The discovery of bifenazate, a novel carbazate acaricide

Article abstract of DOI:10.2533/000942903777678533

A history of the discovery of the novel carbazate acaricide, bifenazate, is outlined. When a novel ortho-biphenyl substituted hydrazide compound showed acaricidal activity in the pesticide discovery screen, a small number of analogs were made to confirm and explore acaricidal effects. An ortho-biphenylcarbazate analog gave significantly greater acaricidal activity. Thereafter, several hundred structurally-diverse biphenylsubstituted carbazate analogs were synthesized and evaluated in a bioassay with the two-spotted spider mite (Tetranychus urticae Koch) in order to optimize the acaricidal activity. As a result of the optimization process, bifenazate, the analog with a methoxybiphenyl substituent to the terminal nitrogen atom of isopropyl carbazate, was selected for development and registration.

Full text of DOI:10.2533/000942903777678533

CROP PROTECTION RESEARCH
702
CHIMIA 2003, 57, No.11
Chimia 57 (2003) 702–704
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
The Discovery of Bifenazate, a Novel
Carbazate Acaricide
Mark A. Dekeyser*, Paul T. McDonalda, and Gilbert W. Angle, Jr.a
Abstract: A history of the discovery of the novel carbazate acaricide, bifenazate, is outlined. When a novel
ortho-biphenyl substituted hydrazide compound showed acaricidal activity in the pesticide discovery screen,
a small number of analogs were made to confirm and explore acaricidal effects. An ortho-biphenylcarbazate
analog gave significantly greater acaricidal activity. Thereafter, several hundred structurally-diverse biphenyl-
substituted carbazate analogs were synthesized and evaluated in a bioassay with the two-spotted spider
mite (Tetranychus urticae Koch) in order to optimize the acaricidal activity. As a result of the optimization
process, bifenazate, the analog with a methoxybiphenyl substituent to the terminal nitrogen atom of isopropyl
carbazate, was selected for development and registration.
Keywords: Acaricide · Bifenazate · Carbazate · Discovery
Introduction
with novel chemistries are highly toxic to
phytophagous mites but have a wide margin
The two-spotted spider mite, Tetranychus of safety to non-target beneficial organ-
urticae Koch, is one of the most important isms. Such acaricides are favored by regu-
pest species in agricultural and ornamental latory agencies and are also highly recom-
crops worldwide [1]. Control of mites is a mended by pest control advisors, modern
continual struggle because they possess the growers and consumers. Acaricide discov-
capacity to rapidly develop resistance to ery, which relies heavily on serendipity in
acaricides due to their high reproductive the traditional screening approaches main-
potential and their short life cycles. The re- ly conducted by agrochemical companies,
liance upon only a few effective acaricides has brought to the market a diverse range of
has increased the likelihood of acaricide re- chemical classes, often directed against
sistance problems. In several crops, both in- novel biochemical and physiological tar-
tegrated pest-management programs (IPM) gets [2]. The best of these have minimal ef-
with beneficials and judicious use of acari- fects on humans and the environment and
cides to avoid resistance are practiced. An are compatible with IPM for the crop sys-
acaricide sub-group of the Insecticide Re- tems in which they are used.
H
N
O
CH3
CH3
N
H
C
O
OCH3
bifenazate
Fig.1. Structure of bifenazate
Discovery of the Lead Compound
sistanceAction Committee (IRAC) also ad-
Bifenazate (Fig. 1) is a new type of aca-
dresses issues related to the optimal use of ricide belonging to the carbazate class.
Crompton research on acaricidal car-
acaricide products. Selective acaricides From among several hundred carbazate bazates was initiated in 1990 when fungi-
derivatives synthesized and evaluated for cidal phenylhydrazide compounds were
acaricidal activity in the early 1990s, discovered to have some acaricidal activity
the methoxybiphenyl-substituted carbazate in the pesticide discovery screen. An ortho-
(bifenazate) was selected for development biphenyl-substituted hydrazide 1 (Fig. 2)
[3]. In the USA, bifenazate was first ap- possessed a modest level of acaricidal ac-
proved and registered as a reduced-risk aca- tivity (90% control of mites at 500 ppm).
ricide for the ornamental market and soon The activity of this compound was interest-
*Correspondence: Dr. M.A. Dekeyser
Research Laboratories
Crompton Co./Cie
thereafter for crops such as apples, pears, ing because several phenylhydrazide com-
peaches, plums, grapes, cotton, strawber- pounds previously evaluated in the mite
ries, and hops. Bifenazate is now under screen had not shown activity. We speculat-
worldwide development for the selective ed that, in this case, the acaricidal activity
control of spider mites in both agricultural was due to the presence of the ortho-
and ornamental markets and is sold under biphenyl group. Furthermore, our earlier
the trade names ‘Floramite’, ‘Acramite’, experience in screening oxadiazinone com-
and ‘Mitekohne’. This report outlines a pounds had indicated that ortho-biphenyl
120 Huron Street
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Tel: +0 1 519 822 3790
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E-Mail: mark.dekeyser@cromptoncorp.com
aNew Product Research
Crompton Corp
74 Amity Road
Bethany, CT, USA 06524-3402
short history of its discovery.
substitution on a nitrogen atom in the ring

