Efficient and green method for the synthesis of highly substituted cyclohexadiene derivatives in aqueous media

Article abstract of DOI:10.1080/00397910903040237

Three-component reaction of aromatic aldehyde, malononitrile, and 2-(1-(3-chlorophenyl)propylidene)malononitrile in aqueous media catalyzed by tetraethylbenzylammonium chloride (TEBAC) at 90C gave 2-amino-6-(3-chlorophenyl) -5-methyl-4-arylcyclohexa-1,5-d

Full text of DOI:10.1080/00397910903040237

Synthetic Communications1, 40: 1065–1073, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903040237
EFFICIENT AND GREEN METHOD FOR THE SYNTHESIS
OF HIGHLY SUBSTITUTED CYCLOHEXADIENE
DERIVATIVES IN AQUEOUS MEDIA
Xiang-Shan Wang,1,2 Jie Zhou,1 Ke Yang,1 and
Mei-Mei Zhang2
1School of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu, China
2Key Laboratory of Biotechnology on Medical Plant, Xuzhou, Jiangsu, China
Three-component reaction of aromatic aldehyde, malononitrile, and 2-(1-(3-
chlorophenyl)propylidene)malononitrile in aqueous media catalyzed by tetraethylbenzyl-
ammonium chloride (TEBAC) at 90 ꢀC gave 2-amino-6-(3-chlorophenyl)-5-methyl-
4-arylcyclohexa-1,5-diene-1,3,3-tricarbonitrile derivatives. The structure of 4e was further
confirmed by x-ray diffraction. This three-component reaction had the advantages of green
solvent, good yield, and operational simplicity.
Keywords: Aqueous media; cyclohexadiene; malononitrile; TEBAC
INTRODUCTION
Multicomponent reactions (MCRs), defined as one-pot reactions in which at
least three functional groups join through covalent bonds, have been steadily gaining
importance in synthetic organic chemistry.[1] The reagents employed may be differ-
ent molecules or different functional groups of the same reagent. Speed, diversity,
efficiency, and environmental friendliness are some of the key features of this class
of reactions. Up to seven starting components have been used, and MCRs have often
produced better yields than classical chemistry.[2] They provide a powerful tool for
the one-pot synthesis of diverse and complex compounds as well as small and
drug-like heterocycles.[3]
The organic reactions in water without harmful organic solvents have been a
current focus, especially in the ecologically conscious environment of today, since
Breslow and Rideout,[4] who showed that hydrophobic effects could strongly
enhance the rate of several organic reactions, rediscovered the use of water as a sol-
vent in organic chemistry in 1980s. Water has recently attracted considerable interest
as a solvent for a large number of organic transformations[5] because it is abundant,
nontoxic, and environmentally friendly. As part of our ongoing program to
Received February 23, 2009.
Address correspondence to Xiang-Shan Wang, School of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou, Jiangsu 221116, China. E-mail: xswang1974@yahoo.com
1065

