Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lepidoptera insecticide acting on nicotinic acetylcholine receptors1,2

Article abstract of DOI:10.1016/j.bmcl.2017.01.002

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 that led to the identification o

Full text of DOI:10.1016/j.bmcl.2017.01.002

Accepted Manuscript
Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lep-
idoptera insecticide acting on nicotinic acetylcholine receptors1,2
Wenming Zhang, Caleb W. Holyoke Jr., James Barry, Daniel Cordova, Robert
M. Leighty, My-Hanh T. Tong, Kenneth A. Hughes, George P. Lahm, Thomas
F. Pahutski, Ming Xu, Twyla A. Briddell, Stephen F. McCann, Yewande T.
Henry, Yuzhong Chen
PII:
S0960-894X(17)30003-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.01.002
BMCL 24578
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 December 2016
3 January 2017
4 January 2017
Please cite this article as: Zhang, W., Holyoke, C.W. Jr., Barry, J., Cordova, D., Leighty, R.M., Tong, M.T., Hughes,
K.A., Lahm, G.P., Pahutski, T.F., Xu, M., Briddell, T.A., McCann, S.F., Henry, Y.T., Chen, Y., Mesoionic
pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lepidoptera insecticide acting on nicotinic
acetylcholine receptors1,2, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.01.002
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Bioorganic & Medicinal Chemistry Letters
Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a
lepidoptera insecticide acting on nicotinic acetylcholine receptors1,2
Wenming Zhang, Caleb W. Holyoke Jr., James Barry, Daniel Cordova, Robert M. Leighty, My-Hanh T.
Tong, Kenneth A. Hughes, George P. Lahm, Thomas F. Pahutski, Ming Xu, Twyla A. Briddell, Stephen F.
McCann, Yewande T. Henry, Yuzhong Chen
DuPont Crop Protection, Stine-Haskell Research Center, 1094 Elkton Road, Newark, DE 19711, USA
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 that led to the identification of dicloromezotiaz as a potent
insecticide to control a broad range of lepidoptera. 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
Dicloromezotiaz
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 well-
established targets for insect control with a number of successful
commercial insecticide products developed. This includes
traditional neonicotinoid insecticides, as well as the more
recently discovered sulfoximines and butenolides.3,4
contain a 2-chlorothiazol-5-yl group connected to the 1-position
of mesoionic core ring via a methylene linkage. Such compounds
possess exceptional biological activity against a number of
hopper species, including corn planthopper (Peregrinus maidis
(Ashmead), CPH), potato leafhopper (Empoasca fabae (Harris),
PLH), brown planthopper (Nilaparvata lugens (Stål), BPH), and
rice green leafhopper (Nephotettix virescens (Distant), GLH).1
Interestingly, 3 also shows very potent activity against two
representative lepidopteran species diamondback moth (Plutella
xylostella (Linnaeus), DBM) and fall armyworm (Spodoptera
frugiperda (J.E. Smith), FAW).
We recently reported our discovery of mesoionic insecticides
originating from DuPont internal compound 1 (see Fig. 1).1,5 As a
result of the optimization effort in this area, triflumezopyrim (2,
ISO common name approved in August, 2013, DuPont
Pyraxalt®) was identified as a novel and highly potent hopper
insecticide for Asian rice market.2,6
Lepidoptera is a large order of insect species with significant
importance in global agriculture. Based on the observed
lepidoptera activity of 3, the DuPont research team dedicated
It has been established that traditional neonicotinoids,
sulfoximines, and butenolides bind to the orthosteric
(acetylcholine binding) site stimulating nAChR activation which
results in acute excitatory poisoning in insects.7 Mode of action
studies of representative mesoionic analogs showed that this
novel class of insecticides also binds to the orthosteric site of the
nicotinic acetylcholine (nAChR) receptor, but acts primarily via
inhibition of the binding site and leads to lethargic poisoning
among different insect species.8 Despite of the concise mode-of-
action difference of neonicotinoids, sulfoximines, butenolides,
and triflumezopyrim, all are potent insecticides controlling
primarily hemipteran insect species, particularly hoppers. In
general, neonicotinoids, such as acetamiprid and thiacloprid,
offer limited utility for lepidopteran pest control.9
efforts to find
a
mesoionic insecticide providing highly
efficacious control of lepidopteran pests.
Ultimately,
dicloromezotiaz (4, ISO common name approved in Dec. 2014)
was identified.10 In this communication, we present our efforts in
this optimization program, focusing on varying the substituents
on the mesoionic core ring and on the 3-phenyl group, leading to
the discovery of dicloromezotiaz. We will report our efforts in
discovery, synthesis, structure-activity relationship elucidation,
and biological activity evaluation related to dicloromezotiaz.
1
2 (triflumezopyrim)
2a
3
4 (dicloromezotiaz)
4a
In the mesoionic insecticide optimization program, we
prepared analogs, such as compound 3 (see Fig. 1), which
Figure 1. Mesoionic insecticides, triflumezopyrim (2), dicloromezotiaz (4), and alternative representations of 2 and 4 (2a and 4a)
Triflumezopyrim (2) and dicloromezotiaz (4) are represented
in the SciFinder® database as structure 2 and 4 shown in Fig. 1,
with the negative charge located on the carbon at the 3-position
of the mesoionic core. However, it is worth noting that mesoionic
compounds cannot be satisfactorily represented by any single
covalent or ionic structure.11 The authors have been using the
drawing pattern as shown for compounds 1, 2a (alternative
drawing of triflumezopyrim), and 4a (alternative drawing of
dicloromezotiaz). 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 mesoionic
compounds. The drawing pattern of 2a and 4a will be used
throughout this article.
In our previous reports,1,2 a number of synthetic routes have
been presented for accessing mesoionic pyrido[1,2-
a]pyrimidinones. Over the course of the optimization program,
more straightforward routes and more efficient methods have
been developed as described in Schemes 1-6. Analogs with
various substitution at 6- to 9-postions were the first set of
molecules prepared and their synthesis is outlined in Scheme 1.
Substituted pyridine 7 was prepared by direct alkylation onto the
2-amino group of compound 5 with chlorothiazole alkylating
agent 6 at high temperature in a microwave apparatus. Malonic
acid 8 was converted to malonyl chloride 9 which was then
combined with aminopyridine 7 in the presence of triethylamine
to generate the desired product 10 in good overall yield.

