Iodine as a mild, efficient, and cost-effective reagent for the synthesis of cis-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids

Article abstract of DOI:10.1055/s-2007-983899

Arylimines generated in situ from aromatic aldehydes and anilines undergo smooth coupling with homophthalic anhydride in the presence of 10 mol% of molecular iodine under mild and neutral conditions to afford the corresponding cis-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids in excellent yields with high cis selectivity. The use of iodine makes this procedure simple, convenient, and cost-effective. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983899

PAPER
3191
Iodine as a Mild, Efficient, and Cost-Effective Reagent for the Synthesis of
cis-1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids
Synthesis
.of cis-1-Oxo
S
-1,2,3,4-tetrah
.
ydroisoquino
Y
line-4-carboxylic
a
A
cids dav,* B. V. Subba Reddy, A. Ramesh Reddy, A. V. Narsaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 23 April 2007; revised 18 July 2007
expensive and readily available reagents would extend the
scope of this transformation in natural product synthe-
sis.3,4
Abstract: Arylimines generated in situ from aromatic aldehydes
and anilines undergo smooth coupling with homophthalic anhy-
dride in the presence of 10 mol% of molecular iodine under mild
and neutral conditions to afford the corresponding cis-1-oxo-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids in excellent
yields with high cis selectivity. The use of iodine makes this proce-
dure simple, convenient, and cost-effective.
In recent years, molecular-iodine-catalyzed or -mediated
reactions have gained importance in organic synthesis as
an inexpensive, nontoxic, and readily available method
for various organic transformations, affording the corre-
sponding products in high selectivity and excellent
yields.9 The mild Lewis acidity associated with iodine en-
hances its usage in organic synthesis, so that several or-
ganic transformations can be performed at stoichiometric
to catalytic levels. The advantages associated with this
eco-friendly catalyst has led to molecular iodine being ex-
plored as a powerful reagent in organic synthesis.10
Key words: three-component reaction, iodine, isoquinolines, het-
erocycles, carboxylic acids
Tetrahydroquinoline derivatives make up an important
class of compounds in the field of pharmaceuticals, and
exhibit a wide spectrum of biological activities including
psychotropic, antiallergenic, anti-inflammatory, and es-
trogenic behavior.1 Oxoisoquinolinecarboxylic acids pos-
sess a vast range of pharmacological activities.2 Also,
oxoisoquinolinecarboxylic acids are useful precursors for
the total synthesis of naturally occurring phenanthridine
alkaloids3 such as corynoline, oxocorynoline, and epico-
rynoline as well as indenoisoquinolines4 possessing sig-
nificant antitumor activity.
In continuation of our interest in the use of molecular io-
dine for various transformations,11 we herein report the
direct synthesis of highly substituted oxoisoquinoline-
carboxylic acids from homophthalic anhydride and
arylimines in the presence of molecular iodine under neu-
tral conditions. Accordingly, treatment of homophthalic
anhydride (1), benzaldehyde (2a), and aniline (3a) with
iodine in dichloromethane at room temperature afforded
the corresponding cis-oxoisoquinolinecarboxylic acid de-
rivative 4a in 85% yield (Scheme 1).
The cycloaddition of homophthalic anhydride with aldi-
mines provides a useful access to the preparation of ox-
oisoquinolinecarboxylic acids.5 The cycloaddition of
homophthalic anhydride with imines has been reported to
occur under base catalysis or without a catalyst under
thermal conditions;6,7 this often produces a mixture of cis-
and trans-isomers, with the cis-isomer favored. Recently,
trimethyl orthoformate has also been employed for the
synthesis of trans-oxoisoquinolinecarboxylic acids.8
However, many of these classical methods often involve
the use of expensive reagents, extended reaction times,
and also generate a mixture of products.6,7 Therefore, the
development of a simple and efficient protocol using in-
Similarly, several arylimines (generated in situ from alde-
hydes 2 and amines 3) reacted well with homophthalic an-
hydride (1) to give the corresponding cis-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic acids 4 in 72–92%
yield (Table 1). It is noteworthy that benzylamine (3b)
and phenethylamine (3f) (Table 1, entries 2, 9, and 11)
gave higher yields than arylamines. In all cases, the reac-
tions proceeded smoothly at room temperature under mild
conditions. However, aliphatic aldehydes such as n-deca-
nal and cyclohexanecarbaldehyde failed to produce the
desired product under similar conditions. This method
O
O
O
N
I2
H
PhCHO
PhNH2
+
+
CH2Cl2, r.t.
O
H
CO2H
1
2a
3a
4a
Scheme 1
SYNTHESIS 2007, No. 20, pp 3191–3194
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983899; Art ID: Z10207SS
© Georg Thieme Verlag Stuttgart · New York

