Toward a continuous-flow synthesis of Boscalid

Article abstract of DOI:10.1002/adsc.201000646

A two-step continuous-flow protocol for the synthesis of 2-amino-4′-chlorobiphenyl, a key intermediate for the industrial preparation of the fungicide Boscalid is described. Initial tetrakis(triphenylphosphine)palladium-catalyzed high-temperature Suzuki-Miyaura cross-coupling of 1-chloro-2-nitrobenzene with 4-chlorophenylboronic acid in a microtubular flow reactor at 160°C using the tert-butanol/water/potassium tert-butoxide solvent/base system provides 4′-chloro-2-nitrobiphenyl in high yield. After in-line scavenging of palladium metal with the aid of a thiourea-based resin, subsequent heterogeneous catalytic hydrogenation is performed over platinum-on-charcoal in a dedicated continuous-flow hydrogenation device. The overall two-step homogeneous/heterogeneous catalytic process can be performed in a single operation providing the desired 2-amino-4′- chlorobiphenyl in good overall yield and high selectivity. Copyright

Full text of DOI:10.1002/adsc.201000646

UPDATES
DOI: 10.1002/adsc.201000646
ꢀ
Toward a Continuous-Flow Synthesis of Boscalid
a
a,
Toma N. Glasnov and C. Oliver Kappe *
a
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens University
Graz, Heinrichstrasse 28, A-8010 Graz, Austria
Fax : (+43)-316-380-9840; phone: (+43)-316-380-5352; e-mail: oliver.kappe@uni-graz.at
Received: August 18, 2010; Published online: November 9, 2010
[
1]
Abstract: A two-step continuous-flow protocol for
the synthesis of 2-amino-4’-chlorobiphenyl, a key
intermediate for the industrial preparation of the
ous fruits and vegetables.
Introduced into the
market by BASF in 2003, the current total production
volume of this fungicide is more than 1000 tons/
year. Although not described in full detail in the rel-
evant patent literature, the industrial synthesis of
Boscalid outlined in Scheme 1 relies on the Pd(0)-
catalyzed Suzuki–Miyaura cross-coupling of 1-chloro-
2-nitrobenzene (1) with 4-chlorophenylboronic acid
(2). The obtained 4’-chloro-2-nitrobiphenyl intermedi-
ate (3) can then be selectively reduced to the corre-
sponding aniline 4, thus preserving the halogen func-
tionality, which plays an important role for fungicidal
activity. In the final step, aniline 4 is reacted with 2-
chloronicotinoyl chloride (5) to produce Boscalid
(6). The key Pd(0)-catalyzed carbon-carbon cross-cou-
pling step leading to biaryl 3 is currently one of the
largest known industrial applications of the Suzuki–
ꢀ
[2]
fungicide Boscalid is described. Initial tetrakis(tri-
[
3]
phenylphosphine)palladium-catalyzed high-temper-
ature Suzuki–Miyaura cross-coupling of 1-chloro-2-
nitrobenzene with 4-chlorophenylboronic acid in a
microtubular flow reactor at 1608C using the tert-
butanol/water/potassium tert-butoxide solvent/base
system provides 4’-chloro-2-nitrobiphenyl in high
yield. After in-line scavenging of palladium metal
with the aid of a thiourea-based resin, subsequent
heterogeneous catalytic hydrogenation is performed
over platinum-on-charcoal in a dedicated continu-
ous-flow hydrogenation device. The overall two-
step homogeneous/heterogeneous catalytic process
can be performed in a single operation providing
the desired 2-amino-4’-chlorobiphenyl in good over-
all yield and high selectivity.
ꢀ
[
1]
ꢀ
[
2,4]
Miyaura reaction.
In the past few years, the use of microreactors and
continuous-flow technology in general has become in-
creasingly popular in synthetic organic chemistry.
Because of the high surface-to-volume ratio in micro-
reactors, heat transfer is very efficient and reaction
temperatures in microreactors can be changed effi-
ciently by application or removal of heat. Enhanced
mass transfer characteristics and the ability to effi-
ciently optimize reaction conditions by control of resi-
dence time add value to the technology. In addition,
[5,6]
Keywords: cross-coupling; flow chemistry; hetero-
geneous catalysis; homogeneous catalysis; hydroge-
nation; microwave chemistry
Introduction
process intensification can readily be achieved by op-
ꢀ
[7]
Boscalid (6) is an important fungicide belonging to erating in a high-temperature/high-pressure regime.
the class of succinate dehydrogenase inhibitors that A particularly attractive feature of microreaction
enables the efficient control of ascomycetes on vari- technology is the ease with which reaction conditions
ꢀ
[3]
Scheme 1. Industrial synthesis of Boscalid .
Adv. Synth. Catal. 2010, 352, 3089 – 3097
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3089

Toma N. Glasnov and C. Oliver Kappe
UPDATES
Table 1. Reaction optimization for the microwave-assisted Pd-catalyzed Suzuki–Miyaura coupling of 1-chloro-2-nitrobenzene
[a]
(
1) with 4-chlorophenylboronic acid (2).
[b]
Entry
Catalyst [mol%]
Base [equiv.]
K PO , [3]
Additive [equiv.]
