Structural diversity-guided convenient construction of functionalized polysubstituted butenolides and lactam derivatives

Article abstract of DOI:10.1016/j.crci.2011.08.005

A molecular diversity-oriented convenient access to multi-substituted butenolides and lactam scaffolds via four different methods from various phenylacetic acid derivatives is described. The target molecules have been identified on the basis of analytical spectra data, and are useful synthons in the fields of medicine and agrochemicals.

Full text of DOI:10.1016/j.crci.2011.08.005

C. R. Chimie 14 (2011) 1071–1079
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www.sciencedirect.com
´
Full paper/Memoire
Structural diversity-guided convenient construction of functionalized
polysubstituted butenolides and lactam derivatives
1
1
*
Shaoyong Ke , Ya-Ni Zhang , Wenming Shu , Zhigang Zhang, Liqiao Shi, Ying Liang,
*
Kaimei Wang, Ziwen Yang
Hubei Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences, Wuhan 430064, P. R. China
A R T I C L E I N F O
A B S T R A C T
Article history:
A molecular diversity-oriented convenient access to multi-substituted butenolides and
lactam scaffolds via four different methods from various phenylacetic acid derivatives is
described. The target molecules have been identified on the basis of analytical spectra
data, and are useful synthons in the fields of medicine and agrochemicals.
Received 21 April 2011
Accepted after revision 16 August 2011
Available online 21 September 2011
´
ß 2011 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Molecular diversity
Butenolides
Lactam
Phenylacetic acid
Synthesis
1. Introduction
binding site of phosphatases and kinases [13–15]. Very
recently, some butenolides and lactam derivatives are also
Many heterocyclic compounds bearing butenolides and
lactam scaffolds are of synthetic interest, since they display
extensive biological activities [1,2], and constitute an
important class of natural (Fig. 1) [3–6] or unnatural
products [7–10]. Moreover, they are extremely versatile
building blocks for the manufacture of bioactive com-
pounds in pharmaceutical drug design and the agrochemi-
cal industry. Nowadays, more and more natural products
containing butenolides and lactam ring systems have been
isolated from a variety of marine and terrestrial organisms,
such as bacteria, moulds, algae, fungi, lichens, and sponges
[11,12]. On the other hand, many butenolides and lactam
derivatives featuring 3-acyl substituents are novel ligands
for their strong ability to chelate biologically important
metal cations and to mimic phosphate groups in the
widely applied as versatile building blocks for the
construction of novel heterocycles and fused heterocycle
system [16–19].
Thus, development of novel functionalized multi-
substituted butenolides and lactam heterocyclic deriva-
tives as pharmaceuticals is still an important area of
interest in life sciences, and the search for an efficient
method for the construction of these heterocyclic deriva-
tives under mild conditions is not only highly desirable but
also necessary. The promising bioactive and structural
diversity of these classes of heteroaryl compounds urged
us to conveniently construct a series of novel structural
variants of multi-substituted butenolides and lactam
derivatives and their related intermediates. In this short
communication, we would like to present a molecular
diversity-oriented convenient procedure for large-scale
access to construct bioactive butenolides or lactam units
(Fig. 2) that exploit mild ring-closure methods and cheap
raw materials, which will have widely applied prospects
because of its easy to obtain raw material and its
convenient operation.
* Corresponding authors.
E-mail addresses: keshaoyong@163.com (S. Ke), lky666888@126.com
(Y.-N. Zhang).
1
These authors contributed equally to this work.
1631-0748/$ – see front matter ß 2011 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2011.08.005

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S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
O
O
H
N
HO
O
H
O
O
HO
OH
HO
OH
HO
O
COOH
Ascorbic acid
Pulvinic acid
Tenuazonic acid
O
O
O
O
O
OH
HO
Cl
HN
N
O
O
HO
5
HO
OH
O
O
Penicillic acid
Pachydermin
Reutericyclin
Fig. 1. Representative structures of naturally occurring butenolides and lactam derivatives.
O
O
O
R1
R2
NH
NH
N
R1
HO
OH
R1
HO
B
O
O
R3
R1
R2
N
X
A
O
R'
C
O
R2
R1
OH
R
OH
R3
HO
D
O
N
R2
R1
HO
Alkyl
Fig. 2. Design strategy for polysubstituted butenolides and lactams.
2. Results and discussion
prepared in a simplified and more efficient method, which
is outlined in Scheme 1.
2.1. Synthesis of multi-substituted butenolides derivatives
For the sake of structural diversity, various easily
available
a-hydroxy acids such as lactic acid, 1-hydro-
Considering the convenient synthesis to construct the
structural diversity of multi-substituted butenolides and
xycyclohexanecarboxylic acid, mandelic acid and their
analogues can be selected as raw materials. As shown in
Scheme 1, the target butenolides derivatives 5 were
conveniently obtained via two steps including esterifica-
tion, one-pot heterocyclization reactions. The cyclization
lactam scaffolds, various amino-acids,
a-hydroxy acids
and suitable phenylacetic acids were selected as raw
materials. Polysubstituted butenolides derivatives 5 were
Table 1
Synthesis of multi-substituted butenolides derivatives 5.
Entry
Compd.
Substituents
R1
Appearance
Yield (%)a
R2
R3
1
2
3
4
5a
5b
5c
5d
4-MeO
4-F
-(CH2)5-
White powder
75
75
78
71
H
H
H
Ph
Ph
Ph
Light yellow powder
Light yellow powder
White powder
2,4-Cl2
4-MeO
a
Yields refer to isolated products.

