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Synthesis of Boscalid via a three-step telescoped

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Cite this: React. Chem. Eng., 2018, 3,

continuous flow process implemented on a MJOD
550 reactor platform†
Audun Drageset, Vijayaragavan Elumalai and Hans-René Bjørsvik *

Received 28th March 2018,
Accepted 22nd June 2018
DOI: 10.1039/c8re00049b
rsc.li/reaction-engineering
A three step continuous/semi-flow process leading to the fungicide Boscalid® is disclosed. The first step of
the process is a Suzuki cross-coupling where 1-chloro-2-nitrobenzene is coupled with
4-chlorophenylboronic acid at a temperature of 80 °C using a solvent mixture of ethanol/water as the re-
action medium with sodium carbonate as the base and tetrakisIJtriphenylphosphine)-palladium as the cata-
lyst. This reaction step was developed as a batch procedure and then adapted and implemented on a
multi-jet oscillating disk (MJOD) continuous flow reactor platform. The intermediate 4′-chloro-2-nitro-1,1′-
biphenyl was achieved in high yield (82%). The second step which was telescoped with the first one in-
volved a nitro group reduction of high efficacy. The reduction method was based on NaBH4/CoSO4·7H2O
as the reduction system. The reduction product 2-amino-4′-chloro-1,1′-biphenyl was achieved in high
yield (79%) at a short reactor residence time (3 min). The final step of the process is composed of a two-
step sequence where 2-amino-4′-chloro-1,1′-biphenyl is transformed into the corresponding imino-
sulfanone intermediate (not isolated), which immediately reacts with the 2-chloronicotinic acid present in
the reaction mixture to form Boscalid® in a yield of >66%. The three-step process provided an overall yield
of >42%, which corresponds to a mean step yield of ≈75%.

Introduction The synthetic manufacturing process leading to Boscalid®

Customarily, process research and development projects
rarely include synthetic route discovery as a part of the pro-
cess re-engineering for the transfer of established batch pro-
cesses into continuous flow operations. In fact, usually identi-
cal synthetic methods are re-cycled in an adapted and
optimized continuous flow process version.
This report reveals results from a process re-engineering
where a batch process leading to Boscalid® is transformed into
a continuous flow process, a transformation that, in addition
to the change of methodology (batch to flow), encompassed
modified procedures and types of reactions. The process is a
three-step telescoped synthetic process that leads to 2-chloro-N-
(4′-chloro-[1,1′-biphenyl]-2-yl)nicotinamide 7, an agro-chemical
product that was developed by BASF and launched onto the
market in 2003 under the tradename Boscalid®.
Boscalid® is a succinate dehydrogenase inhibitor that fa-
cilitates the control of ascomycetes on various fruits and veg-
etables.1 The annual production volume of this agrochemical
was reported2 to be >1000 metric tons per year.
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen,
Norway. E-mail: hans.bjorsvik@kj.uib.no; Tel: +47 55 58 34 52
† Electronic supplementary information (ESI) available: Full spectra and other
recorded analytical data. See DOI: 10.1039/c8re00049b
is an attractive process to investigate for several academic re-
search groups, which have made important contributions in
the form of improved reaction chemistry and, not least, impor-
tant contributions in order to redesign and establish processes
applicable with continuous flow reactor technologies.2,3
Based on the current patent literature,4 a thinkable indus-
trial synthesis of Boscalid® might be that outlined in
Scheme 1.
The first synthetic step involves a PdIJ0)-catalysed Suzuki
cross-coupling reaction where 1-chloro-2-nitrobenzene 1 is
coupled with 4-chloro-phenylboronic acid 2.
The nitro group of the obtained cross-coupling product 4′-
chloro-2-nitro-1,1′-biphenyl 3 is subsequently reduced to the
corresponding substituted aniline 4. The ultimate reaction step
involves amidation where 4′-chloro-[1,1′-biphenyl]-2-amine 4 is
reacted with 2-chloro-nicotinyl chloride 6 to afford the target
product Boscalid® 7. The reagent 2-chloro-nicotinyl chloride 6
is produced by treating 2-chloro-nicotinyl acid 5 with SOCl2.
Results and discussion
Design and development of a flow process to synthesize
Boscalid®
A series of various methods were evaluated in order to identify
reaction protocols suitable for continuous flow processing.

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Scheme 1 Synthesis of 2-chloro-N-(4′-chloro-[1,1′-biphenyl]-2-
yl)nicotinamide (Boscalid®) 7 comprises ① a Suzuki cross-coupling re-
action, ② a nitro group reduction, and finally, ④ an amidation reaction.
We attempted as well to accommodate issues that might im-
prove the environmental contour for each synthetic step.
Our outlined synthetic pathway comprised three distinct
synthetic steps, which at the first glance don't appear very dif-
ferent to the suggested literature route (Scheme 1): namely, ①
a Suzuki cross-coupling using 1-chloro-2-nitrobenzene 1 and
4-chlorophenylboronic acid 2 as reaction partners, ② a reduc-
tion of the nitro group using a method involving CoIJII)
catalysed sodium borohydride reductions, and in the ultimate
step ③ a single step amide bond formation, an operation that
usually requires a separate step (step ④) for the purpose of ac-
tivation of the carboxylic acid reagent.
