Synthesis of C-C-Bridged Bis-Isoflavones
J . Org. Chem., Vol. 65, No. 8, 2000 2307
114.7 (C-6), 113.9 (C-3′, C-5′), 99.8 (C-8), 55.8 (7-OCH3), 55.2
(4′-OCH3), 27.4 (CH2Br); MS m/ z relative intensity 376 and
374 (M+, 24), 295 (100), 279 (27); HRMS C18H15BrO4 requires
374.0153, found 374.0165.
Exp er im en ta l Section
Melting points were determined in open capillary tubes and
are uncorrected. NMR spectra were recorded on a 200 or 300
MHz spectrometer with SiMe4 as an internal standard. The
NMR spectra were assigned using 2D COSY, GHSQCTOCSY,
and GHMBC techniques. Mass spectra were obtained using
EI ionization at 70 eV. Samples were introduced by a direct
inlet probe. IR spectra were recorded from KBr disks. All
compounds were homogeneous on TLC. Combustion analysis
were performed by the Analytische Laboratorien, Lindlar,
Germany.
2,4,4′-Tr ih yd r oxyd eoxyben zoin (1). Dry resorcinol (11 g,
0.10 mol) and 4-hydroxyphenylacetic acid (13.21 g, 0.09 mol)
in BF3‚Et2O (35.5 mL, 0.3 mol) were stirred under reflux for
15 min under Ar. The reaction vessel was then cooled in an
ice bath and the reaction mixture poured into an excess of ice-
water. The resulting yellow precipitate was collected by
filtration and washed with CHCl3 to give 1 (19.72 g, 90%): mp
189-191 °C (lit.14 mp 192 °C).
7,4′-Dih yd r oxy-2-m eth ylisofla von e (2). BF3‚Et2O (14.1
mL, 0.114 mol) was added to 2,4,4′-trihydroxydeoxybenzoin
(1) (7 g, 28.68 mmol) in freshly distilled N,N-dimethylacet-
amide (DMA, 40 mL) under Ar and the reaction mixture
heated to 50 °C. Methanesulfonyl chloride (6.69 mL, 86 mmol
in 10 mL of DMA) was added dropwise and the mixture stirred
at 75 °C for 3 h. The dark brown solution was cooled and the
viscous product poured over crushed ice to afford an orange
precipitate. The solid was collected by filtration, washed with
cold water, and recrystallized from aqueous ethanol to give 2
as a white solid (5.9 g, 77%): mp 315-317 °C (lit.15 mp 315-
317 °C); δH (DMSO-d6) 10.77 (7-OH), 9.56 (4′-OH), 7.93 (d, 1H,
J ) 8.6 Hz, H-5), 7.13 (d, 2H, J ) 8.5 Hz, H-2′,6′), 6.95 (dd,
1H, J ) 8.6, 2.2, H-6), 6.88 (d, 1H, J ) 2.2 Hz, H-8), 6.88 (d,
2H, J ) 8.5 Hz, H-3′,5′), 2.29 (s, 3H, -CH3); δC 175.0 (C-4),
162.2 (C-7, 8a), 156.9 (C-4′), 156.6 (C-2), 131.6 (C-2′,6′), 127.1
(C-5), 123.6 (C-3), 121.9 (C-1′), 115.6 (C-4a), 114.8 (C-3′,5′),
114.6 (C-6), 101.8 (C-8), 19.2 (CH3); HRMS C16H12O4 requires
268.0735, found 268.0740.
7,4′-Dim eth oxy-2-m eth ylisofla von e (3). 7,4′-Dihydroxy-
2-methylisoflavone (2) (5 g, 18.65 mmol) and potassium tert-
butoxide (4.39 g, 39.2 mmol) were stirred in dry DMF (40 mL)
under Ar for 2 h. After addition of methyl iodide (5.955 g, 39.2
mmol), the mixture was stirred at 80 °C overnight, cooled to
rt, and poured into water, and the crude product was filtered
and recrystallized from absolute ethanol to give 3 (5.1 g,
92%): mp 166-167 °C (lit.15 mp 166-168 °C); δH (CDCl3) 8.13
(d, J ) 8.9 Hz, 1H, H-5), 7.22 (d, J ) 8.9 Hz, 2H, H-2′, H-6′),
6.97 (d, J ) 8.9 Hz, 2H, H-3′, H-5′), 6.95 (dd, J ) 8.9, 2.4 Hz,
1H, H-6), 6.83 (d, J ) 2.4 Hz, 1H, H-8), 3.91 (s, 3H, 7-OMe),
3.84 (s, 3H, 4′-OMe), 2.29 (3H, s, -CH3); δC 176.3 (C-4), 163.6
(C-7), 162.5 (C-4′), 158.9 (C-8a), 157.4 (C-2), 131.5 (C-2′, C-6′),
127.5 (C-5), 125.2 (C-3), 122.8 (C-1′), 117.2 (C-4a), 113.9 (C-
6), 113.7 (C-3′, C-5′), 99.7 (C-8), 55.7 (7-OCH3), 55.2 (4′-OCH3),
19.4 (CH3); MS m/ z relative intensity 296 (M+, 100), 146 (17);
HRMS C18H16O4 requires 296.1049, found 296.1048.
