Synthesis and bioactivity of novel (Z,E)-1-(substituted phenyl)-3-[α -(alkyloxyimino)benzylidene]pyrrolidine-2,4-dione derivatives

Article abstract of DOI:10.1515/HC.2011.005

A series of 1-(substituted phenyl)-3-[α-(alkyloxyimino)-benzylidene] pyrrolidine-2,4-dione derivatives as a mixture of two geometrical isomers of Z-configuration and E-configu-ration were synthesized by the reaction of the corresponding α -hydroxybenzylidene analogs with alkyloxyamine hydro-chlorides. The target compounds were confirmed by IR, ¹ H NMR, MS and elemental analysis. The title compounds exhibit inhibitory activity against Echinochloa crusgalli and Brassica campestris. Copyright by Walter de Gruyter Berlin Boston.

Full text of DOI:10.1515/HC.2011.005

Heterocycl. Commun., Vol. 17(1-2), pp. 73–78, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.005
Synthesis and bioactivity of novel (Z,E)-1-(substituted phenyl)-
3-[α-(alkyloxyimino)benzylidene]pyrrolidine-2,4-dione
derivatives
Xiao-Qian Zheng1, Bao-Feng Han1,2, Xian-Feng
Figure 1 (Zhu et al., 2009, 2010) have been found to show
noticeable bioactivities.
Wang1,2, Sheng Qiang3 and Chun-Long Yang1,2,
*
Oxime ether moieties have often been used in the molecular
design of new pesticides. In fact, there are many compounds
containing an oxime moiety that show significant insecticidal,
herbicidal and fungicidal activities (Liu and Yao, 2004; Dai
et al., 2008; Fan et al., 2008). Many commercial herbicides,
such as clethodim, cycloxydim, propaquizafop and tepral-
oxydim have been applied in plant protection. In this article,
alkyloxyamino groups were introduced at the 3-position of
3-(α-hydroxybenzylidene)pyrrolidine-2,4-diones to synthe-
size a series of novel tetramic acid derivatives containing an
oxime ether moiety. The herbicidal activities of the synthe-
sized compounds were also evaluated.
1 Key Laboratory of Monitoring and Management of
Crop Diseases and Pest Insects, Ministry of Agriculture,
Nanjing Agricultural University, Nanjing 210095,
P.R. China
2 Jiangsu Key Laboratory of Pesticide Science, Nanjing
Agricultural University, Nanjing 210095, P.R. China
3 College of Life Science, Nanjing Agricultural University,
Nanjing 210095, P.R. China
*Corresponding author
e-mail: chunlongyang@yahoo.com.cn
Abstract
Results and discussion
Synthesis
A series of 1-(substituted phenyl)-3-[α-(alkyloxyimino)-
benzylidene]pyrrolidine-2,4-dione derivatives as a mixture
of two geometrical isomers of Z-configuration and E-configu-
ration were synthesized by the reaction of the corresponding
α-hydroxybenzylidene analogs with alkyloxyamine hydro-
chlorides. The target compounds were confirmed by IR,
1H NMR, MS and elemental analysis. The title compounds
exhibit inhibitory activity against Echinochloa crusgalli and
Brassica campestris.
The title compounds 5a–t were synthesized by the reaction
of 1-(substituted phenyl)-3-(α-hydroxybenzylidene)pyrro-
lidine-2,4-diones 3 with alkyloxyamine hydrochlorides 4 in
the presence of sodium hydroxide. The synthetic route to the
products 5 is shown in Scheme 1.
Compounds 3 were synthesized from aniline or substituted
anilines, ethyl chloroacetate and ethyl benzoylacetate via a
three-step procedure including substitution, condensation and
cyclization (Fujinami et al., 1976; Zhu et al., 2005b). The
alkyloxyamine hydrochlorides 4 were synthesized according
to the reported methods (Du et al., 2004; Han et al., 2005;
Lu, 2006).
Keywords: herbicidal activity; oxime ether; synthesis;
tetramic acid.
Introduction
Structure
As a metabolic toxin firstly isolated from the culture fil-
trates of Alternaria tenuis, tenuazonic acid [5-sec-butyl-3
-(1-hydroxyethylidene)pyrrolidine-2,4-dione, A in Figure
1] belongs to a class of natural tetramic acids containing a
heterocyclic core of pyrrolidine-2,4-dione (Rosett et al.,
1957). It exhibits a broad spectrum of bioactivities includ-
ing antitumor, antibiotic, insecticidal, antiviral and herbicidal
properties (Gitterman et al., 1964; Gitterman, 1965; Suzuki
et al., 1967; La Croix et al., 1975; Janardhanan and Husain,
1984; Gallardo et al., 2004). It has attracted attention of many
agrochemists because it is easily degraded (Zhou and Qiang,
2007). A number of other substituted pyrrolidine-2,4-diones
have been designed and synthesized, and some compounds
such as B in Figure 1 (Zhu et al., 2005a,b,c, 2007) and C in
The structure of the final compounds was confirmed by IR,
1H NMR, MS and elemental analysis. The IR spectra showed
peaks at 2916–2984 cm-1 due to C-H stretching vibration
and peaks at 1676–1701 cm-1 for the carbonyl groups. The
1H NMR spectra exhibited a singlet at δ 3.88–4.61 assigned
to the protons of the NCH2 group, and multiple signals at δ
6.88–8.02 assigned to aromatic protons. A molecular ion peak
was observed in the mass spectra of all products. Moreover,
the elemental analysis data matched the molecular formulas
of title compounds.
