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M. Brunskole et al. / Bioorg. Med. Chem. 16 (2008) 5881–5889
The resulting suspension was heated to 80 ꢁC for 3 h.
After the reaction was complete, the mixture was filtered
and concentrated under reduced pressure. The residue
was dissolved in EtOAc (250 mL) and washed with
H2O (3· 100 mL) and brine (2· 100 mL). The organic
phase was dried (Na2SO4) and evaporated under re-
duced pressure, and the residue was purified by column
chromatography (petroleum ether/EtOAc, 10:1) to give
the mono- and dibenzylated products, at 1.46 g (15%)
and 4.09 g (31%), respectively. 1-[2-(Benzyloxy)-6-
hydroxyphenyl]ethanone (2) (1.40 g, 5.79 mmol) was
then dissolved in THF (30 mL). After the subsequent
addition of NaH (60%, 255 mg, 6.37 mmol) and BnBr
(4.95 g, 28.95 mmol), the reaction mixture was stirred
at room temperature for 48 h. The reaction mixture
was then diluted with EtOAc (100 mL) and washed with
H2O (2· 100 mL) and brine (100 mL) before being dried
(Na2SO4), and evaporated under reduced pressure. The
residue was dissolved in Et2O (30 mL), treated with pyr-
idine (10 mL) and left at room temperature for 8 h. The
precipitated material was filtered off and washed with
Et2O (2· 30 mL). The mother liquid was washed with
HCl (5%, 2· 30 mL) and brine (30 mL), and then dried
over Na2SO4 and evaporated under reduced pressure.
The residue, yellowish solid, was recrystallized from
the solvent mixture (Et2O/petroleum ether) to give the
dibenzylated product 3 as a white solid, at 1.60 g
(83%). 1-[2-(Benzyloxy)-6-hydroxyphenyl]ethanone (2):
Rf 0.54 (petroleum ether/EtOAc, 5:1); mp 105–107 ꢁC
(109–110 ꢁC)25; IR (mmax/cmÀ1, KBr) 3410, 1626, 1594,
1452, 1362, 1233, 1074, 851, 784, 756, 711, 640; 1H
NMR (300 MHz, CDCl3) d 2.62 (s, 3H), 5.13 (s, 2H),
6.47 (d, 1H, J = 8.5 Hz), 6.59 (dd, 1H, J = 8.5, 1.0 Hz),
7.32 (dd, 1H, J = 8.5, 8.5 Hz), 7.35–7.44 (m, 5H),
13.23 (s, 1H); 13C NMR (75 MHz, CDCl3) d 34.0,
71.1, 102.2, 111.0, 111.5, 127.9, 128.4, 128.7, 135.8,
136.0, 160.6, 164.7, 205.1; MS (EI, 70 eV, m/z, (%))
242 (M+, 11), 91 (100); HRMS (EI) m/z calcd for
C15H14O3: 242.0943; found: 242.0950. 1-[2,6-Bis(benzyl-
oxy)phenyl]ethanone (3): Rf 0.30 (petroleum ether/
7.13 (dd, 1H, J = 8.5, 8.5 Hz), 7.24–7.42 (m, 11H); 13C
NMR (75 MHz, CDCl3). d 36.8, 44.4, 70.2, 100.4,
106.2, 121.9, 126.7, 127.3, 128.1, 129.0, 137.2, 155.0,
190.5; MS (EI, 70 eV, m/z, (%)) 387 (M+, 4%), 91
(100); HRMS (EI) m/z calcd for C25H25NO3: 387.1834,
found: 387.1840; Anal. Calcd for C25H25NO3: C,
77.49; H, 6.50; N, 3.69; found: C, 77.72; H, 6.45; N,
3.63.
4.1.4. 3-[2,6-Bis(benzyloxy)phenyl]-3-oxopropanal (5).
MeONa (407 mg, 7.53 mmol) was suspended in dry
Et2O (20 mL), and a solution of 1-[2,6-bis(benzyl-
oxy)phenyl]ethanone (3) (2.00 g, 6.02 mmol) and
HCO2Et (1.115 g, 15.05 mmol) in dry Et2O (10 mL)
was added. The reaction mixture was stirred at room
temperature for 4 h and then treated with H2O
(30 mL). The layers were separated and the aqueous
phase was washed with Et2O (30 mL), acidified with
HCl (5%, 9.6 mL) and extracted with Et2O (6·
90 mL). The combined organic phases were washed with
H2O (250 mL), and dried (Na2SO4) and evaporated un-
der reduced pressure to give 1.74 g (80%) of pure prod-
uct 5. Rf 0.17 (petroleum ether/EtOAc, 5:1); mp 71–
74 ꢁC; IR (mmax/cmÀ1, KBr) 3028, 1622, 1593, 1470,
1377, 1290, 1256, 1099, 1016, 903, 846, 797, 737, 697;
1H NMR (300 MHz, CDCl3) d 5.14 (s, 4H), 5.85 (d,
1H, J = 4.5 Hz), 6.64 (d, 2H, J = 8.5 Hz), 7.25 (dd, 1H,
J = 8.5, 8.5 Hz), 7.20–7.42 (m, 10H), 7.92 (d, 1H,
J = 4.5 Hz), 14.57 (br s, 1H); 13C NMR (75 MHz,
CDCl3) d 70.5, 106.1, 118.1, 126.8, 127.2, 127.7, 128.5,
131.3, 136.7, 156.7, 173.6, 191.6; MS (EI, 70 eV, m/z,
(%)) 360 (M+, 0.2%), 91 (100); HRMS (EI) m/z calcd
for C23H20O4: 360.1362; found: 360.1369.
