M.A. Alisi et al. / Tetrahedron 68 (2012) 10180e10187
10185
(DMSO-d6):
d
(ppm) 170.3 (C]O), 148.8 (C(4)), 131.0 (C(1)), 124.2
C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.33; H 6.04;
(C(5), C(3)), 119.6 (C(6), C(2)) 38.1 (CH2CH2CH3), 18.7 (CH2CH2CH3),
16.7 (2ꢃCH3), 13.4 (CH2CH2CH3); mp 138.4e139.6 ꢁC (EtOH/H2O),
(lit.44 (i-PrOH/i-Pr2O) 137.5e139 ꢁC). Anal. Calcd for C12H17NO2: C,
69.54; H, 8.27; N, 6.76. Found: C, 69.33; H, 8.07; N, 6.71.
N, 6.61.
5.3.10. N-(4-Hydroxy-3-iso-propyl-1-naphthyl)-acetamide 13. Pale
brown powder. IR (CHCl3): 3234, 1645; 1H NMR (DMSO-d6):
d
(ppm) 1.28 (d, J¼6.9, 6H, CH3CHCH3), 2.29 (s, 3H, CH3CO), 3.54
5.3.4. 20-Chloro-N-(4-hydroxy-3,5-dimethylphenyl)
4. White powder. IR (KBrdDRIFTS): 3258, 1629; 1H NMR (DMSO-
d6):
(ppm) 2.16 (s, 6H, 2ꢃ CH3) 7.26 (s, 2H, HeC(2), HeC(6))
7.38e7.56 (m, 4H, HeC(30), HeC(40), HeC(50), HeC(60)) 8.04 (s, 1H,
OH) 10.06 (s, 1H, NH); 13C NMR (DMSO-d6):
(ppm) 164.2 (C]O),
149.5 (C(4)), 137.3, 130.7, 130.5, 129.9, 129.5, 128.8, 127.1, 124.3
(C(3), C(5)), 120.0 (C(2), C(6)), 16.7 (2ꢃ CH3); mp 211e214 ꢁC
(AcOEt/hexane). Anal. Calcd for C15H14ClNO2: C, 65.34; H, 5.12; N,
5.08. Found: C, 65.11; H, 5.09; N, 5.00.
benzamide
(spt, J¼6.9, 1H, CH3CHCH3), 3.88 (s, 1H, OH), 7.24 (s, 1H, HeC(2))
7.38e7.52 (m, 2H, HeC(6), HeC(7)), 7.03e6.98 (m, 1H, HeC(5)),
7.45e7.39 (m, 1H, HeC(8)); 8.63 (s, 1H, NH); 13C NMR (CD3OD):
d
d
(ppm) 173.6 (C]O), 148.9 (C(4)), 130.5, 130.4, 128.2, 127.1, 127.0,
d
126.5, 124.1, 123.9, 123.8, 28.1 (CH3CHCH3), 23.8 (CH3CHCH3), 23.5
(CH3CO); mp: 202.4e203.6 ꢁC (CHCl3). Anal. Calcd for C15H17NO2: C,
74.05; H, 7.04; N, 5.76. Found: C, 74.03; H, 7.04; N, 5.55.
5.3.11. N-(40-Hydroxy-30-methyl-10-naphthyl)-3-(400-iso-butyl-
phenyl)-propanamide 14. White powder. IR (UATR): 3425, 3290,
5.3.5. N-(3,5-Di-iso-propyl-4-hydroxyphenyl)-acetamide 5.45 White
needles. IR (KBrdDRIFTS): 3450, 3283, 1636; 1H NMR (DMSO-d6):
1641; 1H NMR (DMSO-d6):
d
(ppm) 0.92 (d, J¼6.6, 6H,
CH2CH(CH3)2), 1.80e1.95 (m, 1H, CH2CH(CH3)2), 1.97 (s, 3H, CH3),
2.49 (d, J¼7.2, 2H, CH2CH(CH3)2), 2.80 (t, J¼7.3, 2H, CH2CH2CO), 3.13
(t, J¼7.3, 2H, CH2CH2CO), 6.40 (s, 1H, OH), 7.03 (s, 1H, HeC(20)), 7.08
(s, 1H, NH), 7.09e7.18 (m, 2H), 7.20e7.36 (m, 5H), 7.89e8.01 (m,
d
(ppm) 1.13 (d, J¼6.8, 12H, 4ꢃ CH3), 1.98 (s, 3H, CH3CO), 3.29 (spt,
J¼6.8, 2H, 2ꢃ CH3CHCH3), 7.21 (s, 2H, HeC(6), HeC(2)), 7.80 (s, 1H,
OH), 9.60 (s, 1H, NH); 13C NMR (DMSO-d6):
(ppm) 167.3 (C]O),
d
146.2 (C(4)), 135.4 (C(5), C(3)), 132.0 (C(1)), 114.5 (C(6), C(2)), 26.1
(2ꢃ CH3CHCH3), 23.7 (CH3CO), 22.8 (4ꢃ CH3); mp: 168.6e169.5 ꢁC
(EtOH/H2O) (lit.45 165e166 ꢁC). Anal. Calcd for C14H21NO2: C, 71.46;
H, 8.99; N, 5.95. Found: C, 71.33; H, 8.98; N, 6.11.
