Synthesis of insecticidal fluorinated anthranilic diamides

Article abstract of DOI:10.1016/j.bmc.2007.12.017

A series of highly active fluorinated anthranilic diamide insecticides have been prepared and their biological activity assessed on two aphid species in the search for systemically active compounds that control Hemiptera. In addition, we have demonstrated a new synthesis of N-aryl 3-fluoropyrazoles.

Full text of DOI:10.1016/j.bmc.2007.12.017

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 3163–3170
Synthesis of insecticidal fluorinated anthranilic diamides
David A. Clark,* George P. Lahm, Ben K. Smith, James D. Barry and Don G. Clagg
DuPont Crop Protection, Stine-Haskell Research Center, PO Box 30, Newark, DE 19714, USA
Received 30 October 2007; revised 10 December 2007; accepted 11 December 2007
Available online 18 January 2008
Abstract—A series of highly active fluorinated anthranilic diamide insecticides have been prepared and their biological activity
assessed on two aphid species in the search for systemically active compounds that control Hemiptera. In addition, we have dem-
onstrated a new synthesis of N-aryl 3-fluoropyrazoles.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of the discovery program, indications of
activity on Hemiptera, or sucking insects, were noted.
Indeed, compound 2 shows levels of activity on aphid
and hopper species that approach commercial stan-
dards. Populations of hemipteran insect pests, which
are mobile and feed on plant sap, are typically most
effectively controlled by compounds having physical
properties favoring penetration and systemic transport
in plants. As part of a broader effort to improve the
physical properties of these compounds in order to opti-
mize their plant systemic behavior, we sought to reduce
lipophilicity by replacing each of the halogens with fluo-
rine, both individually and collectively (Fig. 2).
Modern agricultural practice demands protection of
large monocultures from insect pests and diseases which
can otherwise severely reduce crop yields. The continual
search for new methods of insect control for crop pro-
tection is driven by the ability of large, rapidly breeding
populations of insects to develop resistance to current
insecticides. Improved off-target safety and environmen-
tal profiles are also key goals of pesticide research. The
identification of potent and selective insect toxins with
new sites of action is therefore of high importance.
RynaxypyrTM (1, Fig. 1), is a new insecticide for the con-
trol of lepidopteran (caterpillar) and coleopteran (bee-
tle) pests of agriculturally significant crops.1 It is
representative of a new class of anthranilic diamides that
act at the ryanodine receptor, a site of action that is cur-
rently commercially unexploited. Anthranilic diamides
act on the sarcosplasmic reticulum of cardiac and skele-
tal muscle cells to open internal calcium stores causing
muscle contraction, paralysis, and death.2 RynaxypyrTM
demonstrates field use-rates that are significantly less
than current commercial standards, varying from 50 g/
ha to less than 1 g/ha and with good safety toward ben-
eficial insects. In addition to possessing extremely high
levels of potency on insects, RynaxypyrTM shows remark-
able safety to mammals as a result of poor intrinsic
activity on mammalian ryanodine receptors with a mar-
gin of selectivity of the order of 103.
2. Results and discussion
Introduction of fluorine onto the phenyl ring was
accomplished as shown in Scheme 1. Electrophilic chlo-
rination of 4-fluoroanthranilic acid 3 introduces the 2-
substituent, a group that is critical to the biological
Cl
N
N
N
Br
O
Me
NH
O
Cl
Keywords: Fluorination; Ryanodine receptor; Systemic insecticide.
*
NHMe
Corresponding author. Tel.: +1 302 451 4846; fax: +1 302 366
5738; e-mail: david.a.clark@usa.dupont.com
Figure 1. RynaxypyrTM (1).
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.12.017

3164
D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
Y = F/Cl
F
F
H
a,b
NH2
N
O
Cl
Y
A = F/Cl/Me
X
X
O
N
N
O
N
N
N
N
8: X = H
9: X = F
10: X = H
11: X = F
Br
Z
O
Cl
A
NH
NH
c,d
F
Z = F/
Br/CF3
O
O
Cl
X
NH2
NHMe
NHMe
2
O
X = F/Cl
X
OH
Figure 2. Desired sites of fluorination.
12: X = H
13: X = F
e
Br
N
14 = Cl
A
Cl
NH2
Scheme 2. Reagents and conditions: (a) 1.13 equiv Cl3CCH(OH)2,
5 equiv NH2OHÆHCl, 1.25 equiv HCl, 6.7 equiv Na2SO4, H2O, 75 ꢁC,
3 h, X = H, 75%; X = F, 79%; (b) H2SO4, 65 ꢁC, 3 h, X = H, 58%;
X = F, 13%; (c) 1.3 equiv H2O2, HOAc, 2 drops H2SO4, 75–100 ꢁC,
20 min, X = H, 34%; X = F, 9%; (d) 5 equiv NaOH, THF, H2O, rt,
20 min, then 1 N HCl, X = H 30%, X = F, 60%; (e) 1 equiv NCS,
DMF, rt, 3 h, 72%.
N
O
b
N
Cl
O
O
c
F
F
N
OH
3: A = H
5
a
4: A = Cl
by carboxylation with CO2 to give the requisite pyr-
idylpyrazole acid 18 in good yield.
