An expedient approach for the synthesis of 1-Alkyl-4-propionylpyrrolidin-2- ones

Article abstract of DOI:10.1080/00397911.2013.786091

A simple and useful tandem addition-cyclization reaction of primary amines on a prepared α-functionalized propylvinyl ketone 3 in methanol at reflux is a promising route for the synthesis of a new family of 1-alkyl-4- propionylpyrrolidin-2-ones 4. Taylor and Francis Group, LLC.

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An Expedient Approach for the Synthesis
of 1-Alkyl-4-propionylpyrrolidin-2-ones
Fatma Saâdi a , Khaoula Jebali a , Aïcha Arfaoui a & Hassen Amri a
a Laboratory of Selective Organic Synthesis and Biological Activity,
Faculty of Science, El Manar University , Tunis , Tunisia
Accepted author version posted online: 15 Aug 2013.Published
online: 11 Oct 2013.
To cite this article: Fatma Saâdi , Khaoula Jebali , Aïcha Arfaoui & Hassen Amri (2014) An Expedient
Approach for the Synthesis of 1-Alkyl-4-propionylpyrrolidin-2-ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:1, 42-48, DOI:
10.1080/00397911.2013.786091
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Synthetic Communications1, 44: 42–48, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.786091
AN EXPEDIENT APPROACH FOR THE SYNTHESIS OF
1-ALKYL-4-PROPIONYLPYRROLIDIN-2-ONES
ˆ
Fatma Saadi, Khaoula Jebali, A¨ıcha Arfaoui, and Hassen Amri
Laboratory of Selective Organic Synthesis and Biological Activity, Faculty of
Science, El Manar University, Tunis, Tunisia
GRAPHICAL ABSTRACT
Abstract A simple and useful tandem addition–cyclization reaction of primary amines on a
prepared a-functionalized propylvinyl ketone 3 in methanol at reflux is a promising route
for the synthesis of a new family of 1-alkyl-4-propionylpyrrolidin-2-ones 4.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Primary amines; 4-propionylpyrrolidin-2-ones; propylvinyl ketone
INTRODUCTION
The Michael addition reaction, discovered more than a century ago,[1] is one of
the most important organic reactions leading to the formation of a new carbon–
carbon and carbon–heteroatom bonds. These reactions include nucleophilic reagents
(donors) and activated a, b-unsaturated molecules (acceptors)[2] recognized for their
great ability to react with various nucleophiles. Aside from single acceptors, we verify
that some homologous a-functionalized enones 3[3–10] are of considerable importance
in organic synthesis and can act as intermediates in the synthesis of a wide range of
biologically active compounds[11] to skeletal pyrrolidin-2-ones derivatives[12] and
c-butyrolactams.[13,14] Because of the growing importance of some N-heterocyclic
five-membered rings in the development of synthetic intermediates in medicinal chem-
istry and their usefulness as pharmacological molecules, much attention has been
focused on their synthesis and especially that of c-lactams.[15–18] In this article, we
describe an efficient alternative for the preparation of a new family of 1-alkyl-4-
propionylpyrrolidin-2-ones 4 following a tandem Michael-type reaction of primary
Received January 21, 2013.
Address correspondence to Hassen Amri, Laboratory of Selective Organic Synthesis and Biological
Activity, Faculty of Science, El Manar University, 2092 Tunis, Tunisia. E-mail: hassen.amri@fst.rnu.tn
42

1-ALKYL-4-PROPIONYLPYRROLIDIN-2-ONES
43
amines in methanol at reflux on enones 3 whose corresponding adducts undergo
spontaneous cyclization, giving rise to b-acyl-c-butyrolactams 4 in good yields.
RESULTS AND DISCUSSION
The starting point of this development consisted of a judicious use of commer-
cially available heptane-3,5-dione, alkylated[19–21] as reported in the literature and
serving as raw material for the preparation of the enone 3 (Scheme 1).
First, 1 equivalent of sodium hydride (60% suspension in mineral oil) was
added to a solution of dry tetrahydrofuran (THF) under nitrogen at 0 ꢀC, and then
heptane-3,5-dione (1 equiv.) was added dropwise. The mixture was stirred at 0 ꢀC to
allow for complete formation of the 3,5-diketone anion and then stirred at room
temperature for 1 h. Alkylation of 3,5-dione in the presence of ethyl bromoacetate
in THF at reflux for 18 h, offers the ability to isolate, after workup and in good yield,
the alkylated diketone 1. The second approach involved the transformation of the
alkylated b-diketone 1 to prepare the desired Michael acceptor 3 used to achieve
the expected 5-acyl-3-butyrolactams 4. In this context, it was decided to adopt a
method that combines significant aspects such as easy operation under mild con-
ditions, easy accessibility of reactants and workup procedure, absence of competitive
reactions, high atom economy, and the use of water as a green reaction medium.
These restrictions are unfavorable to the use of b-alkylated ketophosphonate 2[22]
in the framework of the Wittig–Horner reaction,[23] which leads to the enone 3 in
poor yield (27%) (Scheme 2).
These above criteria can be satisfied by using our own protocol[10] based on the
deacylative reaction of alkylated 1,3-diketone 1 using 30% aqueous formaldehyde and
concentrated (6–10 molar) aqueous solution of potassium carbonate as base in the
absent of any solvent and phase transfer agent at 0 ꢀC to isolate a-functionalized a,
b-enone 3 in good purity and good yields (Scheme 3).
Given the high functional density of the enone 3, we found it useful to examine
its reactivity in a heterocyclization process to obtain a series of 1-alkyl-4-propionyl-
pyrrolidin-2-ones 4 whose one representative has been reported since 1994.[24] In our
approach, the construction of the nitrogen heterocycle[25] is based on an efficient
coupling of the primary amines and vinyl ketone 3. The latter Michael acceptor 3
Scheme 1. Alkylation procedure of b-diketone.
Scheme 2. Wittig–Hormer synthesis of a-functionalized enone 3.

