An expedient and convenient approach for one-pot synthesis of 1H-isoindole-1,3(2H)-diones

Article abstract of DOI:10.1515/znb-2016-0060

An easy and expedient method for the one-pot synthesis of 1H-isoindole-1,3(2H)-diones has been developed by the reaction of the corresponding cyclic anhydrides with guanidinium chloride as a nitrogen source in the presence of FeCl₃ as a catalyst under mild reaction conditions.

Full text of DOI:10.1515/znb-2016-0060

Z. Naturforsch. 2016; 71(9)b: 941–944
Zeinab Ekhtiari, Forugh Havasi and Farzad Nikpour*
An expedient and convenient approach for one-pot
synthesis of 1H-isoindole-1,3(2H)-diones
DOI 10.1515/znb-2016-0060
benzonitrile, cyanate, thiocyanate, 4-N,N-dimethylamino-
pyridine (DMAP)/ammonium chloride, and ammonium
acetate under microwave irradiations has been reported
[28–31]. Catalysts such as carbonyldiimidazole, DMAP and
AlCl3 have also been used in order to increase the product
yields and/or reduce the reaction times [32, 33]. However,
many of these methods have drawbacks or limitations such
as the use of high temperature or microwave irradiation,
toxic catalysts, hazardous organic solvents and unclean-
Received March 10, 2016; accepted May 3, 2016
Abstract: An easy and expedient method for the one-pot
synthesis of 1H-isoindole-1,3(2H)-diones has been devel-
oped by the reaction of the corresponding cyclic anhy-
drides with guanidinium chloride as a nitrogen source
in the presence of FeCl3 as a catalyst under mild reaction
conditions.
Keywords: 1H-isoindole-1,3(2H)-diones; guanidinium smelling amines as a nitrogen source. Thus, in this research
chloride; heterocyclic transformation; one-pot synthesis; the reaction of some aliphatic and aromatic cyclic anhy-
phthalimides.
drides with guanidinium chloride as a nitrogen source was
used for the preparation of the corresponding cyclic imides.
1 Introduction
2 Results and discussion
Phthalimides as an important class of heterocyclic
compounds have gained considerable attention due to
their wide applications such as industrial [1, 2], biologi-
cal and pharmacological properties [3, 4] and also are
used as starting materials for further transformations in
design and synthesis of heterocyclic compounds [5–8].
Phthalimide analogues have been extensively used in
medicinal chemistry owing to their applications as anti-
microbial and anti-bacterial [9, 10], anti-virial [11], anti-
hypertensive [12], anti-fungal [13], anti-tumour [14, 15],
anxiolytic [16], anti-convulsant [17], hypolipidemic [18],
anti-inflammatory [19], immunomodulatory activities [20]
and anti-HIV-1 agents [21]. They are also useful chromo-
phores [22] due to their photophysical [23] and electro-
chemical characteristics [24].
Because the use of simple and readily available reagents
is a worthwhile effort in organic synthesis and with the
aim to extend synthetic methods in continuation of our
work on the synthesis of 1H-isoindole-1,3(2H)-diones [28,
34], we now disclose an easy and expedient approach
using guanidinium chloride as a good nitrogen source
and cyclic anhydrides in polyethylene glycol 400 (PEG-
400) and in the presence of FeCl3 as an inexpensive and
easy-to-handle catalyst. This procedure produced cyclic
secondary imides under mild reaction conditions in good
to high yields with short reaction times (Scheme 1).
Initially, the reaction of phthalic anhydride with
guanidinium chloride in different solvents, bases and
various amounts of FeCl3 was examined (Table 1). The
results showed that the use of 10 mol% of FeCl3 and
2 mmol of Et3N as a base in PEG-400 at 60°C is the best
condition for the one-pot reaction of phthalic anhydride
(1.0 mmol) with guanidinium chloride (1.0 mmol) (Table 1,
entry 4). Other bases such as K2CO3 and nPr3N and differ-
ent solvents including CH2Cl2, EtOAc and EtOH were tested
and the obtained results were unsatisfactory. Also, the use
of higher amounts of catalyst (15 mol%) does not improve
the result to an appreciable extent (Table 1, entry 5).