Cl
Our standard synthesis of the pyridylpyrazole portion of
the molecules is analogous to that shown in Scheme 3
employing 2,3-dichloropyridine in place of 2-chloro-3-
nitropyridine. By this route, the synthesis of the 3-fluo-
ropyrazole analog 24 shown in Scheme 5 required the
preparation of 3-fluoropyrazole itself.1 This known pyr-
azole, however, is prepared in rather low yield by the
photochemical decomposition of the corresponding dia-
zo-compound in HBF4.3 This route appeared unattrac-
tive and an alternative was sought.
Br
N
N
N
HO
Br
N
N
O
Cl
O
NH
Cl
N
O
F
7
NHMe
6
An improved synthetic route to the acid 7 via the corre-
sponding ester 22 was developed by Freudenberger
et al.4a and involves bromination of the pyrazolinone
19 followed by persulfate oxidation of bromopyrazoline
20 as shown in Scheme 4. This bromopyrazoline is
somewhat sensitive toward hydrolysis and the corre-
sponding chloropyrazoline 21 can undergo halogen ex-
change in HBr to give 20.4b It therefore seemed
reasonable that the target fluoropyrazole might be ob-
tained from 20 or 21 via halogen exchange followed
by oxidation.
Scheme 1. Reagents and conditions: (a) 1.0 equiv NCS, DMF, rt, 14 h,
82%; (b) 7, 1 equiv MsCl, 1 equiv NEt3, CH3CN, rt, 15 min then
1 equiv 4, 2 equiv NEt3, rt, 2 h, then 1 equiv MsCl, rt, 14 h, 47%; (c)
1.3 equiv MeNH2, THF, reflux, 15 min, 59%.
activity of these compounds.1 Coupling to the pyr-
idylpyrazole acid 71b is followed by cyclization to the
benzoxazinone 5 which can then be opened with a vari-
ety of amines to prepare the target diamides.
2-Fluoroanthranilic acids were prepared in modest yield
from commercially available fluoroanilines via the isa-
tins 10/11 (Scheme 2).
Initial experiments with CsF in DMF or DMSO were
promising but gave only small amounts of desired prod-
uct. However, treatment of 20 with AgF in refluxing
CH3CN gave the desired fluoropyrazoline 23 in good
yield (Scheme 5). Silver fluoride has been used on occa-
sion for the fluorination of active halides, especially
cyanuric chloride, but has not seen widespread use.5
Compounds in which Y = F (Fig. 2) were prepared by a
Balz-Schiemann reaction of the aminopyridines 16
(Scheme 3). Lithiation of the pyrazole 17 was followed

D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
3165
Calculated values have been calibrated with empirical
values for 6 compounds representative of A, X, Y, and
Z = F and the chloro standard 2, and are typically high-
er by ꢀ0.4 log units. The fluorinated analogs possess the
desired increase in hydrophilicity and fall within the
optimal logP range of 1–3 for a systemic insecticide.6
Br
Br
N
a,b
N
N
NH2
N
H
N
15
Selected biological data for this series of anthranila-
mides are displayed in Table 2. The EC50 of cotton/mel-
on aphid (CMA; Aphis gossypii Glover) and green peach
aphid (GPA; Myzus persicae (Sulzer)), two agricultur-
ally significant pests of fruit and vegetables, was deter-
mined using a combined contact/systemic plant assay
(CON/SYS). Also shown is the percent mortality of
GPA in systemic only (SYS) plant assay.
16
c
Br
Br
N
N
HO2C
d
N
N
F
F
Compounds 25 and 2, anthranilamide benchmarks of
hemipteran control, possess activity on aphids
approaching that of the commercial standard imidaclo-
prid, an agonist of the nicotinic receptor. They show lit-
tle difference between each other, indicating that the
bromo- and trifluoromethylpyrazoles are essentially
equivalent. A comparison of compounds 26 and 25
and of 6 and 2 indicates that replacement of X = Cl
for X = F diminishes aphicidal activity, albeit only
slightly (1–3·). It can also be seen that the single substi-
tution of A = Cl for A = Me provides compounds with
reduced activity (contrast compounds 27 and 28 with
26 and 6, respectively). Likewise, a comparison of com-
pounds 29 and 36 with the chloro analog 2 and close
analogs 25, 26, 6, and 30 indicates that introduction of
A = F provides compounds that are similarly inferior
to those in which A = Cl, especially on GPA. The flu-
oropyridyl compounds as represented by compounds
30 and 31 (Y = F) possessed equivalent if not better
activity on GPA as compared with compounds 25 and
2. Compound 30 also possesses activity on CMA com-
parable to that of the standards. The activity of the flu-
oropyrazole 32 showed disappointing results with
greatly diminished potency on both aphids relative to
analogs 26 and 6.
N
N
18
17
Scheme 3. Reagents and conditions: (a) K2CO3, 2-chloro-3-nitropyr-
idine, DMF, rt, 14 h; (b) 1 atm H2, PtO2, EtOH, rt, 14 h, 78% for 2
steps; (c) NOBF4, PhCl, rt, 14 h then 90 ꢁC, 1.5 h, 24%; (d) LDA,
THF, À78 ꢁC, 0.5 h, then CO2, À78 ꢁC to rt, 10 min, 90%.
Z
Br
For Z = Br,
K2S2O4
N
N
MeO2C
MeO2C
N
N
Cl
Cl
N
N
19: Z = OH
20: Z = Br
21: Z = Cl
22
PBr3
HBr
H2O
Scheme 4. Alternative synthesis of bromopyrazole 22.
Concomitant with fluorination, AgF also effected oxida-
tion of the pyrazolines to the corresponding pyrazoles.
