An environmentally benign solvent/catalyst-free one-pot synthesis of N-substituted phthalimides via Aza-wittig reaction

Article abstract of DOI:10.1007/s13738-012-0090-7

For the first time an environmentally benign solvent/catalyst-free protocol for the synthesis of a variety of N-substituted phthalimides is submitted. It involves a one-pot coupling of nascent phosphazene generated in situ with phthalic anhydride. The protocol is novel in (1) avoiding toxic solvents, (2) no catalyst is employed and (3) no isophthalimide is formed as noted in the prevailing solution phase/catalysed methodology. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-012-0090-7

J IRAN CHEM SOC (2012) 9:681–685
DOI 10.1007/s13738-012-0090-7
ORIGINAL PAPER
An environmentally benign solvent/catalyst-free one-pot synthesis
of N-substituted phthalimides via Aza-wittig reaction
•
Murugan Sathishkumar Kulandaivel Palanikumar
•
•
•
Arumugam Mariappan Sivasubramaniyan Archana
Alagusundaram Ponnuswamy
Received: 14 June 2011 / Accepted: 21 January 2012 / Published online: 4 May 2012
Ó Iranian Chemical Society 2012
Abstract For the first time an environmentally benign
solvent/catalyst-free protocol for the synthesis of a variety
of N-substituted phthalimides is submitted. It involves a
one-pot coupling of nascent phosphazene generated in situ
with phthalic anhydride. The protocol is novel in (1)
avoiding toxic solvents, (2) no catalyst is employed and (3)
no isophthalimide is formed as noted in the prevailing
solution phase/catalysed methodology.
under refluxing solvents such as acetic acid [13, 14], DMF
[15] and dioxane [16]. Alternatively, N-substituted phthali-
mides are obtained by direct N-alkylation of phthaloyl
dichloride with organic azide and PPh3 [17] or N-alkylation
of imides using modified mitsunobu reaction [18]. Most of
these conventional methods are not environmentally benign
as they are generally solution phase protocols associated with
the hazards due to the organic solvents. Recently, these
drawbacks are overcome by replacing the solution phase
protocols with solvent-free methodologies.
Keywords Phthalic anhydride Á Azide Á Aza-wittig Á
Phthalimide Á Solvent/catalyst-free
Result and discussion
Introduction
In an earlier report [19] preparation of N-substituted
phthalimides has been accomplished via the coupling of
phosphazenes with phthalic anhydride in benzene (carcin-
ogenic) which had resulted in the formation of isoimides
(isophthalimide) along with the expected phthalimides.
Formation of the isoimide further complicated during the
workup affording the monoamide of phthalic acid. Con-
sequently, overall yield of phthalimide has been reported
low. Thus, they have used tetrabutyl ammonium cyanide as
a catalyst in the reaction which has been reported to
isomerise the isoimides to the corresponding thermody-
namically favoured phthalimide (Scheme 1).
Phthalimide and N-substituted phthalimides are interesting
class of compounds exhibiting a variety of bioactivities
such as anti-inflammatory [1, 2], antimicrobial [3], antitu-
bercular [4], antitumor [5], antivirus [6], histone deace-
tylase inhibitory [7], liver X receptor antagonistic [8],
leukotriene D4 receptor antagonistic [9] and angiogenesis
inhibitor properties [10, 11]. Also, N-substituted phthali-
mides serve as potent anticancer and immunomodulatory
agent [12]. In view of this, organic chemists are more
attracted towards their synthesis.
From perusal of the literature, it is understood that
phthalimide derivatives are generally synthesised via the
dehydrative condensation of amines with phthalic anhydride
As part of our on-going studies on solvent-free reaction,
we recently reported a rapid synthesis of amides by sol-
vent-free protocol via the coupling of phosphazenes with
carboxylic acid [20]. In continuation, we herein report the
one-pot synthesis of phthalimide from a mixture of phthalic
anhydride, organic azide and triphenylphosphine in solu-
tion phase and solvent-free condition. The solvent-free
protocol is found to be more advantageous in the sense that
it (1) avoids toxic solvents, (2) needs no catalyst and (3) no
M. Sathishkumar Á K. Palanikumar Á A. Mariappan Á
S. Archana Á A. Ponnuswamy (&)
Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University, Tamilnadu,
Madurai 625-021, India
e-mail: ramradkrish@yahoo.co.in
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J IRAN CHEM SOC (2012) 9:681–685
Scheme 1 Literature protocol
for N-substituted phthalimide
synthesis
R
O
N
Solvent
No Catalyst
O
N R
+
O
O
O
O
O
+
isophthalimide
O
PPh
+
3
Solvent
[CH3(CH2)3]4N+CN-
(Catalyst)
N3
R
N R
O
Table 1 Solvent/solvent-free effect in N-substituted phthalimide synthesis
O
O
Solvent/
Solvent-free
N3
O
PPh3
+
+
N
O
O
Entry
Solvents
Temperature (°C)
Time (min)a
1
2
3
4
5
a
Benzene
80
180
120
45
Toluene
111
145
165
120b
Xylene
Mesitylene
Solvent-free
20
30
1
Time required for completion of reaction monitored by H NMR
b
Optimised temperature
