D. A. Williams et al. / Tetrahedron Letters 54 (2013) 4292–4295
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crude product that was used directly without purification for the cyclization
step.
22. Cyclization general procedure method A: the crude Claisen condensation
produce was dissolved in 20 mL of acetic acid and 15 drops of HCl was then
added. The solution was then placed in an oil bath that was preheated to
120 °C. The solution began to reflux almost immediately and was refluxed for
45 min. While still hot the solution was poured onto approximately 20 g of
crushed ice. The aqueous layer was extracted with 25 mL ethyl acetate three
times. The combined organic layers were then washed with saturated sodium
bicarbonate solution followed by brine. After drying over sodium sulfate the
organic layer was concentrated to yield the crude product that was then
purified in the appropriate manner. Method B: the crude Claisen condensation
produce was dissolved in 20 mL of methanol and 15 drops of HCl was added.
The solution was then placed in an oil bath that was preheated to 90 °C. The
solution began to reflux almost immediately and was refluxed for 45 min. After
cooling to room temperature the solution was made neutral by the drop wise
addition of saturated Na2CO3. The resulting solution was then diluted with
75 mL of dichloromethane. The organic layer was washed once with 25 mL of
sat. NH4Cl, dried over Na2SO4, filtered and concentrated. The cyclized product
was then purified in an appropriate manner.
23.2-Phenethyl-4H-chromen-4-one (3). Purified by column chromatography
eluting with 70:30 hexanes/ethyl acetate. IR cmꢀ1 3075, 2923, 1642, 1600,
1499, 1463, 1379; 1H NMR (400 MHz, CD3CN): d, 8.04–8.02 (1H, dd, J = 1.6 and
7.8 Hz), 7.71–7.69 (1H, dt, J = 1.6 and 6.96 Hz), 7.47 (1H, d, J = 8.4), 7.41–
7.37(1H, dt, J = .92 and 7.0 Hz), 7.29–7.12 (5H, m) 6.04 (1H, s), 3.05 (2H, t,
J = 7.9 Hz), 2.92 (2H, t, J = 8.0 Hz); 13C NMR (100 MHz, CD3CN) d 178.4, 169.9,
157.4, 141.4, 134.7, 129.5, 129.4, 127.3, 126.0, 126.0, 124.6, 119.0, 110.7, 36.5,
33.4.
2-(4-Methoxyphenethyl)-4H-chromen-4-one (4). Purified by column
chromatography eluting with 70:30 hexanes/ethyl acetate. IR cmꢀ1 2930,
28.34 1648, 1609, 1511, 1463, 1243, 846, 821; 1H NMR (400 MHz, CD3CN): d
8.03 (1H, dd, J = 1.52 and 7.96 Hz), 7.69–7.64 (1H, dt, J = 1.56 and 8.48), 7.44
(1H, d, J = 8.36 Hz), 7.37 (1H, t, J = 7.76 Hz) 7.13 (2H, d, J = 8.56), 6.82 (2H, d,
J = 8.6 Hz), 6.03 (1H, s) 3.71 (3H, s), 2.95 (2H, t, J = 7.0 Hz), 2.85 (2H, t,
J = 7.72 Hz); 13C NMR (100 MHz, CD3CN) d 178.4, 170.0, 159.2, 157.4, 134.7,
133.2, 130.4, 126.0, 124.6, 119.0, 114.8, 110.7, 55.8, 36.7, 32.5.
21. General procedures Claisen condensation method A: to a slurry of sodium
hydride (4.0 mmol) in refluxing THF was added drop wise the acetophenone 9
(1.0 mmol) dissolved in 10 mL of THF over 10 min. The solution was then
allowed to reflux further for 1 h. After cooling to room temperature the ester
10 (1.5 mmol) was added drop wise over 15 min and the resulting solution
stirred for 24 h. The reaction mixture was then poured over 50 mL of saturated
NH4Cl and extracted three times with ethyl acetate. The combined organic
layers were dried over Na2SO4 and concentrated to yield the crude product that
was used directly without purification for the cyclization step. Method B: a
solution of the ester 10 (1.5 mmol) and NaH (4.0 mmol) in THF was brought to
reflux while the acetophenone 9 (1.0 mmol) was added dropwise over 3 min.
