Solid-phase synthesis of N-aryl succinimides

Article abstract of DOI:10.1080/00397910802638529

A new method upon adopting a solid-phase strategy for synthesis of N-aryl succinimides is described here, using the silica-bound benzoyl chloride (SBBC) as dehydrating agent in reaction with N-arylsuccinamic acids. The main advantage of this method is the

Full text of DOI:10.1080/00397910802638529

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Solid-Phase Synthesis of N-Aryl
Succinimides
Kurosh Rad-Moghadam a & Leila Kheyrkhah a
a Chemistry Department, University of Guilan,
Rasht, Iran
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Synthetic Communications1, 39: 2108–2115, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802638529
Solid-Phase Synthesis of N-Aryl Succinimides
Kurosh Rad-Moghadam and Leila Kheyrkhah
Chemistry Department, University of Guilan, Rasht, Iran
Abstract: A new method upon adopting a solid-phase strategy for synthesis of
N-aryl succinimides is described here, using the silica-bound benzoyl chloride
(SBBC) as dehydrating agent in reaction with N-arylsuccinamic acids. The main
advantage of this method is the recyclability of SBBC.
Keywords: Silica-bound benzoyl chloride, solid-phase synthesis, succinimide
Over the past two decades, solid-supported chemistry has generated
much research by chemists who are creating environmentally benign syn-
thetic methods using easily separable and recyclable solid reagents.[1–7]
These methods are usually ecofriendly because the solid-supported
reagents can be recovered and reused several times. Solid-phase organic
synthesis has commonly been used in combinatorial synthesis for gener-
ating libraries, and has often been used with high-throughput screening in
modern medicinal chemistry for discovering new drugs.[8,9] Besides the
properly functionalized organic polymers,[10] silica gel–grafted reagents
have also been devised in some solid-phase organic syntheses.[11–13] Com-
pared with organic polymers, silica gel is more robust to fairly drastic
conditions and harsh reagents.
Herein we introduce silica-bound benzoyl chloride (SBBC) as a novel
and efficient means for performing the cyclodehydration of N-arylsucci-
namic acids 2a–g to provide N-aryl succinimides 4a–g. Succinimides and
their congeners, pyrrolidines and pyrrolidone compounds, have been
identified as the constituents of a wide array of natural and bioactive
Received September 11, 2008.
Address correspondence to Kurosh Rad-Moghadam, Chemistry Department,
University of Guilan, P. O. Box 41335-1914, Rasht, Iran. E-mail: radmm880@
gmail.com
2108

Solid-Phase Synthesis of N-Aryl Succinimides
2109
molecules.[14,15] Succinimides have gained numerous applications in
different fields.[16] In medicine, they have been used for the treatment
of arthritis, tuberculosis, convulsion, and epilepsy. In addition, they are
the shared structural feature of compounds that show histone deacetylase
inhibitory effects,[17] irreversible protease inhibitory effects,[18] and 5-
HT1A and 5-HT2A receptor-affinity-producing antidepressant effects.[19]
They have been used as valuable precursors in the synthesis of natural
and synthetic organic molecules.[20–22] Partial or complete reduction of
succinimides has frequently been exploited for production of pyrrolidi-
none and pyrrolidine-embedded alkaloides.[15,23,24] These fascinating fea-
tures justify the contributions allocated to development and modification
of the synthesis of succinimides.[25] Moderate yields of succinimides
were directly obtained from complete condensation of primary amines
with succinic anhydride at greater temperatures, ca. 180ꢀC.[14,16] How-
ever, a popular route for the synthesis of succinimides involves partial
condensation of a primary amine with succinic acid or anhydride at
temperatures less than 100ꢀC followed by cyclodehydration of the formed
N-arylsuccinamic acids. Several dehydrating reagents such as acetic
anhydride,[19,22,23] acetyl chloride,[15] and cyanuric chloride[26] were con-
ventionally employed in this approach. However, use of these dehydrating
agents usually suffers from difficulties encountered in their handling,
separation, and recovering after reaction, therefore sometimes creating
waste. To surmount these disadvantages, we intended to design and
evaluate SBBC for cyclodehydration of N-arylsuccinamic acids 2a–g.
Accordingly, it is introduced here as an efficient and recyclable dehydra-
ting agent for a convenient synthesis of succinimides.
As is depicted in Scheme 1, our approach to the synthesis of SBBC
consists of three steps. In this course, we started from a known reaction
between silica-gel powders and thionyl chloride to obtain the silica
chloride 1.[27–31] On reaction with 4-hydroxybenzoic acid in refluxing
dichloromethane–dimethylformamide (8:1), this compound has provided
SBBA. Conversion of SBBA to the desired acid chloride (SBBC) was
readily attained by refluxing it in thionyl chloride. To the best of our
Scheme 1. Preparation of SBBC.

