Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a potent hopper insecticide1

Article abstract of DOI:10.1016/j.bmcl.2016.11.042

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program which led to the discovery of triflumezopyrim as a highly potent insecticide controlling various hopper species. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented.

Full text of DOI:10.1016/j.bmcl.2016.11.042

Accepted Manuscript
Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a po-
tent hopper insecticide
Wenming Zhang, Caleb W. Holyoke Jr., Thomas F. Pahutski, George P. Lahm,
James D. Barry, Daniel Cordova, Robert M. Leighty, Vineet Singh, Daniel R.
Vicent, My-Hanh T. Tong, Kenneth A. Hughes, Stephen F. McCann, Yewande
T. Henry, Ming Xu, Twyla A. Briddell
PII:
S0960-894X(16)31194-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.042
BMCL 24437
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 October 2016
14 November 2016
15 November 2016
Please cite this article as: Zhang, W., Holyoke, C.W. Jr., Pahutski, T.F., Lahm, G.P., Barry, J.D., Cordova, D.,
Leighty, R.M., Singh, V., Vicent, D.R., Tong, M.T., Hughes, K.A., McCann, S.F., Henry, Y.T., Xu, M., Briddell,
T.A., Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a potent hopper insecticide,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.11.042
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bioorganic & Medicinal Chemistry Letters
Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a potent
hopper insecticide1
Wenming Zhanga,, Caleb W. Holyoke Jr.a, Thomas F. Pahutskia, George P. Lahma, James D. Barrya,
Daniel Cordovaa, Robert M. Leightya, Vineet Singhb, Daniel R. Vicenta, My-Hanh T. Tonga, Kenneth A.
Hughesa, Stephen F. McCanna, Yewande T. Henrya, Ming Xua, Twyla A. Briddella
a DuPont Crop Protection, Stine-Haskell Research Center, 1094 Elkton Road, Newark, DE 19711, USA
b E. I. DuPont India Pvt. Ltd., South Asia Field Experimental Station, Vadodara, Gujarat, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional
insecticidal activity controlling a number of insect species. In this communication, we report the
part of the optimization program which led to the discovery of triflumezopyrim as a highly
potent insecticide controlling various hopper species. Our efforts in discovery, synthesis,
structure-activity relationship elucidation, and biological activity evaluation are also presented.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Mesoionic
Pyrido[1,2-a]pyrimidinone
Insecticide
Triflumezopyrim
Acetylcholine receptor
Inhibitor
———
 Corresponding author. Tel.: +1-302-451-5700; fax: +1-302-366-5738; e-mail: wenming.zhang@dupont.com

Nicotinic acetylcholine receptors (nAChRs) are a well-
established target for insect control with commercial insecticides
that act at multiple binding sites.2 This target has been the subject
of intensive research and it has long been established that nAChR
receptor activation is responsible for acute excitatory symptoms
observed for a number of commercial products. This includes
traditional neonicotinoid insecticides, as well as the more
recently discovered sulfoximines and butenolides.3,4
authors further showed a lack of activation of Xenopus oocytes
expressing chimeric Drosophila 2/chick 2 nAChRs.
Starting from the initial hit compound 1 and through changes
of the n-propyl sidechain of 1 (see Fig. 1),1 analogs have been
discovered with not only increased insecticidal potency, but also
expanded insecticide spectrum to cover a number of insect
species. As a result of this effort, it was revealed that compound
2, containing a 2,2,2-trifluoroethyl sidechain, showed potent
insecticidal activity against a group of hopper species, including
corn planthopper (Peregrinus maidis (Ashmead), CPH) and
potato leafhopper (Empoasca fabae (Harris), PLH), as well as
two key rice hopper species, namely, brown planthopper
(Nilaparvata lugens (Stål), BPH) and rice green leafhopper
(Nephotettix virescens (Distant), GLH). Further, when the
sidechain was changed to a methylene-linked five-membered
heterocycle, namely, a 2-chlorothiazol-5-yl group, the resulting
compound 3 showed not only an expanded spectrum of
insecticidal activity, (controlling two representative lepidoptera
species Diamondback moth (Plutella xylostella (Linnaeus),
DBM) and fall armyworm (Spodoptera frugiperda (J.E. Smith),
FAW)), but also further enhanced activity against all four hopper
species tested.
