O-(3-Fluoro-benzyl)-hydroxylamine hydrochloride synthesis

Yield:-

Reaction Conditions:

with hydrogenchloride in diethyl ether;Inert atmosphere;

Steps:

O-(3-fluorobenzyl)hydroxylamine hydrochloride (16)

General procedure: To a solution of alcohol (1mmol) in freshly distilled THF (5ml) was added triphenylphosphine (1.1mmol) and N-hydroxylphthalimide (1.1mmol). After the solution was cooled to 0°C diisopropylazodicarboxylate (1.1mmol) was added dropwise. The solution was allowed to warm to room temperature over 3h. Reaction progress was monitored by TLC (1:1 heptanes:ethyl acetate). Hydrazine monohydrate (1.1mmol) was then added and the solution was allowed to stir for 30min. The resulting reaction mixture was filtered to remove the white precipitate. The filtrate was concentrated and subjected to flash chromatography (1:1 heptanes/ethyl acetate). The resulting product was dissolved in ether and treated with HCl (2.0M solution in ether) to afford the HCl salt of the O-alkylhydroxylamine. Contaminating diisopropyl hydrazinodicarboxylate could be washed away from the HCl salt with dichloromethane. Synthesized from 3-fluorobenzyl alcohol according to the general procedure to afford 16 as white crystals in 81% yield. Mp=245°C (decomp).¹H NMR (400MHz, CD₃OD) δ 7.45 (t, 1H, ArH, J=8Hz) 7.28-7.15 (m, 3H, ArH), 5.07 (s, 2H, ArCH₂). ¹³C NMR (100MHz, CD₃OD) δ 164.22 (d, J_C-F=240Hz), 136.91 (d, J_C-F=8Hz), 131.80 (d, J_C-F=8Hz), 126.04 (d, J_C-F=3Hz), 117.31 (d, J_C-F=21Hz), 116.85 (d, J_C-F=22Hz), 77.12 (d, J_C-F=2Hz). GC t_R=3.981min.

References:

Malachowski, William P.;Winters, Maria;DuHadaway, James B.;Lewis-Ballester, Ariel;Badir, Shorouk;Wai, Jenny;Rahman, Maisha;Sheikh, Eesha;LaLonde, Judith M.;Yeh, Syun-Ru;Prendergast, George C.;Muller, Alexander J. [European Journal of Medicinal Chemistry,2016,vol. 108,p. 564 - 576]