PDF herunterladen
Synlett 2010(9): 1397-1401  
DOI: 10.1055/s-0029-1219818
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives

Juraj Velcicky*, Daniel Pflieger
Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland
Fax: +41(61)3248847; e-Mail: juraj.velcicky@novartis.com;
Weitere Informationen

Publikationsverlauf

Received 23 January 2010
Publikationsdatum:
13. April 2010 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

Abstract

Synthesis of novel 3-chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives using sequential ortho-formylation/ortho-allylation reactions of 2-chloro-3-fluoropyridine and ring-closing metathesis is described.

Key words

ortho-lithiation - ring-closing metathesis - fluoro pyridine - isoquinolinone - fused-ring system

    References and Notes

  • 1a Hagmann WK. J. Med. Chem.  2008,  51:  4359 
    Google Scholar
  • 1b Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev.  2008,  37:  320 
    Google Scholar
  • 1c Kirk KL. J. Fluorine Chem.  2006,  127:  1013 
    Google Scholar
  • 1d Isanbor C. O’Hagan D.
    J. Fluorine Chem.  2006,  127:  303 
    Google Scholar
  • 1e Böhm H.-J. Banner D. Bendels S. Kansy M. Kuhn B. Müller K. Obst-Sander U. Stahl M. ChemBioChem  2004,  5:  637 
    Google Scholar
  • 2 Olsen JA. Banner DW. Seiler P. Obst-Sander U. D’Arcy A. Stihle M. Müller K. Diederich F. Angew. Chem. Int. Ed.  2003,  42:  2507 
    CrossrefGoogle Scholar
  • 3a Morgenthaler M. Schweizer E. Hoffmann-Röder A. Benini F. Martin RE. Jaeschke G. Wagner B. Fischer H. Bendels S. Zimmerli D. Schneider J. Diederich F. Kansy M. Müller K. ChemMedChem  2007,  2:  1100 
    Google Scholar
  • 3b Schlosser M. Angew. Chem. Int. Ed.  1998,  37:  1496 
    Google Scholar
  • 4 Bégué J.-P. Bonnet-Delpon D. ChemMedChem  2007,  2:  608 
    CrossrefGoogle Scholar
  • 5 Barker AJ. Gibson KH. Grundy W. Godfrey AA. Barlow JJ. Healy MP. Woodburn JR. Ashton SE. Curry BJ. Scarlett L. Henthorn L. Richards L. Bioorg. Med. Chem. Lett.  2001,  11:  1911 
    CrossrefGoogle Scholar
  • 6a Lardenois P. Frost J. Dargazanli G. George P. Synth. Commun.  1996,  26:  2305 
    Google Scholar
  • 6b Nicolaou KC. Baran PS. Zhong Y.-L. J. Am. Chem. Soc.  2001,  123:  3183 
    Google Scholar
  • 7a Caprathe BW. Jaen JC. Wise LD. Heffner TG. Pugsley TA. Meltzer LT. Parvez M. J. Med. Chem.  1991,  34:  2736 
    Google Scholar
  • 7b Chan L. Stefanac T. Turcotte N. Hu Z. Chen Y. Bédard J. May S. Jin H. Bioorg. Med. Chem. Lett.  2000,  10:  1477 
    Google Scholar
  • 7c Hsin L.-W. Chang L.-T. Liou H.-L. Synlett  2008,  2299 
    Google Scholar
  • 8a Kirk KL. Org. Process Res. Dev.  2008,  12:  305 
    Google Scholar
  • 8b Singh RP. Shreeve JM. Acc. Chem. Res.  2004,  37:  31 
    Google Scholar
  • 8c Watson DA. Su M. Teverovskiy G. Zhang Y. García-Fortanet J. Kinzel T. Buchwald SL. Science  2009,  325:  1661 
    Google Scholar
  • 9a Schlosser M. Synlett  2007,  3076 
    Google Scholar
  • 9b Gros P. Fort Y. Eur. J. Org. Chem.  2002,  3375 
    Google Scholar
  • 9c Mongin F. Quéguiner G. Tetrahedron  2001,  57:  4059 
    Google Scholar
  • 9d Marsais F. Queguiner G. Tetrahedron  1983,  39:  2009 
    Google Scholar
  • 10a Deiters A. Martin SF. Chem. Rev.  2004,  104:  2199 
    Google Scholar
  • 10b Schuster M. Blechert S. Angew. Chem. Int. Ed. Engl.  1997,  36:  2036 
    Google Scholar
  • 10c Brown RCD. Satcharoen V. Heterocycles  2006,  70:  705 
    Google Scholar
  • Recent examples on ortho-fluoro lithiation, see:
  • 11a Humphries AC. Gancia E. Gilligan MT. Goodacre S. Hallett D. Merchant KJ. Thomas SR. Bioorg. Med. Chem. Lett.  2006,  16:  1518 
    Google Scholar
  • 11b Bobbio C. Schlosser M.
    J. Org. Chem.  2005,  70:  3039 
    Google Scholar
  • 11c Marzi E. Bobbio C. Cottet F. Schlosser M. Eur. J. Org. Chem.  2005,  10:  2116 
    Google Scholar
  • 11d Ondi L. Volle J.-N. Schlosser M. Tetrahedron  2005,  61:  717 
    Google Scholar
  • 12 Balasubramaniam S. Aidhen IS. Synthesis  2008,  3707 
    Artikel in Thieme ConnectGoogle Scholar
  • 13a Snieckus V. Chem. Rev.  1990,  90:  879 
    Google Scholar
  • 13b Epsztajn J. JóŸwiak A. Szcześniak AK. Curr. Org. Chem.  2006,  10:  817 
    Google Scholar
  • 13c Azzouz R. Bischoff L. Fruit C. Marsais F. Synlett  2006,  1908 
    Google Scholar
  • 14a Townsend CA. Bloom LM. Tetrahedron Lett.  1981,  22:  3923 
    Google Scholar
  • 14b Stagliano KW. Malinakova HC. Tetrahedron Lett.  1998,  39:  4941 
    Google Scholar
  • 15a Comins DL. Synlett  1992,  615 
    Google Scholar
  • 15b Comins DL. Baevsky MF. Hong H. J. Am. Chem. Soc.  1992,  114:  10971 
    Google Scholar
  • 15c Josien H. Ko S.-B. Bom D. Curran DP. Chem. Eur. J.  1998,  4:  67 
    Google Scholar
  • 16a Luo S. Fang F. Zhao M. Zhai H. Tetrahedron  2004,  60:  5353 
    Google Scholar
  • 16b Bjoerk P. Aakermann T. Hoernfeldt A.-B. Gronowitz S. J. Heterocycl. Chem.  1995,  32:  751 
    Google Scholar
  • 19a Uma R. Crévisy C. and Grée R. Chem. Rev.  2003,  103:  27 
    Google Scholar
  • 19b Xu M. Vasella A. Helv. Chim. Acta  2006,  89:  1140 
    Google Scholar
  • 19c Wang PX. White CR. WO 2005/047291 A1
17

