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A novel process concept for the three step

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Boscalid® synthesis†
Cite this: RSC Adv., 2016, 6, 58279
I. Volovych,a M. Neumann,a M. Schmidt,a G. Buchner,a Ji-Yoon Yang,c J. Wölk,c
T. Sottmann,bc R. Strey,c R. Schomäckera and M. Schwarze*ad

Nowadays, the development of chemical processes using environmentally friendly solvents is of high
importance. As an alternative to conventional reaction media based on organic solvents, we show
a novel aqueous surfactant-based process concept which is used for the three step synthesis of the
fungicide Boscalid®. By applying three phase microemulsion systems for the Suzuki coupling reaction,
the first step within the Boscalid® synthesis, a simple product and catalyst separation can be achieved,
whereby the water-soluble homogeneous Pd/SPhos catalyst complex can be reused several times.
Together with an easily recyclable heterogeneous PtIr@TiO2 catalyst, which is applied for the
Received 22nd April 2016
Accepted 6th June 2016
hydrogenation reaction in the second step, followed by base-assisted condensation to the final product
Boscalid® in the third step, overall yields up to 90% are achievable for the whole reaction sequence. This
DOI: 10.1039/c6ra10484c
result was obtained without any purification step in between that requires the use of further solvents. In
www.rsc.org/advances this way the total synthesis costs can be reduced and solvent wastage can be avoided.

Suzuki coupling, (b) hydrogenation (reduction of the nitro

1. Introduction
In the last years, the development of greener chemical processes
has become more and more important in industry because of
decreasing natural resources and due to the high interest of
society in environmental topics. EPA assistant administrators
Paul Anatas and John Warner1 developed and published the 12
principles of “Green Chemistry”, also known as rules for
a sustainable chemistry. The most important aims which would
make a process greener are prevention of waste, ensure atom
economy in reactions, the use of catalytic reactions, and
avoiding hazardous syntheses. In this paper, we show the
development of greener tandem processes based on three phase
microemulsion systems as solvent for which the total synthesis
of the fungicide Boscalid® was selected as an industrially
important model reaction. Boscalid® is produced by BASF SE
and is an important agent applied in agricultural sector for the
protection of plants and trees against gray and blue mold
caused by Botrytis cinerea and Penicillium expansum.2 The total
synthesis which is shown in Fig. 1 consists of three steps: (a)
a
Technische Universität Berlin, Institut für Chemie, Straße des 17 Juni. 124, 10623
Berlin, Germany. E-mail: ms@chem.tu-berlin.de
b
Universität Stuttgart, Institut für Physikalische Chemie, Pfaffenwaldring 55, 70569
Stuttgart, Germany
c
Universität zu Köln, Institut für Physikalische Chemie, Luxemburger Str. 116, 50939
Köln, Germany
d
Technische Universität Berlin, Institut für Prozess-und Verfahrenstechnik, Straße des
17 Juni. 135, 10623 Berlin, Germany
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra10484c
group in the coupling product), and (c) condensation to the
nal product.3,4
To develop practical and efficient methodologies for the
synthesis of Boscalid® we have adopted the principles of green
chemistry. To prevent waste in tandem reactions, the amounts
of solvent have to be minimised (reduced E-factor), e.g. by using
only one solvent in all three reactions. Also safer solvents, e.g.
water and ethanol, should be applied as reaction medium. The
reaction conditions should be moderate, e.g. the pressure for
the hydrogenation reaction and the reaction temperatures
should be lowered to increase the energy efficiency of the
process. Furthermore, all catalysts should be recycled several
times to increase the overall productivity of the process.
Because reactions in water are associated with low solubility of
hydrophobic reactants, the addition of solubilisers such as
surface active detergents (surfactants) is necessary. The so
formed aqueous-micellar solutions can be used as more envi-
ronmentally friendly alternatives to organic solvents in a variety
of chemical reactions.5,6 Enantioselective hydrogenation of ita-
conic acid and its esters catalysed by sol–gel immobilised Rh/
BPPM-complex7 or also homogeneously catalysed hydrogena-
tion of a-acetamidocinnamate8,9 can be carried out in aqueous
CTAB solution. Heck coupling reactions catalysed by (dtbpf)
PdCl2 are possible in aqueous TPGS surfactant solution at room
temperature.10 Epoxidation of 4-methylpentene catalysed by a Pt
[(S,S)chiraphos] complex is carried out in aqueous sodium
dodecylsulfate (SDS) solution.11 One possibility for catalyst
reuse is the extraction of the hydrophobic product with an
organic solvent. Another possibility for separation of catalyst

This journal is © The Royal Society of Chemistry 2016 RSC Adv., 2016, 6, 58279–58287 | 58279

