The discovery of Arylex active and Rinskor active: Two novel auxin herbicides

Article abstract of DOI:10.1016/j.bmc.2015.08.011

Multiple classes of commercially important auxin herbicides have been discovered since the 1940s including the aryloxyacetates (2,4-D, MCPA, dichlorprop, mecoprop, triclopyr, and fluroxypyr), the benzoates (dicamba), the quinoline-2-carboxylates (quinclorac and quinmerac), the pyrimidine-4-carboxylates (aminocyclopyrachlor), and the pyridine-2-carboxylates (picloram, clopyralid, and aminopyralid) In the last 10 years, two novel pyridine-2-carboxylate (or picolinate) herbicides were discovered at Dow AgroSciences This paper will describe the structure activity relationship study that led to the discovery of the 6-aryl-picolinate herbicides Arylex active (2005) and Rinskor active (2010) While Arylex was developed primarily for use in cereal crops and Rinskor is still in development primarily for use in rice crops, both herbicides will also be utilized in additional crops.

Full text of DOI:10.1016/j.bmc.2015.08.011

Bioorganic & Medicinal Chemistry 24 (2016) 362–371
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
TM
TM
The discovery of Arylex active and Rinskor active: Two novel auxin
herbicides
⇑
Jeffrey B. Epp , Anita L. Alexander, Terry W. Balko, Ann M. Buysse, William K. Brewster, Kristy Bryan,
John F. Daeuble, Stephen C. Fields, Roger E. Gast, Renard A. Green, Nicholas M. Irvine, William C. Lo,
Christian T. Lowe, James M. Renga, John S. Richburg, James M. Ruiz, Norbert M. Satchivi,
Paul R. Schmitzer, Thomas L. Siddall, Jeffery D. Webster, Monte R. Weimer, Gregory T. Whiteker,
Carla N. Yerkes
Dow AgroSciences, 9330 Zionsville Rd, Indianapolis, IN 46268, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2015
Revised 6 August 2015
Accepted 12 August 2015
Available online 19 August 2015
Multiple classes of commercially important auxin herbicides have been discovered since the 1940s
including the aryloxyacetates (2,4-D, MCPA, dichlorprop, mecoprop, triclopyr, and fluroxypyr), the ben-
zoates (dicamba), the quinoline-2-carboxylates (quinclorac and quinmerac), the pyrimidine-4-carboxy-
lates (aminocyclopyrachlor), and the pyridine-2-carboxylates (picloram, clopyralid, and aminopyralid).
In the last 10 years, two novel pyridine-2-carboxylate (or picolinate) herbicides were discovered at
Dow AgroSciences. This paper will describe the structure activity relationship study that led to the dis-
covery of the 6-aryl-picolinate herbicides ArylexTM active (2005) and RinskorTM active (2010). While
Arylex was developed primarily for use in cereal crops and Rinskor is still in development primarily
for use in rice crops, both herbicides will also be utilized in additional crops.
Keywords:
Arylex
Rinskor
Halauxifen
Halauxifen-methyl
Picolinate
Ó 2015 Elsevier Ltd. All rights reserved.
6-Aryl-picolinate
1. Introduction
be quite severe and can cause plant death. Since the discovery of
2,4-D and MCPA over 70 years ago, many other herbicides that
About 250 plant species currently cause enough problems in
food production to be classified as weeds. Collectively, these weeds
reduce crop yield and quality, harbor various pests and diseases,
and interfere with the management of crops.1 Accordingly, control
of these weeds is essential for maximizing crop production and for
simplifying crop management. With the discovery of the auxin
herbicides 2,4-D and MCPA in the 1940s, the agricultural practice
of weed management was totally transformed.2 These auxin herbi-
cides reduced the cost and increased the efficiency of controlling a
variety of problematic weeds in many important crops.
act via an auxinic mode of action have been discovered and
commercialized. The most successful commercial auxin herbicides
produced to date are represented by the following classes
(examples): the aryloxyacetates (2,4-D, MCPA, dichlorprop, meco-
prop, triclopyr, and fluroxypyr), the benzoates (dicamba), the
quinoline-2-carboxylates (quinclorac and quinmerac), the pyrim-
idine-4-carboxylates (aminocyclopyrachlor), and the pyridine-2-
carboxylates (picloram, clopyralid, and aminopyralid).
Research efforts at Dow Chemical and Dow AgroSciences have
produced all of the commercial auxin herbicides classified as
A herbicide is classified as an auxin if it induces physiological
and phenotypic effects similar to those induced by indole-3-acetic
acid, a natural plant hormone of the auxin class.3 Since synthetic
auxin herbicides are typically much more stable than indole-3-
acetic acid in planta, the phenotypic effects caused by auxin herbi-
cides (i.e., tissue swelling, root growth inhibition, and epinasty) can
NH2
N
NH2
N
Cl
Cl
Cl
O
Cl
O
Cl
O
OH
OH
OH
OH
N
Cl
N
Cl
O
Picolinic acid
Picloram
Clopyralid
Aminopyralid
⇑
Corresponding author. Tel.: +1 317 337 5515, +1 317 506 5325.
E-mail address: jbepp@dow.com (J.B. Epp).
Figure 1. Picolinic acid and some closely related picolinate auxin herbicides.
http://dx.doi.org/10.1016/j.bmc.2015.08.011
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
363
NH2
N
NH2
acid. N-acyl-aminopyralid-methyl 7 was synthesized by heating
aminopyralid-methyl 6 in acetic anhydride. Methyl 4-acetamido-
3-chloro-6-aryl-picolinates 8–11 were synthesized by the reaction
of N-acyl-aminopyralid-methyl 7 with the appropriate boronic acid
or boronic ester. Methyl 4-amino-3-chloro-6-aryl-picolinates
12–15 were synthesized by dissolving methyl 4-acetamido-3-
chloro-6-aryl-picolinates 8–11 in methanol and treating these
solutions with acetyl chloride. Bromination of methyl 4-amino-3-
chloro-6-aryl-picolinate 15 with NBS afforded methyl 4-amino-5-
bromo-3-chloro-6-aryl-picolinate 16. Hydrolysis of methyl
4-acetamido-3-chloro-6-aryl-picolinates 10 and 11 with sodium
hydroxide in methanol provided 4-amino-3-chloro-6-aryl-picol-
inic acids 17 and 18. Finally, 5-chloro-4-amino-6-aryl-pyridine
19 was synthesized by heating 4-amino-3-chloro-6-aryl-picolinic
acid 18 in dioxane.
4
Cl
O
F
Cl
O
5
6
3
2
OMe
O
OH
N
N
1
O
Cl
F
Cl
F
OMe
OMe
6-Aryl-picolinates
ArylexTM active
RinskorTM active
Figure 2. The 6-aryl-picolinate auxin herbicide class.
pyridine-2-carboxylates to date. The pyridine-2-carboxylate auxin
herbicides are derivatives of picolinic acid (Fig. 1) and are thus also
known as the picolinate auxin herbicides. Picloram (Fig. 1), the first
picolinate auxin herbicide, was serendipitously discovered in the
late 1950s during a Dow Chemical research study that was focused
on the discovery of novel nitrification inhibitors.4,5
As shown in Scheme 3, methyl 4-amino-3-chloro-5-fluoro-6-
aryl-picolinates 21 and 22 were synthesized by the reaction of
5-fluoro-aminopyralid-methyl 209 with the appropriate boronic
acid or boronic ester. Hydrolysis of methyl 4-amino-3-chloro-5-
fluoro-6-aryl-picolinates 21 and 22 with sodium hydroxide in
methanol provided 4-amino-3-chloro-5-fluoro-6-aryl-picolinic
acids 23 and 24. Finally, benzyl 4-amino-3-chloro-5-fluoro-6-
aryl-picolinate 25 was synthesized by the reaction of 4-amino-3-
chloro-5-fluoro-6-aryl-picolinic acid 24 with benzyl bromide.
