A novel and green method for the synthesis of highly substituted isoquinoline derivatives in ionic liquid

Article abstract of DOI:10.1002/jhet.244

(Chemical Equation Presented) A series of new highly substituted isoquinoline derivatives was obtained from the reaction of 2-(1-substituted piperidin-4-ylidene)malononitrile, benzaldehyde and malononitrile or cyanoacetate in ionic liquid at 50°C. This no

Full text of DOI:10.1002/jhet.244

November 2009
A Novel and Green Method for the Synthesis of Highly
Substituted Isoquinoline Derivatives in Ionic Liquid
1355
Xiang-Shan Wang,a,b* Jian-Rong Wu,a Qing Li,a and Mei-Mei Zhangb
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou,
Jiangsu 221116, China
bThe Key Laboratory of Biotechnology for Medical Plant of Jiangsu Province, Xuzhou Normal
University, Xuzhou, Jiangsu 221116, China
*E-mail: xswang1974@yahoo.com
Received April 15, 2009
DOI 10.1002/jhet.244
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of new highly substituted isoquinoline derivatives was obtained from the reaction of 2-(1-
substituted piperidin-4-ylidene)malononitrile, benzaldehyde and malononitrile or cyanoacetate in ionic
liquid at 50ꢀC. This novel procedure was different from the previous method in the synthesis of isoqui-
noline using pyridine fragment as reactant to construct benzene ring, and as well as had the advantages
of one-pot, mild and environmentally benign. A possible mechanism was proposed based on the further
experimental results.
J. Heterocyclic Chem., 46, 1355 (2009).
Molecules with heterocyclic substructures are attrac-
tive targets for synthesis as they often exhibit diverse
and important biological properties, such as isoquinoline
derivatives. They have been reported to possess antifun-
gal activity [3], antitumor activity [4], anticoagulant ac-
tivity [5], anti-inflammatory, and analgesic activity [6].
3-Cyanoisoquinoline I (Fig. 1), was reported as a Kv1.5
antagonist, and evaluated in vitro and in vivo assays
for inhibition of the Kv1.5 potassium channel and its
associated cardiac potassium current. Its derivatives
afforded with excellent potency, selectivity, and oral
bioavailability [7].
INTRODUCTION
Multi-component reactions (MCRs) are economically
and environmentally very advantageous because multi-
step syntheses produce considerable amounts of waste
mainly due to complex isolation procedures often
involving expensive, toxic, and hazardous solvents after
each step. MCRs are perfectly suited for combinatorial
library synthesis, and thus find increasing use in the dis-
covery process for new drugs and agrochemicals [1]. In
addition, ionic liquids have attracted increasing interest
in the context of green synthesis in recent years. They
were initially introduced as alternative green reaction
media because of their unique chemical and physical
properties of nonvolatility, nonflammability, thermal sta-
bility, and controlled miscibility. The possibility of recy-
cling them and the low vapor pressure also ensure their
utility in environmentally friendly technologies. They
have been used as solvents for a large number of or-
ganic transformations [2].
Accordingly, novel strategies for the synthesis of iso-
quinolines continue to receive considerable attention in
the field of synthetic organic chemistry [8], except for
the known classical isquinoline synthetic methods [9(a)–
(f)], e.g. Bischler-Napieralski reaction, Pictet-Gams iso-
quinoline synthesis, Pomeranz-Fritsch reaction, Gabriel-
Colman rearrangement, and Pictet-Spengler isoquinoline
synthesis. Commonly, amines containing benzene ring
C
V
2009 HeteroCorporation

1356
X.-S. Wang, J.-R. Wu, Q. Li, and M.-M. Zhang
Vol 46
for the reaction (Table 1, entries 4–8). In addition, we
also looked into the water and other organic solvent
effect at 50ꢀC for thisþreaction. As showed in Table 1,
ionic liquid of [bmim ] [BFꢁ4 ] gave the most satisfac-
tory result in comparison with other solvents (Table 1,
entries 9–12).
After the reaction was completed, the reaction mix-
tures were cooled to room temperature. Water (5 mL)
was then added to the mixture and the solid was isolated
by filtration. The water in the filtrate was removed by
evaporation at reduced pressure, and the ionic liquid in
the filtrate could be recycled easily at 80ꢀC in vacuum
for 4 h. The recovered ionic liquid could be directly
used for the same reactions. Alternatively, if the ionic
liquid was used for other reactions with different sub-
strates, it was washed with ethyl acetate, followed by
evaporation at 80ꢀC in vacuum for 3 h. Investigations
by using 2-chlorobenzaldehyde, ethyl 4-(dicyanomethy-
lene) piperidine-1-carboxylate, and malononitrile as
model substrates proved the successive reuse of ionic
liquid. Even in the fourth cycle the yield (87%) of prod-
uct 4a is fairly high.
Figure 1. 3-Cyanoisoquinoline.
were used as reactants to construct the pyridine nucleus
to gain the isoquinolines. On the contrary, our interest
was focused on the synthesis of isoquinoline derivatives
using a fragment containing pyridine ring as starting
material to form benzene moiety. Inspired this novel
idea and as part of a continuing effort in our laboratory
toward the new methods for the e biologically relevant
heterocyclic compounds in ionic liquids [10], herein, we
would like to report a novel reaction of 2-(1-substituted-
piperidin-4-ylidene)malononitrile, benzaldehyde, and
malononitrile or cyanoacetate in the synthesis of highly
substituted isoquinoline derivatives.
According to the optimized conditions, we next exam-
ined the utility of this process (Scheme 1) to synthesize
a range of isoquinoline 4. Various arylaldehydes 1,
bearing either electron-withdrawing groups (such as ha-
lide, nitro) or electron-donating groups (such as alkyl
group or alkoxyl group), were subjected to react with 3
to give the corresponding isoquinoline derivatives 4 in
high yields (Table 2, entries 1–16). Replacing the
ethyl 4-(dicyanomethylene)piperidine-1-carboxylate to
2-(1-(3-chlorobenzoyl)piperidin-4-ylidene)malononitrile
RESULTS AND DISCUSSION
The three-component reaction of benzaldehyde 1,
malononitrile 2, and ethyl 4-(dicyanomethylene) piperi-
dine-1-carboxylate 3 (R¼¼OEt) was treated in ionic liq-
uid at 50ꢀC, with ethyl 6-amino-5,7,7-tricyano-3,4,7,8-
tetrahydro-8-arylisoquinoline-2(1H)-carboxylate deriva-
tives 4 being obtained in high yields (Scheme 1).
Firstly, optimizations of the reaction conditions,
including reaction temperature and solvents, were inves-
tigated using 2-chlorobenzaldehyde, malononitrile and
ethyl 4-(dicyanomethylene)piperidine-1-carboxylate as
model reactants. As summarized in Table 1, the results
showed that at room temperature, only trace products
were observed by TLC. (Table 1, entry 1). To our
delight, the reaction proceeded smoothly in high yield at
50ꢀC, higher temperature 90ꢀC gave a complicated sys-
tem, only 52% yield of 4a was isolated by silica gel col-
umn chromatography. Moreover, different ionic liquids
were further tested þas reaction medium and it was
observed that [bmim ] [BFꢁ4 ] was the best ionic liquid
Table 1
Synthesis of 4a at different reaction conditions.a
Entry
T/ꢀC
Solventsb
Yieldsc/%
1
2
3
r.t.
