Efficient microwave-assisted synthesis of 1-aryl-4-dimethylamino methyleno-pyrrolidine-2,3,5-triones

Article abstract of DOI:10.1016/j.tetlet.2012.04.024

A microwave-assisted synthesis of a series of 1-aryl-4- dimethylaminomethylene pyrrolidine-2,3,5-triones from the cyclocondensation reaction of ethyl 5,5,5-trichloro-3-dimethylamino methylene-2,4-dioxopentanoate with aniline, 3- or 4-substituted anilines [where the substituents = 3-Me, 3-OMe, 3-OH, 4-Me, 4-F, 4-Cl, 4-Br, 4-NO₂, and 4-COMe] is reported. This process is an efficient alternative to the conventional thermal heating and furnishes the products in a short reaction time (ca. 13 min), under mild conditions and in moderate to good yields (50-76%).

Full text of DOI:10.1016/j.tetlet.2012.04.024

Tetrahedron Letters 53 (2012) 3131–3134
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient microwave-assisted synthesis of 1-aryl-4-dimethylamino
methyleno-pyrrolidine-2,3,5-triones
Pâmela S. Vargas a, Fernanda A. Rosa b, Lilian Buriol a, Mariane Rotta a, Dayse N. Moreira a,
Clarissa P. Frizzo a, Helio G. Bonacorso a, Nilo Zanatta a, Marcos A.P. Martins a,
⇑
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil
b Departamento de Química, Universidade Estadual de Maringá, Av. Colombo, 5790, 87.020-900 Maringá, Paraná, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave-assisted synthesis of a series of 1-aryl-4-dimethylaminomethylene pyrrolidine-2,3,5-tri-
ones from the cyclocondensation reaction of ethyl 5,5,5-trichloro-3-dimethylamino methylene-2,4-
dioxopentanoate with aniline, 3- or 4-substituted anilines [where the substituents = 3-Me, 3-OMe, 3-
OH, 4-Me, 4-F, 4-Cl, 4-Br, 4-NO2, and 4-COMe] is reported. This process is an efficient alternative to
the conventional thermal heating and furnishes the products in a short reaction time (ca. 13 min), under
mild conditions and in moderate to good yields (50–76%).
Received 5 March 2012
Revised 3 April 2012
Accepted 4 April 2012
Available online 20 April 2012
Keywords:
Pyrrolidinetrione
Ó 2012 Elsevier Ltd. All rights reserved.
Enamines
Microwave-assisted synthesis
Cyclocondensation reactions
Pyrrolidinetriones are important heterocyclic compounds
which showed pharmacological activities such as antiviral1 and
antifungal agents.2 Moreover, these compounds are of considerable
interest because of their facile preparation and their use as build-
ing blocks in heterocyclic chemistry.3 The attainment of pyrrolidin-
etriones with alkyl substituents on the 4-position is possible from
condensation of oxalyl chloride with C-2 substituted phenyl aceta-
(Scheme 1). On the other hand, the search and improvement of
these synthetic methods are still a challenge, and the use of micro-
wave irradiation emerges as an important tool for it.
In many instances, controlled microwave heating under sealed
vessel conditions has been shown to dramatically reduce reaction
times, increase product yields, and enhance product purities by
reducing unwanted side reactions when compared to conventional
synthetic methods.14 In this context, our research group has used
the microwave irradiation in the synthesis of heterocyclic com-
pounds.15 As part of our interest in heterocyclic synthesis by pro-
cedures faster and with better yields, we set out to extend these
findings to the preparation of a series of 1-aryl-4-dimethylamino-
methylene-pyrrolidine-2,3,5-triones. In this paper we employed
the unsymmetrical enamino diketone 2 in the reaction with 3- or
4-substituted anilines 1a–j under conventional and microwave
irradiation methods (Table 1).
In order to find suitable conditions for the synthesis of 1-aryl-4-
dimethylaminomethylene-pyrrolidine-2,3,5-trione 3a (Table 1) in
microwave irradiation method, we selected a set of three different
solvents (dichloromethane, acetonitrile, and ethanol). The reac-
tants aniline 1a and enamino diketone 2 were used in a molar ratio
of 1.1:1, respectively. From Table 1 it is possible to observe that
ethanol led to better yields. In the solvent-free microwave irradia-
tion conditions, the product formation was not observed and the
starting material was recovered.
mides4 and by the cyclization of p-alkyl-
a-cyano-b-hydroxycinna-
mates and hydrogen chloride.5 In addition, Zankowska-Jasin ska
et al. extensively investigated the synthesis of pyrrolidinetriones
(1973–80) through the cyclocondensation reaction of aryl-3-oxo-
acid anilides with oxalyl chloride.6–9 Augustin and Jeschke de-
scribed an alternative route to pyrrolidinetriones via
condensation of 2-hydroxymaleinimide esters with aldehydes.
However, this methodology presents disadvantages, mainly due
to their long reaction time and low to moderate yields (20–84%).10
In recent years, we described an efficient method for obtaining a
series of enamino diketones from C-acylation of enamino ketones
with ethyl oxalyl chloride.11–13 The reaction of these precursors
with N-N or N-C-N dinucleophiles was shown to be highly attrac-
tive for the synthesis of both multi-functionalized pyrazoles,12
ethyl 2,5-disubstituted-4-pyrimidinecarboxylates, and pyrimido-
pyridazinones.13 Thus, the enamino diketones have been shown
as valuable synthetic intermediates for the regiospecific construc-
tion of a wide range of simple nitrogen-containing heterocycles
_
This reaction showed to be very sensitive with regard to the
temperature. Indeed, when the cyclocondensation reaction was
performed at temperatures higher than 50 °C it was observed that
⇑
Corresponding author. Tel./fax: +55 55 3220 8756.
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.024