a
6
5
7
c
b
10
9
8
Scheme 1. Reagents and conditions: (a) NMP, 220 oC (microwave), 33%; (b) (COCl)2, DMF (cat.), CH2Cl2, 25 oC; (c) TEA, CH2Cl2,
25 oC, 79% for two steps.
Preparation of compound 15 is outlined in Scheme 2.
Reaction between 3-bromo-2-aminopyridine (11) and boronic
acid 12 under standard microwave Suzuki reaction conditions
provided coupling product 13 in very good yield. 13, in turn, was
converted to amine 14 through a stepwise reductive amination
reaction.12 Similar cyclization reaction provided mesoionic
compound 15 in reasonable yield. Lower yield in this case is
likely due to imposed steric hindrance upon cyclization.
c
a
b
11
12
13
14
15
Scheme 2. Reagents and conditions: (a) Pd(PPh3)2Cl2, Na2CO3, H2O, 150 oC (microwave), 79%; (b) 2-Chlorothiazole-5-
o
o
carbaldehyde, CH2Cl2, 90 C (rotavapor); NaBH4, MeOH, 25 C, 99% (overall); (c) 2-[3-(Trifluoromethoxy)phenyl]propanedioyl
dichloride, TEA, CH2Cl2, 25 oC, 36%.
Substituted 2-aminopyridines were also prepared via
substitution reaction of 2-fluoropyridine (16), as depicted in
Scheme 3. Reaction between 16 and amine 17 in NMP under
good yield. In this case, malonic acid was activated as the
bis(2,4,6-trichlorophenyl) ester 20 which reacted with amine 18
in toluene and at elevated temperature to form compound 21 in
good yield.
o
microwave radiation at 220 C produced the desired amine 18 in
a
16
17
18
c
b
21
20
19
o
o
Scheme 3. Reagents and conditions: (a) NMP, 220 C (microwave), 52%; (b) 2,4,6-Trichlorophenol, POCl3, 100 C; (c) Toluene,
100 oC, 62%.