As shown in Scheme 4, methyl 4-amino-6-aryl-picolinate 27
was synthesized by the reaction of methyl 6-aryl-tetrahydropy-
ridine-2-carboxylate 2610 with DBU in dichloromethane. Methyl
3-bromo-6-aryl-tetrahydropyridine-2-carboxylate 28 was synthe-
sized by treating methyl 6-aryl-tetrahydropyridine-2-carboxylate
26 with NBS in dichloromethane.10 Methyl 3-bromo-6-aryl-
tetrahydropyridine-2-carboxylate 28 was converted to methyl
4-amino-3-bromo-6-aryl-picolinate 29 by heating it in the
presence of acetic acid.10 Methyl 3-chloro-6-aryl-tetrahydropy-
ridine-2-carboxylate 30 was synthesized by treating methyl
6-aryl-tetrahydropyridine-2-carboxylate 26 with sulfuryl chloride
in dichloromethane.10 Finally, methyl 4-amino-3-fluoro-6-aryl-
picolinate 31 was synthesized by the reaction of methyl
3-chloro-6-aryl-tetrahydropyridine-2-carboxylate 30 with cesium
fluoride in dimethyl sulfoxide.
The second picolinate auxin herbicide, clopyralid (Fig. 1), was
discovered in the early 1960s via a Dow Chemical structure activity
relationship (SAR) study prompted by the discovery of picloram.4,6
Almost 40 years after the discovery of picloram, the picolinate
auxin herbicide aminopyralid (Fig. 1) was discovered at Dow
Chemical when a new electrolysis procedure, originally developed
as a method to produce clopyralid from 3,4,5,6-tetrachloropicolinic
acid, was applied to picloram to determine what compounds the
electrolysis reaction would produce. The major product of that
reaction was aminopyralid.4,7,8
This second serendipitous discovery of a picolinate auxin herbi-
cide with commercial utility catalyzed a more thorough SAR study
of the herbicidal activity associated with the picolinic acid core-
structure. This SAR study eventually resulted in the discovery of
two more picolinate auxin herbicides with commercial utility. In
the years following the discovery of aminopyralid, multiple classes
of picolinate analogs were synthesized and found to exhibit potent
herbicidal activity toward a large number of key weed species. One
of the most potent classes produced to date is the 6-aryl-picolinate
class shown in Figure 2. This report provides a brief description of
the innovative steps that led to the discovery of the 6-aryl-picoli-
nates and ultimately to the discovery of two novel auxin herbi-
cides: ArylexTM active and RinskorTM active (Fig. 2).
Finally, as shown in Scheme 5, methyl 3-chloro-6-aryl-picoli-
nate 33 was synthesized by the Suzuki reaction of clopyralid-
methyl 3211 with the appropriate boronic acid or boronic ester.
2. Results and discussion
2.1. Synthesis
2.2. SAR study that led to first 6-aryl-picolinate auxin herbicides
All of the picolinate analogs included in this report were syn-
thesized by the sequences shown in Schemes 1–5. As shown in
Scheme 1, picloram-methyl 2 was synthesized by treating picloram
15 with thionyl chloride in methanol. Methyl 4-amino-3,5-
dichloro-6-aryl-picolinates 3 and 4 were synthesized by the Suzuki
reaction of picloram-methyl 2 with the appropriate boronic acid or
boronic ester.
The carboxylic acid functional group of picolinate auxin herbi-
cides is necessary for both the phloem trapping that imparts their
systemic herbicidal activity and for the binding interaction that
causes their herbicidal effects. Herbicides that act systemically
must have some type of acidic functional group (i.e., the carboxylic
acid of aminopyralid shown in Fig. 3) that can pass through the
lipophilic walls of the phloem tubes and ionize in the basic (pH
ꢀ8) aqueous medium of the phloem. If the pKa of the acidic
As shown in Scheme 2, aminopyralid-methyl 6 was synthesized
by heating aminopyralid 57 in a mixture of methanol and sulfuric
NH2
NH2
NH2
Cl
Cl
Cl
O
Cl
Cl
Cl
O
Cl
Cl
O
OH
OMe
OMe
a
b
N
1
N
2
N
X
Z
Y
3: X, Y, Z = H, H, H
4: X, Y, Z = Cl, OCH3, F
Scheme 1. Synthesis of picolinate analogs 2–4. Reagents and conditions: (a) MeOH, SOCl2, 0–50 °C, 4 h; (b) boronic acid or boronic ester, Pd(PPh3)2Cl2, CsF, DME/water,
150 °C, 5 min.

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J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
NH2
NH2
N
Br
Cl
O
Cl
O
OMe
OMe
N
e
Cl
F
X
Z
OMe
Y
16
12: X, Y, Z = H, H, H
13: X, Y, Z = Cl, H, H
14: X, Y, Z = Cl, H, F
15: X, Y, Z = Cl, OCH3, F
d
O
NH2
NHR
N
NH
Cl
Cl
O
Cl
O
OH
OMe
OMe
N
a, b
c
Cl
N
5
Cl
O
X
Z
6: R = H
7: R = COCH3
Y
8: X, Y, Z = H, H, H
9: X, Y, Z = Cl, H, H
10: X, Y, Z = Cl, H, F
11: X, Y, Z = Cl, OCH3, F
f
NH2
NH2
Cl
Cl
OH
N
N
g
O
Cl
F
X
Z
OMe
Y
19
17: X, Y, Z = Cl, H, F
18: X, Y, Z = Cl, OCH3, F
Scheme 2. Synthesis of picolinate analogs 6–19. Reagents and conditions: (a) MeOH, H2SO4, reflux, 24 h; (b) Ac2O, reflux, 16 h; (c) boronic acid or boronic ester, Pd(PPh3)2Cl2,
KF, ACN/water, 110 °C, 20 min; (d) acetyl chloride, MeOH, 6 h; (e) NBS, DCM, rt, 3 h; (f) NaOH, MeOH/water, rt, 16 h; (g) dioxane, 100 °C, 3 h.
NH2
NH2
N
NH2
N
F
Cl
O
F
Cl
O
F
Cl
O
OMe
OMe
OH
a
b
Cl
N
X
Z
X
Z
Y
Y
20
21: X, Y, Z = Cl, H, H
22: X, Y, Z = Cl, OCH3, F
23: X, Y, Z = Cl, H, H
24: X, Y, Z = Cl, OCH3, F
c
NH2
F
Cl
O
O
N
Cl
F
OMe
25
Scheme 3. Synthesis of picolinate analogs 21–25. Reagents and conditions: (a) boronic acid or boronic ester, Pd(PPh3)2Cl2, KF, ACN/water, 115 °C, 20 min; (b) NaOH, MeOH/
water, rt, 16 h; (c) benzyl bromide, K2CO3, DMSO, rt, 3 h.
functional group is below 5, the equilibrium constant for the ion-
ization of the acid (i.e., the deprotonation of aminopyralid shown
in Fig. 3) is 103 or higher.