ˆ
F. SAADI ET AL.
44
Scheme 3. Synthesis of a-functionalized enone 3 by hydroxymethylation followed by a fragmentation.
Scheme 4. Synthesis of 1-alkyl-4-propionylpyrrolidin-2-ones 4.
offers the possibility to react with 1 equivalent of primary amine in methanol as
solvent, involving as expected a two-step sequence: conjugate addition of the amine
on the terminal ethylenic carbon leading the c-amino-ester intermediate, which
spontaneously undergoes an intramolecular cyclization via 5-exo-trig process[26] to
provide the corresponding functionalized c-lactam 4 (Scheme 4, Table 1).
EXPERIMENTAL
Tetrahydrofuran (THF) was distilled prior to use from a deep-blue solution of
sodium–benzophenone ketyl. All other reagents and solvents were obtained from
commercial sources and used without further purification. Reactions were routinely
carried out under an atmosphere of dry nitrogen with magnetic stirring. Organic layers
were dried with anhydrous magnesium sulfate before concentration in vacuo. All reac-
tions were monitored by thin-layer chromatography (TLC) on silica-gel plates (Fluka
Kieselgel 60 F254, Merck) and series of lactams was eluted in (AcOEt=hexane, 1:1) as
solvent visualized with a 254-nm UV lamp, aqueous potassium permanganate sol-
ution, and iodine. Crude products were purified using column chromatography on sil-
ica gel; Fluka Kieselgel (70–230 mesh) was used. 1H NMR and 13C NMR spectra were
recorded on Bruker AMX 300 spectrometer working at 300, 282, and 75 MHz respect-
ively for 1H, 19F, and 13C with CDCl3 as the solvent and tetramethylsilane (TMS) as
the internal standard. The chemical shifts (d) and coupling constants (J) are, respect-
ively, expressed in parts per million (ppm) and hertz (Hz). All NMR spectra were
acquired at room temperature. Multiplicity of peaks is indicated by the following: s,
singlet; d, doublet; t, triplet; q, quartet; qt, quintuplet; sept, septuplet; m, multiplet.
Mass spectra were accomplished with an HP 5889A quadripolar spectrometer by
electronic impact EI (70 eV) or chemical ionization CI (500 eV) with NH3 gas.
High-resolution mass spectrometry (HRMS) analyses were performed at the
´
Centre Commun de Spectrometrie de Masse in Lyon (France), on a Micro-TOFOII
Thermofischer Scientific for electrospray ionization (ESI) measurements. Melting
points (mp) were determined on a System Kofler type WME apparatus.

1-ALKYL-4-PROPIONYLPYRROLIDIN-2-ONES
45
Table 1. Synthesis of 1-alkyl-4-propionylpyrrolidin-2-ones 4a–h
Entry
R
Time (h)
Pyrrolidin-3-one 4
Yielda (%)
a
PhCH2
15
91
80
b
p-ClC6H4CH2
20
c
p-FC6H4CH2
48
85
d
e
f
Ph(CH3)CH
72
45
34
75
65
70
g
cC6H14
40
60
60
70
h
iPr
aYields refer to the pure isolated products after chromatography.

ˆ
F. SAADI ET AL.
46
Typical Procedure for the Preparation of Ethyl 3-Methylene-4-
oxohexanoate 3
A mixture of ethyl 4-oxo-3-propionylhexanoate 1 (20 mmol), 30% aqueous
formaldehyde (4 mL), and solution of potassium carbonate (6–10 M) (40 mmol)
was stirred at room temperature for 4 h and then quenched with water (60 mL)
and extracted with diethyl ether (4 ꢁ 50 mL). The organic layer was dried over
MgSO4, and the solvent was removed to leave an oil residue, which was distilled
at reduced pressure, affording the corresponding enone 3. Full experimental detail
1
and H and 13C NMR spectra of 3 can be found via the Supplementary Content
section of this article’s webpage.
General Procedure for the Synthesis of 1-Alkyl-4-
propionylpyrrolidin-2-ones 4a-H
Primary amine (1.76 mmol, 1 equiv.) was added dropwise to a solution of ethyl
3-methylene-4-oxohexanoate 3 (0.3 g, 1.76 mmol) in 6 mL of methanol. The mixture
was stirred at reflux for 15 to 72 h. The reaction mixture was concentrated under
reduced pressure to remove methanol, and then the crude product was purified by
chromatography on silica gel. Full experimental detail and 1H and 13C NMR spectra
of 4a–h can be found via the Supplementary Content section of this article’s
webpage.
CONCLUSION
In summary, we successfully developed through a valuation of a functionalized
enone 3, an expedient and single-step synthetic way to prepare 1-alkyl-4-propionyl-
pyrrolidin-2-ones 4 using commercially available reagents and inexpensive method-
ology, and the prepared 4-functionalized c-lactams 4 may find some applications in
the development of active compounds.
ACKNOWLEDGMENTS
The authors thank the Tunisian Ministry of Higher Education and Scientific
Research for financial support and Professor Jacques Lebreton (University of
Nantes, France) for logistical help.
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