An efficient and facile regioselective synthesis of new substituted (E)-1-(3-aryl-7,8-dihydrocinnoline-5(6H)-ylidene)hydrazines and (1E,2E)-1,2-bis(3-aryl-7,8-dihydrocinnoline-5(6H)-ylidene)hydrazines

Article abstract of DOI:10.1007/s13738-013-0378-2

A study concerning the new substituted cinnoline synthesis is described. The use of a one-pot three-component method allows a simple regioselective and efficient synthesis of cinnoline derivatives via reaction of arylglyoxals with 1,3-cyclohexanedione and dimedone in the presence of hydrazine hydrate.

Full text of DOI:10.1007/s13738-013-0378-2

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0378-2
ORIGINAL PAPER
An efficient and facile regioselective synthesis of new substituted
(E)-1-(3-aryl-7,8-dihydrocinnoline-5(6H)-ylidene)hydrazines
and (1E,2E)-1,2-bis(3-aryl-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazines
•
Jabbar Khalafy Mahnaz Ezzati Mehdi Rimaz
•
•
•
Ahmad Poursattar Marjani Hooman Yaghoobnejad Asl
Received: 11 August 2013 / Accepted: 23 October 2013
Ó Iranian Chemical Society 2013
Abstract A study concerning the new substituted cinn-
oline synthesis is described. The use of a one-pot three-
component method allows a simple regioselective and
efficient synthesis of cinnoline derivatives via reaction of
arylglyoxals with 1,3-cyclohexanedione and dimedone in
the presence of hydrazine hydrate.
cinnoline derivatives are used as drugs such as cinoxacin as
antibiotics, and sinofem as plant regulator.
The method for the synthesis of cinnoline can be clas-
sified to three main groups based on using derivatives of
arenediazonium salts, arylhydrazones and arylhydrazines
as precursors. Richter, Widman-Stoermer and Brosche-
Herbert cyclization include the cyclization of arenediazo-
nium salts [24–30]. In these reactions, o-alkenyl-, o-alky-
nyl- and o-acylaryldiazonium ions cyclize spontaneously to
give cinnolines or cinnolones (Scheme 1).
Keywords Arylglyoxal Á Cinnoline Á
1,3-Cyclohexanedione Á Dimedone Á One-pot Á
Regioselective
Arylhydrazones and arylhydrazines are used as precur-
sors of cinnoline. Ring closing occurs during attack of the
amino group at a CC, CO, or CN multiple bonds [31–38].
Recently, the use of transition metals such as Pd, Co,
and Au for preparation of the cinnoline derivatives has
been reported [39–44]. Also, formation of cinnolines by
means of Diels–Alder reactions is reported [45]. With due
attention to physiological activities of the cinnoline
derivatives, and following these reported annulation
reactions, we decided to prepare cinnoline new derivatives
Introduction
Bicyclic compounds possessing heteroatoms have a wide
range of physiological activities. Cinnoline derivatives
have been found to show a number of therapeutic activities
such as antithrombotic, antitumor, antisecretory, antianal-
gestic, antipyretic, antihistamine, antiarthritic, antiprolif-
erative, antifungal, antileukemic, antimicrobial, herbicides,
antibacterial, anticancer, anti-inflammatory, antiprotozoal,
antianxiety, antiangiogenic, antihypertensive, insecticide,
immunosuppressants and antiallergic [1–23]. Some
via
a green one-pot and three-compound synthetic
protocol.
Experimental
J. Khalafy (&) Á M. Ezzati Á A. P. Marjani
Department of Organic Chemistry, Faculty of Chemistry,
Urmia University, 57154 Urmia, Iran
The chemicals used in this work were obtained from Acros
and Merck companies and were used without purification.
Melting points were measured on an Electrothermal 9200
apparatus and are uncorrected. 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded on a BRUKER
DRX-300 AVANCE spectrometer in CDCl3 using TMS as
the internal reference. FT-IR spectra were recorded via a
Thermonicolet (Nexus 670) spectrometer using KBr discs.
