Journal of Medicinal Chemistry
Article
(E)-N′-(3,4-Dimethoxybenzylidene)-3,4-dimethoxy-N-methylben-
zohydrazide (6b). The title compound was obtained in 91% yield, by
N-alkylation of 5b with methyl iodide, as a powder with mp 115−116
°C. 1H NMR (200 MHz, CDCl3) δ 7.69 (s, 1H), 7.44 (d, 1H, J = 8.3
Hz), 7.38 (s, 1H), 7.15 (s, 1H), 7.06 (d, 1H, J = 8.3 Hz), 6.92−6.81
(m, 2H), 3.96−3.78 (m, 12H), 3.54 (s, 3H). 13C NMR (50 MHz,
CDCl3) δ 170.3, 150.9, 150.6, 149.5, 147.8, 138.6, 128.2, 127.6, 124.3,
121.7, 113.9, 110.9, 109.6, 108.2, 56.1, 55.8, 29.0. IR (KBr) 2958,
2918, 1647, 1599, 1269, 1020. MS m/z [M+] 358 (M+, 4%), 195
(12%), 165 (100%), 163 (4%), 137 (5%). Anal. Calcd for
C19H22N2O5: C, 63.67; H, 6.19; N, 7.82. Found: C, 63.52; H, 6.22;
N, 7.75.
(100%), 121 (13%). Anal. Calcd for C18H18N2O5: C, 63.15; H, 5.30;
N, 8.18. Found: C, 62.80; H, 5.28; N, 7.99.
(E)-4-Chloro-N′-(3,4-dimethoxybenzylidene)-N-methylbenzohy-
drazide (8c). The title compound was obtained in 93% yield, by N-
alkylation of 7d with methyl iodide, as a powder with mp 119−120 °C.
1H NMR (200 MHz, DMSO-d6) δ 7.70 (d, 2H, J = 8.5 Hz), 7.68 (s,
1H), 7.40 (d, 2H, J = 8.5 Hz), 7.04 (s, 1H), 7.02 (d, 1H, J = 8.1 Hz),
6.83 (d, 1H, J = 8.1 Hz), 3.93 (s, 3H), 3.78 (s, 3H), 3.53 (s, 6H). 13
C
NMR (50 MHz, DMSO-d6) δ 170.0, 150.8, 149.5, 139.1, 136.2, 134.1,
131.5, 127.9, 127.5, 121.8, 110.9, 108.0, 56.1, 55.7, 28.7. IR (KBr)
2956−2935, 1657, 1605, 1271, 1053. MS m/z [M+] 334 (M+, 4%),
332 (M+, 12%), 193 (17%), 178 (9%), 163 (100%), 139 (70%), 111
(25%). Anal. Calcd for C17H17ClN2O3: C, 61.36; H, 5.15; N, 8.42.
Found: C, 61.53; H, 5.09; N, 8.25.
(E)-N′-(3,4-Dimethoxybenzylidene)-4-methoxy-N-methylbenzo-
hydrazide (8d). The title compound was obtained in 85% yield, by N-
alkylation of 7e with methyl iodide, as a powder with mp 92−93 °C.
1H NMR (200 MHz, DMSO-d6) δ 7.80 (d, 2H, J = 8.8 Hz), 7.67 (s,
1H), 7.17 (d, 1H, J = 1.7 Hz), 7.03 (dd, 2H, Jax = 8.3 Hz, Jbx = 1.7
Hz), 6.90 (d, 2H, J = 8.7 Hz), 6.83 (d, 1H, J = 8.3 Hz), 3.88 (s, 9H),
3.83 (s, 3H), 3.80 (s, 3H), 3.52 (s, 3H). 13C NMR (50 MHz, DMSO-
d6) δ 170.2, 161.3, 150.4, 149.3, 138.2, 132.4, 128.2, 127.4, 121.6,
112.4, 110.7, 108.0, 55.9, 55.6, 55.3, 28.7. IR (KBr) 2956−2916, 1639,
1607, 1267, 1254, 1049, 1026. MS m/z [M+] 328 (M+, 8%), 165
(15%), 163 (6%), 135 (100%), 107 (7%). Anal. Calcd for
C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C, 65.82; H, 6.04;
N, 8.20.
(E)-N′-(3,4-Dimethoxybenzylidene)-3-methoxy-N-methylbenzo-
hydrazide (8e). The title compound was obtained in 75% yield, by N-
alkylation of (E)-N′-(3,4-dimethoxybenzylidene)-3-methoxybenzohy-
drazide with methyl iodide, as a powder with mp 62−63 °C. 1H NMR
(200 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.25−7.04 (m, 3H), 6.95 (d,
1H, J = 1.7 Hz), 6.92−6.81 (m, 2H), 6.74 (d, 1H, J = 8.2 Hz), 3.81 (s,
9H), 3.74 (s, 3H), 3.68 (s, 3H), 3.50 (s, 3H). 13C NMR (50 MHz,
DMSO-d6) δ 170.6, 156.2, 150.4, 149.2, 137.8, 129.9, 128.2, 127.2,
121.6, 120.1, 110.5, 110.4, 107.4, 55.9, 55.7, 55.5, 28.0. IR (KBr) 2999,
2970, 2935, 2837, 1626, 1603, 1577, 1516, 1269, 1240, 1040, 1030.
