A concise synthesis of azoxystrobin using a Suzuki cross-coupling reaction

Article abstract of DOI:10.3184/174751915X14418863197125

A simple, efficient and eco-friendly process for the synthesis in good yield of azoxystrobin from 2-bromophenol has been developed using phenolic hydroxyl protection, Grignard reaction, Suzuki cross-coupling, hydrogenation and a nucleophilic reaction on a 2-chloropyrimidine.

Full text of DOI:10.3184/174751915X14418863197125

586 RESEARCH PAPER
VOL. 39 OCTOBER, 586–589
JOURNAL OF CHEMICAL RESEARCH 2015
A concise synthesis of azoxystrobin using a Suzuki cross-coupling
reaction
Yong-Gan Liu, Yan Luo* and Yao Lu
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, P.R. China
A simple, efficient and eco-friendly process for the synthesis in good yield of azoxystrobin from 2-bromophenol has been developed using
phenolic hydroxyl protection, Grignard reaction, Suzuki cross-coupling, hydrogenation and a nucleophilic reaction on a 2-chloropyrimidine.
Keywords: strobilurins, Suzuki cross-coupling reaction, azoxystrobin, hydrogenation
Modern agricultural practices rely strongly on the use of the
fungicidal strobilurins, which can increase crop yield to feed
an ever-growing human population with high quality and
inexpensive foods.1 Strobilurins, mainly consisting of 16
compounds, occupy 15% of the total fungicide market share
and represent the second most important fungicide group
worldwide.2 Azoxystrobin, developed by Syngenta is a typical
representative of the strobilurin fungicide family.3 It shows
many excellent properties, such as strong biological activity, a
broad antifungal spectrum, good photochemical stability, low
toxicity towards mammalian cells and benign environmentally
characteristics.4 Due to the positive attributes of azoxystrobin,
its global annual sales were up to $1.2 billion in 2011, and it
is predicted that the global annual sales of azoxystrobin will
exceed $3.5 billion with its global consumption likely to reach
about 13×106 kg in 2015.5
There are numerous ways to synthesise azoxystrobin.
Generally it is preferred to construct the methyl α-phenyl-
β-methoxyacrylate group at an early stage and then build on
the central pyrimidinyloxy and terminal cyanophenoxy rings.
In a typical traditional synthetic approach to azoxystrobin, the
(E)-methyl-2-(2-hydroxyphenyl) -3-methoxyacrylate can be
reacted with 4,6-dichloropyrimidine under alkaline condition
in N,N-dimethylformamide to form (E)-methyl-2-[2-(6-
chloropyrimidin-4-yloxy) phenyl]-3-methoxyacrylate which is
then reacted with 2-cyanophenol in an Ullmann-type coupling
process.6
Although a plethora of reports has been established on the
development of synthetic routes to azoxystrobin, there are still
many problems in its industrial production. Scheme 1 shows
three basic synthetic routes to azoxystrobin. As far as route
1 is concerned, the toxic substance DMS (dimethylsulfate) is
necessary when synthesising the intermediate a, and the total
yield is only 23.8%.7 As for the route 2, the intermediate b is an
allergic substance, and the ring-opening reaction of compound
c generates some non-environmentally friendly by-products,
such as methyl benzofuran-3-carboxylate. Its total yield is
also below 30%.8 In terms of route 3, sodium hydride, which
is inflammable is involved, and high boiling point solvent
NMP, i.e. N-methylpyrrolidone is also employed, which was
prohibited by the European Union in 2003 as a toxic substance
that affects fertility.6
The Suzuki cross-coupling reaction is an efficient and
remarkably effective method for carbon–carbon bond
formation in both the laboratory and industry, especially for
the preparation of advanced materials, agrochemicals and
pharmaceutical compounds.9 The Suzuki cross-coupling
reaction is superior to other coupling reactions, since it can
be carried out under conventional reaction conditions with a
wide range of functional group tolerance. Furthermore, it is
unaffected by aqueous solvent, and it generates non-toxic by-
products which can be separated easily.10
We report here a concise synthetic approach to azoxystrobin,
starting from a raw material with relatively low cost,
2-bromophenol, and using a Suzuki cross-coupling reaction as
the key step.
Result and discussion
As can be seen from Scheme 1, 2-cyanophenol, 4,
6-dichloropyrimidine and (E)-methyl-3-methoxy-2-(2-hydroxy-
phenyl) acrylate make up the main structural framework of
azoxystrobin. Since 2-cyanophenol and 4, 6-dichloropyrimidine
are commercial available, the generation of (E)-methyl-3-
methoxy-2-(2-hydroxyphenyl) acrylate, compound (5),7 becomes
the key step in its synthesis. In our route (Scheme 2), the synthesis
of the precursor of (5), compound (4), from arylboronic acid (2)
and (Z)-methyl-2-iodo-3- methoxyacrylate (3)11 depended on
Suzuki–Miyaura cross-coupling reaction as the crucial step.12, 13
Optimum reaction conditions should be selected in order to obtain
the highest yield. Table 1 records the effects of different mole
ratios of reactants on the yield of compound (4).
