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A. Catalano et al. / European Journal of Medicinal Chemistry 64 (2013) 357e364
(d, J ¼ 8.5 Hz, 2H, Ar), 6.75 (d, J ¼ 9.1 Hz, 2H, Ar), 7.15e7.35 (m, 5H,
Ar); 13C NMR (CDCl3):
31.2 (1C), 32.4 (1C), 67.9 (1C), 116.0 (2C),
116.9 (2C), 126.1 (1C), 128.7 (4C), 139.8 (1C), 141.9 (1C), 152.6 (1C).
ether 1:1) to give 0.93 g (65%) of an orange solid: mp 163e164 ꢂC;
IR (KBr): 3436 (NH2) cmꢃ1; GC/MS (70 eV) m/z (%) 194 (Mþ, 81),
d
165 (100); 1H NMR (DMSO-d6):
d
1.28 (t, J ¼ 6.9 Hz, 3H, CH3), 3.34
(br s, exch D2O, 2H, NH2), 3.96 (quartet, J ¼ 7.0 Hz, 2H, CH2), 6.64e
6.80 (m, 1H, Ar), 7.16e7.28 (m, 2H, Ar); 13C NMR (DMSO-d6):
15.5
4.3.2. 4-(4-Phenylbutoxy)aniline (6h)
d
Prepared as reported above for 6f starting from 3h. Yield: 90%;
(1C), 64.1 (1C), 106.8 (1C), 114.0 (1C), 118.7 (1C), 132.5 (1C), 147.4
(1C), 154.1 (1C), 165.4 (1C). Anal. calcd. for C9H10N2OS$0.17H2O
(197.25) %: C, 54.80; H 5.28; N 14.20. Found: C, 55.02; H 5.13; N
13.92.
brown oil; IR (neat): 3361 (NH2) cmꢃ1; GC/MS (70 eV) m/z (%) 241
(Mþ, 53), 109 (100); 1H NMR (CDCl3):
d 1.72e1.88 (m, 4H,
CH2CH2CH2CH2), 2.62e2.75 (m, 2H, CH2eAr), 3.12 (br s, 2H, NH2),
3.85e3.95 (m, 2H, CH2eOAr), 6.60e6.68 (m, 2H, Ar), 6.70e6.78 (m,
2H, Ar), 7.15e7.35 (m, 5H, Ar); 13C NMR (CDCl3):
d
28.1 (1C), 29.3
4.5.1. 6-Methoxy-1,3-benzothiazol-2-amine (1b)
(1C), 35.9 (1C), 68.7 (1C), 116.0 (2C), 116.7 (2C), 126.0 (1C), 128.5
(2C), 128.7 (2C), 140.0 (1C), 142.5 (1C), 152.6 (1C).
Prepared as reported above for 1c starting from 6b. Yield: 26%;
beige crystals: mp: 162e163 ꢂC (CHCl3/hexane); IR (KBr): 3388
(NH2) cmꢃ1; GC/MS (70 eV) m/z (%) 180 (Mþ, 81), 165 (100); 1H
4.4. General procedure for the synthesis of 4-substituted anilines (5
and 6e,n)
NMR (DMSO-d6):
6.75e6.85 (m, 1H, Ar), 7.15e7.30 (m, 2H, Ar); 13C NMR (CDCl3):
56.1 (1C), 105.6 (1C), 113.9 (1C), 119.9 (1C), 132.9 (1C), 146.4 (1C),
d 3.32 (br s, exch D2O, 2H, NH2), 3.71 (s, 3H, CH3),
d
The
method
adopted
for
the
synthesis
of
4-
155.9 (1C), 164.3 (1C). Anal. calcd. for C8H8N2OS$0.50H2O (189.24)
aminophenylmethanol (5) is described. Catalytic hydrogenation of
4 (1.50 g, 9.8 mmol) in 30 mL of a mixture of MeOH and absolute
EtOH (2/1) was conducted at room temperature for 24 h in the
presence of 10% palladium on carbon at 10 bar. The catalyst was
removed by filtration and the residue taken up with EtOAc and
washed with water. The solvent was removed to give 1.03 g (85%) of
a yellow solid which was recrystallized from EtOAc/petroleum
ether to give 0.65 g of yellowish crystals: mp 65e66 ꢂC; GC/MS
(70 eV) m/z (%) 123 (Mþ, 100). Other spectroscopic data were in
agreement with the literature [36].
