Syntheses and insecticidal activity of new 2-(5-(trifluoromethyl)pyridyloxymethyl)-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/S0022-1139(02)00172-0

Eight 2-(5-(trifluoromethyl)pyridyloxymethyl)-1,3,4-oxadiazoles have been designed and synthesized by four-step synthetic route. The structures of all new compounds were confirmed by ¹H NMR, mass and HR mass spectroscopy. The preliminary bioass

Full text of DOI:10.1016/S0022-1139(02)00172-0

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Journal of Fluorine Chemistry 117 (2002) 63±66
Syntheses and insecticidal activity of new
2-(5-(tri¯uoromethyl)pyridyloxymethyl)-1,3,4-oxadiazoles
Song Caoa,c, Xuhong Qianb,*, Gonghua Songa,c, Qingchun Huangc
aInstitute of Pesticides and Pharmaceuticals, East China University of Science and Technology, P.O. Box 544,
130 Meilong Road, Shanghai 200237, PR China
bState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, PR China
cShanghai Key Laboratory of Chemical Biology, Shanghai 200237, PR China
Received 18 June 2002; received in revised form 15 July 2002; accepted 19 July 2002
Abstract
Eight 2-(5-(tri¯uoromethyl)pyridyloxymethyl)-1,3,4-oxadiazoles have been designed and synthesized by four-step synthetic route. The
structures of all new compounds were con®rmed by 1H NMR, mass and HR mass spectroscopy. The preliminary bioassay tests show that some
compounds, especially those having ¯uorine on the benzene ring (II4 and II5), exhibited a signi®cant insecticidal activity on armyworm,
Leucania separata Walker, at 500 mg lÀ1
.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Tri¯uoromethylpyridyl; 1,3,4-Oxadiazoles; Syntheses; Insecticidal activity
1. Introduction
`pseudo-halogen', has often been found to impart unique
biological activity [13]. In pesticides chemistry, the signi®-
cance of 3-tri¯uoromethylpyridine has been well recog-
nized. More than three commercial pesticides (herbicides:
Fusilade 51, SL 160; insecticide: Jupiter1) containing
tri¯uoromethylpyridine analogs whose superior properties
might be considered to be arisen from 3-tri¯uoromethylpyr-
idine moiety, have been manufactured and used widely [12].
In the last few years, we were pursuing investigations on
the synthesis and reactivity of pyridine containing ¯uorine or
tri¯uoromethyl [14±16]. In an attempt to discover novel
leading compounds with high insecticidal and low toxicity,
and also in continuation of our earlier research, this paper
describes synthesis and biological activities of new 2-(5-
(tri¯uoromethyl)pyridyloxymethyl)-1,3,4-oxadiazoles. The
preliminary bioassay tests show that some compounds (II4,
II5) exhibit a signi®cant insecticidal activity on armyworm,
Leucania separata Walker.
Much attention has been paid to 1,3,4-oxadiazole deri-
vatives in recent years because of their showing antiin¯am-
matory [1,2], antimicrobial [3], insecticidal [4], acaricidal
activities [5]. 2,5-Disubstituted-1,3,4-oxadiazoles were dis-
closed as a broad-spectrum insecticide and acaricide having
potential agricultural use [6,7]. In contrast to traditional
pesticides, they mainly control the growth and development
process of insects by interfering with chitin biosynthesis [8].
But 2,5-disubstituted-1,3,4-oxadiazoles, due to their low
solvent solubility, tend to have a non-optimal use rate and
formulation dif®culties. With this in mind, our attention was
drawn to changing the physical properties associated with
oxadiazoles while attempting to retain or increase their
biological ef®cacy through modi®cation of substituent oxa-
diazoles [9±11].
The chemistry of ¯uorine-containing compounds has
been tremendously developed. Owing to their unique prop-
erties, such as high thermal stability and lipophilicity, ¯uoro
organic compounds have been frequently applied to bio-
related materials, medicines and agrochemicals [12]. In
addition, the tri¯uoromethyl (CF3) group considered a
2. Results and discussion
2.1. Synthesis
Starting from different esters, mono-acylhydrazines,
N,N0-diacylhydrazines and asymmetrical 2,5-disubstituted-
1,3,4-oxadiazoles were prepared (Scheme 1). All the key
* Corresponding author. Tel.: ‡86-21-642-52945;
fax: ‡86-21-642-51386.