RSC Advances
Fig. 1 Scheme for the total synthesis of Boscalid®.
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and product is micellar enhanced ultraltration (MEUF),12,13
a separation method which allows for the development of
a continuous process. In contrast, heterogeneous catalysts can
be separated and reused by simple ltration. Most of the
organic reactions and tandem processes are performed with
very hydrophobic substrates for which the application of
aqueous-micellar solutions is not always desirable. To increase
the solubility and interaction of the reactants, microemulsion
systems can be applied as solvent. Winsor et al. have described
different types of microemulsions and the structures already in
1948.14 The behaviour of the microemulsion systems depends
not only on surfactant concentration but also on temperature
and type of the substrate. To study the behaviour of these
systems, a phase diagram15 usually at a constant water-to-oil
ratio is required. A distinction has to be drawn between the
three phase, the one phase, and the two phase microemulsion
systems.16 Depending on the catalytic system, different types of
microemulsions can be applied. One phase microemulsion
systems are preferably used in combination with heterogeneous
catalysts, which can be separated aer reaction by ltration, e.g.
Heck coupling of iodobenzene and styrene catalysed by sol–gel
immobilized palladium catalysts17 and Suzuki coupling cata-
lysed by carbon supported palladium.18 For reactions with
homogeneous catalyst complexes three or two phase systems
are benecial because of simple separation of product and
catalyst aer reaction by phase separation19 as exemplarily
shown by Nowothnick et al. for a Suzuki coupling reaction
catalysed by a homogeneous Pd/TPPTS complex in three phase
microemulsion systems.20 In this context also organic reactants
can be used as the oil phase in three phase microemulsion
systems as shown by Hamerla et al. for the Rh/sulphoxantphos
catalysed hydroformylation of 1-dodecene which was carried
out in 1-dodecene/water/surfactant microemulsion system.21 In
this paper, we show how a three phase microemulsion system
can be used to develop a tandem process in which a Suzuki
coupling reaction, as the key step, is combined with a hydroge-
nation and a condensation reaction.
2. Experimental part
2.1 Chemicals
2.1.1 Chemicals for the Suzuki coupling reaction. As reac-
tants for the Suzuki coupling reaction 4-chlorobenzeneboronic
acid (CBBA, 98.0% purity, ABCR), 1-chloro-2-nitrobenzene
(CNB, 99.0% purity, Sigma-Aldrich), and potassium carbonate
(K2CO3, 98.0% purity, Carl Roth) were used. For the formation
of the microemulsion system, heptane ($99.0% purity, Carl
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Roth) as the nonpolar compound, distilled water as the polar
compound, and a surfactant as the amphiphile were used. As
surfactants technical grade Novel 6, Novel 7, Novel 8, Marlipal
24/50, Marlipal 24/70, and Marlosol TA3080, as well as the
designer surfactant TPGS were used. For comparison dieth-
yleneglycolbutylether (C4E2, $99.0% purity, Sigma-Aldrich) was
used as the amphiphile. The chemical structures of the
surfactants and C4E2 are shown in Fig. S1 of the ESI.† TPGS was
donated by the group of Prof. Lipshutz (University of California,
Santa Barbara).
2.1.2 Chemicals for the hydrogenation reaction. For the
hydrogenation reaction, the product of the Suzuki coupling
reaction was used. The non-commercial product 40 -chloro-2-
nitrobiphenyl (CNBP, 99.0% purity) was also received in small
amounts for HPLC calibration and reference experiments from
BASF SE. In addition, ethanol (EtOH, 99.9% purity, VWR),
dichlormethane (DCM, $99.8%, Roth), tetrahydrofurane (THF,
$99.5%, Roth), cyclohexane ($99.0%, Sigma-Aldrich), and 2-
propanol (99.9% purity, Carl Roth) were used as further solvents
and 5.0 hydrogen gas (H2, Air Liquide) as reductant. A non-
commercial supported Pt catalyst (PtIr@TiO2) was applied
(see Section 2.2.2).
2.1.3 Chemicals for the condensation reaction. For the
condensation reaction, the product from the hydrogenation
reaction 2-amino-40 -chlorobiphenyl (ACBP) was applied. In
addition, 2-chloronicotinyl chloride (CNC, 98.0% purity, Sigma-
Aldrich) and triethylamine (NEt3, >99.5% purity, Fluka) as base
were used.
2.1.4 Chemicals for catalyst synthesis. As metal precursors
for the catalyst synthesis platin(II)acetylacetonat (Pt(acac)2,
99.9% purity, Alfa Aesar), iridium(III)acetylacetonate (Ir(acac)3,
97.0% purity, Sigma-Aldrich), and palladium(II)acetate
(Pd(OAc)2, 99.0% purity, ABCR) were used. Titanium dioxide
(P25 TiO2, 99.5% purity, Evonik) was used as catalyst support. 2-
(Dicyclohexylphosphino)-2,6-dimethoxysodium salt (SPhos,
97.0% purity, Sigma-Aldrich) was used as water soluble ligand.
Ethanol (EtOH, 99.9% purity, VWR) was used to wash the sup-
ported catalysts aer synthesis. N,N-Dimethylformamid (DMF,
99.8% purity, Carl Roth) was used as solvent in the microwave
assisted catalyst preparation. The chemical structures of SPhos
and the metal precursors are shown in Fig. S2 of the ESI.†
2.2 Catalyst preparation