Unfortunately, no standard method of preparative puri-
fication was found to be able to separate this mixture of
fluoro and bromo pyrazoles. The reaction therefore had
to be run to incomplete conversion and the fluoropyraz-
oline separated from the starting material before being
re-subjected to the same conditions in order to prepare
the pyrazole 24, free of the biologically active bromo-
analog 22. The fluoride exchange proceeded equally well
on the free base as well as the hydrobromide salt of bro-
mopyrazoline 20. Using 3 equivalents of AgF in reflux-
ing CH3CN for 1 hour provides 2:2:3:1 ratio of
20:22:23:24 with an isolated yield of 23 of 33%. Having
fluoropyrazole 24 in hand, standard manipulations of
hydrolysis, benzoxazinone formation, and ring opening
with various amines proceeded smoothly to give the de-
sired anthranilamides.
Despite the threefold lower contact activity of com-
pound 26, it did display 100% control of GPA in a plant
systemic test at 250 ppm. This single piece of data ap-
pears to be an improvement over the chloro- analog
25 with 74% control in the same test. However, systemic
control of GPA was not observed at 50 ppm for com-
pound 26 and the remaining analogs did not show any
significant progress toward the goal of a truly systemic
insecticide.
3. Conclusion
In conclusion, a series of highly active fluorinated
anthranilamide insecticides have been prepared and
their biological activity assessed on two aphid species
in the search for systemically active compounds that
control Hemiptera. Although possessing excellent levels
of contact activity, these compounds failed to show sig-
nificant improvement in activity over their chloro ana-
logs. This is likely due to a reduction in intrinsic
Calculated and measured logP’s for a select group of
N-methyl anthranilamides are displayed in Table 1.

3166
D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
F
Br
F
Br
MeO
MeO
MeO
MeO
N
N
N
N
a
+
Cl
+
N
N
N
N
O
O
O
Cl
Cl
O
Cl
N
N
N
N
HBr.
24
22
23
20
b
Scheme 5. Reagents and conditions: (a) 3 equiv AgF, CH3CN, reflux, 1 h, 33%; (b) AgF, 3 equiv, CH3CN, reflux, 1 h, 40%.
Table 1. Calculated and measured Log P’s for select analogs
Compound
Xa
Aa
Ya
Za
Calculated log P
Measured log P
25
Cl
Cl
F
Cl
Cl
Cl
Cl
Me
Me
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
CF3
Br
CF3
Br
CF3
Br
Br
Br
CF3
F
3.7
3.6
3.1
3.1
3.1
3.0
3.3
3.1
3.1
2.3
2.9
2.9
3.0
2.7
2.0
3.6
2
26
3.0
2.6
6
27
F
F
28
29
F
Cl
Cl
Cl
F
2.9
2.7
30
31
32d
Cl
Cl
Cl
Cl
Me
Me
F
F
Cl
Cl
Cl
F
33
34
Cl
Cl
Cl
F
F
2.6
3.0
F
35
36
Br
Br
F
Cl
Cl
Cl
37
RynaxypyrTM (1)
F
Cl
F
Me
Br
a Refer to Figure 3.
vents where appropriate. Amine bases were dried and
stored over potassium hydroxide. Glassware was oven-
dried before use. Reactions were monitored by TLC
on E. Merck silica gel plates (0.25 mm) and visualized
under UV light (254 nm) and/or heating with phospho-
molybdic acid ethanol solution. Flash chromatography
was performed on E. Merck silica gel (60, particle size
0.040–0.063 mm except where noted). Yields refer to
chromatographically and spectroscopically (1H NMR)
pure materials.
Y
N
N
N
Z
O
A
NH
O
X
NHMe
NMR spectra were recorded at 25 ꢁC. 1H NMR spectra
were recorded at 300 MHz. 13C spectra were recorded at
75 MHz. 19F shifts were recorded at 282 MHz and are
reported relative to CFCl3 as an internal standard. IR
samples were prepared by evaporation of a solution of
the compound from CDCl3 onto a NaCl plate under a
stream of nitrogen. Mass spectra were recorded under
FAB conditions. Melting points are uncorrected.
Figure 3.