S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
1073
OH
a
O
O
R1
R1
R1
O
O
O
R2
R3
b
1
2
One-Pot
HO
5
A
HO R2
O
O
R2
R3
R3
a
OH
OH
O
3
4
R1 = H, 2,4-Cl2, o-Me, 4-F, 4-MeO; R2 = Ph, Substituted-Ph, Me, et c.; R3 = H
R
2 - R3 = Cyclohexyl, Cyclopentyl
Scheme 1. Method A. Synthesis of multi-substituted butenolides derivatives 5. Reaction conditions: a: MeOH, Conc. H2SO4, reflux 6 to 8 h; b: tBuOK or
EtONa, THF, reflux for 8 to 10 h.
COOMe
R3
COOH
NH2
COOMe
b
c
N
NH
2 HCl
R2
R2
R2
H
7
8
9
d
d
B
C
R3
N
R2
O
R2
Cl
O
O
R1
R1
R1
NH
O
6
O
O
O
a
10
11
e
e
OH
R1
R3
O
O
O
1
R1
R2
N
R1
R2
NH
R1 = H, 2-Me, 2,4-Cl2, 4-F, 4-
MeO; R2 = H, 2-Cl, 4-Cl; R3
Alkyl, Benzyl, et c.
=
OH
13
OH
12
Scheme 2. Method B and C. Representative synthetic outline for multi-substituted lactam derivatives based on phenylglycine. Reaction conditions: a.
SOCl2, Toluene, reflux 4-5 h; b. SOCl2, MeOH, r.t. to 50 8C; c. Halides, MeCN, K2CO3, r.t.; d. CH2Cl2, Et3N, ice-bath to r.t.; e. tBuOK, THF, reflux for 10 to 15 h.
reaction was accessed conveniently by the modified one-
pot heterocyclization reaction [20,21] from various substi-
tuted methyl 2-phenylacetate 2 and methyl 1-hydroxy-
carboxylate 4 in good yields (Table 1), which involve a
transesterification step, followed by the Dieckmann
condensation. According to the above-described experi-
mental conditions, the butenolide derivatives 5 were easily
conveniently converted to the various amino-acid ester
hydrochlorides 8 under mild conditions. Subsequently, the
compounds 8 are easy to transfer to the N-substituted
amino-acid ester 9 via N-alkylation reactions. The key
intermediate phenylacetamide derivatives 10 and 11 were
accessed conveniently from intermediates 8, 9 and various
substituted 2-phenylacetyl chlorides, respectively. The
following intramolecular heterocyclization reaction was
treated in the presence of potassium tert-butoxide, and the
several kinds of target compounds (Method B in Fig. 2)
were achieved with a simple disposal and high yields,
which may be propitious to large-scale production. All
newly synthesized compounds were characterized as 4-
hydroxy-3-substituted phenyl-1H-pyrrol-2(5H)-one deri-
vatives on the basis of satisfactory analytical and spectral
data including 1H NMR, 13C NMR, ESI-MS, IR and element
analyses. Mass spectra, in particular, showed the molecu-
lar ion peaks at the appropriate m/z values. The 1H NMR
spectroscopic data are in agreement with the proposed
structures. The general 1H NMR spectra of multi-substi-
tuted butylene lactam derivatives 12 show obvious singlet
peak in the range 11.20-11.40 ppm assigned to the protons
achieved with
a high yield and significantly simple
disposal compared to the reported chromatographic
methods [20,21]. Nowadays, several butenolide deriva-
tives could be obtained for large-scale production (> 500 g)
without column chromatography in our laboratory.
2.2. Synthesis of multi-substituted lactam derivatives
Scheme 2 describes the outline for the construction of
representative multi-substituted lactam compounds 12
and 13, which were conveniently obtained via esterifica-
tion, acylation, N-alkylation and intramolecular hetero-
cyclization reactions. The cheap amino-acids such as
phenylglycine, phenylalanine, proline and its analogues
were all selected as starting materials, which were

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S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
R1
O
R2
Alkyl
O
OH
b
Cl
c
d
a
R1
N
N
R1
R1
R2
O
O
O
HO
Alkyl
O
1
6
16
17
O
R1 = H, 2,4-Cl2, o-Me, 4-F, 4-MeO
O
NH2
Alkyl
R2 = H, 4-Br, 4-iPr
NH
R2
14
R2
15
Scheme 3. Method D. Synthesis of multi-substituted lactam derivatives 17. Reaction conditions: a: SOCl2, reflux 4 to 5 h; b:
30–40 8C; c: CH2Cl2, Et3N, ice-bath to r.t.; d: tBuOK, THF, reflux for 8 to 12 h.
a-Halides, MeCN, Et3N, r.t. to
Table 2
Synthesis of lactam derivatives 17a.
Entry
16
17
Substituents
Alkyl
16b Yield (%)
17c Yield (%)
R1
R2
1
2
3
16a
16b
16c
17a
17b
17c
Me
Me
Me
H
H
H
H
75
70
87
70
63
77
4-Br
4-iPr
a
Representative process for these series derivatives.
Yields were based on LC-MS analysis.