2.2.1 Preparation of the Pd/SPhos catalyst complex. The
homogeneous Pd/SPhos catalyst complex applied in Suzuki
coupling reactions was prepared ex situ by stirring 7.5 mg (0.033
mmol) of the Pd(OAc)2 catalyst precursor and 50.9 mg (0.100
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mmol) of the water soluble ligand SPhos in 2 mL distilled water
for 20 h under argon as inert gas.
2.2.2 Preparation of the PtIr@TiO2 catalyst. The heteroge-
neous PtIr@TiO2 catalyst applied in hydrogenation reactions
was prepared by a microwave assisted impregnation method. At
rst 1000 mg of TiO2 as support, 20.6 mg Pt(acac)2, and 6.3 mg
Ir(acac)3 were placed into the microwave reaction chamber
together with 15 mL DMF and a magnetic stirring bar. Aer
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sonication to dissolve the precursors and disperse the TiO2
support, the reaction chamber was placed into the microwave
setup (model Monowave, Anton Paar) and treated under
rigorous stirring (1200 rpm) by the following temperature
program: (a) heating up to 200  C, (b) keeping the temperature
at 200  C for 60 min, and (c) cooling down to 45  C. Aer
reaction, the supported catalyst was separated from the solvent
by centrifugation (model Biofuge Primo, Heraeus, 15 min, 7800
rpm), washed with ethanol (3 times) and nally freeze dried
(model FreeZone 6, Labconco, 24 h, 40 mbar).
2.3 Reaction procedures
2.3.1 General procedure for the Suzuki coupling reaction.
The Suzuki coupling reactions were performed in a double-
walled glass reactor under nitrogen atmosphere. 3.0 mmol of 4-
chlorobenzeneboronic acid, 3.0 mmol of 1-chloro-2-
nitrobenzene, and 4.0 mmol of K2CO3 were added to 100 mL
solvent. As solvent a three phase microemulsion system con-
sisting of 48 wt% heptane, 48 wt% water, 2.97 wt% surfactant,
and 1.03 wt% reactants was applied. Aer stirring at the
temperature T(3f), where the three phase region for the micro-
emulsion system is obtained, the reaction was started by the
addition of the previously prepared Pd/SPhos catalyst. The reac-
tion progress was followed by withdrawing samples which were
analysed by HPLC. Aer the Suzuki coupling reaction, the reac-
tion mixture was separated into three phases, and the organic
excess phase containing the coupling product as well as small
amounts of by-products was provided for the hydrogenation
reaction. For recycling experiments, also the water excess phase
was removed. The catalyst stayed in the reactor under inert
atmosphere and aer adding water, heptane, and fresh reactants,
the reaction was continued. If necessary, also surfactant and
ligand were added to re-establish the initial concentrations.
2.3.2 General procedure for the hydrogenation reaction.
For the hydrogenation reactions a glass reactor (Parr Instru-
ments, see Fig. S6 in ESI†), pressure-resistant until 10 bar,
equipped with a gas dispersion stirrer was used. 9.6 mmol of 40 -
chloro-2-nitrobiphenyl was hydrogenated at 5 bar, 60  C, and
2000 rpm stirring speed in 200 mL solvent using 300 mg of the
PtIr@TiO2 catalyst. Reactions were performed under nitrogen
atmosphere. 40 -Chloro-2-nitrobiphenyl was obtained from the
Suzuki coupling reaction (see Section 2.3.1). As solvent
a mixture of heptane and a co-solvent was used. The volume
ratio of heptane/co-solvent was xed at 1/1 or 3/1. Samples were
analysed by HPLC.
2.3.3 General procedure for the condensation reaction. For
the condensation reaction 9.6 mmol 2-amino-40 -chlor-
obiphenyl, 2-chloronicotinyl chloride and triethylamine
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(1 : 3 : 1) were stirred at room temperature in 100 mL solution
consisting of heptane and a further solvent (volume ratio
heptane/solvent ¼ 3/1) for 5 minutes. 2-Amino-40 -chlor-
obiphenyl was obtained from the hydrogenation of 40 -chloro-2-
nitrobiphenyl. Aer the reaction, the product was obtained as
a white precipitate.
2.3.4 Total synthesis of Boscalid®. Aer optimising the
three reaction steps, Boscalid® was prepared in three consec-
utive and individually steps (Suzuki coupling, hydrogenation
and condensation) with the procedures described above using
double amounts of reactants. The intermediates were not iso-
lated. The synthesis was carried out in two different reactors:
Suzuki coupling in a double walled stirred glass reactor fol-
lowed by hydrogenation and condensation in a high pressure
reactor glass reactor. The residue amounts of catalyst were
removed by adsorption on silica and the nal product was
separated from solvent by vacuum distillation.
2.4 Analysis
The conversion and selectivity in all reactions were determined
by high performance liquid chromatography (HPLC) using an
Agilent instrument 1200 series with 250  4 mm chromato-
graphic column Multospher 120 RP18-5m from Ziemer Chro-
matographie Langerwehe/Germany. A mixture of acetonitrile/
water (70 vol%/30 vol%) was used as eluent with a ow rate of
1 mL min1, T ¼ 25  C, l ¼ 225 nm, injection volume ¼ 10 mL, p
¼ 110–114 bar and t ¼ 11 min. All samples were dissolved in
acetonitrile (F ¼ 25). The conversion (X) and yield (Y) were
calculated as follows:
 
