# Cs2CO3/[bmim]Br as an Efficient, Green, and Reusable Catalytic System for the Synthesis of N-Alkyl Derivatives of Phthalimide under Mild Conditions

Authors: Alireza Hasaninejad; Abdolkarim Zare; Ahmad Reza Moosavi-Zare; Fatemeh Khedri; Rahimeh Rahimi; Ali Khalafi-Nezhad
Journal: Research Letters in Organic Chemistry
 (2008)

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## Abstract

Aza-conjugate addition of phthalimide toα,β-unsaturated esters efficiently achieves in the presence of catalytic amount of Cs2CO3 and ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) under mild reaction conditions (70∘C) to afford N-alkyl phthalimides in high yields and relatively short reaction times.


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## Body

## 1. Introduction

Over the
past decade, room temperature ionic liquids have been emerged as a new class of
stable and inert solvents. They exhibit high thermal stability, high polarity
due to their ionic nature and a great ability to solubilize polar and nonpolar
organic compounds. To date, various organic reactions have been carried out and
investigated in ionic liquids, such as conjugate addition of sulfonamides [1, 2],
azide ion [3], amines and N-heterocycles [4, 5], indoles [6], thiocyanide ion
[7], active methylenes [8, 9], and thiols [10] to electrophilic alkenes, and other
carbon-carbon, carbon-nitrogen, carbon-oxygen as well as
carbon-sulfur bonds formation [11, 12].N-alkyl derivatives of phthalimide have attracted much interest due to their
potential use as antipsychotic [13], anti-inflammatory
[14], hypolipidemic [15], agents and receptors [16], and so on. Moreover, these compounds are very useful
intermediates in organic synthesis as they can be easily converted to primary
amines (Gabriel synthesis) [17]. Therefore, there is a great deal of interest
in the synthesis of this class of compounds. The aza-conjugate addition
of phthalimide to electrophilic alkenes can be used as a useful synthetic route
toward N-alkylated phthalimides
[18–21]. Several catalysts
have been applied to achieve this transformation such as Na/EtOH [18], AlMe2Cl
[19], ZnO [20], and 1,4-diazabicyclo[2,2,2]octane
[21]. However, these reported methods
are associated with one or more of the following drawbacks: (i) moderate yield,
(ii) relatively long reaction time, (iii) harsh conditions, (iv) the use of
more reactive phthalimide salts instead of phthalimide, (v) difficult
experimental procedure, and (vi) the
necessity of stoichiometric amount of catalyst. Moreover, the
aza-conjugate addition reaction of phthalimide has been scarcely studied. Therefore,
it seems highly desirable to find an efficient new protocol for this reaction.Cesium
carbonate is a commercially available, heterogeneous, and environmentally
benign basic catalyst that has been used in various organic transformations [22–28].Considering
the above subjects and also in continuation of our previous studies on green
organic synthesis
[20, 21, 29–32], we report
here an efficient, green, and simple method for the preparation of N-alkyl
phthalimides via aza-conjugate addition of phthalimide to α,β-unsaturated esters in the
presence of catalytic amount of Cs2CO3 in [bmim]Br
at 70°C (Scheme 1). This present method has none of the above disadvantages
at all.Scheme 1


