The synthesis of 2-(5-(Aryloxymethyl)-1,3,4-thiadiazol-2-ylthio)-N- arylacetamides at room temperature via grinding

Article abstract of DOI:10.1080/10426500903299901

Fifteen 2-(5-(aryloxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-arylacetamides were efficiently synthesized from the reaction of 2-chloro-N-arylacetamide with 5-(aryloxymethyl)-1,3,4-thiadiazole-2-thiol under solvent-free conditions at room temperature via grin

Full text of DOI:10.1080/10426500903299901

Phosphorus, Sulfur, and Silicon, 185:1788–1795, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903299901
THE SYNTHESIS OF 2-(5-(ARYLOXYMETHYL)-1,3,4-
THIADIAZOL-2-YLTHIO)-N-ARYLACETAMIDES AT ROOM
TEMPERATURE VIA GRINDING
Xi-Cun Wang, Sheng-Qing Wang, Xiao-Mei Ding,
and Xue-Fei Chen
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of
Education, Lanzhou, Gansu, China and Gansu Key Laboratory of Polymer
Materials, College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou, Gansu, China
Fifteen 2-(5-(aryloxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-arylacetamides were efficiently
synthesized from the reaction of 2-chloro-N-arylacetamide with 5-(aryloxymethyl)-1,3,4-
thiadiazole-2-thiol under solvent-free conditions at room temperature via grinding. The
key advantages of the method are the short reaction time, high yields, simple workup, and
environmentally friendly conditions compared to conventional heating.
Keywords Acetamides; grinding; synthesis; 1,3,4-thiadiazoles
INTRODUCTION
The 1,3,4-thiadiazole derivatives have attracted continuing interest over the past
several years because of their various biological activities.1–4 In particular, a few vari-
ous substituted 1,3,4-thiadiazoles have been found to exhibit anticancer, antitumor, and
anticonvulsant activities.5–9 Additionally, a large number of N-arylacetamide derivatives
have demonstrated anticancer, antibacterial, antifungal, antimalarial, and anti-HIV activi-
ties.10–13 1,3,4-Thiadiazole and N-arylacetamide moieties are perspective scaffolds for the
design of drugs. There have been some reports on the synthesis of heterocyclic acetanilides.
Shah et al. have completed the preparation of heterocyclic acetanilides by the reaction of
5-(4-acetylanminophenyl)-1,3,4-oxadiazole-2-thione with 2-chloro-N-phenylacetamide in
an aqueous solution of potassium hydroxide at 80◦C for 12 h.14 Recently, Sahu et al.
completed the synthesis of heterocyclic acetanilides by refluxing 4-aminoquinaldine with
2-chloro-N-phenylacetamide in dry DMSO for 8 h.15 More recently, the reaction of 2,3-
dihydroimidazo[1,2-b]isoquinolin-5(1H)-one with 2-chloro-N-phenylacetamide in DMF
Received 26 June 2009; accepted 31 August 2009.
We are thankful for the financial support from the Gansu Key Laboratory of Polymer Materials.
Address correspondence to Xi-Cun Wang, Gansu Key Laboratory of Polymer Materials, College of Chem-
istry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, Gansu, China. E-mail: wangx-
icun@nwnu.edu.cn
1788

SYNTHESIS VIA GRINDING
1789
under microwave irradiation to afford heterocyclic acetanilides was also reported.16 How-
ever, in spite of their potential utility in the preparation of these types of compounds, many
of these methods involve an organic solvent, long reaction times, and unsatisfactory yields.
Furthermore, to the best of our knowledge, there has been no report on the synthesis of
heterocyclic acetanilide analogs containing aryoxylmethyl-1,3,4-thiadiazole scaffold under
grinding at room temperature. Consequently, a simple and efficient approach for the syn-
thesis of aryoxylmethyl-1,3,4-thiadiazole–functionalized N-phenylacetamide was of great
interest to our group.