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X.-S. WANG ET AL.
synthesize organic compounds in an environmentally friendly media,[6] herein we
report a green synthesis of a series of 2-amino-6-(3-chlorophenyl)-5-methyl-4-
arylcyclohexa-1,5-diene-1,3,3-tricarbonitrile derivatives in aqueous media catalyzed
by tetraethylbenzylammonium chloride (TEBAC).
RESULTS AND DISCUSSION
The treatment of aromatic aldehyde 1, malononitrile 2, and 2-(1-(3-
chlorophenyl)propylidene)malononitrile 3 in water in the presence of 10 mol%
TEBAC at 90 ꢀC afforded 2-amino-6-(3-chlorophenyl)-5-methyl-4-arylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile derivatives 4 in good yields (Scheme 1).
Subsequently, the reaction of 3-bromobenzaldehyde, malononitrile, and
2-(1-(3-chlorophenyl)propylidene)malononitrile was used as a model reaction to
optimize the conditions. The reaction was first carried out in water in the absence
of TEBAC. No reaction took place at room temperature (Table 1, entry 1), and only
a trace of 4a was observed by thin-layer chromatography (TLC) when the reaction
temperature was raised to 90 ꢀC (Table 1, entry 2). Similar reactions were then
attempted in the presence of TEBAC with 1, 5, 10, and 20 mol% (Table 1, entries
5–8); just 10 mol% TEBAC at 90 ꢀC in water gave the best yield. More catalyst
did not improve the yield. To find the optimum reaction temperature, the reaction
Scheme 1. The reaction of aromatic aldehyde, malononitrile, and 3 in water.
Table 1. Synthesis of 4a in water under different reaction conditionsa
Entry
Temp. (ꢀC)
Cat. (mol%)
Catalyst
Yieldb (%)
1
2
rt
0
0
—
—
0
Trace
Trace
72
90
rt
3
10
10
10
20
5
TEBAC
TEBAC
4
50
90
90
90
90
90
90
5
TEBAC
TEBAC
88
85
6
7
TEBAC
TEBAC
82
78
8
1
9
10
10
10
CH3(CH2)15NMe3Br
CH3(CH2)11SO3Na
83
82
aReagents and conditions: 1 (0.370 g, 2 mmol), malononitrile 2 (0.145 g, 2.2 mmol),
3 (0.432 g, 2 mmol), TEBAC (0.091 g, 0.2 mmol), H2O (10 mL).
bIsolated yields.

SYNTHESIS OF CYCLOHEXADIENE DERIVATIVES
1067
Table 2. Reactions of aromatic aldehyde, malononitrile, and 2-(1-(3-chloro-
phenyl)propylidene)malononitrile in watera
Entry
Ar
Products
Time (h)
Yields (%)b
1
2
3-BrC6H4
4a
4b
4c
4d
4e
4f
12
10
18
20
14
16
14
16
15
17
14
18
88
90
83
84
87
85
85
83
84
82
80
87
4-NO2C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
2-ClC6H4
3
4
5
6
4-CH3C6H4
3-ClC6H4
7
4 g
4 h
4i
8
3,4-Cl2C6H3
4-ClC6H4
4-BrC6H4
9
10
11
12
4j
2,4-Cl2C6H3
3,4-(CH3)2C6H3
4k
4l
aReagents and conditions: 1 (2 mmol), malononitrile 2 (0.145 g, 2.2 mmol),
3 (0.432 g, 2 mmol), TEBAC (0.091 g, 0.2 mmol), and H2O (10 mL).
bIsolated yields.
was carried out in the presence of TEBAC with 10 mol% at room temperature, 50,
and 90 ꢀC, resulting in the isolation of 4a in trace, 72%, and 88% yield (Table 1,
entries 3–5), respectively. Thus, 10 mol% TEBAC and a reaction temperature of
90 ꢀC were chosen. In addition, CH3(CH2)15NMe3Br and CH3(CH2)11SO3Na
(Table 1, entries 9 and 10) were also tested as catalysts. In these cases, product 4a
was formed in slightly lower yields. The TEBAC catalyst could be reused for the syn-
thesis of 4a without significant loss of activity; even in the fourth round, 4a could be
obtained in good yield (82%).
Figure 1. Crystal structure of the product 4e with the solvent H2O deleted for clarity.