E-mail address: xhqian@ecust.edu.cn (X. Qian).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 1 7 2 - 0

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
64
S. Cao et al. / Journal of Fluorine Chemistry 117 (2002) 63±66
Scheme 1. Conventional synthetic route for 5-aryl-2-chloromethyl-1,3,4-oxadiazoles (I).
Table 1
Percent mortality (%) of II1±9 against armyworms at 500 mg lÀ1
intermediate 5-aryl-2-chloromethyl-1,3,4-oxadiazoles (I)
were prepared by the cyclodehydration of N-chloroacetyl-
N0-aroylhydrazines in boiling POCl3 (Scheme 1). The ®nal
compounds (II1±8) have been obtained by O-alkylation of
3-chloro-5-tri¯uoromethyl-2-pyridone and 3-tri¯uoromethyl
phenol with 5-aryl-2-chloromethyl-1,3,4-oxadiazoles (I) at
80 8C in the presence of phase transfer catalyst and powdery
K2CO3 in DMF (Scheme 2). It is a convenient and useful
method for the preparation of the title compounds.
The lowest-®eld protons in the 1H NMR spectrum appear
at d ˆ 7:95±8.06 which are assigned to protons of II1±8of
aromatic ring. The other protons of aromatic ring appear at
d ˆ 7:49±7.60. These chemical shift values are down®eld
due to stronger electron-withdrawing oxadiazole ring. The
H-4, H-6 of pyridine ring appear at d ˆ 7:70 and 7.90,
respectively, as a doublet with a coupling constant of
2.24 Hz, indicating meta coupling.
Compound
R
Mortality (%)
II1
II2
II3
II4
II5
II6
II7
II8
II9
C6H5
30
28
84
90
96
60
18
25
0
4-C2H5C6H4
4-ClC6H4
4-FC6H4
2-FC6H4
2,4-di-Cl-5-FC6H2
4-CH3OC6H4
4-NO2C6H4
drawing group, NO2, decreased activity. Compound II9
was designed to probe the effect of replacing the pyridyl
with phenyl (Scheme 3). It is clear that such modi®cation led
to loss of biological activity, suggesting that pyridyl is
critical to activity.
2.2. Insecticidal activities
Though these compounds possess only modest biological
activity, they may be useful as lead products for further
structure±activity relationship studies.
We examined the biological activity of the 2-(5-(tri¯uor-
omethyl)pyridyloxymethyl)-5-aryl-1,3,4-oxadiazoles (II)
having a variety of substituents on the benzene ring. The
insecticidal activity of II against armyworm (Leucania
separata Walker) was measured according to the modi®ed
method described previously [9,11], and is shown in Table 1.
Results are presented as percent mortality determined at
500 mg lÀ1. In general, the effect of electron-withdrawing
substituents, such as halogens were more favorable to
activity than those of electron-donating alkyl and alkoxy
groups. The introduction of F on the benzene ring increased
activity, for example, compounds II4, II5 (o-F and p-F) were
the most active compounds. But a strong electron-with-
3. Experimental
All melting points (mp) were obtained with an electro-
thermal digital apparatus made in Shanghai and are
1
uncorrected. H NMR spectra were recorded on a Bruker
WP-500SY (500 MHz) spectrometer with CDCl3 as the
solvent and TMS as the internal standard. Chemical shifts
are reported in d (parts per million) values. Mass spectra
were obtained by Micromass GCT CA055. Analytical thin
layer chromatography (TLC) was carried out on precoated
Scheme 2. Synthesis of 2-(5-(trifluoromethyl)pyridyloxymethyl)-5-aryl-1,3,4-oxadiazoles (II1±8).
Scheme 3. Synthesis of 2-(3-(trifluoromethyl)phenoxymethyl)-5-phenyl-1,3,4-oxadiazole (II9).