3132
P. S. Vargas et al. / Tetrahedron Letters 53 (2012) 3131–3134
O
R
O
O
O
R
ref. 13
ref. 12
OEt
N
N
NH
R
OEt
N
O
N
R2
N
Me2N
O
R1
ref. 13
ref. 13
O
R
O
O
N
CO2Et
N
R
OEt
R2
N
R2
N
Scheme 1. Synthesis of nitrogen-containing heterocycles from enamino diketones.
Table 1
Table 2
Optimization of the reaction conditions to obtain the pyrrolidine-2,3,5-trione 3a
The best reaction conditions to synthesize the pyrrolidine-2,3,5-trionse 3a–j
using different methodologies
NMe2
NMe2
O
O
R
O
O
NH2
i or ii
OEt
NH2
O
O
Cl3C
Me2N
O
O
N
O
O
OEt
N
Cl3C
Me2N
O
O
R
1a
2
3a
1
a-j
2
3a-j
Entry
Method
Solvent
T (°C)
Time
Yielda (%)
i: MW, EtOH, 50 °C, 12-16 min;
ii: EtOH, reflux, 8-16 h.
1
2
3
4
5
6
7
8
9
Microwave
Microwave
Microwave
Microwave
Microwave
Microwave
CH2CH2
MeCN
EtOH
EtOH
—
EtOH
EtOH
EtOH
EtOH
CH2CH2
MeCN
50
50
50
60
50
100
25
25
78
40
82
12 min
13 min
13 min
12 min
12 min
12 min
5 h
8 h
8 h
8 h
8 h
15
52
Product
R
Microwave method
Conventional method
76
66b
Time (min)
Yield (%)
Time (h)
Yield (%)
c
—
55d
50d
46
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
13
13
13
16
13
13
13
13
12
13
76
73
69
70
67
62
62
72
50
58
8
8
8
9
8
8
8
8
16
9
65
45
54
35
46
53
55
65
35
29
Conventionale
Conventional
Conventional
Conventional
Conventional
3-Me
3-OMe
3-OH
4-Me
4-Br
4-Cl
4-F
4-NO2
4-COMe
65
25
32
10
11
a
b
c
Yield of isolated product.
A mixture was isolated with 17% of 2, determined by 1H NMR.
Recuperated starting material 2.
3j
A mixture was isolated with ca. 50% of 2, determined by 1H NMR.
d
e
Heating with oil bath.
In general, the formation of compounds 3 seemed to be gov-
erned by electronic effects of the substituent. Electron withdraw-
ing substituents allow conjugation of electrons pairs of nitrogen
with the ring. This fact causes a decrease on the electron density
of the nitrogen making it less reactive resulting in products in low-
er yields (3i,3j).
All the isolated products were well characterized by their melt-
ing points, 1H and 13C NMR, and mass spectral data. Pyrrolidinetri-
ones 3a–j showed sets of 1H and 13C NMR data that corresponded
to the proposed structures. Compounds 3a–j showed 1H NMR
chemical shifts for the protons of methyl group NMe2 as two sing-
lets, with chemical shifts in the range of 3.41–3.77, and 3.66–
3.81 ppm. The vinylic proton signals were observed in the range
from 7.58 to 7.79 ppm. The same compounds showed typical 13C
NMR chemical shifts for pyrrolidinetriones in the ranges of
161.5–162.6 for the carbonyl neighbor to ketone carbonyl, and
170.6 ppm for the carbonyl carbon of imide group neighbor to
the exocyclic double bond. The chemical shifts of carbonyl carbon
of ketone group were observed in 173.9 ppm.
the enamino diketone underwent cleavage, forming enamino ke-
tone in a classical retro-Claisen reaction. Thus, the synthesis of
3a was satisfactory when the reaction of 1a with enamino diketone
2 was carried out using microwave-assisted method at 50 °C, dur-
ing 13 min. Conventional method (heating with oil bath) was also
evaluated using the previous three solvents (Table 1). When the
reaction was carried out in 5 h, at 25 °C, the compound 3a forma-
tion was observed, however in a mixture with the starting material
2. Thus the reaction time was extended to 8 h, which furnished the
desired product in poor yield. The yield was improved performing
under reflux for 8 h in the conventional method.
Thus, these methodologies were applied to the other anilines
1b–j leading to the corresponding pyrrolidinetriones 3b–j, as
showed in the Table 2.16
The results obtained in this study using conventional method
and using microwave irradiation were compared. In all cases the
microwave-assisted conditions were found to be superior and the
pyrrolidinetriones 3a–j were obtained in moderate to good yields
(50–76%). Not that the conventional method not only took longer
reaction time but also gave a lower product yield.
The structure of compound 3a was also confirmed by crystal X-
ray diffraction (Fig. 1). From this experiment it was possible to

