An expedient method to the synthesis of N-substituted 1H-isoindole-1,3(2H)- diones

Article abstract of DOI:10.3987/COM-08-11383

The synthesis of N-substituted 1H-isoindole-1,3-(2H)-diones is described from the reaction of cyclic anhydrides with Schiff bases as suitable replacing substrates instead of the corresponding amines. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11383

HETEROCYCLES, Vol. 75, No. 9, 2008
2289
HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2289 - 2292. © The Japan Institute of Heterocyclic Chemistry
Received, 8th March, 2008, Accepted, 24th April, 2008, Published online, 28th April, 2008. COM-08-11383
AN EXPEDIENT METHOD TO THE SYNTHESIS OF N-SUBSTITUTED
1H-ISOINDOLE-1,3(2H)-DIONES
Farzad Nikpour* and Baran Mohammadi Mogaddam
Department of Chemistry, Faculty of Sciences, University of Kurdistan, P.O. Box
66315-416, Sanandaj, Iran
Abstract – The synthesis of N-substituted 1H-isoindole-1,3-(2H)-diones is
described from the reaction of cyclic anhydrides with Schiff bases as suitable
replacing substrates instead of the corresponding amines.
Imines with an aryl or a benzyl group on nitrogen (Schiff bases), are stable to oxygen and water. They are
readily prepared and are promising starting materials in biologically important systems and hence attract
broad interest. Due to their diverse reactivity, imines are common substrates in a wide variety of
transformations. For example, they are used in synthesis of β-lactams,1 aziridines,2 1,2-amino alcohols,3
1,3-oxazolidines4 and cycloaddition reactions.5
It is possible to make the α-carbon of the aldehyde adds to the carbonyl carbon of the ketone, by using an
imine instead of an aldehyde.6 Furthermore, the reaction of imines with a wide range of carbon
nucleophiles7 has been known. To extend our previous works on the synthesis of five member cyclic
imides,8 here, we wish to report the use of Schiff bases as expedient substrates in the preparation of
N-substituted 1H-isoindole-1,3-(2H)-diones. We observed that in the presence of suitable electrophiles
such as cyclic anhydrides, imines can react as amine functional groups, by removing of the aldehydes or
the ketones in-situ without need to hydrolysis. The reaction procedure is simple, and the reaction
conditions are mild.9 The cyclic imides 3 are efficiently and rapidly formed from the reaction of cyclic
anhydrides 2 with Schiff bases 1 in EtOH or DMF without need to use any catalyst (Scheme 1). Results
are summarized in Table 1.
O
O
Y
EtOH, reflux
R
+
N Y
O
N
or
Ar
DMF, 70-80oC
O
X
X
O
1
2
3
Y= Ar', CH2Ph
Scheme 1

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HETEROCYCLES, Vol. 75, No. 9, 2008
Table 1. Reaction of Schiff bases 1 with cyclic anhydrides 2 in EtOH
Mp/oC
(lit.)
Ar
Y
R
2
Time/h
3
Yield /%a,b
95
O
O
O
N
a
b
c
d
e
f
p-ClPh
Ph
H
3
205-207
(205-20610)
O
O
O
O
Me
O
N
Ph
Ph
p-MePh
H
H
3
3
90
90
85
85
92
80
201-203
(201-20311)
O
O
O
O
O
N
CH2
PhCH2
116-118
(118.5-119.512)
O
O
O
O
O
N
CH2
Ph
PhCH2 Me
3
115-118
(118.5-119.512)
O
O
Br
Br
O
N
O
O
Br
Br
Br
Br
O
p-ClPh
Ph
H
1.5
1
277-279
(28013)
O
O
Br
Br
Br
Br
O
Br
Br
Br
Br
N
Br
O
p-MePh p-BrPh Me
>250
(>38013)
O
O
Br
NO2
NO2
Br
O
O
O
Me
N
g
Ph
Ph
p-MePh
H
H
3
152-154
O
(155-15614)
O
NO2
O
O
O
N
CH2
h
PhCH2
3
85
140-142
O
(142-14314)
O
NO2
O
N
O
O
O
i
j
Ph
Ph
Ph
Ph
H
H
H
1.5
3
75
80
95
>250
HO2C
HO2C
O
O
(>26015)
O
N
CH2
O
PhCH2
198-201
HO2C
Me
HO2C
Me
(200-20215)
O
O
O
O
k
p-MePh
4
-
N
Me
O
O
O
a The products were identified and characterized by their physical and spectral data and comparison of them with
those of authentic samples. b Isolated yield.
This strategy can be suitable, particularly, in the presence of sensitive substituents which may react with
amines (Table 1, 2i and 2j). Also, some aromatic amines, especially those containing electron donating

