Microwave-assisted synthesis of propesticides 1,3,4-thiadiazole aminophosphonates

Article abstract of DOI:10.1080/00397911003707030

A novel and easy synthetic route to diethyl (5-substituted phenyl-1,3,4-thiadiazol-2-ylamino) (substituted phenyl) methylphosphonates has been achieved by the reaction of substituted benzylidene-5-(substituted phenyl)-1,3,4-thiadiazol-2-amines and diethyl phosphite under microwave irradiation. These 1,3,4-thiadiazole aminophosphonates were identified by infrared, 1H NMR, and elemental analyses. The target compounds were obtained in better yields (71-89%) and shorter time (10min) than with conventional heating.

Full text of DOI:10.1080/00397911003707030

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Microwave-Assisted Synthesis of
Propesticides 1,3,4-Thiadiazole
Aminophosphonates
Rong Wan a , Peng Wang a , Fen Han a , Yao Wang a & Jianqiang
Zhang a
a Department of Applied Chemistry, College of Science, Nanjing
University of Technology, Nanjing, Jiangsu, China
Published online: 25 Feb 2011.
To cite this article: Rong Wan , Peng Wang , Fen Han , Yao Wang & Jianqiang Zhang (2011) Microwave-
Assisted Synthesis of Propesticides 1,3,4-Thiadiazole Aminophosphonates, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:6, 864-870
To link to this article: http://dx.doi.org/10.1080/00397911003707030
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Synthetic Communications1, 41: 864–870, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003707030
MICROWAVE-ASSISTED SYNTHESIS OF
PROPESTICIDES 1,3,4-THIADIAZOLE
AMINOPHOSPHONATES
Rong Wan, Peng Wang, Fen Han, Yao Wang, and
Jianqiang Zhang
Department of Applied Chemistry, College of Science, Nanjing University of
Technology, Nanjing, Jiangsu, China
GRAPHICAL ABSTRACT
Abstract
A novel and easy synthetic route to diethyl (5-substituted phenyl-1,3,4-
thiadiazol-2-ylamino) (substituted phenyl) methylphosphonates has been achieved by the
reaction of substituted benzylidene-5-(substituted phenyl)-1,3,4-thiadiazol-2-amines and
diethyl phosphite under microwave irradiation. These 1,3,4-thiadiazole aminophosphonates
were identified by infrared, 1H NMR, and elemental analyses. The target compounds were
obtained in better yields (71–89%) and shorter time (10 min) than with conventional
heating.
Keywords Microwave irradiation; synthesis; 1,3,4-thiadiazole aminophosphonates
Received May 20, 2009.
Address correspondence to Rong Wan, Department of Applied Chemistry, College of Science,
Nanjing University of Technology, Nanjing, Jiangsu 210009, China. E-mail: rwan@njut.edu.cn
864