Table 1 shows that the yield of compound (4) is already
up to 94% when the mole ratio of arylboronic acid to (Z)-
methyl-2-iodo-3- methoxyacrylate is 1:1. This is due to the
high stereoselectivity of the Suzuki–Miyaura cross-coupling
reaction. If mole ratio and isolated yield are taken into account,
entry 4 represents the optimal conditions.
Table 2 records the effects of varying catalyst amounts on the
yield of compound (4).
As can be seen, the yield of compound (4) reaches a
maximum of 95.7% when the amount of catalyst Pd(PPh3)4 is
0.05 mol per mol of compound (3) (entry 3). Greater amounts
of catalyst affects the efficient separation of product, and results
in a lower yield (entries 5 and 6). In addition, the coordination
compound formed by the catalyst is prone to perform an aryl
Table 1 Effects of mole ratio of reactants on the yields of compound (4)
Entry
Arylboronic acid 2/equiv.
Isolated yield/%
1
2
3
4
5
6
1.0
1.1
1.2
1.3
1.4
1.5
93.9
94.3
95.0
95.7
95.8
95.8
Reaction conditions: iodoacrylate (3) (1.0 equiv.), Pd(PPh3)4 (5 mol%), K3PO4 (3.0 equiv.),
in 1,4-dioxane/H2O (3:1 v/v) (8 mL), 90 °C, 10 h.
* Correspondent. E-mail: luoyan@dhu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2015 587
Scheme 1 Three traditional synthetic routes to azoxystrobin (1, 2 and 3).
Scheme 2 Concise synthesis route of azoxystrobin.

588 JOURNAL OF CHEMICAL RESEARCH 2015
1
97.0%); IR (KBr, νmax/cm–1): 3050, 750; H NMR: δ 7.67 (d, 1H, J =
Table 2 Effects of varying the amounts of Pd(PPh3)4 on the yields of
compound (4) (Scheme 2)
7.76 Hz), 7.58 (d, 2H, J = 7.14 Hz), 7.51–7.48 (m, 2H), 7.44–7.42 (m,
1H), 7.34–7.30 (m, 1H), 7.02 (d, 1H, J = 8.23 Hz), 6.96–6.92 (m, 1H),
5.22 (s, 2H); LC-MS (ESI): calcd for C13H11NaO79Br([M+Na]+): 285.2;
found: 285.0; calcd for C13H11NaO81Br([M+Na]+): 287.2; found: 287.0.
[2-(Benzyloxy)phenyl]boronic acid (2): Magnesium shavings
(0.22 g, 9.13 mmol) and one crystal of iodine were added to a flask
slowly and heated to 35 °C under a nitrogen atmosphere, and then
3–5 drops of solution of compound 1 (2.00 g, 7.61 mmol) in dry THF
(12 mL) were added. After keeping the reaction mixture at 47 °C for
5 min without stirring, the rest of the mixture was added dropwise
into the flask with stirring, during which the iodine started to fade.
Simultaneously, the flask was replenished with dry THF (4 mL). The
reaction mixture was kept at 47 °C for 2 h, and then cooled to room
temperature. Finally, it was added dropwise over a period of 30 min
to a stirred solution of tri-n-butylborate (3.50 g, 15.21 mmol) in
THF (7 mL) at –30 °C. 2 h later, the solution was warmed to room
temperature and stirred for a further 2 h. The reaction was quenched
by adding 37% HCl aqueous (4 mL). 30 min later, the solution was
extracted with ether. The combined ether extracts were then extracted
with 1 M NaOH (45 mL). A grey white precipitate then formed
which was removed by filtration. The resulting precipitate, namely a
basic salt was reacted with 37% HCl aqueous once again to obtain a
white precipitate, which was then collected by vacuum filtration and
washed with a little cold water and dried to afford 2 (1.10 g, 63.3%);
Entry
Pd(PPh3)4/equiv.
Isolated yield/%
1
2
3
4
5
6
1/10
1/15
1/20
1/25
1/30
1/35
84.9
90.6
95.7
91.0
85.9
82.7
Reaction conditions: iodoacrylate (3) (1.0 equiv.), arylboronic acid 2 (1.3 equiv.), K3PO4
(3.0 equiv.), in 1,4-dioxane/H2O (3:1 v/v) (8 mL), 90 °C, 10 h.
