A Sustainable 1-Pot, 3-Step Synthesis of Boscalid Using Part per Million Level Pd Catalysis in Water

Article abstract of DOI:10.1021/acs.oprd.9b00455

Boscalid is an active ingredient in several fungicides marketed by the BASF. Literature approaches use multipot processes, organic solvents, and unsustainable levels of palladium catalysis. Herein is disclosed a 1-pot, 3-step route using nanomicelles in water as the reaction medium and a very low loading (700 ppm or 0.07 mol %) of costly and endangered Pd. The sequence developed involves an initial Suzuki-Miyaura cross-coupling, the product from which is not isolated. The second step relies on a carbonyl iron powder (CIP) reduction of the aryl nitro group, followed by the third and final step involving an acylation with the required 2-chloronicotinyl chloride. The overall isolated yield for these three steps is 83%.

Full text of DOI:10.1021/acs.oprd.9b00455

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Communication
A sustainable 1-pot, 3-step synthesis of
boscalid using ppm level Pd catalysis in water
Balaram S Takale, Ruchita Thakore, Rushil Mallarapu, Fabrice Gallou, and Bruce H. Lipshutz
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00455 • Publication Date (Web): 03 Dec 2019
Downloaded from pubs.acs.org on December 9, 2019
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A sustainable 1-pot, 3-step synthesis of boscalid
using ppm level Pd catalysis in water
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Balaram S. Takale, *,† Ruchita R. Thakore, † Rushil Mallarapu, †,‡ Fabrice Gallou,⁋
Bruce H. Lipshutz*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California
93106, USA
‡Fairfield Ludlowe High School, 785 Unquowa Ave., Fairfield, CT 06890 USA.
⁋Novartis Pharma AG, Basel, Switzerland
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ABSTRACT. Boscalid is an active ingredient in several fungicides marketed by the BASF.
Literature approaches use multi-pot processes, organic solvents, and unsustainable levels of
palladium catalysis. Herein is disclosed a 1-pot, 3-step route using nanomicelles in water as the
reaction medium, and a very low loading (700 ppm or 0.07 mol %) of costly and endangered Pd.
The sequence develops involves an initial Suzuki-Miyaura cross-coupling, the product from
which is not isolated. The second step relies on a carbonyl iron powder (CIP) reduction of the
aryl nitro group, followed by the third and final step involving an acylation with the required
chloronicotinyl chloride. The overall isolated yield for these three steps is 83%.
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KEYWORDS: boscalid, 1-pot synthesis, Suzuki-Miyaura coupling, chemistry in water
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INTRODUCTION
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Boscalid1 is an active ingredient found in several fungicides (Emerald, Endura, and Pristine)
marketed by the BASF beginning in 2003.2 Currently, it is produced in excess of 1000 MTs per
year,3 being used to prevent gray/blue mold produced due to Botrytis cinerea and Penicillium
expansum in plants.4 One common synthetic approach to boscalid is shown in Scheme 1. In the
patented route by BASF, although complete details about the process are lacking, the sequence
involved (1) a Pd(0)-catalyzed Suzuki-Miyaura (SM) coupling; (2) reduction of the nitrobiaryl
intermediate; and (3) an amide bond construction. A few new routes have appeared recently,5
including one utilizing flow chemistry;6 however, all involve use of organic solvents, high
catalyst loadings, and especially high temperatures. Moreover, selective nitro group reduction in
the presence of an aryl chloride required expensive Pt/C under high pressure of hydrogen.5,6
Knochel and co-workers used an alternative approach to replace the Suzuki-Miyaura (SM)
reaction by a Kumada-type coupling leading to the desired biarylamine in 70% yield with 1 mol
% of a Pd catalyst.7 In short, none of these methods offer an environmentally sustainable, benign
approach. In recent years, an awareness of green processes, metrics such as PMI8 and E Factors,9
as well as attention to waste creation and its proper handling have increased dramatically, in part
due to environmental policies.10 Our contributions have focused in large measure on reducing, if
not completely removing, organic solvents as currently used for chemical reactions.11 In addition,
real prospects now exist for reducing use of endangered Pd-catalyst loading to ppm levels for
key Suzuki-Miyaura cross couplings, among other Pd-catalyzed processes,12 thereby significantly
reducing the cost of this precious metal catalysis.13
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Scheme 1. Synthetic pathway towards boscalid
RESULTS AND DISCUSSION
Initially, optimization of the SM coupling was studied using Pd catalysts based on either PPh3 or
SPhos ligands (Table 1). Stirring chloronitrobenzene 1 with boronic acid 2 using Pd(OAc)2:PPh3
(1:2; 0.5 mol %, or 5000 ppm Pd) catalyst under aqueous micellar conditions at 45 oC led to 54%
