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DOI: 10.1055/s-0030-1258047
Three-Component Mannich Couplings En Route to Substituted Aminophenol and Benzoxazine Derivatives
Publication History
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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References and Notes
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.
9Compound 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.
11Compound 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.
12Supplementary 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.
14Compound 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.
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.