Download PDF
Synlett 2009(8): 1245-1250  
DOI: 10.1055/s-0029-1216734
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Polysubstituted Quinolines from 2-Alkynylanilines and α,β-Ynones through a Sequential Conjugate Addition-Cyclization Process

Roberta Berninia, Sandro Cacchi*b, Giancarlo Fabrizib, Eleonora Filistib, Alessio Sferrazzaa
a Dipartimento A.B.A.C., Università degli Studi della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P. le A. Moro 5, 00185 Rome, Italy
Fax: +39(06)49912780; e-Mail: sandro.cacchi@uniroma1.it;
Further Information

Publication History

Received 3 February 2009
Publication Date:
17 April 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

Polysubstituted quinolines have been prepared, usually in good to high yields, from readily available 2-alkynylanilines and α,β-ynones through a sequential process that omits the isolation of the enaminone intermediates. The reaction tolerates several useful functionalities including ether, cyano, ester, and chloro substituents.

Key words

enaminones - cyclization - quinolines - α,β-ynones - 2-alkynylanilines

    References and Notes

  • For recent reviews, see:
  • 1a Elassar A.-ZA. El-Khair AA. Tetrahedron  2003,  59:  8463 
    Google Scholar
  • 1b Stanovnik B. Svete J. Chem. Rev.  2004,  104:  2433 
    Google Scholar
  • 2 Cacchi S. Fabrizi G. Filisti E. Org. Lett.  2008,  10:  2629 
    CrossrefGoogle Scholar
  • For some recent reviews, see:
  • 5a Sikorski JA. J. Med. Chem.  2006,  49:  1 
    Google Scholar
  • 5b White NJ. Lancet Infect. Dis.  2007,  7:  549 
    Google Scholar
  • 5c Bradbury BJ. Pucci MJ. Curr. Opin. Pharm.  2008,  8:  574 
    Google Scholar
  • 5d Michael JP. Nat. Prod. Rep.  2008,  25:  166 
    Google Scholar
  • 6 Sakamoto T. Nagano T. Kondo Y. Yamanaka H. Synthesis  1990,  215 
    Article in Thieme ConnectGoogle Scholar
  • 7 Karpov AS. Muller TJJ. Org. Lett.  2003,  5:  3451 
    CrossrefGoogle Scholar
  • For some selected references on the transition-metal-catalyzed cyclization of 2-(alkynyl)anilines and -anilides, see:
  • 10a (Pd and Au) Iritani K. Matsubara S. Utimoto K. Tetrahedron Lett.  1988,  29:  1799 
    Google Scholar
  • 10b (Cu) Cacchi S. Fabrizi G. Parisi LM. Org. Lett.  2003,  5:  3843 
    Google Scholar
  • While the manuscript was in preparation, an indium-catalyzed cyclization of β-enamino esters [prepared from β-keto esters and 2-(alkynyl)anilines] to N-vinylic indoles was described:
  • 10c Murai K. Hayashi S. Takaichi N. Kita Y. Fujioka H. J. Org. Chem.  2009,  74:  1418 
    Google Scholar
  • 11a Cacchi S. Fabrizi G. Marinelli F. Moro L. Pace P. Synlett  1997,  1363 
    Google Scholar
  • 11b Cacchi S. Fabrizi G. Marinelli F. Synlett  1999,  401 
    Google Scholar
  • 12 Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Synlett  2000,  647 
    Article in Thieme ConnectGoogle Scholar
  • 13 Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Synlett  1993,  65 
    Article in Thieme ConnectGoogle Scholar
  • 14 Arcadi A. Cacchi S. Fabrizi G. Manna F. Pace P. Synlett  1998,  446 
    Article in Thieme ConnectGoogle Scholar
  • For a recent review, see:
  • 17a Kouznetsov VV. Méndez LYV. Gómez MM. Curr. Org. Chem.  2005,  9:  141 
    Google Scholar
  • For other selected references, see:
  • 17b Mitscher LA. Chem. Rev.  2005,  105:  559 
    Google Scholar
  • 17c Glushkov RG. Marchenko NB. Padeiskaya EN. Shipilova LD. Khim.-Farm. Zh.  1990,  24:  24 
    Google Scholar
  • 17d White LA. Storr RC. Tetrahedron  1996,  52:  3117 
    Google Scholar
  • 17e Clemencin-Le Guillou C. Remuzon P. Bouzard D. Quirion J.-C. Giorgi-Renault S. Husson H.-P. Tetrahedron  1998,  54:  83 
    Google Scholar
  • 17f Liu Y. Yu C.-Y. Wang M.-X. ARKIVOC  2003,  (ii):  146 
    Google Scholar
  • 17g Ding D. Li X. Wang X. Du Y. Shen J. Tetrahedron Lett.  2006,  47:  6997 
    Google Scholar
  • 17h Park C.-H. Lee J. Jung HY. Kim MJ. Lim SH. Yeo HT. Choi EC. Yoon EJ. Kim KW. Cha JH. Kim S.-H. Chang D.-J. Kwon D.-Y. Li F. Suh Y.-G. Bioorg. Med. Chem.  2007,  15:  6517 
    Google Scholar
  • 17i Al-Hiari YM. Al-Mazari IS. Shakya AK. Darwish RM. Abu-Dahab R. Molecules  2007,  12:  1240 
    Google Scholar
  • 17j Zewge D. Chen C.-y. Deer C. Dormer PG. Hughes DL. J. Org. Chem.  2007,  72:  4276 
    Google Scholar
  • 17k Jones CP. Anderson KW. Buchwald SL. J. Org. Chem.  2007,  72:  7968 
    Google Scholar
3

