One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones by Solvent-Free and Bi2O3-Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells

Article abstract of DOI:10.1002/jhet.2921

Multifunctionalized 2-pyrrolinones were synthesized from the formal aza-[3?+?2] cycloaddition reaction of acyclic enaminones and diphenylcyclopropenone. For primary enaminones, solventless reaction under microwave heating was developed. On the other hand, catalysis by Bi₂O₃ under conventional heating was the more suitable strategy when secondary enaminones were employed. These conditions allowed the synthesis of a set of 2-pyrrolinones with two vicinal phenyl substituents, which were evaluated for cytotoxicity against U251 and C6 glioblastoma cells. In general, all tested 2-pyrrolinones with two vicinal phenyl rings were more active than those without this structural moiety, and 1-butyl-5-methyl-5-(2-oxopropyl)-3,4-diphenyl-1,5-dihydro-2H-pyrrol-2-one was the most cytotoxic and appears to be a new possibility as an antitumor scaffold to this aggressive brain tumor.

Full text of DOI:10.1002/jhet.2921

Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones by Solvent-Free and
Bi2O3-Catalyzed Approaches and Cytotoxicity Screening Against Glioma
Cells
Silvio Cunha,a,b
José Claudio Serafim,a,b Lourenço Luis Botelho de Santana,a,b Fabiano Damasceno,a,b
*
José Tiago Menezes Correia,a,b Airam Oliveira Santos,a,b Mona Oliveira,c,d Janaína Ribeiro,c,d Jéssika Amparo,c,d and
Silvia Lima Costac,d
*
aInstituto de Química, Universidade Federal da Bahia, Campus de Ondina, 40170-115 Salvador, Bahia, Brazil
bINCT em Energia e Ambiente, Instituto Nacional de Ciência e Tecnologia, Universidade Federal da Bahia, Campus de
Ondina, Salvador, Bahia 40170-290, Brazil
cInstituto de Ciências da Saúde, Departamento de Biofunção/Bioquímica, Laboratório de Neuroquímica e Biologia
Celular, Salvador, Bahia 40.110-100, Brazil
dINCT em Neurociência Translacional, Instituto Nacional de Ciência e Tecnologia, Universidade Federal da Bahia,
Salvador, Bahia 40170-290, Brazil
*
E-mail: silviodc@ufba.br; costasl@ufba.br
Received January 13, 2017
DOI 10.1002/jhet.2921
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Multifunctionalized 2-pyrrolinones were synthesized from the formal aza-[3 + 2] cycloaddition reaction
of acyclic enaminones and diphenylcyclopropenone. For primary enaminones, solventless reaction under
microwave heating was developed. On the other hand, catalysis by Bi2O3 under conventional heating was
the more suitable strategy when secondary enaminones were employed. These conditions allowed the
synthesis of a set of 2-pyrrolinones with two vicinal phenyl substituents, which were evaluated for
cytotoxicity against U251 and C6 glioblastoma cells. In general, all tested 2-pyrrolinones with two vicinal
phenyl rings were more active than those without this structural moiety, and 1-butyl-5-methyl-5-(2-
oxopropyl)-3,4-diphenyl-1,5-dihydro-2H-pyrrol-2-one was the most cytotoxic and appears to be a new
possibility as an antitumor scaffold to this aggressive brain tumor.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
compounds, among other precursors [14–24]. In this
scenario, the formal aza-[3 + 2] cycloaddition of
enaminones emerges as a versatile strategy to the
preparation of five-membered N-heterocycles because two
sigma bonds are formed in a single step, and catalysis by
metal salts and metal-free annulations have already been
reported [25–32] (Fig. 1).
Some characteristic features emerge from Figure 1: the
adequate selection of the reaction conditions and
electrophile affords the synthesis of pyrrole or
pyrrolinone with regiochemical control of the
substituents, and the heterocycles are formed by
incorporating two carbons of the applied electrophile and
two carbons and the nitrogen of the ─N─C═C─ moiety
The 2-pyrrolinone core is present in several compounds
that possess interesting biological activities [1–7]. Because
of this aspect, the synthesis of densely substituted 2-
pyrrolinone is a theme of ongoing interest, and the
development of practical synthetic routes to access this
heterocycle demands continuous improvements [8–13]. In
a subclass of this δ-lactam, the occurrence of two vicinal
phenyl substituents is a relevant structural scaffold
because it increases the biological effect [1].
Acyclic enaminones are attractive as building blocks
to the synthesis of polysubstituted heterocycles,
because they can be easily prepared from 1,3-dicarbonyl
© 2017 Wiley Periodicals, Inc.

Vol 000
S. Cunha, J. C. Serafim, L. L. B. de Santana, F. Damasceno, J. T. M. Correia, A. O. Santos,
M. Oliveira, J. Ribeiro, J. Amparo, and S. L. Costa
Figure 1. Examples of the formal aza-[3 + 2] cycloaddition of enaminones with newly formed sigma bonds in black. [Color figure can be viewed at
wileyonlinelibrary.com]
of the enaminone [25–31], forming two new sigma
bonds.
of green bismuth catalysis [48,49] in the formal
aza-[3 + 2] cycloaddition of acyclic enaminones with
Despite the diversity of approaches that employ the
formal aza-[3 + 2] cycloaddition of enaminones 1 as a
direct route to 2-pyrrolinone [18–20,22,24–32], the
one-step synthesis of such δ-lactam with two vicinal
phenyl substituents is still scarce. On the other hand, the
use of diphenylcyclopropenone 2 is strategic when two
adjacent phenyl rings are required in planned targets
[33–36]. Recently, we described the synthesis of
1-azabicyclic alkaloid-like compounds, which were
obtained by the reaction of cyclic enaminones with
diphenylcyclopropenone [37], which represents an
improved synthesis of 1-azabicyclo[3.3.0]octanes as
compared to that synthesized by the reaction of acyclic
enaminones and diphenylcyclopropenone [38,39].
