A facile synthesis of novel herbicidal 1-phenyl-piperazine-2,6-diones

Article abstract of DOI:10.3390/10091119

Novel 1-phenyl-piperazine-2,6-diones were prepared by a new facile synthetic route using methyl N-substituted iminomonoacetate as starting material. The structures of these compounds were established by ¹H-NMR, ¹³C-NMR and GC/MS. 2-(

Full text of DOI:10.3390/10091119

Molecules 2005, 10, 1119-1125
molecules
ISSN 1420-3049
http://www.mdpi.org
A Facile Synthesis of Novel Herbicidal 1-Phenyl-piperazine-2,6-diones
Bin Li 1,2, Dong Xiang 2, Chi-Tung Hsu 3, Zhen-Long Liu 2, Chao Wu 1 and Hua-Zheng Yang 1,*
1
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China
2
Agrochemicals Division, Shenyang Research Institute of Chemical Industry, Shenyang, 110021,
China
3
Applied Chemistry Department, Chaoyang University of Technology, Taichung, 41349, Taiwan,
China
* Author to whom correspondence should be addressed; email: libinjia@yahoo.com.cn
Received: 23 April 2005 / Published: 30 September 2005
Abstract: Novel 1-phenyl-piperazine-2,6-diones were prepared by a new facile synthetic route
using methyl N-substituted iminomonoacetate as starting material. The structures of these
compounds were established by 1H-NMR, 13C-NMR and GC/MS. 2-(4-Chloro-5-cyclo-pentyl-
oxy-2-fluorophenyl)-tetrahydro-2H-pyrido-[1,2-a]-pyrazine-1,3-(4H,6H)-dione displayed the
greatest herbicidal activity.
Keywords: 1-Phenyl-piperazine-2,6-dione; 2-phenyl-tetrahydro-2H-pyrido-[1,2-a]-pyrazine-
1,3-(4H,6H)-dione; 2-phenyl-tetrahydropyrrolo[1,2-a]pyrazine-1,3(2H,4H)- dione; herbicide;
synthesis.
Introduction
The N-substituted phenyl heterocyclic carboxamides are an important class of herbicides as
protoporphyrinogen-IX oxidase inhibitors with advantages such as high resistance to soil leaching, low
toxicity to birds, fish, and mammals, and slow development of weed resistance [1]. Some
1-phenyl-piperazine-2,6-diones were found in the 1960s to have pharmaceutical activity [2,3]. In an
attempt to find new herbicidal compounds we have investigated the synthesis and herbicidal activity of
a novel class of 1-(2-fluorinated) phenyl-piperazine-2,6-diones.

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Results and Discussion
Chemistry
Henry employed N-substituted iminodiacetic acids as building blocks in the construction of the
piperazine-2,6-dione ring system (Scheme 1). One disadvantage of this three-step method is the
necessity to isolate the unstable morpholine-2,6-diones. The other one is the limited reaction scope,
because hindered primary amines could not be converted into the corresponding cyclic amides [4].
Scheme 1
O
O
O
O
CO2H
CO2H
CONHR1
CO2H
R N
R N
R N
R N
N R1
O
Kruse and Troost developed a single-step process to prepare a wide variety of
piperazine-2,6-diones using N-substituted iminodiacetic acids and N,N’-carbonyldiimidazole (CDI)
(Scheme 2) [5]. The disadvantage of this single-step method is the limited availability of N-substituted
iminodiacetic acids and need to use high quality N,N’-carbonyldiimidazole.
Scheme 2
O
O
N
N
N
CO2H
CO2H
CDI
R N
R N
N R1
O
R N
2 equiv.
N
O
In an attempt to develop methodology for the rapid solution-phase parallel synthesis of novel
1-phenyl-piperazine-2,6-diones, the following synthetic route was studied (Scheme 3):
Scheme 3
O
O
F
F
O
R2
Et3N/CH2Cl2
250C
R1
N
HN
Cl
+
Br
HN
Cl
H3CO HN R1
CO2CH3
2a-q
R2
X
X
1
LiOH/THF,H2O
250C
O
F
O
F
ACOAC/ACONa
R1
N
HN
Cl
R1
N
N
Cl
Reflux
CO2H
R2
X
R2
O
X
3a-q
4a-q