Solvent [v/v]
Product distribution 1/3/D [%]
1
2
3
4
5
7
8
9
Pd
Pd
Pd
Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) [1.0]
TBAB [0.1]
TBAB [0.1]
–
DMF:H O, [1:1]
22/53/25
97/0/3
31/50/19
26/58/16
100/0/0
64/36/0
8/90/2
0/89/11
0/99/1
0/99/1
2
3
4
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) [1.0]
A
H
U
G
R
N
N
(i-Pr) NEt, [1.5]
DMF:H O, [1:1]
2
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) [1.0]
KOH, [1.5]
KOH, [1.5]
NaOH [2.0]
NaOH [2.0]
NaOH [2.0]
KOH [1.3]
NaOH [1.3]
NaOH [1.3]
NaOEt [2]
DMF:H O, [6:1]
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) [5.0]
TBAB [0.5]
THF:H O, [6:1]
2
2
PdCl [0.15]
PPh [0.006]
THF:H O, [3:1]
2
3
2
Pd/C [0.25]
Pd/C [0.5]
PPh [0.01]
THF/H O [1:1]
3
2
PPh [0.02]
THF/H O [1:1]
3
2
Pd
Pd
Pd
Pd
Pd
Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.5]
–
THF/H O [6:1]
3
4
2
[
[
c]
c]
10
11
12
13
14
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.25]
TBAB [0.025]
THF/H O [1:1]
3
3
4
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.25]
–
–
–
–
THF/H O [1:1]
4
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.25]
EtOH
t-BuOH
0/99/1
0/98/2
0/99/1
3
3
4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.25]
K-t-OBu [1.3]
K-t-OBu [1.3]
4
[
c]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh ) [0.25]
t-BuOH/H O [4:1]
3
4
2
[
a]
General reaction conditions: 0.2 mmol 1-chloro-2-nitrobenzene (1), 0.22 mmol (1.1 equiv.) 4-chlorophenylboronic acid (2),
mL of solvent, sealed vessel single-mode microwave irradiation (Monowave 300, Anton Paar GmbH). See the Experi-
2
mental Section for further information.
Product distribution refers to relative peak area (%) ratios of crude GC-MS traces: starting material 1/product 3/dehalo-
genated product (nitrobenzene).
[
[
b]
c]
Only these protocols were sufficiently homogeneous to be transferred to a flow process.
can be scaled through the operation of multiple sys- achieving high throughput in continuous-flow synthe-
[
7,8]
tems in parallel or other techniques, thereby readily sis.
achieving production scale capabilities.
[
8]
The starting point for our studies involved the
With this background in mind we herewith describe adaptation of the originally disclosed
[3]
Suzuki–
a continuous-flow protocol for the generation of the Miyaura cross-coupling of 1-chloro-2-nitrobenzene (1)
ꢀ
key Boscalid intermediate 2-amino-4’-chlorobiphenyl with 4-chlorophenylboronic acid (2) to 4’-chloro-2-ni-
(
4, Scheme 1) employing a combination of two pro- trobiphenyl (3) into a high-speed microwave protocol.
cess intensified microreactor steps.
The most favourable reaction conditions for this
cross-coupling described in the patent literature uti-
lize either a combination of a Pd(II) salt and phos-
Results and Discussion
phine ligand [PPh , (t-Bu) P], or Pd ACHTUNGTRNNEU(G PPh ) complex
3 3 3 4
as transition metal catalyst (catalyst loading 0.15–
[
3]
Although in recent years a number of alternative 3.5 mol%). In a typical coupling experiment either
transition metal-catalyzed cross-coupling protocols for THF, DME or toluene is used as solvent in combina-
the synthesis of the initial 4’-chloro-2-nitrobiphenyl tion with aqueous NaOH or Na CO as base. Re-
[3]
2
3
intermediate 3 have been disclosed in the litera- ported reaction times to achieve complete conversion
[9–14]
ꢀ
ture,
our continuous-flow route toward Boscalid
for this Suzuki–Miyaura cross-coupling are between 8
is based on the original Suzuki–Miyaura BASF strat- and 18 h at 65–1008C, clearly unsuitable for continu-
egy (Scheme 1) as this appeared to be the most prac- ous-flow processing where reaction times (=residence
[
5–8]
tical and economical route. Following the “micro- times) of a few minutes are generally desired.
[
15,16]
wave-to-flow” optimization paradigm,
all three
In our hands, performing the Suzuki–Miyaura
reaction steps were first investigated on a small scale cross-coupling under controlled microwave conditions
using sealed vessel batch microwave heating as a pro- in a dedicated single-mode reactor with accurate in-
cess intensification method in order to derive at the ternal temperature control (Monowave 300, Anton
[
17]
shortest possible reaction times, a prerequisite for Paar GmbH) proceded very well.
For most of
the evaluated catalyst systems [in particular for
3090
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3089 – 3097

ꢀ
Toward a Continuous-Flow Synthesis of Boscalid
[3]
Pd ACHTUNGTRENNUNG( PPh ) ], solvents and additive combinations, high comparing conventional heating (65–1008C, 8–22 h)
3 4
conversions were achieved employing 1.1 equivalents with microwave heating (1608C, 15 min, Table 1)
of the boronic acid and selecting 1608C as the reac- were in fact only due to a thermal effect and not to a
tion temperature and 15 min as reaction time direct involvement of the electromagnetic field, and
[18]
(
Table 1).
Lower reaction temperatures or shorter therefore could be mimicked in a conventionally
times led to a slower cross-coupling, less attractive for heated flow system. For this purpose the two opti-
subsequent flow processing, whereas higher tempera- mized sets of conditions (Table 1, entries 11 and 14)
tures produced more undesired side products. Special were repeated in the microwave batch reactor em-
attention was paid to the selection of a proper base ploying a reaction vessel made out of strongly micro-
for this transformation, keeping the general require- wave absorbing silicon carbide. This technology
ment for homogeneous reaction conditions in the con- allows separation of thermal from electromagnetic
[
5–8]
[20]
tinuous-flow process in mind.
