Download PDF
Synthesis 2010(6): 1000-1008  
DOI: 10.1055/s-0029-1218632
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Direct, Copper-Catalyzed Functionalization of Pyridines with Alkynes

Ramsay E. Beveridgea,b, Bruce A. Arndtsen*a
a Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax: +1(514)3982382; e-Mail: bruce.arndtsen@mcgill.ca;
b Pfizer Global Research and Development, Groton, CT 06340, USA
e-Mail: ramsay.beveridge@pfizer.com;
Further Information

Publication History

Received 6 November 2009
Publication Date:
04 January 2010 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

A one-pot, copper-catalyzed method to construct 2-alk­ynylpyridines is presented. This provides a route to access these products directly from terminal alkynes and the parent pyridine, and without prefunctionalization of the pyridine core. In addition, (Z)-alk-2-enylpyridines can be prepared via a related procedure. These reactions are used to synthesize a number of new alkynyl- and alkenyl­-substituted pyridines in one pot.

Key words

pyridine - copper - catalytic - alkyne - alkene

    References

  • Selected examples:
  • 1a Nunez MJ. Guadano A. Jimenez IA. Ravelo AG. Gonzalez-Coloma A. Bazzocchi IL. J. Nat. Prod.  2004,  67:  14 
    Search in Google Scholar
  • 1b Kitamura A. Tanaka J. Ohtani II. Higa T. Tetrahedron  1999,  55:  2487 
    Search in Google Scholar
  • 1c O’Hagan D. Nat. Prod. Rep.  2000,  17:  435 
    Search in Google Scholar
  • 1d Duan H. Takaishi Y. Momota H. Ohmoto Y. Taki T. Jia Y. Li D. J. Nat. Prod.  2001,  64:  582 
    Search in Google Scholar
  • 1e Tsukamoto S. Takahashi M. Matsunaga S. Fusetami N. van Soet RWM. J. Nat. Prod.  2000,  63:  682 
    Search in Google Scholar
  • 1f Chang F.-R. Hayashi K.-I. Chen I.-H. Liaw C.-C. Bastow KF. Nakanishi Y. Nozaki H. Cragg GM. Wu Y.-C. Lee KH. J. Nat. Prod.  2003,  66:  1416 
    Search in Google Scholar
  • 1g Horiuch M. Murakami C. Fukami N. Yu D. Chen T.-H. Bastow KF. Zhang D.-C. Takaishi Y. Imakura Y. Lee K.-H. J. Nat. Prod.  2006,  69:  1271 
    Search in Google Scholar
  • Pyridines are used extensively as ligands, for reviews in this area, see:
  • 2a Dumur F. Dumas E. Mayer CR. Targ. Heterocycl. Syst.  2007,  11:  70 
    Search in Google Scholar
  • 2b von Zelewsky A. Coord. Chem. Rev.  1999,  190-192:  811 
    Search in Google Scholar
  • 2c van Koten G. Albrecht M. Angew. Chem. Int. Ed.  2001,  40:  3750 
    Search in Google Scholar
  • 2d Belda O. Moberg C. Coord. Chem. Rev.  2005,  249:  727 
    Search in Google Scholar
  • 2e Desimoni G. Faita G. Quadrelli P. Chem. Rev.  2003,  103:  3119 
    Search in Google Scholar
  • 2f Chelucci G. Thummel R. Chem. Rev.  2002,  102:  3129 
    Search in Google Scholar
  • 3a Shifrina ZB. Rajadurai MS. Firsova NV. Bronstein LM. Huang X. Rusanov AL. Muellen K. Macromolecules  2005,  38:  9920 
    Search in Google Scholar
  • 3b Rauckhorst MR. Wilson PJ. Hatcher SA. Hada CM. Parquette JR. Tetrahedron  2003,  59:  3917 
    Search in Google Scholar
  • 4a Zheng JY. Feng XM. Bai WB. Qin JG. Zhan CM. Eur. Polym. J.  2005,  41:  2770 
    Search in Google Scholar
  • 4b duBois CJ. Abboud KA. Reynolds JR. J. Phys. Chem. B  2004,  108:  8550 
    Search in Google Scholar
  • 4c Yamamoto T. Yamaguchi I. Yasuda T. Adv. Polym. Sci.  2005,  177:  181 
    Search in Google Scholar
  • 5a Alagille D. Baldwin RM. Roth BL. Wroblewski JT. Grajkowska E. Tamagnan GD. Bioorg. Med. Chem.  2005,  13:  197 
