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B. I. Roman et al. / Bioorg. Med. Chem. 20 (2012) 4812–4819
a
a TeflonÒ ‘snap-on’ cap, and the mixture is heated at 70 °C under
microwave irradiation for 3 h. The resulting precipitate is the desired
propenone 12a, which can be isolated by filtration, washing and
thorough drying.
d 43.51 (C ), 56.33 (2x OCH3), 60.98 (OCH3), 77,16 (t, CDCl3),
0
0
82.90 (Cb), 102.81 (C2, C6), 116.07 (d, JCF = 21.9 Hz, C3 , C5 ),
0
0
0
125.80 (d, JCF = 3.5 Hz, C1 ), 128.82 (d, JCF = 8.1 Hz, C2 , C6 ), 136.49
(C4), 137.97 (C1), 153.71 (C3, C5), 155.44 (C@N), 163.96 (d,
0
JCF = 251.5 Hz, C4 ); ESI-MS (+) m/z: 332.1 ([M+H]+, 100), 333.1
4.1.5. 2-Benzotriazol-1-yl-1-(4-fluorophenyl)-3-(3,4,5-trime-
thoxyphenyl) propenone (12a)
([M+H+1]+, 22), 457.2 (73), 458.2 (23).
Yield: 51%, as white crystals; mp: 179.1–180.7 °C; IR (ATR,
4.1.9. 5-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihyd-
roisoxazole (13b)
cmꢀ1
)
m
max: 998, 1051, 1070, 1130, 1148, 1241, 1261, 1333,
1505; 1H NMR (CDCl3, 300 MHz, ppm): d 3.42 (6H, s, 2x OMe),
Yield: 34%, as white crystals; mp: 115.8–117.4 °C; IR (ATR,
00
00
3.79 (3H, s, OMe), 5.98 (2H, s, H2 , H6 ), 7.12 (2H, dd, Jvic = 8.6 Hz,
cm ꢀ1 max = 826, 838, 914, 1005, 1132, 1215, 1374; 1H NMR
) m
0
0
JHF = 8.6 Hz, H3 , H5 ), 7.25 (1H, td, Jvic = 7.2 Hz, Jallyl = 1.1 Hz, H5 or
H6), 7.39 (1H, td, Jvic = 7.2 Hz, Jallyl = 1.1 Hz, H5 or H6), 7.46 (1H,
dd, Jvic = 7.2 Hz, Jallyl = 1.1 Hz, H4 or H7), 7.76 (1H, s, Hb), 7.84 (2H,
(CDCl3, 300 MHz, ppm): d 3.20 (1H, dd, Jgem = 16.5 Hz, Jvic = 8.3 Hz,
CHaHb), 3.78 (1H, dd, Jgem = 16.5 Hz, Jvic = 10.9 Hz, CHaHb), 3.88
(3H, s, OCH3), 3.89 (6H, s, 2x OCH3), 5.73 (1H, dd, Jvic.1 = 10.9 Hz,
00
00
0
0
dd, Jvic = 8.8 Hz, JHF = 5.5 Hz, H2 , H6 ), 8.11 (1H, dd, Jvic = 7.2 Hz,
Jallyl = 1.1 Hz, H4 or H7); 13C NMR (CDCl3, 75 MHz, ppm): d 55.77
Jvic.2 = 8.3 Hz, Hb), 6.92 (2H, s, H2 , H6 ), 7.07 (2H, dd, Jvic = 8.8 Hz,
JHF = 8.8 Hz, H3, H5), 7.37 (2H, dd, Jvic= 8.8 Hz, JHF = 5.5 Hz, H2, H6);
00
00
(2x OMe), 60.98 (OMe), 77.16 (t, CDCl3), 107.71 (C2 , C6 ), 110.20
13C NMR (CDCl3, 75 MHz, ppm): d 43.31 (C ), 56.26 (2x OCH3),
a
0
0
0
0
(C5 or C6), 115.97 (d, JCF = 21.9 Hz, C3 , C5 .), 120.14 (C4 or C7),
60.93 (OCH3), 77.16 (t, CDCl3) 82.08 (Cb), 104.14 (C2 , C6 ), 115.67
0
124.67 (C5 or C6), 126.05 (Cq), 128.72 (C4 or C7), 130.16 (Cq),
(d, JCF = 21.9 Hz, C3, C5), 124.75 (C1 ), 127.69 (d, JCF = 8.1 Hz, C2,
0
0
0
0
0
0
131.79 (d, JCF = 9.2 Hz, C2 , C6 ) 133.09 (d, JCF = 2.3 Hz, C1 ), 133.32
C6), 136.71 (d, JCF = 2.3 Hz, C1), 139.99 (C4 ), 153.39 (C3 , C5 ),
156.00 (C@N), 162.59 (d, JCF = 246.9 Hz, C4); ESI-MS (+) m/z:
332.1 ([M+H]+, 100), 333.0 ([M+H+1]+, 22).
