1,2-Dichloroethane → 2-Isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile

Participants

Reaction Conditions

Reaction Steps

Prepared using General Procedure 2. To a solution of 3-cyano-4-isopropoxybenzoic acid (0.122 g, 0.60 mmol) in DMF (1.5 mL) was added HOBt (0.132 g, 0.86 mmol) and EDC (0.165 g, 0.86 mmol) at room temperature. The reaction was stirred for 0.5 h until the complete formation of the HOBt-acid complex. N-hydroxy-3-methylisonicotinimidamide INT-69 (0.100 g, 0.66 mmol) was added and the mixture was stirred at room temperature for 0.5 h until formation of the intermediate N-(3-cyano-4-isopropoxybenzoyloxy)-3-methylisonicotinimidamide was observed. The reaction mixture was then heated at 80° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product recrystallized from MeOH (3 mL) and the resulting crystals were filtered and washed with cold MeOH to yield product as a white crystalline solid. To the product was added Et2O (0.5 mL) followed by 2N HCl in Et2O (0.6 mL). The mixture was stirred at room temperature for 10 minutes then dried under nitrogen and subsequently under vacuum to afford 0.087 g (45%) of 2-isopropoxy-5-(3-(3-methylpyridin-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 70 as the HCl salt. LCMS-ESI (m/z) calculated for C18H16N4O2: 320.3; found 321.1 [M+H]+, tR=8.82 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=17.5, 2H), 8.70 (d, J=5.7, 1H), 8.44 (d, J=2.2, 1H), 8.36 (dd, J=8.9, 2.2, 1H), 7.18 (d, J=9.1, 1H), 4.83 (dt, J=12.2, 6.1, 1H), 2.95 (s, 3H), 1.49 (d, J=6.1, 6H). 13C NMR (101 MHz, DMSO) δ 173.90, 166.58, 162.81, 147.11, 142.99, 137.55, 135.01, 134.79, 134.06, 125.00, 115.42, 115.17, 115.00, 102.57, 72.66, 21.48, 18.69.

Provenance & Evidence