Sustainable and Cost-Effective Suzuki-Miyaura Couplings toward the Key Biaryl Subunits of Arylex and Rinskor Active

Article abstract of DOI:10.1021/acs.orglett.0c01625

Challenging Suzuki-Miyaura cross couplings associated with novel crop protection active ingredients from Corteva Agriscience, Arylex and Rinskor, can be performed in water using parts per million (ppm) levels of a Pd catalyst. Each coupling required a distinct set of reaction conditions to achieve maximum selectivities and chemical yields. By way of comparison, this chemistry is not only performed under environmentally responsible aqueous micellar conditions, but also involves lowering loadings (3-5 times) of endangered palladium than used previously to attain a more sustainable process.

Full text of DOI:10.1021/acs.orglett.0c01625

pubs.acs.org/OrgLett
Letter
Sustainable and Cost-Effective Suzuki−Miyaura Couplings toward
the Key Biaryl Subunits of Arylex and Rinskor Active
Balaram S. Takale,* Ruchita R. Thakore, Nicholas M. Irvine, Abraham D. Schuitman, Xiaoyong Li,
and Bruce H. Lipshutz*
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ABSTRACT: Challenging Suzuki−Miyaura cross couplings asso-
ciated with novel crop protection active ingredients from Corteva
Agriscience, Arylex and Rinskor, can be performed in water using
parts per million (ppm) levels of a Pd catalyst. Each coupling
required a distinct set of reaction conditions to achieve maximum
selectivities and chemical yields. By way of comparison, this
chemistry is not only performed under environmentally responsible
aqueous micellar conditions, but also involves lowering loadings
(3−5 times) of endangered palladium than used previously to
attain a more sustainable process.
rop management is a highly challenging process, as
and toxicity profile.8 Nonetheless, in the laboratory, syntheses
of Rinskor, as well as that of its predecessor, Arylex, are
continuously evolving, with efforts aimed at exploring
improvements most notably with regard to sustainability.
The route to Arylex first disclosed in 2016 uses microwave
heating at 110 °C in a 1:1 mixture of acetonitrile and water,6 or
in a toluene:water:acetonitrile mixture at 65 °C.9 Considering
the endangered status of Pd, the loading of non-recycled
palladium catalyst used for this coupling is high (2−5 mol %,
or 20 000−50 000 ppm). Similarly, an earlier route involving
biaryl coupling en route to Rinskor requires high levels of Pd
catalyst (3 mol %) in an acetonitrile:dimethoxyethane:water
mixture and affords the biaryl in a modest 58% yield.10
Reducing palladium usage is of continuing interest and focus
during process development and optimization.12b
C
weeds1 can be very effective competitors for essential
nutrients.2 Moreover, control of weeds is oftentimes quite
demanding, and consequently, can lead to decreased overall
crop production.3 As the world’s population continues to
increase, improved approaches to maximize crop production
are essential. Corteva Agriscience has been actively involved in
developing several classes of herbicides, especially those within
the auxinic family, given their known effectiveness against
broadleaf weeds. The discovery of “2,4-D” in 1945 propelled
herbicide use as a weed killer for crop protection (Figure 1).4
Our continuing efforts to provide new technologies based on
sustainable chemistry11 in recyclable water, using Nature as the
perfect model, utilize nanomicelles as nanoreactors.12 As an
integral part of these studies, we have shown that this approach
enables especially valued13 Pd-catalyzed cross coupling
reactions to be run at the parts per million (ppm) level.14
More recently, our focus has broadened to include applications
to numerous target molecules of synthetic interest. Here, most,
if not all, of the chemistry involved is performed in water,
much of which can be telescoped (i.e., where several steps can
Figure 1. Evolution of herbicides used in crop protection.
Today, however, far more than just the activity of herbicides is
required5 and, hence, two recent herbicides, Arylex and
Rinskor,6 have been commercialized and studied in detail by
Corteva. These offer numerous advantages, relative to previous
molecules in this class (Figure 1). These new properties, in
particular, include (a) dramatic reduction in residual levels of
metabolites in soil due to hydrolysis, (b) reduction in use rate,
and (c) an increase in their range of effectiveness toward
various weeds.7 These and related advances in herbicide
science in the field by the team responsible for development of
Rinskor led to an ACS Presidential Green Chemistry
Challenge Award, acknowledging its favorable environmental
Received: May 12, 2020
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be performed in a single pot).15 In this report, we describe the
“greening” of the crucial biaryl syntheses of both Arylex and
Rinskor. Hence, not only can these couplings now be done
using water with minimal organic cosolvent as the reaction
medium, but also, with only a few thousand ppm of Pd catalyst
(a 10-fold reduction), these biaryls can now be realized making
these couplings far more environmentally attractive.
