Ultrasound-Promoted Environmentally Friendly Synthesis of 5-(3,3,3-Trifluoro-2-oxopropylidene)pyrrolidin-2-ones

Article abstract of DOI:10.1080/00397911.2014.978504

A facile, one-pot, ultrasound-promoted synthesis of N-substituted 5-(3,3,3-trifluoro-2-oxopropylidene)pyrrolidin-2-ones from methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-enoate and a wide range of primary alkyl(aryl)amines using ethanol as a green solvent

Full text of DOI:10.1080/00397911.2014.978504

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Ultrasound-Promoted Environment-Friendly Synthesis
of 5-(3,3,3-Trifluoro-2-oxopropylidene)pyrrolidin-2-
ones
Márcia S. F. Francoa, Gleison A. Casagrandea, Cristiano Raminellib, Sidnei Mourac, Marcelo
Rossattod, Frank H. Quinae, Claudio M. P. Pereiraf, Alex F. C. Floresg & Lucas Pizzutia
a Grupo de Pesquisa em Síntese e Caracterização Molecular, Faculdade de Ciências Exatas e
Tecnologia, Universidade Federal da Grande Dourados, Dourados, MS, Brazil
b Departamento de Ciências Exatas e da Terra, Universidade Federal de São Paulo, Diadema,
SP, Brazil
c Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil
d Instituto Federal Farroupilha, Panambi, RS, Brazil
e Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo,
São Paulo, SP, Brazil
f Instituto de Química e Geociências, Universidade Federal de Pelotas, Pelotas, RS, Brazil
g Universidade Federal do Rio Grande, Escola de Química e Alimentos, Rio Grande, RS, Brazil
Accepted author version posted online: 17 Nov 2014.
To cite this article: Márcia S. F. Franco, Gleison A. Casagrande, Cristiano Raminelli, Sidnei Moura, Marcelo Rossatto, Frank H.
Quina, Claudio M. P. Pereira, Alex F. C. Flores & Lucas Pizzuti (2014): Ultrasound-Promoted Environment-Friendly Synthesis
of 5-(3,3,3-Trifluoro-2-oxopropylidene)pyrrolidin-2-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.978504
To link to this article: http://dx.doi.org/10.1080/00397911.2014.978504
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Ultrasound-Promoted Environment-Friendly Synthesis of 5-(3,3,3-Trifluoro-2-
Oxopropylidene)Pyrrolidin-2-Ones
Márcia S. F. Franco1, Gleison A. Casagrande1, Cristiano Raminelli2, Sidnei Moura3,
Marcelo Rossatto4, Frank H. Quina5, Claudio M. P. Pereira6, Alex F. C. Flores7, Lucas
Pizzuti1
1Grupo de Pesquisa em Síntese e Caracterização Molecular, Faculdade de Ciências
Exatas e Tecnologia, Universidade Federal da Grande Dourados, Dourados, MS, Brazil,
2Departamento de Ciências Exatas e da Terra, Universidade Federal de São Paulo,
Diadema, SP, Brazil, 3Universidade de Caxias do Sul, Caxias do Sul, RS, Brazil,
4Instituto Federal Farroupilha, Panambi, RS, Brazil, 5Departamento de Química
Fundamental, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil,
6Instituto de Química e Geociências, Universidade Federal de Pelotas, Pelotas, RS,
Brazil, 7Universidade Federal do Rio Grande, Escola de Química e Alimentos, Rio
Grande, RS, Brazil
Address correspondence to Lucas Pizzuti, Grupo de Pesquisa em Síntese e Caracterização
Molecular, Faculdade de Ciências Exatas e Tecnologia, Universidade Federal da Grande
Dourados, Rua João Rosa Góes, 1761, 79825-070 Dourados, MS, Brazil. E-mail:
lucas.pizzuti@gmail.com
Abstract
A facile one pot ultrasound-promoted synthesis of N-substituted 5-(3,3,3-trifluoro-2-
oxopropylidene)pyrrolidin-2-ones from methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-
enoate and a wide range of primary alkyl(aryl)amines using ethanol as a green solvent
and employing TEA as a base is described.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
1

KEYWORDS: Pyrrolidin-2-ones, 5-alkylidenepyrrolidin-2-ones, γ-alkylidene-γ-lactams,
[CCCC+N] cyclocondensations, trifluoromethyl, ultrasound
INTRODUCTION
Pyrrolidin-2-one or γ-lactam derivatives have been attracted much attention in the
last decade due to the well-established nootropic, post traumatic neuroprotective and anti-
epileptic effects of piracetam-like compounds.[1] In nature, the pyrrolidin-2-one core has
been found in the structure of natural compounds that possess a wide spectrum of
biological activities.[2] The related 5-alkylidenepyrrolidin-2-ones or γ-alkylidene-γ-
lactams are important functionalities in natural products chemistry,[2,3] and they are
commonly found as building blocks for a wide variety of derivatives including naturally
occurring pyrrolidines[4] and other compounds with potential bioactivities.[5] Furthermore,
they form the skeleton of biologically important tetrapyrroles such as chlorins,
isobacteriochlorins and corrins.[6]
For these reasons, numerous procedures have been reported for the preparation of
5-alkylidenepyrrolidin-2-ones, such as 5-exo-dig cyclization of alkynylamides,[4a,4b,5b,7]
intramolecular cyclization of 4-aminoesters,[3b,5a,8] lactamization of 5-
2