%: C, 50.78; H 4.79; N 14.80. Found: C, 50.82; H 4.21; N 14.43.
4.5.2. 6-Phenoxy-1,3-benzothiazol-2-amine (1d)
Prepared as reported above for 1c starting from 6d. Yield: 65%;
brown crystals: mp: 171e172 ꢂC (EtOAc/petroleum ether); GC/MS
(70 eV) m/z (%) 242 (Mþ, 100). Anal. calcd. for C13H10N2OS$0.20H2O
(245.90) %: C, 63.50; H 4.26; N 11.39. Found: C, 63.80; H 3.89; N
11.41. Other spectroscopic data were in agreement with the litera-
ture [13].
4.5.3. 6-(Benzyloxy)-1,3-benzothiazol-2-amine (1e)
4.4.1. 4-Benzyloxyaniline (6e)
Prepared as reported above for 1c starting from 6e. Yield: 20%;
brown crystals: mp: 152e153 ꢂC (EtOAc/petroleum ether); IR (KBr):
3436 (NH2) cmꢃ1; GC/MS (70 eV) m/z (%) 256 (Mþ,15),165 (100); 1H
Prepared as reported above for 5 starting from 3e. Yield: 90%;
dark green solid: mp 68e69 ꢂC; IR (KBr): 3355 (NH2) cmꢃ1; GC/MS
(70 eV) m/z (%) 199 (Mþ, 19), 108 (100); LC/MS m/z (%): 200
(Mþ þ H). Other spectroscopic data were in agreement with the
literature [24].
NMR (CDCl3):
(dd, J ¼ 8.8, 2.5 Hz, 1H, Ar benzothiazole), 7.20 (d, J ¼ 2.5 Hz, 1H, Ar
benzothiazole), 7.28e7.48 (m, 6H, Ar); 13C NMR (CDCl3):
71.1 (1C),
d 5.09 (s, 2H, CH2), 5.21 (br s, exch D2O, 2H, NH2), 6.98
d
106.9 (1C), 114.8 (1C), 120.0 (1C), 127.7 (2C), 128.2 (1C), 128.8 (2C),
132.9 (1C), 137.2 (1C), 146.6 (1C), 155.1 (1C), 164.2 (1C). Anal. calcd.
for C14H12N2OS$0.33H2O (262.32) %: C, 64.10; H 4.87; N 10.68.
Found: C, 64.27; H 4.75; N 10.32.
4.4.2. Synthesis of 4-[(4-chlorobenzyl)oxy]aniline (6n)
Prepared as reported above for 5 starting from 3n. This reaction
was carried out at room temperature for 20 min in the presence of
10% palladium on carbon at 3 bar. Yield: 49%; brown crystals: mp
108e109 ꢂC (EtOAc/hexane); IR (KBr): 3366 (NH2) cmꢃ1; GC/MS
4.5.4. 6-(2-Phenylethoxy)-1,3-benzothiazol-2-amine (1f)
(70 eV) m/z (%) 233 (Mþ, 14), 108 (100); 1H NMR (CDCl3):
d
3.44 (br
Prepared as reported above for 1c starting from 6f. Prepared as
reported above for 1c starting from 6f. Yield: 59%; brown crystals:
mp 116e117 ꢂC (EtOAc/hexane); IR (KBr): 3432 (NH2) cmꢃ1; GC/MS
s, exch D2O, 2H, NH2), 4.95 (s, 2H, CH2), 6.58e6.67 (m, 2H, Ar),
6.75e6.85 (m, 2H, Ar), 7.34 (s, 4H, Ar).