    Search in Google Scholar
  • 5b Yu M. Tueckmantel W. Wang X. Zhu A. Kozikowski AP. Brownell A.-L. Nucl. Med. Biol.  2005,  32:  631 
    Search in Google Scholar
  • 5c Jakopec S. Dubravcic K. Polanc S. Kosmrlj J. Osmak M. Toxicol. in Vitro  2006,  20:  217 
    Search in Google Scholar
  • 5d Jacguemard U. Routier S. Dias N. Lansiaux A. Goossens J.-F. Bailly C. Merour J.-Y. Eur. J. Med. Chem.  2005,  40:  1087 
    Search in Google Scholar
  • 5e Zhou X.-F. Yang X. Wang Q. Coburn RA. Morris ME. Drug Metab. Dispos.  2005,  33:  1220 
    Search in Google Scholar
  • Recent reviews on the construction and functionalization of pyridines:
  • 6a Schlosser M. Mongin F. Chem. Soc. Rev.  2007,  36:  1161 
    Search in Google Scholar
  • 6b Varela JA. Saa C. Synlett  2008,  2571 
  • 6c Henry G. Tetrahedron  2004,  60:  6043 
    Search in Google Scholar
  • Selected recent examples of new methods:
  • 7a Dash J. Lechel T. Reissig H.-U. Org. Lett.  2007,  9:  5541 
    Search in Google Scholar
  • 7b Sasada T. Sakai N. Korakahara T. J. Org. Chem.  2008,  73:  6905 
    Search in Google Scholar
  • 7c Eidamshaus C. Reissig H.-U. Adv. Synth. Catal.  2009,  351:  1162 
    Search in Google Scholar
  • 7d Kobayashi T. Hatano S. Tsuchikawa H. Katsumura S. Tetrahedron Lett.  2008,  49:  4349 
    Search in Google Scholar
  • 7e Kiss LE. Ferreira HS. Learmonth DA. Org. Lett.  2008,  10:  1835 
    Search in Google Scholar
  • 7f Donohoe TJ. Fishlock LP. Procopiou PA. Synthesis  2008,  2665 
  • 8a A review: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
    Search in Google Scholar
  • 8b Blachut D. Czarnocki Z. Wojtasiewicz K. Synthesis  2006,  2855 
  • 8c Cailly T. Fabis F. Bouillon A. Lemaitre S. Sopkova de Oliveira Santos J. Rault S. Synlett  2006,  53 
  • 8d Couve-Bonnaire S. Carpentier J.-F. Mortreux A. Castanet Y. Tetrahedron  2003,  59:  2793 
    Search in Google Scholar
  • 9a Joubert N. Pohl R. Klepetarova B. Hocek M. J. Org. Chem.  2007,  72:  6797 
    Search in Google Scholar
  • 9b Mei K. Wang J. Hu X. Synth. Commun.  2006,  36:  2525 
    Search in Google Scholar
  • 9c Masselot D. Charmant JPH. Gallagher T. J. Am.Chem. Soc.  2006,  128:  694 
    Search in Google Scholar
  • 9d Lachance N. April M. Joly M.-A. Synthesis  2005,  2571 
  • 9e Zhao J. Yang X. Jia X. Luo S. Zhai H. Tetrahedron  2003,  59:  9379 
    Search in Google Scholar
  • 10a Lechel T. Dash J. Brudgam I. Reibig H.-U. Eur. J. Org. Chem.  2008,  3647 
  • 10b Krauss J. Bracher F. Arch. Pharm. Pharm. Med. Chem.  2004,  337:  371 
    Search in Google Scholar
  • 10c Feuerstein M. Doucet H. Santelli M. Tetrahedron Lett.  2005,  46:  1717 
    Search in Google Scholar
  • 10d Sonogashira K. In Handbook of Organopalladium Chemistry for Organic Synthesis   Negishi E.-I. Wiley-Interscience; New York: 2002.  p.493 
  • 10e Sonogashira K. In Metal-Catalyzed Cross-Coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998.  p.203 
  • 11a Mudadu MS. Singh A. Thummel RP. J. Org. Chem.  2006,  71:  7611 
    Search in Google Scholar
  • 11b Hervet M. Thery I. Gueiffier A. Enguehard-Gueffier C. Helv. Chim. Acta  2003,  86:  3461 
    Search in Google Scholar
  • 11c Heller M. Schubert US. J. Org. Chem.  2002,  67:  8269 
    Search in Google Scholar
  • Pyridine and related aza-aromatic N-oxides in palladium catalyzed biaryl cross-couplings:
