Synthesis of 2-Benzylidene-benzofuran-3-ones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9 1745
Micromass Platform II spectrometer, and high-resolution mass
spectra were obtained on a Finnigan MAT 900 spectrometer.
10.45 (br s 3H), 8.17 (d J ) 7.5 Hz, 1 H), 7.56 (d J ) 8.0 Hz,
1 H), 7.52 (m, 1 H), 7.42 (m, 1 H), 6.84 (s, 1 H), 6.23 (s, 1 H),
3.50 (m, 2 H), 3.21 (m, 1H), 3.0 (m obscured by water peak),
2.83 (s, 3 H), 2.41 (m, 2 H), 1.93 (m, 2 H); 13C NMR (125 MHz,
DMSO-d6) δ 179.0, 165.7, 165.0, 157.0, 148.6, 133.8, 131.4,
130.4, 129.9, 129.9, 128.1, 104.9, 102.2, 102.1, 98.1, 54.2, 43.0,
30.3, 24.4; LCMS (ESI) tR ) 9.13 min, m/z 386.2 [M + H+].
HRMS (ESI) calcd for C21H20ClNO4 [M + H+] m/z 386.1159;
found, 386.1159.
4,6-Dih yd r oxy-7-(1-m eth yl-p ip er id in -4-yl)-2-[1-(4-n itr o-
p h en yl)-m eth -(E)-ylid en e]-ben zofu r a n -3-on e (6): Follow-
ing the procedure used in the preparation of compound 4, 6
was prepared from 13 and 4-nitrobenzaldehyde: 17% yield;
HPLC tR ) 5.96 min1H NMR (500 MHz, DMSO-d6) δ 11.26 (s,
1 H), 11.06 (s, 1 H), 9.25 (br s, 1 H), 8.36 (d J ) 8.9 Hz, 2 H),
8.13 (d J ) 8.9 Hz, 2 H), 6.76 (s, 1 H), 6.22 (s, 1 H), 3.55 (m,
2 H), 3.17 (m, 1H), 3.10 (m, 2 H), 2.83 (d, J ) 4.1 Hz, 3 H),
2.36 (m, 2 H), 1.91 (m, 2 H); 13C NMR (125 MHz, DMSO-d6) δ
178.9, 165.8, 165.0, 157.1, 149.3 146.6, 139.3, 131.3, 130.7,
124.2, 123.7, 105.2, 105.1, 102.1, 98.2, 54.3, 43.1, 30.2, 27.5;
LCMS (ESI) tR ) 5.74 min, m/z 397.2 [M+H+]; HRMS (ESI)
calcd for C21H20N2O6 [M+H+] m/z 397.1400; found, 397.1397.
3,5-Dim eth oxy-2-(1-m eth yl-1,2,3,6-tetr a h yd r o-p yr id in -
4-yl)-p h en ol (11).19 HCl gas was bubbled through a mixture
of dimethoxy phenol (19.7 g, 128 mmol) and 1-methyl-4-
piperidone (15.2 g, 140 mmol) in acetic acid (120 mL) for 1 h.
The reaction mixture was stirred at room temperature for 24
h, the solvent was removed under reduced pressure, and
recrystallization of the residue from ethanol/ether afforded the
hydrochloride salt of 11 as a yellowish solid (17.9 g, 62%): mp
1
222-229 °C; HPLC tR ) 4.4 min; H NMR (200 MHz, CDCl3)
δ 6.14 (d, 1 H), 6.02 (d, 1 H), 5.72 (m, 1 H), 3.76 (s, 3 H), 3.72
(s, 3 H), 3.12 (m, 2 H), 2.67 (m, 2 H), 2.42 (br s, 5 H); MS (ESI)
m/z 250 [M + H+].
3,5-Dim eth oxy-2-(1-m eth yl-p ip er id in -4-yl)-p h en ol (12).
Compound 11 (17.9 g, 57.6 mmol) was hydrogenated in acetic
acid-water (10:1, 220 mL) over Pd/C (1.8 g) at normal pressure
and room temperature for 20 h. The reaction mixture was
filtered over Celite, the solvent evaporated under reduced
pressure, and recrystallization of the residue from ethanol
afforded the hydrochloride salt of 12 as a white solid (15.8 g,
87%): mp 235-237 °C; HPLC tR ) 4.9 min; IR (KBr) 2918,
2800, 1603, 1507 cm-1
;
1H NMR (400 MHz, CDCl3) δ 11.25
4-[4,6-Dih yd r oxy-7-(1-m eth yl-p ip er id in -4-yl)-3-oxo-3H-
ben zofu r an -(2E)-yliden em eth yl]-ben zen esu lfon am ide (7).
