Cu(OTf)2 catalyzed cross-coupling reaction of 1,3-dicarbonyl derivatives with 2-oxo-1-pyrrolidine compounds

Article abstract of DOI:10.1016/j.tet.2012.07.017

An efficient method for the cross-coupling reactions of 1,3-dicarbonyl compounds with 2-oxo-1-pyrrolidine compounds 1 was developed. Cu(OTf) ₂ catalyzed C-C bond forming reactions using substrates 1 with 1,3-dicarbonyl compounds in chloroform,

Full text of DOI:10.1016/j.tet.2012.07.017

Tetrahedron 68 (2012) 8340e8346
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cu(OTf)2 catalyzed cross-coupling reaction of 1,3-dicarbonyl derivatives with
2-oxo-1-pyrrolidine compounds
*
*
Hai-Yan Xu, Shun-Yi Wang, Ran Jiang, Xiao-Ping Xu , Xue-Qiang Chu, Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the cross-coupling reactions of 1,3-dicarbonyl compounds with 2-oxo-1-
pyrrolidine compounds 1 was developed. Cu(OTf)2 catalyzed CeC bond forming reactions using sub-
strates 1 with 1,3-dicarbonyl compounds in chloroform, providing the corresponding compounds of 2-
oxo-1-pyrrolidine bearing 1,3-dicarbonyl moiety in moderate to good yields.
Received 18 April 2012
Received in revised form 1 July 2012
Accepted 6 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cu(OTf)2
Cross-coupling
1,3-Dicarbonyl derivatives
2-Oxo-1-pyrrolidine compound
1. Introduction
The functionalization of activated methylene units, such as 1,3-
dicarbonyl compounds, is one of the most utilized types of carbon-
ecarbon bond forming reactions.1 Typically, this transformation is
performed with alkyl halides in presence of at least an equimolar
amount of base, which results in the generation of large quantities of
waste salts2 (Scheme 1, Path A). Consequently, the development of
alternative methods that make use of inexpensive and readily
available electrophiles, mild reaction conditions and environmen-
tally friendly catalysts has become very topical. Recently, a lot of
works were dedicated to the addition of 1,3-dicarbonyl derivatives
Scheme 1. State of the art on CeC bond formation of 1,3-dicarbonyl compounds.
to alcohols. It has been reported that addition of b-diketones, and b-
2-Oxo-1-pyrrolidine moieties have attracted much attention
for their importance as drug molecules and building blocks. 2-
keto esters to benzhydryl alcohols could be promoted by a stoi-
chiometric amount of Lewis acid, such as BF3$OEt2,3 InCl3,4 FeCl3,5
Oxo-1-pyrrolidine
derivatives,
for
example,
N-(2,6-
6
Bi(OTf)3,1 Yb(OTf)3 and a ruthenium complex.7 Additionally, mo-
dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide, which is
known as Nefiracetam, is a commonly used drug for the treatment
of cerebrovascular disease (Fig. 1). Other analogues of above
pharmaceuticals, especially in which another biologically active
lecular iodine8 and a series of Brønsted acids, such as H-montmor-
illote,9 p-toluenesulfonic acid,10 triflic acid11 and phosphotungstic
acid,12 have been explored as effective catalysts for this type reaction
(Scheme 1, Path B). However, it’s not until more recently, the cross-
coupling reaction of 1,3-dicarbonyl compounds 2-oxo-1-pyrrolidine
compounds to construct carbonecarbon bond has remained un-
explored (Scheme 1, Path C).
* Corresponding authors. Tel./fax: þ86 512 65880307; e-mail addresses:
Fig. 1. Typical structure of pharmaceuticals containing 2-oxo-1-pyrrolidine fragment.
chemjsj@suda.edu.cn, shunjun@suda.edu.cn (S.-J. Ji).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.017

H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
8341
alkaloid motif incorporated, also exhibit good activities in the
therapy of common diseases, such as attention deficit hyperac-
tivity disorder (ADHD), cardiac arrhythmia and asthmatic syn-
drome.13 Therefore, the discovery of new synthetic methodology
and structural modification for the establishment of containing 2-
oxo-1-pyrrolidine moieties pharmaceutical library was highly
desirable. It’s not until more recently, only we14 and Zhang’s
group15 have reported Fe(III)-promoted FriedeleCrafts reactions of
tert-enamides with indoles for the synthesis of 2-oxo-1-
pyrrolidine compounds, respectively.
With the optimal conditions in hands, the scope of substrates
was subsequently investigated. As illustrated in Table 2, the
cross-coupling reactions of 1-phenylbutane-1,3-dione 2a with 2-
oxo-1-pyrrolidine derivatives 1 under the established conditions
could be accomplished with good generality. The substrate 1
bearing Ar with strong electron-withdrawing groups, such as
nitro, cyano and methylsulfonyl, efficiently underwent reactions
Table 2
Cu(OTf)2 catalyzed cross-coupling of 1-phenylbutane-1,3-dione 2a with 2-oxo-1-
17
As a continual of our previous work,16 we described Cu(OTf)2
pyrrolidine derivatives 1 in chloroforma
catalyzed CeC bond forming reaction of 1,3-dicarbonyl de-
rivatives with 2-oxo-1-pyrrolidines.
2. Results and discussion
Initial reaction was carried out using 1a and 2a under different
conditions. As shown in Table 1, the model reaction did not occur in
the absence of any catalyst (Table 1, entry 1). After screening a se-
ries of catalysts, such as metallic Lewis acid, molecular iodine, as
well as Brønsted acid, it was fortunately found that 10 mol % of
Cu(OTf)2 was sufficient to promote the reaction (Table 1, entries
2e14). The desired CeC formation product was obtained in 63%
yield after 24 h. Further optimization of the reaction conditions by
changing the solvent and molar ratio were carried out using
10 mol % Cu(OTf)2 as a catalyst (Table 1, entries 15e21). It was found
that the model reaction could proceed effectively in CHCl3 under
reflux conditions. The optimized conditions were that the reaction
could perform well in chloroform with a catalytic amount of
Cu(OTf)2 (10 mol %) (Table 1, entry 17).
Entry
1
Ar
R1
Et
Product
Time (h)
24
Yieldb (%)
81(5:2)d
1a
3aa
2
3
1b
1c
Et
Et
3ba
3ca
24
24
87(3:1)
80(10:3)
4
5
6
1d
1e
1f
Et
Et
Et
3da
3ea
3fa
24
24
24
81(2:1)
79(3:1)
63(1:1)
Table 1
Reaction conditions screeninga
7
1g
1h
1i
Et
Et
Et
Et
3ga
3ha
3ia
3ja
24
48
48
48
77(3:1)
68(4:1)
67(4:1)
81c(3:1)
8
9
10
1j
Entry
Catalyst (10 mol %)
Time (h)
Solvent
T (ꢀC)
Yieldb (%)
11
1k
Et
3ka
24
68(5:1)
1
d
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
DCM
40
40
40
40
40
40
40
40
40
40
40
40
40
40
110
60
60
85
78
65
100
60
n.r
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
16c
17c
18c
19c
20c
21c
22c
Cu(OTf)2
In(OTf)3
La(OTf)3
Zn(OTf)2
Bi(NO3)3
FeCl3
CuBr2
InCl3
AgOTf
AgClO4
SnCl2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Tol.
