Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-substituted- pyrrolidine-2,4-dione derivatives

Article abstract of DOI:10.1016/j.cclet.2012.07.002

Ten novel 5-substituted derivatives of 3-(1-hydroxyethylidene)pyrrolidine- 2,4-dione were synthesized. The compounds were confirmed by IR, ¹H NMR, MS and elemental analysis. The bioassay indicated that these compounds showed noticeable herbicid

Full text of DOI:10.1016/j.cclet.2012.07.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1023–1026
www.elsevier.com/locate/cclet
Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-
substituted-pyrrolidine-2,4-dione derivatives
Bao Feng Han a,b, Qing Ming Shi a,b, Xian Feng Wang a,b, Jian Bo Liu b,
Sheng Qiang c, Chun Long Yang a,b,
*
a Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Ministry of Agriculture, Nanjing Agricultural University,
Nanjing 210095, China
b Jiangsu Key Laboratory of Pesticide Science, Nanjing Agricultural University, Nanjing 210095, China
c College of Life Science, Nanjing Agricultural University, Nanjing 210095, China
Received 7 May 2012
Available online 18 July 2012
Abstract
Ten novel 5-substituted derivatives of 3-(1-hydroxyethylidene)pyrrolidine-2,4-dione were synthesized. The compounds were
confirmed by IR, 1H NMR, MS and elemental analysis. The bioassay indicated that these compounds showed noticeable herbicidal
activities, and compounds 6f and 6j exhibited excellent inhibitory activities against the stalk of Echinochloa crusgalli, with EC50
values of 94.4 and 72.7 mg/L, respectively.
# 2012 Chun Long Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Tenuazonic acid; Pyrrolidine-2,4-dione; Synthesis; Herbicidal activity
Natural tetramic acids with a heterocyclic core of pyrrolidine-2,4-dione have been found to exhibit remarkable
antibiotic or antiviral activity [1,2]. A superior example, tenuazonic acid (5-sec-butyl-3-(1-hydroxyethylidene)-
pyrrolidine-2,4-dione, TeA), which is isolated from Alternaria tenuis [3,4], was an attractive representative because of
its broad spectrum bioactivities, including antitumor, antibiotic, insecticidal, antiviral and herbicidal activities [5–11].
Its herbicidal activity has especially evoked the interest of agrochemists. TeA exhibited the ability to kill the seedlings
of mono- and dicotyledonous weeds [12,13]. Further studies indicated that TeA is a new type of inhibitor against
photosystem II, interfering with electron transport from QA to QB [14]. In addition, TeA was easily degradable, with a
half-life of approximately 3.22 days under field conditions and a residual period of 20 days in soil [15].
Series of pyrrolidine-2,4-dione derivatives were designed and synthesized, and many compounds showed
remarkable herbicidal activities [16–21]. Current research showed that the substituted groups at the 5-position of
tetramic acid played an important role in affecting the herbicidal activity [14]. In this article, alkyl, substituted benzyl,
cinnamyl and hypnone groups were introduced at the 5-postion of the heterocyclic pyrrolidine to synthesize a series of
* Corresponding author at: Key Laboratory of Monitoring and Management of Crop Diseases and Pest Insects, Ministry of Agriculture, Nanjing
Agricultural University, Nanjing 210095, China.
E-mail address: chunlongyang@yahoo.com.cn (C.L. Yang).
1001-8417/$ – see front matter # 2012 Chun Long Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.07.002

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B.F. Han et al. / Chinese Chemical Letters 23 (2012) 1023–1026
3-(1-hydroxyethylidene)-5-substituted-pyrrolidine-2,4-dione derivatives. These modifications were expected to
improve the herbicidal activity.
1. Experimental
The melting points of the products were determined on a WRS-1B digital melting point apparatus. IR spectra were
recorded on a Bruker Tensor 27 FT-IR spectrometer with a KBr disk. Elemental analyses were performed on an
Elementar Vario-III CHN analyser. Mass spectra were recorded on a GC/MS-QP2010 spectrometer using a direct
1
injection technique. H NMR spectra were taken on a Bruker AV 400MHz spectrometer with TMS as the internal
reference and CDCl3 as the solvent.
