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S. Mavel et al. / Bioorg. Med. Chem. 18 (2010) 236–241
N(CH3)2), 3.54 (s, 2H, CH2); 6.52(dd, 1Har, J = 9 Hz,J = 2 Hz), 6.89–6.95 (m,
2Har), 7.30–7.55 (m, 2Har), 7.83 (s, 1Har). 13C NMR (CDCl3): d 20.4, 45.0
(2C), 56.5, 105.3 (2JC–F = 24 Hz), 111.0 (2JC–F = 20 Hz), 120.7, 125.1, 125.9,
132.3 (3JC–F = 9 Hz), 134.1, 134.9, 140.8, 147.4, 155.0 (3JC–F = 10 Hz),
162.1 (1JC–F = 247 Hz).
J = 1.8 Hz), 6.72–6.91 (m, 3Har), 7.12 (dd, 1Har, J = 8.8 Hz, J = 3 Hz).
13C NMR (CDCl3): d 20.9, 45.1 (2C), 58.0, 114.7 (2JCF = 23 Hz), 117.0,
117.2 (3JCF = 7 Hz), 117.5 (2JCF = 23 Hz), 118.5, 120.1, 129.7
(3JCF = 7 Hz), 134.6, 138.8, 141.0, 152.0, 157.5 (1JCF = 240 Hz). MS:
m/z = 274 (24), 228 (63), 166 (58), 152 (34), 58 (44), 44 (100).
6.1.4.3. 5-Fluoro-N,N-dimethyl-2-(2-nitro-4-toloxy)benzylamine
6.1.5.4. 4-Methoxy-N,N-dimethyl-2-(2-amino-4-methylphenoxy)
benzylamine (12a). Compound 12a (73% yield). 1H NMR (CDCl3): d 2.30
(s, 9H, CH3, N(CH3)2), 3.55 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 4.25 (br s,
NH2), 6.44 (d, J = 2.5 Hz, 1Har), 6.50–6.62 (m, 3Har), 6.86 (d, J = 8 Hz,
1Har), 7.21 (d, J = 8.3 Hz, 1Har). 13C NMR (CDCl3): d 20.9, 44.9 (2C),
55.2, 58.1, 102.1, 106.7, 116.9, 118.2, 119.9, 121.1, 131.8, 134.8, 139.3,
140.2, 157.4, 160.1.
1
(6c). Compound 6c (57% yield). H NMR (CDCl3): d 2.35 (br s, 9H, CH3,
N(CH3)2), 4.09 (s, 2H, CH2), 6.60–7.41 (m, 6Har). 13C NMR (CDCl3): d
20.2, 50.2 (2C), 60.4, 117.1 (2JC–F = 24 Hz), 118.7 (2JC–F = 23 Hz), 120.2
(3JC–F = 8 Hz), 121.3, 123.8 (3JC–F = 7 Hz), 125.8, 134.6, 135.1, 140.8,
146.9, 151.5, 157.9 (1JC–F = 244 Hz).
6.1.4.4. 4-Methoxy-N,N-dimethyl-2-(2-nitro-4-toloxy)benzyl-
amine (11a)
.
Compound 11a (95% yield). 1H NMR (CDCl3): d 2.23 (s,
6.1.5.5. 5-Methoxy-N,N-dimethyl-2-(2-amino-4-methylphenoxy)
benzylamine (12b). Compound 12b (71% yield). 1HNMR(CDCl3): d2.28 (s,
9H, N(CH3)2, CH3), 3.53 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 4.30 (br s, NH2), 6.40
(dd, J = 8 Hz,J = 1.8 Hz, 1Har), 6.50 (d, J = 1.8 Hz, 1Har), 6.70–6.84 (m, 3Har),
6.95(d,J = 2.8 Hz, 1Har). 13CNMR(CDCl3):d20.9, 45.4(2C), 55.6, 58.4,113.3,
116.3, 116.8, 117.6, 118.3, 119.4, 129.6, 133.8, 138.5, 141.8, 149.6, 154.9.
