348 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 Synthesis of compounds 7a–l
5-(4-Pentylphenyl)-1,3,4-thiadiazol-2-amine (3k): 1H NMR
(DMSO-d6, 300 MHz) δ 0.86 (t, 3H, CH3), 1.27 (m, 4H, –CH2CH2–),
1.58 (m, 2H, –CH2–), 2.60 (t, 2H, Ar–CH2), 7.26 (s, 2H, NH2), 7.28–
7.66 (m, 4H, ArH), 7.64; IR(KBr)υ: 3253 (N–H), 3095 (C–H), 1616
(C=N), 1508 (C=C), 1328 (C–N) cm–1. Anal. calcd for C13H17N3S: C,
63.12; H, 6.93; N, 16.99; found: C, 63.17; H, 6.90; N, 16.91%.
5-(3,5-Dinitro-4-methylphenyl)-1,3,4-thiadiazol-2-amine (3l):
1H NMR (DMSO-d6, 300 MHz) δ 2.48 (s, 3H, CH3), 7.72 (s, 2H, NH2),
8.52 (s, 2H, ArH); IR(KBr)υ: 3267 (N–H), 3086 (C–H), 1624 (C=N),
1504 (C=C), 1348 (C–N) cm–1. Anal. calcd for C9H7N5O4S: C, 38.43; H,
2.51; N, 24.90; found: C, 38.38; H, 2.56; N, 24.82%.
Entry
R
Time/h
Yield/%
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
16
20
18
18
16
24
20
18
20
18
18
24
76
82
71
80
85
77
80
85
80
73
70
68
3-Methyl
4-Methoxy
3,4,5-Trimethoxy
2-Bromine
4-Chloro
2-Bromine-4-nitro
3,4-Difluoro
3,5-Difluoro
2-Chloro
7j
7k
7l
4-n-Pentyl
3,5-Nitro-4-methyl
Synthesis of 6; general procedure
The solution of KOH (0.012 mol) with 5 mL H2O was added dropwise
to the mixture of benzisothiazolinone 4 (0.01 mol) and 10 mL H2O.
The mixture was stirred for 1 h at the temperature of 60°C. Then,
the solution of chloroacetic acid 5 (0.01 mol) with 10 mL H2O was
added into the mixture dropwise. The mixture was heated and stirred
for another 5 h at 90°C. The pH was adjusted by 50% KOH solution
to 9–10. After completion of the reaction, crude compound 6 was
obtained by cooling and filtering. The pure compound was obtained by
recrystallisation from ethanol with a yield of 79% as a white solid, m.p.
232–233°C (lit.23 229–230°C).
Experimental
Melting points were recorded on an X-4 binocular microscope
melting point apparatus. 1H NMR spectra were recorded on an
Avance Bruker-500 instrument or Avance Bruker-300 instrument
and chemical shifts in ppm are reported with TMS as the internal
standard. IR spectra in KBr were recorded by a PerkinElmer PE-683
IR spectrometer. Elemental analyses were performed on an Elementer
Vario EL III elementary analysis instrument.
Synthesis of 7a–l; general procedure
Synthesis of 3; general procedure16,17
A mixture of compounds 3a–l (0.01 mol) and 6 (0.0105 mol) in DMF
(30 mL) was added to EDCI (0.012 mol) and HOBT (0.012 mol). The
mixture was stirred for 24 h at room temperature. After completion of
the reaction, the mixture was poured into water. The crude precipitated
was filtered and washed with water to obtain the crude product. Using
column chromatography (ethyl acetate: petroleum ether=1:1) the
crude products were identified as compounds 7a–l.
2-(3-Oxo-1,2-benzothiazol-2(3H)-yl)-N-(5-phenyl-1,3,4-thiadiazole-
2-yl)acetamide (7a): Yield 76%; m.p. 238–239°C; 1H NMR(DMSO-d6,
500 MHz) δ 5.37 (s, 2H, N–CH2), 7.52–8.11 (m, 9H, ArH), 13.07 (s, 1H,
N–H); IR(KBr)υ: 3177 (N–H), 2919 (C–H), 1722, 1640 (C=O), 1568
(C=C), 1310 (C–N) cm–1. Anal. calcd for C17H12N4O2S2: C, 55.42; H,
3.28; N, 15.21; S, 17.41; found: C, 55.26; H, 3.11; N, 15.50; S, 17.11%.
2-(3-Oxo-1,2-benzothiazol-2(3H)-yl)-N-(5-(m-tolyl)-1,3,4-
thiadiazole-2-yl)acetamide (7b): Yield 82%; m.p. 217–218°C;
1H NMR(DMSO-d6, 500 MHz) δ 2.38 (s, 3H, CH3), 5.36 (s, 2H, N–
CH2), 7.33–8.11 (m, 8H, ArH), 13.05 (s, 1H, N–H); IR(KBr)υ: 3177
(N–H), 2918 (C–H), 1709, 1672 (C=O), 1568 (C=C), 1307 (C–N) cm–1.
Anal. calcd for C18H14N4O2S2: C, 56.53; H, 3.69; N, 14.65; S, 16.77;
found: C, 56.58; H, 3.55; N, 14.61; S, 16.43%.
A
mixture of substituted benzoic acid
1
(0.1 mol) and
thiosemicarbazide (0.1 mol) was treated with POCl3 (0.3 mol) dropwise
at 0–5°C and maintained for 30 minutes. The reaction mixture was
allowed to raise temperature to 70 °C and stirred for 4 h. After cooling,
water (50 mL) was added dropwise into the reaction mixture. The pH of
the reaction solution was adjusted to the range of 8–9 with 50% NaOH
solution. The crude product precipitated, filtered, washed with water,
dried and recrystallised from ethanol to afford compound 3 as shown
in Table 2.