Various organic and field effects. As expected, the results using genuine
inorganic bases such as (i-Pr) NEt, K CO , Cs CO , microwave dielectric heating and heating by conduc-
2
2
3
2
3
NaOMe, NaOEt and t-BuOK were tested and com- tion in the silicon carbide vessel were identical.
[
3]
pared to the originally reported NaOH and Na CO .
Employing the flow reactor system we initially at-
2
3
Similarly, different solvents including MeOH, EtOH, tempted to perform the Suzuki–Miyaura reaction fol-
n-BuOH, t-BuOH, DMF, DME and solvent mixtures lowing the THF/H O conditions (Table 1, entry 11).
2
containing varying amounts of water were also evalu- Using the 16 mL reaction coil, a flow speed of
ꢀ
1
ated as possible reaction media. Different sources of 1 mLmin and 1608C coil temperature were selected
catalytic Pd such as PdCl and Pd(OAc) were also (=16 min residence time) in order to attain compara-
AHCTUNGTRENNUNG
2
2
examined. From this reagent matrix we were able to ble conditions to the microwave experiments (1608C,
[
16]
identify the two optimal sets of conditions which 15 min reaction time). Although flow processing of
worked particularly well under batch microwave con- the reaction mixture (0.1M concentration) was suc-
ditions and fulfilled the criteria of short reaction cessfully performed through the reactor, only minor
times and reaction homogeneity throughout the over- amounts of the desired biaryl product 3 were detected
all process: (i) THF/H O (1:1) as a solvent mixture, (<5%, GC-MS) and most of the starting materials
2
0.25 mol% Pd
ACHTUNGTRENNUNG( PPh ) as a catalyst and 1.3 equivalents were recovered from the reaction mixture. Careful re-
3 4
of NaOH as a base; or (ii) t-BuOH/H O (4:1) as a sol- evaluation of the initial microwave batch experiments
2
vent mixture, 0.25 mol% Pd CAHTUNGTRENN(UG PPh ) as a catalyst and showed that while the initial THF/H O reaction mix-
3 4 2
1.3 equivalents of t-BuOK as a base (see Table 1, en- ture was completely homogeneous, after microwave
tries 11 and 14). Utilizing these conditions, the processing two clearly separated phases had devel-
Suzuki–Miyaura cross-couplings were remarkably oped. We speculated that while in the batch micro-
clean in the concentration range of 0.1–1.0M with wave runs using intense magnetic stirring this was not
only minute amounts of dehalogenated side product a problem, the laminar flow regime likely experienced
(
nitrobenzene, traces) being observable by GC-MS in a tubular/coil flow reactor may lead to inefficient
analysis of the crude reaction mixture. Employing a mixing of reaction components (starting materials,
reaction temperature of 1608C (~10 bar) and a reac- base, catalyst) dissolved in the two phases and thus to
tion time of 15 min, full conversion was observed for
a
low conversion. Gratifyingly, by adding
both protocols, providing 4’-chloro-2-nitrobiphenyl (1) 0.025 equivalent (2.5 mol%) of tetrabutylammonium
in 91% isolated yield after chromatographic purifica- bromide (TBAB) as a phase-transfer catalyst this
tion.
issue was resolved and under these modified condi-
Continuous-flow experimentation was performed in tions full and clean conversion in both the microwave
a high-temperature, high-pressure microtubular flow run (Table 1, entry 10) and the flow experiment was
unit that can be used for processing homogeneous re- observed, with a 90% isolated yield of 4’-chloro-2-ni-
action mixtures (X-Cube Flash, Thales Nanotechnolo- trobiphenyl (3) being produced from the flow reactor.
[19]
gy Inc.). The reactor uses stainless steel coils (i.d.
When using the t-BuOH/H O conditions (Table 1,
2
1000 mm) of variable length (4, 8, and 16 mL volume) entry 14) no TBAB addition was required since the
that can be directly heated across their full length by reaction mixture did not show any phase separation
electric resistance heating to temperatures up to and flow processing at 1608C (16 min residence time)
3508C. The reaction mixture is introduced to the reac- resulted in full conversion providing 89% isolated
tor block containing the steel coils and a heat ex- yield of the target 4’-chloro-2-nitrobiphenyl (3). The
changer via one or more standard HPLC pumps (flow high-temperature continuous-flow conditions intro-
ꢀ
1
rate: 0.01–10.0 mLmin ). The system pressure valve duced herein for the Suzuki–Miyaura cross-coupling
sets and stabilizes the set pressure value between a involving an aryl chloride compare favourably with
pressure range of 50–180 bar. Before moving to a the throughput achieved in previous continuous-flow
[
21,22]
flow format we ensured that the rate enhancements Suzuki–Miyaura reactions.
seen for the Suzuki–Miyaura cross-coupling 1+2!3
Adv. Synth. Catal. 2010, 352, 3089 – 3097
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3091

Toma N. Glasnov and C. Oliver Kappe
UPDATES
[
25]
For the selective reduction of the nitro group in 4’- fer hydrogenations.
Previous studies from our
chloro-2-nitrobiphenyl (3) we have envisaged a group have found that microwave-assisted transfer hy-
heterogeneous transition metal-catalyzed hydrogena- drogenations of aromatic nitro compounds can be ef-
ACHTUNGTRENNUNG
tion protocol as these methods generally can be easily fectively carried out using Pd/C as a catalyst under
transformed into a scalable continuous-flow process microwave conditions at 1608C (EtOH, cyclohexene)
[
23]
employing a fixed-bed catalyst reactor. To the best providing the corresponding anilines in high yields
[
26]
of our knowledge, in the context of the synthesis of after only 2 min reaction time.