① The Suzuki cross-coupling5
Our group has previously developed a Suzuki cross-coupling
method for the synthesis of 2-nitro-1,1′-biphenyls 3 using
cheap and readily available chloronitroarenes and
phenylboronic acids as the coupling partners, a protocol that
exploits PdIJPPh3)4 as the catalytic system.6 Kappe and
Table 1 Screening of solvent mixtures for the Suzuki cross-coupling reaction
# Solvent T [°C]
1 MeOH/H2O 120
2 MeOH/H2O 120
3 MeOH/H2O 90
4 MeOH/H2O 110
Reaction procedure: in a microwave vial, 1-chloro-2-nitrobenzene 1 (1 mmol), 4-chloro phenylboronic acid 2 (1.5 mmol), Na2CO3 (1.1 mmol), the
phase transfer catalyst tetrabutylammoniumbromide (TBAB; 0.08 mmol), and PdIJPPh3)4 (0.026 mmol, 2.6 mol%) were added. The vial was
sealed and argon was flushed through the septum before a mixture of MeOH (4 mL) and water (1 mL) was added. The vial was submerged in
the microwave cavity for 30 min at 120 °C. The isolated yields were reported.
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collaborator3b disclosed previously a method applicable for
conducting continuous flow Suzuki cross-coupling, a method
that required an elevated temperature (160 °C), which was in-
cluded as a reaction step in their attempt to construct a contin-
uous flow synthesis of Boscalid®. Schwarze and collaborators3d
reported a batch synthetic method that could be conducted at
a low temperature (80 °C), but this method demanded expen-
sive and more sophisticated ligands and additives to facilitate
the Suzuki cross-coupling reaction. Compared with the previ-
ously reported methods, our new Suzuki cross-coupling
method utilises environmentally benign solvents, a base and
the simple and cheap ligand PPh3. Moreover, our method re-
quires a short reaction time and a substantially lower reaction
temperature (80 °C) in continuous flow (in batch: 120 °C) to
obtain the target intermediate 4′-chloro-2-nitro-1,1′-biphenyl 3
in excellent yield (82–85%).
Solvent screening
One of the vital goals to achieve a simple and smoothly inter-
connected multi-step synthesis is telescoped synthetic steps.
This might be solved by 1) including one or more in-line ar-
rangements for solvent exchange, or 2) identifying a solvent
(or solvent mixture) that could be used throughout the three
synthetic steps of the process. The simplest and most elegant
solution would be to find a solvent that is compatible with
all of the three steps that constitute the process. Thus, we
performed solvent screening experiments in batch adapted
for the synthesis of compound 3, Table 1. Our Suzuki cross-
coupling method worked out perfectly with most of the
solvent-water mixtures that were investigated, but the etha-
nol/water mixture was revealed to be an excellent reaction
medium for the flow process, as this solvent mixture allows
the all-embracing telescoping of reaction steps ① and ②,
Scheme 2.
② Nitro group reduction
Numerous methods for the reduction of nitro compounds to
the amino group have previously been reported.7 A recently
Conv. [%] Yield [%]
100 85
100 85
75 64
100 83
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Scheme 2 Batch and continuous flow syntheses leading to Boscalid® 7.
published work from our group utilized indium metal pow-
der as the reducing agent for the reduction of the nitro group
to the amino group. Even if this method provides high selec-
tivity and requires a simple work-up,8 it is not suitable for
continuous flow operation due to the difficulty of pumping
and feeding exact quantities of solids as homogeneously dis-
tributed slurries. In our search for a potential reduction
method that does not involve pressurized hydrogen gas, we
came across a method utilized within the field of fuel cell
technology.9 The method comprises a sodium borohydride
reduction of transition metal ions producing hydrogen and a
transition metal boride, Scheme 3.
Previous disclosures reveal that the method might be used
as a reduction method for organic functional groups.10 We in-
vestigated therefore this protocol as a potential nitro group re-
duction method. We conducted a screening of various cobaltIJII)
salts with sodium borohydride as the reductant, from which
we could establish a reduction method appropriate for the re-
duction of several functional groups, including the nitro group
Scheme 3 Sodium borohydride reduction of CoIJII) ions that produce
hydrogen gas and nano-sized solid di-cobalt boride.
552 | React. Chem. Eng., 2018, 3, 550–558
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which was one of our primary tasks. From our studies using
the NaBH4/CoII reduction system, we elaborated a proposal for
the reaction mechanism that suggests that the solid nano-
particle sized side product Co2B operates as a mediator for the
reduction of the nitro group,11 summarized in Scheme 4.
The experiments revealed that neither the dicobalt boride
alone nor dicobalt boride under hydrogen could reduce the
nitro compound to the corresponding amine. However, mix-
tures of Co2B with NaBH4 rapidly (3–10 min) catalyzed the ni-
tro → amine conversion (reduction) in high yield.
