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Synlett 2012(2): 285-289  
DOI: 10.1055/s-0031-1290069
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Room-Temperature Palladium-Catalyzed Coupling of Heteroaryl Amines with Aryl or Heteroaryl Bromides

Thomas A. Moss*, Matthew S. Addie, Thorsten Nowak, Michael J. Waring
AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK
e-Mail: thomas.moss@astrazeneca.com;
Further Information

Publication History

Received 6 October 2011
Publication Date:
04 January 2012 (online)

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Abstract

Heteroaryl amines readily undergo Buchwald-Hartwig amination reactions with a range of aryl and heteroaryl bromides at room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu. The pharmaceutically attractive biaryl amines are generally formed in short reaction times (0.5-16 h) and in good to excellent yields.

Key words

amination - biaryl amine - coupling - heteroaryl amine - palladium

    References and Notes

  • 1a Torborg C. Beller M. Adv. Synth. Catal.  2009,  351:  3027 
    Google Scholar
  • 1b Horton DA. Bourne GT. Smythe ML. Chem. Rev.  2003,  103:  893 
    Google Scholar
  • 2a Guram AS. Rennels RA. Buchwald SL. Angew. Chem., Int. Ed. Engl.  1995,  34:  1348 
    Google Scholar
  • 2b Louie J. Hartwig JF. Tetrahedron Lett.  1995,  36:  3609 
    Google Scholar
  • 3a Surry DS. Buchwald SL. Chem. Sci.  2011,  2:  27 
    Google Scholar
  • 3b Maiti D. Fors BP. Henderson JL. Nakamura Y. Buchwald SL. Chem. Sci.  2011,  2:  57 
    Google Scholar
  • 3c Hartwig JF. Acc. Chem. Res.  2008,  41:  1534 
    Google Scholar
  • 3d Marion N. Nolan SP. Acc. Chem. Res.  2008,  41:  1440 
    Google Scholar
  • 3e Shen Q. Ogata T. Hartwig JF. J. Am. Chem. Soc.  2008,  130:  6586 
    Google Scholar
  • 3f Marion N. Navarro O. Mei JG. Stevens ED. Scott NM. Nolan SP. J. Am. Chem. Soc.  2006,  128:  4101 
    Google Scholar
  • 4a Anderson KW. Tundel RE. Ikawa T. Altman RA. Buchwald SL. Angew. Chem. Int. Ed.  2006,  45:  6523 
    Google Scholar
  • 4b Tundel RE. Anderson KW. Buchwald SL. J. Org. Chem.  2006,  71:  430 
    Google Scholar
  • 4c Usui S. Suzuki T. Hattori Y. Etoh K. Fujieda H. Nishizuka M. Imagawa M. Nakagawa H. Kohda K. Miyata N. Bioorg. Med. Chem. Lett.  2005,  15:  1547 
    Google Scholar
  • 4d Byth KF. Culshaw JD. Green S. Oakes SE. Thomas AP. Bioorg. Med. Chem. Lett.  2004,  14:  2245 
    Google Scholar
  • 5 Schulte JP. Tweedie SR. Synlett  2007,  2331 
    Google Scholar
  • 6a Biscoe MR. Fors BP. Buchwald SL. J. Am. Chem. Soc.  2008,  130:  6686 
    Google Scholar
  • 6b Kinzel T. Zhang Y. Buchwald SL. J. Am. Chem. Soc.  2010,  132:  14073 
    Google Scholar
  • 7 Buchwald has described a system for preactivating Pd(OAc)2/X-Phos systems in water, see: Fors BP. Krattiger P. Strieter E. Buchwald SL. Org. Lett.  2008,  10:  3505 
    Google Scholar
  • 8a Aryl iodides have been shown to undergo Kumada-Corriu cross-coupling reactions with Grignard reagents at -20 ˚C: Martin R. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3844 
    Google Scholar
  • 8b Benzophenone imine has been used as an ammonia surrogate in Buchwald-Hartwig aminations: Bhagwanth S. Adjabeng GM. Hornberger KR. Tetrahedron Lett.  2009,  50:  1582 
    Google Scholar
  • 9a Bikker JA. Brooijmans N. Wissner A. Mansour TS. J. Med. Chem.  2009,  52:  1493 
    Google Scholar
  • 9b Quintas-Cardama A. Kantarjian H. Cortes J. Nat. Rev. Drug Discovery  2007,  6:  834 
    Google Scholar
  • 10 Henderson JL. Buchwald SL. Org. Lett.  2010,  12:  4442 
    Google Scholar
  • 11a Shen Q. Ogata T. Hartwig JF. J. Am. Chem. Soc.  2008,  130:  6586 
    Google Scholar
  • 11b Shen QL. Shekhar S. Stambuli JP. Hartwig JF. Angew. Chem. Int. Ed.  2005,  44:  1371 
    Google Scholar
  • 11c Paul F. Patt J. Hartwig JF. Organometallics  1995,  14:  3030 
    Google Scholar
  • 12a Lippa B. Morris J. Corbett M. Kwan TA. Noe MC. Snow SL. Gant TG. Mangiaracina M. Coffey HA. Foster B. Knauth EA. Wessel MD. Bioorg. Med. Chem. Lett.  2006,  16:  3444 
    Google Scholar
  • 12b Park S.-E. Kang SB. Jung K.-J. Won J.-E. Lee S.-G. Yoon Y.-J. Synthesis  2009,  815 
    Google Scholar
  • 13 Evans RC. Wiselogle FY. J. Am. Chem. Soc.  1944,  67:  60 
    Google Scholar
14

Representative General Procedure; Coupling of Pyrazole 2 and 2-Bromopyridine: 3-Methylpyrazol-
5-amine (2; 1.50 mmol, 146 mg), t-BuXPhos Pd(II) phenethylamine chloride 1 (0.015 mmol, 10.3 mg), t-BuXPhos (0.015 mmol, 6.4 mg) and NaOt-Bu (3.15 mmol, 303 mg) were charged into a round-bottom flask which was evacuated and back-filled with nitrogen (3 ×), then purged with a stream of nitrogen for 10 min. t-BuOH (5 mL) and
2-bromopyridine (1.88 mmol, 296 mg) were added via syringe and the reaction was stirred at r.t. for 4 h. The solvent was removed then H2O, sat. aq NH4Cl and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc-MeOH, 9:1) to give the biaryl amine as a white solid (229.5 mg, 88%); mp 177-179 ˚C. IR: 3521 (br), 2995 (m), 1525 (s), 1503 (m), 1495 (m), 1420 (s), 1281 (m) cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.19 (s, 3 H, Me), 6.04 (s, 1 H, CHpyrazole), 6.68 (m, 1 H, CHAr), 7.22 (m, 1 H, CHAr), 7.52 (dd, 1 H, J = 7.2, 7.0 Hz, CHAr), 8.09 (d, 1 H, J = 4.1 Hz, CHAr), 9.00 (s, 1 H, NH), 11.73 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 10.95, 94.12, 109.22, 113.60, 137.12, 138.87, 147.40, 149.06, 155.39. MS (ES): m/z (%) = 175 [M + H]+(100), 158 (100), 134 (80), 107 (25). HRMS: m/z [M + H]+ calcd for C9H11N4: 175.09782; found: 175.09778.