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This method was facile and efficient, especially for the compounds in which the R2 group was not
hydrogen. The acetamide 1 was prepared by the reaction of aniline with bromoacetyl bromide without
difficulty. The intermediate ester 2 was prepared readily from 2-bromo-N-phenylacetamide and methyl
N-substituted iminomonoacetate with triethylamine as base at room temperature. The yield was above
90%. The ester 2 was hydrolyzed into acid 3 by conventional methods in high yield and purity. The
target compound 4 was obtained by refluxing acid 3 in acetic acid anhydride with sodium acetate as
catalyst. The resulting mixture was treated with excess aqueous sodium carbonate and extracted with
ethyl acetate to afford 1-phenyl-piperazine-2,6-diones 4, which were usually pure enough for
biological screening. This methodology might be applicable for the solution-phase parallel synthesis of
1-phenyl-piperazine-2,6-dione analogues. The structures of all compounds 4 (Table 1) are fully
consistent with 1H-NMR data. The structure of compound 4a is further characterized by 13C-NMR and
GC/MS.
Table 1. Synthesized 1-phenyl-piperazine-2,6-diones
Compound
R1
(CH2)4
R2
X
4a
4b
4c
4d
4e
4f
H
(CH2)4
(CH2)4
(CH2)4
(CH2)3
Cl
OCH3
cyclopentyloxy
cyclopentyloxy
OCH2CO2C2H5
propargyloxy
cyclopentyloxy
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
4g
4h
4i
CH3
CH3
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
benzyl
benzyl
benzyl
benzyl
benzyl
4j
OCH3
4k
4l
propargyloxy
cyclopentyloxy
H
4m
4n
4o
4p
4q
Cl
OCH2CO2C2H5
CO2CH(CH3)2
cyclopentyloxy
Herbicidal activity.
The compounds 4 showed promising post-emergence herbicidal activities towards broadleaf
weeds, as shown by the results presented in Table 2 , in which 0 equals no activity and 100 equals total
control. The most sensitive weed to the 1-phenyl-piperazine-2,6-diones was velvetleaf. For the
compounds with the same phenyl moiety, the order of the herbicidal activity is as follows:
4d>4h>4e>4l>4q.

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Table 2. Herbicidal activity of 1-phenyl-piperazine-2,6-diones at 1200g/ha (% control)
compound marigold tomato
velvetleaf
4a
4b
4c
4d
4e
4g
4h
4l
15
0
35
75
15
60
0
80
90
50
90
50
95
75
25
0
0
10
0
0
75
0
0
0
0
4p
0
10
Conclusions
Seventeen target compounds were prepared and tested for their herbicidal activities. A new facile
synthetic route was developed with methyl N-substituted iminomonoacetate as starting material. The
collective results show that 2-phenyl-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,3(4H,6H)-dione provided
better herbicidal activity.
Acknowledgements
Thanks go to Mr. M. Nunez for herbicidal activity testing. Thanks also go to Dr. S Shaber and Dr. J
Renga of DowAgroSciense for their help in the preparation of this paper. This project is financially
supported by the National Agrochemicals R&D Key Project 2004BA308A22-6 of China.
Experimental
General
All reagents were purchased from commercial sources and used without further purification.
Melting points were determined in capillary tubes and are uncorrected. Thin-layer chromatography
(TLC) was run on Baker-flex plastic sheets coated with silica gel IB2-F. The selected GC/MS were run
1
13
on an MD 800 instrument. H-NMR and selected C-NMR spectra were recorded on a Mercury-300
MHz instrument by using solutions in CDCl3 and TMS as an internal reference.
General Method for the Preparation of 1-Phenyl-piperazine-2,6-diones 4a-q.
A solution of bromoacetyl bromide (11 mmol) in dichloromethane (10 mL) was added dropwise
with stirring at room temperature to a solution of aniline (10 mmol) and triethylamine (11 mmol) in
dichloromethane (20 mL). The reaction was monitored by TLC (ethyl acetate/hexane=1:1 to 1:5). The
reaction came to completion usually in 1h and then ethyl acetate (200 mL) was added. The organic
layer was washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100