Mass spectra were recorded on a Varian Matt 311
e-mail: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir
M. Rimaz
Department of Chemistry, Payame Noor University,
P.O. Box 19395-3697 Tehran, Iran
H. Y. Asl
Department of Chemistry, Missouri University of Science and
Technology, Rolla, MO 65409, USA
123

J IRAN CHEM SOC
Scheme 1 Cyclization of
arendiazonium salts
R
R
N
O
Me
O
N
N
N
H
N2
N2
N2
spectrometer and relative abundances of fragments are
2H, Ar), 7.56 (d, J = 8.4 Hz, 2H, Ar), 7.37 (bs, 2H, NH2),
3.02 (t, J = 5.7 Hz, 2H, CH2), 2.44 (t, J = 5.7 Hz, 2H,
CH2), 1.91 (quin, J = 5.7 Hz, 2H, CH2); 13C-NMR
(DMSO-d6) d (ppm): 157.77, 156.32, 136.32, 136.06,
134.80, 133.72, 129.43, 128.74, 115.05, 29.821, 23.34,
20.22; FT-IR mmax 3346, 3307, 3196, 3086, 3051, 2944,
2935, 2896, 2875, 1652, 1594, 1553, 1489, 1427, 1406,
1388, 1145, 1086, 1026, 1009, 926, 837, 770, 737, 726,
quoted in parentheses after the m/z values.
General procedure for the synthesis of products
(E)-1-(3-Aryl-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazines (4a–m)
To a mixture of b-diketones (1 mmol) and arylglyoxal
(1 mmol) in water/ethanol (2 mL, with 1:1 ratio), was
successively added hydrazine hydrate 80 % (5 mmol) at
room temperature; the resultant mixture was stirred for
35–60 min. After an appropriate time, the reaction mixture
was solidified; the obtained solid was filtered and washed
with 2 mL water then recrystallized from ethanol to obtain
pure products in moderate to excellent yields (47–97 %).
672, 491, 466 cm-1
.
(E)-1-(3-(4-Chlorophenyl)-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazine (4c)
1
Yellow crystals, yield: 93 %, mp 176–177 °C; H-NMR
(CDCl3) d (ppm): 8.27 (s, 1H, Ar), 8.05 (d, J = 8.7 Hz,
2H, Ar), 7.47 (d, J = 8.7 Hz, 2H, Ar), 5.61 (bs, 2H, NH2),
3.22 (t, J = 6.3 Hz, 2H, CH2), 2.52 (t, J = 6.3 Hz, 2H,
CH2), 2.08 (quin, J = 6.3 Hz, 2H, CH2); FT-IR mmax 3423,
3347, 3306, 3196, 3058, 2944, 2934, 2895, 2875, 1649,
1594, 1553, 1489, 1406, 1388, 1145, 1086, 1010, 838, 769,
(1E,2E)-1,2-Bis(3-aryl-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazines (5a–f)
738, 726, 671, 466 cm-1
.
To a mixture of 1,3-cyclohexanedione (1 mmol) and
arylglyoxal (1 mmol) in water (5 mL), was gradually
added hydrazine hydrate 80 % (5 mmol) at 40 °C. The
reaction mixture was stirred for 1–2 h. The solid was fil-
tered, and washed with excess water in ambient tempera-
ture, then recrystallized from ethanol to obtain pure
products 5a–f to good yields (42–89 %).
(E)-1-(7,8-Dihydro-3-(4-nitrophenyl)cinnoline-5(6H)-
ylidene)hydrazine (4d)
1
Orange crystals, yield: 97 %, mp 220–221 °C; H-NMR
(DMSO-d6) d (ppm): 8.27–8.34 (m, 5H, Ar), 7.43 (bs, 2H,
NH2), 3.06 (t, J = 5.7 Hz, 2H, CH2), 2.44 (quin,
J = 5.7 Hz, 2H, CH2), 1.93 (t, J = 5.7 Hz, 2H, CH2); 13C-
NMR (DMSO-d6) d (ppm): 158.44, 155.56, 148.46,
143.32, 136.02, 133.92, 128.25, 124.54, 115.94, 29.88,
23.29, 20.13; FT-IR mmax 3442, 3294, 3153, 2946, 1548,
1507, 1407, 1341, 1109, 867, 846, 694 cm-1; MS m/z (%):
283 (M?, 100), 254 (39), 208 (53), 193 (22), 165 (24), 152
(22), 139 (18), 106 (35), 77 (17), 63 (19), 51 (21).
(E)-1-(3-Phenyl-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazine (4a)
Pale yellow crystals, yield: 75 %, mp 163–164 °C; 1H-NMR
(DMSO-d6) d (ppm): 8.14 (s, 1H, Ar), 8.03 (d, J = 7.2 Hz,
2H, Ar), 7.47–7.52 (m, 3H, Ar), 7.34 (bs, 2H, NH2), 3.03 (t,
J = 6 Hz, 2H, CH2), 2.45 (t, J = 6 Hz, 2H, CH2), 1.91
(quin, J = 6 Hz, 2H, CH2); 13C-NMR (DMSO-d6) d (ppm):
158.01, 157.57, 137.25, 136.47, 133.61, 129.90, 129.42,
126.94, 115.06, 29.80, 23.37, 20.26; FT-IR mmax 3370, 3293,
3178, 2920, 2856, 1633, 1544, 1495, 1405, 1334, 1153, 1119,
1032, 1019, 908, 863, 774, 688 cm-1; MS m/z (%): 238 (M?,
100), 209 (84), 193 (19), 181 (22), 165 (31), 152 (28), 139
(31), 115 (28), 106 (42), 77 (41), 51 (33).