Table 2 Physical constants of products 3a–l
Compd
R
Yield/%
M.p. /oC
M.p. (lit.)/oC
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
80
85
70
75
79
74
68
82
77
82
78
72
225–227
238–240
209–211
221–223
191–192
213–215
218–220
202–204
227–228
220–222
186–189
218–222
225–22618
3-Methyl
4-Methoxy
3,4,5-Trimethoxy
2-Bromine
4-Chloro
2-Bromine-4-nitro
3,4-Difluoro
3,5-Difluoro
2-Chloro
4-n-Pentyl
3,5-Dinitro-4-methyl
240–24119
210–21218
22020
192–19421
214–21622
/
/
/
N-(5-(4-Methoxyphenyl)-1,3,4-thiadiazole-2-yl)-2-(3-oxo-1,2-
benzothiazol-2(3H)-yl)acetamide (7c): Yield 71%; m.p. 239–241°C;
1H NMR(DMSO-d6, 500 MHz) δ 3.82 (s, 3H, OCH3), 5.35 (s, 2H, N–
CH2), 7.06–8.11 (m, 8H, ArH), 12.98 (s, 1H, N–H); IR(KBr)υ: 3178 (N–
H), 2917 (C–H), 1718, 1691 (C=O), 1570 (C=C), 1318 (C–N) cm–1. Anal.
calcd for C18H14N4O3S2: C, 54.26; H, 3.54; N, 14.06; S, 16.09; found: C,
54.30; H, 3.72; N, 14.82; S, 16.01%.
3j
3k
3l
220–22118
/
/
2-(3-Oxo-1,2-benzothiazol-2(3H)-yl)-N-(5-(3,4,5-trimethoxy-
phenyl)-1,3,4-thiadiazole-2-yl)acetamide (7d): Yield 80%; m.p.
232–234°C; 1H NMR(DMSO-d6, 500 MHz) δ 3.79 (s, 9H, OCH3), 5.36
(s, 2H, N–CH2), 7.19–8.11 (m, 6H, ArH), 13.05 (s, 1H, N–H); IR(KBr)
υ: 3172 (N–H), 2918 (C–H), 1704, 1676 (C=O), 1586 (C=C), 1310 (C–
N) cm–1. Anal. calcd for C20H18N4O5S2: C, 52.39; H, 3.96; N, 12.22; S,
13.99; found: C, 52.17; H, 3.52; N, 12.29; S, 13.51%.
N-(5-(2-Bromophenyl)-1,3,4-thiadiazole-2-yl)-2-(3-oxo-1,2-
benzothiazol-2(3H)-yl)acetamide (7e): Yield 85%; m.p. 248–49°C;
1H NMR(DMSO-d6, 500 MHz) δ 5.38 (s, 2H, N–CH2), 7.46–8.11 (m,
8H, ArH), 13.13 (s, 1H, N–H); IR(KBr)υ: 3160 (N–H), 2918 (C–H),
1711, 1668 (C=O), 1568 (C=C), 1307 (C–N), 1152 (C–Br) cm–1. Anal.
calcd for C17H11BrN4O2S2: C, 45.64; H 2.48; N 12.52, S, 14.34; found: C,
45.55; H, 2.28; N, 12.72, S, 14.14%.
1
5-(2-Bromo-4-nitrophenyl)-1,3,4-thiadiazol-2-amine (3g): H NMR
(DMSO-d6, 300 MHz) δ 7.67 (s, 2H, NH2), 8.21–8.54 (m, 3H, ArH);
IR(KBr)υ: 3261 (N–H), 3095 (C–H), 1625 (C=N), 1496 (C=C), 1300
(C–N), 1147 (C–C), 514 (C–Br) cm–1. Anal. calcd for C8H5BrN4O2S: C,
31.91; H, 1.67; N, 18.61; found: C, 31.88; H, 1.61; N, 18.58%.
5-(3,4-Difluorophenyl)-1,3,4-thiadiazol-2-amine (3h): 1H NMR
(DMSO-d6, 300 MHz) δ 7.48 (s, 2H, NH2), 7.51–7.87 (m, 3H, ArH);
IR(KBr)υ: 3271 (N–H), 3088 (C–H), 1633 (C=N), 1512 (C=C), 1307
(C–N), 1178 (C–F) cm–1. Anal. calcd for C8H5F2N3S: C, 45.07; H, 2.36;
N, 19.71; found: C, 45.13; H, 2.31; N, 19.64%.
5-(3,5-Difluorophenyl)-1,3,4-thiadiazol-2-amine (3i):1H NMR (DMSO-d6,
300 MHz) δ 7.48 (s, 2H, NH2), 7.28–7.58 (m, 3H, ArH); IR(KBr)υ:
3278 (N–H), 3091 (C–H), 1625 (C=N), 1502 (C=C), 1330 (C–N), 1193
(C–F) cm–1. Anal. calcd for C8H5F2N3S: C, 45.07; H, 2.36; N, 19.71;
found: C, 45.01; H, 2.39; N, 19.68%.
N-(5-(4-Chlorophenyl)-1,3,4-thiadiazole-2-yl)-2-(3-oxo-1,2-
benzothiazol-2(3H)-yl)acetamide (7f): Yield 77%; m.p. 248–250°C;
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