Reaction #436442

Reaction equation

2-(2-nitroethoxy)tetrahydropyran

(2-chloro-phenyl)-propynoic acid ethyl ester

1,4-phenylene diisocyanate

triethylamine

→

title compound

Yield 94.2%

5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester

Yield 94.2%

Solvents

toluene

toluene

Conditions

Workup

1. 1
   Temperatureat reflux for 10 h
2. 2
   Filtrationfilter the reaction mixture through Celite®
3. 3
   Washwashing the solids with EtOAc
4. 4
   WashWash the filtrate with 1N HCl (500 mL) and brine (500 mL)
5. 5
   DryingDry the organics over Na2SO4
6. 6
   Filtrationfilter
7. 7
   Concentrationconcentrate under reduced pressure
8. 8
   OtherPurification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc)

Procedure

Add 2-(2-nitroethoxy)tetrahydropyran (41 mL, 270 mmol) dropwise in toluene (100 mL) to a solution of (2-chloro-phenyl)-propynoic acid ethyl ester (28.3 g, 135 mmol), 1,4-phenylene diisocyanate (67 g, 420 mmol) and triethylamine (15 mL) in toluene (900 mL). Stir at reflux for 10 h. While still warm (˜70° C.), filter the reaction mixture through Celite®, washing the solids with EtOAc. Wash the filtrate with 1N HCl (500 mL) and brine (500 mL). Dry the organics over Na2SO4, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 85:15 Hexanes/EtOAc) gives the title compound (46.5 g, 94%). MS (m/e): 282 (M−C5H8O+H+); 1H NMR (300 MHz, CDCl3) δ 7.35–7.55 (m, 4H), 5.09 (d, J=13 Hz, 1), 4.85–4.91 (m, 2H), 4.15–4.22 (m, 2H), 3.91–4.01 (m, 1H), 3.52–3.61 (m, 1H), 1.49–1.92 (m, 6H), 1.12 (t, J=7 Hz, 3H); TLC Rf=0.53 (7:3 Hexanes/EtOAc).

Source