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Synlett 2009(5): 751-754  
DOI: 10.1055/s-0028-1087817
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Synthesis of N-Arylputrescines and Cadaverines

Natalia P. Link, Jimena E. Díaz, Liliana R. Orelli*
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junín 956, 1113 Buenos Aires, Argentina
Fax: +54(11)49648250; e-Mail: lorelli@ffyb.uba.ar;
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Publication History

Received 9 July 2008
Publication Date:
16 February 2009 (online)

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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

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.

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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.