Bernini R., Cacchi S., Fabrizi G., Sferrazza A.; Synthesis; 2009, in press

4

Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A. Synlett 2009, submitted.

8

Conjugate additions of 2-(alkynyl)anilines to 1,3-diphenyl-propynones (MeOH, 120 ˚C) were carried out using a Carousel Tube Reaction (Radley Discovery).

9

Enaminones 3 can also be prepared by treating the conjugate addition products derived from 2-iodonilines and 1,3-diaryl-propynones with terminal alkynes. Using this procedure, 3a, 3q, and 3r were isolated in 77%, 74%, and 70% overall yields, respectively. This protocol, however, appeared less suited for the development of a sequential process that would omit the isolation of the enaminone intermediates (Scheme  [4] ).

Scheme 4

15

Typical Procedure for the Cyclization of Enaminones 3 to Quinolines 4 To a stirred solution of 3a (80 mg, 0.2 mmol) in anhyd DMSO (1.5 mL), Cs2CO3 (66 mg, 0.2 mmol) was added at r.t. The reaction mixture was warmed at 35 ˚C and stirred for 2 h. After cooling, the reaction mixture was diluted with EtOAc, washed with 2 N HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 85:15] to afford 64 mg (92% yield) of 4a.
Light brown solid; mp 137-139 ˚C. IR (KBr): 3059, 2924, 1662 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.31-8.29 (m, 1 H), 8.11-8.08 (m, 1 H), 7.80-7.78 (m, 1 H), 7.63-7.54 (m, 5 H), 7.38-7.36 (m, 1 H), 7.29-7.13 (m, 10 H), 4.49-4.41 (m, 2 H). ¹³C NMR (100.6 MHz, CDCl3): δ = 198.0, 156.4, 148.1, 144.4, 140.0, 138.6, 137.4, 133.3, 133.2, 130.4, 130.1, 129.3, 128.6, 128.5, 128.4, 128.21, 128.17, 127.2, 126.3, 126.0, 125.0, 35.3. Anal. Calcd for C29H21NO: C, 87.19; H, 5.30. Found: C, 87.25; H, 5.36.

16

Typical Procedure for the Preparation of Quinolines 4 from 2-(Alkynyl)anilines 1 and α,β-Ynones 2 To a stirred solution of 1b (45.5 mg, 0.2 mmol) in anhyd MeOH (0.5 mL), 2b (47.3 mg, 0.2 mmol) was added at r.t. The reaction mixture was warmed at 120 ˚C and stirred for 48 h. After that period the volatile materials were evaporated at reduced pressure, Cs2CO3 (65.2 mg, 0.2 mmol) and anhyd MeCN (1.5 mL) were added. The resulting reaction mixture was warmed at 60 ˚C and stirred for 1.5 h. After cooling, the reaction mixture was diluted with EtOAc, washed with 2 N HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 85:15] to afford 71.0 mg (76% yield) of 4b.
White solid; mp 167-169 ˚C. IR (KBr): 3072, 2943, 1664 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.30-8.28 (m, 1 H), 8.02-8.00 (m, 1 H), 7.82-7.78 (m, 1 H), 7.63-7.56 (m, 3 H), 7.29-7.28 (m, 3 H), 7.17-7.09 (m, 6 H), 7.03-7.01 (m, 1 H), 6.96-6.94 (m, 1 H), 4.43-4.32 (m, 2 H), 3.73 (s, 3 H). ¹³C NMR (100.6 MHz, CDCl3): δ = 197.8, 159.5, 156.4, 148.1, 143.7, 139.9, 138.7, 137.1, 133.2, 132.2, 130.6, 130.2, 129.8, 129.31, 129.28, 128.7, 128.6, 128.2, 127.4, 125.7, 124.7, 122.5, 120.1, 113.0, 55.3, 34.7. Anal. Calcd for C30H22ClNO2: C, 77.66; H, 4.78. Found: C, 77.52; H, 4.70.