(E)-1-(7,8-Dihydro-3-(4-methoxyphenyl)cinnoline-5(6H)-
ylidene)hydrazine (4e)
Pale yellow crystals, yield: 63 %, mp 180–181 °C; 1H-
NMR (DMSO-d6) d (ppm): 8.08 (s, 1H, Ar), 7.90 (d,
J = 8.4 Hz, 2H, Ar), 7.29 (bs, 2H, NH2), 7.00
(d, J = 8.4 Hz, 2H, Ar), 3.80 (s, 3H, OCH3), 2.99 (t,
J = 5.4 Hz, 2H, CH2), 2.43 (quin, J = 5.4 Hz, 2H, CH2),
1.89 (t, J = 5.4 Hz, 2H, CH2); 13C-NMR (DMSO-d6) d
(ppm): 160.88, 157.03, 156.99, 136.71, 133.45, 129.57,
128.26, 144.80, 144.31, 55.69, 29.78, 23.39, 20.32;
(E)-1-(3-(4-Bromophenyl)-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazine (4b)
1
Yellow crystals, yield: 89 %, mp 178–179 °C; H-NMR
(DMSO-d6) d (ppm): 8.15 (s, 1H, Ar), 8.07 (d, J = 8.4 Hz,
123

J IRAN CHEM SOC
(E)-1-(3-(4-Chlorophenyl)-7,7-dimethyl-7,8-
FT-IR mmax 3419, 3395, 3298, 3185, 2941, 2837, 1605,
1551, 1511, 1405, 1246, 1172, 1030, 834, 662, 576 cm-1
;
dihydrocinnoline-5(6H)-ylidene)hydrazine (4i)
MS m/z (%): 268 (M?, 100), 239 (39), 224 (38), 209 (15),
197 (19), 181 (20), 169 (18), 153 (18), 132 (20), 115 (21),
106 (35), 89 (21), 77 (23), 63 (21).
1
Yellow crystals, yield: 81 %, mp 184–185 °C; H-NMR
(DMSO-d6) d (ppm): 8.16 (s, 1H, Ar), 8.08 (d, J = 8.4 Hz,
2H, Ar), 7.56 (d, J = 8.4 Hz, 2H, Ar), 7.39 (bs, 2H, NH2),
2.92 (s, 2H, CH2), 2.30 (s, 2H, CH2), 0.98 (s, 6H,
2 9 CH3); 13C-NMR (DMSO-d6) d (ppm): 156.69, 156.26,
136.05, 135.57, 134.81, 133.10, 129.44, 128.76, 114.59,
43.02, 36.68, 30.04, 28.74; FT-IR mmax 3364, 3302, 3175,
295, 2872, 1539, 1490, 1408, 1088, 1010, 836, 696,
(E)-1-(7,8-Dihydro-3-(3,4-dimethoxyphenyl)cinnoline-
5(6H)-ylidene)hydrazine (4f)
Pale yellow crystals, yield: 78 %, mp 213–214 °C; 1H-
NMR (DMSO-d6) d (ppm): 8.11 (s, 1H, Ar), 7.66 (s, 1H,
Ar), 7.50 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H, Ar), 7.29 (bs,
2H, NH2), 7.00 (d, J = 8.4 Hz, 1H, Ar), 3.84 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.00 (t, J = 5.4 Hz, 2H, CH2),
2.44 (quin, J = 5.4 Hz, 2H, CH2), 1.90 (t, J = 5.4 Hz, 2H,
CH2); 13C-NMR (DMSO-d6) d (ppm): 157.07, 150.57,
149.49, 136.73, 133.43, 129.76, 119.57, 114.50, 112.33,
110.02, 56.01, 55.96, 29.82, 23.42, 20.34; FT-IR mmax
3368, 3201, 2931, 2830, 1552, 1513, 1403, 1258, 1217,
1144, 1019, 869, 761, 652 cm-1; MS m/z (%): 298 (M?,
31), 283 (10), 252 (12), 222 (21), 212 (31), 194 (100), 179
(31), 163 (39), 138 (50), 77 (46), 65 (34), 51 (31).
546 cm-1
.
