Azine derivatives as a new generation of insect growth regulators

Article abstract of DOI:10.2533/000942903777678560

A new generation of insect-growth-regulator insecticides, the azines, are presented. They inhibit the chitin biosynthesis process and are active against lepidopteran pests. Their synthesis and a structure-activity relationship will be discussed.

Full text of DOI:10.2533/000942903777678560

CROP PROTECTION RESEARCH
705
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 705–709
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Azine Derivatives as a New Generation
of Insect Growth Regulators
Martin Eberlea, Saleem Farooqa, André Jeanguenata*, Deborah Mousseta, Arthur Steigera, Stephan
Traha, Werner Zambacha, and Alfred Rindlisbacherb
Abstract: A new generation of insect-growth-regulator insecticides, the azines, are presented. They inhibit
the chitin biosynthesis process and are active against lepidopteran pests. Their synthesis and a struc-
ture–activity relationship will be discussed.
Keywords: Chitin biosynthesis · Insecticide · 1,2,4-Triazines
Introduction
Chitin is a highly organized polymer of urea group of the BPUs could be replaced
N-acetylglucosamine and is a major con- by a number of 6-membered ring hetero-
The mode of action of many modern syn- stituent of the cell wall of most fungal cycles, leading to extremely potent lepi-
thetic insecticides is linked to ubiquitous species as well as insects. It is rarely found doptericides (e.g. 6). Comparing the X-ray
targets such as the nervous system or the in vertebrates and plants, where the analo- structure of teflubenzuron (1a) [8] with
respiration chain [1]. Although excellent gous structural polymers are collagen and oxazolines and our heterocyclic derivatives
selectivities for the target insects have been cellulose, respectively. During the insect allows us to conclude that the new genera-
achieved with many insecticides, undesir- molting process, a cocktail of chitin-related tion IGRs are possibly mimics of the best
able effects on non-target organisms (toxic- enzymes work towards the degradation of conformation of the BPUs (Fig.). We pres-
ity) and on the environment remain a recur- the old cuticle and the synthesis of the new ent here the synthesis of a range of hetero-
rent problem. Specific insect targets, which one [3]. Inhibition of these processes has cyclic derivatives.
are not found in other organisms have been been a very successful approach towards
previously recognized to play a prominent the development of new classes of insecti-
role for the discovery of safe new insecti- cides or fungicides [4]. The biosynthesis of Chemistry
cides. Insect growth regulators (IGR) such chitin was targeted as early as 1972 at the
as molting hormones (ecdysones, juvenile Phillips-Duphar company, where the insec- Synthesis of 1,2,4-Triazines A and B
hormones, [2]) and chitin metabolism regu- ticidal benzoylphenylurea family (BPU,
We were interested in the synthesis of
lators are particularly attractive in this re- e.g. teflubenzuron (1a) and lufenuron (1b) 1,2,4-triazines of type A and B (Scheme 1).
spect (see [1a], chap. 20).
Fig.) [5] was discovered. The BPUs disrupt There are numerous ways to synthesize the
the formation of chitin; the exact site of ac- 1,2,4-triazine core structure [9]. However
tion has still not been elucidated. These selective methods for 3,5- or 3,6-disubsti-
compounds have a relatively limited insec- tuted 1,2,4-triazines (A or B) are rare. In a
ticidal spectrum (lepidoptera) and are slow first approach, we decided to use a non-
acting, as the insects will die only after the selective synthesis and separate both
next regular molt. Closely related are the isomers by flash-chromatography. Cou-
tetrazole acaricide clofentezine (2) [6a] pling of the α-keto-oxime 7 with the BOC-
and the experimental triazole insecticides amidrazone 8 delivered a 3:2 mixture of
(e.g. 3) [6b]. Ethoxazole 4 is a new genera- isomers 9 and 10. Both isomers were easily
tion acaricidal IGR with an oxazoline ring separated by flash-chromatography and
[6c]. Broad-spectrum insecticide-accari- elaborated to the final compounds via a
cides with an oxazoline moiety (e.g. 5a) Suzuki coupling (Scheme 1).
*Correspondence: Dr. A. Jeanguenata
Tel.: +41 61 323 36 42
Fax: +41 61 323 85 29
E-Mail: andre.jeanguenat@syngenta.com
aSyngenta Crop Protection AG
Research Chemistry: Optimization
WRO-1060.2.10
were recently discovered [6d]. Their syn-
As the linear isomers of type B turned
thesis was possible by taking advantage of out to be much more potent than the iso-
modern Pd-catalyzed aryl-aryl coupling re- mers A in the insecticidal screening, a se-
actions [7]. Pyrrolines 5b and imidazolines lective method for B was investigated. The
5c represent the latest developments de- cyclization of amidoximes 11 with α-keto-
scribed in recent patent literature [6e][6f]. oximes 12 was already published (Scheme
We discovered by serendipity that the acyl- 2, path a: [10] in collaboration with re-
Schwarzwaldallee 215
CH-4002 Basel
bSyngenta Crop Protection AG
Research Biology
Insect Control
Schaffhauserstr. 101
CH-4332 Stein

