Simple and efficient synthesis of N-alkyl and N-aryl succinimides in hot water

Article abstract of DOI:10.1080/00397911.2016.1258479

A new, simple synthesis of succinimides is described. The reactions were carried out under the ultimate green conditions excluding both catalyst and organic solvent by applying simple stirring at 100 °C. A wide variety of N-susbstituted succinimides have been prepared in high yields by using succinic acid and primary amines in hot water. Yield of N-alkyl substituted succinimides were found to be higher than those of N-aryl substituted succinimides.

Full text of DOI:10.1080/00397911.2016.1258479

Simple and Efficient synthesis of N-alkyl and N-aryl succinimides in hot water
Burcu Bozdoğan1, Mehmet Erşatır1, Onur Demirkol1, Dilek Akbaşlar1, E. Sultan Giray1,
1Department of Chemistry, Art&Science Faculty, Çukurova University, Adana, Turkey
Corresponding author: E.Sultan Giray, Department of Chemistry, Art&Science Faculty,
Çukurova University, 01330 Adana, Turkey. Email: esgiray@cu.edu.tr
Abstract
A new, extremly simple synthesis of succinimides is described. The reactions were
carried out under the ultimate green conditions excluding both catalyst and organic
solvent by applying simple stirring at 100 oC. A wide variety of N-susbstituted
succinimides have been prepared in high yields by using succinic acid and primary
amines in hot water. Yield of N-alkyl substituted succinimides were found to be higher
than those of N-aryl substituted succinimides.
Graphical Abtract:
1

KEYWORDS: Green Chemistry, succinimides, water, catalyst free, primary amines,
hydrazines
INTRODUCTION
Development of simple and general synthetic routes for widely used organic compounds
from simple and readily available reagents is very important in organic synthesis.
Succinimides and cylicimide compounds such as maleimides, glutarimides, phtalimides
and related compounds are biologically active and important compounds in synthetic
chemistry. Due to their antibacterial, antifungal, analgesic and antitumor activities they
received a great deal of attention. [1-5] Succinimides are also important building blocks
and often present in natural products and drugs, for example, phensuximide,
ethosuximide, and andrimid which are biologically active natural products and drugs
includes succinimide moiety. [6-10]
Since they have wide applicability, efficient and simple environmentally benign synthetic
procedures to prepare succinimides is necessary. The most direct method to prepare
succinimides is condensation of succinic anhydride and amine compounds at high
temperature or cyclization of amic acid intermediates in the presence of an acid catalyst
[11]
For synthesis of N-substituted succinimides, many catalyst such as Lewis acids and
hexamethyldisilazine and dehydrating reagents such as acetic anhydride, acetylchloride
or cyanuric chloride have been widely used. [12-14] However, low yields, numerous by-
2

product formation, using expensive dehydration reagents and long reaction times are
main drawbacks of these methods. Milder methods such as using microwave heating,
subcritical water as solvent and synthesis in the presence of DPPOX and Et3N were also
reported. [15-17] Synthesis of N-alkyl and N-aryl substituted imides were also reported in
the presence of ionic liquids. [18] An alternative, fast and clean method was reported using
sub-critical water for the synthesis of substituted succinimide by reaction of succinic acid
with aniline in water at 280 ºC for 30 min with high yield. [19] In the light of these
literature surveys, it is clear that development of a simple, relatively mild, efficient and
environmentally more benign method for cyclic imide synthesis is still urgent.
Recently, due to environmental concerns the use of water as solvent in organic reactions
has become more important. [18-20] Lack of inflammability and being non- explosive,
cheap and environmentally benign, make water a desirable one in organic synthesis.
Conversely, high specific heat capacity, high polarity and the network of hydrogen
bonding are other unique properties of water that make it less attractive in organic
synthesis.
In continuation of our efforts in developing green alternative methods for organic
synthesis,[21-23] we have synthesized N-substituted succinimides in water without using
any catalyst with simple work-up procedures and moderate to excellent yields were
obtained. Herein, we describe an extremely simple way of carrying out this
transformation. This method is also efficient, clean, relatively fast and a mild approach
3