MS m/z [M+] 328 (M+, 11%), 164 (35%), 135 (100%), 107 (35%), 92
(8%), 77 (22%). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N,
8.53. Found: C, 65.78; H, 6.23; N, 8.49.
(E)-N′-(Benzo[d][1,3]dioxol-5-ylmethylene)-3,4-dimethoxy-N-
methylbenzohydrazide (6c). The title compound was obtained in
93% yield, by N-alkylation of 5c with methyl iodide, as a powder with
1
mp 189−190 °C. H NMR (200 MHz, CDCl3) δ 7.68 (s, 1H), 7.44
(dd, 1H, Jax = 8.6 Hz, Jbx = 2.1 Hz), 7.38 (d, 1H, J = 2.1 Hz), 7.08 (s,
1H), 6.99 (d, 1H, J = 8.6 Hz), 6.90 (d, 1H, J = 8.6 Hz), 6.79 (d, 1H, J
= 8.6 Hz), 3.95 (s, 3H), 3.93 (s, 3H), 3.53 (s, 3H). 13C NMR (50
MHz, CDCl3) δ 170.3, 151.0, 149.1, 148.5, 147.9, 138.8, 129.7, 127.4,
124.3, 123.3, 113.8, 109.8, 108.4, 105.7, 101.5, 56.1, 29.2. IR (KBr)
2966, 2914, 1641, 1601, 1269, 1029. MS m/z [M+] 342 (M+, 3%), 195
(15%), 165 (100%), 147 (13%), 146 (22%), 137 (5%). Anal. Calcd for
C18H18N2O5: C, 63.15; H, 5.30; N, 8.18. Found: C, 62.94; H, 5.31; N,
7.99.
(E)-N′-(4-Chlorobenzylidene)-3,4-dimethoxy-N-methylbenzohy-
drazide (6d). The title compound was obtained in 97% yield, by N-
alkylation of 5d with methyl iodide, as a powder with mp 109−110 °C.
1H NMR (200 MHz, CDCl3) δ 11.76 (s, 1H), 8.45 (s, 1H), 7.74 (d,
2H, J = 8.1 Hz), 7.59−7.49 (m, 4H), 7.08 (d, 1H, J = 8.4 Hz), 3.84 (s,
6H). 13C NMR (50 MHz, CDCl3) δ 170.5, 151.2, 148.0, 137.6, 135.5,
133.6, 129.2, 128.4, 127.2, 124.4, 113.8, 109.9, 56.1, 29.2. IR (KBr)
2960−2935, 1660, 1601, 1269, 1026. MS m/z [M+] 334 (M+, 1%),
332 (M+, 3%), 195 (6%), 165 (100%), 139 (3%), 137 (13%). Anal.
Calcd for C17H17ClN2O3: C, 61.36; H, 5.15; N, 8.42. Found: C, 61.11;
H, 5.15; N, 8.26.
(E)-3,4-Dimethoxy-N′-(4-methoxybenzylidene)-N-methylbenzo-
hydrazide (6e). The title compound was obtained in 98% yield, by N-
alkylation of 5e with methyl iodide, as a powder with mp 57−58 °C.