However, in the
ꢀ
Boscalid such an approach has never been consid- case of 4’-chloro-2-nitrobiphenyl (3), the use 1 mol%
ered, and most of the published methods employ of a standard 10% (w/w) Pd/C catalyst led to a signifi-
[
10,12]
more traditional reducing agents such as SnCl
or cant over reduction, producing ~25% (GC-MS) of
2
[13]
Fe/NH Cl. Following the “microwave-to-flow” opti- the undesired 2-aminobiphenyl by-product (7, see
mization regime, initial experiments were carried out Table 2) in addition to the target Boscalid intermedi-
4
ꢀ
in a batch microwave reactor. Although it is possible ate 2-amino-4’-chlorobiphenyl (4). Gratifyingly, using
[
27]
to perform hydrogenations with molecular hydrogen 1 mol% of a 5% (w/w) Pt/C catalyst and 5 equiva-
under pressure using controlled microwave condi- lents of cyclohexene at 1508C in EtOH, clean and
[24]
tions, we considered a catalytic transfer hydrogena- complete reduction of the nitro group was obtained
tion protocol for safety and convenience reasons, not providing 2-amino-4’-chlorobiphenyl (4) within 30 min
requiring a specialized microwave apparatus that in 81% isolated yield after solvent removal and subse-
allows pre-pressurization of the sealed reaction vial quent flash chromatography. Under these conditions
with hydrogen gas. For the nitro group reduction in only trace amounts of the dehalogenated 2-aminobi-
4’-chloro-2-nitrobiphenyl (3), cyclohexene was found phenyl product (7) were observed (GC-MS, <1%).
to be a hydrogen donor of appropriate reactivity, not The use of different solvents like MeOH, THF/H O
2
necessitating the use of more reactive 1,4-cyclohexa- (1:1) or t-BuOH/H O (4:1) did not have any signifi-
2
diene or 1-methyl-1-cyclohexene which have recently cant effect on the reaction outcome.
been reported for microwave-assisted catalytic trans-
[a]
Table 2. Reaction optimization for the continuous flow hydrogenation of 4’-chloro-2-nitrobiphenyl (3).
Entry
Catalyst
[w/w%]
Solvent,
concentration [M]
Temp. [8C]/
Pressure [bar]
Flow rate
Product distribution
3/4/7 [%]
[b]
ꢀ1
[c]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A[ mLmin ]
H
U
G
R
N
N
1
2
3
4
5
6
7
8
9
Pd/C, 10
RaNi
RaNi
MeOH, 0.1
MeOH, 0.1
MeOH, 0.1
MeOH, 0.1
MeOH, 0.2
40/50
40/50
40/50
40/50
40/50
40/50
75/atm
60/atm
45/atm
30/atm
30/atm
1.0
1.0
1.5
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0/25/75
7/43/50
14/64/22
0/99/1
Pt/C, 10
Pt/C, 10
Pt/C, 10
Pt/C, 10
Pt/C, 10
Pt/C, 10
Pt/C, 10
Pt/C, 10
0/99/1
THF/H O 1:1, 0.1
0/91/9 [
2
d]
t-BuOH/H O 4:1, 0.05
0/48/23
2
t-BuOH/H O 4:1, 0.05
0/80/20
0/94/6
0/99/1
0/99/1
2
t-BuOH/H O 4:1, 0.05
2
1
1
0
1
t-BuOH/H O 4:1, 0.05
2
t-BuOH/H O 4:1, 0.1
2
[
a]
General reaction conditions: H-Cube, substrate 3 dissolved in 2 mL of solvent were pumped at the given flow rate
through the reactor, 30ꢂ4 mm i.d. catalyst cartridge, ~150 mg catalyst. For further details, see the Experimental Section.
atm=full-H mode: the instrument is working at atmospheric pressure, applying all of the generated H from the elec-
[
b]
2
2
trolysis cell to the processed reaction mixture; 50 bar=controlled-H mode: the instrument is maintaining the selected H2
2
pressure using only a part of the generated H2.
Product distribution refers to relative peak area (%) ratios of crude GC-MS traces: starting material 3/product 4/over-re-
duced product 7.
The remaining ~30% consists of a mixture of hydrogenation products where one or both of the aromatic rings in the bi-
phenyl skeleton were fully reduced (GC-MS).
[
[
c]
d]
3092
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3089 – 3097

ꢀ
Toward a Continuous-Flow Synthesis of Boscalid
ꢀ
Before moving to a flow format we confirmed that
The final step in the Boscalid synthesis requires
the use of microwave irradiation did not produce se- the formation of a standard amide bond (Scheme 1).