  • 12a Campeau L.-C. Rousseaux S. Fagnou K. J. Am. Chem. Soc.  2005,  127:  18020 
    Search in Google Scholar
  • 12b Leclerc J.-P. Fagnou K. Angew. Chem. Int. Ed.  2006,  45:  7781 
    Search in Google Scholar
  • Examples of catalytic pyridine N-oxide CH functionalization:
  • 13a Cho SH. Hwang SJ. Chang S. J. Am. Chem. Soc.  2008,  130:  9254 
    Search in Google Scholar
  • 13b Kanyiva KS. Nakao Y. Hiyama T. Angew. Chem. Int. Ed.  2007,  46:  8872 
    Search in Google Scholar
  • 14 Larivée A. Mousseau JJ. Charette AB. J. Am. Chem. Soc.  2008,  130:  52 
    Search in Google Scholar
  • Reviews on this topic:
  • 15a Eicher T. Hauptmann S. The Chemistry of Heterocycles   Wiley-VCH; Weinheim: 2003. 
  • 15b Joule JA. Mills K. Heterocyclic Chemistry   Blackwell Science; Oxford: 2000. 
  • 15c Lavilla R. J. Chem. Soc., Perkin Trans. 1  2002,  1141 
  • 15d Meyers AI. Stout D. Chem. Rev.  1982,  82:  223 
    Search in Google Scholar
  • 15e Eisner U. Kuthan J. Chem. Rev.  1972,  72:  1 
    Search in Google Scholar
  • 15f Comins DL. O’Connor S. Adv. Heterocycl. Chem.  1988,  44:  199 
    Search in Google Scholar
  • 15g Comins DL. Joseph S. Adv. Nitrogen Heterocycl.  1996,  2:  251 
    Search in Google Scholar
  • Specific examples:
  • 16a Lyle RE. Comins DL. J. Org. Chem.  1976,  41:  3250 
    Search in Google Scholar
  • 16b Comins DL. Abdullah AH. J. Org. Chem.  1982,  47:  4315 
    Search in Google Scholar
  • 16c Comins DL. Brown J. Tetrahedron Lett.  1984,  25:  3297 
    Search in Google Scholar
  • 17a Black DA. Beveridge RE. Arndtsen BA. J. Org. Chem.  2008,  73:  1906 
    Search in Google Scholar
  • 17b Black DA. Arndtsen BA. Org. Lett.  2004,  6:  1107 
    Search in Google Scholar
  • 18 Additional report of copper-catalyzed enantioselective addition of activated terminal alkynes to N-acylpyridinium salts: Sun Z. Yu S. Ding Z. Ma D. J. Am. Chem. Soc.  2007,  129:  9300 
    CrossrefPubMedSearch in Google Scholar
  • Recent reports where the isolated N-acyl-2-alkynyl-1,2-dihydropyridine precursor was generated via in situ stoichiometric copper-acetylide formation:
  • 19a Yadav JS. Reddy BVS. Sreenivas M. Sathaiah K. Tetrahedron Lett.  2005,  46:  8905 
    Search in Google Scholar
  • 19b Yamada S. Toshimitsu A. Takahashi Y. Tetrahedron  2009,  65:  2329 
    Search in Google Scholar
  • 20a Davis JL. Dhawan R. Arndtsen BA. Angew. Chem. Int. Ed.  2004,  43:  590 
    Search in Google Scholar
  • 20b Black DA. Arndtsen BA. Org. Lett.  2006,  8:  1991 
    Search in Google Scholar
  • 20c Black DA. Arndtsen BA. J. Org. Chem.  2005,  70:  5133 
    Search in Google Scholar
  • Copper salts are known to mediate oxidative organic transformations, see:
  • 21a Schultz MJ. Sigman MS. Tetrahedron  2006,  62:  8227 
    Search in Google Scholar
  • 21b Mukherjee R. Comp. Coord. Chem. II  2004,  6:  747 
    Search in Google Scholar
  • 21c Puzari A. Baruah JB. J. Mol. Cat. A: Chem.  2002,  2:  149 
    Search in Google Scholar
  • 21d Feringa B. Bioinorg. Chem. Copper  1993,  306 
  • Base mediated aromatizations of dihydropyridines to pyridines are known:
  • 23a Fraenkel G. Cooper JW. Fink CM. Angew. Chem., Int. Ed. Engl.  1970,  9:  523 
    Search in Google Scholar
  • 23b Corey EJ. Tian Y. Org. Lett.  2005,  7:  5535 
    Search in Google Scholar
  • 23c Singh RP. Eggers GV. Shreeve JM. Synthesis  2002,  1009 
  • 23d