ct
X ¼ 1 100% (1)
c0
 
nP
Y¼ 100% (2)
nE
In eqn (1), c0 and ct are the initial and nal concentration
aer the respective reaction time t. In eqn (2), nP and nE are the
moles of the desired product and initial reactant. The residue
solutions from different reactions were analysed for palladium
and phosphorus content using a Varian 715-ES Optical Emis-
sion Spectrometer (ICP-OES) to determine catalyst leaching.
Calibration of the instrument was performed with commercial
palladium and phosphorus standards from Sigma Aldrich.
3. Results and discussion
3.1 Suzuki coupling in three phase microemulsion systems
First step of the Boscalid® synthesis is the Suzuki coupling of 4-
chlorophenylboronic acid with 1-chloro-2-nitrobenzene to 40 -
chloro-2-nitrobiphenyl in the presence of the inorganic base
K2CO3 and the water-soluble catalyst complex Pd/SPhos. Beside
the main coupling product different by-products can be ob-
tained, e.g. 4,40 -dichlorobiphenyl, biphenyl and 4-biphenylbor-
onic acid (Fig. 2).
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Fig. 2 Scheme for the Suzuki coupling reaction (step 1).

The water soluble ligand SPhos was selected for the Suzuki The temperature of the three phase region T(3F), which is
coupling reactions because it shows the best performance for needed for the catalyst and product separation, was determined
nitrogen heterocycles or unreactive compounds, e.g. chloro- from phase diagrams.15 T(3F) increases with an increasing
substituted aromatic reactants.22,23 To allow for separation of number of ethoxylic groups within the surfactant structure. For
the catalyst and the product aer reaction and also to remove the investigated surfactants, T(3F) is in the range of 70 to 85  C.
the inorganic salts produced during the coupling reaction, As shown in Table 1, the Suzuki coupling reaction was per-
a conventional organic solvent was replaced by an aqueous formed with good yields, e.g. 91% for the surfactant Novel 8,
three phase microemulsion system containing a surfactant, with homo-coupling by-products less than 10%. Because of the
heptane, water, and the coupling reactants.20 Aer reaction, the fact that the product of the Suzuki coupling has to be processed
coupling product is obtained from the organic excess phase of further in the hydrogenation reaction applying the organic
the microemulsion system for its use in the consecutive reac- phase of step 1, also the distribution of the product between the
tions while the catalyst stays inside of the reactor (for gure of different phases is crucial. For the applied surfactants, 80 to
the microemulsion system see Fig. S3 in ESI†). The location of 90% of the product is in the organic excess phase. The rest of
the catalyst complex in the middle phase is due to the appli- the product is located in the middle phase together with the
cation of water soluble ligands which seem to have amphiphilic catalyst. In addition to classical surfactants, we also investi-
properties so that they might act as co-surfactants.24,25 The gated the short-chain amphiphile C4E2 for the coupling reac-
reaction can be performed applying a large variety of surfactants tion. To obtain a three phase system, higher amphiphile
at the same microemulsion composition (Table 1). concentration is necessary. The reaction itself gives good
results, but non-favourable product distribution with almost
half of the product in the middle phase is obtained, because
C4E2 acts only as a solvent and does not have the same prop-
Table 1 Suzuki coupling in three phase microemulsion systemsa
erties like surfactants, e.g. the formation of micellar structures.
Surfactant T(3F) ( C) Yield (%) Product, orgb To test the recyclability and stability of the homogenous Pd/
SPhos catalyst complex, the organic and the aqueous excess
Novel 6 70 44 n.d. phases were removed and the catalyst was kept under inert
Novel 7 70 70 88 conditions in the reactor. Aer adding fresh reactants the
Novel 8 77 91 90
reaction was continued. The homogeneous catalyst complex
Marlipal 24/50 80 87 86
Marlipal 24/70 85 63 87 can be recycled several times, which increases the productivity
Marlosol TA3080 75 84 79 of the Suzuki coupling reaction. The composition of single
C4E2c 60 88 56 phases was measured by ICP-OES for metal and ligand leaching,
a
Reaction conditions: 3 mmol 4-chlorophenylboronic acid, 3 mmol 1- surfactant concentration was determined, too. We found that
chloro-2-nitrobenzene, 4 mmol K2CO3, Pd(OAc)2 : SPhos ¼ 1 : 3 (0.07 about 30% of the water soluble SPhos ligand leaches into the
mmol Pd), 100 mL microemulsion consisting of 2.97 wt% surfactant, aqueous phase and about 30% of the surfactant leaches into the
48 wt% heptane, 48 wt% H2O, 1.03 wt% reactants, reaction time ¼ 30
min. b Product in the oil excess phase aer phase separation. organic phase. Ligand leaching has a strong impact on the yield
c
15% wt%. of the Suzuki coupling reaction and surfactant leaching shis

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the three phase region to higher temperatures. To compensate
these losses aer each run, the recycling experiments were
performed with the addition of 30% of SPhos and 30% of the
amphiphile, e.g. Marlipal 24/50. Furthermore, argon was used
as inert gas instead of nitrogen to reduce the possibility of
catalyst oxidation. Under these conditions, a stable yield of
about 80 to 85% is obtained in the following runs. Without any
modications, the yield drops signicantly aer the second run
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(Fig. 3).
3.2 Hydrogenation
In the second step of the Boscalid® synthesis, the hydrogena-
tion of the nitro group within the Suzuki coupling product to
the respective 2-amino-40 -chlorobiphenyl is investigated (Fig. 4).
We put our focus on the selection of an appropriate solvent
system rather than on the catalyst synthesis, because the solvent
Fig. 3 Catalyst recycling after Suzuki coupling reaction. Reaction
conditions: 3 mmol 4-chlorophenylboronic acid, 3 mmol 1-chloro-2-
nitrobenzene, 4 mmol K2CO3, Pd(OAc)2 : SPhos ¼ 1 : 3 (0.07 mmol
Pd), 100 mL microemulsion consisting of 2.97 wt% Marlipal 24/50, 48
wt% heptane, 48 wt% water, 1.03 wt% reactants, T(3f) ¼ 80  C,
reaction time ¼ 20 min.
Fig. 4 Scheme for the hydrogenation of the Suzuki coupling product (step 2).
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system should be processed further to the condensation reac-
tion. In literature, it is already reported that transition metals,
such as platinum,26,27 palladium,28 iridium,29 rhodium,30
ruthenium,31 and nickel32 are known as active hydrogenation
catalysts also for the selective reduction of nitro to amino
substituents. Unfortunately, in the case of chloro-substituted
substrates during the hydrogenation reaction a hydro-
dechlorination reaction (defunctionalisation) is oen observed
simultaneously. To overcome this problem alloys of these
metals33 can be used and promoter metals can be added.34,35 In
addition, the optimisation of the reaction conditions can have
a positive effect on selectivity. In contrast to the homogeneous
catalyst complex, where the SPhos ligand is denitively needed
to achieve high yields, a variety of homogeneous and hetero-
geneous catalysts can be used for the hydrogenation reaction.
We decided to apply a supported platinum catalyst which can be
easily removed by, e.g. ltration. Several supported Pt catalysts
were synthesised and tested using 1-chloro-2-nitrobenzene as
model substrate and based on its good performance (see Fig. S8
in ESI†), PtIr@TiO2, where iridium acts as promoter, was
selected for the hydrogenation within the Boscalid® synthesis.
For catalyst characterisation see ESI.†
The organic excess phase from the Suzuki coupling reaction
should be directly used in the hydrogenation reaction, whereby
the main solvent is heptane. If the hydrogenation of 40 -chloro-2-
nitrobiphenyl is carried out in pure heptane or in the organic
excess phase which contains also small amounts of leached
surfactant the conversion is low (see Fig. S9 in ESI†). The main
problem is the produced water which stays adsorbed at the
catalyst. Only if a polar co-solvent is added that can dissolve the
water, the reaction rate increases. In Table 2, the yields for
different solvent mixtures with heptane are shown, and the best
results are obtained for ethanol or 2-propanol.
The yield drops, if the ratio in the solvent mixture is shied
to higher heptane contents. However, too high amounts of
ethanol will cause problems in the condensation reaction (see
Section 3.3). For the hydrogenation beside the catalyst and
reactant concentrations also the hydrogen solubility is impor-
tant. Hydrogen solubility in ethanol is higher as in heptane or
cyclohexane, for which the reaction rate increases, and nally
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Table 2 Yields for the hydrogenation of 40 -chloro-2-nitrobiphenyla in 3.3 Condensation