Table 3 Effects of varying the solvent composition on the yields of
compound (4) (Scheme 2)
Entry
v1,4-Dioxane:v H2O
Isolated yield/%
1
2
3
4
5
6
1:1
3:1
5:1
10:1
20:1
35.4
95.7
88.7
84.8
73.6
71.5
No water
Reaction conditions: iodoacrylate (3) (1.0 equiv.), arylboronic acid (2) (1.3 equiv.),
Pd(PPh3)4 (5 mol%), K3PO4 (3.0 equiv), solvent (8 mL), 90 °C, 10 h.
1
m.p. 108–109 °C; IR (KBr, νmax/cm–1): 3400, 1341, 759; H NMR: δ
7.89 (d, 1H, J = 7.29 Hz), 7.48–7.39 (m, 6H), 7.10–7.06 (m, 1H), 7.01
(d, 1H, J = 8.22 Hz), 5.74 (s, 2H), 5.17 (s, 2H); LC-MS (ESI): calcd for
C13H11BO3([M-2H]+): 226.1; found: 226.2.
exchange reaction. Lower amounts of catalyst also lowers the
yield (entries 1 and 2)
Table 3 records the effects of solvent composition on the
(Z)-Methyl-2-iodo-3-methoxyacrylate (3): Iodine (6.57 g,
25.86 mmol) dissolved in CCl4/pyridine (1:1 v/v) (60 mL) was added
dropwise, under an atmosphere of nitrogen to a solution of (E)-methyl
methoxyacrylate (1.00 g, 8.62 mmol) in CCl4/pyridine (1:l v/v) (20 mL)
at 0 °C. The mixture was stirred for 72 h during which time it was
allowed to warm to room temperature. The mixture was diluted with
ether (100 mL) and washed successively with H2O (50 mL), 37% HCl
(2 x 4 mL), H2O (50 mL), Na2S2O3 (5.00 g) and dried over anhydrous
MgSO4, and the filtrate was concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel using
(hexane/EtOAc=8:1 v/v) as eluent, to afford 3 (1.48 g, 70.9%); m.p.
51–52 °C (lit.14 51–51.5 °C); IR (KBr, νmax/cm–1): 1711, 1621, 754;
1H NMR: δ 7.67 (s, 1H), 3.77 (s, 3H), 3.97 (s, 3H); LC-MS (ESI): calcd
for C5H7O3I ([M]+):242.0; found:242.1.
yields of compound (4).
As the data indicate, suitable amounts of water promote the
reaction (entries 1–6). According to the reaction mechanism
of the Suzuki reaction, a tetravalent borate intermediate with
strong electronegativity can be formed by arylboronic acid and
alkali. The intermediate can accelerate the nucleophilic reaction
of organic groups on the boron atom. The presence of water
favours of the formation of the tetravalent borate intermediate,
and causes the higher yield.
Therefore, the optimum reaction conditions for the preparation
of compound (4) in the key step of the synthesis of azoxystrobin
is iodoacrylate (3) (1.0 equiv.), arylboronic acid (2) (1.3 equiv.),
Pd(PPh3)4 (5 mol%), K3PO4 (3.0 equiv), in 1,4-dioxane/H2O (3:1
v/v) (8 mL), at 90 °C for 10 h.
(E)-Methyl-3-methoxy-2-(2-phenoxyphenyl)acrylate (4): A mixture
of iodoacrylate 3 (1.00 g, 4.13 mmol), arylboronic acid 2 (1.23 g,
5.37 mmol), K3PO4 (2.63 g, 12.40 mmol) and Pd(PPh3)4 (0.24 g, 0.21
mmol) in a mixture of dioxane (6 mL) and water (2 mL), previously
degasified by bubbling nitrogen under ultrasonic irradiation for a
period of 15 min, was stirred under nitrogen at 90 °C for 10 h. Then
the reaction mixture was cooled, poured into water and extracted with
EtOAc. After evaporation of the solvent, the residue was purified by
flash chromatography on silica gel using (hexane/EtOAc=8:1 v/v)
as eluent, to afford 4 (1.18 g, 95.7%); m.p. 76–77°C (lit.15 76–77 °C);
All compounds were characterised by their IR, 1H NMR and
LC-MS spectra.
Experimental
NMR spectra were obtained on a Bruker AM-400 spectrometer in
CDCl3 using TMS as an internal standard. Chemical shifts (d) are
given in ppm and coupling constants (J) are given in Hz. ESI mass
spectra were determined on a Varian-310 LC-MS spectrometer
(Varian, China). IR spectra were obtained on a 640-IR FTIR
spectroscopy (Varian, USA) using KBr powder as diluent. Melting
points were determined on a RY-1 apparatus (Tianfen, China).
Commercial reagents and solvents were provided by Sinopharm
Chemical Reagent Co. (China). All chemicals were analytical reagent
grade and were used without any pretreatment, except tetrahydrofuran
which was distilled immediately before use from sodium-
benzophenone ketyl.