Yields refer to isolated products.
b
c
of the hydroxy linked to lactam heterocycle. The signals in
the range 4.10-5.07 ppm indicated the corresponding
methine protons next to the N atom in the heterocycle.
Having efficient access to butylene lactam derivatives
12 and 13, we could envisage another convenient method
for preparation of multi-substituted butylene lactam
compounds from easily available aromatic amines. As
in Table 2, the electron-donating substituents (4-iPr) and
electron-withdrawing groups (4-Br) lead to obviously
different reactive activity; the latter need longer reaction
time and relatively lower yields. The cooperative effect for
N,N-disubstituents of the reactant 16 may be the key factor
for the different reactivity. Compound 16c containing 4-
isopropyl group has the relatively stable amide bond, which
lead to the higher reactivity for the adjacent alpha-carbon of
carbonyl group. Generally, these procedures that exploit
very easily available raw materials, which will have the
widely applied prospects to construct multi-substituted
lactam derivatives.
outlined in Scheme 3,
a synthetic route for multi-
substituted butylene lactam compounds 17 was described,
these were conveniently obtained via three steps including
N-alkylation, acylation and intramolecular heterocycliza-
tion reactions.
Thevarious aromatic amines 14were selected as starting
materials, which were conveniently converted to the N-
substituted amino-acid ester 15 via N-alkylation reactions
under ambient conditions. Subsequently, the acylation and
intramolecular heterocyclization reactions are processed
with the same as aforementioned procedures with good
yields (Table 2). Based on the representative data as shown
Mechanicistically, the one-pot process leading to the
formation of butenolides 5 is most probably involving a
transesterification and a Dieckmann condensation as the
two main steps (Scheme 4), with subsequent acidification
to give target compounds.
For the formation of butylene lactams, the intramolec-
ular heterocyclization reaction is very likely initiated by a
COOMe
R1
R2
O
R2
O
O
R2
O
O
R3
R3
R3
R1
O
COOMe
OH
OK
OH-
O
O
O
R1
R2
R1
O
H+
O
O
R3
COOMe
R2
R3
R2
R1
O
R3
HO
Scheme 4. The mechanism of one-pot heterocyclization to provide butenolides.

S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
1075
O
R2
O
O
R2
N
O
O
R2
R3
R2
R3
R1
R1
R1
N
R1
OH-
N
H+
N
R3
R3
O
O
O
O
HO
Scheme 5. The mechanism of intramolecular heterocyclization reaction to afford lactam.
nucleophilic attack of the
a
-methyl carbon to the carbonyl
4.2. General synthetic procedure for multi-substituted
carbon of the ester leading to an intermediate, with
subsequent keto-enol tautomerism leading to the forma-
tion of target compounds. The possible mechanism of ring-
closure reaction formation target compounds is shown in
Scheme 5.
butenolides derivatives 5
The multi-substituted butenolides 5 were prepared
following the modified one-pot cyclization methods [23].
The typical procedure is as follows: to a solution of
substituted phenylacetate (10 mmol, 1 equiv) and
a-
hydroxy acids esters (12 mmol, 1.2 equiv) in anhydrous
THF was added a solution of potassium tert-butoxide 2.46 g
(22 mmol, 2.2 equiv) in THF. The suspension obtained was
then refluxed under nitrogen overnight. After cooling to
ambient temperature, the reaction mixture was acidified
with 5% HCl aqueous to pH 2-3, and then was extracted
three times with ethyl acetate. The combined organic
layers were then washed with water and dried over
Na2SO4. After filtration and concentration under vacuum,
the residue was taken up into little ethyl acetate and
filtered in vacuo to give the corresponding multi-substi-
tuted butenolides 5 as powders. The physicochemical
properties and spectral data for representative compounds
are as follows:
3. Conclusions
In conclusion, we have described a molecular diversity-
oriented convenient process for the assembly of multi-
substituted butenolides and lactam derivatives that are
important building blocks in the fields of medicine and
agrochemicals. In the above-described experimental con-
ditions, the heterocyclization reaction reached completion
with a very simple disposal and high yield compared to the
reported similar cyclization methods, and a number of
functional groups are tolerated by our reaction conditions,
including electron-withdrawing and electron-donating
groups. Thus, our process represents a versatile access to
multi-substituted butenolides and lactam scaffolds using
readily available reagents and is a useful tool for the
further synthesis of biologically active molecules. The
further preparation of other related heterocycles by similar
methods is currently underway.
4.2.1. 4-Hydroxy-3-(4-methoxyphenyl)-1-oxaspiro[4.5]dec-
3-en-2-one 5a
White powder, yield 75%, m.p. 240.3–241.5 8C (245 8C
Lit. [21]); IR (KBr pellet) nmax 833, 969, 1180, 1248, 1388,
1610, 1646, 1686, 2634, 2941, 3437 cmÀ1
;
1H NMR
4. Experimental
(600 MHz, DMSO-d6) d 12.19 (bs, 1H, OH), 7.81 (d,
J = 7.8 Hz, 2H, Ph-H), 6.94 (d, J = 8.4 Hz, 2H, Ph-H), 3.75
4.1. Instrumentation and chemicals
(s, 3H, CH3O), 2.03-1.17 (m, 10H); 13C NMR (100 MHz,
DMSO-d6):
d = 178.97, 171.80, 158.40, 128.84, 123.52,
All melting points (m.p.) were obtained using a digital
model X-5 apparatus and are uncorrected. IR spectra were
recorded on a Thermo Nicolet FT-IR Avatar 330 instrument.