(Cq), 141.09 (C4), 142.21 (Cb), 145.92 (Cq), 153.12 (C3, C5), 165.51
0
(d, JCF = 255.0 Hz, C4 ), 189.66 (C@O); ESI-MS (+) m/z: 434.1
([M+H]+, 100), 435.3 ([M+H+1]+, 28).
4.1.10. 5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihyd-
roisoxazole (13c)
4.1.6. General synthetic procedure for chalcones (1–3)
15 mmol of an acetophenone, 0.1 equiv of LiOH.H2O and 20 mL
of absolute EtOH are brought into a round bottomed flask, and the
resulting suspension is stirred for 15 min. Subsequently, 1 equiv of
the appropriate benzaldehyde is added and the mixture is stirred
until conversion has reached its maximum, as monitored by TLC
and/or LC/MS. The reaction is quenched with a 10 mL of a 1% aque-
ous solution of HCl, followed by 10 mL of H2O.
When a precipitate is obtained, it is isolated by filtration and
thoroughly washed with water until the filtrate turns clear. Recrys-
tallization of the precipitate in absolute EtOH furnishes crystals of
chalcone in high purity. If, upon quenching, the product separates
as a thick oily layer at the bottom of the bulb, it is extracted with
Et2O (2 ꢂ 20 mL). The combined organic layers are subsequently
washed with brine (2 ꢂ 20 mL) and dried over MgSO4. Solvent
evaporation under reduced pressure furnishes the crude chalcone
3 as a solid, which can be purified by recrystallization in absolute
EtOH.
Spectral data are in full accordance with those reported earlier
by Mizuno.22
Yield: 94%, as white crystals; mp: 128.3–129.4 °C; IR (ATR,
cmꢀ1
) mmax = 808, 834, 862, 892, 1021, 1091, 1177, 1254, 1491,
1606, 2853, 2922.03, 2955; 1H NMR (CDCl3, 300 MHz, ppm): d
3.27 (1H, dd, Jgem = 16.7 Hz, Jvic = 7.8 Hz, CHaHb), 3.76 (1H, dd,
Jgem = 16.7 Hz, Jvic = 11.0 Hz, CHaHb), 3.84 (3H, s, OCH3), 5.68 (1H,
0
0
dd, J1 = 11.0 Hz, J2 = 7.8 Hz, Hb), 6.93 (2H, d, Jvic = 9.2 Hz, H3 , H5 ),
0
0
7.34 (4H, br. m, H2, H6, H3, H5), 7.62 (2H, d, Jvic = 9.2 Hz, H2 , H6 );
a
13C NMR (CDCl3, 75 MHz, ppm): d 42.46 (C ), 54.34 (OCH3), 80.48
0
0
0
0
(Cb), 113.17 (C3 , C5 ), 120.74 (C1 ), 126.24 (C2, C6), 127.27 (C2 ,
0
C6 ), 127.87 (C3, C5), 132.91, 138.63 (C1, C4), 154.62 (C@N), 160.16
0
(C4 ); ESI-HRMS (+) m/z: Anal. Calcd for C16H14ClNO2 (M+H)+:
288.0786. Found: 288.0790.
4.1.10.1. Synthesis of 5-(4-chlorophenyl)-3-(4-methoxyphenyl)-
4,5-dihydro-1H-pyrazole (20).