o
conversion to the desired biaryl product 3 (entry 1). Increasing the temperature to 55 C did not
increase the extent of conversion (entry 2). Also, increasing the ratio of Pd:L to 1:4 did not
significantly change the outcome of this coupling (entry 3). Raising the temperature further to 70
oC increased the yield (entry 4); however, the extent of completion even after simultaneously
increasing the Pd loading (entry 5) was not satisfactory. In efforts to minimize the amount of Pd
required, the ligand was then switched to SPhos. In this case, reaction was complete using 5000
ppm Pd at 45 °C (entry 6). Further lowering the catalyst loading to only 700 ppm of Pd in
combination with 1400 ppm of SPhos sufficed to arrive at quantitative conversion, in this case
achieved by increasing the reaction temperature to 55 °C (entry 7). Further lowering of the Pd
loading to 300-500 ppm under these reaction conditions reduced the conversion to product to
o
only 57-73% (entries 8, 9). Nonetheless, with another ten degree temperature rise to 65 C, the
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Pd loading could be reduced to 400 ppm while maintaining a 100% conversion to product (entry
10). Screening of surfactants in the presence of 10% THF as co-solvent suggested that both
TPGS-750-M and Brij-30 are interchangeable; each led to excellent conversion (Scheme 2). By
contrast, the same coupling run under otherwise identical conditions, but using pure THF as
reaction medium gave an inferior result compared to aqueous micellar system.
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Table 1. Catalyst screening for SM couplingsa
NO2
NO2 (HO)2B
PCy2
O
Pd(OAc)2:L (ppm)
O
K3PO4•H2O (2 equiv)
2 wt % TPGS-750-M/H2O [0.5 M]
10% THF, T oC, 12 h
Cl
Cl
Cl
1
2
3
SPhos
entry
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2
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4
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8
9
Pd : L (ppm)
T (° C)
45
55
45
70
70
45
55
55
conv. to 3 (%)b
Pd(OAc)2 : PPh3 (5000:10000)
Pd(OAc)2 : PPh3 (5000:10000)
Pd(OAc)2 : PPh3 (5000:20000)
Pd(OAc)2 : PPh3 (5000:20000)
Pd(OAc)2 : PPh3 (7000:28000)
Pd(OAc)2 : SPhos (5000:8000)
Pd(OAc)2 : SPhos (700:1400)
Pd(OAc)2 : SPhos (500:1000)
Pd(OAc)2 : SPhos (300:600)
Pd(OAc)2 : SPhos (400:800)
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60
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72
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100
100
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57
100c
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65
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aReaction conditions: 0.5 mmol 1, 0.55 mmol 2, 1 mmol K3PO4•H2O, and Pd : L catalyst were stirred in 1 mL 2 wt % TPGS-
750-M/H2O : THF (9:1) for 12 h at the given temperature. bConversion determined by GC-MS. c 22 h.
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Scheme 2. Reaction medium screening for SM coupling of 1 + 2
We next focused on optimization of the nitro group reduction, screening a wide variety of
reductions using the same aqueous micellar system (Table 2). The most commonly used reagent,
Pd/C along with a balloon of hydrogen at 45 oC, led to full conversion but resulted in only a 44%
yield of the isolated product, along with dechlorination (of the reduced product) as the major,
undesired product (51%; entry 1). An attempt to replace Pd/C with Pt/C, using a hydrogen
balloon, led to 68% of the isolated product along with the formation of an unknown impurity.
Similar results were obtained when Fe/ppm Pd+Ni nanoparticles were used (entry 3).14 In this
case the desired product was isolated in 70% yield, along with 25% dechlorinated material.
Ultimately, carbonyl iron powder (CIP) together with NH4Cl at 45 °C afforded an 85% yield of
the desired aniline with some starting material recovered (entry 5).15
Table 2. Optimization of nitro group reductiona
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entry
reductant
1 mol % Pd/C, H2 balloon
0.5 mol % Pt/C, H2 balloon
T (° C)
conv. to 4 (%)b
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2
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4
5
45
45
rt
rt
45
44c
68d,f
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Fe/ppm Pd+Ni NPs, NaBH4 (3 equiv)
CIP (5 equiv), NH4Cl (3 equiv)
CIP (5 equiv), NH4Cl (3 equiv)
70e
50
89 (85)f
aReaction conditions: 0.5 mmol 3, stirred along with the reducing system in 1 mL 2 wt % TPGS-750-M/H2O at a given
temperature. Conversion determined by GC-MS. 1 wt % Pd/C was used, dechlorinated product obtained (51%). 5 wt % Pt/C
was used. Dechlorinated product obtained (25%). fIsolated yield in parenthesis.
b
c
d
e
The last step in the synthesis, acylation of the aniline 4, was optimized leading to quantitative
conversion of 4 to 6 (Table 3). Thus, while Hünig’s base (i-Pr2NEt) led to complete conversion
(entry 2), other bases such as triethylamine (entry 1) and pyridine (entry 3) gave far lower levels
of product formation. In the absence of base, the reaction was especially slow (entry 4).