50
90
50
50
50
50
50
50
50
50
50
[bmimþ][BFꢁ4 ]
[bmimþ][BFꢁ4 ]
[bmimþ][BFꢁ4 ]
[emimþ] Brꢁ
[pmimþ] Brꢁ
[bmimþþ]Brꢁ
[emim ][BFꢁ4 ]
[pmimþ][BFꢁ4 ]
H2O
Trace
93
52
4
82
85
85
86
84
72
78
67
5
6
7
8
9
10
11
12
EtOH
THF
DMF
Scheme 1
83
a Reaction conditions: ionic liquid (2 mL), 2-chlorobenzaldehyde
(0.281 g, 2 mmol), ethyl 4-(dicyanomethylene)piperidine-1-carboxylate
(0.438 g, 2 mmol), malononitrile (0.132 g, 2 mmol) and other solvents
10 mL.
b bmim ¼ 1-butyl-3-methylimidazolium; emim ¼ 1-ethyl-3-methyli
midazolium; pmim¼1-methyl-3-propylimidazolium.
c Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Green Method for the Synthesis of Highly Substituted
Isoquinoline Derivatives in Ionic Liquid
1357
Table 2
The reactions of 2-(1-substitutedpiperidin-4-ylidene) malononitrile, benzaldehyde, and malononitrile in ionic liquid.a
Entry
Ar
R
Products
Time /h
Yieldsb/%
1
2
2-ClC6H4
3,4-Cl2C6H4
2,4-Cl2C6H4
4-NO2C6H4
4-CH3C6H4
2-NO2C6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
2-FC6H4
2,3-Cl2C6H4
2-CNC6H4
4-FC6H4
2-BrC6H4
4-ClC6H4
2,3-OMe2C6H3
3-ClC6H4
2-FC6H4
OEt
OEt
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
8
10
8
93
92
94
89
90
95
90
87
93
95
87
83
90
95
93
87
84
86
85
85
3
4
OEt
OEt
7
5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
11
6
10
9
6
7
8
9
9
10
11
12
13
14
15
16
17
18
19
20
7
8
9
OEt
OEt
8
7
OEt
OEt
8
10
10
9
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
2-BrC6H4
2-ClC6H4
9
4t
9
a Reaction conditions: ionic liquid (2 mL), benzaldehyde (2 mmol), ethyl 4-(dicyanomethylene)piperidine-1-carboxylate (0.438 g, 2 mmol), malono-
nitrile (0.132 g, 2 mmol).
b Isolated yields.
also gave the satisfactory results (Table 2, entries
17–20). As expected, the substrate of malononitrile
could be extended to other active methylene com-
pound. Methyl cyanoacetate was also chosen as reac-
tant to treat with benzaldehyde, 4-(dicyanomethylene)
piperidine-1-carboxylate (Scheme 2), and was found to
generate the corresponding 2-ethyl 7-methyl 6-amino-
5,7-dicyano-3,4,7,8-tetrahydro-8-arylisoquinoline-2,7(1H)-
dicarboxylate derivatives (5a–5f) (Scheme 2) in high
yields (Table 3).
ethyl cyanoacetate could not? This also stimulated us to
carry out new experiments to find the reason as well as
explore the reaction mechanism.
In our continued study, we find the reaction of benz-
aldehyde and methyl cyanoacetate could be proceeded
smoothly to give corresponding methyl 2-cyano-3-(2-
chlorophenyl)acrylate 6 in ionic liquid, while other cya-
noacetates, such as ethyl or propyl cyanoacetate could
not react with benzaldehyde. Perhaps, the reaction activ-
ity of ethyl cyanoacetate is less than that of methyl cya-
noacetate or malononitrile. The results were agreed to
those of the same reactions in water [11] or ethanol [12]
without catalyst. Subsequently, we also tested the reac-
tion of 6 and ethyl 4-(dicyanomethylene)piperidine-1-
However, to our surprise, we failed to get the
expected products when ethyl cyanoacetate was used
(Scheme 2). This raised an interesting question: why
could the methyl cyanoacetate give good results, while
Table 3
Scheme 2
The reactions of ethyl 4-(dicyanomethylene)piperidine-1-carboxylate,
benzaldehyde, and methyl cyanoacetate in ionic liquid.a
Entry
Ar
Products
Time /h
Yieldsb
%
1
2
3
4
5
6
2-ClC6H4
5a
5b
5c
5d
5e
5f
12
15
11
15
14
15
86
83
87
85
87
90
2,3-OMe2C6H3
2,3-Cl2C6H3
4-BrC6H4
3,4-Cl2C6H3
4-ClC6H4
a Reaction conditions: ionic liquid (2 mL), benzaldehyde (2 mmol),
ethyl 4-(dicyanomethylene)piperidine-1-carboxylate (0.438 g, 2 mmol),
methyl cyanoacetate (0.198 g, 2 mmol).
b Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1358
X.-S. Wang, J.-R. Wu, Q. Li, and M.-M. Zhang
Vol 46
Scheme 3
Scheme 5
CONCLUSION
In conclusion, we have disclosed a green and novel
method to synthesize of new highly substituted isoqui-
noline derivatives was obtained from the reaction of
2-(1-substituted piperidin-4-ylidene)malononitrile, benz-
aldehyde and malononitrile or cyanoacetate in ionic liq-
uid at 50ꢀC. The note-worthy features of this procedure
are different from the previous method in the synthesis
of isoquinoline using pyridine fragment as reactant to
construct benzene ring, mild reaction conditions, one-
pot, high yield, operational simplicity and the environ-
mentally friendly procedure. Meanwhile, [bmimþ]
[BFꢁ4 ] could be reused for several rounds without signif-
icant loss of activity.
carboxylate 3 in ionic liquid at the same temperature,
the desired 2-ethyl 7-methyl 6-amino-5,7-dicyano-
3,4,7,8-tetrahydro-8-(2-chlorophenyl)isoquinoline-2,7(1H)-
dicarboxylate 5a was obtained successfully in high yield
of (total yield 78%) (Scheme 3).
According to the above results, a sequential reaction
of the Knoevenagel condensation, Michael addition
reaction cyclization and isomerization may take place to
give the final products 4. A tentative mechanism was
outlined in Scheme 4.
Encouraged by this result and to obtain the desired
diethyl isoquinoline-2,7-dicarboxylate derivatives, a num-
ber of ethyl 2-cyano-3-arylacrylate 7 were synthesized by
the known Knoevenagel condensation [13] of benzalde-
hydes and ethyl cyanoacetate in EtOH firstly, and then
applied to react with 3 in ionic liquid (Scheme 5). Simi-
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on a TENSOR 27 spec-
trometer in KBr pellet. 1H NMR spectra were obtained from
solution in DMSO-d6 or CDCl3 with Me4Si as internal stand-
ard using a Bruker-400 spectrometer. HRMS analyses were
carried out using Bruker-micro TOF-Q-MS analyzer.
ꢀ
larly, 7 smoothly reacted in ionic liquid at 50 C to give
the corresponding diethyl-6-amino-5,7-dicyano-3,4,7,8-
tetrahydro-8-arylisoquinoline-2,7(1H)-dicarboxy late
derivatives 8 in high yields (Table 4) as expected. The
results were listed in Table 4.
Table 4
The reactions of ethyl 2-cyano-3-arylacrylate and ethyl 4-
(dicyanomethylene) piperidine-1-carboxylate in ionic liquid.a
Scheme 4
Entry
Ar
Products
Time /h
Yieldsb%
1
2
3
4
5
6
7
2-NO2C6H4
4-MeC6H4
2-ClC6H4
8a
8b
8c
8d
8e
8f
6
8
94
96
92
94
90
95
92
7
2,4-Cl2C6H3
3,4-Me2C6H3
3-ClC6H4
7
10
9
4-OMeC6H4
8g
10
a Reaction conditions: ionic liquid (2 mL), ethyl 2-cyano-3-arylacrylate
(2mmol), ethyl 4-(dicyanomethylene)piperidine-1-carboxylate (0.438 g,
2 mmol).
b Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Green Method for the Synthesis of Highly Substituted
Isoquinoline Derivatives in Ionic Liquid
1359
(s, 1H, ArH), 8.37–8.49 (m, 2H, ArH). HRMS-ESI. calcd for
C21H18N6NaO4, M þ Naþ: 441.1287, found: 441.1272.
General procedure for the syntheses of 6-amino-8-aryli-
soquinoline derivatives 4. A dry 50 mL flask was charged
with arylaldehyde (2.0 mmol), malononitrile (0.132 g, 2.0
mmol), 2-(1-substitutedpiperidin-4þ-ylidene)malononitrile (2.0
mmol), and ionic liquid of [bmim ][BFꢁ4 ] (2 mL). The reac-
tion mixture was stirred at 50ꢀC for 7–11 h, and then cooled
to room temperature. The generated yellow solid was filtered
off, and the ionic liquid in filtrate was then recovered for reuse
by evaporating at 80ꢀC several h at vacuum. The crude yellow
products were washed with water and purified by recrystalliza-
tion from DMF and water, followed by being dried at 50ꢀC
several h at vacuum to give 4.