Preparation of compound 15: t-BuLi (1.7 m in heptane, 14.1 mL, 24 mmol) was added within 15 min to a solution of 2-chloro-3-fluoropyridine (3 g, 22.8 mmol) in anhydrous THF (70 mL) at -78 ˚C. After stirring for 1 h at -78 ˚C, N-formyl-l-N,N′,N′-trimethylethylene-1,2-diamine (3.21 g, 24 mmol) was added slowly and the reaction mixture was left to warm to -40 ˚C, followed by addition of n-BuLi (1.6 m in hexane, 21.4 mL, 34.2 mmol). The red-brown solution was stirred for 3 h at -30 ˚C before CuBr (4.25 g, 29.6 mmol) was added. The reaction mixture was then allowed to reach 0 ˚C and was stirred at this temperature for 1 h. After cooling back to -30 ˚C, a solution of allylbromide (3.1 mL, 36.5 mmol) in anhydrous THF (50 mL) was added. After stirring for 1 h at -10 ˚C, the mixture was quenched by addition of sat. aq NH4Cl, filtered over Hyflo® and rinsed with diethyl ether. The organic layer was then washed with sat. aq NH4Cl and brine. After drying over Na2SO4 and filtration, the mixture was concentrated under vacuum. The crude mixture was further purified by gradient MPLC (ethyl acetate-cyclohexane, 5→15%), followed by a second MPLC (diethyl ether-cyclohexane, 10→15%) to provide the product 15 (1.85 g, 41%) as a yellow oil. Spectral data for compound 15: ¹H NMR (500 MHz, DMSO-d 6): δ = 10.31 (s, 1 H), 8.32 (s, 1 H), 5.97 (m, 1 H), 5.07 (dd, J = 10.2, 1.5 Hz, 1 H), 5.00 (dd, J = 17.2, 1.6 Hz, 1 H), 3.72 (d, J = 6.3 Hz, 2 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 187.6, 153.0 (d, J C,F = 268 Hz), 146.3 (d, J C,F = 7 Hz), 136.4 (d, J C,F = 20 Hz), 135.2, 128.8 (d, J C,F = 6 Hz), 116.6, 32.2; ESI-HRMS: m/z [M + H]+ calcd for C9H8ClFNO: 200.0278; found: 200.0274.

