Room temperature ionic liquids promoted three-component coupling reactions: A facile synthesis of cis-isoquinolonic acids

Article abstract of DOI:10.1016/S0040-4020(03)00076-0

Room temperature ionic liquids are found to catalyze efficiently the three component-coupling reactions of aldehydes, amines and homophthalic anhydride under mild and convenient conditions to afford the corresponding cis-isoquinolonic acids in excellent yields with high cis-selectivity.

Full text of DOI:10.1016/S0040-4020(03)00076-0

Tetrahedron 59 (2003) 1805–1809
Room temperature ionic liquids promoted three-component
coupling reactions: a facile synthesis of cis-isoquinolonic acids
*
J. S. Yadav, B. V. S. Reddy, K. Saritha Raj and A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 5 July 2002; revised 9 December 2002; accepted 9 January 2003
Abstract—Room temperature ionic liquids are found to catalyze efficiently the three component-coupling reactions of aldehydes, amines
and homophthalic anhydride under mild and convenient conditions to afford the corresponding cis-isoquinolonic acids in excellent yields
with high cis-selectivity. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Tetrahydroquinoline derivatives are an important class of
compounds in the field of pharmaceuticals and exhibit a
wide spectrum of biological activities including psycho-
tropic, anti-allergenic, anti-inflammatory and estrogenic
behaviour. In particular, isoquinolonic acids are found to
In view of the emerging importance of the ionic liquids as
novel reaction media, we wish to explore the use of ionic
liquids as promoters for the synthesis of cis-quinolonic
acids. Thus treatment of benzaldehyde, aniline and homo-
phthalic anhydride in 1-butyl-3-methylimidazolium tetra-
fluoroborate ([bmim]BF ) ionic liquid at ambient
4
temperature afforded the corresponding cis-isoquinolonic
acid derivative 4 in 90% yield (Scheme 1).
1
2
possess a vast range of pharmacological activities.
Particularly, isoquinolonic acids are useful precursors for
the total synthesis of naturally occurring phenanthridine
3
alkaloids such as corynoline, oxocorynoline and epi-
4
corynoline as well as indenoisoquinolines possessing
significant antitumor activity. The cycloaddition of homo-
phthalic anhydride with aldimines provides a useful access
5
to the preparation of isoquinolonic acids. The cyclo-
addition of homophthalic anhydride with imines has been
reported using a base catalysis or no catalyst under thermal
conditions, which often produce a mixture of cis- and
trans-isomers, favoring cis-isomer. Recently, trimethyl
orthoformate has also been employed for the synthesis of
Scheme 1.
6
,7
Similarly, several aryl imines reacted smoothly with
homophthalic anhydride to give the corresponding iso-
quinolonic acids in 75–91% yield. In all reactions, the
product was obtained as a cis-diastereomer, which was
assigned based on the coupling constants of the hydrogens
8
trans-isoquinolonic acids.
Room temperature ionic liquids, especially those based on
the 1-N-alkyl-3-methylimidazolium cation, have shown
great promise as an attractive alternative to conventional
solvents. They are non-volatile, recyclable, non-explosive,
1
in the H NMR spectrum of the product. The stereo-
chemistry of the product was further confirmed by the direct
comparison of spectroscopic data with authentic com-
pounds. In all cases, the reactions proceeded efficiently at
ambient temperature under mild conditions to afford the
corresponding isoquinolonic acids in high yields. However,
in the absence of ionic liquids, the reaction did not yield any
product even after a long reaction time (10–15 h). The
reactions are clean and highly diastereoselective, affording
exclusively the corresponding cis-isomer in high yields. All
9
easy to handle, and thermally robust. In many cases, the
products are weakly soluble in the ionic phase so that the
products can be easily separated by simple extraction with
1
0
ether. Because of the great potential of room temperature
ionic liquids as novel reaction media for catalytic processes,
much attention has been currently focused on organic
1
1
reactions promoted by ionic liquids.
1
the products were characterized by H NMR, IR and mass
spectroscopy. In this reaction, the efficiency of ionic liquid
was strongly influenced by the nature of the anion. The
reactions of various aldehydes, amines and homophthalic
Keywords: ionic melts; aldimines; cyclization; cis-isoquinolonic acids.
