Synthesis, characterization, and herbicidal activities of new 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles derivatives bearing (r)-5-chloro-3-fluoro-2-phenoxypyridine

Article abstract of DOI:10.1002/jhet.950

Synthesis of some novel 1,2,4-triazoles, 1,3,4-oxadiazoles and 1,3,4-thiadiazoles bearing a (R) 5-(1-(4-(5-chloro-3-fluoropyridin-2-yloxy) phenoxy)ethyl) unit, as a moiety of commercial herbicide, using their thiosemicarbazides in an alkaline, iodine and acidic media is reported, respectively. The structure of the synthesized compounds was characterized by IR, ¹H, ¹³C NMR spectroscopic data, and elemental analyses. The herbicidal activities of synthesized compounds were evaluated against Echinochloa cruss-galli, Avena fatua, and Sorgum halepense weeds. Compounds 7 and 12a showed potential herbicidal activity against gramineous weeds. Our results may provide some guidance for synthesis development of some novel oxa or thiadiazole and triazole-based herbicidal lead structures.

Full text of DOI:10.1002/jhet.950

220
Synthesis, Characterization, and Herbicidal Activities of New
1,3,4‐Oxadiazoles, 1,3,4‐Thiadiazoles, and 1,2,4‐Triazoles
Derivatives Bearing (R)‐5‐Chloro‐3‐fluoro‐2‐phenoxypyridine
Vol 50
a
b
*
Mehdi Kalhor and Akbar Dadras
aDepartment of Chemistry, Payame Noor University, Tehran 19395–4697, Iran
bIndustrial Pesticide Research Center, Alborz‐Tehran, Iran
*
E-mail: mekalhor@gmail.com
Received February 7, 2011
DOI 10.1002/jhet.950
Published online 20 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of some novel 1,2,4‐triazoles, 1,3,4‐oxadiazoles and 1,3,4‐thiadiazoles bearing a (R) 5‐(1‐(4‐(5‐
chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl) unit, as a moiety of commercial herbicide, using their
thiosemicarbazides in an alkaline, iodine and acidic media is reported, respectively. The structure of the syn-
thesized compounds was characterized by IR, 1H, 13C NMR spectroscopic data, and elemental analyses. The
herbicidal activities of synthesized compounds were evaluated against Echinochloa cruss‐galli, Avena fatua,
and Sorgum halepense weeds. Compounds 8 and 12a showed potential herbicidal activity against gramine-
ous weeds. Our results may provide some guidance for synthesis development of some novel oxa or
thiadiazole and triazole‐based herbicidal lead structures.
J. Heterocyclic Chem., 50, 220 (2013).
INTRODUCTION
synthesis of new series of 5‐membered heterocyclic
titled compounds, bearing the (R)‐5‐(1‐(4‐(5‐chloro‐
3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl) and their her-
bicidal activities.
Until now, a variety of heterocyclic compounds
containing nitrogen, oxygen, and sulfur atoms have signif-
icantly contributed too many current commercial drugs and
agrochemicals. Among these heterocyclic compounds,
1,3,4‐oxa and thiadiazoles possess a wide range of biological
activities such as antitumor, antiviral, antimicrobial, anti‐
inflammatory, and antifungal [1–7]. Also, the biological
activity of 1,2,4‐triazoles including antidepressive, anti‐
inflammatory, antibacterial, antifungal, insecticidal, and
antimicrobial properties [8–11], have been the subject of
many literature reports in recent years. Furthermore, it
has been reported that many compounds bearing these
heterocyclic nucleus have a broad spectrum of potential
herbicidal activities [12–15].
On the other hand, aryloxyphenoxypropionate herbicides
(APPH) are known as interesting and highly effective class
of herbicides in the international market over the past decade
[16]. They are used effectively in a number of crops
including soybeans and cereal grains, such as wheat, Barley
and rice, to control grass weeds [17]. However, the continuous
application of APPH has resulted in the evolution of resistant
weeds [18]. In view of these highlights, the urgent synthetic
development of herbicides with newer chemical structures is
needed.
RESULTS AND DISCUSSION
The general synthetic route for synthesis of target
compounds is outlined in Scheme 1. The structure of syn-
thesized compounds was established by means of their
1
IR, H NMR, 13C NMR spectra, and elemental analyses.
The ester 1 was synthesized according to the literature
method [23], which then treated with 1.1 equivalents of
hydrazine monohydrate to give acylhydrazine derivative 2.
