Download PDF
Synlett 2010(16): 2425-2428  
DOI: 10.1055/s-0030-1258047
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Three-Component Mannich Couplings En Route to Substituted Aminophenol and Benzoxazine Derivatives

Sonia Barrosoa, Ana M. Abreua, Ana C. Araújoa, Ana M. Coelhoa, Nuno Maulide*b, Ana M. Martins*a
a Centro de Química Estrutural, Instituto Superior Técnico, Avenida Rovisco Pais, 1049-001 Lisboa, Portugal
e-Mail: ana.martins@ist.utl.pt; Fax: +351(21)8464457;
b Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
e-Mail: maulide@mpi-muelheim.mpg.de;
Further Information

Publication History

Received 21 July 2010
Publication Date:
19 August 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

The three-component Mannich coupling of phenols, primary amines, and aldehydes was investigated. Unexpectedly, benzoxazine products were obtained in most cases, even in instances where steric hindrance would seem to militate against benzoxazine formation. The stereoselective synthesis of such benzoxazines, their hydrolysis to aminophenol derivatives, and the mechanisms involved are presented and discussed.

Key words

benzoxazines - phenols - aldehydes - multicomponent reaction - Mannich bases

    References and Notes

  • 1 For a general review, see: Bujnowski K. Adamczyk A. Synoradzki L. Org. Prep. Proced. Int.  2007,  39:  417 
    CrossrefGoogle Scholar
  • 2a Burke WJ. Smith RP. Weatherbee C. J. Am. Chem. Soc.  1952,  74:  602 
    Google Scholar
  • 2b Tramontini M. Synthesis  1973,  703 
    Google Scholar
  • 2c Tramontini M. Angiolini L. Tetrahedron  1990,  46:  1791 
    Google Scholar
  • 2d Burke WJ. J. Am. Chem. Soc.  1949,  71:  609 
    Google Scholar
  • 3a Kasapoglu F. Cianga J. Yagci Y. Takecihi T.
    J. Polym. Sci. Polym. Chem.  2003,  41:  3320 
    Google Scholar
  • 3b Agag T. Takeichi T. Macromolecules  2003,  36:  6010 
    Google Scholar
  • 3c Ejfler J. Krauzy-Diedzic K. Szafert S. Lis T. Sobota P. Macromolecules  2009,  42:  4008 
    Google Scholar
  • 4a Burke WJ. Weatherbee C. Lau H. Van Lear G. Goken G. J. Am. Chem. Soc.  1964,  29:  909 
    Google Scholar
  • 4b Moloney GP. Craik DJ. Iskander MN. J. Pharm. Sci.  1992,  81:  692 
    Google Scholar
  • 4c Colin JL. Loubinoux B. Tetrahedron Lett.  1982,  23:  4245 
    Google Scholar
  • 5a Woodgate PD. Horner GM. Maynard NP. Rickard CEF. J. Organomet. Chem.  1999,  592:  180 
    Google Scholar
  • 5b Lyle RE. Walsh DA. J. Organomet. Chem.  1974,  67:  363 
    Google Scholar
  • 5c Chirachanchai S. Laobuthee A. Phongtamburg S. Siripatanasarakit W. Ishida H. J. Appl. Polym. Sci.  2000,  77:  2561 
    Google Scholar
  • 6 Barroso S. Cui J. Carretas JM. Cruz A. Santos IC. Duarte MT. Telo JP. Marques N. Martins AM. Organometallics  2009,  28:  3449 
    CrossrefGoogle Scholar
  • 7 Tshuva EY. Versano M. Goldberg I. Kol M. Weitman M. Goldschmidt Z. Inorg. Chem. Commun.  1999,  2:  371 
    CrossrefGoogle Scholar
  • For isolated examples, see:
  • 10a Morimura S. Heterocycles  1980,  1331 
    Google Scholar
  • 10b Neuvonen K. Pihlaja K. Acta Chem. Scand.  1993,  47:  695 
    Google Scholar
  • 10c

    For a discussion of how steric hindrance around the phenol OH affects benzoxazine formation, see ref. 4a.

