Y.H. Eissa Mohammed et al.
Biomedicine&Pharmacotherapy95(2017)375–386
4.2.2.6. 2-(2-Isopropylphenoxy) acetic acid (4f). Yield 69%; M.P.
132–135 °C; FT-IR (KBr, νmaxcm−1): 1715–1735 (C]O), 1249–1258
(Ar–OeC), 3355–3473 (OH); 1H NMR (400 MHz, DMSO) δ (ppm): 1.17
(d, J = 8 Hz, 6H, CH3), 3.11 (m, H, CH), 4.89 (s, 2H, OCH2), 6.92-8.01
(m, 4H, Ar-H), 14.02 (bs, 1H, OH); LC–MS m/z 195 [M+1]. Anal.
Calcd. for C11H14O3 (194): C, 68.02; H, 7.27. Found: C, 68.00H, 7.19%.
4.2.4. General synthetic procedure for N'-(6-chloropyridazin-3-yl)-2-
phenoxyacetohydrazide analogues (6a-l)
To phenoxyacetic acids (4a-l, 2 mmol) stirring in dry DCM (20 ml),
lutidine (3 mmol) was added at 25–30 °C, followed by the addition of 3-
chloro-6-hydrazinylpyridazine (5b, 2 mmol). The reaction mixture was
stirred at the same temperature for 30 min. After reducing the tem-
perature to 0–5 °C, TBTU (2 mmol) was added to the mixture. The
temperature was maintained below 5 °C over a period of 30 min. The
reaction mass was stirred overnight and monitored by TLC. The solvent
was evaporated under reduced pressure, quenched by the addition of
crushed ice and the obtained solid was filtered, dried. This crude pro-
duct was subjected to column chromatography and eluted with the
solvent mixture of ethyl acetate: hexane (8:2) to get the pure product
and was recrystallized to afford compounds 6a-l in good yield.
4.2.2.7. 2-(4-Fluorophenoxy)acetic acid (4g). Yield 73%; M.P. 103–106
°C; FT-IR (KBr, νmaxcm−1): 1725–1755 (C]O), 1250–1260 (Ar–OeC),
3345–3380 (OH); 1H NMR (400 MHz, DMSO) δ (ppm): 4.59 (s, 2H,
OCH2), 7.09 (d, J = 8.80 Hz, 2H, Ar-H), 7.02-7.09 (d, J = 8.80 Hz, 2H,
Ar-H), 13.93 (bs, 1H, OH); LC–MS m/z 170 [M+]. Anal. Calcd. for
C8H7FO3 (170): C, 56.48; H, 4.15. Found: C, 56.39; H, 4.09%.
4.2.2.8. (4-Methylphenoxy)acetic acid (4 h). Yield 81%; M.P.
142–144 °C; FT-IR (KBr, νmaxcm−1): 1730–1745 (C]O), 1253–1262
(Ar–OeC), 3375–3380 (OH); 1H NMR (400 MHz, DMSO) δ (ppm): 2.39
(s, 3H, CH3), 4.66 (s, 2H, OCH2), 6.79-6.84 (d, J = 8.80 Hz, 2H, Ar-H),
7.03-7.09 (d, J = 8.80 Hz, 2H, Ar-H), 13.13 (bs, 1H, OH); LC–MS m/z
167 [M+1]. Anal. Calcd. for C9H10O3 (166): C, 65.05; H, 6.07. Found:
C, 65.02; H, 6.04%.
4.2.4.1. N'-(6-Chloropyridazin-3-yl)-2-phenoxyacetohydrazide
(6a). Yield 82%; M.P 160–162 °C; FT-IR (KBr, νmaxcm−1): 1674 (C]
O), 3120–3220 (NHeNH); 1H NMR (400 MHz, DMSO) δ (ppm): 4.76 (s,
2H, OCH2), 7.92–7.75 (m, 7H, Ar-H), 10.10 (s, 1H, NH), 10.30 (s, 1H,
NH); 13C NMR (100 MHz, DMSO): δ 66.82, 115.16, 120.08, 121.25,
129.25, 130.55, 154.3, 159.50, 162.01, 167.74; LC–MS m/z 279 [M+]
281 [M+2]. Anal. Calcd. For C12H11ClN4O2 (279): C, 51.72; H, 3.98; N,
20.10. Found: C, 51.78; H, 3.94; N, 20.06%.
4.2.2.9. 2-(4-Chloro-2-fluorophenoxy)acetic acid (4i). Yield 76%; M.P.