1068
X.-S. WANG ET AL.
Scheme 2. The possible mechanism for the formation of products 4.
To extend the reaction (Scheme 1) to a library system, various kinds of
aromatic aldehydes 1 were reacted with malononitrile and 2-(1-(3-chlorophenyl)
propylidene)malononitrile, giving the corresponding 2-amino-6-(3-chlorophenyl)-
5-methyl-4-arylcyclohexa-1,5-diene-1,3,3-tricarbonitrile derivatives 4 successfully
(Table 2). All of 1 gave expected products in good yields, either bearing
electron-withdrawing groups (such as halide or nitro) or electron-donating groups
(such as alkyl or alkoxyl) under the same reaction condition (Table 2). The structure
of 4e was confirmed by x-ray diffraction analysis, shown in Fig. 1.
Although the detailed mechanism of this reaction has not been clarified, the
formation of 2-amino-6-(3-chlorophenyl)-5-methyl-4-arylcyclohexa-1,5-diene-1,3,3-
tricarbonitrile derivatives 4 could be explained by a possible mechanism as presented
in Scheme 2. The Knoevenagel condensation of aromatic aldehydes and malononi-
trile may occur to generate a,b-unsaturated dinitriles I first, then Michael addition
reaction takes place between the reactant 3 and I to give II, and the anion in II then
attacks one of the cyano groups to afford III, which then isomerizes to yield the final
product 4.
CONCLUSION
In conclusion, we found a simple and green method for the synthesis of
2-amino-6-(3-chlorophenyl)-5-methyl-4-arylcyclohexa-1,5-diene-1,3,3-tricarbonitrile
derivatives by three-component reaction of aromatic aldehyde, malononitrile, and
2-(1-(3-chlorophenyl)propylidene)malononitrile in aqueous media catalyzed by
TEBAC at 90 ꢀC. This three-component reaction had advantages of green solvent,
good yields, and operational simplicity.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. Infra-
red (IR) spectra were recorded on a Tensor 27 spectrometer in KBr pellets. 1H NMR

SYNTHESIS OF CYCLOHEXADIENE DERIVATIVES
1069
spectra were obtained from solution in dimethylsulfoxide (DMSO-d6) with Me4Si as
internal standard using a Bruker-400 spectrometer. High-resolution mass spec-
trometry (HRMS) analyses were carried out using a Bruker micro-TOF-Q-MS
analyzer.
General Procedure for the Syntheses of 2-Amino-6-(3-chlorophenyl)-