Furthermore, the reduction method could utilize the post-
reaction mixture from the Suzuki cross-coupling directly
without any need for work-up or purification, Scheme 2.
③ Amidation
The final step in the synthesis of the target molecule
Boscalid® 7 encompasses amidation. The previously pub-
lished method, outlined in step ③ of Scheme 1 comprises
Scheme 4 Sodium borohydride reduction of the nitro group
mediated by cobaltIJII) boride.
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the reaction between an amine and an acid chloride using

DCM as the reaction medium with the presence of an amine
base (triethylamine). The acid chloride is produced before-
hand in a separate synthetic step ④. We initially examined
this reaction as a batch procedure, which afforded a high
yield of the target molecule Boscalid®. By serendipity, during
our reaction investigations, we (re-)discovered an alternative
pathway that requires identical reagents and substrates as
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the those of the classical amidation method, but that could

be conducted in one pot, namely 4 + SOCl2 → [8]‡ + 5 → 7.
The amine and thionyl chloride can react to form imino-
sulfanone12 (here intermediate 8), which subsequently reacts
with carboxylic acid 5 to produce the corresponding amide
7.13 During the screening trials in our laboratory, an experi-
ment was carried out with the amine 4, 2-chloronicotinic acid
5, and thionyl chloride in one pot. The crude reaction mix-
ture was analysed with GC-MS, which revealed ((4′-chloro-
[1,1′-biphenyl]-4-yl)imino)-sulfanone 8. The reaction mixture
was left stirring and ultimately worked-up. Analysis of the iso-
lated product revealed, surprisingly to us, the target product
Boscalid® 7 in an excellent yield (97%). This reaction step
was further investigated and developed in an attempt to find
a more environmentally benign solvent as the reaction me-
dium. This work was aided by means of a statistical experi-
mental design14 and multivariate regression.15 From this pro-
cess improvement, we revealed that the amidation via the
iminosulfanone intermediate 8 could be conducted in ethyl
acetate as the reaction medium with pyridine as the amine
base using a reaction temperature of 70 °C and a flow reactor
residence time of 10 min.
Details of this process improvement/optimization study
are provided in the ESI.†
Fig. 1 Process flow diagram for the continuous flow synthesis of
16 Boscalid® including semi-continuous work-up unit operations. Pump
Continuous flow process flow rates: P1 = 0.90 mL min−1, P2 = 1.65 mL min−1, P3 = 0.45 mL
Our design for a continuous flow process for Boscalid® 7 is min−1, P4 = 14.48 mL min−1, P5 = 4.34 mL min−1, P6 = 2.17 mL min−1,
outlined in the process flow diagram, Fig. 1, and in the lower P11 = 8.95 mL min−1, P12 = 0.05 mL min−1, P13 = 6 mL min−1. The flow
rate into R7-STH is 3 mL min−1. Volume of each (a–f) of the
part (“continuous flow synthesis”) of Scheme 2. crystallisation tanks R7-SHT is 5000 mL, which results in a filling time
Our research group has previously designed, developed, of ≈4h per R7-SHT unit.
and realized a continuous flow reactor platform, a flow chem-
istry approach that we named multi-jet oscillating disk
(MJOD) continuous flow reactor described in detail in ref. 17. can be used for the reduction of alkenes, alkynes, azides, ni-
Various MJOD flow reactor platforms have successfully been triles, and nitroarenes.11 The latter process is also used
utilized in a series of assorted applications in organic synthe- herein for the nitro group reduction.
sis, including the synthesis of phenylboronic acids at cryo- The Suzuki cross-coupling, step ① of Scheme 2, was
genic temperatures under argon, a process that also involved conducted in a multi-jet oscillation disk continuous flow re-
handling of BuLi,18 organocatalyzed epoxidation of alkenes actor MJOD1, which was heated to 80 °C using a heat-oil cir-
using molecular oxygen as a terminal oxidant,19 organometal- cuit (HE-1). The multi-jet disk rack that is placed in the cen-
lic (Ru) catalyzed olefin metathesis reactions,20 synthesis of tre of the reactor tube of the MJOD1 was oscillated at a
the iodination agent 1,3-diiodo-5,5-dimethyl-imidazolidine- frequency of f = 2 Hz using the oscillator cam mechanism O1
2,4-dione (DIH) in a telescoped process including product iso- that was propelled by a speed adjustable electric motor.
lation by means of semi-continuous filtration,21 mono- and The various reagents were placed as solutions in the reser-
di-iodination of the imidazole backbone, processes that in- voirs R1–R3 and pumped (pumps P1–P3) into the MJOD1
corporated continuous flow extraction as an integrated opera- flow reactor at the lower input section point of the flow reac-
tion of the process,22 and recently, a high rate (3–10 min) tor. The pump rates (for the pumps P1–P3) were mutually ad-
Co2B mediated sodium borohydride reduction process that justed to afford accurate stoichiometry for the reaction

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mixture concomitantly affording a predefined residence time
(t = 30 min). The flow reactor residence time was based on
experience from batch experiments. The crude reaction mix-
ture was collected at the output section on top of the MJOD1
reactor and transferred via tubing to the hold-up tank (R4-
HT).