2110
K. Rad-Moghadam and L. Kheyrkhah
Scheme 2. A plausible mechanism for synthesis of succinimides 4a–g.
knowledge, there is no report on the preparation and use of SBBC in any
synthetic procedure. In comparison with commonly used acid chlorides
such as acetyl chloride and benzoyl chloride, which are more hygroscopic
and difficult to handle, SBBC can be used simply and stored more safely.
In addition, SBBC is not wasteful to the environment because it is readily
recovered after reaction and can be reused several times.
SBBC was mixed with each N-arylsuccinamic acid 2a–g and then
refluxed in dichloromethane (Scheme 2). The progress of the reaction
was monitored by thin-layer chromatography (TLC) using ethyl
acetate–petroleum ether as eluent. After completion of the reaction, the
hot slurry of the reaction mixture was filtered to separate the SBBA resi-
due. The SBBA residue was washed with dichloromethane and recovered
by refluxing it in thionyl chloride.
To optimize the required amount of SBBC, the reactions with two
reactants, N-phenylsuccinamic acid 2a and N-(4-methoxyphenyl)succi-
namic acid 2b, were chosen as models. Table 1 summarizes the yields
of relevant succinimides 4a,b obtained using different amounts of SBBC
in model reactions.
Table 1. Optimization of the amount of SBBC needed in the
reaction with 1 mmol of substrate
Amount of
SBBC used (g)
Yields
(%)
Product
Ar
4a
4a
4a
4b
4b
4b
Ph
Ph
Ph
0.6
0.8
1
0.6
0.8
1
70
78
78
73
83
83
4-MeO ꢁ C6H4
4-MeO ꢁ C6H4
4-MeO ꢁ C6H4

Solid-Phase Synthesis of N-Aryl Succinimides
2111
Table 2. Results of reaction between 2a–g and SBBC
Reaction
time (min)
Yields
(%)
Mp
(ꢀC)
Lit.
mp (ꢀC)
Product
Ar
4a
4b
4c
4d
4e
4f
Ph
4-MeOꢁC6H4
40
30
55
30
40
30
30
78
83
71
88
79
83
84
155–156
160–162
164–165
137–138
110–111
152–154
153–155
157[32]
—
4-ClꢁC6H4
167[32]
—
—
4-EtꢁC6H4
3-MeꢁC6H4
4-MeꢁC6H4
4-EtOꢁC6H4
154[32]
155[32]
4g
According to the results of these optimization reactions, 0.8 g of
SBBC was used in the reaction with 1 mmol of each N-aryl succinamic
acid, and the relative products were obtained in good yields (Table 2).
Also, it is interesting to note that under similar conditions and reaction
times, the treatment of N-aryl succinamic acids with silica chloride 1
has not furnished the relative succinimides.
Furthermore, to investigate the recoverability of SBBC, three model
reactions were chosen. After completion of each model reaction, the solid
support was separated by filtration, washed with dichloromethane, dried
in an oven, and then refluxed in excess thionyl chloride. The recovered
SBBC was subjected to the next run of the reaction process with the same
substrate. The results of the first experiment and subsequent experiments
were almost consistent in yields after three runs (Table 3).
A reasonable mechanism for the formation of succinimides 4a–g is
indicated in Scheme 2. This mechanism involves the formation of puta-
tive mixed anhydride 3a–g, which undergo thermal cyclo-elimination
through intramolecular nucleophilic substitution of the nitrogen atom
in favor of producing succinimide and leaving SBBA. As is apparent in
Table 3. Results of reusability of SBBC in model reactions
Yields (%) of reaction from successive run
with recovered SBBC
First
use
First
recovery
Second
recovery
Product
Ar
4b
4c
4g
4-MeOꢁC6H4
4-ClꢁC6H4
83
71
84
81
69
82
80
66
81
4-EtOꢁC6H4