The IR spectrum of acid hydrazide 2 showed the N-H
stretching absorption near 3356, 3277 cm−1 and the C═O
stretching one at 1677 cm−1. Reaction of hydrazide 2 with
excess amount of ethylorthoformiate in the presence of silica
sulfuric acid (SSA) as a catalyst [24] afforded intermediate
formylhydrazide 3, which converted to oxadiazole 4 in
refluxing ethylorthoformate. 1,3,4‐Thiadiazole 5 was formed
by reaction of intermediate 3 with P2S5 in xylene under reflux
condition. In the IR spectra of the synthesized compounds 4
and 5, the absence of NH groups associated with other
spectroscopic data such as 1H NMR, 13C NMR, and elemental
analysis are in support of the expected reactions. Oxadiazole
2‐thiol, 6 was prepared via cyclization of compound 2 with
As part of ongoing studies on the synthesis and biological
consideration of heterocycles [19–22], we wish to report the
© 2013 HeteroCorporation

Synthesis, Characterization, and Herbicidal Activities of New 1,3,4-Oxadiazoles, 1,3,4-
March 2013
221
Thiadiazoles and 1,2,4-Triazoles Derivatives Bearing (R)-5-Chloro-3-fluoro-2-phenoxypyridine
Scheme 1. Conditions: (a) N2H5OH, MeOH, 15 min, reflux; (b) CH(OEt)3/SSA; (c) 21 h, Reflux; (d) P2S5, xylene, K2CO3, 12 h, reflux; (e) CS2/NaOH,
EtOH; (f) N2H5OH, BuOH; (g) triphosgene, THF, rt, 24 h; (h) R‐NCS, EtOH, 4–8 h, reflux; (i) H2SO4, 0°C, 0.5 h; (j) I2/KI, NaOH, 3–4 h; (k) 2N NaOH, 4
h, reflux.
carbon disulphide in the presence of potassium hydroxide in
refluxing ethanol as previously reported methods [20].
Amino‐1,2,4‐triazole‐3‐thiol 7 was obtained by reaction of 6
and hydrazine hydrate. The absorption band observed at
3295–3193 cm−1 of the IR spectrum of 6 could be attributed
1598 cm−1 due to C═N stretching vibration. The disap-
pearance of CONH and CSNH signals of 11b and also
the appearance of the NH signal at 6.27 ppm confirm the
formation of oxadiazole ring.
Triazole‐3‐thiols 12a–c were obtained by refluxing the
corresponding thiosemicarbazides in 2N NaOH solution,
followed by acidification. The 1H NMR spectra of compounds
12a–c showed singlets at 12.65–12.85 ppm attributed to the
resonance of the SH protons. All other required peaks were
appeared at the exhibited region of the spectra.
Herbicidal activity and crop safety. Herbicidal activity
against three weeds and crop safety of barley and wheat
were evaluated for compounds 1, as a reference, 4–8 and
(9–12a–c) at 125 g a.i/ha application postemergence by
previously reported method [26] that their results are
summarized in Table 1. As shown in Table 1, all
compounds showed good to excellent level of activity
against all weeds tested without or with slight injury. The
highest herbicidal activity was observed for compounds
8 and 12a. Also, it was clarified that the activity of 12a
against Avena fatua was more potent without showing
crop damage against Barley than that of clodinafop
propargyl 1, as a practical herbicide. Besides, it was
considerable that 1,2,4‐triazole structure have been useful
for the improvement of herbicidal activity and crop
selectivity.
1
to the NH2 group. In the H NMR spectrum of 7, the reso-
nance of NH2 and SH groups was appeared as a singlet at
4.89 and 11.80 ppm, respectively, confirms the expected struc-
ture. Condensation of intermediate 2 with triphosgene in THF
afforded the oxadiazole‐2‐one 8 according to the literature
method [25]. Spectroscopic data of all synthesized compound
were consistent with their structures.
The preparation of thiosemicarbazides 9a–c was
achieved by reaction of the corresponding substituted
hydrazide 2 with ammonium, methyl or phenyl isothiocya-
nate [20]. The IR spectra of thiosemicarbazides 9a–c
showed characteristic absorption at 1138–1199, 1615–
1691, and 3185–3420 cm−1 for the -C═S, C═O, and -
1
NH stretching vibration, respectively. H NMR spectra of
9a–c showed singlet signals at 8.80–9.63 ppm due to the
resonance of -NH-CS-NH and -CO-NH protons, respec-
tively. The 13C NMR spectrum of compound 9b showed
fourteen signals including a signal at 171.3 ppm for the -
C═S and a signal at 180.2 ppm for the carbonyl carbon
atom, which are in support of the expected structures.
Thiosemicarbazide derivatives 9a–c underwent an intra-
molecular cyclization under basic, acidic or iodine
conditions to produce 1,3,4‐thiadiazoles 10a–c, 1,3,4‐
oxadiazoles 11a–c, and 1,2,4‐triazole‐3‐thiols 12a–c
(Scheme 1). The IR spectra of 10a–c showed absorption
bands at 3412–3414 cm−1, the characteristic of the NH
group. Also in the 1H NMR spectra of all 1,3,4‐
thiadiazoles, the singlet at 7.01 and 10.56–10.78 ppm
was attributed to the resonance of the NH proton. The IR
spectrum of oxadiazole 11b showed absorption band at
In conclusion, we have described the synthesis of some
novel 1,2,4‐triazoles, 1,3,4‐oxadiazoles, and 1,3,4‐thiadiazoles
bearing
a
(R) 5‐(1‐(4‐(5‐chloro‐3‐fluoropyridin‐2‐yloxy)
phenoxy)ethyl) unit, as a moiety of commercial herbicide,
2–8 and (9–12a–c) with good to high yields. We also evaluated
their herbicidal activities against three weeds. Moreover,
the present investigation demonstrated the compounds
8 and 12a could be a practical herbicide that is ongoing
in this regard.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

222
M. Kalhor and A. Dadras
Vol 50
1075 (N═C-O) cm−1; H NMR (CDCl3, 300 MHz): δH 8.42 (s,
1H, oxadiazole), 7.77 (s , 1Hpy.), 7.43 (d, J = 8.7 Hz, 1Hpy.),
7.01–6.87 (m, 4H, ph), 5.60 (q, J = 6.5 Hz, 1H‐chiral), 1.75 (d,
J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): δC 19.3,
67.5, 116.7, 122.4, 124.9, 140.0, 145.0, 147.3, 148.5, 151.1,
153.7, 154.2, 165.6; Anal. Calcd. for C15H11ClFN3O3: C,
53.66; H, 3.30; N, 12.52. Found: C, 53.54; H, 3.31; N, 12.55.