[
24]
[3,13]
lective heating phenomena on the Pt/C catalyst ap- In agreement with the literature,
we find that this
[
20]
plying the silicon carbide reaction vial procedure,
amide coupling can be readily performed at room
and that therefore the results achieved in the micro- temperature using commercially available 2-chloroni-
wave reactor were of purely thermal origin. Hydroge- cotinoyl chloride (5) in the presence of a base (Et N,
3
ꢀ
nations under continuous flow conditions were per- THF) providing Boscalid in 89% yield within
formed in a high pressure hydrogenator enabling het- 10 min. Although it is evident that process intensifica-
erogeneous hydrogenations at temperatures up to tion is not required for this last step we nevertheless
1
008C and 100 bar of hydrogen pressure in continu- have evaluated a direct microwave-assisted amidation
[26]
ous-flow mode (H-Cube, Thales Nanotechnology protocol that involves heating 2-amino-4’-chlorobi-
Inc.). The pre-packed, replaceable cartridge of the phenyl (4) with 2-chloronicotinic acid in MeCN in the
[28]
heterogeneous catalyst (30ꢂ4 mm i.d., circa 100– presence of 1 equivalent of PCl . Microwave heating
3
ꢀ
200 mg catalyst/cartridge) contained in the system, at 1508C for 10 min provided Boscalid in 87% yield
allows a uniform substrate flow (mixed with hydro- after chromatographic purification.
gen) without catalyst leaching, circumventing the
Our ultimate goal in this project was to merge the
need to filter the catalyst from the substrate after the Suzuki–Miyaura cross-coupling and the hydrogena-
hydrogenation process is completed. The substrate/hy- tion in a two-step flow process to generate the key
ꢀ
drogen mixture flows through the packed catalyst Boscalid intermediate 2-amino-4’-chlorobiphenyl (4)
bed, leading to a very high ratio between the active in a single synthetic operation. Performing multi-step
area catalyst and the amount of hydrogen and sub- continuous-flow syntheses is considerable more chal-
[28]
strate. The flow hydrogenation of 4’-chloro-2-nitro- lenging than carrying out individual transformations
biphenyl (3) was initially performed in MeOH solu- in flow since all substrates (including concentration
tion using catalyst cartridges filled with Pd/C, RaNi levels), reagents, catalysts, additives, and the solvents
and Pt/C. As can be seen from the data presented in used in the first step must be compatible with all the
[
29]
Table 2, only the use of Pt/C – similar to the transfer subsequent reaction steps. In addition, if an uninter-
hydrogenation experiments described above – provid- rupted line of flow systems is employed, the flow
ed a high selectivity for nitro group reduction. For ex- rates and back pressures also have to be adjusted ac-
ample, selective hydrogenation (~99% selectivity) cordingly. In our initial experiments, the reaction mix-
over a standard Pt/C catalyst (10% w/w) was obtained ture (0.1M concentration) resulting from the opti-
by using a 0.1M stock solution at a flow rate of mized Suzuki–Miyaura cross-coupling flow process
ꢀ
1
3
mLmin at 408C under 50 bar hydrogen pressure using t-BuOH/H O (4:1) as reaction medium (see
2
(
Table 2, entry 4). Based on the measured dead above) was flowed into the H-Cube hydrogenator
volume of around 140 mL of the catalyst cartridge using Pt/C as a catalyst and flow conditions similar to
30ꢂ4 mm i.d., 150 mg Pt/C), a residence time of less those described in Table 2, entry 10, providing a 95%
than 3 s for hydrogenation over the catalyst can be overall conversion. Disappointingly, the desired 2-
(
ꢀ
1
calculated by applying a 3.0 mLmin flow rate (the amino-4’-chlorobiphenyl product (4) was contaminat-
residence time in the complete H-Cube system is ed with ~12% of the over-reduced 2-aminobiphenyl
around 50 s at this flow rate). Having the eventual (7). This drop in selectivity can be rationalized by Pd
combination of the Suzuki–Miyaura cross-coupling metal used as homogeneous catalyst for the Suzuki–
and the hydrogenation step in mind (see below), flow Miyaura cross-coupling in step 1 entering the hydro-
hydrogenation experiments were also performed with genation apparatus and contaminating the heteroge-
[
30]
THF/H O or t-BuOH/H O as solvent mixtures, result- neous Pt/C catalyst cartridge. In order to eliminate
2
2
ing in similar high selectivities under carefully opti- this problem Pd metal was scavenged in-line using a
TM
mized conditions. Notably, lower temperatures pro- macroporous Quadrapure TU (thiourea) resin car-
[
31]
vided higher selectivities for the desired nitro group tridge
housed in an X-Cube flow reactor (Thales
[
32]
reduction (Table 2, compare entries 7–11). Too high Nanotechnology Inc.) placed between the X-Cube
hydrogenation temperatures in combination with the Flash and the H-Cube flow devices (Figure 1). Using
Pt/C catalyst produced hydrogenation products where this experimental configuration the formation of over-
in addition to functional group hydrogenation one or hydrogenated side product 7 was reduced to <1%
both of the aromatic rings in the biphenyl skeleton utilizing appropriate hydrogenation conditions
were fully reduced (Table 2, entry 7). Utilizing the op- (Figure 1). The desired key intermediate in the
ꢀ
timized conditions however (Table 2, entry 11), a 10- Boscalid synthesis, 2-amino-4’-chlorobiphenyl (4),
mL experiment delivered 93% (>96% purity, GC- could therefore be obtained in 77% overall yield
MS) crude yield of the desired 2-amino-4’-chlorobi- (after chromatography, 90% crude yield) in a single
phenyl product (4).
operation combining a Pd-catalyzed Suzuki–Miyaura
Adv. Synth. Catal. 2010, 352, 3089 – 3097
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3093

Toma N. Glasnov and C. Oliver Kappe
UPDATES
Figure 1. Schematic diagram and reaction conditions for the two-step continuous-flow synthesis of 2-amino-4-chlorobiphenyl
’
(
4).
ꢀ
1
was increased in 258Cmin steps up to 3008C and kept at
008C for 1 min. The carrier gas was helium and the flow
cross-coupling reaction with a Pt-catalyzed selective
heterogeneous hydrogenation step.