It is worthy to point out that protons at the 5-position
of the pyrrolidine-2,4-dione moiety and protons of the
group R4 each show two groups of signals with a similar
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74 X.-Q. Zheng et al.
H
O
O
O
OH
H
H
R2
H
N
OH
CH3
O
R3
R1
R1
O
H3C
R2
N
N
N
H3C
CH3
H
O
O
A
C
B
Figure 1 Structures of some bioactive tetramic acids.
A is a naturally occurring tetramic acid (tenuazonic acid), B and C are synthetic tetramic acids.
O
O
NH2
NHCH2COOC2H5
R3
O
R3
R1
(1)
R1
ClCH2COOC2H5
(2) CH3ONa
R2
R2
2
1
O
H
N
R1
O
R4
R1
R1
O
O
N
R4ONH2•HCl 4
N
N
R2
N
R2
R2
O
O
R4
O
H
R3
1% NaOH
R3
R3
OH
O
5Z
3
5E
5a-e: R1=R2=R3=H; 5f-j: R1=CH3, R2=H, R3=C2H5; 5k-o: R1=OC2H5, R2=R3=H;
5p-s: R1=R3=CH3, R2=H; 5t: R1=R3=H, R2=CH3.
5a, 5f, 5k, 5p, 5t: R4=n-C3H7; 5b, 5g, 5l, 5q: R4=i-C3H7; 5c, 5h, 5m, 5r: R4=CH2CH=CH2;
5d, 5i, 5n, 5s: R4=n-C4H9; 5e, 5j, 5o: R4=CH2C6H5.
Scheme 1 Synthetic route to compounds 5 (a mixture of geometrical isomers).
1
Biological evaluation
ratio of integration area in H NMR spectra. This result
is consistent with the presence of two isomers for each
final product 5. Tetramic acid derivations can exist in
four tautomeric forms (Athanasellis et al., 2001; Siegel
et al., 2009), which for the corresponding structures
of the products 5 is shown in Scheme 2. By using 15N
NMR spectroscopy, it has been shown that a related com-
pound, 3-(1-anilinoethylidene)pyrrolidine-2,4-dione, exists
primarily in two isomers, namely in Z-configuration and
E-configuration of a ketoamine form (Yamaguchi et al.,
1976). The X-ray diffraction crystallography studies have
also shown that 3-(1-(propyloxyamino)ethylidene)-1-cyclo-
hexylpyrrolidine-2,4-dione and 5-sec-butyl-3-(2,6-dimeth-
ylphenylamino)ethylidene-1H-pyrrolidine-2,4-dione exist in
aketoamineform(Wangetal.,2010;Zhuetal.,2010).Itcanbe
speculated that the target compounds exist in ketoamine form
with two isomers of 5α and 5γ (Scheme 2). With target com-
pound 5a as a representative, its four isomers 5aα, 5aβ, 5aγ,
and 5aδ were calculated at the B3LYP/6-31+G* level and the
respectively relative energies of 1.38, 12.73, 0.00 and 30.48
kJ/mol were obtained (Skylaris et al., 2003). This result sug-
gests that 5aγ (Z-configuration) and 5aα (E-configuration)
are the most stable isomers. Moreover, it can be suggested
that the Z-isomer 5aγ is the major product in the mixture.
The final products 5 were evaluated for herbicidal activities
againstB. campestrisandE. crusgalliinvitroattheconcentration
of 100 mg/l (Luo and Yang, 2007). The results are summarized
in Table 1. The data indicate that almost all compounds display
certain inhibitory activities against the root of two tested plants,
but no obvious bioactivity against the stem was found. Seven
O
H
O
H
N
R1
R4
R4
R1
N
O
O
N
N
R2
O
O
R3
R2
R3
5α
5β
O
O
R1
R1
N
N
R2
N
N
R2
O
R4
O
R4
O
O
R3
H
R3
H
5γ
5δ
Isomer 5α: E-configuration
Isomer 5γ: Z-configuration
1
For all products 5 the intensities of the corresponding H
Isomer 5β: s-trans conformation
Isomer 5δ: s-syn conformation
NMR signals tentatively assigned to the Z and E isomers are
60%–69% and 31%–40%, respectively.
Scheme 2 Structures of four possible isomers of compounds 5.
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Synthesis and bioactivity of novel pyrrolidine-2,4-diones 75
Table 1 Herbicidal activities of compounds 5a–t against B. campe-
stris and E. crusgalli (100 µg/ml, inhibitory rate percent).