CROP PROTECTION RESEARCH
706
CHIMIA 2003, 57, No.11
Cl
Cl
Cl
F
F
CF2CFHCF3
Cl
N
N
H
F
N
F
Cl
N
N
N
F
O
F
N
Cl
F
O
F
HN
Cl
N
N
H
O
N
H
O
F3C
1a Teflubenzuron
1b Lufenuron
2 Clofentezine
(acaricide)
3 triazoles
(acaricides)
CF3
F
O
N
F
X
N
N
N
CF3
F
N
F
O
F
F
4 Ethoxazole
(acaricide)
5a X = O: Oxazolines
5b X = CH2: Pyrrolines
6 Triazines
5c X = NH: Dihydroimidazoles
Fig. Insecticidal and acaricidal IGRs: from the BPUs to the triazines
searchers of Polyphor, Allschwil, CH). Un-
der optimized conditions, linear triazines
such as 13 were obtained in 75–85% yield
BOC
F
F
S
F
NH
1) Na2S, NEt3
2) MeI
F
HN
F
CN
F
with only minor formation of triazines of
type A. Another selective approach is the
condensation of a thioimidate 14 with a hy-
drazino-oxime 15 [11]. We obtained the lin-
ear triazine exclusively in 40% yield. Suzu-
ki coupling with arylboronic acids gave the
final compounds B in high yields (85–97%,
Scheme 2, path b).
BOC-NHNH2
quant.
NH.HI
NH.HI
61%
8
O
O
iPent-ONO
1) NaOAc, AcOH
2) Flash-chrom. separation
N
OH
Compound 16 is a very versatile inter-
mediate. While a bromine–metal exchange
was not possible, Pd-mediated reactions
proved to be very valuable (Scheme 3, [7]).
Suzuki arylation (route a and b/c), Heck
coupling (route d), Sonogashira coupling
(route e) and Buchwald-Hartwig amination
(route f) delivered a set of compounds with
a high diversity in physico-chemical prop-
erties. In each case the conditions had to be
optimized (catalyst, ligands, solvent, base).
The reported conditions are valid for a very
diverse set of coupling partners.
Br
Br
7
Br
N
N
N
F
N
F
F
N
F
N
+
Br
30%
9
10
21%
Ar-B(OH)2
PdCl2(PPh3)2
Na2CO3, H2O, DME
85-98%
Ar
N
N
Synthesis of Pyridines C
F
N
F
F
N
F
Pyridine analogues of B were easily
prepared via cyclocondensation of triazines
B with bicyclo[2.2.1]hepta-2,5-diene, fol-
lowed by molecular nitrogen extrusion and
a retro-Diels-Alder reaction [12]. Pyridines
C were obtained in 30 to 75% yield
(Scheme 4).
N
N
+
Ar
A
B
Scheme 1. Synthesis of 3,5- and 3,6-disubstituted 1,2,4-triazines A and B