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mL), dried over MgSO4 and concentrated under reduced pressure to afford the intermediate ester
amide 1. The yields were from 92% to 98%. The purities ranged from 95% to 99%, as estimated by
1H-NMR.
To a solution of methyl N-substituted iminomonoacetate (6 mmol) and triethylamine (6 mmol) in
dichloromethane (10 mL) the solution of 2-bromo-N-phenylacetamide (5 mmol) in dichloromethane
(10 mL) was added dropwise with stirring at room temperature. The reaction was monitored by TLC
(ethyl acetate/hexane=1:1 to 1:5). The reaction came to completion usually in 4h and then ethyl acetate
(100 mL) was added. The organic layer was washed with water (60 mL), brine (60 mL), dried over
MgSO4 and concentrated under reduced pressure to afford the intermediate ester 2. The yields were
from 88% to 96%. The purity was from 90% to 99% as estimated by 1H-NMR.
To a mixture of the above ester 2 (4 mmol) in THF (10 mL) and water (10 mL) lithum hydroxide
(6 mmol) was added with stirring at room temperature. The reaction was monitored by TLC (ethyl
acetate/hexane=1:1 to 1:5). The reaction came to completion usually in 2h and then ethyl acetate (50
mL) and water (30 mL) were added. The organic layer was washed with water (20 mL). The aqueous
layers were combined, acidified with 2N HCl to pH=3, and extracted with ethyl acetate (2 X 50 mL).
The combined organic layer was washed with brine (60 mL), dried over MgSO4 and concentrated
under reduced pressure to afford the intermediate acid 3. The yields were from 81% to 90%. The
purity was from 95% to 99% as estimated by 1H-NMR.
The intermediate acid 3 (2 mmol) and catalytic amount of sodium acetate was added to acetic
anhydride (10 mL) with stirring at room temperature. The reaction mixture was heated to reflux. The
reaction was monitored by TLC (ethyl acetate/hexane=1:1 to 1:5). The reaction came to completion
usually in 1h. After cooled down to room temperature, water (100 mL) and excess sodium carbonate
was added to maintain the mixture basic (pH=7-9). The mixture was extracted with ethyl acetate (2 x
100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over
MgSO4 and concentrated under reduced pressure to afford the target compound 4. The yields ranged
from 50% to 85%. The purity was from 85% to 95% as estimated by 1H-NMR.
2-(4-Chloro-2-fluorophenyl)-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,3(4H,6H)-dione (4a): yield 80%;
oil; 1H-NMR δ 1.238-1.409 (m, 1H), 1.608-1.778 (m, 4H), 2.192-2.306 (m, 2H), 2.963-3.017 (m, 2H),
3.346 (dd, J1 = 16.8 Hz, J2 = 12 Hz, 1H, COCH2N), 3.755 (dd, J1 = 16.8 Hz, J2 = 1.5 Hz, 1H,
COCH2N), 7.083-7.254 (m, 3H); 1C-NMR δ 23.53 ; 25.15, 27.49, 55.10, 59.14, 64.02, 117.87, 120.88,
125.47, 131.63, 136.33, 158.05 (d, J = 253 Hz, CF), 169.18 (NCOCH2N), 171.46 (NCOCHN); MS m/z
=296 (M+, 5%), 268 (20%), 97 (100%).
2-(4,5-Dichloro-2-fluorophenyl)-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,3(4H,6H)-dione (4b): yield
71%; oil; 1H-NMR δ 1.237-1.425 (m, 1H), 1.615-1.784 (m, 4H), 2.048-2.310 (m, 2H), 2.975-3.031 (m,
2H), 3.287 (dd, J1 = 16.8 Hz, J2 = 12.3 Hz, 1H, COCH2N), 3.433 (dd, J1 = 16.8 Hz, J2 = 3.6 Hz, 1H,
COCH2N), 7.291-7.360 (m, 2H).
2-(4-Chloro-2-fluoro-5-methoxy phenyl)-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,3(4H,6H)-dione (4c):
1
yield 65%; semi-solid; H-NMR δ 1.308-1.479 (m, 1H), 1.529-1.892 (m, 4H), 2.212-2.401 (m, 2H),
2.974-3.125 (m, 2H), 3.355 (dd, J1 = 16.8 Hz, J2 = 1.2 Hz, 1H, COCH2N), 3.775 (dd, J1 = 16.8 Hz, J2 =
0.5 Hz, 1H, COCH2N), 6.750 (d, J=6Hz, 1H), 7.289 (d, 9Hz, 1H).

