G. Righi et al. / Tetrahedron 66 (2010) 1294–1298
1297
diluted with water (14 mL) and extracted with ethyl acetate
(3ꢁ14 mL). The extracts were washed with brine (20 mL), dried over
anhydrous Na2SO4 and the solvent evaporated under reduced
pressure. Compound 2 (620 mg, 1.72 mmol) was obtained as yellow
d6)
6.41 (1H, s), 3.98 (3H, s), 3.96 (3H, s). 13C NMR (chloroform-d1)
(ppm): 177.4, 162.7, 160.8, 160.3, 160.2, 131.4, 131.0, 128.9, 126.1,
109.6, 108.1, 92.2, 90.9, 56.5, 56.4. HRMS: calcd for C17H13BrO4
382.9895; found 382.9853.
d
(ppm): 7.96 (2H, dd, J¼2.2, 8.0 Hz), 7.47 (3H, m), 6.71 (1H, s),
d
gummy liquid. IR n(max) (CHCl3) 1640, 1350, 1165 cmꢂ1
.
1H NMR
(ppm): 7.90 (2H, dd, J¼2.1, 8.0 Hz), 7.45 (3H, m),
6.73 (1H, s), 6.41 (1H, s), 3.97 (3H, s), 3.95 (3H, s). 13C NMR (chloro-
form-d1) (ppm): 177.0, 161.0,160.5, 160.2, 154.9,131.5,130.5, 128.8,
(chloroform-d1)
d
4.1.7. 6,7-Dimethoxy-5-hydroxyflavone (mosloflavone, 11). To a sus-
pension of CuBr (104 mg, 0.73 mmol) in DMF (2.2 mL) a 25% so-
lution of sodium methoxide in methanol (6.63 mL, 29.15 mmol)
was added at rt and left under stirring until a bright blue colour
appeared (about 1 h). The mixture was added to a solution of 9
(354 mg, 0.91 mmol) in DMF (3 mL) at 120 ꢀC in 2 mL portions.
The mixture was left stirring for 40 min, then cooled to rt,
quenched with a cold 2 M solution of HCl in water (13 mL) and
extracted with ethyl acetate (3ꢁ20 mL). The extracts were
washed with brine (3ꢁ10 mL), dried over anhydrous Na2SO4 and
the solvent evaporated under reduced pressure. Compound 11
(254 mg, 0.85 mmol, 93.4% yield) was obtained as yellow pow-
dered. Compound 11 was also obtained by the same procedure
starting from the mixture of 4 and 5 leaving stirring for 5 h to
allow the Wessley–Moser rearrangement to occur. In this case
from 454 mg (1.31 mmol) of mixture 333 mg (1.11 mmol) of 11
was obtained after chromatography on silica gel (hexane/ethyl
acetate 8:2). Data agreed with those reported in literature,26 mp
d
126.0, 108.9, 107.3, 96.7, 92.4, 58.9, 56.7. HRMS: calcd for
C17H13BrO4Naþ (MþNaþ) 382.9895; found 382.9885.
4.1.3. 5-Hydroxy-7-methoxyflavone (3). Compound 3 was prepared
via the same procedure as for 1 stopping the reaction after 1.5 h.
Analytical data were in agreement with those reported in litera-
ture,24 mp 166–168 ꢀC (lit. 166.6). 1H NMR (chloroform-d1)
d (ppm):
0
0
12.720 (1H, s, C5-OH), 7.88–7.91 (2H, m, C2 -H, C6 -H), 7.55–7.53 (3H,
0
0
m, C3 -H, C4 -H, C5 -H), 6.64 (1H, s, C3-H), 6.50 (1H, d, J¼2 Hz), 6.38
(1H, d, J¼2 Hz), 3.88 (3H, s, CH3O).
4.1.4. 6-Bromo-5-hydroxy-7-methoxyflavone (4) and 8-bromo-5-
hydroxy-7-methoxyflavone (5). To
a solution of 3 (500 mg,
1.86 mmol) in chloroform (7 mL), TBATB (793 mg, 1.86 mmol) was
added in one portion. The mixture was left stirring at rt for 2 h, then
worked up as for 2. A 2:1 mixture of 4 and 5 (626 mg, 1.80 mmol)
was obtained as yellow powder. The two isomers were inseparable
by common techniques and were characterised as the acetate after
chromatography on silica gel (hexane/ethyl acetate 8:2). The mix-
ture was stirred overnight with a 1:1 solution of pyridine and acetic
anhydride (6 mL). The mixture was poured in cold water (20 mL)
and extracted with ethyl acetate (3ꢁ5 mL). The organic layers were
washed with a 2 M solution of HCl in water (2ꢁ5 mL) and a satu-
rated solution of NaHCO3 (3ꢁ5 mL). Evaporation of the solvent
under reduced pressure gave a 2:1 mixture of 9 and 10 in almost
quantitative yield. Compound 9 (65% yield from 3), Rf 0.36. IR n(max)
159–160 (lit. 159–160), 1H NMR (chloroform-d1)
d (ppm): 12.67
0
0
(1H, s, C50 -OH), 07.87–7.84 (2H, m, C2 -H, C6 -H), 7.55–7.53 (3H, m,
0
C3 -H, C4 -H, C5 -H), 6.64 (1H, s), 6.54 (1H, s), 3.95 (3H, s, CH3O),
3.91 (3H, s, CH3O).
