3-(2-fluorophenyl)prop-2-ynal

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of NaH2PO4 (37 g, 0.3 mol, 0.3 equiv) in water (330 mL) buffered to pH 2 with conc. HCl and H2O2 (30%, 112 mL, 1.1 mol, 1.1 equiv) was added to a solution of 3-(2-fluorophenyl)prop-2-ynal (151 g, 1.02 mol) in CH3CN (830 mL). The resulting mixture was cooled in an ice bath and was treated slowly with a solution of NaClO2 (102 g, 1.1 mol, 1.1 equiv) in water (1.1 L), keeping the temperature below 10° C. After 30 min a solution of NaClO2 (5.8 g, 64 mmol, 0.06 equiv) in water (50 mL) was added. After another 30 min the layers were separated and the aqueous layer was washed with EtOAc (3×500 mL). The organic layers were combined and back-extracted with a saturated NaHCO3 solution (3×500 mL). The aqueous layers were combined, acidified to pH 1 with conc. HCl and extracted with EtOAc (3×500 mL). The combined organic layers were washed with a saturated NaCl solution (1 L), dried (Na2SO4) and concentrated under reduced pressure to give 3-(2-fluorophenyl)prop-2-ynoic acid (144 g, 86%) as a yellow solid: TLC (1% AcOH/CH2Cl2) Rf 0.34; 1H NMR (CDCl3+d4-MeOH) δ 6.98-7.08 (m, 2H), 7.29-7.48 (m, 2H), 12.77 (br s, 1H); 13C NMR (CDCl3+d4-MeOH) δ 78.3, 85.7 (d, JC−F=2.5 Hz, 1C), 108.3 (d, JC−F=15.8 Hz, 1C), 115.4 (d, JC−F=20.7 Hz, 1C), 124.0, 132.1 (d, JC−F=7.3 Hz, 1C), 134.1 (d, JC−F=9.8 Hz, 1C), 135.2, 154.8, 163.1 (d, JC−F=256.1 Hz, 1C). The resulting mixture was cooled in an ice bath the temperature below 10° C After another 30 min the layers were separated the aqueous layer was washed with EtOAc (3×500 mL) back-extracted with a saturated NaHCO3 solution (3×500 mL) extracted with EtOAc (3×500 mL) The combined organic layers were washed with a saturated NaCl solution (1 L) dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxalyl chloride (102 mL, 1.18 mol, 1.2 equiv) in CH2Cl2 (3L) at −78° C. was slowly added DMSO (167 mL, 2.35 mol, 2.4 equiv) while keeping the reaction temperature below −59° C. The mixture was stirred for 10 min and treated with a solution of 3-(2-fluorophenyl)prop-2-yn-1-ol (147 g, 0.98 mol) in CH2Cl2 (100 mL), keeping the reaction temperature below −65° C. The resulting thick white slurry was stirred for 15 min, then treated with Et3N (682 mL, 4.90 mol, 5 equiv). After 10 min the reaction mixture was allowed to warm to 0° C. and treated with water (2 L). The organic layer was washed with water (3×1L), dried (Na2SO4) and concentrated under reduced pressure to afford 3-(2-fluorophenyl)prop-2-ynal (148 g, 100%) as a brown oil which was stored suspended in frozen benzene (0.5 L): 1H NMR (CDCl3) δ 7.03-7.14 (m, 2H), 7.37-7.52 (m, 2H), 9.36 (s, 1H); 13C NMR (CDCl3) δ 88.1, 92.4 (d, JC−F=2.4 Hz, 1C), 108.2 (d, JC−F=14.5 Hz, 1C), 115.9 (d, JC−F=19.6 Hz, 1C), 124.4 (d, JC−F=3.6 Hz, 1C), 133.3 (d, JC−F=8.5 Hz, 1C), 134.8 162.6 (d, JC−F=246.3 Hz, 1C), 176.4; GCMS m/z (rel abundance) 149 (MH+, 75%). at −78° C. the reaction temperature below −59° C the reaction temperature below −65° C The resulting thick white slurry was stirred for 15 min After 10 min the reaction mixture was allowed The organic layer was washed with water (3×1L) dried (Na2SO4) concentrated under reduced pressure