Results of the reaction of various cyclic anhydrides
with guanidinium chloride have been summarised in
Table 2. It is shown that a wide range of aromatic and
Conventional syntheses of cyclic imides use the reac-
tion of cyclic anhydrides with reactants including ammonia,
urea, formamide, lithium nitride and cyclisation reaction
of acidamide functionalities [25–27]. Moreover, the reac-
tion of cyclic anhydrides with urea or thiourea, formamide,
*Corresponding author: Farzad Nikpour, Department of Chemistry,
Faculty of Sciences, University of Kurdistan, PO Box 66315-416,
Sanandaj, I.R. Iran, e-mail: fnikpour@uok.ac.ir;
farzad_nikpour@yahoo.com
Zeinab Ekhtiari and Forugh Havasi: Department of Chemistry,
Faculty of Sciences, University of Kurdistan, Sanandaj, I.R. Iran
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ꢀꢀꢀꢁ
942ꢀ
ꢀZ. Ekhtiari et al.: One-pot synthesis of 1H-isoindole-1,3(2H)-diones
O
O
NH
HCl
NH2
FeCl3
O
NH
H2N
PEG, Et3N
O
O
3
2
1
Br
O
O
O
O
O
O
Br
Br
NH HN
NH
NH
NH
NH
HOOC
O
O
O
O
O
O
NO2
Br
3a
3b
3c
3d
3e
O
O
O
O
NH
O
NH
NH
NH
O
O
O
3g
3i
3f
3h
Scheme 1:ꢀReaction of cyclic anhydrides with guanidinium chloride in the presence of FeCl3.
Table 1:ꢀOptimisation of different parameters for the synthesis of
1H-isoindole-1,3(2H)-dione (3a).a
Table 2:ꢀOne-pot synthesis of cyclic imides from the reaction of
cyclic anhydride (1 mmol) with guanidinium chloride (1 mmol) in the
presence of Et3N (1 mmol) and FeCl3 (0.1 mmol) in PEG-400 (0.5 mL).
Entryꢁ
Cat. (mol%)ꢁ
Temp. (°C)ꢁ
Time (min)ꢁ
Yield 3a (%)b
Entryꢁ
Productꢁ
Temp.ꢁ
Timeꢁ
(min)
Yieldꢁ
(%)a,b
M.p. (°C)
1c
2c
3
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
0ꢂ
10ꢂ
10ꢂ
10ꢂ
15ꢂ
100
100
rt
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
240ꢂ
240ꢂ
240ꢂ
10ꢂ
0
30
60
95
96
(°C)
[Reference]
1
2
3
4
5
6
7
8
9
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
3a
3b
3c
3d
3e
3f
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
60ꢂ
60ꢂ
10ꢂ
5ꢂ
95ꢂ
95ꢂ
92ꢂ
80ꢂ
90ꢂ
75ꢂ
70ꢂ
88ꢂ
72ꢂ
236–238 [28]
ꢂ>ꢂ320 [28]
213–215 [28]
223–230 [28]
ꢂ>ꢂ320 [35]
135–137 [28]
96–98 [28]
120–122 [28]
135–138 [28]
4
60
5
60
10ꢂ
60ꢂ
10ꢂ
60ꢂ
10ꢂ
rt: Room temperature.
60ꢂ
15ꢂ
aReaction conditions: phthalic anhydride (1.0 mmol), guanidinium
chloride (1.0 mmol), Et3N (2.0 mmol), solvent ꢂ=ꢂ PEG-400.
bIsolated yields.
100ꢂ
100ꢂ
100ꢂ
100ꢂ
100ꢂ
90ꢂ
3g
3h
3i
120ꢂ
120ꢂ
cIn the absence of Et3N.
aAll the products were identified and characterised by comparison of
their physical and spectral data with those of authentic samples.
bIsolated yields.
aliphatic cyclic anhydrides react smoothly with guanidin-
ium chloride and give compounds 3 in good to excellent
yields.