The nitro-group reduction (flow synthesis step ② of
Scheme 2) was conducted in the continuous flow reactor
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1-chloro-2-nitrobenzene 1 from the Suzuki cross-coupling step
undergoing subsequent reduction and amidation.
The MJOD flow reactor
The technical specifications for the MJOD continuous flow re-
actors (MJOD1–MJOD3) used in the present work are pro-
vided in Fig. 2. The MJOD continuous flow reactor is
constructed from a stainless steel tube (height, H) as the re-

MJOD2. In the centre of the reactor tube, the multi-jet disk action chamber. This reactor tube is placed in a vertical di-
rack was adjusted to oscillate at a frequency of f = 3 Hz using rection. The flow reactor utilizes an active mixing system to
the oscillator O2. The reactor temperature was adjusted to T = produce turbulence independent of the actual liquid flow
21 °C using the heating/cooling circuit HE-2. rate. This is achieved with a multi-jet disk assembly placed in
The collected crude intermediate of reservoir R4-HT was the center of the reactor tube. The multi-jet disk assembly is
pumped (P4) into the MJOD2 reactor together with a solution composed of a certain number N of multi-jet disks and disk
of the reducing reagent NaBH4 (placed in reservoir R5) and spacers (N − 1). The internal multi-jet assembly is connected
the cobalt sulphate solution (R6) at rates that afforded a total to a cam mechanism that is driven by a speed regulated elec-
reactor residence time of t = 3 min. tric motor where the amplitude A and oscillating frequency f
The reaction mixture was filtered (F1) the reactor outlet in can be adjusted. The temperature of the reactors is regulated
order to remove the di-cobalt boride (Co2B), a by-product that by means of a jacket that encloses the reactor tube along its
operates as a catalyst for the reduction process.11 The liquid
flow was collected in one of the semi-continuous crystallizers
(R7-SHT a–f) where 4′-chloro-[1,1′-biphenyl]-2-amine 4 crystal-
lized over an 18–20 h period. However, in this work, we used
only two R7-STH (a-b) units of 1 L each and conducted the
crystallization outside the flow set-up.
The crude crystals of 4′-chloro-[1,1′-biphenyl]-2-amine 4
were filtered off using one of the semi-continuous filters (F2
a, b) and dried (batch) (D1). The isolated product from D1
was transferred to a dissolving and hold-up tank (R10-STH)
and dissolved in dry ethyl acetate.
The flow reactor MJOD3 was heated to 70 °C using HE-3.
The oscillator O1 was adjusted at a frequency of f = 2 Hz. A
semi-continuous reagent handling arrangement was used for
the reagent feeding of 2-chloronicotinic acid 5 in ethyl acetate
(from the reservoir R8) and pyridine (from the reservoir R9),
which were transferred and mixed in a hold-up tank (R10-
STH). The contents of R10-STH were transferred to reservoir
R11 whereupon R10-STH could be used to prepare another
batch. The mixture of the reagents 2-chloronicotinic acid 5,
pyridine, and 4′-chloroij1,1′-biphenyl]-2-amine 4 (placed in
R11) and neat thionyl chloride (placed in R12) were pumped
(using the pumps P11 and P12) into the input/mixing zone of
the flow reactor MJOD3. The feeding flows were adjusted to
afford an overall residence time of t = 10 min. The reaction
mixture was in-line quenched by pumping (using pump P13)
water (from reservoir R13, 20 °C) at a position close in dis-
tance to the output section of the continuous flow reactor
MJOD3.
The quenched post-reaction mixture was collected in a liq-
uid–liquid separator (R14-LS), whereof the organic layer was
collected and transferred to reservoir R15 for final isolation
by means of a rotatory evaporator at a reduced pressure to
obtain the target product Boscalid® in an overall yield of
42%, which corresponds to ≈75% in each of the three steps.
The crude product contained 2-chloro-N-(2-chlorophenyl)- Fig. 2 Specifications of the MJOD continuous flow reactors MJOD1–
nicotinamide as a by-product as a result of unconverted MJOD3.

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entire length. This jacket is connected to a pump that circu-
lates a heating/cooling liquid in the spacing between the
outer jacket and the reactor tube. The reservoir tank
containing the cooling/heating liquid is temperature regu-
lated by means of a heat exchanger. The reactants are
pumped into the input section (located at the bottom of the
reactor) at programmed flow rates.
One-way valves were incorporated into the feeding lines in
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order to prevent kick-back to the feeding pumps caused by
the oscillating MJOD assembly. The post reaction mixture
was collected at the output section that is located on top of
the reactor.
Experimental
General methods
All chemicals were used as received from suppliers. GC analy-
ses were performed using a capillary gas chromatograph
equipped with a fused silica column (L 25 m, 0.20 mm i.d.,
0.33 mm film thickness) with a split less/split injector and a
flame ionization detector at a helium pressure of 200 kPa.
