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

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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8

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.