of benzoxazepine derivatives by Schmidt rearrange-
9
ment,
and benzodioxepin-2-one derivatives by
10
Baeyer–Villiger rearrangement. In the latter case a
large excess of meta-chloroperbenzoic acid (m-CPBA),
that cannot be stored in pure form because of the
explosion hazards, are required. A catalytic Baeyer–Vil-
liger rearrangement of flavanones, by use of transition
metal compounds for the activation of the environmen-
The presence of the methoxyl group on the C-5 or C-7
positions of the A-aromatic ring appear to improve
both yields and conversions with respect to unsubsti-
tuted flavanone 1 (entries 2–3, Table 1).
11
tally friendly hydrogen peroxide, can be easily pre-
Noteworthy, in the case of 3 a demethoxylation/acetyl-
ation process was also operative at the C-7 position. In
compounds 6–8 the change in carbonyl functionality
from ketone to lactone was reflected in a significant
Keywords: Baeyer–Villiger reactions; lactonisation; flavanones;
flavonoids.
−
1
*
Corresponding authors.
shift (ca. 50 cm ) of the IR carbonyl absorption band
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01005-X

5
402
R. Bernini et al. / Tetrahedron Letters 42 (2001) 5401–5404
R4
R4
R4
R3
R3
R3
B
O
O
R2
O
R2
O
O
O
Catalyst
A
C
+
2
5-80°C, H2O2 35%
OCH3
AcOH/MeOH
or EtOH
O
R1
O
R1
R1
O
1
2
3
4
5
: R =R =R =R =H
6: R =R =R =R =H
9: R1=R3=OCH3; R4=H
10: R1= R3=R4=OCH3
1
2
3
4
1
2
3
4
: R =OCH ; R =R =R =H
7: R =OCH ; R =R =R =H
1
3
2
3
4
1 3 2 3 4
: R =OCH ; R =R =R =H
8: R =OCOCH ; R =R =R =H
2 3 1 3 4
2
3
1
3
4
: R =R =R =OCH ; R =H
11: R =R =R =R =OCH
1
2
3
3
4
1 2 3 4 3
: R =R =R =R =OCH
3
1
2
3
4
Scheme 1.
Table 1.
Entry
Substrate
T (°C)
H O (equiv.)
Product (s)
Yield (%)a
Conversiona (%)
2
2
1
2
3
4
5
6
7
1
2
3
2
4
5
5
80
25
80
25
80
25
25
6.0
2.0
6.0
5.0
6.0
2.0
2.0
6
7
8
7
63
\98
95
92
\98
93
75
\98
\98
\98
\98
\98
\98
9
10
10 (11)
18 (64)
a
Conversions and yields calculated after purification of the reaction mixture.
to higher frequencies. Products 6–8 were assigned to be
tions). These intermediates might be further oxidized
with concomitant C-7 demethoxylation to 9 and 10.
The acidic character of MTO may be, at least in part,
responsible for the ring-opening of the lactone moiety.
For example, in MTO epoxidations of alkenes the
1,5-benzodioxepin-5-ones rather than the isomeric 1,4-
1 13
benzodioxepin-5-ones (not shown) by H and C NMR
spectroscopy, in accord with data previously reported
1
0,18,19
in the literature.
Adam and coworkers reported
2
3
that in MTO mediated oxidation of phenols and
oxiranyl ring is opened quite readily to the diol. To
avoid such detrimental side reaction pyridine and pyra-
2
0
2
methoxybenzenes the actual oxidant was the h -diper-
21
24
oxo rhenium complex without any participation of in
situ freshly generated peracetic acid. On the basis of
these data, it is reasonable to suggest that the MTO
catalyzed Baeyer–Villiger rearrangement of flavanones
zole have been proposed as Lewis acid buffers. Thus,
when the oxidation of 8 was performed in the presence
of pyridinium acetate (ratio substrate:salt=1:2), lactone
11 was recovered as the main product and the para-qui-
none 10 as by product (Table 1, entry 7). Compounds
1–10, were evaluated for the inhibition of radish
(Raphanus sativus L.) and wheat (Triticum durum) ger-
1
–3 proceeds through the formation of an intermediate
11
peroxometallacyclic species for which spectroscopic
evidences have been recovered in the case of cyclic
1
6
25
ketones. This hypothesis is further supported by a
peracetic acid free control experiment in which 5-
mination, by in vitro dose–response assays. Com-
pounds 5 and 9 were the most active on wheat
germination with a ID50 (amount of compound that
cause 50% inhibition) of 14 and 56 mM, respectively.