Recently, many solventless organic reactions have been studied.17 Compared to the
reactions in an organic solvent, solventless reactions are often rapid, occur in high yields,
and have environmental and economic advantages. Solventless organic reactions based on
grinding of two macroscopic particles together mostly involve the formation of a liquid
phase prior to reaction, i.e., formation of a eutectic melt of uniform distribution where the
reacting components, being in close proximity, are poised to react in a controlled way.
Based on the above background, we have designed and synthesized a series of new
compounds containing the 1,3,4-thiadiazole ring and N-arylacetamide under grinding at
room temperature.
N
N
N
N
N
N
R1
R1
R1
O
O
NaNO2
O
H2NCSNH2
80oC ,3h
NH2
Cl
SH
S
S
S
HCl, Cu
1a~c
R2
2a~c
3a~c
H
N
H
N
Cl
N
S
N
R1
O
O
4a~e
S
R2
K2CO3 Grinding
O
5a-o
1a: R1 = H, 1b: R1 = 4-CH3, 1c: R1 = 2-Cl;
4a: R2 = H, 4b: R2 = 4-CH3, 4c: R2 = 4-Cl, 4d: R2 = 4-NO2, 4e: R2 = 2-NO2.
Scheme 1
RESULTS AND DISCUSSION
As described in Scheme 1, the starting material 2-amino-5-(aryloxymethyl)-1,3,4-
thiadiazoles (1a–c) were synthesized according to previously work.18 In a typical ex-
perimental procedure, 2-chloro-5-(aryloxymethyl)-1,3,4-thiadiazoles (2a–c) were obtained
from the reaction of compounds 1a–c with sodium nitrite in water, in the presence of con-
centrated hydrochloric acid and metallic copper powder. A mixture of compounds 2a–c
and excess thiourea in ethanol was refluxed to afford compounds 3a–c. Treatment of com-
pound 3a, compound 4a, and K2CO3 at room temperature under solventless conditions via
grinding afforded compound 5a in excellent yield (Table II, entry 1) .
To optimize the reaction conditions for the preparation of compound 5, the reaction
of 3a with 4a was selected as a model reaction. The reaction time, the nature of the base,
and the influence of 3a:4a molar ratios on the yield of the reaction are summarized in
Table I. According to these data, the best reaction time is 10 min. We also screened

1790
X.-C. WANG ET AL.
Table I Influence of reaction time, catalyst, and 3a:4a molar ratio
Entry
Basea
Time (min)
3a:4a
Yieldb (%)
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOH
10
10
10
5
15
10
10
10
10
1:1.1
1:1.2
1:1.3
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
90
93
93
80
94
90
95
85
82
NaOH
aReaction conditions: base (1 equiv), at room temperature with grinding.
bIsolated yields of purified compounds.
different inorganic bases for their ability to catalyze the reaction. Inorganic bases such as
K2CO3, Na2CO3, Cs2CO3, KOH, and NaOH all furnished the desired products (Table I).
However, salts of carbonate (K2CO3, Na2CO3, and Cs2CO3) were found to be the effective
catalysts for this transformation. Taking the above experiment data and the cost of the base
into account, we selected K2CO3 as a base to promote the reaction using a molar ratio of
compounds 3a:4a as 1:1.2 with grinding for 10 min at room temperature.
Under the optimized conditions, 15 compounds (5a–o) were efficiently synthesized
from the reaction of 3a–c with 4a–e under solvent-free conditions at room temperature
via grinding (Table II). To compare this procedure with the conventional method, we also
carried out these reactions under reflux conditions in ethanol for 2 h and observed that
Table II The synthesis of arylacetamides 5a–o at room temperature via grinding
Yield (%)a
Entry
Product
R1
R2
Refluxb
Grindingc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
H
H
H
H
H
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
H
4-CH3
4-Cl
4-NO2
2-NO2
H
4-CH3
4-Cl
4-NO2
2-NO2
H
4-CH3
4-Cl
85
83
86
65
71
83
82
85
67
62
80
83
85
60
65
93
94
94
79
74
83
87
93
73
77
89
92
90
72
81
4-NO2
2-NO2
aIsolated yield of purified product.
bReaction conditions: 3a (2 mmol), K2CO3 (2 mmol), 4a (2.4 mmol), in 3 mL ethanol was refluxed for 2 h.
cReaction conditions: 3a (2 mmol), K2CO3 (2 mmol), 4a (2.4 mmol), at room temperature, grinding for 10
min.