1H); 13C NMR (DMSO-d6):
d (ppm) 171.0 (C]O), 147.6 (C(4)), 138.6,
138.4, 128.8, 128.3, 128.1, 126.5, 125.5, 125.2, 124.6, 122.8, 121.9, 44.2
(CH2CH(CH3)2), 37.3 (CH2CH2CO), 30.8 (CH2CH2CO), 29.6
(CH2CH(CH3)2), 22.1 (CH2CH(CH3)2), 16.3 (CH3); mp: 169e170 ꢁC
(AcOEt/hexane). Anal. Calcd for C24H27NO2 : C, 79.74; H, 7.53; N,
3.87. Found: C, 79.44; H, 7.66; N, 3.95.
5.3.6. N-(3,5-Di-tert-butyl-4-hydroxyphenyl)-acetamide 6.46 White
needles. IR (KBrdDRIFTS): 3626, 3313, 1656; 1H NMR (DMSO-d6):
d
(ppm) 1.36 (s, 18H, 6ꢃ CH3), 1.97 (s, 3H, CH3CO), 6.71 (s, 1H, OH),
7.36 (s, 2H, HeC(6), HeC(2)), 9.59 (s, 1H, NH); 13C NMR (DMSO-d6):
(ppm) 167.4 (C]O), 149.4 (C(4)), 139.6 (C(5), C(3)), 131.8 (C(1),
5.4. Procedure for the preparation of 4-{2-[(4-hydroxy-3,5-
dimethylphenyl)amino]-2-oxoethyl}-4-methylmorpholin-4-
ium iodide 8
d
116.1 (C(6), C(2)), 34.6 (2ꢃ CeCH3)3, 30.3 (6ꢃ CH3), 23.7; mp:
171.3e173.1 ꢁC (EtOH/H2O) (lit.46 170.0e170.5 ꢁC). Anal. Calcd for
C16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C, 72.90; H, 9.33;
N, 5.40.
To a solution of the known carboxylic acid 1716 (1.6 g, 8.6 mmol)
and DMAP (2.1 g, 17 mmol) in CH2Cl2 (30 mL), DCC (3.6 g, 17 mmol)
was added at rt. After 5 min, the 4-amino-2,6-dimethylphenol
(1.1 g, 7.7 mmol) was slowly added and the mixture was stirred
overnight. The reaction was filtered and the filtrate washed with
a saturated aqueous solution of NH4Cl and brine. After solvent
evaporation, the crude residue was purified by flash chromatog-
raphy (hexane/AcOEt¼7/3) and by crystallization (AcOEt), to afford
N-(4-hydroxy-3,5-dimethylphenyl)-2-morpholin-4-ylacetamide
(1.3 g, 4.9 mmol). A solution of N-(4-hydroxy-3,5-dimethylphenyl)-
2-morpholin-4-ylacetamide (1.0 g, 3.8 mmol) and CH3I (4.0 mL,
64 mmol) in THF (20 mL) was refluxed overnight. After solvent
evaporation, the crude residue was purified by crystallization (hex-
ane/AcOEt) to afford 4-{2-[(4-hydroxy-3,5-dimethylphenyl)amino]-
2-oxoethyl}-4-methylmorpholin-4-ium iodide 8 (0.70 g, 1.7 mmol,
yield 45%).
5.3.7. 2-Chloro-N-(20-hydroxy-[1,10; 30,100]terphenyl-50-yl)-benzamide
7. White powder. IR (UATR): 3544, 3522, 3435, 3270, 1615; 1H NMR
(DMSO-d6):
(m, 6H), 7.61 (s, 2H, HeC(60), HeC(40)), 8.16 (s, 1H, OH), 10.37 (s, 1H,
NH); 13C NMR (DMSO-d6): (ppm) 164.5 (C]O), 146.7 (C(20)),138.6,
d (ppm) 7.31e7.40 (m, 2H), 7.40e7.50 (m, 6H), 7.51e7.60
d
137.0,132.0,131.2,130.9,129.6,129.3,128.9,128.2,127.2,126.9,121.3;
mp: 147e149 ꢁC (AcOEt). Anal. Calcd For C25H18ClNO2: C, 75.00; H,
4.54; N, 3.50. Found: C, 74.63; H, 4.36; N, 3.48.