5-methyl-4-aryl-cyclohexa-1,5-diene-1,3,3-tricarbonitrile Derivatives
A 50-mL flask was charged with aromatic aldehyde (2.0 mmol), malononitrile
(2.2 mmol, 0.145 g), 2-(1-(3-chlorophenyl)propylidene)malononitrile (2.0 mmol,
0.432 g), TEBAC (0.2 mmol, 0.091 g), and water (10 mL). The reaction mixture
was stirred at 90 ꢀC for 10–20 h; the solid was isolated by filtration. The filtrate
together with TEBAC could be used again directly for the same reaction. The
crude products were washed with water, purified by recrystallization from dimethyl-
formamide (DMF) and water, and dried at 80 ꢀC for several hours in a vacuum to
give 4.
2-Amino-4-(3-bromophenyl)-6-(3-chlorophenyl)-5-methylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4a)
Mp 187 ꢁ 189 ꢀC. IR (KBr): 3411, 3322, 3054, 2201, 1644, 1591, 1567, 1474,
1
1427, 1406, 1216, 1180, 1095, 1078, 998, 879, 795, 783 cmꢁ1. H NMR (DMSO-d6,
400 MHz): 1.55 (s, 3H, CH3), 4.73 (s, 1H, CH), 7.19 (d, J ¼ 7.2 Hz, 1H, ArH),
7.28 (s, 1H, ArH), 7.43–7.52 (m, 4H, ArH), 7.64–7.68 (m, 4H, ArH þ NH2). HRMS
(ESI, m=z): calcd. for C22H14BrClN4Na (M þNaþ) 470.9988; found 470.9988.
2-Amino-6-(3-chlorophenyl)-5-methyl-4-(4-nitrophenyl)cyclohexa-
1,5-diene-1,3,3-tri carbonitrile (4b)
Mp 209 ꢁ 210 ꢀC. IR (KBr): 3426, 3328, 2199, 1713, 1637, 1590, 1567, 1523,
1478, 1396, 1348, 1218, 1108, 863, 826, 793, 751 cmꢁ1 1H NMR (DMSO-d6,
.
400 MHz): 1.54 (s, 3H, CH3), 4.95 (s, 1H, CH), 7.22 (d, J ¼ 6.8 Hz, 1H, ArH),
7.48 (s, 1H, ArH), 7.49–7.54 (m, 2H, ArH), 7.70 (s, 2H, NH2), 7.78 (d, J ¼ 8.8 Hz,
2H, ArH), 8.32 (d, J ¼ 8.8 Hz, 2H, ArH). HRMS (ESI, m=z): calcd. for
C22H14ClN5O2Na (M þNaþ) 483.0734; found 438.0732.
2-Amino-6-(3-chlorophenyl)-4-(methoxyphenyl)-5-methylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4c)
Mp 202 ꢁ 204 ꢀC. IR (KBr): 3439, 3315, 3009, 2976, 2215, 1646, 1594, 1566,
1
1511, 1464, 1418, 1390, 1303, 1253, 1214, 1177, 1025, 840, 802, 757 cmꢁ1. H NMR
(DMSO-d6, 400 MHz): 1.53 (s, 3H, CH3), 3.77 (s, 3H, CH3O), 4.59 (s, 1H, CH),
7.00 (d, J ¼ 8.4 Hz, 2H, ArH), 7.18 (d, J ¼ 6.8 Hz, 1H, ArH), 7.25 (s, 1H, ArH),
7.38 (d, J ¼ 8.4 Hz, 2H, ArH), 7.48–7.51 (m, 2H, ArH), 7.57 (s, 2H, NH2). HRMS
(ESI, m=z): calcd. for C23H17ClN4ONa (M þNaþ) 423.0989; found 423.0985.

