Dichloromethane → 4-(4-(1-Hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrile

Participants

Reaction Conditions

Reaction Steps

To the solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.53 g, 13.61 mmol), 1-(3-bromopyridin-4-yl)ethanol (2.50 g, 12.37 mmol) and PdCl2(dppf). CH2Cl2 adduct (505 mg, 0.62 mmol) in DMF (60 mL) was added 2M Na2CO3 solution (12.3 ml, 24.6 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction and separation, the extracts were concentrated and purified by ISCO 40 g (10% MeOH/DCM=0-25%) to give 4-(4-(1-hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrile (2.1 g, 67%) as a white solid; ESI-MS m/z: 255 [M+1]+, Retention time 1.24 min. 1H-NMR (MeOD, 400 MHz) δ 1.36 (d, J=6.4 Hz, 3H), 3.98 (s, 3H), 4.88 (q, J=6.4 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.18 (s, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 8.36 (s, 1H), 8.58 (d, J=5.2 Hz, 1H). The racemate was separated by HPLC (ChiralPak IA-H, 5% MeOH/5% EtOH/Heptane) to give 4-[4-((R)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-1) retention time: 16.18 min) and 4-[4-((S)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-2), retention time: 19.07 min).

Provenance & Evidence