General procedure for the preparation of the title
compounds 5a–t
A solution of aniline or substituted aniline 1 (0.05 mol), ethyl chloro-
acetate (0.06 mol) and sodium acetate (0.06 mol) in ethanol (100 ml)
was heated under reflux for 8 h.After cooling, the mixture was treated
with water (80 ml) and extracted with ether (3×25 ml). The combined
organic layers were dried with anhydrous MgSO4 and the solvent
was removed under reduced pressure to give the presumed liquid
product 2 (see Scheme 1). Then, a solution of the crude intermediate
product 2 and ethyl benzoylacetate (0.06 mol) in dry xylenes (50 ml)
was stirred for 24 h at 125–130°C. Then, a solution of sodium meth-
oxide (0.12 mol) in methanol (40 ml) was added and the mixture
was heated under reflux for 24 h. After cooling to room temperature,
water was added (100 ml), and the aqueous layer was acidified to
pH=2–3 with 20% hydrochloric acid. The mixture was extracted with
chloroform (3×25 ml), and the combined organic layers were dried
with anhydrous MgSO4, and concentrated under reduced pressure
to obtain crude 1-(substituted phenyl)-3-(α-hydroxybenzylidene)-
pyrrolidine-2,4-dione 3, which was purified by crystallization from
ethanol/chloroform, 4:1. To the solution of compound 3 (3 mmol)
and O-substituted hydroxylamine hydrochloride 4 (3 mmol) in etha-
nol (25 ml) or chloroform (25 ml), a 1% solution of NaOH (4.4 ml)
was added. The mixture was heated under reflux, and the progress of
the reaction was monitored by TLC. Then the mixture was extracted
with chloroform (3×25 ml), and the extract was dried over anhydrous
MgSO4. The solvent was removed under reduced pressure and the
residue was crystallizated from ethanol/chloroform, 3:1 to afford the
desired compound 5a–t.
Compounds
B. campestris
E. crusgalli
E. crusgalli
root
root
stem
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
50.0 3.2
21.8 1.4
30.9 3.8
41.6 0.9
51.5 3 .5
53.4 1.8
43.2 3.4
67.3 2.1
45.9 3 .3
6 .5 2 .7
6.8 1.6
32.2 3.2
62.3 1.8
52.6 1.6
5 .5 0.9
-5.3 0.8
7. 5 1.2
12.3 2.4
-4.8 1.3
2.2 1.5
- 1 5 .1 2.7
-10.2 3.8
-8.9 1.4
- 2 6 .6 2.8
-20.9 3.2
-13.6 4.2
6.0 1.2
68.2 3 .3
47.2 3.7
62.0 1.9
7 2 .3 0 .9
2 5 .7 3.0
18.6 2.5
32.1 1.7
2 2 .4 1.3
33.1 2.8
41.6 2 .4
71.7 4.2
5 9 .8 4.1
76.5 1.3
-9.2 1. 5
51.5 3.5
97.8 0.4
28.0 0.6
38.0 3.4
7 .3 1 .9
7.3 3.7
15.4 1.2
17.8 3.0
51.6 2.5
54.6 3 .2
27.6 2.7
58.6 2.3
34.5 1.6
92.6 1.0
-1.7 2.4
- 1 0 .2 1.7
3.1 1.2
-3.0 1.8
17.8 2.2
6.3 2.6
-3.8 1.0
43.1 2.9
5t
TeA
The values are expressed as means SD of the replicates; n=3 for all
groups. TeA, tenuazonic acid.
(Z,E )-1-Phenyl-3-[α-(propoxyamino)benzylidene]pyrrolidine-
2,4-dione (5a): White powder; yield 30%; mp 160.0–160.2°C; 1H
NMR: δ for Z-isomer (65%) 0.78 (t, J=7.8 Hz, 3H, CH3), 1.51–1.64
(m, 2H, CH2CH3), 3.86 (t, J=6.3 Hz, 2H, OCH2), 4.23 (s, 2H, NCH2),
7.10–7.64 (m, 10H, PhH); δ for E-isomer (35%) 1.03 (t, J=7.5 Hz,
3H, CH3), 1.81–1.92 (m, 2H, CH2CH3), 4.36 (t, J=6.6 Hz, 2H,
OCH2), 4.45 (s, 2H, NCH2), 7.10–7.64 (m, 10H, PhH); IR: 3065,
2965, 1696, 1580, 1500, 1477, 1307, 1225, 916 cm-1; MS (EI) m/z:
336 (M+), 278, 145, 105 (100), 77, 57, 45. Analysis: calculated for
C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.37; H, 5.84;
N, 8.24.
compounds5a,5e,5f,5h,5p,5qand5sshowmoderateherbicidal
activities against the root of B. campestris, with their inhibitory
rates exceeding 50%. Nine compounds 5c, 5d, 5f, 5h, 5i, 5p, 5q,
5r and 5t exhibit inhibitory rates of over 50% against the root of
E. crusgalli.
Conclusions
A series of novel 3-benzylidene-substituted tetramic acid
derivatives containing a substituted phenyl group at the
1-position and oxime ether group at the 3-position were
synthesized. These compounds exist as a mixture of two
geometrical E/Z isomers. The bioassay indicated that these
compounds exhibit herbicidal activities against the root of B.
campestris and E. crusgalli at the concentration of 100 µg/ml
in vitro.