NMR spectra were recorded on Brucker spectrometer
apparatus (1H at 400 MHz or 600 MHz and 13C at 100 MHz
with CDCl3 or DMSO-d6 as the solvent). Chemical shifts are
114.14, 97.52, 81.50, 55.69, 32.76, 24.59, 22.34.
4.2.2. 3-(4-Fluorophenyl)-4-hydroxy-5-phenylfuran-2(5H)-
one 5b
Light yellow powder, yield 75%, m.p. 173.4–175.0 8C; IR
(KBr pellet) nmax 697, 834, 1023, 1162, 1381, 1512, 1638,
reported as
d
values (parts per million) relative to internal
1707, 2635, 2941, 3408 cmÀ1 1H NMR (600 MHz, DMSO-
;
tetramethylsilane. Coupling constants nJ are reported in
Hertz (Hz). Standard abbreviations indicating multiplicity
are used as follows: s = singlet, d = doublet, dd = doublet of
doublets, t = triplet, q = quadruplet, m = multiplet and
br = broad. Mass spectra were performed on a MicroMass
Quattro microTM API instrument. Elemental analysis was
performed on a Vario EL III elemental analysis instrument.
Analytical thin-layer chromatography (TLC) was carried
out on precoated plates, and spots were visualized with
ultraviolet light. All chemicals or reagents were purchased
from standard commercial supplies. Anhydrous CH2Cl2,
CH3OH and THF were prepared by standard methods [22].
All other solvents and reagents were analytical grade and
used directly without purification.
d6) d 12.60 (bs, 1H, OH), 8.07–8.04 (m, 2H, Ph-H), 7.44-7.18
(m, 7H, Ph-H), 5.75 (s, 1H, CH-O); ESI-MS: calcd for
C
C
16H11FO3 m/z 270.1; found, 269.4 (M)+. Anal. Calcd for
16H11FO3: C, 71.11; H, 4.10. Found: C, 71.24; H, 4.02.
4.2.3. 3-(2,4-Dichlorophenyl)-4-hydroxy-5-phenylfuran-
2(5H)-one 5c
Light yellow powder, yield 78%, m.p. 162.5–163.4 8C; IR
(KBr pellet) nmax 698, 996, 1062, 1133, 1260, 1483, 1645,
1713, 2941, 3402 cmÀ1 1H NMR (600 MHz, DMSO-d6)
; d
12.80 (bs, 1H, OH), 7.73 (s, 1H, Ph-H), 7.52–7.42 (m, 7H, Ph-
H), 6.00 (s, 1H, CH-O); ESI-MS: calcd for C16H10Cl2O3 m/z
320.0; found, 319.3 (M+). Anal. Calcd for C16H10Cl2O3: C,
59.84; H, 3.14. Found: C, 59.98; H, 3.07.

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S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
4.2.4. 4-Hydroxy-3-(4-methoxyphenyl)-5-phenylfuran-
2(5H)-one 5d
6 (2.2 mmol) dissolved in dry dichloromethane was added
dropwise to a solution of the substituted amino-acid ester
hydrochloride (2 mmol), and Et3N (5 mmol) in dry dichlor-
omethane under ice-bath. The resultant solution was stirred
at room temperature for 2 to 5 h, which was detected by TLC.
Then the mixture was washed to neutral with water and
dried via anhydrous Na2SO4. After filtration and concentra-
tion, the organic residues were used for the next cyclization
reaction without further purification. The N-substituted
phenylacetamidederivatives11wereconveniently obtained
with the similar procedure as that for compounds 10.
White powder, yield 71%, m.p. 190.5–192.1 8C; IR (KBr
pellet)
1639, 1697, 2645, 2967, 3441 cmÀ1
DMSO-d6) 7.88 (d, J = 9.0 Hz, 2H, Ph-H), 7.44 (s, 3H, Ph-H),
n
max 696, 835, 1023, 1163, 1248, 1383, 1517, 1609,
;
1H NMR (600 MHz,
d
7.37 (d, J = 6.0 Hz, 2H, Ph-H), 6.98 (d, J = 8.4 Hz, 2H, Ph-H),
5.88 (s, 1H, CH-O), 3.77 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6):
d = 174.56, 173.01, 158.58, 136.00, 130.04,
129.52, 128.78, 128.74, 127.33, 123.35, 114.27, 99.12,
78.92, 55.74; ESI-MS: calcd for C17H14O4 m/z 282.1; found,
283.4 (M + H)+. Anal. Calcd for C17H14O4: C, 72.33; H, 5.00.
Found: C, 72.51; H, 4.94.
