590371-73-6

4-Iodo-2-(trifluoromethyl)pyridine is used as a reagent in the synthesis of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors which exhibit in vivo brain reduction of β-amyloid peptides.

4-Iodo-2-(trifluoromethyl)pyridine could be cleanly deprotonated by LIDA in tetrahydrofuran at –75 °C[1]. Trapping of the organometallic intermediates with dry ice followed by neutralization gave the 4-iodo-2-(trifluoromethyl)pyridine-3-carboxylic acid (16, 31%). a: LIDA in THF at –75 °C for 2 h; b: (1.) Excess solid carbon dioxide, (2.) Hydrochloric acid.

The general procedure for the synthesis of 4-iodo-2-(trifluoromethyl)pyridine from 3-iodo-2-trifluoromethylpyridine was as follows: a hexane solution (7.2 mL) of 2.5 M butyl lithium was diluted in tetrahydrofuran (30 mL) and cooled to -78 °C in a dry ice/acetone bath. Subsequently, diisopropylamine (2.5 mL) and 3-iodo-2-trifluoromethylpyridine (4.9 g) obtained in Step A were added dropwise to this cooled solution. The reaction mixture was stirred continuously at -78 °C for 2 h. The reaction was subsequently quenched with methanol (2 mL) at the same temperature. The reaction mixture was concentrated and purified by fast column chromatography (silica gel, cyclohexane/ethyl acetate as eluent) to afford 4-iodo-2-(trifluoromethyl)pyridine as yellow acicular crystals (1.6 g, 32% yield). The structure of the product was confirmed by 1H-NMR (CDCl3): δ = 8.40 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H).

[1] Schlosser M, et al. Further Metalations and Functionalizations of Chloro-, Bromo- and Iodo(trifluoromethyl)pyridines. Synthesis, 2004; 10: 1619-1624.