Ethyl 6-amino-5,7,7-tricyano-3,4,7,8-tetrahydro-8-p-tolyli-
soquinoline-2(1H)-carboxylate 4e. Mp. 244–246ꢀC. IR (KBr)/
cmꢁ1 3345, 3164, 3061, 3032, 2982, 2929, 2851, 2211, 1670,
1635, 1517, 1487, 1395, 1344, 1299, 1279, 1190, 1050, 1026,
1
882, 524, 813, 783, 773, 751. H NMR (DMSO-d6, 400 MHz)
dH 1.14–1.17 (m, 3H, CH3), 2.36–2.40 (s, 4H, CH3þCH), 2.94
(b, 1H, CH), 3.68–3.74 (m, 3H, 3CH), 4.00–4.03 (m, 2H,
CH2O), 4.29–4.37 (m, 1H, CH), 5.67 (s, 1H, CH), 7.29–7.38
(m, 3H, ArH), 7.50–7.51 (m, 1H, ArH), 7.61 (s, 2H, NH2).
HRMS-ESI. calcd for C22H21N5NaO2, M þ Naþ: 410.1593,
found: 410.1587.
Ethyl 6-amino-8-(2-chlorophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4a. Mp 230–232ꢀC.
IR (KBr)/cmꢁ1 3346, 3207, 3028, 2992, 2937, 2845, 2211,
1655, 1603, 1574, 1486, 1467, 1440, 1396, 1378, 1339, 1299,
1242, 1135, 1028, 1007, 941, 883, 818, 775, 750, 704. 1H
NMR (DMSO-d6, 400 MHz) dH 1.12–1.15 (m, 3H, CH3),
2.37–2.40 (m, 1H, CH), 3.04–3.06 (m, 1H, CH), 3.57–3.81 (m,
2H, 2CH) 3.92–4.05 (m, 3H, CH2OþCH), 4.27–4.37 (m, 1H,
CH), 5.72 (s, 1H, CH), 7.55–7.61 (m, 2H, ArH), 7.67–7.69 (m,
3H, ArHþNH2), 7.81–7.83 (m, 1H, ArH). 13C NMR (DMSO-
d6, 100 MHz) dC 14.4, 33.8, 40.0, 40.2, 41.2, 43.4, 61.0, 80.1,
111.1, 111.6, 112.7, 115.5, 128.0, 129.99, 130.02, 130.6,
135.1, 136.1, 144.2, 164.1. HRMS-ESI. calcd for
C21H18ClN5NaO2, M þ Naþ: 430.1047, found: 430.1018.
Ethyl 6-amino-8-(3,4-dichlorophenyl)-5,7,7-tricyano-3,4,7,
8-tetrahydroisoquinoline-2(1H)-carboxylate 4b. Mp 264–
265ꢀC. IR (KBr)/cmꢁ1 3343, 3159, 3063, 2994, 2980, 2209,
1656, 1605, 1488, 1468, 1444, 1396, 1343, 1298, 1248, 1207,
1189, 1136, 1115, 1032, 1007, 896, 814, 981, 761, 728. 1H
NMR (DMSO-d6, 400 MHz) dH 1.15–1.18 (m, 3H, CH3),
2.35–2.40 (m, 1H, CH), 2.97–3.05 (m, 1H, CH), 3.66–3.78 (m,
2H, 2CH), 3.88–4.03 (m, 3H, CH2O þ CH), 4.28–4.41 (m,
1H, CH), 5.69 (s, 1H, CH), 7.46–7.66 (m, 1H, ArH), 7.67 (s,
2H, NH2), 7.77–7.92 (m, 2H, ArH). 13C NMR (DMSO-d6, 100
MHz) dC 14.4, 32.7, 40.0, 40.2, 42.4, 43.4, 61.0, 80.1, 111.7,
111.8, 112.7, 115.6, 127.3, 131.1, 131.3, 131.4, 132.5, 134.7,
144.1, 167.0. HRMS-ESI. calcd for C21H18Cl2N5O2, M þ Hþ:
442.0838, found: 442.0835.
Ethyl 6-amino-5,7,7-tricyano-3,4,7,8-tetrahydro-8-(2-nitro-
phenyl)isoquinoline-2(1H)-carboxylate 4f. Mp. 227–228ꢀC.
IR (KBr)/cmꢁ1 3345, 3217, 3022, 2989, 2860, 2212, 1675,
1603, 1535, 1485, 1466, 1435, 1399, 1357, 1299, 1236, 1192,
1132, 1026, 941, 883, 862, 820, 763, 731, 696. 1H NMR
(DMSO-d6, 400 MHz) dH 1.08–1.15 (m, 3H, CH3), 2.59–
2.67 (m, 1H, CH), 3.19–3.22 (m, 1H, CH), 3.68–3.84 (m,
2H, 2CH), 3.94–4.03 (m, 2H, CH2O), 4.22–4.40 (m, 2H,
2CH), 5.73 (s, 1H, CH), 7.66 (s, 2H, NH2), 7.80–7.84 (m,
1H, ArH), 7.95–8.02 (m, 1H, ArH), 8.06 (d, J ¼ 7.6 Hz,
1H, ArH), 8.14 (d, J ¼ 8.0 Hz, 1H, ArH). HRMS-ESI.
calcd for C21H18N6NaO4,
441.1263.
M
þ
Naþ: 441.1287, found:
Ethyl 6-amino-8-(4-bromophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)carboxylate 4g. Mp. 247–248ꢀC.
IR (KBr)/cmꢁ1 3344, 3166, 2983, 2210, 1687, 1660, 1605,
1491, 1468, 1443, 1413, 1394, 1342, 1299, 1273, 1246, 1190,
1133, 1077, 1051, 1024, 1012, 883, 833, 814, 778, 767, 754.
1H NMR (DMSO-d6, 400 MHz) dH 1.15 (s, 3H, CH3), 2.34–
2.41 (m, 1H, CH), 2.95–2.99 (m, 1H, CH), 3.65–3.85 (m, 3H,
3CH), 3.99–4.05 (m, 2H, CH2O), 4.28–4.39 (m, 1H, CH), 5.68
(s, 1H, CH), 7.40–7.42 (m, 1H, ArH), 7.59–7.62 (m, 1H,
ArH), 7.64 (s, 2H, NH2), 7.72–7.81 (m, 2H, ArH). HRMS-ESI.
calcd for C21H18BrN5NaO2, M þ Naþ: 474.0542, found:
474.0542.
Ethyl 6-amino-8-(3-chlorophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4h. Mp. 241–243ꢀC.
IR (KBr)/cmꢁ1 3342, 3171, 2994, 2849, 2210, 1668, 1602,
1575, 1488, 1469, 1442, 1393, 1377, 1344, 1298, 1247, 1203,
1189, 1132, 1049, 1025, 1008, 888, 814, 798, 781, 750, 711.
1H NMR (DMSO-d6, 400 MHz) dH 4.15–4.18 (m, 3H, CH3),
2.34–2.41 (m, 1H, CH), 2.97–3.03 (m, 1H, CH), 3.65–3.78 (m,
2H, 2CH), 3.83–3.89 (m, 1H, CH), 4.02–4.03 (m, 2H, CH2O),
4.28–4.41 (m, 1H, CH3), 5.69 (s, 1H, CH), 7.43–7.62 (m, 4H,
ArH), 7.66 (s, 2H, NH2). HRMS-ESI. calcd for
C21H18ClN5NaO2, M þ Naþ: 430.1047, found: 430.1046.
Ethyl 6-amino-8-(3-bromophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4i. Mp. 265–267ꢀC.
IR (KBr)/ cmꢁ1 3343, 3169, 2995, 2980, 2851, 2208, 1662,
1602, 1571, 1487, 1466, 1441, 1391, 1344, 1297, 1248, 1188,
1122, 1077, 1044, 1024, 1008, 882, 812, 793, 782, 748, 694.