Following the procedure used in the preparation of compound
4, 7 was prepared from 13 and 4-formyl-benzenesulfonamide:
(br s, 1 H), 6.02 (d, J ) 2.3 Hz, 1 H), 5.91 (d, J ) 2.3 Hz, 1 H),
3.78 (s, 3 H), 3.76 (s, 3 H), 3.15-2.90 (m, 5 H), 2.46 (s, 3 H),
2.14 (m, 2 H), 1.48 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ
159.0, 158.9, 158.4, 112.6, 94.9, 89.6, 57.3, 55.9, 55.1, 46.6, 31.7,
27.6; MS (ESI) m/z ) 252 [M + H+].
1
14% yield; HPLC tR ) 4.83 min; H NMR (500 MHz, DMSO-
d6) δ 11.19 (s, 1 H), 10.99 (s, 1 H), 9.27 (br s, 1 H), 8.05 (d J )
8.5 Hz, 2 H), 7.95 (d J ) 8.5 Hz, 2 H), 7.44 (s, 2H), 6.66 (s, 1
H), 6.21 (s, 1 H), 3.54 (m, 2 H), 3.19 (m, 1 H), 3.12 (m, 2 H),
2.84 (d J ) 4.5, 2 H), 2.38 (m, 2 H), 1.91 (m, 2 H);13C NMR
(125 MHz, DMSO-d6) δ 179.1, 165.6, 165.0, 156.9, 148.5, 143.6,
135.6, 130.8, 126.4, 106.1, 104.9, 102.2, 98.1, 54.3, 43.0, 30.2,
27.4; LCMS (ESI) tR ) 5.39 min, m/z 431.2 [M + H+]. HRMS
(ESI) calcd for C21H22N2O6S [M + H+] m/z 431.1277; found,
431.1278.
4,6-Dim eth oxy-7-(1-m eth yl-piper id in -4-yl)-ben zofu r a n -
3-on e (13). Chloro-acetyl chloride (6.3 mL) was added drop-
wise to 12 (6.6 g, 21.2 mmol) at 0 °C. The mixture was stirred
for 3.5 h at 50 °C and cooled to 0 °C, and aluminum trichloride
(6.6 g, 49.4 mmol) was added in small portions. The reaction
mixture was finally stirred for 1 h at 100 °C, cooled to room
temperature, and quenched with an ice-water solution. The
aqueous solution was neutralized with sodium hydrogencar-
bonate and extracted with DCM. The combined organic layers
were dried over sodium sulfate, filtered, and concentrated
under reduced pressure. Flash chromatography of the residue
on silica gel eluting with DCM/methanol/ammoniac (9:1:0.1)
gave the desired benzofuranone 13 as a white solid (3.1 g,
50%): mp 203-209 °C; HPLC tR ) 4.1 min; IR (DCM) 2941,
2846, 2786, 1699, 1617, 1596 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.04 (s, 1 H), 4.57 (s, 2 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.00-
2.97 (m, 3 H), 2.38-2.05 (m, 2 H), 2.34 (s, 3 H), 2.05 (m, 2 H),
1.56 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 195.8, 173.7, 166.6,
157.4, 110.2, 104.7, 86.6, 56.8, 56.1, 56.0, 46.7, 31.7, 29.5; MS
(ESI) m/z 292 [M + H+]. Anal. (C16H21NO4.1/4H2O) C, H, N.
4,6-Dih yd r oxy-7-(1-m eth yl-p ip er id in -4-yl)-2-[1-p h en yl-
m eth -(E)-ylid en e]-ben zofu r a n -3-on e (4). To a solution of
13 (200 mg, 0.7 mmol) and benzaldehyde (72 mg, 0.7 mmol)
in ethanol (10 mL) was added potassium hydroxide (75 mg,
1.3 mmol) at room temperature. The reaction mixture was
stirred for 1 h; the product, which precipitated, was filtered
and directly mixed with pyridinium hydrochloride (1500 mg,
13 mmol) and heated at 180 °C for 3 h. The reaction mixture
was allowed to cool to room temperature and was dissolved in
methanol/water (1:1, 3 mL). Reverse phase MPLC chroma-
tography afforded after lyophilization the trifluoroacetic salt
of 4 as an orange powder (98 mg, 30%): HPLC tR ) 5.61 min;
1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1 H), 10.89 br s, 1
H), 9.30 (br s, 1 H), 7.89 (d J ) 7.6 Hz, 2 H), 7.51 (m, 2 H),
7.42 (m, 1 H), 6.61 (s, 1 H), 6.20 (s, 1 H), 3.53 (m, 2 H), 3.10
(m, 2 H), 2.83 (d, J ) 4.5 Hz, 3 H), 2.39 (m, 2 H), 1.91 (m, 2
H); 13C NMR (125 MHz, DMSO-d6) δ 179.3, 165.4, 165.0, 156.7,
147.4, 132.3, 130.7, 129.1, 129.0, 108.0, 104.7, 102.5, 98.0, 54.3,
43.0, 30.3, 27.5; LCMS (ESI) tR ) 6.12 min, m/z 352.2 [M +
H+]. HRMS (ESI) calcd for C21H21NO4 [M + H+] m/z 352.149;
found, 352.1550.