1H NMR (200 MHz, CDCl3) δ 7.72 (s, 1H), 7.49 (d, 2H, J = 8.3 Hz),
7.45 (dd, 1H, Jax = 8.2 Hz, Jbx = 1.6 Hz), 7.38 (d, 1H, J = 1.6 Hz),
6.90 (d, 1H, J = 8.2 Hz), 6.86 (d, 2H, J = 8.3 Hz), 3.94 (s, 3H), 3.87
(s, 3H), 3.80 (s, 3H), 3.55 (s, 3H). 13C NMR (50 MHz, CDCl3) δ
170.3, 160.9, 151.0, 147.8, 138.9, 128.7, 127.8, 127.5, 124.3, 114.3,
113.9, 109.8, 56.0, 55.5, 29.1. IR (KBr) 2962−2935, 1637, 1609, 1261,
1022. MS m/z [M+] 328 (M+, 3%), 195 (20%), 165 (100%), 137
(5%), 133 (10%). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N,
8.53. Found: C, 65.69; H, 6.26; N, 8.23.
(E)-N′-(3,4-Dimethoxybenzylidene)-N-methylbenzohydrazide
(8a). The title compound was obtained in 93% yield, by N-alkylation
of 7a with methyl iodide, as a powder with mp 105−106 °C. 1H NMR
(200 MHz, CDCl3) δ 7.68 (s, 1H), 7.30 (d, 2H, J = 8.0 Hz), 7.42−
7.36 (m, 3H), 7.09 (s, 1H), 7.20 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J =
8.0 Hz), 3.88 (s, 3H), 3.74 (s, 3H), 3.55 (s, 3H). 13C NMR (50 MHz,
CDCl3) δ 171.0, 150.5, 149.4, 138.5, 135.6, 130.0, 129.8, 128.0, 127.2,
121.8, 110.7, 107.8, 56.0, 55.6, 28.6. IR (KBr) 2956−2914, 1640, 1603,
1269, 1026. MS m/z [M+] 298 (M+, 18%), 293 (12%), 163 (98%),
134 (11%), 105 (100%), 77 (57%). Anal. Calcd for C17H18N2O3: C,
68.44; H, 6.08; N, 9.39. Found: C, 68.22; H, 6.03; N, 9.23.
(E)-N′-(3,4-Dimethoxybenzylidene)-2-methoxy-N-methylbenzo-
hydrazide (8f). The title compound was obtained in 91% yield, by N-
alkylation of (E)-N′-(3,4-dimethoxybenzylidene)-2-methoxybenzohy-
1
drazide with methyl iodide, as a powder with mp 103−104 °C. H
NMR (200 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.31−7.20 (m, 2H), 6.93
(d, 1H, J = 7.7 Hz), 6.86−6.87 (m, 3H), 6.69 (d, 1H, J = 8.2 Hz), 3.78
(s, 9H), 3.67 (s, 3H), 3.56 (s, 3H), 3.43 (s, 3H). 13C NMR (50 MHz,
DMSO-d6) δ 170.8, 158.7, 150.6, 149.4, 138.6, 136.8, 128.2, 128.0,
122.3, 121.8, 115.9, 115.1, 110.6, 107.8, 55.9, 55.5, 55.3, 28.6. IR (KBr)
3080, 3001, 2945, 2910, 2837, 1668, 1604, 1512, 1261, 1034, 1018.
MS m/z [M+] 328 (M+, 8%), 163 (11%), 135 (100%), 92 (9%), 77
(18%). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53.
Found: C, 65.88; H, 6.12; N, 8.28.
General Procedure for the Preparation of N-Methyl-NAH
Compounds 6f,g and 8g,h. To a solution of the corresponding N-
methyl-hydrazide derivative 16a−c (0.83 mmol), prepared as
described previously,53 in absolute ethanol (7 mL) containing one
drop of 37% hydrochloric acid was added 0.87 mmol of the
corresponding aldehyde derivative. The mixture was stirred at room
temperature for 1.5 h. Next, the solvent was partially concentrated at
reduced pressure, and the resulting mixture was poured into ice. After
neutralization with 10% aqueous sodium bicarbonate solution, the
precipitate formed was collected by filtration and dried under vacuum
to afford the desired N-methyl-NAH derivatives 6f,g and 8g,h.
(E)-N′-(4-Hydroxybenzylidene)-3,4-dimethoxy-N-methylbenzohy-
drazide (6f). The title compound was obtained in 72% yield, by
condensing 16a with 4-hydroxybenzaldehyde, as a powder with mp
164−165 °C. 1H NMR (200 MHz, CDCl3) δ 7.74 (s, 1H), 7.48−7.37
(m, 5H), 6.90 (d, 1H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 3.83 (s,
3H). 13C NMR (50 MHz, CDCl3) δ 170.8, 158.3, 151.1, 147.8, 140.1,
(E)-N′-(3,4-Dimethoxybenzylidene)-N-methylbenzo[d][1,3]-
dioxole-5-carbohydrazide (8b). The title compound was obtained in
92% yield, by N-alkylation of 7b with methyl iodide, as a powder with
1
mp 204−205 °C. H NMR (200 MHz, CDCl3) δ 7.67 (s, 1H), 7.34
(d, 1H, J = 8.0 Hz), 7.27 (s, 2H), 7.27 (s, 1H), 7.07 (s, 1H), 6.98 (d,
1H, J = 8.0 Hz), 6.83 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz),
6.03 (s, 2H), 5.98 (s, 2H), 3.52 (s, 3H). 13C NMR (50 MHz, CDCl3)
δ 162.9, 150.3, 148.0, 148.0, 134.4, 130.1, 128.9, 128.9, 127.2, 122.9,
108.1, 107.7, 101.9, 29.2. IR (KBr) 2964−2918, 1647, 1607, 1269/
1033. MS m/z [M+] 342 (M+, 6%), 179 (12%), 162 (5%), 149
7539
dx.doi.org/10.1021/jm300514y | J. Med. Chem. 2012, 55, 7525−7545