We recently reported our initial efforts toward the discovery
and optimization of mesoionic insecticide which originated from
the screening of the DuPont internal collection of compounds.1,5
Mode of action studies of representative analogs showed that this
novel class of insecticides binds to the orthosteric site of the
nicotinic acetylcholine (nAChR) receptor and acts primarily via
inhibition of the binding site.6 Although mesoionics compete for
the same binding site as neonicotinoid insecticides, their
physiological effect differs significantly. Cordova et al.,
demonstrated that mesoionic insecticides were highly potent
inhibitors of the American cockroach (Periplaneta americana)
nAChR, with minimal receptor activation at concentrations
below 100 M. The inhibitory action is consistent with lethargic
poisoning symptoms observed across multiple species. The
1
2
3
4 (triflumezopyrim)
4a
Figure 1. Mesoionic insecticides, triflumezopyrim (4, DuPont Pyraxalt®), and its alternative representation (4a)
Rice is the primary food source for half of the world’s
population. More than 90% of the world’s rice is grown and
consumed in Asia where 60% of the earth’s people live.7
Planthoppers are the most serious insect threat to rice production,
causing reduction in plant growth, wilting, and infection by rice
viral pathogens.8 Planthopper control has relied heavily on the
use of neonicotinoids. However, resistance development over the
a
b
5
7
6
c
8
9

past decade has left growers with limited options.9,10
o
Scheme 1. Reagents and conditions: (a) NaH, BnBr, DMF, 0 to 25 C; (b) TFA, CH2Cl2, H2O, 25 oC, 85% for 2 steps; (c) neat, 210
oC, 44%.
With the potent insecticidal activity against hopper species
mesoionic compounds. The drawing pattern of 4a will be used
shown by mesoionic chemistry, our research team pursued the
discovery of a mesoionic compound to control hopper species for
the Asian rice market. As a result of extensive optimization,
triflumezopyrim (4, ISO common name approved in August,
2013, DuPont Pyraxalt®) was identified as a novel and highly
potent insecticide to control hoppers in rice,11 including BPH
populations resistant to imidacloprid, the representative
traditional neonicotinoid insecticide. Important registrations of
this molecule are expected between 2017-2018 and commercial
launch from 2018 onward. In this communication, we report our
effort on the optimization of mesoionic chemistry with a focus on
analogs with a methylene linkage between the mesoionic core
ring and six-membered heterocycle groups, which led to
triflumezopyrim discovery. Our efforts in synthesis, SAR
elucidation, and biological activity evaluation are also reported.
throughout this article.
The compounds shown in Table 1 were prepared as described
in Schemes 1-5. N-Benzyl analog 9 was the first molecule
prepared and its synthesis is outlined in Scheme 1. N-Benyl-2-
aminopyridine 7 and arylmalonate 8 were prepared according to
the literature.13,14 Boc-protected 2-aminopyridine
5
was
benzylated in the presence of sodium hydride to generate the
alkylation product 6. Compound 6, in turn, was subjected to
aqueous trifluoroacetic acid (TFA) to remove the Boc group. The
resulting aminopyridine
phenylmanolate (8) as a neat mixture and heated at 210 C to
7
was mixed with diethyl
o
generate the desired product 9 in reasonable yield.
A number of analogs were prepared in the same fashion,
accessing the required 2-aminopyridine intermediates as
described above.