The synthetic routes for the title compounds were illustrated in Scheme 1. KOH (50 mmol), K2CO3 (50 mmol) and
TEBA (5 mmol) were suspended in 100 mL dichloromethane (or acetonitrile when R1 = alkyl). A solution of aldimine
1 (30 mmol), which was prepared according to the reported method [22], and halide 2 (30 mmol) in 15 mL
dichloromethane (or acetonitrile when R1 = alkyl) was added gently. The mixture was refluxed for 10 h. After
terminating the reaction, the mixture was filtered and the filtrate was concentrated to obtain a yellow liquid 3. The
intermediate 3 was dissolved in ether and washed with saturated salt solution. The combined organic layer was then
added to 100 mL 4% HCl aqueous solution and stirred over night at room temperature. The water layer was
concentrated after extraction with ether, and the yellow residue was recrystallized with MeOH to give the intermediate
4 [23]. The next steps were followed by the reported method [20,21] to obtain the title compounds 6a–j with yields of
60–76% based on the intermediate 4.
(1)
H
C
H
C
1
CH COOCH
N
N
CHCOOCH
+
R CH X
2
3
3
2
1
CH R
2
1
2a-j
3
HN COCH COCH
3
(3)
2
(2)
H N
HCl
CHCOOCH
2
3
CHCOOCH
3
O
1
CH R
H C
(4)
2
O
1
2
CH R
2
4
5
O
O
CH
3
CH
OH
3
OH
N
N
H
6f-g
3
R
O
N
2
O
R
H
O
(5)
(6)
6a-e
O
O
CH
CH
3
3
( )
n
OH
N
OH
O
O
H
H
6i-j
6h
Scheme 1. (2a) R1 = 4-Cl-C6H4, X = Cl; (2b) R1 = 2-Cl-C6H4, X = Cl; (2c) R1 = 4-NO2-C6H4, X = Cl; (2d) R1 = 4-CH3O-C6H4, X = Cl; (2e)
R1 = 2,4-Cl2-C6H3, X = Cl; (2f) R1 = 4-CH3O-C6H4CO, X = Br; (2g) R1 = C6H5CO, X = Br; (2h) R1 = C6H5CH = CH, X = Cl; (2i) R1 = n-C3H7,
X = Br; (2j) R1 = n-C5H11, X = Br; (6a) R2 = 4-Cl; (6b) R2 = 2-Cl; (6c) R2 = 4-NO2; (6d) R2 = 4-CH3O; (6e) R2 = 2,4-Cl2, (6f) R3 = 4-CH3O; (6g)
R3 = H; (6i) n = 2; (6j) n = 4. Condition and regent: (1) KOH, K2CO3, TEBA; (2) 4% HCl; (3) CH3ONa; (5) CH3ONa, CH3OH; (6) 20% HCl.

B.F. Han et al. / Chinese Chemical Letters 23 (2012) 1023–1026
1025
Table 1
Herbicidal activities of the target compounds against E. crusgalli and B. campestris (100 mg/L, inhibitory %).a
Compd.
E. crusgalli
B. campestris
Compd.
E. crusgalli
B. campestris
Stalk
Root
Root
Stalk
Root
Root
6a
6b
6c
6d
6e
6f
37.8 Æ 3.1
35.7 Æ 7.2
41.6 Æ 3.5
41.2 Æ 1.1
19.1 Æ 1.4
62.6 Æ 6.8
49.6 Æ 7.4
37.3 Æ 6.6
64.3 Æ 1.1
32.8 Æ 5.1
31.6 Æ 3.8
61.5 Æ 3.3
89.7 Æ 0.8
41.8 Æ 6.6
45.7 Æ 8.2
62.9 Æ 2.4
59.3 Æ 5.3
45.9 Æ 3.6
6g
6h
6i
36.4 Æ 5.3
42.5 Æ 6.6
32.3 Æ 3.5
66.9 Æ 7.8
51.0 Æ 1.6
47.9 Æ 5.1
54.0 Æ 8.6
38.5 Æ 4.2
47.8 Æ 6.0
91.0 Æ 1.2
66.9 Æ 6.3
90.4 Æ 2.0
46.3 Æ 4.2
43.1 Æ 9.1
96.5 Æ 0.7
6j
TeA
a
Values are the mean Æ S.D. of three replicates.
2. Results and discussion
1
The structure of all the target compounds was confirmed by IR, H NMR, MS and elemental analysis. The IR
spectrum showed peaks at 3338–3456 cmÀ1 due to OH group at the 3-postion of the heterocyclic pyrrolidine, peaks at
3173–3232 cmÀ1 due to N–H stretching vibration, and peaks at 1611–1718 cmÀ1 assigned to the carbonyl groups. The
1H NMR spectrum of all the target compounds showed a peak at d 2.47–2.52 ppm for CH3 proton at the 3-postion of
the pyrrolidine, peaks between d 6.04 and 6.59 ppm for the proton of N–H, and broad peaks between d 11.16 and
12.38 ppm for the proton of OH group. Moreover, 9 target compounds showed [M+] or [M++2] peaks except
compound 6e. And all the elemental analysis data matched the molecular formulas of target compounds.
