10.1002/cmdc.202100209
ChemMedChem
FULL PAPER
mmol) in 1 mL of water were added and the mixture was kept under
stirring for 5 h. The precipitate formed was filtered and washed with
distilled water. This intermediate compound was then solubilized in DMF
(2 mL) and slowly added to an aqueous solution of the appropriate
amine/hydrazine/hydrazide derivative (1.8 mmol). A catalytic amount of
4N HCl was added and the solution was left under stirring at room
temperature for 24 h. The mixture was extracted with CHCl3 (3 x 15 mL),
the organic phase abundantly washed with H2O to remove the DMF and
dried with Na2SO4. The solvent was evaporated under reduced pressure
to give the crude product that was purified by column chromatography
with hexane/ethyl acetate: 6/4 or 7/3 v/v as the mobile phase.
DMSO-d6) δ 3.68 (s. 3H, OCH3), 6.76 (d, J = 4.1 Hz, 1H, furan), 6.84 (d,
J = 9.9 Hz, 2H, arom.), 7.00 (d, J = 9.9 Hz, 2H, arom.), 7.30 (d, J =3.5 Hz,
1H, furan), 7.72 (s, 1H, aldimine) 7.84-7.89 (m, 4H, arom.), 10.36 (brs,
1H, NH). ESI-MS (C19H14N3O2, [M–H]-) calcd. m/z = 316.1083, found
316.1099. MP 138-140 °C.
4-(5-((2-(4-(methylsulfonyl)phenyl)hydrazono)methyl)furan-2-
yl)benzonitrile (11). Dark-orange crystals; yield: 25%; 1H NMR (300
MHz, DMSO-d6) δ 3.10 (s. 3H, CH3), 6.95 (d, J = 4.1 Hz, 1H, furan), 7.19
(d, J = 8.7 Hz, 2H, arom.), 7.35 (d, J = 3.5 Hz, 1H, furan), 7.73 (d, J = 8.7
Hz, 2H, arom.), 7.72 (s, 1H, aldimine), 7.87-7.94 (m, 4H, arom.), 11.12
(brs, 1H, NH). ESI-MS (C19H16N3O3S, [M+H]+) calcd. m/z = 366.0909,
found 366.0906. MP 175 °C (dec).
N'-((5-(4-nitrophenyl)furan-2-yl)methylene)thiophene-2-
carbohydrazide (1). Yellow crystals; yield: 25%. 1H NMR (300 MHz,
DMSO-d6) δ 7.14 (d, J = 3.5 Hz, 1H, furan), 7.23 (t, J = 3.5 Hz, 1H,
thiophene), 7.47 (d, J = 3.5, 1H, furan), 7.89-8.40 (m, 7H arom.), 12.20
(brs, 1H, NH). ESI-MS (C16H10N3O4S, [M–H]-) calcd. m/z = 340.0390,
found: 340.0392. MP 241-243 °C.
((5‐ (4‐ cyanophenyl)furan‐ 2‐ yl))methylidene)hydrazin-1-
yl)benzene-1-sulfonamide (12). Dark-orange crystals; yield: 32%; 1H
NMR (300 MHz, DMSO-d6) δ 6.92 (d, J =3.5 Hz, 1H, furan), 7.08 (brs,
2H, NH2), 7.13 (d, J = 8.2 Hz, 2H, arom.), 7.35 (d, J = 3.5 Hz, 1H, furan),
7.67 (d, J = 8.7 Hz, 2H, arom.), 7.84-7.96 (m, 5H, arom., aldimine), 10.91
(brs, 1H, NH). ESI-MS (C18H13N4O3S, [M–H]-) calcd. m/z = 365.0706,
found 365.0699. MP 217-219 °C.