2112
K. Rad-Moghadam and L. Kheyrkhah
Table 2, substrates having electron-donating groups in the para position
to the nitrogen substituent gave better yields under the reaction condi-
tions. This result clearly shows a direct dependence of reaction kinetics
on electron density at the nitrogen atom and therefore its nucleophilic
character. To this end, it is reasonable to consider the thermal cyclo-
elimination reaction as the rate-limiting step. Meanwhile, the starting
materials, N-aryl succinamic acids, appear to be loaded more easily onto
the solid-supported reagent.
1
The infrared (IR), H NMR, and MS data of all the products are in
good agreement with their structures. In addition, the melting points
correspond to those of the literature[32] as well as the authentic samples
prepared from the previously reported methods.
In conclusion, we have developed a new solid-phase synthesis proto-
col for the preparation of N-aryl succinimides. The main advantages of
this process are the recyclability of the solid support and easy release
of products from the linker as a concomitant of their formation. We
anticipate the preliminary results are worthy of further investigation
for the synthesis of other classes of heterocyclic compounds.
EXPERIMENTAL
Melting points were measured on an Electrothermal apparatus and
are uncorrected. Chemicals were obtained from Merck (Darmstadt,
Germany) and were used without further purification. The required
N-aryl succinamic acid substrates 2a–g were prepared near quantitatively
from condensation between succinic anhydride and an equivalent amount
of an aromatic amine in refluxing ethanol (95.5%) solutions.
Procedure for Preparation of Silica-Bound Benzoyl Chloride (SBBC)
SOCl2 (25 mL) was added to 5.0 g of well-dried fine powders of silica gel
60 (0.063–0.200 mm) in a flask. The mixture was refluxed for about 3 h
and then distilled to remove the excess SOCl2. To 4.0 g of obtained white
powders of silica chloride, a solution of 4-hydroxybenzoic acid (2.0 g) in
CH2Cl2 (30 mL) and DMF (4 mL) was added and then refluxed for about
6 h. The suspension was filtered to separate the SBBA powders, and the
precipitate was washed with 20 mL of 1:8 mixture of DMF=CH2Cl2 and
dried at 100ꢀC to give 5.62 g of SBBA. SOCl2 (25 mL) was added to 5.0 g
of SBBA and refluxed for about 3 h. The excess SOCl2 was removed at
reduced pressure, and the obtained white powder of SBBC (5.49 g) was
stored in a dry bottle.

Solid-Phase Synthesis of N-Aryl Succinimides
2113
General Procedure for Preparation of Succinimides (4a–g)
SBBC (0.8 g) was added to a mixture of N-arylsuccinamic acid (1 mmol in
each case of 2a–g) in dry CH2Cl2. The mixture was refluxed according to
the time mentioned in Table 2 and then was hot filtered. The filtered
solids were washed with additional CH2Cl2 (20 mL). The combined solu-
tions of CH2Cl2 were evaporated, and the residue was further purified by
chromatography on silica gel using petroleum ether=ethyl acetate (2:1) as
eluent to give the succinimides (4a–g). The residue of SBBC was renewed
by washing it with 5 mL of dichloromethane, drying it in 60ꢀC, and then
refluxing it (3 h) in 8 mL of SOCl2. The excess SOCl2 was removed under
reduced pressure.
Selected Data for Compound 4b
1
IR (KBr) tmax ¼ 3074, 2984 (C-H); 1712, 1703 (C¼O) cmꢂ1. H NMR
(CDCl3) d ¼ 7.23 (d, J 8.8 Hz, 2H); 7.03 (d, J 8.8 Hz, 2H); 3.87 (s, 3H);
2.92 (s, 4H) ppm. MS: m=z (%) ¼ 204 (Mþ, 100), 189 (3), 176 (6), 161
(10), 148 (9), 133 (10), 123 (19), 107 (11).
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council
of the University of Guilan.
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