Synthesis and structure-activity relationships of benzophenone hydrazone derivatives with insecticidal activity

Article abstract of DOI:10.1002/1526-4998(200102)57:2<191::AID-PS275>3.0.CO;2-O

A broad range of benzophenone hydrazone derivatives was prepared and tested against selected chewing insect pests, allowing the analysis of structure-activity relationships. Good activity was found only when the aromatic rings were substituted at the 4-positions with an halogen atom and a triflate or perhaloalkoxy group. In contrast, a number of substituents on the hydrazone part led to active compounds, the best results being achieved with acyl-type substituents. The excellent laboratory and greenhouse activity of the best representatives was confirmed in semi-field trials against Spodoptera littoralis. ° 2001 Society of Chemical Industry.

Full text of DOI:10.1002/1526-4998(200102)57:2<191::AID-PS275>3.0.CO;2-O

Pest Management Science
Pest Manag Sci 57:191±202 (2001)
Synthesis and structure–activity relationships
of benzophenone hydrazone derivatives
with insecticidal activity
Manfred Bo¨ger, Dieter Durr, Laurenz Gsell, Roger G Hall, Friedrich Karrer,
¨
Odd Kristiansen, Peter Maienfisch, Alfons Pascual* and Alfred Rindlisbacher
Novartis Crop Protection AG, 4002 Basel, Switzerland
Abstract: A broad range of benzophenone hydrazone derivatives was prepared and tested against
selected chewing insect pests, allowing the analysis of structure-activity relationships. Good activity
was found only when the aromatic rings were substituted at the 4-positions with an halogen atom and a
tri¯ate or perhaloalkoxy group. In contrast, a number of substituents on the hydrazone part led to
active compounds, the best results being achieved with acyl-type substituents. The excellent laboratory
and greenhouse activity of the best representatives was con®rmed in semi-®eld trials against
Spodoptera littoralis.
# 2001 Society of Chemical Industry
Keywords: benzophenone hydrazones; insecticides; Spodoptera littoralis; Heliothis virescens
1
INTRODUCTION
The amidinohydrazones represent a class of com-
pounds with broad pharmacological properties,1 for
instance activity against malaria.2 In 1973, researchers
at DuPont described for the ®rst time the insecticidal
properties of some simple benzophenone hydrazones.3
The work of Copping and coworkers at Boots at the
end of the 1970s included for the ®rst time substituted
hydrazones of type 1 (Fig 1), which showed an
interesting level of activity against lepidopteran and
other insect pests.4±6 Carbamate types (1, R=OR') in
particular lead to a strong insecticidal activity. The
biological results of compounds 1 were summarised
brie¯y by the same research group in 1984.7 In 1990,8
Sumitomo workers described the insecticidal activity
of a novel type of hydrazone structure 2 (Fig 1;
R1=R2=R3=CH3), while researchers at FMC dis-
closed some benzoheterocyclyl derivatives based on
previously described compounds.9
Figure 1. Benzophenone hydrazone derivatives disclosed by Boots (1)
and Sumitomo (2).
To this aim, we investigated especially two main
areas of structural variations (Fig 2) including:
a) selected substitution patterns at the hydrazone part
(compounds 3 to 6, 8 to 10) and
b) modi®cations on the aromatic rings (eg com-
pounds 7 and 11), together with heteroaromatic
ring substitutions.
At the same time Ciba-Geigy was interested in
compounds showing a broad spectrum of activity
against chewing insect pests, particularly in cotton and
vegetables. At the end of 1990, in the light of the
glasshouse activity of some of the benzophenone
hydrazone derivatives described in the patent litera-
ture, we started a programme based on general
structures 1 and 2 with the aim of exploring a broad
range of substitution patterns. We wanted to under-
stand the structure-activity relationships of these
compounds, in order to be able to design compounds
with superior performance.
In the course of our optimisation programme we
discovered several modi®cations10±15 of the original
structures with improved biological properties. A short
summary of part of this work has been published
recently.16
In the present communication some of the chemical
and biological results, with emphasis on structure-
activity relationships for selected substitution patterns,
are discussed.
* Correspondence to: Alfons Pascual, Novartis Crop Protection AG, 4002 Basel, Switzerland
(Received 13 April 2000; revised version received 8 August 2000; accepted 20 September 2000)
# 2001 Society of Chemical Industry. Pest Manag Sci 1526±498X/2001/$30.00
191

M BoÈger et al
Figure 2. General structures of the compounds discussed in the text.