SYNTHESIS VIA GRINDING
1791
these reactions can also be completed smoothly to afford the desired products (Table II).
According to Table II, it is evident that R1 groups, such as methyl or chlorine, reacted
smoothly with 2-chloro-N-phenylacetamide to produce high yields of products. However,
when R2 is NO2, lower yields of the products were witnessed (Table II, entries 4, 5, 9,
10, 14, and 15). The structures of the synthesized compounds 5a–o were confirmed by
elemental analyses and spectroscopic data (1H NMR, 13C NMR, MS, and IR). The yields,
physicochemical properties, and the spectroscopic data of the prepared compounds are
given in the Experimental section.
The IR spectrum of 5 displayed bands at 3360–3310 cm−1 and 1690–1660 cm−1
due to NH and C O stretching frequencies, respectively. The 1H NMR spectrum of
5 exhibited two singlets at δ 4.07 and 5.40, which accounts for four methylene protons
attributed to the SCH2- and OCH2- protons, respectively. Aromatic protons resonated
as a multiplet at δ 6.99–7.55 and a singlet at δ 9.46, which accounts for the NH proton.
The 13C NMR of 5 displayed peaks that account for all the carbon atoms in the molecules.
In conclusion, we have developed a simple and efficient method for the synthesis of
2-(5-(aryloxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-arylacetamides derivatives via grinding
at room temperature in solvent-free conditions. The mildness of the reaction conditions,
experimental simplicity, compatibility with various functional groups, efficient yields, short
reaction times, and easy workup make this procedure attractive for the synthesis of a variety
of these derivatives.
EXPERIMENTAL
All reagents were obtained commercially and used without further purification. 2-
Chloro-N-arylacetamide derivatives (4a–e) were synthesized according to the methods in
the literature.[19] Melting points were determined on an XT-4 electrothermal micromelting-
point apparatus and are uncorrected. IR spectra were recorded using KBr pellets on a
Digilab Merlin FT-IR spectrophotometer. NMR spectra were recorded at 400 (1H) and 100
(13C) MHz, respectively, on a Varian Mercury plus-400 instrument using DMSO or CDCl3
as solvent and TMS as internal standard. Mass spectroscopy (MS) spectra were recorded
on a Trace DSQ mass spectrometer. Elemental analyses were performed on a Carlo-Erba
1106 Elemental Analysis instrument.
General Synthetic Procedure for Compounds (2a–c)
Compound 1a (2.07 g, 10.0 mmol) was ground with an excess of NaNO2 (2.07 g,
30.0 mmol) and the mixture was introduced in small portions and with stirring into an ice-
cooled solution of conc. HCl (30 mL) and water (13 mL) containing Cu powder (0.50 g).
The reaction mixture was allowed to reach room temperature and stirred for an additional
4 h then heated to 55◦C until the evolution of gas ceased. The reaction mixture was cooled
and extracted with CHCl3 (3 × 40 mL). The combined extracts were washed with aqueous
dilute H2SO4 and aqueous saturated NaHCO3 solution, and then dried over anhydrous
MgSO4. The solvent was evaporated to give crude 2a. The product was recrystallized from
ethanol to give 1.4 g of 2a in 62% yield; mp 54–56◦C.
2-Chloro-5-(phenoxymethyl)-1,3,4-thiadiazole (2a). Yield: 62%. Yellow
1
crystal; Mp: 54–56◦C. H NMR (400 MHz, CDCl3) δ = 5.41 (s, 2H, OCH2), 6.98–7.07
(m, 3H, ArH), 7.19–7.27 (m, 2H, ArH). IR (KBr) ν: 3067, 2924, 2860, 1690, 1594 cm−1
.