Both recycling and scale-up reactions were performed on a
10 mmol scale, and, as expected,15 each reaction led to a
similar yield. Moreover, the aqueous system could easily be
recycled several times with essentially identical yields being
obtained (see Scheme 1). The calculated E factor, which is
Scheme 1. Recycling and E Factor Determination for ppm-
Initially, in our academic laboratories, the Suzuki−Miyaura
coupling toward Arylex was investigated, involving an extensive
screening of the associated ligands on Pd. The presence of 10%
cosolvent imparted an important element, i.e., facile stirring of
reaction mixtures, with ethyl acetate being observed as the
preferred choice (see the elecronic Supporting Information
(ESI)). Unfortunately, none of the ligands generally used for
SM couplings led to acceptable results (i.e., poor chemical
yields; see Table 1, entries 1−5). Note that, in all of these
Level Pd-Catalyzed Suzuki−Miyaura Coupling toward the
a
Biaryl Portion of Arylex
Table 1. Optimization toward ppm-Level Pd-Catalyzed
a
Suzuki−Miyaura Coupling in the Synthesis of Arylex
based on the amount of product (given in grams) divided by
the amount of waste generated (including water) (also given in
grams) was found to be 2.4, which was well below Sheldon’s16
E factor associated with the pharmaceutical industry.
The analogous Suzuki−Miyaura coupling involved in the
synthesis of the biaryl portion of Rinskor was studied next.
Typically, a trichloropicolinic acid (4) is the electrophilic
coupling partner used in this step. Previously optimized
conditions involving Arylex were applied here, albeit with twice
the catalyst loading. Surprisingly, none of the desired biaryl
product 9 was formed (see Scheme 2). We speculated that,
under the basic conditions, the corresponding (polar)
carboxylate salt might not gain entry to the inner lipophilic
micellar core, presumably where the reaction generally occurs.
Therefore, different esters of this acid were prepared
Scheme 2. Use of Optimized Conditions for Suzuki−
Miyaura Coupling toward the Rinskor Biaryl
a b
,
Intermediate
a
Reaction conditions, unless otherwise mentioned: 1 mmol of 1, 1.2
mmol of 2, 2500 ppm (0.25 mol %) of Pd(OAc)2, 5000 ppm ligand,
and 2 equiv of base, stirred in 2 wt % TPGS-750-M/H2O, along with
b
c
10 vol % EtOAc at 45 °C for 12 h. Isolated yield. Reaction was
performed at 70 °C. dReaction was performed using the
corresponding boronic acid at 70 °C.
trials, starting material was hydrolyzed, and hence, this
observation indicated a need for a milder base. We eventually
found that potassium fluoride (KF)10 supplied the required
activation for an efficient coupling without hydrolyzing either
amide or ester functionality (Table 1, entry 6). In addition,
instead of the initially used, expensive XPhos ligand, we found
that triphenylphosphine could be used to give the desired
coupling product in similar yield (Table 1, entry 7). A modest
increase in temperature led to excellent conversion, and thus, a
very good isolated yield of biaryl 3 (Table 1, entry 8).
Replacing boronic ester 2 with the corresponding boronic acid
led to a significant decrease in chemical yield (Table 1, entry
9).
a
Reaction conditions unless otherwise noted: 1 mmol of 4/5/6/7, 1.2
mmol of 8, 5000 ppm of Pd(PPh3)2Cl2, 2 equiv of KF, stirred in 2
wt % TPGS-750-M/H2O, along with 10 vol % EtOAc at 45 °C.
b
c
Isolated yields. Substrate 2 was used instead of 8.
B
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(compounds 5−7) and, as anticipated, this added lipophilicity
influenced reactivity, leading to some conversion (products
10−12). The most lipophilic substrate in this series, i.e., the
ester derived from 2-ethyl-hexanol, gave the best results,
including the observed stability of this ester toward the basic
reaction conditions. This added stability allowed use of a
stronger base, K3PO4·H2O, relative to KF, leading to a 35%
isolated yield of 12. Both the methyl and benzyl esters were
partially hydrolyzed when K3PO4·H2O was used as a base.
Since the previously optimized conditions for Arylex (Table
2) were seemingly not applicable to the biaryl of Rinskor, we
but with a simple change in base to triethylamine, the
optimized conditions were in hand, both in terms of chemical
yield and cleanliness of the reaction profile (Table 2, entry 10).