THIADIAZOLE AMINOPHOSPHONATES
865
INTRODUCTION
The discovery of new structures is one of the most important topics of research
in medicinal and pesticide chemistry. Among various biological heterocyclic com-
pounds, 1,3,4-thiadiazole derivatives have attracted specific interest because of their
promising biological activity. For example, some 1,3,4-thiadiazole derivatives have
been reported to possess anti-inflammatory, antiproliferative, antibacterial, and
fungicidal activities.[1–5]
a-Aminophosphonate derivatives have received wide attention in medicinal,
bioorganic, and organic chemistry. The applications of a-amino phosphonates have
ranged from agriculture to medical uses such as anticancer agents,[6] enzyme inhibi-
tors,[7] peptide mimetics,[8] antibiotics, and herbicides.[9]
In view of this research and our desire to develop new insecticidal agents of
high potency, we fused biological 1,3,4-thiadiazole and aminophosphonate struc-
tures to obtain compounds possessing better biological activity.
Conventional organic synthesis reactions suffered from drawbacks such as the
use of high-boiling solvents, long reaction times, and poor yields. Microwave (MW)
irradiation is currently used to carry out a wide range of reactions.[10,11] Compared
with traditional reactions under refluxing, the MW reaction technique is often rapid
and more convenient and has environmental and economic advantages.
In this study, we have designed and synthesized a series of new compounds
containing 1,3,4-thiadiazole and aminophosphonate under MW irradiation.
RESULTS AND DISCUSSION
The diethyl (5-substituted phenyl-1,3,4-thiadiazol-2-ylamino) (substituted phe-
nyl) methylphosphonates (4a–k) were designed and prepared by the reaction of
N-(substituted benzylidene)-5-(substituted phenyl)-1,3,4-thiadiazol-2-amines (3a–k)
and diethyl phosphite under MW irradiation as shown in Scheme 1. The compounds
3a–k were prepared by the reaction of 5-(substituted phenyl)-1,3,4-thiadiazol-2-
amines (2a–k) with substituted benzaldehydes in toluene under a Dean–Stark trap.
Compounds 2a–k were synthesized by substituted benzoic acids with thiosemicarba-
zide in the presence of phosphorus oxychloride.
Preliminary experiments to examine the reaction time and irradiation power
were performed using 3a (10 mmol) and diethyl phosphite (50 mmol) as a model sys-
tem to synthesize the compound 4a (Table 1). Various reaction times and irradiation
power were tested (Table 1, entries 1–5). All comparative reactions were conducted
under optimized conditions, and compound 4a was obtained under MW irradiation.
The best yield of 4a (85%) was obtained by carrying out the reaction under MW
irradiation (300 W) for 10 min. The reaction was also carried out with conventional
heating (Table 1, entry 7), which required more heating time (8 h) but gave a lesser
yield (60%).
The formation of diethyl aryl (5-aryl-1,3,4-thiadiazol-2-ylamino) methylpho-
sphonates (4a–k) was confirmed by recording elemented analyses (EA), infrared
1
(IR), and H NMR. The IR spectrums of 4a–k displayed bands at 3188–3274 cmꢀ1
,
1652 cmꢀ1, 1220–1278 cmꢀ1, and 1020–1058 cmꢀ1 due to N-H, C N, P O, and
1
P-O stretching frequencies, respectively. The H NMR spectrum of 4a exhibited a
=
=

866
R. WAN ET AL.
Scheme 1. Synthesis route of compounds 4a–k. R1 ¼ 2,4-dichloro (a), 3-methyl (b), 3,5-dimethyl (c),
4-methoxy (d), 2,4-dichloro (e), 4-nitro (f), 4-fluoro (g), 3,5-dimethyl (h), 3,5-dimethyl (i), 3-methyl-4-nitro
(j), and 3-fluoro (k). R2 ¼ 4-methoxy (a), 4-chloro (b), 4-chloro (c), 4-fluoro (d), H (e), 4-methoxy (f), H (g),
4-methoxy (h), 2,4-dichloro (i), 4-chloro (j), and 4-chloro (k).
singlet at d8.28, which accounts for the NH proton; a multiplet appeared at d6.85–
8.13, which accounts for the aromatic protons of the phenyl ring; a doublet appeared
at d5.50, which accounts for CH proton; a multiplet appeared at d3.86–4.24, which
accounts for the CH2 proton; and a triplet appeared at d1.14–1.32, which accounts
for CH3 proton.
In conclusion, we have developed a fast, convenient, and efficient method
for the preparation of diethyl (5-substituted phenyl-1,3,4-thiadiazol-2-ylamino)
(substituted phenyl) methylphosphonates under MW irradiation. The simp-
lification of the reaction procedure together with very short reaction time and a
greater yield made this procedure more useful and attractive than the currently
available methods.
Table 1. Synthesis of 4a
Entry
Mode of activation
Time
Power=temp.
Yield (%)b
1
2
3
4
5
6
7
MW
MW
MW
MW
MW
MW
Da
3 min
7 min
10 min
15 min
10 min
10 min
8 h
300 W
300 W
300 W
300 W
200 W
400 W
80 ꢁC
40
55
85
85
60
77
60
MW, microwave irradiation; D, conventional heating.
aThe reaction was conducted with 3a (10 mmol) and diethyl phosphite (50 mmol) at 80 ꢁC.
All the products were investigated thoroughly by 1H NMR, IR, and elemental analysis.
bIsolated yields.

