The design and synthesis of β-trifluoromethylenol phosphates as potential insecticides

Article abstract of DOI:10.1002/hc.10147

A new group of compounds, β-trifluoromethylenol phosphates [(RO)₂P(O)OCR=CHCF₃], has been designed and prepared by several methods. Some of them showed good insecticidal activities. In the molecular structure, the designed leaving group can rearrange to a powerful electrophilic agent, β,β-difluorovinyl ketone, which would be a potential enzyme inhibitor.

Full text of DOI:10.1002/hc.10147

Heteroatom Chemistry
Volume 14, Number 4, 2003
The Design and Synthesis
of β-Trifluoromethylenol Phosphates
as Potential Insecticides
Yixiang Ding and Xiaogen Huang
The Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
200032 Shanghai, People’s Republic of China
Received 19 November 2002
and inhibit the action of cholinesterase, although in
ABSTRACT: A new group of compounds, ꢀ-trifluoro-
some instances the inhibition of other vital enzyme
methylenol phosphates [(RO)2P(O)OCR CHCF3],
is believed to be involved.
has been designed and prepared by several meth-
It has been demonstrated that their toxic
ods. Some of them showed good insecticidal activ-
action is the result of progressive inhibition of
ities. In the molecular structure, the designed leav-
cholinesterase in mammals and insects. The com-
ing group can rearrange to a powerful electrophilic
plete chemical and physical structure of the enzyme
agent, ꢀ,ꢀ-difluorovinyl ketone, which would be a
AChE is still not known. The enzyme has two known
ꢀ
C
potential enzyme inhibitor.
2003 Wiley Periodicals,
active sites [1], one is the esteratic site because
it attracts ester groups to it; the other is anionic
or negative site because it attracts a cation (or
an electrically positive section of a compound).
Present theory [2] poisoning proposes that an
organophosphorus molecule (an ester) forms an
intimate complex with AChE, then the serine-OH of
AChE is phosphorylated. Thus, AChE cannot split
acetylcholine due to the stability of its phosphory-
lated derivative and is inhibited. The results may
probably be considered as indicating that when
other condition (especially the steric ones) are sim-
ilar the inhibitory power depends essentially on the
phosphorylating power. Organophosphorus insecti-
cides with the following general structure (RO)2P(O
or S)X are often designed to have a good leaving
group X for increasing its phosphorylating power.
Crop protection continually needs the discov-
ery of novel insecticides, particularly, those acting
via novel modes of action. Recently, Widlauski [3]
reported the synthesis of enol phosphates having
leaving group at the 1-position that are mechanism-
based phosphatase or phosphodiesterase inhibitors.
On the basis of this idea, we designed a new group of
Inc. Heteroatom Chem 14:304–308, 2003; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.10147
INTRODUCTION
Enol phosphates are a class of important organic
compounds. For example, phosphenol pyruvate
(PEP) is a well known as high-energy species that
play a vital role in a number of biological processes.
Further efforts have been made in the preparation
of bioactive enol phosphates. As pesticide, they are
a kind of very potent insecticide that has wide field
of application. Despite their diverse structure, they
own their activity to their capacity to phosphorylate
Correspondence to: Yixiang Ding; e-mail:dingyx@pub.sioc.ac.cn.
Present address of Xiaogen Huang: Institute of Organic Chem-
istry, BCH, CH-1015 Lausanne-Dorigny, Switzerland.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 29772047.
c
ꢀ
2003 Wiley Periodicals, Inc.
304

Design and Synthesis of ꢀ-Trifluoromethylenol Phosphates 305
insecticide, ꢀ-trifluoromethylenol phosphates. Dur-
ing the course of the phosphorylation of the serine-
OH of AChE (or hydrolysis by phosphatase), this
compound can give rise to an intermediate that
would undergo a rapid chemical rearrangement to a
highly reactive compound, ꢀ,ꢀ-difluorovinyl ketone,
which is a powerful electrophilic agent to other nu-
cleophilic residues of enzyme. That is, the leaving
group X would also be a potential enzyme inhibitor.
