Journal of Agricultural and Food Chemistry
ARTICLE
Data for Compound I-7. White solid; yield, 72.7%; mp 196ꢀ198 °C.
1H NMR (400 MHz, CDCl3): δ 10.60 (brs, 1H, CONHCO), 8.84
(brs, 1H, CONHAr), 7.65 (d, J = 8.6 Hz, 2H, ArꢀH), 7.50ꢀ7.61
(m, 3H, ArꢀH), 7.07 (t, J = 8.6 Hz, 2H, ArꢀH), 5.21 (dd, J = 10.3,
7.7 Hz, 1H, OCH), 3.83 (s, 3H, COOCH3), 3.60ꢀ3.74 (m, 2H, CH2).
Anal. Calcd. for C19H15F2N3O5: C, 56.58; H, 3.75; N, 10.42. Found: C,
56.33; H,3.77; N, 10.48.
Data for Compound I-8. White solid; yield, 82.8%; mp 156ꢀ158 °C.
1H NMR (400 MHz, CDCl3): δ 10.58 (brs, 1H, CONHCO), 9.10
(brs, 1H, CONHAr), 7.64 (d, J = 8.6 Hz, 2H, ArꢀH), 7.53ꢀ7.57 (m,
3H, ArꢀH), 7.06 (t, J = 8.5 Hz, 2H, ArꢀH), 4.87ꢀ4.94 (m, 1H, OCH),
3.51ꢀ3.66 (m, 4H, CH2OCH2CH2), 3.39 (dd, J = 16.5, 10.7 Hz, 1H,
CH2CdN), 3.24 (dd, J = 16.6, 7.4 Hz, 1H, CH2CdN), 1.53ꢀ1.60 (m,
2H, OCH2CH2CH2CH3), 1.32ꢀ1.41 (m, 2H, CH2CH2CH3), 0.91 (t,
J = 7.3 Hz, 3H, CH2CH3). Anal. Calcd. for C22H23F2N3O4: C, 61.25; H,
5.37; N, 9.74. Found: C, 61.30; H, 5.33; N, 9.64.
Data for Compound I-9. White solid; yield, 88.5%; mp 175ꢀ177 °C.
1H NMR (400 MHz, CDCl3): δ 10.57 (brs, 1H, CONHCO), 8.56
(brs, 1H, CONHAr), 7.48ꢀ7.73 (m, 5H, ArꢀH), 7.07 (t, J = 8.7 Hz, 2H,
ArꢀH), 4.89ꢀ4.97 (m, 1H, OCH), 3.97 (q, J = 8.6 Hz, 2H, OCH2CF3),
3.79ꢀ3.84 (m, 2H, CH2O), 3.43 (dd, J = 16.7, 9.2 Hz, 1H, CH2CdN),
3.43 (dd, J = 16.7, 7.5 Hz, 1H, CH2CdN). Anal. Calcd. for
C20H16F5N3O4: C, 52.52; H, 3.53; N, 9.19. Found: C, 52.34; H, 3.66;
N, 9.31.
CHCdN), 1.08ꢀ1.12 (m, 1H, CH2), 0.45ꢀ0.49 (m, 1H, CH2). HRMS
(ESI) m/z calcd for C18H13F2N3O3: (MþNa)þ 380.0817; found,
380.0820.
Synthesis of 3-(4-Fluorophenyl)-5-(4-nitrophenyl)-4,5-dihydroisox-
azole (II-1a). A mixture of 4-fluorobenzaldehyde (1.24 g, 10 mmol),
THF (30 mL), hydroxylamine hydrochloride (0.83 g, 12 mmol), and
pyridine (0.95 g, 12 mmol) was stirred at room temperature, and the
reaction was monitored by TLC. When the reaction was completed,
most of the THF was removed by vacuum distillation, and water was
added. The mixture was extracted by ethyl acetate (20 mL ꢁ 2). The
organic layer was successively washed by 5% aqueous HCl solution and
saturated salt solution, and dried over anhydrous magnesium sulfate.
The mixture was filtered, and the filtrate was concentrated under
reduced pressure to give 4-fluorobenzaldehyde oxime as a pale yellow
solid (1.32 g, 95.0%); mp 86ꢀ88 °C.
A solution of 4-fluorobenzaldehyde oxime (0.68 g, 4.9 mmol) in
propan-2-ol and 1,2-dichloroethane (DCE) (v/v = 1:4, 12 mL) was
cooled to ꢀ10 °C. Then a solution of butyl hypochlorite (0.63 g, 5.8
mmol) in DCE (5 mL) was slowly added at ꢀ10 °C. The mixture was
stirred for 1 h at ꢀ10 °C. Then the solvent was evaporated off under
reduced pressure to give the crude product 4-fluoro-N-hydroxybenzi-
midoyl chloride as a yellow solid (0.83 g, 88.1%), which was used in the
next step without purification.