2
METHODS
isolation. The only noticeable side reaction with this
reagent was with R2=H, where the CHO group was
also reduced to methyl to a small extent. Bisacylated
compounds 10h±i were prepared as described above
for compounds 4j±k and 5c.
Melting points were measured on a Ko¯er heating
block (Fa Reichert, Vienna) or on BuÈchi's apparatus.
Solvents and reagents were obtained from commercial
sources and used without further puri®cation.
2.1 Synthesis
2.1.2 Synthesis of imino compounds 3 and (thio)
semicarbazones 8 and 9 (Fig 3 and Table 1)
In Figs 3 to 7 the preparation of the compounds
discussed in the text is shown in due detail to dispense
with the inclusion of extensive experimental proce-
dures. Special synthetic problems are dealt with below
and appropriate detail is given. Some physical data are
shown together with biological data in the correspond-
ing tables. Most benzophenone hydrazone derivatives
were isolated as syn/anti mixtures at the C=N bond
and used as such.
Intermediate hydrazones 13 (Fig 3) were used for the
direct synthesis of semicarbazones 8 by, for example,
reaction with phosgene followed by the addition of the
corresponding amine, and for the preparation of
sulfonylimines 3 as indicated. Compounds 3 were also
obtained through reaction of chlorimine 14 with a
substituted sulfonamide in the presence of HuÈnig's
base. The thiosemicarbazones 9 were prepared from
8a±c via chlorimine 15 analogously to the thioacyl
compounds 6.
2.1.1 Synthesis of acyl-type compounds 4, 5, 6 and 10
(Fig 3; see Tables 1 and 2 for the list of substituents)
The benzophenone 12 was converted to the hydrazone
13 and acylated to compounds 4a±i and 5a±b by
standard procedures. Compounds 6a±b were obtained
from 4 where R1=H via formation of the chlorimine 14
and subsequent reaction with hydrogen sul®de. Oxalic
acid amides 5d±e were prepared from the correspond-
ing esters 5a±c by treatment with primary and
secondary amines. Bisacylated compounds 4j±k and
5c were obtained by acylation of 4a or 5a in the
presence of HuÈnig's base and DMAP. Attempted
reduction of the acylated derivatives 4 or 5 to com-
pounds 10 with NaBH4 either alone, in polyethylene-
glycols17 or in the presence of crown ethers under
phase transfer catalysis18 gave in all cases mixtures of
several products. Although catalytic hydrogenation of
4a over Pd/C in ethyl acetate yielded 10a in 41% yield,
the procedure of choice was the reduction of 4 with
NaBH3CN19 providing good yields and allowing easy
2.1.3 Synthesis of benzophenones 7 (Figs 4±6 and Table
3)
These compounds were prepared from intermediate
benzophenones 18 by the methods already mentioned.
The benzophenones themselves were prepared as
follows: a Friedel±Crafts reaction led to intermediates
16, which were demethylated to phenols 17 with either
HBr in acetic acid,20 pyridinium hydrochloride21 or
BBr3 (Fig 4).22,23
In a few cases, however, special methods had to be
applied. The synthesis of 71 (Fig 5) involved 22,
prepared via Grignard reaction of 4-chlorostyrene 19
with silyl-protected 4-hydroxybenzaldehyde 2024 to
give alcohol 21, which was oxidised25 to vinylbenzo-
phenone 22. Compound 7m was prepared as shown in
Fig 6. For the intermediate benzophenone, 28, a new
synthesis had to be designed. Attempted demethyla-
tion of 27 with HBr in acetic acid, BBr3, pyridinium
192
Pest Manag Sci 57:191±202 (2001)

Benzophenone hydrazone derivatives with insecticidal activity
Figure 3. Synthesis of the derivatives 3, 4, 5, 6 and 8 to 10. (a) R1NHNH2, EtOH, AcOH (catalyst), reflux 10–24h; (b) acylation: R2COCl, toluene (or THF), Et3N
(catalyst), 0°C to room temp., or ClCOCOOR, CH2Cl2, pyridine (1.5 eq), 0°C to room temp., 16h; formylation: CH3COOCHO, ether, 0°C to room temp.,
(c) H2NNR1COR2, EtOH, AcOH (catalyst), reflux 2–24h; (d) PCl5 (1.1 eq), xylene, reflux 10h; (e) H2S (6 eq), THF, Et3N, 30°C 3h; (f) RCOCl, toluene, Et(i-Pr)2N
(1.1 eq), DMAP (catalyst), 0°C to room temp., (g) Amine, MeOH, 10°C, then room temp.; (h) NaBH3CN (4 eq), THF, p-TsOH, room temp., 2h; (i) ClCON(OR3)R2
(1.1 eq), Et3N (1.1 eq), THF, room temp., 1h and then reflux 2h; (j) (1) 13, AcOEt; COCl2 (in toluene, 1.1 eq), 25°C to room temp., overnight; (2) HN([O]nR3)R2
(1.1 eq), 0°C 10min; (3) AcOH, ice, 0°C to room temp.; (k) EtOC(R2)=NSO2R3 (2.0 eq), toluene, Et3N reflux 16h; (l) H2NSO2R3 (1.2 eq), Et(i-Pr)2N (1.2 eq),
toluene:xylene 1:1, reflux 24h.