Furthermore, 10 was active against radish germination
at low concentration (ID =3 mM). This level of activ-
methoxyflavanone 2 (1 mmol) was treated with H O2
2
(
4.0 mmol; 35% aq. solution) in ethanol (5 ml) in the
presence of MTO (2 mol%) and HBF4 (1 ml; 54%
diethyl ether solution) at 25°C to give 7 in good yield
50
(
Table 1, entry 4). When methylated naringenin 4 and
ities is comparable to many commercial herbicide, and
−4
hesperetin 5 were treated with the MTO/H O system
concentrations greater than 1×10 M are considered
26
2
2
under similar experimental conditions the para-
quinones 9 and 10 were obtained as the only recovered
products in high yields (Scheme 1, Table 1, entries
beyond the range of interest for agronomic purposes.
2
2
10
Supplementary material
5
–6). In accord with results previously described, the
first formed lactones might be opened at the C-ring via
a solvolytic transesterification, to give the correspond-
ing phenols (not recovered in our experimental condi-
1
13
H NMR and C NMR spectra were recorded on a
Bruker 200 MHz spectrometer in CDCl as the solvent.
3

R. Bernini et al. / Tetrahedron Letters 42 (2001) 5401–5404
5403
All chemical shifts are reported in parts per million
ppm) against internal tetramethylsilane. Coupling con-
stants JHH were measured in Hz. IR spectra were
recorded on a Perkin–Elmer Paragon 500 FT-IR spec-
3H), 5.36 (d, J=2.0 Hz, 1H), 4.86 (d, J=2.0 Hz, 1H),
(
4.03 (m, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.69 (s, 3H),
1
3
3.51 (s, 3H), 3.04 (dd, 1H, J=12.0, 17.2 Hz).
C
NMR: 193.2, 175.2, 174.6, 164.8, 148.7, 148.5, 126.1,
119.0, 111.0, 110.7, 95.9, 94.0, 56.3, 56.2, 55.8, 51.9,
32.7. Anal. calcd for C H O : C, 60.63; H, 5.36; O,
trometer in CHCl solution and positions are reported
3
−
1
in cm . Elemental analyses were performed by a Carlo
Erba 1106 analyzer.
19
20
8
34.01. Found C, 60.61; H, 5.36; O, 34.0.
2
,3-Dihydro-5,7-dimethoxy-2-(4%-methoxyphenyl)4H-1-
3,4-Dihydro-5,7-dimethoxy-4-(3%,4%-dimethoxyphenyl)2H-
1,5-Benzodioxepin-2-one (11). IR (wmax): 3040, 2850,
Benzopyran-4-one (Methylated naringenin) (4). IR
1
1
(
7
(
1
wmax): 3036, 2840, 1670, 1608, 1458, 1254. H NMR:
.27 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.99
dd, J=2.3, 9.3 Hz, 2H), 5.22 (dd, J=3.0, 12.9 Hz,
H), 3.75 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 2.77 (dd,
1760, 1604, 1475, 1250. H NMR: 6.99–6.84 (m, 3H),
6.12 (dd, 2H, J=2.1, 12.0 Hz), 5.70 (t, J=6.8 Hz, 1H),
3.88 (s, 3H), 3.86 (s, 6H), 3.76 (s, 3H), 3.12 (dd, J=1.7,
13
5.9 Hz, 2H); C NMR: 168.3, 156.6, 151.4, 150.2,
148.1, 137.9, 121.8, 117.7, 107.7, 99.0, 97.6, 83.4, 56.3,
55.8, 55.62, 55.5, 38.2. Anal. calcd for C H O : C,
13
J=12.9, 16.6 Hz, 2H). C NMR: 190.3, 166.3, 165.2,
1
5
6
62.3, 159.9, 130.8, 127.7, 114.1, 105.7, 93.7, 93.0, 78.9,
5.9, 55.6, 55.3, 45.2. Anal. calcd for C H O : C,
19
20
7
63.33; H, 5.59; O, 3.08. Found C, 63.30; H, 5.58; O,
3.04.
1
8
18
5
8.78; H, 5.77. Found C, 68.68; H, 5.71.