In a round-bottomed flask
kept under a nitrogen atmosphere, 0.01 mol (3.15 g) of chalcone
2 is dissolved in 20 mL of absolute EtOH. Subsequently, 6 equiv
(3 g) of NH2NH2.H2O and 7 equiv (3.91 g) of KOH are added. The
resulting mixture is stirred at reflux for 24 h. Upon cooling, water
(20 mL) is added and the pyrazole is extracted with EtOAc
(2 ꢂ 15 mL). The combined organic layers are dried over MgSO4;
solvent removal by rotary evaporation furnishes the desired pyraz-
oline 20 as a solid residue.
4.1.7. Synthesis of 3,5-diaryl-4,5-dihydroisoxazoles (13a–c)
In a round-bottomed flask containing 20 mL of absolute ethanol
and kept under a nitrogen atmosphere, 0.1 mmol of a chalcone,
6 equiv (41.7 mg) of NH2OH.HCl and 7 equiv (39.3 mg) of KOH
are added respectively. The resulting mixture is stirred at reflux
and under a nitrogen atmosphere for 24 h. Upon cooling of the con-
tents to ambient temperature, an equal volume of H2O is added
and the resulting suspension is extracted with ethyl acetate
(2 ꢂ 20 mL). The combined organic layers are subsequently dried
over MgSO4, and the solvent is removed under reduced pressure.
The resulting solid can be recrystallized in absolute ethanol, fur-
nishing the pure isoxazoline 13.
4.1.11. Synthesis of isoxazoles (4a–c)
A microwave vial is loaded with 0.9 mmol of an isoxazoline 13,
6 mL of benzene, 10 equiv (0.89 g) of activated MnO2 and 2.4 equiv
(0.26 g) of MgSO4. Electrolytically precipitated, active MnO2 (88%)
from Acros was used in this reaction. Next, the vial is sealed and
heated at 100 °C under microwave irradiation during 1.5 h. Subse-
quently, the reaction mixture is filtered over CeliteÒ, and the resi-
due is washed with CH2Cl2. Solvent removal from the filtrate
furnishes the pure isoxazole 4 as a solid residue.
4.1.8. 3-(4-Fluorophenyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihyd-
roisoxazole (13a)
Yield: 30%, as white crystals; mp: 125.4–126.9 °C; IR (ATR,
cmꢀ1
) mmax: 832, 896, 1007, 1123, 1218, 1236, 1324, 1426, 1509,
1592; 1H NMR (CDCl3, 300 MHz, ppm): d: 3.33 (1H, dd,
Jgem = 16.5 Hz, Jvic = 8.3 Hz, CHaHb), 3.75 (1H, dd, Jgem = 16.5 Hz,
Jvic = 10.0 Hz, CHaHb), 3.84 (3H, s, OCH3), 3.87 (6H, s, 2x OCH3),
5.69 (1H, dd, Jvic,1 = 10.0 Hz, Jvic,2 = 8.3 Hz, Hb), 6.61 (2H, s, H2, H6),
4.1.12. 5-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl) isoxazole
(4b)
Yield: 65%, as white crystals; 1H NMR (CDCl3, 300 MHz, ppm):
0
0
a
7.11 (2H, dd, Jvic = 8.5 Hz, JHF = 8.5 Hz, H3 , H5 ), 7.69 (2H, dd,
d = 3.91 (3H, s, OCH3), 3.95 (6H, s, 2x OCH3), 6.75 (1H, s, H ), 7.08
0
0
00
00
0
0
Jvic = 8.8 Hz, JHF = 5.5 Hz, H2 , H6 ); 13C NMR (CDCl3, 75 MHz, ppm):
(2H, s, H2 , H6 ), 7.19 (2H, dd, Jvic = 8.5 Hz, JHF = 8.5 Hz, H3 , H5 ),