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Synlett 2002(11): 1823-1826
DOI: 10.1055/s-2002-34884
LETTER
© Georg Thieme Verlag Stuttgart · New York

Alkylation of Active Methylenes via Benzhydryl Cations

Fabrice Bisaro, Guillaume Prestat, Maxime Vitale, Giovanni Poli*
Laboratoire de Chimie Organique, UMR 7611 CNRS, Université Pierre et Marie Curie, Tour 44-45, 4, Place Jussieu, Boîte 183, 75252, Paris, Cedex 05, France
Fax: +33(1)44277567; e-Mail: poli@ccr.jussieu.fr;
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Publication History

Received 26 July 2002
Publication Date:
21 October 2002 (online)

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Abstract

The acid mediated reaction between active methylenes and benzhydryl alcohols, or their derivatives, is reported. Ethyl acetoacetate, acetylacetone, and N,N-dibenzyl-malonamic acid methyl ester are benzhydrylated in quantitative yields in the presence of molar amounts of BF3·OEt2 in CH2Cl2 at r.t. TMSOTf and H2SO4 appear to be equally efficient. Use of benzhydryl acetate in place of the starting free alcohol allows lowering of the Lewis acid to catalytic amounts. A general mechanism for this scarcely studied C-C bond formation is presented. Due to the easier availability of alcohols with respect to halides the method may favorably compare with the more classical halide-based basic conditions.

Key words

boron - carbocations - enols - Lewis acids - benzhydryl­ation

    References

  • 1 Valenta V. Metys J. Protiva M. Collect. Czech. Chem. Commun.  1982,  47:  984 
    Google Scholar
  • 3a Adams JT. Abramovitch B. Hauser CR. J. Am. Chem. Soc.  1943,  65:  552 
    Google Scholar
  • 3b Adams JT. Levine R. Hauser CR. Org. Synth., Coll. Vol. 3   John Wiley and Sons Ltd.; New York: 1955.  p.405 
    Google Scholar
  • 3c Sawicki E. Olivero VT. J. Org. Chem.  1956,  21:  183 
    Google Scholar
  • 3d Crimmins TF. Hauser CR. J. Org. Chem.  1967,  32:  2615 
    Google Scholar
  • 3e Ohshima E. Kumazawa T. Obase H. Chem. Pharm. Bull.  1993,  41:  36 
    Google Scholar
  • 3f Gálvez N. Molins E. Moreno-Mañas M. Sebastián RM. Serra N. Trepat E. Vallribera A. J. Heterocyclic Chem.  2000,  37:  895 
    Google Scholar
  • 3g For a Lewis acid catalyzed intramolecular alkylation of alkene-containing active methylenes see: Reetz MT. Chatziiosifidis I. Schwellnus K. Angew. Chem., Int. Ed. Engl.  1981,  20:  687 
    Google Scholar
  • For Lewis acid mediated alkylation of silyl enol ethers with SN1 reactive halides see:
  • 4a Paterson I. Fleming I. Tetrahedron Lett.  1979,  23:  2179 
    Google Scholar
  • 4b Reetz MT. Hüttenhain S. Walz P. Löwe U. Tetrahedron Lett.  1979,  51:  4971 
    Google Scholar
  • 4c Reetz MT. Maier WF. Chatziiosifidis I. Giannis A. Heimbach H. Loewe U. Chem. Ber.  1980,  113:  3741 
    Google Scholar
  • 6 For a recent application of BF3·OEt2 mediated symmetrical ether synthesis see: Díaz DD. Martín VS. Tetrahedron Lett.  2000,  41:  9993 
    CrossrefGoogle Scholar
  • 8a Gautert P. El-Ghammarti S. Legrand A. Couturier D. Rigo B. Synth. Commun.  1996,  26:  707 
    CrossrefGoogle Scholar
  • 8b Balfe MP. Kenyon J. Thain EM. J. Chem. Soc.  1952,  790 
    CrossrefGoogle Scholar
  • 8c Burton H. Cheesman GWH. J. Chem. Soc.  1953,  986 
    CrossrefGoogle Scholar
  • 8d Bartlett P. McCollum JD. J. Am. Chem. Soc.  1956,  78:  1441 
    CrossrefGoogle Scholar
  • 9a Giambastiani G. Poli G. J. Org. Chem.  1998,  63:  9608 
    CrossrefGoogle Scholar
  • 9b Tamaru Y. Horino Y. Araki M. Tanaka S. Kimura M. Tetrahedron Lett.  2000,  41:  5705 
    CrossrefGoogle Scholar
  • For an example of complexation between BF3·OEt2 and tetronic derivatives during acylations see:
  • 11a Jones RF. Peterson GE. Tetrahedron Lett.  1983,  24:  4757 
    CrossrefGoogle Scholar
  • 11b Jones RF. Begley MJ. Peterson GE. Sumaria S. J. Chem. Soc. Perkin Trans. 1  1990,  1959 
    CrossrefGoogle Scholar
  • For examples of active methylene enolization by means of metal salts see:
  • 12a Moreno-Mañas M. Marquet J. Vallribera A. Tetrahedron  1996,  52:  3377 
    CrossrefGoogle Scholar
  • 12b Gómez-Bengoa E. Cuerva JM. Mateo C. Echavarren AM. J. Am. Chem. Soc.  1996,  118:  8553 
    CrossrefGoogle Scholar
  • 12c Christoffers J. Chem. Commun.  1997,  943 
    CrossrefGoogle Scholar
  • 12d Christoffers J. Eur. J. Org. Chem.  1998,  1259 
    CrossrefGoogle Scholar
  • 12e Bartoli G. Bosco M. Bellucci MC. Marcantoni E. Sambri L. Torregiani E. Eur. J. Org. Chem.  1999,  617 
    CrossrefGoogle Scholar
  • 13a Bolm C. Muniz K. Chem. Commun.  1999,  1295 
    CrossrefGoogle Scholar
  • 13b Bolm C. Hermanns N. Hildebrand JP. Muniz K. Angew. Chem. Int. Ed.  2000,  39:  3465 
    CrossrefGoogle Scholar
  • 13c Bolm C. Kesselgruber M. Hermanns N. Hildebrand JP. Raabe G. Angew. Chem. Int. Ed.  2001,  40:  1488 
    CrossrefGoogle Scholar
2

