A stereoselective three-component reaction: KAl(SO4) 2·12H2O, an efficient and reusable catalyst for the one-pot synthesis of cis-isoquinolonic acids

Article abstract of DOI:10.1021/jo049138g

(Chemical Equation Presented). KAl(SO₄)₂· 12H₂O is found to catalyze efficiently the stereo-selective one-pot three-component cyclocondensation of homophthalic anhydride, aldehydes, and amines under mild conditions to afford the corresponding cis-isoquinolonic acids in good yields.

Full text of DOI:10.1021/jo049138g

A Stereoselective Three-Component
SCHEME 1. Synthesis of the cis-Isoquinolonic
Acids 4a-m
Reaction: KAl(SO
4
)
2
‚12H O, an Efficient
2
and Reusable Catalyst for the One-Pot
Synthesis of cis-Isoquinolonic Acids
Javad Azizian,* Ali A. Mohammadi, Ali R. Karimi, and
Mohammad R. Mohammadizadeh
Department of Chemistry, Faculty of Science, Shahid
Beheshti University, P.O. Box 19395-4716, Tehran, Iran
8
isoquinolonic acids, and ionic liquids have been employed
for the synthesis of cis isomers.
Multicomponent condensations (MCCs) constitute an
especially attractive synthetic strategy for rapid and
efficient library generation due to the fact that the
products are formed in a single step and the diversity
can be achieved simply by varying the reacting compo-
nents. Very recently, we have reported the preparation
j-azizian@cc.sbu.ac.ir
Received May 22, 2004
9a
9b
of quinazolinediones, γ-spiroiminolactones, and pyr-
roles9 via multicomponent reactions. Along this line, we
have designed the stereoselective three-component one-
step synthesis of cis-isoquinolonic acids. In this direction,
c
the use of a KAl(SO
nontoxic and inexpensive, is the center of our study. In
the course of our research on application of KAl(SO
2H O in organic reactions, we have found that alum was
an effective promoter in the preparation of cis-isoquino-
lonic acids.
4
)
2
‚12H
2
O (alum), which is relatively
1
0
4 2
) ‚
KAl(SO4)2‚12H2O is found to catalyze efficiently the stereo-
selective one-pot three-component cyclocondensation of ho-
mophthalic anhydride, aldehydes, and amines under mild
conditions to afford the corresponding cis-isoquinolonic acids
in good yields.
1
2
When a mixture of homophthalic anhydride 1, aniline
a, and benzaldehyde 3a in acetonitrile was stirred at
2
rt in the presence of a catalytic amount of alum, the
reaction was completed within 8 h. Workup of the
reaction mixture showed that isoquinolonic acid 4a was
prepared in 88% 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 stereoisomers.
After screening a small number of Lewis acids (L.A.),
it has been found that alum promotes the reaction of
homophthalic anhydride, benzaldehyde, and aniline to
afford the cis-isoquinolonic acid scaffold in very good
results (Table 1).
Encouraged by this success, we extended this reaction
of homophthalic anhydride with a range of other amines
2b-m and aldehydes 3b-m under similar conditions,
furnishing the respective cis-isoquinolonic acids 4b-m
in good yields. The optimized results are summarized in
Table 2. The all-cis stereochemistry of cycloadducts 4 was
attributed from the two doublets (J ) 4.6-6.9 Hz)
observed close to 4.52-4.99 and 4.96-5.97 ppm for the
H-3 and H-4 hydrogens, respectively.
Isoquinolonic acids have been reported as starting
materials for the total synthesis of natural compounds
1
such as nitidine chloride, 4-epicorynoline, corynoline,
2
3
6
-oxocorynoline, and decumbenine B. In addition, iso-
quinolonic acids show some pharmacological and biologi-
cal activities including antiinflammatory and psycho-
4
tropic.
There exist numerous methods for the synthesis of
5
isoquinolonic acids and their derivatives. By various
catalysts such as Lewis acids (ZnCl
acids (CH COOH, HCl), or bases (TEA, DIEA), etc., a
mixture of cis and trans products or complicated mixtures
2 3 3
, FeCl , AlCl ), protic
3
6
were formed. Recently, BF
3
‚Et
2
O and trimethyl ortho-
7
formate have been employed for the preparation of trans-
(
1) Cushman, M.; Cheng, L. J. Org. Chem. 1978, 43, 286-288.
2) Cushman, M.; Abbaspour, A.; Gupta, Y. P. J. Am. Chem. Soc.
(
1
983, 105, 2873-2879.
(
3) Xu, X. Y.; Qin, G. W.; Xu, R. S.; Zhu, X. Z. Tetrahedron 1998,
4, 14179-14188.
4) (a) Johnson, J. V.; Rauckman, S.; Baccanari, P. D.; Roth, B. J.
5
(
Med. Chem. 1989, 32, 1942-1949. (b) Stanoeva, E.; Haimova, M. Khim.
Geterotsikl. Soedin. 1984, 1587-1589. (c) Haimova, M. A.; Mollov, N,
M.; Ivanova, S. C.; Dimitrova, A. I.; Ognyanov, V. I. Tetrahedron 1977,
(8) Yadav, J. S.; Reddy, B. V. S.; Saritha Raj, K.; Prasad, A. R.
Tetrahedron 2003, 59, 1805-1809.
(9) (a) Azizian, J.; Mohammadi, A. A.; Karimi, A. R. Synth. Commun.
2003, 33, 415-420. (b) Azizian, J.; Karimi, A. R.; Mohammadi, A. A.
Synth. Commun. 2003, 33, 387-391. (c) Azizian, J.; Karimi, A. R.;
Arefrad, H.; Mohammadi, A. A.; Mohammadizadeh, M. R. Molecular
Diversity 2003, 6, 223-226.
(10) Azizian, J.; Mohammadi, Ali, A.; Karimi, Ali R.; Mohammad-
izadeh, M. R. J. Chem. Res., in press. (c) 6th International Symposium
on Catalysis Applied to Fine Chemicals, April 6-10, 2003, Delft
University of Technology, The Netherlands. (c) 10th Blue Danube
Symposium on Heterocyclic Chemistry, Sept 3-6, 2003, Vienna,
Austria.
3
3, 331-336. (d) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umeu, K.
Biochem. Pharmacol. 1992, 44, 1211-1213.
(
5) (a) Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907-
9
4
15. (b) Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977,
2, 1111-1116. (c) Bonnaud, B.; Carlessi, A.; Bigg, D. C. H. J.
Heterocycl. Chem. 1993, 30, 257-265. (d) Haimova, M. A.; Mollov, N.
M.; Ivanova, S. C.; Dimitrova, A. I.; Ognyanov, V. I. Tetrahedron 1977,
3
3, 331-336. (e) Stoyanova, M. P.; Kozekov, I. D.; Palamareva, M. D.
J. Heterocycl. Chem. 2003, 40, 795-803.
(
6) Yu, N.; Bourel, L.; Deprez, B.; Gesquiere, J. C. Tetrahedron Lett.
998, 39, 829-832.
7) Yu, N.; Poulain, R.; Gesquiere, J. C. Synlett 2000, 355-356.
1
(
10.1021/jo049138g CCC: $30.25 © 2005 American Chemical Society
350
J. Org. Chem. 2005, 70, 350-352
Published on Web 12/09/2004

