Insecticidal quinoline and isoquinoline isoxazolines

Article abstract of DOI:10.1016/j.bmcl.2014.06.004

A series of quinoline and isoquinoline isoxazolines have been designed as pesticides for crop protection. Herein we reported the chemical synthesis, biological activity and structure-activity relationships. The isoquinoline derivative, such as 3i, is discovered as potent new class of isoxazoline insecticide which is competitive with commercial insecticide Indoxacarb.

Full text of DOI:10.1016/j.bmcl.2014.06.004

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4026–4030
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Insecticidal quinoline and isoquinoline isoxazolines
⇑
Ming Xu , Ty Wagerle, Jeffrey K. Long, George P. Lahm, James D. Barry, Rejane M. Smith
DuPont Crop Protection, Stine-Haskell Research Center, 1094 Elkton Road, Newark, DE 19711, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of quinoline and isoquinoline isoxazolines have been designed as pesticides for crop protection.
Herein we reported the chemical synthesis, biological activity and structure–activity relationships. The
isoquinoline derivative, such as 3i, is discovered as potent new class of isoxazoline insecticide which is
competitive with commercial insecticide Indoxacarb.
Received 1 May 2014
Revised 30 May 2014
Accepted 2 June 2014
Available online 11 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoline
Quinoline
Isoquinoline
Insecticide
Due to the ability of insects to develop resistance to conven-
tional pesticides, there is an ongoing need for the discovery and
development of new products, particularly those that either repre-
sent novel chemical classes or work by new biochemical mecha-
nisms. This is coupled with the need to identify new insecticides
with low toxicity, favorable environmental profiles and good mar-
gins of safety toward beneficial insects, such as pollinator bees, to
replace older products with less favorable attributes. New isoxaz-
oline insecticides, such as those of structure 1, were recently
reported by Nissan (Fig. 1).1 We also reported that 4-azolylphenyl
isoxazoline of structure 2 is a highly effective insecticide and naph-
thalene isoxazoline of Afoxolaner is a new veterinary drug for dogs
against fleas and ticks.2 These isoxazoline classes exhibit their
activity through inhibition of the GABA-gated chloride channel. 2,3
We envisioned that the ortho-methyl substituent could be tied
back into the central aromatic ring to provide new heterocyclic
systems and provide new chemotypes of isoxazolines as poten-
tially new insecticides (see Fig. 2).4 Here we describe the synthesis
and insecticidal activity from these types of quinoline and isoquin-
oline isoxazolines of structure 3. Target molecules of 3, with each
of the A being replaced by one nitrogen atom were synthesized
for insecticidal evaluation.
The isoquinoline isoxazoline 3a, wherein N is at the 2 position,
was prepared from 4-bromoisoquinoline 4 as outlined in Scheme 1.
4-Bromo-1-methylisoquinoline 5 was prepared from the commer-
cially available 4-bromo-isoquinoline 4 according to the literature
procedure in an overall yield of 50%.5 Oxime 6 was obtained by
treating 5 with n-BuLi and DMF to convert bromide to aldehyde,
then reacting with NH2OH. Styrene 7 can be prepared from
coupling of 2-bromo-3,3,3-trifluoropropene and 3,5-dic-
hlorophenylboronic acid.1 Cycloaddition of the oxime 6 and the
styrene 7 was accomplished to give isoxazoline 8 with NCS in
CF3
O
N
CF3
O
N
1
Cl
Cl
H
N
N
N
N
Cl
Cl
CN
Me
O
N
2
Figure 1. Isoxazoline insecticides.
⇑
Corresponding author. Tel.: +1 3023665706.
E-mail address: ming.xu@dupont.com (M. Xu).
http://dx.doi.org/10.1016/j.bmcl.2014.06.004
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

M. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4026–4030
4027
F3C
O
CF3
O
N
N
3
A
Cl
Cl
4
A 2
H
N
N
5 A
6 A
N
1
N
Cl
Cl
A
O
Me
1
O
8
A
7
3
Figure 2. Novel quinoline and isoquinoline derivatives.
O
N
Br
Br
Cl
CF3
a
b
+
N
N
N
Cl
4
6
5
7
CF3
O
8
N
CF3
O
9
N
Cl
Cl
c
N
d
N
O
Cl
Cl
O
CF3
O
N
Cl
N
e
N
N
Cl
O
3a
Scheme 1. Reagents and conditions: (a) (i) 30% H2O2, HOAc, 93%; (ii) NCCH2COOEt, Ac2O, pyridine, 60%; (iii) 30% H2SO4, 90%; (b) (i) n-BuLi, DMF, THF, 90%; (ii) NH2OH, EtOH,
98%; (c) NCS, Et3N, DMF, 50%; (d) (i) SeO2, 1,4-dioxane; (ii) KMnO4, CH3COCH3, pH = 7 buffer solution; (e) (COCl)2, 2-(aminomethyl)pyridine, Et3N, CH2Cl2, 50%.
CF3
O
N
Br
Br
10
Cl
N
a
b
N
N
Br
Cl
HON
5
11
CF3
O
N
Cl
N
c
N
N
Cl
O
3b
Scheme 2. Reagents and conditions: (a) (i) SeO2, 1,4-dioxane, 75%; (ii) NH2OH, EtOH, 98%; (c) NCS, styrene 6, Et3N, DMF, 35%; (c) CO, 2-(aminomethyl)pyridine, PdCl2dppf,
Et3N, toluene, 55%.

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M. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4026–4030
Br
Br
Br
c
b
a
N
N
N
O
HON
12
14
13
CF3
O
N
N
CF3
O
N
N
Cl
Cl
d
N
Br
N
Cl
Cl
O
15
3c
Scheme 3. Reagents and conditions: (a) (i) NBS, AIBN, CCl4, then NaOAc, DMF, 80%; (ii) MeOH, K2CO3, then Dess–Martin periodinane, CH2Cl2, 73%; (b) NH2OH, EtOH, 99%; (c)
NCS, styrene 6, Et3N, DMF, 45%; (c) CO, 2-(aminomethyl)pyridine, PdCl2dppf, Et3N, toluene, 72%.
O
Br
Br
Br
b
a
N
N
N
N
+
Br
O
16
O
18
N
17
19
NOH
20
CF3
Cl
c
d
N
18
Br
Cl
N
Br
Cl
21
CF3
O
N
e
N
N
Cl
N
O
3d
NOH
CF3
O
N
Cl
g
f
19
N
Br
Cl
Br
N
22
23
CF3
O
N
Cl
h
N
N
Cl
O
N
3e
Scheme 4. Reagents and conditions: (a) NBS, H2SO4, 60%; (b) n-BuLi, DMF, THF, 35% of 18 & 7% of 19; (c) NH2OH, EtOH, 98%; (c) NCS, styrene 6, Et3N, DMF, 20%; (c) CO, 2-
(aminomethyl)pyridine, PdCl2dppf, Et3N, toluene, 60%; (f) NH2OH, EtOH, 95%; (c) NCS, styrene 6, Et3N, DMF, 20%; (c) CO, 2-(aminomethyl)pyridine, PdCl2dppf, Et3N, toluene,
35%.

M. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4026–4030
4029
CF3
O
NOH
N
Cl
a
b
Br
N
N
Cl
N
Br
Br
24
25
26
CF3
O
N
Cl
c
N
N
Cl
N
O
3f
Scheme 5. Reagents and conditions: (a) (i) NBS, AIBN, CCl4, then NaOAc, DMF, 75%; (ii) MeOH, K2CO3, then Dess–Martin periodinane, CH2Cl2, 85%; (iii) NH2OH, EtOH, 98%; (c)
NCS, styrene 6, Et3N, DMF, 61%; (c) CO, 2-(aminomethyl)pyridine, PdCl2dppf, Et3N, toluene, 10%.
Table 1
the presence of Et3N in DMF in 50% yield. Oxidation of 8 with SeO2,
then KMnO4 in acetone/buffer solution6 gave acid 9 which was
Insecticidal activity of quinoline and isoquinoline isoxazolines
F3C
O
used for next step directly. Amide formation of the acid 9 with
2-(aminomethyl)pyridine provided the isoquinoline isoxazoline
3a in 50% yield with three steps.
N
3
A
Cl
4
A 2
H
N
As outlined in Scheme 2, target 3b was prepared from the same
intermediate 4-bromo-1-methylisoquinoline 5. Oxime 10 was
obtained from oxidation of 4 with SeO2 to aldehyde, followed by
reacting with NH2OH. Same cycloaddition reaction of oxime 10
with styrene 7 gave isoxazoline 11. Aminocarbonylation reaction
of 11 with 2-(aminomethyl)pyridine in the presence of PdCl2dppf
provided the isoquinoline isoxazoline 3b in 55% yield.7
The quinoline isoxazoline 3c, wherein N is at the 5 position, was
prepared from 5-bromo-8-methylquinoline 12 as shown in
Scheme 3. The 8-methyl group was converted to acetate by bro-
mination with NBS and ester exchange with NaOAc in 80% yield.
The aldehyde 13 was then obtained by hydrolysis and oxidation.
Oxime formation and cycloaddition gave quinoline derivative 15
in 45% yield. The final aminocarbonylation with 2-(amino-
methyl)pyridine gave target 3c in 72%.
5 A
6 A
N
1
Cl
A
O
8
A
7
Entry
Aa
Pxb,c
Sfb,c
Mp,c
Efc
Fob,c
3a
3b
3c
3d
3e
3f
2
3
5
6
7
8
10
2
50
50
0.4
50
50
50
250
>50
2
>250
250
>250
>250
50
250
50
250
>250
>50
>250
>250
50
>250
>250
>50
>250
>250
>250
a
b
c
Denotes positional isomer of nitrogen atom.
Lowest rate tested (ppm) providing greater than 80% feeding protection.
Lowest rate tested (ppm) providing greater than 80% insect mortality.
The synthesis of isoquinoline isoxazolines 3d and 3e, wherein
nitrogen atoms are at the 6 and 7 positions correspondingly, was
outlined in Scheme 4. We started with isoquinoline 16. Bromina-
tion of 16 with NBS in H2SO4 gave dibromide 17.8 By treating 17
with n-BuLi at À78oC, then quenching with DMF, we obtained both
aldehydes 18 and 19 which were separable by chromatography.
Both of them were converted to the final targets 3d and 3e accord-
ing to the chemistry discussed previously.
CF3
O
N
Cl
a
23
3g R: CH2CH3
3h R: CH2CF3
3i R: CH2(CHCH2CH2)
3j R: CH2CONHCH2CF3
N
R
Cl
O
N
3
The last quinoline isoxazoline 3f with N at the 8 position was
prepared from 8-bromo-5-methyl-quioline 24 as shown in
Scheme 5. Oxime 25 was obtained by converting methyl group of
the starting 24 to aldehyde, then condensation with NH2OH.
Isoxazoline 26 was prepared from the cyclization of the oxime 25
and the styrene 7 in a yield of 61%. A similar aminocarbonylation
coupling of 24 with 2-(aminomethyl)pyridine gave quinoline
isoxazoline 3f in low yield.
Insecticidal activity of quinoline and isoquinoline isoxazolines
is summarized in Table 1. Compounds were applied to plants and
evaluated against a series of insects under standard laboratory pro-
cedures.9 Potency was evaluated on diamondback moth (Plutella
xylostella, Px), fall armyworm (Spodoptera frugiperda, Sf), green
peach aphid (Myzus persicae, Mp), potato leafhopper (Empoasca
fabae, Ef), and western flower thrips (Frankliniella occidentalis, Fo).
Scheme 6. Reagents and conditions: (a) CO, RNH2, PdCl2dppf, Et3N, toluene,
20–50%.
Observations were taken six days after application on plant protec-
tion (Px, Sf, and Fo) and mortality (Mp and Ef). Isoquinolines 3e was
found to be the most active of the positional isomers showing
excellent activity on both species of Lepidoptera, Px and Sf, two
key indicators used to assess the global market potential on lepi-
dopteran insects, currently valued at greater than $4 billion annu-
ally. Insecticidal activity was changed dramatically by moving
nitrogen atom to a different position of the fused bicyclic ring.
With this exceptional insecticidal activity of 3e, more isoquinoline
analogs with N at the 7 position were designed and synthesized by