activity owing to weaker hydrophobic interactions with
the receptor. In the cases where A = F, a lessening of the
twist angle in the neighboring amide might also be
responsible for the decrease in potency.1 In addition,
we have demonstrated a new synthesis of N-aryl 3-
fluoropyrazoles.7
Ethyl 1-(3-chloro-2-pyridinyl)-3-fluoro-4,5-dihydro-1H-
pyrazole-5-carboxylate 23: To a solution of bromopy-
razoline hydrobromide 20 (12.3 g, 29.8 mmol) in
CH3CN (100 mL) was added anhydrous AgF (11.3 g,
89.4 mmol) and the mixture was heated at reflux for
1 h. The mixture was cooled in an ice bath, diluted with
EtOAc, and washed with a saturated aqueous solution
of NaHCO3. The mixture was filtered through a pad
of Celiteꢂ, the aqueous phase was separated and ex-
4. Experimental
4.1. General techniques
Reactions were carried out under an atmosphere of dry
nitrogen using commercially available anhydrous sol-

D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
3167
Table 2. Insecticidal activity for compounds evaluated on cotton/melon aphid (CMA) and green peach aphid (GPA)
Compound
Cotton/melon aphid-EC50 (CON/SYS)a
Green peach aphid-EC50 (CON/SYS)a
GPA-% mortality (SYS)b
25
2.1 (1.4,3.5)
1.6 (0.9, 2.4)
5.5 (4.0, 8.1)
2.5 (1.1, 4.7)
63.4 (26, 201)
11.3 (7.2, 18.5)
5.5 (3.0, 9.5)
<2c
3.4 (2.7, 4.6)
2.1 (1.4, 3.2)
9.2 (7.2, 12.9)
7.8 (4.0, 23.2)
30.8 (6.7, 84.3)
>300
74
22
2
26
100
2
6
27
8
28
29
<80
NT
29
>300
1.8
30
31
9.1 (5.8, 16.3)
<100d
3.4 (1.5, 7.0)
<100d
58
32
33
NT
2
6.2 (4.4, 8.9)
>100
20.6 (15.9, 26.8)
>300
34
35
NT
29
3.7 (2.0, 6.4)
<50e
<250g
11.3 (8.7, 15.2)
<250f
<250h
36
37
14
NT
Imidacloprid
RynaxypyrTM (1)
0.4 (0.3, 0.6)
3.1 (2.0,4.7)
0.3 (0.2, 0.3)
12.4 (6.0, 27.2)
12
a Upper and lower bounds (95% confidence limits) are shown in parentheses for contact/systemic (CON/SYS) plant assay. All data in ppm.
b Percent mortality of GPA at 250 ppm in a systemic-only (SYS) plant assay. NT, not tested.
c At 2 ppm the mortality was 89%, no EC50 was calculated.
d At 100 ppm the mortality was 65% for GPA and 89% for CMA, no EC50 was calculated.
e At 50 ppm the mortality was 85%, no EC50 was calculated.
f At 250 ppm the mortality was 90%, no EC50 was calculated.
g At 250 ppm the mortality was 70%, no EC50 was calculated.
h At 250 ppm the mortality was 100%, at 50 ppm the mortality was less than 80%, no EC50 was calculated.
tracted with EtOAc. The organic phases were combined,
washed with saturated solutions of NaHCO3 and then
NaCl, and dried (MgSO4). After concentration, the
material was purified by flash chromatography (silica
gel, 15–40 l, 9:1 to 4:1 hexane:EtOAc) to afford the flu-
oropyrazoline 23 as a colorless oil (2.31 g, 33% account-
ing for 1.24 g of recovered bromopyrazoline 20 as its
free base). Colorless oil. Rf 0.27 (silica gel, 4:1 hex-
ane:EtOAc). 1H NMR (CDCl3) d 8.08 (dd, J = 4.8,
1.5 Hz, 1H); 7.64 (dd, J = 7.8, 1.5 Hz, 1H); 7.44 (dd,
J = 7.8, 4.8 Hz, 1H); 5.41 (dd, J = 9.3, 11.7 Hz, 1H);
4.19 (q, J = 7.2 Hz, 2H); 3.32 (ddd, J = 17.1, 11.7,
6.3 Hz, 1H); 3.17 (ddd, J = 17.1, 9.3, 5.4 Hz, 1H); 1.21
(t, J = 7.2 Hz, 3H). F19 NMR (CDCl3) À105.77
(J = 5.1 Hz). C13 NMR (CDCl3) d 168.2, 160.9, 157.3,
150.6, 143.2, 138.1, 118.8, 116.9, 60.7 (d, J = 102 Hz),
30.14 (d, J = 26 Hz), 12.4. HRMS calcd for
C11H12N3O2ClF 272.0602; Found 272.0595. IR (film)
mmax 2983, 1744, 1672, 1580, 1460, 1373, 1197, 1094,
phy (silica gel, 4:1 to 7:3 hexane:EtOAc) to afford the
fluoropyrazole 24 as a white solid (0.47 g, 40%). mp
54–56 ꢁC. Rf 0.27 (silica gel, 7:3 hexane:EtOAc). 1H
NMR (CDCl3) d 8.50 (dd, J = 4.8, 1.6 Hz, 1H); 7.91
(dd, J = 8.1, 1.6 Hz, 1H); 7.44 (dd, J = 8.1, 4.8 Hz,
1H); 6.59 (d, J = 6.0 Hz, 1H); 4.23 (q, J = 7.2 Hz, 2H);
1.21 (t, 3H, J = 7.2Hz, 3H). F19 NMR (CDCl3)
À127.65 (J = 5.9 Hz). C13 NMR (CDCl3) d 163.5,
160.2, 156.3, 147.3, 145.4, 137.4, 134.2, 128.0, 124.3,
94.1 (d, J = 23 Hz), 60.2, 12.4. LRMS (M + H+)
269.99, 271.98. HRMS calcd for C11H10N3O2ClF:
270.0446; Found: 270.0435. IR (film) mmax 2984, 1732,
1575, 1551, 1479, 1426, 1304, 1248 cmÀ1. Elemental
analysis calcd for C11H9N3O2ClF: C, 49.00; H, 3.36;
N, 15.58; Cl, 13.15; F, 7.05. Found C, 48.97; H, 3.22;
N, 15.45; Cl, 13.03; F, 6.88.
1-(3-Chloro-2-pyridinyl)-3-fluoro-1H-pyrazole-5-carbox-
ylic acid (38). To a solution of ester 24 (2.45 g,
9.0 mmol) in 1,4-dioxane (90 mL) was added NaOH
(9.9 mL, 1.0 N aqueous solution) and the mixture
was stirred at ambient temperature overnight. The mix-
ture was diluted with 1 N NaOH (50 mL) and extracted
twice with Et2O. The aqueous phase was acidified with
concd HCl (ꢀ7 mL) and extracted twice with CH2Cl2.