2
1
,3-Dihydro-5,7-dimethoxy-2-(3%,4%-dimethoxyphenyl)4H-
-Benzopyran-4-one (Methylated hesperetin) (5). IR
Acknowledgements
1
(
wmax): 3040, 2840, 1670, 1465, 1264. H NMR: 6.99–
6
.84 (m, 3H), 6.10 (dd, J=2.2, 12.4 Hz, 1H), 5.32 (dd,
J=3.0, 13.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 3.79 (s,
We are grateful to Consorzio I.N.C.A., Venice who has
supported this research with a grant. A grant from
MURST 5% is also acknowledged.
1
3
3H), 2.89 (dd, J=13.0, 16.5 Hz, 2H). C NMR: 188.8,
165.6, 164.6, 161.9, 149.1, 148.9, 131.0, 118.5, 110.9,
109.2, 105.6, 93.5, 92.8, 78.8, 55.8, 55.7, 55.2, 45.3.
Anal. calcd for C H O : C, 66.27; H, 5.86; O, 27.87.
Found C, 66.20; H, 5.86; O, 27.86
1
9
20
6
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3
,4-Dihydro-5-methoxy-4-phenyl-2H-1,5-Benzodioxepin-
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2
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1
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(
5
6
1
8
5
.69 (t, J=6.8 Hz, 1H), 3.87 (s, 3H), 3.11 (dd, J=1.1,
13
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16
14
4
.22; O, 23.68. Found C, 71.07; H, 5.22; O, 23.60.
3
,4-Dihydro-7-acethoxy-4-phenyl-2H-1,5-Benzodioxepin-
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2
-one (8). IR (wmax): 3040, 2838, 1760, 1600, 1475, 1250.
1
H NMR: 7.55–7.24 (m, 8H), 6.14 (dd, J=5.0, 8.9 Hz,
13
1
H), 2.90 (dd, J=8.9, 16.2 Hz, 2H), 2.08 (s, 3H).
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27.7, 126.1, 125.9, 120.6, 113.9, 111.3, 83.3, 38.4, 21.0.
Anal. calcd for C H O : C, 68.45; H, 4.73; O, 26.82.
C
1
1
7
14
5
Found C, 68.41; H, 4.73; O, 26.82.
para-Benzoquinone derivative (9). IR (wmax): 3034, 2840,
1
1786, 1668, 1613, 1461, 1254. H NMR: 6.99 (d, J=2.2
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1
3
1
1
H), 4.84 (d, J=1.9 Hz, 1H), 4.03 (m, 1H), 3.75 (s, 3H),
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.69 (s, 3H), 3.49 (s, 3H), 3.02 (dd, J=11.7, 17.2 Hz,
1
3
H). C NMR: 193.2, 175.4, 174.5, 164.6, 159.2, 128.8,
28.4, 113.5, 95.7, 93.9, 56.4, 55.8, 55.1, 51.5, 32.8.
Anal. calcd for C H O : C, 62.42; H, 5.24; O, 32.34.
Found C, 62.40; H, 5.24; O, 32.31.
1
8
18
7
para-Benzoquinone derivative (10). IR (wmax): 3035,
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1
2
840, 1794, 1669, 1445, 1264. H NMR: 6.75–6.55 (m,

5
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R. Bernini et al. / Tetrahedron Letters 42 (2001) 5401–5404
1
1
1
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2
2. The presence of absorption proton signals in the typical
1
7. Flavanone 1 was purchased from Sigma–Aldrich. 5-
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hesperitin 5 have been prepared starting from naringenin
1
region located l 6.3 and 7.3 in the H NMR spectra as
well as the presence of new quaternary absorption carbon
13
signal in the C NMR spectra were diagnostic for the
quinonoid structures.
and hesperetin by treatment with CH I in dry DMF at
3
23. (a) Al-Ajlouni, A. M.; Espenson, J. H. J. Org. Chem.
2
5°C.
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1
13
W.; Rauch, M. U. J. Mol. Cat. A 1994, 86, 243–266.
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of the theoretical values) elemental analyses. Selected
data for 3,4-dihydro-4-phenyl-1,5-Benzodioxepin-2-one 6:
2
2
1
Oil; IR (wmax): 3038, 1770. 1602, 1474, 1252. H NMR:
7
.55–7.00 (m, 9H, ar-H), 5.71 (t, J=6.9, 1H, 4-H), 3.11
13
(
dd, J=1.8, 6.0, 2H, 3-H). C NMR: 167.2, 146.0, 138.5,
26. Dayan, F. E.; Romagni, J. G.; Duke, S. O. J. Chem.
Ecol. 2000, 26, 2079–2094.
1
35.5, 128.8, 128.5, 126.0, 125.5, 115.7, 109.0, 83.2, 38.4.
.