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Synlett 2008(5): 645-648  
DOI: 10.1055/s-2008-1032106
LETTER
© Georg Thieme Verlag Stuttgart · New York

Expedient Entry into 1,4-Dihydroquinoxalines and Quinoxalines via a Novel Variant of Isocyanide-Based MCR

Mikhail Krasavin*,, Vladislav Parchinsky
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 114401, Russia
Fax: +7(495)9954942; e-Mail: myk@chemdiv.com;
Further Information

Publication History

Received 12 September 2007
Publication Date:
26 February 2008 (online)

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Abstract

A novel multicomponent reaction of o-phenylenediamines with aldehydes and isonitriles yields 1,4-dihydroquinoxalines. These intermediates are unstable under reaction conditions. They undergo oxidation with DDQ to furnish 33-54% isolated yields of the respective quinoxalines. This reaction is general for aromatic 1,2-diamines. Monoalkylated aryl 1,2-diamines lead to stable 1,4-dihydroquinoxalines.

Key words

combinatorial chemistry - dehydrogenations - multicomponent reactions - isocyanides - quinoxalines

    References and Notes

  • 2 Dömling A. Chem. Rev.  2006,  106:  17 
    CrossrefPubMedGoogle Scholar
  • 3 Groebke K. Weber L. Mehlin F. Synlett  1998,  661 
    Article in Thieme ConnectGoogle Scholar
  • 4 Bienaymé H. Bouzid K. Angew. Chem. Int. Ed.  1998,  37:  2234 
    CrossrefPubMedGoogle Scholar
  • 5 Ilyn AP. Loseva MV. Vvedensky VY. Putsykina EB. Tkachenko SE. Kravchenko DV. Khvat AV. Krasavin MY. Ivachtchenko AV. J. Org. Chem.  2006,  71:  2811 
    CrossrefGoogle Scholar
  • 6 Mironov MA. Ivantsova MN. Mokrushin VS. Mol. Diversity  2003,  6:  193 
    Google Scholar
  • 7a Pirrung MC. Das Sharma K. J. Am. Chem. Soc.  2004,  126:  444 
    CrossrefPubMedGoogle Scholar
  • 7b Kanizsai I. Gyónfalvi S. Szakonyi Z. Sillanpää R. Fülöp F. Green Chem.  2007,  9:  357 
    CrossrefPubMedGoogle Scholar
  • 8 Parchinsky VZ. Shuvalova O. Ushakova O. Kravchenko DV. Krasavin M. Tetrahedron Lett.  2006,  47:  947 
    CrossrefGoogle Scholar
  • 9 Parchinsky VZ. Koleda VV. Shuvalova O. Kravchenko DV. Krasavin M. Tetrahedron Lett.  2006,  47:  6891 
    CrossrefGoogle Scholar
  • 10a One example of an aliphatic diamine participating in the intramolecular Ugi-type MCR has been reported in: Keung W. Bakir F. Patron AP. Rogers D. Priest CD. Darmohusodo V. Tetrahedron Lett.  2004,  45:  733 
    CrossrefGoogle Scholar
  • 10b An account of the use of ethylene diamines appeared in print when the present manuscript was in preparation: Kysil V. Tkachenko S. Khvat A. Williams C. Tsirulnikov S. Churakova M. Ivachtchenko A. Tetrahedron Lett.  2007,  48:  6239 
    CrossrefGoogle Scholar
  • 11a

    One of the redundant byproducts was identified as 2-(R1)-substituted benzimidazole, presumably formed from the oxidative cyclization of the intermediate aldimine. This observation is in accordance with our previous results, see ref. 11b. The unwanted benzimidazole formation could be minimized by thorough exclusion of air from the reaction medium.
  • 11b Krasavin M. Kobak VV. Bondarenko TY. Kravchenko DV. Heterocycles  2005,  65:  2189 
    Google Scholar
  • 14 Loriga M. Fiore M. Sanna P. Paglietti G. Il Farmaco  1995,  50:  289 
    Google Scholar
  • 15 Ding S. Gray NS. Wu X. Ding Q. Schultz PG. J. Am. Chem. Soc.  2002,  124:  1594 
    CrossrefPubMedGoogle Scholar
  • 19 Kajiki T. Moriya H. Hoshino K. Kuroi T. Kondo S. Nabeshima T. Yano Y. J. Org. Chem.  1999,  61:  9679 
    Google Scholar
  • 20 Linden AA. Johansson M. Hermanns N. Bäckvall J.-E. J. Org. Chem.  2006,  71:  3849 
    CrossrefGoogle Scholar
1

New address: M. Krasavin, Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada.