This extract was dried (MgSO4) and concentrated to pro-
vide the acid as a white solid (2.17 g, 99%). mp 192–
194 ꢁC. Rf 0.08 (silica gel, 1:4 MeOH: CH2Cl2). 1H
NMR (DMSO-d6) d 14.0 (br s, 1H), 8.55 (dd, J = 4.8,
1.6 Hz, 1H); 8.24 (dd, J = 8.1, 1.6 Hz, 1H); 7.67 (dd,
J = 8.1, 4.8 Hz, 1H); 6.90 (d, J = 5.7 Hz, 1H). C13 NMR
1032 cmÀ1
.
Elemental
analysis
calcd
for
C11H11N3O2ClF: C, 48.63; H, 4.08; N, 15.47; Cl,
13.05; F, 6.99. Found C, 48.42; H, 3.96; N, 15.39; Cl,
12.89; F, 6.68.
Ethyl 1-(3-chloro-2-pyridinyl)-3-fluoro-1H-pyrazole-5-
carboxylate 24: To a solution of fluoropyrazoline 23
(1.17 g, 4.31 mmol) in CH3CN (30 mL) was added anhy-
drous AgF (2.74 g, 21.6 mmol) and the mixture was
heated at reflux for 14 h in the dark. The mixture was
cooled, diluted with CH2Cl2, and a saturated solution
of NaHCO3 was added. The mixture was filtered
through a pad of Celiteꢂ, the phases were separated,
and the organic phase was dried (MgSO4). After concen-
tration, the residue was purified by flash chromatogra-
(THF d8)
137.0, 134.6, 127.3, 124.2, 93.3 (d, J = 22.5 Hz). MS
d
163.1, 159.8, 156.6, 147.3, 145.1,
(M+H+) 242.02, 244.00; (MÀH+) 240.08, 242.08. IR

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D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
(film) mmax 3152, 2922, 2594, 1728, 1556, 1480, 1433, 1305,
1251 cmÀ1
was filtered through a pad of silica gel and concentrated.
The residue was dissolved in hot hexanes, filtered and
pale yellow needles were collected upon cooling.
12.6 g, 78% over 2 steps. NMR (CDCl3) d 8.43 (d,
1H), 7.80 (dd, 1H), 7.13 (dd, 1H), 7.05 (dd, 1H), 6.47
(d, 1H), 5,43 (br s, 2H).
.
2-[1-(3-Chloro-2-pyridinyl)-3-fluoro-1H-pyrazol-5-yl]-
6,8-dichloro-4H-3,1-benzoxazin-4-one (39): To a solu-
tion of acid 38 (74 mg, 0.31 mmol) in CH3CN (3 mL)
was added MeSO2Cl (24 lL, 0.31 mmol) followed by
NEt3 (43 lL, 0.31 mmol) and the mixture was stirred
at ambient temperature for 10 min. 2,5-Dichloroanthra-
nilic acid (63 mg, 0.31 mmol) was then added, followed
by NEt3 (86 lL, 0.62 mol), and the mixture was stirred
at ambient temperature for a further 2 h. MeSO2Cl
(24 lL, 0.31 mmol) was then added and the mixture
was stirred at ambient temperature overnight. Concen-
tration of the mixture and purification by flash column
chromatography (silica gel, 9:1 to 4:1 hexane:EtOAc)
provided benzoxazinone 39 as a yellow solid (64 mg,
2-(3-Bromopyrazolyl)-3-fluoropyridine 17: Aminopyri-
dine 16 (12.6 g, 52.7 mmol) was dissolved in chloroben-
zene (150 mL) and cooled in an ice bath. NOBF4 (6.8 g,
57.8 mmol) was added and the mixture was allowed to
warm to ambient temperature and stirred overnight be-
fore being heated at 90 ꢁC for 1.5 h. The cooled mixture
was treated with aqueous NaHCO3 and extracted with
Et2O. Non-soluble material was treated with NaOH
(1 N) and extracted with Et2O. The combined ether ex-
tracts were dried and concentrated, and the residue was
purified by distillation (0.5 mmHg, 162–178 ꢁC) fol-
lowed by flash chromatography of the distillate (silica
gel, 10% to 20% ethyl acetate in hexanes) to give a yel-
1
32%). Rf 0.22 (silica gel, 4:1 hexane:EtOAc). H NMR
(CDCl3) d 8.53 (dd, J = 4.8, 1.6 Hz, 1H); 8.05 (d,
J = 2.3 Hz, 1H); 7.96 (dd, J = 8.1, 1.6 Hz, 1H); 7.72 (d,
J = 2.3 Hz, 1H); 7.47 (dd, J = 8.1, 4.8 Hz, 1H); 6.85 (d,
J = 5.7 Hz). F19 NMR (CDCl3) À127.05 (J = 6.2 Hz).
C13 NMR (CDCl3) d 163.8, 160.5, 154.7, 146.9, 145.7,
139.7, 137.8, 135.3, 133.2, 133.1, 131.4, 128.3, 125.4,
124.5, 117.7, 94.2 (d, J = 25 Hz). MS (M+H+) 411,
413, 415, IR (film) mmax 3120, 1778, 1639, 1542, 1485,
1
low/orange solid. 3.1 g, 24%. H NMR (CDCl3) d 8.33
(ddd, 1H), 8.21 (dd, 1H), 7.64 (ddd, 1H), 7.30 (ddd,
1H), 6.54 (d, 1H). F19 NMR (CDCl3) À127.13 (dd).