(Z,E)-3-[α-(Isopropoxyamino)benzylidene)-1-phenylpyrro-
lidine-2,4-dione (5b): White powder; yield 36%; mp 167.1–
169.3°C; 1H NMR: δ for Z-isomer (69%) 1.16 [d, J=6.0 Hz, 6H,
CH(CH3)2], 3.93–4.11 (m, 1H, OCH), 4.23 (s, 2H, NCH2), 7.10–
7.66 (m, 10H, PhH); δ for E-isomer (31%) 1.42 [d, J=6.0 Hz, 6H,
CH(CH3)2], 4.62–4.75 (m, 1H, OCH), 4.45 (s, 2H, NCH2), 7.10–7.66
(m, 10H, PhH); IR: 3455, 3061, 2972, 1698, 1585, 1500, 1433, 1378,
1229, 1177, 964 cm-1; MS (EI) m/z: 336 (M+), 276, 145, 105 (100),
77, 51, 45. Analysis: calculated for C20H20N2O3: C, 71.41; H, 5.99;
N, 8.33. Found: C, 71.26; H, 5.87; N, 8.11.
Experimental section
(Z,E)-3-[α-(Allyloxyamino)benzylidene]-1-phenylpyrrolidine-
2,4-dione (5c): White powder; yield 30%; mp 144.5–144.9°C; 1H
NMR: δ for Z-isomer (66%) 4.25 (s, 2H, NCH2), 4.38 (d, J=6.0 Hz,
2H, OCH2), 5.24–5.50 (m, 2H, CH=CH2), 5.78–5.91 (m, 1H,
CH=CH2), 7.05–7.64 (m, 10H, PhH); δ for E-isomer (34%) 4.40
(s, 2H, NCH2), 4.85 (d, J=6.0 Hz, 2H, OCH2), 5.24–5.50 (m, 2H,
CH=CH2), 6.09–6.18 (m, 1H, CH=CH2), 7.05–7.64 (m, 10H, PhH);
IR: 3451, 3053, 2916, 1698, 1573, 1501, 1439, 1377, 1227, 1158,
924 cm-1; MS (EI) m/z: 334 (M+), 276, 145, 105 (100), 77, 57, 45.
Melting points were determined on a WRS-1B digital melting-point
apparatus and are not corrected. The IR spectra were recorded on
a Bruker Tensor 27 FT-IR spectrometer in KBr disks. Elemental
analyses were performed on a Varian CHN analyzer. Mass spectra
(electron impact) were recorded on a GC/MS-QP2010 spectrometer
using direct injection technique. The 1H NMR spectra were taken on
a Mercury plus Varian-300 spectrometer at 300 MHz in CDCl3 with
TMS as the internal reference.
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76 X.-Q. Zheng et al.
Analysis: calculated for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38.
Found: C, 70.97; H, 5.86; N, 8.52.
PhCH3), 2.49–2.62 (m, 2H, PhCH2), 4.39 (s, 2H, NCH2), 4.88 (d,
J=6.3 Hz, 2H, OCH2), 5.25–5.51 (m, 2H, CH=CH2), 5.95–6.19 (m,
1H, CH=CH2), 7.12–7.75 (m, 8H, PhH); IR: 3023, 2971, 1686, 1581,
1470, 1418, 1216, 1185, 987 cm-1; MS (EI) m/z: 376 (M+), 318, 146,
132, 105, 69, 57 (100), 45. Analysis: calculated for C23H24N2O3: C,
73.38; H, 6.43; N, 7.44. Found: C, 72.96; H, 6.88; N, 7.57.
(Z,E)-3-[α-(Butoxyamino)benzylidene]-1-phenylpyrrolidine-
2,4-dione (5d): White powder; yield 30%; mp 144.5–144.9°C; 1H
NMR: δ for Z-isomer (67%) 0.81 (t, J=7.2 Hz, 3H, CH3), 1.15–1.22
(m, 2H, CH2CH3), 1.47–1.58 (m, 2H, OCH2CH2), 3.88 (t, J=5.4
Hz, 2H, OCH2), 4.20 (s, 2H, NCH2), 7.09–7.65 (m, 10H, PhH); δ
for E-isomer (33%) 0.99 (t, J=7.2 Hz, 3H, CH3), 1.36–1.41 (m, 2H,
CH2CH3), 1.77–1.95 (m, 2H, OCH2CH2), 4.39 (t, J=6.9 Hz, 2H,
OCH2), 4.43 (s, 2H, NCH2), 7.09–7.65 (m, 10H, PhH); IR: 3457,
3039, 2933, 1701, 1583, 1500, 1439, 1303, 1223, 1177, 960 cm-1;
MS (EI) m/z: 350 (M+), 276, 145, 105 (100), 77, 56, 45. Analysis:
calculated for C21H22N2O3: C, 71.89; H, 6.33; N, 7.99. Found: C,
71.97; H, 6.26; N, 7.72.
