T. K. Venkatachalam et al.
reaction took place forming a dark brown slurry. The reaction mixture was
heated to 220°C and stirred for additional 8 h maintaining the temperature.
After this period, the mixture was allowed to cool to 100°C, and the viscous
dark liquid was carefully poured into a beaker containing 500 ml of ice/
water mixture. A precipitate was obtained, which was filtered and washed
with 4 × 250 ml of water. The resulting solid was once again placed in an
Erlenmeyer flask and a solution of sodium carbonate (50g/250 ml water)
was added, and the mixture was stirred for 1h. The insoluble precipitate
was filtered off and washed with additional water (2 × 200 ml) and dried
under vacuum to yield a light greenish yellow powder. The product was
further purified by crystallization using methanol/water (80:20) to furnish
the required p-aminophenyl benzothiazole as light yellow needles (5.4g,
0.22 mol, 66% yield). Selected IR bands:3429, 3178, 1636, 1604, 1475,
p-N-Butyl-aminophenyl benzothiazole
1H-NMR (CDCl3) δ ppm: 7.97–7.95 (d, 1H, J = ), 7.89–7.88 (d, 2H, J = ), 7.82–
7.80 (d, 1H, J = ), 7.42–7.39 (t, 1H), 7.30–7.28 (t, 1H), 6.63–6.61 (d, 2H, J = ),
4.01 (bs, 1H), 3.18–3.15 (t, 2H), 1.65–1.59 (m, 2H), 1.45–1.41 (m,2H), 0.97–
0.94 (t, 3H); 13C-NMR (CDCl3):δ ppm: 168.8, 154.4, 150.8, 134.5, 129.1,
125.9, 124.2, 122.4, 122.3, 121.3, 112.2, 43.2, 31.5, 20.2, 13.9.
o-N-Butyl-aminophenyl benzothiazole
1H-NMR (CDCl3) δ ppm: 8.93 (bs, 1H), 7.92–7.90 (d, 1H, J = ), 7.85–7.83
(d, 1H, J = ), 7.72–7.70 (d, 1H, J=), 7.44–7.42 (t, 1H), 7.33–7.27 (m,2H), 6.78–
6.76 (d, 1H, J = ), 6.66–6.64 (t, 1H), 3.32–3.29 (m,2H), 1.80–1.75 (m, 2H),
1.59–1.54 (m,2H), 1.02–0.99 (t, 3H); 13C-NMR (CDCl3):δ ppm: 147.7,
132.1, 130.7, 125.9, 124.7, 122.2, 121.1, 114.8, 111.3, 42.7, 31.3, 20.5, 13.9.
1433, 1312, 1250, 1228, 1182, 1159, 963, 827, 760 cmÀ1 1H-NMR
;
(400MHz) (d6-DMSO), δ ppm: 8.02–7.98 (m, 2H), 7.77–7.73 (d, 2H,
J= 8.0Hz), 7.45–7.44 (t, 1H), 7.36–7.31 (t, 1H), 6.69–6.65(d, 2H, J= 8.0Hz),
5.89 (s, 2H); ES+ mass: m/z calculated for C13H10N2S: 226; found 227 (M + 1}
o-N-Isopropyl-aminophenyl benzothiazole
The use of potassium carbonate in acetonitrile did not yield the required
compound. However, a modification in the synthetic procedure was
adopted for this precursor. In a flask was placed 0.113 g (0.5 mmol) of
o-aminophenyl benzothiazole and 10 ml of dimethyl sulfoxide, and the
mixture was stirred to form a homogenous solution. To this mixture
was added 20 mg (0.5 mmol) of powdered sodium hydroxide resulting
into a deep orange brown solution. To this was added 0.062 g (0.5 mmol)
of isopropyl bromide, and the resulting mixture was stirred at room
temperature for 6 h. The contents were added to 50 ml of ice/water
mixture to obtain a precipitate. The precipitated product was extracted
with ethyl acetate (50 ml), and the organic layer was separated and dried
over anhydrous sodium sulfate. Filtration and rotary evaporation yielded a
residue, which was further purified by preparative thin layer
chromatography to yield a deep yellow product (10% yield). 1H-NMR
(CDCl3):8.94 (1h < NH), 7.93 (d, J = 7.92 Hz, 1H), 7.85 (d, J = 8.27 (1H), 7.72
(d, J = 8.27 Hz, 1H), 7.43 (t, J = 7.24 Hz, 1H), 7.33 (t, J = 7.58 Hz, 1H), 7.29
(t, J = 7.58 Hz, 1H), 6.79 (d, J = 8.62 Hz, 1H), 6.64 (t, J = 7.24 Hz, 1H), 3.82
(m, 1H), 1.36 (d, J = 6.2 Hz, 6H); 13C-NMR (CDCl3) 169.6, 153.6, 146.7,
133.1, 132.0, 130.9, 125.9, 124.7, 122.2, 121.1, 114.6, 114.4, 111.8, 43.6, 22.9.