3
ꢀ
1
rate 1.0 mLmin in constant-flow mode. The identity of the
peaks in the chromatograms was confirmed by computerized
comparison with the NIST library. Low-resolution mass
spectra were obtained on a Shimadzu LCMS-QP2020 instru-
ment using electrospray ionization (ESI) in positive or nega-
Conclusions
In summary, we have developed a two-step continu- tive mode. The pre-analysis was carried out on a C18 re-
ous-flow process for the preparation of 2-amino-4’- versed-phase (RP) analytical column (150ꢂ4.6 mm, particle
chlorobiphenyl (4), an important intermediate in the size 5 mm) at 258C using a mobile phase A [water/acetoni-
ꢀ
trile 90:10 (v/v)+0.1% TFA] and B (MeCN+0.1% TFA) at
synthesis of the fungicide Boscalid (6), currently pro-
ꢀ
1
a flow rate of 0.6 mLmin . The following gradient was ap-
plied: linear increase from solution 30% B to 100% B in
1
duced in more than 1000 tons/year quantity. Our
method is based on a Pd(0)-catalyzed high-tempera-
ture flow Suzuki–Miyaura cross-coupling transforma-
tion constructing the central biaryl unit in 4’-chloro-2-
nitrobiphenyl (3), coupled with a highly chemoselec-
tive heterogeneous Pt/C-catalyzed nitro group reduc-
5 min, hold at 100% solution B for 2 min. All chemicals,
solvents, catalysts and ligands were obtained from Aldrich
Chem. Co. or Acros Organics and were used without any
further purification. Microwave irradiation experiments
were carried out in a Monowave 300 (Anton Paar GmbH,
tion to produce the target aniline structure 4. Key to Graz, Austria) in Pyrex or SiC microwave process vials
[
17,20]
the success of this method is a change of transition using standard procedures.
Reaction times refer to hold
metal from Pd (homogeneous) to Pt (heterogeneous) times at the temperature indicated, not to total irradiation
times. The temperature was measured using an internal
in order to achieve complete selectivity for nitro
fiber-optic temperature sensor. The flow chemistry examples
group reduction leaving the chlorine functionality in
described herein were performed using X-Cube Flash, H-
Cube or X-Cube flow reactors (ThalesNano Nanotechnolo-
gy Inc.) according to established principles.
thesized compounds were purified using an automated chro-
matography system (SP1ꢃ, Biotage) using cartridges
packed with KP-SIL, 60 ꢄ (40–63 mm particle size) and
2-amino-4’-chlorobiphenyl (4) intact. Although the
current protocol using laboratory-scale flow reactors
does not allow the preparation of large product quan-
tities, a first proof-of-concept for the continuous-flow
manufacturing of this important target structure has
[19,28,32]
The syn-
been established. Future work will focus on improved ethyl acetate (or ethyl acetate containing 0.5% Et N for the
3
methods for the scavenging and recovery of the Pd purification of aniline 4)/petroleum ether mixtures as eluent.
catalyst employed in the Suzuki–Miyaura cross-cou- All products synthesized in this study are known in the liter-
ature and have been identified and characterized by melting
pling and on developing engineering solutions for al-
lowing this flow protocol to be performed on a pro-
1
point, H NMR and MS analysis.
duction scale.
4’-Chloro-2-nitrobiphenyl (3)
Batch Microwave Conditions (Table 1, entry 14): To a
stirred mixture of 1-chloro-2-nitrobenzene (1) (32 mg,
Experimental Section
0
0
.2 mmol, 0.1M), 4-chlorophenylboronic acid (2) (35 mg,
.22 mmol, 1.1 equiv.), t-BuOK (30 mg, 0.26 mmol,
General Remarks
1
13
H NMR and C NMR spectra were recorded on a Bruker
00 MHz instrument. Chemical shifts (d) are expressed in
1.3 equiv.) and t-BuOH/H O (4:1) (1 mL) in a 10 mL Pyrex
microwave vial, 1 mL of a 0.0005M stock solution of
2
3
ppm downfield from TMS as internal standard. The letters s,
d, t, q, and m are used to indicate singlet, doublet, triplet,
quadruplet, and multiplet. GC/MS (FOCUS-GC/DSQ II
MS, ThermoFisher) monitoring was based on electron
impact ionization (70 eV) using a HP/5MS column (30 mꢂ
Pd ACHTUNGTNERUNG( PPh ) in t-BuOH/H O (4:1) (0.6 mg, 0.25 mol%) was
3 4 2
added. The reaction mixture was stirred for 30 s, capped
with a Teflon septum and subjected to microwave heating
for 15 min (hold time) at 1608C and subsequently cooled to
508C. The resulting reaction mixture was concentrated
under reduced pressure and the residue purified by flash
0.250 mmꢂ0.025 mm). After 1 min at 508C the temperature
3094
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3089 – 3097

ꢀ
Toward a Continuous-Flow Synthesis of Boscalid
chromatography to afford 4’-chloro-2-nitrobiphenyl (3) as a
The results achieved in a SiC reaction vial under other-
[20]
yellowish oil, which upon standing provided brown crystals;
wise identical conditions
provided identical results with
[
11c,13]
yield: 43 mg (91%): mp 61–638C, lit.
m 60–628C;
respect to the GC-MS crude reaction profile.