(Z,E)-3-[α-(Butoxyamino)benzylidene]-1-(2-ethyl-6-methyl-
phenyl)pyrrolidine-2,4-dione (5i): Pink powder; yield 33%; mp
1
142.8–145.2°C; H NMR: δ for Z-isomer (64%) 0.82 (t, J=7.2 Hz,
3H, CH2CH3), 1.23 (t, J=6.6 Hz, 3H, PhCH2CH3), 1.33–1.60 (m,
4H, CH2CH2), 2.21 (s, 3H, PhCH3), 2.56 (q, J=6.6 Hz, 2H, PhCH2),
3.88 (s, 2H, NCH2), 4.21 (t, J=6.0 Hz, 2H, OCH2), 7.12–7.73 (m, 8H,
PhH); δ for E-isomer (36%) 0.99 (t, J=6.6 Hz, 3H, CH2CH3), 1.23 (t,
J=7.5 Hz, 3H, PhCH2CH3), 1.68–1.93 (m, 4H, CH2CH2), 2.21 (s, 3H,
PhCH3), 2.56 (q, J=7.5 Hz, 2H, PhCH2), 4.00 (s, 2H, NCH2), 4.41 (t,
J=6.3 Hz, 2H, OCH2), 7.12–7.73 (m, 8H, PhH); IR: 3023, 2963, 1691,
1582, 1471, 1417, 1216, 1183, 976 cm-1; MS (EI) m/z: 392 (M+), 319,
174, 146 (100), 104, 77, 56. Analysis: calculated for C24H28N2O3: C,
73.44; H, 7.19; N, 7.14. Found: C, 73.23; H, 7.09; N, 7.32.
(Z,E)-3-[α-(Benzyloxyamino)benzylidene]-1-phenylpyrro-
lidine-2,4-dione (5e): White powder; yield 40%; mp 177.0–
1
177.8°C; H NMR: δ for Z-isomer (60%) 4.21 (s, 2H, NCH2), 4.89
(s, 2H, OCH2), 7.04–7.76 (m, 15H, PhH); δ for E-isomer (40%) 4.39
(s, 2H, NCH2), 5.39 (s, 2H, OCH2), 7.04–7.76 (m, 15H, PhH); IR:
3063, 2926, 1701, 1585, 1501, 1442, 1379, 1230, 1178, 954 cm-1;
MS (EI) m/z: 384 (M+), 276, 145, 105 (100), 77, 52. Analysis: calcu-
lated for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29. Found: C, 74.97;
H, 5.26; N, 7.63.
(Z,E)-3-[α-(Benzyloxyamino)benzylidene]-1-(2-ethyl-6-methyl-
phenyl)pyrrolidine-2,4-dione (5j): White powder; yield 36%; mp
1
171.3–177.0°C; H NMR: δ for Z-isomer (63%) 1.22 (t, J=6.9 Hz,
3H, PhCH2CH3), 2.19 (s, 3H, PhCH3), 2.48–2.59 (m, 2H, PhCH2),
4.02 (s, 2H, NCH2), 4.88 (s, 2H, OCH2), 7.12–7.76 (m, 13H, PhH); δ
for E-isomer (37%) 1.22 (t, J=7.5 Hz, 3H, PhCH2CH3), 2.19 (s, 3H,
PhCH3), 2.48–2.59 (m, 2H, PhCH2), 4.15 (s, 2H, NCH2), 5.41 (s, 2H,
OCH2), 7.12–7.76 (m, 13H, PhH); IR: 3032, 2971, 1695, 1581, 1469,
1391, 1213, 1178, 971 cm-1; MS (EI) m/z: 426 (M+), 320, 146, 132,
108, 91 (100), 51. Analysis: calculated for C27H26N2O3: C, 76.03; H,
6.14; N, 6.57. Found: C, 76.14; H, 6.16; N, 6.44.
(Z,E)-1-(2-Ethyl-6-methylphenyl)-3-[α-(propoxyamino)ben-
zylidene]pyrrolidine-2,4-dione (5f): Pink powder; yield 23%; mp
1
155.9–157.5°C; H NMR: δ for Z-isomer (61%) 0.77 (t, J=7.8 Hz,
3H, CH2CH3), 1.22 (t, J=6.0 Hz, 3H, PhCH2CH3), 1.51–1.62 (m,
2H, CH2CH3), 2.20 (s, 3H, PhCH3), 2.49–2.60 (m, 2H, PhCH2), 3.85
(t, J=6.3 Hz, 2H, OCH2), 3.99 (s, 2H, NCH2), 7.11–7.73 (m, 8H,
PhH); δ for E-isomer (39%) 0.93 (t, J=7.5 Hz, 3H, CH2CH3), 1.22
(t, J=6.0 Hz, 3H, PhCH2CH3), 1.85–1.94 (m, 2H, CH2CH3), 2.20 (s,
3H, PhCH3), 2.49–2.60 (m, 2H, PhCH2), 4.19 (s, 2H, NCH2), 4.36
(t, J=6.3 Hz, 2H, OCH2), 7.11–7.73 (m, 8H, PhH); IR: 3450, 3023,
1681, 1582, 1500, 1475, 1372, 1227, 1157, 960 cm-1; MS (EI) m/z:
378 (M+, 100), 319, 146, 132, 77, 58, 45. Analysis: calculated for
C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.87; H, 6.88;
N, 7.51.