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
S. Cao et al. / Journal of Fluorine Chemistry 117 (2002) 63±66
65
plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light.
J ˆ 2:35 Hz, 1H, PyH), 7.56 (m, 1H, ArH), 7.49 (m, 2H,
‡
ArH), 5.53 (s, 2H, CH2). MS: m/z 355 (M , 100), 159 (8),
105 (19). HRMS Calc. for C15H9ClF3N3O2: 355.7033;
Found: 355.7062.
3.1. Preparation of 3-chloro-5-trifluoromethyl-2-pyridone
Preparation of 3-chloro-5-tri¯uoromethyl-2-pyridone was
performed according to the known method [17].
3.4.2. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(4-ethylphenyl)-1,3,4-oxadiazole (II2)
Yield 74%, mp 143±146 8C, 1H NMR (CDCl3) d 7.95 (d,
2H, ArH), 7.91 (d, J ˆ 2:15 Hz, 1H, PyH), 7.70 (d,
J ˆ 2:19 Hz, 1H, PyH), 7.33 (d, 2H, ArH), 5.52 (s, 2H,
CH2), 2.71 (q, 2H, CH2), 1.25 (t, 3H, CH3). MS: m/z 383
3.2. Preparation of N-chloroacetyl-N0-aroylhydrazines
Preparation of N-chloroacetyl-N0-aroylhydrazines were
‡
1
performed according to the quoted literature [18]. The H
(M , 83), 187 (22), 133 (100). HRMS Calc. for
C17H13ClF3N3O2: 383.0648; Found: 383.0651.
NMR and melting point for the typical compound N-chlor-
oacetyl-N0-(2,4-dichloro-5-¯uorophenyl)hydrazine: d 4.39
(s, 2H, CH2), 7.64 (d, 1H, ArH), 8.09 (d, 1H, ArH),
10.69 and 11.23 (2s, 2H, CONHNHCO), mp 194±195 8C.
3.4.3. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(4-chorophenyl)-1,3,4-oxadiazole (II3)
1
Yield 69%, mp 118±120 8C, H NMR (CDCl3) d 7.98
3.3. General synthetic procedure for 5-aryl-2-
chloromethyl-1,3,4-oxadiazoles (I)
(d, 2H, ArH), 7.90 (d, J ˆ 2:21 Hz, 1H, PyH), 7.71 (d,
J ˆ 2:24 Hz, 1H, PyH), 7.21 (d, 2H, ArH), 5.51 (s, 2H,
‡
CH2). MS: m/z 389 (M , 68), 193 (16), 139 (100).
HRMS Calc. for C15H8Cl2F3N3O2: 388.9946; Found:
388.9944.
The mixture of the N-chloroacetyl-N0-aroylhydrazine
(5 mmol) and POCl3 (10 ml) was re¯uxed for 3 h [18].
After cooling to room temperature, it was poured slowly
into an ice and water mixture. The resulting precipitate was
®ltered, washed, dried and recrystallized from ethanol to
3.4.4. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(4-fuorophenyl)-1,3,4-oxadiazole (II4)
1
1
produce the pure oxadiazole I. The H NMR and melting
point for the typical compounds: 5-(4-chlorophenyl)-2-
Yield 77%, mp 158±159 8C, H NMR (CDCl3) d 8.05
(m, 2H, ArH), 7.89 (d, J ˆ 2:23 Hz, 1H, PyH), 7.71 (d,
chloromethyl-1,3,4-oxadiazole
d 4.78 (s, 2H, CH2),
J ˆ 2:24 Hz, 1H, PyH), 7.21 (m, 2H, ArH), 5.51 (s, 2H,
‡
7.50(d, 2H, ArH), 8.04 (d, 2H, ArH), mp 130±131 8C; 5-
(2,4-chloro-5-¯uorophenyl)-2-chloromethyl-1,3,4-oxadia-
zole d 4.80 (s, 2H, CH2), 7.65 (d, 1H, ArH), 7.87 (d, 1H,
ArH), mp 100±101 8C; 5-(4-¯uorophenyl)-2-chloromethyl-
1,3,4-oxadiazole d 4.78 (s, 2H, CH2), 7.19 (m, 2H, ArH),
7.90 (m, 2H, ArH), mp 79±80 8C.