ß-Bromoenol phosphates 1a–f were prepared by
Perkow reaction [5] of trialkyl phosphite with 1-aryl-
2,2-dibromo-ethanones which were obtained from
bromination of the corresponding 1-aryl-ethanones
[6]. 1a–f were mixtures of Z and E isomers in
which the Z isomer predominated. ß-Bromoenol
phosphates are also prepared from Atherton–Todd
reaction [7]. The separation of pure E isomer failed.
In the presence of CuI, 1a–f reacted with
FO2SCF2CO2Me in DMF at 80◦C to give 1-aryl-3,3,3-
trifluoro-1-propenyl phosphates (method A) in low
yield. Trifluoromethylation maintains configuration
[8], trifluoromethylenol phosphates made from Z-ß-
bromoenol phosphates are also Z-isomers. The E and
Z configurations of all enol phosphates were deter-
mined using the Tobey–Pascual substituent shielding
constant method [9] and NOE observation in NMR.
The study in details proved that the cleavage of
O P in trifluoromethylenol phosphates by the at-
tack of fluoride ion led to the loss of the phosphoryl
group to form trifluoromethyl ketones. If the reac-
tion time was prolonged only trifluoromethylketones
were formed [10].
Because of the poor yield of above method,
Wittig-type reactions [11,12] that were tried
(Scheme 2), but the yields were not improved.
RESULTS AND DISCUSSION
Synthesis
We attempted to prepare ꢀ-trifluoromethylenol
phosphates from the phosphorylation of the eno-
lates of ꢁ-trifluoromethylated ketones. But the ex-
periments showed that the ꢁ-trifluoromethylated ke-
tones could not be formed by the reaction of ꢁ-bromo
or ꢁ-iodoketones with trifluoromethylating agent
FO2SCF2CO2Me under the conditions described in
the literature [4]. Enol phosphates are versatile inter-
mediates in organic synthesis. They can be thought
of as an active form of ketones. So we imagined
that ꢀ-haloenol phosphates may be more reactive
substrates than ꢁ-haloketones in trifluoromethyla-
tion. In this paper ꢀ-trifluoromethylenol phosphates
2 have been synthesized from the reaction of ꢀ-
bromoenol phosphates 1 with FO2SCF2CO2Me, as
outlined in Scheme 1.
Insecticidal Activity
The compounds were screened for their insecticidal
activity against Mythimna separata (Walker), Aphis
laburni (Kaltenback), and Tetranychus cirinabari-
nus (Boisduval). Two of the synthesized compounds
showed significant insecticidal activities. At concen-
tration of 500 ppm/insect, compound 2a showed a
broad spectrum of insecticidal activity: 77% mortal-
ity against Mythimna separata, 75% mortality against
Aphis laburni, and 67% mortality against Tetranychus
cirinabarinus. Compound 2d showed specific insec-
ticidal activity: 100% mortality against Aphis laburni,
only 8% mortality against Tetranychus cirinabari-
nus, and no insecticidal activity against Mythimna
SCHEME 1 Method A.
SCHEME 2 Methods B and C.

306 Ding and Huang
separata. All other compounds showed lower activ-
ity and did not show any activity against Mythimna
separata particularly. The examination of the true in-
secticidal mechanism is in progress.
Dimethyl 1- ( 4 -chlorophenyl ) -2- bromoethenyl
phosphate 1e [13]: H NMR (CCl4, 90 MHz): 7.38
1
(m, 4H); 6.20 (s, 1H); 3.76 (d, J = 10 Hz, 6H).
Dimethyl 1-(3,4-dichlorophenyl)-2-bromoethenyl
phosphate 1f: oil, yield 75%. 1H NMR (CDCl3,
90 MHz): 7.52 (m, 3H); 6.30 (d, J = 2 Hz, 1H); 3.80
(d, J = 10 Hz, 6H). 31P NMR: −4.170. IR (film): 3080,
1618, 1554, 1475, 1390, 1300, 1045, 933; EI-MS: 374
(M+, 4.11), 294 (100.00), 250 (2.99), 235 (41.35),
127 (2.74), 109 (53.40), 93 (10.10). Anal. calcd. for
C10H10BrCl2O4P: C 31.94, H 2.68; Found: C 32.63, H
2.65.
EXPERIMENTAL
Instrumentation
All melting points were uncorrected. IR spectra were
measured with a Y-Zoom CURSOR spectrometer.