26
hydrochloride, or BCl3
and C2H5SH/NaH in
achieved via Grignard reaction of benzonitrile
29,15,16 whereas a one-pot procedure32 (¯uorination
in HF of 31 followed by Friedel±Crafts reaction in the
presence of BF3) allowed the preparation of inter-
mediate 30c. Finally, compounds 11h and 11i were
obtained through oxidation of 11g with m-CPBA. The
benzophenone 30g could be prepared via Friedel±
Crafts reaction of tri¯uoromethylthiobenzene.33
DMF27 led to mixtures of products involving addition
to the triple bond and polymerisation. We circum-
vented this problem by using the intermediate 25,
prepared from benzophenone 24 via Heck reaction.28
Reaction of 25 with sodium hydroxide in isopropa-
nol29 allowed the simultaneous hydrolysis of the ester
group to the phenol and deprotection of the acetylene
bond to 26 in very good yields and selectively.
2.1.5 Preparation of miscellaneous compounds 32 (Table
5)
2.1.4 Preparation of haloalkoxy derivatives 11 (Fig 7
and Table 4)
Compounds 32a±f were prepared via Friedel±Crafts
reaction as already described in Fig 4. Some starting
heterocyclic carboxylic acids were not commercially
available and were prepared as follows. 5-Chlorothio-
phene-3-carboxylic acid was formed by Friedel±Crafts
reaction of 2,5-dichlorothiophene to 3-acetyl-2,5-
dichlorothiophene (68%),34,35 selective reduction of
Compounds 11 were synthesised according to Fig 7.
Freonisation of 4-chloro-4'-hydroxybenzophenone
with CF2Br2,15,16,30 BrCF2CF2Br,31 or CF2 =CF2
led to the intermediate benzophenones 30b, 30e and
30f; treatment with ClCF2CONH2 gave 30d in low
yield. The introduction of the OCF3 group was
Pest Manag Sci 57:191±202 (2001)
193

M BoÈger et al
Figure 4. Synthesis of the derivatives 7a–k. (a) and (b) see Fig 3; (m) anisole, AlCl3 (1.2 eq), ClCH2CH2Cl 0°C to room temp, (in some cases 40°C); (n) HBr
(48%), AcOH 120°C 1h or Py.HCl, 200°C 2h, or BBr3, CH2Cl2 70°C to room temp.; (o) (CF3SO2)2O (1.2 eq), pyridine, 0°C to room temp. For the list of
substituents see Table 3.
Figure 5. Synthesis of the compound 7i. (a) and (b) see Fig 3; (o) see Fig 4; (p) (1) 19, Mg, THF, reflux 40min, (2) 20, THF, 30°C, then 50°C 15min; (3) HCl/H2O;
(q) CrO3/H2SO4, room temp, 2h.
Figure 6. Synthesis of the compound 7m. (a) and (b) see Fig 3; (o) see Fig 4; (r) HOC(CH3)2CꢀCH, PdCl2(PPh3)2 (catalyst), Cu2I2 (catalyst), Et3N, THF 60°C
8h; (s) NaOH (3 eq), i-PrOH, reflux 3h.
194
Pest Manag Sci 57:191±202 (2001)

Benzophenone hydrazone derivatives with insecticidal activity
Figure 7. Synthesis of fluoroalkoxy derivatives 11a–i. (a) and (b) see Fig 3; (t) (1) 29, Et2O, reflux 24h; (2) H2SO4 (50%), 30°C 1h; (u) (1) HF, 20°C;
(2) chlorobenzene, BF3 (6 eq), 5°C 40h; (v) (1) NaH (1.1 eq), DMF 90min; (2) CF2Br2 (2.0 eq), room temp, 2h; 3) t-BuOK (1.0 eq), room temp, 16h; (w) (1)
K2CO3 (1.5 eq), KI (0.15 eq), MeCOEt, room temp, 10min; (2) ClCF2CONH2 (1.3 eq), reflux 36h; (x) (1) KH (1.05 eq), DMF, 10°C 30min; (2) BrCF2CF2Br (1.10
eq), 10°C; then 120°C 6h; (y) Et3N (1.0 eq), KOH (1.1 eq), DMF:H2O (93:7), 100°C; CF2=CF2 (excess), 110°C 30min; (z) HF, BF3 (excess), 0°C; room temp,
4h; (zz) m-CPBA (1.2 eq), CHCl3, room temp, 48h.