Mass spectra were obtained on a GC-MS instrument, using a
gas chromatograph equipped with a fused silica column (L
30 m, 0.25 mm i.d., 0.25 mm film thickness) and helium as
the carrier gas. DART-mass spectra were obtained using PEG
as the internal standard in the positive ionization mode with
a TOF mass analyzer. 1H-NMR and 13C-NMR spectra were
recorded at ambient temperature at a frequency of 500 and
125 MHz, respectively.
The chemical shifts were reported in ppm relative to resid-
ual CHCl3 for proton (δ = 7.26) and CDCl3 for carbon (δ =
77.0) and residual DMSO-d6 for proton (δ = 2.50) and for car-
bon (δ = 39.51) using TMS as the external reference. Flash
chromatography was performed by means of the hexane (mix-
ture of isomers) and ethyl acetate solvent system using silica
gel (230–400 mesh).
The microwave-assisted experiments were performed by
means of a Biotage Initiator Sixty EXP Microwave System,
that operates at 0–400 W at 2.45 GHz, in the temperature
range of 40–250 °C, a pressure range of 0–20 bar (2 MPa, 290
psi), and with reactor vial volumes of 0.2–20 mL.
4′-Chloro-2-nitro-1,1′-biphenyl 3. To a microwave reactor
tube, 1-chloro-2-nitrobenzene 1 (0.25 g, 1.58 mmol),
4-chlorophenylboronic acid 2 (0.373 g, 2.39 mmol), Na2CO3
(0.184 g, 1.75 mmol), the phase transfer catalyst tetrabutyl
ammonium bromide (TBAB, 0.041 g, 0.13 mmol), and
PdIJPPh3)4 (0.047 g, 0.042 mmol) were added. The reactor tube
was sealed and argon was flushed through the septum, and
then, a mixture of EtOH (4 mL) and water (1 mL) was added.
After stirring for 10 s, the reactor tube was submerged into
the microwave cavity for 30 min at 120 °C. The solvent etha-
nol was then removed under reduced pressure using a rotary
evaporator. The reaction mixture was diluted in diethyl ether
(50 mL) and washed with water (50 mL). The aqueous phase
was extracted with diethyl ether (2 × 50 mL) and the organic
phases were combined and dried over Na2SO4. The drying
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agent was filtered off and the crude product was purified by
flash column chromatography [EtOAc : Hx, 10 : 90] to afford
the title compound 3 as a pale-yellow solid (0.315 g, 85%). Rf
= 0.55 (EtOAc/hexane, 10 : 90). 1H-NMR (500 MHz, CDCl3): δ
(ppm) = 7.79–7.82 (dd, J = 1.0, 8.0 Hz, 1H), 7.54–7.57 (td, J =
1.5, 8.0 Hz, 1H), 7.41–7.45 (td, J = 1.5, 8 Hz, 1H), 7.32–7.34
(m, 3H), 7.17–7.18 (m, 2H); 13C-NMR (125 MHz, CDCl3): δ
(ppm) = 149.1, 135.9, 135.2, 134.5, 132.5, 131.9, 129.3, 128.9,
128.6, 124.3; HR-MS (EI): (M)+: calcd for C12H835ClNO2+
233.02381; found 233.02417; calcd for C12H1837ClNO2
235.02086; found 235.02146; MS (EI): m/z (%) = 232.8 (22, M
+), 198.0 (24), 170.0 (29), 168.0 (30), 153.0 (16), 152.0 (100),
151.0 (52), 142.0 (41), 139.0 (39), 126.0 (29), 115 (52), 87 (18),
76 (55), 75 (53), 74 (30), 63 (38), 62 (16).
4′-Chloro-[1,1′-biphenyl]-2-amine 4. 4′-Chloro-2-nitro-1,1′-
biphenyl 3 (119 mg, 0.51 mmol) was dissolved in ethanol (5
mL). To the stirred solution, CoSO4·7H2O (143 mg, 0.51
mmol) dissolved in water (0.7 mL) was added. The reaction
mixture was cooled to 0 °C, whereupon NaBH4 (77 mg, 2.04
mmol) dissolved in ethanol (1.5 ml) was added slowly. In-
stantly, a black granular precipitate (Co2B) and copious quan-
tities of hydrogen were formed. The reaction mixture was
stirred at ambient temperature for 10 min. The reaction mix-
ture was then filtered using a Buchner funnel to remove the
precipitate. The filtered solution was diluted with EtOAc (50
mL) and washed with water (50 mL). The aqueous layer was
then extracted with EtOAc (2 × 50 mL). The organic layers
were combined and dried over Na2SO4. The drying agent was
filtered off and the solvent was evaporated under reduced
pressure to obtain the title compound 4 as a brown solid
(0.099 g, 95%). Rf = 0.63 [(EtOAc : Hx, 30 : 70)]; 1H-NMR (500
MHz, CDCl3): δ (ppm) = 7.41–7.42 (m, 4H), 7.16–7.19 (td, J =
1.5 Hz, 8 Hz, 1H), 7.09–7.11 (dd, J = 1.5 Hz, 7.5 Hz, 1H), 6.82–
6.85 (td, J = 1 Hz, 7.5 Hz, 1H), 6.76–6.78 (dd, J = 1 Hz, 8 Hz,
1H), 3.73 (s, br, 2H); 13C-NMR (125 MHz, CDCl3): δ (ppm) =
143.4, 138.0, 133.1, 130.5, 130.3, 129.0, 128.8, 126.3, 118.8,
115.7; HR-MS (DART+): (M + H)+: calcd for C12H1135ClN+
204.05745; found 204.05764; calcd for C12H1137ClN 206.05450;
found 206.05148; MS (EI): m/z (%) = 205 (29), 204 (16), 203
(95, M+), 168 (56), 167 (100), 141 (10), 140 (12), 139 (20), 115
(12), 89 (7), 84 (12), 83.4 (19), 70.5 (12).