63
n.rd
Trace
24
12
13
14
1l
Et
Et
Et
3la
48
48
48
45(3:1)
73c(3:2)
63(5:1)
n.r
28
1m
1n
3ma
3na
Trace
<10%
Trace
Trace
n.r
Trace
Trace
72
24
79
74
5
15
16
17
1a
1j
CH3
CH3
CH3
3aa
3ja
3ea
24
48
48
68(3:1)
80(3:1)
81(3:1)
I2
PTSAe
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CH3CN
CHCl3
ClCH2CH2Cl
EtOH
THF
1e
52
72
55
18
1a
iPr
3aa
48
62(3:1)
CH3NO2
CHCl3
a
Unless otherwise specified, all reactions were performed with pyrrolidin-2-ones
a
General conditions: Compound 1a (0.4 mmol), 2a (0.4 mmol).
Isolated yield.
derivatives
(10 mol %) in CHCl3 (2 ml) at 60 ꢀC.
1 (0.6 mmol), 1-phenylbutane dione 2a (0.4 mmol), and Cu(OTf)2
b
c
b
Molar ratio 1a/2a¼1.5: 1.
Isolated yield after flash column chromatography.
d
e
c
n.r means no reaction.
A larger amount of 1 (0.8 mmol) was employed.
d
Ratio of the diastereomers determined by 1H NMR spectroscopic analysis.
PTSA¼p-toluenesulfonic acid.

8342
H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
with 1-phenylbutane-1,3-dione (2a) to afford the desired prod-
ucts (3aaeda) in 80e87% yields (Table 2, entries 1e4). The sub-
strate 1 bearing Ar with weak electron-withdrawing groups, such
as halogens, also worked well, while affected a bit by the steric
effect (Table 2, entries 5e7). Substrates 1 bearing Ar with
electron-donating groups, such as methoxy and dimethylamino,
gave the moderate results when compared to those with
electron-withdrawing groups, which reflecting the electronic
effect on the cross-coupling reactions (Table 2, entries 8e12).
Other substrates 1 bearing aryls, such as naphthalene-2-yl and
thiophen-2-yl, were also demonstrated to be good candidates for
this reaction (Table 2, entries 13e14). Influence of other leaving
groups on the cross-coupling of 1-phenylbutane-1,3-dione (2a)
was investigated as well. It was found that methoxy and iso-
propoxy substituents exhibited comparable reactivity to ethoxy
group, furnishing the expected products in good yields (Table 2,
entries 15e18).
dicarbonyl were selected to reacted with 1-(methoxy(4-ni-
trophenyl)methyl)pyrrolidin-2-one (1a), but no desired products
were obtained (Table 3, entries 8e9).
The mechanism of addition of
b-dicarbonyl compounds to
alcohols by Lewis acids is generally thought to involve the for-
mation of a carbocation intermediate and subsequent SN1 attack
on the b-dicarbonyl compounds to yield the addition product. To
better understand the mechanism of our reaction, five control
reactions were carried out in different conditions (Scheme 2).
When the reaction of 1a and 2a catalyzed by 10 mol % TfOH, only
53% desired product was obtained. When 10 mol % CuBr2 was
used as the catalyst instead of Cu(OTf)2 and HOTf, only trace
desired product was formed. However, an 83% yield of 3aa was
obtained by co-catalysts of 10 mol % CuBr2 and 10 mol % HOTf.
Then, when we carried out the reaction of 1a and 2f catalyzed by
not only 10 mol % Cu(OTf)2 but also 10 mol % HOTf under stan-
dard conditions, almost no desired product was formed. Basing
on these results, a possible mechanism for this Cu(OTf)2 cata-
lyzed cross-coupling reaction of 1,3-dicarbonyl compounds was
suggested in Scheme 3. By strong coordination of 1,3-dicarbonyl
compounds to Cu(OTf)2, the intermediate A was facilely formed
via a ligand-exchange reaction. At the same time, elimination of
one molecular HOTf occurred. Then, the CeO bond of 1-(eth-
oxy(4-nitrophenyl)methyl)pyrrolidin-2-one (1a) was activated by
HOTf to generate a stable N-acyliminium species B accompanying
Further expansion to other
nucleophile was also explored. The results were listed in Table 3.
Obviously, the reaction of -diketones including acetylacetone and
b-dicarbonyl compounds 2 as
b
dibenzoylmethane with 1-(ethoxy(4-nitrophenyl)methyl)pyrroli-
din-2-one (1a) gave the corresponding products in good yields
(Table 3, entries 1 and 3). Unexpectedly, the substrate 1 bearing
strong electron-donating groups, such as methoxy in the Ar could
not react with acetylacetone under standard conditions to give the
target product, which might be due decompose to corresponding
aldehyde as a side-product (Table 3, entry 2). What’s more, b-keto
esters, such as ethyl 3-oxobutanoate and ethyl 3-oxo-3-
phenylpropanoate, also proceeded smoothly to give the corre-
sponding products in 49% and 81% yields, respectively (Table 3,
entries 6e7). The malonate derivatives as candidates for 1,3-
Table 3
Cu(OTf)2 catalyzed cross-coupling of
b-dicarbonyl compounds 2 with 2-oxo-1-
pyrrolidine derivatives 1 in chloroforma
Entry
1
Ar
R1
R2
R3
Product Time (h) Yieldb (%)
1a
1j
Et 2b CH3 CH3 3ab
Et 2b CH3 CH3 3jb
Et 2c Ph Ph 3ac
Et 2c Ph Ph 3jc
Et 2d CH3 OEt 3ad
Et 2e Ph OEt 3ae
Et 2f OH OH 3af
48
24
24
48
24
48
24
64
2
3
5
6
7
8
0
1a
1j
79
61
1a
1a
1a
49(1:1)c
81(3:2)
0
9
1a
Et 2g OEt OEt 3ag
24
0
a
Unless otherwise specified, all reactions were performed with 2-oxo-1-
a Isolated yield after flash column chromatography. b The desired
product was monitored by LCMS.
pyrrolidine derivatives 1a (0.6 mmol), b-dicarbonyl compounds 2 (0.4 mmol), and
Cu(OTf)2 (10 mol %) in CHCl3 (2 ml) at 60 ꢀC.
b
Isolated yield after flash column chromatography.
c
Ratio of the diastereomers determined by 1H NMR spectroscopic analysis.
Scheme 2. Mechanism study.

H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
8343
by flash column chromatography by using ethyl acetate and pe-
troleum ether as eluents to afford pure product.
4.2.1. 2-((4-Nitrophenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3aa). Yield (122.6 mg, 81%). White solid.
