Syntheses and characterization of 2-amino-5-aryl-1,3,4-oxadiazoles containing trifluoroethoxy groups

Article abstract of DOI:10.1016/S0022-1139(98)00269-3

In order to develop an effective synthetic route to 2-amino-5-aryl-1,3,4-oxadiazoles containing trifluoroethoxy groups, a novel intermediate 2-amino-5-[4-(2′,2′,2′-trifluoroethoxy)-phenyl]-1,3,4- oxadiazole was prepared and its structure was confirmed by

Full text of DOI:10.1016/S0022-1139(98)00269-3

Journal of Fluorine Chemistry 93 (1999) 39±43
Syntheses and characterization of 2-amino-5-aryl-1,3,4-oxadiazoles
containing tri¯uoroethoxy groups
Rong Zhang, Xuhong Qian*, Zhong Li
Institute of Pesticides and Pharmaceuticals, East China University of Science and Technology, PO Box 544, 130 Meilong Road, Shanghai 200237, China
Received 3 June 1998; accepted 11 August 1998
Abstract
In order to develop an effective synthetic route to 2-amino-5-aryl-1,3,4-oxadiazoles containing tri¯uoroethoxy groups, a novel
intermediate 2-amino-5-[4-(20,20,20-tri¯uoroethoxy)-phenyl]-1,3,4-oxadiazole was prepared and its structure was con®rmed by mass
spectrometry and 1H NMR spectroscopy. The chlorine atom was not substituted by tri¯uoroethoxy groups, when syntheses of the
intermediate by direct tri¯uoroethoxylation of 2-amino-5-(4-chlorophenyl)-1,3,4-oxadiazole was tried. The resulting product was
characterized as N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-chlorobenzamide. A possible reaction mechanism is suggested. # 1999
Elsevier Science S.A. All rights reserved.
Keywords: Oxadiazole; Tri¯uoroethoxylation; Synthesis; Characterization; Mechanism
1. Introduction
Initially, we undertook the typical procedure given in
Scheme 1 and succeeded in synthesizing the desired com-
pound. To begin with, the tri¯uoroethoxy group was intro-
duced into the starting material (1) to yield (2), and then (2)
took four steps through corresponding benzamide (3) ben-
zoylhydrazide (4) and benzoylthiosemicarbazide (5), and
®nally by oxidative cyclization of (5) with iodine in potas-
sium iodide solution to give the product (6).
The found elemental composition analyses were in good
agreement with calculations. 1H NMR spectroscopy
revealed a ±CH2± quartet (JH,Fˆ8.0 Hz) at 4.76 ppm corre-
sponding to the tri¯uoroethoxy group. The protons at posi-
tions 3,5 of the phenyl ring were affected by the electron-
donating ability of the neighboring tri¯uoroethoxy group,
and their resonance values are slightly higher than the
protons at positions 2,6. The amino protons could not be
observed because of exchange. Mass spectra data were the
most effective in elucidating the structure of this compound.
We show a fragmentation pattern in Scheme 2 with the
important ions observed in the mass spectra. It was in close
conformity with reported results [5]. The intermediate 2-
amino-5-(4-chlorophenyl)-1,3,4-oxadiazole (8) had a simi-
lar result (see Section 3.2 for spectral data).
2,5-Disubstituted-1,3,4-oxadiazoles have strong insecti-
cidal and antibiotic activities [1,2]. Previously, we synthe-
sized a series of N-(5-aryl-1,3,4-oxadiazol-2-yl)-substituted
amides containing the tri¯uoroethoxyl group [3] and
reported that tri¯uoroethoxy anions can even replace all
the ¯uorine atoms of a tri¯uoromethyl group attached to a
pyridine ring [4]. Herein, we report the alternative synthesis
of 2-amino-5-[4-(20,20,20-tri¯uoroethoxy)phenyl]-1,3,4-oxa-
diazole via tri¯uoroethoxylation by two routes. However,
one line failed to give the desired product, the resulting
product was identi®ed as N-[5-(4-chlorophenyl)-1,3,4-oxa-
diazol-2-yl]-4-chlorobenzamide.
2. Results and discussion
In order to study an effective synthetic method for intro-
ducing tri¯uoroethoxy groups into 2-amino-5-aryl-1,3,4-
oxadiazoles, we designed two routes to synthesize the useful
intermediate
2-amino-5-[4-(20,20,20-tri¯uoroethoxy)phe-
nyl]-1,3,4-oxadiazole (6) via tri¯uoroethoxylation, and
compared the reaction behavior and discussed the possible
mechanism.
Although this route is convenient to prepare the desired
oxadiazole, it was long, and gave low total yield, therefore
we sought a shorter effective synthetic route. A method
described in the literature [6] for the synthesis of 4-tri¯uor-
omethyl-5-ethoxyl-2-[4-(20,20,20-tri¯uoroethoxy)phenyl]-1,
*Corresponding author. Tel.: +86-21-64252774; fax: +86-21-64251386;
e-mail: xhgian@ecust.edu.cn
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 2 6 9 - 3

