Ultrasound-assisted synthesis and preliminary bioactivity of novel 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives containing fluorine

Article abstract of DOI:10.1016/j.cclet.2012.03.005

Eight novel 5,7-disubstituted-2-{5-methyl-3-(4-trifluoromethylphenyl) isoxazol-4-ylcarbonylimino}-2H-1,2,4-thiadiazolo[2,3-a]pyrimidines were synthesized by multi-step reactions in yields 68-85%. Reactions were carried out either by ultrasound irradiation

Full text of DOI:10.1016/j.cclet.2012.03.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 561–564
www.elsevier.com/locate/cclet
Ultrasound-assisted synthesis and preliminary bioactivity
of novel 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives
containing fluorine
*
Mao Rong Wang, Lin Jiang , Shao Fang Zhou, Ze Yuan Zhang, Zeng Chen Ji
College of Chemistry and Material Science, Shandong Agricultural University, Tai’an 271018, China
Received 20 December 2011
Available online 18 April 2012
Abstract
Eight novel 5,7-disubstituted-2-{5-methyl-3-(4-trifluoromethylphenyl)isoxazol-4-ylcarbonylimino}-2H-1,2,4-thiadiazolo[2,3-
a]pyrimidines were synthesized by multi-step reactions in yields 68À85%. Reactions were carried out either by ultrasound
irradiation or conventional method, and found it was faster and more efficient under ultrasonic irradiation. Preliminary herbicidal
activities against Echinochloa crus-galli, Digitaria sanguinalis and Chenopodium serotinum were also evaluated by flat-utensil
method, and the results indicated that the target compounds exhibited significant activities, some were even higher than the control
herbicide.
# 2012 Lin Jiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2H-1,2,4-Thiadiazolo[2,3-a]pyrimidine; Synthesis; Ultrasound; Bioactivity
The fused heterocycles with a pyrimidine ring are important pyrimidine derivatives and exhibit excellent biological
activities, such as anti-virus, antitumor, antihypertensive, antifungal and herbicidal activities [1–5]. Among the
derivatives, substituted 2H-1,2,4-thiadiazolo[2,3-a]pyrimidines possess high herbicidal activity, being inhibitors of
acetohydroxyacid synthase (AHAS) [6–8].
On the other hand, isoxazole derivatives are widely used in medicine and pesticide fields owing to their exceptional
biological activities. Many isoxazole compounds have been developed into herbicide, fungicide, insecticide and other
agricultural chemicals [9,10]. In particular, their excellent herbicidal activity attracts many pesticide chemists’
attention, and more than 10 isoxazole herbicides have been discovered, such as isoxaben [11] and isoxaflutole [12].
Nowadays, ultrasound-assisted synthesis as an effective technique is widely used in chemical reactions, which
exhibits many advantages including higher yield, shorter reaction time and milder reaction condition when compared
with conventional methods [13]. Motivated by these findings, herein we introduced a trifluoromethyl phenyl moiety to
the isoxazole ring, followed by linking a 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine moiety though a carbonylimino
bridge, to synthesize eight novel 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives. Their herbicidal activities were
evaluated against selected weeds.
* Corresponding author.
E-mail address: jiangl@sdau.edu.cn (L. Jiang).
1001-8417/$ – see front matter # 2012 Lin Jiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.03.005