Particularly noteworthy is the heterocycle formed by
incorporating three carbons of the cyclopropenone ring
and two continuous atoms (─N─C─) of the enaminone
instead of ─N─C═C─ moiety (Fig. 1), being a rare
example of such reaction patterns to the formal [3 + 2]
aza-annulations of this class of compounds [21,38–40],
and in contrast with the other examples shown in
Figure 1 [25–31].
diphenylcyclopropenone, in search of
a
practical
synthesis of polysubstituted 2-pyrrolinones with two
vicinal phenyl substituents. In addition, the cytotoxicity
against glioma cells was evaluated, and some
2-pyrrolinones without vicinal phenyl rings were
synthesized to compare biological activity. New candidate
molecules to treat glioma are a theme of huge importance
because this is the most aggressive brain tumor in
adults [50].
RESULTS AND DISCUSSION
The formal aza-[3 + 2] cycloaddition of enaminones
with diphenylcyclopropenone was first described by
Kascheres and coworkers [32]. This elegant route to 2-
pyrrolinone was further applied to the synthesis of more
elaborated polysubstituted derivatives [38,39]. Despite
this achievement, reaction time is long when primary
enaminones were employed (3 days), and the method is
also very limited in scope and slower with secondary
enaminones in toluene under reflux (6 days). To be useful
in the medicinal chemistry arena, it needs be improved.
Thus, to circumvent this and obtain a small set of 2-
pyrrolinones in a quick way, the synthesis of known 2-
pyrrolinones 3 and 4 was reinvestigated as model
reactions, with the goal of the development of a greener
practical reaction conditions (Scheme 1).
Because of the synthetic potential of the formal
cycloadditions of enaminones [40–45] as well as
alkaloids and alkaloid-like compounds as privileged
cytotoxic scaffolds in glial cells [46,47], we investigated
herein the combination of solvent-free condition,
microwave (MW)-assisted organic synthesis and the use
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones and Cytotoxicity Screening
Against Glioma Cells
Scheme 1. Synthetic route to vicinal 3,4-diphenyl-2-pyrrolinones. [Color figure can be viewed at wileyonlinelibrary.com]
Although primary enaminones 1a–1c are liquid
compounds or solids of low melting points, a solvent-
free reaction of these enaminones and solid
diphenylcyclopropenone 2 was investigated aimed at
obtaining the 2-pyrrolinones with a relatively short
reaction time in relation to the described route [32] to
such compound (3 days for 3 and 4) (Scheme 1). To
this end, the effect of MW heating and the use of
bismuth salts catalysts were evaluated, with results
summarized in Table 1.
Table 1
Conditions to the synthesis of 3,4-diphenyl-2-pyrrolinones by formal aza-[3 + 2] cycloaddition of enaminones with diphenylcyclopropenone.
MW heatinga
Time (min)
Conventional heatingb
Time (day) Yield (%)
Catalyst
(10 mol%)
Entry
Product
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3
3
4
4
5
5
7
7
7
7
8
8
8
8
9
9
9
—
—
—
—
—
—
—
—
—
—
—
—
—
10
30
10
30
10
30
30
—
90
90
10
—
30
90
30
—
90
90
90
—
90
90
25
41c
64
—
—
—
76
—
—
—
—
CM
36
42
—
CM
26
70
—
CM
CM
75
—
18
—
d
—
—
—
—
—
7
76c
57
—
—
60c
23
—
16
36
25
—
18
26
CM
—
CM
CM
CM
—
CM
20
Toluene
Toluene
Toluene
—
Toluene
Toluene
Toluene
—
Toluene
Toluene
Toluene
—
Toluene
Toluene
Toluene
e
Bi(NO3)3
Bi2O3
—
5
4
—
7
4
2
—
7
5
5
—
Bi(NO3)3
Bi2O3
—
—
Bi(NO3)3
Bi2O3
—
—
Bi(NO3)3
Bi2O3
9
10
10
10
10
—
7
2
38
70
5
CM, complex mixture.
aMicrowave heating, 150 °C.
bConventional oil bath heating, under reflux (with solvent) or at 120 °C (solvent free).
cWith two equivalents of enaminone.
dTime: 90 min.
eBi(NO3)3·5H2O.
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S. Cunha, J. C. Serafim, L. L. B. de Santana, F. Damasceno, J. T. M. Correia, A. O. Santos,
M. Oliveira, J. Ribeiro, J. Amparo, and S. L. Costa
Equimolar amounts of 1a and 2 were reacted under MW
heating condition, and 3 could be isolated, however in a
poor yield (Table 1, entry 1). The same transformation
was also performed by employing twice the amount of
enaminone, and compound 3 was formed in a better yield
(entry 2). These reaction conditions were extended to
primary enaminones 1b and 1c, and pyrrolinones 4 and 5
were formed. In general, obtained yields with primary
enaminones were somewhat increased when an excess of
the enaminone (1a–1c) was used (entries 3–6), and very
short reaction times were observed when compared to the
condition previously described to the thermal-induced
formal aza-[3 + 2] cycloaddition reaction (reflux in
toluene, 3 days) [32]. A tentative bromination [51] of the
phenyl rings of 4 resulted only in the acid 6 through ester
hydrolysis (Scheme 1).
reactions time and complex mixture formation. To
circumvent these serious limitations in the synthesis of
N-substituted 2-pyrrolinones from secondary enaminones,
other experimental conditions were investigated.
We recently discovered that Bi(NO3)3·5H2O was
efficient as a catalyst in the formal aza-[3 + 3]
cycloaddition of enaminones [40,41]. Thus, we extended
the bismuth salt catalysis (10 mol%) to the formal
aza-[3
+
2] cycloaddition of enaminones with
diphenylcyclopropenone, en route to the synthesis of
N-substituted 2-pyrrolinones (Table 1).