Synthesis of (R)‐5‐chloro‐3‐fluoro‐2‐[4‐(1‐[1,3,4]thiadiazol‐2‐
yl‐ethoxy)‐phenoxy]‐pyridine (5). To a solution of 3 (3.54 g,
10 mmol) in xylene (100 mL), phosphorous pentasulphide (2.22 g,
10 mmol) was added. The mixture was refluxed for 12 h, then
filtered, washed with K2CO3 solution, and water. The solvent was
evaporated and the residue was recrystallized from toluene/n‐hexane,
Yield 56%, mp 101–102°C; IR (KBr): 3056 (C-H), 1598, 1501,
1
Table 1
Herbicidal activities of compounds 1, 4–8, and (9–12a–c).
Herbicidal activity (%)a
Damage (%)
Echinochloa Avena Sorgum
crussgalli fatua halepense
Compounds
Barley Wheat
1b
4
5
6
7
8
100
90
80
85
75
100
70
80
75
90
80
85
100
85
90
85
80
65
75
60
85
60
70
65
80
70
75
95
65
85
80
60
60
55
40
70
45
50
40
60
45
45
80
60
70
35
10
5
10
0
0
0
5
0
10
5
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
10a
10b
10c
11a
11b
11c
12a
12b
12c
1
1448, 1410 (C═N, C═C), 1084, 1029 (N═C-S) cm−1; H NMR
(CDCl3, 300 MHz): δH 9.06 (s, 1H, thiadiazole), 7.71 (s , 1Hpy.),
7.38 (d, J = 8.7 Hz, 1Hpy.), 7.00–6.89 (m, 4H, Ph), 5.78 (q, J = 6.5
Hz, 1H, Hchiral), 1.71 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3,
75 MHz): δC 22.7, 72.3, 116.6, 122.4, 124.9, 139.9, 145.0, 147.1,
148.5, 151.0, 152.8, 154.0, 172.8; Anal. Calcd. for
C15H11ClFN3O2S: C, 51.21; H, 3.15; N, 11.94; S, 9.11. Found: C,
51.40; H, 3.14; N, 12.10; S, 9.14.
Synthesis of (R)‐5‐(1‐(4‐(5‐chloro‐3‐fluoropyridin‐2‐yloxy)
phenoxy)ethyl)‐4‐amino‐4H‐1,2,4‐triazole‐3‐thiol (7). A mixture
of compound 6 (1.83 g, 5 mmol) and hydrazine hydrate (98%) (1
g, 20 mmol) was refluxed in butanol (50 mL) for 6 h. After
cooling, KOH (0.56 g, 10 mmol) was added to the reaction media
and the formed precipitate was filtered. Then it was acidified with
HCl (37%), washed with water and recrystallized from toluene,
Yield 71%, mp 137–139°C; IR (KBr): 3295–3193 (N-H), 2752 (S-
H), 1633, 1572, 1504, 1469, 1414 (C═N, C═C), 1234 (N-N),
1203 (C═S) cm−1; 1H NMR (CDCl3, 300 MHz): δH 11.80 (br, 1H,
SH), 7.86 (s, 1Hpy.), 7.52 (d, J = 8.7 Hz, 1Hpy.), 7.11–7.01 (m, 4H,
ph), 5.54 (q, J = 6.5 Hz, 1H, Hchiral), 4.89 (s, 2H, NH2), the SH
and NH2 protons disappeared on D2O addition, 1.78 (d, J = 6.5
Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): δC 17.8, 69.0, 117.2,
122.5, 125.1, 140.0, 145.2, 147.4, 148.6, 151.1, 151.5, 154.18,
167.01; Anal. Calcd. for C15H13ClFN5O2S: C, 47.19; H, 3.43; N,
18.34; S, 8.40. Found: C, 47.26; H, 3.42; N, 18.29; S, 8.44.
0
aApplication: 125 g ha−1, activity: 0 (no weed control or crop damage)–
100 (complete killing of weed and crop).
bClodinafop‐propargyl as commercial herbicide.
EXPERIMENTAL
All the solvents and materials are of reagent grade and purified
as required. Melting points were determined using an electro ther-
mal digital apparatus and are uncorrected. 1H NMR and 13C
NMR spectra were recorded on Bruker spectrophotometer (300
MHz) in CDCl3 using Me4Si as an internal standard. Chemical
shifts are reported in ppm from TMS as the internal standard. El-
emental analyses were performed on a Vario EL III elemental an-
alyzer. The purity of all compounds was confirmed on silica gel
coated aluminum plates (Merck). The ester 1 was synthesized as
previously reported method [21, 23].
