One-pot synthesis of 5-oxopyrrolidine-2-carboxamides via a tandem Ugi 4CC/SN cyclization starting from Baylis-Hillman bromides

Article abstract of DOI:10.1016/j.tet.2013.03.058

A one-pot base-mediated synthesis of 5-oxopyrrolidine-2-carboxamides was developed. The reaction of Baylis-Hillman bromides 1, primary amines 2, isocyanides 3 and arylglyoxals 4 produced the 5-oxopyrrolidine-2-carboxamides 6 in good yields via a tandem Ugi condensation and intramolecular substitution at room temperature in the presence of Cs₂CO₃.

Full text of DOI:10.1016/j.tet.2013.03.058

Tetrahedron 69 (2013) 3823e3828
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of 5-oxopyrrolidine-2-carboxamides via a tandem
Ugi 4CC/SN cyclization starting from BayliseHillman bromides
,
,
Xiao-Hua Zeng a b, Hong-Mei Wang b, Lei Wu a, Ming-Wu Ding a
*
a Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
b Institute of Medicinal Chemistry, Hubei University of Medicine, Shiyan 442000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot base-mediated synthesis of 5-oxopyrrolidine-2-carboxamides was developed. The reaction of
BayliseHillman bromides 1, primary amines 2, isocyanides 3 and arylglyoxals 4 produced the 5-
oxopyrrolidine-2-carboxamides 6 in good yields via a tandem Ugi condensation and intramolecular
substitution at room temperature in the presence of Cs2CO3.
Received 4 January 2013
Received in revised form 5 March 2013
Accepted 15 March 2013
Available online 20 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
lengthy reaction steps or are compatible with few functional
groups.
Multicomponent reactions (MCRs) constitute a superior tool for
diversity-oriented and complexity-generating synthesis of various
heterocycles, which are particularly well-represented among nat-
ural products and pharmaceuticals.1 The Ugi reaction is one of the
two main isocyanide-based multicomponent reactions (I-MCRs)
(the Ugi reaction and the Passerini reaction) and is a powerful,
atom-economical reaction of isonitrile, amino, aldehyde (or ketone)
The BayliseHillman (BeH) reaction has become a powerful
synthetic tool for the preparation of densely functionalized mole-
cules through construction of CeC bonds in an operationally simple
one-pot procedure.13 The densely functionalized products, which
are usually known as BayliseHillman adducts, have been employed
recently in further preparations of various heterocyclic compounds,
such as 4(3H)-pyrimidinones, quinolines, pyrroles, 1,3-thiazin-4-
ones, and pyrrolo[1,2-a]pyrazines.14 We envisioned that the Bay-
liseHillman acid may be used as one reactant of the Ugi reaction,
which might produce various multisubstituted heterocycles in one-
pot fashion. Continuing our interest in I-MCR mediated synthesis of
with carboxylic acid. It generates a significantly more complex a-
acylamino-carboxamide adduct that have received increased at-
tention in view of its utility in the synthesis of nitrogen heterocyclic
compounds.2
The derivatives of heterocycles containing the pyrrolidinone
moiety are of great importance because they have wide application
in pharmaceutical, chemical and other fields. They proved to show
significant antimuscarinic,3 antiepileptic,4 anti-AIDS,5 and antiviral
activities.6 The classic synthetic methodology for the construction
of a pyrrolidinone scaffold have been focused primarily on cycli-
zation of the dialkyl itaconate with different primary amines.7 For
example, some chemists utilized the method of combinatorial
chemistry following this strategy to prepare various pyrrolidinone
derivatives.8 Kenda et al. also described the synthesis of pyrrolidi-
none based on a sequential alkylation or reductive amination fol-
lowed by cyclization.4 In addition, pyrrolidinones have been
heterocycles,15 herein we report
a direct synthesis of 5-
oxopyrrolidine-2-carboxamides by Ugi reaction of BayliseHillman
acid, primary amines, arylglyoxals and isocyanides.
2. Results and discussion
Initially, we selected the BayliseHillman bromide 1a, 4-
bromophenylglyoxal 2a, n-propylamine 3a and tert-butylisocya-
nide 4a as the reactants (Scheme 1). When the BayliseHillman
bromide 1a, 4-bromophenylglyoxal 2a, n-propylamine 3a and tert-
butylisocyanide 4a was stirred in methanol at room temperature
for 24 h, the 5-oxopyrrolidine-2-carboxamide derivative 6a was
directly obtained albeit in low yield (34%). The expected Ugi
product 5a might produced but cyclized directly to give 5-
oxopyrrolidine-2-carboxamide 6a under the reaction condition.
Further study of the reaction time revealed that nearly the same
yields (32e34%) of the product 6a were obtained as the reactions
were carried out for 2e48 h (Table 1, entry 2e5) whereas relative
lower yield (12%) was reached when the reaction time was reduced
to 1 h (Table 1, entry 1). The detection of reaction mixture also
prepared by other methods, such as rearrangement of b
-lactam,9
the radical additionecyclization reaction,10 cycloaddition re-
action,11 and transition-metal-catalyzed intramolecular allylic al-
kylation reaction.12 However, these strategies typically require
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041; e-mail
addresses: ding5229@yahoo.com.cn, mwding@mail.ccnu.edu.cn (M.-W. Ding).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.058

3824
X.-H. Zeng et al. / Tetrahedron 69 (2013) 3823e3828
under the acidic condition. Although the Ugi intermediates 5 or 50
were not isolated from the reaction mixture, some similar Ugi ad-
ducts from arylglyoxals 2, primary amines, isocyanides and car-
boxylic acid were reported to exist exclusively as the enol forms.16
COOH
Br
O
Ph
n-PrNH2
3a
Ph
N
O
Base
1a
+
Br
MeOH
O
O
NH
COOH
NC
Ar1
O
Br
R1NH2
R1
Br
CHO
Ar1
N
4a
O
Br
Cs2CO3
MeOH
3
1
5a
2a
+
Ar2
NHR2
Br
O
O
O
R2 NC
Ar2
N
CHO
O
5
4
2
-HBr
HN
O
O
O
R1
R1
O
Ar1
N
Ar1
N
OH
-HBr
Br
Ar2
6a
Br
O
R2HN
Ar2
NHR2
O
Scheme 1. Preparation of compound 6a.
6
5'
Table 1
Scheme 2. Preparation of compounds 6.