Continuous Flow Processing (Table 2, entry 11): A 10 mL
stock solution of 4’-chloro-2-nitrobiphenyl (3) with a 0.1M
1
H NMR (CDCl , 300 MHz, 258C): d=7.27 (dm, 2H, J=
3
8.5 Hz), 7.42 (dm, 3H, J=8.5 Hz), 7.52 (dt, 1H, J=1.5 and
7
1
.8 Hz), 7.65 (dt, 1H, J=1.5 and 7.8 Hz), 7.90 (dd, 1H, J=
.2 and 8.1 Hz); MS (pos. ESI): m/z=233 (M ), 279 (M +
concentration in t-BuOH/H
2
O (4:1) was prepared in a glass
+
+
vial. The reaction parameters (Full-H
mode, 308C and
2
ꢀ
1
HCO H).
1 mLmin flow rate) were selected on the H-Cube hydro-
genator. The instrument was fitted with a 30 mm 10% Pt/C
CatCart and the processing was started, whereby initially
only pure solvent was pumped through the system until the
instrument had achieved the desired reaction parameters
and stable processing was achieved. At that point the
sample inlet line was switched to the vial containing the sub-
strate. A total reaction volume of 15 mL was collected and
the cartridge subsequently washed with pure solvent for
2
For preparative purposes, the reaction was also performed
equally efficiently at 1.0M concentration providing biaryl 3
on a gram scale. The results achieved in a SiC reaction vial
[20]
(
0.1M concentration) under otherwise identical conditions
provided identical results compared to the Pyrex run with
respect to the GC-MS crude reaction profiles.
Continuous-Flow Processing: To a stirred mixture of 1-
chloro-2-nitrobenzene (1) (64 mg, 0.4 mmol, 0.1M), 4-
5
min to remove any substrate/product still adsorbed on the
catalyst. Evaporation of the solvent affords 2-amino-4’-
chlorobiphenyl (4) as oil (93% crude yield), which was puri-
chloro
ACHTUNGTRENNUNGp henylboronic acid (2) (70 mg, 0.44 mmol, 1.1 equiv.),
t-BuOK (60 mg, 0.52 mmol, 1.3 equiv.) and t-BuOH/H O
2
AHCTUNGTRENNUNG
(
4:1) (3 mL) in a 5 mL glass vial, 1 mL of a 0.001M stock so-
fied by flash chromatography to provide a pale yellow solid,
identical in all respects with a sample prepared under micro-
wave conditions; yield: 161 mg (78%).
lution of Pd(PPh ) in t-BuOH/H O (4:1) (1.17 mg,
ACHTUNGTRENNUNG
3
4
2
0
3
.25 mol%) was added. The reaction mixture was stirred for
0 s. At the same time the X-cube Flash reactor was
equipped with a stainless steel reaction coil (16 mL volume,
ꢀ
1
1
6 min residence time at 1 mLmin flow rate). The reaction
ꢀ
1
2-Chloro-N-(4’-chlorobiphenyl-2-yl)nicotinamide (6)
parameters temperature (1608C), 1 mLmin flow rate and
pressure (75 bar) were selected on the flow reactor, and
processing was started, whereby initially only solvent t-
ꢀ
(
Boscalid )
To a stirred mixture of freshly distilled 2-amino-4’-chlorobi-
phenyl (4) (100 mg, 0.5 mmol) and acetonitrile (2 mL) in a
BuOH/H O (4:1) was pumped through the system until the
2
instrument had achieved the desired reaction parameters
and stable processing was achieved. At that point the inlet
tube was switched from the solvent flask to the 5-mL glass
vial containing the freshly prepared reaction mixture. After
processing through the flow reactor, the inlet tube was
dipped back into the flask containing solvent and processed
for an additional 10 min, thus washing from the system any
remaining reaction mixture. The reaction was concentrated
under vacuum and the product was isolated as described
above in 89% yield identical in all respects with a sample
prepared under microwave conditions.
5
-mL Pyrex microwave vial, 2-chloronicotinic acid (85 mg,
0
.54 mmol, 1.1 equiv.) was added, followed by dropwise ad-
dition of PCl (135 mg, 86 mL, 1 mmol, 2 equiv.). The suspen-
3
sion was stirred for 10 s before being subjected to micro-
wave heating for 10 min (hold time) at 1508C. After cooling
to ambient conditions and evaporation of solvent the resi-
due was purified by flash chromatography to afford 2-
chloro-N-(4’-chlorobiphenyl-2-yl)nicotinamide (6) (Bos-
ꢀ
A
H
U
G
R
N
N
calid ) as a white solid; yield: 146 mg (87%); mp 142–
[13]
1
1
448C, lit. mp 1438C; H NMR (CDCl , 300 MHz, 258C):
3
d=7.28–7.51 (m, 8H), 8.17 (d, 2H, J=6.0 Hz), 8.43–8.49 (m,
+
+
2
H); MS (pos. ESI): m/z=343 (M ), 284 (M +CH CN).
3
Alternatively, N-(4’-chlorobiphenyl-2-yl)nicotinamide (6)
was obtained by reacting solution of a freshly distilled 2-
amino-4’-chlorobiphenyl (4) (100 mg, 0.5 mmol) in 2 mL of
CH Cl with 2-chloronicotinoyl chloride (89 mg, 1.02 equiv)
Synthesis 2-Amino-4’-chlorobiphenyl (4)
2
2
Batch Microwave Conditions: To a stirred mixture of 4’-
chloro-2-nitrobiphenyl (3) (515 mg, 2.2 mmol) and t-BuOH/
in the presence of Et N (127 mg, 163 mL, 1 mmol, 2 equiv.)