TABLE 1. Screening of Lewis Acidsa
Lewis acidb
time (h)
yield (%)
c
LiCl
KCl
30
30
30
30
30
7
0
0
LiBr
0
KBr
0
30
88
NH4Al(SO4)2‚12H2O
KAl(SO4)2‚12H2O
a
Comparison effect of different Lewis acids on the reaction of
b
homophthalic anhydride 1, aniline 2a, and benzaldehyd 3a. For
c
all reactions, 0.5 mmol of Lewis acid was used. Isolated yields
based on homophthalic anhydride.
TABLE 2. Reaction of Homophthalic Anhydride,
Amines, and Aldehydesa
c
product
time yield
lit.
mp
b
R2
R1
4
(h)
(%)
mp
8
a
b
c
d
e
f
Ph
Ph
Ph
Ph
4-ClC
Ph
Ph
Ph
4-ClC
4-MeC
7
6.5
6
7.5
8
8.5
9
88
90
91
88
87
84
85
201-3
198
182
178
8
8
6
H
6
4
H
200-1
4
187-8
179-80
180-1
168-70
222-4 dec
PhCH
PhCH
PhCH
2
6
H
4
2
2
CH
2
g
2-benzimid-
azolyl
h
i
l
m
4-NO
4-BrC
3-ClC
2-BrC
2
C
6
H
H
6
H
H
4
4
4-MeC
6
H
4
7.5
7
8
8.5
86
89
87
81
246-8 dec
225-6 dec
210-1 dec
216-8
4-ClC
4-ClC
6
H
H
4
6
4
6
4
6
4
PhCH
2
a
All reactions were run with homophthalic anhydride (162 mg,
1
(
mmol), 1.2 mmol of aldehydes, 1 mmol of amines, and 0.24 g
b
0.5 mmol) of alum in (8-10 mL) of acetonitrile at rt. Prepared
c
according to Scheme 1. Yields based on homophthalic anhydride.
FIGURE 1. Proposed intermediates for the reaction: inter-
1
13
mediates 5 were isolated and characterized by IR, H and
C
NMR, and MS spectra and elemental analyses, but imines 6
were not detected.
Although never previously tested, we have found that
alum acts as a reusable Lewis acid to catalyze the
reaction of homophthalic anhydride, aldehydes, and
amines for the synthesis of cis-isoquinolonic acids in
acetonitrile.
It is noticeable that when the homophthalic anhydride
, amines 2a-m, and aldehydes 3a-m in the presence
1
of alum were stirred for within 1.5 h, in all cases the
reaction led to the formation of the intermediates 5 which
were isolated and characterized by spectroscopic methods
1
FIGURE 2. Comparison H NMR for 4b (a) after 1.5 h, (b)
after 4 h, and (c) after 6.5 h.
(
4
(
Figure 1). Furthermore, the continuation of reaction for
h led to a mixture of 4a-m and intermediates 5
monitored by TLC and spectroscopic methods), mean-
Notably, imines 6 were not detected in the above reaction
pathway.
According to the results, the reaction can be mecha-
nistically considered to proceed via the initial formation
of the intermediates 5 from homophthalic anhydride and
amines, and the noted reaction can be considered through
while after the times indicated in Table 2 just 4a-m were
obtained and the intermediates 5 were not detected in
the final mixture (Figure 2, Supporting Information).
J. Org. Chem, Vol. 70, No. 1, 2005 351