N-(4-methylpiperazin-1-yl)-1-(5-(4-nitrophenyl)furan-2-
yl)methanimine (3). Red crystals; yield: 50%. 1H NMR (300 MHz,
DMSO-d6) δ 2.21 (s, 3H, CH3), 2.41-2.50 (m, 4H, piperazine), 3.13 (t, J =
5.2 Hz, 4H, piperazine), 6.70 (d, J = 4.1 Hz, 1H, furan) 7.35 (d, J = 4.1 Hz,
1H, furan), 7.54 (s, 1H, aldimine), 7.91 (d, J = 8.5 Hz, 2H, ArNO2), 8.26
(d, J = 8.5 Hz, 2H, ArNO2). ESI-MS (C16H19N4O3, [M+H]+) calcd. m/z =
315.1453, found 315.1456. MP 122-124 °C.
Synthesis of compound 13
The procedure was the same as for compounds 1-12, using 3-
methoxybenzaldehyde (0.27 g, 2.0 mmol) instead of 2-furaldehyde, and
2-thiophenecarboxylic acid hydrazide (0.43 g, 3.0 mmol). After
evaporation of organic extract, the crude product obtained was purified
by crystallization from absolute ethanol.
N'-((5-(4-cyanophenyl)furan-2-yl)methylene)thiophene-2-
carbohydrazide (4). Yellow crystals; yield: 20%. 1H NMR (300 MHz,
DMSO-d6) δ 7.11 (d, J = 3.5 Hz, 1H, furan), 7.23 (t, J = 4.7 Hz, 1H,
thiophene), 7.40 (d, J = 3.5 Hz, 1H, furan), 7.80-8.05 (m, 6H, arom.), 8.37
(s, 1H, aldimine), 11.86 (brs, 1H, NH). ESI-MS (C17H12N3O2, [M+H]+)
calcd. m/z = 322.0648, found 322.0643. MP 245 °C (dec).
N'-[(4'-cyano-2-methoxy[1,1'-biphenyl]-4-yl)methylidene]thiophene-
2-carbohydrazide (13). White ivory crystals; yield: 24%. 1H NMR (300
MHz, DMSO-d6) δ 3.82 (s. 3H, OCH3), 7.01 (d, J =7.2 Hz, 1H, arom.),
7.19 (t, J = 3.5 Hz, 1H, thiophene), 7.30-8.20 (m, 8H, arom.), 8.39 (s, 1H,
aldimine), 11.86 (brs, 1H, NH). ESI-MS (C20H16N3O2S, [M+H]+) calcd. m/z
= 362.0690, found 362.0699. MP 255 °C (dec).
N'-((5-(4-cyanophenyl)furan-yl)methylene)isonicotinohydrazide (5).
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Yellow crystals; yield: 30%. H NMR (300 MHz, DMSO-d6) δ 7.14 (d, J =
3.5 Hz, 1H, furan), 7.40 (d, J = 3.5 Hz, 1H, furan), 7.80 (d, J = 5.8 Hz, 2H,
pyridine), 7.91 (d, J = 8.5 Hz, 2H, ArCN), 7.96 (d, J = 8.5 Hz, 2H, ArCN),
8.03 (brs, 1H, NH), 8.40 (s, 1H, aldimine), 8.75 (d, J = 5.8 Hz, 2H,
pyridine). ESI-MS (C18H11N4O2, [M–H]-) calcd. m/z = 315.0880, found
315.0879. MP 240 °C (dec).
Synthesis of compounds 14-21
2.0 mmol of aldehyde (2-furaldehyde for 14-18; 3-methoxybenzaldehyde
for 19 and 20; 3,4,5-trimethoxybenzaldehyde for 21) were solubilized in 5
mL of acetone and slowly added to the aqueous solution of the
N'-((5-(4-cyanophenyl)furan-2-yl)methylene)acetohydrazide
(6).
appropriate amine/hydrazine/hydrazide derivative, with
a catalytic
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Orange crystal; yield: 35%. H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H,
CH3), 7.00 (d, J = 3.6 Hz, 1H, furan), 7.35 (d, J = 3.6 Hz, 1H, furan), 7.87-
7.94 (m, 4H, arom.), 8.07 (s, 1H, aldimine), 11.33 (brs, 1H, NH). ESI-MS
(C14H11N3O2, [M+Na]+) calcd. m/z = 276.0747, found 276.0743. MP
190 °C (dec).
amount of HCl 4N. The mixture was stirred at room temperature for 24 h,
then extracted with ethyl acetate (3 x 15 mL) and the organic layer dried
over anhydrous Na2SO4. Compound 21 was filtered after precipitation
from the acetone/water mixture. The solvent was evaporated under
reduced pressure to give the crude product that was purified by
crystallization from absolute ethanol.
