A Simple and Efficient Copper-Catalyzed Synthesis of N-Alkynylimidazoles

Abstract

A simple and efficient method for the synthesis of N-alkynylheteroarenes from 1,1-dibromo-1-alkenes was developed via a copper-catalyzed cross-coupling reaction. Generally superior yields and functional-group tolerance were obtained with TMEDA as ligand using imidazole and benzimidazole substrates in dioxane.

Key words

N-alkynylimidazoles - 1,1-dibromo-1-alkenes - copper - cross-coupling reaction - alkynylation

References and Notes

• For reviews and representative references to recent advances in copper-catalyzed coupling reactions, see:
• 1a Qiao J. Lam PYS. Synthesis  2011,  829 
• 1b Bellina F. Rossi R. Adv. Synth. Catal.  2010,  352:  1223 
• 1c Kabir MS. Lorenz M. Namjoshi OA. Cook JM. Org. Lett.  2010,  12:  464 
• 1d Coste A. Karthikeyan G. Couty F. Evano G. Angew. Chem. Int. Ed.  2009,  48:  4381 
• 1e Larsson P.-F. Correa A. Carril M. Norrby P.-O. Bolm C. Angew. Chem. Int. Ed.  2009,  48:  5691 
• 1f de Parrodi CA. Walsh PJ. Angew. Chem. Int. Ed.  2009,  48:  4679 
• 1g Altman RA. Anderson KW. Buchwald SL. J. Org. Chem.  2008,  73:  5167 
• 1h Yao P.-Y. Zhang Y. Hsung RP. Zhao K. Org. Lett.  2008,  10:  4275 
• 1i Evano G. Blanchard N. Toumi M. Chem. Rev.  2008,  108:  3054 
• 1j Beletskaya IP. Cheprakov AV. Coord. Chem. Rev.  2004,  248:  2337 
• 1k Kunz K. Scholz U. Ganzer D. Synlett  2003,  2428 
• 1l Ley SV. Thomas AW. Angew. Chem. Int. Ed.  2003,  42:  5400 
• 1m Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc.  2001,  123:  7727 
• For representative references, see:
• 2a Evano G. Tadiparthi K. Couty F. Chem. Commun.  2011,  47:  179 
• 2b Legrand F. Jouvin K. Evano G. Isr. J. Chem.  2010,  50:  588 
• 2c Fang Y. Lifchits O. Lautens M. Synlett  2008,  413 
• 2d Fang Y.-Q. Lautens M. Org. Lett.  2005,  7:  3549 
• 3 Corey EJ. Fuchs PL. Tetrahedron Lett.  1972,  13:  3769 
• 4a Soderquist JA. Leon G. Colberg JC. Martinez I. Tetrahedron Lett.  1995,  36:  3119 
• 4b Thielges S. Meddah E. Bisseret P. Eustache J. Tetrahedron Lett.  2004,  45:  907 
• 4c Bryan CS. Braunger JA. Lautens M. Angew. Chem. Int. Ed.  2009,  48:  7064 
• 4d Wang L. Shen W. Tetrahedron Lett.  1998,  39:  7625 
• 4e Shen W. Wang L.
  J. Org. Chem.  1999,  64:  8873 
• 4f Coste A. Couty F. Evano G. Org. Lett.  2009,  11:  4454 
• 4g Rao MMN. Jadhav DN. Dspgupta P. Org. Lett.  2010,  12:  2048 
• 4h Berciano BP. Lebrequier S. Besselievre F. Piguel S. Org. Lett.  2010,  12:  4038 
• For a review of N-alkynylheterocycles, see:
• 5a Dekorver KA. Li HY. Lohse AG. Hayashi R. Lu ZJ. Zhang Y. Hsung RP. Chem. Rev.  2010,  110:  5064 
• 5b Evano G. Coste A. Jouvin K. Angew. Chem. Int. Ed.  2010,  49:  2840 
• 5c Tracey MR. Hsung RP. Antoline J. Kurtz KCM. Shen L. Slafer BW. Zhang Y. Sci. Synth.  2005,  21:  404 
• 5d Katritzky AR. Jiang R. Singh SK. Heterocycles  2004,  63:  1455 
• 5e Mulder JA. Kurtz KCM. Hsung RP. Synlett  2003,  1379 
• 6a Ishihara T. Mantani T. Konno T. Yamanaka H. Tetrahedron  2006,  62:  3783 
• 6b Xu ZQ. Joshi RV. Zemlicka J. Tetrahedron  1995,  51:  67 
• 7a Xu ZQ. Joshi RV. Zemlicka J. Tetrahedron  1995,  51:  67 
• 7b Joshi RV. Xu ZQ. Ksebati MB. Kessel D. Corbett TH. Drach JC. Zemlicka J. J. Chem. Soc., Perkin Trans. 1  1994,  1089 
• 8a Katritzky AR. Jiang R. Singh SK. Heterocycles  2004,  63:  1455 
• 8b Brandsma L. Mal’kina AG. Trofimov BA. Synth. Commun.  1994,  24:  2721 
• 8c Okamoto Y. Kundu SK. J. Org. Chem.  1970,  35:  4250 
• 9 Katritzky AR. Abdel-Fattah AAA. Wang M. J. Org. Chem.  2002,  67:  7526 
• 10a Huang J. Xiong H. Hsung RP. Rameshkumar C. Mulder JA. Grebe TP. Org. Lett.  2002,  4:  2417 
• 10b Wei L.-L. Mulder JA. Xiong H. Zificsak CA. Douglas CJ. Hsung RP. Tetrahedron  2001,  57:  459 
• 11 Kitamura T. Tashi N. Tsuda K. Chen H. Fujiwara T. Heterocycles  2000,  52:  303 
• 12a Burley GA. Davies DL. Griffith GA. Lee M. Singh K. J. Org. Chem.  2010,  75:  980 
• 12b Laroche C. Li J. Freyer MW. Kerwin SM. J. Org. Chem.  2008,  73:  6462 
• 12c Das B. Reddy GC. Balasubramanyam P. Salvanna N. Synlett  2011,  816 

13

Typical Procedure for the Synthesis of N -Alkynyl-imidazole A vessel with a magnetic stir bar was charged with imidazole (1a, 68 mg, 1 mmol), CuI (10 mg, 0.05 mmol), Cs₂CO₃ (1.3 g, 4 mmol), and TMEDA (12 mg, 0.1 mmol) under a nitrogen atmosphere. The reaction vessel was evacuated and backfilled with nitrogen three times. In a separate flask, a solution of dry dioxane (2 mL) containing the (2,2-dibromo-vinyl)benzene (2a, 1.5 mmol) was evacuated and back-filled with nitrogen gas three times. The dioxane solution was then added to the reaction flask with a syringe, and the reaction mixture was heated to 80 ˚C for 24 h. The reaction mixture was cooled to r.t., quenched with a sat. NH₄Cl solution (5 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over anhyd Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography with EtOAc and PE (1:4) as eluent to afford the 1-(phenylethynyl)-1H-imidazole (3a) as a yellow oil; yield 82%. ^¹H NMR (500 MHz, CDCl₃): δ = 7.82 (s, 1 H), 7.61-7.45 (m, 2 H), 7.42-7.32 (m, 3 H), 7.20 (d, J = 1.1 Hz, 1 H), 7.09 (s, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 140.2, 131.9, 129.4, 129.2, 128.7, 121.9, 78.2, 70.6. ESI-MS: m/z = 169.1 [M + H]⁺.