(E)-1-(3-(4-Fluorophenyl)-7,8-dihydro-7,7-
dimethylcinnoline-5(6H)-ylidene)hydrazine (4j)
Pale yellow crystals, yield: 63 %, mp 233–234 °C; 1H-
NMR (DMSO-d6) d (ppm): 8.13 (s, 1H, Ar), 8.09 (bd,
J = 6 Hz, 2H, Ar), 7.28–7.39 (m, 4H, Ar ? NH2), 2.91 (s,
2H, CH2), 2.30 (s, 2H, CH2), 0.98 (s, 6H, 2 9 CH3); 13C-
NMR (DMSO-d6) d (ppm): 163.53 (d, J = 245 Hz, 13C–
1
F), 156.44, 135.68, 133.72 (d, 4J = 2.93 Hz, 13C–C–C–C–
F), 133.05, 129.23 (d, J = 8.53 Hz, 13C–C–C–F), 116.30
3
(d, 2J = 21.51 Hz, 13C–C–F), 114.50, 42.99, 36.68, 30.04,
28.74; FT-IR mmax 3394, 3317, 3193, 2956, 2892, 2869,
1601, 1542, 1507, 1466, 1408, 1222, 1209, 1156, 836, 721,
586 cm-1; MS m/z (%): 284 (M?, 100), 267 (85), 183 (31),
157 (67), 133 (50), 120 (95), 107 (46), 95 (90), 75 (66), 63
(39), 55 (58).
(E)-1-(7,8-Dihydro-3-(4-hydroxy-3-
methoxyphenyl)cinnoline-5(6H)-ylidene)hydrazine (4g)
White crystals, yield: 69 %, mp 187–188 °C; 1H-NMR
(DMSO-d6) d (ppm): 9.42 (bs, 1H, OH), 8.06 (s, 1H, Ar),
7.63 (s, 1H, Ar), 7.43 (d, J = 8.1 Hz, 1H, Ar), 7.26 (bs,
2H, NH2), 6.88 (d, J = 8.1 Hz, 1H, Ar), 3.84 (s, 3H,
OCH3), 2.99 (t, J = 5.7 Hz, 2H, CH2), 2.43 (t, J = 5.7 Hz,
2H, CH2), 1.89 (quin, J = 5.7 Hz, 2H, CH2); 13C-NMR
(DMSO-d6) d (ppm): 157.29, 156.84, 148.64, 148.41,
136.82, 133.37, 128.36, 119.87, 116.22, 114.30, 110.46,
56.03, 29.77, 23.42, 20.34; FT-IR mmax 3391, 3366, 3308,
3189, 2935, 1594, 1555, 1517, 1412, 1272, 1214, 1133,
(E)-1-(7,8-Dihydro-7,7-dimethyl-3-(4-
nitrophenyl)cinnoline-5(6H)-ylidene)hydrazine (4k)
1
Yellow crystals, yield: 83 %, mp 273–274 °C; H-NMR
(DMSO-d6) d (ppm): 8.32–8.22 (m, 5H, Ar), 7.47 (bs, 2H,
NH2), 2.95 (s, 2H, CH2), 2.31 (s, 2H, CH2), 0.99 (s, 6H,
2 9 CH3); 13C-NMR (DMSO-d6) d (ppm): 157.36, 155.50,
148.46, 143.32, 135.24, 133.30, 128.26, 124.54, 115.49,
43.06, 36.64, 30.01, 28.73; FT-IR mmax 3372, 3319, 3172,
2961, 2926, 2892, 2869, 1535, 1511, 1408, 1340, 1289,
1028, 789, 586 cm-1
.
(E)-1-(7,8-Dihydro-7,7-dimethyl-3-phenylcinnoline-5(6H)-
1106, 849, 692 cm-1
.
ylidene)hydrazine (4h)
Pale yellow crystals, yield: 69 %, mp 189–190 °C; 1H-
NMR (DMSO-d6) d (ppm): 8.14 (s, 1H, Ar), 8.03 (bd,
J = 5.7 Hz, 2H, Ar), 7.45–7.53 (m, 3H, Ar), 7.36 (bs, 2H,
NH2), 2.91 (s, 2H, CH2), 2.29 (s, 2H, CH2), 0.98 (s, 6H,
2 9 CH3); 13C-NMR (DMSO-d6) d (ppm): 157.33, 156.47,
137.25, 135.78, 132.98, 129.91, 129.41, 126.95, 114.59,
43.04, 36.70, 30.06, 28.76; FT-IR mmax 3401, 3304, 3219,
3067, 2955, 2866, 1640, 1540, 1495, 1408, 1388, 1160,
1017, 919, 869, 775, 693, 652 cm-1; MS m/z (%): 266
(M?, 100), 250 (82), 223 (33), 165 (36), 139 (75), 115 (48),
102 (57), 91 (34), 77 (96), 63 (35), 51 (53).
