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3.2.5. Synthesis of Different Carbohydrazide Derivatives (7, 8)

MN Manar I. Nagy
KD Khaled M. Darwish
SK Safaa M. Kishk
MT Mohamed A. Tantawy
AN Ali M. Nasr
MQ Mona Qushawy
SS Shady A. Swidan
SM Samia M. Mostafa
IS Ismail Salama
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Equimolar amount of appropriate aromatic aldehyde was added to a solution of the hydrazide compound (6) (10 mmol) in absolute ethanol (5 mL), in presence of catalytic amount of glacial acetic acid (0.4 mL). Reaction mixture was allowed to reflux with continuous stirring for about 1.5 h and poured into ice/water mixture. The precipitate was filtered, washed with cold water and purified by flash column chromatography using gradient elution of EtOAc: n-hexane to give the corresponding carbohydrazide [67,68,69].

N′-benzylidene-1H-indole-2-carbohydrazide (7a) [67].

Prepared from benzaldehyde, yield 0.045 g (45%), as an off-white powder. M.p. 111–113 °C. TLC (EtOAc: n-Hexane 1:2), Rf: 0.40. 1H NMR (DMSO-d6): δ 7.08 (d, J = 7.34 Hz, 2H, CH, Ar), 7.28 (s, 1H, CH, indole), 7.54–7.59 (m, 5H, CH, Ar), 7.78 (d, J = 6.11 Hz, 2H, CH, Ar), 8.47 (s, 1H, CH=N), 11.76 (s, 1H, NH, indole), 11.92 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 111.1 (CH, Ar), 114.9 (CH, Ar), 119.8 (CH, Ar), 120.7 (CH, Ar), 121.7 (CH, Ar), 128.8 (2 × CH, Ar), 129.3 (2 × CH, Ar), 131.3 (C, Ar), 133.7 (C, Ar), 138.5 (C, Ar), 139.8 (C, Ar), 146.8 (2 × CH, Ar), 157.6 (C=O). MS (EI+) m/z: 263.55 [M+]. Anal. Calcd for C16H13N3O (263.30): C, 72.99; H, 4.98; N, 15.96. Found: C, 72.92; H, 5.03; N, 16.14

N′-(4-methoxybenzylidene)-1H-indole-2-carbohydrazide (7b) [69].

Prepared from 4-methoxybenzaldehyde, yield 0.03 g (30%), as an off-white powder. M.p. 104–106 °C (Lit. M.p. 98.9 °C). TLC (EtOAc: n-Hexane 1:2), Rf: 0.35. 1H NMR (DMSO-d6): δ 4.33 (s, 3H, CH3), 7.18 (d, J = 7.33 Hz, 2H, CH, Ar), 7.29 (s, 1H, CH, indole), 7.56–7.63 (m, 5H, CH, Ar), 7.82 (d, J = 6.15 Hz, 2H, CH, Ar), 8.49 (s, 1H, CH=N), 11.79 (s, 1H, NH, indole), 11.97 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 55.3 (CH3), 111.3 (CH, Ar), 115.2 (CH, Ar), 120.1 (CH, Ar), 120.8 (CH, Ar), 121.6 (CH, Ar), 129.1 (2 × CH, Ar), 129.5 (2 × CH, Ar), 131.7 (C, Ar), 133.5 (C, Ar), 138.4 (C, Ar), 140.1 (C, Ar), 146.5 (2 × CH, Ar), 157.4 (C=O). MS (EI+) m/z: 293.87 [M+]. Anal. Calcd for C17H15N3O2 (293.30): C, 69.61; H, 5.15; N, 14.30. Found: C, 69.9; H, 5.11; N, 14.35

N′-(4-(dimethylamino)benzylidene)-1H-indole-2-carbohydrazide (7c) [69].

Prepared from 4-(dimethylamino)benzaldehyde, yield 0.04 g (35%), as a yellow powder. M.p. 90–92 °C (Lit. M.p. 82 °C). TLC (EtOAc: n-Hexane 1:2), Rf: 0.35. 1H NMR (DMSO-d6): δ 3.05 (m, 6H, 2 × CH3), 6.77 (t, J = 7.33 Hz, 1H, CH, Ar), 7.07 (s, 1H, CH, indole), 7.19 (d, J = 7.34 Hz, 2H, CH, Ar), 7.24 (d, J = 7.34 Hz, 2H, CH, Ar), 7.55 (d, J = 7.35 Hz, 2H, CH, Ar), 7.63–7.65 (m, 1H, CH, Ar), 8.31 (s, 1H, CH=N), 11.64 (s, 1H, NH, indole), 11.82 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 41.3 (2 × CH3), 103.1 (CH, Ar), 111.8 (2 × CH, Ar), 112.3 (CH, Ar), 119.9 (CH, Ar), 121.6 (CH, Ar), 121.8 (CH, Ar), 123.6 (C, Ar), 127.1 (CH, Ar), 128.4 (CH, Ar), 130.4 (C, Ar), 136.8 (2C, Ar), 148.1 (CH, Ar), 151.4 (C, Ar), 157.2 (C=O). MS (EI+) m/z: 306.82 [M+]. Anal. Calcd for C18H18N4O (306.37): C, 70.57; H, 5.92; N, 18.29. Found: C, 70.51; H, 5.94; N, 17.91.