The plausible mechanism is proposed in Scheme 2. It
seems that enhancing the electrophilicity of the carbonyl elimination of a molecule of urea. It is notable that cyclisa-
group of anhydride has occurred using FeCl3 as a Lewis tion of intermediate I for aromatic derivatives, where the
acid catalyst. Thus, the intermediate I is formed by the aromatic ring and the two adjacent carbonyl groups are
reaction of guanidine with activated anhydride. Cyclisa- in one plane and thus form a flat structure, is easier than
tion of intermediate I, following with hydrolysis of inter- for alicyclic ones. Thus, the synthesis of cyclic imides 3f–i
mediate II under the same reaction conditions, leads was carried out at higher temperature and needed longer
to the desired NH-isoindole-1,3(2H)-diones 3 with the reaction times in comparison with 3a–e.
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Z. Ekhtiari et al.: One-pot synthesis of 1H-isoindole-1,3(2H)-dionesꢃ
ꢃ943
Scheme 2:ꢀProposed mechanism in the synthesis of 1H-isoindole-1,3(2H)-diones using guanidinium chloride in the presence of FeCl3.
PEG-400 was used as an excellent green solvent. It points were measured with Electrothermal 9100 appara-
is water miscible; therefore, in the work-up process, it is tus. IR spectra were recorded as KBr pellets on a VERTEX
simple to remove the solvent, FeCl3, Et3NHCl and the pro- 70 model Bruker FT-IR spectrophotometer. NMR spectra
duced urea by washing of the reaction mixture with water. were recorded with a Bruker AVANCE DPX-250 (250 MHz
1
The identification and characterisation of the prod- for H). Chemical shifts are given in ppm (δ) relative to
ucts were carried out by their physical and spectroscopic internal tetramethylsilane (TMS) and coupling constants
data and comparison of them with those of authentic J are reported in Hz. Mass spectra were recorded with an
samples.
Agilent-5975C inert XL MSD mass spectrometer operating
at an ionisation potential of 70 eV.
3 Conclusions
4.2 General reaction procedure
In summary, a simple and efficient approach has been
described for the one-pot synthesis of some cyclic second-
ary imides by the reaction of cyclic anhydrides with guani-
dinium chloride in PEG-400 as a green solvent and in the
presence of FeCl3 as a catalyst. Some attractive features
of this protocol are a simple procedure under mild reac-
tion conditions, high yields of the products in high purity,
short reaction times and use of guanidinium chloride as
a commercially available, inexpensive and easy-to-handle
reagent in comparison to many of nitrogen sources.
A mixture of a cyclic anhydride 1 (1 mmol), guanidinium
chloride (2) (1 mmol), Et3N (2 mmol) and FeCl3 (10 mol%)
in PEG-400 (0.5 mL) at 60°C for aromatic derivatives and
at 100°C for aliphatic derivatives was stirred for an appro-
priate time. The reaction progress was monitored by thin-
layer chromatography. After the completion of the reaction,
the reaction mixture was cooled to room temperature and
then was extracted with H2O and EtOAc. The organic layer
was dried over MgSO4 and then evaporated under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel using n-hexane-EtOAc (7:3). The desired
1H-isoindole-1,3(2H)-diones were obtained in 70–95%
yields. Spectroscopy data for compounds 3 are in good
agreement with those previously reported.
4 Experimental section
4.1 Materials and apparatus
4.2.1 11,3-Dioxoisoindoline-5-carboxylic acid (3d)
The cyclic anhydrides, guanidinium chloride, triethyl-
amine, FeCl3 and solvents were purchased from Merck and White solid, m.p. 225–230°C [22]. – IR (KBr): υ (cm−1) ꢀ=ꢀ
1
Aldrich and used without further purification. Melting 3218–2540, 1780, 1709, 1685. – H NMR (250 MHz, [D6]
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944ꢀ ꢀZ. Ekhtiari et al.: One-pot synthesis of 1H-isoindole-1,3(2H)-diones
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