(Z,E)-1-(2-Ethoxyphenyl)-3-[α-(propoxyamino)benzylidene]-
pyrrolidine-2,4-dione (5k): White powder; yield 36%; mp
1
152.4–153.5oC; H NMR: δ for Z-isomer (68%) 0.77 (t, J=7.2 Hz,
3H, CH2CH3), 1.40 (t, J=7.5 Hz, 3H, OCH2CH3), 1.52–1.60 (m,
2H, CH2CH3), 3.83 (t, J=6.3 Hz, 2H, OCH2), 4.06 (q, J=6.9 Hz, 2H,
OCH2CH3), 4.45 (s, 2H, NCH2), 6.91–7.70 (m, 9H, PhH); δ for E-
isomer (32%) 0.93 (t, J=7.5 Hz, 3H, CH2CH3), 1.40 (t, J=6.9 Hz,
3H, OCH2CH3), 1.67–1.75 (m, 2H, CH2CH3), 4.06 (q, J=7.5 Hz,
2H, OCH2CH3), 4.19 (t, J=6.3 Hz, 2H, OCH2), 4.58 (s, 2H, NCH2),
6.91–7.70 (m, 9H, PhH); IR: 3045, 2953, 1680, 1608, 1502, 1391,
1229, 1167, 914 cm-1; MS (EI) m/z: 380 (M+), 320, 120 (100), 103,
77, 65, 45. Analysis: calculated for C22H24N2O4: C, 69.46; H, 6.36;
N, 7.36. Found: C, 69.32; H, 6.53; N, 7.28.
(Z,E)-1-(2-Ethyl-6-methylphenyl)-3-[α-(isopropoxyamino)ben-
zylidene]pyrrolidine-2,4-dione (5g): White powder; yield 22%;
mp 159.4–163°C; 1H NMR: δ for Z-isomer (64%) 1.14 [d, J=6.0 Hz,
6H, CH(CH3)2], 1.22 (t, J=5.1 Hz, 3H, PhCH2CH3), 2.20 (s, 3H,
PhCH3), 2.49–2.61 (m, PhCH2), 3.99 (s, 2H, NCH2), 4.68–4.77 (m,
1H, OCH), 7.08–7.77 (m, 8H, PhH); δ for E-isomer (36%) 1.22 (t,
J=7.5 Hz, 3H, PhCH2CH3), 1.43 [d, J=6.3 Hz, 6H, CH(CH3)2], 2.20
(s, 3H, PhCH3), 2.49–2.61 (m, 2H, PhCH2), 4.19 (s, 2H, NCH2),
4.49–4.55 (m, 1H, OCH), 7.08–7.77 (m, 8H, PhH); IR: 3451, 3030,
2978, 1686, 1580, 1500, 1389, 1221, 1178, 981 cm-1; MS (EI)
m/z: 378 (M+, 100), 319, 146, 132, 77, 45. Analysis: calculated for
C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.92; H, 6.76;
N, 7.62.
(Z,E)-1-(2-Ethoxyphenyl)-3-[α-(isopropoxyamino)benzylidene]-
pyrrolidine-2,4-dione (5l): White powder; yield 34%; mp 153.0–
153.9°C; 1H NMR: δ for Z-isomer (64%) 1.17 [d, J=6.0 Hz, 6H,
CH(CH3)2], 1.45 (t, J=6.3 Hz, 3H, OCH2CH3), 4.06 (q, J=6.9 Hz,
2H, OCH2CH3), 4.25 (s, 2H, NCH2), 4.68 (m, 1H, OCH), 6.92–
7.73 (m, 9H, PhH); δ for E-isomer (36%) 1.29 [d, J=6.3 Hz, 6H,
CH(CH3)2], 1.45 (t, J=6.9 Hz, 3H, OCH2CH3), 4.06 (q, J=6.3 Hz,
2H, OCH2CH3), 4.47 (s, 2H, NCH2), 4.74 (m, 1H, OCH), 6.92–7.73
(m, 9H, PhH); IR: 3450, 3033, 2976, 1677, 1610, 1500, 1389, 1229,
1173, 925 cm-1; MS (EI) m/z: 380 (M+), 320, 120 (100), 103, 77,
45. Analysis: calculated for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36.
Found: C, 69.35; H, 6.50; N, 7.21.