N′-(pyridin-3-ylmethylene)-1H-indole-2-carbohydrazide (7d) [68].

Prepared from nicotinaldehyde, yield 0.03 g (29%), as an off-white powder. M.p. 252–254 °C (Lit. M.p. 250–251 °C). TLC (EtOAc: n-Hexane 1:2), Rf: 0.29. 1H NMR (DMSO-d6): δ 6.23 (t, J = 7.56 Hz, 2H, CH, Ar), 7.44–7.64 (m, 4H, CH, Ar), 7.33 (d, J = 7.56 Hz, 1H, CH, Ar), 7.66 (s, 1H, CH, Ar), 7.78 (d, J = 7.44 Hz, 2H), 8.34 (s, 1H, CH=N), 11.66 (s, 1H, NH, indole), 11.83 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 103.8 (CH, Ar), 112.4 (CH, Ar), 120.1 (CH, Ar), 121.9 (CH, Ar), 124.1 (CH, Ar), 126.9 (CH, Ar), 129.8 (C, Ar), 130.2 (C, Ar), 133.4 (CH, Ar), 136.9 (C, Ar), 144.3 (C, Ar), 148.7 (CH, Ar), 150.7 (2 × CH, Ar), 157.7 (C=O). MS (EI+) m/z: 264.75 [M+]. Anal. Calcd for C15H12N4O (264.29): C, 68.17; H, 4.58; N, 21.2. Found: C, 68.21; H, 4.55; N, 20.90.

N′-((3-(4-ethylphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8a).

Prepared from 3-(4-ethylphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (12a), yield 0.04 g (41%), as an off-white powder. M.p. 254–256 °C. TLC (EtOAc: n-Hexane 1:1), Rf: 0.42. 1H NMR (DMSO-d6): δ 1.24 (t, J = 7.56 Hz, 3H, CH3), 2.69 (q, J = 7.56 Hz, 2H, CH2), 6.23 (t, J = 7.22 Hz, 1H, Ar), 6.35 (t, 1H, Ar), 6.43 (s, 1H, Ar), 6.51–6.59 (m, 3H, CH, Ar), 6.71 (d, J = 8.25 Hz, 2H, CH, Ar), 6.89 (d, J = 7.56 Hz, 2H, CH, Ar), 6.95 (d, J = 8.25 Hz, 2H, CH, Ar), 7.20 (d, J = 7.56 Hz, 2H, CH, Ar), 7.71 (s, 1H, CH, Ar), 8.33 (s, 1H, CH=N), 11.76 (s, 1H, NH, indole), 11.85 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 15.6 (CH3), 28.2 (CH2), 103.2 (CH, Ar), 112.3 (C, Ar), 116.8 (CH, Ar), 118.8 (2 × CH, Ar), 119.9 (CH, Ar), 121.7 (CH, Ar), 123.7 (CH, Ar), 126.8 (2 × CH, Ar), 126.9 (CH, Ar), 128.2 (CH), 128.5 (CH, Ar), 129.4 (3 × CH, Ar), 129.6 (C, Ar), 130.2 (C, Ar), 136.7 (2C, Ar), 139.1 (CH, Ar), 140.4 (C, Ar), 144.3 (C, Ar), 152.1 (C, Ar), 157.3 (C=O). MS (EI+) m/z: 233.14 [M+]. Anal. Calcd for C27H23N5O (433.52): C, 74.81; H, 5.84; N, 15.35. Found: C, 74.85; H, 5.49; N, 15.24.

N′-((1-phenyl-3-(4-propylphenyl)-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8b).