3192
J. S. Yadav et al.
PAPER
was successful only with imines derived from aromatic al- Compared to conventional syntheses, this method avoids
dehydes 3 (Table 1). In the absence of iodine, the reac- the preparation and isolation of unstable imines. Most of
tions did not yield the desired products even after a long the conventional Lewis acids, such as boron trifluoride–
reaction time (8–16 h). As solvent, dichloromethane ap- diethyl ether, titanium(IV) chloride, and tin(IV) chloride,
peared to give the best results. The reactions were clean were decomposed or deactivated by amines and water
and the products were obtained in excellent yields and during imine formation. However, iodine was found to be
with high diastereoselectivity as determined by 1H NMR compatible with the amines and water present during
analysis of the crude products. In all reactions, the product imine formation, and also effectively activate the imines
was obtained as a cis-diastereomer, the structure of which (formed in situ from aldehydes and amines) to undergo
was established on the basis of the coupling constants of cyclization. The results of the scope and generality of this
the hydrogens in the 1H NMR spectra of the products. The process with respect to various aldehydes, amines, and ho-
stereochemistry of the products was further confirmed by mophthalic anhydride are presented in Table 1.
direct comparison of the spectroscopic data of the prod-
ucts with authentic samples.12 All the products were char-
1
acterized by H NMR and IR spectroscopy, and mass
spectrometry.
Table 1 Iodine-Catalyzed Preparation of cis-1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids 4 from Aldehydes 2, Amines 3, and
Homophthalic Anhydride (1)
Entry
1
Ar in ArCHO
2
R in RNH2
3
Producta
4
Time (h) Yieldb (%)
O
Ph
2a
Ph
3a
4a
6.0
6.5
7.0
85
90
82
N
H
H
CO2H
O
N
Ph
2
3
Ph
Ph
2a
2a
Bn
3b
3c
4b
4c
H
H
CO2H
Cl
O
N
4-ClC6H4
H
H
CO2H
Me
O
N
4
5
6
Ph
2a
2a
2b
Tol
3d
3e
3c
4d
4e
4f
6.5
7.0
6.0
80
83
85
H
H
CO2H
OMe
O
N
Ph
PMP
H
H
CO2H
Cl
O
N
3,4-(MeO)2C6H3
4-ClC6H4
H
OMe
OMe
H
CO2H
Synthesis 2007, No. 20, 3191–3194 © Thieme Stuttgart · New York

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Synthesis of cis-1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids
3193
Table 1 Iodine-Catalyzed Preparation of cis-1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids 4 from Aldehydes 2, Amines 3, and
Homophthalic Anhydride (1) (continued)
Entry
Ar in ArCHO
2
R in RNH2
3
Producta
4
Time (h) Yieldb (%)
Me
O
N
7
4-ClC6H4
2c
Tol
3d
4g
6.0
81
H
H
CO2H
Cl
Me
O
N
8
9
4-O2NC6H4
2d
2e
2b
Tol
Bn
Ph
3d
3b
3a
4h
4i
7.0
6.0
6.0
72
91
86
H
H
CO2H
O
NO2
N
Ph
PMP
H
H
CO2H
OMe
O
N
10
3,4-(MeO)2C6H3
4j
H
OMe
OMe
H
CO2H
O
Ph
N
11
12
4-ClC6H4
2-thienyl
2e
2f
(CH2)2Ph
3f
4k
4l
6.0
5.5
92
84
H
H
CO2H
OMe
O
Ph
H
N
Ph
3a
S
H
CO2H
a All products were characterized by 1H NMR and IR spectroscopy, and mass spectrometry.
b Yields refer to pure products after column chromatography.
of samples in CDCl3 were recorded on Gemini-200 and Varian
Bruker-300 spectrometers using TMS as internal standard. Mass
spectra were recorded on a Finnigan MAT 1020 mass spectrometer
operating at 70 eV.
In summary, molecular iodine was proved to be a useful
and novel catalyst for the synthesis of cis-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic acids by the three-
component coupling of aldehydes, amines, and homo-
phthalic anhydride under mild and neutral conditions. The
experimental procedure is simple and convenient and the
reaction conditions are amenable to scale-up. This method
provides an easy access to highly substituted 1-oxo-
1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids with
diverse chemical structures.
cis-1-Oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids 4;
General Procedure
A mixture of aldehyde 2 (1 mmol), amine 3 (1 mmol), homophthalic
anhydride (1; 1 mmol), and I2 (10 mol%) in CH2Cl2 (5 mL) was
stirred at 23 °C for the specified amount of time (Table 1). After
completion of the reaction as indicated by TLC, the reaction mix-
ture was quenched with H2O (10 mL) and extracted with EtOAc
(2 × 10 mL). The combined organic layers were washed with aq
Na2S2O3 (2 × 10 mL) and brine (2 × 10 mL) and dried over anhyd
Na2SO4. Removal of the solvent followed by purification by column
chromatography (silica gel, Merck, 100–200 mesh, EtOAc–hexane,
Melting points were recorded on a Buchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr discs. 1H and 13C NMR spectra
Synthesis 2007, No. 20, 3191–3194 © Thieme Stuttgart · New York