*
Corresponding author. Tel.: þ91-40-7160512; fax: þ91-40-27160512;
e-mail: yadav@iict.ap.nic.in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00076-0

1806
J. S. Yadav et al. / Tetrahedron 59 (2003) 1805–1809
Table 1. Ionic liquids-promoted synthesis of cis-isoquinolonic acids
Entry
Amine
Aldehyde
Product
[bmim]BF
4
[bmim]PF
6
a
a
Time (h)
Yield (%)
Time (h)
Yield (%)
a
b
c
d
e
f
g
h
I
j
k
l
m
n
o
p
X¼H
Y¼4-MeO
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
2.0
2.5
3.0
3.5
4.0
3.0
4.0
3.5
3.0
3.0
6.5
5.5
3.5
3.5
5.0
2.5
89
87
90
85
87
91
90
85
90
87
75
80
89
78
80
3.5
3.0
4.0
4.5
5.0
4.0
5.5
5.0
4.0
4.5
8.0
6.0
4.5
4.5
6.5
3.5
83
85
87
81
83
85
82
81
85
83
72
78
80
75
78
X¼4-Me
X¼H
Y¼H
Y¼H
X¼4-Cl
X¼4-Br
X¼4-MeO
X¼H
Y¼2-Me
Y¼H
Y¼2-Me
Y¼4-N(Me)
Y¼H
2
X¼3,4,5-(MeO)
X¼4-Me
X¼4-Cl
X¼H
3
Y¼4-MeO
Y¼H
Y¼2-NO
Y¼4-CN
2
X¼H
Benzyl amine
2-Phenylethylamine
Y¼4-MeO
Y¼4-MeO
X¼H
2-Naphthaldehyde
Thiophene-2-carboxaldehyde
b
b
X¼H
Isolated and unoptimized yields after column chromatography.
85
81
a
b
1
0% trans-isomer was also obtained.
anhydride were studied in hydrophilic [bmim]BF4 and
hydrophobic [bmim]PF ionic liquids. Among these ionic
liquids, [bmim]BF was found to be superior in terms of
4
SnCl were decomposed or deactivated by amines and water
4
that exist during imine formation. However, ionic liquids
are stable with amines and water and also effectively
activate the imines (formed in situ from aldehydes and
amines) to undergo cyclization. To know the role of ionic
liquid in this transformation, the reaction was carried out in
dichloromethane both in the presence of 10 mol%
6
yields and reaction rates (Table 1). The advantage of the use
of ionic liquids as novel reaction media for this transform-
ation is that these ionic liquids can be easily recovered and
recycled in subsequent reactions. Since the products were
weakly soluble in the ionic phase, they were easily separated
by simple extraction with ether. The rest of the viscous ionic
liquid was thoroughly washed with ether and reused in
subsequent reactions without further purification. However,
the products were obtained of the same purity as in the first
run, the yields gradually decreased in runs carried out using
recycled ionic liquid. For example, the reaction of
benzaldehyde, aniline and homophthalic anhydride afforded
the corresponding cis-isoquinolonic acid in 90, 87, 85, and
[bmim]BF ionic liquid and in the absence of ionic liquid.
4
High conversions were obtained in a short reaction time in
the combined solvent system i.e. [bmim]BF ionic liquid in
4
dichloromethane. Other polar organic solvents such as
methanol and acetonitrile were also used to study the role of
ionic liquids in this transformation. In these solvents, the
reactions proceeded only at high temperature (70–808C)
and also took longer reaction times (8–15 h). Moreover, the
products were obtained in low to moderate yields (45–
60%). In further reactions, the efficiency of various
quaternary ammonium salts was studied. The three-
component condensation was not successful in other molten
8
2% yields over four cycles. However, the activity of ionic
liquid was consistent in runs and no decrease in yield was
obtained when the recycled ionic liquid was activated at
8
08C under vacuum in each cycle. Compared to conven-
salts such as n-tetrabutyl ammonium chloride (n-Bu NCl) or
4
tional methods, this method avoids the preparation and
isolation of unstable imines prior to the reactions. Most of
the conventional Lewis acids such as BF .OEt , TiCl and
in 1-n-butyl-3-methylimidazolium chloride ([bmim]Cl.