2-Chloronicotinoyl chloride 6. To a stirred solution of
2-chloronicotinic acid 5 (0.30 g, 1.59 mmol) in diethyl ether
(10 mL), pyridine (0.16 ml, 3.18 mmol) and thionyl chloride
(0.24 mL, 3.18 mmol) were added slowly under a N2 atmo-
sphere at 0 °C. After the addition, the reaction mixture was
stirred at ambient temperature for 60 min. Water (20 mL)
was then added and the resulting mixture was extracted with
diethyl ether (2 × 50 mL). The organic layers were combined
and dried over Na2SO4. The drying agent was filtered off and
the solvent was removed under reduced pressure to afford
the title compound 6 as a white powder (0.270 g, 96%). 1H-
NMR (500 MHz, DMSO-d6): δ (ppm) = 8.55–8.56 (dd, J = 2 Hz,
5 Hz, 1H), 8.22–8.24 (dd, J = 2 Hz, 7.5 Hz, 1H), 7.53–7.55 (m,
1H); 13C-NMR (125 MHz, DMSO-d6): δ (ppm) = 165.7, 151.7,
147.7, 140.0, 128.1, 123.1.
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2-Chloro-N-(4′-chloro-[1,1′-biphenyl]-2-yl)nicotinamide 7
Method 1. To a stirred solution of 2-amino-4′-
chlorobiphenyl 4 (0.050 g, 0.246 mmol) in CH2Cl2 (10 mL),
triethylamine (0.068 mL, 0.492 mmol) and 2-chloronicotinoyl
chloride 6 (0.043 g, 0.246 mmol) were added slowly at 0 °C
under an inert atmosphere. After the addition, the reaction
mixture was stirred at room temperature for 10 min. After the
reaction time, the reaction mixture was quenched with water
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(40 mL) and extracted with CH2Cl2 (2 × 40 mL). The organic
extracts were combined and dried over Na2SO4. The drying
agent was filtered off and the solvent was removed using a
rotary evaporator. The crude product was purified by using
flash chromatography [EtOAc : Hx, 15 : 85] to afford the title
compound 7 as a white solid (0.070 g, 83%). Rf = 0.13
[(EtOAc : Hx, 15 : 85)]; 1H-NMR (500 MHz, CDCl3): δ (ppm) =
8.38–8.39 (dd, J = 2 Hz, 5 Hz, 1H), 8.34–8.36 (d, J = 8 Hz, 1H),
8.07–8.09 (m, 2H), 7.36–7.38 (m, 2H), 7.26–7.30 (m, 3H), 7.19–
7.20 (m, 3H); 13C-NMR (125 MHz, CDCl3): δ (ppm) = 162.5,
151.4, 146.7, 140.2, 136.3, 134.5, 134.4, 132.2, 131.1, 130.8,
130.2, 129.3, 128.9, 125.3, 122.9, 122.1; HR-MS (DART+): (M +
H)+: calcd for C18H13Cl2N2O+ 343.03994; found 343.03789;
calcd for C18H1335Cl37ClN2O+ 345.03699; found 345.03581;
calcd for C18H1337Cl2N2O+ 347.03404; found 347.03422; MS
(EI): m/z (%) = 341.9 (3, M+), 204.0 (3), 167.0 (11), 166.0 (10),
142.0 (30), 141.0 (8), 140.0 (100), 139.0 (12), 138.0 (3), 114.0
(31), 111.9 (44), 76.0 (12).