Following the successful Suzuki−Miyaura coupling that
provided ester 12, its hydrolysis under aqueous conditions was
performed to give intermediate acid 9 (see Scheme 3). Using 4
Scheme 3. Hydrolysis of Ester 12 to the Desired Acid 9
Table 2. Optimization of the ppm-Level Pd-Catalyzed
Suzuki−Miyaura Coupling toward the Biaryl Section of
a
Rinskor
equiv of NaOH at room temperature led to a 40% isolated
yield, whereas, at 55 °C, run overnight, a quantitative yield of
the desired acid was obtained. The reaction time could be
further reduced to 5 h by increasing the temperature to 70 °C.
These individually optimized steps, each performed in an
aqueous micellar medium, were then combined into a 1-pot
sequence. As seen in the images below (Scheme 4), NaOH was
Scheme 4. Large-Scale, One-Pot Synthesis of Rinskor Acid
Intermediate 9
a
Reaction conditions unless otherwise mentioned: 1 mmol of 7, 1.2
mmol of 8, 5000 ppm (0.50 mol %) of Pd(OAc)2, and 2 equiv of base,
stirred in 2 wt % TPGS-750-M/H2O, along with 10 vol % toluene at
c
45 °C. bIsolated yield. Reaction was performed at 55 °C. dPd-
(XantPhos)Cl2, 5000 ppm was used at 55 °C. eReaction was
performed using Et3N as a base at 55 °C.
were forced to perform another screening of catalysts for this
SM coupling. Again, neither XPhos nor EvanPhos gave any
product (Table 2, entries 1 and 2). Remarkably, bidentate
ligands proved to be effective, with DPEPhos affording a 61%
yield of the targeted product (Table 2, entry 4), while
XantPhos increased the yield further to 73% (Table 2, entry 7).
Ferrocene-based ligands diphenylphosphinoferrocene (DPPF)
and di-t-butylphosphinoferrocene (DTBPF) showed moderate
conversions (Table 2, entries 5 and 6); however, each led to a
series of byproducts, with only DTBPF giving any of the
desired product (20% yield; see Table 2, entry 6). With
XantPhos, a 10 °C increase in reaction temperature improved
the yield even further (Table 2, entry 8). Use of the same
catalyst but in the preformed state (i.e., Pd(XantPhos)Cl2) led
to similar results (Table 2, entry 9). With this same catalyst,
added to the initial, smoothly stirred reaction slurry observed
in the SM coupling (Scheme 4, image a), resulting in an
orange-yellow colored emulsion (Scheme 4, image b). Once
saponification was complete, dilution with water: diethyl ether
(4:1) (Scheme 4, images c and d) and acidification of this
mixture with concentrated H2SO4 (Scheme 4, image e) led to
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the formation of a white precipitate of product (Scheme 4,
images f and g) which could be easily filtered to afford acid 9 in
an overall yield of 82%.
Although ester 12 is an important intermediate en route to
Rinskor, this target herbicide is a benzyl ester (recall Figure 1),
in which case the direct use of the benzyl ester analogue of 12
in the SM coupling might avoid the in situ hydrolysis and re-
esterification steps. Therefore, coupling between aryl halide 6
and arylboronic acid 8 under the same conditions (55 °C for
18 h; see Scheme 5) gave biaryl 11, albeit in only 54% yield.
Nicholas M. Irvine − Corteva Agriscience, Indianapolis, Indiana
46268, United States; orcid.org/0000-0001-6391-4721
Abraham D. Schuitman − Corteva Agriscience, Indianapolis,
Indiana 46268, United States
Xiaoyong Li − Corteva Agriscience, Indianapolis, Indiana
46268, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01625
Author Contributions
All authors have given approval to the final version of the
manuscript.
Scheme 5. SM Coupling of Benzyl Ester 6 to Biaryl 11
Notes
The authors declare no competing financial interest.
Arylex and Rinskor are trademarks of Dow AgroSciences,
DuPont, or Pioneer and their affiliated companies or respective
owners.
ACKNOWLEDGMENTS
■
Financial support provided by the NSF (No. 18-56406) and
PHT International (via a postdoctoral fellowship to B.S.T.) is
warmly acknowledged with thanks.
All of the aryl halide was consumed; however, most of the
remaining reaction material was attributed to the hydrolysis of
starting ester. By lowering the reaction temperature to 45 °C,
and then to 35 °C, the hydrolysis was slower, but the desired
biaryl benzyl ester 11 could be obtained in 79% yield. Under
these conditions, an attempt to perform this coupling at rt led
to 11 in only 60% yield.
