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Synlett 2004(4): 688-692  
DOI: 10.1055/s-2004-817764
LETTER
© Georg Thieme Verlag Stuttgart · New York

Substituted 2-(Cyanomethyl-amino)-acetamides by a Novel Three-Component Reaction

Dirk Behnke*a, Roswitha Taubea, Katrin Illgena, Sven Nerdingera, Eberhardt Herdtweckb
a Morphochem AG, Gmunder Strasse 37-37a, 81379 München, Germany
Fax: +49(89)78005555; e-Mail: dirk.behnke@morphochem.de;
b Anorganisch Chemisches Institut der Technischen Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany
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Publikationsverlauf

Received 22 December 2003
Publikationsdatum:
10. Februar 2004 (online)

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Abstract

A novel three-component, one-pot reaction between ­primary (S)-amino acid amides, aldehydes and isocyanides in the presence of acetic acid yielding substituted 2-(cyanomethyl-amino)-acetamides 4 in good yields, is described. First efforts to ­investigate the mechanism of this reaction were undertaken.

Key words

multi-component condensation - MCRs - Ugi reaction - isocyanides - aliphatic nitriles

    References

  • 1 Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
    CrossrefPubMedGoogle Scholar
  • 2 Weber L. Curr. Med. Chem.  2002,  9:  1241 
    Google Scholar
  • 3 Schreiber S.-L. Science  2000,  287:  1964 
    CrossrefPubMedGoogle Scholar
  • 4 Dömling A. Curr. Opin. Chem. Biol.  2000,  4:  318 
    CrossrefGoogle Scholar
  • 5 Ugi I. Werner B. Dömling A. Molecules  2003,  8:  53 
    CrossrefGoogle Scholar
  • 6 Weber L. Drug Discovery Today  2002,  7:  143 
    CrossrefGoogle Scholar
  • 7a Ugi I, and Steinbrückner C. inventors; DE-B  1,103,337. 
    Crossref
  • 7b Ugi I. Steinbrückner C. Chem. Ber.  1961,  94:  734 
    CrossrefGoogle Scholar
  • 7c Ugi I. Dömling A. Hörl W. Endeavour  1994,  18:  115 
    CrossrefGoogle Scholar
  • 8 Zhang JD. Jacobson A. Rusche JR. Herlihy W. J. Org. Chem.  1999,  64:  1074 
    CrossrefGoogle Scholar
  • Reviews:
  • 9a Orru RVA. de Greef M. Synthesis  2003,  1471 
    Google Scholar
  • 9b Maracaccini S. Torroba T. Org. Prep. Proc. Int.  1993,  25:  141 
    Google Scholar
  • 9c Armstrong RW. Combs AP. Tempest P. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 
    Google Scholar
  • 9d Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem.-Eur. J.  2000,  6:  3321 
    Google Scholar
  • 10 Janvier P. Bienaymé H. Zhu J. Angew. Chem. Int. Ed.  2002,  41:  4291 
    CrossrefPubMedGoogle Scholar
  • 16a

    X-ray single crystal structure determination of compound 4u′. Crystal data: C19H21N3O, M r = 307.39, colorless crystal, 0.46 × 0.61 × 0.79 mm3, orthorhombic, space group P212121 (No. 19), a = 6.1962(1), b = 11.8249(1), c = 22.9857(2) Å, V = 1684.15(3) Å3, Z = 4, ρcalcd = 1.212 g cm-3, F(000) = 656, µ (Mo-K α) = 0.077 mm-1, T = 173 K. Data collection: Nonius MACH3 κ-axis CCD-diffractometer, Mo-Kα radiation (λ = 0.71073 Å), unit cell parameters by least-squares for 1827 reflections. A total of 29452 reflections were integrated [16b] and scaled. [16c] After merging (R int = 0.029) 3076 [2974: I o>2σ(I o)] independent reflections remained and all were used to refine 292 parameters. Structure solution and refinement: The structure was solved by a combination of direct methods [16d] and difference-Fourier syntheses. [16e] All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were found and refined with individual isotropic displacement parameters. Full-matrix least-squares refinements were carried out by minimizing Σw(F o 2-F c 2) [2] and converged with R1 = 0.0273 [I o>2σ(I o)], wR2 = 0.0686 [all data], GOF = 1.084 and shift/error <0.001. As indicated by Flack’s parameter ε = 0.3(11) the correct enantiomer could not be assigned reliably by diffraction methods. Thermal ellipsoids the ORTEP-style representation of the molecular structures of compound 4u′ in the solid state are drawn are at the 50% probability level. [16f] Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-223310 (4u′). Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: (internat.) +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
    Crossref
  • 16b

    Data Collection Software for Nonius KappaCCD, Delft, The Netherlands, 2001.
    Crossref
  • 16c Otwinowski Z. Minor W. Methods Enzymol.  1997,  276:  307 
    CrossrefGoogle Scholar
  • 16d Altomare A. Cascarano G. Giacovazzo C. Guagliardi A. Burla MC. Polidori G. Camalli M. J. Appl. Crystallogr.  1994,  27:  435 
    CrossrefGoogle Scholar
  • 16e Sheldrick GM. SHELXL-97   University of Göttingen; Göttingen, Germany: 1998. 
    CrossrefGoogle Scholar
  • 16f Spek AL. ‘Platon’: A Multipurpose Crystallographic Tool   Utrecht University; Utrecht, The Netherlands: 2001. 
    CrossrefGoogle Scholar
  • 17a Klingler O. Matter H. Schudok M. Bajaj SP. Czech J. Lorenz M. Nestler HP. Schreuder H. Wildgoose P. Bioorg. Med. Chem. Lett.  2003,  13:  1463 
    CrossrefGoogle Scholar
  • 17b TOTU: O-[(Ethoxycarbonyl)-cyanmethylenamino]-N,N,N′,N′-tetramethyluronium-tetrafluoroborat: König W. Proc. Eur. Pept. Symp. 21st   Leiden; Netherlands: 1991.  p.143 
    CrossrefGoogle Scholar
11

