KAL(SO4)2·12H2O: An efficient catalyst for the stereoselective synthesis of cis-isoquinolonic acids

Article abstract of DOI:10.3987/COM-04-10121

KAl(SO₄)_2·12H₂O is found to catalyze efficiently the stereoselective cyclocondensation of homophthlic anhydride with imines under mild conditions to afford the corresponding cis-isoquinolonic acids in good yields.

Full text of DOI:10.3987/COM-04-10121

HETEROCYCLES, Vol. 63, No. 9, 2004, pp. 2013 - 2017
Received, 17th May, 2004, Accepted, 30th July, 2004, Published online, 3rd August, 2004
KAL(SO4)2.12H2O: AN EFFICIENT CATALYST FOR THE
STEREOSELECTIVE SYNTHESIS OF CIS-ISOQUINOLONIC
ACIDS
Javad Azizian,* Ali A. Mohammadi, Ali R. Karimi, Mohammad R.
Mohammadizadeh, and M. Koohshari
Department of Chemistry, Faculty of Science, Shahid Beheshti University, P. O.
Box 19395-4716, Tehran, Iran, E-mail: j-azizian@cc.sbu.ac.ir
Abstract – KAl(SO4)2.12H2O is found to catalyze efficiently the stereoselective
cyclocondensation of homophthlic anhydride with imines under mild conditions
to afford the corresponding cis-isoquinolonic acids in good yields.
Isoquinolonic acids have been reported as starting materials for the total synthesis of natural compounds
such as nitidine chloride,1 4-epicorynoline, corynoline, 6-oxocorynoline2 and decumbenine B.3 In addition,
isoquinolonic acids show some pharmacological and biological activities4 including anti-inflammatory
and psychotropic.
There exist numerous methods for the synthesis of isoquinolonic acids and their derivatives.5 By various
catalysts such as Lewis acids (ZnCl2, FeCl3, AlCl3), protic acids (CH3COOH, HCl), or bases (TEA,
DIEA) etc., a mixture of cis- and trans- products or complicated mixtures were formed. Recently,
BF3-Et2O6 and trimethyl orthoformate7 have been employed for the preparation of trans-isoquinolonic
acids, and ionic liquids8 have been employed for the synthesis of cis-isomers.
In view of our general interest in the chemistry of imines,9 we wish to report the stereoselective synthesis
of cis-isoquinolonic acids. In this direction, the use of a KAl(SO4)2.12H2O (alum), which is relatively
nontoxic and inexpensive, is the center of our study.10 In the course of our research on application of
KAl(SO4)2.12H2O in organic reactions, we have found that alum was an effective promoter in the
preparation of cis-isoquinolonic acids.
When a mixture of homophthalic anhydride (1) and imine11 (2a) in acetonitrile was stirred at rt in the
presence of a catalytic amount (0.5 equiv. mol) of alum, the reaction was completed within 8 h. Work-up
of the reaction mixture showed that isoquinolonic acid (3a) was prepared in 91% yield (Scheme 1).

Interestingly, we have found that this reaction is highly stereoselective in the preparation of
cis-isoquinolonic acid, since there is no evidence for the formation of trans-diasteroisomer (4).
O
R1
N
O
R
O
Alum
R1 N
C
H
R
3a-m
CO2H
R1
MeCN/rt
O
O
1
2a-m
N
R
Scheme 1
4
CO2H
Promoted by this success, we extended this reaction of homophthalic anhydride with a range of other
imines (2b-i) under similar conditions, furnishing the respective cis-isoquinolonic acids (3b-i) in good
yields. The optimized results are summarized in Table 1. The all cis-stereochemistry of cycloadducts (3)
was attributed from the two doublets (J=4.6-6.9 Hz) observed close to 4.52-4.99 ppm and 4.96-5.97 ppm,
for the H-3 and H-4 hydrogen’s, respectively.
1
13
The structures of the products were characterized by IR, H NMR, C NMR spectra, MS spectra, and
elemental analyses.
Table 1. Alum-catalyzed reaction of homophthalic anhydride with imines
a
Product
3
R
R1
Time
(h)
mp
Lit.
mp
Yield
(%)
91
89
90
87
89
86
87
A
B
C
D
E
F
G
H
Ph
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
PhCH2
6.5
6
6
7
8
8
8.5
7
201-203
200-201
187-188
179-180
180-181
1988
1828
1788
Ph
-
-
-
-
-
-
4-ClC6H4
Ph
PhCH2
PhCH2CH2
2-Benzimidazolyl
4-MeC6H4
4-ClC6H4
168-170
Ph
222-224 (decomp)
246-248 (decomp)
225-226 (decomp)
4-NO2C6H4
4-BrC6H4
86
85
I
7.5
a
Yields based on homophthalic anhydride.
In summary, we have described a successful strategy, efficient and convenient green synthesis for the
preparation of tetrahydroisoquinolonic acids in cyclocondensation reaction of homophthalic anhydride
with imines using the inexpensive, non-toxic, and easily available KAl(SO4)2.12H2O catalyst. The
method offers several advantages including high yield of products, recyclable of the catalyst and easy
experimental work-up procedure. Surprisingly, this reaction is stereoselective in the preparation of
cis-isoquinolonic acids, since no detectable amount of trans-isomers, which makes it a useful process for
the synthesis of cis-isoquinolonic acids.