the chlorine atom in position-2 with zinc in acetic acid
(82%)36 to 3-acetyl-5-chlorothiophene and oxidation
with NaOCl (90%).36 3-Haloisoxazole-5-carboxylic
acids were prepared by treatment of furfural with
nitromethane (88%)37 followed by either reaction with
HBr in acetic acid (48%)38,39 or with concentrated
hydrochloric acid in 1-octanol (23%)37 to the corre-
sponding 3-(3-haloisoxazol-5-yl)propionic acids and
subsequent oxidation (45±50%) by means of CrO3.39
The synthesis of 32g has already been described by
us.40
2.2.1 Heliothis virescens: ovolarvicidal action
Eggs of H virescens deposited on ®lter paper were
immersed for a short time in a water/acetone solution
containing the test compound at a concentration of
100, 50, 12 or 3mg litre 1. After the test solution had
dried, the eggs were incubated in Petri dishes. After 4
days, the percentage hatching of the larvae, and after 7
days, the percentage of dead larvae were evaluated in
comparison with untreated control batches (percen-
tage reduction in hatching and larval mortality). The
results of this test are shown in Tables 1 to 5 under the
heading Heliothis egg and Heliothis L1.
2.2 Biological assays
2.2.2 Heliothis virescens: larvicidal action
The biological assays were conducted against the
tobacco budworm, Heliothis virescens F, and the
Egyptian cotton leafworm, Spodoptera littoralis Boisd.
Tests were performed mostly at 26 (Æ2)°C in semi-
darkness, excepted for test 2.2.3, which was con-
ducted at 23 (Æ1)°C in a dark climate chamber. Test
2.2.5 was performed under arti®cial daylight condi-
tions (14:10h light:dark). In the tables, the concentra-
tion in mg litre 1 at which 80% or more effect occurs
(reduction of fertile eggs or larval mortality) is
indicated.
Young soybean plants were sprayed with an aqueous
emulsion containing the test compound at a concen-
tration of 100, 50, 12 or 3mg litre 1. After the spray
coating had dried, each of the plants was infested with
10 third-instar H virescens larvae and placed in a plastic
container. Evaluation was made 5 days later as
percentage mortality. The results of this test are shown
in Tables 1 to 5 under the heading Heliothis L3.
2.2.3 Heliothis virescens: special test
Leaf discs (2cm) of young cotton plants were sprayed
Pest Manag Sci 57:191±202 (2001)
195

M BoÈger et al
Table 1. Structures and biological activitiesa of compounds 3, 4, 5, 6, 8 and 9
Heliothis
L1
Special tests
Compound
mp (°C)
R1
R2
X
Egg
L3
Spod
Spod 16d
Heliothis
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
121±129
Resin
H
H
NSO2CH3
NSO2CH3
NSO2CH3
3
100
12
12
12
3
12
50
3
50
50
12
50
Ð
12
3
50
12
12
50
i
Ð
12
12
50
Ð
3
Ð
50
12
50
Ð
50
12
50
50
50
12
50
Ð
50
12
12
100
12
12
50
50
i
H
CH3
H
Amorph
Resin
CH3
H
H
NSO2(i-C3H7)
NSO2C6H5
12
100
3
177±178
138±142
68±74
H
H
H
CH3
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
3
CH3
CH3
CH3
CH3
<3
3
3
3
3
80±82
CH3
i-C3H7
C6H5
H
3
12
12
50
3
3
3
145±148
Resin
3
12
50
3
12
12
3
50
12
3
12
3
Oil
C2H5
i-C3H7
t-C4H9
CH2CꢀCH
CHO
COCH3
H
4g
4h
4i
Resin
H
<3
i
3
12
i
3
50
Ð
12
3
Resin
CH3
CH3
CH3
CH3
i
i
Resin
3
12
3
50
12
3
12
12
12
50
12
12
3
4j
137±142
Resin
<3
12
50
3
4k
5a
5b
5c
5d
5e
6a
6b
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
3
12
>50
50
12
3
157±158
Resin
COOC2H5
COOC2H5
COOC2H5
CONHC2H5
CONHC2H5
H
50
12
3
50
12
3
CH3
COCH3
H
Resin
3
137±139
143±144
110±112
Resin
3
12
12
12
3
12
12
12
12
50
12
50
50
100
Ð
Ð
100
50
Ð
COCH3
H
12
12
3
12
50
12
100
3
50
50
12
Ð
12
50
Ð
Ð
Ð
Ð
Ð
50
Ð
H
CH3
N(CH3)2
S
50
Ð
50
i
138±142
102±104
130±145
112±116
Oil
H
O
O
O
O
O
S
50
3
100
12
12
50
50
i
H
N(CH3) (OCH3)
NH(OC2H5)
NHCH3
H
12
12
12
12
i
3
CH3
CH3
H
100
50
Ð
Ð
i
Ð
Ð
Ð
Ð
Ð
50
Ð
N(CH3) (OCH3)
NHCH3
N(CH3)2
165±170
154±157
201±203
Oil
H
S
i
CH3
CH3
H
NHCH3
N(CH3)2
N(CH3) (OCH3)
S
12
3
100
12
50
S
12
Ð
136±137
S
50
1
a Concentration in mg litre at which 80% or more mortality was observed.