4-Fluoro-N-hydroxybenzimidoyl chloride (0.83 g, 4.8 mmol) was
dissolved in dichloromethane (40 mL), and freshly prepared 1-nitro-
4-vinylbenzene (0.69 g, 4.6 mmol) was added.21 Then the mixture was
cooled to ꢀ10 °C, and triethylamine (0.53 g, 5.3 mmol) in dichlor-
omethane (10 mL) was added dropwise. The reaction stood overnight at
room temperature. When the reaction was completed, the mixture was
successively washed by 5% aqueous HCl solution and saturated salt
solution. The organic layer was dried over anhydrous magnesium sulfate
and filtered, and the filtrate was concentrated under reduced pressure to
give the crude product. The product was purified by flash column
chromatography on silica gel (5:1 petroleum ether/ethyl acetate) to give
compound II-1a (0.78 g, 59.1%) as a yellow solid; mp 87ꢀ90 °C.
1H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.6 Hz, 2H, ArꢀH), 7.67
(dd, J = 8.0, 5.8 Hz, 2H, ArꢀH), 7.57 (d, J = 8.5 Hz, 2H, ArꢀH), 7.11
(t, J = 8.5 Hz, 2H, ArꢀH), 5.84 (dd, J = 11.0, 7.7 Hz, 1H, OCH), 3.87
(dd, J = 16.6, 11.2 Hz, 1H, CH2), 3.29 (dd, J = 16.6, 7.6 Hz, 1H, CH2).
Synthesis of 4-(3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl)aniline
(II-1b). Intermediate II-1b was obtained as a yellow solid (yield, 97.8%,
mp 85ꢀ87 °C) by following the same procedure as that for compound
I-1b. 1H NMR (400 MHz, CDCl3): δ 7.62ꢀ7.70 (m, 2H, ArꢀH), 7.18
(d, J = 7.8 Hz, 2H, ArꢀH), 7.10 (t, J = 8.3 Hz, 2H, ArꢀH), 6.68
(d, J = 7.6 Hz, 2H, ArꢀH), 5.63 (t, J = 9.7 Hz, 1H, OCH), 3.66 (dd,
J = 16.6, 10.6 Hz, 1H, CH2), 3.30 (dd, J = 16.3, 8.9 Hz, 1H, CH2).
Synthesis of 2,6-Difluoro-N-(4-(3-(4-fluorophenyl)-4,5-dihydroisox-
azol-5-yl)phenylcarbamoyl)benzamide (Target Compound II-1).
Compound II-1 was obtained as a white solid (yield, 87.2%, mp
192ꢀ194 °C) by following the same procedure as that for compound
I-1. 1H NMR (400 MHz, CDCl3): δ 10.48 (brs, 1H, CONHCO), 9.38
(brs, 1H, CONHAr), 7.69 (dd, J = 8.6, 5.4 Hz, 2H, ArꢀH), 7.41ꢀ7.58
(m, 3H, ArꢀH), 7.32 (d, J = 8.4 Hz, 2H, ArꢀH), 7.11 (t, J = 8.6 Hz, 2H,
ArꢀH), 7.03 (t, J = 8.4 Hz, 2H, ArꢀH), 5.70 ꢀ 5.75 (m, 1H, OCH), 3.75
(dd, J = 16.6, 10.9 Hz, 1H, CH2), 3.30 (dd, J = 16.6, 8.4 Hz, 1H, CH2).
HRMS (ESI) m/z calcd for C23H16F3N3O3 (M þ Na)þ 462.1036;
found, 462.1036.
Data for Compound I-10. White solid; yield, 82.4%; mp 197ꢀ199 °C.
1H NMR (400 MHz, CDCl3): δ 10.59 (brs, 1H, CONHCO), 9.00 (brs,
1H, CONHAr), 7.66 (d, J = 8.6 Hz, 2H, ArꢀH), 7.52ꢀ7.59 (m, 3H,
ArꢀH), 7.32ꢀ7.41 (m, 5H, ArꢀH), 7.07 (t, J = 8.5 Hz, 2H, ArꢀH), 5.75
(dd, J = 10.8, 8.4 Hz, 1H, OCH), 3.79 (dd, J = 16.6, 11.0 Hz, 1H, CH2),
3.35 (dd, J = 16.6, 8.3 Hz, 1H, CH2). Anal. Calcd. for C23H17F2N3O3: C,
65.55; H, 4.07; N, 9.97. Found: C, 65.78; H, 3.97; N, 9.71.