different solvent systems
For the last reaction step of the total synthesis of Boscalid®,
Solvent system Y (%) preliminary experiments with commercially available 2-amino-
biphenyl as benchmark were carried out (see ESI†). The stan-
Heptane : EtOH 100
dard reaction procedure was similar as reported in the
Heptane : 2-propanolc 95
Heptane : EtOHc 79 literature36,37 with NEt3 as base and THF as solvent at room
Heptane : cyclohexanec 74 temperature. The conditions obtained from the best results
Heptane : THFc 38 were transferred to the synthesis of Boscalid® (Table 3), which
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Heptane : DCMc 18 was synthesised from 2-chloronicotinyl chloride and 2-amino-

a
Reaction conditions: 1.5 mmol 40 -chloro-2-nitrobiphenylb, 300 mg 40 -chlorobiphenyl (Fig. 5). The main reactant 2-amino-40 -chlor-
PtIr@TiO2, 200 mL solvent (heptane/co-solvent ¼ 1/1), 60  C, 5 bar obiphenyl was obtained from the hydrogenation of 2-nitro-40 -
H2, 2 h, n ¼ 2000 rpm. b 40 -Chloro-2-nitrobiphenyl was prepared by
chlorobiphenyl.
Suzuki coupling reaction in a three phase microemulsion system with
C4E2 as the amphiphile. c Volume ratio heptane/co-solvent ¼ 3/1. To nd the reaction conditions to obtain high yields, the
condensation reactions were tested with different stoichiometry
of 2-chloronicotinyl chloride, triethylamine, and 2-amino-
biphenyl using the same solvent system as for the hydrogena-
results in higher yields. In summary, a polar solvent with good tion reaction (volume ratio heptane/ethanol ¼ 1/1). The best
water and hydrogen solubility is benecial for the hydrogena- results are obtained for the reactions with the threefold amount
tion reaction. Although, we tested DCM as co-solvent, with of 2-chloronicotinyl chloride, whereas the concentration of the
respect to green chemistry its use should be avoided and base has no inuence on the reaction rate. The addition of the
replaced by e.g. ethyl acetate. base was only necessary to neutralise the formation of the
hydrochloric acid obtained as by-product of the condensation
reaction. Unfortunately, the reactions in protic solvents, e.g.
Table 3 Conversion and yield for the condensation reaction to ethanol or water, adherent with the decomposition of chloride
Boscalid®, for different solvent systemsa to nicotinic acid, decrease the yield. That's why we have carried
out the same reaction in aprotic solvents, e.g. THF or DCM and
Solvent X (%) Y (%) in a 1/1 mixture of heptane/co-solvent. The results for the
condensation of 2-aminobiphenyl (see ESI†) show that in these
Heptane : EtOH 33 26
Heptane : DCM 77 59 cases there is no decrease in activity and 100% of the product is
Heptane : THF 70 57 formed.
Heptane : EtOHb 57 51 The optimised conditions were applied in the total synthesis
Heptane : DCMb 99 95 of Boscalid® from threefold amount of 2-chloronicotinyl chlo-
Heptane : THFb 96 95
ride, 2-amino-40 -chlorobiphenyl and triethylamine (Table 3) in
Heptane : cyclohexaneb,c 95 95
Heptane : 2-propanolb,c 96 96 different protic and aprotic solvents. High yields are achieved
Heptane : EtOHb,c 95 77 for the synthesis in aprotic solvents heptane/DCM or heptane/
Heptane : DCMb,c 83 72 THF, and also in heptane/2-propanol with only small amounts
Heptane : THFb,c 96 89 of the alcohol (volume ratio heptane/2-propanol ¼ 3/1). These
a
Reaction conditions: 9.6 mmol 2-amino-40 -chlorobiphenyld, 2- results agree well with our preliminary experiments.
chloronicotinyl chloride : NEt3 : 2-amino-40 -chlorobiphenyl ¼ 1 : 1 : 1,
reaction volume ¼ 100 mL (heptane/co-solvent ¼ 1/1), reaction
temperature (20  2)  C, reaction time ¼ 5 min. b 2-Chloronicotinyl
chloride : NEt3 : 2-aminobiphenyl ¼ 3 : 1 : 1. c Volume ratio heptane/ 3.4 Boscalid® synthesis as tandem reaction
co-solvent ¼ 3/1. d Prepared from 40 -chloro-2-nitrobiphenyl by
hydrogenation (see Section 3.2). Three different reactions as parts of the total synthesis of
Boscalid®, namely Suzuki coupling reaction, hydrogenation

Fig. 5 Scheme for the condensation reaction to Boscalid® (step 3).