In this case (pKa <5), the anionic form of the herbicide predom-
inates the neutral form by a factor of 1000:1 or higher in the
phloem. Since anions cannot easily pass through the lipophilic
walls of the phloem tube, the anionic form of the herbicide concen-
trates in the phloem in a process called phloem trapping. This pro-
cess leads to relatively high concentrations of the herbicide within
the phloem where the herbicide can be transported to the growing
points of the plant and more effectively interfere with plant devel-
opment. For picolinate auxin herbicides (i.e., clopyralid, picloram,

J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
365
O
S
O
O
S
O
O
N
O
N
NH2
N
Br
O
OMe
OMe
OMe
a
O
b
N
H
N
H
Cl
F
O
OMe
Cl
F
Cl
F
OMe
OMe
28
26
27
c
d
O
S
O
O
N
NH2
N
NH2
N
Br
O
F
Cl
O
OMe
OMe
OMe
e
O
N
H
Cl
F
Cl
F
OMe
OMe
Cl
F
29
OMe
30
31
Scheme 4. Synthesis of picolinate analogs 27–31. Reagents and conditions: (a) DBU, DCM, rt, 1 h; (b) NBS, DCM, rt, 1 h (see US8252938 for details); (c) AcOH, 150 °C, 5 min
(see US8252938 for details); (d) SO2Cl2, DCM, 0–25 °C, 1 h (see US8252938 for details); (e) CsF, DMSO, rt, 30 min.
Cl
Two examples of this are shown in Figure 5 where the average
herbicidal activity of picloram 1 and aminopyralid 5 are compared
Cl
OMe
N
OMe
a
Cl
N
with the average herbicidal activity of their corresponding methyl
esters (2 and 6, respectively). The fact that the average herbicidal
activity for each of these herbicide pairs (i.e., picloram 1 and piclo-
ram-methyl 2) is similar supports the assertion that picloram-
methyl 2 and aminopyralid-methyl 6 are both rapidly and effi-
ciently converted in planta to picloram 1 and aminopyralid 5,
respectively. Since the average herbicidal activity of the methyl
esters discussed in this paper were all similar to the average herbi-
cidal activity of their corresponding carboxylic acids, the activity
data for the remaining SAR discussion was limited to that associ-
ated with the methyl esters alone.
The serendipitous discovery of aminopyralid 5 set in motion an
exhaustive SAR study of the picolinate auxin herbicide class. This
SAR study soon led to the discovery of the 6-aryl-picolinate auxin
herbicide class. The first 6-aryl-picolinate analog synthesized was
methyl 4-amino-3,5-dichloro-6-phenylpicolinate 3. While 3 exhib-
ited significant herbicidal activity, its average broadleaf activity
was substantially less than that exhibited by aminopyralid-methyl
6 (Fig. 6). The third 6-aryl-picolinate analog synthesized, methyl
4-amino-3-chloro-6-phenylpicolinate 12, was substantially more
active than 3 but still less active than aminopyralid-methyl 6
(see Fig. 6). However, the herbicidal activity associated with 12
provided a clear focus for the SAR development. The positive
direction of this focus was quickly confirmed when the sixth
6-aryl-picolinate analog synthesized, methyl 4-amino-3-chloro-6-
(4-chlorophenyl)-picolinate 13, exhibited an average herbicidal
activity that was equal to that exhibited by aminopyralid-methyl
6 (Fig. 6).
O
Cl
F
O
OMe
32
33
Scheme 5. Synthesis of picolinate analog 33. (a) Boronic acid or boronic ester, Pd
(OAc)2, DPPB, CsF, ACN, reflux, 2 h.
NH2
N
NH2
N
Cl
O
Cl
O
+
H+
OH
O-
Cl
Cl
Figure 3. Ionization of aminopyralid.
aminopyralid, ArylexTM active, and RinskorTM active), the carboxylic
acid functional group is also involved in a key binding interaction
at the target site for the auxin mode of action.12
However, it is important to note that some carboxylate esters of
picolinate auxin herbicides exhibit an average herbicidal activity
that is approximately equal to that exhibited by their correspond-
ing carboxylic acids. This is true because many plants rapidly con-
vert primary carboxylate esters (i.e., methyl esters) to their
corresponding carboxylic acids13 (see Fig. 4 for an example of this).
Since the in planta enzymatic conversion of methyl esters to car-
boxylic acids is often a fast and efficient process for picolinate auxin
herbicides, the herbicidal activity of a picolinate auxin methyl ester
and its corresponding carboxylic acid are often very similar.
2.3. SAR study that led to ArylexTM active
The 6-aryl-picolinate SAR pattern that eventually led to the dis-
covery of ArylexTM active, a novel auxin herbicide recently launched
by Dow AgroSciences, started with lead compound 13 (Fig. 7).
While many compounds were synthesized in the development of
the SAR, two of the most herbicidally active analogs were methyl
4-amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicolinate 21 and
methyl 4-amino-3-chloro-6-(4-chloro-2-fluorophenyl)picolinate
14. As shown in Figure 7, the average herbicidal activity of 21
and 14 were both significantly higher than that associated with
NH2
N
NH2
N
Cl
O
Cl
O
Plant
OMe
OH
Cl
Metabolism
Cl
Figure 4. In many plants, conversion of aminopyralid-methyl into aminopyralid by
enzymatic hydrolysis is rapid and efficient.

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J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
900
800
700
600
500
400
300
200
100
0
NH2
Cl
NH2
N
Cl
O
OH
Cl
N
OMe
Cl
O
NH2
N
Cl
Cl
Cl
O
NH2
N
OMe
Cl
Cl
Cl
O
OH
1
2
5
6
Compound Number
Figure 5. Herbicidal activity of picloram 1, picloram-methyl 2, aminopyralid 5, and aminopyralid-methyl 6.
900
NH2
800
NH2
Cl
Cl
700
OMe
N
OMe
Cl
N
O
Cl
600
500
400
300
200
100
0
O
NH2
N
Cl
O
OMe
NH2
N
Cl
Cl
O
OMe
6
3
12
13
Compound Number
Figure 6. The discovery of aminopyralid catalyzed a thorough SAR study that uncovered the 6-aryl-picolinate auxin herbicide class via analogs 3, 12, and 13.
900
800
NH2
NH2
N
F
Cl
O
NH2
N
700
600
500
400
300
200
100
0
Cl
O
NH2
N
Cl
O
OMe
Cl
O
N
OMe
OMe
OMe
Cl
Cl
F
Cl
F
Cl
OMe
13
21
14
15
Compound Number
Figure 7. The SAR path that led to ArylexTM active 15.
NH2
NH2
activity profiles of 23 and 17 were compelling for some targeted
commercial applications, the soil half-life for these analogs
appeared to be too long (>240 days) to meet the regulatory
requirements for the targeted commercial applications.