4.7. General synthetic procedure for target compounds
lactam derivatives 12 and 13
4.3. General synthetic procedure for intermediates
substituted 2-phenylacetyl chloride 6
To a solution of phenylacetamide derivatives 10
(10 mmol, 1 equiv) in anhydrous THF was added in
batches with potassium tert-butoxide (12 mmol, 1.2
equiv). The suspension mixture obtained was then
refluxed under nitrogen overnight. After cooling to
ambient temperature, the reaction mixture was acidified
with 5% HCl aqueous to pH 2-3, and then extracted three
times with ethyl acetate. The combined organic layers
were then washed with water and dried over Na2SO4. After
filtration and concentration under vacuum, the residue
was taken up with ethyl acetate and filtered in vacuo to
give the corresponding multi-substituted lactam deriva-
tives 12. The N-substituted lactam derivatives 13 were
prepared according to the above-described method. The
physicochemical properties and spectral data for repre-
sentative compounds are as follows:
Appropriate substituted phenylacetic acid 1 (10 mmol),
10 mL of toluene and thionyl chloride (5 mL) were placed in
a dried round-bottomed flask containing a magnetic stirrer
bar and stirred at about 60 8C for 3-6 h. Then the superfluous
thionyl chloride was removed by distillation in vacuo at
room temperature, and the residue was dissolved in dry
CH2Cl2 and the solvent removed as before; this procedure
was repeated twice to give intermediates 6, which were
used for the next reaction without further purification.
4.4. General synthetic procedure for various amino-acid ester
hydrochlorides 8
A suspension of the amino-acid (10 mmol) in absolute
methanol (30 mL) was cooled to 0 8C, and thionyl chloride
(25 mmol) was added dropwise over 20 min. The cold bath
was removed, and the homogeneous solution was heated
at reflux for 4 to 6 h. The solvent was removed in vacuo, the
resulting residue was dissolved in water (50 mL), and the
aqueous solution was extracted with ethyl acetate and
then evaporated in vacuo to the corresponding amino-acid
ester hydrochlorides 8.
4.7.1. 5-Benzyl-4-hydroxy-3-phenyl-1H-pyrrol-2(5H)-one
12a
White floccule, yield 80%, m.p. 212.0–214.0 8C; IR (KBr
pellet)
n
max 692, 784, 1090, 1274, 1304, 1458, 1610, 1637,
2926, 3434 cmÀ1
;
1H NMR (400 MHz, DMSO-d6)
d
11.35
(bs, 1H, OH), 7.78 (d, J = 7.9 Hz, 2H, Ph-H), 7.49 (s, 1H, NH),
7.27–7.09 (m, 8H, Ph-H), 4.23 (s, 1H, CH-N), 3.12 (q,
J = 6.0 Hz, 1H, CH2), 2.94 (q, J = 6.0 Hz, 1H, CH2); ESI-MS:
calcd for C17H15NO2 m/z 265.1; found, 266.6 (M + H)+. Anal.
Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
76.90; H, 5.75; N, 5.34.
4.5. General synthetic procedure for N-substituted amino-
acid ester 9
To a solution of the corresponding amino-acid ester
hydrochlorides (10 mmol) in anhydrous acetonitrile
(30 mL) was added K2CO3 (25 mmol) in batches over
20 min. The cold bath was removed, and various halides
added to the aforementioned reaction mixture. The
heterogeneous solution was stirred at ambient condition
for 5 to 8 h. The solvent was removed in vacuo, the
resulting residue was dissolved in water (50 mL), and the
aqueous solution was extracted with ethyl acetate and
then evaporated in vacuo to the corresponding N-
substituted amino-acid ester 9, which were used for the
next reaction without further purification.
4.7.2. 5-Benzyl-3-(2,4-dichlorophenyl)-4-hydroxy-1H-
pyrrol-2(5H)-one 12b
White powder, yield 70%, m.p. 113.5–115.1 8C; IR (KBr
pellet) nmax 702, 751, 823, 1235, 1364, 1475, 1561, 1643,
1737, 2950, 3268, 3449 cmÀ1 1H NMR (400 MHz, DMSO-
;
d6)
d 8.60 (d, J = 8.0 Hz, 1H, Ph-H), 7.53 (s, 1H, NH), 7.34–
7.22 (m, 7H, Ph-H), 4.54-4.48 (m, 1H, CH-N), 3.06 (q,
J = 5.4 Hz, 1H, CH2), 2.90 (q, J = 9.5 Hz, 1H, CH2); ESI-MS:
calcd for C17H13Cl2NO2 m/z 333.0; found, 334.6 (M + H)+.
Anal. Calcd for C17H13Cl2NO2: C, 61.10; H, 3.92; N, 4.19.
Found: C, 61.17; H, 3.86; N, 4.24.
4.6. General procedure for synthesis of intermediates 10 and
11
4.7.3. 5-Benzyl-3-(4-fluorophenyl)-4-hydroxy-1H-pyrrol-
2(5H)-one 12c
Light yellow powder, yield 75%, m.p. 203.0–205.0 8C; IR
(KBr pellet) nmax 733, 840, 1084, 1237, 1297, 1318, 1511,
The typical process for synthesis of phenylacetamide
derivatives 10 is as follows: The freshly formed acylchloride
1610, 1655, 2926, 3068, 3438 cmÀ1 1H NMR (400 MHz,
;

S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
1077
DMSO-d6)
d
11.40 (bs, 1H, OH), 7.86 (q, 4J = 5.8 Hz,
1483, 1584, 1623, 1659, 2607, 2912, 3259, 3441 cmÀ1
;
1H
J = 8.9 Hz, 2H, Ph-H), 7.52 (s, 1H, NH), 7.25–7.06 (m, 7H,
Ph-H), 4.23 (t, J = 4.7 Hz, 1H, CH-N), 3.12 (q, J = 4.0 Hz, 1H,
CH2), 2.94 (q, J = 4.0 Hz, 1H, CH2); 13C NMR (100 MHz,
NMR (400 MHz, DMSO-d6) 11.28 (bs, 1H, OH), 7.74 (s, 1H,
d
NH), 7.61 (d, J = 2.1 Hz, 1H, Ph-H), 7.40 (q, 4J = 2.1 Hz,
J = 8.3 Hz, 1H, Ph-H), 7.27 (d, J = 8.3 Hz, 1H, Ph-H), 4.10 (t,
J = 4.6 Hz, 1H, CH-N), 2.12–1.69 (m, 7H, CH2CH2SCH3); ESI-
MS: calcd for C13H13Cl2NO2S m/z 317.0; found, 318.6
(M + H)+. Anal. Calcd for C13H13Cl2NO2S: C, 49.07; H, 4.12;
N, 4.40. Found: C, 49.15; H, 4.06; N, 4.44.