Eth yl 2-Cyan o-2,2-bis[(7-m eth oxy-3-(4-m eth oxyph en yl)-
4-oxo-4H-ch r om en -2-yl)m eth yl]a ceta te (5). Ethyl cyano-
acetate (0.24 g, 2.1 mmol) was added slowly to a suspension
of anhyd K2CO3 (0.294 g, 2.1 mmol) in freshly distilled DMF
(10 mL) under Ar. After being stirred for 2 h at ambient
temperature, the solution was transferred with a syringe to a
solution of 4 (0.2 g, 0.533 mmol) in dry DMF (10 mL) at room
temperature. The dark red solution was stirred for a further
4 h at room temperature and quenched with water and the
crude product filtered. Recrystallization from ethanol gave 5
(0.12 g, 64%): mp 201-202 °C; IR 2250, 1737, 1647 cm-1; λmax
(MeCN) nm (log ꢀ) 232 (4.67), 240 (4.66), 248 (4.62), 296 (4.30),
306 (4.27); δH (CDCl3) 8.01 (d, J ) 9.3 Hz, 2H, H-5′), 6.96 (d,
J ) 9.0 Hz, 4H, H-2′′,6′′), 6.88 (dd, J ) 9.3, 2.4 Hz, 2H, H-6′),
6.74 (d, J ) 9 Hz, 4H, H-3′′,5′′), 6.59 (d, J ) 2.4 Hz, 2H, H-8′),
4.23 (q, J ) 7.2 Hz, 2H, H-5), 3.80 (s, 6H, 7′-OMe), 3.71 (s,
6H, 4′′-OMe), 3.12 (AB quartet, 4H, H-3a,3b), 1.15 (t, J ) 7.2
Hz, 3H, H-6); δC 175.8 (C-4′), 167.1 (C-1), 164.1 (C-7′), 159.3
(C-4′′), 157.3 (C-2′), 156.9 (C-8a′), 131.3 (C-2′′, C-6′′), 127.6 (C-
5′), 125.4 (C-3′), 123.2 (C-1′′), 117.1 (C-4), 117.0 (C-4a′), 114.4
(C-6′), 113.9 (C-3′′, C-5′′), 99.6 (C-8′), 63.5 (C-5), 55.7 (7′-OMe),
55.1 (4′′-OMe), 45.5 (C-2), 37.9 (C-3), 13.9 (C-6); MS m/ z
relative intensity 701 (M+, 9), 405 (42), 376 (41), 332 (65), 295
(100); HRMS C41H35 NO10 requires 701.2261, found 701.2247.
Anal. Calcd for C41H35 NO10
: C, 70.18; H, 5.03; N, 2.00.
Found: C, 69.84; H, 4.96; N, 1.91.
2,2-Bis-[(7-m e t h oxy-3-(4-m e t h oxyp h e n yl)-4-oxo-4H -
ch r om en -2-yl)m eth yl]a cetic Acid (6). Concentrated H2SO4
(2 mL) was added slowly with stirring to a mixture of 5 (0.3 g,
0.43 mmol), acetic acid (2 mL), and water (2 mL). After being
refluxed for 4 h, the reaction mixture was poured into ice-
water (300 mL) and kept overnight at 5 °C. The precipitate
was filtered off and dissolved in warm 5% sodium hydrogen
carbonate solution (50-60 °C), and the solution was washed
with ether. After filtration, the cooled aqueous solution was
acidified with concentrated HCl, and the precipitate was
filtered, washed thoroughly with water, dried, and crystallized
from ethanol to give 0.21 g (76%) of 6: mp 265-66 °C; IR
3500-2462, 1714, 1636 cm-1; λmax (MeCN) nm (log ꢀ) 231
(4.77), 240 (4.78), 247 (4.76), 292 (4.41), 303 (4.37); δH (DMSO-
d6) 7.90 (d, J ) 9.1 Hz, 2H, H-5′), 7.04 (dd, J ) 9.1, 2.4 Hz,
2H, H-6′), 6.98 (d, J ) 8.8 Hz, 4H, H-2′′, H-6′′), 6.90 (d, J )
2.4 Hz, 2H, H-8′), 6.81 (d, J ) 8.8 Hz, 4H, H-3′′, 5′′); 3.88 (s,
6H, 7-OMe); 3.70 (s, 6H, 4′′-OMe); 3.28 (quintet, J ) 7.1, 1H,
H-2), 2.86 (dd, J ) 15.4, 7.1 Hz, 2H, H-3a), 2.74 (dd, J ) 15.4,
7.3 Hz, 2H, H-3b); δC 175.2 (C-4′), 174.3 (C-1), 163.6 (C-7′),
162.4 (C-2′), 158.5 (C-4′′),156.7 (C-8a′), 131.4 (C-2′′, C-6′′), 126.7
(C-5′), 124.2 (C-3′), 122.8 (C-1′′), 116.3 (C-4a′), 114.5 (C-6′),
113.3 (C-3′′, 5′′), 99.9 (C-8′), 55.9 (7′-OMe), 54.9 (4′′-OMe), 40.2
(C-2), 33.2 (C-3). For MS measurements, 5 mg of the acid 6
was derivatized to the corresponding methyl ester with diaz-
omethane: MS m/ z relative intensity 662 (M+, 20), 366 (54),
307 (100), 295 (30); HRMS C39H34O10 requires 662.2152, found
662.2131.