alkylidenelactones,[9] addition of Grignard reagents to pyrrolidin-2,5-diones[4e,4f,10] and
others.[11] However, these methods often involve employment of unsafe solvents,
uncommon catalysts as well as time-consuming reaction and work-up steps that can be
problematic when planning their application in scaled-up processes. Interestingly, we
were surprised to find that environment-friendly methodologies were not employed in the
synthesis of 5-alkylidenepyrrolidin-2-ones yet.
Given these precedents, we decided to explore the viability of using ultrasonic
irradiation to promote the reaction of methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-
enoate with primary alkyl(aryl)amines to prepare 5-(3,3,3-trifluoro-2-oxopropylidene)-
pyrrolidin-2-ones.
RESULTS AND DISCUSSION
The methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-enoate (1) was prepared from
levulinic acid, a material derived from wood-processing and agricultural waste,[12]
according to published methodology.[8b]
Initially, the reaction of methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-enoate (1)
with aniline 2k was carried out in acetonitrile, chloroform, ethanol and water to choose
the best solvent (Table I). It was found that acetonitrile and chloroform were not suitable
since a mixture of β-enaminoketone 3k and the desired pyrrolidinone 4k was obtained
after 120 min of sonication (Table I, entries 1 and 2). When the same transformation was
performed in water for 120 min, only the desired product was observed by GC but the
3

yield was disappointing (Table I, entry 3). When the reaction was carried out in ethanol
the yield of isolated pyrrolidinone 4k increased substantially although a little amount of
the β-enaminoketone 3k was observed by GC after 120 min (Table I, entry 4). Based on
these results further examinations were made using ethanol as solvent. An experiment
was performed in order to check the importance of the base TEA for the reaction (Table
I, entry 5). When the reaction was carried out without base, only the β-enaminoketone 3k
was detected by GC. In order to show the beneficial effect of the ultrasonic irradiation in
the synthesis, two control experiments were performed in the absence of ultrasonic
irradiation: first, the starting material 1 was allowed to react with aniline 2k for 120 min
under room temperature in ethanol; then, the reaction was repeated under reflux for 120
min. Under the former silent condition, the formation of product 4k was not observed
(Table I, entry 6). The reaction conducted under reflux furnished a mixture of 3k and 4k
in the ratio of 1:1, as determined by GC (Table I, entry 7). These results show that the
ultrasonic irradiation plays an important role in the proposed synthesis, mainly in the
cyclization of the intermediate 3k.
To examine the scope of this methodology, the reaction of methyl 7,7,7-trifluoro-
4-methoxy-6-oxohept-4-enoate (1) with 1 equivalent of various alkyl(aryl)amines (2a-t)
in the presence of 1 equivalent of TEA under sonication were studied (Table II).
When 1 was allowed to react with methyl esters of valine 2a or methionine 2b
only the β-enaminoketones 3a or 3b were obtained, respectively (Table II, entries 1 and
2). On the other hand, when methyl esters of alanine 2c or phenylalanine 2d were used as
4

nucleophiles, mixtures of β-enaminoketones and cyclic products were obtained after
sonication for 120 min (Table II, entries 3 and 4). For the less hindered aminoester 2e, the
reaction furnished exclusively the desired cyclic product 4e after 90 min in 83% of yield
(Table II, entry 5). Results of experiments 1-5 show that the success of the reaction of 1
with aminoester derivatives depends on the steric hindrance exerted by the substituent
bonded to the nitrogen. Accordingly, by performing the reaction of glycinamide
hydrochloride 2f with 1 for 60 min, only the pyrrolidinone 4f was isolated in 81% of
yield (Table II, entry 6). When methyl 7,7,7-trifluoro-4-methoxy-6-oxohept-4-enoate (1)
was allowed to react under ultrasonic irradiation with n-propylamine (2g), the
pyrrolidinone 4g was obtained in excellent yield of 94% (Table II, entry 7). Similar
results were obtained when 2-chloroethylamine hydrochloride (2h) (Table II, entry 8), n-
butylamine (2i) (Table II, entry 9) or benzylamine (2j) (Table II, entry 10) were used as
nucleophiles. Afterwards, reactions of 1 with several aromatic amines bearing electron-
donating groups or electron-withdrawing groups and a variety of substitution patterns
were also performed. In general, these reactions were slower than the reactions of
alkylamines 2e-j, moreover the N-arylpyrrolidinones were isolated in poorer yields than
N-alkylpyrrolidinones. As can be seen in Table II, entry 11-20, the electronic effects of
the groups attached to the benzene ring did not show a linear response on the reactivity
and yields. Finally, the β-enaminoketones 3a,b and the pyrrolidin-2-ones 4e-t were fully
characterized by low and high resolution mass spectrometry as well as 1H and 13C NMR.
The spectral data are in accordance with the proposed structures. The structure of the
pyrrolidinone 4e was further confirmed by single-crystal X-ray crystallographic studies.
As can be seen in Figure I, the olefinic moiety shows the E configuration.
5

