Synlett 2008(9): 1313-1316  
DOI: 10.1055/s-2008-1072787
LETTER
© Georg Thieme Verlag Stuttgart · New York

Solvent- and Catalyst-Free Three-Component Reaction with β-Ketoamides for the Stereoselective One-Pot Access to 1,4-Diazepines

Enrique Sotoca, Thierry Constantieux*, Jean Rodriguez*
Institut des Sciences Moléculaires de Marseille, iSm2 CNRS UMR 6263, Aix-Marseille Université, Centre Saint Jérôme, Service 531, 13397 Marseille Cedex 20, France
Fax: +33(4)91288841; e-Mail: jean.rodriguez@univ-cezanne.fr;
Further Information

Publication History

Received 6 March 2008
Publication Date:
07 May 2008 (online)

Abstract

The stereoselective one-pot synthesis of polysubstituted 1,4-diazepine derivatives has been achieved via a new solvent- and catalyst-free multicomponent domino reaction from β-ketoamides. This green and experimentally simple sequence is conducted from easily accessible achiral starting materials, does not require any harmful reagents, and results in a high increase in molecular complexity and diversity. Moreover, water is the only byproduct liberated during the reaction.

    References and Notes

  • 1a Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 
  • 1b Ramon DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
  • 1c Dömling A. Chem. Rev.  2006,  106:  17 
  • 2a Domino Reactions in Organic Synthesis   Tietze LF. Brasche G. Gericke KM. Wiley-VCH; Weinheim: 2006. 
  • 2b Padwa A. Bur SK. Tetrahedron  2007,  63:  5341 
  • 3a Schreiber SL. Science  2000,  287:  1964 
  • 3b Vugts DJ. Koningstein MM. Schmitz RF. de Kanter FJJ. Groen MB. Orru RVA. Chem. Eur. J.  2006,  12:  7178 
  • 3c Nielsen TE. Schreiber SL. Angew. Chem. Int. Ed.  2008,  47:  48 
  • Step economy:
  • 4a Wender PA. Baryza JL. Brenner SE. Clarke MO. Gamber GG. Horan JC. Jessop TC. Kan C. Pattabiraman K. Williams TJ. Pure Appl. Chem.  2003,  75:  143 
  • 4b Wender PA. Baryza JL. Brenner SE. Clarke MO. Craske ML. Horan JC. Meyer T. Curr. Drug Discovery Technol.  2004,  1:  1 
  • 4c Wender PA. Gamber GG. Hubbard RD. Pham SM. Zhang L. J. Am. Chem. Soc.  2005,  127:  2836 
  • Atom-economy:
  • 5a Trost BM. Science  1991,  254:  1471 
  • 5b Trost BM. Angew. Chem., Int. Ed. Engl.  1995,  34:  258 
  • 5c Trost BM. Acc. Chem. Res.  2002,  35:  695 
  • 6 For a special issue in environmental chemistry, see: Chem. Rev.  1995,  95: 
  • 7 Tanaka K. Solvent-Free Organic Synthesis   Wiley-VCH; Weinheim: 2003. 
  • 8a For a special issue in green chemistry, see: Chem. Rev.  2007,  107:  2167 
  • 8b Tucker JL. Org. Process Res. Dev.  2006,  10:  315 
  • For recent reviews on the utilization of 1,3-dicarbonyl derivatives in MCR, see:
  • 9a Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 
  • 9b Liéby-Muller F. Simon C. Constantieux T. Rodriguez J. QSAR Comb. Sci.  2006,  25:  432 
  • 10a Simon C. Peyronel JF. Rodriguez J. Org. Lett.  2001,  3:  2145 
  • 10b Simon C. Liéby-Muller F. Peyronel J.-F. Constantieux T. Rodriguez J. Synlett  2003,  2301 
  • 10c Liéby-Muller F. Constantieux T. Rodriguez J. J. Am. Chem. Soc.  2005,  127:  17176 
  • 10d Liéby-Muller F. Simon C. Imhof K. Constantieux T. Rodriguez J. Synlett  2006,  1671 
  • 10e Liéby-Muller F. Constantieux T. Rodriguez J. Synlett  2007,  1323 
  • 11a Habib-Zahmani H. Hacini S. Charonnet E. Rodriguez J. Synlett  2002,  1827 
  • 11b Habib-Zahmani H. Viala J. Hacini S. Rodriguez J. Synlett  2007,  1037 
  • 12a Filippini MH. Rodriguez J. J. Chem. Soc., Chem. Commun.  1995,  33 
  • 12b Charonnet E. Filippini MH. Rodriguez J. Synthesis  2001,  788 
  • 13 While this work was in progress, a related acid-catalyzed transformation with β-ketoesters in 1,2-dichloroethane as solvent was reported: Fujioka H. Murai K. Kubo O. Ohba Y. Kita Y. Org. Lett.  2007,  9:  1687 
  • 14 For recent biological activity investigations with respect to these heterocycles, see for example: Tanaka T. Muto T. Maruoka H. Imajo S. Fukami H. Tomimori Y. Fukuda Y. Nakatsuka T. Bioorg. Med. Chem. Lett.  2007,  17:  3431 
  • 15 Wender PA. Verma VA. Paxton TJ. Pillow TH. Acc. Chem. Res.  2008,  41:  40 
  • For recent contributions in this field, see for example:
  • 21a Iden HS. Lubell WD. Org. Lett.  2006,  8:  3425 
  • 21b Van Brabandt W. Vanwalleghem M. D’hooghe M. De Kimpe N. J. Org. Chem.  2006,  71:  7083 
  • 21c Wlodarczyk N. Gilleron P. Millet R. Houssin R. Hénichart J.-P. Tetrahedron Lett.  2007,  48:  2583 
  • 21d Maruoka H. Muto T. Tanaka T. Imajo S. Tomimori Y. Fukuda Y. Nakatsuka T. Bioorg. Med. Chem. Lett.  2007,  17:  3435 
16