Ð: not tested.
i: less than 30% mortality or inactive at the highest concentration tested.
>100: 30±70% mortality at the highest concentration tested.
<3: 100% mortality was still observed at the lowest concentration tested.
with an aqueous emulsion containing the test com-
pound at a concentration of 100, 50, 12 or 3mg
litre 1. After the spray coating had dried, the discs
were put into Petri dishes and a single ®rst-instar H
virescens larva was placed on the disc and incubated for
6 days. Thirty discs were used for each concentration.
Evaluation was made on percentage mortality. The
results of this test are shown in Tables 1 to 5 under the
heading Special tests, Heliothis.
S littoralis (third instar) instead of H virescens. The test
evaluation was done in the same way. The results of
this test are shown in Tables 1 to 5 under the heading
Spod.
2.2.5 Spodoptera littoralis: persistence test in the
glasshouse
Young cotton plants (Gossypium barbadensis Hutchins,
Delta Pine variety) were sprayed with an aqueous
emulsion containing the test compound at a concen-
tration of 50, 12 or 3mg litre 1. After 16 days, leaves
were cut out, placed in Petri dishes and infested with
2.2.4 Spodoptera littoralis: larvicidal action
The test in Section 2.2.2 was followed, using larvae of
196
Pest Manag Sci 57:191±202 (2001)

Benzophenone hydrazone derivatives with insecticidal activity
Table 2. Structures and biological activitiesa of compounds 10
Heliothis
L1
Special tests
Spod 16d Heliothis
Compound
mp (°C)
Resin
R1
R2
R6
Egg
L3
Spod
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
H
H
CH3
H
H
H
H
H
H
H
12
3
3
3
12
12
50
12
50
12
12
Ð
i
3
12
50
12
12
12
12
Ð
12
3
12
Ð
12
Ð
12
12
Ð
12
12
50
Ð
50
Ð
50
50
Ð
Ð
Oil
n-C3H7
t-C4H9
C2H5
C6H5
H
Resin
50
12
12
3
50
12
50
12
12
Ð
50
Resin
CH3
CH3
C2H5
COCH3
H
112±114
Resin
Resin
CH3
CH3
12
i
138±139
Amorphous
COCH3
COCH3
CH3
C6H5
50
a
See Table 1.
10 third-instar larvae of S littoralis. Evaluation was
made 5 days later of percentage mortality. Each test
concentration was repeated three times. The results of
this test are shown in Tables 1 to 4 under the heading
Special tests, Spod 16d.