1H NMR (DMSO-d6, 400 MHz) dH 1.16–1.17 (m, 3H, CH3),
2.34–2.41 (m, 1H, CH), 2.96–3.01 (m, 1H, CH), 3.65–3.78 (m,
2H, 2CH), 3.82–3.87 (m, 1H, CH), 3.95–4.03 (m, 2H, CH2O),
4.29–4.41 (m, 1H, CH), 5.69 (s, 1H, CH), 7.48–7.58 (m, 2H,
ArH), 7.66 (s, 2H, NH2), 7.70–7.79 (m, 2H, ArH). HRMS-ESI.
calcd for C21H18BrN5NaO2, M þ Naþ: 474.0542, found:
474.0542.
Ethyl 6-amino-8-(2,4-dichlorophenyl)-5,7,7-tricyano-3,4,7,
8-tetrahydroisoquinoline-2(1H)-carboxylate 4c. Mp 241–
243ꢀC. IR (KBr)/cmꢁ1 3340, 3194, 3029, 2984, 2933, 2895,
2847, 2212, 1692, 1653, 1604, 1559, 1478, 1439, 1395, 1341,
1299, 1242, 1110, 1052, 1025, 1005, 884, 864, 821, 783, 771.
1H NMR (DMSO-d6, 400 MHz) dH 1.14–1.15 (m, 3H, CH3),
2.35–2.42 (m, 1H, CH), 3.02–3.08 (m, 1H, CH), 3.52–3.80 (m,
2H, 2CH), 4.02–4.06 (m, 3H, CH2O þ CH), 4.27–4.40 (m,
1H, CH), 5.71 (s, 1H, CH), 7.67 (s, 2H, NH2), 7.75 (dd, J ¼
8.4 Hz, 2.0, 1H, ArH), 7.84 (d, J ¼ 8.4 Hz, 1H, ArH), 7.89 (d,
J
¼
2.4 Hz, 1H, ArH). HRMS-ESI. calcd for
C21H17Cl2N5NaO2, M þ Naþ: 464.0657, found: 464.0658.
Ethyl 6-amino-5,7,7-tricyano-3,4,7,8-tetrahydro-8-(4-nitro-
phenyl)isoquinoline-2(1H)-carboxylate 4d. Mp 243–244ꢀC. IR
(KBr)/cmꢁ1 3430, 3331, 3222, 3079, 2984, 2213, 1679, 1645,
1603, 1526, 1476, 1420, 1386, 1353, 1297, 1277, 1229, 1127,
1111, 1022, 867, 841, 822, 783, 725. 1H NMR (DMSO-d6,
400 MHz) dH 1.15 (s, 3H, CH3), 2.37–2.43 (m, 1H, CH),
3.04–3.10 (m, 1H, CH), 3.66–3.79 (m, 2H, 2CH), 4.01–4.10
(m, 3H, CH2O þ CH), 4.29–4.39 (m, 1H, CH), 5.71 (s, 1H,
CH), 7.69 (s, 2H, NH2), 7.76 (d, J ¼ 8.0 Hz, 1H, ArH), 7.95
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1360
X.-S. Wang, J.-R. Wu, Q. Li, and M.-M. Zhang
Vol 46
1
1016, 941, 883, 835, 815, 778, 757. H NMR (DMSO-d6, 400
MHz) dH 1.15 (s, 3H, CH3), 2.34–2.44 (m, 1H, CH), 2.98 (s,
1H, CH), 3.65–3.78 (m, 2H, CH2), 3.85 (d, J ¼ 12.8 Hz, 1H,
CH), 3.99–4.05 (m, 2H, CH2O), 4.26–4.42 (m, 1H, CH), 5.69
(s, 1H, CH), 7.47–7.60 (m, 2H, ArH), 7.64–7.67 (m, 4H,
ArHþNH2). HRMS-ESI. calcd for C21H18ClN5NaO2, M þ
Naþ: 430.1047, found: 430.1025.
Ethyl 6-amino-5,7,7-tricyano-8-(2-fluorophenyl)-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4j. Mp. 252–254ꢀC.
IR (KBr)/ cmꢁ1 3337, 3182, 3032, 2993, 2937, 2844, 2212,
1650, 1602, 1491, 1444, 1397, 1341, 1299, 1247, 1198, 1181,
1136, 1053, 1028, 1007, 884, 864, 818, 773, 759. 1H NMR
(DMSO-d6, 400 MHz) dH 1.14–1.15 (m, 3H, CH3), 2.43–2.46
(m, 1H, CH), 3.03–3.18 (m, 1H, CH), 3.64–3.78 (m, 2H,
2CH), 3.90–4.04 (m, 3H, CH2OþCH), 4.28–4.39 (m, 1H, CH),
5.70 (s, 1H, CH), 7.33–7.47 (m, 2H, ArH), 7.54–7.64 (m, 3H,
ArHþNH2), 7.72–7.76 (m, 1H, ArH). RMS-ESI. calcd for
C21H18FN5NaO2, M þ Naþ: 414.1342, found: 414.1342.
Ethyl 6-amino-8-(2,3-dichlorophenyl)-5,7,7-tricyano-3,4,7,
8-tetrahydroisoquinoline-2(1H)-carboxylate 4k. Mp. 234–
235ꢀC. IR (KBr)/ cmꢁ1 3336, 3174, 2993, 2978, 2933, 2844,
2209, 1653, 1487, 1467, 1444, 1391, 1340, 1298, 1274, 1246,
1185, 1164, 1048, 1028, 1008, 889, 817, 800, 780, 757, 741,
697. 1H NMR (DMSO-d6, 400 MHz) dH 1.10–1.15 (m, 3H,
CH3), 2.39–2.43 (m, 1H, CH), 3.07 (s, 1H, CH), 3.61–3.80 (m,
2H, 2CH), 3.93–4.02 (m, 2H, CH2O), 4.16 (d, J ¼ 12.8 Hz,
1H, CH). 4.28–4.38 (m, 1H, CH), 5.72 (s, 1H, CH), 7.64–7.68
(m, 3H, ArHþNH2), 7.81–7.86 (m, 2H, ArH). HRMS-ESI.
calcd for C21H17Cl2N5NaO2, M þ Naþ: 464.0557, found:
464.0552.
Ethyl 6-amino-5,7,7-tricyano-3,4,7,8-tetrahydro-8-(2,3-
dimethoxyphenyl)isoquinoline-2(1H)-carboxylate 4p. Mp.
229–231ꢀC. IR (KBr)/ cmꢁ1 3377, 3334, 3191, 2971, 2946,
2837, 2210, 1661, 1605, 1482, 1445, 1393, 1340, 1296, 1271,
1240, 1171, 1137, 1097, 1073, 1044, 1003, 819, 794, 766,
724. 1H NMR (DMSO-d6, 400 MHz) dH 1.14 (b, 3H, CH3),
2.35–2.41 (m, 1H, CH), 2.85–2.88 (m, 1H, CH), 3.59–3.69 (m,
2H, 2CH), 3.78 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 3.91–4.03
(m, 3H, CH2O þ CH), 4.28–4.39 (m, 1H, CH), 5.69 (s, 1H,
CH), 7.19–7.20 (m, 2H, ArH), 7.25–7.28 (m, 1H, ArH), 7.60
(s, 2H, NH2). HRMS-ESI. calcd for C23H24N5O4, M þ Hþ:
434.1828, found: 434.1806.
Ethyl 6-amino-2-(3-chlorobenzoyl)-8-(3-chlorophenyl)-1,2,
3,4-tetrahydroisoquinoline-ꢁ5,17,7(8H)-tricarbonitrile 4q. Mp.
263–265ꢀC. IR (KBr)/ cm 3333, 3192, 2843, 2211, 1642,
1595, 1568, 1481, 1462, 1442, 1397, 1372, 1347, 1300, 1258,
1114, 1085, 1025, 1000, 884, 800, 786, 742, 711, 693. 1H
NMR (DMSO-d6, 400 MHz) dH 2.67–2.72 (m, 1H, CH), 3.11–
3.19 (m, 1H, CH), 3.72–4.18 (m, 3H, 3CH), 4.65–4.70 (m, 1H,
CH), 5.78 (s, 1H, CH), 7.30–7.61 (m, 8H, ArH), 7.68 (s, 2H,
NH2). HRMS-ESI. calcd for C25H17Cl2N5NaO, M þ Naþ:
496.0708, found: 496.0708.
Ethyl 6-amino-5,7,7-tricyano-8-(2-cyanophenyl)-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4l. Mp. 220–222ꢀC.