Anal.calcd for C9H7ClN2OS: C, 47.69; H, 3.11; N, 12.36. Found: C, 47.83; H, 3.21; N,
12.20.

1792
X.-C. WANG ET AL.
2-((4-Methylphenoxy)methyl)-5-chloro-1,3,4-thiadiazole (2b). Yield: 81%.
Yellow crystal; Mp: 66–68◦C. 1H NMR (400 MHz, CDCl3) δ = 2.30 (s, 3H, CH3), 5.40 (s,
2H, OCH2), 6.87 (d, J = 8.4 Hz, 2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH). IR (KBr) ν:
3067, 2919, 2856, 1614, 1511 cm−1. Anal. calcd for C10H9ClN2OS: C, 49.90; H, 3.77; N,
11.64. Found: C, 50.07; H, 3.59; N, 11.50.
2-((2-Chlorophenoxy)methyl)-5-chloro-1,3,4-thiadiazole (2c). Yield: 75%.
1
Yellow crystal; Mp: 117–119◦C. H NMR (400 MHz, CDCl3) δ = 5.42 (s, 2H, OCH2),
6.99–7.05 (m, 2H, ArH), 7.08–7.12 (m, 1H, ArH), 7.23–7.28 (m, 1H, ArH). IR (KBr) ν:
3065, 2919, 2857, 1610, 1515 cm−1. Anal. calcd for C9H6Cl2N2OS: C, 41.40; H, 2.32; N,
10.73. Found: C, 41.21; H, 2.43; N, 10.55.
General Synthetic Procedure for Compounds (3a–c)
A mixture of 2a (2.27 g, 10 mmol) and excess thiourea (2.34 g, 30 mmol) in 20 mL
ethanol was refluxed for 3 h. After cooling, conc. HCl (3 mL) and water (20 mL) were
added, and the solids isolated by filtration were washed with water and recrystallized from
EtOH-H2O giving 1.9 g 3a in 85% yield; mp 123–124◦C.
5-(Phenoxymethyl)-1,3,4-thiadiazole-2-thiol (3a). Yield: 85%. Yellow crys-
tal; Mp: 123–124◦C. 1H NMR (400 MHz, CDCl3) δ = 5.42 (s, 2H, OCH2), 6.99–7.09 (m,
3H, ArH), 7.19–7.25 (m, 2H, ArH), 14.75 (s, 1H, SH). IR (KBr) ν: 3107, 1710, 1591 cm−1
.
Anal. calcd for C9H8N2OS2: C, 48.19; H, 3.95; N, 12.49. Found: C, 48.08; H, 4.08; N,
12.35.
5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazole-2-thiol (3b). Yield: 89%.
Brown crystal; Mp: 155–157◦C 1H NMR (400 MHz, CDCl3) δ = 2.23(s, 3H, CH3), 5.41
(s, 2H, OCH2), 6.86 (d, J = 8.4 Hz, 2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 14.76 (s,
1H, SH). IR (KBr) ν: 3108, 1708, 1590 cm−1. Anal. calcd for C10H10N2OS2: C, 50.40; H,
4.23; N, 11.72. Found: C, 50.58; H, 4.36; N, 11.60.
5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazole-2-thiol (3c). Yield: 85%.
Brown crystal; Mp: 184–186◦C. 1H NMR (400 MHz, CDCl3) δ = 5.42 (s, 2H, OCH2),
6.98–7.05 (m, 2H, ArH), 7.07–7.12 (m, 1H, ArH), 7.22–7.26 (m, 1H, ArH), 14.75 (s, 1H,
SH). IR (KBr) ν: 3107, 1705, 1583 cm−1. Anal. calcd for C9H7ClN2OS2: C, 41.78; H,
2.73; N, 10.83. Found: C, 41.60; H, 2. 85; N, 10.96.