Mp 164.5e165.3 ꢀC. IR (KBr):
n
¼3428, 3065, 2958, 1674, 1514,
1424, 1267, 1175, 857 cmꢁ1. Characterized as a 5:2 diastereomeric
mixture. 1H NMR (400 MHz, CDCl3):
d
¼8.10 (d, J¼8.7 Hz, 2H), 7.96
(d, J¼8.7 Hz, 2H), 7.65e7.45 (m, 5H), 6.10 (d, J¼11.4 Hz, 1H), 5.88
(d, J¼11.4 Hz, 1H), 3.49e3.43 (m, 1H), 3.22e3.16 (m, 1H),
2.39e2.34 (m, 2H), 2.23 (s, 3H), 1.97e1.92 (m, 2H) ppm. Isomer 1H
NMR (400 MHz, CDCl3):
d
¼8.21 (d, J¼8.6 Hz, 2H), 8.13 (d, J¼8.6 Hz,
2H), 7.76 (d, J¼8.2 Hz, 2H), 7.67e7.62 (m, 4H), 6.47 (d, J¼11.4 Hz,
1H), 5.46 (d, J¼11.4 Hz, 1H), 3.46e3.43 (m, 1H), 3.35e3.34 (m, 1H),
2.19e2.17 (m, 2H), 1.97 (s, 3H), 1.92e1.86 (m, 2H) ppm. 13C NMR
(75 MHz, CDCl3):
129.1, 128.2, 123.9, 63.9, 55.4, 45.3, 31.2, 27.6, 18.3 ppm. Isomer 13C
NMR (75 MHz, CDCl3):
d
¼201.2, 192.7, 175.6, 147.5, 144.3, 135.8, 134.5,
d
¼201.2, 192.8, 175.6, 147.7, 145.0, 136.2,
134.2, 128.8, 128.6, 126.9, 121.7, 58.3, 48.7, 31.6, 30.5, 29.6,
18.2 ppm. HRMS: calcd for C21H20N2O5: [M]þ 380.1372; found,
380.1264.
Scheme 3. Proposed mechanism.
4.2.2. 2-((4-(Methylsulfonyl)phenyl)(2-oxopyrrolidin-1-yl)methyl)-
1-phenylbutane-1,3-dione (3ba). Yield (144.0 mg, 87%). White solid.
with formation of one molecular EtOH. Under this circumstance,
B was fast attacked by the enolate fragment from A to afford final
product.
Mp 201.3e202.8 ꢀC. IR (KBr):
n
¼3427, 2968, 1674, 1424, 1293,
1151 cmꢁ1. Characterized as a 3:1 diastereomeric mixture. 1H NMR
(400 MHz, CDCl3):
d¼7.97 (d, J¼7.7 Hz, 2H), 7.82 (d, J¼7.7 Hz, 2H),
3. Conclusion
7.54e7.46 (m, 5H), 6.15 (d, J¼11.4 Hz, 1H), 5.84 (d, J¼11.4 Hz, 1H),
3.48e3.44 (m, 1H), 3.17e3.11 (m, 1H), 2.98 (s, 3H), 2.38e2.36 (m,
2H), 2.23 (s, 3H), 1.99e1.95 (m, 2H) ppm. Isomer 1H NMR (400 MHz,
In summary, we have reported an efficient method for the
cross-coupling of
pyrrolidine derivatives. The reactions proceeded efficiently in
the presence of a catalytic amount of Cu(OTf)2 (10 mol %) in
chloroform, generating 2-oxo-1-pyrrolidine derivatives bearing b-
b-dicarbonyl compounds with 2-oxo-1-
CDCl3):
d
¼8.13 (d, J¼7.4 Hz, 2H), 7.94 (d, J¼8.2 Hz, 2H), 7.78 (d,
J¼8.2 Hz, 2H), 7.63e7.58 (m, 3H), 6.44 (d, J¼11.4 Hz, 1H), 5.49 (d,
J¼11.4 Hz, 1H), 3.37e3.34 (m, 1H), 3.34e3.32 (m, 1H), 3.07 (s, 3H),
2.16e2.14 (m, 2H), 1.99 (s, 3H), 1.85e1.78 (m, 2H) ppm. 13C NMR
dicarbonyl moiety in moderate to good yields. The method using
N,O-acetal compound as alkylating reagent provides a new way
to synthesize of a wide variety of potential pharmaceutically ac-
tive compounds bearing 2-oxo-1-pyrrolidine scaffold. Asymmetric
synergistic catalyzed cross-coupling reaction of 1,3-dicarbonyl
derivatives with 2-oxo-1-pyrrolidine compounds will be repor-
ted in due course.
(75 MHz, CDCl3):
129.5, 129.1, 128.8, 127.9, 63.9, 55.3, 45.1, 44.3, 31.2, 27.5, 18.3 ppm.
Isomer 13C NMR (75 MHz, CDCl3):
140.4, 136.2, 134.2, 129.5, 129.1, 128.8, 127.8, 58.2, 49.4, 48.5, 44.3,
31.6, 29.7, 18.3 ppm. HRMS: calcd for C22H23NO5S: [M]þ 413.1297;
found, 413.1184.
d
¼201.5, 192.8, 175.6, 143.3, 140.4, 136.2, 134.2,
d¼200.2, 192.5, 175.6, 143.8,
4.2.3. 4-(2-Benzoyl-3-oxo-1-(2-oxopyrrolidin-1-yl)butyl)benzoni-
trile (3ca). Yield (115.6 mg, 81%). White solid. Mp 116.3e117.5 ꢀC. IR
4. Experimental section
4.1. General
(KBr):
n
¼3422, 2928, 2227, 1678, 1420, 1266, 980 cmꢁ1. Character-
ized as a 10:3 diastereomeric mixture. 1H NMR (400 MHz, CDCl3):
d
¼7.92 (d, J¼7.7 Hz, 2H), 7.64 (d, J¼7.7 Hz, 2H), 7.46e7.39 (m, 5H),
Melting points were recorded on an Electrothermal digital
melting point apparatus and were uncorrected. IR spectra were
recorded on a Varian FT-1000 spectrophotometer using KBr optics.
1H NMR and 13C NMR spectra were recorded on a Varian INOVA 300
or 400 MHz (1H NMR) and 75 or 100 MHz (13C NMR) spectrometer
using CDCl3 or DMSO-d6 as solvent and TMS as internal standard.
High resolution mass spectra were obtained using GCT-TOF in-
strument with EI or ESI source.
6.03 (d, J¼11.7 Hz, 1H), 5.81 (d, J¼11.7 Hz, 1H), 3.41e3.37 (m, 1H),
3.16e3.12 (m, 1H), 2.37e2.34 (m, 2H), 2.22 (s, 3H), 1.94e1.91 (m,
2H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
d¼8.11 (d, J¼7.6 Hz,
2H), 7.70e7.59 (m, 4H), 7.54e7.52 (m, 3H), 6.42 (d, J¼11.3 Hz, 1H),
5.41 (d, J¼11.3 Hz, 1H), 3.46e3.44 (m, 1H), 3.31e3.29 (m, 1H),
2.22e2.14 (m, 2H), 1.96 (s, 3H), 1.85e1.82 (m, 2H) ppm. 13C NMR
(75 MHz, CDCl3):
129.5, 128.6, 118.5, 112.4, 64.1, 55.9, 45.5, 31.8, 27.8, 18.5 ppm. Iso-
mer 13C NMR (75 MHz, CDCl3):
134.3, 132.8, 129.5, 129.2, 128.4, 112.5, 64.1, 58.9, 49.2, 31.9, 30.6,
18.4 ppm. HRMS: calcd for C22H20N2O3: [M]þ 360.1474; found,
360.1546.
d
¼201.6, 192.7, 175.6, 142.6, 136.1, 134.4, 132.8,
d
¼200.3, 192.6, 175.8, 143.3, 136.1,
4.2. Typical experimental procedure for Cu(OTf)2 catalyzed
cross-coupling of b-dicarbonyl derivatives with 2-oxo-1-
pyrrolidine compounds
1-Phenylbutane-1,3-dione (0.4 mmol, 0.0648 g), Cu(OTf)2
(0.04 mmol, 0.0158 g, 10 mol %), 1-(ethoxy(phenyl)methyl)pyrroli-
din-2-one (0.6 mmol, 0.1584 g), and CHCl3 (2 ml) were added into
a flask. Then the mixture was vigorously stirred at 60 ꢀC until
1-phenylbutane-1,3-dione or 1-(ethoxy(phenyl)methyl)pyrrolidin-
2-one was completely consumed as monitored by TLC analysis.