These results indicate that both cation and anion play an
important role as the reaction media. The scope and
3
2
4
3
Table 2. InCl -Catalyzed synthesis of cis-isoquinolonic acids
a
Entry
X–Ar NH
2
Y–ArCHO
Product
5% InCl
3
–[bmim]BF
4
3 2 2
5% InCl –CH Cl
b
b
Time (h)
Yield (%)
Time (h)
Yield (%)
a
b
c
d
e
f
g
h
i
X¼H
Y¼4-MeO
Y¼H
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.0
1.0
0.5
1.5
1.0
1.5
2.5
2.0
1.5
92
90
95
91
89
92
87
89
91
2.0
1.5
1.0
2.0
2.5
2.0
3.5
3.0
2.5
81
85
87
83
80
82
75
78
82
X¼4-Me
X¼H
Y¼H
X¼4-Cl
X¼4-Br
X¼4-MeO
X¼H
Y¼2-Me
Y¼H
Y¼2-Me
Y¼4-N(Me)
Y¼H
2
X¼3,4,5-(MeO)
X¼4-Me
3
Y¼4-MeO
a
All products were obtained as cis-isomers in both solvents at room temperature.
Yields refer to after purification.
b

J. S. Yadav et al. / Tetrahedron 59 (2003) 1805–1809
1807
Figure 1. Structures of products 4(a–p).
generality of this process is illustrated with respect to
various aldehydes, amines and homophthalic anhydride in
ionic liquids and the results are presented in the Table 1. We
have also performed these three-component coupling
reactions using indium trichloride in ionic liquids as well
as in dichloromethane to compare the efficiency of ionic
liquids and the results are presented in Table 2. Although,
these cyclization reactions proceeded smoothly in the
presence of 5 mol% indium trichloride in both solvents,
the recovery and reuse of indium trichloride is especially
simple in ionic liquids. In contrast to organic solvents,
enhanced reaction rates, improved yields and high
selectivity are the features obtained in ionic liquids. For
example, the treatment of benzaldehyde and aniline with
CDCl using TMS as internal standard. Mass spectra were
3
recorded on a Finnigan MAT 1020 mass spectrometer
operating at 70 eV. CHN analyses were recorded on a Vario
EL analyzer. [Bmim]BF and [bmim]PF ionic liquids were
4
6
prepared according to the procedures reported in the
1
literature.
2
4.1. General procedure
Method A. A mixture of aldehyde (2 mmol), amine
(2 mmol), and homophthalic anhydride (2 mmol) in
1-butyl-3-methylimidazolium tetrafluoroborate or 1-butyl-
3-methylimidazolium hexafluorophosphate (2 mL) was
stirred at ambient temperature for the appropriate time
(Table 1). After completion of the reaction, as indicated by
TLC, the reaction mixture was washed with diethyl ether
(3£10 mL). The combined ether extracts were concentrated
in vacuo and the resulting product was directly charged on
small silica gel column and eluted with a mixture of ethyl
acetate: n-hexane (2:8) to afford pure isoquinolonic acid. On
the other hand, the combined ether layers were concentrated
in vacuo and the resulting product was recrystallized in a
mixture of ether and pentane solvent system to afford the
pure product. The rest of the viscous ionic liquid was further
washed with ether and dried at 808C under reduced pressure
to retain its activity in subsequent runs.
homophthalic anhydride in [bmim]BF ionic liquid for 3.0 h
4
afforded the corresponding cis-isoquinolonic acid in 90%
yield whereas the same reaction in refluxing methanol after
8
.0 h gave the product in 60% yield as a mixture of cis- and
trans-isomers in 3:1 ratio. In most cases, the reactions gave
mixtures of cis- and trans-products along with homo-
phthalic amides under refluxing conditions. The use of ionic
liquids as reaction media for this transformation avoids the
use of moisture sensitive reagents or high temperature
reaction conditions to promote the reaction. This clearly
indicates the efficiency of ionic liquids for this
transformation.