IR (KBr)/ cmꢁ1 3406, 3340, 3222, 3017, 2987, 2225, 2210,
1693, 1634, 1609, 1481, 1435, 1390, 1339, 1301, 1278, 1237,
1130, 1049, 1026, 1007, 888, 822, 776, 759. 1H NMR
(DMSO-d6, 400 MHz) dH 1.11–1.15 (m, 3H, CH3), 2.58–2.62
(m, 1H, CH), 3.18 (s, 1H, CH), 3.53–3.77 (m, 3H, 3CH),
3.90–4.02 (m, 2H, CH2O), 4.29–4.39 (m, 1H, CH), 5.76 (s,
1H, CH), 7.24–7.79 (m, 3H, ArH), 7.99 (s, 2H, NH2), 8.08 (d,
J ¼ 7.6 Hz, 1H, ArH). HRMS-ESI. calcd for C22H18N6NaO2,
M þ Naþ: 421.1389, found: 421.1367.
Ethyl 6-amino-2-(3-chlorobenzoyl)-8-(2-fluorophenyl)-1,2,3,
4-tetrahydroisoquinoline-5,ꢁ7,17(8H)-tricarbonitrile
4r. Mp.
248–250ꢀC. IR (KBr)/ cm 3448, 3342, 3191, 2215, 1647,
1602, 1564, 1492, 1451, 396, 1345, 1306, 1285, 1250, 1235,
1
1127, 1089, 1039, 836, 812, 798, 759, 742, 718, 690. H NMR
(DMSO-d6, 400 MHz) dH 2.76–2.79 (m, 1H, CH), 3.10–3.13
(m, 1H, CH), 3.72–4.20 (m, 3H, 3CH), 4.64–4.69 (m, 1H,
CH), 5.78 (s, 1H, CH), 7.21–7.54 (m, 8H, ArH), 7.66 (s, 2H,
NH2). HRMS-ESI. calcd for C25H17ClFN5NaO, M þ Naþ:
480.1003, found: 480.1003.
Ethyl 6-amino-5,7,7-tricyano-8-(4-fluorophenyl)-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4m. Mp. 240–242ꢀC.
IR (KBr)/ cmꢁ1 3342, 3172, 2984, 2934, 2851, 2211, 1668,
1602, 1515, 1487, 1468, 1443, 1396, 1233, 1299, 1280, 1164,
1
1134, 1024, 882, 841, 811, 786, 777, 760. H NMR (DMSO-
Ethyl 6-amino-2-(3-chlorobenzoyl)-8-(2-bromophenyl)-1,2,
3,4-tetrahydroisoquinoline-ꢁ5,17,7(8H)-tricarbonitrile 4s. Mp.
170–172ꢀC. IR (KBr)/ cm 3381, 3168, 2966, 2882, 2213,
1630, 1598, 1440, 1375, 1342, 1281, 1246, 1196, 1160, 1117,
1081, 1049, 1025, 922, 835, 799, 752, 714, 694. 1H NMR
(DMSO-d6, 400 MHz) dH 2.65–2.71 (m, 1H, CH), 2.99–3.03
(m, 1H, CH), 3.75–4.09 (m, 3H, 3CH), 4.64–4.68 (m, 1H,
CH), 5.80 (s, 1H, CH), 7.30–7.50 (m, 6H, ArH), 7.64–7.69 (m,
2H, ArH), 7.71 (s, 2H, NH2). HRMS-ESI. calcd for
C25H17ClBrN5NaO, M þ Naþ: 540.0203, found: 540.0215.
Ethyl 6-amino-2-(3-chlorobenzoyl)-8-(2-chlorophenyl)-1,2,
d6, 400 MHz) dH 1.15 (s, 3H, CH3), 2.34–2.44 (m, 1H, CH),
2.94–2.98 (m, 1H, CH), 3.65–3.78 (m, 2H, 2CH), 3.83 (d, J ¼
12.8 Hz, 1H, CH), 3.99–4.02 (m, 2H, CH2O), 4.29–4.39 (m,
1H, CH), 5.68 (s, 1H, CH), 7.35–7.46 (m, 3H, ArH), 7.51 (s,
2H, NH2), 7.63–7.68 (m, 1H, ArH). HRMS-ESI. calcd for
C21H18FN5NaO2, M þ Naþ: 414.1342, found: 414.1325.
Ethyl 6-amino-8-(2-bromophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4n. Mp. 222–224ꢀC.
IR (KBr)/ cmꢁ1 3346, 3202, 2991, 2933, 2861, 2212, 1662,
1648, 1602, 1486, 1473, 1398, 1339, 1298, 1242, 1130, 1050,
1026, 941, 884, 819, 775, 747. 1H NMR (DMSO-d6, 400
MHz) dH 1.08–1.15 (m, 3H, CH3), 2.35–2.41 (m, 1H, CH),
3.07 (s, 1H, CH), 3.54–3.82 (m, 2H, 2CH), 3.90–4.01 (m, 3H,
CH2OþCH), 4.27–4.37 (m, 1H, CH), 5.72 (s, 1H, CH), 7.45–
7.49 (m, 1H, ArH), 7.63–7.67 (m, 1H, ArH), 7.70 (s, 2H,
NH2), 7.80–7.86 (m, 2H, ArH). HRMS-ESI. calcd for
C21H18BrN5NaO2, M þ Naþ: 474.0542, found: 474.0523.
Ethyl 6-amino-8-(4-chlorophenyl)-5,7,7-tricyano-3,4,7,8-tet-
rahydroisoquinoline-2(1H)-carboxylate 4o. Mp. 238–240ꢀC.
IR (KBr)/ cmꢁ1 3342, 3169, 2987, 2850, 2211, 1687, 16610
1604, 1494, 1442, 1395, 1342, 1299, 1275, 1239, 1132, 1096,
3,4-tetrahydroisoquinoline-5,7,7(8H)-tricarbonitrile
4t. Mp.
235–237ꢀC. IR (KBr)/ cmꢁ1 3326, 3192, 3069 2941, 2881,
2842, 2212, 1641, 1605, 1568, 1478, 1440, 1398, 1374, 1341,
1301, 1288, 1255, 1120, 1080, 1058, 1039, 813, 799, 774,
748, 707. 1H NMR (DMSO-d6, 400 MHz) dH 2.67–2.70 (m,
1H, CH), 3.01–3.16 (m, 1H, CH), 3.77 (d, J ¼ 19.6 Hz, 1H,
CH), 3.96–4.14 (m, 2H, 2CH), 4.67 (d, J ¼ 19.6 Hz, 1H, CH),
5.79 (s, 1H, CH), 7.32–7.52 (m, 7H, ArH), 7.65–7.70 (m, 3H,
ArH þ NH2). HRMS-ESI. calcd for C25H18Cl2N5O, M þ Hþ:
474.0888, found: 474.0881.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Green Method for the Synthesis of Highly Substituted
Isoquinoline Derivatives in Ionic Liquid
1361
1189, 1132, 1078, 1012, 889, 840, 771. 1H NMR (DMSO-d6,
400 MHz) dH 1.15 (b, 3H, CH3), 2.40–2.46 (m, 1H, CH),
2.87–2.92 (m, 1H, CH), 3.58 (s, 3H, CH3O), 3.63–3.75 (m,
3H, 3CH), 4.00–4.05 (m, 2H, CH2O), 4.29–4.38 (m, 1H, CH),
5.62 (s, 1H, CH), 6.98 (d, J ¼ 8.0 Hz, 1H, ArH), 7.15 (s, 2H,
NH2), 7.53–7.59 (m, 2H, ArH), 7.76 (d, J ¼ 8.0 Hz, 1H,
ArH). HRMS-ESI. calcd for C22H21BrN4NaO4, M þ Naþ:
507.0644, found: 507.0643.