1070
X.-S. WANG ET AL.
2-Amino-6-(3-chlorophenyl)-4-(3,4-dimethoxyphenyl)-5-methyl-
cyclohexa-1,5-diene-1,3,3-tricarbonitrile (4d)
Mp 168 ꢁ 171 ꢀC. IR (KBr): 3432, 3310, 3056, 3005, 2971, 2933, 2213, 1649,
1586, 1567, 1515, 1444, 1420, 1275, 1214, 1159, 1142, 1024, 852, 795, 772 cmꢁ1
.
1H NMR (DMSO-d6, 400 MHz): 1.56 (s, 3H, CH3), 3.76 (s, 3H, CH3O), 3.78 (s,
3H, CH3O), 4.57 (s, 1H, CH), 7.00–7.04 (m, 2H, ArH), 7.08 (d, J ¼ 2.4 Hz, 1H,
ArH), 7.21 (d, J ¼ 6.8 Hz, 1H, ArH), 7.24 (s, 1H, ArH), 7.49–7.51 (m, 2H, ArH),
7.61 (s, 2H, NH2). HRMS (ESI, m=z): calcd. for C24H19ClN4O2Na (M þNaþ)
453.1094; found 453.1080.
2-Amino-6-(3-chlorophenyl)-4-(2-chlorophenyl)-5-methylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4e)
Mp 196 ꢁ 198 ꢀC. IR (KBr): 3434, 3311, 2973, 2215, 1650, 1594, 1565, 1471,
1
1441, 1416, 1392, 1216, 1165, 1080, 1057, 1040, 896, 796, 757, 702 cmꢁ1. H NMR
(DMSO-d6, 400 MHz): 1.51 (s, 3H, CH3), 4.84 (s, 1H, CH), 7.20 (d, J ¼ 6.4 Hz,
1H, ArH), 7.31 (s, 1H, ArH), 7.47–7.55 (m, 5H, ArH), 7.62–7.64 (m, 1H, ArH),
7.77 (s, 2H, NH2). HRMS (ESI, m=z): calcd. for C22H14Cl2N4Na (M þNaþ)
427.0493; found 427.0499.
2-Amino-6-(3-chlorophenyl)-5-methyl-4-(4-methylphenyl)cyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4f)
Mp 242 ꢁ 245 ꢀC. IR (KBr): 3434, 3311, 3028, 2214, 1651, 1588, 1564, 1509,
1473, 1456, 1417, 1395, 1217, 1190, 1078, 888, 805, 788, 758 cmꢁ1 1H NMR
.
(DMSO-d6, 400 MHz): 1.53 (s, 3H, CH3), 2.32 (s, 3H, CH3), 4.59 (s, 1H, CH),
7.18 (d, J ¼ 7.2 Hz, 1H, ArH), 7.24 (d, J ¼ 8.0 Hz, 2H, ArH), 7.25 (s, 1H, ArH),
7.34 (d, J ¼ 8.0 Hz, 2H, ArH), 7.48–7.51 (m, 2H, ArH), 7.58 (s, 2H, NH2). HRMS
(ESI, m=z): calcd. for C23H17ClN4Na (M þNaþ) 407.1039; found 407.1056.
2-Amino-4,6-di(3-chlorophenyl)-5-methylcyclohexa-1,5-diene-
1,3,3-tricarbonitrile (4g)
Mp 178 ꢁ 181 ꢀC. IR (KBr): 3413, 3323, 3065, 2995, 2200, 1644, 1592, 1570,
1476, 1430, 1406, 1216, 1184, 1096, 1081, 879, 785, 764, 713 cmꢁ1 1H NMR
.
(DMSO-d6, 400 MHz): 1.55 (s, 3H, CH3), 4.74 (s, 1H, CH), 7.19 (d, J ¼ 6.8 Hz,
1H, ArH), 7.27 (s, 1H, ArH), 7.42–7.43 (m, 1H, ArH), 7.47–7.53 (m, 5H, ArH),
7.68 (s, 2H, NH2). HRMS (ESI, m=z): calcd. for C22H14Cl2N4Na (M þNaþ)
427.0493; found 427.0499.
2-Amino-6-(3-chlorophenyl)-4-(3,4-dichlorophenyl)-5-
methylcyclohexa-1,5-diene-1,3,3-tricarbonitrile (4h)
Mp 211 ꢁ 213 ꢀC. IR (KBr): 3410, 3323, 2994, 2904, 2200, 1643, 1590, 1564,
1
1474, 1404, 1330, 1215, 1185, 1095, 1079, 1033, 961, 880, 807, 792, 767 cmꢁ1. H
NMR (DMSO-d6, 400 MHz): 1.54 (s, 3H, CH3), 4.78 (s, 1H, CH), 7.19 (d,
J ¼ 6.8 Hz, 1H, ArH), 7.30 (s, 1H, ArH), 7.43 (dd, J ¼ 8.4 Hz, J0 ¼ 2.0 Hz, 1H,