Synthesis of (R)‐2‐[4‐(5‐chloro‐3‐fluoro‐pyridin‐2‐yloxy)‐
phenoxy]‐propionic acid hydrazide (2).
A
mixture of
Synthesis of (R)‐5‐(1‐(4‐(5‐chloro‐3‐fluoropyridin‐2‐yloxy)
phenoxy)ethyl)‐1,3,4‐oxadiazol‐2(3H)‐one (8). To a solution of
the acid hydrazide 2 (3.25 g, 10 mmol) in 50 mL of THF was
added a solution of triphosgene (2.2 g, 7.5 mmol) in 50 mL of tert‐
butyl methyl ether. After stirring for 24 h at room temperature, 50
mL of 5% Na2CO3 solution was added to the reaction mixture; the
organic layer was washed with 5% NaHCO3 solution, brine and
dried over Na2SO4. Post‐removal of the solvent, the residue was
recrystallized from isopropanol to give 8, Yield 90%, mp 132–134°
C; IR (KBr): 3249 (N-H), 1769 (C═O), 1620, 1506 (C═N, C═C),
compound 1 (3.5 g, 10 mmol) and hydrazine hydrate (98%)
(1 g, 20 mmol) was refluxed in methanol (50 mL) for 15 min,
and the reaction mixture was cooled and the precipitate
obtained was filtered, washed with water, and dried. The
product was crystallized from isopropanol to give white
crystals 2, Yield 94%, mp 150–152°C; IR (KBr): 3356, 3277
(N-H), 1677 (C═O), 1620, 1504 (C═N, C═C), 1197 (N-N)
1
cm−1; H NMR (CDCl3, 300 MHz): δH 7.82 (s, 1Hpy.), 7.47
(d, J = 8.7 Hz, 1Hpy.), 7.05–6.89 (m , 4H, ph), 5.90 (s, 1H,
NH), 5.25 (q, J = 6.5 Hz, 1H, H‐chiral), 4.70 (br, 2H, NH2),
1.55 (d, J = 6.5 Hz, 3H, CH3) ppm; 13C NMR (CDCl3, 75 MHz):
δC 18.7, 75.0, 116.3, 122.6, 125.1, 140.5, 145.1, 147.2, 148.6,
151.2, 154.1, 172.2 (C═O) ppm; Anal. Calcd. for C14H13ClFN3O3:
C, 51.62; H, 4.02; N, 12.90. Found: C, 51.58; H, 4.03; N, 12.94.
Synthesis of (R)‐5‐chloro‐3‐fluoro‐2‐[4‐(1‐[1,3,4]oxadiazol‐2‐
yl‐ethoxy)‐phenoxy]‐pyridine (4). Acid hydrazide 2 (3.25 g,
10 mmol) and 0.02 g of SSA were refluxed in 30 mL of
ethylorthoformate for 3 h affording intermediate formylhydrazide
3. This reaction was refluxed for 21 h to obtain compound 4. The
product was isolated after cooling and recrystallized from toluene,
Yield 86%, mp 98–100°C; IR (KBr): 3151, 3068 (C-H), 2936
(C-H), 1601, 1576, 1508, 1451 (C═N, C═C), 1298 (N-N),
1
1205 (C-O) cm−1; H NMR (CDCl3, 300 MHz): δH 9.60 (s, 1H,
NH.), the NH proton disappeared on D2O addition, 7.89 (s, 1Hpy.),
7.53 (d, J = 8.7 Hz, 1Hpy.), 7.13–7.03 (m, 4H, ph), 5.21 (q, J = 6.5
Hz, 1H, Hchiral), 1.75 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3,
75 MHz): δC 18.7, 68.9, 117.5, 122.8, 125.4, 140.5, 146.3, 148.0,
148.5, 151.7, 154.6, 155.2, 156.9; Anal. Calcd. for
C15H11ClFN3O4: C, 51.22; H, 3.15; N, 11.95. Found: C, 51.28; H,
3.16; N, 11.91.
General procedure for synthesis of the Thiosemicarbazides
(9a‐c). Acid hydrazide 2 (3.25g, 0.01 mol) was suspended in 50
mL of absolute ethanol and 0.011 mol of ammonium
thiocyanate and 0.011 mol HCl 37% or 0.011 mol of methyl,
phenyl isothiocyanate was added. The reactions was refluxed
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Synthesis, Characterization, and Herbicidal Activities of New 1,3,4-Oxadiazoles, 1,3,4-
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Thiadiazoles and 1,2,4-Triazoles Derivatives Bearing (R)-5-Chloro-3-fluoro-2-phenoxypyridine
for 4–8 h and monitored by TLC using the system of mobile
phase ethyl acetate/hexane 1:1. The solids obtained were filtered
and washed with water and recrystallized from toluene.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐N‐
methyl‐1,3,4‐thiadiazol‐2‐amine (10b). Yield 67%, mp 155–158°C,
IR (KBr): 3414 (N-H), 3067 (C-H), 1640, 1575, 1505, 1455, 1410
(C═N, C═C), 1236 (N-N), 1202 (C-N), 1034 (C-O) cm−1; 1H
NMR (CDCl3, 300 MHz): δH 10.78 (s, 1H, NH), 7.83 (s, 1Hpy.),
7.49 (d, J = 8.7 Hz, 1Hpy.), 7.2–6.92 (m, 4H, ph), 5.48 (q, J = 6.5
Hz, 1H, Hchiral), 3.36 (s, 3H, NCH3), 1.81 (d, J = 6.5 Hz, 3H, CH3);
13C NMR (CDCl3, 75 MHz): δC 21.4, 33.4, 72.0, 116.7, 122.6,
125.1, 140.1, 145.1, 147.8, 148.6, 151.0, 153.3, 160.0, 167.0; Anal.