Optimization of the reaction conditions about 6a
Entry
Base
Condition
Yield (%)a
Table 2
Preparation of compounds 6
1
2
3
4
5
6
7
8
9
d
rt/1 h
rt/2 h
12
32
34
34
33
64
71
75
83
d
d
rt/12 h
rt/24 h
rt/48 h
rt/12 h
rt/12 h
rt/12 h
rt/12 h
Ar1
Ar2
R1
R2
Yield
(%)a
d
d
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
n-Pr
PhCH2
n-Pr
n-Pr
PhCH2
n-Pr
i-Pr
i-Pr
n-Bu
Me
Me
t-Bu
t-Bu
83
86
84
82
82
71
81
79
73
71
75
73
75
89
85
86
91
87
68
65
NEt3
K2CO3
NaHCO3
Cs2CO3
c-C6H11
t-Bu
n-Bu
n-Bu
c-C6H11
t-Bu
a
Isolated yields based on BayliseHillman bromide 1a.
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
t-Bu
t-Bu
revealed that the pH of the solution decreased from 7 to 4 during
the reaction process and reached the minimum in 2 h, after which
the reaction took place slowly accompanying side reactions. This
evidence implies that the intramolecular substitution reaction of
intermediate 5a occurs even under acidic condition and is pH de-
pendant. So it’s understandable that good yields of 6a were ob-
tained (Table 1, entry 6e9) when a base was added to adjust the pH
of the solution to 6 during the reaction process. The best result was
reached as Cs2CO3 was utilized as a base (Table 1, entry 9) probably
due to its good solubility in the solvent. In the 4-
bromophenylglyoxal 2a, there were two carbonyl groups, which
might both involve into the reaction. But we didn’t isolate the
byproduct resulted from the ketone carbonyl group. This is prob-
ably due to the higher reactivity of the aldehyde carbonyl group
compared with the ketone carbonyl one.
With the optimized condition, various BayliseHillman bromides
1, arylglyoxal 2, amine 3 and isocyanide 4 were employed for the
reaction with Cs2CO3 as a base to adjust the pH of the solution to 6
during the reaction process (Scheme 2). All reactions proceeded
smoothly to give the corresponding 5-oxopyrrolidine-2-
carboxamides 6 (Table 2) in 65e91% yields. As shown in Table 2,
the yields of the products were related to the R1 group of amine 3.
When various aliphatic amines were used, the reaction produced 5-
oxopyrrolidine-2-carboxamides 6 in good to high yields (71e91%,
Table 2, compounds 6aer). However, as the aromatic amine was
utilized, moderate yields of the products 6s and t were obtained
(65e68%, Table 2). The electron-donating ability of the R1 group
might be an important influencing factor for the yields of the
products. The formation of the 5-oxopyrrolidine-2-carboxamides 6
can be rationalized in terms of an initial Ugi reaction to give the
adduct 5, which directly undergoes intramolecular nucleophilic
substitution to give 6 through the enol form of intermediate 50
c-C6H11
t-Bu
c-C6H11
c-C6H11
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
Et
PhCH2
n-Pr
PhCH2
PhCH2
i-Pr
4-ClC6H4
4-ClC6H4
t-Bu
a
Isolated yields based on BayliseHillman bromide 1.
The compounds 6aet was confirmed by their spectrum data.
For example, the 1H NMR spectrum of 6a shows two doublets at
3.78 and 3.32 ppm due to the CH2 of the pyrrolidine ring. The
signals of CONH are found at 6.15 ppm as singlet. The signals of
NCH2 appear at 3.62e3.57 and 3.19e3.14 ppm as two multiplets.
The signals of CH2 and CH3 appear at 1.74e1.46, 1.35 and 0.87 ppm
as multiplets, singlet and triplets, respectively. The signals attrib-
utable to the AreHs and vinyleH are found at 7.72e7.32 ppm as
multiplets and singlet. The 13C NMR spectrum data in 6a showed
the signals of C]O and CON carbon at 196.0, 169.8 and 167.5 ppm.
The quaternary carbon of the pyrrolidine ring absorbs at 74.8 ppm.
The MS spectrum of 6a shows molecular ion peak and
MþꢀCONHBu-t at m/z 496 and 397 with 2% and 21% abundance.
Furthermore a single crystal of 5-oxopyrrolidine-2-carboxamide
6c was obtained from the CH2Cl2/ethanol solution of 6c, and X-
ray structure analysis verified the proposed structure (Fig. 1). In
the solid state, the five-membered ring of the pyrrolidinone sys-
tem adopts a planar conformation and the configuration of the
product 6c is E form.

X.-H. Zeng et al. / Tetrahedron 69 (2013) 3823e3828
3825
CHa2), 3.62e3.57 (m, 1H, NCH2a), 3.32 (d, J¼18.0 Hz, 1H, CHb2),
3.19e3.14 (m, 1H, NCHb2), 1.74e1.46 (m, 2H, CH2), 1.35 (s, 9H, 3CH3),
0.87 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,150 MHz):
d 196.0,169.8,
167.5,134.9,132.5,132.1,132.0,131.9,130.6,129.7,129.6,129.1,128.8,
128.7, 126.5, 74.8, 52.6, 46.0, 35.5, 28.3, 21.3, 11.7. MS m/z (%): 496
(Mþ, 2), 397 (21), 313 (89), 214 (43), 185 (100), 115 (72). Anal. Calcd
for C26H29BrN2O3: C, 62.78; H, 5.88; N, 5.63. Found: C, 62.94; H,
6.03; N, 5.44.
4.2.2. (E)-1-Benzyl-4-benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-
5-oxopyrrolidine-2-carboxamide (6b). Operation as above with ben-
zylamine (0.11 g, 1 mmol) and 4-chlorophenylglyoxal 4b (Ar2¼4-
ClC6H4, 0.17 g, 1 mmol), compound 6b (0.43 g, 86%) was also isolated
as white solid. Mp: 194e195 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.73 (d,
J¼8.4 Hz, 2H, AreH), 7.53 (s, 1H, ]CH), 7.44 (d, J¼7.2 Hz, 2H, AreH),
7.40e7.14 (m, 10H, AreH), 6.01 (s, 1H, NH), 5.12 (d, J¼16.2 Hz, 1H,
NCHa2), 4.49 (d, J¼16.2 Hz, 1H, NCH2b), 3.95 (d, J¼18.0 Hz, 1H, CHa2), 3.41
(d, J¼18.0 Hz, 1H, CHb2), 0.99 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
194.2, 170.3, 165.8, 139.9, 136.6, 134.5, 132.4, 132.1, 131.4, 130.5, 130.4,
129.7, 129.4, 128.8, 128.7, 128.5, 128.4, 128.3, 128.2, 126.8, 126.7, 126.6,
126.0, 75.0, 52.3, 46.7, 34.8, 27.5. MS m/z (%): 500 (Mþ, 2), 400 (24), 361
(37), 262 (18),139 (35), 91 (100). Anal. Calcd for C30H29ClN2O3: C, 71.92;
H, 5.83; N, 5.59. Found: C, 71.91; H, 5.97; N, 5.46.