Table 3. Final step: amide formationa
entry
base
conv. to 6 (%)b
65
100 (97)c
68
1
2
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4
Et3N (2 equiv)
i-Pr2NEt (2 equiv)
pyridine (2 equiv)
none
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aReaction conditions: 0.5 mmol 4, 0.75 mmol 5 and 1.0 mmol of base were stirred for 12 h in 1 mL 2 wt % TPGS-750-M/H2O at
45 oC. bConversion determined by GC-MS. cIsolated yields in parenthesis.
Once optimization conditions associated with each step had been determined, the feasibility of
this sequence being conducted in water on a larger 5 mmol scale was examined, all in a single
reaction vessel (Scheme 3). Initial SM coupling went smoothly, leading with quantitative
conversion to biaryl 3 (confirmed with GC-MS). Without workup or isolation, reduction to
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amine 4 followed via addition of CIP, which was complete in 12 h. The newly formed amine was
treated directly with 2-chloronicotinyl chloride 5 in the presence of Hünigs base. Upon full
conversion, 1.42 g of boscalid could be isolated in 83% overall yield.
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Scheme 3. Gram scale 1-pot synthesis of boscalid. Reaction conditions: a) 5 mmol 1, 5.5 mmol 2, 10 mmol of
K3PO4•H2O, Pd(OAc)2:SPhos (700:1400 ppm), 10 mL 2 wt % TPGS-750-M/H2O:THF (9:1), 55 oC, 12 h. b) CIP (5
equiv), NH4Cl (3 equiv), 45 oC, 12 h c) 2.0 equiv i-Pr2NEt, 1.5 equiv 5, 45 oC, 16 h.
CONCLUSION
In summary, an overall high yielding, 1-pot, environmentally responsible synthesis of boscalid, a
widely used fungicide, has been demonstrated. Each of the three steps can be carried out in water
containing nanomicelles as reaction medium. The key Suzuki-Miyaura coupling requires only
700 ppm (0.07 mol %) Pd in the presence of commercially available ligand (SPhos, 1400 ppm or
0.14 mol %). This sequence is representative of the potential for chemistry in water using
nanoparticle technology to significantly reduce not only the cost, but simultaneously waste
creation, two issues typically associated with traditional syntheses in organic solvents.
EXPERIMENTAL SECTION
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A solution of 2 wt % surfactant/H2O was prepared by dissolving the desired surfactant in
degassed HPLC grade water and was stored under argon. TPGS was made as previously
described.16 All commercially available reagents were used without further purification. THF
was taken from an Innovative Technologies Solvent Purification System (SPS) and used
immediately. Thin layer chromatography (TLC) was done using Silica Gel 60 F254 plates
(Merck, 0.25 mm thick). Flash chromatography was done in glass columns using Silica Gel 60
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1
13
(EMD, 40-63 µm). H and C NMR were recorded at 23° C on a Varian Unity Inova 500 MHz
spectrometer in CDCl3 with residual CHCl3 (1H = 7.26 ppm, 13C = 77.20 ppm) as internal
standard. Chemical shifts are reported in parts per million (ppm).
The stock solution for ppm Pd use. In a 2-dram vial, 3.9 mg of Pd(OAc)2 and 14.4 mg
ligand (Sphos) were added. The vial was capped with a rubber septum and evacuated, and then
backfilled with argon (repeated 3 times), and 5.0 mL of degassed THF was added under positive
argon flow. The amount of THF was manipulated so that it served as 10% co-solvent for the
reaction scale used in Suzuki-Miyaura coupling (vide infra). For example, for 0.5 mmol scale
reaction 0.079 mg Pd(OAc)2 and 0.29 mg SPhos in 100 µL THF which corresponds to 700 ppm
Pd/0.5 mmol scale reaction.