1H NMR spectra were recorded on FX-90Q spec-
trometer using TMS as internal standard. 31P NMR
were recorded on an AM-300 spectrometer at
161.97 MHz using CDCl3 as solvent and 85% of
H3PO4 as external standard. 19F NMR spectra were
recorded on an EM-360L spectrometer at 56.4 MHz
using TFA as the external standard with positive
for upfield shifts. Mass spectra were taken on a
Finnigan-4021 spectrometer and HR-MS spectra
on a Finnigan MAT8430 spectrometer. Elemental
analyses were done by the Elemental Analyses Group
of SIOC.
Dimethyl 1-(dimethoxyphosphinyl)-1-(p-chloro-
phenyl)methyl phosphate was prepared from the
reaction of 4-chlorobenzoylphosphonate with
dimethyl phosphite according to the reference
1
method [14]. H NMR (CDCl3, 90 MHz): 7.46 (m,
4H); 5.60 (d–d, J1 = 12 Hz, J2 = 9 Hz, 1H); 3.80
(m, 12H). EI-MS: 358 (M+, 2.95), 248 (100.00), 232
(12.07), 218 (10.86), 187 (10.71), 139 (14.03), 109
(77.92).
PREPARATION OF
ꢀ-TRIFLUOROMETHYLENOL PHOSPHATES
Material
ß-Bromoenol phosphates 1a–f were prepared by
Perkow reaction [13] of trialkyl phosphite with 1-
aryl-2,2-dibromo-ethanones [6] with purity of >95%
(GC). The known compounds were identified in
agreement with the literature data, and only the
NMR data are reported here.
Dimethyl 1-(4-methoxylphenyl)-2-bromoethenyl
phosphate 1a: oil, yield 80%. 1H NMR (CCl4,
90 MHz): 6.77–7.67 (m, 4H); 6.40 (s, 0.38 HE); 6.00
(s, 0.62 Hz); 3.73 (d, J = 10 Hz, 6H); 3.80 (s, 3H).
31P NMR: −4.1713, −3.5413. IR (film): 3093, 2959,
1608, 1513, 1285, 1256, 1182, 1039. EI-MS: 336 (M+,
6.76), 257 (100.00), 229 (9.85), 199 (5.07), 132 (7.95),
109 (42.62), 93 (21.73). Anal. calcd. for C11H14BrO5P:
C 39.18, H 4.19; Found: C 38.97, H 4.25.
Dimethyl 1-( 4-methylphenyl )-2 - bromoethenyl
phosphate 1b: oil, yield 82%. 1H NMR (CCl4, 90
MHz): 7.20 (m, 4H); 6.38 (m, 0.2HE); 6.08 (s,
0.8 Hz); 3.74 (d, J = 10 Hz, 6H); 2.38 (s, 3H). 31P
NMR: −4.2095, −3.5928. IR (film): 3105, 2959, 1625,
1509, 1299, 1180, 1048, 906. EI-MS: 320 (M+, 10.96),
241 (100.00), 219 (3.85), 195 (2.56), 127 (5.20), 109
(9.48), 93 (4.25). Anal. calcd. for C11H14BrO4P: C
41.14, H 4.40; Found: C 40.87, H 4.34.
Method A:
A
mixture of 1a–f (1 mmol),
FO2SCF2CO2Me (1.5 mmol), CuI (1.5 mmol),
and DMF (5 ml) was stirred at 80◦C for 3 h under
a nitrogen atmosphere. Then the reaction mix-
ture was cooled, filtered, poured into water and
extracted with diethyl ether. The organic extract
was combined, washed with brine and dried over
anhydrous Na2SO4. After removal of the solvent,
the crude product was purified by flash column
chromatography using a mixture of petroleum ether
(bp 60–90◦C) and ethyl acetate (20–25:1) to give
2a–f.
Dimethyl 1-(4-methoxylphenyl)-2-trifluoroethenyl
phosphate 2a: oil, yield 11%. 1H NMR (CCl4, 90 MHz):
7.45 (d, J = 7 Hz, 2H); 6.85 (d, J = 7 Hz, 2H); 5.44
(q, J = 6 Hz, 1H); 3.73 (m, 9H). 19F NMR (CCl4):
−20.5 (d, J = 6 Hz). 31P NMR:−4.917. EI-MS: 326
(M+, 10.20), 306 (3.93), 243 (30.19), 214 (16.79), 200
(100.00), 181 (22.75), 109 (18.80): IR (film): 3080,
2964, 1669, 1610, 1516, 1338, 1135, 1039, 929. Anal.
calcd. for C12H14F3O5P: C 44.18, H 4.33; Found: C
43.71, H 4.48.
Dimethyl 1-(4-methylphenyl)-2-trifluoroethenyl
phosphate 2b: oil, yield 16.2%. 1H NMR (CCl4,
90 MHz): 6.50 (d, J = 7 Hz, 2H); 6.25 (d, J = 7 Hz,
2H); 5.60 (q, J = 7 Hz, 1H); 3.75 (d, J = 12 Hz, 6H);
2.42 (s, 3H). 19F NMR (CCl4): −20.2 (d, J = 7 Hz).
31P NMR: −4.963. EI-MS: 310 (M+, 38.60), 291
(100.00), 241 (25.48), 198 (5.03), 184 (9.63), 165
(12.04), 127 (22.77). IR (film): 2964, 1671, 1453,
Dimethyl 1-phenyl-2-bromoethenyl phosphate 1c
[9]: 1H NMR (CCl4, 90 MHz): 7.40 (m, 5H); 6.20 (m,
1H); 3.75 (d, J = 10 Hz, 6H).
Diethyl 1-phenyl-2-bromoethenyl phosphate 1d
1
[13]: H NMR (CCl4, 90 MHz): 7.36 (m, 5H); 6.20
(M, 1H); 4.07 (m, 4H); 1.22 (t, 6H).

Design and Synthesis of ꢀ-Trifluoromethylenol Phosphates 307
(d, J = 12 Hz, 6H); 1.80 (s, 3H). 19F NMR (CDCl3):
−17.00. 31P NMR: −4.610. EI-MS: 344 (M+, 5.89),
323 (5.66), 288 (6.88), 218 (46.23), 183 (100.00), 149
(23.14), 127 (13.28). IR (film): 2963, 1680, 1597,
1493, 1336, 1267, 1133, 1060, 891. HR-MS: 344.0179
(M+: C12H13ClF3O4P, calcd. 344.0192).
1336, 1282, 1127, 1039, 1017, 929. HR-MS: 310.0567
(M+: C12H14F3O4P, calcd. 310.0582).
Dimethyl 1-phenyl-2-trifluoroethenyl phosphate
2c: oil, yield 20%. 1H NMR (CCl4, 90 MHz): 7.40 (m,
5H); 5.55 (q, J = 7.5 Hz, 1H); 3.70 (d, J = 12 Hz, 6H).
19F NMR (CCl4): −20.3. 31P NMR: −4.911. EI-MS:
296 (M+, 39.58), 256 (5.12), 227 (6.30), 184 (8.16),
170 (100.00), 151 (19.09), 127 (7.06). IR (film): 3076,
2964, 1672, 1450, 1340, 1281, 1134, 1043, 934. HR-
MS: 296.0425 (M+: C11H12F3O4P, calcd. 296.0425).
Diethyl 1-phenyl-2-trifluoroethenyl phosphate 2d:
Method C: n-BuLi (1.6 M, 1.3 mmol) was
added dropwise to a stirred solution of dimethyl
1-(dimethoxyphosphinyl)-1-(p-chlorophenyl)methyl
phosphate 450 mg (1.3 mmol) in absolute THF
(15 ml) at −78◦C under N2. The mixture was stirred
at −78◦C for further 30 min, and (CF3CO)2O (1.3
mmol) was added to it in one portion. Stirring
was continued for 1 h at −78◦C then warmed to
−10◦C, after which PhMgBr (2.6 mmol) in THF
was added dropwise to the mixture, which was
stirred for 5 h at −10◦C. The reaction mixture was
acidified with acetic acid, then diluted with ether,
washed and dried over Na2SO4. Evaporation of the
solvent gave a residue which was purified by flash
column chromatography, eluting with petroleum
ether (60–90◦C) and ethyl acetate to give dimethyl
1-(4-chlorophenyl)-2-trifluoro-2-phenylethenyl phos-
1
oil, yield 22%. H NMR (CCl4, 90 MHz): 7.30 (m,
5H); 5.45 (q, J = 7.5 Hz, 1H); 3.90 (m, 4H); 1.10 (t,
J = 7 Hz, 6H). 19F NMR (CCl4): −25.0. 31P NMR:
−7.421. EI-MS: 324 (M+, 18.60), 305 (50.17), 257
(13.28), 229 (6.45), 198 (25.19), 170 (100.00), 151
(49.15). IR (film): 2989, 1672, 1450, 1341, 1279, 1134,
1040, 985. Anal. calcd. for C13H16F3O4P: C 48.15, H
4.98; Found: C 48.22, H 4.99.
Dimethyl 1-(4-chlorophenyl)-2-trifluoroethenyl
phosphate 2e: mp 50–51◦C, yield 17%. 1H NMR
(CDCl3, 90 MHz): 7.45 (m, 4H); 5.60 (q, J = 7.5 Hz,
1H); 3.75 (d, J = 10 Hz, 6H). 19F NMR (CDCl3):
−20.0 (d, J = 7.5 Hz). 31P NMR: −4.934. EI-MS: 330
(M+, 41.79), 311 (6.99), 261 (4.92), 247 (5.59), 218
(6.38), 204 (100.00), 109 (45.52). IR (KBr): 3093,
1673, 1496, 1337, 286, 1127, 1081, 1019, 927. Anal.
calcd. for C11H11ClF3O4P: C 39.96, H 3.36; Found: C
39.84, H 3.15.
Dimethyl 1-(3,4-dichlorophenyl)-2-trifluoroeth-
enyl phosphate 2f: mp 82◦C, yield 11%. 1H NMR
(CDCl3, 90 MHz): 7.50 (m, 3H); 5.62 (q, J = 7 Hz,
1H); 3.80 (d, J = 10 Hz, 6H). 19F NMR (CDCl3):
−20.0 (d, J = 7 Hz). 31P NMR: −4.863. EI-MS: 364
(M+, 2.30), 344 (37.74), 294 (6.14), 237 (55.40), 219
(16.09), 173 (35.37), 109 (46.57). IR (KBr): 3093,
2962, 1677, 1477, 1392, 1289, 1129, 1028, 946. Anal.
calcd. for C11H10Cl2F3O4P: C 36.19, H 2.77; Found: C
36.55, H 2.57.
1
phate 2h 130 mg, mp 63–64◦C, yield 25%. H NMR
(CDCl3, 90 MHz): 7.50 (m, 9H), 3.20 (d, J = 12 Hz,
6H). 19F NMR (CDCl3): −21.0 and −19.5. 31P NMR:
−4.661 (q, J = 5.4 Hz) and −4.854 (q, J = 5.4 Hz).
EI-MS: 406 (M+, 23.81), 384 (39.15), 281 (38.61),
246 (16.56), 214 (8.97), 165 (11.96), 139 (58.64). IR
(KBr): 2960, 1667, 1495, 1334, 1282, 1172, 1105,
1016. Anal. calcd. for C17H15ClF3O4P: C 50.19, H
3.72; Found: C 50.36, H 3.73.
ACKNOWLEDGMENT
We thank Professor G. Z. Yang of Shanghai Institute
of Pesticide for his testing of the insecticidal activity
of the experimental compounds.
Method B: n-BuLi (1.6 M, 1.2 mmol) was
added dropwise to a stirred solution of dimethyl
1-(dimethoxyphosphinyl)-1-(p-chlorophenyl)methyl
phosphate 430 mg (1.2 mmol) in absolute THF
(15 ml) at −78◦C under N2. The mixture was stirred
at −78◦C for further 15 min, and CH3COCF3 134 mg
(1.2 mmol) was added to it. Stirring was continued
for 2 h at −78◦C then warmed to r.t. The reaction
mixture was acidified with acetic acid, then diluted
with ether, washed and dried over Na2SO4. Evap-
oration of the solvent gave a residue which was
purified by flash column chromatography, eluting
with a mixture of petroleum ether (60–90◦C) and
ethyl acetate to give dimethyl 1-(4-chlorophenyl)-2-
trifluoro-2-methylethenyl phosphate 2g 70 mg, yield
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