PDF herunterladen
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
Weitere Informationen

Publikationsverlauf

Received 19 May 2008
Publikationsdatum:
22. August 2008 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

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

  • 1a Hadjeri M. Peiller E.-L. Beney C. Deka N. Lawson MA. Dumontet C. Boumendjel A. J. Med. Chem.  2004,  47:  4964 
    Google Scholar
  • 1b Joseph B. Darro F. Béhard A. Lesur B. Collignon F. Decaestecker C. Frydman A. Guillaumet G. Kiss R. J. Med. Chem.  2002,  45:  2543 
    Google Scholar
  • 1c Tabarrini O. Cecchetti V. Fravolini A. Nocentini G. Barzi A. Sabatini S. Miao H. Sissi C. J. Med. Chem.  1999,  42:  2136 
    Google Scholar
  • 2 Traxler P. Green J. Mett H. Sequin U. Furet P. J. Med. Chem.  1999,  42:  1018 
    CrossrefPubMedGoogle Scholar
  • 3 Gungor T. Chen Y. Golla R. Ma Z. Corte JR. Northrop JP. Bin B. Dickson JK. Stouch T. Zhou R. Johnson SE. Seethala R. Feyen JHM. J. Med. Chem.  2006,  49:  2440 
    CrossrefGoogle Scholar
  • 4a Black DSC. Bowyer MC. Condie GC. Craig DC. Kumar N. Tetrahedron  1994,  50:  10983 
    Google Scholar
  • 4b Bullington JL. Dodd JH. J. Org. Chem.  1993,  58:  4833 
    Google Scholar
  • 5 Roth B. Aig E. Rauckmann BS. Strelitz JZ. Phillips AP. Ferone R. Bushby SRM. Sigel CW. J. Med. Chem.  1981,  24:  933 
    CrossrefGoogle Scholar
  • 6 Roth HJ. Kok W. Arch. Pharm.  1975,  308:  301 
    CrossrefGoogle Scholar
  • 7 Kursanov DN. Parnes ZN. Bolestova GI. Belenkii LI. Tetrahedron  1975,  31:  311 
    CrossrefGoogle Scholar
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.