3-Bromo-1-(3-fluoro-2-pyridinyl)-1H-pyrazole-5-carbox-
ylicacid18: n-BuLi (2.5 M inhexanes, 5.4 mL, 13.4 mmol)
was added to i-Pr2NH (1.96 mL, 14.1 mmol) in THF
(100 mL) at À20 to 0 ꢁC. The mixture was stirred for
15 min before being cooled to À70 ꢁC. Pyrazole 17
(3.1 g, 12.8 mmol) in THF (10 mL) was added via cannula
such that the reaction temperature did not exceed À63 ꢁC.
After stirring at À78 ꢁC for 0.5 h, CO2 was introduced for
several minutes. The reaction was quenched by the cau-
tious addition of NaOH (1 N) and the reaction mixture
was allowed to warm to ambient temperature. The mix-
ture was extracted with Et2O (2·) which was discarded.
The aqueous layer was acidified with conc. HCl, extracted
with CH2Cl2 (2·), and the combined extracts were dried
(MgSO4) and concentrated to afford acid 18 as a white so-
lid. 3.3 g, 90%. 1H NMR (DMSO-d6) d 14.02 (br s, 1H),
8.44 (ddd, 1H), 8.07 (ddd, 1H), 7.73 (ddd, 1H), 7.27 (s,
1H). F19 NMR (DMSO-d6) À127.13 (dd).
1424, 1300, 1265, 1054, 1017 cmÀ1
.
N-[2,4-Dichloro-6-[(methylamino)carbonyl]phenyl]-1-(3-
Chloro-2-pyridinyl)-3-fluoro-1H-pyrazole-5-carbox-
amide (33): To a solution of benzoxazinone 39 (64 mg,
0.14 mmol) in THF (2 mL) was added MeNH2 (1 mL,
2.0 M solution in THF) and the mixture was stirred at
ambient temperature for 15 min. The mixture was con-
centrated and triturated with 1-chlorobutane to provide
anthranilamide 33 as a white solid (52 mg, 76%). Mp
1
215–217 ꢁC. Rf 0.34 (silica gel, 1:4 hexane/EtOAc). H
NMR (CDCl3) d 9.65 (s, 1H), 8.45 (dd, J = 4.8, 1.6 Hz,
1H); 7.85 (dd, J = 8.1, 1.6 Hz, 1H); 7.39–7.34 (m, 2H);
7.27 (d, 1H); 6.77 (d, 5.7 Hz, 1H), 6.27 (br q, J = 4.8 Hz,
1H), 2.91 (d, J = 4.8 Hz, 3H). F19 NMR (CDCl3)
À127.06 (J = 5.6 Hz). C13 NMR (CDCl3) d 165.8, 155.5,
147.5, 145.2, 137.3, 135.9, 133.5, 130.9, 130.8, 129.2,
127.9, 127.6, 124.8, 124.1, 106.4, 92.5 (d, J = 24 Hz),
25.5. LRMS (M+H+) 442, 444, 446 (MÀH+) 440, 442,
444. HRMS calcd for C17H12N5O2Cl3F: 442.0041; Found
:442.0030. IR (film) mmax 3251, 1666, 1643, 1549, 1470,
1307 cmÀ1. Elemental analysis calcd for C17H11N5O2
Cl3F: C, 46.13; H, 2.50; N, 15.82. Found C, 46.13; H,
2.16; N, 15.64.
The following compounds were obtained by the proce-
dure described above for the synthesis of 33 from the
respective anthranilic acid and pyrazole 5-carboxylic
acid:
1
25: H NMR (CDCl3) d 9.89 (br s, 1H), 8.48 (dd, 1H),
7.89 (dd, 1H), 7.51 (s, 1H), 7.42 (dd, 1H), 7.39 (d,
1H), 7.28 (d, 1H), 6.21 (q, 1H), 2.92 (d, 3H).
3-Amino-2-(3-bromopyrazolyl)pyridine 16: 3-Bromopy-
razole (10 g, 68 mmol), 2-chloro-3-nitropyridine (10.8 g,
68 mmol), and K2CO3 (14 g, 101 mmol) were combined
in DMF (60 mL) and stirred overnight at ambient tem-
perature. Water (300 mL) was added and the precipi-
1
2: H NMR (CDCl3) d 9.65 (s, 1H), 8.46 (dd, 1H), 7.85
(dd, 1H), 7.38 (m, 2H), 7.27 (m, 1H), 7.19 (s, 1H), 6.26
(q, 1H), 2.92 (d, 3H).
1
1
tated white solid was collected by filtration. 19.9 g. H
26: H NMR (CDCl3) d 9.73 (br s, 1H), 8.48 (dd, 1H),
NMR (CDCl3)d 8.60 (dd, 1H), 8.28 (d, 1H), 8.07 (dd,
1H), 7.41 (dd, 1H), 6.53 (d, 1H). The solid was dissolved
in ethanol (300 mL) and PtO2 (200 mg) was added. The
vessel was evacuated and purged with N2 (3·) and H2
(2·), and then stirred under a balloon of H2 overnight.
