5566
P. Bo6icelli et al. / Tetrahedron Letters 43 (2002) 5563–5567
OCH3
OCH3
CH3O
OCH3
X
CH3O
O
O
CH3O
X
O
O
O
+
X
CH3O
CH3O
O
CH3O
11
9
10
Method A: a solution of substrate, oxone and NaBr in acetone was treated with water
Method B: a solution of substrate and HCl in acetone was treated with a DMD solution in acetone
Scheme 4. Halogenation of naringenin trimethyl ether.
Table 4. Halogenation of naringenin trimethyl ether11
Entry
Substrate
X
Substrate/reagents ratio
Acetone/H2O volume ratio
T (°C)
t (min)
Product
Yield%
1
2
3
9
9
9
Br 1/1/2a
Br 1/1/4a
Cl
5/1
1/1
1/1
25
25
25
45
45
60
8-Br
6,8-Br
6-Cl
\98
\98
30
1/1/4a
8-Cl
6,8-Cl
65
96
4
9
Cl
1/3/10b
1/1
−20
60
a Method A: substrate/oxone/Nax molar ratio.
b Method B: substrate/DMD/HCl molar ratio.
conjugated with the aromatic ring and the methoxy car-
bon deshielded to 59.5–63.6 ppm. Significant NMR data
of relevant compounds: 6-bromoflavanone: 1H NMR l
6.95 (1H, d, J=8.8 Hz, H-8); 7.57 (1H, dd, J=2.5, 8.8
Hz, H-7); 8.02 (1H, d, J=2.5 Hz, H-5). 13C NMR l
114.3 (C-Br), 120.2 (C-8), 122.1 (C-10), 129.5 (C-5), 138.2
(C-7), 160.4 (C-9). 6-chloroflavanone: 1H NMR l 6.98
(1H, d, J=8.7 Hz, H-8); 7.42 (1H, dd, J=2.8, 9.7 Hz,
H-7); 7.87 (1H, d, J=2.9 Hz, H-5). 13C NMR l 119.8
(C-8), 121.7 (C-10), 126.1 (C-5), 135.9 (C-7), 127.2 (C-Cl),
159.9 (C-9). 3%,6-dibromo-4%-methoxyflavanone: 1H NMR
l 6.92 (1H, d, J=8.6 Hz, H-5%); 6.93 (1H, d, J=9 Hz,
H-8); 7.34 (1H, dd, J=2.2, 8.6 Hz); 7.56 (1H, dd, J=2.5,
9 Hz, H-7); 7.67 (1H, d, J=2.2 Hz, H-2%); 8.01 (1H, d,
J=2.5 Hz, H-5). 13C NMR l 56.3 (CH3O), 114.2 and
114.4 (C-Br), 122.1 (C-10), 156.1 (C-4%); 160.4 (C-9).
3%,6-dichloro-4%-methoxyflavanone: 1H NMR l 6.95 (1H,
d, J=8.6 Hz, H-5%); 6.97 (1H, d, J=9 Hz, H-8); 7.30 (1H,
dd, J=2.2, 8.6 Hz, H-6%); 7.41 (1H, dd, J=2.9, 8.7 Hz,
H-7); 7.52 (1H, d, J=2.2 Hz, H-2%); 7.56 (1H, dd, J=2.5,
9 Hz, H-7); 7.86 (1H, d, J=2.9 Hz, H-5). 13C NMR l
56.2 (CH3O), 116.6 and 127.2 (C-Cl), 121.7 (C-10), 155.3
(C-4%); 161.0 (C-9). 8-bromo-5-methoxyflavanone: 1H
NMR l 6.47 (1H, d, J=8.9 Hz, H-6); 7.62 (1H, d, J=8.9
Hz, H-7). 13C NMR l 56.3 (CH3O), 102.4 (C-Br), 105.2
(C-6), 112.4 (C-10), 138.8 (C-7), 158.7 (C-9) 160.0 (C-5).
References
1. Zanoli, P.; Avallone, R.; Baraldi, M. Fitoterapia 2000, 71,
S117–S123.
2. Medina, J. H.; Vioila, H.; Wolfman, C.; Marder, M.;
Wasowski, C.; Calvo, D.; Paladini, A. C. Neurochem.
Res. 1997, 22, 419–425.
3. Sternbach, L. H. Prog. Drug Res. 1978, 44, 1340–1344.
4. De la Mare, P. B. Electrophilic Halogenation; Cambridge
University Press: Cambridge, 1976; Chapter 5.
5. Goldberg, Y.; Alper, H. J. Mol. Cat. 1994, 88, 377.
6. (a) Clague, M. H.; Butler, A. J. Am. Chem. Soc. 1995,
117, 3475; (b) Hanson, J. R.; Harpel, S. R.; Medina, I.
C.; Rose, D. J. Chem. Res. 1997, 432.
7. Roche, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetra-
hedron Lett. 2000, 41, 2083–2086.
8. Roy, S. C.; Guin, C.; Rana, K. K.; Maiti, G. Tetrahedron
Lett. 2001, 42, 6941–6942.
9. Yaipakdee, P.; Robertson, L. W. Phytochemistry 2001,
57, 341–347.
10. Bovicelli, P.; Mincione, E.; Antonioletti, R.; Bernini, R.;
Colombari, M. Synth. Commun. 2001, 31, 2955–2963.
11. All products were obtained as oils and isolated by flash
chromatography, when possible, and afforded spectral
data and CH analysis consistent with the structures pro-
posed. 13C NMR data allowed the identification of cor-
rect structures on the basis of NMR studies reported in
the literature for flavonoids carrying methoxy groups on
the A-ring (Panichpol, K.; waterman, P. G. Phytochem-
istry 1978, 17, 1363 and references cited therein). A
methoxy substituent on an aromatic system lies in the
plane of the ring. In this conformation there is the
maximum overlap between the lone pair of the oxygen
and the p-orbitals of the aromatic ring. The methyl
carbon is then shielded by the conjugated electrons and
chemical shifts occur between 55.0 and 56.5 ppm. When
the methoxy group is between bulky substituents, this
conformation is disfavoured, the oxygen is not fully
1
6,8-dibromo-5-methoxyflavanone: H NMR l 7.93 (1H, s,
H-7). 13C NMR l 61.8 (CH3O), 100.0 (C-Br), 102.0
(C-Br), 110.7 (C-10), 141.3 (C-7), 156.7 (C-9), 158.1 (C-
1
5). 8-chloro-5-methoxy-flavanone: H NMR l 6.50 (1H, d,
J=9.0 Hz, H-6), 7.48 (1H, d, J=9.0 Hz, H-7). 13C NMR
l 56.7 (CH3O), 117.5 (C-Cl). 6,8-dichloro-5-methoxy-
flavanone: 1H NMR l 7.59 (1H, s, H-7). 13C NMR l
117.0 (C-Cl), 118.7 (C-Cl), 121.6 (C-10), 135.7 (C-7),
154.9 and 156.5 (C-5 and C-9). 6-bromo-7-methoxyfla-
1
vanone: H NMR l 6.52 (1H, s, H-8); 8.08 (1H, s, H-5).
13C NMR l 56.7 (CH3O), 100.6 (C-8), 105.4 (C-10), 115.5
(C-Br), 129.0 (C-5), 161.7 and 162.5 (C-7 and C-9).