Download PDF
Synlett 2010(11): 1688-1690  
DOI: 10.1055/s-0030-1258095
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Improved Palladium-Catalysed Synthesis of α-Benzyl-β-keto Esters

Nicholas J. Bennett*a, Anne Goldbyb, Rachel Pringlec
a Chemistry Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
Fax: +44(1509)645571; e-Mail: Nicholas.bennett@astrazeneca.com;
b School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
c Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK
Further Information

Publication History

Received 28 January 2010
Publication Date:
15 June 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

This paper describes the development of an imporved protocol for the synthesis of α-benzyl-β-keto esters from aryl bromides via Heck reaction. The use of this protocol to synthesise a variety of diverse α-benzyl-β-keto esters for use in the preparation of new pharmaceutical agents is demonstrated.

Key words

palladium - Heck reaction - arylation - Baylis-Hillman - α-benzyl-β-keto ester

    References and Notes

  • 1a Doucet H. Hierso J.-C. Curr. Opin. Drug Discovery Dev.  2007,  10:  672 
    Google Scholar
  • 1b Larsen RD. Curr. Opin. Drug Discovery Dev.  1999,  2:  651 
    Google Scholar
  • 2a Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4442 
    Google Scholar
  • 2b Whitcombe NJ. Hii KK. Gibson SE. Tetrahedron  2001,  57:  7449 
    Google Scholar
  • 2c Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
    Google Scholar
  • 2d Cabri W. Cardian I. Acc. Chem. Res.  1995,  28:  2 
    Google Scholar
  • 3a Basavaiah D. Muthukumaran K. Tetrahedron  1998,  54:  4943 
    Google Scholar
  • 3b Kumareswaran R. Vankar YD. Synth. Commun.  1998,  28:  2291 
    Google Scholar
  • 3c Sundar N. Bhat SV. Synth. Commun.  1998,  28:  2311 
    Google Scholar
  • 4 Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Addison Wesley Longman; Harlow: 1997. 
    Google Scholar
  • 7 Aggarwal VK. Emme I. Fulford SY. J. Org. Chem.  2003,  68:  692 
    CrossrefPubMedGoogle Scholar
5

The reaction was completed in a closed tube with a bursting disc fitted in the top of the tube. The reaction was completed behind a blast screen and these important safety measures should be implemented when completing this reaction particularly when scaling up the procedure.

6

Typical Procedure for Heck Reaction
1-Bromo-2-methoxybenzene (0.958 mL, 7.75 mmol), methyl 3-hydroxy-2-methylenebutyrate (0.942 ml, 7.75 mmol) and N-methyldicyclohexylamine (4.98 mL, 23.26 mmol) were added to a suspension of Pd(dbpf)Cl2 (0.126 g, 0.19 mmol) and TBAC (0.431 g, 1.55 mmol) in DMF (10 ml) under nitrogen. The resulting suspension was stirred
at 100 ˚C in a closed tube for 18 h (see ref. 5 for safety measures). The solution was diluted with EtOAc (50 mL) and extracted with H2O (50 mL) and brine (2 × 50 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The residue was diluted with MeCN (30 mL) and loaded on to a 70 g SCX cartridge. The product was washed through with MeCN (100 mL) and the filtrate evaporated to give methyl 2-(2-methoxybenzyl)-3-oxo-butanoate (1.558 g, 85%) as an orange oil. ¹H NMR (400 MHz, CDCl3): δ = 7.20 (ddd, J = 8.9, 7.6, 2.1 Hz, 1 H, CH), 7.11 (dd, J = 6.8, 3.0 Hz, 1 H, CH) 6.87-6.82 (m, 2 H, CH), 3.92 (dd, J = 8.4, 7.2 Hz, 1 H, CH), 3.83 (s, 3 H, CH3), 3.67 (s, 3 H, CH3), 3.19 (dd, J = 13.9, 7.2 Hz, 1 H, CH2), 3.10 (dd, J = 13.9, 8.2 Hz, 1 H, CH2), 2.18 (s, 3 H, CH3). ¹³C NMR (125 MHz, CDCl3): δ = 203.1, 169.9, 157.3, 130.8, 128.1, 126.2, 120.5, 110.2, 59.0, 55.2, 52.2, 29.5, 29.4. HRMS (TOF-LCMS): m/z calcd for C13H17O4 [M + H]+: 237.1121; found: 237.1122.