2,2-Bis-[(7-h yd r oxy-3-(4-h yd r oxyp h e n yl)-4-oxo-4H -
ch r om en -2-yl)m eth yl]a cetic Acid (7). An excess of 1 M
BBr3/CH2Cl2 (5.54 mL, 20 equiv) was added dropwise with
stirring to a solution of 6 (0.18 g, 0.277 mmol) in CH2Cl2 (2
mL) under Ar at room temperature. The mixture was stirred
for 72 h and then heated with water under reflux for 3 h. CH2-
Cl2 was evapor ated, the resulting product was filtered off and
recrystallized from aqueous ethanol to give 7 (0.13 g, 79%):
mp 233-234 °C; IR 3500-2460, 1718, 1636 cm-1; λmax (MeCN)
nm (log ꢀ) 230 (4.65), 239 (4.65), 247 (4.62), 292 (4.30), 303
(4.26); δH (DMSO-d6) 12.60 (br s, 1H, COOH), 10.77 (s, 2H,
7′-OH), 9.51 (s, 2H, 4′′-OH), 7.91 (d, 2H, J ) 8.8 Hz, H-5′),
6.96 (dd, 2H, J ) 8.8, 1.8 Hz, H-6′), 6.95 (d, 4H, J ) 8.4 Hz,
H-2′′, 6′′), 6.80 (d, 2H, J ) 1.8 Hz, H-8′), 6.77 (d, 4H, J ) 8.4
Hz, H-3′′ and 5′′), 3.29 (quintet, 1H, J ) 7.1 Hz, H-2), 2.89
(dd, 2H, J ) 15.2, 7.7 Hz, H-3a), 2.77 (dd, 2H, J ) 15.2, 6.8
Hz, H-3b); δC 175.1 (C-4′), 174.5 (C-1), 162.4 (C-7′), 161.9 (C-
2-(Br om om eth yl)-7,4′-d im eth oxyisofla von e (4). N-Bro-
mosuccinimide (0.992 g, 5.57 mmol), dibenzoyl peroxide (1 mg),
and the isoflavone 3 (1.5 g, 5 mmol) in CCl4 (100 mL) were
heated under reflux for 6 h under irradiation (Hg lamp, Osram
HQL-R 250). The mixture was then filtered hot to remove the
resultant succinimide and the solvent removed to give an
orange gummy product. The dichloromethane-soluble materi-
als were chromatographed over silica gel using CH 2Cl2/EtOAc
(9:1) as eluent to give 4 (1.55 g, 82%): mp 152-154 °C; δH
(CDCl3) 8.13 (d, J ) 8.8 Hz, 1H, H-5), 7.33 (d, J ) 8.5 Hz, 2H,
H-2′, H-6′), 7.00 (d, J ) 8.5 Hz, 2H, H-3′, H-5′), 6.97 (dd, J )
8.8, 2.2 Hz, 1H, H-6), 6.91 (d, J ) 2.2 Hz, 1H, H-8), 4.27 (s,
2H, CH2Br), 3.94 (s, 3H, 7-OMe), 3.86 (s, 3H, 4′-OMe); δC 176.3
(C-4), 164.2 (C-7), 159.4 (C-4′), 158.4 (C-8a), 157.4 (C-2), 131.0
(C-2′, C-6′), 127.6 (C-5), 123.9 (C-3), 123.5 (C-1′), 117.2 (C-4a),
(14) Walz, E. Liebigs Ann. Chem. 1931, 489, 118.
(15) Seshadri, T. R.; Varadarajan, S. Proc. Indian Acad., Sect. A
1953, 37, 784.