The resulting solution was refluxed for 4 h. The reaction mixture was then
poured into water and the pH was adjusted to neutral by dropwise addition of
3 M HCl. The aqueous layer was extracted three times with dichloromethane
(CH2Cl2). The combined CH2Cl2 layers were dried over Na2SO4 and
concentrated to yield the crude product that was used directly without
purification for the cyclization step. Method C: to a slurry of the corresponding
base (3.0 mmol) in THF at 0 °C was added drop wise the acetophenone 9
(1.0 mmol). The resulting solution was allowed to stir at room temperature for
1 h. The ester 10 was then added drop wise and the solution allowed to stir at
room temperature for 24 h. The reaction mixture was poured over 50 mL of
saturated NH4Cl and extracted three times with 25 mL of ethyl acetate. The
combined organic layers were dried over Na2SO4 and concentrated. Method D:
to a slurry of sodium hydride (4.0 mmol) at reflux in THF was added drop wise
over 10 min the acetophenone 9 (1.0 mmol) dissolved in 10 mL of THF. The
solution was then allowed to reflux further for 1 h. While still at reflux the
ester 10 (1.5 mmol) was then added drop wise over 15 min and the resulting
solution stirred at reflux for 4 h. The reaction mixture was then poured over
50 mL of saturated NH4Cl and extracted three times with ethyl acetate. The
combined organic layers were dried over Na2SO4 and concentrated to yield the
5-Hydroxy-2-phenethyl-4H-chromen-4-one
(5).
Purified
by
column
chromatography by gradient elution from 50:50 dichloromethane/hexane to
100% dichloromethane. IR cmꢀ1 2934, 1653, 1616, 1480, 1409, 1258, 845, 802;
1H NMR (400 MHz, CDCl3): d 12.51 (1H, s, 5-OH), 7.44 (1H, t, J = 8.32 Hz), 7.18–
7.32 (5H, m), 6.85 (1H, dd, J = 8.4 and 0.8 Hz), 6.76 (1H, dd, J = 8.4 and 0.8 Hz)
6.06 (1H, s), 3.05 (2H, t, J = 7.0 Hz), 2.92 (2H, t, J = 6.8 Hz); 13C NMR (100 MHz
,CDCl3) d 183.5, 169.8, 160.8, 156.7, 139.4, 135.1, 128.7, 128.2, 126.6, 111.2,
110.6, 108.8, 106.6, 36.0, 32.8.
5-Hydroxy-2-(2-hydroxyphenethyl)-4H-chromen-4-one (6). Purification was
done by stirring the crude solid in minimal dichloromethane and collecting the
undissolved solid. IR cmꢀ1 3153, 2944, 1650, 1618, 1487, 1583, 1259, 845, 801;
1H NMR (400 MHz, DMSO-d6): d 12.63 (1H, br. s, 5-OH), 9.48 (1H, br s, 20-OH),
7.62 (1H, t, J = 8.32 Hz), 7.08–699 (3H, m), 6.78 (2H, t, J = 8.4 Hz), 6.69 (1H, t,
J = 7.4 Hz) 6.23 (1H, s), 2.95 (4H, s,); 13C NMR (100 MHz, DMSO-d6) d 182.9,
171.4, 159.9, 156.2, 155.2, 135.6, 129.8, 127.4, 125.8, 118.8, 114.9, 110.7, 109.8,
108.1, 107.0, 33.5, 27.0.
7-Hydroxy-2-phenethyl-4H-chromen-4-one
(7).
Purified
by
column
chromatography by elution with 95:5 dichloromethane/MeOH. IR cmꢀ1 3026,
1621, 1548, 1495, 1421, 1256, 852, 823; 1H-NMR (400 MHz, acetone-d6): d
9.45 (1H, s, 7-OH), 7.96–7.90 (1H, m) 7.28–7.18 (5H, m,), 6.94 (1H, d,
J = 8.68 Hz), 6.87 (1H, s), 6.00 (1H, s), 3.08 (2H, t, J = 7.76 Hz), 2.95 (2H, t,
J = 6.08 Hz); 13C NMR (100 MHz , acetone-d6) d 177.2, 168.7, 163.1, 159.1,
141.2, 129.29, 129.26, 127.7, 127.1, 117.8, 115.2, 110.3, 103.3, 36.2, 33.4.