SYNTHESIS OF CYCLOHEXADIENE DERIVATIVES
1071
ArH), 7.48–7.51 (m, 2H, ArH), 7.71–7.76 (m, 4H, ArH þ NH2). HRMS (ESI,
m=z): calcd. for C22H13Cl3N4Na (M þNaþ) 461.0103; found 461.0105.
2-Amino-6-(3-chlorophenyl)-4-(4-chlorophenyl)-5-methylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4i)
Mp 192 ꢁ 194 ꢀC. IR (KBr): 3414, 3325, 2200, 1642, 1591, 1566, 1490, 1478,
1408, 1298, 1216, 1095, 1016, 960, 879, 835, 804, 792, 766 cmꢁ1 1H NMR
.
(DMSO-d6, 400 MHz): 1.53 (s, 3H, CH3), 4.73 (s, 1H, CH), 7.19 (d, J ¼ 6.8 Hz,
1H, ArH), 7.29 (s, 1H, ArH), 7.37–7.55 (m, 6H, ArH), 7.63 (s, 2H, NH2). HRMS
(ESI, m=z): calcd. for C22H14Cl2N4Na (M þ Naþ) 427.0493; found 427.0501.
2-Amino-4-(4-bromophenyl)-6-(3-chlorophenyl)-5-methylcyclohexa-
1,5-diene-1,3,3-tricarbonitrile (4j)
Mp 191 ꢁ 194 ꢀC. IR (KBr): 3413, 3325, 2199, 1642, 1590, 1567, 1486, 1406,
1
1215, 1077, 1013, 959, 803, 791 cmꢁ1. H NMR (DMSO-d6, 400 MHz): 1.53 (s,
3H, CH3), 4.71 (s, 1H, CH), 7.19 (d, J ¼ 6.8 Hz, 1H, ArH), 7.28 (s, 1H, ArH),
7.42 (d, J ¼ 8.8 Hz, 2H, ArH), 7.48–7.53 (m, 2H, ArH), 7.65–7.68 (m, 4H,
ArH þ NH2). HRMS (ESI, m=z): calcd. for C22H14BrClN4Na (M þ Naþ)
470.9988; found 470.9976.
2-Amino-6-(3-chlorophenyl)-4-(2,4-dichlorophenyl)-5-
methylcyclohexa-1,5-diene-1,3,3-tricarbonitrile (4k)
Mp 195 ꢁ 196 ꢀC. IR (KBr): 3443, 3309, 2218, 1651, 1594, 1561, 1470, 1415,
1387, 1214, 1187, 1146, 1107, 1081, 1054, 893, 847, 811, 795, 756, 729, 700 cmꢁ1
.
1H NMR (DMSO-d6, 400 MHz): 1.50 (s, 3H, CH3), 4.82 (s, 1H, CH), 7.19 (d,
J ¼ 6.8 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.48–7.58 (m, 4H, ArH), 7.79 (s, 2H,
NH2), 7.81 (d, J ¼ 8.8 Hz, 1H, ArH). HRMS (ESI, m=z): calcd. for C22H13Cl3N4Na
(M þ Naþ) 461.0103; found 461.0110.
2-Amino-6-(3-chlorophenyl)-4-(3,4-dimethylphenyl)-5-
methylcyclohexa-1,5-diene-1,3,3-tricarbonitrile (4l)
Mp 219 ꢁ 221 ꢀC. IR (KBr): 3411, 3324, 2923, 2199, 1643, 1591, 1564, 1502,
1
1475, 1405, 1215, 1078, 808, 796, 765 cmꢁ1. H NMR (DMSO-d6, 400 MHz): 1.52
(s, 3H, CH3), 2.227 (s, 3H, CH3), 2.234 (s, 3H, CH3), 4.53 (s, 1H, CH), 7.14–7.23
(m, 5H, ArH), 7.48–7.53 (m, 2H, ArH), 7.57 (s, 2H, NH2). HRMS (ESI, m=z): calcd.
for C24H19ClN4Na (M þ Naþ) 421.1196; found 421.1228.
X-Ray Crystallography for 4e
Empirical formula C22H14.5Cl2N4O0.25, FW ¼ 409.78, T ¼ 294(2) K, triclinic,
ꢀ
˚
˚
˚
space group P ꢁ 1, a ¼ 7.443(2) A, b ¼ 11.387(3) A, c ¼ 13.351(4) A, a ¼ 79.785(5) ,
b ¼ 84.205(5)ꢀ, c ¼ 84.219(5)ꢀ, V ¼ 1103.8(5) A , Z ¼ 2, Dc ¼ 1.233 Mg=m3,
3
˚
k(MoKa) ¼ 0.71073 A, m ¼ 0.309 mmꢁ1
,
F(000) ¼ 421. 2.76ꢀ < h < 25.02ꢀ, R ¼
˚
ꢁ3
˚
0.0637, wR ¼ 0.1539, S ¼ 1.087, largest diff. peak and hole: 0.690 and -0.231 e ꢂ A
.

1072
X.-S. WANG ET AL.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(20802061), the Natural Science Foundation (08KJD150019), and Qing Lan Project
(08QLT001) of Jiangsu Education Committee for financial support.
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