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
i
O
H
N
H
N
R
NH2
N
H
O
O
O
H
N
H
N
C(CH3)3
N
H
C(CH3)3
N
H
O
3
4
O
i: ClCO2R, pyridine, ethyl acetate
R = alkyl
H
N
R
O
1
2
N
H
Fig. 2. Early hydrazide and carbazate hits
Scheme 1. Synthesis of ortho-biphenylcarba-
5
zates
Fig. 3. meta-Biphenylcarbazates
system enhanced activity [4]. Therefore, we oriented para to the pendant phenyl group in intermediate 8 was reduced to an amino
synthesized and evaluated a few structural- as shown in Scheme 2. Two approaches group by tin chloride [8] and the resulting
ly-diverse ortho-biphenyl-substituted hy- were taken in preparing substituted meta- substituted meta-biphenylamine was con-
drazine derivatives.
biphenylcarbazates 9. In the first, we dis- verted into the carbazate 9 using the
placed the bromine atom in the commer- methods described for ortho-biphenylcar-
cially available compound 6 with the sodi- bazates. The structure–activity relation-
um salts of alkyl thiols or alkyl sulfinic ships for substituted meta-biphenylcar-
acids, generating intermediates of the type bazates are summarized in Fig. 4. Several
ortho-Biphenylcarbazate Analogs
The ortho-biphenylcarbazate analog 2 8 in which X = S or SO2 and R1 = alkyl. In carbazates of type 9 were more efficacious
(Fig. 2), corresponding to the initial active the second, we alkylated the commercially than the most active carbazates of type 4 or
ortho-biphenylhydrazide 1, gave signifi- available phenol 7 with alkyl halides, 5. The most potent carbazates of type 9
cantly greater acaricidal activity (96% con- generating intermediates of type 8 in which were those with X = O, R = isopropyl, sec-
trol of mites at 100 ppm). Phenylcarbazates X = O and R1 = alkyl. Next, the nitro group butyl or tert-butyl and R1 = methyl, ethyl or
were reported to possess fungicidal activity
[5] but biphenylcarbazates were not de-
scribed in the literature. The improved
level of mite control demonstrated by the
ortho-biphenylcarbazate analog 2 depend-
ed on the presence of its biphenyl moiety.
Therefore we synthesized and tested a
i
ii
variety of alkyl ortho-biphenylcarbazates.
Alkyl ortho-biphenylcarbazates of the type
4 were synthesized by reaction of ortho-
biphenylhydrazine 3, readily prepared from
commercially available ortho-biphenyl-
amine by diazotization followed by SnCl2
reduction, with alkyl chloroformates
(Scheme 1) [6]. Optimal activity (80–100%
control of mites at 100 ppm) in this series
was obtained when the ester function con-
sisted of a straight- or branched-chain alkyl
group of three or four carbon atoms.
NO2
NO2
NO2
Br
OH
X-R1
8
6
7
iii, iv, v, vi
meta-Biphenylcarbazate Analogs
H
N
O
N
R
Isomeric alkyl meta-biphenylcar-
bazates 5 (Fig. 3) were synthesized from
meta-biphenylhydrazine in a similar way to
that for the ortho-biphenylcarbazates [7].
The acaricidal activities of alkyl meta-
biphenylcarbazates paralleled their ortho-
biphenyl-substituted counterparts with op-
timal acaricidal control of 80-100% at 100
ppm when the ester function consisted of
three or four carbon length alkyl groups.
Additional modifications of the meta-
biphenylcarbazate structure were explored
by introducing different substituents
H
X-R1
O
9
i: NaXR1, methanol; ii: alkyl halide, K2CO3; iii: SnCl2, ethyl acetate;
iv: NaNO2, HCl; v: SnCl2; vi: ClCO2R, pyridine, ethyl acetate
R,R1 = alkyl; X = O, S, SO2
Scheme 2. Synthesis of substituted meta-biphenylcarbazates

