A new and efficient synthetic method for the herbicide carfentrazone-ethyl based on the Heck reaction

Article abstract of DOI:10.1007/s11164-014-1702-x

The herbicide carfentrazone-ethyl (1) was prepared by a new and improved synthetic method. The common and inexpensive reagent ethyl acrylate was employed to replace commercially unavailable ethyl 3-hydroxy-2-methylenebutanoate, which was used in the synthetic route reported previously. Starting from iodination of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (2), an intermediate 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (3) was afforded in an excellent yield. Then, an intermediate ethyl 3-[2-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate (4) was synthesized by Heck coupling of 3 with ethyl acrylate. Next, oxidative addition-elimination of 4 with OXONE/HCl-Et₃N in one pot produced ethyl 2-chloro-3-[2-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate (5). Finally, the target product 1 was obtained via reduction of 5 by H₂. This new synthetic method exhibits the advantages of mild conditions, atom economy, low-cost, and efficiency.

Full text of DOI:10.1007/s11164-014-1702-x

Res Chem Intermed
DOI 10.1007/s11164-014-1702-x
A new and efficient synthetic method for the herbicide
carfentrazone-ethyl based on the Heck reaction
•
Jianjian Fan Juan Yu Xinghua Fu Rui Liu
•
•
•
•
Guangke He Hongjun Zhu
Received: 13 February 2014 / Accepted: 3 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract The herbicide carfentrazone-ethyl (1) was prepared by a new and
improved synthetic method. The common and inexpensive reagent ethyl acrylate
was employed to replace commercially unavailable ethyl 3-hydroxy-2-methylene-
butanoate, which was used in the synthetic route reported previously. Starting from
iodination of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-
5-oxo-1H-1,2,4-triazole (2), an intermediate 1-(4-chloro-2-fluoro-5-iodophenyl)-4-
difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (3) was afforded in
an excellent yield. Then, an intermediate ethyl 3-[2-chloro-5-(4-difluoromethyl-4,5-
dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate
(4)
was synthesized by Heck coupling of 3 with ethyl acrylate. Next, oxidative addi-
tion–elimination of 4 with OXONEÒ/HCl-Et3N in one pot produced ethyl 2-chloro-
3-[2-chloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-
yl)-4-fluorophenyl]-2-propenoate (5). Finally, the target product 1 was obtained via
reduction of 5 by H2. This new synthetic method exhibits the advantages of mild
conditions, atom economy, low-cost, and efficiency.
Keywords Carfentrazone-ethyl Á Herbicide Á Triazolinone Á
Heck reaction Á OXONEÒ Á Hydrogenation
Introduction
Carfentrazone-ethyl (1) (Fig. 1) [1, 2], chemically known as ethyl a,2-dichloro-5-[4-
(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)]-4-fluoroben-
zenepropanoate is a kind of commercial herbicide, which is widely utilized due to
J. Fan Á J. Yu Á X. Fu Á R. Liu Á G. He Á H. Zhu (&)
Department of Applied Chemistry, College of Science, Nanjing Tech University, Nanjing 211816,
China
e-mail: zhuhj@njtech.edu.cn
123