THIADIAZOLE AMINOPHOSPHONATES
867
EXPERIMENTAL
Instrumentation and Chemicals
All nonaqueous reactions were carried out under a nitrogen atmosphere.
Unless otherwise noted, all reagents and solvents were used as received. Reactions
were monitored by thin-layer chromatography (TLC) with visualization by ultra-
violet light.
Melting points were recorded on an X-4 binocular microscope melting-point
apparatus (Beijing Tech Instruments Co., Beijing, China) and were corrected in
advance. Elemental analyses were performed on an Elementer Vario EL III elemen-
1
tary analysis instrument. H NMR spectra were obtained in CDCl3 and dimethyl-
sulfoxide (DMSO-d6), and they were recorded on a Bruker DRX500 spectrometer.
Resonances were given in parts per million (ppm, d) relative to tetramethylsilane
(TMS), and peak multiplicity is reported as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), or b (broad). IR spectra in KBr were recorded by a
Perkin-Elmer PE-683 infrared spectrometer. MW experiments were carried out on
a WF-4000M microwave fast reaction system (Shanghai Qiyao Analysis Instrument
Co., Shanghai, China).
General Synthetic Procedure for the Preparation of 5-(Substituted
phenyl)-1,3,4-thiadiazol-2-amines (2a–k)
To a mixture of substituted benzoic acid 1 (0.1 mol) and thiosemicarbazide
(0.1 mol), POCl3 (0.3 mol) was added dropwise at 0–5 ꢁC and maintained for
30 min. The temperature reaction mixture was allowed to rise until reflux, and the
mixture was stirred for 4 h. After cooling, 50 mL water were added into the reaction
mixture. The pH of the reaction solution was adjusted to the range of 8–9 with a
solution of 50% NaOH. The crude product was precipitated, filtered, washed
with water, dried, and recrystallized from ethanol to afford compounds 2a–k.
General Synthetic Procedure for the Preparation of N-(Substituted
benzylidene)-5-(substituted phenyl)-1,3,4-thiadiazol-2-amines
(3a–k)
A mixture of 2 (5 mmol) and substituted benzaldehyde was stirred and allowed
to rise in temperature until reflux in toluene under a Dean–Stark trap. The reaction
was monitored by TLC until the reaction ended. After the reaction, the toluene was
evaporated under reduced pressure. The crude product was precipitated, filtered,
washed with ethanol, dried, and recrystallized from acetone to afford compounds
3a–k.
General Synthetic Procedure for the Preparation of Diethyl
(5-substituted phenyl-1,3,4-thiadiazol-2-ylamino)(substituted
phenyl) Methylphosphonates (4a–k)
A mixture of 3 (10 mmol) and diethyl phosphite (50 mmol) was stirred in an
open vessel and irradiated in an experimental MW instrument at 300 W for 10 min