4.1.8. 5-Hydroxy-7,8-dimehtoxyflavone (12). The same procedure
as for 11 was used starting from 10 (300 mg, 0.77 mmol). The
mixture was left stirring for 5 h to allow the Wessely–Moser rear-
rangement and worked up as usual. After chromatography (hex-
ane/ethyl acetate 8:2) 11 (185 mg, 0.62 mmol, 80.5% yield) and 12
(19 mg, 0.06 mmol, 8% yield) were obtained as a gummy liquid. 13C
(CHCl3) 1715, 1650, 1350, 1165 cmꢂ1
.
1H NMR (chloroform-d1)
0
0
d
(ppm): 7.81 (2H, dd, J¼2.2, 8.0 Hz, C2 -H, C6 -H), 7.54–7.48 (3H, m,
NMR, d (ppm): 182.7, 163.9, 158.7, 157.6, 149.5, 131.9, 131.4, 129.1,
0
0
0
C3 -H, C4 -H, C5 -H), 6.91 (1H, s), 6.61 (1H, s), 4.01 (3H, s, CH3O), 2.49
126.3, 105.3, 105.0, 95.9, 61.6, 56.3. Other data agreed with those
(3H, s, CH3COO). 13C NMR (chloroform-d1)
d (ppm): 175.6, 168.3,
reported in literature.26
162.0, 160.0, 157.5, 148.0,131.6, 131.2, 129.0, 126.1, 112.2,108.5, 105.7,
98.0, 57.0, 20.9. HRMS: calcd for C18H13BrO5Naþ (MþNaþ)
410.9844; found 411.9839. Compound 10 (32% yield from 3), Rf 0.33.
4.1.9. 5,6-Dihydroxy-7-methoxyflavone (negletein, 13). A solution of
11 (283 mg, 0.95 mmol) in acetic acid (15.3 mL) and hydro-
bromidic acid (7.6 mL, 47% in water) was refluxed for 3 h, and
then the solution was cooled to rt and poured into ice. The
resulting precipitate was filtered washing with water and dried in
oven (60 ꢀC) overnight. Compound 13 (260 mg, 0.91 mmol, 96%
IR n(max) (CHCl3) 1715, 1645, 1350, 1160 cmꢂ1. 1H0NMR (chloroform-
0
d1)
d
(ppm): 7.98 (2H, dd, J¼2.2, 8.0 Hz, C2 -H, C6 -H), 7.51–7.55 (3H,
0
0
0
m, C3 -H, C4 -H, C5 -H), 6.68 (1H, s), 6.66 (1H, s), 4.01 (3H, s, CH3O),
2.45 (3H, s, CH3COO). 13C NMR (chloroform-d1)
d (ppm): 176.3,
169.4, 162.2, 160.0, 154.7, 149.9, 131.8, 131.0, 129.1, 126.4, 111.9, 107.7,
104.3, 97.5, 57.0, 21.1. HRMS: calcd for C18H12BrO5Naþ (MþNaþ)
410.9844; found 410.9848.
yield) was obtained as yellow powder. 13C NMR,
d (ppm): 182.7,
164.3, 153.1, 150.8, 145.8, 131.9, 129.8, 129.2, 126.5, 126.4, 105.8,
105.6, 90.6, 56.6. Other data agreed with those reported in
literature.27
4.1.5. 6,8-Dibromo-5,7-dihydroxyflavone (7). To a solution of 6
(500 mg, 1.97 mmol) in chloroform (7 mL), TBATB (1.67 g,
3.94 mmol) was added in one portion. After 2.5 h under stirring at
rt the mixture was diluted with water (20 mL) and extracted with
ethyl acetate (3ꢁ20 mL) to give pure 7 (746 mg, 1.8 mmol, 92%
yield) as a pale yellow oil. Analytical data were in agreement with
4.1.10. 5,6,7-Trihydroxyflavone (baicalein, 14). A solution of 13
(260 mg, 0.91 mmol) in acetic acid (14 mL) and hydrobromidic acid
(7 mL, 47% in water) was heated to reflux for 18 h, and then the
solution was cooled to rt and poured into ice. The resulting pre-
cipitate was filtered washing with water and dried in oven (60 ꢀC)
overnight. Compound 14 (207 mg, 0.77 mmol, 85% yield) was
obtained as yellow powder and data were identical to that of an
original sample from Sigma–Aldrich Co.
the literature.25 1H NMR (aceton-d6)
d
(ppm): 13.71 (1H, s, 0C5-OH0),
0
0
0
8.12–8.09 (2H, m, C2 -H, C6 -H), 7.62–7.59 (3H, m, C3 -H, C4 -H, C5 -
H), 7.03 (1H, s, C3-H).
4.1.6. 8-Bromo-5,7-dimethoxyflavone (8). To
a solution of 1
(200 mg, 0.71 mmol) in DMF (5 mL), NBS (132 mg, 0.71 mmol) was
added in one portion. The mixture was left to stir for 2.5 h then
quenched with a cold 2 M solution of HCl (5 mL) and extracted with
ethyl acetate (3ꢁ10 mL), dried over anhydrous Na2SO4 and the
solvent evaporated under reduced pressure. Compound 8 (149 mg,
0.57 mmol, 80% yield) was obtained as yellow oil. 1H NMR (acetone-
Acknowledgements
The work described in this article has been partially supported
by ‘Ministero dell’Universita e della Ricerca, Direzione Generale per
le strategie e lo sviluppo dell’internazionalizzazione della ricerca
scientifica e tecnologica’.
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