J. Fan et al.
its safety, low toxicity, and high efficiency. It exhibits excellent post-emergence
cereal and corn herbicidal activities [3–6] and has been mainly used in the control of
broadleaf weeds and sedge weeds, such as cleavers, abutilon, hearts quinoa,
petunias, etc. Furthermore, it also shows good herbicidal activity against weeds
resistant to sulfonylurea herbicides, which attracts sustained attention in the field of
pesticide chemistry [7].
In the past two decades, synthetic chemists made great efforts in the preparation
of 1. Early in 1990, FMC Corporation firstly disclosed a synthetic method for
preparing 1 by using 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-
methyl-5-oxo-1H-1,2,4-triazole (triazolinone 2) as a starting material, which
comprised nitration, reduction, diazotization, and Meerwein arylation [8]. Later,
in 1997, Ager and coworkers [9] modified the above method in order to develop an
industrial synthetic route by selecting different reagents, catalysts, and solvents in
the process of diazotization. In 1999, Crispino and coworkers [10] developed
another synthetic method (shown in Scheme 1) by using triazolinone 2 as the raw
material, which reacted with iodine crystals in the presence of oleum to afford an
intermediate 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-
methyl-5-oxo-1H-1,2,4-triazole (3). Then, compound 3 was coupling with ethyl
3-hydroxy-2-methylenebutanoate in the presence of a palladium catalyst and a
tertiary amine via Heck reaction and subsequently rearranged to give an
intermediate ethyl a-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-
oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (6). Finally, product 1 was
obtained by substitution-elimination of 6. In fact, this method has not been
commercialized yet, possibly because the raw material ethyl 3-hydroxy-2-
methylenebutanoate using in Heck reaction was not commercially available. In
addition, taking atom economy into account, extra efforts should also be made to
improve this method.
Actually, as one of the widely used methods forming a C–C bond in modern
organic synthesis, the Heck reaction has recently been developed to a convenient
method in mild conditions with high yields [11]. In this work, we present an
improved method by modification of the reported route in Scheme 1, employing the
inexpensive and readily available reagent ethyl acrylate to replace the commercially
unavailable reagent ethyl 3-hydroxy-2-methylenebutanoate. Starting from triazoli-
none 2, the target compound 1 was synthesized via iodination, Heck coupling,
oxidative addition–elimination and reduction, as shown in Scheme 2. This new
method has potential application in preparing product 1 in mild conditions with low
cost and high efficiency.
Experimental
All solvents and reagents for synthesis were purchased from commercial sources
and used without further purification except that N,N-dimethylformamide (DMF)
was distilled by calcium hydride. The starting material 2 was an industrial product
from Jiangsu Kuaida Agrochemical Co., Ltd with the content of 97 % tested by
HPLC. Reactions were monitored by high-performance liquid chromatography
123

Method for the herbicide carfentrazone-ethyl
Fig. 1 Chemical structure of
carfentrazone-ethyl (1)
F
N
N
N
CHF2
O
Cl
O
O
Cl
1
OH
O
F
N
N
F
N
N
N
O
CHF2
N
CHF2
oleum
I2
O
O
Pd(Cat), R3N, MeCN
Cl
Cl
I
2
3
62.1 %-92.5 %
F
N
F
N
N
N
O
CHF2
N
N
CHF2
NaOCl, Acid, Alcohol
Base
O
Cl
O
Cl
O
O
O
O
Cl
49.6 %-87.9 %
6
88.0 %-96.0 %
1
Scheme 1 Reported synthetic route of 1 by G. Crispino and coworkers
(HPLC) on a Varian 1200 chromatograph using Hypersil ODS2 (5 lm) column
1
(150 9 4.6 mm). Content by HPLC refers to chromatographic area percentage. H
NMR and 13C NMR spectra were recorded on a Bruker 400-MHz spectrometer
using tetramethylsilane (TMS) as an internal standard and CDCl3 as a solvent. Mass
spectra were recorded on a mass spectrometry (MS) spectrometer VG12-250 MS.
Melting points (m.p.) were taken on an X-4 microscope electro thermal apparatus.
General procedure for synthesis of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-
difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (3)
To a 250-ml, three-neck, round-bottom flask equipped with a mechanical stirrer and
a thermometer was added 25 % oleum (12 wt % triazolinone 2 in the oleum),
followed by the triazolinone 2 (0.05 mol). The mixture was cooled in an ice bath
and then iodine (0.05 mol) was added. The reaction mixture was then warmed to
25–60 °C. After completion of the reaction monitored by TLC, the mixture was
123