All the synthesized target compounds were evaluated for herbicidal activities against Brassica campestris and
Echinochloa crusgalli at the concentration of 100 mg/L [20,24]. The results were summarized in Table 1. All the
compounds showed moderate to excellent herbicidal activities. Most compounds exhibited better activities against the
root than the stalk, similar to the leading compound TeA. The inhibitive activities of compounds 6f and 6j against the
stalk of E. crusgalli were 62.6% and 66.9%, respectively, higher than that of TeA, which demonstrated an inhibition
rate of 51.0%. The inhibitive activities of compounds 6a and 6h against the root of B. campestris were 89.7% and
90.4%, respectively.
The EC50 values of some selected compounds were determined. The results showed that the EC50 values of
compounds 6f and 6j against the stalk of E. crusgalli were 94.4 and 72.7 mg/L respectively, these values were lower
than the EC50 97.7 mg/L of TeA. Compounds 6a and 6h gave the EC50 values 25.5 and 39.2 mg/L against the root of B.
campestris respectively, but these values were higher than that 15.0 mg/L of TeA.
The structure–activity relationships of these target compounds revealed that modifying the 5-postion of the
heterocyclic pyrrolidine-2,4-dione and introducing proper chemical groups was a feasible route in designing new
pesticide compounds with TeA as a leading compound.
Acknowledgments
This work was financially supported by the National High-Tech R&D Program of China (863 Program, No.
2011AA10A206) and the National Key Technologies R&D Program of China (No. 2011BAE06B04).
Appendix A
The title compounds were prepared according to the reported procedure [20–23]. Selected characterization data: (6a):
Colourless powder; mp: 175.6–176.4 8C; IR (KBr, cmÀ1) n: 3345, 3203, 1716, 1692, 1647; 1H NMR (400 MHz, CDCl3):
d 11.68 (br, 1H, OH), 7.29 (d, 2H, J = 8.3 Hz, ArH), 7.13 (d, 2H, J = 8.3 Hz, ArH), 6.36 (br, 1H, CHNH), 4.01 (dd, 1H,
J = 9.6, 3.7 Hz, CHNH), 3.23 (dd, 1H, J = 14.0, 3.7 Hz, ArCH2), 2.69 (dd, 1H, J = 14.0, 9.6 Hz, ArCH2), 2.47 (s, 3H,
CH3CO); MS: m/z (%): 265 [M+] (33). (6b): Colourless powder; mp: 130.1–132.2 8C; IR (KBr, cmÀ1) n: 3341, 3203,
1719, 1658, 1613; 1H NMR (400 MHz, CDCl3): d 12.05 (br, 1H, OH), 7.41–7.25 (m, 4H, ArH), 6.24 (br, 1H, CHNH),
4.20 (dd, 1H, J = 9.5, 3.4 Hz, CHNH), 3.54 (dd, 1H, J = 14.0, 3.5 Hz, ArCH2), 2.82 (dd, 1H, J = 13.8, 9.7 Hz, ArCH2),
2.51 (s, 3H, CH3CO); MS: m/z (%): 265 [M+] (4). (6c): Colourless powder; mp: 180.1–182.0 8C; IR (KBr, cmÀ1) n: 3350,

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B.F. Han et al. / Chinese Chemical Letters 23 (2012) 1023–1026
3210, 1713, 1661, 1612; 1H NMR (400 MHz, CDCl3): d 11.90 (br, 1H, OH), 8.20 (d, 2H, J = 8.1 Hz, ArH), 7.40 (d, 2H,
J = 8.3 Hz, ArH), 6.43 (br, 1H, CHNH), 4.12 (dd, 1H, J = 8.7, 3.4 Hz, CHNH), 3.37 (dd, 1H, J = 13.9, 3.7 Hz, ArCH2),