Fig. 1. ORTEP drawing of 6c with 50% probability thermal ellipsoids (with only one
enantiomer shown).
4.2.3. (E)-4-Benzylidene-2-(4-chlorobenzoyl)-N-cyclohexyl-1-propyl-5-
oxopyrrolidine-2-carboxamide (6c). Operation as above with cyclo-
hexylisocyanide (0.11 g, 1 mmol) and 4-chlorophenylglyoxal 4b
(Ar2¼4-ClC6H4, 0.17 g, 1 mmol), compound 6c (0.40 g, 84%) was also
isolated as white solid. Mp: 205e206 ꢁC. 1H NMR (CDCl3, 600 MHz):
3. Conclusion
We have developed an efficient synthesis of 5-oxopyrrolidine-2-
carboxamides via a new one-pot Ugi 4CC/SN cyclization reaction.
Due to the mild reaction condition, good yields and easily accessible
starting material, we think that this new synthetic approach dis-
cussed here has the potential in synthesis of various 5-
oxopyrrolidine-2-carboxamides, which are of considerable in-
terest as potential biological active compounds or pharmaceuticals.
d
7.80 (d, J¼7.8 Hz, 2H, AreH), 7.41 (d, J¼8.4 Hz, 2H, AreH), 7.34e7.28
(m, 6H, AreH and ]CH), 6.64 (d, J¼7.2 Hz,1H, NH), 3.88e3.85 (m, 2H,
NCH and CHa2), 3.63e3.60 (m, 1H, NCH2a), 3.33 (d, J¼17.2 Hz, 1H, CHb2),
3.26e3.22 (m, 1H, NCHb2), 1.92e1.11 (m, 12H, 6CH2), 0.85 (t, J¼7.2 Hz,
3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 194.9, 169.6, 167.4, 140.1, 134.7,
131.8, 131.4, 130.6, 130.5, 129.6, 129.4, 129.0, 128.8, 128.5, 126.5, 74.5,
49.5, 45.7, 35.2, 32.1, 24.8, 21.3, 11.6, 11.2. MS m/z (%): 478 (Mþ, 2), 353
(17), 339 (100), 214 (22), 139 (34). Anal. Calcd for C28H31ClN2O3: C,
70.21; H, 6.52; N, 5.85. Found: C, 70.34; H, 6.58; N, 5.79.
4. Experimental
4.1. General
Melting points were determined using a X-4 model apparatus
and were uncorrected. MS were measured on a Finnigan Trace MS
spectrometer. IR were recorded on a PE-983 infrared spectrometer
as KBr pellets with absorption in cmꢀ1. NMR were recorded in
CDCl3 or DMSO-d6 on a Varian Mercury 600 spectrometer and
resonances relative to TMS. Elementary analyzes were taken on
a Vario EL III elementary analysis instrument. The X-ray diffraction
data were collected on a Bruker SMART AXS CCD diffractometer,
4.2.4. (E)-4-Benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-1-propyl-
5-oxopyrrolidine-2-carboxamide (6d). Operation as above with 4-
chlorophenylglyoxal 4b (Ar2¼4-ClC6H4, 0.17 g, 1 mmol), compound
6d (0.37 g, 82%) was also isolated as white solid. Mp: 186e187 ꢁC. 1H
NMR (CDCl3, 600MHz):
d
7.81(d, J¼7.8Hz, 2H, AreH), 7.43 (d, J¼7.8 Hz,
2H, AreH), 7.37e7.30 (m, 6H, AreH and ]CH), 6.32 (s,1H, NH), 3.83 (d,
J¼18.0 Hz, 1H, CHa2), 3.65e3.60 (m, 1H, NCHa2), 3.32 (d, J¼18.0 Hz, 1H,
CHb2), 3.22e3.17 (m, 1H, NCH2b), 1.74e1.52 (m, 2H, CH2), 1.36 (s, 9H,
MoKa, 2q
¼1.86e27.50ꢁ.
3CH3), 0.87 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d
195.4,
169.6, 167.4, 140.2, 134.8, 131.9, 131.6, 130.5, 129.5, 128.9, 128.8, 128.6,
126.5, 74.8, 52.5, 45.9, 35.4, 28.2, 21.2,11.4. MS m/z (%): 452 (Mþ, 2), 352
(74), 313 (100), 139 (79). Anal. Calcd for C26H29ClN2O3: C, 68.94; H,
6.45; N, 6.18. Found: C, 68.67; H, 6.60; N, 6.33.
4.2. One-pot synthesis of 5-oxopyrrolidine-2-carboxamide 6
4.2.1. (E)-4-Benzylidene-2-(4-bromobenzoyl)-N-(tert-butyl)-5-oxo-
1-propylpyrrolidine-2-carboxamide (6a). A mixture of the 2-(bro-
momethyl)-3-phenyl-2-propenoic acid17 1a (Ar1¼Ph, 0.24 g,
1 mmol) and n-propylamine 3a (R1¼n-Pr, 0.06 g, 1 mmol) was
stirred in methanol (5 mL) at room temperature for 10 min, then
tert-butylisocyanide 3a (R2¼t-Bu, 0.08 g, 1 mmol) and the 4-
bromophenylglyoxal 4a (Ar2¼4-BrC6H4, 0.21 g, 1 mmol) were
added consecutively to the solution. The mixture was stirred at
room temperature and the pH value of the solution was adjusted to
6 using Cs2CO3 during the reaction process. After stirring for 12 h,
the mixture was chilled and the resulted solid were then filtered,
recrystallized from ether to give product 6a as white solid (0.41 g,
4.2.5. (E)-1-Benzyl-4-benzylidene-N-butyl-2-(4-chlorobenzoyl)-5-
oxopyrrolidine-2-carboxamide (6e). Operation as above with ben-
zylamine (0.11 g, 1 mmol), 4-chlorophenylglyoxal 4b (Ar2¼4-
ClC6H4, 0.17 g, 1 mmol) and n-butylisocyanide (0.08 g, 1 mmol),
compound 6e (0.41 g, 82%) was also isolated as white solid. Mp:
135e136 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
7.71 (d, J¼7.8 Hz, 2H,
AreH), 7.41e7.10 (m, 13H, AreH and ]CH), 6.74 (s, 1H, NH), 5.14 (d,
J¼16.2 Hz, 1H, NCHa2), 4.55 (d, J¼16.2 Hz, 1H, NCHb2), 4.05 (d,
J¼18.0 Hz, 1H, CHa2), 3.34 (d, J¼18.0 Hz, 1H, CHb2), 2.81e2.69 (m, 2H,
NCH2), 1.11e0.85 (m, 4H, CH2), 0.74 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
83%). Mp: 196e197 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
7.72 (d,
(CDCl3, 150 MHz): d 194.4, 170.3, 167.4, 140.1, 136.4, 134.7, 132.7,
J¼7.8 Hz, 2H, AreH), 7.61 (d, J¼7.8 Hz, 2H, AreH), 7.43 (s, 1H, ]CH),
131.6, 130.5, 129.7, 129.0, 128.8, 128.7, 128.2, 127.3, 127.0, 126.0, 74.1,
7.41e7.32 (m, 5H, AreH), 6.15 (s, 1H, NH), 3.78 (d, J¼18.0 Hz, 1H,
46.7, 40.0, 35.1, 30.4, 19.9, 13.5. MS m/z (%): 500 (Mþ, 3), 400 (8), 361

3826
X.-H. Zeng et al. / Tetrahedron 69 (2013) 3823e3828
(52), 262 (51), 91 (100). Anal. Calcd for C30H29ClN2O3: C, 71.92; H,
5.83; N, 5.59. Found: C, 71.64; H, 5.99; N, 5.56.
