Download PDF
Synlett 2007(12): 1893-1896  
DOI: 10.1055/s-2007-984537
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of New Chiral 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazines from α-Amino Acid Derivatives under Mild Conditions

Debendra K. Mohapatra*, Pradip K. Maity, Rajesh G. Gonnade, Mukund S. Chorghade, Mukund K. Gurjar
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
e-Mail: dk.mohapatra@ncl.res.in;
Further Information

Publication History

Received 3 April 2007
Publication Date:
27 June 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

A practical and efficient regioselective synthesis of several new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is described from α-amino acid derivatives following intramolecular ‘click’ reaction as the key step. The method obviates product ­purification; to obtain the pure triazole products, only the solvent needs to be evaporated.

Key words

pyrazine - 1,2,3-triazole - α-amino acid - click chemistry - 1,3-dipolar cycloaddition

    References and Notes

  • 1 Dolle RE. Nelson KH. J. Comb. Chem.  1999,  1:  235 
    CrossrefPubMedGoogle Scholar
  • 2 Franzen RG. J. Comb. Chem.  2000,  2:  195 
    CrossrefGoogle Scholar
  • 3 Dolle RE. J. Comb. Chem.  2001,  3:  1 
    CrossrefGoogle Scholar
  • 4 Nicolaou KC. Pfefferkorn JA. Solid-Phase Synthesis of Natural Products and Natural Product-Like Libraries, In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials   Vol. 2:  Nicolaou KC. Hanko R. Hartwig W. Wiley-VCH; Weinheim: 2002.  p.611-642  
    Google Scholar
  • 5 Dolle RE. Solid-Phase Synthesis of Heterocyclic Systems (Heterocycles Containing One Heteroatom), In Handbook of Combinatorial Chemistry. Drugs, Catalysts, Materials   Vol. 2:  Nicolaou KC. Hanko R. Hartwig W. Wiley-VCH; Weinheim: 2002.  p.643-684  
    Google Scholar
  • 6 Pernestorfer J. In Molecular Design and Combinatorial Chemistry. Drugs, Catalysts, Materials   Vol. 2:  Nicolaou KC. Hanko R. Hartwig W. Wiley-VCH; Weinheim: 2002.  p.725-742  
    Google Scholar
  • 7 Dörwald FZ. Organic Synthesis on Solid Phase   2nd ed.:  Wiley-VCH; Weinheim: 2002.  p.1-504  
    Google Scholar
  • 8 Hanessian S. McNaughton-Smith G. Lombart H.-G. Lubell WD. Tetrahedron  1997,  53:  12789 
    CrossrefGoogle Scholar
  • 9a Norcross RD. Paterson I. Chem. Rev.  1995,  95:  2041 
    CrossrefGoogle Scholar
  • 9b Faulkner DJ. Nat. Prod. Rep.  2002,  19:  1 
    CrossrefGoogle Scholar
  • 9c Askin D. Eng KK. Rossen K. Purick RM. Wells KM. Volante RP. Reider PJ. Tetrahedron Lett.  1994,  35:  673 
    CrossrefGoogle Scholar
  • 9d Rossen K. Weissman SA. Sagar J. Reamer A. Askin DA. Volante RP. Reider PJ. Tetrahedron Lett.  1995,  36:  6419 
    CrossrefGoogle Scholar
