Imidazole-promoted synthesis of n-substituted phthalimide from N,N'-disubstituted ureas in solventless conditions

Article abstract of DOI:10.1080/00397911.2011.651677

A series of N-substituted phthalimides was synthesized by a thermal reaction between N,N0-disubstituted ureas and phthalic acid catalyzed by imidazole in solventless conditions. The products have been obtained in moderate to good yields (53-92%). Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.651677

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Imidazole-Promoted Synthesis of N-
Substituted Phthalimide from N,N′-
Disubstituted Ureas in Solventless
Conditions
Ricardo A. W. Neves Filho a , Mieder A. T. Palm-Forster b & Ronaldo
N. de Oliveira a
a Departamento de Ciências Moleculares, Laboratório de Síntese
de Compostos Bioativos (LSCB), Universidade Federal Rural de
Pernambuco, Rua Dom Manoel de Medeiros S/N, Dois Irmãos, Recife,
Brazil
b Leibniz-Institut für Pflanzenbiochemie, Abteilung Stress- und
Entwicklungsbiologie, Halle (Saale), Germany
Accepted author version posted online: 17 May 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Ricardo A. W. Neves Filho , Mieder A. T. Palm-Forster & Ronaldo N. de Oliveira
(2013): Imidazole-Promoted Synthesis of N-Substituted Phthalimide from N,N′-Disubstituted Ureas in
Solventless Conditions, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 43:11, 1571-1576
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Synthetic Communications1, 43: 1571–1576, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.651677
IMIDAZOLE-PROMOTED SYNTHESIS OF
N-SUBSTITUTED PHTHALIMIDE FROM N,N’-
DISUBSTITUTED UREAS IN SOLVENTLESS
CONDITIONS
Ricardo A. W. Neves Filho,1 Mieder A. T. Palm-Forster,2 and
Ronaldo N. de Oliveira1
1
ˆ
´
´
Departamento de Ciencias Moleculares, Laboratorio de Sıntese de
Compostos Bioativos (LSCB), Universidade Federal Rural de Pernambuco,
Rua Dom Manoel de Medeiros S=N, Dois Irma˜os, Recife, Brazil
2Leibniz-Institut fu¨r Pflanzenbiochemie, Abteilung Stress- und
Entwicklungsbiologie, Halle (Saale), Germany
GRAPHICAL ABSTRACT
Abstract A series of N-substituted phthalimides was synthesized by a thermal reaction
between N,N0-disubstituted ureas and phthalic acid catalyzed by imidazole in solventless
conditions. The products have been obtained in moderate to good yields (53–92%).
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Imidazole; phthalimide; solventless; urea
INTRODUCTION
N-Substituted phthalimides are well known for exhibiting a wide range of
biological profiles as described in a recent review by Sharma and coworkers.[1] In
Received November 22, 2011.
Address correspondence to Ronaldo N. de Oliveira, Departamento de Cieˆncias Moleculares,
´
´
Laboratorio de Sıntese de Compostos Bioativos (LSCB), Universidade Federal Rural de Pernambuco,
Rua Dom Manoel de Medeiros S=N, Dois Irma˜os, 52171-900, Recife, PE, Brazil. E-mail:
ronaldonoliveira@dcm.ufrpe.br
1571

