Rapid Synthesis of 4-Benzyl-4-aminopiperidines by Addition of Grignard Reagents to N-(1-Boc-Piperidin-4-ylidene)-tert-butanesulfinyl Imine

Abstract

Two concise methods for the synthesis of aryl-substituted 4-benzyl-4-aminopiperidines by the addition of benzyl Grignard ­reagents to sulfinyl imines were developed. The hydration-prone tert-butanesulfinyl imine derived from N-Boc-piperidin-4-one was trapped as a stable α-(N-sulfinyl)aminonitrile, which underwent displacement of the nitrile on treatment with Grignard reagents. Alternatively, benzyl and allyl Grignards added to the sulfinyl imine in situ in a one-pot procedure. Acid deprotection provided various substituted 4-benzyl-4-aminopiperidines.

Key words

heterocycles - piperidines - imines - Grignard reactions - tandem reactions

References and Notes

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7

Compound 4: ¹H NMR (500 MHz, DMSO): δ = 1.11 (s, 9 H), 1.39 (s, 9 H), 1.66-1.69 (m, 4 H), 3.11-3.14 (m, 2 H), 3.45-3.50 (m, 2 H), 5.30 (s, 1 H), 5.52 (s, 1 H, signal removed on addition of D₂O). ¹³C NMR (125 MHz, DMSO): δ = 22.6, 28.1, 37.2, 38.0, 54.5, 78.5, 81.4, 153.8. MS (ES+): m/z = 343 [M + Na⁺], 303 [M + H⁺ - H₂O].

13

tert -Butyl 4-Cyano-4-( tert -butanesulfinamido)piper-idine-1-carboxylate (5): A solution of N-Boc-piperidin-4-one (1; 0.90 g, 4.52 mmol), tert-butanesulfinamide (0.58 g, 4.8 mmol) and Ti(OEt)₄ (1.9 mL, 9 mmol) in anhyd THF (20 mL) was refluxed under N₂ for 20 h. The red solution was cooled, TMSCN (0.66 mL, 5 mmol) was added and the solution was refluxed for 3 h. The cooled solution was diluted with brine (20 mL) and EtOAc (20 mL). The suspension was filtered through Celite, washing with further EtOAc. The filtrate was separated and the organic layer was dried (Na₂SO₄) and concentrated. Flash column chromatography, eluting with EtOAc, gave 5 as a white powder (0.851 g, 2.58 mmol, 57%). ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (s, 9 H), 1.46 (s, 9 H), 1.70-1.78 (m, 1 H), 1.81-1.90 (m, 1 H), 2.20-2.30 (m, 2 H), 3.15-3.25 (m, 2 H), 3.65 (br s, 1 H), 3.95-4.15 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.3, 28.4, 36.2, 37.5, 40.0, 56.9, 80.5, 119.6, 154.2. MS (ES+): m/z = 352 [M + Na⁺], 329 [M + H⁺].tert -Butyl 4-Benzyl-4-( tert -butanesulfinamido)piper-idine-1-carboxylate(6a); Via Nitrile 5: A solution of 5 (0.206 g, 0.625 mmol) and benzylmagnesium chloride (2 M in THF, 0.70 mL, 1.4 mmol) in anhyd THF (3 mL) was refluxed under N₂ for 3 h. The cooled reaction mixture was diluted with sat. aq NH₄Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The extracts were dried (Na₂SO₄) and concentrated. Flash column chromatography, eluting with EtOAc, gave 6a as a straw-coloured oil (0.122 g, 0.309 mmol, 49%). ¹H NMR (500 MHz, CDCl₃): δ = 1.25 (s, 9 H), 1.25-1.32 (m, 1 H), 1.46 (s, 9 H), 1.52-1.60 (m, 1 H), 1.72-1.80 (m, 1 H), 2.37-2.42 (m, 1 H), 2.71 (d, J = 13.0 Hz, 1 H), 2.94-3.15 (m, 2 H), 3.21 (d, J = 13.0 Hz, 1 H), 3.32 (s, 1 H), 3.72-3.95 (m, 2 H), 7.25-7.39 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.0, 24.2, 28.4, 33.7, 36.5, 39.0, 49.0, 55.6, 56.5, 79.6, 126.7, 128.2, 131.8, 135.6, 154.8. MS (ES+): m/z = 416 [M + Na⁺], 395 [M + H⁺].Direct Synthesis: A solution of 1 (0.615 g, 3.09 mmol), tert-butylsulfinamide (0.390 g, 3.21 mmol) and Ti(OEt)₄ (1.26 mL, 6.00 mmol) in anhyd THF (15 mL) was refluxed under N₂ for 14 h. The solution was cooled to 0 °C and a solution of benzylmagnesium chloride (2 M in THF, 0.77 mL, 15.45 mmol) was added. After stirring for 20 h at r.t., the crude reaction mixture was absorbed onto silica gel. Flash column chromatography, eluting with EtOAc-hexane (2:1), gave 6a (0.473 g, 1.20 mmol, 39%).4-Benzylpiperidin-4-amine (3a): A solution of 6a (0.094 g, 0.238 mmol) in MeOH (5 mL) and 4 M HCl-dioxane (5 mL) was stirred for 24 h. Concentration and purification by ion-exchange on an SCX-2 Isolute column, eluting with MeOH then 2 M NH₃-MeOH, gave 3a as a yellow oil (0.036 g, 0.189 mmol, 80%). ¹H NMR (500 MHz, MeOD): δ = 1.38-1.43 (m, 2 H), 1.60-1.66 (m, 2 H), 2.74 (s, 2 H), 2.84-2.92 (m, 4 H), 7.21-7.32 (m, 5 H). ¹³C NMR (125 MHz, MeOD): δ = 32.2, 38.5, 49.2, 50.8, 127.6, 129.2, 131.8, 138.2. MS (ES+): m/z (ES+) = 191 [M + H⁺], 174 [M + H⁺ - NH₃].