592 JOURNAL OF CHEMICAL RESEARCH 2007
H3CO
OH
aqueous NaHCO3 solution (5%, 10 ml), removing the insoluble
matter by filtration and acidifying the filtrate to pH 1–2 with conc.
HCl to obtain the required acid (10) (0.83 g) as off-white solid which
was sufficiently pure to be subjected to the next reaction.
Yield: 90%; m.p. 115°C.
H3CO
O
O
i
CHO
6-Methoxy-4-(2-phenylethyl) benzofuran (1):
A mixture of
2-formyl-5-methoxy-3-(2-phenylethyl)phenoxyethanoic acid (10)
(0.5 g, 1.6 mmol) and freshly fused NaOAc (0.4 g, 4.88 mmol) in
acetic acid (2.5 ml) and acetic anhydride (2.5 ml) was heated in an
oil bath at 140°C for 1 h. The reaction mixture was poured onto ice
(25 g). The resultant oil was extracted with ether (2 ¥ 20 ml).
The ether layer was washed successively with water (2 ¥ 10 ml),
satd. NaHCO3 solution (2 ¥ 10 ml), brine (2 ¥ 10 ml) and dried
over anhydrous Na2SO4. Removal of the solvent under reduced
pressure provided the crude product which was purified by column
chromatography over silica gel using hexane as eluent to obtain the
required natural product 6-methoxy-4-(2-phenylethyl)benzofuran (1)
(0.25 g) as colourless viscous oil.
(7)
(3)
Scheme 3 Reagents and conditions: (i) Ph3P =CHCOOEt,
dry toluene, reflux, 48 h.
Yield: 77%; m.p. oil, (lit4. m.p. oil); 1H NMR: d 2.86 (brs, 4H),
3.72 (s, 6H), 6.29 (m, 3H), 7.17 (m, 5H); Anal. calcd. for C16H18O2:
C, 79.65; H, 8.39. Found: C, 79.3; H, 8.1.
Yield: 63%; m.p. oil, (lit1. m.p. oil); 1H NMR: d 2.96 (m, 2H),
3.06 (m, 2H), 3.83 (s,3H), 6.67 (dd, J = 1.0, 2.2 Hz, 1H), 6.70 (d,
J = 2.2 Hz, 1H), 6.90 (brs, 1H), 7.20 (m, 5H) 7.51 (d, J = 2.2 Hz, 1H);
13C NMR: d 35.8, 38.0, 55.9, 93.6, 105.2, 110.9, 120.1, 126.0, 128.0,
128.6, 135.2, 141.5, 143.5, 156.0, 157.8; Anal. calcd. for C17H16O2:
C, 80.95; H, 6.34. Found: C, 81.2; H, 6.1.
2,4-Dimethoxy-6-(2-phenylethyl)benzaldehyde (7): To a complex
prepared from dry DMF (0.7 ml, 9.1 mmol) and POCl3 (0.9 ml,
9.62 mmol) at 0ºC was added 1,3-dimethoxy-5-(2-phenylethyl)
benzene (6) (2 g, 8.26 mmol). The mixture was stirred and heated
at 50°C for 5 h. The reaction mixture was poured into a beaker
containing a satd. solution of NaOAc (50 ml) and the resultant oil was
extracted with ethyl acetate (2 ¥ 20 ml), washed successively with
water (10 ml), satd. NaHCO3 solution (10 ml) and again with water
(10 ml). The organic layer was dried over anhydrous Na2SO4, filtered
and concentrated under reduced pressure and the crude reside was
purified by silica gel column chromatography using hexane as eluent
to afford the required compound (7) (1.34 g) as colourless solid.
Yield: 60%; m.p. 83°C; IR: 1674 cm-1; 1H NMR: d 2.81 (t,
J = 8.0 Hz, 2H), 3.22 (t, J = 8.0 Hz, 2H), 3.77 (s, 3H), 3.86 (s, 3H),
6.20 (d, J = 2.4 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 7.25 (m, 5H), 10.5
(s, 1H); Anal. calcd. for C17H18O3: C, 75.55; H, 6.66. Found: C, 75.9;
H, 6.4.