## 2. Results and Discussion

We have
found previously Cs2CO3 acts as an efficient basic reagent
for N3-alkylation of N1-substituted pyrimidines [22], and N-arylation of
nucleobases [23]. Moreover, this base has been frequently applied for
alkylation and arylation reactions
[24–28]. These
subjects encouraged us to use Cs2CO3 as catalyst for N-alkylation of phthalimide
via aza-conjugate addition reaction. Therefore, firstly we used
different amounts of Cs2CO3 to accomplish aza-conjugate addition of phthalimide (2 mmol) to ethyl acrylate (2.4 mmol) in [bmim]Br (1 g) at range of 25–100ºC to provide
compound 1a (Scheme 1). The
results showed that the reaction proceeded efficiently in the presence of 20
mol% of Cs2CO3 at 70ºC and the product was obtained in 98%
yield after 90 minutes. We also examined the reaction in the presence of sodium
and potassium carbonate in which the product was produced in 59 and 82% within 240
and 180 minutes, respectively. Thus, we selected  Cs2CO3 as catalyst for our reaction.To
compare the efficiency of ionic liquid versus the conventional solvents, we
examined the reaction between phthalimide (2 mmol) and ethyl acrylate (2.4 mmol) using Cs2CO3 (20 mol%) in some conventional
solvents (10 mL) at 70ºC (Table 1). As it can be seen from Table 1, higher
yield and shorter reaction time were obtained in [bmim]Br.
The
reaction was also tested in solvent-free conditions; however, these conditions
were not efficient  (Table 1). Therefore, ionic liquid is an essential factor to
promote our reaction.Table 1
Comparing the
reaction of phthalimide with ethyl acrylate in conventional solvents versus [bmim]Br.
EntrySolventTime (min)Yield(%)a1[bmim]Br90982CH3CN180493EtOH120614H2O120375DMSO120896DMF120867HMPTA120758Solvent-free24013Isolateda
yield.After
optimization of the reaction conditions, we reacted phthalimide with differentα,β-unsaturated esters. The results are summarized in Table 2. As Table 2
indicates, all reactions proceeded efficiently and the N-alkyl phthalimides
were produced in excellent yields and relatively short reaction times.Table 2
Synthesis of N-alkyl phthalimides using Cs2CO3/[bmim]Br
catalytic system.
RProductaTime (min)Yield(%)bCH3CH21a9098CH3(CH2)2CH21b9098CH3(CH2)4CH21c9097C6H5CH21d10096C6H5CH2CH21e10096C6H5CH=CHCH21f10095o-CH3O-C6H4OCH2CH(OH)CH21g13093C6H51h70961i7094Alla compounds are known and their structures were identified by comparison of their
melting points and spectral data with those in the authentic samples.
Isolatedb
yield.The
interesting behavior of [bmim]Br/Cs2CO3 system lies in
the fact that it can be reused after simple washing with Et2O,
rendering this process
more economical. The yields of compound 1a (model compound) in the 2nd
and 3rd uses of the [bmim]Br/Cs2CO3 were almost as high
as in the first use (see Table 3).Table 3
Aza-conjugate addition of phthalimide to ethyl acrylate in the presence
of recycled Cs2CO3/[bmim]Br.
EntryCycleTime (min)Yield(%)a11st use909822nd use909633rd use10095Isolateda yield.


## 3. Experimental

All
chemicals were purchased from Merck, (Germany) or Fluka, (Switzerland) Chemical Companies. TheH1
NMR (250 MHz) and C13 NMR (62.5 MHz) were run on a Bruker Avance
DPX-250, FT-NMR spectrometer. Mass spectra were recorded on a
Shimadzu GC MS-QP 1000 EX apparatus. Melting points were recorded on a Büchi
B-545 apparatus in open capillary tubes.


### 3.1. General Procedure for the Synthesis of N-Alkyl Phthalimides

To a
well-ground mixture of phthalimide (0.294 g, 2 mmol) and Cs2CO3 (0.130 g, 0.4 mmol) in a 10 mL round-bottomed flask connected to a reflux
condenser [bmim]Br (1 g) and α,β-unsaturated ester (2.4 mmol)
were added. The resulting mixture was stirred in an oil bath (70ºC) for the
times reported in Table 1. Afterward, the
reaction mixture was cooled to room temperature and was extracted with Et2O
(3  ×  50 mL). The organic extracts were then combined. After
removal of the solvent, the crude product was purified by short column
chromatography on silica gel eluted with EtOAc/n-hexane (1/3). After
isolation of the product and evaporation
of the remaining Et2O in ionic liquid, the ionic liquid containing
the catalyst (Cs2CO3/[bmim]Br) was used for the next run under
identical reaction conditions.