3
at 258C for 10 min. After the removal of solvent under re-
duced pressure, the residue was purified as described above
H O (4:1) (3 mL) in a 10-mL Pyrex microwave vial, cyclo-
2
hexene (905 mg, 11 mmol, 5 equiv., 1.12 mL) was added, im-
mediately followed by 10% (w/w) Pt/C (86 mg, 0.022 mmol,
to afford 2-chloro-N-(4’-chlorobiphenyl-2-yl)nicotinamide
ꢀ
(
6) (Boscalid ) as a white solid; yield: 149 mg (89%).
1
mol%). The reaction mixture was stirred for 10 s, capped
Two-step Flow Protocol (Figure 1): To a stirred mixture
of 1-chloro-2-nitrobenzene (1) (64 mg, 0.4 mmol, 0.1M), 4-
chlorophenylboronic acid (2) (70 mg, 0.44 mmol, 1.1 equiv.),
with a Teflon septum and subjected to microwave heating
for 30 min (hold time) at 1508C and subsequently cooled to
508C. The resulting reaction mixture was concentrated
t-BuOK (60 mg, 0.52 mmol, 1.3 equiv.) and t-BuOH/H O
2
under reduced pressure and the residue purified by flash
chromatography to afford 2-amino-4’-chlorobiphenyl (4) as
an oil, which upon standing provided pale yellow crystals;
(4:1) (3 mL) in a 5-mL glass vial, 1 mL of a 0.001M stock
solution of Pd CAHTUNGTRNEUGN( PPh ) in t-BuOH/H O (4:1) (1.17 mg,
3 4 2
0.25 mol%) was added. The X-Cube Flash reactor was
equipped with a stainless steel reaction coil (16 mL volume,
[33]
yield: 364 mg (81%); mp 45–478C, lit.
m 47–488C;
1
ꢀ1
H NMR (CDCl , 300 MHz, 258C): d=3.43 (br s, 2H), 6.50
16 min residence time at 1 mLmin flow rate). The reaction
3
ꢀ
1
(
dd, 1H, J=0.7 and 7.9 Hz), 6.57 (dt, 1H, J=1.1 and
parameters temperature (1608C), 1 mLmin flow rate and
7
1
.5 Hz), 6.84 (dd, 1H, J=1.3 and 7.6 Hz), 6.82–6.94 (m,
pressure (75 bar) were selected on the flow reactor, and
+
H), 7.15 (s, 4H); MS (pos. ESI): m/z=204 (M ), 245
processing was started, whereby only solvent t-BuOH/H O
2
+
+
(
M +CH CN), 286 (M +2CH CN).
(4:1) was pumped through the system until the instrument
3
3
Adv. Synth. Catal. 2010, 352, 3089 – 3097
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3095

Toma N. Glasnov and C. Oliver Kappe
UPDATES
had achieved the desired reaction parameters and stable
processing was achieved. The outlet of the X-Cube flash was
connected to the CatCart holder on the X-Cube reactor,
equipped with a Quadrapure-TU cartridge (70ꢂ4 mm i.d.,
33846, 1997; e) S. Engel, T. Oberding, (BASF AG, Lud-
wigshafen), WO Patent 2006/092429, 2006.
[4] A. M. Rouhi, Chem. Eng. News 2004, 82 (36), 49.
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Eur. J. Org. Chem. 2008, 1655; d) T. Fukuyama, M. T.
Rahman, M. Sato, I. Ryu, Synlett 2008, 151; e) B.
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~
122 mg loading), able to remove the residual Pd form the
CꢀC coupling step. The reaction parameters for the selec-
ꢀ
1
tive nitro reduction (Full-H mode, 308C, 1 mLmin flow
2
rate) were at the same time selected on the H-Cube hydro-
genator. The instrument was fitted with a 10% (w/w) Pt/C
CatCart (30ꢂ4 mm i.d., 150 mg Pt/C) and the processing
was started, whereby initially only pure solvent t-BuOH/
H O (4:1) was pumped through the system until the instru-
2
ment had achieved the desired reaction parameters and
stable processing was achieved. At that point the sample
inlet line of the H-Cube was switched to a vial containing
[
6] a) Microreactors in Organic Synthesis and Catalysis,
1
mL of the solvent and at the same time the outlet of the
(
Ed.: T. Wirth), Wiley-VCH, Weinheim, 2008; b) Hand-
X-Cube was inserted. At that time the inlet tube of the X-
Cube Flash instrument was switched from the solvent flask
to the 5-mL glass vial containing the 4 mL aliquot sample of
the freshly prepared reaction mixture. The whole reaction
process through the X-Cube Flash, X-Cube and H-Cube in-
struments was continued for 30 min–20 min reaction time
plus an additional 10 min washing with pure solvent thus
washing from the system any remaining reaction mixture. A
total reaction volume of 30 mL was collected. Evaporation
of the solvent affords 2-amino-4’-chlorobiphenyl (4) as an
oil (90% crude yield; 96% purity by GC-MS). Purification
by flash chromatography provided 63 mg (77%) of analyti-
cally pure product identical in all respects to the samples
prepared via the methods described above.
book of Micro Reactors, (Eds.: V. Hessel, J. C. Schout-
en, A. Renken, Y. Wang, J.-i. Yoshida), Wiley-VCH,
Weinheim, 2009; c) J.-I. Yoshida, Flash Chemistry –
Fast Organic Synthesis in Microsystems, Wiley-VCH,
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This work was supported by a grant from the Christian Dop-
pler Research Society (CDG).
[
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2
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3097