General Synthetic Procedure for Compounds (5a–o)
A mixture of 3a (0.45 g, 2 mmol), 4a (0.41g, 2.4 mmol), and K2CO3 (0.28 g, 2 mmol)
was thoroughly mixed in a mortar followed by grinding until the completion of the reaction
as indicated by TLC (10–20 min). The resulting material was washed with water to afford
the crude product. The pure product was obtained by recrystallization from DMF-EtOH.
2-(5-(Phenoxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-phenylacetamide (5a).
Yield: 93%. Grey crystal; Mp: 127–129◦C. 1H NMR (400 MHz, CDCl3) δ = 4.07 (s, 2H,
SCH2), 5.44 (s, 2H, OCH2), 6.97–7.11 (m, 4H, ArH), 7.25–7.37 (m, 4H, ArH), 7.52–7.55
(m, 2H, ArH), 9.50 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ = 37.5, 64.6, 114.8,
119.8, 122.3, 124.4, 128.9, 129.8, 137.8, 157.2, 165.9, 167.7, 168.2. MS: m/z 357 (M+).
IR (KBr) ν: 3300, 1671, 1597 cm−1. Anal. calcd for C17H15N3O2S2: C, 57.12; H, 4.23; N,
11.76. Found: C, 57.29; H, 4.41; N, 11.61.
2-(5-(Phenoxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-methylphenoxy)ace
tamide (5b). Yield: 94%. Yellow crystal; Mp: 156–158◦C. 1H NMR (400 MHz,
DMSO-d6) δ = 2.21 (s, 3H, CH3), 4.03 (s, 2H, SCH2), 5.36 (s, 2H, OCH2), 6.92–7.11 (m,

SYNTHESIS VIA GRINDING
1793
3H, ArH), 7.14–7.17 (m, 2H, ArH), 7.25–7.38 (m, 2H, ArH), 7.51–7.54 (m, 2H, ArH),
9.60 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 20.2, 37.5, 64.7, 114.3, 118.6,
121.3, 122.5, 129.4, 129.8, 137.2, 156.6, 165.8, 167.4, 167.6. MS: m/z 371 (M+). IR (KBr)
ν: 3300, 1671, 1597 cm−1. Anal. calcd for C18H17N3O2S2: C, 58.20; H, 4.21; N, 11.31.
Found: C, 58.37; H, 4.36; N, 11.47.
2-(5-(Phenoxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-chlorophenyl)aceta
mide (5c). Yield: 94%. White crystal; Mp: 165–167◦C. 1H NMR (400 MHz, CDCl3) δ =
4.08 (s, 2H, SCH2), 5.49 (s, 2H, OCH2), 6.95–7.13 (m, 3H, ArH), 7.17–7.21 (m, 2H, ArH),
7.26–7.37 (m, 2H, ArH), 7.51–7.55 (m, 2H, ArH), 9.67 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ = 37.5, 65.6, 114.6, 120.7, 123.2, 127.6, 129.7, 130.8, 136.7, 156.9, 165.8,
168.2, 169.1. MS: m/z 393 (M+2+). IR (KBr) ν: 3310, 1670, 1597 cm−1. Anal. calcd for
C17H14ClN3O2S2: C, 52.10; H, 3.60; N, 10.72. Found: C, 52.25; H, 3.77; N, 10.61.
2-(5-(Phenoxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-nitrophenyl)aceta
mide (5d). Yield: 79%. Yellow crystal; Mp: 165–167◦C. 1H NMR (400 MHz, DMSO-d6)
δ = 4.43 (s, 2H, SCH2), 5.39 (s, 2H, OCH2), 6.97–7.15 (m, 3H, ArH), 7.25–7.31 (m, 2H,
ArH), 7.64–7.78 (m, 2H, ArH), 7.99–8.04 (m, 2H, ArH), 10.97 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) δ = 38.0, 65.5, 114.7, 120.4, 123.2, 125.6, 129.6, 143.7, 145.4,
157.0, 164.4, 168.3, 168.9. MS: m/z 402 (M+). IR (KBr) ν: 3302, 1675, 1597 cm−1. Anal.
calcd for C17H14N4O4S2: C, 50.74; H, 3.51; N, 13.92. Found: C, 50.57; H, 3.65; N, 13.75.