Synthesis of dicloromezotiaz (4) starts from 3-methyl-2-
aminopyridine (22) as showed in Scheme 4. Compound 22 was
first formylated to generate compound 23 in excellent yield. 23
was alkylated with the desired 2-chloro-5-(chloromethyl)thiazole
and then treated with sodium hydroxide to remove the formyl
group and produce product 24 in very good overall yield.13,14
Treatment of aryl acetonitrile (25) with sodium methoxide and in
the presence of dimethyl carbonate afforded the desired
cyanoacetate which was then transformed to malonate 26 through
imidate formation and subsequent methanolysis. Malonate 26
was converted to the corresponding malonic acid potassium salt
in the presence of potassium hydroxide. An excellent yield of the
salt was obtained after removal of solvent water.15 The resulting
potassium salt was converted to the malonic chloride 27 which,
in turn, reacted with amine 24 to form dicloromezotiaz (4) in
excellent overall yield.16
a
b, c
22
23
24
f
d
e
4 (dicloromezotiaz)
25
26
27
Scheme 4. Reagents and conditions: (a) HCO2H, Ac2O, EtOAc, 25 to 48 oC, 90%; (b) 2-Chloro-5-(chloromethyl)thiazole, K2CO3, n-
Bu4NBr (cat.), i-PrOH, rt to 75 oC; (c) aq. NaOH, 50 to 10 oC , 77% for 2 steps; (d) NaOMe, CO(OMe)2, toluene-MeOH, 50 oC; HCl in
MeOH, H2O, 45-50 oC, 60%; (e) aq. KOH, 30 oC, drying; (COCl)2, DMF (cat.), toluene, rt; (f) TEA, toluene, 3 oC to rt, 92% for 2 steps.
Besides optimizing the substituents on the mesoionic core and
sidechain at the 1-position, analogs with various substitutions on
the phenyl ring were also prepared and evaluated. Synthesis of
3,5-dichloro-2-methoxy-phenyl analog 40 is outlined in Scheme
5. Subsequent O-methylation and reduction of aldehyde 28
provided benzyl alcohol 29 in high yield. This alcohol was then
converted into benzyl chloride which, in turn, was transformed to
the corresponding aryl acetonitrile 30 in good yield.17 30
underwent ethoxycarbonylation to form cyanoacetate 31 which
was subjected to alcoholysis in the presence of hydrogen chloride
to form the desired diethyl malonate 36. Amide 32 was also
isolated as a by-product from this reaction. One alternative
synthesis of 36 is also presented in Scheme 5. Iodonation of
phenol 33 and subsequent O-methylation provided anisole 35 in
good overall yield.18 35 underwent a copper-catalyzed coupling
reaction with diethyl malonate to produce aryl malonate 36 in
reasonable yield.19 Low reactivity of the C-1 site of iodobenzene
35 is evident and 30% of 35 was recovered even after prolonged
a
b
c
28
29
30
31
d
32
e
f
g
33
34
35
36
h
37
j
i
40
39
38