16.8m2 (four rows to 0.7mÂ6m) was used. For each
compound, a rate of 200gAI ha 1 in a spray volume of
300 litresha 1 of an EC formulation was applied onto
two of the above plots. After drying, 40 leaves per plot
were marked with yellow plastic strips, to ensure that
treated leaves are taken at the time of sampling. At
application and 6 and 12 days after application, ®ve
leaves were taken from each plot and each infested
with 20L2 larvae. The evaluation was made 5 days
after infestation on percentage mortality. Compound
2.2.6 Spodoptera littoralis: persistence semi-field test
under sub-tropical conditions
These trials were conducted on cotton, variety Giza 75
at the Kaha Research Station, Egypt. A plot size of
Table 3. Structures and biological activitiesa of compounds 7
Heliothis
Special tests
Compound
mp (°C)
X
Egg
L1
L3
Spod
Spod 16d
Heliothis
7a
7b
7c
7d
7e
7f
7g
7h
7i
135±140
146±149
110±128
140±145
138±143
150±152
199±200
142±143
162±164
137±148
113±117
109±113
Oil
4-F
12
3
3
12
12
i
3
12
12
Ð
12
50
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
50
50
50
Ð
4-Br
3
4-CH3
4-t-C4H9
3-Cl
Ð
i
i
Ð
Ð
Ð
50
Ð
Ð
i
Ð
i
Ð
i
100
Ð
Ð
2-Cl
i
Ð
50
Ð
Ð
Ð
Ð
i
Ð
3,4-Cl2
2,4-Cl2
4-C6H5
4-SCH3
4-OC6H5
4-CH=CH2
4-CꢀCH
50
50
Ð
Ð
i
Ð
i
100
i
Ð
Ð
7j
7k
7l
Ð
Ð
Ð
i
Ð
Ð
i
50
12
Ð
7m
50
12
50
>50
a
See Table 1.
Pest Manag Sci 57:191±202 (2001)
197

M BoÈger et al
Table 4. Structures and biological activitiesa of compounds 11
Heliothis
L1
Special tests
Compound mp (°C)
Y
R1
R2
Egg
L3
Spod Spod 16d Helothis
11a
11b
11c
11d
11e
11f
11g
11h
11i
119±121 OCF3
H
CH3
CH3
CH3
CH3
CH3
CH3
H
12
3
12
3
12
12
12
50
Ð
50
3
50
12
12
Ð
Ð
50
Ð
Ð
Ð
50
12
12
Ð
118±120 OCF2Br
135±137 OCF2Cl
99±100 OCF2H
H
H
3
12
50
50
12
100
i
12
50
Ð
50
i
H
50
50
12
50
i
128±143 OCF2CF2Br
102±115 OCF2CF2H
H
Ð
H
50
100
i
100
Ð
90±94
Oil
Oil
SCF3
SOCF3
SO2CF3
CH3
CH3 CH3
CH3 CH3
i
Ð
50
i
100
i
Ð
a
See Table 1.
4b was used as standard in all tests performed; an
excellent agreement between the results of different
seasons (1993 to 1997) for the controls was observed.
The results of this test are shown in Table 6.
for sul®nylimines of type 3 are shown in Table 1.
Special tests 2.2.3 and 2.2.5 with the best compounds
3b±d showed 3c to be interesting enough (>80%
1
control at 12mg litre
or less throughout) to be
checked in semi-®eld trials (see Table 6), but
unfortunately it was not persistent. This type of
substitution was, therefore, deemed unsuitable for
further study.
3
RESULTS AND DISCUSSION
Different stages of several chewing insect pests of
particular relevance for the cotton and vegetable
markets were used for biological screening. For the
present analysis of structure-activity relationships, the
results for two insect pests were adequate: the tobacco
budworm, H. virescens, and the Egyptian cotton
leafworm, S. littoralis.
Biological screening at the discovery level consisted
of a three-stage procedure. After general screening
against a broad range of insect pests (results not
reported here), the activity limit for the active
compounds was determined against both S littoralis
and H virescens (tests 2.2.1, 2.2.2 and 2.2.4) and
thereafter, a selection of the best substances in the
above tests was examined in a further stage, which
included a special test against H virescens (test 2.2.3)
and a persistence test against S littoralis (test 2.2.5).
Compounds with excellent activity on all or most of
the above tests (generally giving >80% control at
12mg litre 1 or less) were selected for semi-®eld trials
against S littoralis on cotton in Egypt (test 2.2.6) to
determine their usefulness under subtropical ®eld
conditions.
The acyl hydrazones 4, 5 and 6 and the (thio)semi-
carbazones 8 and 9 were then examined. Compounds
4 showed interesting activity levels, as well as a broad
spectrum of action. Selected compounds and their
biological data are shown in Table 1. Compounds with
small R1 and R2 possess high levels of insecticidal
activity. Comparison of 4a and 4b shows that 4b is
more effective than 4a against the H virescens by a
factor of up to four, close relatives of 4a (R1=H; data
not shown) never surpassed the activity of compound
4a. The secondary tests 2.2.3 and 2.2.5 showed 4b to
be also very good (values of 12 or 3mg litre 1). In the
®eld (see Table 6) 4b demonstrated excellent persis-
tence (93% mortality after 12 days), whereas the
activity of 4a decayed after 6 days. These results
prompted us to concentrate on the series with
R1=alkyl.