N'-((5-(4-cyanophenyl)furan-2-yl)methylene)-2-phenyl-
acetohydrazide (8). Orange crystals; yield: 35%. 1H NMR (300 MHz,
DMSO-d6) δ 3.99 (s, 2H, CH2), 7.05 (d, J = 3.5 Hz, 1H, furan), 7.29-7.40
(m, 6H, arom.), 7.88-7.97 (m, 4H, arom.), 8.15 (s, 1H, aldimine), 11.45
(brs, 1H, NH). ESI-MS (C20H16N3O2, [M+H]+) calcd. m/z = 330.1239,
found 330.1236. MP 197 °C (dec).
1-(Furan-2-yl)-N-(4-methylpiperazin-1-yl)methanimine (16). Brown oil;
yield: 38%; 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H, CH3), 2.66 (t, J
= 3.1 Hz, 4H, 2xCH2), 3.24 (t, J = 3.1 Hz, 4H, 2xCH2), 6.41 (t, J = 1.5 Hz,
1H, furan), 6.45 (dd, J = 1.5 Hz, 1H, furan), 7.26 (s, 1H, aldimine), 7.41 (d,
J = 2.0 Hz, 1H, furan). ESI-MS (C10H16N3O, [M+H]+) calcd. m/z =
194.1290, found 194.1286.
(4-(5-(((2-chloro-4-hydroxyphenyl)imino)methyl)furan-2-
yl)benzonitrile (9). Yellow crystals; yield: 25%. 1H NMR (500 MHz,
DMSO-d6) δ 6.76 (dd, J = 8.5 Hz, 1H, arom.), 6.90 (d, J = 2.9 Hz, 1H,
arom.), 7.22 (d. J = 8.8 Hz, 1H, arom.), 7.28 (d, J = 3.6 Hz, 1H, furan),
7.45 (d, J = 3.6 Hz, 1H, furan), 7.93 (d, J = 8.5 Hz, 2H, arom.), 7.99 (d, J
= 8.5 Hz, 2H, arom.), 8.41 (s, 1H, aldimine), 9.95 (brs, 1H, OH). ESI-MS
(C18H10ClN2O2, [M–H]-) calcd. m/z = 321.0429, found 321.0432. MP 196-
198 °C.
N'-((furan-2-yl)methylidene)-2-phenylacetohydrazide (17). White ivory
crystals; yield: 46%. 1H NMR (300 MHz, DMSO-d6) δ 3.50 (s, 2H, CH2),
6.50 (t, J = 2.1 Hz, 1H, furan), 6.86 (d, J = 2.0 Hz, 1H, furan), 7.18-7.30
(m, 5H, arom.), 7.80 (d, J = 2.1 Hz, 1H, furan), 7.88 (s, 1H, aldimine),
11.30 (brs, 1H, NH). ESI-MS (C13H13N2O2, [M+ H]+) calcd. m/z =
229.0974, found 229.0980. MP 156-160 °C.
4-(-2-((furan-2-yl)methylidene)hydrazinyl)benzene-1-sulfonamide
(18). Orange crystals; yield: 47%. 1H NMR (300 MHz, DMSO-d6) δ 6.57 (t,
J = 1.6 Hz, 1H, furan), 6.72 (d, J = 1.6 Hz, 1H, furan), 7.04 (brs, 2H, NH2),
4‐ ((5-(2‐ (4‐ methoxyphenyl)hydrazin‐ 1‐ ylidene)methyl)furan‐
2yl))benzonitrile (10). Orange crystals; yield: 40%; 1H NMR (300 MHz,
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