J. Fan et al.
F
N
O
N
F
N
N
CHF2
F
N
N
N
N
CHF2
N
i
ii
CHF2
O
O
Cl
O
O
Cl
E
Cl
I
O
O
2
3
4
F
N
N
F
N
N
N
N
CHF2
CHF2
iii
iv
O
O
Cl
O
Cl
O
O
O
Cl
Cl
5
1
Scheme 2 Modified synthetic route of 1. Reagents and conditions: (i) 25 % oleum (5H2SO4Á2SO3), I2;
(ii) catalysts, bases; (iii) oxidative addition–elimination reaction, ꢀ OXONEÒ/HCl ` Et3N; (iv) H2, Pd/C,
methanol
poured into ice to give the brown precipitated solid. Then the resulting mixture was
extracted with methylene chloride (2 9 50 ml). The organic extracts were
combined and washed with an aqueous 10 % potassium carbonate solution, an
aqueous 5 % sodium bisulfite solution, and an aqueous saturated sodium chloride
solution, respectively. The organic layer was dried with magnesium sulfate, filtered,
and removed the solvent under vacuum to yield the intermediate 3. Yellow solid;
1
m.p.: 125–127 °C (Lit. [10]: 125–127 °C); H NMR (400 MHz, CDCl3, d ppm):
2.47 (s, 3H), 7.04 (t, J = 58.0 Hz, 1H), 7.38 (d, J = 9.8 Hz, 1H), 7.98 (d,
J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, d ppm): 157.45, 154.88, 142.98,
139.71, 137.51, 123.24, 118.14, 107.67, 91.49, 12.74; ESI-MS m/z: 403.93
(M ? H)?.
General procedure for synthesis of ethyl 3-[2-chloro-5-(4-difluoromethyl-4,5-
dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate (4)
A Schlenk tube equipped with a magnetic stirrer and a condenser was evacuated and
filled with nitrogen three times. Then the intermediate 3 (2.50 mmol), ethyl acrylate
(2.90 mmol), base and catalyst in solvent (5 ml) were placed in the tube under
nitrogen atmosphere. The mixture was heated and monitored by TLC. After
completion of the reaction, the mixture was allowed to cool to room temperature.
Then, H2O (10 ml) was added and the resulting mixture was extracted with ethyl
acetate (3 9 20 ml). The combined organic layers were dried with magnesium
sulfate and concentrated in vacuum. The crude material was purified by flash
chromatography on silica gel with ethyl acetate and petroleum ether to give 4 as
white solid. m.p.: 134–136 °C; 1H NMR (400 MHz, CDCl3, d ppm): 1.34 (t,
J = 7.1 Hz, 3H), 2.49 (s, 3H), 4.28 (q, J = 7.1 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H),
7.06 (t, J = 58.0 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.98
123

Method for the herbicide carfentrazone-ethyl
(d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, d ppm): 166.10, 157.76,
155.16, 150.01, 142.91, 138.28, 135.40, 130.08, 125.74, 122.29, 119.04, 107.68,
60.99, 14.37, 12.72; ESI-MS m/z: 376.06 (M ? H)?.
General procedure for the synthesis of ethyl 2-chloro-3-[2-chloro-5-(4-
difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-
fluorophenyl]-2-propenoate (5)
To a 250-ml, three-neck, round-bottom flask equipped with a magnetic stirrer and a
thermometer was added the intermediate 4, CCl4 (15 ml), OXONEÒ, hydrochloric
acid. The mixture was heated and the process of reaction was monitored by HPLC.
Then Et3N was added cautiously and the mixture was stirred at room temperature
for 2 h. The resulting mixture was extracted with methylene chloride (2 9 50 ml).
The combined organic layers were dried with magnesium sulfate and concentrated
in vacuum. The crude material was purified by flash chromatography on silica gel
with ethyl acetate and petroleum ether to give the desired compound 5 as white
solid. m.p.: 111–114 °C; 1H NMR (400 MHz, CDCl3, d ppm): 1.40 (t, J = 7.2 Hz,
3H), 2.49 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 7.07 (t, J = 58.0 Hz, 1H), 7.38 (d,
J = 9.2 Hz, 1H), 8.07 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3, d ppm): 162.60, 157.53, 154.89, 150.10, 142.89, 135.75, 131.64, 128.89,
128.56, 122.52, 118.72, 107.72, 63.10, 14.30, 12.77; ESI-MS m/z: 410.03
(M ? H)?.
General procedure for the synthesis of the herbicide carfentrazone-ethyl (1)
To a 100-ml, three-necked, round-bottom flask was added the compound 5
(1.50 mmol) and Pd/C. Then the flask was purged, flushed, and maintained with
hydrogen atmosphere. After CH3OH (15 ml) added into the mixture, the resulting
mixture was heated to 35 °C. The mixture was filtered and concentrated in vacuum.
The crude product was then purified by flash chromatography on silica gel with
1
ethyl acetate and petroleum ether to give the product 1 as yellow liquid. H NMR
(400 MHz, CDCl3, d ppm): 1.26 (t, J = 7.2 Hz, 3H), 2.47 (s, 3H), 3.28 (dd,
J1 = 14.0 Hz, J2 = 8.0 Hz, 1H), 3.50 (dd, J1 = 14.0 Hz, J2 = 6.8 Hz, 1H),
4.19–4.26 (m, 2H), 4.55 (dd, J1 = 8.0 Hz, J2 = 6.8 Hz, 1H), 7.06 (t,
J = 58.0 Hz, 1H), 7.31 (d, J = 9.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3, d ppm): 168.61, 156.41, 153.84, 149.83, 142.52, 134.66, 130.59,
122.29, 118.32, 107.60, 62.29, 54.81, 37.94, 13.82, 12.63; ESI-MS m/z: 412.05
(M ? H)?.
Ethyl 2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-
triazol-1-yl]-4-fluorobenzenepropanoate (8)
1H NMR (400 MHz,CDCl3,d ppm): 1.23 (t, J = 7.2 Hz, 3H), 2.45 (s, 3H), 2.63 (t,
J = 7.6 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 7.04 (t,
J = 58.0 Hz, 1H), 7.26 (d, J = 9.6 Hz, 1H), 7.41(d, J = 7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3, d ppm): 171.32, 155.12, 152.48, 149.09, 141.63, 134.14, 127.51,
123