(Z,E)-3-[α-(Allyloxyamino)benzylidene]-1-(2-ethyl-6-methyl-
phenyl)pyrrolidine-2,4-dione (5h): White powder; yield 19%;
mp 168.5–169.1°C; 1H NMR: δ for Z-isomer (68%) 1.20 (t, J=7.5 Hz,
3H, PhCH2CH3), 2.20 (s, 3H, PhCH3), 2.49–2.62 (m, 2H, PhCH2),
4.05 (s, 2H, NCH2), 4.76 (d, J=7.5 Hz, 2H, OCH2), 5.25–5.51 (m, 2H,
CH=CH2), 5.79–5.91 (m, 1H, CH=CH2), 7.12–7.75 (m, 8H, PhH); δ
for E-isomer (32%) 1.20 (t, J=7.5 Hz, 3H, PhCH2CH3), 2.20 (s, 3H,
(Z,E)-3-[α-(Allyloxyamino)benzylidene]-1-(2-ethoxyphenyl)-
pyrrolidine-2,4-dione (5m):
White powder; yield 33%; mp
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Synthesis and bioactivity of novel pyrrolidine-2,4-diones 77
1
(Z,E)-3-[α-(Allyloxyamino)benzylidene]-1-(2,6-dimethylphe-
nyl)pyrrolidine-2,4-dione (5r): White powder; yield 20%; mp
160.7–161.2oC; 1H NMR: δ for Z-isomer (68%) 2.20 (s, 6H, 2PhCH3),
4.03 (s, 2H, NCH2), 4.75 (d, J=6.0 Hz, 2H, OCH2), 5.33–5.38 (m, 2H,
CH=CH2), 5.79–5.96 (m, 1H, CH=CH2), 7.09–7.72 (m, 8H, PhH);
δ for E-isomer (32%) 2.20 (s, 6H, 2PhCH3), 4.39 (s, 2H, NCH2), 4.86
(d, J=6.9 Hz, 2H, OCH2), 5.43–5.49 (m, 2H, CH=CH2), 6.04–6.22
(m, 1H, CH=CH2), 7.09–7.72 (m, 8H, PhH); IR (KBr) ν/cm-1: 3024,
2972, 1677, 1585, 1477, 1414, 1211, 1178, 910 cm-1; MS (EI) m/z:
362 (M+), 306, 174, 144, 132 (100), 102, 77, 57. Analysis: calculated
for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C, 72.79; H,
6.33; N, 7.70.
136.0–137.7°C; H NMR: δ for Z-isomer (65%) 1.39 (t, J=6.9 Hz,
3H, OCH2CH3), 4.05 (q, J=6.9 Hz, 2H, OCH2CH3), 4.45 (s, 2H,
NCH2), 4.75 (d, J=6.3 Hz, 2H, OCH2), 5.20–5.33 (m, 2H, CH=CH2),
5.75–5.99 (m, 1H, CH=CH2), 6.92–8.02 (m, 9H, PhH); δ for E-
isomer (35%) 1.47 (t, J=6.9 Hz, 3H, OCH2CH3), 4.14 (q, J=6.9 Hz,
2H, OCH2CH3), 4.59 (s, 2H, NCH2), 4.89 (d, J=6.0 Hz, 2H, OCH2),
5.35–5.51 (m, 2H, CH=CH2), 6.07–6.20 (m, 1H, CH=CH2), 6.92–
8.02 (m, 9H, PhH); IR: 3452, 3025, 2982, 1676, 1606, 1501, 1391,
1229, 1102, 924 cm-1; MS (EI) m/z: 378 (M+), 320, 120, 103 (100),
77, 57. Analysis: calculated for C22H22N2O4: C, 69.83; H, 5.86; N,
7.40. Found: C, 69.81; H, 5.67; N, 7.25.
(Z,E)-3-[α-(Butoxyamino)benzylidene]-1-(2-ethoxyphenyl)-
pyrrolidine-2,4-dione (5n): White powder; yield 43%; mp
157.6–158.1°C; H NMR: δ for Z-isomer (64%) 0.82 (t, J=7.2 Hz,
(Z,E)-3-[α-(Butoxyamino)benzylidene]-1-(2,6-dimethylphenyl)-
pyrrolidine-2,4-dione (5s): White powder; yield 27%; mp 152.8–
155.9oC; 1H NMR: δ for Z-isomer (62%) 0.81 (t, J=7.2 Hz, 3H,
CH2CH3), 1.18–1.48 (m, 4H, OCH2CH2), 2.21 (s, 6H, 2PhCH3), 3.89
(t, J=6.6 Hz, 2H, OCH2), 3.99 (s, 2H, NCH2), 7.09–7.72 (m, 8H, PhH);
δ for E-isomer (38%) 0.97 (t, J=6.9 Hz, 3H, CH2CH3), 1.49–1.86 (m,
4H, OCH2CH2), 2.28 (s, 6H, 2PhCH3), 4.23 (s, 2H, NCH2), 4.37 (t,
J=6.6 Hz, 2H, OCH2), 7.09–7.72 (m, 8H, PhH); IR: 3450, 3068, 2955,
1682, 1610, 1501, 1390, 1229, 1182, 924 cm-1; MS (EI) m/z: 378 (M+),
306 (100), 132, 103, 77, 55. Analysis: calculated for C23H26N2O3: C,
72.99; H, 6.92; N, 7.40. Found: C, 72.66; H, 6.97; N, 7.68.