1572
R. A. W. NEVES FILHO, M. A. T. PALM-FORSTER, AND R. N. de OLIVEIRA
1950, a drug based on the phthalimide scaffold, (Talidomide) was marketed as a
sedative, although 11 years later it was withdrawn from the market because of tera-
togenic effects. It has recently returned for use in the treatment of AIDS, leprosy,
and other related diseases.[1] Other promising drugs, such as the in vivo
anti-inflammatory LASSBio-468 and anti-androgenic DIMP also possess a phthali-
mide moiety as the pharmacophoric group.[2] The applications of these compounds
are not limited only to therapeutics but also have been mentioned as having an effect
in regulation of plant growth. For example, the N-substituted phthalimide AC
94,377 can act as an analog of exogenous gibberellins, stimulating germination of
dormant seeds in Avena fatua, Brasica kaber, Rumex crispus, Thlaspi arvense, Phace-
lia tanacetifolia, and Solanum nigrum (Fig. 1).[3]
Other N-substituted phthalimides have displayed various properties such as
hypolipidemic,[4] antimicrobial,[5] antifungal,[6] anticonvulsivant,[7] antihistaminic,[8]
histone-deacetylase-inhibitory,[9] and HIV-1 transcriptase inhibitory[10] activities.
Apart from the biological applications, the usefulness of phthalimide-containing
compounds in the fields of liquid crystals,[11] functional materials,[12] and polymer
and supramolecular chemistry has also been reported.[13] The multidisciplinary inter-
est in this class of compounds is clearly evident.[14]
The most employed method for synthesizing N-substituted phthalimide is the
thermal cyclodehydratation between phthalic anhydride and secondary amines.[1]
There are several described protocols for performing this reaction, including reflux-
ing in acetic acid,[13] toluene,[15] nitrobenzene,[4b] PEG400,[16] and solvent-free micro-
wave irradiation.[17] Some have reported procedures where urea has been successfully
employed as an ammonia equivalent.[18] Although the synthetic method described is
often employed for synthesizing N-substituted phthalimides, it still suffers certain
drawbacks, for example, reactions involving low-molecular-mass or gaseous amines,
such as ammonia and methyl amine, are difficult to perform. Further, these reagents,
in particular aromatic amines, undergo oxidation during storage and require further
purification before use. The same problem is found for phthalic anhydride, which
decomposes spontaneously to phthalic acid. Urea and N,N0-disubstituted ureas are
usually stable,[19] solid, and widely available reagents.[20] The thermal decomposition
Figure 1.

IMIDAZOLE-PROMOTED SYNTHESIS OF N-PHTHALIMIDE
1573
Scheme 1.
of these reagents releases amines and carbon dioxide. Because of this feature they
have been employed in several reactions as a source of amines.[21] The decomposition
of urea can be catalyzed by imidazole and it plays a fundamental role in the
urea-urease binding in living organisms.[22] Recently, this catalyst has been employed
in the direct synthesis of primary amides from carboxylic acids and urea under
heating.[23]
It would be very advantageous to develop a method that allows the preparation
of N-substituted phthalimide directly from phthalic acid and more stable sources of
amines. With this in mind we set out to demonstrate that the thermal reaction
between phthalic acid and urea or N,N0-disubstituted ureas catalyzed by imidazole
could yield N-substituted phthalimides (Scheme 1).
RESULTS AND DISCUSSION
With the aim to determine the proper conditions for the reaction, we performed
the thermal reaction between equimolar amounts of phthalic acid 1 and urea 2a under
several conditions, summarized in in Table 1. First, the reaction was carried out at
100 ꢀC during 3 h under solvent-free conditions; this experiment gave the desired
phthalimide 3a in 25% yield (Table 1, entry 1). It is already reported that the addition
of small amounts of high-boiling-point polar solvents is beneficial for some solvent-
less reactions. Therefore, to improve the yields, the experiment was repeated along
with the addition of few drops of dimethylformamide (DMF) (3 drops=mmol of 1)
Table 1. Effect of conditions on yields
Entry
Conditions=temperature=time (h)
Yield of 3a (%)a
1
2
3
4
Neat =100 ꢀC=3 h
25
47
76
92
3 drops DMF=100 ꢀC=3 h
3 drops DMF=150 ꢀC=3 h
3 drops DMF=150 ꢀC=3 hb
aChemical yield of pure product after recrystallization from ethanol.
bExperiment performed employing 2 eq. of urea and 1.5 eq. of imidazole.