12

Analytical Data for Selected CompoundsCompound 5b: pale yellow solid, mp 156-157ºC. 1H NMR (300 MHz, DMSO-d 6): δ = 7.50-7.59 (m, 7 H), 7.21-7.31 (m, 5 H), 6.34 (s, 1 H, NH), 3.64 (unresolved dd, 2 H, NHCH2), 2.93 (unresolved t, 2 H, NHCH2CH2), 2.37 (s, 3 H), 2.33 (s, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 150.0, 145.7, 140.3, 140.1, 139.6, 137.3, 135.5, 133.5, 129.6, 129.2 (two signals overlapped), 128.9, 128.8, 128.2, 126.4, 125.7, 42.9, 34.7, 20.2, 19.7. LCMS: m/z = 354 [M + 1]. HRMS (EI): m/z calcd for C24H23N3: 353.4710; found: 353.4711.Compound 5g: grey solid, mp 203 °C (decomp.). 1H NMR (400 MHz, DMSO-d 6): δ = 12.95 (br s, 1 H, COOH), 8.33 (d, J = 1.5 Hz, 1 H), 8.04 (dd, J = 8.6, 1.8 Hz, 1 H), 7.74 (m, 2 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.55 (m, 3 H), 6.61 (d, J = 6.6 Hz, 1 H, NH), 4.46 (m, 1 H, NHCH), 2.00 (m, 2 H), 1.65 (m, 2 H), 1.54 (m, 4 H). 13C NMR (75 MHz, DMSO-d 6): δ = 167.5 (COOH), 150.9, 148.2, 144.3, 136.7, 135.6, 130.8, 130.1, 129.8, 129.3, 128.9, 126.1, 125.8, 52.9, 32.2, 24.0. LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd for C20H19N3O2: 333.3933; found: 333.3932.Compound 5h: yellow sticky solid, mp 68-69 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 7.86 (dd, J = 3.8, 0.9 Hz, 1 H), 7.83 (dd, J = 5.1, 0.9 Hz, 1 H), 7.78 (dd, J = 8.2, 1.1 Hz, 1 H), 7.62 (dd, J = 8.4, 1.1 Hz, 1 H), 7.55 (ddd, J = 8.4, 6.8, 1.1 Hz, 1 H), 7.37 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.27 (dd, J = 5.1, 3.8 Hz, 1 H), 6.87 (t, J = 5.3 Hz, NHCH2), 3.70 (dt, J d = 5.3, J t = 5.1 Hz, 2 H, NHCH2), 3.62 (t, J = 5.1 Hz, 2 H, MeOCH2), 3.31 (s, 3 H, OCH3). 13C NMR (75 MHz, DMSO-d 6): δ = 149.4, 140.9, 140.8, 140.0, 136.4, 130.3, 130.0, 128.7, 128.4, 128.2, 125.9, 124.8, 70.3, 58.4, 40.7. LCMS: m/z = 286 [M + 1]. HRMS (EI): m/z calcd for C15H15N3OS: 285.3703; found: 285.3703.

13

Crystallographic data (excluding structure factors) for the structure 5b have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 671798. 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].

16

Characterization Data for 8Brown oil. 1H NMR (300 MHz, DMSO-d 6): δ = 8.79 (dd, J = 5.1, 1.8 Hz, 1 H), 8.50 (d, J = 7.3 Hz, 1 H), 7.73 (br s, 1 H, NH), 7.64 (m, 2 H), 7.53-7.59 (m, 4 H), 7.28-7.35 (m, 4 H), 7.22 (m, 1 H), 3.72 (dd, J = 14.2, 7.2 Hz, 2 H, NHCH2CH2), 2.98 (t, J = 7.2 Hz, 2 H, NHCH2CH2). 13C NMR (75 MHz, DMSO-d 6): δ = 158.4, 151.6, 147.0, 142.1, 136.7, 135.0, 134.9, 133.6, 130.1, 129.6, 128.5, 127.9, 127.2, 126.4, 125.8, 43.6, 35.2. LCMS: m/z = 327 [M + 1]. HRMS (EI): m/z calcd for C21H18N4: 326.4044; found: 326.4047.

17

Characterization Data for 10Off-white solid, mp 110-112 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 7.24 (m, 3 H), 7.15 (m, 2 H), 6.86 (m, 1 H), 6.83 (m, 1 H), 6.72 (ddd, J = 7.6, 7.5, 1.6 Hz, 1 H), 6.53 (dd, J = 7.5, 1.6 Hz, 1 H), 5.47 (s, 1 H, dihydroquinaxoline-NH), 4.24 (br s, 1 H, NH-cycloC 7H13), 3.52 (s, 3 H, NCH3), 3.48 (m, 1 H, NHCH), 1.72-1.82 (m, 2 H), 1.44-1.67 (m, 8 H), 1.18-1.35 (m, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 149.8, 140.5, 132.1, 132.0, 128.8, 127.7, 126.4, 120.3, 119.9, 114.5, 113.0, 58.7, 53.4, 37.2, 36.6, 30.6, 28.3, 28.1, 24.7, 24.5. LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd for C22H27N3: 333.4806; found: 333.4803.

18

Characterization Data for 12Brown viscous oil. 1H NMR (400 MHz, DMSO-d 6): δ = 8.33 (dd, J = 4.9, 1.3 Hz, 1 H), 7.89 (dd, J = 7.6, 1.3 Hz, 1 H), 7.56 (m, 2 H), 7.51 (m, 3 H), 7.07 (dd, J = 4.9, 7.6 Hz, 1 H), 4.55 (t, J = 6.3 Hz, 2 H, MeOCH2), 3.65 (t, J = 6.3 Hz, 2 H, NHCH2), 3.30 (s, 3 H, OCH3), 3.24 (m, 1 H, NHCH), 1.44 (m, 2 H), 1.30-1.40 (m, 6 H), 1.21 (m, 2 H), 0.95 (m, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 154.2, 149.0, 146.1, 139.8, 139.5, 136.1, 130.0, 129.0, 127.4, 117.1, 114.2, 68.3, 58.4, 58.0 (one signal obscured by DMSO sept). LCMS: m/z = 379 [M + 1]. HRMS (EI): m/z calcd for C23H30N4O: 378.5218; found: 378.5221.