62–65 °C; FT-IR (KBr, νmaxcm−1): 1735–1755 (C]O), 1247–1257
(Ar–OeC), 3354–3386 (OH); 1H NMR (400 MHz, DMSO) δ (ppm):
4.78 (s, 2H, OCH2), 6.83-8.85 (m, 3H, Ar-H), 12.98 (bs, 1H, OH);
LC–MS m/z 205 [M+], 207 [M+2]. Anal. Calcd. for C8H6ClFO3 (205):
C, 46.97; H, 2.96. Found: C, 46.89; H, 2.87%.
4.2.4.2. 2-(2-Bromophenoxy)-N'-(6-chloropyridazin-3-yl)acetohydrazide
(6b). Yield 78%; M.P 170–172 °C; FT-IR (KBr, νmaxcm−1): 1644 (C]
O), 3109–3121 (NHeNH); 1H NMR (400 MHz, DMSO) δ (ppm): 4.79 (s,
2H, OCH2), 6.83–8.09 (m, 6H, Ar-H), 8.90 (s, 1H, NH), 11.03 (s, 1H,
NH);13C NMR (100 MHz, DMSO): δ 67.01, 111.12, 113.29, 120.09,
123.91, 129.18, 130.18, 133.99, 151.50, 154.9, 162.04, 166.74; LC–MS
m/z 358 [M+] 360 [M+2] 362 (M+4). Anal. Calcd. For
4.2.2.10. 2-(2,4-Diisopropylphenoxy)acetic acid (4j). Yield 78%; M.P.
82–85 °C; FT-IR (KBr, νmaxcm−1): 1725–1748 (C]O), 1258–1260
(Ar–OeC), 3348–3399 (OH); 1H NMR (400 MHz, DMSO) δ (ppm):
1.21 (d, J = 8 Hz, 12H, 4CH3), 3.09 (m, 2H, 2CH), 4.69 (s, 2H, OCH2),
5.99-7.45 (m, 3H, Ar-H), 13.26 (bs, 1H, OH); LC–MS m/z 237 [M+1].
Anal. Calcd. for C14H20O3 (236): C, 71.16; H, 8.53. Found: C, 71.06; H,
8.48%.
C12H10BrClN4O2: C, 40.31; H, 2.82; N, 15.67. Found: C, 40.29; H,
2.80; N, 15.64%.
4.2.4.3. 2-(4-Chloro-3-methylphenoxy)-N'-(6-chloropyridazin-3-yl)
acetohydrazide (6c). Yield 76%; M.P 129–131 °C; FT-IR (KBr,
νmaxcm−1): 1663 (C]O), 3137–3250 (NHeNH); 1H NMR (400 MHz,
DMSO) δ (ppm): 2.35 (s, 3H, CH3), 4.01 (s, 2H, OCH2), 7.01-7.99 (m,
5H, Ar-H), 9.06 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (100 MHz,
DMSO): δ 21.28, 67.79, 114.08, 114.59, 119.99, 128.92, 129.55
130.17, 133.81, 152.39, 158.59, 163.03, 166.95; LC–MS m/z 327 [M
+] 329 [M+2] 331 [M+4]. Anal. Calcd. For C13H12Cl2N4O2 (327): C,
47.73; H, 3.70; N, 17.13. Found: C, 47.73; H, 3.69; N, 17.11%.
4.2.2.11. 4-Chlorophenoxyacetic acid (4k). Yield 88%; M.P. 155–158 °C;
FT-IR (KBr, νmaxcm−1): 1701–1725 (C]O), 1243–1253 (Ar–OeC),
3375–3376 (OH); 1H NMR (400 MHz, DMSO) δ (ppm): 4.58 (s, 2H,
OCH2), 7.09 (d, J = 8.80 Hz, 2H, Ar-H), 7.38 (d, J = 8.80 Hz, 2H, Ar-
H), 14.02 (bs, 1H, OH); LC–MS m/z 187 [M+], 189 [M+2]. Anal.