    See also ref. 15.

  • 24a Agaw a T. Miller SI. J. Am. Chem. Soc.  1961,  83:  449 
    Search in Google Scholar
  • 24b Chen C. Wang B. Munoz B. Synlett  2003,  2404 
  • References for known 2-alkynylpyridine compounds:
  • 25a 2-Phenylethynylpyridine (2): Wang B. Bonin M. Micouin L. Org. Lett.  2004,  6:  3481 
    Search in Google Scholar
  • 25b See also: Shirakawa E. Kitabata T. Otsuka H. Tsuchimoto T. Tetrahedron  2006,  61:  9878 
    Search in Google Scholar
  • 25c Table 3, entry 2: Alagille D. Baldwin RM. Roth BL. Wroblewski JT. Grajkowska E. Tamagnon GD. Bioorg. Med. Chem.  2005,  13:  197 
    Search in Google Scholar
  • 25d Table 3, entry 1: Tilley JW. Zawoiski S. J. Org. Chem.  1988,  53:  386 
    Search in Google Scholar
  • 25e Table 2, entry 4: Sakamoto T. Shiga F. Yasuhara A. Uchiyama D. Kondo Y. Yamanaka H. Synthesis  1992,  746 
  • 25f Table 3, entry 3 has not been reported, however, the other o-phenylalkynyl regioisomer has been reported: Yue D. Larock RC. Org. Lett.  2004,  6:  1581 
    Search in Google Scholar
  • 25g See also: Roesch KR. Larock RC. J. Org. Chem.  2002,  67:  86 
    Search in Google Scholar
  • 25h Table 2, entry 5: Novak I. Ng S.-C. Mok C.-Y. Huang H.-H. Fang J. Wang KK.-T. J. Chem. Soc., Perkin Trans. 2  1994,  1771 
  • References for known 2-alkenylpyridine compounds:
  • 26a 2-phenylethenylpyridine (3): Chen C. Wang B. Munoz B. Synlett  2003,  2404 
  • 26b Table 5, entry 2: Heimgärtner G. Raatz D. Reiser O. Tetrahedron  2005,  61:  643 
    Search in Google Scholar
  • 26c Table 5, entry 3: Ciutolini MA. Byrne NE. J. Chem. Soc., Chem. Commun.  1988,  1230 
22

Minor amounts of the 2,5-substituted pyridine isomer are observed with the product in Table  [³] , entry 2.

27

The coupling constant J for trans-isomers is always larger (>10 Hz) than cis-isomers and is typically ∼15 Hz for E-alkenylpyridines (see ref. 25).