After evacuating excess hydrogen, the reaction mixture
7.89 (dd, 1H), 7.53 (s, 1H), 7.42 (dd, 1H), 7.13 (dd,
1H), 7.03 (dd, 1H), 6.23 (q, 1H), 2.91 (d, 3H). 19F
NMR (CDCl3) d À62.90, (s), À111.13 (t).
1
6: H NMR (CDCl3) d 9.49 (br s, 1H), 8.46 (dd, 1H),
7.86 (dd, 1H), 7.38 (dd, 1H), 7.19 (s, 1H), 7.14 (dd,

D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
3169
1H), 7.03 (dd, 1H), 6.28 (q, 1H), 2.91 (d, 3H). 19F NMR
4.2. Assessment of biological activity
(CDCl3) d À111.35 (t).
Control of cotton/melon aphid (Aphis gossypii Glover).
An open container containing a 6–7-days old cotton
plant was infested with 30–40 aphids and the soil was
subsequently covered with a layer of sand. Compounds
were formulated in a solvent comprising 10% acetone,
90% water, and 300 ppm X-77ꢂ Spreader Low-Foam
Formula non-ionic surfactant and applied in 1 mL vol-
umes through an atomizing sprayer to the test unit.
Good foliar and soil coverage was achieved to allow
for assessment of contact and soil systemic activity,
respectively. Each test was performed in triplicate and
when possible with a 3–5· factor of dilution between
rates. The units were allowed to dry for 1 h before being
capped and held for 6 days at 19–21 ꢁC and 50–70% rel-
ative humidity. The units were then visually inspected
with a stereomicroscope to assess mortality. Probit anal-
yses of the mortality data were used to generate EC50’s
(Table 2). The mortality in the untreated control and
solvent check was ꢀ1% and ꢀ10%, respectively.
1
27: H NMR (CDCl3) d 10.04 (br s, 1H), 8.48 (dd, 1H),
7.88 (dd, 1H), 7.42 (dd, 1H), 7.39 (s, 1H), 6.95 (m, 2H),
6.15 (q, 1H), 2.91 (d, 3H), 2.19 (s, 3H). 19F NMR
(CDCl3) d À62.83, (s), À114.94 (t).
1
28: H NMR (CDCl3) d 9.89 (br s, 1H), 8.45 (dd, 1H),
7.85 (dd, 1H), 7.37 (dd, 1H), 7.10 (s, 1H), 6.95 (m,
2H), 6.17 (q, 1H), 2.94 (d, 3H), 2.19 (s, 3H). 19F
NMR (CDCl3) d À115.08 (t).
1
29: H NMR (CDCl3) d 10.04 (br s, 1H), 8.46 (dd, 1H),
7.87 (dd, 1H), 7.38 (dd, 1H), 7.25–7.20 (m, 2H), 7.04 (s,
1H), 6.21 (q, 1H), 2.98 (d, 3H). 19F NMR (CDCl3) d
À109.35 (d).
1
30: H NMR (DMSO-d6) d 10.8–10.6, (br s, 1H), 8.42
(m, 1H), 8.4 (br m, 1H), 8.03 (ddd, 1H), 7.85 (d, 1H),
7.75 (s, 1H), 7.72 (m, 1H), 7.52 (d, 1H), 2.66 (d, 3H).
À60.71, À126.83 (d,
19F NMR (DMSO-d6)
J = 9.9 Hz).
d
Green peach aphids (Myzus persicae (Sulzer)) were trea-
ted in the same manner using a 12–15 days old radish
plant in place of the cotton plant. In the systemic-only
assay, formulated compounds were applied directly to
the soil, avoiding any direct contact with test species.
The mortality in the untreated control and that in the
solvent check were both ꢀ2%.
1
31: H NMR (DMSO-d6) d 10.54 (s, 1H), 8.38 (d, 1H),
8.34 (br s, 1H); 7.98 (ddd, 1H), 7.85 (d, 1H), 7.66
(ddd, 1H), 7.51 (d, 1H), 7.40 (s, 1H), 2.66 (d, 3H). 19F
NMR (CDCl3) d À126.67 (d).
1
32: H NMR (CDCl3) d 9.39 (br s, 1H), 8.45 (dd, 1H),
7.86 (dd, 1H), 7.38 (dd, 1H), 7.19 (dd, 1H), 7.06 (dd,
1H), 6.72 (d, 1H), 6.21 (br s, 1H), 2.92 (d, 3H). 19F
NMR (CDCl3) d À111.46 (t), À127.13 (d).
34: 1H NMR (CDCl3) d 10.05, (br s, 1H), 8.45 (dd, 1H),
7.85 (dd, 1H), 7.37 (dd, 1H), 7.27 (d, 1H), 7.23 (d, 1H),
6.66 (d, 1H), 6.13 (br m, 1H), 2.96 (d, 3H), 2.20 (s, 3H).
Acknowledgments
We would like to thank Billy Annan, Elaine McClurg,
Molly Waddell, Mary Koechert, and Anna Stoops for
biological testing, Cheryl Bellin for HPLC log P mea-
surements, and John Freudenberger for a generous gift
of compound 20.
35: 1H NMR (DMSO-d6) d 10.31, (s, 1H), 8.37 (m, 1H),
8.25 (br m, 1H), 7.98 (ddd, 1H), 7.65 (ddd, 1H), 7.48 (d,
1H), 7.34 (d, 1H), 7.33 (s, 1H), 2.67 (d, 3H), 2.17 (s, 3H).