Fortunately, an effort designed to incorporate a metabolic han-
dle into the structure of 14 quickly led to compound 15 (ArylexTM
active), a potent and broad spectrum auxin herbicide with excel-
lent selectivity to wheat and barley.4,14 A specific hypothesis that
the introduction of a methoxy group at the phenyl tail 3-position
of 14 would generate an analog with decreased soil half-life and
high herbicidal potency was developed from two observations:
(1) There are examples of methoxy groups serving as metabolic
handles in commercial herbicides,4 and (2) An analog of 12 with
F
Cl
O
Cl
O
OH
OH
N
N
Cl
Cl
F
23
17
Figure 8. The carboxylic acid forms of 21 and 14 (23 and 17, respectively) are both
highly active herbicides but probably too soil-persistent to meet regulatory
requirements for the targeted commercial applications.
lead compound 13. Accordingly, the carboxylic acid forms of 21
and 14 (compounds 23 and 17, respectively, Fig. 8) were subjected
to extensive greenhouse and field testing. While the herbicidal

J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
367
NH2
N
NH2
N
were found to be essential for the expression of its potent, broad-
spectrum herbicidal activity. Accordingly, the des-2-methoxycar-
bonyl analog of Arylex (compound 19) is essentially inactive at the
17.5 g/ha application rate (Fig. 10), and the des-4-amino analog of
Arylex (compound 33) is substantially less active than Arylex 15
(Fig. 10).
Cl
O
Cl
O
Plant or soil
metabolism
OMe
OH
Cl
F
Cl
F
OMe
OMe
Halauxifen (18)
Arylex active (15)
™
While less critical than the 2-methoxycarbonyl and 4-amino
functional groups of Arylex, the 3-chlorine functional group of
Arylex is still important for expression of its potent, broad-
spectrum herbicidal activity. Thus, the des-3-chloro analog of
Arylex (compound 27) is substantially less active than Arylex 15
(Fig. 10). As shown in Figure 11, the 3-fluoro and 3-bromo analogs
of Arylex (compounds 31 and 29, respectively) were substantially
more active than 27 but significantly less active than Arylex 15.
While studying the SAR of the Arylex picolinate head 5-position,
a second 6-aryl-picolinate auxin herbicide with commercial utility
was discovered. Based on previous SAR work with 6-aryl-picolinate
analogs (data not shown), we expected the 5-fluoro analog of
Arylex (compound 22) to be as active as Arylex 15, and the
5-chloro and 5-bromo analogs of Arylex (compounds 4 and 16,
respectively) to be significantly less active than Arylex 15. As
depicted in Figure 12, these expectations were correct.
More importantly, the 5-fluoro analog of Arylex (compound 22)
exhibited potent and broad spectrum herbicidal activity with excel-
lent selectivity to rice. In addition, the corresponding carboxylic
acid form of 22 (compound 24) exhibited a commercially accept-
able soil half-life range of 10–30 days (Fig. 13). Optimization of
the ester form of 24 eventually led to benzyl ester 25 (RinskorTM
active) as an optimal derivative of 24 (Fig. 13).15 Initial registrations
of RinskorTM active for use in rice and other crops are anticipated in
2017–2018. Rinskor has not yet received a common name.
or halauxifen-methyl
Figure 9. The plant and soil metabolic conversion of ArylexTM active 15 to its
carboxylic acid form: halauxifen 18.
a methoxy group at the phenyl tail 3-position (methyl 4-amino-3-
chloro-6-(3-methoxyphenyl)picolinate) was found to be substan-
tially more active than 12 on some key weed species (structure
and data not shown).4
This hypothesis was confirmed when 15 (ArylexTM active) was
found to exhibit herbicidal activity similar to 14, and when its cor-
responding carboxylic acid form (compound 18) was found to
exhibit a significantly lower soil half-life range of 10–30 days
(Fig. 9). The carboxylic acid form of Arylex (compound 18) received
the common name halauxifen in 2013. Since Arylex is the methyl
ester of halauxifen, Arylex is also known commercially as halaux-
ifen-methyl (Fig. 9). ArylexTM active was launched in 2014 for use
in cereals and other crops.
2.4. SAR study that led to RinskorTM active
While probing the SAR of ArylexTM active 15, several important
features of the Arylex picolinate head were identified. For example,
the 2-methoxycarbonyl and the 4-amino functionalgroups of Arylex
800
NH2
700
Cl
OMe
600
N
O
Cl
F
500
400
300
200
100
0
OMe
NH2
Cl
OMe
N
NH2
N
OMe
O
N
Cl
F
Cl
O
OMe
Cl
F
OMe
Cl
F
OMe
15
19
33
27
Compound Number
Figure 10. SAR of ArylexTM active (15) picolinate head.
900
800
700
600
500
400
300
200
100
0
NH2
Cl
NH2
OMe
Br
O
NH2
N
N
F
O
Cl
F
OMe
N
OMe
OMe
NH2
N
F
Cl
O
OMe
Cl
F
OMe
OMe
O
Cl
F
OMe
27
31
15
29
Compound Number
Figure 11. SAR of ArylexTM active (15) picolinate head 3-position.

368
J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
900
800
700
600
500
400
300
200
100
0
NH2
F
Cl
O
NH2
N
Cl
O
OMe
N
NH2
N
OMe
Cl
F
Cl
Cl
O
NH2
N
OMe
Cl
F
Br
Cl
O
OMe
OMe
OMe
Cl
F
OMe
Cl
F
OMe
15
22
4
16
Compound Number
Figure 12. SAR of ArylexTM active (15) picolinate head 5-position.
NH2
N
NH2
OptiMelt Automated Melting Point System purchased from
Stanford Research Systems and are uncorrected. Proton nuclear
magnetic resonance (1H NMR), fluorine nuclear magnetic reso-
F
Cl
O
F
Cl
O
Plant or soil
metabolism
OR
OH
N
nance
(
19F NMR), and carbon nuclear magnetic resonance
Cl
F
Cl
F
(
13C NMR) spectra were recorded at 300, 400, or 600 MHz in
OMe
OMe
CDCl3, DMSO-d6, or acetone-d6. Chemical shifts are expressed in
parts per million (d scale) downfield from tetramethylsilane.
Mass spectra were obtained using a Waters Micromass ZQ mass
spectrometer (LC/MS) or an Agilent 6890 Gas Chromatograph
(GC) equipped with an Agilent 5973N Mass Selective Detector
(MSD) (GC/MS).
22 R = CH3
25 R = CH2Ph
24
Figure 13. The plant and soil metabolic conversion of 22 and RinskorTM active (25)
to their common carboxylic acid form 24.
3. Conclusion
4.1.2. Methyl 4-amino-3,5,6-trichloropicolinate (2)
A solution of compound 1 (5 g, 20 mmol, see US3285925 for
preparation) in methanol (105 mL) was cooled to 0 °C. Thionyl
chloride (1.95 mL, 26 mmol) was added dropwise at 0 °C and the
resulting reaction mixture was stirred at 50 °C for 4 h. The reaction
mixture was then concentrated under vacuum and the residue was
dissolved in EtOAc (100 mL), washed with water (50 mL), and
washed with brine (50 mL). The organic phase was dried, filtered,
and concentrated under vacuum to provide compound 2 as a pale
yellow solid (4 g, 78% yield): mp 122–123 °C; 1H NMR (400 MHz,
CDCl3) d 5.40 (s, 2H), 3.97 (s, 3H); 13C NMR (101 MHz, CDCl3) d
163.86, 149.03, 146.83, 144.04, 115.40, 114.73, 53.34; EIMS m/z
254.
The serendipitous discovery of the picolinate auxin herbicide
aminopyralid in 1998 catalyzed an extensive SAR study that
uncovered a novel class of auxin herbicides: the 6-aryl-picolinates.