After the completion of reaction, the residue was directly purified
4.2.4. 2-((3-Nitrophenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3da). Yield (124.6 mg, 81%). White solid.
Mp 135.9e147.5 ꢀC. IR (KBr):
n
¼3436, 2963, 1674, 1427, 1294,
770 cmꢁ1. Characterized as a 2:1 diastereomeric mixture. 1H NMR
(400 MHz, CDCl3):
d¼8.42 (s, 1H), 7.96 (d, J¼7.6 Hz, 3H), 7.55e7.43
(m, 5H), 6.13 (d, J¼11.7 Hz, 1H), 5.87 (d, J¼11.7 Hz, 1H), 3.49e3.37
(m, 1H), 3.22e3.18 (m, 1H), 2.39e2.34 (m, 2H), 2.24 (s, 3H),

8344
H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
1.98e1.93 (m, 2H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
110.0e111.5 ꢀC. IR (KBr):
1090, 1018, 798, 692, 563 cmꢁ1. Characterized as a 4:1 di-
astereomeric mixture. 1H NMR (400 MHz, CDCl3):
n
¼3424, 3055, 2954, 1670, 1424, 1268,
d
¼8.23e8.11 (m, 3H), 8.06 (d, J¼8.1 Hz, 1H), 7.63e7.55 (m, 5H), 6.46
(d, J¼11.7 Hz, 1H), 5.51 (d, J¼11.7 Hz, 1H), 3.42e3.37 (m, 1H),
d¼7.90 (d,
2.86e2.83 (m, 1H), 2.17e2.14 (m, 2H), 2.02 (s, 3H), 1.85e1.79 (m,
J¼7.5 Hz, 2H), 7.45e7.38 (m, 5H), 7.20e7.14 (m, 3H), 6.13 (d,
J¼11.8 Hz,1H), 5.63 (d, J¼11.8 Hz,1H), 3.43e3.35 (m,1H), 3.05e3.03
(m, 1H), 2.28e2.26 (m, 2H), 2.17 (s, 3H), 1.88e1.84 (m, 2H) ppm.
2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼201.4, 192.6, 175.5, 148.3,
139.2, 134.9, 134.5, 134.4, 129.9, 128.8, 123.2, 122.4, 63.9, 55.4, 45.2,
31.2, 27.6 ppm. Isomer 13C NMR (75 MHz, CDCl3):
d¼200.0, 192.9,
Isomer 1H NMR (400 MHz, CDCl3):
7.54e7.50 (m, 3H), 7.29e7.24 (m, 5H), 6.24 (d, J¼11.5 Hz, 1H), 5.42
(d, J¼11.8 Hz, 1H), 3.32e3.31 (m, 1H), 2.79e2.76 (m, 1H), 2.13e2.09
(m, 2H), 1.88 (s, 3H), 1.69e1.67 (m, 2H) ppm. 13C NMR (100 MHz,
d
¼8.04 (d, J¼7.5 Hz, 2H),
175.6, 148.2, 139.7, 136.2, 134.9, 134.2, 129.9, 129.1, 128.8, 123.4,
122.3, 58.1, 48.6, 31.5, 30.6, 30.4, 18.3 ppm. HRMS: calcd for
C21H20N2O5: [M]þ 380.1372; found, 380.1263.
CDCl3):
127.9, 64.7, 55.6, 44.6, 31.5, 27.4, 18.4 ppm. Isomer 13C NMR
(100 MHz, CDCl3):
d
¼202.8, 193.3, 175.4, 137.0, 136.5, 134.3, 129.1, 128.9, 128.3,
4.2.5. 2-((4-Bromophenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3ea). Yield (133.3 mg, 79%). Yellow solid.
d¼201.4, 193.0, 175.4, 137.5, 136.5, 134.1, 129.1,
Mp 118.3e119.5 ꢀC. IR (KBr):
n
¼3432, 2964, 1670, 1421, 1269 cmꢁ1
.
128.7, 128.3, 127.9, 64.6, 49.6, 47.8, 31.6, 27.4, 18.2 ppm. HRMS: calcd
Characterized as a 3:1 diastereomeric mixture. 1H NMR (400 MHz,
for C21H21NO3: [M]þ 335.1521; found, 335.1611.
CDCl3):
d
¼7.96 (d, J¼7.6 Hz, 2H), 7.48e7.41 (m, 3H), 7.36 (d,
J¼8.2 Hz, 2H), 7.16 (d, J¼8.2 Hz, 2H), 6.08 (d, J¼11.7 Hz, 1H), 5.71 (d,
J¼11.7 Hz, 1H), 3.45e3.38 (m, 1H), 3.16e3.10 (m, 1H), 2.34e2.25 (m,
2H), 2.23 (s, 3H), 1.97e1.90 (m, 2H) ppm. Isomer 1H NMR (400 MHz,
4.2.9. 2-((2-Oxopyrrolidin-1-yl)(p-tolyl)methyl)-1-phenylbutane-
1,3-dione (3ia). Yield (94.2 mg, 67%). White solid. Mp
125.6e126.2 ꢀC. IR (KBr):
n
¼3429, 2927, 1678, 1421, 1262,
1086 cmꢁ1. Characterized as a 4:1 diastereomeric mixture. 1H NMR
(400 MHz, CDCl3):
CDCl3):
d
¼8.11 (d, J¼7.9 Hz, 2H), 7.62e7.58 (m, 3H), 7.51e7.41 (m,
4H), 6.33 (d, J¼11.4 Hz, 1H), 5.40 (d, J¼11.4 Hz, 1H), 3.45e3.43 (m,
d
¼7.98 (d, J¼7.6 Hz, 2H), 7.47e7.30 (m, 4H),
1H), 3.30e3.28 (m, 1H), 2.17e2.14 (m, 2H), 1.97 (s, 3H), 1.94e1.90
7.17e7.13 (m, 3H), 7.02 (d, J¼7.9 Hz, 2H), 6.20 (d, J¼11.8 Hz,1H), 5.65
(d, J¼11.8 Hz, 1H), 3.45e3.40 (m, 1H), 3.12e3.08 (m, 1H), 2.34e2.31
(m, 2H), 2.24 (s, 6H), 1.92e1.89 (m, 2H) ppm. Isomer 1H NMR
(m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼201.9,192.6, 173.3,136.5,
136.1, 134.3, 131.9, 129.4, 128.9, 122.2, 64.3, 58.1, 47.6, 29.7, 18.1 ppm.