General procedure for the syntheses of 2-ethyl 7-methyl
6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-arylisoquinoline-
2,7(1H)-dicarboxylate derivatives 5. A dry 50 mL flask was
charged with arylaldehyde (2.0 mmol), methyl cyanoacetate
(0.198 g, 2.0 mmol), ethyl 4-(dicyanomethylene)piperidine-1-
carboxþylate (0.438 g, 2.0 mmol), and ionic liquid of
[bmim ][BFꢁ4 ] (2 mL). The reaction mixture was stirred at
50ꢀC for 11–15 h, and then cooled to room temperature. The
generated yellow solid was filtered off, and the ionic liquid in
filtrate was then recovered for reuse by evaporating at 80ꢀC
several hours at vacuum. The crude yellow products were
washed with water and purified by recrystallization from DMF
and water, followed by being dried at 50ꢀC several hours at
vacuum to give 5.
2-Ethyl
7-methyl
6-amino-8-(3,4-dichlorophenyl)-5,7-
dicyano-3,4,7,8-tetrahydroisoquinoline-2,7(1H)-dicarboxylate
5e. Mp. 270–271ꢀC. IR (KBr)/ cmꢁ1 3350, 3205, 3025, 2994,
2853, 2205, 1759, 1651, 1598, 1487, 1470, 1455, 1435, 1401.
1
1298, 1250, 1186, 1133, 1033, 1014, 882, 818, 772. H NMR
(DMSO-d6, 400 MHz) dH 1.15–1.18 (m, 3H, CH3), 2.50–2.54
(m, 1H, CH), 2.90–2.96 (m, 1H, CH), 3.44 (d, J ¼ 12.8 Hz,
1H, CH), 3.60 (s, 3H, CH3O), 3.62–3.78 (m, 1H, CH), 4.01–
4.05 (m, 3H, CH2O þ CH), 4.29–4.39 (m, 1H, CH), 5.63 (s,
1H, CH3), 7.04–7.35 (m, 3H, ArHþNH2), 7.59–7.68 (m, 1H,
ArH), 7.79–7.86 (m, 1H, ArH). HRMS-ESI. calcd for
C22H20Cl2N4NaO4, M þ Naþ: 497.0759, found: 497.0760.
2-Ethyl 7-methyl 6-amino-8-(4-chlorophenyl)-5,7-dicyano-
3,4,7,8-tetrahydroisoquinoline-2,7(1H)-dicarboxylate 5f. Mp.
250–252ꢀC. IR (KBr)/ cmꢁ1 3352, 3207, 2980, 2850, 2206,
1759, 1656, 1597, 1489, 1468, 1437, 1397, 1339, 1300, 1249,
1188, 1130, 1096, 1048, 1016, 923, 883, 840, 814, 771, 751,
722. 1H NMR (DMSO-d6, 400 MHz) dH 1.15 (b, 3H, CH3),
2.39–2.47 (m, 1H, CH), 2.86–2.92 (m, 1H, CH), 3.64–3.76 (m,
6H, CH3Oþ3CH), 3.99–4.05 (m, 2H, CH2O), 4.26–4.41 (m,
1H, CH), 5.62 (s, 1H, CH), 7.05 (d, J ¼ 8.0 Hz, 1H, CH),
7.16 (s, 2H, NH2), 7.45 (d, J ¼ 8.0 Hz, 1H, ArH), 7.62–7.64
(m, 2H, ArH). HRMS-ESI. calcd for C22H21ClN4NaO4, M þ
Naþ: 463.1149, found: 463.1129.
General procedure for the syntheses of diethyl-6-amino-
5,7-dicyano-3,4,7,8-tetrahydro-8-arylisoquinoline-2,7(1H)-
dicarboxylate derivatives 8. A dry 50 mL flask was charged
with ethyl 2-cyano-3-arylacrylate (2.0 mmol), ethyl 4-(dicya-
nomethylene)piperidine-1-carboxylate (0.438 g, 2.0 mmol),
and ionic liquid of [bmimþ][BFꢁ4 ] (2 mL). The reaction mix-
ture was stirred at 50ꢀC for 6–10 h, and then cooled to room
temperature. The generated yellow solid was filtered off, and
the ionic liquid in filtrate was then recovered for reuse by
evaporating at 80ꢀC several h at vacuum. The crude yellow
products were washed with water and purified by recrystalliza-
tion from DMF and water, followed by being dried at 50ꢀC
several h at vacuum to give 8.
2-Ethyl 7-methyl 6-amino-8-(2-chlorophenyl)-5,7-dicyano-
3,4,7,8-tetrahydroisoquinoline-2,7(1H)-dicarboxylate 5a. Mp.
249–251ꢀC. IR (KBr)/ cmꢁ1 3342, 3206, 2986, 2842, 2204,
1758, 1651, 1593, 1483, 1434, 1396, 1328, 1299, 1287, 1248,
1185, 1127, 1018, 926, 881, 816, 781, 749, 705. 1H NMR
(DMSO-d6, 400 MHz) dH 1.09–1.14 (m, 3H, CH3), 2.31–2.37
(m, 1H, CH), 2.93–3.07 (m, 1H, CH), 3.61 (s, 3H, CH3O),
3.73–3.77 (m, 2H, 2CH), 3.91–4.05 (m, 3H, CH2OþCH),
4.26–4.3 (m, 1H, CH), 5.64 (s, 1H, CH), 7.26 (s, 2H, NH2),
7.41–7.47 (m, 1H, ArH), 7.54–7.56 (m, 2H, ArH), 7.77–7.79
(m, 1H, ArH). 13C NMR (DMSO-d6, 100 MHz) dC 14.3, 33.8,
40.2, 41.4, 43.1, 53.2, 54.2, 60.9, 79.5, 115.4, 116.4, 128.5,
128.9, 129.8, 130.4, 130.8, 131.8, 133.1, 134.1, 148.9, 164.1,
197.2. 1HRMS-ESI. calcd for C27H21ClN4NaO4, M þ Naþ:
463.1149, found: 463.1123.
2-Ethyl 7-methyl 6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-
(2,3-dimethoxyphenyl)isoquinoline-2,7(1H)-dicarboxylate 5b. Mp.
260–263ꢀc. IR (KBr)/ cmꢁ1 3347, 3203, 2982, 2957, 2935,
2838, 2204. 1758, 1650, 1595, 1481, 1434, 1397, 1335, 1249,
1
1189, 1168, 1128, 1096, 1065, 1009, 809, 777, 754. H NMR
(DMSO-d6, 400 MHz) dH 1.14 (b, 3H, CH3), 2.32–2.42 (m,
1H, CH), 2.77–2.83 (m, 1H, CH), 3.60–3.72 (m, 8H,
2CH3þ2CH), 3.78–4.02 (m, 6H, CH3O þ 2CH2O þ CH),
4.72–4.38 (m, 1H, CH), 5.61 (s, 1H, CH),7.08–7.10 (m, 1H,
ArH), 7.15 (s, 2H, NH2), 7.16–7.20 (m, 2H, ArH). 13C NMR
(DMSO-d6, 100 MHz) dC 14.4, 33.8, 40.2, 42.1, 43.4, 54.0,
54.1, 55.7, 60.5, 60.9, 79.5, 112.7, 113.0, 115.6, 116.5, 119.0,
124.0, 127.3, 130.7, 147.5, 149.5, 152.2, 164.4, 197.3. HRMS-
ESI. calcd for C24H26N4NaO6, M þ Naþ: 489.1750, found:
489.1747.
2-Ethyl
7-methyl
6-amino-8-(2,3-dichlorophenyl)-5,7-
Diethyl 6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-(2-nitro-
phenyl) isoquinoline-2,7(1H)-dicarboxylate 8a. Mp. 235–
236ꢀC. IR (KBr)/ cmꢁ1 3404, 3348, 3303, 3237, 2993, 2880,
2844, 2205, 1752, 1662, 1590, 1536, 1479, 1428, 1391, 1352,
1299, 1247, 1194, 1126, 1022, 973, 881, 863, 845, 821, 788,
dicyano-3,4,7,8-tetrahydroisoquinoline-2,7(1H)-dicarboxylate
5c. Mp. 253–255ꢀC. IR (KBr)/ cmꢁ1 3340, 3286, 3200, 2986,
2958, 2844, 2203, 1758, 1652, 1591, 1483, 1456, 1433, 1397,
1339, 1300, 1250, 1182, 1163, 1128, 1106, 1045, 1015, 887,
1
814, 785, 750, 722. H NMR (DMSO-d6, 400 MHz) dH 1.07–
1
773, 765, 718. H NMR (CDCl3, 400 MHz) dH 1.14–1.26 (m,
1016 (m, 3H, CH3), 2.34–2.41 (m, 1H, CH), 2.92–2.98 (m,
1H, CH), 3.48–3.75 (m, 5H, CH3Oþ2CH), 3.71–4.00 (m, 3H,
CH2OþCH), 4.27–4.34 (m, H, CH3), 5.65 (s, 1H, CH3), 7.28
(s, 2H, NH2),7.57–7.61 (m, 1H, ArH). 7.74–7.79 (m, 2H,
ArH). HRMS-ESI. calcd for C22H20Cl2N4NaO4, M þ Naþ:
497.0759, found: 497.0727.