J. Fan et al.
121.22, 117.36, 106.71, 59.80, 32.75, 27.31, 13.27, 11.69; ESI–MS m/z: 378.08
?
(M ? H)
.
Results and discussion
Our synthetic route for 1 is depicted in Scheme 2. The starting material 2 was treated
with iodine in the oleum to produce 3. The intermediate 3 reacted with ethyl acrylate to
furnish the intermediate ethyl 3-[2-chloro-5-(4-difluoromethyl-4,5-dihydro-3-
methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate (4) in the absence
of ligands under N2 atmosphere via Heck reaction according to the research of Bradley
et al. [12]. Then, oxidative addition–elimination of 4 with OXONEÒ/HCl-Et3N in one-
pot gave the intermediate ethyl 2-chloro-3-[2-chloro-5-(4-difluoromethyl-4,5-dihy-
dro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)-4-fluorophenyl]-2-propenoate (5) based
on the study of Kim et al. [13]. Finally, the intermediate 5 was reduced by H2 in the
presence of Pd/C [14] in methanol to afford the target compound 1.
Synthesis of the intermediate 3 with iodine in the oleum
The iodination of the triazolinone 2 to produce 3 was carried out in the 25 % oleum
[10] (12 wt % triazolinone 2 in the oleum) using two forms of iodine at different
temperature from 25 to 60 °C in good to excellent yields. The results are
summarized in Table 1. With regard to the influence on the forms of iodine, the
reaction needed a longer reaction time using graininess of iodine than powder of
iodine, which probably increased the contact area between 2 and iodine to accelerate
the rate of the reaction (Table 1, entries 1–2). The investigation on the effects of the
temperature over the reaction revealed that the yields of 3 firstly increased from 25
to 35 °C and then decreased slowly from 35 to 60 °C (entries 3–8). However, the
reaction time was shortened sharply from 28 to 2.5 h, probably because the oleum,
as a solvent and an oxidant, has more activity at high temperature, whereas too high
temperature might cause volatilization of oleum to reduce the yield of 3 slightly.
Thus, the iodination reaction at 35 °C using powder of iodine provided 3 with the
highest yield of 97.6 % and 96.8 % purity by HPLC.
Synthesis of the intermediate 4 based on the Heck reaction
The intermediate 4 was obtained from the intermediate 3 with ethyl acrylate in the
absence of ligands via the Heck reaction [12]. Structurally, the coupling product 4
was E configuration for the coupling constant of the hydrogen on the C–C double
bond is 16.0 Hz [15], which was similar to the structures of most reported products
synthesized by the Heck reaction [16, 17]. By the way, an isolated by-product was
observed. The by-product was proved to be a small amount of the compound 2. It
was speculated that the deiodination of 3 formed 2 during the Heck reaction.
Further, the coupling reaction of 3 using commercially available catalysts and
different bases in various solvents was investigated as shown in Table 2. Recently,
many new and convenient catalysts such as CuCl [18] and Pd/C [19] were reported
123