  • 9e Dorsey BD. Levin RB. McDaniel SL. Vacca JP. Guare JP. Darke PL. Zugay JA. Emini EA. Schleif WA. Quintero JC. Lin JH. Chen I.-W. Holloway MK. Fitzgerald PMD. Axel MG. Ostovic D. Anderson PS. Huff JR. J. Med. Chem.  1994,  37:  3443 
    CrossrefGoogle Scholar
  • 9f Choudhary P. Kumar R. Verma K. Bioorg. Med. Chem.  2006,  14:  1819 
    CrossrefGoogle Scholar
  • 9g Upadhayaya RS. Sinha N. Jain S. Kishore N. Chandra R. Arora SK. Bioorg. Med. Chem.  2004,  12:  2225 
    CrossrefGoogle Scholar
  • 9h Kimura M. Masuda T. Yamada K. Kobuta N. Kawakatsu N. Mitani M. Kishi K. Inazu M. Namiki T. Bioorg. Med. Chem. Lett.  2002,  12:  1947 
    CrossrefGoogle Scholar
  • 9i Ryckebusch A. Poulain R. Maes L. Debreu-Fontaine M.-A. Mouray E. Grellier P. Sergheraert C. J. Med. Chem.  2003,  46:  542 
    CrossrefGoogle Scholar
  • 9j Yevich JP. New JS. Smith DW. Lobeck WG. Catt JD. Minielli JL. Eison MS. Taylor DP. Riblet LA. Temple DL. J. Med. Chem.  1986,  29:  359 
    CrossrefGoogle Scholar
  • 10a Alvarez R. Velazquez S. San-Felix A. Aquaro S. De Clercq E. Perno C.-F. Karlsson A. Balzarini J. Carmarasa MJ. J. Med. Chem.  1994,  37:  4185 
    Google Scholar
  • 10b Velaquez S. Alvarez R. Perez C. Gogo F. De C. Balzarini J. Carmarasa M. J. Antiviral Chem. Chemother.  1998,  9:  481 
    Google Scholar
  • 11 Brockunier LL. Parmee ER. Ok OH. Candelore MR. Cascieri MA. Collwel LF. Deng L. Feeney WP. Forest M.-J. Wyvratt MJ. Fisher MH. Weber ME. Bioorg. Med. Chem. Lett.  2000,  10:  2111 
    CrossrefGoogle Scholar
  • 12 Genin MJ. Allwine DA. Anderson DJ. Barbachyn MR. Emmert DE. Garmon SA. Graber DR. Grega KC. Hester JB. Hutchinson DK. Morris J. Reischer RJ. Ford CW. Zurenko GE. Hamel JC. Schaadt RD. Stapert D. Yagi BH. J. Med. Chem.  2000,  43:  953 
    CrossrefGoogle Scholar
  • 13a Buckle DR. Rockell CJM. J. Chem. Soc., Perkin Trans. 1  1982,  627 
    CrossrefGoogle Scholar
  • 13b Buckle DR. Outred DJ. Rockell CJM. Smith H. Spicer BA. J. Med. Chem.  1983,  26:  251 
    CrossrefGoogle Scholar
  • 13c Buckle DR. Rockell CJM. Smith H. Spicer BA. J. Med. Chem.  1986,  29:  2262 
    CrossrefGoogle Scholar
  • 14a Tullis JS. VanRens JC. Natchus MG. Clark MP. De B. Hsieh LC. Janusz MJ. Bioorg. Med. Chem. Lett.  2003,  13:  1665 
    Google Scholar
  • 14b Kim D.-K. Kim J. Park H.-J. Bioorg. Med. Chem. Lett.  2004,  14:  2401 
    Google Scholar
  • 15a Cunha AC. Figueiredo JM. Tributino JLM. Miranda ALP. Castro HC. Zingali RB. Fraga CAM. DeSouza MCBV. Ferreira VF. Barreiro EJ. Bioorg. Med. Chem.  2003,  11:  2051 
    CrossrefGoogle Scholar
  • 15b Dabak K. Seuer . Akar A. Anac O. Eur. J. Med. Chem.  2003,  215 
    CrossrefGoogle Scholar
  • 15c Tornoe CW. Sanderson SJ. Mottram JC. Coombs GH. Meldal M. J. Comb. Chem.  2004,  6:  312 