40
R. Zhang et al. / Journal of Fluorine Chemistry 93 (1999) 39±43
Scheme 1. Route 1 for synthesis of 2-amino-5-[4-(20,20,20-trifluoroethoxy)phenyl]-1,3,4-oxadiazole (6).
Scheme 2. Mass spectral fragmentation pattern of 2-amino-5-[4-(20,20,20-trifluoroethoxy)phenyl]-1,3,4-oxadiazole (6).
3-oxazole via direct nucleophilic displacement reaction
appeared to proceed via a reaction mechanism similar to
that we have suggested in Scheme 3 (route 2). The major
difference between routes 1 and 2 was that the tri¯uoro-
ethoxy group in route 1 was introduced prior to cyclization,
whereas in route 2, the reaction proceeded ®rst by cycliza-
tion to form the 2-amino-5-(4-chlorophenyl)-1,3,4-oxadia-
zole (8), after which the tri¯uoroethoxy group attempted to
replace the chlorine atom in (8). However, (8) was not
converted into the desired compound (6) in using the
modi®ed procedure described by Idoux et al. [6]. First of
all, the isolated product did not have the same melting point
as the above authentic sample (6), and the ¯uorine elemental
analyses clearly indicated that there was no ¯uorine in this
product. The chlorine atom had not been substituted by
tri¯uoroethoxy group.
We have previously shown, [1,2], that the tri¯uoroethoxy
anion was a weak nucleophilic reagent because of the strong
electronegativity of the ¯uorine atoms, and tri¯uoroethoxy
nucleophilic substitution could only take place where the
aromatic compounds such as substituted phenyl, pyridyl,
naphthyl possess an easy leaving group (e.g. NO2, Cl) and a
corresponding strong electron-attracting group such as ±
CN, ±NO2, ±COOCH3 etc.
Similarly comparing the reactions shown in Scheme 3, we
found that the starting material 4-tri¯uoromethyl-5-ethoxyl-

R. Zhang et al. / Journal of Fluorine Chemistry 93 (1999) 39±43
41
Scheme 3. Route 2 for trying to synthesis of 2-amino-5-[4-(20,20,20-trifluoroethoxy)phenyl]-1,3,4-oxadiazole.
2-(4-chlorophenyl)-1,3-oxazole possesses a strongly elec-
tron-attracting tri¯uoromethyl group at position 4 of the 1,3-
oxazole ring affecting the neighboring phenyl ring of the
1,3-oxazole ring, and resulting in decreased electron density
at the chlorine atom. The chlorine atom was ®nally sub-
stituted by a nucleophilic reagent. On the contrary, the 1,3,4-
oxadiazole ring did not have a strong electron-attracting
group at position 4 instead of a strong electron-donating
amino group at position 5, so the chlorine atom was in an
inactivated state for substitution and could not be replaced
by tri¯uoroethoxy group.
This isolated product was characterized as N-[5-(4-chlor-
ophenyl)-1,3,4-oxadiazol-2-yl]-4-chlorobenzamide (9) as
shown in Scheme 3, an analogue of a compound we have
reported [3].
We assume that during the reaction, the starting material
(8) (prepared in Section 3.2) ®rst underwent oxadiazole ring
opening and further hydrolysis to give the carboxylic acid,
followed by the acylation of carboxylic acid with the amino
group to give the ®nal product (9) (Scheme 4). This could be
employed to illustrate the similar reaction behavior reported
by Carlsen et al. [7].
Scheme 4. A possible reaction mechanism for formation of (9).