Table 1 includes derivatives 4b±k selected from this
series. Compounds with R1 and R2 of chain length up
to C3 maintain activity against S littoralis, although a
larger R1 works well only when the group R2 is
hydrogen or methyl, and vice versa (compare 4f and 4g
with 4d). Much larger groups (as in 4e) are detri-
mental to biological activity. Nevertheless, excellent
activity against H virescens in the special test seems to
be limited to the smallest R groups (eg 4b, 4f, 4j).
Interestingly, it is possible to introduce a second
carbonyl group into the hydrazone moiety while
keeping good to excellent activity (see 4j and 4k).
The in¯uence of the substitution patterns of the
hydrazone part upon the insecticidal activity was ®rst
examined. Preliminary experiments had shown that
the tri¯ate group in 2 possesses an improved biological
activity in terms of both activity level and persistence
compared with compounds 1;4±6 hence (Fig 2) the
tri¯ate group was used as reference. Biological results
198
Pest Manag Sci 57:191±202 (2001)

Benzophenone hydrazone derivatives with insecticidal activity
Table 5. Structures and biological activitiesa of miscellaneous compounds 32
Heliothis
L1
Compound number
mp (°C)
W
Egg
L3
Spod
32a
157±158
b
b
32b
131±133
>100
>100
>100
50
32c
32d
155±160
121±122
b
b
b
b
32e
32f
136±138
158±164
b
b
b
b
b
b
32g
129±132
Ð
a
See Table 1.
b
Inactive in the preliminary screening.
Halogen-containing groups, even the smallest ones,
are nevertheless detrimental; groups such as CH2Cl or
COCF3 (data not shown) lead to very weak or inactive
compounds.
5d±e: Table 1) were similar in activity to compounds
4, except for 5a which was unexpectedly weak. The
oxalic esters were slightly better than the correspond-
ing oxalic amides (eg 5c and 5e). Ethyl esters were
much better than the methyl or isopropyl ones (data
not shown). Compound 5c, the best of this series, was
tested under semi-®eld conditions (see Table 6), but
showed insuf®cient persistence compared with that of
4b.
Compounds 4f and 4j were selected for semi-®eld
trials due to their excellent overall activity in the
special tests; compound 4c because of the results
against S littoralis and 4e to examine the effect of a
phenyl substituent. Results (see Table 6) show that
compound 4c possesses very good persistence, com-
parable to that of compound 4b. Compound 4e has no
persistence whatsoever, whereas compounds 4f and 4j
show intermediate behaviour. In the above tests,
compounds 4b and 4c were shown to be the best
compounds of the whole series.
Thiocarbonyl compounds 6 (Table 1) were much
weaker than the corresponding oxo compounds 4.
Only 6b was comparable in the glasshouse to 4a, but
its performance under ®eld conditions was poor (see
Table 6).
Semicarbazones
showed much weaker activity (Table 1), although in
8
and thiosemicarbazones
9
Oxalic acid derivatives 5 (esters 5a±c and amides
Pest Manag Sci 57:191±202 (2001)
199

M BoÈger et al
Table 6. Semi-field trials on cotton against Spodoptera
From the above results we concluded that the
simple acylation pattern in 4 led to the best results,
both in the glasshouse and under semi-®eld condi-
tions. We considered, henceforth, this substitution
pattern at the hydrazone part as the optimum one
within our experimental set, and then studied mod-
i®cations on the benzene rings.
littoralis L2
Mortality (%)
6 days
Compound a
0 days
12 days
3c
4a
4b
4c
4e
4f
4j
5c
6b
10a
11b
11c
60
100
100
100
80
0
88
100
96
28
81
85
53
25
86
2
Ð
17
93
72
Ð
25
53
16
Ð
43
Ð
0
First, we exchanged the chlorine atom in structure 4
(Fig 2) for other substituents, leaving the ring contain-
ing the tri¯ate group intact, as shown in compounds 7.
Table 3 shows the biological results of this work. Most
modi®cations were ineffective. The substituent must
be in the 4-position on the aromatic ring under
consideration, and then only halogens are allowed.
The only exception to the rule, as far as we know, is the
acetylenic substitution 7m, which gave an acceptable
level of activity, but in the special tests this compound
was weak.
97
100
90
59
100
45
96
49
a
1
At 200mg litre
.
Ð: not measured.
Second, the substitution pattern of the benzene ring
bearing the tri¯ate group was examined. Preliminary
experiments with 2-, 3- and 4-substituted derivatives
had shown that the 4-position of the tri¯ate group in
structure 4 is essential to reach any biological activity.