A SAR study of the 6-aryl-picolinates quickly identified two highly
active 6-aryl-picolinate herbicides: 21 and 14. While the activity
profiles of these two herbicides were compelling, the soil half-life
exhibited by the corresponding carboxylic acid forms of 21 and
14 were both >240 days and considered too long to meet regula-
tory requirements for the targeted commercial herbicide concepts.
To address this soil half-life issue, an analog of 14 with a meth-
oxy group at the phenyl tail 3-position was designed and synthe-
sized. The novel analog, ArylexTM active, exhibited potent and
broad spectrum herbicidal activity with excellent safety to cereal
crops, and its corresponding carboxylic acid form exhibited a com-
mercially acceptable soil half-life range of 10–30 days. The herbi-
cide ArylexTM active was launched by Dow AgroSciences in 2014
for use in cereals and other crops.
While conducting a SAR study of the Arylex picolinate head, the
5-fluoro analog of Arylex (compound 22) was found to exhibit her-
bicidal activity equal to or better than Arylex for many key weed
species. In addition, the corresponding carboxylic acid form of 22
(compound 24) exhibited a commercially acceptable soil half-life
range of 10–30 days. In a subsequent optimization study, the ben-
zyl ester of 24 (compound 25 or RinskorTM active) was found to exhi-
bit potent and broad spectrum herbicidal activity with excellent
safety to rice crops. Initial registrations of the herbicide RinskorTM
active for use in rice and other crops are anticipated in 2017–2018.
4.1.3. Methyl 4-amino-3,5-dichloro-6-(4-chloro-2-fluoro-3-
methoxyphenyl)picolinate (4)
Compound 2 (0.500 g, 1.957 mmol), 2-(4-chloro-2-fluoro-3-
methoxyphenyl)-1,3,2-dioxaborinane (0.622 g, 2.54 mmol), bis
(triphenylphosphine)palladium(II)-chloride (0.137 g, 0.196 mmol),
and cesium fluoride (0.595 g, 3.91 mmol) were combined in 1,2-
dimethoxyethane (4 mL) and water (4 mL) in a microwave reactor
vessel. The reaction mixture was irradiated in a microwave reactor
at 150 °C for 5 min. The cooled reaction mixture was partitioned
between ethyl acetate and water. The organic phase was dried
and concentrated onto Celite before purification by flash chro-
matography (ethyl acetate/hexanes gradient) to provide com-
pound 4 (0.5 g, 67% yield) as a white solid: mp 162–164 °C; 1H
NMR (400 MHz, CDCl3) d 7.25 (dd, J = 8.4, 1.3 Hz, 1H), 7.08 (dd,
J = 8.4, 6.8 Hz, 1H), 5.34 (s, 2H), 3.98 (d, J = 1.2 Hz, 3H), 3.97 (s,
3H); ESIMS m/z 379 [(M+H)+].
4. Experimental
4.1. Chemistry
Another compound synthesized by a similar method was:
4.1.3.1.
Methyl
4-amino-3,5-dichloro-6-phenylpicolinate
(3). White solid, mp 126–128 °C; 1H NMR (400 MHz, CDCl3) d
7.68–7.62 (m, 2H), 7.47–7.40 (m, 3H), 5.32 (s, 2H), 3.97 (s, 3H);
ESIMS m/z 297 [(M+H)+].
4.1.1. General
All commercial reagents and solvents were used as received
unless otherwise noted. Melting points were obtained on an

J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
369
4.1.4. Methyl 4-amino-3,6-dichloropicolinate (6)
(d, J = 8.4 Hz, 2H), 3.94 (s, 3H), 2.24 (s, 3H); ESIMS m/z 339
To a 2 L, 3-neck round bottom flask with overhead stirrer,
temperature probe, nitrogen inlet, and condenser was added com-
pound 5 (207 g, 1 mol, see US6352635 for preparation) and metha-
nol (850 mL). Concentrated sulfuric acid (118 g, 1.2 mol) was
added via addition funnel over a 25 min period. The reaction mix-
ture was then heated at reflux for 24 h. At this point, a LCMS anal-
ysis indicated that the reaction was about 85% complete. The
reaction mixture was allowed to cool to room temperature then
transferred to a round bottom flask and concentrated under vac-
uum. The residue was diluted with ethyl acetate, and the pH was
adjusted to about 9 with 37% ammonium hydroxide. The organic
phase was collected and the aqueous phase was washed with ethyl
acetate (2 Â 300 mL). The organic extracts were combined, washed
with water, washed with brine, dried, and filtered. The solution
was concentrated and then diluted with hexanes. The product
was allowed to crystallize for 1 h at room temperature then
filtered and dried under vacuum to provide compound 6 (180 g,
81% yield) as a pink-purple solid: mp 138–139 °C; 1H NMR
(400 MHz, CDCl3) d 6.75 (s, 1H), 4.95 (s, 2H), 3.97 (s, 3H); ESIMS
m/z 221 [(M+H)+].
[(M+H)+].
4.1.6.3.
Methyl
4-acetamido-3-chloro-6-(4-chloro-2-fluo-
rophenyl)-picolinate (10). White solid, mp 140–143 °C; 1H
NMR (300 MHz, DMSO-d6) d 9.02 (s, 1H), 7.93 (m, 2H), 7.22 (m,
2H), 4.01 (s, 3H), 2.32 (s, 3H); EIMS m/z 356.
4.1.7. Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-meth-
oxyphenyl)picolinate (15)
Acetyl chloride (0.8 g, 10 mmol) was slowly added to a solution
of compound 11 (0.8 g, 2.0 mmol) in 150 mL of methanol and stir-
red for 6 h. The reaction was checked by HPLC and found to be 90%
complete. Additional acetyl chloride (0.8 g, 10 mmol) was added
and the reaction mixture was stirred overnight to complete the
conversion. The methanol was removed under vacuum to leave a
white solid. This solid was stirred with ethyl acetate (150 mL)
and saturated aqueous NaHCO3 (20 mL) for 1 h to allow all the
solids to dissolve. About 0.5 g of K2CO3 was added to the aqueous
phase and the resulting mixture was stirred for 20 min. The organic
phase was dried, filtered, and concentrated under vacuum to pro-
vide compound 15 (0.7 g, 99% yield) as a white solid: mp 144–
145 °C; 1H NMR (400 MHz, DMSO-d6) d 7.58 (dd, J = 8.6, 7.9 Hz,
1H), 7.41 (dd, J = 8.7, 1.7 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 6.89 (s,
2H), 3.93 (d, J = 0.8 Hz, 3H), 3.88 (s, 3H); 19F NMR (376 MHz,
DMSO) d À131.48; ESIMS m/z 345 [(M+H)+].
4.1.5. Methyl 4-acetamido-3,6-dichloropicolinate (7)
Compound 6 (2.0 g, 9 mmol) was dissolved in acetic anhydride
(20 mL) and heated at reflux for 16 h. The cooled reaction mixture
was concentrated under vacuum to remove the excess acetic anhy-
dride. The residue was dissolved in ethyl acetate, the solution
poured slowly into water, and the phases thoroughly mixed. Brine
was added to aid phase separation. The organic phase was washed
with saturated sodium bicarbonate, dried, and concentrated under
vacuum. The major products were determined to be mono- and
di-acetylated analogs of compound 6 in roughly a 1:1 ratio.
Purification by flash chromatography (1:2 ethyl acetate to hex-
anes) provided compound 7 (920 mg, 39% yield) as a yellow solid:
mp 102–103 °C; 1H NMR (400 MHz, CDCl3) d 8.65 (s, 1H), 8.00 (s,
1H), 3.99 (s, 3H), 2.32 (s, 3H); ESIMS m/z 263 [(M+H)+].