42
R. Zhang et al. / Journal of Fluorine Chemistry 93 (1999) 39±43
In addition, it might be explained that the strong base
potassium iodide solution (5%) was added into the solution
until the colour of iodine persisted. After re¯uxing the
mixture for 2±3 h, the reaction mixture was poured into
100 ml of ice-water, ®ltered and washed with water and
warm carbon disulphide, and recrystallized from 75% etha-
nol to give white needles, yield 70%, m.p. 243.0±244.08C.
1H NMR ꢀ: 4.76 (q, JH,Fˆ8.0 Hz, 2H, ±CH2±); 7.25 (d,
Jˆ8.0 Hz, 2H, Ar 2,6H); 7.85 (d, Jˆ8.0 Hz, 2H, Ar 3,5H).
MS (FD), (m/e, %): 259 (100) [M]; 260 (12.571) [M‡1];
216 (35.308) [M±HCNO]; 203 (58.410) [M±CN3H2]; 175
(3.688) [M±CN3H2±CO]; 133 (53.214) [M±HCNO±
CF3CH2]; 105 (18.015) [M±CN3H2±CO±CF3H]; 92
(14.131) [M±HCNO±N2±CF3CH=CH2]; 76 (14.604) [M±
HCNO±N2±CF3CH=CH2±O]; 64 (11.646) [M±HCNO±N2±
CF3CH=CH2±CO]. Analysis: Calc. for C10H8F3N3O2
(259.19): C, 46.34; H, 3.11; N, 16.21%. Found: C, 46.33;
H, 3.09; N, 16.22%.
sodium tri¯uoroethoxide in dimethylformamide played an
important role for the acylation reactions in order that the
reaction can proceed at room temperature smoothly during
one day. It is necessary for the reported reaction to be heated
in a sealed tube at 1508 and for two days if the base is not
present to accelerate the reaction in allylamine [7]. The
product was isolated (30%) and identi®ed as N-allylbenz-
amide by comparison with the authentic sample.
3. Experimental
Melting points were taken on a digital melting point
apparatus made in Shanghai. Infrared spectra were mea-
sured on KBr using a Nicolet FT-IR-20SX instrument. Mass
spectra were measured on a Hitachi M80 instrument.
1H NMR spectra were obtained using a Brucker WP-
100SY(100 MHz) spectrometer with (CD3)2CO as the sol-
vent and TMS as internal standard. Combustion analyses for
elemental composition were made with an Italian
MOD.1106 analyser. All reactions were monitored by TLC.
3.2.
The intermediate 4-chlorobenzaldehyde semicarbazone
(7) was prepared according to the method described in [11]
given in Scheme 2, yield 90%, m.p. 224.4±225.28C; 2-
amino-5-(4-chlorophenyl)-1,3,4-oxadiazole (8) was pre-
pared according to a similar procedure [12], yield 76%,
m.p. 273.6±274.78C. This agreed well with the reported data
[5] and had MS (EI 70 eV), (m/e, %): 195 (100) [M]; 197
(33.557) [M‡2]; 152 (84.517) [M±HCNO]; 139 (53.84)
[M±CN3H2]; 125 (31.692) [M±HCNO±N2]; 111 (44.519)
[M±CN3H2±CO]; 89 (27.977) [M±HNCO±N2±HCl]; 75
(38.361) [M±CN3H2±CO±HCl].
3.1.
The intermediates (1)±(4) were prepared according to our
reported procedures [1,8] shown in Scheme 1, their yields
and melting points are listed as follows:
ꢀ 4-Nitrobenzonitrile (1): 94.6%, m.p. 146.0±146.98C [8].
ꢀ 4-(20,20,20-Trifluoroethoxy)-benzonitrile (2): 95.0%,
m.p. 60.6±61.58C [8].
ꢀ 4-(20,20,20-Trifluoroethoxy)-benzamide (3): 80%, m.p.
175.6±176.28C [9].
3.2.1. Preparation of N-[5-(4-chlorophenyl)-1,3,4-
oxadiazol-2-yl]-4-chlorobenzamide (9)