2-(5-(Phenoxymethyl)-1,3,4-thiadiazol-2-ylthio)-N-(2-nitrophenyl)aceta
mide (5e). Yield: 74%. Yellow crystal; Mp: 140–142◦C. 1H NMR (400 MHz, DMSO-d6)
δ = 4.49 (s, 2H, SCH2), 5.37 (s, 2H, OCH2), 6.95–7.15 (m, 3H, ArH), 7.23–7.30 (m, 2H,
ArH) 7.64–7.72 (m, 1H, ArH), 7.84–7.92 (m, 2H, ArH), 8.09–8.15 (m, 1H, ArH), 10.69
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 38.1, 65.4, 114.9, 120.1, 121.5, 122.5,
125.4, 129.8, 134.6, 135.4, 141.6, 155.7, 165.6, 166.8, 168.2. MS: m/z 402 (M+). IR (KBr)
ν: 3300, 1670, 1597 cm−1. Anal. calcd for C17H14N4O4S2: C, 50.74; H, 3.51; N, 13.92.
Found: C, 50.55; H, 3.63; N, 13.80.
2-(5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-phenylacet
amide (5f). Yield: 83%. White crystal; Mp: 141–143◦C. 1H NMR (400 MHz, DMSO-d6)
δ = 2.23 (s, 3H, CH3), 4.05 (s, 2H, SCH2), 5.43 (s, 2H, OCH2), 6.89 (dd, J = 6.0 Hz, J =
2.0 Hz, 2H, ArH), 6.97–7.11 (m, 3H, ArH), 7.25–7.33 (m, 2H, ArH), 7.51–7.55 (m, 2H,
ArH), 9.51 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 21.2, 37.5, 64.6, 114.8,
119.7, 124.5, 128.5, 130.0, 130.4, 137.8, 157.0, 165.8, 167.7, 168.1. MS: m/z 371 (M+).
IR (KBr) ν: 3315, 1675, 1597 cm−1. Anal. calcd for C18H17N3O2S2: C, 58.20; H, 4.61; N,
11.31. Found: C, 58.03; H, 4.72; N, 11.47.
2-(5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-methyl
phenoxy)acetamide (5g). Yield: 87%. White crystal; Mp: 168–170◦C. 1H NMR (400
MHz, DMSO-d6) δ = 2.21 (s, 3H, CH3), 2.23 (s, 3H, CH3), 4.06 (s, 2H, SCH2), 5.44
(s, 2H, OCH2), 6.87 (dd, J = 6.0 Hz, J = 2.0 Hz, 2H, ArH), 7.04 (d, J = 8.4 Hz, 2H,
ArH), 7.23–7.37 (m, 2H, ArH), 7.45–7.51 (m, 2H, ArH), 9.47 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ = 20.2, 21.3, 37.5, 64.6, 114.8, 120.6, 128.5, 130.0, 130.3, 134.2,
137.8, 156.8, 165.8, 166.2, 168.0. MS: m/z 385 (M+). IR (KBr) ν: 3309, 1678, 1597 cm−1
.
Anal. calcd for C19H19N3O2S2: C, 59.20; H, 4.97; N, 10.90. Found: C, 59.01; H, 4.82; N,
11.05.
2-(5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-chloro
1
phenyl)acetamide (5h). Yield: 93%. Grey crystal; Mp: 174–176◦C. H NMR (400
MHz, CDCl3) δ = 2.21 (s, 3H, CH3), 4.09(s, 2H, SCH2), 5.44 (s, 2H, OCH2), 6.90 (dd,
J = 6.4 Hz, J = 2.0 Hz, 2H, ArH), 7.07 (d, J = 8.0 Hz, 2H, ArH), 7.25–7.37 (m, 2H, ArH),

1794
X.-C. WANG ET AL.
