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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)

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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

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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.

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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.

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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.

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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.

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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.