Isomer 13C NMR (75 MHz, CDCl3):
d¼200.8, 192.9, 173.3, 136.5,
(400 MHz, CDCl3):
d
¼8.11 (d, J¼7.6 Hz, 2H), 7.60e7.57 (m, 4H),
136.1, 133.9, 132.0, 130.2, 129.4, 128.9, 122.5, 58.1, 48.0, 31.7, 30.9,
30.2, 18.1 ppm. HRMS: calcd for C21H20BrNO3: [M]þ 413.0627;
found, 413.0693.
7.04e7.02 (m, 3H), 6.26 (d, J¼11.6 Hz, 1H), 5.49 (d, J¼11.6 Hz, 1H),
3.39e3.35 (m, 1H), 3.26e3.25 (m, 1H), 2.18e2.14 (m, 2H), 1.96 (s,
6H), 1.71e1.69 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d¼202.7,
192.8, 175.1, 137.8, 136.4, 134.0, 133.7, 129.4, 128.8, 128.7, 127.6, 64.6,
4.2.6. 2-((2-Bromophenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
54.9, 44.2, 31.3, 27.1, 18.1 ppm. Isomer 13C NMR (75 MHz, CDCl3):
phenylbutane-1,3-dione (3fa). Yield (102.5 mg, 63%). Yellow solid.
d
¼201.6, 193.3, 175.1, 138.2, 136.6, 134.2, 133.7, 129.6, 128.7, 128.3,
Mp 130.7e131.5 ꢀC. IR (KBr):
n
¼3246, 2964, 1976, 1688, 1440, 1284,
1171, 994, 762, 685, 534 cmꢁ1. Characterized as a 1:1 diastereomeric
mixture. 1H NMR (400 MHz, CDCl3):
127.6, 64.4, 58.0, 49.4, 47.4, 31.7, 27.1, 21.1, 17.6 ppm. HRMS: calcd for
C22H23NO3: [M]þ 349.1678; found, 349.1759.
d¼8.13 (d, J¼7.8 Hz, 2H), 8.05
(d, J¼7.8 Hz, 2H), 7.94 (d, J¼7.8 Hz, 2H), 7.63e7.49 (m, 6H),
7.44e7.41 (m, 3H), 7.36 (t, J¼7.6 Hz, 1H), 7.15e7.11 (m, 2H), 7.05 (t,
J¼7.6 Hz, 1H), 6.62 (d, J¼11.3 Hz, 1H), 6.27 (d, J¼11.4 Hz, 1H), 6.01 (d,
J¼11.4 Hz,1H), 6.83 (d, J¼11.3 Hz,1H), 3.64e3.60 (m,1H), 3.58e3.52
(m, 1H), 3.51e3.39 (m, 1H), 3.20e3.14 (m, 1H), 2.46e2.44 (m, 2H),
2.29 (s, 3H), 2.12e2.08 (m, 2H), 1.97 (s, 3H), 1.84e1.77 (m, 2H) ppm.
4.2.10. 2-((4-Methoxyphenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3ja). Yield (88.0 mg, 61%). White solid. Mp
81.2e82.2 ꢀC. IR (KBr):
n
¼3436, 2963, 1675, 1426, 1261, 1031,
805 cmꢁ1. Characterized as a 3:1 diastereomeric mixture. 1H NMR
(400 MHz, CDCl3):
d¼7.97 (d, J¼7.6 Hz, 2H), 7.46 (t, J¼7.5 Hz, 3H),
7.15 (d, J¼8.4 Hz, 2H), 6.75 (d, J¼8.4 Hz, 2H), 6.14 (d, J¼11.8 Hz, 1H),
5.66 (d, J¼11.8 Hz, 1H), 3.72 (s, 3H), 3.42e3.35 (m, 1H), 3.15e3.11
(m, 1H), 2.38e2.31 (m, 2H), 2.24 (s, 3H), 1.93e1.89 (m, 2H) ppm.
13C NMR (75 MHz, CDCl3):
d
¼207.3, 206.1, 198.2, 197.8, 180.5, 141.7,
141.3, 139.5, 137.2, 137.1, 136.2, 136.1, 135.4, 134.7, 134.4, 133.9, 132.1,
130.3, 129.6, 129.1, 128.9, 127.7, 127.4, 69.5, 62.8, 60.2, 53.2, 49.8,
36.9, 36.5, 35.5, 32.4, 23.4, 23.3 ppm. HRMS: calcd for C21H20BrNO3:
[M]þ 413.0627; found, 413.0693.
Isomer 1H NMR (400 MHz, CDCl3):
d¼8.11 (d, J¼7.6 Hz, 2H), 7.59 (t,
J¼7.5 Hz, 3H), 7.51 (d, J¼7.5 Hz, 2H), 6.87 (d, J¼7.5 Hz, 2H), 6.25 (d,
J¼11.5 Hz, 1H), 5.46 (d, J¼11.5 Hz, 1H), 3.80 (s, 3H), 3.27e3.24 (m,
1H), 3.87e3.84 (m, 1H), 2.16 (s, 3H), 2.04e2.00 (m, 2H), 1.81e1.77
4.2.7. 2-((4-Fluorophenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3ga). Yield (109.5 mg, 77%). White solid.
(m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼202.8, 193.0, 175.3,
159.4, 136.5, 134.2, 129.8, 129.5, 129.1, 128.9, 114.4, 64.9, 57.9, 55.3,
Mp 106.5e107.1 ꢀC. IR (KBr):
n
¼3438, 2920, 1676, 1507, 1424, 1271,
812, 695 cmꢁ1. Characterized as a 3:1 diastereomeric mixture. 1
NMR (400 MHz, CDCl3):
44.5, 31.6, 27.3, 18.2 ppm. Isomer 13C NMR (100 MHz, CDCl3):
H
d
¼201.8, 193.6, 175.1, 159.7, 136.8, 134.9, 129.5, 128.9, 114.3, 64.6,
d
¼7.94 (d, J¼7.7 Hz, 2H), 7.55e7.41 (m, 4H),
55.1, 49.6, 47.5, 31.9, 30.8, 17.8 ppm. HRMS: calcd for C22H23NO4:
[M]þ 365.1627; found, 365.1701.
7.03 (t, J¼8.5 Hz, 1H), 6.90 (t, J¼8.5 Hz, 2H), 6.08 (d, J¼11.8 Hz, 1H),
5.73 (d, J¼11.8 Hz, 1H), 3.45e3.39 (m, 1H), 3.16e3.10 (m, 1H),
2.36e2.31 (m, 2H), 2.22 (s, 3H), 1.95e1.89 (m, 2H) ppm. Isomer 1H
4.2.11. 2-((3-Methoxyphenyl)(2-oxopyrrolidin-1-yl)methyl)-1-
NMR (400 MHz, CDCl3):
d
¼8.10 (d, J¼7.6 Hz, 2H), 7.58e7.50 (m, 4H),
phenylbutane-1,3-dione (3ka). Yield (99.5 mg, 68%). White solid.