7.51–7.56 (m, 2H, ArH), 9.55 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 21.2,
37.5, 64.6, 114.9, 119.7, 122.1, 124.4, 129.0, 130.6, 137.7, 156.9, 165.8, 165.9, 167.4. MS:
m/z 407 (M+2+). IR (KBr) ν: 3310, 1674, 1597 cm−1. Anal. calcd for C18H16ClN3O2S2:
C, 53.26; H, 3.97; N, 10.35. Found: C, 53.39; H, 3.81; N, 10.18.
2-(5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-nitrophe
nyl)acetamide (5i). Yield: 73%. Brown crystal; Mp: 159–161◦C. 1H NMR (400 MHz,
DMSO-d6) δ = 2.23 (s, 3H, CH3), 4.32 (s, 2H, SCH2), 5.46 (s, 2H, OCH2), 6.94 (dd, J =
6.4 Hz, J = 2.0 Hz, 2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 7.61–7.76 (m, 2H, ArH),
7.97–8.03 (m, 2H, ArH), 10.57 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 21.2,
37.6, 64.1, 115.0, 122.4, 124.3, 129.0, 130.4, 141.6, 141.9, 155.2, 165.8, 165.9, 167.5.
MS: m/z 416 (M+). IR (KBr) ν: 3306, 1669, 1597 cm−1. Anal. calcd for C18H16N4O4S2:
C, 51.91; H, 3.87; N, 13.45. Found: C, 57.84; H, 3.80; N, 13.59.
2-(5-((4-Methylphenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(2-nitrophe
nyl)acetamide (5j). Yield: 77%. Brown crystal: Mp: 130–132◦C. 1H NMR (400 MHz,
DMSO-d6) δ = 2.22 (s, 3H, CH3), 4.35 (s, 2H, SCH2), 5.49 (s, 2H, OCH2), 6.93 (dd,
J = 6.4 Hz, J = 2.0 Hz, 2H, ArH), 7.10–7.14 (m, 2H, ArH), 7.38–7.43 (m, 1H, ArH),
7.72–7.77 (m, 2H, ArH), 8.00 (d, J = 3.6 Hz, 1H, ArH), 10.61 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ = 21.2, 37.6, 64.1, 115.0, 125.1, 125.3, 125.8, 130.1, 130.7, 130.9,
134.4, 141.9, 155.2, 165.9, 165.9, 167.5. MS: m/z 416 (M+). IR (KBr) ν: 3305, 1677, 1597
cm−1. Anal. calcd for C18H16N4O4S2: C, 51.91; H, 3.87; N, 13.45. Found: C, 52.05; H,
3.75; N, 13.57.
2-(5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-phenylacet
1
amide (5k). Yield: 89%. White crystal; Mp: 155–157◦C. H NMR (400 MHz, CDCl3)
δ = 4.09 (s, 2H, SCH2), 5.46 (s, 2H, OCH2), 6.99–7.04 (m, 2H, ArH), 7.23–7.26 (m, 2H,
ArH), 7.37–7.42 (m, 3H, ArH), 7.48–7.51 (m, 2H, ArH), 9.51 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ = 37.4, 65.8, 114.3, 120.9, 123.4, 123.6, 127.9, 129.0, 129.8, 130.8,
136.8, 152.8, 165.9, 167.8, 168.2. MS: m/z 393 (M+2+). IR (KBr) ν: 3300, 1670, 1597
cm−1. Anal. calcd for C17H14ClN3O2S2: C, 52.10; H, 3.60; N, 10.72. Found: C, 52.28; H,
3.75; N, 10.58.