    CrossrefGoogle Scholar
  • 16a Dehne H. In Methoden der organischen Chemie (Houben-Weyl)   Vol. E8d:  Schaumann E. Thieme; Stuttgart: 1994.  p.305-405  
    Google Scholar
  • 16b Dehne H. In Methoden der organischen Chemie (Houben-Weyl)   Vol. E8d:  Schaumann E. Thieme; Stuttgart: 1994.  p.406-478  
    Google Scholar
  • 16c Tome AC. Science of Synthesis   Vol. 13:  Storr RC. Gilchrist TL. Thieme; Stuttgart: 2004.  p.415 
    Google Scholar
  • 16d Fan W.-Q. Katritzky AR. In Comprehensive Heterocyclic Chemistry II   Vol. 4:  Katritzky AR. Rees CR. Scriven EFV. Pergamon; Oxford: 1996.  p.1-126  
    Google Scholar
  • 16e Willis RJ, and Marlow ID. inventors; EP  400842.  ; Chem. Abstr. 1991, 114, 164247b
  • 17a Fuks R. Viehe HG. In Chemistry of Acetylenes   Viehe HG. Marcel Dekker; New York: 1969.  p.425-593  
    Google Scholar
  • 17b Bastide J. Henri-Rousseau O. In The Chemistry of the Carbon-Carbon Triple Bond   Patai S. Interscience Publishers; London: 1978.  p.447-552  
    Google Scholar
  • 18a Huisgen R. In 1,3-Dipolar Cycloaddition Chemistry   Padwa A. Wiley; New York: 1984.  p.1-176  
    CrossrefGoogle Scholar
  • 18b Kolb HC. Sharpless KB. Drug Discovery Today  2003,  8:  1128 
    CrossrefGoogle Scholar
  • 18c Biagi G. Giorgi I. Livi O. Scartoni V. Betti L. Giannaccini G. Trincavelli ML. Eur. J. Med. Chem.  2002,  565 ; and references therein
    CrossrefGoogle Scholar
  • 19a Mohapatra DK. Datta A. Synlett  1996,  1129 
    CrossrefGoogle Scholar
  • 19b Mohapatra DK. Datta A. Bioorg. Med. Chem. Lett.  1997,  7:  2527 
    CrossrefGoogle Scholar
  • 19c Gurjar MK. Pal S. Mohapatra DK. Heterocycles  1999,  50:  109 
    CrossrefGoogle Scholar
  • 19d Mohapatra DK. Synth. Commun.  1999,  29:  4261 
    CrossrefGoogle Scholar
  • 19e Mohapatra DK. Datta A. J. Org. Chem.  1999,  64:  6879 
    CrossrefGoogle Scholar
  • 19f Karmakar S. Mohapatra DK. Synlett  2001,  1326 
    CrossrefGoogle Scholar
  • 19g Mohapatra DK. J. Chem. Soc., Perkin Trans. 1  2001,  1851 
    CrossrefGoogle Scholar
  • 19h Gurjar MK. Karmakar S. Mohapatra DK. Phalgune D. Tetrahedron Lett.  2002,  43:  1897 
    CrossrefGoogle Scholar
  • 19i Mohapatra DK. Mondal D. Gonnade RG. Chorghade MS. Gurjar MK. Tetrahedron Lett.  2006,  47:  6031 
    CrossrefGoogle Scholar
  • 19j Mohapatra DK. Mondal D. Chorghade MS. Gurjar MK. Tetrahedron Lett.  2006,  47:  9215 
    CrossrefGoogle Scholar
  • 20 McKennon MJ. Meyers AI. J. Org. Chem.  1993,  58:  3568 
    CrossrefGoogle Scholar
  • 21 Rawal VH. Cava MP. Tetrahedron Lett.  1985,  26:  6141 
    CrossrefGoogle Scholar
  • 24 Sheldrick GM. SHELX-97 Program for Crystal Structure Solution and Refinement   University of Göttingen; Germany: 1997. 
    Google Scholar
22