When the alkylating agents are not
Triflumezopyrim (4) is represented in the SciFinder® database
as structure 4 shown in Fig. 1, with the negative charge located
on the carbon at 3-position of the mesoionic ring. However, it is
worth noting that mesoionic compounds cannot be satisfactorily
represented by any single covalent or ionic structure.12 The
authors have been using the drawing pattern as shown for
compounds 1-3 and 4a (an alternative drawing of
triflumezopyrim). This drawing pattern has been employed in
the patent application cases filed by DuPont and has been
adopted in the SciFinder® database to represent all other
commercially available, they were prepared from other
commercially available starting materials. One example is
depicted in Scheme 2. Thus, 5-methyl-2-fluoropyridine (10) was
subjected to standard radical reaction conditions in the presence
of NBS to produce 5-(bromomethyl)-2-fluoropyridine (11) in fair
yield.15 This compound was then applied in the same sequence of
alkylation and deprotection reactions to give desired
aminopyridine 13, which was further cyclized with diethyl
malonate 8 to generate compound 14.
a
b
10
11
12
c
8
d
14
13
o
o
Scheme 2. Reagents and conditions: (a) NBS, AIBN, CCl4, 76 C, 37-57%; (b) NaH, N-Boc-2-aminopyridine (2), DMF, 0-25 C,
95%; (c) TFA, CH2Cl2, H2O, 25 oC, 95%; (d) tetralin, 190 oC, 27%.
An alternative route towards N-substituted 2-aminopyridine
derivatives was through N-arylation reactions of appropriate
amines. This route provides a more straightforward synthesis of
2-aminopyridine derivatives, as represented in Scheme 3. 5-
(Aminomethyl)-2-methylpyridine (16) was mixed with excessive
2-chloropyridine (15) and the resultant mixture was heated in a
microwave reactor at 210 C for 2 hours to give the desired
product 17 in good yield. 17 was further subjected to standard
cyclization reaction conditions to generate compound 18.
o
8
a
b
15
16
17
18

Scheme 3. Reagents and conditions: (a) neat, 2-chloropyridine (15) in excess, 210 oC (microwave), 60%; (b) tetralin, 210 oC, 25%.
2-Aminopyridine derivatives were also prepared via stepwise
reductive amination reactions,16 as described in Scheme 4. 2-
Aminopyridine (19) was mixed with desired aldehyde 20 in
dichloromethane. The resulting mixture was then heated in a
rotavapor apparatus to remove water and produce imine 21. The
imine function of compound 21 was reduced by sodium
borohydride to generate desired amine 22. Further cyclization
reaction gave mesoionic compound 23.
b
a
20
21
22
19
c
8
23
Scheme 4. Reagents and conditions: (a) CH2Cl2, 90 oC (rotavapor), 99%; (b) NaBH4, MeOH, 0 oC, 76%; (c) tetralin, 190 oC, 70%.
Alternatively, a one-pot reductive amination reaction was also
employed for analog preparations.16 One example is illustrated in
Scheme 5. 2-Aminopyridine (19) was combined with aldehyde
24 and treated with sodium triacetoxyborohydride at room
temperature to generate desired amine product 25. In this case,
compound 25 was reacted with malonyl chloride 26 in the
presence of trimethylamine to generate the mesoionic product 27
in reasonable yield. In general, this is a preferred way to prepare
mesoionic pyrido[1,2-a]pyrimidinone compounds.
26
a
b
19
24
25
27
Scheme 5. Reagents and conditions: (a) NaBH(OAc)3, CH2Cl2, 25 oC, 49%; (e) TEA, CH2Cl2, 0 to 25 oC, 45%.

Preparation of triflumezopyrim (4) is presented in Scheme 6.