p-N-Methyl-aminophenyl benzothiazole
A similar procedure was adopted for the preparation of this compound
except p-N-methyl amino benzoic acid was used and the greenish gray
product was further recrystallized using methanol/water mixture (75/25) to
obtain dark shiny crystals of the desired product (3.5 g, 0.014 mol, 35% yield).
IR: 3307, 1654, 1609, 1540,1513, 1466, 1440, 1416, 1342, 1316, 1286,
1255, 1227, 1181, 1161, 1111, 1074, 1007, 962, 864, 824, 758 cmÀ1
;
1H-NMR (200 MHz) (d6-DMSO)δ ppm: 8.0–7.89 (m, 2H), 7.84–7.80(d, 2H,
J = 8.0 Hz), 7.48–7.45 (t, 1H), 7.35–7.28 (t, 1H), 6.66–6.62 (d, 2H,
J = 8.0 Hz), 6.47 (bs, 1H), 3.28 s, 3H); 13C-NMR (d6-DMSO )δ ppm: 168.8,
154.6, 153.2, 134.4, 129.4, 126.9, 124.9, 122.6, 122.4, 120.7, 112.2, 29.9;
EI mass calculated for C14H12N2S: 240, found: 241 (M + 1).
Mono alkylation of aminophenyl bezothiazoles
The mono alkylation reaction was achieved using a standard procedure
described in the succeeding text. The appropriate alkyl iodide/bromide
was used for the mono alkylation reactions. As an example, to prepare
p-N-isopropyl-aminophenyl benzothiazole, 0.452 g (2 mmol) of
p-aminophenyl benzothiazole was placed in a round bottom flask,
40 ml of acetonitrile was added and the contents stirred to form a
homogenous solution. To this mixture was added, with stirring, 0.3 g
(2.2 mmol) of anhydrous potassium carbonate. Using a dry syringe,
0.250 g (2 mmol) of isopropyl bromide was introduced into the flask
and the contents were allowed to reflux for 9 h. After completion of the
reaction, the contents were cooled to room temperature, and the
mixture was filtered. The solvent was removed under vacuum and the
contents were taken up in ethyl acetate (30 ml) and washed with water
and dried over anhydrous sodium sulfate and filtered. Rotary evaporation
of the solvent gave a residue that was column chromatographed over an
alumina basic column using hexane/ethylacetate (90:10) to obtain the
desired compound. (0.136 g, 50% yield). 1H-NMR (CDCl3)δ ppm; 7.99–
7.96 (d,1H, J = 9.0 Hz), 7.92–7.89 (d, 2H, J = 9.0 Hz), 7.85–7.82 (1H, d,
J = 9.0 Hz); 7.46–7.41 (t, 1H), 7.33–7.26 (t, 1H), 6.63–6.60 (d, 2H,
J = 9.0 Hz); 3.92 (s, 1H), 3.75–3.67 (m,1H), 1.25–1.24 (d, 3H, J = 6.0 Hz);
EI mass calculated for C16H16N2S: 268, found: 269 (M + 1).
