Efficient one-pot synthesis of 1,3-dihydro-2H-pyrrol-2-one derivatives via aza-oxyallylic cations

Article abstract of DOI:10.1016/j.tetlet.2017.01.048

An efficient synthesis of functionalized 1,3-dihydro-2H-pyrrol-2-one was developed based on a [3+2] cycloaddition reaction of aza-oxyallylic cations and alkynes. With this novel method, a variety of substituted alkynes were readily converted into their co

Full text of DOI:10.1016/j.tetlet.2017.01.048

Accepted Manuscript
Efficient one-pot synthesis of 1,3-dihydro-2H-pyrrol-2-one derivatives via aza-
oxyallylic cations
Gangqiang Wang, Rongxing Chen, Minghu Wu, Shaofa Sun, Xing Luo, Zhi
Chen, Haibing Guo, Carlos Chong, Yalan Xing
PII:
S0040-4039(17)30070-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.048
TETL 48551
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
10 November 2016
5 January 2017
13 January 2017
Please cite this article as: Wang, G., Chen, R., Wu, M., Sun, S., Luo, X., Chen, Z., Guo, H., Chong, C., Xing, Y.,
Efficient one-pot synthesis of 1,3-dihydro-2H-pyrrol-2-one derivatives via aza-oxyallylic cations, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.048
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Efficient One-pot Synthesis of 1,3-Dihydro-2H-pyrrol-2-one
Derivatives via Aza-oxyallylic Cations
Gangqiang Wang, a, Rongxing Chen, a Minghu Wu, Shaofa Sun*,a Xing Luo,a Zhi Chen,a
Haibing Guo,a Carlos Chong,b Yalan Xing,*,b
a). School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and
Technology, Xianning 437100, China; b). Department of Chemistry, William Paterson University,
300 Pompton Rd, Wayne, NJ 07470, USA
Abstract: An efficient synthesis of functionalized 1,3-dihydro-2H-pyrrol-2-one was developed
based on a [3+2] cycloaddition reaction of aza-oxyallylic cations and alkynes. With this novel
method, a variety of substituted alkynes were readily converted into their corresponding
pyrrolidinone analogues at room temperature. The protocol features easy operation, ambient
temperature, good yields, readily available starting materials, and broad functional group
tolerance.
Key word: Aza-oxyallylic Cation; Alkynes; Cycloaddition
Introduction
Recently, the aza-oxyallylic cation has emerged into a useful synthetic intermediate for the
construction of heterocycles due to its unique chemical features. 1 The existence of the
aza-oxyallylic cation was first proposed by Sheehan in 1960s2 and confirmed by Sakamoto in
1993.3 However, the first reported application of the aza-oxyallylic cation in organic synthesis
was not until 2011 by Jeffrey in his [4+3] cycloaddition reaction of aza-oxyallylic cations with
dienes. 4 Later on, Wu group and Liao group utilized [3+2] cycloaddition reactions of
aza-oxyallylic cations and alkenes for the synthesis of heterocycles.5
As part of our effort to develop efficient methodologies for the synthesis of bio-active
heterocyclic compounds, we decided to explore the [3+2] cycloaddition reaction of aza-oxyallylic
cations and alkynes to prepare pyrrolidinones structures. To the best of our knowledge, the [3+2]
cycloaddition of aza-oxyallylic cations and alkynes has not been reported. Pyrrolidinones are often
found in biologically active natural products.6 They are also valuable starting materials in organic
synthesis due to their ability to react as acceptors in conjugate addition reactions of

organocuprates, enolates, and nitrogen nucleophiles.7 Moreover, Pyrrolidinones are essential key
intermediates for the synthesis of pyrrolidines which exhibit very important biological activities.8
Scheme 1 Synthesis of 1,3-Dihydro-2H-pyrrol-2-ones Derivatives
There are only a few practical synthetic routes for the synthesis of pyrrolidinones available in
literature, and the reported syntheses employ harsh reaction conditions such as high temperature
9
and pressure or the use of transition metal catalysts. Herein, we report our studies on the
efficient synthesis of 1,3-dihydro-2H-pyrrol-2-one derivatives using the cycloaddition of
aza-oxyallylic cations and alkynes.
Results and Discussion
First, α-haloamide 1a was chosen as the model substrate to react with phenylacetylene 2a for
the investigation of the optimal reaction conditions. Na2CO3 served as the base to generate
aza-oxyallylic cation from α-haloamide 1a. Many different solvents such as CH3CN, THF, DCM,
DMF, CH3OH, CF3CH2OH, and Hexafluoroisopropanol (HFIP) (entries 1-7) were tested; HFIP
was found to give the best yield of the pyrrolidinone 3a (90%) and shortest reaction time (10 h).
We believe HFIP is a good solvent for this reaction because the aza-oxyallylic cation intermediate
is more stable in a strong polar solvent.4,5 Next, we explored different bases using HFIP as the
optimal solvent. Organic bases such pyridine, DBU and TEA (entry 8-10), did not produce the
desired product. When inorganic bases such as K2CO3, NaOAc, and NaOH (entries 11-13) were
utilized as bases, desired products were generated in moderate yields.