Method B. A mixture of aldehyde (2 mmol), amine
(2 mmol), homophthalic anhydride (2 mmol) and InCl3
3. Conclusion
(5 mol%) in [bmim]BF ionic liquid (2 mL) or dichloro-
4
The paper describes a novel and efficient method for the
synthesis of tetrahydroisoquinolonic acids involving three
component-coupling reactions of aldehydes, amines and
homophthalic anhydride using ionic liquids as reaction
media as well as promoters. The notable features of
this procedure are mild reaction conditions, greater cis-
selectivity, improved yields, cleaner reaction profiles,
enhanced rates, ease of recovery and reuse of this novel
reaction medium, which make it a simple and convenient
method for the synthesis of isoquinoline derivatives of
biological importance.
methane (5 mL) was stirred at ambient temperature for
0.5–1.5 h. After completion of the reaction as indicated by
TLC, the reaction mixture was diluted with water and the
resulting solid was separated by filtration. The crude
product was recrystallized in a mixture of ether and pentane
solvent system to afford pure cis-isoquinolonic acids in
80–90% yields (Fig. 1).
4.1.1. 3-(4-Methoxyphenyl)-1-oxo-2-phenyl-1,2,3,4-
tetrahydro-4-isoquinoline-carboxylic acid (4a). White
1
solid, m.p. 1108C; H NMR (CDCl ) d: 3.70 (s, 3H), 4.80
3
(
d, 1H, J¼6.0 Hz), 5.38 (d, 1H, J¼6.0 Hz), 6.63 (d, 2H,
J¼8.4 Hz), 6.97 (d, 2H, J¼8.4 Hz), 7.18 (d, 2H, J¼8.3 Hz),
7.20–7.37 (m, 3H), 7.40–7.58 (m, 2H), 7.65 (d, 1H,
J¼8.2 Hz), 8.18 (dd, 1H, J¼2.1, 8.2 Hz). IR (KBr) n: 2925,
4
. Experimental
2
1
Melting points were recorded on Buchi R-535 apparatus and
are uncorrected. IR spectra were recorded on a Perkin–
1733, 1603, 1508, 1252, 1171, 1025, 784 cm . EIMS: m/z:
þ
373[M ], 258, 181, 166, 143, 95, 70, 42. Anal. Calcd for
1
Elmer FT-IR 240-c spectrophotometer using KBr optics. H
NMR spectra were recorded on Gemini-200 spectrometer in
C
74.07; H, 5.18; N, 3.737.
23
H
19NO
4
(373.40): C, 73.98; H, 5.13; N, 3.75. Found: C,

1808
J. S. Yadav et al. / Tetrahedron 59 (2003) 1805–1809
þ
Calcd for C H N O (384.44): C, 74.59; H, 5.74; N, 7.25.
Found: C, 74.60; H, 5.76; N, 7.23.
4.1.2. 2-(4-Methylphenyl)-1-oxo-3-phenyl-1,2,3,4-tetra-
hydro-4-isoquinoline-carboxylic acid (4b). Pale yellow
solid, m.p. 1788C; H NMR (CDCl ) d: 2.30 (s, 3H), 4.85 (d,
3
m/z: 384[M ], 372, 356, 237, 165, 135, 93, 77, 65. Anal.
2
4 22 2 3
1
1
7
H, J¼6.0 Hz), 5.40 (d, 1H, J¼6.0 Hz), 7.05–7.35 (m, 7H),
.40–7.60 (m, 3H), 7.70 (d, 2H, J¼8.0 Hz), 8.20 (dd, 1H,
4.1.8. 1-Oxo-3-phenyl-2-(3,4,5-trimethoxyphenyl)-
1,2,3,4-tetrahydro-4-isoquinoline carboxylic acid (4h).
J¼2.0, 8.0 Hz). IR (KBr) n: 2927, 1736, 1625, 1510, 1435,
175, 698 cm2 . EIMS: m/z: 357[M ], 350, 308, 278, 252,
1
þ
1
1
2
White solid, m.p. 1928C; H NMR (CDCl ) d: 3.60 (s, 6H),
3
08, 191, 174, 133, 106, 79, 42. Anal. Calcd for C H NO
3
3.75 (s, 3H), 4.85 (d, 2H, J¼6.0 Hz), 5.30 (d, 1H,
J¼6.0 Hz), 6.28 (s, 2H), 7.15–7.05 (m, 5H), 7.40–7.58
(m, 2H), 7.68 (d, 1H, J¼8.0 Hz), 8.20 (d, 1H, J¼8.0 Hz). IR
2
3
19
(
5
357.40): C, 77.29; H, 5.36; N, 3.92. Found: C, 77.31; H,
.34; N, 3.95.