Other compounds synthesized by a similar method include:
4.1.7.1.
(12).
Methyl
4-amino-3-chloro-6-phenylpicolinate
Yellow solid, mp 131–134°C; 1H NMR (400 MHz, DMSO-
d6) d 7.88 (m, 2H), 7.48 (m, 3H), 7.30 (s, 1H), 6.80 (s, 2H), 3.91 (s,
3H); ESIMS m/z 261 [(MÀH)À].
4.1.7.2. Methyl 4-amino-3-chloro-6-(4-chlorophenyl)picolinate
(13).
White solid, mp 120–122°C; 1H NMR (400 MHz, DMSO-d6)
d 7.90 (m, 2H), 7.54 (m, 2H), 7.29 (s, 1H), 6.79 (s, 2H), 3.90 (s, 3H);
ESIMS m/z 297 [(M+H)+].
4.1.6. Methyl 4-acetamido-3-chloro-6-(4-chloro-2-fluoro-3-
methoxyphenyl)picolinate (11)
4.1.7.3. Methyl 4-amino-3-chloro-6-(4-chloro-2-fluorophenyl)-
picolinate (14).
White solid, mp 117–119 °C; 1H NMR
Compound 7 (0.400 g, 1.520 mmol), 2-(4-chloro-2-fluoro-3-
methoxyphenyl)-1,3,2-dioxaborinane (0.483 g, 1.977 mmol), bis
(triphenylphosphine)-palladium(II) chloride (0.053 g, 0.076 mmol),
and potassium fluoride (0.230 g, 3.95 mmol) were combined in ace-
tonitrile (2.5 mL) and water (2.5 mL). The reaction mixture was irra-
diated in a microwave at 110 °C in a sealed vial for 20 min. The
cooled reaction mixture was partitioned between ethyl acetate
and water. The organic phase was dried and concentrated. The pro-
duct was purified by flash chromatography (5–40% ethyl acetate in
hexanes gradient) to provide compound 11 (0.397 g, 0.995 mmol,
65.4% yield) as a white solid: mp 156–159°C; 1H NMR (400 MHz,
DMSO-d6) d 10.01 (s, 1H), 8.68 (d, J = 1.1 Hz, 1H), 7.67–7.59 (m,
1H), 7.47 (dd, J = 8.7, 1.6 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.25 (s,
3H); 19F NMR (376 MHz, DMSO) d À131.54; ESIMS m/z 387 [(M
+H)+].
(400 MHz, DMSO-d6) d 7.90 (t, J = 8.6 Hz, 1H), 7.57 (dd, J = 11.3,
2.1 Hz, 1H), 7.41 (m, 1H), 7.24 (d, J = 1.6 Hz, 1H), 6.88 (s, 2H),
3.89 (s, 3H); 19F NMR (376 MHz, DMSO) d À113.49; EIMS m/z 314.
4.1.8. Methyl 4-amino-5-bromo-3-chloro-6-(4-chloro-2-fluoro-
3-methoxyphenyl)picolinate (16)
To a solution of compound 15 (200 mg, 0.58 mmol) in DCM was
added NBS (113 mg. 0.64 mmol). The reaction mixture was stirred
at ambient temp for 3 h. The reaction mixture was concentrated
onto silica gel and purified by flash chromatography (0–50% ethyl
acetate in petroleum ether) to provide compound 16 (212 mg, 86%
yield) as a light tan solid: mp 124–125 °C; 1H NMR (300 MHz,
DMSO-d6) d 7.43 (dd, J = 8.5, 1.7, 1H), 7.16 (dd, J = 8.4, 7.1, 1H),
7.10 (s, 2H), 3.92 (d, J = 1.1, 3H), 3.87 (s, 3H); HRMS (FAB) calcu-
lated for C14H10Cl2BrFN2O3 421.923; found: m/z 422.931 [(M+H)+].
Other compounds synthesized by a similar method include:
4.1.9. 4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-
phenyl)picolinic acid (18)
4.1.6.1.
(8).
Methyl
4-acetamido-3-chloro-6-phenylpicolinate
White solid, mp 155–157 °C; 1H NMR (400 MHz, DMSO-
To
a reaction vessel containing compound 11 (0.830 g,
d6) d 9.98 (s, 1H), 8.71 (s, 1H), 7.96 (m, 2H), 7.52 (m, 3H), 3.96 (s,
2.144 mmol) was added methanol (21.44 mL) and 2 N sodium
hydroxide (4.29 mL, 8.57 mmol). The reaction mixture was stirred
overnight at room temperature then acidified by adding a slight
excess of 2 N HCl. The mixture was concentrated and the precipi-
tate that formed was washed with water and dried under vacuum
to provide compound 18 (0.700 g, 97% yield) as a white solid: mp
3H), 2.26 (s, 3H); ESIMS m/z 305 [(M+H)+].
4.1.6.2. Methyl 4-acetamido-3-chloro-6-(4-chlorophenyl)picoli-
nate (9).
DMSO-d6) d 9.98 (s, 1H), 8.71 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.57
White solid, mp 154–156 °C; 1H NMR (400 MHz,

370
J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
167–169 °C; 1H NMR (400 MHz, DMSO-d6) d 13.58 (s, 1H), 7.61 (t,
J = 8.2 Hz, 1H), 7.42 (dd, J = 8.7, 1.6 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H),
6.81 (s, 2H), 3.93 (d, J = 0.8 Hz, 3H)19F NMR (376 MHz, DMSO) d
À131.50. ESIMS m/z 331 [(M+H)+].
(400 MHz, DMSO-d6) d 7.92–7.84 (m, 2H), 7.60–7.55 (m, 2H),
6.93 (s, 2H); 19F NMR (376 MHz, DMSO) d À141.03; ESIMS m/z
301 [(M+H+].
Another compound synthesized by a similar method was:
4.1.13. Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-meth-
oxyphenyl)-5-fluoropicolinate (25)
4.1.9.1. 4-Amino-3-chloro-6-(4-chloro-2-fluorophenyl)picolinic
acid (17).
DMSO-d6) d 13.58 (s, 1H), 7.93 (t, J = 8.6 Hz, 1H), 7.57 (dd,
To a solution of compound 24 (43.0 g, 123 mmol) in dimethyl
sulfoxide (250 mL) was added potassium carbonate (25.5 g,
185 mmol) fairly quickly with magnetic stirring. Then benzyl bro-
mide (23.17 g, 135 mmol) was added dropwise over a time period
of about 10 min. The resulting reaction mixture was stirred for 3 h
at room temperature. When LC analysis showed 2.8% starting
material remained, more benzyl bromide (0.8 g) was added and
the reaction mixture was stirred at room temperature overnight.
The reaction mixture was partitioned between ethyl acetate and
water. The organic phase was washed with water, dried, filtered,
and concentrated under vacuum to a volume of about 300–
400 mL. Heptane was added slowly and the product crystallized
out. The product crystals were collected by filtration and washed
with pentane. The filtrate gave a second crop upon standing for
1 h that was also collected it by filtration. The mother liquors were
combined and concentrated to about 150 mL to provide a third
crop. All three crops were combined and dried under vacuum at
50 °C (<1 mm) for 3 h to provide compound 25 (51.4 g, 95% yield)
as a white fluffy solid: mp 143–144.5 °C; 1H NMR (400 MHz,
DMSO-d6) d 7.47 (dd, J = 7.4, 1.2 Hz, 3H), 7.44–7.33 (m, 3H), 7.30
(dd, J = 8.5, 7.1 Hz, 1H), 7.12 (s, 2H), 5.39 (s, 2H), 3.93 (d,
J = 0.9 Hz, 3H); ESIMS m/z 439 ([M+H]+); Elemental Analysis: C,
54.69; H, 3.21; N, 6.38. Found: C, 54.37; H, 3.25; N, 6.27.