heating at 80 oC. Malonate 37 was also isolated as a side
product, derived from arylation at the para-position of anisole
35. The remaining steps took place uneventfully. Malonate 36
was hydrolyzed to form malonic acid 38 which was further
converted to activated ester 39 in excellent overall yield. Heating
a mixture of 39 and aminopyridine 24 led to formation of product
40 in reasonable yield.
Scheme 5. Reagents and conditions: (a) MeI, K2CO3, DMF, 25 oC; NaBH4, EtOH, 0 oC, 88% (overall); (b) SOCl2, CHCl3, 25 0 oC;
o
NaCN, NaI, tetrabutylammonium iodide, benzene, H2O, 70 oC, 75% (overall); (c) NaH, diethyl carbonate, THF, 0 to 70 C, 80%; (d)
o
o
o
SOCl2, EtOH, 25 C; H2O, 71% (36:32 = 1:1); (e) I2, KI, NaOH, H2O, 0 C; (f) K2CO3, MeI, CH3CN, 25 C, 75% for 2 steps; (g)
diethyl malonate, CuI, picolinic acid, Cs2CO3, dioxane, 80 oC, 48% (36:37 = 2:1); (h) 20% NaOH, H2O, 60 oC; HCl; (i) (COCl)2, 2,4,6-
trichlorophenol, DMF (cat.), CH2Cl2, 25 oC, 94%; (j) Aminopyridine 24, toluene, 110 oC, 48%.
Compound 46, with the extra methoxy group at the 4-position
of the phenyl ring, was prepared according to Scheme 6.
Bromobenzene 41 underwent copper-catalyzed halogen exchange
to generate iodobenzene 42 in excellent yield. 42 was then
subjected to copper-catalyzed arylation of malonate to produce
aryl malonate 43 in good yield. The same sequence of
saponification, activated ester formation, and cyclization gave
product 46 in good yield.
(Spodoptera exigua (Hübner), BAW); and corn earworm
(Helicoverpa zea (Boddie), HZ).1,20 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 of mesoionic compounds with various
substituents on the pyridine ring moiety is showed in Table 1. In
general, compounds with a substituent at 6-, 7- , or 8-position of
the mesoionic core show no activity for compounds 10a-f or very
limited biological activity for 10g. For 9-substituted analogs,
observed activity depends on both the substituent at the 9-
position and the sidechain at the 1-position. 9-Chloro-1-n-propyl
analog 10h and 9-methyl-1-(3-methoxypropyl) analog 21 show
no insecticidal activity while 1-(2-chlorothiazol-5-yl)methyl
analogs with a substituent at the 9-position, such as 10i (9-Me)
and 10 (9-Cl), possess good to strong activity against lepidoptera
species DBM and FAW. 9-Methyl analog 10i also gives very
potent activity against two hopper species CPH and PLH.
Insecticidal activity of the mesoionic compounds is
summarized in Table 1-3. 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 corn
planthopper (Peregrinus maidis (Ashmead), CPH); potato
leafhopper (Empoasca fabae (Harris), PLH); diamondback moth
(Plutella xylostella (Linnaeus), DBM); fall armyworm
(Spodoptera frugiperda (J.E. Smith), FAW); beet armyworm
b
a
41
42
43
c
e
d
45
46
44
o
Scheme 6. Reagents and conditions: (a) NaI, CuI, N,N-dimethylethylenediamine, dioxane, 117 C, 97%; (b) Diethyl malonate, CuI,
picolinic acid, Cs2CO3, dioxane 80 oC, 56%; (c) 20% NaOH, H2O, 60 oC; HCl; (d) (COCl)2, 2,4,6-trichlorophenol, DMF (cat.), CH2Cl2,
25 oC; (e) Aminopyridine 24, toluene, 110 oC, 75%.
Table 2 presents 1-(2-chlorothiazol-5-yl)methyl analogs with
various substitution at the 9-position. The parent hydrogen
compound 15a shows balanced potent activity against all four
insect species.1 9-Halo analogs and methoxy compound 15b-e
and 10j are less active than the unsubstituted compound 15a.
This is in contrast to the 9-methyl analog 10i (see Table 1.)
which is more potent than the 9-hydro compound 15a. Replacing
hydrogen atoms on the 9-methyl group with 1-3 fluorine atoms
(15f-h) results in loss of activity.
substituents (15i-k and 15) also lead to diminished activity.
Analogs with larger
Analogs with different substituents on the 3-phenyl group
were also prepared and evaluated. As close analogs of
dicloromezotiaz (4), compounds 40 and 46 are attractive targets
from a process standpoint. Insecticidal potency of both analogs is
presented on Table 3, in comparison with dicloromezotiaz (4)

and corresponding 9-hydrogen analog 4b. 4b shows strong
biological activity against CPH, DBM, and FAW but
Dicloromezotiaz (4) is significantly more potent, particularly on
controlling lepidopteran species DBM and FAW. Further
evaluations show that dicloromezotiaz (4) also possesses potent
activity against other lepidopteran species, such as beet
armyworm (BAW) and corn earworm (HZ). Compounds 40 and
46, unfortunately, showed only limited insecticidal activity.
Dicloromezotiaz (4) was eventually selected for further
development evaluation due to its insecticidal potency against a
broad range of insect species.
identified for controlling hopper and lepidopteran insect species,
respectively. This class of compounds bind to the orthosteric site
of the nicotinic acetylcholine (nAChR) receptor, and modulate
receptors function through potent inhibition with very weak
activation at high concentrations.8,21
Triflumezopyrim (2)
promises to be a powerful insecticide for control of susceptible
and resistant rice hopper species throughout Asia. Given that
orthosteric-binding nicotinic insecticides represent an
underutilized mode of action for lepidopteran insect species,21
dicloromezotiaz (4) may prove be a useful control tool for these
pests.
In summary,
a novel class of mesoionic pyrido[1,2-
a]pyrimidinone compounds have been discovered as potent
insecticides, with triflumezopyrim (2) and dicloromezotiaz (4)
Table 1. Insecticidal potency of mesoionic compounds with various substituent on the pyridine ring moietya
6
7
8
9
R'
A
Entry
10a
10b
10c
10d
10e
10f
10g
10h
21
R
R’
CPH
>250
>250
>250
>250
>250
>50
PLH
>250
>250
>250
>250
>250
>50
DBM
>250
>250
>250
>250
>250
>50
FAW
No data
No data
No data
No data
No data
>50
6-Me
6-Cl
7-Me
7-Cl
8-Me
8-Me
8-Cl
9-Cl
9-Me
9-Me
9-Cl
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
(2-chlorothiazol-5-yl)methyl
(2-chlorothiazol-5-yl)methyl
n-Pr
10
>250
>250
>50
>250
>250
>10
>250
>250
>50
>250
3-methoxypropyl
(2-chlorothiazol-5-yl)methyl
(2-chlorothiazol-5-yl)methyl
>10
10i
<0.4
>250
<0.4
10
<0.4
10
10
10
>10
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); 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.
Table 2. Insecticidal potency of 9-substituted mesoionic compoundsa
R'
B
Entry
R
H
R’
CPH
<2
PLH
<2
DBM
<2
FAW
6.4
15ab
H