868
R. WAN ET AL.
(max. temp. 120 ꢁC). After completion of the reaction, the remaining diethyl
phosphite was evaporated under reduced pressure. The resulting viscous liquid
was recrystallized form EtOH to obtain 4a–k. The physical constants and spectral
analyses are listed.
Data
1
Compound 4a. Yield: 85%. Yellow crystals. Mp 150–152 ꢁC (153 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.14–1.32 (t, 6H, CH3), 3.76 (s, 3H, CH3),
3.86–4.24 (m, 4H, CH2), 5.50 (d, 1H, CH), 6.85–8.13 (m, 7H, Ph), 8.28 (s, 1H,
NH). IR (KBr) n: 3226, 3012, 2935, 1652, 1506, 1456, 1301, 1261, 1222, 1186,
1091, 1054 cmꢀ1. Anal. calcd. for C20H22Cl2N3O4PS: C, 47.82; H, 4.41; N, 8.36; S,
6.38. Found: C, 47.61; H, 4.32; N, 8.18; S, 6.19.
1
Compound 4b. Yield: 87%. White crystals. Mp 184–185 ꢁC (187 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.18–1.32 (t, 6H, CH3), 2.36 (s, 3H, CH3),
3.94–4.22 (m, 4H, CH2), 5.47 (d, 1H, CH), 7.17–7.57 (m, 7H, Ph), 7.86 (s, 1H,
NH). IR (KBr) n: 3242, 3016, 2929, 2906, 1652, 1506, 1456, 1269, 1234, 1180,
1089, 1045 cmꢀ1. Anal. calcd. for C20H23ClN3O3PS: C, 53.16; H, 5.13; N, 9.30; S,
7.10. Found: C, 53.01; H, 4.98; N, 9.22; S, 6.89.
1
Compound 4c. Yield: 80%. White crystals. Mp 173–176 ꢁC (179 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.18–1.32 (t, 6H, CH3), 2.32 (s, 6H, CH3),
3.93–4.19 (m, 4H, CH2), 5.39 (d, 1H, CH), 7.01–7.54 (m, 7H, Ph). IR (KBr) n:
3274, 3031, 2985, 2910, 1652, 1506, 1456, 1271, 1244, 1195, 1091, 1049 cmꢀ1. Anal.
calcd. for C21H25ClN3O3PS: C, 54.13; H, 5.41; N, 9.02; S, 6.88. Found: C, 53.89; H,
5.32; N, 8.89; S, 6.76.
1
Compound 4d. Yield: 89%. White crystals. Mp 160–164 ꢁC (160 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.16–1.32 (t, 6H, CH3), 3.83 (s, 3H, CH3),
3.90–4.22 (m, 4H, CH2), 5.52 (d, 1H, CH), 6.87–7.98 (m, 7H, Ph), 8.08 (s, 1H,
NH). IR (KBr) n: 3215, 3026, 2987, 2935, 1652, 1506, 1456, 1299, 1255, 1218,
1081, 1031 cmꢀ1. Anal. calcd. for C20H23FN3O4PS: C, 53.21; H, 5.14; N, 9.31; S,
7.10. Found: C, 53.01; H, 5.02; N, 9.11; S, 6.95.
1
Compound 4e. Yield: 79%. White crystals. Mp 168–170 ꢁC (170 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.11–1.33 (t, 6H, CH3), 3.83–4.24 (m, 4H,
CH2), 5.59 (d, 1H, CH), 7.25–8.50 (m, 8H, Ph), 8.66 (s, 1H, NH). IR (KBr) n:
3215, 3012, 2937, 2904, 1652, 1506, 1456, 1232, 1220, 1105, 1047, 1020 cmꢀ1. Anal.
calcd. for C19H20Cl2N3O3PS: C, 48.32; H, 4.27; N, 8.90; S, 6.79. Found: C, 48.18; H,
4.06; N, 8.76; S, 6.62.
1
Compound 4f. Yield: 82%. White crystals. Mp 175–178 ꢁC (176 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.17–1.34 (t, 6H, CH3), 3.76 (s, 3H, CH3),
3.89–4.24 (m, 4H, CH2), 5.53 (d, 1H, CH), 6.84–8.21 (m, 8H, Ph), 8.24 (s, 1H,
NH). IR (KBr) n: 3218, 3026, 2979, 2904, 1652, 1515, 1506, 1456, 1251, 1230,
1182, 1049, 1024 cmꢀ1. Anal. calcd. for C20H23N4O6PS: C, 50.21; H, 4.85; N,
11.71; S, 6.70. Found: C, 50.15; H, 4.68; N, 11.62; S, 6.56.