1-(Benzyloxy)-2-dibromobenzene (1): Benzyl bromide (1.19 g, 6.94
mmol) was added to a solution of 2-bromophenol (1.00 g, 5.78 mmol)
and anhydrous K2CO3 (0.88 g, 6.36 mmol) in dry DMF (11.6 mL)
under a nitrogen atmosphere. The mixture was stirred at 30 °C for 3.5
h, poured into water and extracted with EtOAc. After evaporation of
the solvent, the residue was purified by flash chromatography on silica
gel using hexane as eluent, to afford 1 as a colourless liquid (1.48 g,
1
IR (KBr, νmax/cm–1): 1703, 1641; H NMR: δ 7.53 (s, 1H), 7.43–7.32
(m, 5H), 7.31–7.29 (m, H), 7.27–7.23 (m, 1H), 7.03–6.97 (m, 2H),
5.10 (s, 2H), 3.82 (s, 3H), 3.67 (s, 3H); LC-MS (ESI): calcd for
C18H19O4([M+H]+): 299.3; found: 299.2.
(E)-Methyl-3-methoxy-2-(2-hydroxyphenyl) acrylate (5):
A
mixture of 10 wt % Pd/C (0.35 g, 0.17 mmol) and compound 4 (2.00 g,
6.71 mmol) in 47 mL EtOAc was stirred under H2 atmosphere (1 atm)
at 35 °C for 12 h. The reaction mixture was filtered through celite,
and the filtrate was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel using (hexane/
EtOAc=3:1 v/v) as eulent, to afford 5 (1.38 g, 98.6%); m.p. 125–126 °C
(lit.15 125–126 °C); IR (KBr, νmax/cm–1): 3401, 1679; 1H NMR: δ 7.66 (s,
1H), 7.25 (d, 1H, J = 7.86 Hz), 7.19 (d, 1H, J = 7.92 Hz),7.01–6.95 (m,
2H), 6.20 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H); LC-MS (ESI): calcd for
C11H12NaO4([M+Na]+): 231.2; found: 231.1.

JOURNAL OF CHEMICAL RESEARCH 2015 589
(E) -Methyl-2- (2- ((6-chloropyrimidin-4-yl)oxy)phenyl) -3-
methoxyacrylate (6):7 A mixture of compound 5 (2.00 g, 9.62 mmol),
K2CO3 (2.65 g, 19.23 mmol) and 4,6-dichloropyrimidine (2.87 g,
19.23 mmol) was dissolved in dry DMF (69.2 mL) at 0 °C under
nitrogen. The mixture was stirred at this temperature for 12 h, poured
into water and extracted with EtOAc. After evaporation of the solvent,
the residue was purified by flash chromatography on silica gel using
(hexane/EtOAc=8:1 v/v) as eluent, to afford 6 (2.56 g, 83.1%); m.p.
103–104 °C (lit.16 103–104 °C); IR (KBr, νmax/cm–1): 1708, 1631;
1H NMR: δ 8.60 (s, 1H), 7.49 (s, 1H), 7.46–7.42 (m, 1H), 7.38–7.34 (m,
2H), 7.19 (d, 1H, J = 8.00 Hz), 6.81 (s, 1H), 3.76 (s, 3H), 3.62 (s, 3H);
LC-MS (ESI): calcd for C15H13ClO4N2([M]+): 320.7; found: 321.0.
Azoxystrobin (7): 5 A mixture of compound 6 (2.00 g, 6.24 mmol),
Cs2CO3 (4.07 g, 12.48 mmol) and 2-cyanophenol (1.49 g, 12.48 mmol)
in dry DMF (43 mL) was stirred at 85 °C under nitrogen for 7 h. The
resulting orange suspension was cooled to room temperature, poured
into water and extracted with EtOAc. After evaporation of the solvent,
the residue was purified by flash chromatography on silica gel using
(hexane/EtOAc=4:1v/v) as eluent, to afford 7 (2.45 g, 97.5%); m.p.
115–116 °C (lit.17 117–118 °C); IR (KBr, νmax/cm–1): 2230, 1707;
1H NMR: δ 8.43 (s, 1H), 7.75–7.67 (m, 2H), 7.52 (s, 1H), 7.44–7.32 (m,
5H), 7.25 (d, 1H, J = 7.87 Hz), 6.44 (s, 1H), 3.78 (s, 3H), 3.66 (s, 3H);
LC-MS (ESI): calcd for C22H18O5N3([M+H]+): 404.4; found: 404.1.
Received 6 August 2015; accepted 7 September 2015
Paper 1503530 doi: 10.3184/174751915X14418863197125
Published online: 2 October 2015
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The authors gratefully acknowledge the financial support of
Shanghai High Victory Fine Chemical Co., Ltd, China.