(
KBr) n: 3438, 2967, 1736, 1648, 1519, 1428, 1260, 1172,
2
1
þ
141, 105, 91, 69. Anal. Calcd for C H NO (433.45): C,
4
line-carboxylic acid (4c). White solid, m.p. 1988C; H
.1.3. 1-Oxo-2,3-diphenyl-1,2,3,4-tetrahydro-4-isoquino-
1
1042, 813, 759 cm . EIMS: m/z: 433[M ], 414, 271, 256,
2
5
23
6
NMR (CDCl ) d: 4.85 (d, 1H, J¼6.0 Hz), 5.40 (d, 1H,
69.27; H, 5.35; N, 3.23. Found: C, 69.30; H, 5.37; N, 3.25.
3
J¼6.0 Hz), 7.05 (m, 8H), 7.40 (m, 3H), 7.70 (d, 1H,
J¼8.0 Hz), 8.20 (dd, 1H, J¼2.1, 8.0 Hz). IR (KBr) n: 3033,
4.1.9. 3-(4-Methoxyphenyl)-2-(4-methylphenyl)-1-oxo-
1,2,3,4-tetrahydro-4-isoquinoline carboxylic acid (4i).
2
1
1
3
724, 1633, 1494, 1222, 1023, 770, 696 cm . EIMS: m/z:
43[M ], 182, 134, 106, 89, 78.Anal. Calcd for C H NO
þ
1
White solid, m.p. 1808C; H NMR (CDCl ) d: 2.30 (s,
3
2
2
17
3
(
4
343.38): C, 76.95; H, 4.99; N, 4.08. Found: C, 76.97; H,
.97; N, 4.10.
3H), 3.70 (s, 3H), 4.90 (d, 1H, J¼5.9 Hz), 5.30 (d, 1H,
J¼5.9 Hz), 6.65 (d, 2H, J¼8.1 Hz), 6.90–7.20 (m, 5H),
7
.45–7.60 (m, 4H), 8.30 (d, 1H, J¼8.0 Hz). IR (KBr) n:
2
1
4
1
.1.4. 2-(4-Chlorophenyl)-3-(2-methylphenyl)-1-oxo-
,2,3,4-tetrahydro-4-isoquinoline carboxylic acid (4d).
2932, 1748, 1610, 1580, 1249, 1182, 1035, 778, 682 cm .
FAB mass: m/z: 387[M ], 370, 342, 237, 225, 154, 136,
þ
107, 91, 77, 69, 55. Anal. Calcd for C H NO (387.43): C,
74.40; H, 5.46; N, 3.62. Found: C, 74.43; H, 5.48; N, 3.65.
1
Pale yellow solid, m.p. 1868C; H NMR (CDCl ) d: 2.25 (s,
3
24 21
4
3
7
8
1
1
7
H), 4.80 (d, 1H, J¼6.0 Hz), 5.38 (d, 1H, J¼8.0 Hz), 7.10–
.35 (m, 5H), 7.40–7.55 (m, 5H), 7.65 (d, 1H, J¼8.0 Hz),
.20 (dd, 1H, J¼2.1, 8.0 Hz). IR (KBr) n: 2927, 1736, 1625,
4.1.10. 2-(4-Chlorophenyl)-1-oxo-3-phenyl-1,2,3,4-tetra-
hydro-4-isoquinolinecarboxylic acid (4j). Pale yellow
2
1
þ
510, 1435, 1175, 698 cm . EIMS: m/z: 391[M ], 229,
1
27, 84, 66, 46. Anal. Calcd for C H ClNO (391.85): C,
3
solid, m.p. 1828C; H NMR (CDCl ) d: 4.95 (d, 1H,
3
2
3
18
0.50; H, 4.63; Cl, 9.05; N, 3.57. Found: C, 70.53; H, 4.67;
J¼6.0 Hz), 5.50 (d, 1H, J¼6.0 Hz), 7.15–7.65 (m, 12H),
Cl, 9.10; N, 3.59.