Calcd. for C16H14ClFN4O2S: C, 50.46; H, 3.71; N, 14.71; S, 8.42.
Found: C, 50.28; H, 3.72; N, 14.68; S, 8.45.
(R)‐1‐(2‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)
propanoyl) thiosemicarbazide (9a). Yield 65%, mp 184–186°C, IR
(KBr): 3318 (NH2), 3291, 3185 (N-H), 1692 (C═O), 1615, 1505,
1451 (C═N, C═C), 1238 (C═S) cm−1; 1H NMR (CDCl3, 300
MHz): δH 9.63 (s, 1H, NH), 8.82 (s, 1H, NH), 7.87 (s, 1Hpy.), 7.51
(d, J = 8.7 Hz, 1Hpy.), 7.02–7.10 (m, 4H, ph), 6.74 (s, 2H, NH2),
4.82 (q, J = 6.5 Hz, 1H, Hchiral ), 1.65 (d, J = 6.5 Hz, 3H, CH3);
13C NMR (CDCl3, 75 MHz): δC 18.5, 75.1, 116.8, 122.6, 125.1,
140.1, 145.2, 147.5, 148.3, 151.2, 153.9, 170.4 (C═S), 179.2
(C═O); Anal. Calcd. for C15H14ClFN4O3S: C, 46.82; H, 3.67; N,
14.56; S, 8.33. Found: C, 47.00; H, 3.69; N, 14.51; S, 8.31.
5‐((R)‐1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐N‐
phenyl‐1,3,4‐thiadiazol‐2‐amine (10c). Yield 81%, mp 118–120°C,
IR (KBr): 3412, 3280 (N-H), 3059 (C-H), 1602, 1552, 1503, 1448
1
(R)‐1‐(2‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)
propanoyl)‐4‐methyl thiosemicarbazide (9b). Yield 92%, mp
152–154°C, IR (KBr): 3420, (NH2), 3318, 3185 (NH), 2997,
2940, 1691 (C═O), 1565, 1506, 1449, 1413 (C═N, C═C),
(C═N, C═C), 1199 (C-N), 1061 (C-O) cm−1; H NMR (CDCl3,
300 MHz): δH 10.56 (s, 1H, NH), the NH proton disappeared
on D2O addition, 7.85 (s, 1Hpy.), 7.48 (d, J = 8.7 Hz, 1Hpy.),
7.3–6.75 (m, 9H, ph), 5.55 (q, J = 6.5 Hz, 1H, Hchiral), 1.69 (d,
J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): δC 21.9,
72.2, 116.6, 119.5, 122.4, 125.0, 127.6, 129.8, 139.1, 140.0,
145.1, 147.3, 147.5, 151.1, 153.8, 160.6, 168.1; Anal. Calcd.
for C21H16ClFN4O2S: C, 56.95; H, 3.64; N, 12.65; S, 7.24.
Found: C, 57.10; H, 3.64; N, 12.60; S, 7.22.
General procedure for synthesis of the 1,3,4‐oxadiazoles
(11a–c). To a cooled and well‐stirred solution of thiosemicarbazides
9a–c (2 mmol) in ethanol (50 mL) was added a solution of 5 N
NaOH (1 mL). To this clear solution, a solution of 5% KI/I2 was
added until a permanent tinge color of iodine persisted at room
temperature. The reaction mixture was refluxed for 3–4 h. The result
was concentrated and cooled to room temperature to give the solid
product, which was filtered, air dried, and recrystallized from ethanol.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
1,3,4‐oxadiazol‐2‐amine (11a). Yield 68%, 177–178°C, IR (KBr):
3415–3314 (N-H), 3118 (C-H), 1650, 1613, 1505, 1455 (C═N,
C═C), 1204 (C-N), 1037 (C-O) cm−1; 1H NMR (CDCl3, 300
MHz): δH 7.80 (s, 1Hpy.), 7.61 (d, J = 8.7 Hz, 1Hpy.), 7.28–7.04
(m, 4H, ph), 6.50 (br, 2H, NH2 ), 5.40 (q, J = 6.5 Hz, 1H, Hchiral),
1.95 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz): δC
18.9, 67.6, 116.8, 122.4, 125.0, 140.0, 147.1, 151.1, 153.8, 154.2,
163.2, 169.4, 173.8; Anal. Calcd. C15H12ClFN4O3: C, 51.37; H,
3.45; N, 15.97. Found: C, 51.20; H, 3.47; N, 15.87.