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M. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4026–4030
Table 2
lepdidopteran insects (Px and Sf) down to 0.4 ppm. Most of the
analogs screened here show great activity on Px, Sf and Fo below
2 ppm.
Insecticidal activity of isoquinoline isoxazolines
CF3
O
N
Cl
In summary, a series of quinoline and isoquinoline isoxazolines
have been designed and synthesized as novel insecticides. Insecti-
cidal screen results show that isoquinoline derivatives with N at
the 7 position, the structure of 3e, have excellent insecticidal activ-
ity. Further optimization of this class has identified compound 3i to
be more active than the commercial insecticide Indoxacarb on
several species tested. This promising new class of chemistry for
the modern crop protection industry is worth further exploration.
N
R
Cl
O
N
Entry
A
Pxa,b
Sfa,b
Mpb
Foa,b
3g
3h
3i
3j
Et
CH2CF3
0.4
0.4
0.4
50
2
0.4
2
0.4
50
2
50
—
10
>250
0.4
2
2
2
10
10
CH2(cPr)
CH2CONHCH2CF3
References and notes
Indoxacarb
1. (a) Mita, T.; Kikuchi, T.; Mizukoshi, T.; Yaosaka, M.; Komoda, M. PCT Int. Appl.
WO 05/085216, 2005; Chem. Abstr. 2005, 143, 306321.; (b) Mita, T.; Furukawa,
H.; Masuzawa, Y.; Komoda, M. JP 07/016017, 2007; Chem. Abstr. 2007, 146,
163097.
a
Insecticidal activity reported as lowest rate tested providing greater than 80%
feeding protection in ppm.
b
Insecticidal activity reported as lowest rate tested providing greater than 80%
2. (a) Lahm, G. P.; Cordova, D.; Barry, J. D.; Pahutski, T. F.; Smith, B. K.; Long, J. K.,
et al. Bioorg. Med. Chem. Lett. 2013, 23, 3001; (b) Shoop, W. L.; Hartline, E. J.;
Gould, B. R.; Waddell, M. E.; McDowell, R. G.; Kinney, J. B., et al. Vet. Parasitol.
2014, 201, 179.
insect mortality in ppm.
3. (a) Ozoe, Y.; Asahi, M.; Ozoe, F.; Nakahira, K.; Mita, T. Biochem. Biophys. Res.
Commun. 2010, 391, 744; (b) García-Reynaga, P.; Zhao, C.; Sarpong, R.; Casid, J. E.
Chem. Res. Toxicol. 2013, 26, 514.
4. (a) Lahm, G. P.; Wesley, S. L.; Xu, M. PCT Int. Appl. WO 07/079162, 2007; Chem.
Abstr. 2007, 147, 166307.; (b) Xu, M.; Wagerle, T.; Long, J. K.; Lahm, G. P.
Abstracts of Papers, 244th ACS National Meeting & Exposition, Philadelphia, PA,
United States, August 19–23, 2012.
5. Liu, M.; Lin, T.; Penketh, P.; Sartorelli, A. C. J. Med. Chem. 1995, 38, 4234.
6. Bartmann, W.; Konz, E.; Ruger, W. Heterocycles 1989, 29, 707.
7. Horino, H.; Sakaba, H.; Arai, M. Synthesis 1989, 715.
exchanging 2-(aminomethyl)pyridine with other amines to further
improve their biological activity (Scheme 6).
As outlined in Scheme 6, the bromide 23 was converted to var-
ious amides via aminocarbonylation reaction as discussed before.
Among them, cyclopropyl methylamine derivative 3i shows excel-
lent insecticidal activity in our screen.
Their insecticidal activity was summarized in Table 2 and Ind-
oxacarb was used as the commercial standard. Analog 3i, the
cyclopropyl methyl amine derivative, shows unbroken activity on
8. Brown, W. D.; Gouliaev, A. H. Synthesis 2002, 83.
9. Beck, G.; Heitzer, H. U.S. Patent 5,708,180, 1998; Chem. Abstr. 1996, 124, 343116.