In summary, aqueous micellar technology has been
efficiently applied to Suzuki−Miyaura couplings for the
syntheses of key biaryl subsections associated with Arylex
and Rinskor active ingredients from Corteva Agriscience. The
required catalyst loading was significantly lower than reported
for the preparation of these key intermediates, suggesting that
the adoption of processes akin to those described herein are
not only sustainable, but are also economically attractive.
REFERENCES
■
(1) (a) Riar, D. S.; Norsworthy, J. K.; Steckel, L. E.; Stephenson, D.
O.; Eubank, T. W.; Scott, R. C. Assessment of weed management
practices and problem weeds in the midsouth United States
Soybean: A consultant’s perspective. Weed Technol. 2013, 27, 612−
622. (b) Miller, M. R.; Norsworthy, J. K. Row Crop Sensitivity to Low
Rates of Foliar-Applied Florpyrauxifen-Benzyl. Weed Technol. 2018,
32, 398−403.
(2) Cobb, A. H.; Reade, J. P. H. Herbicides and Plant Physiology, 2nd
Edition; Wiley−Blackwell: United Kingdom, 2010.
(3) Walsh, T. A.; Schmitzer, P. R.; Masters, R. A.; Lo, W. C.; Gast, R.
E.; Claus, J. S.; Finkelstein, B. L. Chapter 5: New Auxin Mimics and
Herbicides. In Modern Crop Protection Compounds, 2nd Edition;
Wiley−VCH: Weinheim, Germany, 2012; Vol. 1, pp 277−304.
(4) Quastel, J. H. ″2,4-Dichlorophenoxyacetic Acid (2,4-D) as a
Selective Herbicide″. Agricultural Control Chemicals. Adv. Chem. Ser.
1950, 1, 244−249.
ASSOCIATED CONTENT
* Supporting Information
■
(5) Grossmann, K. Auxin Herbicides: Current Status of Mechanism
and Mode of Action. Pest Manage. Sci. 2009, 66, 113−120.
(6) Epp, J. B.; Alexander, A. L.; Balko, T. W.; Buysse, A. M.;
Brewster, W. K.; Bryan, K.; Daeuble, J. F.; Fields, S. C.; Gast, R. E.;
Green, R. A.; Irvine, N. M.; Lo, W. C.; Lowe, C. T.; Renga, J. M.;
Richburg, J. S.; Ruiz, J. M.; Satchivi, N. M.; Schmitzer, P. R.; Siddall,
T. L.; Webster, J. D.; Weimer, M. R.; Whiteker, G. T.; Yerkes, C. N.
The discovery of Arylex active and Rinskor active: Two novel auxin
herbicides. Bioorg. Med. Chem. 2016, 24, 362−371.
(7) Canturk, B.; Johnson, P.; Taylor, J.; Kister, J.; Balcer, J.
Identification and Synthesis of a Nitrophenyl Metabolite of Rinskor
Active from Terrestrial Aerobic Soil Studies. Org. Process Res. Dev.
2019, 23, 2234−2242.
(8) 2018 Green Chemistry Challenge Awards announced, https://cen.
acs.org/environment/green-chemistry/2018-Green-Chemistry-
Challenge-Awards/96/web/2018/10 (accessed Feb. 20, 2020).
(9) Fisk, J. S.; Li, X.; Muehlfeld, M.; Bauman, R. S.; Oppenheimer,
J.; Tu, S.; Nitz, M. A.; Chakrabarti, R.; Feist, S. D.; Ringer, J. W.;
Leng, R. B. Synthesis of 6-Aryl-4-Aminopicolinates and 2-Aryl-6-
Aminopyrimidine-4-Carboxylates by Direct Suzuki Coupling. Interna-
tional Patent No. WO 2017/201377 A1 2017.
(10) (a) Zhu, Y.; Whiteker, G. T.; Renga, J. M.; Arndt, K. E.; Roth,
G.; Podhorez, D. E.; West, S. P.; Cheng, Y. Process for the
preparation of 4-amino-5-fluoro-3-halo-6-(substituted) picolinates.
U.S. Patent No. US 2014/0206881 A1, 2014. (b) Renga, J. M.;
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01625.
