2-hydroxy-3-methylbutanenitrile

2-Hydroxy-3-Methylbutanenitrile for the Synthesis of Polysubstituted Indolizine

Kucukdisli, Murat, et al. European Journal of Organic Chemistry, 2012, 24, 4555-4564.

This work created polysubstituted indolizines from the [3+2] cycloaddition reaction of nitroolefins and pyridine ylides. From 2-hydroxy-3-methylbutanenitrile, it was converted to the corresponding 1-(1-cyanoalkyl)pyridinium salt 2b and indolizine 4i.
Synthesis procedure
· 1-Cyano-2-methylpropyl trifluoromethanesulfonate (1b): Prepared by reacting 2-hydroxy-3-methylbutanenitrile (1.98 g, 20.0 mmol), Tf2O (6.77 g, 24.0 mmol) and pyridine (1.90 g, 24.0 mmol) in 100 mL of CH2Cl2. The residual solution was cleaned by filtration through neutral Al2O3, and the oil was 1-cyano-2-methylpropyl trifluoromethanesulfonate (3.4 g, 74% yield).
· Synthesis of Ylide precursor 1-(1-Cyano-2-methylpropyl)pyridinium Triflate (2b): 1b (1.20 g, 5.19 mmol) was stirred in excess pyridine (1.98 g, 25 mmol) in anhydrous diethyl ether (1 mL/1 mmol) for 2 hours at room temperature. This brute was recrystallised using EtOAc and diethyl ether, leaving 2b (1.54 g, 5.07 mmol, 98%) as a solid.
· 2-(4-Chlorophenyl)-1-isopropyl-3-methylindolizine (4i): Solution of KOtBu (4 mmol) in anhydrous DMF (5.0 mL) slowly added to a stirring solution of pyridinium salt 2b (310 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (3a; 198 mg, 1.00 mmol) in anhydrous DMF (10 mL) at 0 °C and in an argon atmosphere. The solution was stirred at 0 °C while the reaction was followed with thin-layer chromatography (TLC). The crude solution was removed via filtration through silica (1:10), which gave us 4i (157 mg, 0.55 mmol, 55%) as a yellow solid.