2-Aminopyridine (19) reacted with pyrimidine-5-carbaldehyde
(28) to form the imine 29 in excellent yield. Compound 29, in
turn, was exposed to reductive amination conditions to generate
presence of cesium carbonate.14 Malonate 33 was then converted
to the corresponding malonic acid potassium salt in excellent
yield through saponification in the presence of potassium
hydroxide and then removal of solvent water.17 The anhydrous
potassium salt was treated with oxalyl chloride to form the
malonic chloride 18 which, in turn, reacted with the amine 30 to
form triflumezopyrim (4) in good overall yield.
the desired amine 30 in reasonable yield.
The desired
arylmalonate 33 was prepared in good yield by the reaction
between 1-iodo-3-(trifluoromethyl)benzene (31) and dimethyl
malonate (32), catalyzed by CuI-phenanthroline and in the
a
b
19
28
29
30
c
d, e
31
32
33
34
f
4 (triflumezopyrim)
Scheme 6. Reagents and conditions: (a) CHCl3, 25 oC, 99%; (b) NaBH4, MeOH, THF, rt, 64%; (c) Cs2CO3, CuI (cat.),
o
o
o
phenanthroline (cat.), 1,4-dioxane, 90 C, 58%; (d) aq. KOH, 2-25 C, drying, 97%; (e) (COCl)2, DMF (cat.), toluene, 3 C to rt; (f)
TEA, toluene, 3-25 oC, 50% for 2 steps starting from the malonate salt.
Insecticidal activity of the mesoionic compounds is
summarized in Table 1. Test compounds were formulated using a
solution containing 10% acetone, 90% water and 300 ppm of X-
77® spreader surfactant (Loveland industries, Inc. Greeley,
Colorado, USA). The formulated compounds were sprayed on
the foliage of plants at 2–5 rates and tests were replicated three
times. Efficacy was evaluated on the following test units: 3–4
day-old corn for CPH; 5–6 day-old bean for PLH; 10-12 day-old
rice for 3rd instar nymphs of BPH; 10-12 day-old rice for 3rd
instar nymphs of GLH; 12–15 day-old radish plant for DBM; and
4-5 day-old corn for FAW.4 Mortality was evaluated 6 days after
application for all insects. Insecticidal activity is reported as an
LC50 (the lethal concentration required for 50% mortality) in ppm
(mg/kg).
insecticidal activity against all four hopper species (CPH, PLH,
BPH, GLH). When the side chain is replaced by a (2-
chlorothiazol-5-yl)methyl group, it leads to compound 3 with
further improved hopper activity as well as expanded insecticide
spectrum to include lepidoptera species (DBM and FAW).
Despite of apparent broad compatibility of the side chain moiety,
the corresponding benzyl and 4-chlorobenzyl analogs 9 and 9a
show no insecticidal activity at the rate tested at 250 ppm.
When the benzyl group of 9 is replaced by a pyridylmethyl
group, analogs with pyridine nitrogen atom ortho-, para- or
meta- to the methylene moiety are obtained (see compounds 9b,
9d, and 9e in Table 1.). Observed insecticidal activity of these
analogs varies depending on the position of nitrogen atom. The
4-pyridyl analog 9d shows only trace of CPH activity while 2-
pyridyl and 3-pyridyl analogs 9b and 9e display roughly
comparable activity. In terms of substitution on the pyridine
ring, 4-chloro-2-pyridylmethyl compound 9c shows no
significant change of activity when compared to the parent 2-
pyridyl compound 9b. Substituents on the 3-pyridyl ring,
however, have a huge impact on the observed insecticidal
activity. 6-Chloro-3-pyridyl analog 15 showed significantly
improved insecticidal activity against all four hopper species
when compared with parent 3-pyridyl analog 9e. For 6-
Insecticidal potency data of compounds 1-4 and all analogs
with a six-membered heterocycle ring linked to the mesoionic
core ring via a methylene linkage is presented in Table 1.