Poli, G.; Giambastiani, G. J. Org. Chem., 2002 in press.

5

Representative experimental procedure: To a stirred solution of benzhydryl alcohol (202 mg, 1.1 mmol) and ethyl acetoacetate (127 µL, 1 mmol) in CH2Cl2 (20 mL) under nitrogen was added BF3·OEt2 (217 µL, 1.2 mmol) at r.t. The mixture was stirred for 1 hour before saturated NaHCO3 solution (10 mL) was added. The aqueous layer was extracted with CH2Cl2 (10 mL). The organic layers were washed with brine (10 mL) dried (MgSO4) and concentrated under reduced pressure. Short column chromatography (hexane/EtOAc = 8:2) afforded quantitatively ethyl 2-benzhydryl-3-oxo-butanoate. 1H NMR (CDCl3, 400 MHz): δ(ppm) 7.5-7.1 (m, 10 H, H), 4.81 (d, 1 H, 3 J = 12.3 Hz), 4.58 (d, 1 H, 3 J = 12.3 Hz), 4.01 (q, 2 H, 3 J = 7.1 Hz), 2.12 (s, 3 H), 1.02 (t, 3 H, 7.1). 13C NMR: δ(ppm) 201.7, 167.6, 141.5, 141.2, 128.8-126.8, 65.2, 61.4, 50.8, 30.0, 13.7.

7

Experiments with dimethyl malonate, methyl phenylsulfonyl acetate and bis-phenylsulfonylmethane gave back the unreacted methylene plus benzhydryl alcohol dismutation. Meldrum’s acid gave an alkylated/transesterified product. Ethyl malononitrile gave a complex mixture.

10

1H NMR (CDCl3, 400 MHz): coordinated keto form δ = 4.17 (q, 3 J = 7 Hz, 2 H), 3.38 (br s, 2 H); 2.24 (br s, 3 H), 1.26 (t, 3 J = 7 Hz, 3 H); coordinated enol form δ = 11,98 (s, 1 H), 5.32 (s, 1 H), 4.47 (q, 3 J = 7 Hz, 2 H), 2.14 (s, 3 H), 1.38 (t, 3 J = 7 Hz, 3 H).