### 3.2. Selected Physical and Spectral Data

Ethyl 3-Phthalimido Propanoate (1a)
Colorless solid; mp 59-60C° (Lit. [20] mp 60-61C°); IR (KBr):
3051, 2968, 1774, 1716 cm−1; H1 NMR (CDCl3): δ
1.11 (t, 3H, J = 7.1 Hz, CH3), 2.57 (t, 2H, J = 7.2 Hz,
O=CCH2), 3.86 (t, 2H, J = 7.2 Hz, NCH2), 4.06 (q, 2H, J = 7.1 Hz, OCH2), 7.57–7.70 (m, 4H); C13 NMR
(CDCl3): δ 13.8, 32.7, 33.5, 64.3, 122.9, 131.7, 133.8, 167.5,
170.6; MS (m/z): 247 (M+).2-Hydroxy-3-(2-Methoxyphenoxy)Propyl 3-Phthalimido Propanoate (1g)
Pale yellow oil (Lit. [21] oil); IR
(neat): 3480, 3049, 2948, 1770, 1715 cm−1; H1 NMR (CDCl3):
δ 2.63 (t, 2H, J = 7.0 Hz, O=CCH2), 3.67 (s, 3H, CH3),
3.80–390 (m, 5H), 4.11–4.19 (m, 3H), 6.73–6.80 (m, 4H), 7.54 (m, 2H), 7.68 (m, 2H); C13 NMR (CDCl3): δ 32.8, 33.6, 55.7, 65.7, 67.9, 70.5,
111.9, 114.2, 120.9, 121.8, 123.2, 131.7, 134.0, 147.8, 149.3, 168.0, 170.8; MS
(m/z): 399 (M+).


## 3.1. General Procedure for the Synthesis of N-Alkyl Phthalimides

To a
well-ground mixture of phthalimide (0.294 g, 2 mmol) and Cs2CO3 (0.130 g, 0.4 mmol) in a 10 mL round-bottomed flask connected to a reflux
condenser [bmim]Br (1 g) and α,β-unsaturated ester (2.4 mmol)
were added. The resulting mixture was stirred in an oil bath (70ºC) for the
times reported in Table 1. Afterward, the
reaction mixture was cooled to room temperature and was extracted with Et2O
(3  ×  50 mL). The organic extracts were then combined. After
removal of the solvent, the crude product was purified by short column
chromatography on silica gel eluted with EtOAc/n-hexane (1/3). After
isolation of the product and evaporation
of the remaining Et2O in ionic liquid, the ionic liquid containing
the catalyst (Cs2CO3/[bmim]Br) was used for the next run under
identical reaction conditions.


## 3.2. Selected Physical and Spectral Data

Ethyl 3-Phthalimido Propanoate (1a)
Colorless solid; mp 59-60C° (Lit. [20] mp 60-61C°); IR (KBr):
3051, 2968, 1774, 1716 cm−1; H1 NMR (CDCl3): δ
1.11 (t, 3H, J = 7.1 Hz, CH3), 2.57 (t, 2H, J = 7.2 Hz,
O=CCH2), 3.86 (t, 2H, J = 7.2 Hz, NCH2), 4.06 (q, 2H, J = 7.1 Hz, OCH2), 7.57–7.70 (m, 4H); C13 NMR
(CDCl3): δ 13.8, 32.7, 33.5, 64.3, 122.9, 131.7, 133.8, 167.5,
170.6; MS (m/z): 247 (M+).2-Hydroxy-3-(2-Methoxyphenoxy)Propyl 3-Phthalimido Propanoate (1g)
Pale yellow oil (Lit. [21] oil); IR
(neat): 3480, 3049, 2948, 1770, 1715 cm−1; H1 NMR (CDCl3):
δ 2.63 (t, 2H, J = 7.0 Hz, O=CCH2), 3.67 (s, 3H, CH3),
3.80–390 (m, 5H), 4.11–4.19 (m, 3H), 6.73–6.80 (m, 4H), 7.54 (m, 2H), 7.68 (m, 2H); C13 NMR (CDCl3): δ 32.8, 33.6, 55.7, 65.7, 67.9, 70.5,
111.9, 114.2, 120.9, 121.8, 123.2, 131.7, 134.0, 147.8, 149.3, 168.0, 170.8; MS
(m/z): 399 (M+).


## 4. Conclusions

In
summary, we have developed a new method for the synthesis of N-alkyl
phthalimides as biologically interesting compounds via aza-conjugate addition reaction.
This new strategy has the advantage of high yield, short reaction time, mild
conditions, ease of product isolation, potential for recycling of the catalytic
system, and compliance with the green chemistry protocols.



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*Source: 419054-2008-12-18.xml*