4.1.5. 2,3-Dihydro-2,5-dihydroxy-4H-chromen-4-one (6).
3-[2,6-Bis(benzyloxy)phenyl]-3-oxopropanal
(1.74 g,
4.83 mmol) was dissolved in EtOH (70 mL) and hydro-
genated over Pd/C (10%, 670 mg) at 50 psi in a Parr
hydrogenation apparatus for 26 h. The solution was fil-
tered through Celite, rinsed with MeOH (50 mL) and
EtOAc (50 mL). Removal of the solvent under reduced
pressure at room temperature gave a mixture of com-
pounds 6 and 7, which were separated by column chro-
matography (petroleum ether/Et2O, 5:1) yielding 278 mg
(33%) of compound 6 and 45 mg (6%) of compound 7.
2,3-Dihydro-2,5-dihydroxy-4H-chromen-4-one (6): Rf
0.13 (petroleum ether/EtOAc, 5:1); mp 105–107 ꢁC
(103–104 ꢁC)15; IR (mmax/cmÀ1, KBr) 3357, 3059, 1622,
1462, 1330, 1268, 1223, 1110, 1030, 1000, 887, 793,
710; 1H NMR (300 MHz, CDCl3) d 2.91 (dd, 1H,
J = 17.0, 4.0 Hz), 3.09 (dd, 1H, J = 17.0, 3.5 Hz), 3.44
(br s, 1H), 5.87 (br s, 1H), 6.47 (d, 1H, J = 8.5 Hz),
6.58 (d, 1H, J = 8.5 Hz), 7.40 (dd, 1H, J = 8.5, 8.5 Hz),
11.61 (s, 1H); 13C NMR (75 MHz, CDCl3) d 43.0,
94.4, 107.8, 108.1, 110.2, 138.4, 157.6, 161.7, 196.3;
MS (EI, 70 eV, m/z, (%)) 180 (M+, 62%), 108 (100);
HRMS (EI) m/z calcd for C9H8O4: 180.0423; found:
180.0426; Anal. Calcd for C9H8O4: C, 60.00; H, 4.48;
N, 0; found: C, 60.14; H, 4.37; N, 0. 5-Hydroxy-4H-
chromen-4-one (7): Rf 0.24 (petroleum ether/EtOAc,
EtOAc, 5:1); mp 68–70 ꢁC (68.5–70 ꢁC)26; IR (mmax
/
cmÀ1, KBr) 1705, 1592, 1451,1355, 1269, 1232, 1107,
1
775, 733, 695; H NMR (300 MHz, CDCl3) d 2.55 (s,
3H), 5.12 (s, 4H), 6.65 (d, 2H, J = 8.5 Hz), 7.23 (dd,
1H, J = 8.5, 8.5 Hz), 7.31–7.46 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 32.3, 70.4, 105.8, 121.8, 127.0,
127.8, 128.5, 130.4, 136.6, 155.7, 202.2; MS (EI, 70 eV,
m/z, (%)) 332 (M+, 0.5%), 91 (100); HRMS (EI) m/z
calcd for C22H20O3: 332.1413; found: 332.1421.
4.1.3.
1-[2,6-Bis(benzyloxy)phenyl]-3-(dimethylamino)
prop-2-en-1-one (4). A mixture of 1-[2,6-bis(benzyl-
oxy)phenyl]ethanone (3) (673 mg, 2.03 mmol) and
DMFDMA (482 mg, 4.05 mmol) in THF (5 mL) was
heated under reflux for 4 h. The solvent was then evap-
orated under reduced pressure, and the residue purified
by column chromatography (petroleum ether/EtOAc,
1:1) to give dimethylamino derivate 4 as a yellowish so-
lid, at 329 mg (42%). Rf 0.11 (petroleum ether/EtOAc,
1:1); mp 71–74 ꢁC; IR (mmax/cmÀ1, KBr) 3032, 1734,
1
1591, 1451, 1384, 1308, 1258, 1100, 1072, 900, 741; H
5:1); mp 121-125 ꢁC (125.5–127.5 ꢁC)27; IR (mmax/cmÀ1
,
KBr) 3075, 1661, 1620, 1475, 1427, 1364, 1260, 1217,
NMR (300 MHz, CDCl3) d 2.88 (s, 6H), 5.13 (s, 4H),
5.41 (d, 1H, J = 13.0 Hz), 6.59 (d, 2H, J = 8.5 Hz),
1
1165, 1047, 1001, 837, 797, 741; H NMR (300 MHz,