1291 (N&&bond;;N), 1238 (C═S) cm−1 1H NMR (CDCl3,
;
300 MHz): δH 9.36 (s, 1H, NH), 8.80 (s, 1H, NH), 7.84 (s,
1Hpy.), 7.50 (d, J = 8.7 Hz, 1Hpy.), 7.10–6.93 (m, 4H, ph),
6.72 (s, 1H, NHMe), the NH protons disappeared on D2O
addition, 4.85 (q, J = 6.5 Hz, 1H, Hchiral), 3.02 (s, 3H,
NCH3), 1.67 (J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 75
MHz): δC 18.3, 31.5, 74.7, 116.6, 122.7, 125.2, 140.0,
145.2, 147.5, 148.3, 151.2, 153.8, 171.3 (C═S), 180.2
(C═O); Anal. Calcd. for C16H16ClFN4O3S: C, 48.18; H,
4.04; N, 14.05; S, 8.04. Found: C, 47.99; H, 4.04; N, 14.10;
S, 8.07.
(R)‐1‐(2‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy) phenoxy)
propanoyl)‐4‐phenyl thiosemicarbazide (9c). Yield 94%, mp
138–140°C, IR (KBr): 3420, 3374, 3297 (N-H), 3060, 2940,
1685 (C═O), 1506, 1450, 1412 (C═N, C═C), 1239 (N-N),
1199 (C═S) cm−1 1H NMR (CDCl3, 300 MHz): δH 9.79 (s,
;
1H, NH), 9.32 (s, 1H, NH), 9.02 (s, 1H, NH), 7.80 (s, 1Hpy.),
7.50 (d, J = 8.7 Hz, 1Hpy.), 7.40–6.97 (m, 9H, ph), 4.81 (q, J
= 6.5 Hz, 1Hchiral), 1.60 (d, J = 6.5 Hz, 3H, CH3); 13C NMR
(CDCl3, 75 MHz): δC 18.3, 74.7, 116.8, 122.5, 124.3, 125.1,
126.1, 128.9, 137.5, 140.0, 145.1, 147.4, 148.6, 151.1, 154.0,
170.3 (C═S), 179.8 (C═O); Anal. Calcd. for C21H18
ClFN4O3S: C, 54.72; H, 3.94; N, 12.16; S, 6.96. Found: C,
54.79; H, 3.93; N, 12.13; S, 6.96.
General procedure for synthesis of the 1,3,4‐thiadiazoles
(10a–c). The thiosemicarbazides 9a–c (10 mmol) was added
slowly to a concentrated sulfuric acid (5 mL), which was stirred
and kept at 0°C. The reaction mixture was stirred in ice bath for
0.5 h. It was then poured into ice‐water and neutralized with
concentrated aqueous ammonia. The precipitate was filtered,
washed with water, dried and recrystallized from ethanol to give
pure 10a–c.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
N‐methyl‐1,3,4‐oxadiazol‐2‐amine (11b). Yield 72%, mp
168–169°C, IR (KBr): 3414 (N-H), 3067 (C-H), 1632, 1598,
1
1504, 1448 (C═N, C═C), 1199 (C-N), 1090 (C-O) cm−1; H
NMR (CDCl3, 300 MHz): δH 7.81 (s, 1Hpy.), 7.47 (d, J = 8.7
Hz, 1Hpy.), 7.2–7.00 (m, 4H, ph), 6.27 (s, 1H, NH ), the NH
proton disappeared on D2O addition, 5.39 (q, J = 6.5 Hz, 1H,
Hchiral), 2.95 (s, 3H, NCH3 ), 1.71 (d, J = 6.5 Hz, 3H, CH3);
13C NMR (CDCl3, 75 MHz): δC 19.1, 67.7, 116.6, 122.3,
125.0, 140.0, 145.1, 147.1, 148.6, 151.2, 154.4, 159.0, 164.6;