with methylamine (0.08 g, 40%,1 mmol) and 4-chlorophenylglyoxal
4b (Ar2¼4-ClC6H4, 0.17 g, 1 mmol), compound 6j (0.30 g, 71%) was
also isolated as white solid. Mp: 237e238 ꢁC. 1H NMR (CDCl3,
4.2.6. (E)-4-Benzylidene-N-butyl-2-(4-chlorobenzoyl)-1-propyl-5-
oxopyrrolidine-2-carboxamide (6f). Operation as above with 4-
chlorophenylglyoxal 4b (Ar2¼4-ClC6H4, 0.17 g, 1 mmol) and n-
butylisocyanide (0.08 g,1 mmol), compound 6f (0.32 g, 71%) was also
isolated as white solid. Mp: 199e200 ꢁC. 1H NMR (CDCl3, 600 MHz):
600 MHz):
d
7.81 (d, J¼8.4 Hz, 2H, AreH), 7.45 (d, J¼8.4 Hz, 2H,
AreH), 7.43e7.34 (m, 6H, AreH and ]CH), 6.08 (s, 1H, NH), 3.77 (d,
J¼18.0 Hz, 1H, CHa2), 3.34 (d, J¼18.0 Hz, 1H, CH2b), 3.05 (s, 3H, CH3),
1.36 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d 195.6, 169.6, 167.0,
140.3,134.8,132.3,130.5,129.8,129.6,129.1,129.0,128.9,126.2, 74.9,
52.6, 35.3, 29.1, 28.4. MS m/z (%): 424 (Mþ, 2), 325 (38), 285 (71),186
(50), 139 (100). Anal. Calcd for C24H25ClN2O3: C, 67.84; H, 5.93; N,
6.59. Found: C, 67.56; H, 6.07; N, 6.54.
d
7.79 (d, J¼7.8 Hz, 2H, AreH), 7.41 (d, J¼7.8 Hz, 2H, AreH), 7.33e7.30
(m, 6H, AreH and ]CH), 7.11 (s,1H, NH), 3.84 (d, J¼18.0 Hz,1H, CHa2),
3.57e3.53 (m, 1H, NCH2a), 3.37e3.27 (m, 4H, CHb2, NCH2b and NCH2),
1.59e1.24 (m, 6H, 3CH2), 0.90 (t, J¼7.2 Hz, 3H, CH3), 0.82 (t, J¼7.2 Hz,
3H, CH3).13C NMR (CDCl3,150 MHz):
d
195.1,169.8,168.7,140.1,134.7,
4.2.11. (E)-4-Benzylidene-2-(4-chlorobenzoyl)-N-cyclohexyl-1-
methyl-5-oxopyrrolidine-2-carboxamide (6k). Operation as above
with methylamine (0.08 g, 40%, 1 mmol), cyclohexylisocyanide
(0.11 g, 1 mmol) and 4-chlorophenylglyoxal 4b (Ar2¼4-ClC6H4,
0.17 g, 1 mmol), compound 6k (0.34 g, 75%) was also isolated as
132.0, 131.8, 131.7, 130.5, 129.6, 129.0, 128.7, 126.5, 74.3, 45.9, 40.2,
35.5, 31.0, 21.1, 20.1, 13.6, 11.5. MS m/z (%): 452 (Mþ, 2), 352 (17), 313
(100), 214 (27), 139 (39). Anal. Calcd for C26H29ClN2O3: C, 68.94; H,
6.45; N, 6.18. Found: C, 68.89; H, 6.42; N, 5.97.
white solid. Mp: 246e248 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.81 (d,
4.2.7. (E)-4-Benzylidene-2-(4-chlorobenzoyl)-N-cyclohexyl-1-
isopropyl-5-oxopyrrolidine-2-carboxamide (6g). Operation as above
with i-propylamine (0.06 g, 1 mmol), 4-chlorophenylglyoxal 4b
(Ar2¼4-ClC6H4, 0.17 g, 1 mmol) and cyclohexylisocyanide (0.11 g,
1 mmol), compound 6g (0.39 g, 81%) was also isolated as white solid.
J¼6.0 Hz, 2H, AreH), 7.43 (d, J¼6.6 Hz, 2H, AreH), 7.35e7.27 (m, 6H,
AreH and ]CH), 6.77 (s, 1H, NH), 3.88e3.84 (m, 1H, NCH), 3.75 (d,
J¼16.8 Hz, 1H, CHa2), 3.42 (d, J¼16.2 Hz, 1H, CH2b), 3.04 (s, 3H, CH3),
1.96e1.18 (m, 10H, 5CH2). 13C NMR (CDCl3, 150 MHz):
d 195.3, 169.7,
167.3,140.1,134.5,132.2, 131.9,130.6, 129.5, 129.1,128.8,128.6,126.1,
74.3, 49.3, 35.4, 32.9, 29.2, 24.8, 21.7. MS m/z (%): 450 (Mþ, 2), 325
(24), 311 (100), 186 (84), 139 (93). Anal. Calcd for C26H27ClN2O3: C,
69.25; H, 6.03; N, 6.21. Found: C, 69.03; H, 6.20; N, 5.98.