p-N-Dimethyl-aminophenyl benzothiazole
This compound was prepared using a similar procedure as before except
that methyl iodide and p-methy-aminophenyl benzothiazole was used as
reactants in the presence of sodium hydroxide in dimethyl sulfoxide. The
product was further purified by preparative thin layer chromatography
using hexane/ethyl acetate (80:20) (<15% yield):1H-NMR (CDCl3)δ ppm:
7.96–7.93 (m, 3H), 7.82–7.80 (d, 1H, J = ), 7.42–7.39 (t, 1H), 7.29–7.27
(t, 1H), 6.73–6.71 (d, 2H) J = ), 3.03 (s, 6H); 13C-NMR (CDCl3)δ ppm: 168.8,
154.3, 152.1, 134.5, 128.8,125.9, 124.1, 122.2, 121.3, 111.7, 29.34
o-N-Methyl-aminophenyl benzothiazole
Column chromatography using 100:5 hexane/ethyl acetate gave a deep
yellow product. (yield <15%). 1H-NMR (CDCl3): 8.79 (1H, NH), 7.96
(d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.7, 1H), 7.44
(t, J = 7.7 Hz, 1H), 7.34 (m, 2H), 6.77 (d, J = 8.25 Hz, 1H), 6.69 (t, J = 7.36
1H), 3.04 (d, J = 4.96 Hz, 3H); 13C-NMR (CDCl3) 169.1, 153.2, 148.0, 132.7,
131.7, 130.2, 125.5, 124.3, 121.8, 120.7, 114.6, 114.3, 110.4, 29.3.
p-N-Crotyl-aminophenyl benzothiazole
IR: 3399, 3002, 1611, 1529, 1474, 1455, 1336, 1313, 1255, 1226, 1179,
1123, 1101, 963, 827, 752,1H-NMR (CDCl3)δ ppm: 8.0–7.81 (m, 4H), 7.47–
7.43 (t, 1H), 7.34–7.26 (t, 1H), 6.67–6.63 (d, 2H, J = 8.0 Hz), 5.84–5.51
(m,2H), 3.77–3.74 (d,2H, J = 6.0 Hz), 1.76–1.71 (d, 3H); EI mass calculated
for C17H16N2S: 280, found: 281 (M + 1).
p-N-Ethyl-aminophenyl benzothiazole
1H-NMR (CDCl3)δ ppm: 7.97–7.95 (d, 1H, J = ), 7.90–7.88 (d, 2H, J = ), 7.42–
7.39 (t, 1H), 7.29–7.26 (t, 1H), 6.63–6.61 (d, 2H, J = ), 3.95 (bs, 1H), 3.24–3.20
(m, 2H), 1.29–1.26 (t, 3H); 13C-NMR (CDCl3):δ ppm: 168.7, 154.4, 150.7,
134.5, 129.1, 125.9, 124.2, 122.5, 122.3, 121.3, 112.3, 38.1, 14.7.
o-N-Crotyl-aminophenyl benzothiazole was prepared in analogous
method to that for the preparation of p-N-crotyl-aminophenyl benzothiazole.
o-N-Ethyl-aminophenyl benzothiazole
o-N-Crotyl-aminophenyl benzothiazole
(d, 1H, J = ), 7.74–7.72 (d, 1H, J = ), 7.46–7.43 (t, 1H), 7.36–7.30 (m,2H), 1H-NMR (CDCl3)δ ppm: 9.02 (bs, 1H), 7.96–7.95 (d, 1H, J = ), 7.85–7.84
6.79–6.78 (d, 1H, J = ), 6.69–6.67 (t, 1H), 3.40–3.34 (m,2H), 1.44–1.40 (d, 1H, J = ), 7.74–7.73 (d, 1H, J = ), 7.45–7.43 (t, 1H), 7.34–7.32 (t, 1H),
1H-NMR (CDCl3) δ ppm:8.85 (bs, 1H), 7.96–7.94 (d, 1H, J = ), 7.87–7.85
(t, 3H); 13C-NMR (CDCl3):δ ppm: 169.6, 153.6, 147.5, 132.0, 130.7, 125.9,
124.7, 122.2, 121.2, 114.9, 111.3, 31.6, 14.6.
7.30–7.29 (t, 1H), 6.78–6.77 (d, 1H, J = ), 6.69–6.67 (t, 1H), 5.83–5.80
(m, 1H), 5.69–5.67 (d, 1H, J = ), 3.92 (d, 2H), 1.76–1.75 (d, 3H, J = ),
J. Label Compd. Radiopharm 2014, 57 566–573
Copyright © 2014 John Wiley & Sons, Ltd.