19F NMR (DMSO-d6) d À60.66, À127.01 (dd).
36: 1H NMR (CDCl3) d 9.83, (s, 1H), 8.46 (dd, 1H), 7.87
(dd, 1H), 7.38 (dd, 1H), 7.04 (s, 1H), 7.01–6.92 (m, 2H),
6.27–6.16 (br s, 1H), 2.97 (d, 3H), 2.20 (s, 3H). 19F
NMR (CDCl3) d À107.87 (m), À111.05 (m).
37: 1H NMR (CDCl3) d 9.84, (s, 1H), 8.45 (dd, 1H), 7.86
(dd, 1H), 7.37 (dd, 1H), 7.00-6.91 (m, 2H), 6.63 (d, 1H),
6.26 (br q, 1H), 2.95 (d, 3H), 2.20 (s, 3H). 19F NMR
(CDCl3) d À108.22 (t), À110.98 (q), À127.18 (d).
References and notes
1. (a) Lahm, G. P.; Selby, T. P.; Freudenberger, J. H.;
Stevenson, T. M.; Myers, B. J.; Seburyamo, G.; Smith, B.
K.; Flexner, L.; Clark, C. E.; Cordova, D. Bioorg. Med.
Chem. Lett. 2005, 15, 4898; (b) Lahm, G. P.; Stevenson, T.
M.; Selby, T. P.; Freudenberger, J. H.; Cordova, D.;
Flexner, L.; Bellin, C. A.; Dubas, C. M.; Smith, B. K.;
Hughes, K. A.; Hollingshaus, J. G.; Clark, C. E.; Benner,
E. A. Bioorg. Med. Chem. Lett. 2007, 17, 6274.
2. Cordova, D.; Benner, E. A.; Sacher, M. A.; Rauh, J. J.;
Sopa, J. S.; Lahm, G. P.; Selby, T. P.; Stevenson, T.
M.; Flexner, L.; Gutteridge, S.; Rhoades, D. F.; Wu, L.;
Smith, R. M.; Tao, Y. Pestic. Biochem. Physiol. 2006,
84, 196.
3. Vilarrasa, J.; Galvez, C.; Calafell, M. Anal. Quim. 1975, 71,
631; Reimlinger, H.; Van Overstraeten, A. Chem. Ber. 1966,
99, 3350.
4. (a) Freudenberger, J. H.; Lahm, G. P.; Selby, T. P.;
Stevenson, T. M., WO 2003016283, 2003.; (b) Annis, G. D.,
WO 2004011453, 2004.
Log P’s were calculated using Biobyte c log P software.
Measured values were determined on a 2.1 mm ·
50 mm Zorbax SB C18 column at 40 ꢁC using a flow
rate of 1.0 mL/min with a gradient from 99% 5 mM
ammonium acetate, pH 7, buffer to 99% 5 mM ammo-
nium acetate in acetonitrile over 5 min. Retention times
were compared with a calibration curve created from
retention times of compounds with known values of
shake-flask octanol–water partition coefficients (P) in
the same system.
5. For selected fluorinations with AgF, see: Mitsch, R. A.;
Ogden, P. A. J. Org. Chem. 1966, 31, 3833; Josey, A. D.;
Dickinson, C. L., Jr.; Dewhirst, K. C.; McKusick, B. C. J.
Org. Chem. 1967, 32, 1941; Studentsov, E. P.; Ivin, B. A.;

3170
D. A. Clark et al. / Bioorg. Med. Chem. 16 (2008) 3163–3170
Slesarev, V. I.; Sochilin, E. G.; SU 453406, 1974; Feiring, A.
Soc., Perkin Trans. 1 1982, 7, 1593; Blackwell, G. B.;
Haszeldine, R. N.; Taylor, D. R. J. Chem. Soc., Perkin
Trans. 1 1982, 9, 2207–2210; Hatton, L. R.; Hawkins, D.
W.; Parnell, E. W.; Pearson, C. J.; Roberts, D. A., WO
8703781, 1987; Bargamova, M. D.; Motsishkite, S. M.;
Knunyants, I. L. Izvestiya Akademii Nauk SSSR, Seriya
Khimicheskaya 1990, 11, 2583–2589; Ichikawa, J.; Kobay-
ashi, M.; Noda, Y.; Yokota, N.; Amano, K.; Minami, T. J.
Org. Chem. 1996, 61, 2763–2769; Chi, K.-W.; Kim, S.-J.;
Park, T.-H.; Gatilov, Y. V.; Bagryanskaya, I. Y.; Furin, G.
G. J. Fluorine Chem. 1999, 98, 29–36.
E.; Sheppard, W. A. J. Org. Chem. 1975, 40, 2543.
6. Bromilow, R. H.; Chamberlain, K. Monograph—British
Plant Growth Regulator Group, 18 (Mech. Regul. Transp.
Processes) 1989, 113–128; Kleier, D. A. Pestic. Sci. 1994,
42, 1; Satchivi, N. M.; Stoller, E. W.; Wax, L. M.; Briskin,
D. P. Pestic. Biochem. Physiol. 2006, 84, 83–97; Sicbaldi, F.;
Sacchi, G. A.; Trevisan, M.; Del Re, A. A. M. Pestic. Sci.
1997, 50, 111–119.
7. For alternative syntheses of N-substituted fluoropyrazoles,
see, for example Banks, R. E.; Hitchen, S. M. J. Chem.