2-Ethyl 7-methyl 6-amino-8-(4-bromophenyl)-5,7-dicyano-
3,4,7,8-tetrahydroisoquinoline-2,7(1H)-dicarboxylate 5d. Mp.
257–258ꢀC. IR (KBr)/ cmꢁ1 3194, 2981, 1846, 2207, 1759,
1681, 1595, 1505, 1487, 1455, 1435, 1394, 1337, 1299, 1250,
6H, 2CH3), 2.75–2.79 (m, 1H, CH), 3.08–3.15 (m, 1H, CH),
3.72–4.06 (m, 7H, 2CH2Oþ3CH), 4.46–4.51 (m, 1H, CH),
4.73 (s, 2H, ArH), 5.92 (s, 1H, CH), 7.54–7.57 (m, 1H, ArH),
7.74–7.81 (m, 2H, ArH), 8.06–8.08 (m, 1H, ArH). 13C NMR
(DMSO-d6, 100 MHz) dC 12.8, 14.4, 34.3, 40.2, 41.4, 43.4,
54.1, 60.9, 64.0, 79.4, 114.8, 115.2, 116.2, 125.1, 127.4, 128.2,
128.7, 130.4, 133.5, 148.8, 150.8, 163.8, 198.3. HRMS-ESI.
calcd for C23H23N5NaO6,
488.1536.
M
þ
Naþ: 488.1546, found:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1362
X.-S. Wang, J.-R. Wu, Q. Li, and M.-M. Zhang
Vol 46
Diethyl 6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-p-tolyliso-
Diethyl
6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-(4-
8g. Mp.
quinoline-2,7(1H)-dicarboxylate 8b. Mp. 223–224ꢀC. IR
(KBr)/ cmꢁ1 3354, 3214, 3026, 2983, 2931, 2855, 2205, 1754,
1664, 1597, 1518, 1487, 1468, 1441, 1399, 1345, 1298, 1241,
1130, 1020, 885, 857, 817, 771, 748. 1H NMR (CDCl3, 400
MHz) dH 1.14–1.26 (m, 6H, 2CH3), 2.35–2.41 (m, 4H,
CH3þCH), 3.04–3.07 (m, 1H, CH), 3.27 (d, J ¼ 12.8 Hz, 1H,
CH), 3.71–3.76 (m, 1H, CH), 3.92–4.19 (m, 5H, 2CH2O þ
CH), 4.43–4.54 (m, 1H, CH), 4.65 (s, 2H, NH2), 5.87 (s, 1H,
CH), 6.89–7.35 (m, 3H, ArH), 7.58–7.63 (m, 1H, ArH). 13C
NMR (DMSO-d6, 100 MHz) dC 13.3, 14.4, 20.7, 32.8, 40.2,
42.7, 43.4, 54.8, 60.8, 63.3, 79.5, 112.0, 115.6, 116.4, 125.9,
129.0, 129.4, 131.1, 138.1, 149.1, 164.1, 196.7. HRMS-ESI.
methoxyphenyl)isoquinolinꢁe-12,7(1H)-dicarboxylate
185–186ꢀC. IR (KBr)/ cm 3354, 3214, 2982, 2934, 2839,
2205, 1752, 1655, 1518, 1487, 1468, 1441, 1398, 1345, 1241,
1183, 1129, 1035, 941, 884, 856, 842, 817, 771. 1H NMR
(DMSO-d6, 400 MHz) dH 0.95–0.99 (m, 3H, CH3), 1.15 (b,
3H, CH3), 2.33–2.43 (m, 1H, CH), 2.81–2.92 (m, 1H, CH),
2.23 (d,
J
¼
12.8 Hz, 1H, CH), 3.60–3.82 (m, 5H,
CH3Oþ2CH), 3.98–4.07 (m, 4H, 2CH2O), 4.32–4.38 (m, 1H,
CH), 5.60 (m, 1H, CH), 6.88–7.10 (m, 4H, NH2þArH), 7.36–
7.59 (m, 2H, ArH). HRMS-ESI. calcd for C24H26N4NaO5, M
þ Naþ: 473.1801, found: 473.1774.
calcd for C24H26N4NaO4,
457.1844.
M
þ
Naþ: 457.1852, found:
Acknowledgments. The authors are grateful to the National Nat-
ural Science Foundation of China (20802061), the Natural Science
Foundation (08KJD150019), and Qing Lan Project (08QLT001)
of Jiangsu Education Committee for financial support.
Diethyl 6-amino-8-(2-chlorophenyl)-5,7-dicyano-3,4,7,8-tet-
rahydroisoquinoline-2,7(1H)-dicarboxylate 8c. Mp. 251–
252ꢀC. IR (KBr)/ cmꢁ1 3350, 3222, 3072, 2988, 2940, 2843,
2204, 1751, 1648, 1593, 1487, 1440, 1396, 1340, 1297, 1244,
1201, 1127, 1081, 1023, 883, 855, 816, 773, 751, 704. 1H
NMR (CDCl3, 400 MHz) dH 1.06–1.24 (m, 6H, 2CH3), 2.43–
2.47 (m, 1H, CH), 2.99–3.04 (m, 1H, CH), 3.74–3.86 (m, 2H,
2CH), 4.03–4.22 (m, 5H, 2CH2Oþ1CH), 4.43–4.54 (m, 1H,
CH), 4.69 (s, 2H, NH2), 5.90 (s, 1H, CH), 7.31–7.34 (m, 1H,
ArH), 7.41–7.46 (m, 2H, ArH), 7.91 (d, J ¼ 7.6 Hz, 1H,
ArH). HRMS-ESI. calcd for C23H23ClN4NaO4, M þ Naþ:
477.1306, found: 477.1288.
Diethyl 6-amino-8-(2,4-dichlorophenyl)-5,7-dicyano-3,4,7,8-
tetrahydroisoquinoline-2,7(1H)-dicarboxylate 8d. Mp. 215–
216ꢀC. IR (KBr)/ cmꢁ1 3353, 3173, 3033, 2983, 2204, 1758,
1673, 1601,1560, 1482, 1437, 1391, 1338, 1296, 1237, 1112,
1046, 1023, 888, 875, 862, 832, 815, 768. 1H NMR (CDCl3,
400 MHz) dH 1.13–1.26 (m, 6H, 2CH3), 2.40–2.45 (m, 1H,
CH), 2.96–3.00 (m, 1H, CH), 3.73–3.81 (m, 2H, 2CH), 3.98–
4.25 (m, 5H, 2CH2OþCH), 4.44–4.56 (m, 1H, CH), 4.79 (s,
2H, NH2), 5.89 (s, 1H, CH), 7.41–7.44 (m, 2H, ArH), 7.84 (d,
J ¼ 8.4 Hz, 1H, ArH). HRMS-ESI. calcd for C23H23Cl2N4O4,
M þ Hþ: 489.1096 found: 489.1077.
REFERENCES AND NOTES
[1] (a) Vijay, N.; Rajesh, U. A.; Vinod, S.; Bindu, A. R.; Sree-
kanth, J. S.; Lakshmi, B. Acc Chem Res 2003, 36, 899; (b) Albert,
P.; Scott, K. B.; Tetrahedron 2006, 63, 5341; (c) Shin–Ichi, I. Acc
Chem Res 2000, 33, 511; (d) Tietze, L. F. Chem Rev 1996, 96, 115;
(e) Bunce, R. A. Tetrahedron 1995, 51, 13103; (f) Shi, C. L.; Shi, D.