5.3.8. N-(40-Hydroxy-30,50-dimethylphenyl)-3-(400-iso-butylphenyl)-
propanamide 11. Off-white powder. IR (UATR): 3445, 3296, 1654;
1H NMR (DMSO-d6):
d
(ppm) 0.84 (d, J¼6.6, 6H, CH2CH(CH3)2),
1.70e1.88 (m, 1H, CH2CH(CH3)2), 2.12 (s, 6H, 2ꢃ CH3), 2.39 (d, J¼7.1,
White powder. IR (UATR): 3385, 3255, 1672; 1H NMR (DMSO-
2H, CH2CH(CH3)2), 2.52 (t, J¼7.4, 2H, CH2CH2CO), 2.84 (t, J¼7.4, 2H,
d6):
d
(ppm) 2.14 (s, 6H, 2ꢃ CH3), 3.41 (s, 3H, CH3N), 3.58e3.79 (m,
CH2CH2CO), 7.01e7.17 (m, 6H), 7.91 (s, 1H, OH), 9.45 (s, 1H, NH); 13
C
4H), 3.89e4.08 (m, 4H), 4.40 (s, 2H, CH2CO), 7.12 (s, 2H, HeC(6),
NMR (DMSO-d6):
d
(ppm) 169.7 (C]O), 149.0 (C(40)), 138.6, 138.5,
HeC(2)), 8.16 (s, 1H, OH), 10.19 (s, 1H, NH); 13C NMR (DMSO-d6):
131.0 (C(C10)), 128.9, 128.0, 124.3, 119.7, 44.3 (CH2CH(CH3)2), 37.9
(C(2)), 30.7 (C(3)), 29.6 (CH2CH(CH3)2), 22.2 (CH2CH(CH3)2), 16.8
(2ꢃ CH3); mp: 149e150 ꢁC (AcOEt). Anal. Calcd for C21H27NO2: C,
77.50; H, 8.36; N, 4.30. Found: C, 77.10; H, 8.45; N, 4.28.
d (ppm) 160.2 (C]O), 149.9 (C(4)), 128.6 (C(1)), 124.4 (C(3), C(5)),
120.3 (C(2), C(6)), 62.8 (CH2eCO), 60.2 (C(30), C(50)), 59.6 (C(20),
C(60)), 48.2 (CH3N), 15.9 (2ꢃ CH3); mp: 176e178 ꢁC (hexane/AcOEt).
Anal. Calcd for C15H23IN2O3: C, 44.35; H, 5.71; N, 6.90. Found: C,
44.38; H, 5.60; N, 6.70.
5.3.9. N-(4-Hydroxy-3-methyl-1-naphthyl)-acetamide 12.47 Pale-
pink powder. IR (KBrdDRIFTS): 3355, 3263, 1656; 1H NMR (DMSO-
5.5. Preparation of [1-(propan-2-yl)-1H-indazol-3-yl]acetic
d6):
d
(ppm) 2.13 (s, 3H, CH3CO), 2.33 (s, 3H, CH3), 7.29 (s, 1H,
acid 18b
HeC(2)), 7.35e7.52 (m, 2H, HeC(6), HeC(7)), 7.76e7.96 (m, 1H,
HeC(8)), 8.15e8.32 (m, 1H, HeC(5)), 9.03 (s, 1H, OH), 9.65 (s, 1H,
Indazol-3-acetic acid (40 g; 0.23 mol, prepared as in Ref. 18) was
esterified by heating for 4 h in the presence of CH3OH (500 mL) and
H2SO4 (5 mL); the reaction was quenched by adding cold water (1 L)
and the solid methyl ester was filtered off. A part of the solid ob-
tained (30 g) was dissolved in CH3CN (1 L), 2-bromopropane
NH); 13C NMR (DMSO-d6):
d (ppm) 168.8 (C]O), 147.5 (C(4)), 128.1
(C(1)), 126.4 (C(7)), 125.4 (C(9)), 125.3 (C(3)), 124.7, 124.6, 122.6
(C(5)), 121.9 (C(2)), 117.5 (C(10)), 23.0 (CH3CO), 16.3 (CH3); mp:
206.7e208.5 (CHCl3/CH3OH); (lit.47 208e210 ꢁC). Anal. Calcd for