CH2). MS: m/z 373 (M , 100), 177 (22), 123 (85).
HRMS Calc. for C15H8ClF4N3O2: 373.0241; Found:
373.0266.
3.4.5. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(2-fuorophenyl)-1,3,4-oxadiazole (II5)
Yield 70%, mp 124±125 8C, 1H NMR (CDCl3) d 7.96 (m,
1H, ArH), 7.84 (d, J ˆ 2:05 Hz, 1H, PyH), 7.64 (d,
J ˆ 2:04 Hz, 1H, PyH), 7.50 (m, 1H, ArH), 7.22 (m, 2H,
3.4. General procedure for the preparation of
2-(5-(trifluoromethyl)pyridyloxymethyl)-
‡
5-aryl-1,3,4-oxadiazoles (II1±8
)
ArH), 5.47 (s, 2H, CH2). MS: m/z 373 (M , 100), 177 (8),
123 (56). HRMS Calc. for C15H8ClF4N3O2: 373.0241;
Found: 373.0244.
A
mixture of 3-chloro-5-tri¯uoromethyl-2-pyridone
(2.5 mmol), anhydrous potassium carbonate (8 mmol), tetra-
butyl ammonium bromide (0.2 mmol) and dry DMF (5 ml),
was stirred at 90 8C for 0.5 h. To the mixture was added
5-aryl-2-chloromethyl-1,3,4-oxadiazole (I) (2.5 mmol) and
dry DMF (5 ml). The reaction mixture was stirred at 90 8C
for 2±4 h. After cooling, the mixture was treated with water
(30 ml), and extracted with chloroform (3 Â 15 ml). The
organic layer was washed with water, dried with MgSO4
and concentrated. The residue was chromatographed over a
column of silica gel and eluted with petroleum ether (60±
90 8C) and ethyl acetate. The title compound was obtained.
3.4.6. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(2,4-dichoro-5-fluorophenyl)-1,3,4-oxadiazole (II6)
Yield 75%, mp 149±150 8C, H NMR (CDCl3) d 7.88
1
(m, 1H, ArH), 7.84 (d, J ˆ 2:35 Hz, 1H, PyH), 7.72 (d,
J ˆ 2:38 Hz , 1H, PyH), 7.64 (m, 1H, ArH), 5.53 (s, 2H,
‡
CH2). MS: m/z 441 (M , 64), 238 (19), 191 (100).
HRMS Calc. for C15H6Cl3F4N3O2: 440.9462; Found:
440.9458.
3.4.7. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(4-methoxyphenyl)-1,3,4-oxadiazole (II7)
Yield 73%, mp 168±169 8C, 1H NMR (CDCl3) d 7.90 (d,
2H, ArH), 7.82 (d, J ˆ 2:04 Hz, 1H, PyH), 7.63 (d,
J ˆ 2:05 Hz, 1H, PyH), 6.93 (d, 2H, ArH), 5.43 (s, 2H,
3.4.1. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-phenyl-1,3,4-oxadiazole (II1)
Yield 71%, mp 113±114 8C, 1H NMR (CDCl3) d 8.03 (m,
2H, ArH), 7.93 (d, J ˆ 2:31 Hz, 1H, PyH), 7.70 (d,
‡
CH2), 3.78 (t, 3H, OCH3). MS: m/z 385 (M , 100), 189 (37),

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
66
S. Cao et al. / Journal of Fluorine Chemistry 117 (2002) 63±66
135 (77). HRMS Calc. for C16H11ClF3N3O3: 385.0441;
Found: 385.0445.
Acknowledgements
We express our gratitude to the National Natural Science
Foundation of China and Shanghai Foundation of Science
and Technology for ®nancial support.