for the synthesis of N- substituted succinimides from succinic acid, several primary
amine compounds and hydrazines without using any catalyst in water.
RESULTS AND DISCUSSION
In this study, N-alkyl and N-aryl substituted succinimides were synthesised in hot water
without using any catalyst (Scheme 1). Hot water is a suitable media for organic
synthesis because with increasing temperature, the H- bonds of water break down and the
orientational preference of water molecules decrease and then organic reactions can take
place[22]
.
In an effort to develop a simple system to synthesize succinimides, succinic acid 1 and
aniline 2 were selected as test substrates. Stirring the mixture of compounds 1 and 2 in
water at 100 oC was completed after 60 min. To our delight, the corresponding compound
1-phenylpyrrolidine-2,5-dione 1a was gained with a good yield (65 %). Based on these
initial results, we planned to demonstrate the applicability of the methodology for
different primary amines and hydrazines. In this respect, primary aliphatic and aromatic
amines, phenylhydrazine and hydrazine were used (Table 1). One of the most attractive
features of this novel method is its extreme ease of synthesis of succinimides.
It is well known that the aliphatic amines are more nucleophilic or more basic than those
of aromatic amines. In this study, it was seen that the corresponding adducts of aliphatic
amines gave higher yields than those of aromatic amines in hot water. Reaction of
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succinic acid 1 with an alkyl amine such as propylamine, ethylendiamine, butylamine,
propargylamine and benzylamine gave target products 1m, 1i, 1j, 1k, 1f, respectively
(Table 1, entries 6,9,10,11and 13) in excellent yields (84-98%). In the case of aromatic
amines, reaction proceeded much slower. Reaction of anilines which had electron
donating substituents such as NH2, OH and OCH3 with succinic acid 1 were much
slower relative to those of aliphatic amines. This resulted in a lowering of the yield
(Table 1, entries 2,3 and 4) while an aniline with a -Cl and -OH substituent at the 2 and 5
positions, respectively, gave the corresponding adduct 1e in very good yield (81%).
Notably, 1-furanomethylamine reacted significantly slower than other aryl substituted
alkylamines (Table 1 entry 12). Moreover, we were delighted that this very simple and
clean procedure worked also with hydrazines with good yields. Succinic acid 1 and
phenylhydrazine or hydrazine gave products 1n and 1o with good yields (75 – 92%).
Reaction of 3-aminopyridine and 3-methylpyridin-2-amine with succinic acid 1 also
worked successfully in this simple method ( Table 1 entries 16 and 17).
We also used 4-methylbenzohydrazide as a nucleophile and the product 1r was obtained
with a moderate yield (45%) .
Generally, the synthesis of succinimides is usually carried out under acidic conditions
and start from the anhydride which then forms the corresponding amic acid followed by
cyclization. In the course of our catalyst free reaction in hot water studies, we explored
the preparation of succinic anhydride from succinic acid in hot water. Although, we
didn’t observe any side product while monitoring the reaction medium by GC-MS, we
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checked for the formation of succinic anhydride under our conditions. For this, succinic
acid 1 was reacted with water at 100 ˚C. After 12 hours we did not observe any formation
of succinic anhydride. Hence it was concluded that succinimide is directly synthesized
from succinic acid and the primary amine (Figure 1). Our results show that water at the
boiling point creates an ideal medium for the synthesis of N-alky and N-aryl substituted
succinimides. A plausible mechanism is shown in Figure 1.
To prove the effect of hot water, we attempted to use toluene, THF and dichloromethane
as reaction media at their boiling point and without using any catalyst (Table 2). In each
case the corresponding adduct 1a was not observed after 24 h. In this respect, we carried
out same reaction in water at 25˚C and the corresponding adduct 1a was not observed
even after 24 h.
Finally, we have compared the performance of this extremely simple method with
literature procedures performed using different conditions (Table 3). When some of the
results of this study are compared to their counterparts in the literature, it is obviously
seen that our method can compete with these examples on the bases of yields and being
extremly simple and efficient.
CONCLUSION
In conclusion, a catalyst free green approach has been illustrated for the synthesis of a
variety of succinimide derivatives by using water as an environmentally benign solvent.
It was revealed that the reaction conditions were suitable to primary alkylamines. The
6

