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Synlett 2007(7): 1169-1171  
DOI: 10.1055/s-2007-977424
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© Georg Thieme Verlag Stuttgart · New York

Radical 6-endo-trig Cyclization of β,β-Difluoro-o-isocyanostyrenes: A Facile Synthesis of 3-Fluoroquinolines and Their Application to the ­Synthesis of 11-Alkylated Cryptolepines

Takashi Mori, Junji Ichikawa*
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)5841-4345; e-Mail: junji@chem.s.u-tokyo.ac.jp;
Further Information

Publication History

Received 1 December 2006
Publication Date:
13 April 2007 (online)

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Abstract

o-Isocyano-substituted β,β-difluorostyrenes undergo tin-mediated radical cyclization in a 6-endo-trig fashion, followed by: (i) transformation of the C-Sn bond, and (ii) dehydrofluorination or reduction, leading to 2,4-disubstituted 3-fluoroquinolines or 3,3-difluorotetrahydroquinolines. This sequence was successfully applied to the synthesis of 11-alkylated cryptolepines.

Key words

alkenes - radical reactions - fluorine - quinolines - fused-ring systems

    References and Notes

  • For reviews, see:
  • 1a Dolbier WR. Chem. Rev.  1996,  96:  1557 
    Google Scholar
  • 1b Dolbier WR. Top. Curr. Chem.  1997,  192:  97 
    Google Scholar
  • 1c Améduri B. Boutevin B. Top. Curr. Chem.  1997,  192:  165 
    Google Scholar
  • 2 Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum; New York: 1994. 
    Google Scholar
  • 3a Lopin C. Gautier A. Gouhier G. Piettre SR. J. Am. Chem. Soc.  2002,  124:  14668 ; and references therein
    CrossrefGoogle Scholar
  • 3b Okano T. Nakajima A. Eguchi S. Synlett  2001,  1449 
    CrossrefGoogle Scholar
  • 3c Bumgardner CL. Burgess JP. J. Fluorine Chem.  2000,  102:  5478 
    CrossrefGoogle Scholar
  • 3d Herpin TF. Motherwell WB. Roberts BP. Roland S. Weibel J.-M. Tetrahedron  1997,  53:  15085 
    CrossrefGoogle Scholar
  • For reports on the radical cyclization of fluoroalkenes, see:
  • 4a Morikawa T. Uchida J. Hasegawa Y. Taguchi T. Chem. Pharm. Bull.  1991,  39:  2462 
    CrossrefGoogle Scholar
  • 4b Morikawa T. Nishiwaki T. Iitaka Y. Kobayashi Y. Tetrahedron Lett.  1987,  28:  671 
    CrossrefGoogle Scholar
  • 5 Ichikawa J. Wada Y. Miyazaki H. Mori T. Kuroki H. Org. Lett.  2003,  5:  1455 
    CrossrefGoogle Scholar
  • 6 Ichikawa J. Wada Y. Fujiwara M. Sakoda K. Synthesis  2002,  1917 
    Article in Thieme ConnectGoogle Scholar
  • 7 Tokuyama H. Fukuyama T. Chem. Rec.  2002,  2:  37 
    CrossrefGoogle Scholar
  • 8a Beckwith ALJ. Chem. Soc. Rev.  1993,  143 ; and references therein
    CrossrefGoogle Scholar
  • 8b Curran DP. Porter NA. Giese B. Stereochemistry of Free Radical Reactions   VCH; Weinheim: 1996. 
    CrossrefGoogle Scholar
  • For recent reports on radical 6-endo-trig cyclizations, see:
  • 9a Tojino M. Otsuka N. Fukuyama T. Matsubara H. Ryu I. J. Am. Chem. Soc.  2006,  128:  7712 
    CrossrefGoogle Scholar
  • 9b Ishibashi H. Chem. Rec.  2006,  6:  23 ; and references therein
    CrossrefGoogle Scholar
  • 9c Chapelon A.-S. Ollivier C. Santelli M. Tetrahedron Lett.  2006,  47:  2747 ; and references therein
    CrossrefGoogle Scholar
  • 9d Bennasar M.-L. Roca T. Ferrando F. J. Org. Chem.  2006,  71:  1746 ; and references therein
    CrossrefGoogle Scholar
  • 9e Mal SK. Some S. Ray JK. Synlett  2005,  1951 ; and references therein
    CrossrefGoogle Scholar
  • 9f Flisinska-Luczak J. Lesniak S. Nazarski RB. Tetrahedron  2004,  60:  8181 
    CrossrefGoogle Scholar
  • 10a Sheffy F. Godschalx JP. Stille JK. J. Am. Chem. Soc.  1984,  106:  4833 
    Google Scholar
  • 10b Stille JK. Groh BL. J. Am. Chem. Soc.  1987,  109:  813 
    Google Scholar
  • 10c Echavarren AM. Stille JK. J. Am. Chem. Soc.  1987,  109:  5478 
    Google Scholar
  • For reports on the effect of alkene substitution in radical 5-exo-trig/6-endo-trig cyclizations, see:
  • 12a Hartung J. Kneuer R. Rummey C. Bringmann G. J. Am. Chem. Soc.  2004,  126:  12121 ; and references therein
    CrossrefPubMedGoogle Scholar
  • 12b Della EW. Graney SD. J. Org. Chem.  2004,  69:  3824 ; and references therein
    CrossrefPubMedGoogle Scholar
  • 13 Kato T. Saeki K. Kawazoe Y. Hakura A. Mutat. Res.  1999,  439:  149 ; and references therein
    CrossrefGoogle Scholar
  • 14a Ackermann L. Born R. Spatz JH. Meyer D. Angew. Chem. Int. Ed.  2005,  44:  7216 
    Google Scholar
  • 14b Mongin F. Mojovic L. Guillamet B. Trécourt F. Quéguiner G. J. Org. Chem.  2002,  67:  8991 
    Google Scholar
  • 14c Rocca P. Marsais F. Godard A. Quéguiner G. Tetrahedron  1993,  49:  49 
    Google Scholar
  • 15 Olajide OA. Heiss EH. Schachner D. Wright CW. Vollmar AM. Dirsch VM. Bioorg. Med. Chem.  2007,  15:  43 ; and references therein
    CrossrefGoogle Scholar
  • 16 Hadden CE. Sharaf MHM. Guido JE. Robins RH. Tackie AN. Phoebe CH. Schiff PL. Martin GE. J. Nat. Prod.  1999,  62:  238 
    CrossrefGoogle Scholar
  • 17 Arzel E. Rocca P. Grellier P. Labaeïd M. Frappier F. Guéritte F. Gaspard C. Marsais F. Godard A. Quéguiner G. J. Med. Chem.  2001,  44:  949 
    Google Scholar
  • For reports on the synthesis of cryptolepine, see:
  • 18a Dhanabal T. Sangeetha R. Mohan PS. Tetrahedron  2006,  62:  6258 
    CrossrefGoogle Scholar
  • 18b Onyeibor O. Croft SL. Dodson HI. Feiz-Haddad M. Kendrick H. Millington NJ. Parapini S. Phillips RM. Seville S. Shnyder SD. Taramelli D. Wright CW. J. Med. Chem.  2005,  48:  2701 
    CrossrefGoogle Scholar
  • 18c Ho T.-L. Jou D.-G. Helv. Chim. Acta  2002,  85:  3823 ; and references therein
    CrossrefGoogle Scholar
  • 18d Bierer DE. Dubenko LG. Zhang P. Lu Q. Imbach PA. Garofalo AW. Phuan P.-W. Fort DM. Litvak J. Gerber RE. Sloan B. Luo J. Cooper R. Reaven GM. J. Med. Chem.  1998,  41:  2754 
    CrossrefGoogle Scholar
11

