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Synlett 2010(20): 3039-3044  
DOI: 10.1055/s-0030-1259058
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

N,N-Diisopropylformamidine (DIFA) Protection of Anilines in Metalation Reactions

Paul E. Zhichkin*, Sergiy G. Krasutsky, Ravi Krishnamoorthy
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212, USA
Fax: +1(518)5122079; e-Mail: paul.zhichkin@verizon.net;
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Publication History

Received 20 September 2010
Publication Date:
19 November 2010 (online)

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Abstract

A novel N,N-diisopropylformamidine (DIFA) protecting group for anilines was studied. Metalation is often metal-directed by this weakly coordinating and bulky group, making it complementary to ortho-metalation directed by tert-butylcarbamate and pivaloylamide groups and to regular electrophilic reactions of anilines. Importantly, DIFA is removed under nucleophilic conditions and is stable toward acids, thus being orthogonal to tert-butylcarbamate, N-tert-butylamide, and other acid-labile protecting groups.

Key words

protecting groups - regioselectivity - metalation - form­amidine

    References and Notes

  • 1a Chevallier F. Mongin F. Chem. Soc. Rev.  2008,  37:  595 
    Google Scholar
  • 1b Schlosser M. Mongin F. Chem. Soc. Rev.  2007,  36:  1161 
    Google Scholar
  • 1c Majewski M. Snieckus V. Science of Synthesis   Vol. 8a:  Thieme; Stuttgart: 2006.  p.5 
    Google Scholar
  • 1d Schlosser M. Angew. Chem. Int. Ed.  2005,  44:  376 
    Google Scholar
  • 1e Anctil EJ.-G. Snieckus V. Metal-Catalyzed Cross-Coupling Reactions   2nd ed., Vol. 2:  Wiley-VCH; Weinheim: 2004.  p.761 
    Google Scholar
  • 2a Takagishi S. Katsoulos G. Schlosser M. Synlett  1992,  360 
    Google Scholar
  • 2b Baston E. Maggi R. Friedrich K. Schlosser M. Eur. J. Org. Chem.  2001,  3985 
    Google Scholar
  • 2c Leroux F. Castagnetti E. Schlosser M. J. Org. Chem.  2003,  68:  4693 
    Google Scholar
  • For example, see:
  • 3a Schlecker W. Huth A. Ottow E.
    J. Org. Chem.  1995,  60:  8414 
    Google Scholar
  • 3b Carroll W. Zhang X. Tetrahedron Lett.  1997,  38:  2637 
    Google Scholar
  • For the background on N,N-dimethylformamidine protection, see:
  • 4a Hanaya T. Toyota H. Yamamoto H. Synlett  2006,  2075 
    Google Scholar
  • 4b Saneyoshi H. Seio K. Sekine M. J. Org. Chem.  2005,  70:  10453 
    Google Scholar
  • 4c Hikishima S. Minakawa N. Kuramoto K. Fujisawa Y. Ogawa M. Matsuda A. Angew. Chem. Int. Ed.  2005,  44:  596 
    Google Scholar
  • 4d Gudmundsson KJ. Johns BA. Org. Lett.  2003,  5:  1369 
    Google Scholar
  • 4e Wuts PGM. Greene TW. Greene’s Protective Groups in Organic Synthesis   4th ed.:  Wiley-Interscience; Hoboken: 2007.  p.830 
    Google Scholar
  • 5 Varchi G. Jensen AE. Dohle W. Ricci A. Cahiez G. Knochel P. Synlett  2001,  477 
    Google Scholar
  • 6 Review: Meyers A. Aldrichimica Acta  1985,  18:  59 
    Google Scholar
  • 7 Zhichkin P. Peterson L. Beer C. Rennells M. J. Org. Chem.  2008,  73:  8954 
    CrossrefGoogle Scholar
  • 8a Yang X. Knochel P. Synthesis  2006,  2618 
    Google Scholar
  • 8b Staubitz A. Dohle W. Knochel P. Synthesis  2003,  233 
    Google Scholar
  • 8c Lindsay DM. Dohle W. Jensen AE. Kopp F. Knochel P. Org. Lett.  2002,  4:  1819 
    Google Scholar
  • 9 Gall M. McCall JM. TenBrink RE. VonVoigtlander PF. Mohrland JS. J. Med. Chem.  1988,  31:  1816 
    CrossrefGoogle Scholar
  • 12 Li W. Nelson DP. Jensen MS. Hoerrner RS. Cai D. Larsen RD. Reider PJ. J. Org. Chem.  2002,  67:  5394 
    CrossrefGoogle Scholar
  • 14a In THF PhLi/PMDTA is more reactive than PhLi/TMEDA, see: Reich HJ. Green DP. Medina MA. Goldenberg WS. Gudmundson B. Dykstra RR. Phillips NH. J. Am. Chem. Soc.  1998,  120:  7201 
    Google Scholar
  • 14b In Et2O s-BuLi/PMDTA is less reactive than s-BuLi/TMEDA, see: McGrath MJ. Bilke JL. O’Brien P. Chem. Commun.  2006,  2607 
    Google Scholar
  • 14c In hydrocarbons, LDA/PMDTA is less reactive than LDA/TMEDA, see: Remenar JF. Collum DB. J. Am. Chem. Soc.  1998,  120:  4081 
    Google Scholar
  • 16 Maggi R. Schlosser M. J. Org. Chem.  1996,  61:  5430 
    CrossrefGoogle Scholar
  • 18 Inspired by LiMgBuTMP2 base, see: Hawad H. Bayh O. Hoarau C. Trécourt F. Quéguiner G. Marsais F. Tetrahedron  2008,  64:  3236 
    CrossrefGoogle Scholar
  • 19 Huang CQ. Wilcoxen K. McCarthy JR. Haddach M. Webb TR. Gu J. Xie Y.-F. Grigoriadis DE. Chen C. Bioorg. Med. Chem. Lett.  2003,  13:  3375 
    CrossrefGoogle Scholar
10

An aliquot of the reaction mixture was quenched with 5% AcOH in H2O, and the HPLC areas of des-Br 2a or des-Br 2b were compared with those for decomposition products.

11

The anion of 2b obtained using n-BuLi had a half-life of only 1 h at -30 ˚C due to its reaction with 1-bromobutane, a side product of the metal-halogen exchange. After warming to r.t., N′-(4-butylphenyl)-N,N-diisopropylformamidine could be isolated in 90% yield (see Supporting Information for details).

13

See Supporting Information for detailed procedures.

15

No literature on DOM of derivatives of aminobenzoic acids could be found, and only two papers (see ref. 3) dealt with the lithiation of derivatives of aminoheteroarylcarboxylic acids.

17

Confirmed through NOE experiments with 9b and 9c (see Supporting Information).