Anal. Calcd. for C16H14ClFN4O3: C, 52.68; H, 3.87; N,
15.36. Found: C, 52.59; H, 3.86; N, 15.33.
5‐((R)‐1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
N‐phenyl‐1,3,4‐oxadiazol‐2‐amine (11c). Yield 74%, mp 121–
124°C, IR (KBr): 3413, 3317 (N-H), 3067 (C-H), 1622, 1573,
1504, 1452 (C═N, C═C), 1205 (C-N), 1078 (C-O) cm−1; 1H
NMR (CDCl3, 300 MHz): δH 9.59 (s, 1H, NH), 7.85 (s, 1Hpy.),
7.51 (d, J = 8.7 Hz, 1Hpy.), 7.46–7.00 (m, 9H, ph), 5.49 (q, J =
6.5 Hz, 1H, Hchiral), 1.81 (d, J = 6.5 Hz, 3H, CH3); 13C NMR
(CDCl3, 75 MHz): δC 19.1, 67.8, 116.9, 117.7, 122.4, 125.0,
125.1, 129.3, 137.8, 140.1, 145.2, 147.3, 147.4, 151.3, 154.5,
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
1,3,4‐thiadiazol‐2‐amine (10a). Yield 64%, mp 177–178°C, IR
(KBr): 3412–3279 (NH), 3105 (C-H), 1617, 1504, 1450, 1413
1
(C═N, C═C), 1239 (N-N), 1202 (C-N) cm−1; H NMR (CDCl3,
300 MHz): δH 7.97 (s, 1Hpy.), 7.85 (d, J = 8.7 Hz, 1Hpy.),
7.49–7.28 (m, 4H, ph), 7.01–6.50 (br, 2H, NH2 ), the NH and
NH2 protons disappeared on D2O addition, 5.50 (q, J = 6.5 Hz,
1H, Hchiral), 1.74 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3,
75 MHz): δC 22.2, 72.3, 116.7, 122.3, 124.9, 140.0, 147.1,
151.1, 153.8, 154.1, 163.2, 169.4, 173.8; Anal. Calcd. for
C15H12ClFN4O2S: C, 49.12; H, 3.30; N, 15.27; S, 8.74. Found:
C, 49.24; H, 3.32; N, 15.33; S, 8.76.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

224
M. Kalhor and A. Dadras
Vol 50
159.4, 161.0; Anal. Calcd. for C21H16ClFN4O3: C, 59.09; H, 3.78;
N, 13.13. Found: C, 59.27; H, 3.80; N, 13.24.
samples treated with each compound and a sample treated with
distilled water (Table 1). Range %0 means no effect and %100
means complete killing (eq. 1).
General procedure for synthesis of the 1,2,4‐triazoles (12a‐c).
A solution of 10 mmol thiosemicarbazide 9a‐c in 2N sodium
hydroxide (25 mL) was heated under reflux for 4 h. After cooling
to room temperature, diluted hydrochloric acid for neutralizing
was added. The precipitate was filtered and washed several times
with water. The compounds were recrystallized from toluene/n‐
hexane.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
4H‐1,2,4‐triazole‐3‐thiol (12a). Yield 55%, mp 176–178°C; IR
(KBr): 3412, 3233 (N-H), 2529 (S-H), 1615, 1505, 1449 (C═N,
C═C), 1200 (C═S), 846 (C-S) cm−1; 1H NMR (CDCl3, 300
MHz): δH 12.75 (s, 1H, SH.), 10.36 (s, 1H, NH), the SH and NH
protons disappeared on D2O addition, 7.81 (s, 1Hpy.), 7.46 (d, J =
8.7 Hz, 1Hpy.), 7.02–6.96 (m, 4H, ph), 5.25 (q, J = 6.5 Hz, 1H,
Hchiral), 1.70 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (CDCl3, 75
MHz): δC 19.1, 68.2, 116.5, 122.2, 124.9, 139.8, 145.6, 146.8,
147.9, 151.3, 153.6, 161.5, 170.5; Anal. Calcd. for
C15H12ClFN4O2S: C, 49.12; H, 3.30; N, 15.27; S, 8.74. Found: C,
48.94; H, 3.32; N, 15.32; S, 8.70.
%Herbicidal activity ¼ Wb ¼ Wt=Wbñ100
(1)
Wb = biomass of blank; Wt = biomass of treated
Acknowledgments. The authors express their deep gratitude to
Department of Chemistry, Payame Noor University for providing
financial support and also thank the Industrial Pesticide Research
Center for the evaluating of herbicidal activities.
REFERENCES AND NOTES
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P. L. Acta Pharm 2008, 58, 135.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
4‐methyl‐4H‐1,2,4‐triazole‐3‐thiol (12b). Yield 76%, mp
120–125°C; IR (KBr): 3413 (NH), 3099, 2935 (C-H), 2752
(SH), 1598, 1574, 1504, 1448, (C═N, C═C), 1233 (N-N),
[2] Gaonkar, S. L.; Rai, K. M. L.; Prabhuswamy, B. Eur J Med
Chem 2006, 41, 841.
[3] Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur J Med
Chem 1996, 31, 819.
[4] Li, Y.; Liu, J.; Zhang, H.; Yanga, X.; Liub, Z. Bioorg Med
Chem Lett 2006, 16, 2278.
1198 (C═S), 732 (C-S) cm−1 1H NMR (CDCl3, 300 MHz):
;
δH 12.85 (br, 1H, SH), 7.85 (s, 1Hpy.), 7.48 (d, J = 8.7 Hz,
1Hpy.), 7.24–7.06 (m, 4H, ph), 5.50 (q, J = 6.5 Hz, 1H,
Hchiral), 3.66 (s, 3H, NCH3), 1.76 (d, J = 6.5 Hz, 3H, CH3);
13C NMR (CDCl3, 75 MHz): δC 18.2, 31.3, 68.5, 116.4,
122.6, 125.1, 140.1, 145.1, 147.5, 148.6, 151.1, 151.5, 153.6,
168.0; Anal. Calcd. for C16H14ClFN4O2S: C, 50.46; H, 3.71;
N, 14.71; S, 8.42. Found: C, 50.60; H, 3.71; N, 14.69; S, 8.43.
(R)‐5‐(1‐(4‐(5‐Chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl)‐
4‐phenyl‐4H‐1,2,4‐triazole‐3‐thiol (12c). Yield 94%, mp
169–171°C, IR (KBr): 3413 (N-H), 3100, 2920 (C-H), 1615,
1598, 1503, 1447 (C═N, C═C), 1235 (N-N), 1199 (C═S)
[5] Karegoudar, P.; Prasad, D. J.; Ashok, M.; Mahalinga, M.;
Poojary, B.; Holla, B. S. Eur J Med Chem 2008, 43, 808.
[6] Mamolo, G.; Vio, L.; Banfi, E. Il Farmaco 1996, 51, 71.
[7] Labanauskas, L.; Kalcas, V.; Udrenaite, E.; Gaidelis, P.;
Brukstus, A.; Dauksas, A. Pharmazie 2001, 56, 617.
[8] Misra, U.; Hitkari, A.; Saxena, A.; Gurtu, S.; Shanker, K. Eur J
Med Chem 1996, 31, 629.
[9] Goswami, B. N.; Kataky, C. J. S.; Baruah, J. N. J Heterocycl
Chem 1984, 21, 1225.
[10] Luo, Y. P.; Long Lin, L.; Yang, G. F. J Heterocycl Chem
2007, 44, 937.
[11] Bayrak, H.; Demirbas, A.; Karaoglu, S. A.; Demirbas, N. Eur J
Med Chem 2009, 44, 1057.
[12] Liu, Z.; Yang, G.; Qin, X. J Chem Technol Biotechnol 2001,
76, 1154.
[13] Kennedy, D.; Summers, L. J Heterocycl Chem 1981, 18, 401.
[14] Baker, D. R.; Fenys, J. G.;Lahm, G. P.;Selby, T. P.;Stevenson, T. M.
ACS Symposium series 800, 2002, 9.
[15] Soonsung, H.; Naotaka, Y.; Akiko, H.; Shinya, K.; Eichi, K. J
Pestic Sci 2005, 30, 406.
cm−1 1H NMR (CDCl3, 300 MHz): δH 12.65 (br, 1H, SH),
;
7.85 (s, 1Hpy.), 7.48 (d, J = 8.7 Hz, 1Hpy.), 7.3–6.75 (m, 9H,
ph), 5.21 (q, J = 6.5 Hz, 1H, Hchiral), 1.63 (d, J = 6.5 Hz, 3H,
CH3); 13C NMR (CDCl3, 75 MHz): δC 17.9, 68.4, 117.1,
122.3, 125.1, 128.2, 129.6, 130.2, 133.0, 140.1, 140.2,
145.1, 147.5, 148.6, 151.1, 151.5, 153.6; Anal. Calcd. for
C21H16ClFN4O2S: C, 56.95; H, 3.64; N, 12.65; S, 7.24.
Found: C, 56.82; H, 3.63; N, 12.68; S, 7.26.
[16] Li, H. P. Pestic Sci Adm 2004, 25, 28.
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[18] Rubin, B.; Tal, A.; Yasuor, H. Acta Herbologica 2004, 13,
277.
[19] Mobinikhaledi, A.; Foroughifar, N.; Kalhor, M.; Mirabolfathy
M. J Heterocycl Chem 2010, 47, 77.
Herbicidal testing. The herbicidal activities of new cyclic
compounds 4–8 and 9–12a–c were evaluated for post‐
emergence inhibitory effect against Echinochloa cruss‐galli
(Ech), Avena fatua (Ave), and Sorgum halepense (Sor) weeds
using known procedure [21, 26]. For these tests, an emulsion
concentrate at EC 8% was formulated by mixing eight parts of
the active ingredients (a.i.), 14 parts of blended emulsifiers MS
and FF4 (trade name), 10 parts of cyclohexanone, 30 parts of
pine oil and added sunflower oil up to 100 mL. Herbicidal
testing was carried out at the three‐ to four‐leaf stage by a
sprayer at the rate of 125 g a.i/ha with a spelling volume of
1000 L ha−1. All the treatments were replicated three times in a
completely randomized design. Three weeks after the treatment,
weed control and crop damage were calculated as the inhibition
percent by making a biomass reduction comparison between
[20] Kalhor, M.; Mobinikhaledi, A.; Dadras, A.; Tohidpour, M. J
Heterocycl Chem 2011, Impress.
[21] Tajik, H.; Dadras, A. J Pestic Sci 2011, 36, 27.
[22] Mobinikhaledi, A.; Foroughifar, N.; Kalhor, M.; Ebrahimi, S.;
Bodaghi Fard, M. A. Phosphorus Sulfur Silicon Relat Elem 2011, 186, 67.
[23] Zhong, P.; Hu, H.; Guo, S. Synth Commun 2004, 34, 4301.
[24] Dabiri, M.; Salehi, P.; Baghbanzadeh, M.; Zolfigol, M. A.;
Bahramnejad, M. Synth Commun 2007, 37, 1201.
[25] Yamada, N.; Kataoka, Y.; Nagami, T.; Hong, S.; Kawai, S.;
Kuwano, E. J Pestic Sci 2004, 29, 205.
[26] Chen, T.; Shen, P.; Li, Y.; He, H. J Fluorine Chem 2006, 127,
291.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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