An Efficient Synthesis of N-Arylputrescines and Cadaverines

Abstract

We present a two-step, general synthesis of N-aryl­putrescines and cadaverines, by cesium carbonate mediated alkylation of anilines with ω-chloronitriles and subsequent reduction. The cesium-mediated alkylation shows remarkable selectivity towards the monoalkylation product. The method is straightforward and leads to satisfactory global yields.

Key words

alkylations - amines - cesium - nitriles - nitrogen

References and Notes

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14

Representative Procedure for the Synthesis of Compounds 2
A solution of 4-chlorobutyronitrile (2.5 mmol) in DMF (1 mL) was added during 1.5 h to a mixture of aniline (2.5 mmol), Cs₂CO₃ (2.5 mmol), and KI (5 mmol) in DMF (4 mL). The mixture was stirred 2.5 h at 95 ˚C. After completion of the reaction, as indicated by TLC, the mixture was treated with Et₂O (50 mL) and H₂O (10 mL). The aqueous phase was separated and extracted with Et₂O (30 mL). The combined organic layers were dried over anhyd Na₂SO₄ and filtered. The solvent was evaporated in vacuo. The crude product was purified by column chromatography (SiO₂, hexane-CHCl₃) to furnish 4-(phenylamino)butyro-nitrile in 69% yield as an oil.
Spectral and Analytical Data for Selected Compounds 4-(Phenylamino)butyronitrile (2a) was obtained as an oil (69%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.17-7.22 (2 H, m), 6.74 (1 H, dt, J = 7.4, 1.0 Hz), 6.61 (2 H, dd, J = 8.8, 1.0 Hz), 3.68 (1 H, br s), 3.33 (2 H, t, J = 6.7 Hz), 2.49 (2 H, t, J = 7.0 Hz), 1.93-2.02 (2 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 147.63, 129.43, 119.50, 117.91, 112.87, 42.31, 25.26, 14.81. Anal. Calcd for C₁₀H₁₂N₂: C, 74.97; H, 7.55; N, 17.48. Found: C, 74.87; H, 7.65; N, 17.42.
N,N-Bis(3-cyanopropyl)aniline (3a) was obtained as an oil. ^¹H NMR (300 MHz, CDCl₃): δ = 7.24-7.27 (3 H, m), 6.80 (1 H, t, J = 7.3 Hz), 6.75 (2 H, d, J = 8.0 Hz), 3.44 (4 H, t, J = 7.1 Hz), 2.38 (4 H, t, J = 7.0 Hz), 1.90-1.96 (4 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 147.08, 129.64, 119.28, 118.30, 114.10, 50.26, 23.09, 14.73. Anal. Calcd for C₁₄H₁₇N₃: C, 73.98; H, 7.54; N, 18.49. Found: C, 73.84; H, 7.59; N, 18.51.
5-(Phenylamino)valeronitrile (2i) was obtained as an oil (65%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.18-7.21 (2 H, m), 6.72 (1 H, dt, J = 7.0, 1.0 Hz), 6.60 (2 H, dd, J = 8.7, 1.0 Hz), 3.62 (1 H, br s), 3.18 (2 H, t, J = 6.5 Hz), 2.40 (2 H, t, J = 6.8 Hz), 1.71-1.89 (4 H, m). Anal. Calcd for C₁₁H₁₄N₂: C, 75.82; H, 8.10; N, 16.08. Found: C, 75.76; H, 8.14; N, 16.10.

16

General Procedure for the Synthesis of Compounds 1
A solution of compound 2 (2 mmol) in THF (60 mL) was treated with with freshly generated borane. The solution was refluxed for 1 h, cooled, and treated with MeOH. The solvent was then eliminated in vacuo. The residue was refluxed with 10% HCl (60 mL), filtered and made alkaline with 10% aq NaOH. The alkaline mixture was extracted with CH₂Cl₂ (2  40 mL). The organic phase was washed with H₂O (10 mL), dried over Na₂SO₄, and filtered. The solvent was eliminated in vacuo. The crude product was purified by column chromatography (SiO₂, CH₂Cl₂-2-PrNH₂).
Spectral and Analytical Data for Selected Compounds N-Phenyl-1,4-butanediamine (1a) was obtained as an oil (80%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.15-7.20 (2 H, m), 6.69 (1 H, tt, J = 7.3, 1.0 Hz), 6.60 (2 H, td, J = 7.5, 1.0 Hz), 3.13 (2 H, t, J = 6.8 Hz), 2.77 (2 H, t, J = 6.7 Hz), 2.45 (2 H, br s), 1.56-1.70 (4 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 148.37, 129.19, 117.17, 112.69, 43.72, 41.64, 30.63, 26.83. Anal. Calcd for C₁₀H₁₆N₂: C, 73.13; H, 9.82; N, 17.06. Found: C, 73.06; H, 9.85; N, 17.01.
N-(Phenyl)-1,5-pentanediamine (1i) was obtained as an oil (82%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.14-7.17 (2 H, m), 6.68 (1 H, dt, J = 7.9, 0.9 Hz), 6.60 (2 H, dd, J = 7.9, 0.9 Hz), 3.11 (2 H, t, J = 7.0 Hz), 2.71 (2 H, t, J = 6.7 Hz), 1.85 (2 H, br s), 1.53-1.70 (4 H, m), 1.37-1.52 (2 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 144.90, 125.68, 113.59, 109.13, 40.33, 38.41, 29.71, 25.85, 20.90. Anal. Calcd for C₁₁H₁₈N₂: C, 74.11; H, 10.18; N, 15.71. Found: C, 74.01; H, 10.21; N, 15.67.
Spectral and analytical data of compounds 1b-h,j-l are available as Supporting Information.