6H, N(CH3)2), 2.40 (s, 3H, CH3), 3.42 (s, 2H, CH2), 3.75 (s, 3H, OCH3),
6.44 (d, J = 2.5 Hz, 1Har), 6.75 (dd, J = 8.5 Hz, J = 2.5 Hz, 1Har), 6.85 (d,
J = 8.5 Hz, 1Har), 7.29 (dd, J = 8.5 Hz, J = 2 Hz, 1Har), 7.77 (d, J = 2 Hz,
1Har). 13C NMR (CDCl3): d 20.4, 34.8, 38,5, 55,5, 62,5, 105.0, 110.2,
120.5, 121.5, 125.4, 129.7, 133.8, 135.1, 147.6, 152.5, 161.4, 167.9.
6.1.4.5. 5-Methoxy-N,N-dimethyl-2-(2-nitro-4-toloxy)benzyl-
amine (11b). Compound 11b (93% yield). 1H NMR (CDCl3): d 2.24
(s, 6H, N(CH3)2), 2.38 (s, 3H, CH3), 3.42 (s, 2H, CH2), 3.85 (s, 3H,
OCH3), 6.70 (d, J = 8.5 Hz, 1Har), 6.81 (dd, J = 8.5 Hz, J = 3 Hz,
1Har), 6.91 (d, J = 8.5 Hz, 1Har), 7.12 (d, J = 3 Hz, 1Har), 7.25 (dd,
J = 8.5 Hz, J = 2.3 Hz, 1Har), 7.75 (d, J = 2.3 Hz, 1Har). 13C NMR
(CDCl3): d 20.2, 45.4 (2C), 55.6, 57.3, 114.0, 115.5, 117.7, 121.2,
125.6, 131.8, 132.0, 134.5, 139.7, 146.5, 149.8, 156.9.
6.1.6. Synthesis of compounds (13a,b)
General procedure: To a solution of 12a,b (0.35 mmol) in CH2Cl2
freshly distilled (50 mL), at ꢀ40 °C, was added BBr3 (0.306 g,
1.23 mmol). The reaction mixture was stirred at rt overnight. The
residue was then dissolved in MeOH and stirred during 1 h at rt.
The CH2Cl2 and MeOH were removed under vacuo and the crude
product was treated with H2O, basified with a solution of NaHCO3.
The mixture was extracted with EtOAc. The crude compound is
purified on aluminium oxide (CH2Cl2/MeOH: 90/10).
6.1.5. Synthesis of compounds (7a–c) and (12a,b)
General procedure: To a solution of compound 6a–c or 11a,b
(0.11 mmol), 10 N HCl (1 mL) and MeOH (3.5 mL) was added by
portion below 5 °C SnCl2 (0.71 g, 0.38 mmol). The reaction mixture
was stirred at rt overnight. MeOH was eliminated under reduce
pressure and the crude product was treated with H2O (1 mL),
basified with 10 N NaOH solution to pH 10 and extracted with
EtOAc (3 ꢁ 3 mL). The organic phase was dried and removed under
vacuo and flash chromatography on silica gel (EtOAc/MeOH 100/0
to 90/10).
6.1.6.1. 3-(2-Amino-4-methylphenoxy)-4-[(dimethylamino)
methyl]phenol (13a). Compound 13a (71% yield). 1H NMR
(CDCl3): d 2.25 (s, 9H, CH3, N(CH3)2), 3.47 (s, 2H, CH2), 4.99 (br s,
3H, NH2, OH), 6.10 (d, 1H, J = 2.0 Hz), 6.30 (dd, 1Har, J = 8.2 Hz,
J = 2.0 Hz), 6.47 (d, 1Har, J = 8 Hz), 6.57(s, 1Har), 6.66 (d, 1Har,
J = 8.2 Hz), 7.00 (d, 1Har, J = 8.2 Hz). 13C NMR (CDCl3): d 20.8,
43.9 (2C), 56.6, 103.8, 110, 115.23, 117.2, 119.1, 120.2, 132.8,
134.5, 138.5, 140.5, 157.2, 158.6.
6.1.6.2. 4-(2-Amino-4-methylphenoxy)-3-[(dimethylamino)
methyl]phenol (13b). Compound 13b (57% yield). 1H NMR
(CDCl3): d 2.27 (s, 3H, CH3), 2.40 (s, 6H, N(CH3)2), 3.60 (s, 2H,
CH2), 4.18 (br s, 3H, NH2, OH), 6.48 (dd, 1Har, J = 8.1 Hz,
J = 1.5 Hz), 6.59 (d, 1Har, J = 8.1 Hz), 6.66–6.80 (m, 3Har), 6.83 (s,
1Har). 13C NMR (CDCl3): d 20.9, 44.5 (2C), 57.1, 116.9, 117.0,
118.0, 118.6, 118.9 (2C), 126.6, 133.6, 137.7, 142.4, 148.6, 152.5.