8.15 (d, 1H, J¼8.0 Hz). IR (KBr) n: 2931, 2815, 1732, 1481,
1
1
389, 1234, 1168, 779 cm2 . FAB mass: m/z: 377[M ],
þ
4.1.5. 2-(4-Bromophenyl)-1-oxo-3-phenyl-1,2,3,4-tetra-
hydro-4-isoquinoline-carboxylic acid (4e). Yellow solid,
332, 307, 290, 272, 216, 176, 154, 136, 120, 107, 89, 77, 63.
Anal. Calcd for C H ClNO (377.82): C, 69.94; H, 4.27;
Cl, 9.38; N, 3.71. Found: C, 69.96; H, 4.31; Cl, 9.40; N,
3.74.
2
2
16
3
1
m.p. 1808C; H NMR (CDCl ) d: 4.80 (d, 1H, J¼6.0 Hz),
3
5
5
.40 (d, 1H, J¼6.0 Hz), 7.05–7.20 (m, 6H), 7.30–7.45 (m,
H), 7.65 (d, 1H, J¼8.0 Hz), 8.18 (d, 1H, J¼8.0 Hz). IR
(
KBr) n: 3034, 1727, 1634, 1575, 1487, 1384, 1227, 1164,
010, 811, 724 cm . EIMS: m/z: 421[M ], 343, 178, 140,
4.1.11. 3-(2-Nitrophenyl)-1-oxo-2-phenyl-1,2,3,4-tetra-
hydro-4-isoquinoline carboxylic acid (4k). Yellow solid,
2
1
þ
17, 77, 65. Anal. Calcd for C H BrNO (422.27): C,
1
1
6
1
m.p. 2228C; H NMR (CDCl ) d: 4.90 (d, 1H, J¼5.9 Hz),
2
2
16
3
3
2.58; H, 3.82; Br, 18.92; N, 3.32. Found: C, 62.60; H, 3.85;
5.60 (d, 1H, J¼5.9 Hz), 7.15–7.70 (m, 10H), 7.95 (d, 1H,
Br, 18.90; N, 3.35.
J¼2.0 Hz), 8.10 (d, 1H, J¼8.0 Hz), 8.25 (dd, 1H, J¼8.0,
2
.0 Hz). IR (KBr) n: 3318, 1728, 1659, 1527, 1438, 1273,
21
þ
4
1
.1.6. 2-(4-Methoxyphenyl)-3-(2-methylphenyl)-1-oxo-
,2,3,4-tetrahydro-4-isoquinoline carboxylic acid (4f).
1178, 1048, 748, 674 cm . FAB mass: m/z: 388[M ], 369,
339, 313, 307, 289, 273, 259, 241, 227, 211, 107, 91, 77.
Anal. Calcd for C H N O (388.37): C, 68.04; H, 4.15; N,
1
White solid, m.p. 1508C; H NMR (CDCl ) d: 2.23 (s,
3
22 16 2 5
3
H), 3.85 (s, 3H), 4.80 (d, 1H, J¼6.0 Hz), 5.28 (d, 1H,
7.21. Found: C, 68.02; H, 4.17; N, 7.23.
J¼6.0 Hz), 6.70–6.83 (m, 3H), 6.98–7.05 (m, 2H), 7.40–
7
1
1
2
.55 (m, 5H, J¼2.4 Hz), 7.65 (d, 1H, J¼8.0 Hz), 8.20 (d,
H, J¼8.0 Hz). IR (KBr) n: 3027, 1728, 1682, 1512, 1415,
4.1.12. 3-(4-Cyanophenyl)-1-oxo-2-phenyl-1,2,3,4-tetra-
hydro-4-isoquinoline carboxylic acid (4l). Pale yellow
2
1
þ
1
275, 1171, 1033, 821, 717 cm . EIMS: m/z: 387[M ],
85, 225, 123, 108, 90, 63. Anal. Calcd for C H NO
4
solid, m.p. 1808C; H NMR (CDCl ) d: 4.85 (d, 1H,
3
J¼5.9 Hz), 5.50 (d, 1H, J¼5.9 Hz), 7.10–7.65 (m, 12H),
8.20 (d, 1H, J¼8.0 Hz). IR (KBr) n: 3414, 2925, 1703, 1619,
1528, 1267, 755, 615 cm2 . EIMS: m/z: 368 M , 206, 181,
þ
2
4
21
(
5
387.43): C, 74.40; H, 5.46; N, 3.62. Found: C, 74.43; H,
.48; N, 3.65.