P. S. Vargas et al. / Tetrahedron Letters 53 (2012) 3131–3134
3133
ring and phenyl ring was 60.10(10)°, which indicates small elec-
tron delocalization between the rings.
Crystallographic data for compound 3a reported in this paper
have been deposited with the Cambridge Crystallographic Data Cen-
ter (CCDC Number 843617). Copies of the data can be obtained, free
of charge, on application to CCDC 12 Union Road, Cambridge CB2
1EZ, UK (Fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
The product identified can be explained by an addition/elimina-
tion reaction in which the amino group of the aniline attacks the
carbonyl carbon atom of the CCl3 group of compound 2 to form ad-
duct I, which suffers an elimination of chloroform to form the
intermediate II. Then, the subsequent heterocyclization was ob-
tained from the second attack of the amide group to the carbonylic
carbon of the ester group, with ethanol elimination to form the
product pyrrolidine-2,3,5-trione (Scheme 2). This mechanism
may be related to the strong electron withdrawing effect of the tri-
chloromethyl group which increases the electron deficiency of the
carbonyl carbon linked to this group, making this center more elec-
trophilic than the carbonyl of the ester moiety.
In conclusion, we developed an efficient method for preparing
pyrrolidinetriones in good yields and under mild conditions. The
method using microwave irradiation is more efficient than other
reported methodologies and the conventional method, thus, it
should find application in the synthesis of these heterocyclic build-
ing blocks.
Acknowledgments
The authors are grateful to Conselho Nacional de Desenvolvi-
Figure 1. ORTEP17 obtained from crystal structure of 4-dimethylamino methylene-
1-phenylpyrrolidin-2,3,5-trione (3a).
mento Científico
e Tecnológico (CNPq/Universal Proc. No.
578426/2008-0; 471519/2009-0), Fundação de Amparo à Pesquisa
do Estado do Rio Grande do Sul (FAPERGS/CNPq-PRONEX Edital No.
008/2009, Proc. No. 10/0037-8), and Coordenação de Aperfeiçoa-
mento de Pessoal de Nível Superior (CAPES/PROEX) for financial
support. The fellowships from CNPq (M.A.P.M., N.Z., H.G.B.,
D.N.M.), CAPES (P.S.V., C.P.F., L.B.), and FAPERGS (M.R.) are also
acknowledged.
R
N
H
H
O
O
O
O
OEt
OEt
H2N R
Cl3C
Me2N
Cl3C
O
O
O
Me2N
I
Supplementary data
Supplementary data (1H NMR, 13C NMR, MS and melting points)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.04.024.
- CHCl3
NMe2
O
O
References and notes
R
OEt
O
O
OEt
N
H
Me2N
O
N
R
1. Gerzon, K. U.S. 3.285–933, 1966.
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Zankowska-Jasinska, W.; Zaleska, B.; Walocha, K. Zesz. Nauk., Uniw. Jagiellon.,
Pr. Chem. 1973, 18, 137.
NMe2
_
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O
_
8. (a) Zankowska-Jasinska, W.; Zaleska, B.; Walocha, K. Zesz. Nauk., Uniw.
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11. Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.; Bonacorso, H. G.; Zanatta,
N.; Martins, M. A. P. Synlett 2007, 3165.
O
O
_
N
R
Scheme 2. Proposal of mechanism to obtain the compounds 3.
12. Rosa, F. A.; Machado, P.; Vargas, P. S.; Bonacorso, H. G.; Zanatta, N.; Martins, M.
A. P. Synlett 2008, 1673.
13. Rosa, F. A.; Machado, P.; Fiss, G. F.; Vargas, P. S.; Fernandes, T. S.; Bonacorso, H.
G.; Zanatta, N.; Martins, M. A. P. Synthesis 2008, 3639.
14. (a) Kremsner, J. M.; Stadler, A.; Kappe, C. O. Top. Curr. Chem. 2006, 266, 233; (b)
Glasnov, T. N.; Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395; (c)
Ondruschka, B.; Bonrath, W.; Stuerga, D. In Microwaves in Organic Synthesis;
Loupy, A., Ed., 2nd ed.; Wiley-VCH: Weinheim, Germany, 2006; p 62. Chapter
confirm that exocyclic double bond C(4)@C(41) of compounds 3a
are in configuration E. The interplanar angle found between the
maleimide ring and the C(41)–N(42)–C(43)–C(44) fragment was
21.74(21)°. The interplanar angle found between the heterocyclic