To amplify the scope of the bismuth compound as a
catalyst in the aza-cycloaddition of enaminones, we
tested Bi(NO3)3·5H2O and Bi2O3, the cheapest Bi(III)
compounds available. Although the two heating
conditions allowed isolation of desirable heterocycles
7–10, the association of MW heating and bismuth
catalysis was deleterious to the isolated yields as
compared to conventional heating, being the catalysis by
Bi2O3 more efficient than Bi(NO3)3·5H2O (compare
entries 9 and 10, 13 and 14, 17 and 18, and 21 and 22;
Table 1 and Scheme 1).
Under Bi(III) catalysis condition, the mechanism for the
formation of 2-pyrrolinones by formal aza-[3 + 2]
cycloaddition can be tentatively rationalized as an ionic
stepwise process (Scheme 2). Thus, coordination of
Bi(III) catalyst with the oxygen atom of the
diphenylcyclopropenone should increase its dipolar
contribution 20, and then a sequence of transformations is
initiated [32] by attachment of the nitrogen of the
secondary enaminones 1d and 1e to the carbonyl carbon
A
three-component reaction to the synthesis of
2-pyrrolinones 3–5 was also studied, using the
corresponding 1,3-dicarbonyl compound,
diphenylcyclopropenone, and ammonium acetate as an
NH3 source to form enaminone in situ, but only complex
mixtures were formed under conventional and MW heating.
To test the influence of MW heating in the solvent-free
method, a control reaction was undertaken, wherein
equimolar amounts of enaminone 1b and 2 were reacted
under conventional heating. In this condition, pyrrolinone
5 was isolated in yield identical to the best MW heating
condition, however with threefold reaction time (compare
entries 3 and 4, Table 1). Therefore, the association of
MW and solvent-free condition is beneficial to N–H 2-
pyrrolinones synthesis from primary enaminones.
With the analysis of the 13C-NMR spectra of obtained
compounds, the amide-type regiochemistry [32,37] for
heterocycles 3–5 is deduced from the chemical shifts of
the endocyclic carbonyl (169 ppm) and beta vinyl carbon
(159 ppm) of the N─(C═O)─C(Ph)═C(Ph)─C moiety
of 3–5.
Scheme 2. Mechanistic proposal for the Bi(III) catalysis in the formal
aza-[3
+
2] cycloaddition. [Color figure can be viewed at
wileyonlinelibrary.com]
Besides, the regiochemical assignment of compound 3
was investigated by 1H, 13C long-range correlation
experiment, which showed a correlation (3J) involving
the hydrogen of CH3 at position 5 of the 2-pyrrolinone
nucleus and the beta vinyl carbon of the C═C─C═O
moiety. This kind of correlation would not be observed
for the opposite regiochemistry.
With a practical reaction condition developed to primary
enaminones in hand, the synthesis of new N-substituted 2-
pyrrolinones 7–10 was investigated (Scheme 1). However,
the solvent-free reaction under the MW heating
methodology was disappointing for the reaction involving
secondary enaminones, affording low yields of 7 and 8
(23–25%, Table 1, entries 7 and 11) or complex mixtures
of 9 and 10 (entries 15 and 19). Worse results were
observed when conventional heating in toluene was
applied (entries 8, 12, 16, and 20) because of long
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones and Cytotoxicity Screening
Against Glioma Cells
of 2 via a hard–hard interaction. Adduct i is thus formed,
which in sequence gives ii after proton shift. This late
suffers a concomitant ring expansion and Michael
reaction forming enol iii, which affords the 2-
pyrrolinones 7–10.
To amplify the set of dihydro-2-pyrrolinones to the
cytotoxicity screening against glioblastoma cells, but now
without two vicinal phenyl substituents, and thus
compare the influence of this structural characteristic in
the biological activity, some other derivatives were
prepared. Toward this, we envisioned the known
synthesis of dihydro-2-pyrrolinones via formal
aza-[3 + 2] cycloaddition of enaminones with maleic
methoxyphenyl)-2-pyrrolidone [50]. Thus, with a set of
dihydro-2-pyrrolinones with (3–10) and without (12–14)
two vicinal phenyl substituents prepared, the in vitro
cytotoxicity against U251 and C6 glioma cells was
investigated, in search of new potential antitumor
activity of synthesized molecules. For comparative
purposes, succinimide–enaminones 15 and 16 were
evaluated as well. Under the biological test conditions,
esters 4 and 5 were partially converted into acid 6 and,
together with compounds 9 and 10, did not show
reproducible results. Considering these facts, the
cytotoxic evaluation of nine compounds was
investigated, as indicated in Figure 2.
anhydride 11a and N-arylmaleimides
(Scheme 3) [29,45,52].
Derivatives 12 and 13 were easily obtained, but
formation of analogous 2-pyrrolinone 14 from reaction of
11b–11d
N-Butyl derivative 7 was the most active in the two
glioma cell lines evaluated. As a general trend, all tested
2-pyrrolinones with two vicinal phenyl rings (3 and 6–8)
were more active than those without this structural
moiety (12–14). Apparently, the presence of a 2-
pyrrolinone core is not sufficient to be cytotoxic against
tested cells, because the activity levels of 12–14 were
comparable to those of 15 and 16 (Fig. 2).
To examine the biological effect of the most active N-
butyl dihydro-2-pyrrolinone 7, C6 tumor cells were
treated with it at different concentrations (1, 10, 50, and
100 μM) during 24 and 72 h (Fig. 3). A dose-dependent
effect was observed, and cytotoxicity at 10, 50, and
100 μM was observed only after 72 h of exposure of C6
tumor cells (Fig. 3A).
N-(4-nitrophehyl)-maleimide
11b
with
primary
enaminone 1a was reluctant. Reaction in acetonitrile,
benzene, or toluene under reflux afforded succinimide–
enaminone 15 exclusively, and similar results were
observed to N-arylmaleimides 11c and 11d yielding 16
and 17. Formation of 14 through the formal aza-[3 + 2]
cycloaddition was achieved by catalysis of AcOH in
acetonitrile, and alternatively, by conversion of 15 under
similar reaction conditions (Scheme 3).