1
3H, CH2CH3), 1.22–1.50 (m, 4H, CH2CH2), 1.42 (t, J=7.5 Hz, 3H,
OCH2CH3), 3.88 (t, J=6.3 Hz, 2H, OCH2), 4.15 (q, J=6.9 Hz, 2H,
OCH2CH3), 4.26 (s, 2H, NCH2), 6.92–7.70 (m, 9H, PhH); δ for E-
isomer (36%) 0.93 (t, J=7.2 Hz, 3H, CH2CH3), 1.44 (t, J=7.5 Hz,
3H, OCH2CH3), 1.53–1.84 (m, 4H, CH2CH2), 4.03 (t, J=6.3 Hz,
2H, OCH2), 4.46 (q, J=7.5 Hz, 2H, OCH2CH3), 4.61 (s, 2H, NCH2),
6.92–7.70 (m, 9H, PhH); IR: 3441, 3023, 2955, 1683, 1610, 1502,
1391, 1230, 1121, 924 cm-1; MS (EI) m/z: 394 (M+), 279, 167, 149,
81, 69 (100), 53. Analysis: calculated for C23H26N2O4: C, 70.03; H,
6.64; N, 7.10. Found: C, 69.92; H, 6.67; N, 7.23.
(Z,E)-3-[α-(Propoxyamino)benzylidene]-1-(p-tolyl)pyrrolidine-
2,4-dione (5t): White powder; yield 33%; mp 158.8–159.8oC;
1H NMR: δ for Z-isomer (64%) 0.79 (t, J=7.2 Hz, 3H, CH2CH3),
1.54–1.61 (m, 2H, CH2CH3), 2.33 (s, 3H, PhCH3), 3.85 (t, J=6.3 Hz,
2H, OCH2), 4.19 (s, 2H, NCH2), 7.14–7.71 (m, 9H, PhH); δ for E-
isomer (36%) 1.04 (t, J=7.2 Hz, 3H, CH2CH3), 1.83–1.90 (m, 2H,
CH2CH3), 2.39 (s, 3H, PhCH3), 4.35 (t, J=6.3 Hz, 2H, OCH2), 4.40
(s, 2H, NCH2), 7.14–7.71 (m, 9H, PhH); IR: 3025, 2966, 1699, 1581,
1515, 1442, 1379, 1226, 1175, 971 cm-1; MS (EI) m/z: 350 (M+), 290
(100), 119, 91, 77, 57, 45. Analysis: calculated for C21H22N2O3: C,
71.98; H, 6.33; N, 7.99. Found: C, 72.04; H, 6.25; N, 7.82.
(Z,E)-3-[α-(Benzyloxyamino)benzylidene]-1-(2-ethoxyphenyl)-
pyrrolidine-2,4-dione (5o): White powder; yield 47%; mp 162.8–
162.9°C; 1H NMR: δ for Z-isomer (69%) 1.34 (t, J=7.5 Hz, 3H,
OCH2CH3), 4.03 (q, J=7.5 Hz, 2H, OCH2CH3), 4.28 (s, 2H, NCH2),
4.87 (s, 2H, OCH2), 6.89–7.72 (m, 14H, PhH); δ for E-isomer (31%)
1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 4.05 (q, J=7.5 Hz, 2H, OCH2CH3),
4.40 (s, 2H, NCH2), 5.38 (s, 2H, OCH2), 6.89–7.72 (m, 14H, PhH);
IR: 3026, 2984, 1682, 1609, 1501, 1391, 1229, 1125, 949 cm-1; MS
(EI) m/z: 428 (M+), 322, 120, 105, 77 (100), 65. Analysis: calculated
for C26H24N2O4: C, 72.88; H, 5.65; N, 6.54. Found: C, 72.75; H,
5.47; N, 6.39.
(Z,E )-1-(2,6-Dimethylphenyl)-3-[α-(propoxyamino)ben-
zylidene]pyrrolidine-2,4-dione (5p): White powder; yield 29%;
mp 159.0–160.2oC; 1H NMR: δ for Z-isomer (61%) 0.84 (t, J=7.2 Hz,
3H, CH2CH3), 1.45–1.53 (m, 2H, CH2CH3), 2.17 (s, 6H, 2PhCH3),
3.74 (t, J=7.5 Hz, 2H, OCH2), 3.89 (s, 2H, NCH2), 7.05–7.53 (m, 8H,
PhH); δ for E-isomer (39%) 1.04 (t, J=7.2 Hz, 3H, CH2CH3), 1.60–
1.69 (m, 2H, CH2CH3), 2.17 (s, 6H, 2PhCH3), 4.37 (t, J=7.5 Hz,
2H, OCH2), 4.09 (s, 2H, NCH2), 7.05–7.53 (m, 8H, PhH); IR: 3444,
3022, 2966, 1700, 1585, 1474, 1391, 1220, 1184, 961 cm-1; MS (EI)
m/z: 364 (M+), 305, 174, 132 (100), 117, 104, 77, 57. Analysis: cal-
culated for C22H24N2O3: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.66;
H, 6.52; N, 7.80.
Acknowledgments
This work was supported by the National High Technology Research
and Development Program of China (2006AA10A214), and the
Fundamental Research Funds for the Central Universities of China
(KYZ200918). We are grateful to Lu, A.M. for MS analysis.
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Received March 27, 2011; accepted April 24, 2011
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