7.26e7.24 (m, 4H), 6.32 (d, J¼11.5 Hz, 1H), 5.42 (d, J¼11.5 Hz, 1H),
Mp 112.5e113.0 ꢀC. IR (KBr):
n
¼3428, 2947, 1673, 1596, 1423, 1272,
1173, 1054, 989, 760 cmꢁ1. Characterized as a 5:1 diastereomeric
mixture. 1H NMR (400 MHz, CDCl3):
3.39e3.37 (m, 1H), 3.31e3.27 (m, 1H), 2.16e2.14 (m, 2H), 1.91 (s,
3H), 1.78e1.70 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
d¼197.8,
d¼7.98 (d, J¼7.6 Hz, 2H), 7.59
188.4, 170.9, 159.1, 156.6, 131.8, 129.8, 128.4, 125.8, 124.5, 115.0, 60.1,
(t, J¼7.5 Hz, 2H), 7.54e7.40 (m, 3H), 6.81e6.74 (m, 2H), 6.20 (d,
J¼11.8 Hz, 1H), 5.65 (d, J¼11.8 Hz, 1H), 3.69 (s, 3H), 3.44e3.43 (m,
1H), 3.12e3.10 (m, 1H), 2.35e2.34 (m, 2H), 2.24 (s, 3H), 1.91e1.83
50.7, 40.3, 27.3, 26.9, 13.7 ppm. Isomer 13C NMR (100 MHz, CDCl3):
d
¼196.8, 188.7, 170.9, 159.4, 156.9, 132.0, 129.5, 129.0, 125.0, 124.4,
111.3, 53.6, 45.2, 43.6, 26.3, 25.3, 13.5 ppm. HRMS: calcd for
C21H20FNO3: [M]þ 353.1427; found, 353.1502.
(m, 2H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
d
¼8.11 (d,
J¼7.5 Hz, 2H), 7.29e7.25 (m, 2H), 7.13e7.07 (m, 2H), 6.84e6.81 (m,
1H), 6.74e6.71 (m, 2H), 6.25 (d, J¼11.6 Hz, 1H), 5.52 (d, J¼11.6 Hz,
1H), 4.13e4.10 (m, 1H), 3.81 (s, 3H), 3.36e3.27 (m, 1H), 2.20e2.16
(m, 2H), 2.06e2.02 (m, 2H), 1.99 (s, 3H) ppm. 13C NMR (75 MHz,
4.2.8. 2-((2-Oxopyrrolidin-1-yl)(phenyl)methyl)-1-phenylbutane-
1,3-dione (3ha). Yield (88.6 mg, 68%). White solid. Mp

H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
8345
CDCl3):
119.6, 114.1, 113.6, 64.4, 55.2, 49.4, 44.2, 31.3, 27.1, 18.1 ppm. Isomer
13C NMR (75 MHz, CDCl3):
133.7,129.9,128.7,120.5,113.8,113.5, 64.2, 58.2, 55.1, 47.4, 31.6, 29.9,
17.6 ppm. HRMS: calcd for C22H23NO4: [M]þ 365.1627; found,
365.1519.
d
¼202.5, 193.2, 175.2, 159.8, 138.3, 136.3, 134.1, 129.7, 128.9,
123.2e124.2 ꢀC. IR (KBr):
n
¼3409, 3111, 2966, 2866, 1687, 1519,
1419, 1354, 1265, 1168, 807,704 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
¼201.4, 192.7, 175.2, 159.7, 138.7, 136.5,
d
¼8.81 (d, J¼8.7 Hz, 2H), 7.54 (d, J¼8.7 Hz, 2H), 5.67 (d, J¼11.9 Hz,
1H), 5.17 (d, J¼11.9 Hz, 1H), 337e3.31 (m, 1H), 3.24e3.17 (m, 1H),
2.35e2.25 (m, 5H), 2.12 (s, 3H), 1.97e1.86 (m, 2H) ppm. 13C NMR
(75 MHz, CDCl3):
74.8, 60.8, 51.2, 36.5, 36.4, 33.6, 23.4 ppm. HRMS: calcd for
C16H18N2O5: [M]þ 318.1216; found, 318.1302.
d
¼205.7, 205.4, 180.7, 152.9, 149.4, 134.2, 129.4,
4.2.12. 2-((4-(Dimethylamino)phenyl)(2-oxopyrrolidin-1-yl)methyl)-
1-phenylbutane-1,3-dione (3la). Yield (67.4 mg, 45%). White solid.
Mp 100.0e101.5 ꢀC. IR (KBr):
n
¼3380, 2921, 1674, 1525, 1423, 1354,
1266, 1170, 812, 691 cmꢁ1. Characterized as a 3:1 diastereomeric
mixture. 1H NMR (400 MHz, CDCl3):
4.2.16. 2-((4-Nitrophenyl)(2-oxopyrrolidin-1-yl)methyl)-1,3-
diphenylpropane-1,3-dione (3ac). Yield (139.5 mg, 79%). White
d
¼7.96 (d, J¼7.8 Hz, 2H),
solid. Mp 86.4e87.1 ꢀC. IR (KBr):
n
¼3441, 3054, 2920, 1670, 1520,
7.50e7.39 (m, 3H), 7.08 (d, J¼8.5 Hz, 2H), 6.52 (d, J¼8.5 Hz, 2H), 6.14
(d, J¼11.7 Hz, 1H), 5.57 (d, J¼11.7 Hz, 1H), 3.40e3.39 (m, 1H),
3.10e3.07 (m, 1H), 2.84 (s, 6H), 2.33e2.29 (m, 2H), 2.25 (s, 3H),
1278, 1104, 1005, 857, 695 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼8.02
(t, J¼8.0 Hz, 4H), 7.80 (d, J¼7.7 Hz, 2H), 7.68 (d, J¼7.7 Hz, 2H),
7.53e7.29 (m, 7H), 5.53 (d, J¼11.0 Hz, 1H), 3.57e3.55 (m, 1H),
3.46e3.44 (m, 1H), 2.23e2.18 (m, 2H), 1.90e1.86 (m, 2H) ppm. 13C
1.92e1.87 (m, 2H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
d¼8.08 (d,
J¼7.7 Hz, 2H), 7.55 (t, J¼6.7 Hz, 1H), 7.33 (d, J¼8.2 Hz, 2H), 6.64 (d,
J¼8.3 Hz, 2H), 6.14 (d, J¼11.7 Hz, 1H), 5.46 (d, J¼11.7 Hz, 1H),
3.29e3.25 (m,1H), 3.25e3.20 (m,1H), 2.92 (s, 6H), 2.15e2.13 (m, 2H),
1.96 (s, 3H), 1.72e1.67 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
¼193.3, 176.2, 147.5, 145.1, 136.2, 135.8,
134.0, 133.8, 129.6, 128.8, 128.7, 132.7, 60.3, 57.5, 49.8, 31.9,
29.6 ppm. HRMS: calcd for C26H22N2O5: [M]þ 442.1529; found,
442.1414.
d
¼208.3, 198.8, 180.2, 155.5, 141.7, 139.1, 134.5, 133.9, 133.7, 129.4,
117.5, 70.1, 59.9, 49.2, 45.5, 36.6, 34.9, 32.2, 23.2 ppm. Isomer 13C NMR
(75 MHz, CDCl3):
133.7, 129.6, 117.5, 62.8, 60.8, 52.2, 45.5, 36.9, 34.9, 32.2, 23.2 ppm.
HRMS: calcd for C23H26N2O3: [M]þ 378.1943; found, 378.1817.