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M.R. Wang et al. / Chinese Chemical Letters 23 (2012) 561–564
Scheme 1. Reagents and conditions: (i) SOCl2, reflux 4 h; (ii) KSCN, CH3CN, PEG-400, reflux 3 h; (iii) 2-amino-4,6-disubstituentedpyrimidines,
TBAB, CH3CN, reflux 2 h; (iv) Br2, CHCl3, USI, r.t. 1–2 h.
The target compounds were synthesized using the strategy described in Scheme 1. The starting materials 5-methyl-
3-(4-trifluoromethylphenyl)isoxazole-4-formic acid 1 and 2-amino-4,6-disubstituented pyrimidines were prepared
according to the literature [14] and [15], respectively. The synthesis began by treating 1 with SOCl2 to yield 5-methyl-
3-(4-trifluoromethylphenyl)isoxazole-4-carbonyl chloride 2, followed by reacting with KSCN in anhydrous
acetonitrile to give acyl isothiocyanate 3 [7]. Then, the unpurified isothiocyanate solution was slowly added to a
mixture of 2-amino-4,6-disubstituented pyrimidine and tetrabutyl ammonium bromide (TBAB) in acetonitrile to
afford corresponding acyl thiourea 4. Finally, 4 was cyclized using Br2 as oxidant in chloroform to generate the target
compound 5, and the reaction was carried out either by ultrasound irradiation with power 250 W (USI method) or stir
at room temperature (conventional method). The use of ultrasound irradiation could afford the target compounds in
short time and moderate to good yield (Table 1). For example, the yields of 5a, 5b, 5d and 5e were more than 80%, and
their reaction times were 60–100 min. However, the yields were only 48–57%, and the reaction times were from 180 to
300 min by conventional method.
The structures of the target compounds were confirmed by IR, NMR and elemental analyses as shown in Ref. [16].
The reaction mechanism of acyl thiourea 4 with Br2 may be that a bromine molecule attacks the two active H atoms
in the N–H bonds, while the S atom in C S bond attacks one N atom in the pyrimidine ring. Moreover, if two
substituents at 4,6-positions of pyrimidine are different, the S atom will mainly attacks the N atom with larger charge
density to generate the target compound [7]. Herein, we calculated the charges of the two N atoms in the pyrimidine
ring by B3LYP/6-31G(d) according to density functional theory, and the result was listed in Table 2. In compounds 4c–
4h, when R1 was OCH3, OH, Cl, SCH3, Cl and OCH3, respectively, the charge density of N1 atom was larger, so the S
atom linked with N1 atom. Therefore, we assigned the positions of R1 and R2 as shown in Table 1 and suggested a
possible reaction mechanism (Scheme 2).
In vitro herbicidal activity of the target compound 5 was evaluated by flat-utensil method according to the literature
[7]. Three kinds of weeds, Digitaria sanguinalis, Chenopodium serotinum and Echinochloa crus-galli, were used in
Table 1
Data of synthesis (USI), in vitro herbicidal activitya for the target compounds 5a–5h.
Compd.
R1
R2
Time (min)
Yield (%)
C. serotinum
D. sanguinalis
E. crus-galli
I
II
III
I
II
III
I
II
III
5a
5b
5c
5d
5e
5f
CH3
OCH3
OCH3
OH
CH3
60
60
85
85
72
83
80
68
76
68
93.7
89.8
95.1
70.4
77.1
83.8
75.3
68.2
90.5
81.9
82.5
86.5
47.6
63.6
70.4
64.7
57.3
87.5
53.8
55.3
58.9
36.6
50.6
46.8
54.1
50.6
55.7
88.9
83.2
65.4
58.1
80.1
60.3
73.5
77.9
80.7
73.5
67.0
61.7
50.7
64.9
45.5
50.0
42.6
52.4
56.1
37.5
50.3
25.4
43.9
29.4
29.7
30.8
33.8
87.1
84.3
77.1
76.2
86.6
85.5
90.5
79.3
82.2
84.9
59.8
64.8
65.9
58.6
61.5
84.3
63.7
49.2
54.8
46.4
48.6
49.7
43.0
50.3
50.9
58.1
36.8
OCH3
CH3
60
CH3
90
Cl
CH3
100
90
SCH3
Cl
CH3
5g
5h
CK
OCH3
SCH3
90
OCH3
90
a
Herbicidal activities are expressed with inhibition rate for root length (%); I, II and III represent the tests at concentrations of 100, 50 and 10 mg/
L, respectively.

M.R. Wang et al. / Chinese Chemical Letters 23 (2012) 561–564
563
Table 2
Atom charges of N1 and N2 for compounds 4c–4h.
Compd.
R1
R2
Atom charge
N1
N2
4c
4d
4e
4f
OCH3
OH
CH3
À0.599
À0.601
À0.525
À0.565
À0.548
À0.577
À0.508
À0.509
À0.487
À0.498
À0.525
À0.559
CH3
Cl
CH3
SCH3
Cl
CH3
4g
4h
OCH3
SCH3
OCH3
S
R1
R2
R1
N
S
R1
R2
O
O
N
N
O
N
N
C
S
C
. .
N
N
2HBr
C
N
H
N
C
N
H
C
N
Ar
R2
Ar
Ar
N
H
Br
Br
HBr
Br
Note: Ar =
F3C
CH3
N
O
Scheme 2. A suggested mechanism for synthesis of the target compound.
the test. Nicosulfuron, a commercial herbicide, was used as control (CK). As seen from Table 1, 5a and 5b exhibited
good herbicidal activities against the three tested weeds at a dose of 100 mg/L, with inhibitory rates of 84.3–93.7%,
near to or higher than nicosulfuron. In addition, 5c possessed excellent activity against Chenopodium serotinum at
100 mg/L and 50 mg/L; 5e displayed good activity against Digitaria sanguinalis at the two doses. Moreover, 5e, 5f
and 5g showed considerable activities against Echinochloa crus-galli in comparison with the control.
Acknowledgment
This project was supported by Shandong Province Natural Science Foundation (No. ZR2009BM044).
References
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[16] Analytic data for target compounds. 5a: mp 220–221 8C. 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 3H), 2.53 (s, 3H), 2.72 (s, 3H), 7.03 (s, 1H),
6.80–7.45 (m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.6, 166.5, 162.7, 161.0, 158.6, 158.1, 152.9, 135.2, 133.9, 132.4, 129.7, 128.0,
125.5, 112.8, 21.4, 20.7, 12.0. Anal. Calcd. for C19H14F3N5O2S: C 52.65, H 3.26, N 16.16; found: C 52.45, H 3.16, N 16.20. 5b: mp 233–