Procedure for Suzuki-Miyaura coupling. In a 1-dram vial containing a Teflon-coated stir
bar, 78.8 mg (0.50 mmol) of 2-chloronitrobenzene 1, 86.0 mg (0.55 mmol) of 4-
chlorophenylboronic acid 2, 230.3 mg (1.0 mmol) of K3PO4•H2O were added, and the vial was
evacuated-backfilled with argon (this process was repeated three times). Finally, 100 µL of the
above stock solution, corresponding to 700 ppm Pd (0.07 mol %), and 0.9 mL of 2 wt % aqueous
surfactant solution were added under argon. The vial was quickly screw capped and then stirred
at 55 oC until completion (as monitored on TLC or GC-MS). The reaction mixture was absorbed
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on silica and purified by flash column using a hexanes:EtOAc (9:1) gradient to obtain the desired
product (114.2 mg; 98%) as light yellow oil.
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Procedure for nitro reduction using CIP and NH4Cl. In a 1-dram vial with Teflon-coated
stir bar were added 116.5 mg nitrobiphenyl 3 (0.5 mmol, 1.0 equiv), 139.6 mg carbonyl Fe
powder (CIP; 2.5 mmol, 5.0 equiv), and 80.4 mg NH4Cl (1.5 mmol, 3.0 equiv). To this vial, 1.0
mL of 2 wt % TPGS-750-M/H2O was added, the vial was capped and stirred vigorously at 45 oC
for 12 h. The contents of the reaction mixture were then directly absorbed on silica and purified
by flash column using a hexanes:EtOAc (9:1) gradient to obtain the desired product as yellow oil
(86.23 mg; 85%) which solidified on cooling.
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Procedure for amide condensation. In a 1-dram vial with Teflon-coated stir bar were added
101.5 mg aminobiphenyl 4 (0.5 mmol, 1.0 equiv), 174.7 µL i-Pr2NEt (1.0 mmol, 2.0 equiv), and
1.0 mL 2 wt % TPGS-750-M/H2O. The reaction mixture was stirred gently at rt before addition
131.2 mg 2-chloronicotinyl chloride 5 (0.75 mmol, 1.5 equiv). The reaction mixture was then
stirred vigorously at 45 oC until complete conversion of the amine to the amide was observed by
TLC. The contents of the reaction mixture were directly absorbed on silica and purified flash
column using hexanes:EtOAc (9:1 to 1:9) gradient to obtain the desired product as a white
powder (165.9 mg; 97%).
Procedure for 1-pot, large-scale synthesis of boscalid in water. In a 25 mL round bottom flask
were added 0.79 g (5.0 mmol) of 2-chloronitrobenzene 1, 0.86 g (5.5 mmol) of 4-
chlorophenylboronic acid 2, 2.30 g (10 mmol) of K3PO4•H2O, and the flask was evacuated and
backfilled with argon (this process was repeated three times). Finally, 1.0 mL from the stock
solution containing 700 ppm of Pd was added before adding 9.0 mL of 2 wt % TPGS-750-
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M/H2O. The reaction mixture was stirred vigorously at 55 oC for 15 h under argon. The reaction
mixture was cooled to rt and 1.34 g carbonyl Fe powder (CIP; 25 mmol, 5.0 equiv) and 0.81 g
NH4Cl (15 mmol, 3.0 equiv) were added. The reaction flask was placed again in an oil bath and
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heated at 45 C for 12 h. The flask was then cooled to rt and 1.8 mL i-Pr2NEt (10.0 mmol, 2.0
equiv), 0.44 g of 2-chloronitotinyl chloride (2.5 mmol, 0.5 equiv) was added at one time. It was
o
then heated at 45 C for 2 h. Second portion, 0.44 g (2.5 mmol, 0.5 equiv) of 2-chloronicotinyl
chloride was added all at once and stirring was then continued for another 2 h after which the
final portion, 0.44 g (0.5 equiv) of 2-chloronicotinyl chloride was added again, all at one time.
The reaction was allowed to stir at 45 oC for 12 h (total 16 h reaction time), and upon completion
(monitored on TLC), the reaction mixture was extracted with EtOAc (4 x 10 mL). The organic
layer was evaporated and the material was further purified using flash chromatography to afford
1.42 g of boscalid 6 (83% overall yield). Boscalid could also be recrystallized by a known
literature method.1a Spectral data for the isolated material matched that in the literature.5
ASSOCIATED CONTENT
Supporting Information. Compound characterization data and NMR spectra for 3, 4 and 6
(PDF).
AUTHOR INFORMATION
Corresponding Author
*Email: lipshutz@chem.ucsb.edu, balaram_takale@ucsb.edu.
ORCID
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Balaram S. Takale: 0000-0001-8279-944X
Fabrice Gallou: 0000-0001-8996-6079
Bruce H. Lipshutz: 0000-0001-9116-7049
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT. Financial support provided by the NSF (18-56406) is warmly
acknowledged with thanks.
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