P.L. Bosquesi, et al.
Bioorganic Chemistry 100 (2020) 103948
CDCl
3
d, δ ppm) δ: 7.56 (2H; d; Jortho = 8.7 Hz), 7.31 (2H; d;
ortho = 8.7 Hz), 7.09 (1H; d; Jtrans = 16.2 Hz), 7.01 (1H; d;
trans = 16.2 Hz), 6.68 (2H; d; Jmeta = 2.4 Hz), 6.43 (1H; t;
meta = 2.4 Hz), 3.85 (6H; s), 2.23 (3H; s). C NMR (75 MHz, CDCl d, δ
to enhance the styrene (15) consumption. The product was isolated by
diluting the reaction medium with approximately 100 mL of di-
chloromethane. The organic phase was washed with distilled water
(4 × 15 mL) and dried with sodium sulfate. After filtration, the organic
phase was concentrated under reduced pressure to produce the crude,
which was purified by column chromatography (flash silica; eluent:
hexane: ethyl acetate, 7:3 (v/v)) providing the compound 10g at a yield
of 41%.
J
J
J
1
3
3
ppm) δ: 162.54, 160.87, 151.87, 138.79, 135.25, 129.36, 127.78,
1
27.49, 119.59, 106.34, 104.69, 100.02, 55.23, 7.33. Calculated for
. C, 64.4; H, 5.12; N, 7.91. Found: C, 64.7; H, 5.15; N, 7.87.
C
19
H
18
N
O
2 5
5
.3.2. (E)-4-(4-(3,5-dimethoxystyryl)phenoxy)-3-phenyl-1,2,5-oxadiazole
-N-oxide (10e)
2
5.4.1. 3,5-dimethyl-4-(4-vinylphenyl)isoxazole (15)
1
Yellow powder; yield, 60%; mp 101.7–102.2 °C. Rf: 0.75, eluent
Yellowish powder; yield, 55%. H NMR (300 MHz, CDCl
3
d, δ ppm)
−1
petroleum ether: dichloromethane 7: 3 (v/v). IR Vmax (cm ; KBr
δ: 7.48 (2H; d), 7.22 (2H; d), 6.74 (1H; dd; Jcis = 10.7 Hz and
pellets): 3084 (CeH aromatic), 2966 and 2833 (CeH alkyl), 1604 (C]C
J
J
trans = 17.5 Hz), 5.81 (1H; d; Jtrans = 17.5 Hz), 5.30 (1H; d;
1
13
alkene), 1504 (C]C aromatic), 1336 (NeO oxide), 1215 (CeOeC ether).
H
cis = 10.7 Hz), 2.39 (3H; s), 2.27 (3H; s). C NMR (75 MHz, CDCl
3
d, δ
NMR (300 MHz, DMSOd
6
, δ ppm) δ: 8.09 (2H; dd; Jortho = 8.6 Hz), 7.72
ppm) δ: 165, 159, 137, 136, 129, 128, 125, 116, 114, 11, 9.
(
2H; d;
J
ortho
=
8.7 Hz), 7.67–7.59 (3H; m), 7.54 (2H; d;
ortho = 8.7 Hz), 7.34 (1H; d; Jtrans = 16.5 Hz), 7.21 (1H; d;
trans = 16.5 Hz), 6.80 (2H; d; Jmeta = 2.1 Hz), 6.43 (1H; t;
meta = 2.1 Hz), 3.78 (6H; s). C NMR (75 MHz, DMSOd , δ ppm) δ:
62.13, 160.70, 152.06, 138.94, 135.36, 130.95, 129.14, 128.02,
J
J
J
5.4.2. (E)-4-(4-(4-methoxystyryl)phenyl)-3,5-dimethylisoxazole (10g)
Yellowish powder; yield, 41%; mp 158.4–164.4 °C. Rf: 0.65, eluent
1
3
−1
6
hexane: ethyl acetate 7: 3 (v/v). IR Vmax (cm ; KBr pellets): 3022
1
1
(CeH aromatic), 2931 (CeH alkyl), 1598 (C]C alkene), 1508 (C]C aro-
1
27.72, 126.68, 121.75, 120.47, 108.35, 104.57, 100.06, 55.25.
matic), 1249 (CeOeC ether). H NMR (300 MHz, CDCl
3
d, δ ppm) δ: 7.56
Calculated for C24
H, 4.88; N, 6.77.