0.08 g (2.7 mmol) sodium hydride (80%) was placed in
ꢀ 4-(20,20,20-Trifluoroethoxy)-benzoylhydrazide (4): 78%,
m.p. 121.7±123.08C [10].
Ê
15 ml of dimethylformamide (dried over 4 A molecular
sieves) and 0.175 ml of 2,2,2-tri¯uoroethanol (0.24 g,
2.4 mmol) was added dropwise. After stirring for 10 min
at room temperature, 0.39 g (2 mmol) 2-amino-5-(4-chloro-
phenyl)-1,3,4-oxadiazole (8) was added and the reaction
mixture stirred for one day at room temperature. After
cautious addition of 35 ml of 20% hydrochloric acid, the
mixture was extracted with ether (3Â10 ml), washed with
3Â2 ml of water, dried over magnesium sulfate, and the
solvent removed in vacuo to give a yellow crude product
0.26 g in 38% yield. After recrystallization from 75%
ethanol pale yellow prisms were obtained, m.p. 279.3±
279.58C. MS (EI 70 eV), (m/e, %): 333 (9.098) [M]; 335
(4.12) [M‡2]; 139 (100) [M±ClC6H4C2N2ONH]; 141
(36.0) [M‡2ClC6H4C2N2ONH]; 111 (34.8) [M±ClC6H4C2-
N2ONH±CO]; 113 (11.1) [M‡2ClC6H4C2N2ONH±CO]. IR
(KBr): 3400 (NH); 1740 (C=O); 1650 (C=N); 1600; 1400;
3.1.1. Preparation of 4-(20,20,20-trifluoroethoxy)-
benzoylthiosemicarbazide (5)
This was prepared by re¯uxing a suspension of 2.24 g
(10 mmol)
4-(20,20,20-tri¯uoroethoxy)-benzoylhydrazide
(4), 1.94 g (20 mmol) potassium thiocyanate, 10 ml of
36% hydrochloric acid and 200 ml of water for 3.5 h. After
cooling, the white solid was ®ltered, washed with water,
dried and recrystallized from ethanol to give the product,
yield 78%, m.p. 214.5±216.08C. IR (KBr): 3260 (NH); 1670
1
(C=O); 1350 (C=S); 1250; 1165; 930; 850; 830 cm
.
Analysis: Calc. for C10H10F3N3O2S (293.26): C, 40.96;
H, 3.44; N,14.33%. Found: C, 40.85; H, 3.41; N,14.37%.
3.1.2. Preparation of 2-amino-5-[4-(20,20,20-
trifluoroethoxy)phenyl]-1,3,4-oxadiazole (6)
1
To a suspension of 0.44 g (1.5 mmol) 4-(2,020,20-tri¯uor-
oethoxy)benzoylthiosemicarbazide (5) in 50 ml of 95%
ethanol was added 0.75 ml of sodium hydroxide (4 N)
and which with stirring gave a clear solution. Iodine in
1100; 1090; 840; 750 cm . 1H NMR ꢀ: 7.20±8.05 (m, 8H).
Analysis: Calc. for C15H9Cl2N3O2(334.16): C, 54.05; H,
2.72; N, 12.67; F, 0%. Found: C, 53.90; H, 2.75; N, 12.64;
F, 0%.

R. Zhang et al. / Journal of Fluorine Chemistry 93 (1999) 39±43
43
[3] X. Qian, R. Zhang, CN1 126 208A (1996).
Acknowledgements
[4] X. Qian, R. Zhang, J. Tang, W. Chen, J. Fluorine Chem. 67 (1994)
57.
We express our gratitude to the National Natural Science
Foundation of China, and Shanghai Foundation of Science
and Technology for the partial ®nancial support.
[5] R.K. Bansal, G. Bhagchandani, J. Indian Chem. Soc. 59 (1982) 277.
[6] J.P. Idoux, C. Liu, Huaxue Shiji 16 (1994) 110.
[7] P.H.J. Carlsen, K.B. Jorgensen, J. Heterocyclic Chem. 31 (1994) 805.
[8] R. Zhang, X. Qian, W. Zhou, Org. Prep. Proced. Int. (1998), in press.
[9] C. Colon, MS Thesis, University of Central Florida, December 1983.
[10] C. Moorefield, MS Thesis, University of Central Florida, December
1983.
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