(E)-1-(7,8-Dihydro-3-(4-methoxyphenyl)-7,7-
dimethylcinnoline-5(6H)-ylidene)hydrazine (4l)
Pale yellow crystals, yield: 47 %, mp 212–213 °C; 1H-
NMR (DMSO-d6) d (ppm): 8.09 (s, 1H, Ar), 8.00 (d,
J = 8.7 Hz, 2H, Ar), 7.33 (bs, 2H, NH2), 7.05 (d,
J = 8.7 Hz, 2H, Ar), 3.80 (s, 3H, OCH3), 2.88 (s, 2H,
CH2), 2.29 (s, 2H, CH2), 0.97 (s, 6H, 2 9 CH3); 13C-NMR
(DMSO-d6) d (ppm): 160.89, 156.94, 155.89, 135.94,
132.86, 129.51, 128.28, 114.80, 113.86, 55.69, 43.01,
36.73, 30.07, 28.76; FT-IR mmax 3352, 3321, 3161, 2956,
123

J IRAN CHEM SOC
2866, 2836, 1656, 1606, 1544, 1510, 1462, 1407, 1368,
1303, 1250, 1218, 1170, 1130, 1031, 1014, 828, 726, 589,
525 cm-1; MS m/z (%): 296 (M?, 100), 280 (27), 253 (35),
196 (23), 169 (23), 152 (23), 134 (32), 129 (28), 120 (33),
89 (38), 43 (90), 77 (41), 63 (30).
127.18, 119.77, 29.04, 27.11, 20.40; FT-IR mmax 3061,
3036, 2944, 2874, 1608, 1577, 1040, 911, 874, 774, 692,
668, 598, 501 cm-1; MS m/z (%): 444 (M?, 2), 193 (24),
178 (27), 165 (53), 152 (64), 139 (100), 127 (24), 115 (58),
102 (62), 89 (26), 77 (97), 63 (31), 51 (53).
(E)-1-(7,8-Dihydro-3-((S)-3,4-dimethoxyphenyl)-7,7-
1,2-Bis(3-(4-chlorophenyl)-7,8-dihydrocinnoline-5(6H)-
dimethylcinnoline-5(6H)-ylidene)hydrazine (4m)
ylidene)hydrazine (5b)
1
White crystals, yield: 58 %, mp 248–249 °C; 1H-NMR
(DMSO-d6) d (ppm): 8.11 (s, 1H, Ar), 7.67 (s, 1H, Ar),
7.57 (d, J = 8.4 Hz, 1H, Ar), 7.33 (bs, 2H, NH2), 7.07 (d,
J = 8.4 Hz, 1H, Ar), 3.84 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.89 (s, 2H, CH2), 2.29 (s, 2H, CH2), 0.98 (s, 6H,
2 9 CH3); 13C-NMR (DMSO-d6) d (ppm): 161.16, 157.01,
155.96, 149.47, 135.98, 132.80, 129.75, 119.58, 114.04,
112.30, 110.04, 55.99, 55.94, 43.06, 36.77, 30.08; FT-IR
mmax 3394, 3182, 2996, 2957, 2929, 1656, 1602, 1553,
1516, 1461, 1407, 1266, 1224, 1138, 1017, 871 cm-1; MS
m/z (%): 326 (M?, 25), 162 (73), 147 (49), 139 (21), 128
(21), 119 (77), 101 (29), 91 (100), 76 (80), 65 (73), 51 (72).
Brown crystals, yield: 78 %, mp 297 °C (dec); H-NMR
(CDCl3) d (ppm): 8.52 (s, 2H, Ar), 8.11 (d, J = 7.8 Hz,
4H, Ar), 7.52 (d, J = 7.8 Hz, 4H, Ar), 3.34 (t, J = 6.3 Hz,
4H, 2 9 CH2), 2.79 (t, J = 6.3 Hz, 4H, 2 9 CH2), 2.11
(quin, J = 6.3 Hz, 4H, 2 9 CH2); 13C-NMR (CDCl3) d
(ppm): 158.73, 157.65, 154.69, 136.51, 134.46, 131.07,
129.31, 128.31, 118.46, 29.50, 27.14, 20.56; FT-IR mmax
3058, 2949, 2872, 1596, 1491, 1403, 1328, 1089, 1007,
820, 739 cm-1; MS m/z (%): 514 (M? ?2, 9), 512 (M?,
12), 486 (7), 390 (21), 347 (9), 298 (13), 272 (100), 257
(70), 243 (59), 228 (80), 193 (41), 178 (37), 165 (56), 152
(45), 139 (42), 107 (19), 75 (17).