(70 eV) m/z (%) 270 (Mþ, 100); 1H NMR (CDCl3):
d
3.10 (t, J ¼ 7.1 Hz,
4.5. General procedure for the synthesis of 6-substituted-2-amino-
1,3-benzothiazoles (1bei)
2H, CH2eAr), 4.18 (t, J ¼ 7.0 Hz, 2H, CH2eOAr), 5.19 (br s, exch D2O,
2H, NH2), 6.90 (dd, J ¼ 8.8, 2.5 Hz, 1H, Ar), 7.12 (d, J ¼ 2.5 Hz, 1H, Ar),
7.20e7.37 (m, 5H, Ar), 7.43 (d, J ¼ 8.8 Hz, 1H, Ar); 13C NMR (CDCl3):
The synthesis of 6-ethoxy-1,3-benzothiazol-2-amine (1c), ob-
tained following a general procedure for the preparation of ami-
nobenzothiazoles described in the literature [13,14] is described.
Aniline 6c (1.0 g, 7.36 mmol) and NH4SCN (1.6 g, 21.9 mmol) were
d 36.1 (1C), 69.8 (1C), 106.6 (1C), 114.6 (1C), 119.9 (1C), 126.7 (1C),
128.7 (2C), 129.2 (2C), 132.8 (1C), 138.4 (1C), 146.3 (1C), 155.1 (1C),
164.2 (1C). Anal. calcd. for C15H14N2OS (270.35) %: C, 66.64; H 5.22;
N 10.36. Found: C, 66.27; H 5.22; N 10.26.
dissolved in
a 20% formic acideglacial acetic acid mixture
(100 mL) and cooled to ꢃ3 ꢂC with stirring, under N2. With the
exclusion of light from the reaction mixture, bromine (0.30 mL
dissolved in 20 mL of glacial acetic acid) was added dropwise,
while the reaction temperature was kept between ꢃ3 ꢂC and 0 ꢂC.
The light shield was removed and the mixture was allowed to
warm to room temperature overnight. Sodium hydroxide pellets
and ice were added with stirring until pH 11 was attained, and the
mixture was extracted with EtOAc. The organic layer was sepa-
rated and filtered through celite to remove polythiocyanogen
(SCN)n. The organic layer was then washed with water, saturated
NaHCO3 and brine; then, the solvent was evaporated in vacuo. The
residue was purified by flash chromatography (EtOAc/petroleum
4.5.5. 6-(3-Phenylpropoxy)-1,3-benzothiazol-2-amine (1g)
Prepared as reported above for 1c starting from 6g. Yield: 41%;
gold crystals: mp 126e127 ꢂC (EtOAc/hexane); IR (KBr): 3419
(NH2) cmꢃ1; GC/MS (70 eV) m/z (%) 284 (Mþ, 81), 166 (100); 1H
NMR (CDCl3):
d
2.05e2.20 (m, 2H, CH2CH2CH2), 2.82 (t, J ¼ 7.6 Hz,
2H, CH2eAr), 3.96 (t, J ¼ 6.3 Hz, 2H, CH2eOAr), 5.18 (br s, exch D2O,
2H, NH2), 6.91 (dd, J ¼ 8.5, 2.6 Hz, 1H, Ar), 7.11 (d, J ¼ 2.5 Hz, 1H, Ar),
7.15e7.35 (m, 5H, Ar), 7.44 (d, J ¼ 8.5 Hz, 1H, Ar); 13C NMR (CDCl3):
d
31.1 (1C), 32.4 (1C), 67.9 (1C), 106.4 (1C), 114.6 (1C), 119.9 (1C),
126.2 (1C), 128.8 (4C), 132.8 (1C), 141.7 (1C), 146.3 (1C), 155.3 (1C),
164.1 (1C). Anal. calcd. for C16H16N2OS (284.38) %: C, 67.58; H 5.67;
N 9.85. Found: C, 67.52; H 5.60; N 9.81.