H
20
N
2
O
5
. C, 69.22; H, 4.84; N, 6.73. Found: C, 69.28;
(2H; d; J = 8.3 Hz), 7.48 (2H; d; J = 8.8 Hz), 7.24 (2H; d; J = 8.3 Hz),
7.12 (1H; d; Jtrans = 16.1 Hz), 7.00 (1H; d; Jtrans = 16.1 Hz), 6.92 (2H;
1
3
d; J = 8.8 Hz), 3.84 (3H; s), 2.43 (3H; s), 2.30 (3H; s). C NMR
5
.3.3. (E)-4-(4-(3,5-dimethoxystyryl)phenoxy)-3-(phenylsulfonyl)-1,2,5-
(75 MHz, DMSOd , δ ppm) δ: 165.33, 159.62, 137.08, 129.44, 129.31,
6
oxadiazole 2-N-oxide (10f)
128.96, 127.96, 126.71, 125.94, 114.34, 55.50, 11.81, 11.04.
White powder; yield, 30%; mp 125.5–132.1 °C. Rf: 0.67, eluent
Calculated for C20
H, 6.30; N, 4.55.
H
19NO . C, 78.66; H, 6.27; N, 4.59. Found: C, 78.65;
2
−1
petroleum ether: dichloromethane 7: 3 (v/v). IR Vmax (cm ; KBr
pellets): 3066 (CeH aromatic), 2935 and 2839 (CeH alkyl), 1593
(
C]C alkene), 1500 (C]C aromatic), 1373 (N-oxide), 1296 (CeOeC
5.4.3. Synthesis of compound (E)-3-(4-(4-methoxystyryl)phenoxy)-4-
methyl-1,2,5-oxadiazole (10h)
1
ether), 1151 (S]O). H NMR (300 MHz, CDCl
3
d, δ ppm) δ: 7.85 (2H; d;
J
J
J
ortho = 8.2 Hz), 7.68 (1H; t), 7.54 (2H; d; Jortho = 8.2 Hz), 7.41 (2H; d;
ortho = 9 Hz), 6.94 (4H; m), 6.63 (2H; d; Jmeta = 2.2 Hz), 6.40 (1H; t;
meta = 2.2 Hz), 3.82 (6H; s). C NMR (75 MHz, CDCl d, δ ppm) δ:
61.14, 153.22, 148.94, 138.99, 136.41, 135.47, 134.39, 129.95,
29.30, 128.68, 127.73, 122.77, 119.61, 104.81, 100.33, 55.33.
S. C, 59.99; H, 4.20; N, 5.83. Found: C,
This reaction was adapted according to a previous methodology
[50]. A solution containing (E)-4-(4-(4-methoxystyryl) phenoxy)-3-
methyl-1,2,5-oxadiazole 2-N-oxide (10a) (20 mmol) in trimethyl
phosphite (30 mL; 0.25 mol) was stirred and kept under reflux condi-
tions for 48 h. The reaction was monitored by TLC. Later, the medium
was cooled and added to the water/ice mixture (60 mL), and the pH
was adjusted to 7 with 4 M NaOH. Later on, the aqueous phase was
washed with ethyl acetate (4 × 20 mL) and dried with sodium sulfate.
After filtration, the organic phase was concentrated under reduced
pressure to produce the crude, which was purified by column chro-
matography (flash silica; eluent: hexane: ethyl acetate, 7:3 (v/v)) pro-
viding compound 10h with a yield of 75%.
1
3
3
1
1
Calculated for C24
H
20
N
O
2 7
6
0.02; H, 4.17; N, 5.80.