DMSO-d6):
d = 173.12, 170.20, 161.96, 136.84, 130.29,
129.40, 129.33, 128.47, 127.02, 115.17, 114.96, 103.96,
56.39, 37.73; ESI-MS: calcd for C17H14FNO2 m/z 283.1;
found, 284.7 (M + H)+. Anal. Calcd for C17H14FNO2: C,
72.07; H, 4.98; N, 4.94. Found: C, 72.01; H, 5.04; N, 4.88.
4.7.9. 7-Hydroxy-6-phenyl-2,3-dihydro-1H-pyrrolizin-
5(7aH)-one 12i
White powder, yield 68%, m.p. 212.0–214.0 8C; IR
(KBr pellet) nmax 632, 692, 787, 918, 941, 1230, 1304,
1340, 1572, 1650, 2560, 2896, 2975, 3443 cmÀ1; 1H NMR
4.7.4. 5-Benzyl-4-hydroxy-3-(4-methoxyphenyl)-1H-pyrrol-
2(5H)-one 12d
Yellow powder, yield 77%, m.p. 194.2–195.6 8C; IR (KBr
pellet) nmax 703, 736, 840, 1176, 1251, 1287, 1513, 1611,
1653, 2935, 3057, 3432 cmÀ1
;
1H NMR (400 MHz, DMSO-
(400 MHz, DMSO-d6) d 11.92 (bs, 1H, OH), 7.20-7.99 (m,
d6)
d
11.20 (bs, 1H, OH), 7.73 (d, J = 8.8 Hz, 2H, Ph-H), 7.47
5H, Ph-H), 4.19 (t, J = 6.4 Hz, 1H, CH-N), 1.40–3.09 (m,
6H, CH2CH2CH2); ESI-MS: calcd for C13H13NO2 m/z
215.1; found, 216.6 (M + H)+. Anal. Calcd for
(s, 1H, NH), 7.23–7.15 (m, 5H, Ph-H), 6.84 (d, J = 8.8 Hz, 2H,
Ph-H), 4.22 (t, J = 4.4 Hz, 1H, CH-N), 3.72 (s, 3H, CH3O), 3.11
(q, 2J = 13.7 Hz, J = 3.7 Hz, 1H, CH2), 2.93 (q, 2J = 13.7 Hz,
J = 5.8 Hz, 1H, CH2); ESI-MS: calcd for C18H17NO3 m/z
295.1; found, 296.8 (M + H)+. Anal. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74. Found: C, 73.13; H, 5.86; N, 4.81.
C
13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.46;
H, 6.15; N, 6.43.
4.7.10. 6-(2,4-Dichlorophenyl)-7-hydroxy-2,3-dihydro-1H-
pyrrolizin-5(7aH)-one 12j
4.7.5. 4-Hydroxy-3,5-diphenyl-1H-pyrrol-2(5H)-one 12e
White powder, yield 78%, m.p. 191.4–192.5 8C; IR (KBr
pellet) nmax 692, 703, 775, 918, 1197, 1313, 1382, 1498,
White powder, yield 74%, m.p. 226.0–228.0 8C; IR (KBr
pellet) nmax 638, 772, 820, 870, 1099, 1221, 1367, 1340,
1578, 1608, 1653, 2685, 2887, 2949, 3441 cmÀ1 1H NMR
;
1593, 1659, 2578, 2943, 3069, 3411 cmÀ1
;
1H NMR
(400 MHz, DMSO-d6) d 11.78 (bs, 1H, OH), 7.60 (s, 1H, Ph-
(400 MHz, DMSO-d6)
d
11.25 (bs, 1H, OH), 8.01 (s, 1H,
H), 7.39 (q, 4J = 1.6 Hz, 3J = 8.4 Hz, 1H, Ph-H), 7.26 (d,
J = 8.4 Hz, 1H, Ph-H), 4.16 (t, J = 7.9 Hz, 1H, CH-N), 4.15-3.00
(m, 2H, CH2), 2.17–1.36 (m, 4H, CH2); ESI-MS: calcd for
NH), 7.95 (d, J = 7.2 Hz, 2H, Ph-H), 7.41–7.30 (m, 7H, Ph-H),
7.19 (t, J = 7.4 Hz, 1H, Ph-H), 5.03 (s, 1H, CH-N); ESI-MS:
calcd for C16H13NO2 m/z 251.1; found, 252.6 (M + H)+. Anal.
Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C,
76.39; H, 5.27; N, 5.51.
C
13H11Cl2NO2 m/z 283.0; found, 284.6 (M + H)+. Anal. Calcd
for C13H11Cl2NO2: C, 54.95; H, 3.90; N, 4.93. Found: C,
55.03; H, 3.84; N, 4.85.
