Download PDF
Synlett 2007(15): 2331-2336  
DOI: 10.1055/s-2007-985597
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Couplings of Heteroaryl Amines with Aryl Halides Using Sodium Phenolate as the Stoichiometric Base

James P. Schulte II*, Scott R. Tweedie
Albany Molecular Research, Inc., 21 Corporate Circle, Albany, NY 12203, USA
Fax: +1(518)5122085; e-Mail: James.Schulte@amriglobal.com;
Further Information

Publication History

Received 29 May 2007
Publication Date:
22 August 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

Heteroaryl amines are efficiently coupled (in two hours) to aryl halides with catalytic Pd2(dba)3 and Xantphos to provide the corresponding biaryl amines under microwave and standard thermal conditions. The use of organic-soluble sodium phenolate (NaOPh) as the stoichiometric base promotes facile coupling of a variety of substrates in excellent yields.

Key words

palladium-catalyzed - sodium phenolate - C-N bond-forming - biaryl amine - heteroaryl amine

    References and Notes

  • 1a Okushima H, Narimatsu A, Kobayashi M, Furuya R, and Kitada Y. inventors; US 4 661  484. 
  • 1b Blancafort P. Serradell MN. Castañer J. Thorpe P. Drugs Future  1983,  8:  223 
    Google Scholar
  • 1c Kim KS, Kimball SD, Cai Z.-W, Rawlins DB, Misra RN, Poss MA, Webster KR, Hunt JT, and Han W.-C. inventors; US 6 262  096B1. 
  • 1d Rackur G, and Hoffman I. inventors; US 4 302  468. 
  • 1e Castañer J. Prous J. Drugs Future  1986,  11:  465 
    Google Scholar
  • 2 Yang J.-S. Lin Y.-H. Yang C.-S. Org. Lett.  2002,  4:  777 
    CrossrefGoogle Scholar
  • 3 Yin J. Zhao MM. Huffman MA. McNamara JM. Org. Lett.  2002,  4:  3481 
    CrossrefGoogle Scholar
  • 4 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 
    CrossrefGoogle Scholar
  • 5 Byth KF. Culshaw JD. Green S. Oakes SE. Thomas AP. Bioorg. Med. Chem. Lett.  2004,  14:  2245 
    CrossrefPubMedGoogle Scholar
  • 6 Tundel RE. Anderson KW. Buchwald SL. J. Org. Chem.  2006,  71:  430 
    CrossrefPubMedGoogle Scholar
  • 7 Anderson KW. Tundel RE. Ikawa T. Altman RA. Buchwald SL. Angew. Chem.  2006,  45:  6523 
    CrossrefGoogle Scholar
  • 9a Wolfe JP. Buchwald SL. Tetrahedron Lett.  1997,  38:  6359 
    Google Scholar
  • 9b Ali MH. Buchwald SL. J. Org. Chem.  2001,  66:  2560 
    Google Scholar
  • 9c Wolfe JP. Buchwald SL. J. Org. Chem.  2000,  65:  1144 
    Google Scholar
  • 9d Wolfe JP. Tomori H. Sadighi JP. Yin J. Buchwald SL. J. Org. Chem.  2000,  65:  1158 
    Google Scholar
  • 9e Jensen TA. Liang X. Tanner D. Skaerbaek N. J. Org. Chem.  2004,  69:  4936 
    Google Scholar
  • For examples of NaOPh in Pd-catalyzed couplings of carbamates to aryl halides, see:
  • 10a Hartwig JF. Kawatsura M. Hauck SI. Shaughnessy KH. Alcazar-Roman LM. J. Org. Chem.  1999,  64:  5575 
    CrossrefGoogle Scholar
  • 10b For the use of NaOPh in Suzuki couplings, see: Miyaura N. Yamada K. Suginome H. Suzuki A. J. Am. Chem. Soc.  1985,  107:  972 
    CrossrefGoogle Scholar
  • 10c Komatsu A, Akutagawa S, and Someya T. inventors; U  3859374.  For the use of NaOPh in isoprene dimerization, see:
    CrossrefGoogle Scholar
  • For a study of the effects on reaction rate with the use of sodium 2,4,6-tri-tert-butylphenoxide, NaOt-Bu, and NaOCEt3, see:
  • 11a Shekhar S. Hartwig JF. Organometallics  2007,  26:  340 
    CrossrefGoogle Scholar
  • 11b Alcazar-Roman LM. Hartwig JF. J. Am. Chem. Soc.  2001,  123:  12905 
    CrossrefGoogle Scholar
  • For studies on the scope and limitations of Pd-catalyzed formation of biarylethers from sodium phenolates, see:
  • 14a Mann G. Incarvito C. Rheingold AL. Hartwig JF. J. Am. Chem. Soc.  1999,  121:  3224 
    CrossrefGoogle Scholar
  • 14b Kataoka N. Shelby Q. Stambuli JP. Hartwig JF. J. Org. Chem.  2002,  67:  5553 
    CrossrefGoogle Scholar
  • 14c Aranyos A. Old DW. Kiyomori A. Wolfe JP. Sadighi JP. Buchwald SL. J. Am. Chem. Soc.  1999,  121:  4369 
    CrossrefGoogle Scholar
8

At the time of this manuscript’s preparation, a search via ACD and ACX failed to find any commercially available arylnonaflates.

12

All microwave reactions were conducted in a 2-5 mL Biotage Microwave Vial Kit with sealable cap (code no. 351521) using a magnetic stirbar. Microwave heating was performed with a single-mode cavity Emrys SmithCreator.

13

General Procedure for Compounds Shown in Table 3
A 2-5 mL Biotage microwave vial was charged with the aryl halide (1.10 mmol), sodium phenolate (191 mg, 1.65 mmol), Pd2(dba)3 (12.6 mg, 0.0137 mmol, 2.5 mol% of Pd), and Xantphos (19.1 mg, 0.0330 mmol, 3.0 mol%) followed by degassed 1,4-dioxane (6.50 mL). The mixture was stirred while degassing with argon for 1 min. The heteroaryl amine (1.21 mmol) was added last, the vial was immediately capped and sealed, then heated at 80 °C for 2 h. After cooling to r.t., the mixture was diluted with EtOAc (400 mL), washed with 1 N aq NaOH (3 × 100 mL) and brine (100 mL), dried over anhyd Na2SO4, filtered, and the solvent removed under vacuum. The resulting residue was purified over silica gel (12 g, hexanes-EtOAc) and the product was freeze-dried from MeCN-H2O to provide the pure product.