Data for Compound I-11. White solid; yield, 72.9%; mp
205ꢀ208 °C. 1H NMR (400 MHz, CDCl3): δ 10.58 (brs, 1H,
CONHCO), 9.34 (brs, 1H, CONHAr), 7.49ꢀ7.61 (m, 7H, ArꢀH),
7.38 (t, J = 7.6 Hz, 2H, ArꢀH), 7.26ꢀ7.33 (m, 1H, ArꢀH), 7.05 (t, J =
8.4 Hz, 2H, ArꢀH), 3.50 (q, J = 16.4, 2H, CH2CdN), 1.82 (s, 3H, CH3).
Anal. Calcd. for C24H19F2N3O3: C, 66.20; H, 4.40; N, 9.65. Found: C,
65.98; H, 4.49; N, 9.58.
Data for Compound I-12. White solid; yield, 70.4%; mp
187ꢀ189 °C. 1H NMR (400 MHz, CDCl3): δ 10.57 (brs, 1H,
CONHCO), 9.28 (brs, 1H, CONHAr), 7.50ꢀ7.62 (m, 5H, ArꢀH),
7.06 (t, J = 8.4 Hz, 2H, ArꢀH), 3.05 (s, 2H, CH2CdN), 1.82 (d, J = 5.6
Hz, 4H), 1.63ꢀ1.71 (m, 2H), 1.49 (s, 4H). Anal. Calcd. for
C22H21F2N3O3: C, 63.91; H, 5.12; N, 10.16. Found: C, 63.67; H,
4.98; N, 10.26.
Data for Compound I-13. White solid; yield, 74.5%; mp
193ꢀ195 °C. 1H NMR (400 MHz, CDCl3): δ 10.57 (brs, 1H,
CONHCO), 9.28 (brs, 1H, CONHAr), 7.47ꢀ7.60 (m, 5H, ArꢀH),
7.05 (t, J = 8.4 Hz, 2H, ArꢀH), 3.26 (s, 2H, CH2CdN), 2.13ꢀ2.21
(m, 2H), 1.74ꢀ1.90 (m, 6H). Anal. Calcd. for C21H19F2N3O3: C, 63.15;
H, 4.80; N, 10.52. Found: C, 63.11; H, 4.78; N, 10.34.
Data for Compound I-14. White solid; yield, 84.3%; mp
126ꢀ128 °C. 1H NMR (400 MHz, CDCl3): δ 10.54 (brs, 1H,
CONHCO), 8.83 (brs, 1H, CONHAr), 7.67 (d, J = 8.6 Hz, 2H, ArꢀH),
7.51ꢀ7.59 (m, 3H, ArꢀH), 7.06 (t, J = 8.5 Hz, 2H, ArꢀH), 5.23 (dd, J =
8.6, 4.6 Hz, 1H, OCH), 4.04 (t, J = 8.3 Hz, 1H, CHCdN), 2.19 (dd, J =
12.0, 5.0 Hz, 1H, OCHCH2), 1.68ꢀ1.96 (m, 4H, CH2CH2CHCdN),
1.48ꢀ1.55 (m, 1H, OCHCH2). HRMS (ESI) m/z calcd for
C20H17F2N3O3: (MþNa)þ 408.1130; found, 408.1138.
Synthesis of 3-tert-Butyl-5-(4-nitrophenyl)-4,5-dihydroisoxazole (II-2a).
Intermediate II-2a was obtained as a yellow solid (yield, 90.0%, mp
78ꢀ81 °C) by following the same procedure as that for compound II-1a.
1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 9.0 Hz, 2H, ArꢀH), 7.50
(d, J = 8.4 Hz, 2H, ArꢀH), 5.64 (dd, J = 10.6, 7.4 Hz, 1H, OCH), 3.50
(dd, J = 16.7, 10.9 Hz, 1H, CH2), 2.89 (dd, J = 16.8, 7.2 Hz, 1H, CH2),
1.21 (s, 9H, C(CH3)3).
Data for Compound I-15. White solid; yield, 81.8%; mp 210 °C
1
(dec.). H NMR (400 MHz, CDCl3): δ 10.56 (brs, 1H, CONHCO),
8.23 (brs, 1H, CONHAr), 7.79 (d, J = 7.0 Hz, 2H, ArꢀH), 7.64 (d, J =
6.9 Hz, 2H, ArꢀH), 7.52ꢀ7.59 (m, 1H, ArꢀH), 7.08 (t, J = 9.1 Hz, 2H,
ArꢀH), 5.05 (dd, J = 5.3, 3.3 Hz, 1H, OCH), 2.87ꢀ2.90 (m, 1H,
4854
dx.doi.org/10.1021/jf200395g |J. Agric. Food Chem. 2011, 59, 4851–4859