4.7.6. 3-(2,4-Dichlorophenyl)-4-hydroxy-5-phenyl-1H-
pyrrol-2(5H)-one 12f
4.7.11. 6-(4-Fluorophenyl)-7-hydroxy-2,3-dihydro-1H-
pyrrolizin-5(7aH)-one 12k
Light yellow powder, yield 68%, m.p. 195.2–196.7 8C; IR
(KBr pellet) nmax 697, 748, 828, 1099, 1191, 1322, 1382,
White powder, yield 76%, m.p. 228.6–230.2 8C; IR (KBr
pellet) nmax 644, 775, 834, 941, 1162, 1233, 1299, 1352,
1388, 1418, 1516, 1576, 1653, 2631, 2896, 2971,
; d 11.90 (bs,
3442 cmÀ1 1H NMR (400 MHz, DMSO-d6)
1480, 1581, 1626, 1659, 2515, 2920, 3290, 3437 cmÀ1 1H
;
NMR (400 MHz, DMSO-d6)
d
11.23 (bs, 1H, OH), 8.05 (s, 1H,
NH), 7.63 (s, 1H, Ph-H), 7.44–7.32 (m, 7H, Ph-H), 5.07 (s,
1H, CH-N); ESI-MS: calcd for C16H11Cl2NO2 m/z 319.0;
found, 320.6 (M + H)+. Anal. Calcd for C16H11Cl2NO2: C,
60.02; H, 3.46; N, 4.37. Found: C, 60.13; H, 3.56; N, 4.32.
1H, OH), 8.01 (q, 2H, Ph-H), 7.15 (t, J = 9.0 Hz, 2H, Ph-H),
4.14 (q, J = 8.4 Hz, 1H, CH-N), 3.41–3.02 (m, 2H, CH2),
2.20–1.33 (m, 4H, CH2); ESI-MS: calcd for C13H12FNO2 m/
z
C
233.1; found, 234.6 (M + H)+. Anal. Calcd for
13H12FNO2: C, 66.94; H, 5.19; N, 6.01. Found: C,
4.7.7. 3-(4-Fluorophenyl)-4-hydroxy-5-phenyl-1H-pyrrol-
2(5H)-one 12 g
66.87; H, 5.12; N, 6.07.
Light yellow powder, yield 64%, m.p. 179.2–180.5 8C; IR
(KBr pellet) nmax 576, 701, 784, 843, 1221, 1382, 1507,
4.7.12. 7-Hydroxy-6-o-tolyl-2,3-dihydro-1H-pyrrolizin-
5(7aH)-one 13a
1599, 1634, 1682, 2571, 2918, 3414 cmÀ1
;
1H NMR
White powder, yield 62%, m.p. 165.3–167.7 8C; IR (KBr
pellet) nmax 632, 724, 745, 781, 942, 1227, 1364, 1400,
(400 MHz, DMSO-d6)
d 11.35 (bs, 1H, OH), 8.05–8.01 (m,
3H, NH and Ph-H), 7.41–7.29 (m, 5H, Ph-H), 7.17 (t,
1590, 1611, 2673, 2890, 2965, 3437 cmÀ1 1H NMR
;
J = 9.0 Hz, 2H, Ph-H), 5.03 (s, 1H, CH-N); ESI-MS: calcd for
C
for C16H12FNO2: C, 71.37; H, 4.49; N, 5.20. Found: C, 71.32;
H, 4.56; N, 5.13.
(400 MHz, DMSO-d6) d 11.36 (bs, 1H, OH), 7.20–7.08 (m,
4H, Ph-H), 4.15 (q, J = 6.7 Hz, 1H, CH-N), 3.40–3.02 (m, 2H,
CH2), 2.19–1.38 (m, 7H, CH2 and CH3); 13C NMR
16H12FNO2 m/z 269.1; found, 270.6 (M + H)+. Anal. Calcd
(100 MHz, DMSO-d6):
d = 177.69, 172.54, 137.80,
131.45, 131.34, 130.22, 127.64, 125.69, 106.79, 63.93,
43.90, 29.28, 28.57, 20.41; ESI-MS: calcd for C14H15NO2
m/z 229.1; found, 230.6 (M + H)+. Anal. Calcd for
4.7.8. 3-(2,4-Dichlorophenyl)-4-hydroxy-5-(2-
(methylthio)ethyl)-1H-pyrrol-2(5H)-one 12 h
Light yellow powder, yield 65%, m.p. 185.0–186.0 8C; IR
(KBr pellet) nmax 671, 778, 825, 1099, 1200, 1316, 1409,
C
14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.27;
H, 6.66; N, 6.03.

1078
S. Ke et al. / C. R. Chimie 14 (2011) 1071–1079
4.7.13. 7-Hydroxy-6-(4-methoxyphenyl)-2,3-dihydro-1H-
pyrrolizin-5(7aH)-one 13b
CH-N), 1.33 (d, J = 6.6 Hz, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): = 171.98, 169.35, 138.05, 132.39, 129.41,
d
White solid, yield 72%, m.p. 218.7–220.2 8C; IR (KBr
pellet) nmax 638, 769, 837, 1019, 1177, 1245, 1382, 1432,
128.47, 128.07, 126.68, 124.17, 122.38, 103.49, 54.85,
17.36; ESI-MS: calcd for C17H15NO2 m/z 265.1; found,
266.4 (M + H)+.