In the next step, we probed new types of subtitutions
for the tri¯ate group at the same position. Most
examples (eg CN, NO2, OCH2R, OSO2R, where
R=CN, CF3, SCN, CꢀC, etc) led to very weak or
inactive molecules (data not shown). Only perhaloalk-
oxysubstituents were suf®ciently effective to warrant
further investigation.
some cases, such as 8c, it was still acceptable. No clear
dependence of biological activity on the substitution
pattern for compounds 8 and 9 was be seen, excepted
when R2=H, where activity was reduced.
The corresponding reduced hydrazones 10 (Table
2) showed comparable biological activity and depen-
dence upon R1 and R2 to compounds 4 if R3 was
hydrogen; acylation at this position led to a much
decreased activity (see 10i) or even inactive com-
pounds (eg 10h). This suggests that compounds 10
may be pro-pesticides of the parent structures 4.
Possibly an air oxidation to the double bond is
involved. Substitution at R3 prevents this oxidation,
leading to inactive compounds. Partial hydrolysis of
this substituent in 10i would explain its biological
activity. Compound 10a, with excellent results against
both test insects, was tested under semi-®eld condi-
tions (see Table 6). It showed rather good persistence,
but did not reach the levels of compound 4b.
Table 4 lists the biological activity of selected
compounds 11 bearing perhaloalkoxy substituents. A
detailed account of the in¯uence of the substituents R1
and R2 as well as halogen substitution for chlorine
where Y=OCF3 and Y=OCF2Br upon the biological
activity has already been given,16 so that an overview of
representative Y-substitutions suf®ces. Small groups
R1 and R2 together with groups Y=OCF2Br and
Y=OCF2Cl gave the best results. The length of the
Table 7. Biological data for reference compounds 1 and 2
Heliothis a
Special tests a
Semi-®eld trials on cotton b
Compound
R1
R2
Egg L1
L3 Spod Spod 16d Heliothis 0 days 6 days 12 days
1a
1b
2
H
OC2H5
H
12
12
3
3
50
12
3
50
12
12
12
12
Ð
Ð
17
57
Ð
18
4
Ð
Ð
Ð
CH3
Ð
12 12
12 50
Ð
3
a
1
Concentration in mg litre at which 80% or more mortality was observed.
Compare Table 6.
b
200
Pest Manag Sci 57:191±202 (2001)

Benzophenone hydrazone derivatives with insecticidal activity
substituent Y was very important: C2-chains like
OCF2CF2Br (eg 11e) were much less active, as were
sulfur-containing groups (eg 11g±i). Shorter groups
must be perhalogenated, as shown by compound 11d
(OCF2H), with much reduced performance. Com-
pounds 11b and 11c, the best ones of the series, were
tested in semi-®eld trials (see Table 6), but their
performance was poor.
tions were also synthesised and tested; the results
obtained are consistent with the above conclusions. It
is also of interest to compare our compounds with
some representatives from previous work; biological
results for selected derivatives 1a (carbamate type) and
1b (substitution pattern as in 4b) from Boots'
Laboratories and compound 2 from Sumitomo are
shown for analysis in Table 7. Their performance is
clearly inferior to that of compounds 4. The main goal
of the present work, to establish structure-activity
relationships and to reach a much superior level of
biological activity, was therefore achieved.
Interestingly, it was possible to introduce an
additional substituent (3-Cl, 3-Br) a to the perhaloalk-
oxy group in type 11 while keeping the biological
activity in the normal tests (data not shown). Never-
theless, the results in the special tests were weak. This
combination of substituents, when applied to the
tri¯ate group, surprisingly gave only very weak to
inactive compounds. Double substitution (3,5-Cl2)
yielded inactive compounds.
From this study, compounds 4b and 4c represent
the best combinations and were, therefore, selected for
further studies.
Further work included naphthyl and heteroaromatic
substitution of both aromatic rings (miscellaneous
compounds 32; Table 5). Replacement of the 4-
chlorosubstituted benzene ring in the original struc-
ture 1 was particularly explored. As can be seen from
the table, only the 2-naphthyl substitution (32b)
showed slight activity; all other patterns led to inactive
compounds. Some other heteroaromatics, such as
pyridines, were also synthesised with different sub-
stitution patterns at the hydrazone part of the molecule
and hence are not included in Table 5, although all of
them were inactive. In particular, the complete lack of
biological activity for the thiophene derivative 32c is
very surprising. Compound 32g, its corresponding
heteroaromatic on the tri¯ate moiety, was also
inactive.
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