4-Butyl-3-fluoro-2-phenylquinoline ( 7c)
To a solution of 1a (113 mg, 0.51 mmol) in toluene (4 mL) was added n-Bu3SnH (0.15 mL, 0.56 mmol) and a catalytic amount of AIBN under Ar. The reaction mixture was heated at 80 °C for 1 h and removal of the solvent under reduced pressure. To a solution of the residue in DMF (3 mL) were added PhI (102 mg, 0.50 mmol), Pd(PPh3)4 (48 mg, 0.042 mmol), and CuI (40 mg, 0.21 mmol) at r.t. After the reaction mixture was stirred for 2 h at 80 °C, DBU (0.070 mL, 0.46 mmol) was added, and the reaction mixture was heated at 80 °C for 1 h. The reaction was quenched with phosphate buffer (pH 7), and the mixture was filtered through Celite®. Organic materials were extracted with Et2O three times. The combined extracts were washed with aq KF, brine, and dried over MgSO4. After removal of the solvent under reduced pressure, the residue was purified by preparative TLC on silica gel (hexane-EtOAc, 10:1) to give 7c (100 mg, 70%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ = 0.98 (3 H, t, J = 7.6 Hz), 1.49 (2 H, tq, J = 7.6, 7.6 Hz), 1.67-1.76 (2 H, m), 3.14 (2 H, td J = 7.6 Hz, J HF = 1.9 Hz), 7.49-7.57 (4 H, m), 7.63-7.67 (1 H, m), 7.96 (1 H, d, J = 8.2 Hz), 8.02-8.06 (2 H, m), 8.16 (1 H, d, J = 8.2 Hz). 13C NMR (126 MHz, CDCl3): δ = 13.8, 22.8, 24.7 (d, J CF = 4 Hz), 31.9, 123.3 (d, J CF = 5 Hz), 126.8, 127.8 (d, J CF = 3 Hz), 128.1, 128.4, 129.3, 129.4, 130.8, 132.6 (d, J CF = 15 Hz), 136.2 (d, J CF = 5 Hz), 145.2 (d, J CF = 3 Hz), 148.6 (d, J CF = 17 Hz), 152.9 (d, J CF = 256 Hz). 19F NMR (471 MHz, CDCl3/C6F6): δ = 32.4 (s). IR (neat): 2958, 2929, 2871, 1603, 1458, 1406, 1381, 1362, 1192, 760 cm-1. HRMS-FAB: m/z calcd for C19H19FN: 280.1502 [M + 1]+; found: 280.1495.