1
162, 77, 65. Anal. Calcd for C H N O (368.39): C,
74.99; H, 4.38; N, 7.60. Found: C, 75.01; H, 4.40; N, 7.64.
23 16 2 3
4
1
.1.7. 3-(4-Dimethylaminophenyl)-1-oxo-2-phenyl-
,2,3,4-tetrahydro-4-isoquinoline carboxylic acid (4g).
1
Yellow solid, m.p. 1528C; H NMR (CDCl ) d: 2.80 (s, 6H),
3
4.1.13. 2-Benzyl-3-(4-methoxyphenyl)-1-oxo-1,2,3,4-
tetrahydro-4-isoquinolinecarboxylic acid (4m). White
4
.80 (d, 1H, J¼6.0 Hz), 5.25 (d, 1H, J¼6.0 Hz), 6.40 (d, 1H,
J¼8.2 Hz), 6.80 (d, 1H, J¼8.2 Hz), 6.98 (t, 1H, J¼8.0 Hz),
.15–7.25 (m, 5H), 7.38–7.45 (m, 3H), 7.65 (d, 1H,
J¼8.0 Hz), 8.18 (d, 1H, J¼8.0 Hz). IR (KBr) n: 3421, 3324,
1
solid, m.p. 1988C; H NMR (CDCl ) d: 3.60 (d, 1H,
3
7
J¼14.0 Hz), 3.75 (s, 3H), 4.80 (d, 1H, J¼6.0 Hz), 5.85 (d,
1H, J¼6.0 Hz), 5.70 (d, 1H, J¼14.0 Hz), 6.70 (d, 2H,
J¼8.0 Hz), 6. 90 (d, 2H, J¼8.0 Hz), 7.2–7.35 (m, 6H),
2
1
1
701, 1664, 1539, 1440, 1351, 1265, 754, 695 cm . EIMS:

J. S. Yadav et al. / Tetrahedron 59 (2003) 1805–1809
1809
7
n: 3439, 1741, 1617, 1513, 1257, 1168, 1023, 829,
.58–7.60 (m, 2H), 8.25 (dd, 1H, J¼2.0, 8.0 Hz). IR (KBr)
References
2
1
þ
34, 121, 91, 77, 65. Anal. Calcd for C H NO (387.43):
7
48 cm . EIMS: m/z: 387[M ], 381, 282, 237, 226, 165,
1. (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656–670.
(b) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211. (c) Faber, K.; Stueckler,
H.; Kappe, T. J. Heterocyl. Chem. 1984, 21, 1177–1178.
1
C, 74.40; H, 5.46; N, 3.62. Found: C, 74.43; H, 5.48; N,
2
4
21
4
3
.65.
(
d) Johnson, J. V.; Rauckman, S.; Baccanari, P. D.; Roth, B.
4.1.14. 3-(4-Methoxyphenyl)-1-oxo-2-phenethyl-1,2,3,4-
tetrahydro-4-isoquinoline carboxylic acid (4n). White
solid, m.p. 1668C; H NMR (CDCl ) d: 2.90–3.05 (m, 4H),
3
J. Med. Chem. 1989, 32, 1942–1949.
2. Gray, N.; Dappen, M.; Cheng, B.; Cordi, A.; Biesterfeldt, J.;
Hood, W.; Monahan, J. J. Med. Chem. 1991, 34, 1283–1292.
1
3
6
.70 (s, 3H) 4.40 (d, 1H, J¼5.7 Hz), 4.78 (d, 1H, J¼5.7 Hz),
3
. (a) Cushman, M.; Chen, J. J. Org. Chem. 1987, 52,
517–1521. (b) Fodor, L.; Szabo Bernath, G.; Sohar, P.;
.65 (d, 2H, J¼8.0 Hz), 6.90 (d, 2H, J¼8.0 Hz), 7.25–7.60
1
(
m, 8H), 8.20 (dd, 1H, J¼8.0, 1.8 Hz). IR (KBr) n: 3035,
þ
62, 152, 132, 118, 107, 93, 77, 65, 43. Anal. Calcd for
Maclean, D. B.; Smith, R. W.; Ninommiya, I.; Naito, T.