Q.; Kim, S. H.; Huang, Z. B.; Ji, M. Aust J Chem 2008, 61, 547. (g)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew Chem Int Ed
2006, 45, 7134.
[2] (a) Tietze, L. F.; Beifuss, U. Angew Chem Int Ed Engl
1993, 32, 131; (b) Bunce, R. A. Tetrahedron 1995, 51, 13103; (c)
Welton, T. Chem Rev 1999, 99, 2071; (d) Dupont, J.; Souza de R. F.;
Suarez, P. A. Z. Chem Rev 2002, 102, 3667; (e) Ma, J.; Zhou, X.;
Zang, X.; Wang, C.; Wang, Z.; Li, J.; Li, Q. Aust J Chem 2007, 60,
146; (f) Lu, J.; Ji, S. J.; Teo, Y. C.; Loh, T. P. Tetrahedron Lett 2005,
46, 7435; (g) Huang, J. Y.; Lei, M.; Wang, Y. G. Tetrahedron Lett
2006, 47, 3047.
[3] Tims, M. C.; Batista, C. J Chem Ecol 2007, 33, 1449.
[4] (a) Zhao, Y.; Ding, H. X.; Lu, W. 2007, CN 1896065 A.
Chem Abstr 2007, 146, 229193; (b) Kuo, C.-Y.; Wu, M.-J.; Kuo,
Y.-H. Eur J Med Chem 2006, 41, 940.
Diethyl
6-amino-5,7-dicyano-3,4,7,8-tetrahydro-8-(3,4-
8e. Mp.
dimethylphenyl)isoquinolinꢁe-12,7(1H)-dicarboxylate
201–203ꢀC. IR (KBr)/ cm 3349, 3210, 2983, 2923, 2209,
1758, 1652, 1593, 1505, 1486, 1467, 1436, 1394, 1375, 1343,
1298, 1244, 1165, 1129, 1105, 1023, 881, 856, 831, 811, 771,
744. 1H NMR (DMSO-d6, 400 MHz) dH 0.93–0.97 (m,
3H, CH3), 1.14–1.15 (m, 3H, CH3), 2.17 (s, 3H, CH3), 2.27 (s,
3H, CH3), 2.34–2.44 (m, 1H, CH), 2.83–2.87 (m, 1H, CH),
3.14–3.20 (m, 1H, CH), 3.62–4.05 (m, 6H, 2CH2Oþ2CH),
4.28–4.40 (m, 1H, CH), 5.60 (s, 1H, CH), 6.72–6.77 (m, 1H,
ArH), 7.09 (s, 2H, NH2), 7.28–7.35 (m, 2H, ArH). HRMS-ESI.
[5] Glushkov, V. A.; Arapov, K. A.; Minova, O. N.; Ismailova,
N. G.; Syropyatov, B. Y.; Shklyaev, Y. V. Pharm Chem J 2006, 40,
363.
[6] Glushkov, V. A.; Anikina, L. V.; Vikharev, Y. B.; Feshina,
E. V.; Shklyaev, Y. V. Pharm Chem J 2005, 39, 533.
[7] Wesley, T. B.; Nanda, K. K.; Kett, N. R.; Regan, C. P.;
Lynch, J. J.; Stump, G. L.; Kiss, L.; Wang, J. X.; Spencer, R. H.;
Kane, S. A.; White, R. B.; Zhang, R.; Anderson, K. D.; Liverton, N.
J.; McIntyre, C. J.; Beshore, D. C.; Hartman, G. D.; Dinsmore, C. J.
J Med Chem 2006, 49, 6954.
calcd for C25H28N4NaO4,
471.1993.
M
þ
Naþ: 471.2008, found:
Diethyl 6-amino-8-(3-chlorophenyl)-5,7-dicyano-3,4,7,8-tet-
rahydroisoquinoline-2,7(1H)-dicarboxylate 8f. Mp. 235–236ꢀC.
IR (KBr)/ cmꢁ1 3351, 3212, 2984, 2933, 2207, 1751, 1659,
1596, 1487, 1439, 1396, 1340, 1297, 1245, 1130, 1020, 890,
[8] (a) Shun, S.; John, A.; Porco, J. Org Lett 2007, 9, 4983;
(b) Ahmad, S.; Ebrahim, S.; Jafar, M.-R. Tetrahedron Lett 2008, 49,
1277; (c) Masato, O.; Yoshiyuki, T.; Shinya, N.; Daisuke, H.; Hir-
oyuki, K.; Makoto, S. Tetrahedron Lett 2007, 48, 4255; (d) Yadav, J.
S.; Reddy, B. V. S.; Gupta, M. K.; Prathap, I.; Dash, U. Synthesis
2007, 1077; (e) Kazuhiro, K.; Taiyo, S.; Hiroki, O.; Kenichi, H.;
Osamu, M.; Hisatoshi, K. Bull Chem Soc Jap 2006, 79, 1126; (f)
Kiselyov, A. S. Tetrahedron 2006, 62, 543; (g) Blanco, M. M.;
Shmidt, M. S.; Schapira, C. B.; Perillo, I. A. Synthesis 2006, 1971;
(h) Janin, Y. L.; Decaudin, D.; Monneret, C.; Poupon, M.-F. Tetrahe-
1
856, 809, 770, 710. H NMR (DMSO-d6, 400 MHz) dH 0.94–
0.97 (m, 3H, CH3), 1.15–1.23 (m, 3H, CH3), 2.43–2.47 (m,
1H, CH), 2.86–2.92 (m, 1H, CH), 3.58–3.75 (m, 2H, 2CH),
3.99–4.09 (m, 5H, 2CH2OþCH), 4.28–4.40 (m, 1H, CH), 5.61
(s, 1H, CH), 7.03–7.12 (m, 3H, NH2þArH), 7.38–7.61 (m, 3H,
ArH). HRMS-ESI. calcd for C23H23ClN4NaO4, M þ Naþ:
477.1306, found: 477.1292.
´
dron 2004, 60, 5481; (i) SanMartın, R.; Olivera, R.; Marigorta, E. M.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel and Green Method for the Synthesis of Highly Substituted
Isoquinoline Derivatives in Ionic Liquid
1363
´
Domınguez, E. Tetrahedron 1995, 51, 5361; (j) Huo, Z.; Tomeba, H.;
[10] (a) Wang, X. S.; Zhang, M. M.; Jiang, H.; Shi, D. Q.; Tu,
S. J.; Wei, X. Y.; Zong, Z. M. Synthesis 2006, 4187; (b) Wang, X.
S.; Zhang, M. M.; Jiang, H.; Yao, C. S.; Tu, S. J. Tetrahedron 2007,
63, 4439; (c) Wang, X. S.; Wu, J. R.; Li, Q.; Yao, C. S.; Tu, S.
J. Synlett 2008, 1185.
Yamamoto, Y. Tetrahedron Lett 2008, 49, 5531; (k) Zaher, M. A.;
Judeh, C. B.; Ching, J. B.; McCluskey, A. Tetrahedron Lett 2002, 43,
5089; (l) Chattopadhyay, S. K; Maity, S.; Pal, B. K.; Panja, S. Tetra-
hedron Lett 2002, 43, 5079; (m) Andresen, O. R.; Pedersen, E. B.;
Heterocycles 1982, 19, 1467.
[11] Shi, D. Q.; Chen, J.; Zhuang, Q. Y.; Wang, X. S.; Hu, H.
W. Chin Chem Lett 2003, 14, 1242.
[9] (a) Bischler, A.; Napieralski, B. Chem Ber 1893, 26, 1903;
(b) Pictet, A.; Gams, A. Chem Ber 1910, 43, 2384; (c) Pomeranz, C.
Monatsh 1893, 14, 116; (d) Fritsch, P. Chem Ber 1893, 26, 419; (e)
Gabriel, S.; Colman, J. Chem Ber 1900, 33, 980; (f) Pictet, A.; Spen-
gler, T. Chem Ber 1911, 44, 2030.
[12] Wang, X. S.; Zeng, Z. S.; Li, Y. L.; Shi, D. Q.; Tu, S. J.;
Wei, X. Y. Synth Commun 2005, 35, 1915.
[13] Gao, Y.; Shi, D. Q.; Zhou, L. H.; Dai, G. Y. Chin J Org
Chem 1996, 16, 548.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet