Synthetic studies of fluorine-containing compounds for household insecticides

Article abstract of DOI:10.1016/j.jfluchem.2007.07.016

The discovery stories of three fluorine-containing insecticides in our laboratory are described, i.e. amidoflumet, a new trifluoromethanesulfonanilide with high miticidal activity against various house dust mites, Metofluthrin, a potent new fluorinated pyrethroid with extremely high knockdown activity against various mosquitoes, and a new α-pyrone compound, 3-[1R-trans-(2-trifluoromethyl)cyclopropanecarbonyl]-4-hydroxy-6-methyl-2-pyrone with outstanding insecticidal activity against Blattella germanica.

Full text of DOI:10.1016/j.jfluchem.2007.07.016

Journal of Fluorine Chemistry 128 (2007) 1174–1181
www.elsevier.com/locate/fluor
Synthetic studies of fluorine-containing compounds
for household insecticides
a
a
b
a
Tatsuya Mori a, , Kazuya Ujihara , Osamu Matsumoto , Kazunori Yanagi , Noritada Matsuo
*
a Agricultural Chemicals Research Laboratory, Sumitomo Chemical Co. Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665-8555, Japan
b Genomic Science Laboratory, Dainippon Sumitomo Pharma Co. Ltd., 3-1-98 Kasugadenaka, Konohana, Osaka 554-0022, Japan
Received 12 July 2007; received in revised form 23 July 2007; accepted 30 July 2007
Available online 17 August 2007
Abstract
The discovery stories of three fluorine-containing insecticides in our laboratory are described, i.e. amidoflumet, a new trifluoromethane-
sulfonanilide with high miticidal activity against various house dust mites, Metofluthrin, a potent new fluorinated pyrethroid with extremely high
knockdown activity against various mosquitoes, and a new a-pyrone compound, 3-[1R-trans-(2-trifluoromethyl)cyclopropanecarbonyl]-4-
hydroxy-6-methyl-2-pyrone with outstanding insecticidal activity against Blattella germanica.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Fluorine; Pesticide; Insecticide; Amidoflumet; House dust mite; Metofluthrin; Mosquitoe; Pyrone; Cockroach
1. Introduction
asthma and atopic dermatitis [1]. In order to avoid these
illnesses, it is essential to remove these allergens. Phenyl
salicylate and benzyl benzoate have long been used to control
house dust mites. However their miticidal efficacy is
insufficient against predatory cheyletid mites which often
cause biting damage to humans. There is therefore an urgent
need for the development of a new effective miticide not only
to remove allergens but avoid a biting damage by cheyletid
mites in houses. We had previously found some trifluor-
omethanesulfonanilide compounds having high insecticidal
activity against houseflies and cockroaches [2]. Further
exploratory work in our laboratory resulted in the discovery
of trifluoromethanesulfonanilide derivatives 1–11 as shown in
Fig. 1 with high activity against house dust mites including
cheyletid mites [3].
It is well recognized that the ratio of fluorine-containing
pesticides is increasing along with the progress of fluorine
chemistry. In recent years, one third of new pesticides contains
fluorine atom(s). New synthetic methods and novel fluorinating
reagents have been developed that facilitate introduction of
fluorine or fluorine-containing units into many kinds of
compounds, and in many cases, they have remarkable
biological activity as well as physicochemical properties by
introduction of fluorine atom(s). In this paper, our recent studies
of fluorine-containing compounds for household insecticides in
our laboratory are described.
2. Results and discussion
The miticidal activity of compounds 1–11 against two
species of a house dust mite and one species of a cheyletid mite
was determined by a filter paper contact method. As shown in
Table 1, introduction of a halogen atom at the 4-position of the
benzene ring substantially increased the activity against house
dust mites. Introduction of other groups such as a nitro and a
trifluoromethyl group increased the activity against Tyrophagus
putrescentiae (Tp), but decreased the activity against Derma-
tophagoides farinae (Dp). An electron-donating methyl and a
methoxy group at the 4-position of the benzene ring slightly
decreased the miticidal activity.
2.1. Amidoflumet, a new trifluoromethanesulfonanilide
with high miticidal activity against various house dust
mites
House dust mites and their products are known to be major
household allergens to children and the elderly to cause
* Corresponding author. Tel.: +81 797 74 2035; fax: +81 797 74 2043.
E-mail address: morit7@sc.sumitomo-chem.co.jp (T. Mori).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.07.016

T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
1175
Fig. 3. Synthetic method of 4-substituted 2,3,5,6-tetrafluorobenzyl norchry-
santhemates.
Fig. 1. Synthetic method of 2-alkoxycarbonyltrifluoromethanesulfonanilides.
vapor action of the existing pyrethroids were unsatisfactory to
be used in non-heated formulations. Therefore, we started our
research to find a new pyrethroid with higher vapor action as
well as high activity against mosquitoes.