5
.4. Synthesis of compound (E)-4-(4-(4-methoxystyryl)phenyl)-3,5-
dimethylisoxazole (10g)
The compound 10g was prepared in two steps from 4-bromostyrene
(
12b). First, compound 3,5-dimethyl-4-(4-vinylphenyl)isoxazole (15)
was synthesized through the treatment of the 4-bromostyrene (12b)
5.4.4. (E)-3-(4-(4-methoxystyryl)phenoxy)-4-methyl-1,2,5-oxadiazole
(10h)
(
1.37 mmol) (commercial available reagent), 3,5-dimethylisoxazole-4-
boronic acid pinacol ester (14) (1.5 mmol), tetrakis (triphenylpho-
White powder; yield, 75%; IR Vmax (cm−1; KBr pellets): 3066 (CeH
aromatic), 2974–2839 (CeH alkyl), 1606 (C]C alkene), 1514 (C]C
sphine)palladium (0) (0.07 mmol), and potassium carbonate solution
1
(
2.75 mmol in 0.5 mL distilled water) in a dioxane (8 mL) medium. The
aromatic), 1336 (NeO), 1255 (CeOeC ether). H NMR (300 MHz,
reaction was kept under stirring at 90 °C for 24 h and monitored by
TLC. The solvent was concentrated under reduced pressure, and the
medium was diluted with approximately 60 mL of dichloromethane.
The organic phase was washed with distilled water (4 × 15 mL) and
dried with sodium sulfate. After filtration, the organic phase was con-
centrated under reduced pressure to produce the crude, which was
purified by column chromatography (flash silica; eluent: hexane: ethyl
acetate, 7:3 (v/v)) providing the compound 15 at yields of 55%.
In the second step, a reaction mixture containing tris(dibenzylide-
CDCl d, δ ppm) δ: 7.51 (2H; d; J = 8.2 Hz), 7.44 (2H; d; J = 8.5 Hz),
3
7.30 (2H; d; J = 8.2 Hz), 7.02 (1H; t; J = 15.9 Hz), 6.95 (1H; t;
1
3
J = 15.9 Hz), 6.90 (2H; d; J = 8.5 Hz), 3.83 (3H; s), 2.38 (3H, s).
C
NMR (75 MHz, CDCl d, δ ppm) δ: 163.4, 159.4, 153.2, 144.62, 135.4,
3
129.8, 128.7, 127.7, 127.5, 125.1, 119.0, 114.1, 55.3, 7.4. Calculated
for C18
10.03.
H
16
N
2
O . C, 70.12; H, 5.23; N, 9.09. Found: C, 70.08; H, 5.19; N,
3
5.4.5. (E)-4-(4-(4-hydroxystyryl)phenoxy)-3-methyl-1,2,5-oxadiazole 2-
N-oxide (10i)
neacetone)dipalladium(0) [Pd
2
(dba)
3
] (4% mol), sodium acetate
(15)
(
(
1.74
mmol),
3,5-dimethyl-4-(4-vinylphenyl)isoxazole
Compound 10i was prepared in two steps from 3-methyl-4-nitro-
1,2,5-oxadiazole 2-N-oxide (4). First, in a round bottom flask, 4-iodo-
phenol (2.27 mmol), DBU (2.27 mmol; 340 µL), and 5 mL of anhydrous
dichloromethane were added. This mixture was kept under stirring
conditions and a nitrogen atmosphere (protected from light) at 45 °C for
15 min. Then, 3-methyl-4-nitro-1,2,5-oxadiazole 2-N-oxide (4)
(2.27 mmol), previously solubilized in anhydrous dichloromethane,
0.58 mmol), and dry benzonitrile (2 mL) was stirred under a nitrogen
atmosphere at the room temperature for 10 min. Subsequently, the
reactive 4-methoxybenzenediazonium tetrafluoroborate (0.87 mmol)
was slowly added to the reaction mixture. The reaction was stirred at
room temperature for 3 h and monitored by TLC. When necessary,
additional 4-methoxybenzenediazonium tetrafluoroborate was added
9