Entrya
Base
Solvent
T
Yieldb
1
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
pyridine
DBU
CH3CN
THF
24h
24h
24h
10h
24h
24h
24h
24h
24h
24h
24h
24h
24h
n.r.
n.r.
3
CF3CH2OH
HFIP
n.r.
4
90%
n.r.
5
DCM
6
DMF
n.r.
7
CH3OH
HFIP
n.r.
8
n.r.
9
HFIP
n.r.
10
11
12
13
TEA
HFIP
n.r.
K2CO3
NaOAc
NaOH
HFIP
65%
70%
56%
HFIP
HFIP
a
Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.1 mmol), and base (2 mmol) in solvent (2 mL) was
stirred at room temperature for a certain period of time.
b Yield of isolated product.
Table 1 Optimization of reaction conditions
With the optimal conditions in hand, we next turned our attention to investigating the
substrate scope and limitations of the [3+2] cycloaddition (Table 2-3). When α-haloamide 1a was
used to provide the aza-oxyallylic cation, different alkynes were tested under the optimal
conditions. It was found that aryl alkynes provided the cycloaddition products in good to moderate
yields (Table 2, 3a-3i). Electron withdrawing groups such as fluorine or chlorine and electron
donating groups such as methoxyl, methyl, ethyl and t-butyl groups on the aromatic ring did not
affect reaction yields. Electron donating heterocyclic aromatic rings, such as thiophene, also gave
good yield (93%) of the product. However, pyridine and simple alkyl substituted alkynes did not
provide any desired products (Table 2, 3l-3m). Also, when bulky internal alkynes were used in this
reaction, no desired product formation was observed (Table 2, 3n).

Entry
R'
R'' Yield (%)
3a
3b
3c
3d
3e
3f
Ph
Ph
H
Me
H
90
88
85
81
83
89
70
85
77
93
82
0
4-Me-Ph
3-Me-Ph
4-Et-Ph
4-MeO-Ph
4-tBu-Ph
4-F-Ph
H
H
H
3g
3h
3i
H
H
2-Cl-Ph
2-Thiophenyl
Cyclohex-1-enyl
2-Pyridinyl
Et
H
3j
H
3k
3l
H
H
3m
3n
H
0
Ph
Ph
0
Table 2 Reactions of α-haloamide 1a with alkynes
Not surprisingly, when α-haloamide 1b was used to produce the aza-oxyallylic cation, the
cycloaddition reaction also had a good substrate scope for different alkynes in good yields, except
the 4d and 4i. We reasoned that the ortho (4i) and meta (4d) substitutes on the phenyl ring
increased the steric hindrance which resulted in zero yield of the desired products.
Entry
R'
R'' Yield (%)
4a
4b
4c
4d
4e
4f
Ph
H
Me
H
82
76
85
0
Ph
4-Me-Ph
3-Me-Ph
4-Et-Ph
4-MeO-Ph
H
H
80
87
H

4g
4h
4i
4-tBu-Ph
4-F-Ph
H
H
H
H
H
H
H
Ph
67
85
0
2-Cl-Ph
4j
2-Thiophenyl
Cyclohex-1-enyl
2-Pyridinyl
Et
89
84
0
4k
4l
4m
4n
0
Ph
0
Table 3 Reactions of α-haloamide 1b with alkynes
The mechanism of this reaction is illustrated in scheme 2. First, α-haloamide is treated with
HBr to generate aza-oxyallylic cation. The [3+2] cycloaddition of the resulting cation and
dipolarophile alkyne produces product 3a. The excellent regiochemistry of this reaction can be
explained by the steric effect of the unsymmetrical alkyne substrates and the substitutions on the
aza-oxyallylic cation.
Scheme 2 Proposed mechanism
Conclusion
In summary, a new synthetic method for functionalized 1,3-dihydro-2H-pyrrol-2-one was
developed on the basis of a [3+2] cycloaddition reaction of aza-oxyallylic cations and alkynes.
This reaction shows broad substrate scope and good functional group compatibility. Further
studies on the synthesis of heterocycles using aza-oxyallylic cations are now in progress.1
Acknowledgement
The authors are grateful to the Education Department of Hubei province science and
technology research project (Nos. Q20162803). This research was supported by the Doctoral
Research Fund of Hubei University of Science and Technology (BK1434). The authors are also
grateful to National Natural Science Foundation (21602053). This research was supported (in part)

by a grant from the Center for Research, College of Science and Health, William Paterson
University of New Jersey.
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Highlights




Efficient synthesis of functionalized 1,3-dihydro-2H-pyrrol-2-one
[3+2] Cycloaddition reaction of aza-oxyallylic cations and alkynes
Easy operation, ambient temperature, good yields
Broad functional group tolerance