1516, 1596, 1650, 2676, 2896, 2959, 3458 cmÀ1 1H NMR
;
(400 MHz, DMSO-d6)
d 11.68 (bs, 1H, OH), 7.88 (d,
J = 8.2 Hz, 2H, Ph-H), 6.89 (d, J = 8.2 Hz, 2H, Ph-H), 4.12
(t, J = 7.1 Hz, 1H, CH-N), 3.42–3.35 (m, 1H, CH2), 3.33 (s, 3H,
CH3O), 3.02–3.00 (m, 1H, CH2), 2.21–2.14 (m, 1H, CH2),
2.08-2.03 (m, 2H, CH2), 1.38-1.31 (m, 1H, CH2); ESI-MS:
calcd for C14H15NO3 m/z 245.1; found, 246.7 (M + H)+. Anal.
Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.47; H, 6.23; N, 5.65.
4.9.2. 1-(4-Bromophenyl)-4-hydroxy-5-methyl-3-phenyl-
1H-pyrrol-2(5H)-one 17b
White solid, yield 63%, m.p. 240.2–242.1 8C; IR (KBr
pellet) nmax 596, 701, 778, 810, 897, 1010, 1099, 1194,
1394, 1486, 1590, 1626, 1673, 2697, 2976, 3438 cmÀ1; 1H
NMR (600 MHz, DMSO-d6)
d 7.93 (d, J = 7.8 Hz, 2H, Ph-H),
7.57 (s, 4H, Ph-H), 7.36 (t, J = 7.4 Hz, 2H, Ph-H), 7.22 (t,
J = 7.2 Hz, 1H, Ph-H), 4.85 (d, J = 6.0 Hz, 1H, CH-N), 1.34 (d,
J = 6.6 Hz, 3H, CH3); ESI-MS: calcd for C17H14BrNO2 m/z
343.0; found, 344.4 (M + H)+.
4.7.14. 1-(4-Bromobenzyl)-4-hydroxy-3,5-diphenyl-1H-
pyrrol-2(5H)-one 13c
White powder, yield 74%, m.p. 179.3–181.0 8C; IR (KBr
pellet) nmax 641, 692, 739, 769, 909, 1013, 1072, 1188,
1310, 1376, 1489, 1599, 1623, 1638, 2673, 2920,
4.9.3. 4-Hydroxy-1-(4-isopropylphenyl)-5-methyl-3-
phenyl-1H-pyrrol-2(5H)-one 17c
3446 cmÀ1
;
1H NMR (600 MHz, CDCl3)
d
7.74 (d,
White solid, yield 77%, m.p. 229.0–230.1 8C; IR (KBr
pellet) nmax 703, 781, 837, 906, 1102, 1200, 1284, 1391,
J = 7.8 Hz, 2H, Ph-H), 7.47–7.14 (m, 10H, Ph-H), 6.95 (d,
J = 7.8 Hz, 2H, Ph-H), 5.03 (d, 2J = 15.6 Hz, 1H, CH2-N), 4.67
(s, 1H, CH-N), 3.51 (d, 2J = 15.0 Hz, 1H, CH2-N); 13C NMR
1516, 1596, 1620, 1676, 2695, 2955, 3447 cmÀ1 1H NMR
;
(600 MHz, DMSO-d6)
d 7.95 (s, 2H, Ph-H), 7.46 (d, J = 8 Hz,
(100 MHz, DMSO-d6):
d
= 171.36, 169.70, 138.08, 135.91,
2H, Ph-H), 7.35 (t, J = 7.4 Hz, 2H, Ph-H), 7.26-7.20 (m, 3H,
Ph-H), 4.78 (d, J = 6.6 Hz, 1H, CH-N), 2.88 (t, J = 6.9 Hz, 1H,
CH(CH3)2), 1.32 (d, J = 6.6 Hz, 3H, CH3), 1.22 (d, J = 7.2 Hz,
6H, CH(CH3)2); ESI-MS: calcd for C20H21NO2 m/z 307.2;
found, 308.5 (M + H)+.
132.48, 132.03, 130.44, 129.56, 129.40, 129.14, 128.51,
127.94, 126.75, 120.77, 103.99, 63.22, 42.85; ESI-MS: calcd
for C23H18BrNO2 m/z 419.1; found, 420.4 (M + H)+.
4.8. General procedure for synthesis of intermediates 15
Acknowledgements
The various aromatic amines 14 were selected as
starting materials, which were conveniently converted to
N-substituted amino-acid ester 15 via N-alkylation
reactions under ambient conditions. The typical process-
es are as follows: To a solution of various aromatic amines
(10 mmol) and Et3N (15 mmol) in anhydrous acetonitrile
Financial support from the Special Fund for Agro-
Scientific Research in the Public Interest (200903052) and
the National Natural Science Foundation of China
(31000867) is kindlyacknowledged. The authors also would
like to thank many colleagues of the Hubei Biopesticide
Engineering Research Center and the Hubei Academy of
Agricultural Sciences for valuable advice and assistance.
(20 mL) was added
a-halides (12 mmol) dropwise over
30 min. The mixture was stirred at ambient condition,
which was monitored by TLC. Then the reaction was
worked-up with normal procedure to access to the
corresponding N-substituted amino-acid ester 15, which
were used for the next reaction without further
purification.
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