Molecules 2005, 10
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2-(4-Chloro-5-cyclopentyloxy-2-fluorophenyl)-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,3(4H,6H)-dione
1
(4d): yield 75%; oil; H-NMR δ 1.310-1.489 (m, 3H), 1.518-1.896 (m, 10H), 2.215-2.400 (m, 2H),
2.943-3.155 (m, 2H), 3.382 (dd, J1 = 16.8 Hz, J2 = 1 Hz, 1H, COCH2N), 3.795 (dd, J1 = 16.8 Hz, J2 =
0.3 Hz, 1H, COCH2N), 4.699 (m, 1H), 6.700 (d, J=6Hz, 1H), 7.254 (d, 9Hz, 1H).
2-(4-Chloro-5-cyclopentyloxy-2-fluorophenyl)-tetrahydropyrrolo[1,2-a]pyrazine-1,3(2H,4H)-dione
1
(4e): yield 73%; oil; H-NMR δ 1.508-1.698 (m, 2H), 1.718-1.995 (m, 7H), 2.210-3.108 (m, 5H),
3.345-3.556 (m, 1H), 3.702 (dd, J1 = 17.4 Hz, J2 = 36.3 Hz, 1H, COCH2N), 4.000 (dd, J1 = 17.4 Hz, J2
= 0.9 Hz, 1H, COCH2N), 4.702 (m, 1H), 6.709 (d, J=6Hz, 1H), 7.249 (d, 9Hz, 1H).
1-(4-Chloro-5-ethoxycarbonylmethoxy-2-fluorophenyl)-4-methylpiperazine-2,6-dione (4f): yield 82%;
m.p. 74-77°C; 1H-NMR δ 1.251 (t, J=7.2Hz, 3H), 2.493 (s, 3H), 3.514 (d, JAB=16.5Hz, 2H), 3.581 (d,
JAB=16.5Hz, 2H), 4.244 (q, J=7.2Hz, 2H), 4.643 (s, 2H), 6.730 (d, J=6Hz, 1H), 7.296 (d, 9Hz, 1H).
1-(4-Chloro-5-propargyloxy-2-fluorophenyl)-4-methylpiperazine-2,6-dione (4g): yield 77%; semi-solid;
1H-NMR δ 2.504 (s, 3H), 2.567 (t, J=2.4Hz, 1H), 3.529 (d, JAB=16.5Hz, 2H), 3.621 (d, JAB=16.5Hz,
2H), 4.735 (d, J=2.4Hz, 1H), 6.900 (d, J=6.3Hz, 1H), 7.298 (d, J=9Hz, 1H)
1-(4-Chloro-5-cyclopentyloxy-2-fluorophenyl)-4-methylpiperazine-2,6-dione(4h): yield 55%; m.p.
1
111-113°C; H-NMR δ 1.520-1.662 (m, 2H), 1.790-1.920 (m, 6H), 2.497 (s, 3H), 3.519 (d,
JAB=16.5Hz, 2H), 3.601 (d, JAB=16.5Hz, 2H), 4.665 (m, 1H), 6.690 (d, J=6.3Hz, 1H), 7.250 (d, J=9Hz,
1H).
1
4-tert-Butyl-1-(4-chloro-2-fluorophenyl)piperazine-2,6-dione (4i): yield 71%; m.p. 144-146°C; H-
NMR δ 1.170 (s, 9H), 3.580 (d, JAB=16.5Hz, 2H), 3.750 (d, JAB=16.5Hz, 2H), 7.150-7.270 (m, 3H).
4-tert-Butyl-1-(4-chloro-5-methoxy-2-fluorophenyl)piperazine-2,6-dione (4j): yield 80%; semi-solid;
1H-NMR δ 1.174 (s, 9H), 3.525 (d, JAB=16.5Hz, 2H), 3.749 (d, JAB=16.5Hz, 2H), 3.866 (s, 3H), 6.730
(d, J=6.3Hz, 1H), 7.268 (d, J=9Hz, 1H).
4-tert-Butyl-1-(4-chloro-2-fluoro-5-propargyloxyphenyl)piperazine-2,6-dione (4k): yield 83%; semi-
1
solid; H-NMR δ 1.174 (s, 9H), 2.598 (t, J=2.4Hz, 1H), 3.527 (d, JAB=16.5Hz, 2H), 3.750 (d,
JAB=16.5Hz, 2H), 4.729 (d, J=2.4Hz, 1H), 6.910 (d, J=6.3Hz, 1H), 7.305 (d, J=9Hz, 1H).
4-tert-Butyl-1-(4-chloro-5-(cyclopentyloxy)-2-fluorophenyl)piperazine-2,6-dione (4l): yield 83%; m.p.
142-144°C; 1H-NMR δ 1.175 (s, 9H) 1.522-1.661 (m, 2H), 1.794-1.928 (m, 6H), 3.525 (d, JAB=16.5Hz,
2H), 3.752 (d, JAB=16.5Hz), 4.691 (m, 1H), 6.781 (d, J=6.3Hz, 1H), 7.247 (d, J=9Hz, 1H).
1
4-Benzyl-1-(4-chloro-2-fluorophenyl)piperazine-2,6-dione (4m): yield 85%; Oil; H-NMR δ 3.548 (d,
JAB=16.5Hz, 2H), 3.660 (d, JAB=16.5Hz, 2H), 3.748 (s, 2H), 7.147-7.375 (m, 8H).
4-Benzyl-1-(4,5-dichloro-2-fluorophenyl)piperazine-2,6-dione (4n): yield 60%; semi-solid; 1H-NMR δ
3.584 (d, JAB=16.5Hz, 2H), 3.667 (d, JAB=16.5Hz, 2H), 3.769 (s, 2H), 7.361 (m, 7H).