CROP PROTECTION RESEARCH
707
CHIMIA 2003, 57, No.11
Synthesis of Tetrazines D
and Pyridazines E
Tetrazine analogues of B were prepared
by chlorination of a diacyl-hydrazine 22
followed by cyclization with hydrazine.
Aromatization of the obtained dihydro-
tetrazines 23 (NaNO2, AcOH) and Suzuki
coupling yielded tetrazines D in good
yields (Scheme 5). Pyridazine 25 was read-
ily made by condensation of the tetrazine
intermediate 24 with acetaldehyde enolate
(two steps or concerted cycloaddition) fol-
lowed by nitrogen extrusion and water
elimination [13]. Suzuki coupling gave the
final pyridazines E in high yield.
Br
Br
NH2
dioxane, HCl 4N
n-BuOH, 80oC
F
N
F
N
N
O
F
N
F
NH2
OMe
+
a)
OMe
82%
N
OH
11
12
13
Br
Br
NH.HI
SMe
F
N
N
F
N
F
H2N
nPrOH, reflux
40%
+
N
b)
N
F
OH
14
15
16
Synthesis of Pyrimidines F
and Tetrahydropyrimidines G
Subst.
Pyrimidine analogues of B were pre-
pared by condensation of an amidine 26
with a vinamidinium salt 27 [14]. The con-
ditions of the final Suzuki coupling were
critical, as the chlorine substituents in the
vicinity of the pyrimidine nucleus are acti-
vated for cross coupling (Scheme 6). Cat-
alytic reduction of the pyrimidines F gave
the tetrahydropyrimidines G, which are
close analogues of the imidazolines 5c
(Fig.). Halogen substituents (Cl or Br) did
not survive these conditions and were re-
duced.
Ar-B(OH)2
N
N
PdCl2(PPh3)2
F
N
F
Na2CO3, H2O, DME
85-98%
B
Scheme 2. Selective synthesis of 3, 6-disubstituted 1,2,4-triazines B
Br
N
F
N
F
N
16
f)
a)
OCF3
b)
H
N
e)
d)
N
N
N
CF3
F
N
F
F
N
F
N
O
B
6
21
O
O
N
N
F
N
F
N
17
F
N
F
N
19
F
c)
N
N
F
N
F
20
O
F
F
O
N
N
F
N
F
Conditions: a) Suzuki: ArB(OH)2, PdCl2(PPh3)2, Na2CO3, DME: H2O; b) Bis(pinacolato)diboran,
PdCl2(PPh3)2, KOAc, DMF, 80oC, 97%; c) Suzuki: Ar-X, PdCl2dppf, Na2CO3, DMF: H2O, 80oC;
d) Heck: olefin, Pd(OAc)2, P(o-Tol)3, iPr2NEt, DMF, 100oC; e) Sonogashira: alkyne-H,
PdCl2(PPh3)2, CuI, NEt3, reflux; f) Buchwald-Hartwig: R-NH2, Pd2dba3, dppf, CsCO3, THF, reflux.
18
Scheme 3. Pd-mediated derivatisation of 16

CROP PROTECTION RESEARCH
708
CHIMIA 2003, 57, No.11
Biological Activity
Subst.
These new azines turned out to be ex-
tremely potent in greenhouse assays against
key lepidopteran pests.Activity against cot-
ton leaf worm (Spodoptera littoralis), to-
bacco budworm (Heliothis virescens) and
diamondback moth (Plutella xylostella) for
typical compounds are listed in the Tables 1
and 2. Especially remarkable is the com-
plete control of Spodoptera larvae at con-
centration as low as 0.05 ppm! Some inter-
esting activity was also found against mites
(Tetranychus urticae), white flies (Bemisia
tabaci), thrips (Frankliniella occidentalis),
and scales (Aonidiella aurantii), demon-
strating the potential of this new class of in-
secticides.
Subst.
N
N
F
N
F
F
dichlorobenzene, 145oC
28-76%
N
B
C
F
Scheme 4. Synthesis of pyridine analogues C
O
NH2
Br
N
H
H
N
1) PCl5
F
O
F
Br
Br
Variation of the Heterocycle
HN
F
F
O
F
2) NH2NH2
H
N
Cl
N
N
For each variation except the pyri-
dazines (Table 1, entries 7 and 8), the activ-
ity against Spodoptera was outstanding and
comparable or even better than that of the
most efficient commercial standards (data
of the BPU lufenuron are shown for com-
parison). The triazines displayed a broad
spectrum of activity (entries 1 and 2), which
included sucking insects (data not shown).
N
H
62%
88%
O
F
22
23
Br
Ar
ArB(OH)2,
N
N
N
CsF, DME/MeOH, rt
Pd(OAc)2, P(oTol)3
F
N
F
F
N
NaNO2, HOAc
77%
N
N
N
50-80%
F
24
D
MeCHO, KOH
84%
Variation of the Substituents
on the Triazine Analogues
Ar
Br
ArB(OH)2,
The best substituents X1, X2, and X3 on
the phenyl ring in the position 3 of the tri-
azines are listed in Table 2 (entries 1 to 4).
They are reminiscent of the best sub-
stituents of the BPUs or of the triazoles (see
Fig., 1 and 3). Ortho substituents on the
phenyl ring in the position 6 of the triazine
are tolerated (R, entries 5 and 6). This indi-
cates that the rings are probably not copla-
nar but rather perpendicular as confirmed
by a conformation analysis (data not
shown). Substituents S1, S2, and S3 on the
last phenyl group (entries 7 to 10) dramati-
cally influence the spectrum of activity.
Substituents in position 4 (S1 ≠ H) or
3 (S2 ≠ H) are tolerated.
CsF, DME/MeOH, rt
Pd(OAc)2, P(oTol)3
F
F
N
N
N
N
70-90%
25
F
E
F
Scheme 5. Synthesis of tetrazine and pyridazine analogues D and E
X
NH
NH2.HCl
NOH
F
1) tBuOCl, NH3
X
2) H2, RaNi, EtOH, HCl
Br
70%
F
26
X
N
F
NaOMe,
MeOH
+
X = F, Cl
N
In conclusion we have found a new gen-
eration of IGRs with outstanding activity in
the greenhouse against commercially im-
portant lepidopteran pests and interesting
properties against some sucking pests. The
activity of the triazines was confirmed in
worldwide field trials in cotton and vege-
tables.
N
> 90%
1) POCl3, DMF
2) HClO4
COOH
-
ClO4
N+
27
Br
75%
Br
ArB(OH)2
glyme, H2O
Na2CO3, Pd(OAc)2
88-96%
Subst.
Subst.
F
HN
F
X
N
F
H2, Pd/C
Received: September 15, 2003
N
N
G
F
X = F
75%
X = F, Cl
Scheme 6. Synthesis of pyrimidine and tetrahydropyrimidine analogues F and G

CROP PROTECTION RESEARCH
709
CHIMIA 2003, 57, No.11
Table 1. Structure–activity relationship of the azines B–G
Table 2. Structure–activity relationship of the triazine analogues B
S3
R
S1
S2
F
N
Het.
X1
N
R
N
F
X3
X2
Entry
Het.
R
EC80 values [ppm]a
Heliothis
Entry
X1 X2 X3
R
S1 S2 S3
EC80 values [ppm]a
Spodoptera
littoralis
(Fcon L3)b
Plutella
xylostella
Spodoptera
littoralis
Heliothis
virescens
(ovol La)c
Plutella
xylostella
(Fcon L3)b
virescens
(ovol La)c
(Fcon L3)b
(Fcon L3)b
Lufenuron (PBU)
0.2 md
0.05 gre
0.8 m
0.05 m
3 m
0.2 m
3 gr
0.8 m
3 m
Lufenuron (BPU)
0.2 md
0.05 gre
0.2 m
0.2 m
3 gr
0.8 m
3 m
1
2
F F H
Cl H F
Cl H H
Me H H
F F H
F F H
F F H
F F H
F F H
F F H
H
CF3 H H
CF3 H H
CF3 H H
CF3 H H
CF3 H H
N
N
1
2
CF3
H
0.2 m
3 m
3 m
OCF3
3 gr
50 m
N
N
3
H
0.8 m
50
3
4
CF3
3 m
3 m
25 gr
>100
>100
>100
4
H
>100
3 m
OCF3
5
Me
0.05 m
0.8 m
0.2 m
0.2 m
0.05 gr
3 m
12.5 m
>100
3 m
6
OMe CF3 H H
>100
3 gr
N
N
5
6
CF3
3 m
3 m
>100
>100
>100
7
H
H
H
H
H
Cl Cl
SCF3 H H
CF3
Cl Cl
N
N
OCF3
> 100
8
3 m
3 m
7
8
CF3
>100
>100
>100
>100
ndf
nd
9
H
H
12.5
>100
>100
>100
N
N
10
H
OCF3
9
CF3
0.05 gr
12.5 m
>100
>100
>100
>100
aEC80 value: concentration in ppm for which the tested compound shows at least 80% ac-
tivity (greenhouse trials); bFcon L3: feeding/contact activity against l3 larvae; covol La: ovolar-
vicide test, effect on larvae; dM: mortality effect; egr: growth inhibition.
N
N
10
OCF3
11
CF3
3 m
>100
>100
N
N
H
aEC80 value: concentration in ppm for which the tested compound shows at least 80% ac-
tivity (greenhouse trials); bFcon L3: feeding/contact activity against l3 larvae; covol La: ovolar-
vicide test, effect on larvae; dM: mortality effect; egr: growth inhibition; fnot determined.
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