58284 | RSC Adv., 2016, 6, 58279–58287 This journal is © The Royal Society of Chemistry 2016
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reaction, and condensation reaction were investigated in detail
and optimised for their combination. Different reaction
conditions, catalyst precursors, homogeneous and heteroge-
neous catalysts, solvents and separation concepts for catalysts
and products were discussed. Finally, the three reactions were
combined to a complete Boscalid® synthesis process whereas
the best conditions for the individual steps were selected. First,
Suzuki coupling reaction was carried out in the three phase
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using hydrogen donors. Then, the heterogeneous catalyst was
separated by ltration and the hydrogenation product was
converted to Boscalid® by condensation with 2-chloronicotinoyl
chloride and NEt3 as base. The complete process is shown in
Fig. 6.
In addition to surfactants which were already tested for
optimisation of the Suzuki coupling reaction in microemulsion
systems, TPGS as greener surfactant alternative with sugar-

microemulsion system (surfactant, water, and heptane) in
a small scale ambient pressure glass reactor applying the
homogeneous Pd/SPhos catalyst complex to allow for catalyst
separation and reuse from the middle microemulsion phase.
Aer the reaction the organic phase with the coupling product
was transferred to a high pressure reactor and aer addition of
propanol as co-solvent (volume ratio heptane/propanol ¼ 3/1)
as well as the heterogeneous PtIr@TiO2 catalyst, the coupling
product was hydrogenated at 5 bar. In all our hydrogenation
experiments we used molecular hydrogen from a gas-bottle. As
hydrogen has several disadvantages, e.g. being ammable and
explosive, this step could be changed in the nal process to
avoid an excess of hydrogen. Hydrogen could be generated in
situ by electrolysis or transfer hydrogenation could be applied
shaped structure synthesised by Lipshutz et al.38–40 was tested.
As already mentioned above, the hydrophobic product is placed
in the organic excess phase and could be further processed to 2-
amino-40 -chlorobiphenyl by hydrogenation and nally to
Boscalid® by acylation. As solvent for the hydrogenation and
condensation reaction we selected a volume ratio heptane/
alcohol ¼ 3/1. This ratio was selected based on the investiga-
tion of the individual reactions. Also a vefold amount of
reactants was applied in this tandem reaction to increase the
productivity of the process. The yields for the tandem reaction
are summarised in Table 4.
All yields for the Suzuki coupling reaction are about 80% and
higher, whereas between 80 and 90% of the product is placed in
the organic excess phase, except for C4E2. The hydrogenation is

Fig. 6 Process flowsheet for the Boscalid® synthesis as tandem reaction. (1) Container for H2O, K2CO3, surfactant, and CBBA, (2) container for
heptane and CNB, (3) container for co-solvent, and (4) container for CNC and NEt3.

Table 4 Three step synthesis of Boscalid®

1st stepa 2nd stepb 3rd stepc

Surfactant T(3f) ( C) Y (%) Productorganic phase (%) YClPh2NH2 (%) Solvent YBoscalid® (%) Ytotal (%)

C4E2d 60 87 58 100 Propanol : heptane 1 : 3 76 66

Marlosol TA3080 75 98 79 73 Propanol : heptane 1 : 3 85 61
TPGS 60 94 86 100 Propanol : heptane 1 : 3 97 91
Marlipal 24/50 80 88 86 100 Propanol : heptane 1 : 3 96 84
Marlipal 24/50 80 80 81 81 Propanol : heptane 1 : 2 100 65
Marlipal 24/50 80 81 88 68 Cyclohexane : heptane 1 : 3 100 55
Marlipal 24/50 80 82 88 40 Cyclohexane : heptane 1 : 1 100 33
Marlipal 24/50 80 79 88 100 EtOH : heptane 1 : 3 100 79
Marlipal 24/50e 20 96 86 93 EtOH : heptane 1 : 3 100 89
a
6 mmol CBBA, 6 mmol CNB, 8 mmol K2CO3, Pd(OAc)2 : SPhos ¼ 1 : 3 (0.14 mmol Pd), 200 mL microemulsion consisting of 2.97 wt% surfactant, 48
wt% heptane, 48 wt% H2O, 1.03 wt% reactants, reaction time ¼ 30 min. b 40 -Chloro-2-nitrobiphenyl, 200 mL solvent, 300 mg PtIr@TiO2, pressure ¼
5 bar H2, reaction temperature ¼ 60  C, 2000 rpm, reaction time ¼ 2 h. c 2-Chloronicotinyl chloride : NEt3 : 2-amino-40 -chlorobiphenyl (3 : 1 : 1),
200 mL solvent, reaction temperature ¼ (20  2)  C, reaction time ¼ 5 min. d 15 wt%. e 5 eq. reactants.