Molecules 2005, 10
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4-Benzyl-1-(4-chloro-5-ethoxycarbonylmethoxy-2-fluorophenyl)piperazine-2,6-dione (4o): yield 83%;
oil; 1H-NMR δ 1.260 (t, J=7.2Hz, 3H), 3.590 (d, JAB=16.5Hz, 2H), 3.655 (d, JAB=16.5Hz, 2H), 3.743
(s, 2H), 4.180 (q, J=7.2Hz, 2H), 4.644 (s, 2H), 6.720 (d, J=6.3Hz, 1H), 7.276-7.361 (m, 6H).
4-Benzyl-1-(4-chloro-2-fluoro-5-iso-propoxycarbonylphenyl)piperazine-2,6-dione (4p): yield 70%;
semi-solid; 1H-NMR δ 1.370 (d, J=6.3Hz, 6H), 3.530 (d, JAB=16.5Hz, 2H), 3.651 (d, JAB=16.5Hz, 2H),
3.725 (s, 2H), 5.247 (sept, J=6.3Hz, 1H), 7.300-7.346 (m, 6H), 7.792 (d, J=6.3Hz, 1H).
4-Benzyl-1-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)piperazine-2,6-dione (4q): yield 80%; m.p.
1
128-129°C; H-NMR δ 1.521-1.663 (m, 2H), 1.791-1.925 (m, 6H), 3.450 (d, JAB=16.5Hz, 2H), 3.651
(d, JAB=16.5Hz, 2H), 3.746 (s, 2H), 4.701 (m, 1H), 6.790 (d, J=6.3Hz, 1H), 7.245 (d, J=9Hz, 1H),
7.339-7.379 (m, 5H).
Herbicidal activity evaluation
Three broadleaf plant species: marigold (Tagetes spp), tomato (Lycopersicon esculentus), and
velvetleaf (Abutilon theophrasti) were used for the test. The seeds were allowed to germinate and grow
for 14 days. Test plants were selected for uniformity, size and stage of development and then treated
with the test compound, returned to the greenhouse and watered. Plants not treated with the compound
under evaluation were used as a comparison. The compound to be evaluated was dissolved in acetone
and sprayed using a carrier volume equivalent to 187 liters per hectare at 1200g/ha. Two weeks after
application of the test compounds, the state of the plants was observed. Each species was evaluated on
a scale of 0-100 in which 0 equals no activity and 100 equals total control.
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