General Procedure: To a stirred suspension of the amino acid amide hydrochloride 1 (2 mmol) and aldehyde 2 (2 mmol) in MeOH (4mL) and Et3N (2 mmol) was added. After 15 min the isocyanide 3 (2 mmol) and glacial acetic acid (2 mmol) were given to the reaction mixture. The solution was stirred overnight, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (H2O/MeOH gradient).

12

Spectral data for compound 4a: 1H NMR (400 MHz, CD3OD): δ = 2.73 (s, 3 H, CH3), 3.50 and 3.60 (AB, 2 H, 2 J A,B = 17.6 Hz, CH2CN), 4.36 (s, 1 H, CH), 7.31-7.44 (m, 5 H, Ar-H’s). 13C NMR (100 MHz, CD3OD, DEPT, HSQC): δ = 26.34 (CH3), 35.70 (CH2CN), 66.98 (CH), 118.81 (CN), 128.85 and 129.86 (Ar-C-o,m), 129.54 (Ar-C-p), 139.17 (Ar-C-ipso), 174.25 (CONHCH3). ESI-MS: C11H13N3O (203.24) m/z = 204.1 [M + H]+, 226.1 [M + Na]+.

13

Spectral data for compound 4b: 1H NMR (400 MHz, DMSO-d 6): δ = 3.46 and 3.58 (AB, 2 H, 2 J = 14.8 Hz, CH2Ph), 3.43 and 3.67 (AB of ABX, 2 H, 2 J A,B = 15.4 Hz, 3 J A,X = 6.0 Hz, 3 J B,X = 6.0 Hz, CH2CN), 7.12-7.45 (m, 10 H, Ar-H’s), 8.67 (X of ABX, 1 H, 3 J A,X;B,X = 6.0 Hz, NHCH2CN). 13C NMR (100 MHz, DMSO-d 6, DEPT, gHSQC): δ = 35.56 (CH2Ph), 42.77 (CH2CN), 65.58 (CH), 119.34 (CN), 127.41 and 128.46 (Ar-C-p), 127.74, 128.18, 128.87, 129.01 (Ar-C-o,m), 139.37 and 139.92 (Ar-C-ipso), 171.36 (CO). ESI-MS: C17H17N3O (279.34) m/z = 280.2 [M + H]+, 302.1 [M + Na]+.

14

Spectral data for compound 4u′ (minor diastereoisomer, S,S-configuration): [α]D -44.6 (c 1.0 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.03 (broad s, 1 H, NH), 2.32 (s, 3 H, CH3), 2.51 (d, 3 H, 3 J = 4.6 Hz, NHCH3), 2.94 and 3.14 (AB of ABX, 2 H, 2 J A,B = 13.6 Hz, 3 J A,X = 4.9 Hz, 3 J B,X = 8.9 Hz, CHCH2Ph), 3.67 (X of ABX, 1 H, CHCH2Ph), 4.38 (s, 1 H, CH), 6.17 (broad s, 1 H, NH), 7.12-7.41 (m, 9 H, Ar-H’s). 13C NMR (100 MHz, CDCl3): δ = 21.08 (CH3), 25.92 (CONHCH3), 39.89 (CH2), 50.67 (CHCN), 65.24 (CHCONH), 119.46 (CN), 127.09 (Ar-C), 127.64 (Ar-C), 128.79 (Ar-C), 129.43 (Ar-C), 129.65 (Ar-C), 134.90 (Ar-C), 135.37 and 138.49 (Ar-C-ipso), 170.96 (CO). IR(solid): 2221 (CN) cm-1. ESI-MS: C19H21N3O (307.40) m/z = 308.1 [M + H]+, 330.0 [M + Na]+.

15

Spectral data for compound 4y: 1H NMR (400 MHz, CD3OD): δ = 0.93 (d, 3 H, 3 J = 7.2 Hz, CH3), 0.97 (d, 3 H, 3 J = 6.8 Hz, CH3), 1.90-1.99 (m, 1 H, CH), 3.02 (d, 1 H, 3 J = 5.2 Hz, CH), 3.43 and 3.67 (AB, 2 H, 2 J A,B = 17.2 Hz, CH2CN), 4.39 (s, 2 H, CH2Ph), 7.22-7.32 (m, 5 H, Ar-H’s). 13C NMR (100 MHz, CD3OD, DEPT, HSQC): δ = 17.46 (CH3), 18.59 (CH3), 31.62 [CH(CH3)2], 35.65 (CH2CN), 42.84 (CH2Ph), 67.56 (CH), 118.06 (CN), 127.13 (Ar-C-p), 127.64 and 128.38 (Ar-C-o,m), 138.81 (Ar-C-ipso), 173.97 (CONHCH3). ESI-MS: C14H19N3O (245.32) m/z = 246.2 [M + H]+, 268.2 [M + Na]+.