6-Azaspiro[2.5]octane hydrochloride synthesis

Yield:1037834-62-0 81%

Reaction Conditions:

Stage #1:(1-cyanomethyl-cyclopropyl)-acetonitrile with C₄₆H₁₇₈O₄₁Si₄₂;titanium(IV)isopropoxide in toluene at 60; for 24 h;Inert atmosphere;
Stage #2: with hydrogenchloride;water in toluene at 20; for 4 h;Inert atmosphere;chemoselective reaction;Concentration;Temperature;

Steps:

3 4.4. General procedure for the reduction of dinitriles
General procedure: To a 50 mL round-bottom flask, under nitrogen atmosphere, containing dinitriles 1p (500 mg, 4.2 mmol, 1.0 equiv) in 5.0 mL of toluene were added PMHS (1.0 mL, 16.8 mmol, 4.0 equiv) and Ti(Oi-Pr)₄ (1.3 mL, 4.3 mmol, 1.0 equiv). The mixture was then heated at 100°C for 24 h (the colorless solution turned into deep purple). After cooling to rt, the clear solution was diluted in toluene (30 mL) and hydrolyzed with aqueous 1M HCl (15 mL, 3.6 equiv) for 4 h (until the deep purple solution became yellow). The crude mixture was then concentrated under reduced pressure. The resulting solid was filtered, washed with pentane (60 mL), dissolved in chloroform and filtrate on a pad of Celite. The filtrate was finally concentrated under reduced pressure affording the amine 3p as a hydrochloride salt in 85% yield (yellow powder, 530 mg). ¹H NMR (300 MHz, MeOD) δ 0.48 (s, 4H, 2×CH₂-cyclopropyl), 1.64 (m, 4H, 2×CH₂-CH₂-NH-piperidine), 3.22 (m, 4H, 2×CH₂-CH₂-NH-piperidine). ¹³C NMR (100 MHz, MeOD) δ 12.2, 16.7 (Cq), 32.4, 45.2. MS (CI, NH₃) m/z=112 (MH)⁺.

References:

Laval, Stéphane;Dayoub, Wissam;Pehlivan, Leyla;Métay, Estelle;Favre-Reguillon, Alain;Delbrayelle, Dominique;Mignani, Gérard;Lemaire, Marc [Tetrahedron,2014,vol. 70,# 4,p. 975 - 983] Location in patent:supporting information

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