Traditional neonicotinoid insecticide representative imidacloprid
is also included for comparison. The BPH population in test is a
field population collected in Malasia in 2009-2010, which is
resistant to imidacloprid. When the side chain n-propyl group of
initial hit compound 1 is replaced by a 2,2,2-trifluoroethyl group,
the resulting compound
2 shows significantly improved

substituted-3-pyridylmethyl analogs (14-15, 15a-c, and 18), the
insecticidal activity decreases in the order of: F ~ Cl > Br ~ Me >
H > CN ~ CF3, while methoxy analog 23 diplays no insecticidal
activity. Compounds (15d-e) with larger substituents at the 6-
position of 3-pyridyl ring show generally inferior activity when
compared to parent compound 9e. Analogs with substitution at
other positions of the 3-pyridyl moiety (compounds 15f, 15g, and
27) or analogs with additional substituents in addition to 6-F or
6-Cl (compounds 27a, 27b, and 27c) show significantly
diminished activity. The only exception is 5,6-dichloro-3-pyridyl
analog 15h with good activity against hopper species.
In contrast to compound 3 which contains a 2-chlorothiazol-5-
yl)methyl sidechain and shows potent activity against two
representative lepidoptera species (DBM and FAW), six-
membered heterocycle analogs, 9, 9a-d, 18, 23, 15a-h, 27, 27a-f,
and 4b-c, possess no activity against either DBM or FAW at the
rate tested at 250 ppm.
Triflumezopyrim possesses very low acute toxicity in rats, is
not neurotoxic following single or repeat dosing, nor a
developmental or reproductive toxin. This compound has also
been found to have a very favorable environmental profile with
minimal effects on fish, aquatic invertebrates, avian species,
earthworms, beneficial arthropods, or honeybees.
Insecticidal potency data of various diazine analogs is also
presented in Table 1. 3-Pyridazinyl analogs 27e-f show only a
bit of PLH or CPH activity while 2-pyrazinyl analog 27d gives
better activity against three hopper species tested. Parent 5-
pyrimidinyl analogs 4b shows potent insecticidal activity against
CPH and PLH while 2-methyl-5-pyrimidinyl analog 4c shows
potent activity against all four hopper species (CPH, PLH, BPH,
GLH).
While a number of potent mesoionic compounds were
identified during the optimization effort, triflumezopyrim was
ultimately chosen as development candidate due to its combined
set of attributes of low mammalian toxicity, favorable soil
degradation, and high insecticidal activity against a number of
hopper species. We believe triflumezopyrim will be a valuable
addition to the chemistry of crop protection based on the
combination of outstanding insecticidal potency, its distinct
physioloical action, and favorable toxicology profile.
Small substitutions on the phenyl ring at 3-position of the
mesoionic core are usually tolerated as seen for compound 15i-j.
For the 5-pyrimidinyl series, the analog containing 3’-CF3-Ph
group, i.e., triflumezopyrim (4), display the best overall activity.