EXPERIMENTAL
Melting points were measured on the Electrothermal 9100 apparatus and are uncorrected. IR spectra were
measured on a Shimadzu IR-470 Spectrophotometer. 1H NMR and 13C NMR spectra were determined on
a bruker 500 DRX AVNCE instrument at 500 and 125 MHz, respectively. MS spectra were recorded on a
Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental
analyses were performed using a Heracus CHN-O-Rapid analyzer.
General procedure: A mixture of homophthalic anhydride (162 mg, 1 mmol), imines (1 mmol), alum
(0.24 g, 0.5 mmol), and acetonitrile (8-10 mL) in a 25 mL flask was stirred at rt for the time period as
indicated in Table 1. After completion of the reaction (monitored by TLC, ethyl acetate/n-hexane 1/1), the
solvent was evaporated under reduced pressure, then water (25 mL) was added to the reaction mixture
and the resulting solid was separated by filtration. The crude product was washed with chloroform and
ether to afford pure cis-isoquinolonic acids in 82-94% yields.
General procedure for recovered catalyst: The catalyst in the aqueous phase can be recovered by
removing the water under vacuum then washed with acetone and drying at rt.
Spectral data for new product:
cis-2-Benzyl-1-oxo-3-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxlic acid (3d): White powder, IR
(KBr), (νmax /cm-1): 3025, 2910, 1742, 1613. 1H NMR (DMSO-d6) δH: 3.75 (d, 1H, J=15.3 Hz, CH2), 4.69
(d, 1H, J=6.0 Hz, H3), 4.96 (d, 1H, J=6.0 Hz, H4), 5.31 (d, 1H, J=15.3 Hz, CH2), 6.96-7.57 (m, 13H),
13
8.08 (d, 1H, J=7.5 Hz), 12.99 (br, 1H). C NMR (DMSO-d6) δC: 48.55, 48.57, 61.18, 127.69, 127.93,
127.97, 128.03, 128.25, 128.50, 128.75, 129.01, 129.18, 132.52, 134.15, 137.79, 163.59, 170.72. MS
(m/z, %): 358 (M++1, 25), 357 (35), 269 (30), 207 (25), 136 (30), 118 (80), 116 (75), 91 (100), 77 (35), 62
(30), 51 (35), 39 (30). Anal. Calcd for C23H19NO3: C, 77.29; H, 5.36; N, 3.92. Found: C, 77.20; H, 5.27;
N, 3.83.
cis-2-Benzyl-3-(4-chlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxlic acid (3e): White
powder, IR (KBr), (νmax /cm-1): 3050, 2905, 1737, 1608. 1H NMR (DMSO-d6) δH: 3.83 (d, 1H, J=15.3 Hz,
CH2), 4.70 (d, 1H, J=6.2 Hz, H3), 4.99 (d, 1H, J=6.2 Hz, H4), 5.24 (d, 1H, J=15.3 Hz, CH2), 6.94-7.55
(m, 13H), 8.07 (d, 1H, J=7.5 Hz), 13.02 (br, 1H). 13C NMR (DMSO-d6) δC: 48.52, 48.72, 60.55, 127.69,
128.03, 128.10, 128.49, 128.71, 128.97, 129.03, 130.08, 132.65, 133.39, 133.91, 136.24, 137.67, 163.46,
170.69. MS (m/z, %): 391 (M+, 15), 347 (40), 242 (40), 207 (30), 178 (35), 118 (45), 106 (45), 91 (100),
65 (50), 51 (30), 39(30). Anal. Calcd for C23H18NO3Cl: C, 70.50; H, 4.63; N, 3.57. Found: C, 70.43; H,