Ohno [5] and Elliott [6] independently reported insecticidal
norchrysanthemates in the 1970s. According to their reports,
these norchrysanthemates showed comparable insecticidal
activity to that of the corresponding chrysanthemates.
We directed our attention to the norchrysanthemates because
they had a higher vapor pressure and showed comparable
insecticidal activity to that of correspondong chrysanthemates.
We synthesized various 4-substituted 2,3,5,6-tetrafluorobenzyl
norchrysanthemates as shown in Fig. 3 and screened them by
the standard topical application method [7].
Fig. 2. Structure of amidoflumet.
With respect to the 2-position of the benzene ring, an lower
alkyl ester showed strong activity against Chelacarops moorei
(Cm). Compounds 1–7 completely controlled Dermatopha-
goides farinae (Df) and Tyrophagus putrescentiae (Tp), as well
as Chelacarops moorei (Cm).
Judging from these findings and the availability of the
starting materials, compound 1 (methyl 5-chloro-2-[(trifluor-
omethyl)sulfonyl]aminobenzoate) was selected and has been
developed as a new miticide (amidoflumet) for house dust mites
(Fig. 2) [4].
As a result of the screening, all analogs had much higher
activity against mosquitoes than compound 12 as shown in
Table 2. The relative toxicity reached the maximum with
between two and three carbon atoms 15 and 16 at the 4-
position. Unsaturation and incorporation of an oxygen atom
also showed substantial activity, inter alia, the 4-methox-
ymethyl derivative 19 exhibited the highest lethal potency,
being over twenty five times as active as d-allethrin against
Culex pipiens pallens.
It is conceivable that the trifluoromethanesulfonyl group
plays an important role in the high miticidal activity and
chemical stability in this compound.
2.2. Metofluthrin, a potent new fluorinated pyrethroid with
extremely high knockdown activity against various
mosquitoes
From these compounds, we selected compounds 14, 18 and
19, considering to their molecular weight, basic efficacy, ease
of synthesis and other physical and chemical properties, and
Much attention has recently been directed to the develop-
ment of non-heated formulations such as fan vaporizers because
of their increased safety and ease of use, especially during
outdoor activities. However, the insecticidal activity and/or the
Table 2
Insecticidal activity of 4-substituted-2,3,5,6-tetrafluorobenzyl norchrysanthe-
mates against Culex pipiens pallens
Table 1
Miticidal activity of 2-alkoxycarbonyltrifluoromethanesulfonanilides against
Dermatophagoides farinae (Df) and Tyrophagus putrescentiae (Tp)
No.
Compound
R1
Dosage (g/m2)–activity (%)
R2
d.f. 0.008 (g/m2)
Tp 0.08 (g/m2)
1
2
3
4
5
6
7
8
9
Cl
Me
Et
+++
+++
+++
+++
+++
+++
+++
+++*
–
+++
+++
+++
+++
+++
+++
+++
–
Compound
R
R.E.a
Cl
Cl
nPr
iPr
12
13
14
15
16
17
18
19
H
30
100
200
490
250
500
360
2500
100
Cl
F
Cl
tBu
Me
Me
Me
Me
Me
Me
Me
Br
Et
I
nPr
Me
NO2
OMe
CF3
allyl
OMe
CH2OMe
+++
–
10
11
+*
–
+++
d-allethrin
a
+++: 100% mortality, +: >90% mortality, +: 70–90% mortality, –: almost the
same as untreated sample *: 0.08 (g/m2).
Relative efficacy against Culexpipiens pallens based on LD50 by the topical
application method.

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T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
Table 3
Insecticidal activity of 4-substituted-2,3,5,6-tetrafluorobenzyl norchrysanthe-
mates in the non-heated formulation against Culex pipiens pallens
Compound
R
KT50 [min]a
KD%b
12
14
18
19
H
55
38
52
27
60
94
Me
OMe
CH2OMe
70
Fig. 5. Some natural products containing an a-pyrone skeleton isolated from
medicinal plants.
100
a
Time for 50% knockdown calculated by the probit method.
The average of knockdown mosquitoes after 60 min.
b
evaluated their vapor activities in a non-heated formulation.
Above all, the 4-methoxymethyl derivative 19 clearly showed a
significantly faster action in comparison with other compounds
in the non-heated formulation (Table 3).
As a result, [(2,3,5,6-tetrafluoro-4-methoxymethylphenyl)-
methyl (1R, 3R)-2,2-dimethyl-3-(1-propenyl)] cyclopropane-
carboxylate was selected as a new synthetic pyrethroid
(Metofluthrin) with high vapor activity against mosquitoes
(Fig. 4) [8].
Fig. 6. Synthetic method of 3-substitued a-pyrones.
It is conceivable that the four fluorine atoms on the benzene
ring play an important role in the high insecticidal activity and a
vapor action against mosquitoes in this compound.
Fig. 7. Insecticidal activity of 3-substituted a-pyrones.
2.3. A new a-pyrone compound, 3-[1R-trans-(2-
trifluoromethyl)cyclopropane carbonyl]-4-hydroxy-6-
methyl-2-pyrone with outstanding insecticidal activity
against Blattella germanica
Therefore, We synthesized various 3-[(trans-2-substituted)-
as
cyclopropyl]-carbonyl-4-hydroxy-6-methyl-2-pyrones
shown in Fig. 8 in order to fix the conformation of a butanoyl
group and tested their insecticidal activity.
The results are shown in Fig. 9. Introduction of one carbon
atom at the 2-position of the cyclopropane ring resulted in high
Many kinds of biologically active compounds containing an
a-pyrone skeleton such as 7,8-dihydro-5,6-dehydrokawain [9],
Yangonin [10] and Podoblastin B [11] were isolated from
medicinal plants (Fig. 5).
As a part of our research for a new pesticide, we directed our
next attention to a-pyrone compounds with expectation to find
a new insecticidal compound. We synthesized various 3-
substituted a-pyrones as shown in Fig. 6 and tested their
insecticidal activity by the standard topical application method
against Blattella germanica.
With respect to the length of the acyl group, the compound 22
having a butanoyl group showed the strongest activity against
Blattella germanica among alkanoyl groups as shown in Fig. 7.
Fig. 8. Synthetic method of 3-[(trans-2-substituted)-cycropropyl]-carbonyl-4-
hydroxy-6-methyl-2-pyrones.
Fig. 9. Insecticidal activity of 3-[(trans-2-substituted)-cyclopropyl]-carbonyl-
Fig. 4. Structure of Metofluthrin.
4-hydroxy-6-methyl-2-pyrones.

T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
1177
Fig. 10. Separation of compound 28 into each optical isomers (+)-Form 29 and
(ꢀ)-Form 30.
Fig. 12. Structure of (ꢀ)-Form 30.
Fig. 11. Absolute structure and ORTEP drawing of the crystalline compound 31.
insecticidal activity and the relative toxicity reached the
maximum with a trifluoromethyl derivative 28.
essential requirements for the position and the number of
fluorine in order to enhance biological activities.
Optical resolution of the compound 28 into each optical
isomer 29 and 30 by HPLC method was accomplished using the
chiral column (CHIRALPAK AD) as shown in Fig. 10, and
their insecticidal activity against Blattella germanica was
obtained.
A steady increase in the number of fluorinated new
pesticides and pharmaceutical drugs has been observed, and
the influence of fluorine on compounds in development in both
areas is also increasing. Further development of novel methods
of incorporating fluorine into organic molecules as well as
commercial availability of novel fluorine-containing building
blocks will continue to increase this number.
As a result, the more insecticidal isomer was found to be
(ꢀ)-Form 30 and showed outstanding insecticidal activity over
five times as active as permethrin, which is one of widely used
synthetic pyrethroids for the control of various cockroaches.
We could decide the absolute configuration of the (+)-Form 29
as shown in Fig. 11 by X-ray crystallographic analysis of the
ester 31 derived from (+)-Form 29.
Accordingly, we could decide the absolute structure of the
more insecticidal stereoisomer, (ꢀ)-Form 30 as having a 1R, 2R
configuration (Fig. 12).
4. Experimental
Melting point (mp) data were determined with Yanagimoto
micro melting point apparatus and are uncorrected. Refractive
indexes (nD) were determined with Atago refractive index
apparatus. NMR spectra were measured with a Hitachi R-24B
spectrometer (60 MHz), JEOL EX-300 spectrometer (300 MHz)
or JEOL AL400 spectrometer (400 MHz).
Although the mode of action of these a-pyrone compounds
is still unknown, we believe to find a more active compound
considering preferred comformation of the (ꢀ)-Form.
It is conceivable that the trifluoromethyl group on the
cyclopropane ring plays an important role in the high
insecticidal activity, lipophilicity and chemical stability in this
compound.
4.1. Methyl 5-chloro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 1
To a stirred solution of methyl 2-amino-5-chlorobenzoate
(3.8 g) and triethylamine (3.2 g) in dry chloroform (50 ml) was
added dropwise trifluoromethanesulfonic anhydride (8.7 g)
below 5 8C. After stirring at room temperature for 8 h, the
resulting mixture was poured into ice-cooled water and
extracted twice with chloroform. The organic layers were
combined, washed with water and then dried over anhydrous
sodium sulfate. Evaporation of the solvent gave a residue which
was chromatographed on silica gel with chloroform as the
3. Conclusion
In our discovery research of new insecticides in our
laboratory, the important effects of the fluorine atom(s) were
described. Further studies are necessary to clarify a role of
fluorine atom, and these should provide greater insight into the

1178
T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
eluent to give 1, 3.8 g, 58%; mp 80.7 8C; 1H NMR (250 MHz,
CDCl3): d3.99 (3H, s), 7.53 (1H, dd, J = 2.4, 9.1 Hz), 7.73 (1H,
4.8. Methyl 5-methyl-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 8
d, J = 9.1 Hz), 8.05 (1H, d, J = 2.4 Hz), 11.2 (1H, broad s). 19
F
NMR (376 MHz, C6F6): d85.6 (s, 3F); HRMS: calcd. for
C9H7O4NClF3S, 316.9736; found, 316.9737.
Compounds 2–11 were prepared in a similar manner.
33%; mp 57.8 8C; 1H NMR (400 MHz, CDCl3): d2.42 (3H,
s), 4.02 (3H, s), 7.39 (1H, d, J = 8.8 Hz), 7.67 (1H, d,
J = 8.8 Hz), 7.87 (1H,s), 11.1 (1H, broad s). 19F NMR
(376 MHz, C6F6): d85.7 (s, 3F); HRMS: calcd. for
C10H10O4NClF3S, 297.0282; found, 297.0291.
4.2. Ethyl 5-chloro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 2
4.9. Methyl 5-nitro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 9
58%; mp 65.7 8C; 1H NMR (60 MHz, CDCl3): d1.42 (3H, t,
J = 7.2 Hz), 4.42 (2H, q, J = 7.2 Hz), 7.42 (1H, dd, J = 2.2,
8.6 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.96 (1H, d, J = 2.2 Hz), 11.2
(1H, broad s). 19F NMR (376 MHz, C6F6): d85.6 (s, 3F).
20%; mp 89.5 8C; 1H NMR (400 MHz, CDCl3): d4.07 (3H,s),
7.97 (1H, d, J = 9.3 Hz), 8.44 (1H, d, J = 9.3 Hz), 8.98 (1H, s),
11.7 (1H, broad s). 19F NMR (376 MHz, C6F6): d85.5 (s, 3F).
4.3. n-Propyl 5-chloro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 3
4.10. Methyl 5-methoxy-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 10
62%; nD (25.5), 1.4898; 1H NMR (250 MHz, CDCl3):
d1.05(3H, m), 1.84 (2H, m), 4.35 (2H, m), 7.55 (1H, d,
J = 9.0 Hz), 7.72 (1H, dd, J = 2.0, 9.0 Hz), 8.03 (1H, d,
J = 2.0 Hz), 11.3 (1H, broad s). 19F NMR (376 MHz, C6F6):
d85.6 (s, 3F); HRMS: calcd. for C11H11O4NClF3S, 345.0049;
found, 345.0047.
32%; nD (26.0), 1.4921; 1H NMR (400 MHz, CDCl3): d3.85
(3H, s), 4.01 (3H, s), 7.15 (1H, dd, J = 2.9, 9.2 Hz), 7.54 (1H, d,
J = 2.9 Hz), 7.68 (1H, d, J = 9.2 Hz), 10.8 (1H, broad s). 19F
NMR (376 MHz, C6F6): d85.9 (s, 3F); HRMS: calcd. for
C10H10O5NF3S, 313.0232; found, 313.0244.
4.4. Isopropyl 5-chloro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 4
4.11. Methyl 5-trifluoromethyl-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 11
20%; mp 41.9 8C; 1H NMR (250 MHz, CDCl3): d1.42 (3H,
d,J = 6.2 Hz), 5.30 (1H, m), 7.52 (1H, dd, J = 2.5, 9.2 Hz), 7.73
(1H, d, J = 9.2 Hz), 8.02 (1H, d, J = 2.5 Hz), 11.2 (1H, broad s).
19F NMR (376 MHz, C6F6): d85.6 (s, 3F).
32%; nD (26.0), 1.4632; 1H NMR (400 MHz, CDCl3): d4.03
(3H, s), 7.83 (1H, d, J = 9.0 Hz), 7.95 (1H, d, J = 9.0 Hz), 8.35
(1H, s), 11.6 (1H, broad s); HRMS: calcd. for C10H7O4NF6S,
350.9999; found, 350.9994.
4.5. t-Butyl 5-chloro-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 5
4.12. Evaluation method of the miticidal activity of the test
compounds
14%; mp 87.6 8C; 1H NMR (400 MHz, CDCl3): d1.63 (9H,
s), 7.51 (1H, dd, J = 2.7, 9.0 Hz), 7.72 (1H, d, J = 9.0 Hz), 7.94
(1H, d, J = 2.7 Hz), 11.4 (1H, broad s). 19F NMR (376 MHz,
C6F6): d85.7 (s, 3F); HRMS: calcd. for C12H13O4NClF3S,
316.0206; found, 359.0220.