15b
10j
15c
15d
15e
15f
15g
15h
15i
15j
15
F
4-F
H
50
50
<10
10
>250
>10
10
Cl
>10
50
10
Br
3-CF3
H
50
2
I
10
10
10
>50
>50
>50
>50
>250
50
OMe
4-F
H
>50
>50
50
>50
>50
30
10
CFH2
>50
>50
250
50
CF2H
H
CF3
4-F
3-Br
H
50
50
Et
>50
>50
>50
>50
>50
10
vinyl
>50
>50
50
>50
>50
>50
Ph
3-OCF3
H
>50
>50
15k
CH=CH—CH=CHc
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); 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
c Tied back to 8-position to form an isoquinoline ring moiety.
Table 3. Insecticidal potency of 3-aryl mesoionic compoundsa
R'
B
Entry
4b
4
R’
R
CPH
10
PLH
>50
5
DBM
10
FAW
10
BAW
No data No data
1.47 0.87
HZ
3,5-Cl2
H
3,5-Cl2
Me
Me
Me
2
<0.4
>10
>10
0.28
>10
10
40
3,5-Cl2-2-MeO
3,5-Cl2-4-MeO
>50
>50
30
No data No data
No data No data
46
>50
Insect LC50 values (ppm) are shown for corn planthopper (Peregrinus maidis (Ashmead), CPH); potato leafhopper (Empoasca
fabae (Harris), PLH); diamondback moth (Plutella xylostella (Linnaeus), DBM); fall armyworm (Spodoptera frugiperda (J.E.
Smith), FAW); beet armyworm (Spodoptera exigua (Hübner), BAW); and corn earworm (Helicoverpa zea (Boddie), HZ).
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.
3.
(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.
References and notes
1.
For the initial discovery of mesoionic insecticides, 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.
2.
For the discovery of triflumezopyrim, see: Zhang, W.; Holyoke,
C. W., Jr.; Pahutski, T. F.; Lahm, G. P.; Barry, J. D.; Cordova, D.;
Leighty, R. M.; Singh, V.; Vincent, D. R.; Tong, M.-H. T.;
Hughes, K. A.; McCann, S. F.; Henry, Y. T.; Xu, M.; Briddell, T.
A.; Bioorg. Med. Chem. Lett. 2017, 27, 16.
4.
Zhang, W.; Barry, J. D.; Cordova, D.; McCann, S. F.; Benner, E.
A.; Hughes. K. A. Bioorg. Med. Chem. Lett. 2014, 24, 2188.

5.
6.
(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.
(a) Holyoke, C. W., Jr; Zhang, W.; Tong, M.-H. T. PCT Intl.
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Mesoionic pyrido[1,2-a]pyrimidinones:
Discovery of dicloromezotiaz as a
lepidoptera insecticide acting on nicotinic
acetylcholine receptors
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Wenming Zhang*, Caleb W. Holyoke Jr., James Barry, Daniel Cordova, Robert M. Leighty, My-Hanh T. Tong,
Kenneth A. Hughes, George P. Lahm, Thomas F. Pahutski, Ming Xu, Twyla A. Briddell, Stephen F. McCann,
Yewande T. Henry, Yuzhong Chen
4 (dicloromezotiaz)