White solid, mp 163–165 °C; 1H NMR (400 MHz,
J = 11.3, 2.1 Hz, 1H), 7.41 (dd, J = 8.5, 2.1 Hz, 1H), 7.22 (d,
J = 1.6 Hz, 1H), 6.81 (s, 2H); 19F NMR (376 MHz, DMSO)
À113.50; ESIMS m/z 301 [(M+H)+].
d
4.1.10. 5-Chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyri-
din-4-amine (19)
Compound 18 (0.200 g, 0.6 mmol) was dissolved in 1,4-dioxane
(12.08 mL) and heated at 100 °C for 3 h. The solvent was removed
under vacuum to provide compound 19 (140 mg, 78% yield) as a
white solid: mp 165–167°C; 1H NMR (400 MHz, DMSO-d6) d 8.26
(s, 1H), 7.61 (dd, J = 8.7, 7.9 Hz, 1H), 7.40 (dd, J = 8.7, 1.7 Hz, 1H),
7.15 (d, J = 1.9 Hz, 1H), 6.55 (s, 2H), 3.92 (d, J = 0.9 Hz, 3H); 19F
NMR (376 MHz, DMSO) d À131.63; ESIMS m/z 287 [(M+H)+].
4.1.11. Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-meth-
oxyphenyl)-5-fluoropicolinate (22)
Toamicrowavereactorvessel,compound20(1.5 g, 6.28 mmol),2-
(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (1.994 g,
8.16 mmol), potassium fluoride (0.948 g, 16.32 mmol) and bis(triph-
enylphosphine)palladium(II)chloride (0.440 g, 0.628 mmol) were
combined in acetonitrile (13.5 mL) and water (4.5 mL). The reaction
mixture was then irradiated in a microwave at 115 °C for 20 min.
The cooled reaction mixture was partitioned between ethyl acetate
and water. The organic phase was washed with water then concen-
trated onto 7 g of silica gel. The product was purified by flash chro-
matography (2-20% ethyl acetate in dichloromethane gradient
solvent system) to provide compound 22 (1.5 g, 4.13 mmol, 65.8%
yield) as a white solid: mp 170–172 °C; 1H NMR (400 MHz, DMSO-
d6) d 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 7.31 (dd, J = 11.5, 1.4 Hz, 1H), 7.12
(s, 2H), 3.93 (d, J = 1.0 Hz, 3H), 3.87 (s, 3H);19FNMR(376 MHz, DMSO)
dcÀ129.19 (JF–F = 30 Hz), 137.67 (JF–F = 30 Hz);ESIMSm/z363 [(M+H)+].
Another compound synthesized in a similar manner was:
4.1.14. Methyl 4-amino-6-(4-chloro-2-fluoro-3-methoxy-
phenyl)picolinate (27)
To a solution of compound 26 (280 mg, 0.69 mmol, synthesized
as described in US8252938) in dichloromethane (5 mL) was added
1,8-diazabicycloundec-7-ene (209 mg, 1.38 mmol). The reaction
was exothermic and was heated to reflux by the heat generated
from the reaction. After 1 h at room temperature, the reaction mix-
ture was applied to a silica gel column and eluted with 50% ethyl
acetate in pentane to provide compound 27 (90 mg, 42% yield) as
an off-white solid: mp 159–162°C; 1H NMR (400 MHz, DMSO-d6)
d 7.62 (m, 1H), 7.43 (dd, J = 8.7, 1.6 Hz, 1H), 7.25 (d, J = 2.1 Hz,
1H), 7.08 (t, J = 2.1 Hz, 1H), 6.57 (s, 2H), 3.93 (d, J = 0.9 Hz, 3H),
3.84 (s, 3H); 19F NMR (376 MHz, DMSO) d À131.92; ESIMS m/z
311 [(M+H)+].
4.1.11.1. Methyl 4-amino-3-chloro-6-(4-chlorophenyl)-5-flu-
oro-picolinate (21).
White solid, mp 120–122 °C; 1H NMR
(400 MHz, CDCl3) d 7.95–7.81 (m, 2H), 7.50–7.37 (m, 2H), 4.92 (s,
4.1.15. Methyl 4-amino-6-(4-chloro-2-fluoro-3-methoxy-
phenyl)-3-fluoropicolinate (31)
2H), 3.99 (s, 3H); ESIMS m/z 315 [(M+H)+].
To
a suspension of anhydrous cesium fluoride (0.228 g,
4.1.12. 4-Amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-ph-
enyl)-5-fluoropicolinic acid (24)
1.5 mmol) in dry dimethyl sulfoxide (2 mL) was added compound
30 (0.221 g, 0.5 mmol, synthesized as described in US8252938).
After stirring at room temperature for 30 min, the reaction mixture
was added to diethyl ether (50 mL) and the resulting solution was
washed with water, washed with brine, dried, and concentrated.
The product was purified by preparatory TLC (20% ethyl acetate
in hexanes) to provide compound 31 (0.12 g, 73% yield) as an off-
white solid: mp 170–175 °C; 1H NMR (400 MHz, acetone-d6) d
7.70 (dd, J = 8.6, 7.9 Hz, 1H), 7.44 (dd, J = 6.3, 1.9 Hz, 1H), 7.35
(dd, J = 8.7, 1.8 Hz, 1H), 6.11 (d, J = 6.4 Hz, 1H), 3.97 (s, 3H), 3.91
(s, 3H); 19F NMR (376 MHz, acetone) d À133.05, -148.61; EIMS
m/z 328.
A slurry of compound 22 (10.2 g, 28 mmol) in methanol (60 mL)
was prepared in a 250 mL round bottom flask. A 50% w/w solution
of sodium hydroxide (4.58 g, 57 mmol) was added followed by
10 mL water. The reaction mixture was stirred overnight.
Hydrochloric acid (2 N, 29 mL, 58 mmol) was added causing pre-
cipitation of a solid which was filtered, washed with water, and
dried under vacuum to provide compound 24 (8.90 g, 91% yield)
as a white solid: mp 166–168 °C; 1H NMR (400 MHz, DMSO-d6) d
13.68 (s, 1H), 7.47 (dd, J = 8.5, 1.5 Hz, 1H), 7.30 (dd, J = 8.5,
7.0 Hz, 1H), 7.02 (s, 2H), 3.93 (d, J = 0.9 Hz, 3H); 19F NMR
(376 MHz, DMSO) d À129.10 (JF–F = 30 Hz), 138.67 (JF–F = 30 Hz);
ESIMS m/z 349 [(M+H+].
4.1.16. Methyl 3-chloro-6-(4-chloro-2-fluoro-3-methoxy-
phenyl)picolinate (33)
Another compound synthesized by a similar method was:
Compound 32 (1.0 g, 4.85 mmol, see US20120100990 for prepa-
ration), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxabori-
nane (1.424 g, 5.82 mmol), cesium fluoride (0.737 g, 4.85 mmol),
4.1.12.1. 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropicol-
inic acid (23).