    Google Scholar
  • 13 Higham CS. Dowling DP. Shaw JL. Cetin A. Ziegler CJ. Farrell JR. Tetrahedron Lett.  2006,  47:  4419 ; and references cited therein
    CrossrefGoogle Scholar
  • 15 Bürgi HB. Dunitz JD. Shefter E. J. Am. Chem. Soc.  1973,  95:  5065 
    CrossrefGoogle Scholar
8

Compound 7a: ¹H NMR (300 MHz, CDCl3): δ = 7.20 (m, 5 H, Ar), 7.07 (d, J HH = 2.08 Hz, 1 H, Ar), 6.67 (d, J HH = 2.21 Hz, 1 H, Ar), 4.71 (s, 2 H, NCH2O), 3.90 (s, 2 H, ArCH2N), 3.80 (s, 2 H, CH2Ph), 1.30 [s, 9 H, C(CH3)3], 1.70 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz , CDCl3): δ = 150.7, 142.2, 138.5, 136.7 (C ipso ), 129.2 (2 C, Ar), 128.6 (2 C, Ar), 127.4 (Ar), 122.2 (2 C, Ar), 119.0 (C ipso ), 81.0 (NCH2O), 55.8 (CH2Ph), 51.1 (ArCH2N), 35.0, 34.4 (C(CH3)3), 31.7, 29.8 (C(CH3)3) ppm. Anal. Calcd for C23H31NO: C, 81.85; H, 9.26; N, 4.15. Found: C, 82.12; H, 10.22; N, 3.84.

9

Compound 7d: ¹H NMR (300 MHz, CDCl3): δ = 7.78 (s, 1 H, Ar), 7.75 (s, 1 H, Ar), 7.37 (m, 14 H, Ar), 6.93 (d, J HH = 2.23 Hz, 1 H, Ar), 5.92 (s, 1 H, OCHPhN), 4.98 (s, 1 H, ArCHPhN), 3.94 (d, J HH = 13.95 Hz, 1 H, CH2Ph), 3.49 (d, J HH = 13.96 Hz, 1 H, CH2Ph), 1.66 [s, 9 H, C(CH3)3], 1.37 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 151.1, 144.5, 141.9, 139.5, 138.9, 136.8 (C ipso ), 129.2 (2 C, Ar), 129.1 (2 C, Ar), 128.3 (2 C, Ar), 128.2 (2 C, Ar), 128.0 (2 C, Ar), 127.7, 127.0, 126.9 (Ar), 126.6 (2 C, Ar), 125.2, 122.5 (Ar), 118.5 (C ipso ), 85.7 (ArCHPhN), 60.8 (NCHPhO), 49.4 (CH2Ph), 35.1, 34.3 [C(CH3)3], 31.6, 29.9 [C(CH3)3] ppm. Anal. Calcd for C35H39NO: C, 85.84; H, 8.03; N, 2.86. Found: C, 84.87; H, 8.51; N, 3.56.

11

Compound 7e: ¹H NMR (300 MHz, CDCl3): δ = 7.68 (d, J HH = 7.41 Hz, 2 H, Ar), 7.56 (d, J HH = 7.48 Hz, 2 H, Ar), 7.45 (m, 5 H, Ar), 7.73 (m, 2 H, Ar), 7.07 (d, J HH = 2.23 Hz, 1 H, Ar), 5.78 (s, 1 H, NCHPhO), 5.20 (s, 1 H, ArCHPhN), 3.01 (m, 1 H, CH 2), 2.84 (m, 1 H, CH2), 2.72 (m, 1 H, CH2), 2.55 (m, 1 H, CH2), 2.24 [s, 6 H, N(CH3)2] 1.66 [s, 9 H, C(CH3)3], 1.44 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 152.8, 144.6, 138.7, 137.0, 135.4 (C ipso ), 129.1 (2 C, Ar), 128.0 (4 C, Ar), 126.5 (2 C, Ar), 125.0, 123.8, 122.5 (Ar), 118.9 (C ipso ), 85.7 (NCHPhO), 63.2 (ArCHPhN), 59.1 (CH2), 45.4 [N(CH3)2], 43.2 (CH2), 35.1, 34.8 [C(CH3)3], 31.6, 29.9 [C(CH3)3] ppm. Colourless crystals of 7e suitable for X-ray diffraction were obtained from a MeOH solution at -20 ˚C. Anal. Calcd for C32H42N2O˙C14H22O: C, 81.65; H, 9.29; N, 4.23. Found: C, 81.47; H, 10.11; N, 4.17.

12

Supplementary crystallographic data for 7e and 10e may be obtained from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/cif or by E-mail to data_request@ccdc.cam.ac.uk) under the deposit numbers CCDC 773865 and CCDC 773866, respectively.