Prepared from 1-phenyl-3-(4-propylphenyl)-1H-pyrazole-4-carbaldehyde (12b), yield 0.04 g (39%), as an off-white powder. M.p. 219–221 °C. TLC (EtOAc: n-Hexane 1:2), Rf: 0.51. 1H NMR (DMSO-d6): δ 0.93 (t, J = 7.4 Hz, 3H, CH3), 1.65 (sext, J = 7.3 Hz, 2H, CH2), 2.63 (t, J = 7.4 Hz, 2H, CH2), 6.22 (t, J = 7.56 Hz, 1H, CH, Ar), 6.33 (t, J = 7.56 Hz, 1H, CH, Ar), 6.44 (s, 1H, CH, Ar), 6.55–6.61 (m, 3H, CH, Ar), 6.69 (d, J = 8.25 Hz, 2H, CH, Ar), 6.75 (t, J = 7.90 Hz, 2H, CH, Ar), 6.81 (d, J = 8.25 Hz, 2H, CH, Ar), 7.19 (d, J = 7.56Hz, 2H, CH, Ar), 7.73 (s, 1H, CH, Ar), 8.33 (s, 1H, CH=N), 11.76 (s, 1H, NH, indole), 11.85 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 13.7 (CH3), 24.1 (CH2), 37.9 (CH2), 103.4 (CH, Ar), 112.5 (C, Ar), 116.8 (CH, Ar), 118.8 (2 × CH, Ar), 119.9 (CH, Ar), 121.7 (CH, Ar), 123.8 (CH, Ar), 126.8 (CH, Ar), 126.9 (CH, Ar), 127.1 (CH, Ar), 128.3 (CH), 128.7 (CH, Ar), 129.4 (2 × CH, Ar), 129.5 (2 × CH, Ar), 130.2 (C, Ar), 137.8 (2C, Ar), 139.5 (C, Ar), 140.3 (C, Ar), 143.5 (C, Ar), 152.5 (C, Ar), 156.5 (C=O). MS (EI+) m/z: 447.79 [M+]. Anal. Calcd for C28H25N5O (447.54): C, 75.15; H, 5.63; N, 15.65. Found: C, 75.11; H, 5.89; N, 15.64.

N′-((3-(4-isopropylphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8c).

Prepared from 3-(4-isopropylphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (12c), yield 0.03 g (39%), as an off-white powder. M.p. 219–221 °C. TLC (EtOAc: n-Hexane 1:2), Rf: 0.52. 1H NMR (DMSO-d6): δ 1.26 (d, J = 6.9 Hz, 6H, 2 × CH3), 2.97 (sept, J = 6.8 Hz, 1H, CH), 7.07 (t, J = 7.56 Hz, 1H, CH, Ar), 7.16 (t, J = 7.56 Hz, 1H, CH, Ar), 7.29 (s, 1H, CH, Ar), 7.32–7.39 (m, 3H, CH, Ar), 7.43–7.52 (m, 3H, CH, Ar), 7.61 (d, J = 7.61 Hz, 2H, CH, Ar), 7.73 (d, J = 7.58 Hz, 2H, CH, Ar), 7.94 (d, J = 7.57 Hz, 2H, CH, Ar), 8.52 (s, 1H, CH, Ar), 8.64 (s, 1H, CH=N), 11.79 (s, 1H, NH, indole), 11.93 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 23.8 (2 × CH3), 33.3 (CH), 103.7 (CH, Ar), 113.1 (C, Ar), 116.9 (CH, Ar), 118.8 (2 × CH, Ar), 119.9 (CH, Ar), 121.1 (CH, Ar), 123.7 (CH, Ar), 126.7 (2 × CH, Ar), 126.9 (2 × CH, Ar), 127.0 (2 × CH, Ar), 128.5 (2 × CH, Ar), 129.6 (C, Ar), 130.1 (C, Ar), 136.8 (2C, Ar), 139.1 (CH, Ar), 140.4 (C, Ar), 149.9 (C, Ar), 153.3 (C, Ar), 157.8 (C=O). MS (EI+) m/z: 447.45 [M+]. Anal. Calcd for C28H25N5O (447.54): C, 75.15; H, 5.63; N, 15.65. Found: C, 75.11; H, 5.89; N, 15.85.

N′-((3-(4-isobutylphenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8d).

Prepared from 3-(4-isobutylphenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (12d), yield 0.04 g (42%), as an off-white powder. M.p. 229–231 °C. TLC (EtOAc: Hexane 1:2), Rf: 0.45. 1H NMR (DMSO-d6): δ 0.88 (d, J = 6.7 Hz, 6H, 2 × CH3) 1.88 (m, 1 H, CH), 2.51 (d, J = 6.8 Hz, 2H, CH2), 7.07 (t, J = 6.6 Hz, 1H, CH, Ar), 7.21 (t, J = 7.5 Hz, 1H, CH, Ar), 7.29 (s, 1H, CH, Ar), 7.35 (t, J = 6.9 Hz, 2H, CH, Ar), 7.49–7.56 (m, 2H, CH, Ar), 7.63 (d, J = 7.4 Hz, 2H, CH, Ar), 7.68–7.72 (m, 3H, CH, Ar), 8.03 (d, J = 7.5 Hz, 2H, CH, Ar), 8.53 (s, 1H, CH, Ar), 8.69 (s, 1H, CH=N), 11.78 (s, 1H, NH, indole), 11.92 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 22.1 (2 × CH3), 29.6 (CH), 44.3 (CH2), 103.2 (CH, Ar), 112.4 (C, Ar), 116.8 (CH, Ar), 118.8 (CH, Ar), 119.9 (CH, Ar), 121.7 (CH, Ar), 123.7 (2 × CH, Ar), 126.8 (CH, Ar), 126.9 (CH, Ar), 127 (CH, Ar), 128.2 (CH, Ar), 129.4 (C, Ar), 129.5 (2 × CH, Ar), 129.6 (2 × CH, Ar), 130.1 (C, Ar), 136.8 (C, Ar), 139.1 (C, Ar), 141.3 (C, Ar), 141.8 (CH, Ar), 151.8 (2C, Ar), 157.2 (C=O). MS (EI+) m/z: 461 [M+]. Anal. Calcd for C29H27N5O (461.57): C, 75.46; H, 5.90; N, 15.17. Found: C, 75.30; H, 6.11; N, 15.20.