1,2-Bis(7,8-dihydro-3-phenylcinnoline-5(6H)-
1,2-Bis(3-(4-fluorophenyl)-7,8-dihydrocinnoline-5(6H)-
ylidene)hydrazine (5a)
ylidene)hydrazine (5c)
1
1
Orange crystals, yield: 84 %, mp 282 °C (dec); H-NMR
Yellow crystals, yield: 55 %, mp 305 °C (dec); H-NMR
(CDCl3) d (ppm): 8.62 (s, 2H, Ar), 8.16 (d, J = 7.2 Hz,
4H, Ar), 7.48–7.59 (m, 6H, Ar), 3.39 (t, J = 6 Hz, 4H,
2 9 CH2), 2.82 (t, J = 6 Hz, 4H, 2 9 CH2), 2.13 (quin,
J = 6 Hz, 4H, 2 9 CH2); 13C-NMR (CDCl3) d (ppm):
158.90, 158.40, 154.61, 135.45, 131.91, 130.50, 129.16,
(CDCl3) d (ppm): 8.54 (s, 2H, Ar), 8.12–8.20 (m, 4H, Ar),
7.19–7.28 (m, 4H, Ar), 3.36 (t, J = 6 Hz, 4H, 2 9 CH2), 2.80
(t, J = 6 Hz, 4H, 2 9 CH2), 2.12 (quin, J = 6 Hz, 4H,
1
2 9 CH2); 13C-NMR (CDCl3) d (ppm): 164.21 (d, J =
4
249 Hz, 13C–F), 158.51, 157.76, 154.79, 132.26 (d, J =
Scheme 2 Synthesis of
substituted (E)-1-(3-aryl-7,8-
dihydrocinnoline-5(6H)-
ylidene)hydrazine
NH2
O
N
O
Ar
H
NH2NH2.H2O
Ar
X
N
X
H2O/ EtOH
rt, 35-60 min
O
O
N
1a-h
2-3
4a-m
Ar = C6H5 , 4-BrC6H4 , 4-ClC6H4 , 4-FC6H4 , 4-NO2C6H4 , 3,4-OMeC6H3 , 4-OMeC6H4 , 4-OH-3-OMeC6H3
X = CH2 , C(CH3)2
Scheme 3 Synthesis of
substituted (1E,2E)-1,2-bis(3-
aryl-7,8-dihydrocinnoline-
5(6H)-ylidene)hydrazine
N
N
O
O
Ar
H
NH2NH2.H2O
N
Ar
Water
40 C, 1-2h
N
O
O
Ar
1
2
N
N
5a-f
Ar = C6H5 , 4-ClC6H4 , 4-FC6H4 , 4-NO2C6H4 , 3,4-OMeC6H3 , 4-OMeC6H4
123

J IRAN CHEM SOC
Table 1 List of mono- and bis-(3-aryl-7,8-dihydro cinnoline-5(6H)-ylidene)hydrazine derivatives
N
N
NH2
NH2
N
N
N
N
N
N
N
N
N
N
4a
4h
5a
N
N
Br
Cl
NH2
N
O
N
Cl
Cl
N
N
N
N
N
N
N
4b
4i
5b
N
N
N
N
Cl
F
NH2
NH2
N
N
N
F
F
N
N
N
N
N
N
N
4j
4c
5c
N
O2N
NH2
N
O2N
NH2
N
N
O2N
NO2
N
N
N
N
N
N
N
5d
4d
4k
N
H3CO
NH2
H3CO
NH2
N
N
N
H3CO
OCH3
N
N
N
N
N
N
N
4e
4l
5e
N
N
H3CO
H3CO
H3CO
H3CO
OCH3
OCH3
NH2
NH2
N
N
N
H3CO
H3CO
N
N
N
N
N
N
N
4m
4f
5f
HO
NH2
N
H3CO
N
N
4g
2.7 Hz, 13C–C–C–C–F), 130.95, 129.01 (d, 3J = 9 Hz, 13C–
C–C–F), 118.30, 116.13 (d, 2J = 21.75 Hz, 13C–C–F), 29.53,
27.14, 20.60; FT-IR mmax 3070, 2951, 2872, 1599, 1504, 1404,
1224, 1157, 1109, 850, 809, 557 cm-1; MSm/z (%): 480 (M?,
3), 272 (13), 256 (94), 242 (28), 227 (37), 212 (15), 177 (24),
148 (43), 133 (38), 121 (22), 107 (100), 95 (13).