Mp: 166e167 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
7.80 (d, J¼8.4 Hz, 2H,
AreH), 7.43 (d, J¼8.4 Hz, 2H, AreH), 7.36e7.29 (m, 6H, AreH and ]
CH), 6.54 (s,1H, NH), 3.81e3.78 (m, 2H, CHa2 and NCH), 3.72e3.68 (m,
1H, NCH), 3.21 (d, J¼18.0 Hz, 1H, CHb2), 1.93e1.65 (m, 4H, 2CH2), 1.60
(d, J¼6.6 Hz, 3H, CH3), 1.37 (d, J¼6.6 Hz, 3H, CH3), 1.33e1.09 (m, 6H,
4.2.12. (E)-4-Benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-1-
ethyl-5-oxopyrrolidine-2-carboxamide (6l). Operation as above with
ethylamine (0.11 g, 40%, 1 mmol) and 4-chlorophenylglyoxal 4b
(Ar2¼4-ClC6H4, 0.17 g, 1 mmol), compound 6l (0.32 g, 73%) was also
isolated as white solid. Mp: 183e184 ꢁC. 1H NMR (CDCl3, 600 MHz):
3CH2). 13C NMR (CDCl3, 150 MHz):
d 195.2, 169.0, 167.7, 140.1, 134.8,
132.0, 130.9, 130.4, 129.4, 128.9, 128.7, 128.6, 127.6, 74.7, 49.1, 35.6,
32.4, 32.0, 25.1, 24.6, 19.6. MS m/z (%): 478 (Mþ, 4), 352 (32), 339
(100), 297 (32), 172 (38), 139 (61). Anal. Calcd for C28H31ClN2O3: C,
70.21; H, 6.52; N, 5.85. Found: C, 69.98; H, 6.67; N, 5.71.
d
7.81 (d, J¼8.4 Hz, 2H, AreH), 7.43 (d, J¼8.4 Hz, 2H, AreH),
7.37e7.30 (m, 6H, AreH and ]CH), 6.43 (br, 1H, NH), 3.81 (d,
J¼18.0 Hz, 1H, CHa2), 3.74e3.71 (m, 1H, NCHa2), 3.40e3.37 (m, 1H,
NCHb2), 3.32 (d, J¼18.0 Hz, 1H, CH2a), 1.38 (s, 9H, 3CH3), 1.22 (t,
4.2.8. (E)-4-Benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-1-
isopropyl-5-oxopyrrolidine-2-carboxamide (6h). Operation as above
with iso-propylamine (0.06 g, 1 mmol) and 4-chlorophenylglyoxal
4b (Ar2¼4-ClC6H4, 0.17 g, 1 mmol), compound 6h (0.36 g, 79%)
was also isolated as white solid. Mp: 121e122 ꢁC. 1H NMR (CDCl3,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 195.4, 169.6, 167.6,
140.1, 134.7, 131.9, 131.5, 130.5, 129.7, 129.4, 129.1, 129.0, 128.8, 128.5,
126.5, 74.82, 52.49, 38.91, 35.48, 28.25, 13.33. MS m/z (%): 438 (Mþ,
1), 339 (41), 299 (74), 200 (43), 139 (100). Anal. Calcd for
C25H27ClN2O3: C, 68.41; H, 6.20; N, 6.38. Found: C, 68.23; H, 6.35; N,
6.34.
600 MHz):
d
7.81 (d, J¼8.4 Hz, 2H, AreH), 7.45 (d, J¼8.4 Hz, 2H,
AreH), 7.40e7.32 (m, 6H, AreH and ]CH), 6.29 (s, 1H, NH), 3.72 (d,
J¼18.0 Hz, 1H, CHa2), 3.68e3.66 (m, 1H, NCH), 3.25 (d, J¼18.0 Hz, 1H,
CHb2), 1.59 (d, J¼6.6 Hz, 3H, CH3), 1.41 (d, J¼6.6 Hz, 3H, CH3), 1.35 (s,
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d
195.7, 169.3, 167.8, 140.2,
4.2.13. (E)-4-Benzylidene-2-(4-chlorobenzoyl)-N-cyclohexyl-1-ethyl-
5-oxopyrrolidine-2-carboxamide (6m). Operation as above with
ethylamine (0.11 g, 40%, 1 mmol), cyclohexylisocyanide (0.11 g,
1 mmol) and 4-chlorophenylglyoxal 4b (Ar2¼4-ClC6H4, 0.17 g,
1 mmol), compound 6m (0.35 g, 75%) was also isolated as white
134.8, 132.1, 131.2, 130.5, 129.6, 129.0, 128.8, 128.7, 127.5, 75.1, 52.4,
49.1, 35.9, 28.3, 19.7. MS m/z (%): 452 (Mþ, 6), 352 (50), 313 (100),
172 (42),139 (91). Anal. Calcd for C26H29ClN2O3: C, 68.94; H, 6.45; N,
6.18. Found: C, 68.79; H, 6.61; N, 6.35.
solid. Mp: 183e184 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.80 (d,
4.2.9. (E)-4-Benzylidene-N-(tert-butyl)-1-butyl-2-(4-chlorobenzoyl)-
5-oxopyrrolidine-2-carboxamide (6i). Operation as above with
butylamine (0.07 g, 1 mmol) and 4-chlorophenylglyoxal 4b (Ar2¼4-
ClC6H4, 0.17 g, 1 mmol), compound 6i (0.34 g, 73%) was also isolated
J¼7.8 Hz, 2H, AreH), 7.41 (d, J¼8.4 Hz, 2H, AreH), 7.33e7.29 (m, 6H,
AreH and ]CH), 6.93 (br, 1H, NH), 3.90e3.72 (m, 3H, CH, CHa2 and
NCHa2), 3.45e3.41 (m, 1H, NCH2b), 3.31 (d, J¼18.0 Hz, 1H, CHb2),
1.95e1.11 (m, 13H, 5CH2 and CH3). 13C NMR (CDCl3, 150 MHz):
as white solid. Mp: 174e175 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
7.82 (d,
d 194.9, 169.5, 167.6, 140.0, 134.7, 131.9, 131.4, 130.5, 129.6, 129.4,
J¼8.4 Hz, 2H, AreH), 7.44e7.30 (m, 8H, AreH and ]CH), 6.49 (br,1H,
NH), 3.87 (d, J¼18.0 Hz, 1H, CHa2), 3.72e3.67 (m, 1H, NCHa2), 3.32 (d,
J¼18.0 Hz, 1H, CHb2), 3.28e3.23 (m, 1H, NCHb2), 1.70e1.47 (m, 2H,
CH2), 1.38 (s, 9H, 3CH3), 1.30e1.22 (m, 2H, CH2), 0.88 (t, J¼7.2 Hz, 3H,
128.9,128.8,128.7,128.5,126.6, 74.4, 60.3, 49.6, 38.9, 35.2, 32.1, 24.7,
13.3. MS m/z (%): 464 (Mþ, 2), 339 (22), 325 (100), 200 (58), 139
(94). Anal. Calcd for C27H29ClN2O3: C, 69.74; H, 6.29; N, 6.02. Found:
C, 69.52; H, 6.46; N, 5.76.