Cytotoxicity screening.
Cytotoxicity studies of δ-
lactam in glioblastoma cells are scarce, and the unique
example that caused a decrease in human glioblastoma
cell survival was rolipram, 4-(3-cyclopentyloxy-4-
The morphology patterns of C6 cells in control
conditions and in those treated with vehicle DMSO
Scheme 3. Synthetic route to pyrrolinones and succinimides from enaminones. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Vol 000
S. Cunha, J. C. Serafim, L. L. B. de Santana, F. Damasceno, J. T. M. Correia, A. O. Santos,
M. Oliveira, J. Ribeiro, J. Amparo, and S. L. Costa
Figure 2. Cytotoxicity screening of selected 2-pyrrolinones 3, 6–8, and 12–14 and succinimides 15 and 16 with viability percentage on U251 and C6
glioma cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cells were treated for 72 h with 100 μM of each compound.
(-): Control (cells cultured without vehicle or any compound). DMSO: vehicle control (cells cultured with 0.1% DMSO). Three experiments with R2 ≥ 0.9
were considered (n = 8). The viability was expressed as mean values and standard error medium from three different experiments. One-way analysis of
variance followed by Bonferroni test for multiple comparisons was used. **P < 0.01 and ***P < 0.001.
Figure 3. Cytotoxic study of compound 7. (A) Dose-dependent effect and cytotoxicity at 1, 10, 50, and 100 μM after 24 and 72 h of exposure to tumor C6
cells. (B) Photomicrography of C6 cells after treatment with 1, 10, 50, and 100 μM during 24 h. (C) Photomicrography of C6 cells after treatment with 1,
10, 50, and 100 μM during 72 h, showing time and dependent effects. Objective 10 × 0.20.
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Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones and Cytotoxicity Screening
Against Glioma Cells
(0.1%) as well as those treated with dihydro-2-pyrrolinone
7 in studied concentrations were observed under phase
contrast microscopy and are presented in the
photomicrographs indicated in Figure 3B, C. It can be
inferred that the observed dose-dependent effect is
corroborated, because after 24 h of exposure of C6 cells
to compound 7, a significant reduction in the number of
viable cells was observed only with a concentration of
100 μM. However, after 72 h of treatment with dihydro-
2-pyrrolinone 7 in concentrations of 10, 50, and 100 μM,
as indicated in the photomicrographs presented in
Figure 3B, C, progressive morphological features in
relation to tested concentrations, like cell shrinkage, cell
wall deformation and mainly reduced number of viable
cells were observed, whereas these morphological
features were absent in the control cell conditions and in
cells treated with vehicle DMSO (0.1%).
reactions, under the indicated power that automatically
reaches and maintains the set temperature, specified in
each case, with IR temperature control and medium
stirring speed using cylindrical stir bars (10 × 3 mm) and
a default ramp time of 10 min. Enaminones 1a–1h
[32,38], diphenylcyclopropenone 2 [54], and maleimides
11b–11d [55] were prepared according to known
procedures.
General synthetic procedure for solvent-free synthesis of 3,
4, and 5. To a 10-mL Pyrex pressure vial for closed vessel
for MW heating reaction was added 97 mg (1 mmol) of
enaminone 1a and 103 mg (0.5 mmol) of
diphenylcyclopropenone 2. The mixture was subjected to
MW heating at 150 °C (200 W) for 10 min. The heating
cycle was repeated twice, affording a total reaction time
of 30 min. After this time, the crude residue was
recrystallized from diisopropyl ether/hexane, affording
63 mg (41% yield) of 3.
5-Methyl-5-(2-oxopropyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one
(3). For 3: white solid, m.p. 172.0–172.6 °C (Lit. [32]
171–172 °C). IR (cmꢀ1) 3419, 1720, 1693, 1359, 1217,
1184, 1145, 759, 696. 1H-NMR (CDCl3, 300 MHz) δ
7.36–7.42 (m, 5H), 7.17–7.20 (m, 5H), 2.89 (d, J 18 Hz,
1H), 2.62 (d, J 18 Hz, 1H), 2.15 (s, 3H), 1.55 (s, 3H).
13C-NMR (CDCl3, 75 MHz) δ 206.5, 171.1, 159.8,
133.4, 132.1, 130.7, 129.3, 128.8, 128.6, 128.5, 127.8,
127.7, 61.9, 49.8, 31.8, 22.5.
CONCLUSION
This study represents a green one-step approach to
dihydro-2-pyrrolinones with vicinal phenyl rings via
formal aza-[3 + 2] cycloaddition of enaminones with
diphenylcyclopropenone. For primary enaminones,
solventless reactions under MW heating are adequate,
while for secondary enaminones, catalysis by Bi2O3
constitutes a practical synthetic route. In this way, these
newly developed conditions afford practical access to
multifunctionalized dihydro-2-pyrrolinones with two
vicinal phenyl substituents in a simple way and are
adequate for the purpose of synthesizing a small set of
such δ-lactam in a quick way for biological screening. In
this case, among tested heterocycles, compound 7 was
the most cytotoxic against U251 and C6 glioma cells and
appears to be a new possibility as an antitumor scaffold
[53], paving the way for diaryl-dihydro-2-pyrrolinones to
be further investigated in this aggressive brain tumor [50].
Ethyl
2-(2-methyl-5-oxo-3,4-diphenyl-2,5-dihydro-1H-
pyrrol-2-yl)acetate (4).