HETEROCYCLES, Vol. 75, No. 9, 2008
2291
substituents are unstable and are easily oxidized or polymerized and purification of them is a tedious
effort. However, the use of Schiff bases instead of the mentioned amines is more suitable.
The proposed mechanism is shown in Scheme 2. It is reasonable to assume that 3 results from an initial
addition of Schiff base 1 to the anhydride 2 and subsequent cyclization of the unstable intermediate 4 to
the intermediate 5. Recyclization of 5 under the reaction conditions employed leads to the cyclic imides 3
with removing of the corresponding aryl aldehyde or aryl ketone.
O
O
Y
O
Y
O
+
-
N
O
N
Y
R
R
R
N
Y
O
N
+
- Ar-CO-R
Ar
Ar
X
O
Ar
X
X
O
X
O
O
O
5
1
2
4
3
Y= Ar', CH2Ph
Scheme 2
In conclusion, stable imines to hydrolysis (Schiff bases) are proposed as masked amines in the synthesis
of N-substituted 1H-isoindole-1,3-(2H)-diones. The reactions are carried out under mild reaction
condition without need to use any catalysts. Good to high yields of the products are obtained with easy
work-up. The use of Schiff bases as suitable replacing substrates instead of the corresponding amines is
an improvement over previous methods.
ACKNOWLEDGEMENTS
We are thankful to the University of Kurdistan Research Council for the partial support of this work.
REFERENCES AND NOTES
1. (a) M. R. Linder and J. Podlech, Org. Lett., 2001, 3, 1849. (b) M. Shindo, S. Oya, Y. Sato, and K.
Shishido, Heterocycles, 1998, 49, 113.
2. (a) S. Nagayama and S. Kobayashi, Chem. Lett., 1998, 685. (b) W. W. Liao, X. M. Deng, and Y.
Tang, Chem. Commun., 2004, 1516.
3. D. Guijarro and M. Yus, Tetrahedron, 1993, 49, 7761.
4. S. H. Lee and Y. H. Kim, Bull. Korean Chem. Soc., 2005, 26, 225.
5. (a) P. Buonora, J. C. Olsen, and T. Oh, Tetrahedron, 2001, 57, 6099. (b) C. Hedberg, P. Pinho, P.
Roth, and P. G. Andersson, J. Org. Chem., 2000, 65, 2810. (c) J. S. Sandhu and B. Sain,
Heterocycles, 1987, 26, 777.

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HETEROCYCLES, Vol. 75, No. 9, 2008
6. T. Mukaiyama, Org. React., 1982, 28, 203.
7. (a) G. K. Friestad and A. K. Mathies, Tetrahedron, 2007, 63, 2541. (b) S. Kobayashi and H. Ishitani,
Chem. Rev., 1999, 99, 1069.
8. (a) F. Nikpour, S. Kazemi, and D. Sheikh, Heterocycles, 2006, 68, 1559. (b) M. S. Khajavi, F.
Nikpour, and M. Hajihadi, J. Chem. Res. (S), 1996, 96.
9. General reaction procedure: In a 10 mL round flask, 1 mmol of 1 was dissolved in 2 mL of EtOH.
To this solution, 1 mmol of cyclic anhydrides 2 was added and the mixture was refluxed for the
times as indicated in Table 1. Then, the solvent was removed under reduced pressure and the residue
was washed with cold MeOH and dried in air. For more purification, the products were crystallized
from MeOH or EtOH.
Note: Because of the imine-enamine equilibrium, the aldehydes that are used in the synthesis of the
imines 1 (Ar groups) should not have C-Hα, therefore, aliphatic aldehydes are not suitable here. Also,
due to the steric hindrance and the enamine formation, the R groups larger than methyl, are not
suitable in this synthesis route.
Compound 3k: IR (Liquid film):
(cm-1) = 1772, 1704; 1H NMR (250 MHz, CDCl3): δ (ppm) =
7.12 (d, 3JHH = 8.2 Hz, 2H, Ar-H), 6.97 (d, 3JHH = 8.2 Hz, 2H, Ar-H), 5.83 (bs, 1H, =CH), 3.43-3.40
(m, 2H, 2CH), 2.88-2.85 (m, 2H, 2CH), 1.83 and 1.81 (2s, 6H, 2CH3), 1.65-1.43 (m, 2H, CH2); 13C
NMR (62.9 MHz, CDCl3): δ (ppm) = 178.6, 177.5, 148.0, 132.1, 129.8, 127.1, 126.4, 126.2, 50.2,
49.6, 47.2, 45.7, 42.5, 16.6, 15.3; EI-MS (70 eV): m/z (%) = 267 (M+·, 18).
10. M. J. Hearn and L. E. Lucas, J. Heterocycl. Chem., 1984, 21, 615.
11. P. L. Alvarado, C. Avendaño, and J. C. Menéndez, J. Org. Chem., 1996, 61, 5865.
12. P. Y. Reddy, S. Kondo, T. Toru, and Y. Ueno, J. Org. Chem., 1997, 62, 2652.
13. D. S. Pratt and C. O. Young, J. Am. Chem. Soc., 1918, 40, 1415.
14. J. W. Alexander and S. M. McElvain, J. Am. Chem. Soc., 1938, 60, 2286.
15. M. Dabiri, P. Salehi, M. Baghbanzadeh, M. Shakouri, S. Otokesh, T. Ekrami, and R. Doosti, J. Iran.
Chem. Soc., 2007, 4, 393.