14

Compound 8a: ¹H NMR (300 MHz, CDCl3): δ = 7.57 (d, J HH = 8.3 Hz, 2 H, Ar), 7.50 (d, J HH = 8.1 Hz, 2 H, Ar), 7.22 (d, J HH = 1.9 Hz, 1 H, Ar), 6.69 (d, J HH = 1.8 Hz, 1 H, Ar), 4.94 (s, 1 H, ArCHPhN), 2.75 (m, 2 H, CH2), 2.59 (m, 2 H, CH2), 2.42 (m, 1 H, CH2), 2.21 [s, 6 H, N(CH3)2] 1.44 [s, 9 H, C(CH3)3], 1.21 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 154.4, 146.3, 140.7, 136.7 (C ipso ), 129.6 (Ar), 128,1 (2 C, Ar), 125.9 (2 C, Ar), 123.7, 123.4 (Ar), 68.3 (ArCHPhN), 58.4 (CH2), 45.5 [N(CH3)2], 45.2 (CH2), 35.2, 34.3 [C(CH3)3], 31.8, 29.8 [C(CH3)3] ppm. In this case, small amounts of the corresponding benzoxazine were also detected.
Compound 8b: ¹H NMR (300 MHz, CDCl3): δ = 7.45 (d, J HH = 8.4 Hz, 2 H, Ar), 7.26 (d, J HH = 8.4 Hz, 2 H, Ar), 7.21 (d, J HH = 2.3 Hz, 1 H, Ar), 6.66 (d, J HH = 2.2 Hz, 1 H, Ar), 4.86 (s, 1 H, ArCHPhN), 2.72 (m, 2 H, CH2), 2.58 (m, 1 H, CH2), 2.36 (m, 1 H, CH2), 2.19 [s, 6 H, N(CH3)2], 1.45 [s, 9 H, C(CH3)3], 1.21 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 154.4, 141.3, 140.5, 136.5 (C ipso ), 132.0 (2 C, Ar), 129,6 (2 C, Ar), 123.8 (C ipso ), 132.0, 129.5 (Ar), 121.6 (C ipso ), 67.9 (ArCHPhN), 58.4 (CH2), 45.5 [N(CH3)2], 45.1 (CH2), 35.2, 34.3 [C(CH3)3], 31.8, 29.8 [C(CH3)3] ppm.

16

Compound 10a: ¹H NMR (300 MHz, CDCl3): δ = 7.49 (m, 2 H, Ar), 7.37 (m, 3 H, Ar), 7.31 (d, J HH = 2.20 Hz, 1 H, Ar), 6.96 (d, J HH = 2.15 Hz, 1 H, Ar), 3.92 (s, 2 H, ArCH2N), 3.86 (s, 2 H, CH2Ph), 1.38 [s, 9 H, C(CH3)3], 1.23 [s, 9 H, C(CH3)3] ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 151.3, 144.4, 141.4 (C ipso ), 130.1 (2 C, Ar), 130.0 (C ipso ), 129.4 (Ar), 129.1 (2 C, Ar), 126.9, 125.7 (Ar), 121.3 (C ipso ), 49.4 (ArCH2N), 46.5 (CH2Ph), 35.1, 34.3 [C(CH3)3], 31.4, 30.1 [C(CH3)3] ppm. Anal. Calcd for C22H31NO˙2.12 (CH3OH): C, 73.37; H, 10.13; N, 3.53. Found: C, 73.33; H, 9.80; N, 3.66.
Compound 10b: ¹H NMR (300 MHz, CDCl3): δ = 7.27 (s, 1 H, Ar), 7.07 (s, 1 H, Ar), 3.97 (s, 2 H, ArCH2N), 2.69 (m, 1 H, CH, Cy), 1.97 (m, 2 H, CH2, Cy), 1.73 (m, 2 H, CH2, Cy), 1.62 (m, 1 H, CH2, Cy), 1.42 [s, 9 H, C(CH3)3], 1.29 [s, 9 H, C(CH3)3], 1.19 (m, 5 H, CH2, Cy) ppm. ¹³C-{¹H} NMR (75 MHz, CDCl3): δ = 152.7, 142.8, 129.0 (C ipso ), 125.9, 124,3 (Ar), 121.6 (C ipso ), 56.9 (CH, Cy), 47.1 (ArCH2N), 35.2, 34.4 [C(CH3)3], 31.5, 30.1 [C(CH3)3], 29.8 (2 C, CH2, Cy), 25.3 (CH2, Cy), 24.9 (2 C, CH2, Cy) ppm. Anal. Calcd for C21H35NO˙2.64 (CH3OH): C, 70.62; H, 11.42; N, 3.48. Found: C, 70.54; H, 10.50; N, 3.96.