2-(5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-4-(methyl
1
phenoxy)acetamide (5l). Yield: 92%. White crystal; Mp: 162–164◦C. H NMR (400
MHz, CDCl3) δ = 2.21 (s, 3H, CH3), 4.05 (s, 2H, SCH2), 5.43 (s, 2H, OCH2), 6.92–7.01
(m, 2H, ArH), 7.13–7.19 (m, 3H, ArH), 7.31–7.35 (m, 1H, ArH), 7.48–7.52 (m, 2H, ArH),
9.50 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 20.2, 37.4, 64.6, 114.9, 120.1,
121.3, 122.4, 124.4, 129.5, 131.0, 135.2, 136.5, 152.9, 165.8, 167.7, 168.2. MS: m/z 407
(M+2+). IR (KBr) ν: 3303, 1679, 1597 cm−1. Anal. calcd for C18H16ClN3O2S2: C, 53.26;
H, 3.97; N, 10.35. Found: C, 53.09; H, 3.83; N, 10.50.
2-(5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-chloro
1
phenyl)acetamide (5m). Yield: 90%. White crystal; Mp: 168–170◦C. H NMR (400
MHz, CDCl3) δ = 4.05 (s, 2H, SCH2), 5.55 (s, 2H, OCH2), 6.99–7.05 (m, 2H, ArH),
7.23–7.28 (m, 3H, ArH), 7.41–7.45 (m, 1H, ArH), 7.48–7.51 (m, 2H, ArH), 9.66 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) δ = 37.4, 65.7, 114.3, 120.9, 123.4, 123.5, 127.9,
128.9, 129.3, 130.8, 136.4, 152.8, 165.9, 167.8, 168.2. MS: m/z 426 (M+2+). IR (KBr) ν:
3301, 1671, 1597 cm−1. Anal. calcd for C17H13Cl2N3O2S2: C, 47.89; H, 3.07; N, 9.86.
Found: C, 48.01; H, 3.19; N, 9.70.
2-(5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(4-nitrophe
nyl)acetamide (5n). Yield: 72%. Yellow crystal; Mp: 179–181◦C. 1H NMR (400
MHz, DMSO-d6) δ = 4.37 (s, 2H, SCH2), 5.50 (s, 2H, OCH2), 6.98–7.15 (m, 2H, ArH),

SYNTHESIS VIA GRINDING
1795
7.26–7.33 (m, 2H, ArH), 7.73–7.76 (m, 2H, ArH), 7.96–8.02 (m, 2H, ArH), 10.51 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) δ = 37.2, 65.9, 114.9, 116.4, 121.7, 122.7, 127.5,
128.9, 129.6, 141.4, 141.9, 152.8, 165.9, 167.8, 168.2. MS: m/z 438 (M+2+). IR (KBr) ν:
3306, 1678, 1598 cm−1. Anal. calcd for C17H13ClN4O4S2: C, 46.74; H, 3.00; N, 12.82.
Found: C, 46.60; H, 3.14; N, 12.68.
2-(5-((2-Chlorophenoxy)methyl)-1,3,4-thiadiazol-2-ylthio)-N-(2-nitrophe
nyl)acetamide (5o). Yield: 81%. Yellow crystal; Mp: 134–136◦C. 1H NMR (400
MHz, DMSO-d6) δ = 4.36 (s, 2H, SCH2), 5.52 (s, 2H, OCH2), 6.99–7.05 (m, 2H, ArH),
7.23–7.27 (m, 2H, ArH), 7.38–7.43 (m, 1H, ArH), 7.73–7.76 (m, 1H, ArH), 7.99–8.03
(m 2H, ArH), 10.62 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ = 38.5, 64.2,
115.8, 121.6, 122.2, 122.7, 123.1, 125.4, 127.9, 129.7, 135.1, 139.9, 140.4, 154.8, 165.9,
167.8, 168.2. MS: m/z 438 (M+2+). IR (KBr) ν: 3306, 1675, 1598 cm−1. Anal. calcd for
C17H13ClN4O4S2: C, 46.74; H, 3.00; N, 12.82. Found: Found: C, 46.88; H, 3.15; N, 12.67.
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