SCHEME 2. Mechanism of the Alum-Catalyzed
Reaction of Homophthalic Anhydride, Amines, and
Aldehydes for Preparation of cis-Isoquinolonic
Acids 4a
The structures of the products were characterized by
IR, H NMR, C NMR, and MS spectra and elemental
analyses.
In summary, we have described a successful strategy,
an efficient and convenient green synthesis for the
preparation of tetrahydroisoquinolonic acids in three-
component cyclocondensation reaction of homophthalic
anhydride, aldehydes, and amines using the inexpensive,
1
13
nontoxic, and easily available KAl(SO
4 2 2
) ‚12H O catalyst.
The method offers several advantages including high
yield of products, recyclables of the catalyst, and easy
experimental workup procedure. Surprisingly, this reac-
tion is stereoselective in the preparation of cis-isoquino-
lonic acids, since there is no detectable amount of trans
stereoisomers, which makes it a useful process for the
synthesis of cis-isoquinolonic acids.
Experimental Section
Representative Procedure: Compound 4a. A mixture of
homophthalic anhydride (162 mg, 1 mmol), benzaldehyde (0.12
mL, 1.2 mmol), aniline (0.09 mL 1 mmol), and alum (0.24 g, 0.5
mmol) in acetonitrile (8-10 mL) in a 25 mL flask was stirred at
rt for about 7 h. After completion of the reaction (monitored by
TLC, ethyl acetate/n-hexane 1/1), the solvent was evaporated
under reduced pressure, water (25 mL) was added to the reaction
mixture, and the resulting solid was separated by filtration. The
crude product was washed with chloroform (2 × 3 mL) and
diethyl ether (2 × 5 mL) to afford the product: white powder;
a
Key: (a) by initial reaction of aldehyde with a methylene
group; (b) by initial reaction of aldehyde with the amine N-atom.
two separate approaches which end in the same result.
The former reaction followed by reaction with aldehydes
in the presence of alum gives the intermediate 7 via a
cyclic transition state (a six-membered, cyclic Zimmer-
man-Traxler model).11 Once intermediate 7 is formed,
a nucleophilic attack takes place by the nitrogen group
in conformity with Baldwin’s rules and then elimination
of HO-Alum and the final product produce (Scheme 2,
route a). The later explain that the aldehyde attacks the
-
1
yield 88% (302 mg); mp 201-3 °C; IR (KBr), (νmax/cm ) 3020,
1
2
915, 1723, 1633; H NMR (CD
Hz, H ), 5.49 (d, 1H, J ) 6.9 Hz, H
.60 (m, 3H), 8.07 (d, 1H, J ) 8.7 Hz), 12.04 (broad, 1H);
3
SOCD
4
3 H
) δ 4.94 (d, 1H, J ) 6.9
3
), 7.01-7.30 (m, 10H), 7.57-
13
7
C
3 3 C
NMR (CD SOCD ) δ 49.5, 65.1, 126.6, 128.1, 128.2, 128.3, 128.4,
12
128.4, 128.6, 129.4, 129.6, 132.6, 135.9, 136.1, 137.3, 139.5, 163.2,
-
+
171.1; MS (m/z) 343 (M , 75), 298 (30), 207 (25), 181 (100), 134
(
45), 118 (35), 105 (35), 90 (25), 77 (80), 63 (35), 51 (50), 39 (35).
Anal. Calcd for C22
C, 76.78; H, 4.90; N, 4.00.
3
H17NO : C, 76.95; H, 4.99; N, 4.08. Found:
amine N-atom to form an intermediate N-acyliminium
cation 8, which then attacks the methylene group to
form the final ring (Scheme 2, route b).
1
3
Acknowledgment. We gratefully acknowledge fi-
nancial support from the Research Council of Shahid
Beheshti University.
(
11) (a) Prabhat, A.; Huiping, Q. Tetrahedron 2000, 56, 917-947.
(
b) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1
920-1923. (c) Smite, M. B. In Organic Synthesis, 2nd ed.; Peterson,
K. A., Ed.; McGraw-Hill: New York, 2002; Chapter 9. (d) Carey, F.
A.; Sundberg, R. J. Advanced Organic Chemistry, 3rd ed.; 1993; Part
B, Chapter 2.
Supporting Information Available: General experimen-
1
13
tal procedures, IR, H and C NMR, and MS data, and
elemental analysis for compounds 4a-m, 5a,b, and a mixture
of 4b and 5b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
12) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-
36. (b) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman,
L.; Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736-738.
13) For preparation and reaction of N-acyliminium cation, see:
Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4416-85.
7
(
JO049138G
352 J. Org. Chem., Vol. 70, No. 1, 2005