For 4: 129 mg (1 mmol) of
enaminone 1b and 103 mg (0.5 mmol) of
diphenylcyclopropenone 2 afforded 117 mg (76% yield)
of 4, white solid, m.p. 118.5–119.3 °C (Lit. [32] 120–
125 °C). IR (cmꢀ1) 3070, 1724, 1689, 1363, 1317, 1300,
1271, 1222, 1028, 802, 754, 698. 1H-NMR (CDCl3,
500 MHz) δ 7.34–7.38 (m, 5H), 7.18–7.20 (m, 5H), 7.00
(br, 1H), 4.19 (ddt, J 7 and 14 Hz, 2H), 2.72 (d, J 16 Hz,
1H), 2.60 (d, J 16 Hz, 1H), 1.55 (s, 3H), 1.26 (t, J 7 Hz,
3H); 13C-NMR (CDCl3, 125 MHz) δ 171.0 (2 C), 159.4,
133.7, 132.7, 131.1, 129.8, 129.3, 129.1, 129.0, 128.3 (2
CH), 61.5, 61.2, 42.6, 23.5, 14.6.
Methyl
2-(2-methyl-5-oxo-3,4-diphenyl-2,5-dihydro-1H-
pyrrol-2-yl)acetate (5).
For 5: 117 mg (1 mmol) of
EXPERIMENTAL
enaminone 1c and 113 mg (0.6 mmol) of
diphenylcyclopropenone 2 afforded 192 mg (60% yield)
of 5 as a brown oil, which solidified upon standing, m.p.
118.5–119.8 °C, yellow solid, m.p. 119.5–120.2 °C. IR
(cmꢀ1) 3414, 2935, 1666, 1446, 1419, 1465, 1365, 712,
Chemistry.
Melting points were determined on a
Microquímica MQAPF 301 hot plate apparatus and are
uncorrected. Infrared spectra were recorded as KBr disks
on a SHIMADZU IR Affinity-1 instrument. NMR spectra
were recorded using a Varian Gemini 300 spectrometer, a
Bruker 250 MHz, or a Bruker Advance III 500
spectrometer, and the field strengths are indicated in each
compound. Chemical shifts are reported in parts per
million downfield from reference (internal TMS). MW
heating reactions were performed in a CEM Discover SP
using a 10-mL Pyrex pressure vial for closed-vessel
1
698. H-NMR (CDCl3, 250 MHz) δ 7.32–7.38 (m, 5H),
7.16–7.20 (m, 5H), 7.06 (s, 1H), 3.71 (s, 3H), 2.74 (d,
1H, J 15 Hz), 2.59 (d, 1H, J 15 Hz), 1.54 (s, 3H). 13C-
NMR (CDCl3, 62.5 MHz) δ 171.0, 170.6, 159.0, 133.2,
132.3, 130.6, 129.4, 128.8, 128.7, 128.6, 127.9 (2 CH),
60.8, 52.0, 42.0, 23.1. Anal. Calcd. for C20H19NO3: C,
74.75%; H, 5.96%; N, 4.36%. Found: C, 74.32%; H,
6.21%; N, 4.13%.
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Vol 000
S. Cunha, J. C. Serafim, L. L. B. de Santana, F. Damasceno, J. T. M. Correia, A. O. Santos,
M. Oliveira, J. Ribeiro, J. Amparo, and S. L. Costa
Synthetic procedure for additional solvent-free synthesis
of 3, 4, and 5 (Table 1).
500 MHz) δ 7.32–7.38 (m, 5H), 7.16–7.21 (m, 5H),
3.56 (ddd, 1H, J 14.0, 10.5 and 5.0 Hz), 3.27 (ddd, 1H,
J 14.0, 10.5 and 5.0 Hz), 2.91 (d, 1H, J 16.0 Hz), 2.71
(d, 1H, J 16.0 Hz), 2.04 (s, 3H), 1.59–1.80 (m, 2H),
1.46 (s, 3H), 1.38–1.44 (m, 2H), 0.97 (t, J 7.5 Hz, 3H).
13C-NMR (CDCl3, 125 MHz) δ 204.2, 169.8, 156.2,
134.0, 133.4, 131.8, 131.4, 129.7, 129.3, 128.8, 128.5,
127.9, 127.8, 65.8, 47.2, 40.6, 31.5, 24.2, 20.9, 14.0.
Anal. Calcd. for C24H27NO2: C, 79.74%; H, 7.53%; N,
To a 10-mL Pyrex pressure
vial for closed vessel for MW heating reaction was
added 59 mg (0.5 mmol) of enaminone 1a and 59 mg
(0.6 mmol) of diphenylcyclopropenone 2. The mixture
was subjected to MW heating at 150°C (200 W) for
10 min. After this time, the crude residue was
recrystallized from diisopropyl ether/hexane, affording
40 mg of 3, 25% yield, m.p. 170.0–171.2 °C (Lit. [32]
171–172 °C).
For 4: A mixture of 30 mg (0.2 mmol) of enaminone 1b
and 42 mg (0.2 mmol) of diphenylcyclopropenone 2 was
MW heated at 150 °C (200 W) for 10 min. After this
time, the crude residue was recrystallized from
diisopropyl ether/hexane, affording 43 mg of 4, 64%
yield, m.p. 121.4–122.4 °C (Lit. [32] 120–120.5 °C).
Alternatively, a mixture of 25 mg (0.2 mmol) of
enaminone 1b and 44 mg (0.2 mmol) of
diphenylcyclopropenone 2 was heated at 110 °C in an oil
bath for 90 min. After this time, the crude residue was
recrystallized from diisopropyl ether/hexane, affording
51 mg of 4, 76% yield, m.p. 121.4–122.4 °C (Lit. [32]
120–120.5 °C).
3.87%. Found: C, 80.02%; H, 7.21%; N, 3.41%.