4.54; N, 3.514.54; N, 3.51.
cis-1-Oxo-2-phenylethyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxlic acid (3f): White
1
powder, IR (KBr), (νmax /cm-1): 3025, 2910, 1738, 1614. H NMR (DMSO-d6) δH: 2.67 (m, 1H, CH2),
2.86-2.92 (m, 1H, CH2), 2.98-3.04 (m, 1H, CH2), 4.01-4.06 (m, 1H, CH2), 4.52 (d, 1H, J=6.2 Hz, H3),
4.98 (d, 1H, J=6.2 Hz, H4), 6.97 (d, 2H, J=6.2 Hz), 7.16-7.19 (m, 6H), 7.25-7.28 (m, 2H), 7.41-7.44 (m,
1H), 7.49 (m, 2H), 8.02 (d, 1H, J=6.8 Hz), 12.91 (br, 1H). 13C NMR (DMSO-d6) δC: 34.05, 48.14, 48.45,
62.00, 126.73, 127.70, 127.84, 128.24, 128.34, 128.63, 128.67, 128.89, 129.08, 129.40, 132.31, 134.06,
137.74, 139.54, 163.13, 170.79. MS (m/z, %): 371 (M+, 10), 353 (15), 327 (25), 280 (35), 236 (80), 221
(30), 207 (60), 174 (40), 146 (25), 118 (40), 91 (100), 92 (30), 65 (30), 51 (30), 44 (30), 39(25). Anal.
Calcd for C24H21NO3: C, 77.60; H, 5.70; N, 3.77. Found: C, 77.51; H, 5.64; N, 3.67.
cis-2-(2-1H-Benzoimidazolyl)-1-oxo-3-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxlic acid (3g):
1
White powder, IR (KBr), (νmax /cm-1): 3060, 2915, 1700, 1657. H NMR (DMSO-d6) δH: 4.61 (d, 1H,
J=6.5 Hz, H3), 5.96 (d, 1H, J=6.5 Hz, H4), 7.29-7.43 (m, 7H), 7.47-7.57 (m, 3H), 7.60 (m, 1H), 7.65 (d,
13
1H, J=7.7 Hz), 8.03 (d, 1H, J=7.6 Hz), 12.53 (br, 1H). C NMR (DMSO-d6) δC: 49.19, 79.08, 80.35,
124.91, 126.27, 127.28, 128.08, 128.21, 128.72, 128.93, 128.98, 129.02, 129.23, 129.83, 130.22, 134.40,
134.85, 137.26, 137.97, 163.97, 171.58. MS (m/z, %): 383 (M+, 10), 368 (20), 313 (15), 250 (35), 178
(35), 118 (100), 105 (60), 90 (95), 77 (75), 63 (55), 51 (65), 39(45). Anal. Calcd for C23H17N3O3: C,
72.05; H, 4.47; N, 10.96. Found: C, 71.91; H, 4.40; N, 10.87.
cis-3-(4-Nitrophenyl)-1-oxo-2-p-tolyl-1,2,3,4-tetrahydroisoquinoline-4-carboxlic acid (3h): White
powder, IR (KBr), (νmax /cm-1): 3065, 2915, 1723, 1630, 1598. 1H NMR (DMSO-d6) δH: 2.23 (s, 3H, CH3),
4.99 (d, 1H, J=5.1 Hz, H3), 5.97 (d, 1H, J=5.1 Hz, H4), 7.09 (m, 4H), 7.31 (d, 2H, J=8.2), 7.49-7.61 (m,
13
3H), 8.03 (d, 2H, J=8.2 Hz), 8.08 (d, 1H, J=7.2 Hz), 12.52 (br, 1H). C NMR (DMSO-d6) δC: 48.74,
63.40, 123.04, 127.15, 127.43, 127.73, 127.83, 129.10, 129.27, 132.38, 136.01, 138.59, 144.92, 146.95,
162.68, 170.20. MS (m/z, %): 402 (M+, 10), 383 (15), 356 (50), 295 (40), 252 (25), 240 (50), 193 (30),
165 (20), 118 (70), 106 (100), 90 (60), 77 (30), 63 (35), 51 (30), 39 (50). Anal. Calcd for C23H18N2O5: C,
68.65; H, 4.51; N, 6.96. Found: C, 68.59; H, 4.47; N, 6.87.
cis-3-(4-Bromophenyl)-2-(4-chlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxlic
acid
(3i): White powder, IR (KBr), (νmax /cm-1): 3065, 2920, 1723, 1630. 1H NMR (DMSO-d6) δH: 4.86 (d, 1H,
J=4.9 Hz, H3), 5.54 (d, 1H, J=4.9 Hz, H4), 6.94-6.99 (m, 4H), 7.20-7.28 (m, 4H), 7.36-7.59 (m, 5H), 8.05
(d, 1H, J=7.5 Hz), 2.43 (br, 1H). 13C NMR (DMSO-d6) δC: 48.87, 63.17, 127.57, 127.68, 127.81, 128.48,
128.57, 128.96, 129.21, 129.99, 130.81, 131.00, 132.45, 134.11, 136.40, 139.38, 162.80, 170.24. MS

(m/z, %): 456 (M++1, 15), 412 (55), 345 (50), 301 (60), 267 (45), 257 (35), 223 (25), 193 (30), 178 (20),
118 (60), 106 (100), 90 (50), 77 (35), 63 (30), 51 (30), 39 (55). Anal. Calcd for C22H15NO3BrCl: C,
57.86; H, 3.31; N, 3.07. Found: C, 57.78; H, 3.22; N, 2.98.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the Research Council of Shahid Beheshti
University.
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