Calcd. for C8H7ClO3 (187): C, 51.50; H, 3.78. Found: C, 51.48; H,
3.69%.
4.2.4.4. N'-(6-Chloropyridazin-3-yl)-2-(o-tolyloxy)acetohydrazide
(6d). Yield 83%; M.P 128–130 °C; FT-IR (KBr, νmaxcm−1): 1649 (C]
O), 3119–3259 (NHeNH); 1H NMR (400 MHz, DMSO) δ (ppm): 2.15 (s,
3H, CH3), 5.01 (s, 2H, OCH2), 6.89-7.35 (m, 6H, Ar-H), 8.97 (s, 1H,
NH), 10.49 (s, 1H, NH); 13C NMR (100 MHz, DMSO): δ 16.02, 65.99,
113.22, 119.73, 121.29, 125.77, 126.90, 129.91, 132.06, 152.03,
159.25, 162.19, 167.43; LC–MS m/z 293 [M+] 295 [M+2]. Anal.
Calcd. For C13H13ClN4O2 (293): C, 53.34; H, 4.48; N, 19.14. Found: C,
53.32; H, 4.44; N, 19.11%.
4.2.2.12. 2-(2-Fluoro-4-nitrophenoxy) acetic acid (4l). Yield 87%; M.P.
139–141 °C; FT-IR (KBr, νmaxcm−1): 1722–17265 (C]O), 1244–1254
(Ar–OeC), 3369–3380 (OH); 1H NMR (400 MHz, DMSO) δ (ppm): 4.67
(s, 2H, OCH2), 7.26-8.09 (m, 3H, Ar-H), 12.03 (bs, IH, OH); LC–MS m/z
215 [M+]. Anal. Calcd. for C8H6FNO5 (215): C, 44.66; H, 2.81; N, 6.51.
Found: C, 44.57; H, 2.79; N, 6.47%.
4.2.3. General synthetic procedure for 3-chloro-6-hydrazinylpyridazine
(5b)
After stirring the compound 3,6-dichloropyridazine (5a, 2 mmol) in
ethanol (20 ml) for 15 min at room temperature, hydrazine hydrate
(2 mmol) was added. Further, the reaction was refluxed for 1 h at
100 °C and it was monitored by TLC using hexane: ethyl acetate (2:1) as
the mobile phase. The white product of 3-chloro-6-hydrazinylpyr-
idazine (5b) was filtered, washed and after drying, recrystallized from
ethanol. Yield 62%; M.P. 136–138 °C; FT-IR (KBr, νmaxcm−1):
1178–1181 (C]N), 3327-3139 (hydrazine NHNH2), 1H NMR
(400 MHz, DMSO) δ (ppm): 4.59 (bs, 2H, NH2), 7.21 (d, J = 8 Hz, 2H,
Ar-H), 8.48 (s, 1H, NH); LC–MS m/z 145 [M+] 147 [M+2]. Anal.
Calcd. for C4H5ClN4 (145): C, 33.23; H, 3.49; N, 38.76. Found: C, 33.21;
H, 3.47; N, 38.73%.
4.2.4.5. N'-(6-Chloropyridazin-3-yl)-2-(2,4-difluorophenoxy)
acetohydrazide (6e). Yield 78%; M.P 122–124 °C; FT-IR (KBr,
νmaxcm−1): 1657 (C]O), 3110–3222 (NHeNH); 1H NMR (400 MHz,
DMSO) δ (ppm): 4.55 (s, 2H, OCH2), 7.44-8.11 (m, 5H, Ar-H), 9.05 (s,
1H, NH), 9.99 (s, 1H, NH); 13C NMR (100 MHz, DMSO): δ 67.19,
107.17, 113.11, 118.04, 119.92, 129.82, 146.11, 152.33, 153.04,
154.11, 162.07, 167.08; LC–MS m/z 315 [M+] 317 [M+2]. Anal.
Calcd. For C12H9ClF2N4O2 (315): C, 45.80; H, 2.88; N, 17.80. Found: C,
45.78; H, 2.86; N, 17.76%.
4.2.4.6. N'-(6-Chloropyridazin-3-yl)-2-(2-isopropylphenoxy)
acetohydrazide (6f). Yield 78%; M.P 132–134 °C; FT-IR (KBr,
383