1574
R. A. W. NEVES FILHO, M. A. T. PALM-FORSTER, AND R. N. de OLIVEIRA
Table 2. Imidazole-catalyzed synthesis of N-substituted phthalimides
[Lit.]
Entry
R
Yield (%)
Mp (ꢀC)
Mp (ꢀC)
1
2
H
CH3
92
75
225–226
132–133
160–161
132–133
208–209
205–206
205–206
181–182
168–170
200–201
203–204
145–146
255–256
226–228[24]
130–132[25]
159–161[26]
131–132[26]
210[4]
207–209[26]
206–207[4]
180–181[4]
168–169[4]
200–201[4]
205–206[17]
143–145[26]
250–252[26]
3
C6H11
CH2Ph
Ph
68
73
75 (68)a
74
72
4
5
6
4-CH3Ph
3-FPh
4-FPh
7
8
69
67
9
3-ClPh
4-ClPh
4-BrPh
4-CH3OPh
4-NO2Ph
10
11
12
13
75
68
76
53
aExperiment has been done at 25-mmol scale.
and this generated the desired product 3a in 47% yield (Table 1, entry 2). By increas-
ing the temperature to 150 ꢀC and employing the previously described conditions, the
yield was further improved to 76% (Table 1, entry 3). Then, by using excess of urea 2a
(3 equiv.) and imidazole (1.5 equiv), it was possible to improve the yield of 3a up to
92% (Table 1, entry 4).
After determining the optimal condition, we decided to investigate the application
of our method on other substrates (i.e., N,N0-disubstituted ureas 2b–m). The reaction is
in general quite clean, and some compounds could be purified by recrystallization from
ethanol. In some cases column chromatography had been used for purification. The
reaction worked quite well with N,N0-dialkyl 2b–d (Table 2, entries 2–4) and N,N0-diaryl
ureas 2e–m (Table 2, entries 5–13), generating the desired compounds 3b–m in moderate
to good yields (53–76%). By employing N,N0-diaryl ureas containing electron-donating
groups attached to the phenyl rings, good yields of the desired compounds could be
obtained. Conversely, N,N0-diaryl ureas containing electron-withdrawing groups
appeared to be less reactive. It is noteworthy that the reaction involving N,N0-2-
nitrophenyl urea resulted in a complex mixture of unidentified products. Nevertheless,
2 m was a reactive substrate and resulted in the formation of product 3 m in 53% yield
(Table 2, entry 13). As N-substituted phthalimides are compounds of great interest, it
would be quite beneficial to scale up the present method for multigram synthesis.
So far, we have tested the reaction using 1, 2e, and imidazole at 25-mmol scale and
got results comparable to the earlier experiments. The structures of the obtained
compounds 3a–m have been confirmed by comparison of melting points and 1H
NMR spectra with the values previously described in literature (Table 2).[4,17,24–26]
CONCLUSION
In summary, we have develop a new method for synthesizing N-substituted
phthalimides from phthalic acid and N,N0-dialkyl- or N,N0-diaryl-ureas catalyzed
by imidazole under solventless conditions in moderate to good yields of 53–92%.

IMIDAZOLE-PROMOTED SYNTHESIS OF N-PHTHALIMIDE
1575
EXPERIMENTAL
A mixture of phithalic acid 1 (0.332 g, 2 mmol), imidazole (0.264 g, 3 mmol), and
the suitable urea (4 mmol) were well triturated and placed in a 25-ml flask, followed
by the addition of six drops of DMF. The mixture was heated at 150 ꢀC in an oil bath
for 3 h. The crude material was cooled down, triturated, and stirred in a 10% v=v
aqueous HCl solution for 10 min. The resulting solid residue was filtered off and
purified by recrystallization from ethanol or column chromatography with gradient
ethyl acetate–n-hexane (1:4) to generate the desired pure products.
For complete experimental details, please see the Supplementary Information,
available online.
ACKNOWLEDGMENTS
The authors are grateful to Pernambuco State Foundation of Science and
Technology (FACEPE-PRONEM No. 1232.1.06=10) for financial support and
DQF-UFPE for obtaining the spectral data.
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