Table 1. Insecticidal potency of N-alkyl mesoionic compoundsa
R'
Het
A
Entry
1b
R
Het
R’
H
H
2-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CPH
10.4
1
PLH
33.4
2.2
BPH
>10
GLH
DBM
FAW
>50
H
CH2CH3
CF3
No data 28.1
2b
H
2.4
4.5
2.5
<50
>250
17.1
3b
2-Cl
thiazol-5-yl
phenyl
<2
<2
0.3
<0.4
9
H
>250
>250
50
>250
>250
>50
No data
No data
>10
No data >250
No data >250
No data >250
No data >250
No data >250
No data 50
>250
>250
>250
>250
>250
>250
>250
>250
46.0
9a
4-Cl
phenyl
9b
H
2-pyridyl
2-pyridyl
4-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
3-pyridyl
9c
5-Cl
50
<50
No data
No data
>10
9d
H
250
50
>250
>50
9e
H
18
6-Me
5.1
14.9
>250
4.9
4.9
18.6
>250
23
6-MeO
>250
<2
No data
2.0
No data >250
14
6-F
<2
46.0
<50
15
6-Cl
2.1
<2
<2
2.1
243.4
>250
>250
>250
>250
>250
>250
>250
15a
15b
15c
15d
15e
15f
15g
6-Br
3.0
9.0
>10
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
6-CN
<50
<50
>250
10.6
>250
>250
>250
>250
>250
>250
>250
>250
>50
6-CF3
>10
6-(1’,2’,4’-triazolyl)
6-(3’-MeO-Ph)
5-Br
No data
>10
No data
No data
5-CN

15h
5,6-Cl2
2-Me
6-Cl-4-Me
6-Cl-2-Me
6-F-2-Me
5-Me
6-Cl
3-pyridyl
H
<2
19.7
>250
10
8.3
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
No data >250
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
27
3-pyridyl
H
>250
>250
>250
>250
<50
>250
50
No data
No data
No data
No data
6.7
27a
3-pyridyl
H
27b
3-pyridyl
H
>250
>250
<50
50
27c
3-pyridyl
H
27d
2-pyrazinyl
3-pyridazinyl
3-pyridazinyl
5-pyrimidinyl
5-pyrimidinyl
3-pyridyl
H
27e
H
No data
>10
27f
H
H
>250
<2
4b
H
H
<0.4
1.0
>10
4c
2-Me
6-Cl
H
1.5
1.0
7.5
>250
<250
250
194
>2
15i
2-F
2-F
3-CF3
<2
7.1
0.3
<2
15j
6-F
3-pyridyl
1.3
>10
1.6
0.1
<2
>250
194
4 (Triflumezopyrim)
Imidacloprid
H
5-pyrimidinyl
0.8
0.2
0.5
0.29
0.53
47.4
0.067
<250
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); brown planthopper (Nilaparvata lugens (Stål), BPH); rice green leafhopper (Nephotettix virescens
(Distant), GLH); Diamondback moth (Plutella xylostella (Linnaeus), DBM); and fall armyworm (Spodoptera frugiperda (J.E.
Smith), FAW).
a LC50 values were obtained for multiple test rates, each tested in replicate (n ≥ 3). LC50 calculations were determined by Probit
analysis using a maximum quasi-likelihood curve fitting algorithm. “<2” means that, at 2 ppm the mortality was 100%, however
no LC50 value was calculated; “>250” means that, at 250 ppm the compound showed no activity, therefor no LC50 value was
calculated, etc.
b Data has been reported in literature.1
10. Bass, C.; Carvalho, R. A.; Oliphant, L.; Puinean, A. M.; Field, L.
M.; Nauen, R.; Williamson, M. S.; Moores, G.; Gorman, K. Ins.
Mol. Biol., 2011, 20, 763.
References and notes
11. (a) Holyoke, C. W., Jr; Zhang, W.; Tong, M.-H. T. PCT Intl.
Appl. WO 11/017351, 2011. (b) Pahutski, T. F. PCT Intl. Appl.
1.
For part 1 of this research, see: Zhang, W.; Holyoke, C. W., Jr.;
Barry, J. D.; Leighty, R. M.; Cordova, D.; Vincent, D. R.; Hughes,
K. A.; Tong, M.-H. T.; McCann, S. F.; Xu, M.; Briddell, T. A.;
Pahutski, T. F.; Lahm, G. P. Bioorg. Med. Chem. Lett. 2016, 26,
5444.
WO 12/092115, 2012. (c) Holyoke, C. W., Jr; Zhang, W.; Tong,
M.-H. T.; Pahutski, T. F. U. S. Patent 9,314,025, 2015.
12. For a review of mesoionic compounds and discussion of different
drawing patterns, see: Friedrichsen, W.; Kappe, T., Bottcher, A.
Heterocycles, 1976, 19, 1089-1148.
2.
3.
Millar, N. S.; Denhom, I. Invert. Neurosci. 2007, 7, 53.