2-Acetyl-1,5-dimethoxy-3(-2-phenylethyl)benzene (11): To a solution
of 1,3-dimethoxy-5-(2-phenylethyl)benzene (6) (0.3 g, 1.24 mmol)
in dry DCM (6 ml), a mixture of glacial acetic acid (0.1 ml) and
trifluoroacetic anhydride (0.3 ml) was added. The reaction mixture was
stirred for 3 h at room temperature. The excess solvent was removed
under reduced pressure and the resultant residue was extracted in ether
(25 ml). The organic layer was washed with water (2 ¥ 10 ml), satd.
NaHCO3 solution (2 ¥ 10 ml) and brine (10 ml), dried over anhydrous
Na2SO4, filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography over
silica gel using hexane:ethyl acetate (9:1) as eluent to provide the
required compound (11) (0.23 g) as a light yellow oil.
2-Hydroxy-4-methoxy-6-(2-phenylethyl)benzaldehyde
(8):
A
Yield: 73%; m.p. oil; IR: 1680 cm-1; 1H NMR: d 2.43 (s, 3H), 2.76
(brs, 2H), 2.89 (brs, 2H), 3.73 (s, 3H), 3.86 (s, 3H), 6.30 (brs, 2H),
7.04–7.37 (m, 5H). Anal. calcd. for C18H20O3: C, 76.05; H, 7.04.
Found: C, 76.35; H, 7.2.
suspension of finely powered anhydrous AlCl3 (0.3 g, 2.25 mmol) in
dry DCM (10 ml) was stirred at room temperature for 20 min. To this
mixture, a solution of 2,4-dimethoxy-6-(2-phenylethyl)benzaldehyde
(7) (0.37 g, 1.37 mmol) in dry DCM (5 ml) was added under vigorous
stirring over a period of 10 min. The resultant dark green coloured
mixture was stirred at room temperature for an additional 1 h.
The excess solvent was removed under reduced pressure and the
residue was decomposed using ice cold 1:1 HCl/H2O (20 ml) and
extracted with ethyl acetate (2 ¥ 25 ml). The organic layer was
washed successively with water (2 ¥ 20 ml), satd. NaHCO3 solution
(2 ¥ 20 ml) and again with water (2 ¥ 20 ml) and dried over anhydrous
Na2SO4. Removal of organic solvent under reduced pressure followed
by column chromatographic purification of the crude product over
silica gel using hexane as eluent provided the required compound (8)
(0.3 g) as pale yellow solid.
2-Acetyl-1-hydroxy-5-methoxy-3-(2-phenylethyl)benzene
(12):
A suspension of finely powered anhydrous AlCl3 (0.3 g, 2.25 mmol)
in dry DCM (10 ml) was stirred at room temperature for 20 min.
To this mixture, a solution of (11) (0.4 g, 1.41 mmol) in dry DCM
(5 ml) was added under vigorous stirring over a period of 10 min.
The resultant dark green coloured mixture was stirred at room
temperature for an additional 1 h. Excess solvent was removed under
reduced pressure and the residue was treated with ice-cold 1:1 HCl/
H2O (20 ml) and extracted with ethyl acetate (2 ¥ 25 ml). The organic
layer was washed successively with water (2 ¥ 15 ml), satd. NaHCO3
solution (2 ¥ 15 ml), brine (20 ml) and dried over anhydrous Na2SO4.
Removal of the organic solvent under reduced pressure followed by
column chromatographic purification of the crude product over silica
gel using hexane as eluent provided (12) (0.31 g) as light yellow
viscous oil.
Yield: 87%; m.p. 50°C; IR: 1626 cm-1; 1H NMR: d 2.94 (m, 2H), 3.12
(m, 2H), 3.8 (s, 3H), 6.24 (d, J = 2.44 Hz, 1H), 6.26 (d, J = 2.44 Hz,
1H), 7.17 (m, 5H), 9.94 (s, 1H) 12.45 (s, 1H);Anal. calcd. for C16H16O3:
C, 75.00; H, 6.25. Found: C, 74.8; H, 6.5.