4.2.17. 2-((4-Methoxyphenyl)(2-oxopyrrolidin-1-yl)methyl)-1,3-
diphenylpropane-1,3-dione (3jc). Yield (106.0 mg, 61%). White solid.
d¼207.2,198.8,180.1,155.3,141.9,138.3,134.5,139.8,
Mp 176.2e177.9 ꢀC. IR (KBr):
n
¼3449, 3056, 2937, 1671, 1512, 1437,
1268, 1188, 1023, 760, 693 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d¼8.02
(d, J¼7.7 Hz, 2H), 7.83 (d, J¼7.7 Hz, 2H), 7. 51e7.28 (m, 9H), 6.71 (d,
J¼8.7 Hz, 2H), 5.44 (d, J¼11.0 Hz, 1H), 3.69 (s, 3H), 3.54e3.48 (m,
1H), 3.45e3.42 (m, 1H), 2.24e2.20 (m, 2H), 1.85e1.64 (m, 2H) ppm.
4.2.13. 2-((2-Oxopyrrolidin-1-yl)(thiophen-2-yl)methyl)-1-
phenylbutane-1,3-dione (3ma). Yield (84.1 mg, 62%). White solid.
Mp 128.0e129.5 ꢀC. IR (KBr):
n
¼3433, 3080, 2921, 1670, 1423, 1265,
1148, 964, 784, 697 cmꢁ1. Characterized as a 3:2 diastereomeric
mixture. 1H NMR (400 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
d
¼194.2, 176.1, 159.7, 136.7, 133.6, 130.1,
129.9, 129.1, 128.9, 128.7, 114.1, 60.4, 58.8, 55.4, 49.4, 32.4, 18.5 ppm.
HRMS: calcd for C27H25NO4: [M]þ 427.1784; found, 427.1691.
d
¼8.10 (d, J¼7.8 Hz, 2H),
7.59e7.46 (m, 3H), 7.13 (d, J¼5.1 Hz, 1H), 6.89e6.87 (m, 1H),
6.83e6.81 (m, 1H), 6.46 (d, J¼11.7 Hz, 1H), 5.58 (d, J¼11.7 Hz, 1H),
3.49e3.42 (m, 1H), 3.29e3.23 (m, 1H), 2.35e2.33 (m, 2H), 2.22 (s,
3H), 1.95e1.91 (m, 2H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
4.2.18. Ethyl 2-((4-nitrophenyl)(2-oxopyrrolidin-1-yl)methyl)-3-
oxobutanoate (3ad). Yield (68.2 mg, 49%). Yellow oil. IR (KBr):
n
¼3454, 2932, 1689, 1523, 1354, 1272, 1021, 856, 530 cmꢁ1. Char-
d
¼8.11 (d, J¼7.7 Hz, 2H), 7.60e7.51 (m, 3H), 7.26 (s, 1H), 7.11 (d,
acterized as a 1:1 diastereomeric mixture. 1H NMR (400 MHz,
J¼7.4 Hz, 1H), 6.97e6.94 (m, 1H), 6.18 (d, J¼11.1 Hz, 1H), 5.84 (d,
J¼11.1 Hz, 1H), 3.50e3.48 (m, 1H), 2.87e2.85 (m, 1H), 2.17e2.07 (m,
2H), 2.07 (s, 3H), 1.83e1.74 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
CDCl3):
d
¼8.19 (dd, J¼8.1, 4.8 Hz, 2H, ArH), 7.57 (dd, J¼8.1, 4.8 Hz,
2H, ArH), 5.55 (dd, J¼25.7, 11.9 Hz, 1H, CH), 5.45 (d, J¼11.6 Hz, 1H,
CH), 4.24 (dd, J¼7.1, 4.2 Hz, 1H, OCH2), 4.04 (dd, J¼7.1, 4.2 Hz, 1H,
OCH2), 3.48e3.33 (m, 1H), 3.27e3.22 (m, 1H), 2.37 (s, 1.5H, COCH3),
2.35e2.19 (m, 2H), 2.17 (s, 1.5H, COCH3), 1.89e1.80 (m, 2H), 1.28 (t,
d
¼201.9, 192.8, 175.1, 139.7, 136.2, 134.1, 128.9, 128.8, 126.7, 126.2,
125.4, 66.3, 49.4, 44.2, 31.2, 29.9, 18.1 ppm. Isomer 13C NMR
(75 MHz, CDCl3):
d
¼200.7, 192.7, 175.1, 139.4, 136.3, 133.9, 128.9,
J¼7.1 Hz, 1.5H, OCH2CH3), 1.10 (t, J¼7.1 Hz, 1.5H, OCH2CH3) ppm. 13
C
127.3,126.0,125.3, 65.5, 53.2, 47.2, 31.4, 29.6,18.1 ppm. HRMS: calcd
NMR (75 MHz, CDCl3):
d¼205.6, 204.8, 180.7, 180.3, 171.6, 171.5,
for C19H19NO3S: [M]þ 341.1086; found, 341.0985.
152.9, 152.7, 149.6, 148.7, 134.2, 133.8, 129.2, 128.8, 67.6, 67.2, 66.1,
60.6, 51.7, 51.4, 36.6, 35.8, 35.4, 34.7, 33.7, 23.5, 23.4, 19.2, 19.0 ppm.
HRMS: calcd for C17H20N2O6: [M]þ 348.1321; found, 348.1212.
4.2.14. 2-(Naphthalen-2-yl(2-oxopyrrolidin-1-yl)methyl)-1-
phenylbutane-1,3-dione (3na). Yield (96.5 mg, 63%). White solid.
Mp 81.1e82.5 ꢀC. IR (KBr):
n
¼3435, 3054, 2949, 673, 1419, 1267,
1170, 970, 757 cmꢁ1. Characterized as a 5:1 diastereomeric mixture.
1H NMR (400 MHz, CDCl3):
4.2.19. Ethyl 2-benzoyl-3-(4-nitrophenyl)-3-(2-oxopyrrolidin-1-yl)
propanoate (3ae). Yield (134.9 mg, 81%). White solid. Mp
d
¼7.93 (d, J¼8.0 Hz, 2H), 7.69 (d,
37.4e38.1 ꢀC. IR (KBr):
n
¼3456, 3072, 2958, 1727, 1521, 1348, 1268,
1013, 850, 692 cmꢁ1. Characterized as a 3:2 diastereomeric mixture.