123

J IRAN CHEM SOC
(M?, 6), 480 (9), 429 (13), 396 (18), 268 (44), 253 (63), 239
(27), 224 (66), 210 (55), 182 (30), 165 (37), 135 (100), 107
(37), 92 (53), 77 (88), 63 (44), 41 (37).
1,2-Bis(7,8-dihydro-3-(4-nitrophenyl)cinnoline-5(6H)-
ylidene)hydrazine (5d)
1
Brown crystals, yield: 89 %, mp 230 °C (dec); H-NMR
(CDCl3) d (ppm): 8.44 (s, 2H, Ar), 8.38 (d, J = 8.7 Hz,
4H, Ar), 8.31 (d, J = 8.7 Hz, 4H, Ar), 3.32 (t, J = 6.3 Hz,
4H, 2 9 CH2), 2.56 (t, J = 6.3 Hz, 4H, 2 9 CH2), 2.13
(quin, J = 6.3 Hz, 4H, 2 9 CH2); 13C-NMR (DMSO-d6) d
(ppm): 158.44, 155.56, 148.47, 143.32, 136.03, 133.92,
128.25, 124.54, 115.94, 29.88, 23.28, 20.13; FT-IR mmax
3071, 2957, 2876, 1599, 1556, 1505, 1406, 1343, 1252,
1110, 866, 848, 696 cm-1; MS m/z (%): 534 (M?, 1), 283
(100), 254 (50), 208 (79), 165 (65), 152 (64), 139 (53), 117
(61), 106 (83), 89 (71), 75 (86), 63 (82), 51 (75).
(16E,21E)-1-(7,8-Dihydro-3-((S)-3,4-
dimethoxyphenyl)cinnoline-5(6H)-ylidene)-2-(7,8-dihydro-
3-(3,4-dimethoxyphenyl)cinnoline-5(6H)-
ylidene)hydrazine (5f)
1
Yellow crystals, yield: 66 %, mp 263 °C (dec); H-NMR
(CDCl3) d (ppm): 8.49 (s, 2H, Ar), 7.92 (s, 2H, Ar), 7.60
(d, J = 8.1 Hz, 2H, Ar), 6.99 (d, J = 8.1 Hz, 2H, Ar), 4.01
(s, 6H, 2 9 OCH3), 3.95 (s, 6H, 2 9 OCH3), 3.29 (t,
J = 5.4 Hz, 4H, 2 9 CH2), 2.76 (t, J = 5.4 Hz, 4H,
2 9 CH2), 2.09 (quin, J = 5.4 Hz, 4H, 2 9 CH2); 13C-
NMR (CDCl3) d (ppm): 158.10, 158.04, 154.63, 151.03,
149.65, 130.81, 128.79, 119.70, 117.99, 111.18, 110.01,
56.18, 56.02, 29.56, 27.18, 20.65; FT-IR mmax 3000, 2939,
2836, 1603, 1515, 1456, 1402, 1262, 1215, 1136, 1022,
912, 853, 763, 586 cm-1; MS m/z (%): 564 (M?, 5), 297
(24), 283 (100), 269 (37), 253 (23), 237 (23), 224 (19), 210
(15), 196 (10), 180 (10), 165 (16), 152 (14), 139 (15).
1,2-Bis(7,8-dihydro-3-(4-methoxyphenyl)cinnoline-5(6H)-
ylidene)hydrazine (5e)
1
Yellow crystals, yield: 42 %, mp 301 °C (dec); H-NMR
(CDCl3) d (ppm): 8.52 (s, 2H, Ar), 8.13 (d, J = 8.7 Hz, 4H,
Ar), 7.07 (d, J = 8.7 Hz, 4H, Ar), 3.90 (s, 6H, 2 9 OCH3),
3.32 (t, J = 6 Hz, 4H, 2 9 CH2), 2.79 (t, J = 6 Hz, 4H,
2 9 CH2), 2.10 (quin, J = 6 Hz, 4H, 2 9 CH2); 13C-NMR
(CDCl3) d (ppm): 161.49, 158.30, 157.86, 154.78, 131.19,
128.51, 128.23, 118.33, 114.50, 55.45, 29.36, 27.15, 20.58;
FT-IR mmax 3061, 2945, 2837, 1607, 1405, 1302, 1251,
1176, 1020, 1176, 1020, 836, 572 cm-1; MS m/z (%): 504
Results and discussion
In continuation of our recent report on regioselective syn-
thesis of new substituted 7,8-dihydrocinnoline-5(6H)-ones
Scheme 4 Suggested
OH
O
O
H
N
O
mechanism for regioselective
synthesis of (1E,2E)-1,2-bis(3-
aryl-7,8-dihydrocinnoline-
5(6H)-ylidene)hydrazine
Ar
Ar
H
NH2NH2
-2H2O
+
-H2O
Ar
X
O
X
X
N
O
O
O
1
6
7
8
NH2NH2
NH2
X
O
H
N
N
Ar
X
N
O
2 , 3
4
8
8
X = CH2
X = C(CH3)2
N
N
N.R
Ar
N
N
Ar
N
N
5
123

J IRAN CHEM SOC
[46], here we report the synthesis of mono- and bis-(3-aryl-
7,8-dihydrocinnoline-5(6H)-ylidene)hydrazine derivatives.