Method 2. To a stirred mixture of 2-chloronicotinic acid 5
(0.050 g, 0.317 mmol) in CH2Cl2 (10 mL), thionyl chloride
(0.047 mL, 0.630 mmol) and pyridine (0.077 mL, 0.951 mmol)
were added slowly to the reaction mixture at 0 °C under an
inert atmosphere, followed by the addition of a solution of 4′-
chloro-[1,1′-biphenyl]-2-amine 4 (0.064 g, 0.317 mmol) in
CH2Cl2 (5 mL). The reaction mixture was stirred for 10 min
at room temperature and monitored by using GC-MS; a quan-
titative conversion yield of iminosulfanone intermediate 8 af-
ter 10 min was observed. A prolonged a reaction time (60
min) at room temperature afforded the title compound in
quantitative yield based on GC-MS. After the reaction time,
the reaction mixture was quenched with water (40 mL) and
extracted with CH2Cl2 (2 × 50 mL). The organic layers were
combined and dried over Na2SO4. The drying agent was fil-
tered off and the solvent was removed under reduced pres-
sure using a rotary evaporator to achieve compound 7 as a
pale-white solid (0.105 g, 97%). Rf = 0.30 [(EtOAc : Hx, 30 :
70)]; 1H-NMR (500 MHz, DMSO-d6): δ = 10.15 (s, 1H), 8.47–
8.48 (dd, J = 2 Hz, 4.5 Hz, 1H), 7.86–7.88 (dd, J = 1.5 Hz, 7.5
Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.50–7.52 (m, 3H), 7.45–7.48
(m, 3H), 7.39–7.40 (m, 2H); 13C-NMR (125 MHz, DMSO-d6): δ
= 164.2, 150.3, 146.5, 137.8, 137.7, 136.4, 133.9, 132.9, 132.1,
130.7, 130.2, 128.3, 127.8, 127.4, 126.9, 123.0; HR-MS (ESI +
DI): (M + H)+: calcd for C18H13Cl2N2O+ 343.03994; found
343.04098; calcd for C18H1335Cl37ClN2O+ 345.03699; found
345.03881; calcd for C18H1337Cl2N2O+ 347.03404; found
347.08921; (M + Na)+: calcd for C18H12Cl2N2NaO+ 365.02189;
found 365.02277; calcd for C18H1235Cl37ClN2NaO+ 367.01894;
found 367.02042; calcd for C18H1237Cl2N2NaO+ 369.01599;
556 | React. Chem. Eng., 2018, 3, 550–558
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Reaction Chemistry & Engineering
found 369.02030; MS (EI): m/z (%) = 343.9 (9), 342.9 (3), 341.9
(14, M+), 204 (5), 201.0 (3), 167.0 (13), 166.0 (13), 142 (30),
141.0 (8), 140.0 (100), 139.0 (12), 138.0 (4), 114.0 (30), 111.9
(43), 76.0 (13).
Method 3. 4′-Chloro-[1,1′-biphenyl]-2-amine 4 (0.30 mmol,
66 mg) and 2-chloronicotinic acid 5 (0.36 mmol, 57 mg) were
added to a reaction flask (8 mL) together with a magnetic
stirrer bar and sealed. The flask was flushed with argon and
dry ethyl acetate was added (6 mL). Dry pyridine (1.23 mmol,
0.1 mL) was added and the reaction mixture was heated (70
°C) under vigorous stirring. Thionyl chloride (1.03 mmol,
0.075 mL) was then added dropwise. The reaction mixture
was stirred for 15 min before it was quenched with water (2
mL). The reaction mixture was extracted with ethyl acetate (3
× 3 mL) and washed with brine (2 × 2 mL) before being dried
over sodium sulphate, whereupon the solvents were removed
under reduced pressure. The isolated solid was analysed
using GC-MS revealing the target product 7 in a yield of 93%
(0.28 mmol, 95 mg). GC-MS (EI) m/z (%): 344 (27.0), 342
(40.5), 307 (3.3), 167 (12.8), 142 (31.0), 140 (100), 114 (11.6),
112 (31.9), 76 (9.0).
Continuous flow synthesis protocols
Prior to commencing, using the outlined mini-plant as
shown in Fig. 1, the MJOD continuous flow reactors (MJOD1–
MJOD3) were dried by heating (70 °C) concomitantly passing
a flow of Ar.
Flow synthesis of 4′-chloro-2-nitro-1,1′-biphenyl (3). The
MJOD1 flow reactor was heated to 80 °C (HE-1) and the oscil-
lator (O1) was adjusted to a frequency of f = 2 Hz. 1-Chloro-2-
nitrobenzene 1 (10 mmol, 1.57 g) in ethanol (30 mL) was
placed in reservoir R1 under an argon atmosphere. PdIJPPh3)4
(2.5 mol%, 0.6 g) was then added to R1 and the reservoir was
sonicated in order to reduce the catalyst particle size.
4-Chlorophenylboronic acid 2 (15 mmol, 2.34 g) was placed in
reservoir R2 and partially dissolved in ethanol (55 mL). The
mixtures in R1 and R2 were kept as stable suspensions using
mechanical stirrers. Na2CO3 (22 mmol, 2.3 g) was dissolved in
H2O (15 mL) and placed in the reservoir R3. The reservoirs
R1–R3 were connected to their corresponding pumps (P1–P3),
and the suspensions were pumped into the MJOD1 flow reac-
tor at rates that afforded an overall residence time of 30 min
(P1 = 0.9 mL min−1, P2 = 1.65 mL min−1, and P3 = 0.45 mL
min−1), which correspond to a total flow rate of 3 mL min−1
The post reaction mixture was collected in R4-HT. The second
process step was prepared while filling R4-HT to account for
the difference in flow rates in the two steps (output MJOD1 =
3 mL min−1 vs. crude input of R4 to MJOD2 = 14.48 mL
min−1). The flow reactor MJOD2 was heated to a temperature
of 21 °C (HE-2) and the oscillator was adjusted to 3 Hz (O2).