1-Cyclohexyl-5-methyl-5-(2-oxopropyl)-3,4-diphenyl-1,5-
dihydro-2H-pyrrol-2-one (8). For 8: 44 mg (0.2 mmol)
of enaminone 1e, 42 mg (0.2 mmol) of
diphenylcyclopropenone 2, and 10 mg (0.02 mmol) of
Bi2O3 afforded 60 mg (77% yield) of 8, brown oil, IR
(cmꢀ1) 1713, 1667, 1366, 698. 1H-NMR (CDCl3,
500 MHz) δ 7.36–7.38 (m, 5H), 7.14–7.19 (m, 5H), 3.11
(tt, 1H, J 12.0 and 3.5 Hz), 2.87 (d, 1H, J 17 Hz), 2,65
(d, 1H, J 17 Hz), 2.49–2.60 (m, 2H), 2.04 (s, 3H), 1.83–
1.89 (m, 2H), 1.53–1.61 (m, 3H), 1.49 (s, 3H), 1.27–128
(m, 3H). 13C-NMR (CDCl3, 125 MHz) δ 203.8, 169.2,
155.0, 134.0, 133.9, 131.3, 129.6, 129.9, 128.6, 128.3,
127.6, 127.4, 65.7, 53.7, 46.5, 31.3, 30.02, 29.6, 26.6,
26.5 25.3, 23.7. Anal. Calcd. for C26H29NO2: C, 80.59%;
H, 7.54%; N, 3.61%. Found: C, 80.05%; H, 8.00%; N,
For 5: 31 mg (0.3 mmol) of enaminone 1c and 43 mg
(0.2 mmol) of diphenylcyclopropenone 2 afforded 38 mg
of 5, 57% yield, m.p. 118.5–119.8 °C.
2-(2-Methyl-5-oxo-3,4-diphenyl-2,5-dihydro-1H-pyrrol-2-yl)
acetic acid (6). To a solution of 68 mg (0.2 mmol) of 4 in
3.33%.
1-(2-Hydroxyethyl)-5-methyl-5-(2-oxopropyl)-3,4-diphenyl-1,5-
dihydro-2H-pyrrol-2-one (9).
For 9: 31 mg (0.2 mmol)
of enaminone 1f, 41 mg (0.2 mmol) of
diphenylcyclopropenone 2, and 26 mg (0.05 mmol) of
Bi2O3, 7 days, afforded 29 mg (42% yield) of 9, yellow oil,
5 mL of methanol maintained under magnetic stirring and
ice bath was added 70 μL of 48% hydrobromic acid
(2.1 mmol) and 50 μL of hydrogen peroxide drop by
drop. After 20 h, the reaction mixture was poured into
ice, and a white solid was precipitated. After filtration,
the solid was air dried, leading to 50 mg (80%) of 6. IR
(cmꢀ1) 3426, 2981, 1728, 1683, 1519, 1345, 1199,
1
IR (cmꢀ1) 3361, 2954, 1740, 1643, 1367, 692. H-NMR
(CDCl3, 250 MHz) δ 7.33–7.37 (m, 5H), 7.14–7.21 (m,
5H), 3.78–3.98 (m, 2H), 3.56–3.60 (m, 2H), 2.88 (d, 1H, J
17 Hz), 2.71 (d, 1H, J 17 Hz) 2.03 (s, 3H), 1.48 (s, 3H).
13C-NMR (CDCl3, 62.5 MHz) δ 204.5, 172.0, 157.1,
133.7, 133.2, 131.1, 129.7, 129.1, 129.1, 128.9, 128.1,
66.1, 62.7, 46.5, 44.4, 31.6, 23.8. Anal. Calcd. for
C22H23NO3: C, 75.62%; H, 6.63%; N, 4.01%. Found: C,
75.41%; H, 6.88%; N, 4.73%.
1
1029, 744, 696. H-NMR (CDCl3, 500 MHz) δ 8.75 (br,
1H), 7.33–7.40 (m, 5H), 7.19–7.23 (m, 5H), 3.71 (3H,
s), 2.68 (d, 1H, J 15 Hz), 2.82 (d, 1H, J 15 Hz), 1.68
(3H, s). 13C-NMR (CDCl3, 125 MHz) δ 174.3, 172.8,
160.7, 133.2, 132.0, 130.5, 129.6, 129.1, 128.9, 128.7,
128.23, 128.17, 62.3, 41.7, 22.8. Anal. Calcd. for
C19H17NO3: C, 74.25%; H, 5.58%; N, 4.56%. Found: C,
74.11%; H, 5.67%; N, 4.12%.
Ethyl
2-(1-(2-hydroxyethyl)-2-methyl-5-oxo-3,4-diphenyl-
2,5-dihydro-1H-pyrrol-2-yl)acetate (10).
For 10: 45 mg
(0.3 mmol) of enaminone 1g, 45 mg (0.2 mmol) of
diphenylcyclopropenone 2, and 20 mg (0.04 mmol) of
Bi2O3, 5 days, afforded 59 mg (78% yield) of 10, yellow
General synthetic procedure for 7, 8, 9, and 10.
A
1
oil, IR (cmꢀ1) 3417, 1666, 1419, 1265, 744. H-NMR
mixture of 47 (0.3 mmol) of enaminone 1d, 53 mg
(0.3 mmol) of diphenylcyclopropenone 2, and 12 mg
(0.03 mmol) of Bi2O3 in 5-mL toluene was heated at
110 °C in an oil bath for 4 days. After this time, the
product was purified by column chromatography in
hexane/ethyl acetate 1:1, affording 36 mg (49% yield)
(CDCl3, 500 MHz) δ 7.31–7.37 (m, 7H), 7.18–7.19 (m,
3H), 4.10 (q, 2H, J 7.0 Hz), 3.92 (m, 2H), 3.71 (m, 1H),
3.54 (m, 1H), 2.82 (d, 1H, J 15 Hz), 2.76 (d, 1H, J
15 Hz), 1.43 (s, 3H), 1.21 (t, 3H, J 7.0 Hz). 13C-NMR
(CDCl3, 125 MHz) δ 171.8, 168.7, 157.2, 133.4, 133.0,
130.8, 129.5, 129.3, 128.9, 128.7, 128.1, 128.0, 66.4,
62.8, 61.2, 44.8, 40.1, 23.4, 14.3. Anal. Calcd. for
C23H25NO4: C, 72.80%; H, 6.64%; N, 3.69%. Found: C,
72.76%; H, 6.36%; N, 4.17%.
of 7.