3.4.8. 2-(5-(Trifluoromethyl)pyridyloxymethyl)-
5-(4-nitrophenyl)-1,3,4-oxadiazole (II8)
Yield 78%, mp 161±162 8C, H NMR (CDCl3) d 8.15
1
(d, 2H, ArH), 7.98 (d, J ˆ 2:20 Hz, 1H, PyH), 7.82
(d, J ˆ 2:24 Hz, 1H, PyH), 7.34 (d, 2H, ArH), 5.55 (s,
References
‡
2H, CH2). MS: m/z 400 (M , 100), 250 (28), 150 (68).
HRMS Calc. for C15H8ClF3N4O4: 400.7002; Found:
400.7021.
[1] M. Amir, S. Shahani, Indian J. Heterocycl. Chem. 8 (1998) 107±110.
[2] F.A. Omar, N.M. Mahfouz, M.A. Rahman, Eur. J. Med. Chem. 31
(1996) 819±825.
[3] F.A. Ashour, S.A. AlMazoroa, J. Pharm. Sci. 4 (1990) 29±32.
[4] I.R. Matthews, D.P. Bacon, PCT Int. Appl. WO 9505368 A1 (1995).
[5] U. Kraatz, B. Gallenkamp, A. Marhold, P. Wolfrum, WO
2002006256 A1 (2002).
3.5. Procedure for preparation of 2-(3-
(trifluoromethyl)phenoxymethyl)-5-phenyl-
1,3,4-oxadiazole (II9)
[6] A.K. Sengupta, U. Chandra, Indian J. Chem. Sect. B 17B (1979)
655±666.
A mixture of 3-tri¯uoromethyl phenol (2.5 mmol), anhy-
drous potassium carbonate (8 mmol), tetrabutyl ammo-
nium bromide (0.2 mmol) and dry DMF (5 ml), was
stirred at 90 8C for 0.5 h. To the mixture was added 5-
phenyl-2-chloromethyl-1,3,4-oxadiazoles (2.5 mmol) and
dry DMF (5 ml). The reaction mixture was stirred at 90 8C
for 3 h. After cooling, the mixture was poured slowly into
water. The resulting precipitate was ®ltered, washed, dried
and recrystallized from ethanol to produce white powdery
crystals.
[7] H.L. Plant, R.R. Regis, R.C. Moore, Eur. Pat. Appl. EP 156638 A2
(1985).
[8] J.P. Arrington, L.L. Wade, US Patent 42,151,29 (1980).
[9] W. Shi, X. Qian, G. Song, R. Zhang, J. Fluorine Chem. 106 (2000)
173±179.
[10] X. Qian, R Zhang, J. Chem. Tech. Biotechnol. 67 (1996) 124±130.
[11] W. Shi, X. Qian, R. Zhang, G. Song, J. Agric. Food Chem. 49 (2001)
124±130.
[12] M. Hudlicky, Chemistry of Organic Fluorine Compounds II,
American Chemical Society, Washington, DC, 1995, p. 979, p. 1145.
[13] R. Filler, Y. Kobayashi, Biomedical Aspects of Fluorine Chemistry,
Elsevier Biomedical Press, New York, 1986.
Yield 80%, mp 126±127 8C, 1H NMR (CDCl3) d 8.09 (m,
2H, ArH), 7.57 (m, 1H, ArH), 7.54 (m, 2H, ArH), 7.45 (m,
1H, ArH), 7.33 (m, 2H, ArH), 7.26 (m, 1H, ArH), 5.38 (s,
[14] X. Qian, J.P. Idoux, J. Fluorine Chem. 53 (1991) 143±153.
[15] X. Qian, S. Liu, J. Fluorine Chem. 79 (1996) 9±12.
[16] X. Xu, X. Qian, Z. Li, G. Song, J. Fluorine Chem. 88 (1998) 9±13.
[17] T. Haga, K. Fujikawa, T. Koyanagi, T. Nakajjima, K. Hayashi,
Heterocycles 22 (1984) 117±124.
‡
2H, CH2). MS: m/z 320 (M , 20), 159 (95), 105 (100).
HRMS Calc. for C16H11F3N2O2: 320.2694; Found:
320.2682.
[18] R.T. Vakula, R.V. Srinivasan, Indian J. Chem. 11 (1973) 732±734.