reactions were rapid and the products crystallized out easily in pure form. The current
catalyst-free protocol does not require further purification steps such as column
chromatography. The simplicity of the experimental procedure makes this method
extremely attractive for the synthesis of succinimide derivatives.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 55148 spectrometer. 1H and 13C NMR
spectra were recorded on a Bruker 300-MHz Ultrashield spectrometer or a Bruker
Avance III 600-MHz spectrometer and a Bruker Avance III 400 MHz spectrometer.
Chemical shifts are given in parts per million (ppm) downfield from tetramethylsilane
(TMS) as an internal standard. Melting points were determined using an Electrothermal
9100 instrument.
General Experimental Procedure (1a-1r)
A solution of succinic acid (10 mmol ) and primary amine (10 mmol ) were
dissolved in water (5.0 mL) in a flask and stirred and maintained at boiling for the
appropriate time. The reaction progress was monitored by TLC (1:1 n-hexane/acetone).
After the reaction mixture was cooled to room temperature, the product was filtered and
washed with water. It was recrystallized from methanol. The resulting product was
identified using FT-IR, NMR spectroscopy and GC-MS. Compounds of 1a, 1c, 1f and 1j
were reported in literature and fully characterized by spectral analysis[23-26]
.
1-Phenylpyrrolidine-2,5-Dione (1a)[23]
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white solid; mp 155-156 °C; yield 1.13 g (65%); Rf= 0.75 (n-hexane/acetone, 1:1); υmax
(KBr) 3025, 2986, 1706, 1648, 1625, 1468, 1197 cm-1 ; H (300 MHz, DMSO4-d6) 7.59 (
d, J = 7.5 Hz 2H), 7.48 ( d, J = 7.8 Hz 1H), 7.31-7.25 (m, 2H), 2.66 (s, 4H); δC (75
MHz, DMSO4-d6) 174.1, 139.8, 129.1, 128.6, 127.6, 29.2; GC-MS (m/z): 175.12 (100),
[M+], 147 (15), 119 (85), 93 (61), 77 (47), 55 (90).
ACKNOWLEDGMENTS
The authors are grateful to the support of Scientific Research Committee of Çukurova
University ( FEF2013YL24)
SUPPLEMENTAL MATERIAL
Supporting Information: Full experimental detail, 1H and 13C NMR spectra. This material
can be found via the “Supplementary Content” section of this article’s webpage.
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Table 1. The yield of N-substituted succinimides
Entry
1
R
Product
t (min)
120
Yield (%) M.p. a /
°C
Lit.
M.p./°C
Ph
65
155-156 156-
1a
15723
2
3
2-NH2Ph
120
120
28
66
187-188
1b
1c
4-OCH3Ph
162-163 163-
16424
4
4-OHPh
120
240
120
120
120
180
120
180
150
74
81
84
54
63
92
93
91
36
143-145
1d
1e
1f
5
3-OH-4ClPh
CH2Ph
142-143
6
98-99
194-195
160-162
169-170
oily
99-10025
7
CH2(4-CH3)Ph
CH2(4-OCH3)Ph
CH2CH2NH2
CH3CH2CH2CH2
CH2=CHCH2
1g
1h
1i
8
9
10
11
12
oily26
1j
90-91
oily
1k
1l
12

13
14
15
16
17
CH3CH2CH2
NH2
120
180
120
120
120
98
92
75
67
65
110-111
169-170
222-223
90-92
1m
1n
1o
NHPh
3-Py
1p
1q
3-(2-CH3)Py
97-99
18
NHCO(4-CH3)Ph
150
45
131-132
1r
a Melting points were uncorrected.
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Table 2. Synthesis of some succinimides under different conditions*
Product
Yield%
1a
This work
[Bmim][PF6]5 PEG23
TaCl5-slicagel1 ZnBr2-HMDS12
65
84
93
96
95
97
75
80
91
97
1f
91
1j
*: examples from literature was performed using succinic anhydride.
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Table 3. Screening studies in the terms of solvent
Entry
Solvent
Toluene
THF
t (h)
24
24
24
2
T (˚C)
b.p.
b.p.
b.p.
b.p
Yield %
1
2
3
4
5
-
-
CH2Cl2
H2O
-
65
-
H2O
24
25
15

Scheme 1. Synthesed succinimides in water
16

Figure 1. A reasonable mechanism for N-Substituted succinimide synthesis in hot water.
17