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Synlett 2008(16): 2429-2432  
DOI: 10.1055/s-2008-1078207
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel and Highly Regioselective Friedel-Crafts Alkylation of 3,5-Dimethoxy­aniline Using an Aldehyde and Triethylsilane as Reducing Agent

John Kallikat Augustine*a,b, Yanjerappa Arthoba Naikb, Ashis Baran Mandala, Padma Alagarsamya, Vani Akabotea
a Syngene International Ltd., Biocon Park, Plot Nos. 2 and 3, Bommasandra IV Phase, Jigani Link Road, Bangalore - 560 100, India
Fax: +91(80)28083150; e-Mail: john.kallikat@syngeneintl.com;
b Department of Chemistry, Kuvempu University, Shankaraghatta Post, Shimoga - 577 451, India
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Publication History

Received 19 May 2008
Publication Date:
22 August 2008 (online)

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Abstract

A novel and highly regioselective Friedel-Crafts alkyl­ation, producing p-alkyl 3,5-dimethoxyanilines by the reaction of aldehydes with 3,5-dimethoxyaniline in the presence of trifluoroacetic acid and triethylsilane as reducing agent is reported. This procedure is lauded by its high regioselectivity, simplicity, and adaptability to aromatic, heteroaromatic, and aliphatic aldehydes. This reaction represents a useful way to prepare a variety of 4-substituted 3,5-dimethoxyanilines of potential pharmacological interest.

Key words

Friedel-Crafts alkylation - regioselective - triethyl­silane - activated aniline - nucleophilic

    References and Notes

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Representative Procedure for the Synthesis of 2a
To a mixture of 4-bromobenzaldehyde (10 g, 0.054 mol) and 3,5-dimethoxyaniline (8.26 g, 0.054 mol) in CH2Cl2 (60 mL) was added TFA (12.30 g, 0.108 mol), and the mixture was stirred at r.t. for 10 min. To this was added TES (12.5 g, 0.108 mol) in drops over a period of 10 min, and the reaction was stirred at r.t. for additional 2 h. The completion of reaction was confirmed by TLC (2% MeOH in CH2Cl2). The solvent was removed under vacuum and the residue was diluted with H2O (50 mL) and washed with hexane (2 × 50 mL). The aqueous phase was basified with sat. aq solution of NaHCO3 and extracted with CH2Cl2 (2 × 100 mL). The combined organic phase was washed with H2O (1 × 100 mL), brine (1 × 50 mL), and dried over Na2SO4. The solvent was removed under vacuum to afford 16 g (93%) of 4-(4-bromobenzyl)-3,5-dimethoxyaniline(2a) as an off-white solid; mp 167.9-169.0 ˚C. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.36-7.34 (d, 2 H, J = 8 Hz), 7.04-7.02 (d, 2 H, J = 8 Hz), 5.89 (s, 2 H), 5.24 (br s, 2 H), 3.65 (s, 2 H), 3.63 (s, 6 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 158.6, 148.8, 142.3, 131.1, 130.7, 118.4, 104.0, 91.0, 55.6, 27.6. MS (ESI-APCI): m/z found for C15H16BrNO2: 324 [M + 2])+. Anal. Calcd (%) for C15H16BrNO2: C, 55.92; H, 5.01, N, 4.35. Found: C, 55.99; H, 5.05, N, 4.28.