CH3). 13C NMR (CDCl3, 150 MHz):
d 195.2, 169.5, 167.4, 140.1, 134.7,
131.8, 131.4, 130.5, 129.6, 129.0, 128.7, 128.5, 126.5, 74.8, 52.5, 44.1,
38.8, 35.3, 28.1, 20.4, 13.8. MS m/z (%): 466 (Mþ, 2), 366 (32), 327
(60), 228 (26), 139 (100). Anal. Calcd for C27H31ClN2O3: C, 69.44; H,
6.69; N, 6.00. Found: C, 69.67; H, 6.84; N, 5.75.
4.2.14. (E)-1-Benzyl-4-benzylidene-2-(4-chlorobenzoyl)-N-cyclo-
hexyl-5-oxopyrrolidine-2-carboxamide (6n). Operation as above
with benzylamine (0.11 g, 1 mmol), 4-chlorophenylglyoxal 4b
(Ar2¼4-ClC6H4, 0.17 g, 1 mmol) and cyclohexylisocyanide (0.11 g,
1 mmol), compound 6n (0.47 g, 89%) was also isolated as white
4.2.10. (E)-4-Benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-1-
solid. Mp: 125e126 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
7.69 (d,
methyl-5-oxopyrrolidine-2-carboxamide (6j). Operation as above
J¼8.4 Hz, 2H, AreH), 7.54 (s, 1H, ]CH), 7.43 (d, J¼7.8 Hz, 2H, AreH),

X.-H. Zeng et al. / Tetrahedron 69 (2013) 3823e3828
3827
7.40e7.34 (m, 10H, AreH), 6.22 (s, 1H, NH), 5.02 (d, J¼15.6 Hz, 1H,
NCHa2), 4.51 (d, J¼15.6 Hz, 1H, NCH2b), 3.84 (d, J¼18.6 Hz, 1H, CHa2),
3.50e3.40 (m, 2H, NCH2b and CH2b), 1.53e0.78 (m, 10H, 5CH2). 13C
129.1, 128.9, 128.2, 75.1, 52.5, 49.4, 35.5, 28.5, 19.8. MS m/z (%): 530
(Mþ, 2), 430 (15), 347 (50), 206 (47), 183 (100). Anal. Calcd for
C26H28BrClN2O3: C, 58.71; H, 5.31; N, 5.27. Found: C, 58.65; H, 5.54;
N, 5.47.
NMR (CDCl3, 150 MHz):
d 195.0, 170.4, 166.9, 140.1, 136.4, 134.7,
132.8, 131.9, 130.5, 129.7, 128.9, 128.7, 128.4, 128.2, 127.8, 127.6,
125.9, 74.0, 49.3, 35.6, 32.0, 31.7, 25.2, 24.6. MS m/z (%): 526 (Mþ, 4),
400 (12), 387 (39), 262 (25), 91 (100). Anal. Calcd for C32H31ClN2O3:
C, 72.92; H, 5.93; N, 5.32. Found: C, 72.83; H, 6.07; N, 5.19.
4.2.19. (E)-2-(4-Bromobenzoyl)-N-(tert-butyl)-4-(4-chlorobenzylide-
ne)-1-(4-chlorophenyl)-5-oxopyrrolidine-2-carboxamide
(6s). Operation as above with 4-chlorophenylamine (0.13 g,
1 mmol) and 2-(bromomethyl)-3-(4-chlorophenyl)-2-propenoic
acid 1b (Ar1¼4-ClC6H4, 0.27 g, 1 mmol), compound 6s (0.41 g,
68%) was also isolated as white solid. Mp: 247e248 ꢁC. 1H NMR
4.2.15. (E)-2-(4-Bromobenzoyl)-N-(tert-butyl)-4-(4-chlorobenzylidene)
-1-propyl-5-oxo-pyrrolidine-2-carboxamide (6o). Operation as above
with 2-(bromomethyl)-3-(4-chlorophenyl)-2-propenoic acid 1b
(Ar1¼4-ClC6H4, 0.27 g, 1 mmol), compound 6o (0.45 g, 85%) was
also isolated as white solid. Mp: 201e202 ꢁC. 1H NMR (CDCl3,
(CDCl3, 600 MHz):
d
7.70 (d, J¼8.4 Hz, 2H, AreH), 7.55 (d, J¼8.4 Hz,
2H, AreH), 7.53 (s, 1H, ]CH), 7.37e7.31 (m, 8H, AreH), 6.18 (s, 1H,
NH), 4.05 (d, J¼17.4 Hz,1H, CH2a), 3.35 (d, J¼18.0 Hz,1H, CHb2), 1.16 (s,
600 MHz):
d
7.72 (d, J¼8.4 Hz, 2H, AreH), 7.61 (d, J¼8.4 Hz, 2H,
9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d 196.7, 169.3, 165.5, 135.7,
AreH), 7.38e7.33 (m, 5H, AreH and ]CH), 6.11 (s, 1H, NH), 3.76 (d,
J¼18.0 Hz,1H, CHa2), 3.61e3.57 (m, 1H, NCHa2), 3.26 (d, J¼16.2 Hz,1H,
CHb2), 3.17e3.12 (m, 1H, NCH2b), 1.74e1.49 (m, 2H, CH2), 1.35 (s, 9H,
3CH3), 0.87 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
135.2, 133.2, 133.1, 132.1, 132.0, 131.0, 130.9, 130.4, 13.6, 129.3, 129.1,
129.0, 126.3, 75.6, 52.4, 28.1. MS m/z (%): 600 (Mþ, 2), 500 (16), 415
(27), 185 (100), 57 (40). Anal. Calcd for C29H25BrCl2N2O3: C, 58.02;
H, 4.20; N, 4.67. Found: C, 58.17; H, 4.39; N, 4.43.
d
195.7, 169.4, 167.2, 134.7, 133.2, 132.3, 131.9, 130.5, 130.5, 129.1,
128.9, 128.8, 127.1, 74.7, 52.5, 45.9, 35.2, 28.2, 21.2, 11.6. MS m/z (%):
530 (Mþ, 4), 430 (25), 347 (51), 248 (52), 183 (100). Anal. Calcd for
C26H28BrClN2O3: C, 58.71; H, 5.31; N, 5.27. Found: C, 58.42; H, 5.48;
N, 5.05.