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RSC Advances
quantitative for propanol or ethanol as co-solvents because of
the good water and hydrogen solubility. Mixtures of heptane
and propanol or cyclohexane show lower yields. The highest
yield for the Boscalid® synthesis, about 90%, is obtained for
TPGS. As mentioned earlier, the key step for a successful
tandem reaction is the Suzuki coupling reaction. Here, TPGS
shows a very good performance. Problematically, TPGS is
commercially not available and its synthesis might be accom-
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panied with higher costs. The technical grade surfactant Mar-
lipal 24/50 shows similar results, if the reactant concentration is
increased. The reaction times for the Suzuki coupling, hydro-
genation and acylation reaction are about 30 min, 2 h and 5
min, respectively. In individual cases, the yield can be increased
by increasing the reaction time, e.g. if hydrogenation is too slow
in the selected solvent.
4. Conclusion
Conventional synthetic routes for the total synthesis of
Boscalid® were widely reported in literature and consist of three
individual steps: Suzuki coupling, hydrogenation and conden-
sation reaction, e.g. Glasnov et al. reported Suzuki coupling of 4-
chlorophenylboronic acid and 1-chloro-2-nitrobenzene in
a mixture of butanol and water (tBuOH : H2O ¼ 4 : 1) at 160  C
with Pd(PPh3)4 catalyst.3 Hydrogenation of the product was
realised at 30 bar catalysed by a heterogeneous Pd@C (10 wt%
Pd) catalyst. For the last step the solvent was replaced by
dichloromethane to avoid the decomposition of 2-chlor-
onicotinoyl chloride. Also the total synthesis under milder
conditions is possible and Felpin et al.41 reported palladium
catalysed Suzuki coupling in methanol at room temperature for
12 h with 4-chloro-2-nitrobenzene and ortho-aryldiazonium salt
to obtain the desired product. Aerwards, iron-mediated
reduction of the nitro group and condensation to Boscalid®
were carried out in ethanol and tetrahydrofurane as solvents,
respectively. Also a synthesis route with only two steps as re-
ported by Santra et al.42 is possible. Suzuki coupling of 4-
chlorophenylboronic acid and 2-iodoaniline was catalysed by
palladium nanoparticles on graphite oxide in dioxane as solvent
at 100  C for 24 h. Aer the Suzuki coupling reaction, the
product that already contains the amino group was converted to
Boscalid® by addition of 2-nicotinyl chloride. The main
advantage of this synthetic route is the avoidance of the
hydrogenation step, but the activity and selectivity for the
Suzuki coupling is much lower. However, less attention is
drawn to the recycling of the homogenous catalyst complex in
the Suzuki coupling reaction and how the use of solvents can be
minimised. In our case, we apply a more environmentally
friendly concept for the total synthesis of Boscalid® by the
combination of single reaction steps to a tandem process in
only one solvent system. Using a three phase microemulsion
system for the rst Suzuki coupling step allows for an easier
catalyst separation and recycling from the middle phase. The
organic excess phase, containing the coupling product and
heptane, was further applied in the hydrogenation with
PtIr@TiO2 as the catalyst. This catalyst can be easily recycled. At
least, triethylamine and 2-chloronicotinoyl chloride were added
58286 | RSC Adv., 2016, 6, 58279–58287
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to the reaction mixture and the hydrogenation product was
converted to Boscalid®. In both reactions, hydrogenation and
condensation, the organic excess phase of step one containing
the hydrophobic solvent heptane was used without further
purication and only small amounts of an alcohol (volume ratio
heptane/alcohol ¼ 3/1) were added as co-solvent to optimise the
performance of the second step. Thereby, it is important that
the co-solvent is supporting the acylation reaction rather the
decomposition of 2-nicotinyl chloride. In total, we were able to
synthesize Boscalid® in three steps with a total yield up to 90%.
As the hydrogenation and condensation reaction in general are
easily to perform and could be done almost quantitative, the key
step of the Boscalid® synthesis is the Suzuki coupling reaction.
On the one hand, applying a microemulsion system allows for
catalyst recycling and product isolation, on the other hand,
product accumulates to a certain amount in the catalyst phase.
The surfactant plays an important role in the catalytic reaction
and phase behaviour, and the selection of the technical grade
surfactant Marlipal 24/50 out of a broad range of available
surfactants gave good results.
Acknowledgements
We gratefully acknowledge the nancial support of this project
by the Arbeitsgemeinscha industrieller For-
schungsvereinigungen (AiF, #17368N). We thank Prof. B. Lip-
shutz for a sample of the designer surfactant TPGS. We thank
the BASF Company for providing 40 -chloro 2-nitrobiphenyl.
References
1 P. T. Anastas and J. C. Warner, Green chemistry: theory and
practice, Oxford and New York, Oxford University Press, 1998.
2 C. L. Xiao and R. J. Boal, Plant Dis., 2009, 93, 185–189.
3 T. N. Glasnov and C. O. Kappe, Adv. Synth. Catal., 2010, 352,
3089–3097.
4 Metal-catalysis in Industrial Organic Processes, ed. G. P.
Chiusoli and P. M. Maitlis, The Royal Society of Chemistry,
2008.
5 T. Dwars, E. Paetzold and G. Oehme, Angew. Chem., Int. Ed.,
2005, 44, 7174–7199.
6 G. La Sorella, G. Strukul and A. Scarso, Green Chem., 2015, 17,
644–683.
7 I. Volovych, M. Schwarze, T. Hamerla, J. Blum and
R. Schomäcker, J. Mol. Catal. A: Chem., 2013, 366, 359–367.
8 I. Grassert and E. Paebold, Tetrahedron, 1993, 49, 6605–6612.
9 I. Grassert, U. Schmidt, S. Ziegler, C. Fischer and G. Oehme,
Tetrahedron: Asymmetry, 1998, 9, 4193–4202.
10 B. H. Lipshutz and B. R. Ta, Org. Lett., 2008, 10, 1329–1332.
11 M. Colladon, A. Scarso and G. Strukul, Adv. Synth. Catal.,
2007, 349, 797–801.
12 M. Schwarze, M. Schmidt, L. A. T. Nguyen, A. Drews,
M. Kraume and R. Schomäcker, J. Membr. Sci., 2012, 421–
422, 165–171.
13 T. Dwars, J. Haberland, I. Grassert, G. Oehme and U. Kragl, J.
Mol. Catal. A: Chem., 2001, 168, 81–86.
14 P. A. Winsor, Trans. Faraday Soc., 1948, 376–398.
This journal is © The Royal Society of Chemistry 2016