J. Heterocyl. Chem. 1989, 26, 33–37.
. (a) Cushman, M.; Chen, L. G. J. Org. Chem. 1978, 43,
2
7
1
928, 1727, 1622, 1513, 1472, 1252, 1173, 1031, 762,
02 cm . FAB mass: m/z: 401 M , 356, 337, 255, 238,
2
1
4
5
2
86–288. (b) Bonnaud, B.; Carlessi, A.; Bigg, D. C. H.
C H NO (401.45): C, 74.80; H, 5.77; N, 3.49. Found: C,
2
6
23
4
J. Heterocyl. Chem. 1993, 30, 257–265.
7
4.83; H, 5.78; N, 3.50.
. (a) Govindachari, T. R.; Cinnasamy, P.; Rajeswari, S.;
Chandrasekaran, S.; Pramila, M. S.; Natarajan, S.; Nagarajan,
K.; Pai, B. R. Heterocycles 1984, 22, 585–655. (b) Haimova,
M. A.; Mollov, N. M.; Ivanova, S. C.; Dimitrova, A. I.;
Ognyanov, V. I. Tetrahedron 1977, 33, 331–336.
4.1.15. 3-(2-Naphthyl)-1-oxo-2-phenyl-1,2,3,4-tetra-
hydro-4-isoquinoline-carboxylic acid (4o). White Solid,
1
m.p. 1648C; H NMR (CDCl ) d: 4.85 (d, 1H, J¼6.0 Hz),
3
5
4
.58 (d, 1H, J¼6.0 Hz), 7.10–7.30 (m, 6H), 7.38–7.50 (m,
6
7
. Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907–915.
. Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977,
H), 7.58–7.75 (m, 5H), 8.20 (dd, 1H, J¼2.0, 8.0 Hz). IR
(
KBr) n: 2981, 1736, 1628, 1431, 1383, 1242, 1176, 1037,
52, 694 cm2 . EIMS: m/z: 393[M ], 384, 347, 230, 133,
4
2, 1111–1116.
. (a) Yu, N.; Poulain, R.; Gesquiere, J. C. Synlett 2000,
55–356. (b) Yu, N.; Bourel, L.; Deprez, B.; Gesquiere, J. C.
1
þ
7
1
8
9
04, 77, 43. Anal. Calcd for C H NO (393.44): C, 79.37;
2
6
19
3
3
H, 4.87; N, 3.56. Found: C, 79.40; H, 4.89; N, 3.58.
Tetrahedron Lett. 1998, 39, 829–832.
. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083.
4
4
.1.16. 1-Oxo-2-phenyl-3-(2-thienyl)-1,2,3,4-tetrahydro-
-isoquinoline carboxylic acid (4p). Pale yellow solid,
(
b) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed.
1
2000, 39, 3772–3789.
m.p. 1728C; H NMR (CDCl ) d: 4.90 (d, 1H, J¼5.6 Hz),
3
1
1
0. (a) Sheldon, R. Chem. Commun. 2001, 2399–2407. (b) Le
Boulaire, V.; Gree, R. Chem. Commun. 2000, 2195–2196.
1. Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917–5919.
5
1
.65 (d, 1H, J¼5.6 Hz), 6.80–6.90 (m, 2H), 7.05–7.15 (m,
H), 7.10–7.65 (m, 10H), 8.20 (d, 1H, J¼8.0 Hz). IR (KBr)
n: 3418, 1736, 1651, 1538, 1493, 1339, 1251, 1026, 1007,
24, 762 cm2 . EIMS: m/z: 349 M , 278, 154, 136, 77, 68.
1
þ
12. (a) Park, S.; Kazlauskas, R. J. J. Org. Chem. 2001, 66,
395–8401. (b) BonhOte, P.; Dias, A. P.; Papageorgiou, N.;
Kalyanasundaram, K.; Gratzel, M. Inorg. Chem. 1996, 35,
168–1178.
8
Anal. Calcd for C H ClN O (348.40): C, 68.75; H, 4.33;
N, 4.01; S, 9.18. Found: C, 68.80; H, 4.35; N, 4.05; S, 9.20.
8
2
2
15
2 5
1
Acknowledgements
B. V. S. thanks CSIR New Delhi for the award of a
fellowship.