The miticidal activity against Dermatophagoides Farinae
(Df), Tyrophagus putrescentiae (Tp) and Chelacaropsis moorei
(Cm) was tested by the filter paper contact method. A test
solution (0.2 ml) diluted in acetone was applied to a filter paper
3.8 cm in diameter. The filter paper was placed in an aluminum
dish 4.0 cm in diameter. Sticky material was applied to the rim
of the dish to prevent the escape of the test mites. Twenty to
thirty mites were released on to the filter paper. The mites in the
dish were kept at 25 8C and 70 ꢁ 10% relative humidity, and
the number of dead mites was counted 24 h after the treatment.
Mortality (%) was calculated as follows:
4.6. Methyl 5-bromo-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 6
41%; mp 73.8 8C; 1H NMR (400 MHz, CDCl3): d4.01 (3H,
s), 7.68 (2H, s), 8.20 (1H, s), 11.2 (1H, broad s). 19F NMR
(376 MHz, C6F6): d85.6 (s, 3F); HRMS: calcd. for
C9H7O4NBrF3S, 360.9231; found, 360.9258.
Mortalityð%Þ ¼ No: of dead mites
ꢂ 100
Total no: of mites on the filter paper
4.7. Methyl 5-iodo-2-
[(trifluoromethyl)sulfonyl]aminobenzoate 7
4.13. (2,3,5,6-Tetrafluorophenyl)methyl (1R, 3R)-2,2-
dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate 12
34%; mp 61.2 8C; 1H NMR (400 MHz, CDCl3): d4.05 (3H,
s), 7.52 (1H, m), 7.84 (1H, m), 8.37 (1H, d, J = 2.2 Hz), 11.2
(1H, broad s). 19F NMR (376 MHz, C6F6): d85.6 (s, 3F);
HRMS: calcd. for C9H7O4NF3SI, 408.9093; found, 408.9115.
Diisopropyl azodicarboxylate (a 40% in toluene, 2.0 ml)
was added to a mixed solution of (1R, 3R)-2,2-dimethyl-3-[(Z)-

T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
1179
1-propenyl] cyclopropanecarboxylic acid (0.42 g), (2,3,5,6-
tetrafluorophenyl)methanol (0.49 g), triphenylphosphine
(376 MHz, C6F6): d17.5 (dd, 2F, J = 21.9, 12.8 Hz), 16.9 (dd,
2F, J = 21.9, 12.8 Hz).
(0.93 g) and tetrahydrofuran (20 ml). After 16 h, the reaction
solution was concentrated under reduced pressure, and the
resulting residue was subjected to silica gel column chromato-
graphy with hexane-ethyl acetate (20:1 by volume) as an eluant
to give 12 (0.80 g, 93%) as a colorless oil; 1H NMR (400 MHz,
CDCl3): d1.15 (3H, s), 1.29 (3H, s), 1.47 (1H, d, J = 5.3Hz),
1.70 (3H, dd, J = 6.9, 1.6 Hz), 2.19 (1H, br dd, J = 8.1, 5.3 Hz),
5.12 (1H, ddd, J = 10.6, 8.1, 1.6 Hz), 5.24 (1H, t, J = 1.6 Hz),
5.25 (1H, t, J = 1.6 Hz), 5.60 (1H, dqd, J = 10.6, 6.9, 1.1 Hz),
7.10 (1H, tt, J = 9.7, 7.4 Hz). 19F NMR (376 MHz, C6F6): d22.9
(m, 2F), 19.1 (m, 2F).
4.18. (4-Allyl-2,3,5,6-tetrafluorophenyl)methyl (1R, 3R)-
2,2-dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate
17
1H NMR (400 MHz, CDCl3): d1.13 (3H, s), 1.24 (3H, s),
1.48 (1H, d, J = 5.4 Hz), 1.68 (3H, dd, J = 6.6, 1.4 Hz), 2.03
(1H, br dd, J = 8.2, 5.4 Hz), 3.48 (2H, dt, J = 6.3, 1.3 Hz), 5.07-
5.24 (5H, m), 5.62 (1H, dq, J = 15.1, 6.5 Hz), 5.89 (1H, ddt,
J = 16.7, 10.3, 6.3 Hz).
Compounds 13–18 were prepared in a similar manner.
4.19. (2,3,5,6-Tetrafluoro-4-methoxylphenyl)methyl (1R,
3R)-2,2-dimethyl-3-[(Z)-1-propenyl]
cyclopropanecarboxylate 18
4.14. (2,3,4,5,6-Pentafluorophenyl)methyl (1R, 3R)-2,2-
dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate 13
1H NMR (400 MHz, CDCl3): d1.14 (3H, s), 1.28 (3H, s),
1.45 (1H, d, J = 5.4 Hz), 1.70 (3H, dd, J = 6.9, 1.7 Hz), 2.18
(1H, br dd, J = 8.4, 5.4 Hz), 4.10 (3H, t, J = 1.4 Hz), 5.11 (1H,
ddq, J = 10.5, 8.4, 1.7 Hz), 5.18 (1H, t, J = 1.6 Hz), 5.19 (1H, t,
J = 1.6 Hz), 5.60 (1H, dqd, J = 10.5, 7.1, 1.4 Hz). 19F NMR
(376 MHz, C6F6): d17.8 (dd, 2F, J = 20.2, 8.0 Hz), 3.7 (dd, 2F,
J = 20.2, 8.0 Hz).
1H NMR (400 MHz, CDCl3): d1.15 (3H, s), 1.28 (3H, s),
1.45 (1H, d, J = 5.4Hz), 1.70 (3H, dd, J = 6.8, 1.7 Hz), 2.18
(1H, br dd, J = 8.4, 5.4 Hz), 5.11 (1H, ddq, J = 10.6, 8.4,
1.7 Hz), 5.21 (1H, brs), 5.60 (1H, dqd, J = 10.6, 7.0, 1.2 Hz).
4.15. (2,3,5,6-Tetrafluoro-4-methylphenyl)methyl (1R, 3R)-
2,2-dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate
14
4.20. (2,3,5,6-Tetrafluoro-4-methoxymethylphenyl)methyl
(1R, 3R)-2,2-dimethyl-3-[(Z)-1-propenyl]
cyclopropanecarboxylate 19
1H NMR (400 MHz, CDCl3): d1.14 (3H, s), 1.28 (3H, s),
1.45 (1H, d, J = 5.3 Hz), 1.70 (3H, dd, J = 7.0, 1.7 Hz), 2.17
(1H, br dd, J = 8.4, 5.3 Hz), 2.28 (2H, t, J = 2.1 Hz), 5.11 (1H,
ddq, J = 10.7, 8.4, 1.7 Hz), 5.20 (1H, t, J = 1.5 Hz), 5.21 (1H, t,
J = 1.5 Hz), 5.59 (1H, dqd, J = 10.7, 7.0, 1.3 Hz). 19F NMR
(376 MHz, C6F6): d18.0 (dd, 2F, J = 22.1, 13.0 Hz), 17.3 (dd,
2F, J = 22.1, 13.0 Hz).
(1R, 3R)-2,2-dimethyl-3-[(Z)-1-propenyl] cyclopropanecar-
bonyl chloride (1.82 g) was added to a solution of (2,3,5,6-
tetrafluoro-4-methoxymethylphenyl)methanol (2.24 g) and
pyridine (0.87 g) in tetrahydrofuran (20 ml) under ice-cooling,
and the mixture was stirred for 8 h at room temperature. The
reaction mixture was poured into 100 ml of ice-cooled water
and extracted twice with 100 ml each of ethyl acetate. The
combined ethyl acetate extracts were washed with saturated
brine, dried over anhydrous sodium sulfate and concentrated
under reduced pressure to give a crude product, which was
subjected to silica gel column chromatography with hexane-
ethyl acetate (20:1 by volume) as an eluant to give 19 (3.17 g,
4.16. (4-Ethyl-2,3,5,6-tetrafluorophenyl)methyl (1R, 3R)-
2,2-dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate
15
1H NMR (400 MHz, CDCl3): d1.14 (3H, s), 1.23 (3H, t,
J = 7.6 Hz), 1.28 (3H, s), 1.46 (1H, d, J = 5.4 Hz), 1.70 (3H, dd,
J = 6.8, 1.7 Hz), 2.18 (1H, br dd, J = 8.4, 5.4 Hz), 2.77 (2H, q,
J = 7.6 Hz), 5.10 (1H, ddq, J = 10.7, 8.4, 1.7 Hz), 5.21 (1H, t,
J = 1.3 Hz), 5.22 (1H, t, J = 1.3 Hz), 5.59 (1H, dqd, J = 10.7,
6.8, 1.3 Hz). 19F NMR (376 MHz, C6F6): d17.6 (dd, 2F,
J = 21.9, 12.8 Hz), 16.0 (dd, 2F, J = 21.9, 12.8 Hz).
1
88%) as a colorless oil; H NMR (400 MHz, CDCl3): d1.15
(3H, s), 1.28 (3H, s), 1.46 (1H, d), 1.70 (3H, dd), 2.18 (1H, dd),
3.41 (3H, s), 4.59 (2H, s), 5.08–5.12 (1H, m), 5.24 (2H, s),
5.58–5.62 (1H, m). 19F NMR(376 MHz, C6F6): d18.8 (dd, 2F,
J = 22.1, 13.7 Hz), 18.2 (dd, 2F, J = 22.1, 13.7 Hz).
4.17. (2,3,5,6-Tetrafluoro-4-propylphenyl)methyl (1R, 3R)-
2,2-dimethyl-3-[(Z)-1-propenyl] cyclopropanecarboxylate
16
4.21. Evaluation method of the insecticidal activity of the
test compounds in non-heated formulations
A test compound (100 mg) was dissolved in 20 ml of acetone
and applied onto a sheet of filter paper (20 cm ꢂ 50 cm), the
acetone then being removed by air-drying. In the center of a
28 m3 test chamber (4.3 m ꢂ 2.65 m ꢂ 2.45 m height), the filter
paper was hung from the ceiling with the upper end of the filter
paper 1.7 m in height from the floor. Four nylon-net cages
(cylindrical, 30 cm in diameter and 20 cm in height) each
1H NMR (400 MHz, CDCl3): d0.97 (3H, t, J = 7.5 Hz), 1.13
(3H, s), 1.28 (3H, s), 1.46 (1H, d, J = 5.4 Hz), 1.64 (2H, sext,
J = 7.5 Hz), 1.70 (3H, dd, J = 6.8, 1.7 Hz), 2.18 (1H, dd,
J = 8.4, 5.4 Hz), 2.72 (2H, t, J = 7.5 Hz), 5.11 (1H, ddq,
J = 10.7, 8.4, 1.7 Hz), 5.21 (1H, t, J = 1.3 Hz), 5.22 (1H, t,
J = 1.3 Hz), 5.59 (1H, dqd, J = 10.7, 6.8, 1.3 Hz). 19F NMR

1180
T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
containing 20 female common house mosquitoes (Culex pipiens
pallens) were hung from the ceiling with the base of each cage
60 cm from the floor. One cage was placed in each corner of the
room, 60 cm horizontally from the filter paper. The number of
knocked down mosquitoes was counted at designed intervals for
60 min. In order to circulate air in the chamber, a fan was
positioned under the treated filter paper, and a board was placed
between the fan and the filter paper to prevent direct air flow
between the two.
product, which was subjected to silica gel column chromato-
graphy with hexane–ethyl acetate (10:1 by volume) as an eluant
to give 28 (0.18 g, 12%) as a colorless oil; 1H NMR (400 MHz,
CDCl3): d1.48 (2H, m), 2.30 (3H, s), 2.42 (1H, m), 4.00 (1H,
m), 5.96 (1H, s). 19F NMR (376 MHz, C6F6): d94.9 (d, 3F,
J = 6.1 Hz).
4.23. Separation of 3-(trans-2-trifluoromethyl-cyclopropyl
carbonyl)-4-hydroxy-6-methyl-2-pyrone 28 into each
optical isomer 29 and 30
Compounds 20–27 were prepared in a similar manner as
compound 28.
0.15 g of compound 28 was separated into each optical
isomer 29 {51 mg, [a]D24.0 = + 35.2 (C = 0.52,CHCl3)} and 30
{54 mg, [a]D24.0 = ꢀ34.0 (C = 0.52, CHCl3)} by HPLC
method using the chiral column (CHIRALPAK AD) with n-
hexane/ethanol/trifluoroacetic acid (90:10:0.1) as the moving
phase.
ꢃ 3-Methylcarbonyl-4-hydroxy-6-methyl-2-pyrone 20: 1H
NMR (400 MHz, CDCl3): d2.28 (3H, s), 2.67 (3H, s), 5.94
(1H, s).
1
ꢃ 3-Ethylcarbonyl-4-hydroxy-6-methyl-2-pyrone 21: H NMR
(400 MHz, CDCl3): d16 (3H, t, J = 8.0 Hz), 2.28 (3H, s), 3.12
(2H, q, J = 8.0 Hz), 5.94 (1H, s).
ꢃ 3-n-Propylcarbonyl-4-hydroxy-6-methyl-2-pyrone 22: 1H
NMR (400 MHz, CDCl3): d0.98 (3H, t, J = 8.0 Hz), 1.67
(2H, m), 2.25(3H, s), 3.10 (2H, m), 5.92 (1H, s).
ꢃ 3-n-Butylcarbonyl-4-hydroxy-6-methyl-2-pyrone 23: 1H
NMR (400 MHz, CDCl3): d0.95 (3H, t, J = 8.0 Hz), 1.42
(2H, m), 1.62 (2H, m), 2.27 (3H, s), 3.08 (2H, m), 5.93 (1H,
s).
ꢃ 3-Cyclopropylcarbonyl-4-hydroxy-6-methyl-2-pyrone 24: 1H
NMR (400 MHz, CDCl3): d1.18 (2H, m), 1.32 (2H, m), 2.27
(3H, s), 3.58 (1H, m), 5.92 (1H, s).