13. Krein, D. M.; Lowary, T. L. J. Org. Chem. 2002, 67, 4965.
14. Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
15. Anzalone, L.; Hirsch, J. A. J. Org. Chem. 1985, 50, 2128.
16. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(a) For the most recent review, see: Jeschke, P. Pest Manag. Sci.
2016, 72, 433. (b) Also see references cited in (a) for earlier
reviews. (c) Zhu, Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.;
Rogers, R. B.; Huang, J.; Gerwick, B. C.; Babcock, J. M.; Kelly,
D.; Hegde, V. B. et al.; J. Agric. Food Chem. 2011, 59, 2950. (d)
Jeschke, P.; Velten, R.; Schenke, T.; Schallner, O.; Beck, M.;
Malsam, O.; Nauen, R.; Gorgens, U.; Muller, T.; Arnold, C. PCT
Intl. Appl. WO 07/115643, 2007; Chem. Abstr. 2007, 147,
427230.
17. Zhang, W. U. S. Patent 9,108,965, 2015.
4.
5.
Zhang, W.; Barry, J. D.; Cordova, D.; McCann, S. F.; Benner, E.
A.; Hughes. K. A. Bioorg. Med. Chem. Lett. 2014, 24, 2188.
(a) Holyoke, C. W., Jr; Tong, M.-H. T.; Coats, R. A.; Zhang, W.;
McCann, S. F.; Chan, D. M.-T. U. S. Patent 8,552,007, 2013; (b)
Holyoke, C. W., Jr; Zhang, W. U. S. Patent 9,018,220, 2015; (c)
Holyoke, C. W., Jr.; Zhang, W.; Pahutski, T. F., Jr; Lahm, G. P.;
Tong, M-H.; Cordova, D.; Schroeder, M. E.; Benner, E. A.; Rauh,
J. J.; Dietrich, R. F.; Leighty, R. M.; Daly, R. F.; Smith, R. M.;
Vincent, D. R.; Christianson, L. A. In ACS Symposium Series
(2015), 1204(Discovery and Synthesis of Crop Protection
Products); Lyga, J. W.; Theodoridis, G., Eds; American Chemical
Society: Washington, 2015; pp 365-378.
6.
7.
8.
Cordova, D.; Benner, E. A.; Schroeder, M. E.; Holyoke, C. W.,
Jr.; Zhang, W.; Pahutski, T. F., Jr; Leighty, R. M.; Vincent, D. R.;
Hamm, J. C. Ins. Biochem. and Mol. Biol. 2016, 74, 32.
Subudhi, P. K.; Sasaki, T.; Khush, G. S., In Genome Mapping and
Molecular Breeding in Plants, volume 1, Cereals and Millets;
Kole, C., Ed; Springer-Verlag, Berlin, Heidelberg, 2006; pp 1-8.
Cabaoutan, P. Q.; Cabunagan, R. C.; Choi, I. L-R. In
Planthoppers: New Threats to the Sustainability of Intensive Rice
Production Systems in Asia; Heong, K. L.; Hardy, B., Eds; Int.
Rice Res. Inst, Los Banõs, Phillipines, 2009; pp. 357-368.
Garrood, W. T.; Zimmer, C. T.; Gorman, K. J.; Nauen, R.; Bass,
C.; Davies, T. G. E. Pest Manag. Sci, 2016, 72, 140.
9.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Mesoionic pyrido[1,2-a]pyrimidinones:
Discovery of triflumezopyrim as a potent
hopper insecticide
Leave this area blank for abstract info.
Wenming Zhang*, Caleb W. Holyoke Jr., Thomas F. Pahutski, George P. Lahm, James Barry, Daniel Cordova,
Robert M. Leighty, Vineet Singh, Daniel R. Vincent, My-Hanh T. Tong, Kenneth A. Hughes, Stephen F.
McCann, Yewande T. Henry, Ming Xu, Twyla A. Briddell
4 (triflumezopyrim)