18

Grubbs’ catalysts I and II and Grignard reagents were purchased from Aldrich Co. and used as obtained

20

Characterization of final compounds. 5a: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.40 (s, 1 H), 2.97 (t, J = 6.1 Hz, 2 H), 2.66 (t, J = 6.3 Hz, 2 H), 2.06 (m, 2 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 193.6, 150.5 (d, J C,F = 273 Hz), 145.1 (d, J C,F = 8 Hz), 139.5, 135.8 (d, J C,F = 20 Hz), 126.9, 39.3, 25.0, 21.5; ESI-HRMS: m/z [M + H]+ calcd for C9H8ClFNO: 200.0278; found: 200.0274; 5b: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.38 (s, 1 H), 3.03 (m, 2 H), 2.77 (m, 1 H), 2.14 (m, 1 H), 1.84 (m, 2 H), 1.12 (d, J = 6.6 Hz, 3 H); ¹³C NMR (125 MHz, DMSO-d 6): δ = 197.1, 151.2 (d, J C,F = 274 Hz), 145.9 (d, J C,F = 8 Hz), 140.0, 136.4 (d, J C,F = 20 Hz), 127.5, 42.9, 29.8, 24.7, 14.8; ESI-HRMS: m/z [M + H]+ calcd for C10H9ClFNO: 214.0430; found: 214.0431; 5c: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.26 (s, 1 H), 2.86 (m, 2 H), 2.75 (m, 2 H), 1.79 (m, 4 H); ¹³C NMR (125 MHz, DMSO-d 6): δ = 201.6, 149.4 (d, J C,F = 264 Hz), 145.1, 136.3 (d, J C,F = 20 Hz), 135.9 (d, J C,F = 11 Hz), 135.1, 41.5, 28.3, 24.7, 22.3; ESI-HRMS: m/z [M + H]+ calcd for C10H10ClFNO: 214.0430; found: 214.0430; 5d: ¹H NMR (500 MHz, DMSO-d 6): δ = 8.26 (s, 1 H), 2.91 (m, 1 H), 2.83 (m, 1 H), 2.71 (m, 1 H), 2.65 (m, 1 H), 2.02 (m, 1 H), 1.90 (m, 1 H), 1.48 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H); ¹³C NMR (100 MHz, DMSO-d 6): δ = 198.9, 148.5 (d, J C,F = 263 Hz), 144.5 (d, J C,F = 6 Hz), 135.6, 135.5, 135.1, 49.2, 33.1, 30.1, 27.5, 21.3; ESI-HRMS: m/z [M + H]+ calcd for C11H12ClFNO: 228.0586; found: 228.0586