CROP PROTECTION RESEARCH
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CHIMIA 2003, 57, No.11
fluoroethyl. The best activity (100% con-
trol of mites at 25 ppm) was observed for
the compound in which X = O, R = iso-
propyl and R1 = methyl. By way of com-
parison to a commercial acaricide in the
bioassay testing, this compound was five
times as active as propargite and warranted
development for the acaricide market. This
compound became known as bifenazate.
H
N
O
N
H
R
X-R1
O
9
X = O > S > SO2
Biphenyldiazene Analogs
R1 = CH3 > C2H5 > CH2CH2F > CH2C6H5 > CH(CH3)2
Attention also focused on modifying the
carbazate moiety by derivatization. One
type of derivative that was prepared was the
biphenyldiazene type 10 (Fig. 5). Biphenyl-
diazene analogs were synthesized by the
method of Gaviraghi et al. [9], which in-
volved a palladium-catalyzed oxidation of
carbazates to diazenes. The acaricidal ac-
tivities of the diazenes 10 were parallel to
the corresponding carbazates from which
they were made [10][11]. The best activity
(100% control of mites at 25 ppm) was ob-
served for the compound in which R = iso-
propyl, R1 = phenyl and R2 = methoxy.
Although the activity of this compound was
comparable to bifenazate, the compound
was not as cost-effective.
R = CH(CH3)2 > CH(CH3)C2H5 > C(CH3)3 > CH3 > CH2C6H5
Fig. 4. Structure–activity relationships in substituted meta-biphenylcarbazates
R1
R1
H
O
N
N
O
R
N
R
O
N
O
R2
R2
COCF3
11
10
R = alkyl
R1 = H, C6H5
R = alkyl
Trifluoroacetylcarbazate Analogs
R1 = H, C6H5
We also investigated modification of
the biphenylcarbazates wherein a trifluoro-
acetyl group resided on one of the carba-
zate nitrogens (Fig. 6). Trifluoroacetylcar-
R2 = H, C6H5, OR, SR, SO2R
R2 = H, C6H5, OR, SR, SO2R
bazates 11 were prepared from the corre- Fig. 5. Biphenyldiazenes
sponding carbazates by reaction with
trifluoroacetic anhydride [7]. The acarici-
dal activities of the trifluoroacetylcar-
bazates were generally parallel to those of
the carbazates from which they were made.
The best activity (100% control of mites at
Fig. 6. Trifluoroacetylcarbazates
[9] G. Gaviraghi, M. Pinza, G. Pifferi, Syn-
thesis 1981, 8, 608.
[10] M.A. Dekeyser, P.T. McDonald (Uniroy-
al), US 5438123, 1995.
[11] M.A. Dekeyser, P.T. McDonald, G.W.
Angle Jr., J. Ag. Food Chem. 1995, 43,
1705.
[1] H.R. Boland, ‘World Catalogue of the Spi-
der Mite Family (Acari: Tetranychidae)’,
Eds. H.R. Boland, J. Gutierrez, C.H.W.
Flechtmann, Koninklijke Brill, NV, Lei-
den, 1998.
25 ppm) was observed for the compound in
which R = isopropyl, R1 = phenyl and R2 =
methoxy. However, this compound did not
perform as well as bifenazate under field
conditions.
[2] M.A. Dekeyser, R.G.H. Downer, Pestic.
Sci. 1994, 40, 85.
[3] M.A. Dekeyser, P.T. McDonald, G.W.
Angle Jr., R.C. Moore, Proc. Brighton
Crop Prot. Conf.- Pests Dis. 1996, 2, 487.
[4] M.A. Dekeyser, D.M. Borth, R.C. Moore,
A. Mishra, J. Ag. Food Chem. 1991, 39,
374.
[5] P.E. Frohberger, E. Urbschat, D. Mayer, K.
Sasso (Bayer AG), DE 2223936, 1973.
[6] M.A. Dekeyser, P.T. McDonald, G.W.
Angle Jr., J. Ag. Food Chem. 1994, 42,
1358.
Conclusions
The observation that an ortho-biphenyl
substitution imparted acaricidal activity in
a hydrazide structure was exploited through
synthesis of a variety of biphenylcarbazates
and their diazene and trifluoroacetyl deriv-
atives. Our optimization program led to
identification of the first carbazate acari-
cide bifenazate.
[7] M.A. Dekeyser, P.T. McDonald (Uniroy-
al), US 5367093, 1994.
[8] F. Bellamy, K. Ou, Tetrahedron Lett. 1984,
25, 839.
Received: September 15, 2003