Method for the herbicide carfentrazone-ethyl
Table 1 Effects of reaction conditionsa,b on the yield of the compound 3
Entry
Temperature (oC)
Time (h)
I2-form
Yieldc (%)
1
2
3
4
5
6
7
8
a
25
35
25
30
35
40
50
60
42
17
28
23
6
Graininess
Graininess
Powderd
Powder
80.2
89.4
82.1
88.9
97.6
94.8
93.9
92.6
Powder
3
Powder
2.5
2.5
Powder
Powder
Reaction conditions: the triazolinone 2 (0.05 mol), iodine (0.05 mol) in the 25 % oleum (12 wt %
triazolinone 2 in the oleum)
b
The 25 % oleum was prepared by 50 % oleum and the concentrated sulfuric acid
c
Isolated yield
d
The graininess of iodine was grinned in a mortar by pestle to give the powder of iodine
to have good effects on the Heck reaction, but both of them gave a poor
performance in our reaction system (Table 2, entries 1–2). Conversely, the catalyst
Pd(OAc)2 gave the higher yield of 4 than Pd(PPh3)4 and (PPh3)2PdCl2 (entries 3–5).
Moreover, Et3N was more favored to the reaction than K2CO3 (entries 5–6). It is
clear from the table that DMF as a solvent displayed a better effect than MeCN and
DMF/H2O (entries 5, 7–8). In addition, the molar ratio of catalyst Pd(OAc)2 to 3
was optimized in DMF using Et3N as a base. The results indicated that molar ratio
of catalyst Pd(OAc)2 had a slight effect on the yield of 4 (entries 9–15). Even when
the number of equivalent of Pd(OAc)2 decreased to 1 % equiv., the yield of 4 still
exceeded 85 %, only by prolonging reaction time from 3 h to 33 h. Although the
change of molar ratio of Pd(OAc)2 made little difference to the yield of 4 (entry 15),
it would cut cost to make it possible to develop an acceptable and low-cost protocol.
Taking all these into account, using 2 % equiv. of Pd(OAc)2 and Et3N as a base in
DMF gave the better yield of 4 in 87.7 % yield.
Synthesis of the intermediate 5 by oxidative addition–elimination reaction
The compound 5 was synthesized from the compound 4 with OXONEÒ/HCl-Et3N in
one pot [13], which was a new method for the preparation of a-chloro-a,b-
unsaturated carbonyl compounds, compared to direct addition–elimination method
with Cl2. The preparation of 5 comprised two-steps in one pot where 4 was firstly
oxidized by OXONEÒ/HCl to give an intermediate ethyl a,b,2-trichloro-5-[4-
(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenze-
nepropanoate (7). Then, the elimination of 7 was conducted by Et3N to give 5 as
shown in Scheme 3.
In the initial trial, we found the intermediate 7 was critical to the yield of 5. So,
we focused our attention on optimization of 7 and the reaction was monitored by
HPLC (Table 3). Oxidants such as H2O2 [20] and NaClO were used in quantity for
123

