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Synlett 2002(1): 0113-0115
DOI: 10.1055/s-2002-19328
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Substituted Benzhydrylamines

Yves Dejaegher, Sven Mangelinckx, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: norbert.dekimpe@rug.ac.be;
Further Information

Publication History

Received 26 July 2001
Publication Date:
01 February 2007 (online)

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Abstract

The synthesis of para di- and monosubstituted benzhydrylamines by addition of Grignard reagents to benzonitriles and subsequent reduction, is evaluated and discussed. The reduction step with sodium borohydride allows simple handling and mild conditions. An optimized synthesis of 4,4’-dimethoxybenzhydrylamine by this method is disclosed.

Key words

benzhydrylamines - Grignard reactions - diphenylmethylidenamines - diarylketimines - reductions - protecting groups

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General Procedure for the one-pot synthesis of 4,4’-Dimethoxybenzhydrylamine 3e : In an oven-dry bulb, 1.01 g (43 mmol) of magnesium is suspended in 15 mL dry THF. At r.t., some drops of 4-bromoanisole are added. In order to initiate the reaction, the resulting mixture is scratched with a spatula. If necessary, a crystal of iodine might be added, and the solution might be heated. Once initiated, the remaining of 7.73 g (41 mmol) of 4-bromoanisole were added in 8 mL THF, in order to maintain gentle reflux. When the addition is completed, the mixture is refluxed for another 45 min. After cooling to r.t., 5 g (37.5 mmol) of anisonitrile in 8 mL dry THF is added over 20 min. After additional reflux for 5 h, the reaction mixture is cooled in an ice bath and 30 mL dry methanol is carefully added. After stirring for 20 min, 2.86 g (75 mmol) sodium borohydride is added in portions. The solution is stirred for 1 h at r.t. and 1 h reflux. Subsequently, the mixture is filtered over Celite and the filtrate partially evaporated. The remaining liquid is poured into 200 mL 0.5 N HCl solution and extracted 3 times with 25 mL diethyl ether. After addition of 2 N NaOH untill pH 9-10, the water phase is extracted with 3 times 50 mL CH2Cl2. The combined organic phases are dried (MgSO4). After filtration and evaporation of the solvent, 7.71 g of amine 3e is obtained. Yield: 85%. Spectroscopic data for compound 3e: 1H NMR (270 MHz, CDCl3): δ = 1.79 (2 H, br s, NH 2); 3.78 (6 H, s, 2 × OMe); 5.13 (1 H, s, CHNH2); 6.84 and 7.27 (4 H each, d each, J = 8.6 Hz, CH ar); 13C NMR (68 MHz, CDCl3): δ = 55.24 (2 × OMe); 58.45 (CHNH2); 113.76 and 127. 83 (CHar); 138.15 and 158.45 (C ar,quat.); IR (KBr, cm-1): 3370, 1608, 1585, 1509, 1466; [3c] MS (70eV):
m/z (%) = 243(10) [M+], 242(54), 241(34), 227(9), 226(39), 211(14), 183(6), 135(81), 134(100), 133(47), 109(9); mp (Büchi 540 melting point apparatus, uncorrected): 58-59 °C.