4.2.20. (E)-4-Benzylidene-N-(tert-butyl)-2-(4-chlorobenzoyl)-1-(4-
chlorophenyl)-5-oxopyrrolidine-2-carboxamide (6t). Operation as
above with 4-chlorophenylglyoxal 4b (Ar2¼4-ClC6H4, 0.17 g,
1 mmol) and 4-chlorophenylamine (0.13 g, 1 mmol), compound 6t
(0.34 g, 65%) was also isolated as white solid. Mp: 264e265 ꢁC. 1H
4.2.16. (E)-1-Benzyl-4-benzylidene-2-(4-bromobenzoyl)-N-(tert-bu-
tyl)-5-oxopyrrolidine-2-carboxamide (6p). Operation as above with
benzylamine (0.11 g, 1 mmol), compound 6p (0.47 g, 86%) was also
isolated as white solid. Mp: 183e184 ꢁC. 1H NMR (CDCl3, 600 MHz):
NMR (CDCl3, 600 MHz):
d
7.78 (d, J¼9.0 Hz, 2H, AreH), 7.60 (s, 1H,
]CH), 7.46 (d, J¼7.2 Hz, 2H, AreH), 7.41e7.30 (m, 9H, AreH), 6.26
(s, 1H, NH), 4.06 (d, J¼17.4 Hz, 1H, CHa2), 3.41 (d, J¼18.0 Hz, 1H, CH2b),
1.17 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
d 196.8, 169.5, 165.8,
d
7.65 (d, J¼8.4 Hz, 2H, AreH), 7.52 (d, J¼9.0 Hz, 2H, AreH),
140.6, 135.9, 134.7, 134.0, 133.0, 131.8, 130.4, 129.8, 129.1, 128.8,
127.9, 125.8, 75.6, 52.3, 35.8, 27.9. MS m/z (%): 520 (Mþ, 3), 420 (52),
381 (100), 282 (59),139 (98), 57 (14). Anal. Calcd for C29H26Cl2N2O3:
C, 66.80; H, 5.03; N, 5.37. Found: C, 66.83; H, 5.21; N, 5.21.
7.44e7.14 (m, 11H, AreH and ]CH), 6.06 (s, 1H, NH), 5.11 (d,
J¼16.2 Hz, 1H, NCHa2), 4.51 (d, J¼16.2 Hz, 1H, NCHb2), 3.96 (d,
J¼18.0 Hz, 1H, CHa2), 3.41 (d, J¼18.0 Hz, 1H, CH2b), 0.99 (s, 9H, 3CH3).
13C NMR (CDCl3, 150 MHz):
d 195.5, 170.6, 166.5, 136.6, 134.8, 132.9,
132.3, 131.9, 131.8, 130.5, 129.7, 129.0, 128.7, 128.6, 128.4, 127.5,
127.3, 125.9, 74.6, 52.3, 41.0, 35.4, 27.7. MS m/z (%): 544 (Mþ, 4), 448
(3), 361 (11), 183 (17), 91 (100). Anal. Calcd for C30H29BrN2O3: C,
66.06; H, 5.36; N, 5.14. Found: C, 66.18; H, 5.62; N, 4.93.
5. Crystallographic material
Compound 6c: formula C28H31ClN2O3, colourless crystal. The
ꢀ
3
ꢀ
crystal is of triclinic, space group P21/c with a¼10.5450(11) A,
ꢁ
ꢀ
ꢀ
b¼12.3170(12) A, c¼20.5162(17) A,
b
¼116.566(4) , V¼2383.4(4) A ,
Z¼4, Dc¼1.335 g/cm3, F(000)¼1016,
m
¼0.194 mmꢀ1, R¼0.0395 and
4.2.17. (E)-1-Benzyl-2-(4-bromobenzoyl)-N-(tert-butyl)-4-(4-
chlorobenzylidene)-5-oxopyrrolidine-2-carboxamide (6q). Operation
as above with 2-(bromomethyl)-3-(4-chlorophenyl)-2-propenoic
acid 1b (Ar1¼4-ClC6H4, 0.27 g, 1 mmol) and benzylamine (0.11 g,
1 mmol), compound 6q (0.53 g, 91%) was also isolated as white
wR¼0.1184 for 6880 observed reflections with I>2
s(I0). Crystallo-
graphic data for 6c have been deposited in the Cambridge Crys-
tallographic Data Center as supplementary publication numbers
CCDC 917576. Copies of the data may be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax:
þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
solid. Mp: 183e184 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.65 (d,
J¼8.4 Hz, 2H, AreH), 7.54 (d, J¼8.4 Hz, 2H, AreH), 7.45 (s, 1H, ]CH),
7.36e7.12 (m, 9H, AreH), 6.03 (s, 1H, NH), 5.13 (d, J¼16.2 Hz, 1H,
NCHa2), 4.54 (d, J¼16.8 Hz, 1H, NCH2b), 3.96 (d, J¼18.0 Hz, 1H, CHa2),
3.34 (d, J¼18.0 Hz, 1H, CHb2), 0.98 (s, 9H, 3CH3). 13C NMR (CDCl3,
Acknowledgements
150 MHz):
d 195.4, 170.4, 166.2, 136.5, 135.0, 133.3, 132.2, 131.9,
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21172085,
21032001) and the Shiyan Municipal Science and Technology Bu-
reau (No. ZD2011029).
131.4, 131.0, 130.6, 129.2, 129.0, 128.5, 127.4, 127.2, 126.5, 74.6, 52.5,
47.2, 35.2, 27.6. MS m/z (%): 578 (Mþ,1), 480 (2), 395 (4),183 (15), 91
(100). Anal. Calcd for C30H28BrClN2O3: C, 62.13; H, 4.87; N, 4.83.
Found: C, 62.35; H, 4.71; N, 4.57.