THIADIAZOLE AMINOPHOSPHONATES
869
1
Compound 4g. Yield: 75%. Yellow crystals. Mp 180–183 ꢁC (185 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.13–1.32 (t, 6H, CH3), 3.84–4.21 (m, 4H,
CH2), 5.51 (d, 1H, CH), 7.03–7.72 (m, 9H, Ph). IR (KBr) n: 3230, 3028, 2908,
2866, 1652, 1506, 1456, 1292, 1278, 1228, 1060, 1020 cmꢀ1. Anal. calcd. for
C19H21FN3O3PS: C, 54.15; H, 5.02; N, 9.97; S, 7.61. Found: C, 53.89; H, 4.89; N,
9.63; S, 7.48.
1
Compound 4h. Yield: 83%. White crystals. Mp 154–158 ꢁC (160 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.15–1.30 (t, 6H, CH3), 2.31 (s, 6H, CH3),
3.76 (s, 3H, CH3), 3.88–4.18 (m, 4H, CH2), 5.32 (d, 1H, CH), 6.85–7.52 (m, 7H,
Ph). IR (KBr) n: 3190, 3031, 2933, 2912, 1652, 1506, 1456, 1284, 1249, 1191, 1041,
1020 cmꢀ1. Anal. calcd. for C22H28N3O4PS: C, 57.25; H, 6.12; N, 9.10; S, 6.95.
Found: C, 57.16; H, 5.96; N, 8.91; S, 6.63.
1
Compound 4i. Yield: 82%. Grey crystals. Mp 181–183 ꢁC (185 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.17–1.35 (t, 6H, CH3), 2.31 (s, 6H, CH3),
3.94–4.26 (m, 4H, CH2), 5.87 (d, 1H, CH), 7.01–7.68 (m, 6H, Ph). IR (KBr) n:
3265, 3016, 2975, 2916, 1652, 1506, 1475, 1268, 1255, 1186, 1049, 1037 cmꢀ1. Anal.
calcd. for C21H24Cl2N3O3PS: C, 50.41; H, 4.83; N, 8.40; S, 6.41. Found: C, 50.22; H,
4.62; N, 8.16; S, 6.14.
1
Compound 4j. Yield: 71%. White crystals. Mp 176–179 ꢁC (175 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.19–1.34 (t, 6H, CH3), 2.62 (s, 3H, CH3),
3.94–4.24 (m, 4H, CH2), 5.53 (d, 1H, CH), 7.25–8.01 (m, 7H, Ph). IR (KBr) n:
3218, 3029, 2987, 2906, 1652, 1521, 1506, 1456, 1224, 1178, 1054, 1029 cmꢀ1. Anal.
calcd. for C20H22ClN4O5PS: C, 48.34; H, 4.46; N, 11.27; S, 6.45. Found: C, 48.19; H,
4.29; N, 11.03; S, 6.28.
1
Compound 4k. Yield: 76%. White crystals. Mp 196–199 ꢁC (200 ꢁC[12]). H
NMR (500 MHz, DMSO-d6) d (ppm): 1.18–1.34 (t, 6H, CH3), 3.80–4.25 (m, 4H,
CH2), 5.45 (d, 1H, CH), 7.06–7.53 (m, 8H, Ph). IR (KBr) n: 3188, 3066, 2989,
2850, 1652, 1506, 1280, 1257, 1188, 1091,1049, 1014 cmꢀ1. Anal. calcd. for
C19H20ClFN3O3PS: C, 50.06; H, 4.42; N, 9.22; S, 7.03. Found: C, 49.90; H, 4.43;
N, 9.15; S, 7.00.
ACKNOWLEDGMENTS
This work was supported by the Jiangsu High-Tech Research Project
(Agriculture) (BG2007329) from the Science and Technology Department of Jiangsu
Province and the Youth Teacher Academic Foundation of Nanjing University of
Technology. We thank the Science and Technology Department of Jiangsu Province
for financial support.
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