3134
P. S. Vargas et al. / Tetrahedron Letters 53 (2012) 3131–3134
2; (d) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P.
Chem. Rev. 2009, 109, 4140.
15. (a) Martins, M. A. P.; Beck, P. H.; Moreira, D. N.; Buriol, L.; Frizzo, C. P.; Zanatta,
N.; Bonacorso, H. G. J. Heterocycl. Chem. 2010, 47, 301; (b) Buriol, L.; Frizzo, C.
P.; Marzari, M. R. B.; Moreira, D. N.; Prola, L. D. T.; Zanatta, N.; Bonacorso, H. G.;
Martins, M. A. P. J. Braz. Chem. Soc. 2010, 21, 1037.
equipped with a stir bar. The mixture was irradiated at 50 °C (Table 2), the
power irradiated during the reaction was in the range of 45–80 W, where the
internal pressure was of 31–34 psi. The reaction was performed in
simultaneous cooling mode (power ON) with high magnetic stirring, during
the times and temperatures described in Table 2. After completion of the
reaction, the products 3a–d, 3i, 3j were cooled at room temperature and the
solvent was evaporated under vacuum. The residue was washed with water
(20 mL) and extracted with CH2Cl2 (3 Â 30 mL) and the organic layers were
dried on Na2SO4, and evaporated under vacuum. Recrystallization from hexane
afforded the pure pyrrolidinetriones 3a–d, 3i, 3j. The products 3e–h were
obtained by filtration of the precipitate formed. The precipitate was washed
with EtOH (10 mL) affording the pyrrolidine-2,3,5-triones degree of purity
without need for another method of purification. Representative analytical data
for 3a: Yield: 0.185 g (76%); mp 153–155 °C. 1H NMR (200 MHz, CDCl3):
d = 3.42 (s, 3H, NMe); 3.78 (s, 3H, NMe); 7.36–7.51 (m, 5H, Ph); 7.60 (s, 1H, H6).
13C NMR (50 MHz, CDCl3): d = 43.9 (NMe); 48.5 (NMe); 93.1 (C4); 126.2; 128.0;
128.6; 129.0; 130.2; 131.6 (Ph); 153.6 (C6); 162,6 (C2); 170.6 (C5); 173.9 (C3).
MS (CI): m/z (%) = 245 ([M+H]+, 100); 231 (9); 217 (8), 202 (6); 57 (14); 46 (22).
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C, 64.06; H,
4.75; N, 11.17.
16. Conventional method for the synthesis of 1-aryl-4-dimethylamino
methylenopyrrolidin-2,3,5-triones (3a–j); general procedure:
A mixture of
aniline, 3- or 4-substituted anilines 1a–j (1.1 mmol) and enamino diketone 2
(1 mmol) was stirred under reflux in dry ethanol (5 mL) for 8 h. Then the
mixture was cooled at room temperature and the solvent was evaporated
under vacuum. The residue was washed with water (20 mL) and extracted with
CH2Cl2 (3 Â 30 mL) and the organic layers were dried on Na2SO4, and
evaporated under vacuum. Recrystallization from hexane afforded the pure
pyrrolidinetrione 3a–d, 3i, 3j. The products 3e–h were obtained by filtration of
the precipitate formed. The precipitate was washed with EtOH (10 mL)
affording the pyrrolidine-2,3,5-triones degree of purity without need for
another method of purification. Microwave irradiation for the synthesis of 1-aryl-
4-dimethylamino methylenopyrrolidine-2,3,5-triones (3a–j); general procedure:
Aniline, 3- or 4-substituted anilines 1a–j (1.1 mmol), enamino diketone 2
(1 mmol) and ethanol (2 mL) were placed into
a
10 mL reaction vessel
17. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.