Off-white solid, mp 154–157 °C; 1H NMR

J. B. Epp et al. / Bioorg. Med. Chem. 24 (2016) 362–371
371
411F crop oil concentrate, and TritonÒ X-155 surfactant in a
46:42:12:1.0:0.02 v/v ratio to obtain the spray solutions associated
with the highest application rates. Additional spray solutions for
the lower application rates were obtained by serial dilution of
12 mL of the high rate solution with a solution containing 2 mL
of GPS and 10 mL of an aqueous mixture containing water, GPS,
isopropyl alcohol, Atplus 411F crop oil concentrate, and TritonÒ
X-155 surfactant in a 46:42:12:1.0:0.02 v/v ratio. The resulting
spray solutions were 1/2X, 1/4X, 1/8X and 1/16X of the most con-
centrated, high rate spray solution.
Table 1
Broadleaf weed species utilized in post-emergent herbicide evaluations
Scientific name
Common name
Bayer code
Chenpodium album
Ipomea hederacea
Amaranthus retroflexus
Abutilon theophrasti
Viola tricolor
Polygonum convolvulus
Euphorbia heterophylla
Cirsium arvense
Lambsquarter
Ivyleaf Morningglory
Redroot Pigweed
Velvetleaf
CHEAL
IPOHE
AMARE
ABUTH
VIOTR
POLCO
EPHHL
CIRAR
Viola
Wild Buckwheat
Wild Poinsettia
Canadian Thistle
Sunflower
Helianthus annuus
HELAN
Compound requirements were based upon a 12 mL application
volume at a rate of 187 L/ha. Formulated compounds were applied
to the plant material with an overhead Mandel track sprayer
equipped with a 8002E nozzles calibrated to deliver 187 L/ha over
an application area of 0.503 square meters at a spray height of
18 inches (43 cm) above the average plant canopy height. Control
plants were sprayed in the same manner with the solvent blank.
The treated plants and control plants were placed in a greenhouse
as described above and watered by sub-irrigation to prevent wash-
off of the test compounds. After 14 days, the condition of the test
plants as compared with that of the control plants was determined
visually and scored on a scale of 0 to 100 percent where 0 corre-
sponds to no injury and 100 corresponds to complete kill.
1,4-bis(diphenylphosphino) butane (0.207 g, 0.485 mmol), and
palladium(II) acetate (0.109 g, 0.485 mmol) were combined in ace-
tonitrile (48.5 mL) and heated at reflux for 2 h. The cooled reaction
mixture was partitioned between ethyl acetate and water. The
organic phase was dried, filtered, and concentrated. The product
was purified by flash chromatography (ethyl acetate/hexanes gra-
dient) to provide compound 33 (400 mg, 25% yield) as a white
solid: mp 112–114°C; 1H NMR (400 MHz, DMSO-d6) d 8.26 (d,
J = 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.1 Hz, 1H), 7.63 (m, 1H), 7.49
(dd, J = 8.7, 1.6 Hz, 1H), 3.95 (s, 6H);19F NMR (376 MHz, DMSO) d
À131.51; ESIMS m/z 330 [(M+H)+].
ÒTM
Trademark of The Dow Chemical Company (‘Dow’) or an
affiliated company of Dow.
4.2. Biology
Acknowledgment
4.2.1. Herbicidal assessment of key picolinate and 6-aryl-
picolinate analogs
This work was funded entirely by Dow AgroSciences LLC, a
wholly owned subsidiary of The Dow Chemical Company.
Herbicidal activity was assessed in foliar applications for the
nine dicotyledonous weed species shown in Table 1. Plants were
incubated in a greenhouse and evaluated for percent visual injury
14 days after compound application. For each compound tested,
the percent visual injury values were added together so that the
relative activity of test compounds could be compared graphically.
For these graphical comparisons, the highest possible score would
be 900 and would require 100% percent visual injury (or complete
control) of all nine dicotyledonous weed species tested.
References and notes
1. Cobb, A. H.; Reade, J. P. H. Herbicides and Plant Physiology; Wiley-Blackwell:
United Kingdom, 2010. Chapter 1.
2. Troyer, J. R. Weed Sci. 2001, 2001, 290.
3. Simon, S.; Patrasek, J. Plant Sci. 2011, 180, 454.
4. Schmitzer, P. R.; Balko, T. W.; Daeuble, J. F.; Epp, J. B.; Satchivi, N. M.; Siddall, T.
L.; Weimer, M. R.; Yerkes, C. N. Discovery and SAR of Halauxifen-methyl: A
Novel Auxin Herbicide. In Synthesis of Crop Protection Products; Maienfisch, P.,
Ed.; ACS Books (in press).
5. Johnston, H.; Tomita, M. S. U.S. Patent 3,285,925, 1966.
6. Johnston, H. U.S. Patent 3,317,549, 1967.
7. Krumel, K. L.; Bott, C. J.; Gullo, M. F.; Scortichini, C. L.; Hull, J. W.; Scortichini, C.
L. U.S. Patent 6,352,635, 2002.
8. Fields, S. C.; Alexander, A. L.; Balko, T. W.; Bjelk, L. A.; Buysse, A. M.; Keese, R. J.;
Krumel, K. L.; Lo, W. C.; Lowe, C. T.; Richburg, J. S.; Ruz, J. M. U.S. Patent
6,297,197, 2001.
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4.2.2. Foliar herbicidal activity evaluation
The test plants shown in Table 1 were grown in Metro-mix 360
(SunGro Horticulture, Agawam, MA) in 133 square centimeter
(cm2) plastic pots for 7–21 days in a greenhouse with a 15 h
photoperiod maintained at 23–29 °C during the day and 22–28 °C
during the night. Plants were grown to the 2 to 3 leaf stage prior
to applications.
The concentrated stock solutions were prepared by placing a
weighed amount (determined by the highest rate to be tested) of
each test compound in a 25 mL glass vial and dissolving the test
compound in 4 mL of a 97:3 volume/volume (v/v) mixture of ace-
tone and dimethyl sulfoxide (DMSO), hereafter referred to as the
General Purpose Solvent (GPS). If the test compound did not dis-
solve readily, the mixture was warmed and/or sonicated.
The concentrated stock solutions were diluted with 20 mL of an
aqueous mixture containing water, GPS, isopropyl alcohol, Atplus
11. Whittingham, W. G.; Weber, C. G. B. Patent 2,486,717, 2012.
12. Calderon Villalobos, L. I. A.; Lee, S.; De Oliveira, C.; Ivetac, A.; Brandt, W.;
Armitage, L.; Sheard, L. B.; Tan, X.; Parry, G.; Mao, H.; Zheng, N.; Napier, R.;
Kepinski, S.; Estelle, M. Nat. Chem. Biol. 2012, 8, 477.
13. Hoagland, R. E.; Zablotowicz, R. M. The Role of Plant and Microbial Hydrolytic
Enzymes in Pesticide Metabolism, In Pesticide Biotransformation in Plants and
Microorganisms, ACS Symposium Series, 2001, 777.
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Patent 7,314,849, 2008.
15. Yerkes, C. N.; Lowe, C. T.; Eckelbarger, J. D.; Epp, J. B.; Guenthenspberger, K. A.;
Siddall, T. L.; Schmitzer, P. R. U.S. Patent 8,883,688, 2014.