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M.R. Wang et al. / Chinese Chemical Letters 23 (2012) 561–564
1
234 8C. H NMR (400 MHz, DMSO-d6): d 2.75 (s, 3H), 3.82 (s, 3H), 3.95 (s, 3H), 5.25 (s, 1H), 6.85–7.45 (m, 4H). 13C NMR (100 MHz,
DMSO-d6): d 169.8, 166.4, 162.9, 160.5, 159.1, 158.3, 153.4, 135.5, 133.2, 132.1, 130.5, 128.6, 125.0, 112.7, 55.3, 54.7, 11.8. Anal. Calcd. for
C19H14F3N5O4S: C 49.03, H 3.03, N 15.05; found: C 49.43, H 3.01, N 15.36. 5c: mp 240–241 8C. 1H NMR (400 MHz, DMSO-d6): d 2.62 (s,
3H), 2.79 (s, 3H), 3.93 (s, 3H), 5.75 (s, 1H), 6.96–7.38 (m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.9, 166.0, 163.0, 160.6, 159.1, 158.6,
153.1, 134.9, 133.2, 132.1, 130.8, 128.6, 125.0, 112.7, 54.6, 21.4, 11.8. Anal. Calcd. for C19H14F3N5O3S: C 50.78, H 3.14, N 15.58; found: C
50.63, H 3.28, N 15.28. 5d: mp > 300 8C. 1H NMR (400 MHz, DMSO-d6): d 2.50 (s, 3H), 2.82 (s, 3H), 6.10 (s, 1H), 6.95–7.35 (m, 4H). 13
C
NMR (100 MHz, DMSO-d6): d 169.7, 165.4, 162.4, 160.5, 158.6, 158.4, 153.6, 135.7, 133.2, 132.3, 130.2, 128.3, 125.3, 113.5, 21.9, 11.8.
Anal. Calcd. for C18H12F3N5O3S: C 49.66, H 2.78, N 16.09; found: C 49.48, H 2.52, N 16.18. 5e: mp 252–254 8C. 1H NMR (400 MHz, DMSO-
d6): d 2.50 (s, 3H), 2.72 (s, 3H), 5.90 (s, 1H), 7.16–7.42 (m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.7, 165.4, 162.4, 160.5, 158.6, 158.4,
153.6, 135.7, 133.2, 132.4, 130.2, 128.3, 125.3, 113.5, 21.4, 12.2. Anal. Calcd. for C18H11ClF3N5 O2S: C 47.64, H 2.44, N 15.43; found: C
47.54, H 2.45, N 15.32. 5f: mp 242–244 8C. 1H NMR (400 MHz, DMSO-d6): d 2.43 (s, 3H), 2.63 (s, 3H), 2.72 (s, 3H), 5.91 (s, 1H), 7.34–7.48
(m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.8, 165.9, 163.0, 160.4, 159.2, 158.5, 153.6, 135.2, 133.2, 132.1, 130.1, 128.6, 125.1, 112.7,
21.6, 20.4, 11.9. Anal. Calcd. for C19H14F3N5O2S2: C 49.03, H 3.03, N 15.05; found: C 49.23, H 3.19, N 15.33. 5g: mp 255–256 8C. 1H NMR
(400 MHz, DMSO-d6): d 2.72 (s, 3H), 3.92 (s, 3H), 5.70 (s, 1H), 7.02–7.35 (m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.9, 166.0, 163.0,
160.6, 159.1, 158.5, 153.4, 135.1, 133.4, 132.1, 130.5, 128.7, 125.0, 112.6, 54.5, 11.9. Anal. Calcd. for C18H11ClF3N5 O3S: C 46.02, H 2.36, N
14.91; found: C 46.11, H 2.36, N 14.87. 5h: mp 228–230 8C. 1H NMR (400 MHz, DMSO-d6): d 2.65 (s, 3H), 2.79 (s, 3H), 3.90 (s, 3H), 5.91 (s,
1H), 6.96–7.38 (m, 4H). 13C NMR (100 MHz, DMSO-d6): d 169.8, 165.2, 162.9, 159.6, 159.1, 158.3, 153.0, 135.5, 132.8, 132.1, 130.4, 128.8,
125.1, 112.3, 54.7, 20.6, 12.0. Anal. Calcd. for C19H14F3N5O3S2: C 47.40, H 2.93, N 14.55; found: C 47.50, H 2.85, N 14.42.