4.24. 3-(1S-trans-2-trifluoromethylcyclopropyl carbonyl)-
4-2S-(4-chlorophenyl)-3-methylbutyloxy-6-methyl-2-pyrone
31
2S-(4-chlorophenyl)-3-methylbutyloyl chloride (0.043 g)
was added to a solution of 3-(1S-trans-2-trifluoromethyl)cy-
clopropylcarbonyl-4-hydroxy-6-methyl-2-pyrone 29 (0.04 g)
and 1,8-diazabicyclo [5,4,0] undec-7-ene (0.028 g) in toluene
(4 ml) under ice-cooling, and the mixture was stirred for 4 h at
room temperature. The reaction mixture was poured into 10 ml
of 1% hydrochloric acid and extracted twice with 50 ml each of
ethyl acetate. The combined ethyl acetate extracts were washed
with saturated sodium bicarbonate, brine, dried over anhydrous
sodium sulfate and concentrated under reduced pressure to give
a crude product, which was subjected to silica gel column
chromatography with hexane-ethyl acetate (20:1 by volume) as
an eluant to give 31 (0.039 g, 56%) as a colorless crystal. Single
crystal of compound 31 was obtained by slow recrystallization
from hexane–ether. Crystal data of compound 31 were as
follows; C22H20O5F3Cl3, Mr = 456.84, monoclinic space group
ꢃ 3-(Trans-2-fluorocyclopropylcarbonyl)-4-hydroxy-6-methyl-
1
2-pyrone 25: H NMR (400 MHz, CDCl3): d1.56–1.65 (1H,
m), 1.66–1.78 (1H, m), 2.29 (3H, s), 4.04–4.16 (1H, m), 4.81-
5.03 (1H, m), 5.94 (1H, s). 19F NMR (376 MHz, C6F6):
d226.3 (m, 1F).
ꢃ 3-(Trans-2-methylcyclopropylcarbonyl)-4-hydroxy-6-
1
methyl-2-pyrone 26: H NMR (400 MHz, CDCl3): d0.99–
1.06 (1H, m), 1.22 (3H, d, J = 5.9 Hz), 1.49–1.56 (1H, m),
1.63–1.75 (1H, m), 2.26 (3H, s), 3.32–3.38 (1H, m), 5.90 (1H,
s).
´
´
˚
˚
˚
ꢃ 3-(Trans-2-difluoromethylcyclopropylcarbonyl)-4-hydroxy-
P21(#4), a = 11.906(5) A; b = 5.427(3) A; c = 17.817(8) A;
3
1
6-methyl-2-pyrone 27: H NMR (400 MHz, CDCl3): d1.38
b = 97.02(3)8; V = 1142.5(9) A ; Dcalc = 1.328 g/cm3; Zva-
˚
(1H, m), 1.46 (1H, m), 2.19 (1H, m), 2.23 (3H, s), 3.83 (1H,
m), 5.72 (1H, t, J = 42 Hz), 5.95 (1H, s). 19F NMR (376 MHz,
C6F6): d46.4 (ddd, 1F, J = 284.6, 56.8, 10.3 Hz), 45.1 (ddd,
1F, J = 284.6, 56.8, 10.3 Hz).
lue = 2; crystal size = 0.15 mm ꢂ 0.15 mm ꢂ 0.20 mm. A total
12381 reflections with 2u 2 1368were collected on a Rigaku
RAXIS-RAPID automated four-circle diffractometer using
˚
graphite monochromated Cu Ka radiation (1.54187 A).
Structure was solved by direct methods (SIR92) using 2218
unique reflections and refined by Full-matrix least-squares on F
program. Non-H atoms were assigned with anisotropic thermal
parameters. All H atoms were located in a difference Fourier
map and refined with the equivalent isotopic thermal
parameters to those for the bonded atoms. The final unweighted
R factor was 0.049 after minimized.
4.22. 3-(Trans-2-trifluoromethylcyclopropylcarbonyl)-4-
hydroxy-6-methyl-2-pyrone 28
Dicyclohexylcarbodiimide (1.23 g) was added to a solution
of 4-hydroxy-6-methyl-2-pyrone (0.75 g), trans-2-trifluoro-
methylcyclopropanecarboxylic acid (0.92 g) and 4-dimethyla-
minopyridine (0.15 g) in toluene (12 ml), and the mixture was
stirred for 3 h at room temperature and further stirred for 5 h at
100 8C. After cooling to room temperature, the reaction
mixture was subjected to filtration. The filtrate was washed
twice with toluene (10 ml ꢂ 2). The combined toluene solution
was concentrated under reduced pressure to give a crude
Acknowledgement
We thank Drs. M. Hatakoshi, Y. Shono, Y. Takada and Mr. T.
Iwasaki, Mrs. M. Sugano and Mr. H. Okamoto for their
contribution to the biological evaluations.

T. Mori et al. / Journal of Fluorine Chemistry 128 (2007) 1174–1181
1181
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