2-[1-(4-Br om o-ph en yl)-m eth -(E)-yliden e]-4,6-dim eth oxy-
7-(1-m eth yl-p ip er id in -4-yl)-ben zofu r a n -3-on e (14). To a
solution of 13 (582 mg, 2 mmol) and 4-bromobenzaldehyde (370
mg, 2 mmol) in ethanol (10 mL) was added potassium
hydroxide (224 mg, 4 mmol) at room temperature. The reaction
mixture was stirred for 1 h; the product, which precipitated,
was filtered to afford pure 14 as a yellow crystalline compound
(375 mg, 41%): mp 220-223 °C; HPLC tR ) 6.99 min; 1H NMR
(400 MHz, DMSO-d6) δ 7.9 (d J ) 8.6 Hz, 2 H), 7.63 (d J ) 8.6
Hz, 2 H), 6.68 (s, 1 H), 6.44 (s, 1 H), 3.97 (s, 3 H), 3.95 (s, 3 H),
3.05-2.89 (m, 3 H), 2.32-2.19 (m, 2 H), (2.26 s, 3H), 1.94 (m,
2 H), 1.55 (m, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 178.9,
165.8, 164.3, 157.6, 147.2, 122.3, 109.5, 107.1, 103.6, 91.5, 56.6,
56.1, 56.0, 46.1, 31.4, 29.3. HRMS (ESI) calcd for C23H24BrNO4
[M + H+] m/z 458.0967; found, 458.0965.
4,6-Dim eth oxy-2-[1-[4-(4-m eth yl-p ip er a zin -1-yl)-p h en -
yl]-m eth -(E)-ylid en e]-7-(1-m eth yl-p ip er id in -4-yl)-ben zo-
fu r a n -3-on e (15): A solution of 14 (92 mg, 0.2 mmol),
1-methylpiperazine (42 mg, 0.42 mmol), Pd2(dba)3 (5 mg, 0.006
mmol), racemic-BINAP (9 mg, 0.0014 mmol), and cesium
carbonate (150 mg, 0.46 mmol) was refluxed in dioxan (2 mL)
under argon for 12 h. The reaction mixture was diluted with
ethyl acetate washed with brine, dried over magnesium
sulfate, concentrated under reduced pressure, and crystallized
from 2-propanol to afford the dimethoxy intermediate as a
orange crystalline compound (53 mg, 55%): HPLC tR ) 4.96
1
min; H NMR (500 MHz, DMSO-d6, 353 K) δ 7.78 (d J ) 8.6
Hz, 2 H), 7.06 (d J ) 8.6 Hz, 2 H), 6.59 (s, 1 H), 6.45 (s, 1 H),
3.98 (s, 3 H), 3.96 (s, 3 H), 3.39-3.18 (m, 6 H), 2.63-2.29 (m,
13 H), 1.79 (m, 2 H), 1.04 (m, 2 H). HRMS (ESI) calcd for
C
28H35N3O4 [M + H+] m/z 458.0967; found, 458.0965.
4,6-Dih yd r oxy-2-[1-[4-(4-m eth yl-p ip er a zin -1-yl)-p h en -
yl]-m eth -(E)-ylid en e]-7-(1-m eth yl-p ip er id in -4-yl)-ben zo-
fu r a n -3-on e (8). Compound 15 (32 mg, 0.067 mmol) was
mixed with pyridinium hydrochloride (50 mg, 0.43 mmol) and
heated at 180 °C for 3 h. The reaction mixture was allowed to
cool to room temperature and was dissolved in methanol-
water (1:1, 1 mL). Reverse phase MPLC chromatography
2-[1-(2-Ch lor o-ph en yl)-m eth -(E)-yliden e]-4,6-dih ydr oxy-
7-(1-m eth yl-p ip er id in -4-yl)-ben zofu r a n -3-on e (5). Follow-
ing the procedure used in the preparation of compound 4, 5
was prepared from 13 and 2-chlorobenzaldehyde: 30% yield;
HPLC tR ) 6.13 min; 1H NMR (500 MHz, DMSO-d6, 373 K) δ