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Synlett 2007(5): 0803-0805  
DOI: 10.1055/s-2007-970752
LETTER
© Georg Thieme Verlag Stuttgart · New York

Sulfamic Acid Catalyzed Direct Condensation of Aldehydes, Amines, and TMSCN to α-Aminonitriles at Ambient Temperature

Zhenjiang Li*, Yingjie Sun, Xinghua Ren, Ping Wei, Yuhu Shi, Pingkai Ouyang
College of Life Science and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 210009, P. R. of China
Fax: +86(25)83479464; e-Mail: zjli@njut.edu.cn;
Further Information

Publication History

Received 8 December 2006
Publication Date:
08 March 2007 (online)

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Abstract

A simple and efficient method has been developed for the synthesis of α-aminonitriles by a one-pot three-component ­condensation of aldehydes, amines, and trimethylsilyl cyanide in the presence of a catalytic amount of sulfamic acid at room temperature.

Key words

aldehyde - amine - α-aminonitrile - sulfamic acid - three-component reaction

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Cost of sulfamic acid: 31.5 $/kg; less than one-tenth of the unit price of the least expensive catalyst Lewis acid in ref. 9, see http://www.sigmaaldrich.com/catalog/search/ (accessed 12/2006).

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General Experimental Procedure.
A mixture of aldehyde (2.0 mmol), amine (2.0 mmol) and sulfamic acid (20 mg) in MeCN (5.0 mL) was stirred at r.t. for 20 min and then trimethylsilyl cyanide (1.6 mL, 2.4 mmol) was added. The resulting reaction mixture was stirred at r.t. for the appropriate time. After completion of the reaction (TLC, hexane-EtOAc = 1:5), sulfamic acid was filtered off, the filtrate was extracted with EtOAc (3 × 10 mL), the combined organic phase was washed with H2O (20 mL) and sat. aq NH4Cl (20 mL), dried over anhyd MgSO4 and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (hexane-EtOAc = 1: 3) to afford the pure 3a-v, all of which were thoroughly characterized.
Spectral Data of Representative Compounds.
2-(o-Toluidino)-2-phenylacetonitrile (3b): pale yellow solid; mp 71-72 [lit.9e 72-73] °C. IR (KBr): 3365, 2237 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.20 (s, 3 H), 3.38 (br d, J = 8.1 Hz,1 H, NH), 5.45 (d, J = 8.1 Hz, 1 H), 6.80 (t, J = 7.9 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 7.9 Hz, 1 H), 7.40-7.50 (m, 3 H), 7.50 (d, J = 8.0 Hz, 2 H). ESI-HRMS: m/z calcd for C15H15N2 + [M + H]+: 223.1235; found: 223.1231.
2-Phenyl-2-(pyrrolidin-1-yl)acetonitrile (3l): colorless oil. IR (neat): 2223 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.75 (m, 4 H), 2.71-2.58 (m, 4 H), 5.03 (s, 1 H), 7.43-7.31 (m, 3 H), 7.53-7.49 (m, 2 H). ESI-HRMS: m/z calcd for C12H15N2 + [M+H]+: 187.1235; found: 187.1237.
2-(Benzylamino)-2-(3-methoxyphenyl)acetonitrile (3r): colorless oil. IR (neat): 3323, 2243 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.84 (br s, 1 H), 3.77 (s, 3 H), 3.94 (q, J = 13.0 Hz, 2 H), 4.66 (s, 1 H), 6.86 (dd, J = 2.5, 9.4 Hz, 1 H), 7.23 (m, 2H), 7.83-7.29 (m, 6 H). ESI-HRMS: m/z calcd for C16H17N2O+ [M + H]+: 253.1341; found: 253.1338.
2-(Benzylamino)-3-methylbutanenitrile (3v): colorless oil. IR (neat): 3347, 2228 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.07 (d, J = 6.7 Hz, 3 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.55 (br s, 1 H), 1.98 (m, 1 H), 3.25 (d, J = 6.0 Hz, 1 H), 3.79 (d, J = 13.0 Hz, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 7.36-7.23 (m, 5 H). ESI-HRMS: m/z calcd for C12H17N2 + [M + H]+: 189.1392; found: 189.1390.