Scheme 2 Solvent/catalyst-
free synthesis of N-substituted
phthalimide
O
O
Solvent-free
Catalyst-free
; 120oC
R= Primary
Aryl
PPh3
R N3
+
O
N R
+
Benzyl
Tosyl
O
O
isoimide is formed. Our findings in this regard are dis-
cussed vide infra.
cyanide which was used in the earlier study [19] for the
isomerization of the by-product isoimide to phthalimide.
Further, in view of avoiding the toxicity of the solvent and
difficulties in the processing and removal of the high boiling
solvents, we envisaged the possibility of a one-pot solvent-
free and catalyst-free coupling of a variety of phosphazenes
with phthalic anhydride to afford the corresponding phthal-
imide. To our delight, the methodology suits well resulting in
good yield of the phthalimide (Scheme 2) as the exclusive
product in 20–30 min (Table 2).
At first, we have attempted the one-pot synthesis in
different solvents (Table 1) and noted that the reaction is
temperature dependent, i.e. a clean synthesis of the
phthalimides was achieved without the isoimides in high
boiling solvents.
It is to be mentioned that unlike in the earlier report [19]
wherein phthalimide was obtained along with isoimide in
similar amounts in benzene at room temperature, in our
study in benzene under refluxing condition (Table 1, entry
1), very small amount of isoimide was formed. Further,
replacing benzene with high boiling solvents resulted in
phthalimide as the exclusive product in short reaction time.
Thus, coupling of phosphazene with phthalic anhydride in
high temperature is efficient and appreciable. This clearly
indicated that the reaction is temperature dependent and
there is no need for the catalyst viz tetrabutyl ammonium
The plausible mechanism for the one-pot synthesis is
presented (vide Scheme 3).
The present protocol though fruitful towards phthali-
mide synthesis was not effective in case of the conversion
of maleic anhydride and succinic anhydride to their cor-
responding imides. This may be due to some competitive
reactions. Further investigations in this regard are in
progress.
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J IRAN CHEM SOC (2012) 9:681–685
683
Table 2 Synthesis of N-substituted phthalimides via Aza-wittig reaction
Entry
1
Azide
Product
Yieldb (%)/lit. mp(°C)c
84/118–120 °C
N3
O
N
O
2
81/111–112 °C
O
O
O
O
N3
O
N
O
`
3
4
5
6
7
8
a
79/114–115 °C
82/160–162 °C
80/240–241 °C
75/209–210 °C
78/203–205 °C
83/191–192 °C
O
O
O
O
N3
O
N
O
O
O
O
N3
N
O
O
O
O
S N3
O
N S
O
O
N3
O
N
O
N3
O
Br
N
Br
O
N3
O
N
O
All the reactions were carried out with phthalic anhydride (3.75 mmol), triphenyl phosphine (3.75 mmol), and organic azides (3.75 mmol) at
120 °C for 30 min
b
Isolated yield
c
All the products being known compounds were identified by comparison of physical and spectral data with literature [16–21]
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J IRAN CHEM SOC (2012) 9:681–685
Scheme 3 Plausible
mechanism for phthalimide
synthesis
O
O
Ph
O
O
Ph
Ph
R N P Ph
Ph
R N N N
R N N
P
N
Ph
O
Ph P N
O
P
R
Ph
Ph
Ph
Ph
Ph
Ph
R N P Ph
Ph
O
O
O
O
O
N
Ph
O
N
Ph
Ph
Ph
P Ph
P
N R
Ph
R
O=PPh3
R
O
O
Ethyl 2-(1,3-dioxoisoindolin-2-yl)acetate
Conclusions
To a well ground intimate mixture of triphenyl phosphine
(3.87 mmol, 102 mg) and phthalic anhydride, (3.87 mmol,
570 mg) in a microwave vial (10 mL) equipped with a
magnetic stirring bar, ethyl 2-azidoacetate (3.87 mmol,
500 mg) was added in drops while stirring. Stirring was
continued until liberation of nitrogen ceased and the
reaction vessel was sealed with a septum. It was then
placed into an oil bath and operated at 120 8C for 30 min.
The reaction vessel was then cooled to room temperature
and the residue subjected to column chromatography to get
the pure product. 1H NMR (CDCl3): d (ppm) 1.28 (t,
J = 7.2 Hz, 3H), 4.23 (q, J = 7.2 Hz, 2H), 4.56 (s, 2H),
7.74 (m, 2H, arom), 7.88 (m, 2H, arom).
In conclusion, one-pot, solvent/catalyst-free protocol for
the synthesis of N-substituted phthalimide is submitted. Its
novelty in eradicating the limitations associated with the
prevailing solution phase protocols is significant.
Experimental
All chemicals, reagents and solvents were of commercially
high purity grade purchased from Avra Synthesis Pvt. Ltd.
and Merck Ltd. India. Silica gel (60–120 mesh) was used
for column chromatographic isolation and purification of
the synthesised phthalimides. Organic azides used in the
investigation were prepared according to the literature
procedures. Melting points were obtained on electro-ther-
mal apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded in CDCl3 on Bruker Avance
300 MHz spectrometer and the chemical shifts are reported
as d values in parts per million (ppm) relative to tetra-
methylsilane, with J values in Hertz.
Acknowledgments The author MS thank UGC/CSIR for the sanc-
tion of JRF and IRHPA, DST for providing 300 MHz NMR Instru-
ment for recording the NMR spectra of the compounds synthesised.
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