J. Fan et al.
123

Method for the herbicide carfentrazone-ethyl
F
N
N
F
N
N
F
N
N
N
CHF2
OXONE, HCl
N
N
CHF2
CHF2
Et3N
O
Cl
O
O
Cl
O
Cl
O
Cl
O
O
O
O
Cl
Cl
7
4
5
Scheme 3 Preparation of 5 from 4 by oxidative addition–elimination method in one-pot with OXONEÒ/
HCl-Et3N
the oxidative addition and failed to get 7 with no reaction. Instead, using 2 equiv. of
OXONEÒ in 2 mol/l HCl at 40 °C produced a trace of 7 (Table 3, entry 1).
Encouragingly, increasing to 10 equiv. of OXONEÒ generated 7 in 58.8 % yield
(entry 5). It was noteworthy that yield of 7 did not increase any more until 28 h.
Furthermore, the amount of HCl and its concentration were investigated using 10
equiv. of OXONEÒ. It was observed that 24 equiv. of HCl achieved the better yield
of 7 (entries 5, 7–11). When the amount of HCl was 24 equiv., the concentration of
HCl was 1 mol/l to give better results than that was 2 mol/l (entries 5, 9). The effect
of temperature was also examined. The reaction proceeded in 1 mol/l HCl at room
temperature to provide 7 in 41.9 % yield, which was lower than the yield of 7 at
40 °C (entries 5, 14). Meanwhile, the reaction time was prolonged to 72 h at room
temperature. Contrarily, the reaction proceeded in 2 mol/l HCl at room temperature
to obtain the better yield than that at 40 °C (entries 11, 15), probably due to the
faster volatilization of HCl at 40 °C. In addition, two different adding ways of
OXONEÒ/HCl were investigated. One adding way was that OXONEÒ and HCl were
first to be mixed at 0 °C and then the mixture was added into the reaction system to
give 7 in 51.7 % yield (entry 12). The other was that OXONEÒ and HCl were
directly added into the reaction system in one portion to generate 7 in 58.8 % yield
(entry 5). Thus, using 10 equiv. of OXONEÒ in 1 mol/l HCl at 40 °C gave the better
yield of 7 in 58.8 % yield, while about 7 % of 4 were remained. There were
remainders with content of 34 % in the reaction. The structures of these remains
have not been confirmed. They might be some by-products. To confirm their
structures and to reduce these by-products will be our next work.
Subsequently, the intermediate 7 was eliminated by addition of Et3N cautiously
to afford 5. The elimination proceeded rapidly to give at least 90 % conversion of 7.
The yields of 5 were also listed in Table 3. Overall, the one-pot reaction gave the
highest isolated yield of 5 in 56.7 % yield (entry 5).
Synthesis of carfentrazone-ethyl (1) by reduction of the intermediate 5
The intermediate 5 was a kind of a-halo-a,b-unsaturated esters which were reported
to be reduced by bio-catalytic methods to give a-halo saturated ester [21]. However,
the bio-reduction methods often used expensive enzymes as catalysts. So, in our
initial attempts, organic catalytic methods to prepare 1 were used (Table 4). Firstly,
123

J. Fan et al.
Table 3 Effects of reaction conditionsa on the yield of the intermediate 7 and 5
Entry n(4):n(OXONEÒ) nHCl = CHClÁV(HCl)
(mmol = mol/l 9 ml)
Temperature (°C) Content of 7 by Yield of
HPLCb (%)
5c (%)
1
1.0:2.0
2 9 0.5
1 9 12
1 9 12
1 9 12
1 9 12
1 9 12
1 9 6
40
40
40
40
40
40
40
40
40
40
40
40
40
r.t
5.6
25.3
26.6
38.9
58.8
53.8
29.3
11.2
52.6
44.2
41.6
51.7
41.3
41.9
54.2
Trace
22.5
24.0
35.1
56.7
50.4
26.2
Trace
51.5
40.5
37.6
47.4
36.4
39.7
52.6
2
1.0:5.0
3
1.0:6.0
4
1.0:8.0
5
1.0:10.0
1.0:12.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
1.0:10.0
6
7
8
1 9 3
9
2 9 6
10
11
12d
13d
14e
15e
a
2 9 9
2 9 12
1 9 12
2 9 6
1 9 12
2 9 12
r.t
Reaction condition: the compound 4 (0.5 mmol), OXONEÒ in CCl4 (15 ml) and HCl (12 mmol) were
allowed to react for 28 h and then Et3N (16 ml) was added to stir for 2 h at room temperature
b
The content of the intermediate 7 was monitored by HPLC in the oxidative addition and mobile phase
was a mixture of methanol/water in the ratio 70:30 (v/v); wavelength: 245 nm; flow rate: 1 ml/min
c
Isolated yield of the compound 5
Reagent OXONEÒ and HCl were first to be mixed at 0 °C, then was added to the system
The reaction time was prolonged to 72 h at room temperature
d
e
NaBH4/CuCl as catalysts in methanol [22] were attempted, while we failed to get 1
and an isolated by-product was proved to be ethyl 2-chloro-5-[4-(difluoromethyl)-
4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (8)
by NMR and mass spectrometry (Table 4, entry 1). Then, reaction was unsuccessful
using NaBH4/ZnO [23] as catalysts in absence of solvent (entry 2). Thereafter,
choosing NaBH4 [24] as a catalyst led to none of expected 1 (entry 3).
Next, the hydrogenation of 5 was attempted to be catalyzed by Pd/C in methanol.
Notably, the reduction of a-chloro-a,b-unsaturated esters to give a-chloro saturated
esters by the above catalytic system has not been reported yet. Fortunately, the
target compound 1 was obtained using 5 % Pd/C at 35 °C in 66 % yield determined
1
by H NMR spectroscopy and in 48.5 % isolated yield (entry 4). The reaction
1
simultaneously gave a by-product 8 in 33 % yield by H NMR and in 25.1 %
isolated yield (entry 4). With any decrease in quantity of 5 % Pd/C, the reaction
failed to provide 1 with desired yields (entries 5–9). Moreover, prolonging reaction
time did not improve the yield of 1 (entry 8), and choosing 10 % Pd/C as a catalyst
gave the more yield of 8 (entry 9) (Fig. 2).
It seems likely that chlorine atom in a-position of 5 was replaced by hydrogen
atom in the Pd/C-H2 catalytic system to form the by-product 8, and the chlorine
123