NaBH4 (40 mmol, 1.52 g) was dissolved in a 0.3 M NaOH solu-
tion (30 mL) and placed in reservoir R5. CoSO4·7H2O was
dissolved in H2O (15 mL) and placed in reservoir R6. The
crude reaction mixture from the Suzuki cross-coupling of 4′-
chloro-2-nitro-1,1′-biphenyl 3 in 100 mL EtOH/H2O (in
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Reaction Chemistry & Engineering
reservoir R4) was pumped along with the reagent mixtures in
the reservoirs R5 and R6 into the flow reactor MJOD2 at rates
that afford an overall residence time of 3 min (P4 = 14.48 mL
min−1, P5 = 4.34 mL min−1, and P6 = 2.17 mL min−1). The
crude reaction mixture was filtered (to remove CoB2) on filter
F1 which was placed at the flow reactor outlet while the fil-
trate was collected in the stirred hold-up tanks R7-STHa/b.
The crystallizers were regulated at temperature of 10 °C and
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stirred using a mechanical stirrer while subjected to streams
of inert gas. 4′-Chloro-[1,1′-biphenyl]-2-amine 4 crystallized
overnight. The crystals were collected on the filter F2, where-
upon the isolated crystals were dried in the tumble dryer D1
(45 °C, 200 mbar) before further use. The MJOD3 was heated
to 70 °C (HE-3). The oscillation rate (O3) was adjusted to f = 2
Hz. The dried product (from D1), 4′-chloro-[1,1′-biphenyl]-2-
amine (7.9 mmol, 1.62 g) was added to the stirred hold-up
tank R10 containing dry ethyl acetate (114 mL) under an ar-
gon atmosphere. 2-Chloronicotinic acid (8.7 mmol, 1.36 g)
from R8 and dry pyridine (2.4 mL, 29.8 mmol) from R9 was
added to R10. The contents of R10 were emptied into R11-a/b
after all the solids were dissolved. SOCl2 (0.72 mL, 9.9 mmol)
was prepared in R12. The solutions in reservoirs R11–12 were
pumped using their corresponding pumps into the MJOD re-
actor giving a residence time of 10 min (P11 = 8.95 mL min−1
and P12 = 0.05 mL min−1) The reaction mixture was quenched
in-line with water in R13 (P13 = 6 mL min−1) before it was col-
lected in the liquid–liquid separator R13-LS. The organic
phase was analyzed by means of GC-MS, showing full conver-
sion to the target product. The organic phase was collected
and dried over sodium sulphate. The solvents were then re-
moved under reduced pressure yielding the crude product
(2.39 g), which was isolated using column chromatography
giving a 66% isolated yield of the target product Boscalid
(1.79 g, 5.22 mmol). GC-MS (EI) m/z (%): 344 (27.0), 342
(40.5), 307 (3.3), 167 (12.8), 142 (31.0), 140 (100), 114 (11.6),
112 (31.9), 76 (9.0). Unconverted 1-chloro-2-nitrobenzene 1
from the Suzuki cross-coupling underwent reduction and sub-
sequent amide bond formation to form 2-chloro-N-(2-
chlorophenyl)nicotinamide. GC-MS (EI) m/z (%): 266.0 (5.9),
231.1 (84.2), 140.0 (100), 112 (51.8), 76.1 (20.5).
Conclusions
In summary, we have designed and developed a practical and
efficient three-step telescoped continuous flow synthesis for
the production of 2-chloro-N-(4′-chloro-[1,1′-biphenyl]-2-
yl)nicotinamide 7 (Boscalid®). The multi-step telescoped con-
tinuous flow process was developed and implemented on a
multi-jet oscillating disk (MJOD) reactor platform, which, in
addition, was furnished with semi-continuous unit opera-
tions for purification and work-up. The established flow pro-
cess produced the intermediate 3 at a rate of 3.4 g h−1. In the
subsequent reaction step, the intermediate 4 was produced at
a rate of 10.0 g h−1, and in the ultimate process step, the tar-
get product Boscalid® 7 was produced at a rate of 8.4 g h−1
(which is the throughput of synthesis step 3).
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Paper
One of the highly useful results achieved in this work, the
nitro group reduction, which encompasses the use of sodium
borohydride with cobalt sulphate in the hydrogenation/reduc-
tion method, was proved to be a very versatile method. The
extremely good mixing created by the mechanical up/down
movement of the multi-jet assembly which is located in the
centre of the reactor tube allowed the successful operation of
the MJOD continuous flow reactor even if the solid cobalt bo-
ride formed as a by-product precipitates during the course of
the reaction. These results reveal that the MJOD continuous
flow reactor can even be used as a platform for hydrogena-
tion reactions.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
A. D. and V. E. gratefully acknowledge the Department of
Chemistry at the University of Bergen - Norway for funding
their research fellowships. Dr. Bjarte Holmelid is acknowl-
edged for the excellent technical support with the HRMS
analyses.
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