1-Butyl-5-methyl-5-(2-oxopropyl)-3,4-diphenyl-1,5-dihydro-
2H-pyrrol-2-one (7). Yellow oil, IR (cmꢀ1) 3456, 3055,
1
2958, 1716, 1678, 1404, 1265, 698. H-NMR (CDCl3,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones and Cytotoxicity Screening
Against Glioma Cells
2-(4-(Ethoxycarbonyl)-5-methyl-2-oxo-2,3-dihydro-1H-pyrrol-
3-yl)acetic acid (12). A mixture of 129 mg (1 mmol) of
Ethyl(Z)-3-amino-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-
3-yl)but-2-enoate (15). A mixture of 65 mg (0.5 mmol) of
enaminone 1a and 98 mg of maleic anhydride 11a
(1 mmol) in acetonitrile (5 mL) was magnetically stirred at
room temperature for 0.5 h. After this time, the reaction
mixture was concentrated under reduced pressure, and the
residue was washed with cold acetone, affording 215 mg
enaminone 1a and 111 mg (0.5 mmol) of 11b was heated
under reflux in 5 mL of acetonitrile for 16 h and, after this
time, was allowed to cool to room temperature and
concentrated. The crude residue was triturated with ethyl
acetate (or cold ethanol), yielding 130 mg (75%) of 15,
as an off-white solid, m.p. 167–169 °C. IR (cmꢀ1) 3440,
(95% yield) of 12. 13C-NMR (acetone-D , 75 MHz) δ
6
179.8, 172.5, 164.6, 154.2, 106.7, 69.8, 45.9, 44.4, 39.2,
14.6, 14.2.
3319, 2985, 1708, 1612, 1523, 1344, 1267, 1162, 1024,
1
950, 856, 773, 702. H-NMR (DMSO-D , 300 MHz) δ
6
2-(1-Cyclohexyl-4-(ethoxycarbonyl)-5-methyl-2-oxo-2,3-dihydro-
8.40 (d, J 9.0 Hz, 2H), 7.60 (d, J 9.0 Hz, 2H), 7.22 (sl,
1H), 4.0 (m, 2H), 3.15 (dd, J 18.0 and 9.6 Hz, 1H), 2,60
(dd, J 18.0 and 5.4 Hz, 1H), 2.43 (m, 1H), 2.05, (s, 3H),
1.05 (t, J 7.0 Hz, 3H). Anal. Calcd. for C16H17N3O6: C,
55.33%; H, 4.93%; N, 12.10%. Found: C, 55.07%; H,
5.51%; N, 12.47%.
1H-pyrrol-3-yl)acetic acid (13).
A mixture of 130 mg
(1 mmol) enaminone of 1h and 99 mg (1 mmol) of
anhydride maleic 11a in 5 mL of acetonitrile was
reacted for 30 min under magnetic stirring at room
temperature. After this time, the reaction mixture was
concentrated under reduced pressure, and the residue
was purified by washing with acetone at ꢀ5 °C,
affording 300 mg (97% yield) of 13 as a yellow oil.
Alternatively, a mixture of 65 mg (0.5 mmol) of
enaminone 1a and 111 mg (0.5 mmol) of 11b was heated
under reflux in 5 mL of toluene (or benzene) for 16 h and,
after this time, was allowed to cool to room temperature
and concentrated. The crude residue was triturated with
cold ethanol, affording 100 mg (57%, or 80% in benzene)
of 15, as an off-white solid, m.p. 164–166 °C.
1H-NMR (acetone-D , 300 MHz) δ 4.15 (dd, J 7.0
6
and 13.7 Hz, 2H), 4.13 (m, 1H), 3.70 (tt, J 3.6 and
12 Hz, 1H), 3,32 (m, 1H), 2.86 (dd, J 4.8 and 16.5 Hz,
2H), 2.49 (s, 1H), 2.21 (m, 2H), 1.72 (m, 4H), 1.27 (m,
3H), 1.26 (t, J 7.0 Hz, 3H). 13C-NMR (acetone-D ,
6
Ethyl(Z)-3-amino-2-(2,5-dioxo-1-(o-tolyl)pyrrolidin-3-yl)but-
75 MHz) δ 178.4, 171.8, 164.0, 156.3, 105.9, 59.3, 53.9,
43.3, 33.7, 29.8, 29.4, 26.2, 26.1, 25.4, 14.1, 12.3. Anal.
Calcd. for C16H23NO5: C, 62.12%; H, 7.49%; N, 4.53%.
Found: C, 62.32%; H, 7.21%; N, 4.44%.
Ethyl-2-methyl-4-(2-((4-nitrophenyl)amino)-2-oxoethyl)-5-oxo-
2-enoate (16).
A mixture of 132 mg (1 mmol) of
enaminone 1a and 174 mg (1 mmol) of 11c was heated
under reflux in acetonitrile for 18 h and, after this time,
was allowed to cool to room temperature and
concentrated. The crude residue was triturated with cold
ethyl acetate, yielding 74 mg (25%) of 16, as an off-
white solid, m.p. 139.6–140.1 °C. IR (cmꢀ1) 3477, 3317,
2985, 1703, 1618, 1517, 1380, 1265, 1186, 1101, 1027,
4,5-dihydro-1H-pyrrole-3-carboxylate (14).