CONCLUSION
In conclusion, a facile and intensified one pot route for the preparation of 5-(3,3,3-
trifluoro-2-oxopropylidene)-pyrrolidin-2-ones was developed by applying ultrasound
irradiation. The combination of ultrasonic power, short reaction times, use of ethanol as
solvent and starting material derived from levulinic acid are features that contribute to the
greenness of the process. This simple methodology offers a mild alternative for the
synthesis of pyrrolidin-2-ones which are structurally related to known bioactive
compounds.
EXPERIMENTAL
The full experimental details and characterization data for the preparation of title
compounds are provided in the Supplementary Information, available online. CCDC
1027587 contains the supplementary crystallographic data for 4e. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: (+44) 1223 336 033; or e-mail: deposit@ccdc.cam.ac.uk.
Experimental Procedure For The Synthesis Of Methyl 2-(2-Oxo-5-(3,3,3-Trifluoro-
2-Oxopropylidene)Pyrrolidin-1-Yl)Acetate (4e)
TEA (101 mg, 1.0 mmol) was added to a solution of methyl 7,7,7-trifluoro-4-
methoxy-6-oxohept-4-enoate (1) (240 mg, 1.0 mmol) and glycine methyl ester
hydrochloride (2e) (126 mg, 1.0 mmol) in ethanol (15 mL). The mixture was sonicated
6

for 90 minutes (Table II). Sonication increased the reaction temperature to 55-60ºC after
10 minutes. Ethyl acetate (20 mL) was added and the organic layer was washed with H2O
(3 15 mL), dried with anhydrous MgSO4 and concentrated under reduced pressure to
afford a brownish solid. Purification by silica gel column chromatography (15:7
AcOEt/hexane) afforded the product 4e as a yellowish solid in 83% of yield.
Characterization Data For Methyl 2-(2-Oxo-5-(3,3,3-Trifluoro-2-
Oxopropylidene)Pyrrolidin-1-Yl)Acetate (4e)
Yield: 0.220 g (83%); yellowish solid; mp 111-112°C; 1H NMR (400 MHz,
CDCl3): δ ppm 5.69 (s, 1H), 4.37 (s, 2H), 3.80 (s, 3H), 3.44-3.40 (m, 2H), 2.73-2.70 (m,
2H); 13C NMR (100 MHz, CDCl3): δ ppm 178.8 (q, JCF = 34.4 Hz), 176.4, 167.4, 166.2,
116.2 (q, JCF = 293.4 Hz), 91.4, 52.9, 41.8, 27.1, 26.8; MS-EI: m/z (%) 265 (M, <5), 245
(23), 206 (24), 196 (100), 168 (85), 138 (37), 108 (65), 69 (15); HRMS-ESI: m/z [MH]+
calcd. for C10H10F3NO4: 266.0640, found 266.0635.
ACKNOWLEDGMENTS
We acknowledge Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq, 483021/2013-0) and Fundação de Apoio ao Desenvolvimento do Ensino, Ciência
e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT, 0180/12) for financial
support. We also thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES) for a scholarship to M. S. F. Franco. We are grateful to Prof. Davi F. Back -
Laboratório de Materiais Inorgânicos - Universidade Federal de Santa Maria for the X-
ray crystallographic analysis.
7

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9

Table 1. Solvent, base and ultrasonic irradiation effects in the reaction of methyl 7,7,7-trifluoro-
4-methoxy-6-oxohept-4-enoate (1) with aniline (2k).
Entry Solvent
TEA (eq)
Method
Time (min)
Product (%)a
Yield of 4k (%)
3k
4k
c
MeCN
CHCl3
H2O
1
1
1
1
-
US
US
120
120
120
120
120
120
120
76
42
0
24
58
100
99
0
-
1
2
3
4
5
6
7
c
-
US
16b
95b
EtOH
EtOH
EtOH
EtOH
US
1
c
US
100
91
53
-
c
1
1
rt
9
-
c
reflux
47
-
aDetermined by GC.
bIsolated yield.
cUndetermined yield.
10

Table 2. Selected experimental data for the reaction of methyl 7,7,7-trifluoro-4-methoxy-6-
oxohept-4-enoate (1) with alkyl(aryl)amines (2a-t) under ultrasonic irradiation.
Entry
Amine (2a-t)
Product
Time (min)
60
Yield (%)a
85
1
60
86
2
c
3c + 4c
(1.1:1)b
3d + 4d
(9:1)b
120
120
-
3
4
c
-
11

90
60
83
81
5
6
30
30
94
88
7
8
45
60
65
83
9
10
105
60
95
59
11
12
12

90
61
55
13
14
120
60
120
60
64
45
60
59
15
16
17
18
90
13

120
120
51
25
19
20
aIsolated yield.
bDetermined by GC.
cUndetermined yield.
14

Figure 1. ORTEP diagram of 4e.
15