Paper
15 M. Kahlweit, R. Strey, P. Firman, D. Haase, J. Jen and
R. Schomaecker, Langmuir, 1988, 4, 499–511.
16 R. Schomäcker, M. Schwarze, H. Nowothnick, A. Rost and
T. Hamerla, Chem. Ing. Tech., 2011, 83, 1343–1355.
17 I. Volovych, Y. Kasaka, M. Schwarze, Z. Nairoukh, J. Blum,
M. Fanun, D. Avnir and R. Schomäcker, J. Mol. Catal. A:
Chem., 2014, 393, 210–221.
18 J.-Z. Jiang and C. Cai, J. Dispersion Sci. Technol., 2008, 29,
Published on 16 June 2016. Downloaded by UNIVERSIDAD SAO PAULO on 2/20/2023 5:42:25 PM.
453–456.
19 M. Schwarze, T. Pogrzeba, I. Volovych and R. Schomäcker,
Catal. Sci. Technol., 2015, 5, 24–33.
20 H. Nowothnick, J. Blum and R. Schomäcker, Angew. Chem.,
Int. Ed., 2011, 50, 1918–1921.
21 T. Hamerla, A. Rost, Y. Kasaka and R. Schomäcker,
ChemCatChem, 2013, 5, 1854–1862.
22 R. A. Altman and S. L. Buchwald, Nat. Protoc., 2007, 2, 3115–
3121.
23 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41,
1461–1473.
24 T. Pogrzeba, D. Müller, M. Illner, M. Schmidt, Y. Kasaka,
A. Weber, G. Wozny, R. Schomäcker and M. Schwarze,
Chem. Eng. Process., 2015, 99, 155–166.
25 M. Schmidt, T. Pogrezba, D. Stehl, R. Sachse, M. Schwarze,
R. von Klitzing and R. Schomäcker, Chem. Ing. Tech., 2016,
88, 119–127.
26 H.-U. Blaser, H. Steiner and M. Studer, ChemCatChem, 2009,
1, 210–221.
27 F. Zhao, R. Zhang, M. Chatterjee, Y. Ikushima and M. Arai,
Adv. Synth. Catal., 2004, 346, 661–668.
28 F. Figueras and B. Coq, J. Mol. Catal. A: Chem., 2001, 173,
223–230.
This journal is © The Royal Society of Chemistry 2016
View Article Online
RSC Advances
29 C. Campos, C. Torres, M. Oportus, M. A. Peña, J. L. G. Fierro
and P. Reyes, Catal. Today, 2013, 213, 93–100.
30 C. H. Campos, E. Rosenberg, J. L. G. Fierro, B. F. Urbano,
B. L. Rivas, C. C. Torres and P. Reyes, Appl. Catal., A, 2015,
489, 280–291.
31 B. Zuo, J. Catal., 2004, 222, 493–498.
32 Y. Du, H. Chen, R. Chen and N. Xu, Appl. Catal., A, 2004, 277,
259–264.
33 R. Raja, V. B. Golovko, J. M. Thomas, A. Berenguer-Murcia,
W. Zhou, S. Xie and B. F. G. Johnson, Chem. Commun.,
2005, 2026–2028.
34 X. Han, R. Zhou, G. Lai, B. Yue and X. Zheng, J. Mol. Catal. A:
Chem., 2004, 209, 83–87.
35 X. Han, R. Zhou, G. Lai, B. Yue and X. Zheng, Catal.
Commun., 2003, 89, 255–259.
36 M. C. S. Lourenço, M. V. N. de Souza, A. C. Pinheiro,
M. Ferreira, R. S. B. Gonçalves, T. C. M. Nogueira and
M. A. Peralta, ARKIVOC, 2007, 2007, 181–191.
37 R. J. Cvetovich and L. DiMichele, Org. Process Res. Dev., 2006,
10, 944–946.
38 B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T. Nishikata,
C. Duplais, A. Krasovskiy, R. D. Gaston and R. C. Gadwood, J.
Org. Chem., 2011, 76, 4379–4391.
39 B. H. Lipshutz and S. Ghorai, Aldrichimica Acta, 2008, 41, 59–
72.
40 B. H. Lipshutz, B. R. Ta, A. R. Abela, S. Ghorai,
A. Krasovskiy and C. Duplais, Platinum Met. Rev., 2012, 56,
62–74.
41 F.-X. Felpin, E. Fouquet and C. Zakri, Adv. Synth. Catal.,
2009, 351, 649–655.
42 S. Santra, P. K. Hota, R. Bhattacharyya, P. Bera, P. Ghosh and
S. K. Mandal, ACS Catal., 2013, 3, 2776–2789.
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