Method for the herbicide carfentrazone-ethyl
Table 4 Effects of reaction conditions on the yield of 1
Entry Reagent
Solvent Temperature T (h) Results (%)
(°C)
Note
1/8/5
1
2
3
4
NaBH4/CuCl
MeOH
None
0
7
0a/85.2a/tracea
No reaction
0/0/tracea
48.5a/25.1a/
tracea
NaBH4/ZnO
NaBH4
r.t
1.5
24
22
MeOH r.t
MeOH 35
5 % Pd/
C ? H2
m(5 % Pd/
C) = 100 wt % 9 m(5)
66b/33b/traceb
6.6c/53.7c/0c
5
6
7
8
9
10
a
5 % Pd/
C ? H2
MeOH 35
MeOH 35
MeOH 35
MeOH 35
MeOH 35
MeOH 35
22
22
22
48
22
22
m(5 % Pd/
C) = 30 wt % 9 m(5)
5 % Pd/
C ? H2
6.3c/10.1c/
82.4c
m(5 % Pd/
C) = 20 wt % 9 m(5)
5 % Pd/
C ? H2
7.4c/5.3c/83.1c m(5 % Pd/
C) = 10 wt % 9 m(5)
7.7c/6.2c/81.6c m(5 % Pd/
C) = 10 wt % 9 m(5)
m(5 % Pd/
C) = 5 wt % 9 m(5)
5.8c/66.3c/8.3c m(10 % Pd/
C) = 10 wt % 9 m(5)
5 % Pd/
C ? H2
5 % Pd/
C ? H2
No reaction
10 % Pd/
C ? H2
Isolated yield
Yield determined by 1H NMR spectroscopy
b
c
HPLC yield; mobile phase was a mixture of methanol/water in the ratio 70:30 (v/v); wavelength was
245 nm; flow rate was 1 ml/min
Fig. 2 Chemical structure of
by-product (8)
F
N
N
N
CHF2
O
Cl
O
O
atom might cause Pd/C temporal failure [25, 26]. Thus, how to prevent the
dechlorination in the reduction was the key to improve the yield of 1, which will
encourage us to find a suitable catalytic system in the future work.
Overall, the isolated yield of 1 starting from the raw material 2 through four steps
was 25 %, which did not achieve the expected results.
Conclusions
In conclusion, we demonstrated a new method for the preparation of the herbicide
carfentrazone-ethyl (1) involving iodination, Heck reaction, oxidative addition–
123

J. Fan et al.
elimination reaction, and reduction. The inexpensive reagent ethyl acrylate was
employed to replace commercially unavailable ethyl 3-hydroxy-2-methylenebu-
tanoate to reduce costs and enhance atom economy. The hydrogenation of a-chloro-
a,b-unsaturated esters furnished a-chloro saturated esters in 66 % yield determined
by 1H NMR. The overall isolated yield of 1 was 25 %, which did not achieve good
results as expected. We thought the yield of 1 could be improved by optimizing
oxidative addition–elimination reaction and reduction.
Acknowledgments We greatly acknowledge the National key technology R&D program of the
Ministry of Science and Technology (2011BAE06A07-04), the Technology R&D Program of Jiangsu
province (BE2012363), the Postgraduate innovation fund of Jiangsu province (2012, CXZZ12_0445) and
the Graduate innovation fund of Jiangsu province (2013, CXLX13_399), P.R. China.
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