N′-((3-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8e).

Prepared from 3-(benzo[d][1,3]dioxol-5-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (12e), yield 0.03 g (33%), as an off-white powder. M.p. 239–241 °C. TLC (EtOAc: n-Hexane 1:2), Rf: 0.35. 1H NMR (DMSO-d6): δ 5.29 (s, 2H, CH2), 6.31–6.37 (m, 2H, CH, Ar), 6.49 (s, 1H, CH, Ar), 6.57–6.62 (m, 3H, CH, Ar), 6.62 (d, J = 8.25 Hz, 1H, CH, Ar), 6.73 (d, J = 7.90 Hz, 4H, CH, Ar), 6.89 (d, J = 8.25 Hz, 1H, CH, Ar), 7.20 (s, 1H, CH, Ar), 7.71 (s, 1H, CH, Ar), 8.33 (s, 1H, CH=N), 11.76 (s, 1H, NH, indole), 11.85 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 101.3 (CH2), 103.3 (CH, Ar), 108.6 (CH, Ar), 108.7 (CH, Ar), 112.3 (C, Ar), 116.7 (2 × CH, Ar), 118.8 (C, Ar), 119.9 (CH, Ar), 121.7 (CH, Ar), 122.5 (CH, Ar), 123.7 (CH, Ar), 124.1 (CH, Ar), 126.9 (2C, Ar), 127.2 (CH, Ar), 127.5 (CH, Ar), 130.2 (CH, Ar), 130.5 (CH, Ar), 136.8 (C, Ar), 139.0 (C, Ar), 140.3 (CH, Ar), 147.6 (C, Ar), 147.7 (C, Ar), 151.6 (C, Ar), 157.2 (C=O). MS (EI+) m/z: 449 [M+]. Anal. Calcd for C29H27N5O (461.57): C, 69.48; H, 4.26; N, 15.58. It was Found: H, 4.16; C, 69.03; N, 15.22.

N′-((5-chloro-1-(3,4-dinitrophenyl)-3-methyl-1H-pyrazol-4-yl)methylene)-1H-indole-2-carbohydrazide (8f).

Prepared from 5-chloro-1-(3,4-dinitrophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde, yield 0.04 g (37%), as an off-white powder. M.p. 204–206 °C. TLC (EtOAc: n-Hexane 1:2), Rf: 0.37. 1H NMR (DMSO-d6): δ 1.65 (s, 3H, CH3), 6.24–6.26 (m, 2H, CH, Ar), 6.49 (s, 1H, CH, Ar), 6.59 (d, J = 7.4 Hz, 2H, CH, Ar), 6.78 (d, J = 8.26 Hz, 2H, CH, Ar), 8.02 (s, 1H, CH, Ar), 8.63 (s, 1H, CH=N), 11.76 (s, 1H, NH, indole), 11.85 (s, 1H, NH, amide). 13C NMR (DMSO-d6): δ 18.4 (CH3), 101.8 (CH, Ar), 103.1 (CH, Ar), 112.2 (CH, Ar), 112.3 (C, Ar), 119.6 (C, Ar), 119.8 (C, Ar), 121.3 (CH, Ar), 121.6 (CH, Ar), 123.0 (CH, Ar), 123.6 (CH, Ar), 127.0 (CH, Ar), 127.1 (CH, Ar), 130.1 (C, Ar), 130.4 (C, Ar), 136.2 (C, Ar), 136.6 (C, Ar), 147.7 (C, Ar), 157.3 (C, Ar), 161.3 (C=O). MS (EI+) m/z: 467.79 [M+]. Anal. Calcd for C20H14ClN7O5 (467.83): C, 51.35; H, 3.02; N, 20.96. Found: C, 51.34; H, 3.04; N, 20.91

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