Yield: 82%; m.p. oil; IR: 1670 cm-1; 1H NMR: d 2.69 (s, 3H), 2.93 (m,
2H), 3.20 (m, 2H), 3.82 (s, 3H), 6.30 (m, 2H), 7.04–7.37 (m, 5H), 13.2 (s,
1H). Anal. calcd. for C17H18O3: C, 75.55; H, 6.66. Found: C, 75.8; H, 6.9.
2,2-Dimethyl-7-methoxy-5-(2-phenylethyl)chroman-4-one (13): To a
solution of 2-acetyl-1-hydroxy-5-methoxy-3-(2-phenylethyl)benzene
(12) (0.5 g, 1.85 mmol) in dry benzene (5 ml) was added freshly
distilled pyrrolidine (0.2 ml, 1.85 mmol) and dry acetone
(0.25 ml, 3.70 mmol). The resulting solution was allowed to stand
for 15 min, with intermittent swirling at room temperature and
subsequently refluxed using a Dean Stark separator for 48 h when
TLC analysis indicated completion of the reaction. The reaction
mixture was allowed to attain room temperature. Removal of excess
solvent under vacuum provided a residue which was extracted into
ethyl acetate (30 ml). The organic layer was washed successively
with water (2 ¥ 15 ml), dil. HCl (2 ¥ 15 ml), satd. NaHCO3 solution
(2 ¥ 15 ml), brine (20 ml) and dried over anhydrous Na2SO4. Removal
of the organic solvent under reduced pressure followed by column
chromatographic purification of the crude product over silica gel
using hexane as eluent yielded the required compound (13) (0.37 g)
as a colourless oil.
Ethyl 2-formyl-5-methoxy-3-(2-phenylethyl)phenoxyethanoate (9):
Toasolutionof2-hydroxy-4-methoxy-6-(2-phenylethyl)benzaldehyde
(8) (1 g, 3.9 mmol) in dry DMF (10 ml), anhydrous K2CO3 (0.8 g,
5.86 mmol) was added, followed by ethyl bromoacetate (0.65 g,
3.9 mmol). This mixture was stirred at room temperature for 1 h.
After completion of reaction, the reaction mixture was poured onto
crushed ice (50 g) and the resultant oil was extracted with ethyl
acetate (2 ¥ 20 ml). The organic layer was washed with water, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification of the crude product by column chromatography over
silica gel using hexane-ethyl acetate (3:1) as eluent provided the
required ester (9) as pale yellow crystalline solid (1.14 g).
Yield: 86%; m.p. 71°C; IR: 1753.2 cm-1, 1674 cm-1; 1H NMR:
d 1.29 (t, J = 7.3 Hz, 3H), 2.84 (t, J = 8.0 Hz, 2H), 3.23 (t, J = 8.0 Hz,
2H), 3.79 (s, 3H), 4.30 (q, J = 7.3 Hz, 2H), 4.70 (s, 2H), 6.21 (d,
J = 2 Hz, 1H) 6.25 (d, J = 2 Hz, 1H), 7.26 (m, 5H), 10.62 (s, 1H);
Anal. calcd. for C20H22O5: C, 70.17; H, 6.43. Found: C, 70.4; H, 6.3.
2-Formyl-5-methoxy-3-(2-phenylethyl)phenoxyethanoic acid (10):
A 5% aqueous NaOH solution (5 ml) was added to ethyl 2-formyl-
5-methoxy-3-(2-phenylethyl)phenoxyethanoate (9) (1 g, 2.92 mmol)
and the mixture was heated on a steam bath for 30 min. The solution
was filtered over a pad of celite and the filtrate was acidified to
pH 1–2 with conc. HCl. The precipitated solid was filtered and
washed with water. The solid was further purified by dissolving in
Yield: 65%; m.p. oil; IR: 1688 cm-1; 1H NMR: d 1.40 (s, 3H), 1.60
(s, 3H), 2.6 (brs, 2H), 3.0 (t, J = 6.0 Hz, 2H), 3.5 (t, J = 6.0 Hz, 2H)
3.80 (s, 3H), 6.33 (s, 1H), 6.80 (s, 1H), 7.0–7.3 (m, 5H); Anal. calcd.
for C20H22O3: C, 77.41; H, 7.10. Found: C, 77.7; H, 6.8.
PAPER: 07/4711