6.1.5.1. 4-Fluoro-N,N-dimethyl-2-(2-amino-4-methylphenyl-
thio)benzylamine (7a). Compound 7a (62% yield). 1H NMR
(CDCl3): d 2.32 (s, 3H, CH3), 2.36 (s, 6H, N(CH3)2), 3.59 (s, CH2),
4.20 (br s, 2H, NH2), 6.65 (d, 1Har, J = 7.8 Hz), 6.73 (s, 1Har), 6.93–
7.27 (m, 3Har), 6.78 (dd, 1Har, J = 8.6 Hz, J = 2 Hz). 13C NMR (CDCl3):
d
21.3, 45.2 (2C), 53.4, 114.7 (2JCF = 22 Hz), 115.9, 116.7
(2JCF = 22 Hz), 117.6, 118.5, 119.6, 129.1 (3JCF = 8 Hz), 132.1, 137.1,
137.4, 141.3, 148.5 (3JCF = 12 Hz), 160.9 (1JCF = 244 Hz). MS: m/z =
290 (12), 243 (30), 183 (100), 168 (42), 152 (31), 58 (34), 44 (58).
6.1.7. Synthesis of compounds (14a,b), and (16)
General procedure: Compound 12 (60 mg, 0.2 mmol) was dis-
solved in 5 mL of DMF in presence of Cs2CO3 (143 mg, 0.4 mmol).
The mixture was stirred at room temperature for 10 min and then
was added 1-bromo-2-fluoroethane or 1-bromo-4-fluorobutane
(0.4 mmol). The mixture was stirred at reflux for 4 h. The reaction
mixture was poured into water and extracted with EtOAc. The or-
ganic layers were washed with water, dried and concentrated un-
der reduced pressure to give the crude derivative.
6.1.5.2. 4-Fluoro-N,N-dimethyl-2-(2-amino-4-methylphenoxy)-
benzylamine (7b). Compound 7b (70% yield). 1H NMR (CDCl3): d
2.31 (br s, 9H, CH3, N(CH3)2), 3.58 (s, 2H, CH2), 4.52 (s, 2H, NH2),
6.53–6.70 (m, 4Har), 6.90 (d, 1Har, J = 8 Hz), 7.25 (dd, 1Har,
J = 8 Hz, J = 6.5 Hz). 13C NMR (CDCl3): d 21.1, 45.0 (2C), 58.2,
102.9 (2JCF = 25 Hz), 108.3 (2JCF = 21 Hz), 117.2, 118.3, 121.7,
123.2, 132.0 (3JCF = 9 Hz), 135.6, 139.6, 139.6, 157.8 (3JCF = 10 Hz),
162.9 (1JCF = 246 Hz). MS: m/z = 274 (42), 228 (74), 216 (3), 166
(82), 150 (23), 107 (35), 58 (36), 44 (100).
6.1.7.1. N,N-Dimethyl-4-(2-fluoroethoxy)-2-(2-amino-4-meth-
ylphenoxy)benzylamine (14a). The crude product was purified by
flash chromatography on silica gel (EtOAc/Hex: 4/6) to give 14a as
a white solid (10% yield). 1H NMR (CDCl3): d 2.31 (br s, 9H, N(CH3)2,
CH3), 3.60 (s, CH2), 4.10 (td, J = 28 Hz, J = 4 Hz, OCH2), 4.68 (dt,
J = 47 Hz, J = 4 Hz, CH2F), 6.48 (d, J = 2.5 Hz, 1Har), 6.45 (d,
6.1.5.3. 5-Fluoro-N,N-dimethyl-2-(2-amino-4-methylphenoxy)-
benzylamine (7c). Compound 7c (68% yield). 1H NMR (CDCl3): d
2.30 (s, 3H, CH3), 2.36 (s, 6H, N(CH3)2), 3.61 (s, 2H, CH2), 4.13 (br s,
2H, NH2), 6.54 (dd, 1Har, J = 3 Hz, J = 1.4 Hz), 6.64 (d, 1Har,