Analytical and Spectral Data
Compound 3a: [α]D 25 -47.76 (c 1.2, CHCl3). IR (CHCl3): 3023, 1696, 1497, 1223 cm-1. 1H NMR (200 MHz, CDCl3): δ = 0.92 (d, 3 H, J = 6.6 Hz), 0.99 (d, 3 H, J = 6.5 Hz), 1.50 (s, 9 H), 1.53-1.65 (m, 1 H), 4.22 (dd, 1 H, J = 14.0, 4.5 Hz), 4.33 (m, 2 H), 4.76 (d, 1 H, J = 12.5 Hz), 5.13 (m, 1 H), 7.53 (s, 1 H). 13C NMR (50 MHz, CDCl3): δ = 18.7, 19.5, 26.6, 27.8, 36.1, 46.3, 54.3, 55.6, 80.6, 128.6, 128.9, 153.8. ESI-MS: m/z = 267 [M + H]+. Anal. Calcd (%) for C13H22N4O2: C, 58.62; H, 8.33; N, 21.04. Found: C, 58.51; H, 8.47; N, 20.88.
Compound 3c: [α]D 25 -40.21 (c 1.1, CHCl3). IR (CHCl3): 2980, 1697, 1395, 1218, 1167 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.16 (d, 3 H, J = 7.3 Hz), 1.51 (s, 9 H), 4.32-4.37 (m, 2 H), 4.47 (d, 1 H, J = 13.2 Hz), 4.92 (m, 1 H), 5.07 (d, 1 H, J = 17.4 Hz), 7.56 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 15.7, 28.1, 36.1, 45.0, 50.1, 81.0, 128.9, 129.1, 153.7. ESI-MS: m/z = 239 [M + H]+, 261 [M + Na]+. Anal. Calcd (%) for C11H18N4O2: C, 55.45; H, 7.61; N, 23.51. Found: C, 55.67; H, 7.69; N, 23.42.
Compound 3d: [α]D 25 -30.74 (c 0.95, CHCl3). IR (CHCl3): 3020, 1703, 1508, 1407, 1215 cm-1. 1H NMR (500 MHz, CDCl3): δ = 0.84 (d, 3 H, J = 6.5 Hz), 0.87 (d, 3 H, J = 6.4 Hz), 1.06-1.12 (m, 1 H), 1.25-1.31 (m, 1 H), 1.40 (s, 9 H), 1.43-1.48 (m, 1 H), 4.12 (d, 1 H, J = 17.6 Hz), 4.21 (dd, 1 H, J = 12.8, 4.8 Hz), 4.36 (d, 1 H, J = 12.8 Hz), 4.72 (m, 1 H), 5.04 (d, 1 H, J = 17.6 Hz), 7.41 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 21.9, 22.6, 24.7, 28.1, 35.9, 38.6, 47.3, 49.1, 80.9, 128.7, 128.9, 153.7. ESI-MS: m/z = 281 [M + H]+, 303 [M + Na]+. Anal. Calcd (%) for C14H24N4O2: C, 59.98; H, 8.63; N, 19.98. Found: C, 59.87; H, 8.71; N, 19.76.
Compound 3i: [α]D 25 +98.54 (c 1.1, CHCl3). IR (CHCl3): 3020, 1508, 1409, 1215 cm-1. 1H NMR (500 MHz, CDCl3): δ = 1.61-1.69 (m, 1 H), 1.92-2.05 (m, 2 H), 2.10-2.17 (m, 1 H), 2.36 (q, 1 H, J = 8.8 Hz), 2.68 (m, 1 H), 3.24-3.27 (ddd, 1 H, J = 8.81, 7.5, 2.8 Hz), 3.38 (d, 1 H, J = 14.6 Hz), 3.95 (dd, 1 H, J = 12.5, 10.6 Hz), 4.29 (d, 1 H, J = 14.6 Hz), 4.68 (dd, 1 H, J = 12.5, 3.9 Hz), 7.42 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 22.2, 27.5, 46.8, 51.2, 53.3, 59.6, 128.4, 131.8. ESI-MS: m/z = 165 [M + H]+, 187 [M + Na]+. Anal. Calcd (%) for C8H12N4: C, 58.52; H, 7.37; N, 34.12. Found: C, 58.37; H, 7.11; N, 33.98.

23

X-ray intensity data was collected on Bruker SMART APEX CCD diffractometer with graphite-monochromated (MoKα = 0.71073 Å) radiation at r.t. All the data were corrected for Lorentzian, polarization and absorption effects using Bruker’s SAINT and SADABS programs. SHELX-97 (ShelxTL) [25] was used for structure solution and full matrix least squares refinement on F 2. Hydrogen atoms were included in the refinement as per the riding model.

25

Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 633496 for 3i. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(1223)336033; or e-mail: deposit@ccdc.cam.ac.uk].