Hence, arylglyoxals 1a–h were reacted with 1,3-cyclo-
hexadione 2 and 7,7-dimethyl-1,3-cyclohexadione (dime-
done) 3 in the presence of hydrazine hydrate in H2O and
H2O/EtOH at room temperature or 40 °C, which led to
form the desired products 4a–m and 5a–f in moderate to
good yields as shown in Schemes 2 and 3.
condensation of hydrazine with the carbonyl groups of the
intermediate 7 gives the substituted 7,8-dihydrocinnoline-
5(6H)-ones 8 [46] which is converted to mono-(3-aryl-7,8-
dihydrocinnoline-5(6H)-ylidene)hydrazine derivatives 4 in
the presence of excess amount of hydrazine hydrate. Then,
reaction of 4 with 8 led to the formation of final products 5
(Scheme 4).
Attempts to the preparation of bis-(3-aryl-7,8-dihyd-
rocinnoline-5(6H)-ylidene)hydrazine derivatives using
arylglyoxals 1 and 7,7-dimethyl-1,3-cyclohexadion (dime-
done) 3 were failed and a mixture of cinnolines 8h–m [45]
corresponding mono-derivatives 4h–m were formed
instead. The regioselective formation of mono-3-aryl-
substituted cinnoline hydrazine derivatives 3a–h was
unambiguously secured by X-ray crystal structure, crystal
packing diagram and crystal data analysis of 4i as shown in
Figs. 1, 2 and Table 2, respectively.
All obtained mono- and bis-products are listed in
Table 1. The structure of all synthesized cinnoline deriv-
1
atives was characterized by H-NMR, 13C-NMR, FT-IR
1
and Mass spectral data. In H-NMR spectra of mono-pro-
ducts, the CH of pyridazine ring is deshielded and reso-
nates at low field d (ppm): 8.06–8.27 and the CH protons of
pyridazine rings in bis-products are highly deshielded and
resonates at lower fields d (ppm): 8.22–8.62.
Owing to the high reactivity of the external carbonyl in
comparison with internal carbonyl in an arylglyoxal sys-
tem, the reaction was run through the nucleophilic attack of
enol 6 to the aldehyde carbonyl of arylglyoxal 1 leading to
form the intermediate 7 as a sole product. The subsequent
Table 2 Crystal data and structure refinement details for 4i
Empirical formula
Formula weight
Crystal size, mm3
Crystal color and form
Crystal system
C16H17ClN4
300.79
0.14 9 0.17 9 0.29
Pale brown, needles
Monoclinic
P21/c
Space group
˚
a, A
6.371(7)
15.467(16)
15.925(17)
99.623(16)
1547(3)
˚
b, A
˚
c, A
b, deg
˚
V, A
3
Z
4
D (calc), g cm-3
l, mm-1
1.291
0.246
Fig. 1 Crystal structure of compound 4i
F(000), e
Scan type
h range, deg
Index range
632
x
1.85–28.31
-8 B h B 8, -20 B k B 20,
-21 B l B 21
Measured reflections
Independent reflections
Observed refl. I C 2r(I)
18627
3821
1835
Completeness to
h = 28.31°
Refinement on
98.8 %
F2
Data, restraints,
parameters
3821, 0, 190
R (Fo2 [ 2r(Fo2))
R (all data)
R1 = 0.0604, wR2 = 0.1284
R1 = 0.1468, wR2 = 0.1601
1.010
Goodness-of-fit = S
Weighting parameter a/b
-3
0.0245/0.2715
˚
Dq (max; min), e A
0.297; -0.191
CCDC
948079
Fig. 2 Crystal packing of 4i
123

J IRAN CHEM SOC
Acknowledgments The authors are grateful to Urmia University for
financial support and to Dr. A. Choudhury (Missouri University of
Science and Technology, USA) for his assistance with X-ray
crystallography.
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