Chemical purities were in the range from 80-95% as estimated by NMR. However, flash chromatography purification resulted in a significant lost of pure product, probably due to unrationalized degradation.

17

Stereochemistry of the products has been fully studied by 2D NMR analysis, including a detailed analysis of coupling patterns and constants.

18

A complex mixture of unidentified products was obtained, probably due to degradation of starting materials.

19

Typical Procedure for the Synthesis of Compounds 4
To a 50 mL two-necked round-bottomed flask flushed with Ar, equipped with a magnetic stirring bar and a reflux condenser, were added β-ketoamide 2 (1.28 mmol), aldehyde 3 (1.5 mmol), and diamine 1 (1.28 mmol). The mixture was stirred at 110 °C under Ar for 4 h, diluted with EtOAc (20 mL) after cooling, and filtered through a short pad of Celite. After evaporation, the crude resulting slurry was purified by flash chromatography over SiO2.
Selected Physical Data for Compounds 4a
Amber oil; R f = 0.7 (EtOAc). 1H NMR (300.13 MHz, CDCl3): δ = 1.10-1.40 (m, 1 H), 1.40-1.60 (m, 1 H), 2.10 (br s, 1 H), 2.30-2.40 (m, 2 H), 2.87 (dd, J = 15.0, 6.0 Hz, 1 H), 3.10 (dd, J = 15.0, 6.0 Hz, 1 H), 3.20-3.30 (m, 2 H), 3.42 (d, J = 12.0 Hz, 1 H), 3.51 (d, J = 12.0 Hz, 1 H), 6.60 (br s, 1 H), 6.95 (t, J = 9.0 Hz, 1 H), 7.10-7.30 (m, 7 H), 7.42 (d, J = 9.0 Hz, 2 H), 8.71 (br s, 1 H). 13C NMR (75.47 MHz, CDCl3): δ = 26.9, 27.4, 47.4, 51.4, 54.1, 68.7, 94.4, 119.6 (2 C), 123.0, 127.6, 127.7 (2 C), 128.5 (2 C), 128.7 (2 C), 138.8, 143.3, 166.4, 167.0. MS (EI): m/z (%) = 225 (6), 241 (43)
[M - Ph+], 242 (9), 334 (100) [M + H+], 335 (19).

20

Although it is not clear at the moment why we observed this loss of stereoselectivity, the two diastereomers were easily separable by flash chromatography.