A mixture of
131 mg (1 mmol) of enaminone 1a and 220 mg (1 mmol)
of N-(p-nitrophenyl)maleimide 11b in mL of
5
acetonitrile was added one drop of acetic acid. The
mixture was heated under reflux for 15 h and, after this
time, was allowed to cool to room temperature and
concentrated. The crude residue was recrystallized with
cold ethanol, yielding 72 mg (20%) of 14, as an off-white
solid, m.p. 180–182 °C. IR (cmꢀ1) 3294, 1662, 1620,
1
946, 759, 721. H-NMR (CDCl3, 300 MHz) δ 7.30 (4H,
m), 7.10 (1H, dd) 4.20 (2H, m), 3.8 (1H, dd, J 9.6 and
5.7 Hz), 2.98 (2H, dd), 2.8 (1H, dd, J 18 and 5.7 Hz),
2.7 (3H, t, 21.3 Hz), 2.09 (3H, s), 1.24 (3H, t, J 7.2 Hz).
13C-NMR (CDCl3, 75 MHz) δ (to the major rotamer)
175.7, 168.3, 159.8, 135.5, 131.1, 129.2, 128.0, 127.7,
126.7, 59.4, 40.1, 36.4, 21.5, 17.8, 14.8. Anal. Calcd. for
C17H20N2O4: C, 64.54%; H, 6.37%; N, 8.86%. Found: C,
64.87%; H, 6.69%; N, 8.50%.
Alternatively, a mixture of 190 mg (1 mmol) of
enaminone 1a and 13 mg (1 mmol) of 11c was heated
under reflux in toluene for 2 h and, after this time, was
allowed to cool to room temperature and concentrated.
The crude residue was recrystallized from ethyl acetate
and hexane, yielding 131 mg (76%) of 16 as an off-white
1508, 1340, 1166. 1H-NMR (DMSO-D , 300 MHz) δ
6
10.55 (sl, 1H), 8.17 (d, J 9.0 Hz, 2H), 7.77 (d, J 9.0 Hz,
2H), 4.02 (m, 2H), 2.99 (dd, J 15.6 and 5.1 Hz, 1H), 2.87
(dd, J 15.6 and 5.1 Hz, 1H), 2.50 (sl, 1H), 2.25 (s,3H),
1.12 (t, J 7.2 Hz, 3H). 13C-NMR (DMSO-D , 75 MHz) δ
6
179.2, 169.6, 163.6, 153.9, 145.2, 142.1, 124.9, 118.7,
105.3, 58.9, 43.4, 36.0, 14.2, 13.5. Anal. Calcd. for
C16H17N3O6: C, 55.33%; H, 4.93%; N, 12.10%. Found:
C, 55.58%; H, 5.20%; N, 11.74%.
Alternatively, 14 can be prepared from 15: to a solution
of 35 mg (0.1 mmol) of 15 in 5 mL of acetonitrile was
added one drop of acetic acid, and this mixture was
heated under reflux for 12 h. After this time, the reaction
mixture was allowed to cool to room temperature and
concentrated. The crude residue was triturated with cold
ethanol, affording 13 mg (37%) of 15, as a white solid.
solid, m.p. 139.7–141.1 °C.
Ethyl(Z)-3-amino-2-(1-(4-methoxyphenyl)-2,5-dioxopyrrolidin-
3-yl)but-2-enoate (17). A mixture of 66 mg (0.5 mmol)
of enaminone 1a and 105 mg (0.5 mmol) of 11d was
heated under reflux in acetonitrile for 48 h and, after
this time, was allowed to cool to room temperature and
concentrated. The crude residue was recrystallized from
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Vol 000
S. Cunha, J. C. Serafim, L. L. B. de Santana, F. Damasceno, J. T. M. Correia, A. O. Santos,
M. Oliveira, J. Ribeiro, J. Amparo, and S. L. Costa
ethyl acetate and hexane, yielding 131 mg (76%) of 17,
as an off-yellow solid, m.p. 120.1–122.4 °C. IR (cmꢀ1
Finland). Eight replicate wells were used for each analysis
in three independent experiments. The results were
determined as the average and standard deviation and
expressed as percentages of the control.
)
3465, 3319, 1714, 1614, 1394, 1178, 1031, 769. 1H-
NMR (CDCl3, 250 MHz) δ 8,60 (1H, br), 7.25 (2H, d),
7.05 (2H, d), 4.15 (2H, m), 3.80 (3H, s), 3.70 (1H, dd,
J 9.6 and 5.7 Hz), 3.01 (1H, dd, J 18 and 9.6 Hz), 2.75
(1H, dd, J 18 and 5.7 Hz), 2.10 (3H, s), 1.60 (1H, sl),
1.15 (3H, t). 13C-NMR (CDCl6, 62.5 MHz) δ 179.0,
176.0, 168.5, 159.5, 159.4, 127.5, 125.0, 114.5, 91.0,
59.5, 55.5, 40.0, 35.5, 21.5, 14.5. Anal. Calcd. for
C17H20N2O5: C, 61.44%; H, 6.07%; N, 8.43%. Found:
C, 61.70%; H, 6.22%; N, 8.11%.
Acknowledgments. The authors acknowledge the financial
support of Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES), and Fundação de Amparo
à Pesquisa do Estado da Bahia (FAPESB). We also thank
student fellowships PERMANECER-UFBA and CNPQ to J.C.
Serafim; PIBIC-FAPESB to J. Ribeiro and J. Amparo;
fellowships to L.L.B. Santana (CAPES and CNPQ), M. Oliveira
(FAPESB), and F. Damasceno (CNPq); and research fellowships
to S. Cunha (CNPq) and S. L. Costa (CNPq).
Alternatively, a mixture of 41 mg (0.3 mmol) of
enaminone 1a and 65 mg (0.3 mmol) of 11d was heated
under reflux in toluene for 21 h and, after this time, was
allowed to cool to room temperature and concentrated.
The crude residue was recrystallized from a mixture of
ethyl acetate and hexane, yielding 131 mg (76%) of 17,
as a pale yellow solid, m.p. 120.3–122.7 °C.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones and Cytotoxicity Screening
Against Glioma Cells
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Additional Supporting Information may be found online
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet