The discovery of indoxacarb: Oxadiazines as a new class of pyrazoline-type insecticides

Article abstract of DOI:10.1002/1526-4998(200102)57:2<153::AID-PS288>3.0.CO;2-O

The evolution of the insecticidal pyrazoline moiety that was originally discovered in 1972 has led to the discovery of a new crop insecticide, indoxacarb, which is the first commercialized pyrazoline-type sodium-channel blocker. Both monocyclic and fused-tricyclic pyrazolines and pyridazines, as well as structurally related semicarbazones were examined prior to the discovery of analogous tricyclic oxadiazines which had similarly high activity as well as favorable environmental dissipation rates and low toxicity to non-target organisms. The eventual leading candidate, DPX-JW062, was originally obtained as a racemic molecule, but a chiral synthesis was developed which produces material that is 50% ee in the insecticidal (+)-S-enantiomer (DPX-MP062, indoxacarb).

Full text of DOI:10.1002/1526-4998(200102)57:2<153::AID-PS288>3.0.CO;2-O

Pest Management Science
Pest Manag Sci 57:153±164 (2001)
The discovery of indoxacarb: oxadiazines as a
†
new class of pyrazoline-type insecticides
Stephen F McCann,* Gary D Annis, Rafael Shapiro, David W Piotrowski,
George P Lahm, Jeffery K Long, Kevin C Lee, Margaret M Hughes,
Brian J Myers, Sandra M Griswold, Bonita M Reeves, Robert W March,
Paula L Sharpe, Patrick Lowder, William E Barnette and Keith D Wing
DuPont Crop Protection Products, Stine–Haskell Research Center, PO Box 30, Newark, DE 19714, USA
Abstract: The evolution of the insecticidal pyrazoline moiety that was originally discovered in 1972 has
led to the discovery of a new crop insecticide, indoxacarb, which is the ®rst commercialized pyrazo-
line-type sodium-channel blocker. Both monocyclic and fused-tricyclic pyrazolines and pyridazines,
as well as structurally related semicarbazones were examined prior to the discovery of analogous
tricyclic oxadiazines which had similarly high activity as well as favorable environmental dissipation
rates and low toxicity to non-target organisms. The eventual leading candidate, DPX-JW062, was
originally obtained as a racemic molecule, but a chiral synthesis was developed which produces
material that is 50% ee in the insecticidal (‡)-S-enantiomer (DPX-MP062, indoxacarb).
#
2001 Society of Chemical Industry
Keywords: indoxacarb; oxadiazines; pyrazoline insecticides; sodium-channel blockers; asymmetric synthesis
1
INTRODUCTION
The discovery of insect-control compounds for crop
protection with novel modes of action is vital towards
managing pest strains that are resistant to existing
compounds. The organophosphate and carbamate
classes of cholinesterase-inhibiting insecticide, for
example, have been in use for several decades and
insect resistance to compounds with this mode of
action has become a problem for growers. In addition,
toxicity issues have placed restrictions on the use of
many current compounds. Regulatory agencies world-
wide have placed a premium on crop-protection
chemistry having improved toxicological pro®les
towards non-target organisms. Also, new chemistries
giving decreased environmental persistence and re-
quiring lower use-rates (higher activities) are desired.
The goal is to develop new insect-control compounds
that are active against resistant pest strains, effective at
low use-rates, and safe to people and to the environ-
ment.
Figure 1. Early pyrazoline structures and indoxacarb.
lips±Duphar on pyrazoline analogs with improved
activity, along with the disclosure in 1982 that some
pyrazolines showed activity against organophosphate-
The pyrazoline insecticides represent a class of
chemistry which, until recently, had no commercial
examples, despite being discovered nearly 30 years
ago. The compounds were initially reported in patents
7
resistant insect species, no doubt prompted work by
other companies towards the identi®cation of novel
1
8±12
from Philips±Duphar in 1973 as having high activity
against Lepidopteran and Coleopteran pests (Fig 1).
pyrazoline analogs.
The pyrazolines were reported
13
by Salgado in 1990 to act by blocking the sodium
channel of neurons, a novel insecticidal mode of
2
,3
4±6
Subsequent patents and publications
from Phi-
*
Correspondence to: Stephen F McCann, DuPont Crop Protection Products, Stine–Haskell Research Center, PO Box 30, Newark,
DE 19714, USA
E-mail: stephen.f.mccann@usa.dupont.com
†
Based on a paper presented at the Symposium ‘New Chemistries in Crop Protection’, organised by Dr L Copping and the late Dr J Dingwall
on behalf of the Bioactive Sciences and Crop Protection Groups of the SCI and held at 14/15 Belgrave Square, London, UK on 19 June 2000
(
Received 20 October 2000; accepted 31 October 2000)
#
2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
153

SF McCann et al
action. Synthesis efforts in the area focused on
an inversion of the diazine nitrogens of the pyrazoline
ring, resulting in `upside-down' pyrazolines with high
14
improving the toxicological and environmental-fate
15
18,19
properties of the compounds while maintaining high
insecticidal activity. A notable example is the Rohm
and Haas compound RH3421, which was reported to
have high insecticidal activity, low mammalian toxicity
insecticidal activity.
pyrazolines, known as pyridiazines, were found to be
Ring-expanded forms of the
22
highly active. Attachment of the pyrazoline ring at
C-4 to the C-3 benzo substituent via a 1-, 2-, or 3-
atom bridge resulted in `tied-back' tricyclic pyrazolines
16
and a rapid rate of degradation in the environment.
17,20
The structure of this is similar to the Philips±Duphar
compounds with the exception of having a methoxy-
carbonyl substituent at the 4-postion. Work at DuPont
also focused on the discovery of novel pyrazoline-like
insecticidal compounds with improved bio-ef®cacy
along with favorable toxicological and environmental
(indazoles and oxyindazoles).
Similary, the pyri-
dazines could be `tied-back' into tricyclic forms. The
tricyclic pyrazolines and pyridazines in many cases
showed improved insecticidal activities over their
monocyclic analogs.
The formation of the tricyclic analogs essentially
®xes the conformation of the pyrazoline ring and
17±24
fate pro®les.
The work involving the discovery of
2
6
the oxadiazine analogs of the pyrazoline ring system
which resulted in the new commercial insecticide
forces the angular R-group into an axial orientation.
X-ray crystal structures have shown that substituents
at the pyrazoline 4-position, and in analogous posi-
tions on the semicarbazones and tricyclic pyrazolines
2
2
indoxacarb (Steward , Avaunt ) is described
herein.
24,25
(oxyindazoles), typically adopt the axial orientation in
the preferred conformers (Fig 3). Molecular modeling
calculations also show a preference for axial orienta-
tions for the quasi-angular substituents for analogous
pyridazines and `upside-down' pyrazolines. Structure-
activity relationships (SAR) in the pyrazoline area
indicates the 4-substituent to be a key activity element
in the structure. For example, lower alkyls, aryls and
esters are preferred groups at this position for
insecticidal activity.
2
STRUCTURAL MODIFICATIONS OF THE
PYRAZOLINE NUCLEUS
DuPont research in the pyrazoline area, which began
in the mid-1980s, was directed towards ®nding novel
variations to the pyrazoline ring system that main-
tained high levels of insecticidal activity and favorable
toxicological and environmental characteristics (Fig
2
novel, ring-opened variation of the pyrazoline nu-
). For example, the semicarbazones represented a
21
cleus. These compounds maintained high levels of
insecticidal activity against a similar spectrum of pests
3 TRICYCLIC PYRIDAZINE ANALOGS
The tricyclic pyridazine DPX-JP121 bearing a carbo-
(Lepidoptera and Coleoptera). Another variation was
Figure 2. Modifications to the original pyrazoline structure.
154
Pest Manag Sci 57:153±164 (2001)

Indoxacarb
Figure 3. X-Ray crystal structure conformations of a representative pyrazoline, semicarbazone and oxyindazole.
methoxy substituent in the angular position was found
to be highly active against Spodoptera, Heliothis and
4 OXADIAZINES VIA O- FOR CH - SUBSTITUTION
2
We became interested in further potential modi®-
cations of the pyrazoline structure wherein one of the
carbon atoms in the pyridazine ring of 3 was replaced
22
Plutella spp In addition, DPX-JP121 showed low
acute toxicity to mammals. Unfortunately, the com-
pound showed less-than-ideal soil degradation rates,
with a t1/2 greater than 100 days. In addition, the
synthesis of DPX-JP121 was complicated by the low
yield conversion of the methoxycarbonylindanone (Fig
24
by an oxygen atom (Fig 5). The resulting oxadia-
zine 4 would be predicted to have similar structural
morphology to the pyridazine (with a diazine ring-
size intermediate between pyrazolines and pyrida-
zines due to the slightly shorter C±O vs C±C bond
distances) and, hence, was predicted to have similarly
high levels of insecticidal activity. Additionally, the
fact that the oxadiazine ring contains an O,N-acetal
leads to the prediction that the oxadiazine ring may
be susceptible to acidic hydrolysis, a factor which
may contribute towards realizing shorter soil half-
4
; 1) to the key intermediate 2-(2-bromoethyl)inda-
none 2. The major product was formed as a result of
O-alkylation, with the ratio of O-alkyl vs C-alkyl
isomers being approximately 3:1. The separation of
O-and C-bromoethylated products required careful
¯ash chromatography, hindering efforts for prepara-
tive scale-up.
Figure 4. Preparation of tricyclic pyridazine DPX-JP121.
Pest Manag Sci 57:153±164 (2001)
155

SF McCann et al
lives. Moreover, the proposed synthetic route to these
novel oxadiazines appeared fairly straightforward (Fig
6
). The syntheses were envisaged to involve three key
steps: (1) oxidative hydroxylation at the indanone
-position, (2) formation of the indanone semicarba-
2
zone and (3) ring closure via O,N-acetal formation.
These steps were readily accomplished and the
desired tricyclic oxadiazines were obtained in good
overall yields.
The ®rst step, oxidative hydroxylation of indanones,
was accomplished using a variety of conditions (Fig 7).
In the cases where the 2-position was substituted by an
electron-withdrawing ester group, the relatively high
acidity of the 2-hydrogen allowed oxidation under
Figure 5. Pyridazine structure modification to form an oxadiazine.
Figure 6. Retrosynthetic analysis of tricyclic oxadiazines.
Figure 7. Hydroxylation reactions of indanones.
156
Pest Manag Sci 57:153±164 (2001)

Indoxacarb
Figure 8. Semicarbazone formation from 2-hydroxyindanones.
2
7
mild conditions using, eg MCPBA or hydrogen
zone synthesis procedure, involving reaction of the
hydrazone intermediate with a tertiary carbamoyl
28
peroxide/sodium bicarbonate. When the 2-substitu-
ent was an aromatic group, the use of more basic
conditions (oxone with sodium hydroxide, air with
31
chloride, was a preferred option. Both approaches
gave high yields of the desired semicarbazone pro-
ducts.
29
sodium hydroxide and phase transfer catalyst )
became necessary for hydroxylation. With 2-alkyl
substituted indanones, direct hydroxylation was not
ef®cacious and the alternative two-step Rubottom
The cyclization of the 2-hydroxy semicarbazones to
give the target oxadiazine compounds involved forma-
3
2
tion of an O,N-acetal of formaldehyde (Fig 9). In
cases in which the carboxanilide nitrogen was unsub-
stituted, reactions of 2-hydroxy semicarbazones with
paraformaldehyde in re¯uxing acetonitrile with an acid
catalyst gave the desired tricyclic oxadiazines in good
yields. In cases in which the carboxanilide nitrogen of
the 2-hydroxy semicarbazones was substituted (with
an alkyl, acyl or carbamoyl group), an alternative
cyclization procedure using methylal and phosphorus
30
procedure was used. This method involved initial
formation of the trimethylsilyl enol ether and subse-
quent treatment with an oxidizing agent (MCPBA).
Tetralones and quinolinones, which are ring-
expanded variants of indanones, were hydroxylated
using analogous procedures.
The syntheses of the semicarbazone intermediates
could be achieved using two complementary proce-
dures (Fig 8). One procedure involved initial forma-
tion of the hydrazone followed by reaction with a
phenyl isocyanate to give the semicarbazone precur-
sors to the tricyclic oxadiazines. In cases in which the
desired oxadiazine product contained a substituent on
the carboxanilide nitrogen, an alternative semicarba-
33
pentoxide was preferred for best yields.
This
procedure directly gave oxadiazines substituted at the
carboxanilide nitrogen. Alternatively, these com-
pounds could be obtained by N-alkylation or N-
acylation of N-unsubstituted carboxanilides in the
presence of a strong base (such as sodium hydride).
21
Figure 9. Oxadiazine-ring synthesis via O,N-acetal formation.
Pest Manag Sci 57:153±164 (2001)
157

SF McCann et al
Figure 10. Synthesis of DPX-JT333.
Figure 11. X-ray structure conformation of oxadiazine DPX-JT333.
The formation of DPX-JT333, which is the oxadia-
zine directly analogous to DPX-JP121, was achieved
in good overall yield and required no chromatographic
puri®cations of intermediates (Fig 10). X-ray crystal-
lographic studies of DPX-JT333 showed a fairly
planar conformation of most of the molecule with
the angular carbomethoxy substituent residing outside
the plane, analogous to the other pyrazoline analogs
for DPX-JP121). It therefore appeared that the
possible hydrolytic instability of the O,N-acetal re-
sulted in compounds that degraded more rapidly in
soil.
5
TRIAZINE ANALOGS
Triazines which are analogous to the oxadiazines
could be prepared in a similar manner to the latter
(Fig 11). DPX-JT333 was found to have insecticidal
24
activity and an activity spectrum nearly identical to
those of its pyridazine counterpart, DPX-JP121 (Fig
(Fig 13). The ®rst step involved amination of the
34
indanone using cyclohexyl spiro-oxaziridine. The
resulting 2-amino indanone was isolated as the hydro-
chloride salt. Reaction with an aryl semicarbazide
under acid catalysis gave the 2-amino semicarbazone
1
2). The rate of degradation in soil was clearly much
enhanced in the case of DPX-JT333 (vs DPX-JP121)
which showed a t1/2 of less than 14 days (vs >100 days
Figure 12. Comparison of DPX-JP121 vs DPX-JT333.
158
Pest Manag Sci 57:153±164 (2001)

Indoxacarb
Figure 13. Synthesis of triazines.
(
isolated as the free base) which was then cyclized to
most active analogs, with alkyl substituents and higher
esters giving lower levels of activity. The Z-substituent
on the phenyl ring of the carboxanilide was typically
para for the most active analogs, and the Z-substituent
was usually tri¯uoromethoxy or tri¯uoromethyl.
Finally, methoxycarbonyl or acetyl as Y-substituents
gave the best activity for derivatives substituted at the
carboxanilide nitrogen.
the tricyclic triazine using either Eschenmoser's salt or
ethylal and acid catalysis. In the case of the triazines,
further modi®cations were possible via functionaliza-
tions of either the triazine and/or the carboxanilide
nitrogen atoms.
6
The SAR for oxadiazines against fall armyworm,
STRUCTURE–ACTIVITY RELATIONSHIPS (SAR)
In the cases of ring-expanded tricyclic oxadiazines
(derived from tetralones and quinolinones), SAR for
the R-, X-, Y- and Z-substitutents was nearly
analogous to the indanone-derived compounds in
Fig 14 except for the position of the X-substituent
on the benzo ring, which preferred 5-substitution for
optimum activity (Fig 15). The triazine compounds
had SAR and activities that were comparable to the
analogous oxadiazines.
Spodoptera frugiperda (Smith) is summarized in Fig
1
4. It was found that substitution at the 4- or 5-posi-
tions of the benzo ring (X-substituents) gave analogs
with the highest activity and, of those substituents,
chlorine and bromine, along with tri¯uoroethoxy and
tri¯uoromethyl, were the best. The angular R-group
was either 4-halophenyl or methoxycarbonyl in the
Figure 14. SAR for oxadiazines vs Spodoptera frugiperda. Note: substituents giving highest activities are listed first and relative activities are listed in
descending order.
Pest Manag Sci 57:153±164 (2001)
159

SF McCann et al
Figure 15. SAR summaries for ring-expanded tricyclic oxadiazines and for triazines.
7
SELECTION OF CANDIDATE COMPOUND DPX-
racemic molecule. Since the identity of the angular
substituent at the chiral center of oxadiazines and
other pyrazoline-type compounds had been found to
JW062
Based on overall considerations of insecticidal ef®cacy,
safety to non-target organisms (eg predatory insects,
mammals, birds, ®sh), and rapid dissipation in the
environment, the compound DPX-JW062 was se-
lected for advanced pre-commercialization studies
3
7
be important in determining insecticidal activity, we
sought to prepare the individual enantiomers of DPX-
JW062. The expectations were that one enantiomer
would be more active than the other, possibly twice as
active. The racemic mixture was separated by chiral
HPLC and the resulting enantiomers were tested for
insecticidal activity (Fig 17). The (‡)-enantiomer,
DPX-KN128 [(‡)-DPX-JW062], was found to be
twice as active as the racemic DPX-JW062, while the
(� )-enantiomer was completely inactive. Thus, a
chiral synthesis of (‡)-DPX-JW062 became an im-
portant goal.
(Fig 16). DPX-JW062 was also found to be highly
active against insect strains that had developed
resistance to organophosphates, carbamates and pyr-
25
ethroids. The mode of action of DPX-JW062 was
found to be through the blocking of the sodium
channel in insects, the same as that previously reported
35,36
for insecticidal pyrazolines.
DPX-JW062 contains a chiral center and is a
Figure 16. Characteristics of DPX-JW062 (racemic indoxacarb).
160
Pest Manag Sci 57:153±164 (2001)

Indoxacarb
Figure 17. Separation of the active and inactive enantiomers of DPX-JW062.
8
ASYMMETRIC SYNTHESIS
ee. The use of the Sharpless asymmetric dihydroxyla-
tion procedure, however, was not ideal from the
standpoint of scale-up since the AD-mix reagents
contain osmium (which is both highly toxic and
expensive). Alternative methods for asymmetric hy-
droxylation were therefore necessary for a commercial-
scale synthesis of the enantiomerically enriched
compound.
In the synthesis of DPX-JW062, the introduction of
chirality occurs in the hydroxylation of the 2-carbo-
methoxyindanone 1 to form 5 (Fig 18). An asymmetric
approach to this oxidation was therefore sought.
We found that the use of the Sharpless asymmetric
38
di-hydroxylation reagent (AD-mix)
effected the
asymmetric hydroxylation of 1 directly (possibly via a
di-hydroxylation of the enolic tautomer followed by
hydrolysis). The AD-mix a and AD-mix b reagents
gave 54% and 51% ee, respectively, of the (‡)-and
The chiral camphorsulfonyl±oxaziridine reagents
39
developed by Davis et al were found to effect asym-
metric hydroxylation of 1 in the presence of catalytic
sodium bicarbonate, albeit in only 35% ee (see Fig
20). A number of other procedures were also investi-
(
� )-isomers of the chiral hydroxy-indanone inter-
mediates 5 (see Fig 19). Each enantiomerically
enriched intermediate was carried through the re-
mainder of the synthesis to give the (‡)-and (� )-
isomers of DPX-JW062, each in approximately 50%
40
41
gated (including use of Sharpless and Jacobsen
asymmetric epoxidation procedures) without success.
Finally, a novel procedure was discovered whereby a
Figure 18. Asymmetric hydroxylation of 1.
Pest Manag Sci 57:153±164 (2001)
161

SF McCann et al
Figure 19. Asymmetric hydroxylation of 1 to form the individual enantiomers of 5.
chiral base (cinchonine) catalyzed the reaction of 1
with tert-butyl hydroperoxide to give the (‡)-hydroxy
9 CONCLUSIONS
Indoxacarb represents the ®rst commercialized insec-
ticide that acts by blocking the sodium channel in
neurons, a mode of action ®rst identi®ed in pyrazo-
lines. The discovery of indoxacarb was achieved by an
extensive effort towards optimizing pyrazoline-type
chemistry with regards to insecticidal ef®cacy, safety
towards non-target organisms, and safety towards the
environment. Variations to the pyrazoline nucleus led
to the ®nding that structurally-related oxadiazines
were also highly insecticidal. Optimization of the oxa-
diazines led to the identi®cation of racemic indoxacarb
(DPX-JW062) as a candidate for commercialization.
3
3
indanone 5 in 50% ee. This reaction was amenable
to commercial-scale synthesis. The remaining steps of
carrying 5 through the synthesis to (‡)-DPX-JW062
(50% ee) are shown in Fig 21. In the synthesis, the
oxadiazine ring is formed as the benzyl carbamate
CBz)-protected form which is then de-protected to
(
the somewhat unstable oxadiazine and coupled with
the aniline carbamoyl chloride to yield the ®nal
product, (‡)-DPX-JW062 (50% ee), which was
renamed DPX-MP062. This compound was subse-
quently renamed indoxacarb.
Figure 20. Other chiral syntheses of 5.
162
Pest Manag Sci 57:153±164 (2001)

Indoxacarb
Figure 21. Synthesis of DPX-MP062 (indoxacarb).
Chiral synthesis provided a means of producing
indoxacarb that is enantiomerically enriched in the
active isomer.
substituted phenylcarbamoyl-2-pyrazolines. German Patent
DE 2 700 289 (1978).
9
Hunt JD, Diaryl-substituted pyrazoline carboxanilides, insecti-
cidal compositions and uses thereof, and intermediates there-
for, European Patent EP 4733 (1979).
1
0 Ozawa K, Nakajima Y, Tsugeno M, Ishii S and Hatanaka M,
Insecticidal 3-di¯uoromethoxyphenyl-1-phenylcarbamoyl-2-
pyrazolines, US Patent 4 464 386 (1984).
ACKNOWLEDGEMENTS
We would like to thank Dave Marsden, Steve Riley,
Chris Clark, Bob Daly and Ray Yarnall for carrying
out the insecticidal assays, Dan Linn and Peggy Lucas
for soil dissipation studies, Will Marshall for X-ray
diffraction analyses, Dominic Chan for co-ordinating
the X-ray analyses and John Groce, Gina Blankenship,
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1
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5
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