3194
J. S. Yadav et al.
PAPER
0.5–9.5) gave the pure cis-acid 4. All the products thus obtained
were characterized by IR, NMR, and mass spectroscopy, and as all
products 4 have been reported in the literature, the spectroscopic
data were compared and found to be consistent with authentic sam-
ples.12 Spectral data for selected products are given below.
Acknowledgment
A.R.R. thanks CSIR New Delhi for the award of a fellowship.
References
1-Oxo-2,3-diphenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxyl-
ic Acid (4a)
White solid; mp 198 °C.
IR (KBr): 3035, 1723, 1635, 1496, 1223, 1025, 771, 698 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.86 (d, J = 6.0 Hz, 1 H), 5.41 (d,
J = 6.0 Hz, 1 H), 7.10 (m, 8 H), 7.39 (m, 3 H), 7.71 (d, J = 8.0 Hz,
1 H), 8.19 (dd, J = 2.1, 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 171.2, 163.4, 139.5, 137.2, 136.2,
135.8, 132.7, 129.7, 129.1, 128.9, 128.4, 128.1, 126.7, 65.5, 49.6.
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2-Benzyl-3-(4-methoxyphenyl)-1-oxo-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylic Acid (4i)
White solid; mp 197 °C.
IR (KBr): 3441, 1740, 1619, 1511, 1258, 1169, 1021, 831, 750
cm–1.
1H NMR (200 MHz, CDCl3): d = 3.61 (d, J = 14.0 Hz, 1 H), 3.76 (s,
3 H), 4.79 (d, J = 6.0 Hz, 1 H), 5.86 (d, J = 6.0 Hz, 1 H), 5.69 (d,
J = 14.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 2
H), 7.20–7.36 (m, 6 H), 7.59–7.61 (m, 2 H), 8.24 (dd, J = 2.0, 8.0
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 169.6, 162.6 158.4, 136.1, 132.1,
130.8, 128.1, 127.6, 127.1, 126.9, 126.4, 126.1, 112.6, 59.1, 54.1,
47.1.
MS (EI, 70 eV): m/z = 387 [M+], 381, 282, 237, 226, 165, 134, 121,
91, 77, 65.
3-(4-Methoxyphenyl)-1-oxo-2-phenethyl-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylic Acid (4k)
White solid; mp 166 °C.
IR (KBr): 3033, 2930, 1725, 1625, 1511, 1470, 1251, 1170, 1032,
760, 703 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.89–3.05 (m, 4 H), 3.71 (s, 3 H),
4.41 (d, J = 5.7 Hz, 1 H), 4.79 (d, J = 5.7 Hz, 1 H), 6.64 (d, J = 8.0
Hz, 2 H), 6.90 (d, J = 8.0 Hz, 2 H), 7.26–7.62 (m, 8 H), 8.21 (dd,
J = 8.0, 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 170.4, 162.6 159.1, 139.1, 133.6,
131.8, 128.9, 128.5, 128.1, 127.9, 127.4, 127.1, 126.3, 113.6, 61.1,
55.1, 48.1, 47.5, 33.6.
MS–FAB: m/z = 401 [M+], 356, 337, 255, 238, 162, 152, 132, 118,
107, 93, 77, 65, 43.
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Synthesis 2007, No. 20, 3191–3194 © Thieme Stuttgart · New York