1H NMR (400 MHz, CDCl3):
J¼8.0 Hz, 2H), 7.66e7.52 (m, 3H), 7.39e7.34 (m, 5H), 6.32 (d,
J¼11.8 Hz, 1H), 5.78 (d, J¼11.8 Hz, 1H), 3.45e3.42 (m, 1H), 3.10e3.04
(m, 1H), 2.34e2.25 (m, 2H), 2.24 (s, 3H), 1.88e1.80 (m, 2H) ppm.
d¼8.07 (d, J¼8.5 Hz, 2H), 7.96 (d,
J¼8.5 Hz, 2H), 7.57 (d, J¼8.4 Hz, 2H), 7. 61e7.39 (m, 3H), 5.87 (d,
J¼11.5 Hz, 1H), 5.76 (d, J¼11.5 Hz, 1H), 4.17e4.10 (m, 2H), 3.54e3.49
(m, 1H), 3.36e3.33 (m, 1H), 2.35e2.31 (m, 2H), 1.85e1.64 (m, 2H),
1.14 (t, J¼8.4 Hz, 3H) ppm. Isomer 1H NMR (400 MHz, CDCl3):
Isomer 1H NMR (400 MHz, CDCl3):
d¼8.10 (d, J¼7.8 Hz, 2H), 7.81 (d,
J¼8.9 Hz, 2H), 7.57e7.44 (m, 9H), 6.32 (d, J¼11.5 Hz, 1H), 5.64 (d,
J¼11.5 Hz, 1H), 3.35e3.30 (m, 1H), 3.25e3.24 (m, 1H), 2.17e2.12 (m,
2H), 1.90 (s, 3H), 1.69e1.65 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d
¼8.18 (d, J¼8.4 Hz, 2H), 8.10 (d, J¼8.4 Hz, 2H), 7. 61e7.39 (m, 5H),
d
¼202.5, 192.7, 175.3, 136.4, 134.1, 131.4, 128.9, 128.8, 128.7, 127.9,
127.5, 127.4, 126.5, 126.1, 125.2, 64.6, 55.5, 44.4, 31.4, 27.2, 18.1 ppm.
Isomer 13C NMR (75 MHz, CDCl3):
6.21 (d, J¼11.5 Hz, 1H), 5.35 (d, J¼11.5 Hz, 1H), 3.91e3.87 (m, 2H),
3.54e3.49 (m, 1H), 3.33e3.24 (m, 1H), 2.33e2.24 (m, 1H), 2.31e2.51
(m, 2H), 1.80e1.67 (m, 2H), 0.89 (t, J¼8.4 Hz, 3H) ppm. 13C NMR
d¼201.4, 193.1, 175.3, 136.6, 134.8,
133.0, 128.9, 128.8, 128.7, 128.1, 127.6, 127.4, 126.3, 125.7, 125.2, 64.4,
58.3, 47.5, 31.7, 29.7, 18.1 ppm. HRMS: calcd for C25H23NO3: [M]þ
385.1678; found, 385.1557.
(100 MHz, CDCl3):
d¼192.8, 175.8, 167.5, 147.9, 144.8, 134.4, 129.8,
129.3, 129.0, 128.9, 124.1, 62.5, 58.7, 55.2, 46.4, 31.6, 29.8, 14.1 ppm.
Isomer 13C NMR (100 MHz, CDCl3):
d
¼191.4, 175.5, 167.2, 147.6,
144.7, 134.3, 129.8, 129.1, 129.0, 128.9, 124.0, 62.1, 56.3, 55.6, 49.2,
31.9, 18.6, 13.8 ppm. HRMS: calcd for C22H22N2O6: [M]þ 410.1478;
found, 410.1557.
4.2.15. 3-((4-Nitrophenyl)(2-oxopyrrolidin-1-yl)methyl)pentane-2,4-
dione (3ab). Yield (82.6.5 mg, 64%). White solid. Mp

8346
H.-Y. Xu et al. / Tetrahedron 68 (2012) 8340e8346
6. Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161e5167.
Acknowledgements
7. Liu, P. N.; Zhou, Z. Y.; Lau, C. P. Chem.dEur. J. 2007, 13, 8610e8619.
8. Rao, W.; Tay, A. H. L.; Goh, P. J.; Choy, J. M. L.; Ke, J. K.; Chan, P. W. H. Tetrahedron
Lett. 2008, 49, 122e126.
The work was partially supported by the National Natural Sci-
ence Foundation of China (No. 21042007, 21172162), Natural Sci-
ence Basic Research of Jiangsu Province for Higher Education (No.
10KJB150016), a Research Grant from the Innovation Project for
Graduate Student of Jiangsu Province (CX10B-033Z), Innovation
project for undergraduate student-state level (No. 101028514), and
Key Project in Science & Technology Innovation Cultivation Pro-
gram of Soochow University.
9. Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew.
Chem., Int. Ed. 2006, 45, 2605e2609; Motokura, K.; Nakagiri, N.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. J. Org. Chem. 2007, 72, 6006e6015.
10. Sanz, R.; Martinez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Adv.
Synth. Catal. 2006, 348, 1841e1845; Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-
Gutierrez, J. M.; Rodriguez, F. Org. Lett. 2007, 9, 727e730.
11. Sanz, R.; Miguel, D.; Martinez, A.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Org. Lett.
2007, 9, 2027e2030.
12. Wang, G. W.; Shen, Y. B.; Wu, X. L. J. Org. Chem. 2008, 4999e5004.
13. Kenda B.; Quesnel Y.; Ates A.; Michel P.; Turet L.; Mercier J. WO2006128693,
2006; Gobert J.; Geerts J.-P.; Bodson G. EP0162036, 1985; Schmiesing R. J.;
Murray R. J. U.S. Patent 5,334,720, 1994.
Supplementary data
14. Jiang, R.; Wu, X.-J.; Zhu, X.; Xu, X.-P.; Ji, S.-J. Eur. J. Org. Chem. 2010, 5946e5950.
15. Niu, T. M.; Huang, L. H.; Wu, T. X.; Zhang, Y. H. Org. Biomol. Chem. 2011, 9,
273e277.
16. Jiang, R.; Xu, H.-Y.; Xu, X.-P.; Chu, X.-Q.; Ji, S.-J. Org. Biomol. Chem. 2011, 9,
5659e5669.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.017.
17. Cu(OTf)2 belongs to the most reactive and used catalyst with Lewis acid
properties, has been widely used in organic synthesis. Famous examples, see:
(a) Guo, C.; Song, J.; Luo, S. W.; Gong, L. Z. Angew. Chem., Int. Ed. 2010, 49,
5558e5562; (b) Shao, L. X.; Zhang, Y. P.; Qi, M. H.; Shi, M. Org. Lett. 2007, 9,
117e120; (c) Zhang, Z. P.; Wang, S. P.; Cai, X. B.; Liu, H. J.; Yu, J. J.; Cui, Y. Y. Adv.
Synth. Catal. 2007, 349, 2097e2102; (d) Zhou, J.; Tang, Y. Chem. Commun. 2004,
432e433; (e) Asao, N.; Kashaara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2003,
42, 3504e3506; (f) Taylor, J. G.; Whittall, N.; Hii, K. K. Chem. Commun. 2005,
References and notes
1. Rueping, M.; Nachtsheim, B. J.; Kuenkei, A. Org. Lett. 2007, 9, 825e827.
2. Comprehensive Organic Synthesis; Trost, B. M., Freming, I., Eds.; Pergamon:
Oxford, 1991; p 3.
3. Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002, 1823e1826.
4. Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793e796.
5. Yuan, Y.; shi, Z.; Feng, X.; Liu, X. Appl. Organomet. Chem. 2007, 21, 958e964; Jana,
U.; Biswas, S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4065e4069; Kischel, J.; Mertins,
K.; Michalik, D.; zapf, A.; Beller, M. Adv. Synth. Catal. 2007, 349, 865e870.
5103e5105; (g) For Cu(OTf)2 catalyzed a-amidoalkylation reaction inside of the
piperidine six-member ring see: Onomura, O.; Kanda, Y.; Nakamura, Y.; Maki,
T.; Matsumura, Y. Tetrahedron Lett. 2002, 43, 3229e3231.