Supplementary data
4.2.18. (E)-2-(4-Bromobenzoyl)-N-(tert-butyl)-4-(4-chlorobenzylide-
ne)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (6r). Operation as
above with 2-(bromomethyl)-3-(4-chlorophenyl)-2-propenoic acid
1b (Ar1¼4-ClC6H4, 0.27 g, 1 mmol) and iso-propylamine (0.06 g,
1 mmol), compound 6r (0.46 g, 87%) was also isolated as white
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.058.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
solid. Mp: 135e136 ꢁC. 1H NMR (CDCl3, 600 MHz):
d 7.73 (d,
J¼8.4 Hz, 2H, AreH), 7.63 (d, J¼8.4 Hz, 2H, AreH), 7.35e7.29 (m, 5H,
AreH and ]CH), 6.26 (s, 1H, NH), 3.71e3.65 (m, 2H, CHa2 and NCH),
3.20 (d, J¼18 Hz, 1H, CHb2), 1.58 (d, J¼6.6 Hz, 3H, CH3), 1.40 (d,
J¼6.6 Hz, 3H, CH3), 1.35 (s, 9H, 3CH3). 13C NMR (CDCl3, 150 MHz):
References and notes
1. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
Germany, 2005; (b) Beck, B.; Picard, A.; Herdtweck, E.; Domling, A. Org. Lett.
2004, 6, 39; (c) Choudhury, L. H.; Parvin, T. Tetrahedron 2011, 67, 8213.
€
d
195.9, 168.9, 167.6, 134.6, 133.4, 132.4, 132.1, 131.9, 130.7, 129.6,

3828
X.-H. Zeng et al. / Tetrahedron 69 (2013) 3823e3828
2. (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Domling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168; (c) Sadjadi, S.; Heravi, M. M. Tetrahedron 2011, 67, 2707;
(d) Tyagi, V.; Khan, S.; Bajpai, V.; Gauniyal, H. M.; Kumar, B.; Chauhan, P. M. S. J.
Org. Chem. 2012, 77, 1414; (e) Che, C.; Li, S.; Jiang, X.; Quan, J.; Lin, S.; Yang, Z.
Org. Lett. 2010, 12, 4682.
3. Nilsson, B. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1990, 33, 580.
4. Kenda, B. M.; Matagne, A. C.; Talaga, P. E.; Pasau, P. M.; Differding, E.; Lallemand,
B. I.; Frycia, A. M.; Moureau, F. G.; Klitgaard, H. V.; Gillard, M. R.; Fuks, B.; Mi-
chel, P. J. Med. Chem. 2004, 47, 530.
11. Tan, D. Q.; Atherton, A. L.; Smith, A. J.; Soldi, C.; Hurley, K. A.; Fettinger, J. C.;
Shaw, J. T. ACS Comb. Sci. 2012, 14, 218.
12. (a) Poli, G.; Giambastiani, G.; Malacria, M.; Thorimbert, S. Tetrahedron Lett. 2001,
42, 6287; (b) Vogel, S.; Bantreil, X.; Maitro, G.; Prestat, G.; Madec, D.; Poli, G.
Tetrahedron Lett. 2010, 51, 1459; (c) Giambastiani, G.; Pacini, B.; Porcelloni, M.;
Poli, G. J. Org. Chem. 1998, 63, 804.
13. (a) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110, 5447; (b)
Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1; (c) Singh, V.; Batra,
S. Tetrahedron 2008, 64, 4511.
5. Kraus, J. L.; Bouygues, M.; Courcambeck, J.; Chermann, J. C. Bioorg. Med. Chem.
14. (a) Zhong, Y.; Wu, L.; Ding, M. W. Synthesis 2012, 44, 3085; (b) Pathak, R.;
Lett. 2000, 10, 2023.
Madapa, S.; Batra, S. Tetrahedron 2007, 63, 451; (c) Lee, H. S.; Kim, J. M.; Kim, J.
N. Tetrahedron Lett. 2007, 48, 4119; (d) Sa, M. M.; Fernandes, L.; Ferreira, M.;
€
ꢁ
6. Wunberg, T.; Baumeister, J.; Betz, U.; Jensen, A.; Nikolic, S.; Reefschlager, J.;
Zimmermann, H.; Zumpe, F.; Grosser, R.; Kleymann, G.; Bender, W.; Henninger,
K.; Hewlett, G.; Keldenich, J. PCT Int. Appl. WO2003097595, 2003.
7. Wu, Y. H.; Feldkamp, R. F. J. Org. Chem. 1961, 26, 1519.
8. (a) Irving, M.; Krueger, C. A.; Wade, J. V.; Hodges, J. C.; Leopold, K.; Collins, N.; Chan,
C.; Shaqair, S.; Shornikov, A.; Yan, B. J. Comb. Chem. 2004, 6, 478; (b) Vergnon, A. L.;
Pottorf, R. S.; Winters, M. P.; Player, M. R. J. Comb. Chem. 2004, 6, 903.
9. (a) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005, 7, 3981; (b)
Park, J. H.; Ha, J. R.; Oh, S. J.; Kim, J. A.; Shin, D. S.; Won, T. J.; Lam, Y. F.; Ahn, C.
Tetrahedron Lett. 2005, 46, 1755.
Bortoluzzi, A. J. Tetrahedron Lett. 2008, 49, 1228; (e) Nayak, M.; Pandey, G.;
Batra, S. Tetrahedron 2011, 67, 7563.
15. (a) Zhong, Y.; Wang, L.; Ding, M. W. Tetrahedron 2011, 67, 3714; (b) He, P.; Nie, Y.
B.; Wu, J.; Ding, M. W. Org. Biomol. Chem. 2011, 9, 1429; (c) He, P.; Wu, J.; Nie, Y.
B.; Ding, M. W. Eur. J. Org. Chem. 2010, 1088; (d) He, P.; Wu, J.; Nie, Y. B.; Ding,
M. W. Tetrahedron 2009, 65, 8563; (e) Wu, J.; Liu, J. C.; Wang, L.; Ding, M. W.
Synlett 2011, 2880.
16. (a) Lecinska, P.; Corres, N.; Moreno, D.; García-Valverde, M.; Marcaccini, S.;
~
Torroba, T. Tetrahedron 2010, 66, 6783; (b) Sanudo, M.; García-Valverde, M.;
10. (a) Wang, Z.; Lu, X. Y. Tetrahedron 1995, 51, 2639; (b) Miyabe, H.; Ueda, M.; Fujii,
Marcaccini, S.; Delgado, J. J.; Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74, 2189.
K.; Nishimura, A.; Naito, T. J. Org. Chem. 2003, 68, 5618.
17. Zulykama, Y.; Perumal, P. T. Tetrahedron Lett. 2009, 50, 3892.