Experimental procedures, analytical data, and copies of
NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Bruce H. Lipshutz − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
9116-7049; Email: bhlipshutz@ucsb.edu
Balaram S. Takale − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States; orcid.org/0000-0001-
8279-944X; Email: balaram_takale@ucsb.edu
Authors
Ruchita R. Thakore − Department of Chemistry and
Biochemistry, University of California, Santa Barbara,
California 93106, United States
D
https://dx.doi.org/10.1021/acs.orglett.0c01625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Cheng, Y.; Muhuhi, J. M.; Podhorez, D. E.; Roth, G. A.; West, S. P.;
Whiteker, G. T.; Zhu, Y. Process for the Preparation of 4-Amino-5-
Fluoro-3-Halo-6-(Substituted) Picolinates. International Patent No.
WO 2014/18502 A1, 2014.
(11) (a) Bihani, M.; Ansari, T. N.; Finck, L.; Bora, P. P.; Jasinski, J.
B.; Pavuluri, B.; Leahy, D. K.; Handa, S. Ultrasmall Pd Nanoparticles
in Aqueous Micelles for Scalable α-Arylation of Nitriles: Surprising
Formation of Carbanions. ACS Catal. 2020, 10, 6816−6821.
(b) Duong, U. T.; Gade, A. B.; Plummer, S.; Gallou, F.; Handa, S.
Reactivity of Carbenes in Aqueous Nanomicelles Containing
Palladium Nanoparticles. ACS Catal. 2019, 9, 10963−10970.
(12) (a) Lipshutz, B. H. Catalyst: Imagine Doing Chemistry at No
Cost to the Environment! Chem. 2018, 4, 2004−2012. (b) Lipshutz,
B. H. Synthetic chemistry in a water world. New rules ripe for
discovery. Current. Opin. Green Sus. Chem. 2018, 11, 1−8.
(c) Lipshutz, B. H.; Ghorai, S.; Cortes-Clerget, M. The Hydrophobic
Effect Applied to Organic Synthesis: Recent Synthetic Chemistry ″in
Water″. Chem. - Eur. J. 2018, 24, 6672−6695. (d) Andersson, M. P.;
Gallou, F.; Klumphu, P.; Takale, B. S.; Lipshutz, B. H. Structure of
Nanoparticles Derived from Designer Surfactant TPGS-750-M in
Water, As Used in Organic Synthesis. Chem. - Eur. J. 2018, 24, 6778−
6786.
(13) (a) Gildner, P. G.; Colacot, T. J. Reactions of the 21st Century:
Two Decades of Innovative Catalyst Design for Palladium-Catalyzed
Cross-Couplings. Organometallics 2015, 34, 5497−5508. (b) Deven-
dar, P.; Qu, R.-Y.; Kang, W.-M.; He, B.; Yang, G.-F. Palladium-
Catalyzed Cross-Coupling Reactions: A Powerful Tool for the
Synthesis of Agrochemicals. J. Agric. Food Chem. 2018, 66, 8914−
8934.
(14) (a) Takale, B. S.; Thakore, R. R.; Handa, S.; Gallou, F.; Reilly,
J.; Lipshutz, B. H. A new, substituted palladacycle for ppm level Pd-
catalyzed Suzuki-Miyaura cross couplings in water. Chem. Sci. 2019,
10, 8825−8831. (b) Thakore, R. R.; Takale, B. S.; Gallou, F.; Reilly,
J.; Lipshutz, B. H. N,C-Disubstituted Biarylpalladacycles as
Precatalysts for ppm Pd-Catalyzed Cross Couplings in Water under
Mild Conditions. ACS Catal. 2019, 9, 11647−11657. (c) Zhang, Y.;
Takale, B. S.; Gallou, F.; Reilly, J.; Lipshutz, B. H. Sustainable ppm
level palladium-catalyzed aminations in nanoreactors under mild,
aqueous conditions. Chem. Sci. 2019, 10, 10556−10561.
(15) (a) Takale, B. S.; Thakore, R. R.; Kong, F. Y.; Lipshutz, B. H.
An environmentally responsible 3-pot, 5-step synthesis of the
antitumor agent sonidegib using ppm levels of Pd catalysis in water.
Green Chem. 2019, 21, 6258−6262. (b) Takale, B. S.; Thakore, R. R.;
Mallarapu, R.; Gallou, F.; Lipshutz, B. H. A Sustainable 1-Pot, 3-Step
Synthesis of Boscalid Using Parts Per Million Level Pd Catalysis in
Water. Org. Process Res. Dev. 2020, 24, 101−105.
(16) Sheldon, R. A. The E factor 25 years on: the rise of green
chemistry and sustainability. Green Chem. 2017, 19, 18−43.
E
https://dx.doi.org/10.1021/acs.orglett.0c01625
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