2.93 (dd, 1H, J = 14.0, 9.0 Hz, ArCH2), 2.49 (s, 3H, CH3CO); MS: m/z (%): 278 [M++2] (8). (6d): Colourless powder;
mp: 163.2–164.1 8C; IR (KBr, cmÀ1) n: 3338, 3217, 1706, 1671; 1H NMR (400 MHz, CDCl3): d 12.21 (br, 1H, OH), 7.14
(d, 2H, J = 8.0 Hz, ArH), 6.88(d, 2H, J = 8.1 Hz, ArH), 6.09(br, 1H, CHNH), 4.01(dd, 1H, J = 9.8, 2.4 Hz, CHNH), 3.82
(s, 3H,OCH3), 3.25(dd, 1H, J = 13.9, 4.3 Hz, ArCH2), 2.65(dd, 1H, J = 12.7, 3.2 Hz, ArCH2), 2.49(s,3H,CH3CO);MS:
m/z (%): 261 [M+] (3). (6e): Colourless powder; mp: 182.5–184.0 8C; IR (KBr, cmÀ1) n: 3354, 3173, 1711, 1670, 1611;
1H NMR (400 MHz, CDCl3): d 12.38 (br, 1H, OH), 7.29 (s, 1H, ArH), 7.23 (d, 1H, J = 8.4 Hz, ArH), 7.18 (d, 1H,
J = 8.2 Hz, ArH), 6.04 (br, 1H, CHNH), 4.17 (dd, 1H, J = 8.8, 3.5 Hz, CHNH), 3.48 (dd, 1H, J = 13.9, 3.6 Hz, ArCH2),
2.85 (dd, 1H, J = 13.9, 9.1 Hz, ArCH2), 2.51 (s, 3H, CH3CO); MS: m/z (%): 281 (1). (6f): Yellow powder; mp: 160.6–
162.0 8C; IR (KBr, cmÀ1) n: 3430, 3216, 1706, 1671, 1626; 1H NMR (400 MHz, CDCl3): d 11.42 (br, 1H, OH), 7.95 (d,
2H, J = 8.6 Hz, ArH), 6.97 (d, 2H, J = 8.7 Hz, ArH), 6.59 (br, 1H, CHNH), 4.32 (d, 1H, J = 10.9 Hz, CHNH), 3.91 (s, 3H,
OCH3), 3.76 (d, 1H, J = 18.1 Hz, COCH2), 3.01 (dd, 1H, J = 18.1, 11.1 Hz, COCH2), 2.51 (s, 3H, CH3CO); MS: m/z (%):
289 [M+] (2). (6g): Colourless powder; mp: 166.0–167.4 8C; IR (KBr, cmÀ1) n: 3451, 3232, 1711, 1664, 1624; 1H NMR
(400 MHz, CDCl3): d 11.62 (br, 1H, OH), 7.98 (d, 2H, J = 7.7 Hz, ArH), 7.64 (t, 1H, J = 7.3 Hz, ArH), 7.52 (t, 2H,
J = 7.5 Hz, ArH), 6.51 (br, 1H, CHNH), 4.34 (d, 1H, J = 10.9 Hz, CHNH), 3.82 (d, 1H, J = 18.3 Hz, COCH2), 3.07 (dd,
1H, J = 18.4, 11.0 Hz, COCH2). 2.52 (s, 3H, CH3CO); MS: m/z (%): 259 [M+] (5). (6h): Colourless powder; mp: 151.1–
151.6 8C; IR(KBr, cmÀ1) n: 3367, 3200, 1718, 1660, 1611;1H NMR(400 MHz, CDCl3):d 11.71(br, 1H, OH), 7.37–7.26
(m, 5H, ArH), 6.53 (d, 1H, J = 15.7 Hz, ArCH), 6.35 (br, 1H, CHNH), 6.21–6.05 (m, 1H, ArCHCH), 3.95 (d, 1H,
J = 8.5 Hz, CHNH), 2.88(d, 1H, J = 13.9 Hz, CHCHCH2), 2.49(s, 3H, CH3CO), 2.45–2.35(m, 1H, CHCHCH2);MS:m/
z (%): 257 [M+] (2). (6i): Colourless powder; mp: 85.2–86.2 8C; IR (KBr, cmÀ1) n: 3443, 3206, 1711, 1654, 1619; 1H
NMR (400 MHz, CDCl3): d 12.37 (br, 1H, OH), 6.51 (br, 1H, CHNH), 3.83 (t, 1H, J = 4.0 Hz, CHNH), 2.49 (s, 3H,
CH3CO), 1.92–1.54 (m, 2H, C3H7CH2), 1.47–1.24 (m, 4H. CH3C2H4), 0.94 (t, 3H, J = 7.6 Hz, CH3CH2); MS: m/z (%):
197 [M+] (14). (6j): Colourless powder; mp: 86.6–88.1 8C; IR (KBr, cmÀ1) n: 3456, 3207, 1712, 1655, 1611; 1H NMR
(400 MHz, CDCl3): d 11.16 (br, 1H, OH), 6.41 (br, 1H, CHNH), 3.82 (t, 1H, J = 4.0 Hz, CHNH), 2.49 (s, 3H, CH3CO),
1.90–1.55 (m, 1H, C5H11CH2), 1.70–1.55 (m, 1H, C5H11CH2), 1.48–1.22 (m, 8H, CH3C4H8), 0.90 (t, 3H, J = 8.4 Hz,
CH3CH2); MS: m/z (%): 225 [M+] (18).
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