Solid-phase synthesis of 2-arylamino-5-(4-hydroxyphenyl)-1,3,4-thiadiazole derivatives based on resin-bound acylhydrazines

Article abstract of DOI:10.1080/10426501003664176

A highly efficient, solid-phase synthesis of 2-arylamino-5-(4-hydroxy- phenyl)-1,3,4-thiadiazole derivatives under mild conditions has been developed. The 1,3,4-thiadiazole derivatives were synthesized from resin-bound acylhydrazines in several steps, which gave 78-88% overall yields and excellent purities of the products. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003664176

Phosphorus, Sulfur, and Silicon, 185:2375–2381, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003664176
SOLID-PHASE SYNTHESIS OF 2-ARYLAMINO-5-(4-
HYDROXYPHENYL)-1,3,4-THIADIAZOLE DERIVATIVES
BASED ON RESIN-BOUND ACYLHYDRAZINES
Zhanxiang Liu, Zhaosheng Song, Jinlong Zhao,
and Jianyong Zheng
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou, People’s
Republic of China
A
highly efficient, solid-phase synthesis of 2-arylamino-5-(4-hydroxy-phenyl)-1,3,4-
thiadiazole derivatives under mild conditions has been developed. The 1,3,4-thiadiazole
derivatives were synthesized from resin-bound acylhydrazines in several steps, which gave
78–88% overall yields and excellent purities of the products.
Keywords Resin-bound acylhydrazine; solid phase synthesis; 1,3,4-thiadiazole
INTRODUCTION
Five-membered ring heterocyclic compounds are commonly used scaffolds on which
pharmacophores are arranged to provide potent and selective drugs, which serve as the
core components of a large number of substances that possess a wide range of interesting
biological activities. Among five-membered rings, 2,5-disubstituted 1,3,4-thiadiazoles and
their derivatives appear pharmacologically relevant since they are found in many bioactive
compounds.1 1,3,4-Thiadiazoles and related compounds have attracted significant interest
in medicinal chemistry and many fields of technology. Thiadiazole derivatives are found
to exhibit antitumor,2 hypoglycemic,3 anticonvulsant,4 hypotensive,5 antiproliferative,6 and
antitubercular7 activities. Some of the technological applications involve dyes,8 lubricating
compositions,9 optically active liquid crystals,10 and photographic materials.11
There is a large number of methods for the synthesis of 2-amino-5-substituted 1,3,4-
thiadiazoles with variations. The most universal one is a two-stage method consisting of
acylation of a thiosemicarbazide using carboxylic acid chlorides and subsequent cycliza-
tion of the intermediate acylthiosemicarbazides. Various dehydrating agents are used in
commonly applied methods: sulfuric acid, phosphorus oxychloride, benzoyl chloride, and
acetyl chloride.12–17 Acylthiosemicarbazides can be also obtained in the reaction of acyl-
hydrazine with isothiocyanates. Ring closure to the thiadiazole occurs by heating with
Received 27 December 2009; accepted 30 January 2010.
We are grateful to the National Natural Science Foundation of China (Project No. 20802068), the Education
Department of Zhejiang Province (20070015), and the Science and Technology Department of Zhejiang Province
(2007C2116) for financial support.
Address correspondence to Zhanxiang Liu, Department of Chemistry, Zhejiang University (Campus Xixi),
Hangzhou, 310028, China. E-mail: liuzhanx@zju.edu.cn
2375

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Z. LIU ET AL.
sulfuric or methanesulfonic acid.18, 19 Oxidative cyclization of 1-thioaroylsemicarbazides
with bromine or hydrogen peroxide20 or of thiosemicarbazones with iron(III) chloride gave
also the described compounds.21, 22 For the synthesis of 1.3.4-thiadiazole rings substituted
by other than amine groups, thiohydrazides23 and thioacylamidrazones24 are commonly ap-
plied. Sulfur-containing reagents are used for analogous cyclizations of amidrazones.25 In
the reaction of sulfinyl-bis(2,4-dihydroxythiobenzoyl) (STB) with N3-substituted amidra-
zones, the linear products, N1-thioacyl derivatives, and the cyclic products, 2,5-disubstituted
1,3,4-thiadiazoles, with a considerably higher fungistatic activity, were obtained.26, 27 Many
of the solution-phase methodologies described above possess important drawbacks such as
long reaction times, poor yields, and exhaustive purification protocols.
With the availability of automated techniques, the solid phase synthesis of small
organic molecules is becoming a fundamental method for the rapid and easy preparation
of libraries of organic compounds in order to accelerate the drug discovery process.28 This
approach facilitates the rapid synthesis of a large number of compounds in a short time
frame and facilitates their use in high throughput screening. Solid-phase organic synthesis
is another synthetic route to these compounds, which has been recently developed. Solid-
phase syntheses of 5-acylamino-2-alkylamino-1,3,4-thiadiazoles are developed based on
cyclization of resin-bound thiosemicarbazone using iron (III) chloride.29 Hwang et al.30
reported cyclodehydration of the acyldithiocarbazate resin, followed by oxidation and
treatment with amines, to give the 5-amino-1,3,4-thiadiazoles.
In continuation of our efforts to develop novel and efficient polymer-supported routes
leading to heterocyclic derivatives with potentially attractive pharmacological properties,
we have recently reported an easy method for the preparation of polymer-supported acylhy-
drazines on Merrifield resin.31a We have also reported the synthesis of 1,3,4-oxadiazoline-
5-thiones,31a 1,2,3-thiadiazoles,31b and 4,5-disubstituted 1,2,4-triazol-3-one derivatives31c
from resin-bound acylhydrazines. As the phenol scaffold has important biological activity,
the presence of a 4-hydroxyphenyl substituent in the molecule is responsible first of all
for its amphiphilic character, we wanted to prepare the 2-arylamino-5-(4-hydroxyphenyl)-
1,3,4-thiadiazole derivatives based on resin-bound acylhydrazines.
RESULTS AND DISCUSSION
In this article, we extend our chemistry to solid-phase synthesis of 2-arylamino-5-(4-
hydroxyphenyl)-1,3,4-thiadiazole derivatives.
Scheme 1 shows the synthetic route of 2-arylamino-5-(4-hydroxy-phenyl)-
1,3,4-thiadiazole derivatives. We have prepared resin-bound acylhydrazine 1 from the
O
O
a
H
H
NHNH2
O
N
N R
O
N
H
S
1
2
N N
S
N N
S
c
b
NHR
HO
O
NHR
3
4
Scheme 1 (a) RNCS, EtOH, reflux, 6 h; (b) conc. H2SO4, r.t. 4 h; (c) TFA/CH2Cl2.

SOLID-PHASE SYNTHESIS WITH RESIN-BOUND ACYLHYDRAZINES
2377
Table I Solid-phase synthesis of 2-arylamino-5-(4-hydroxyphenyl)-1,3,4-thiadiazole derivatives
Entry
Product
R
Yielda (%)
Purityb (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
4-CH3O-C6H4
Ph
84
95
90
92
86
88
95
92
86.9
88.5
86
79
85.4
80
4-CH3-C6H4
p-CF3O-C6H4
2,4-F2-C6H3
2-CH3-C6H4
C6H5CH2
4g
aYield of crude product based on the loading of acylhydrazine resin 1.
bDetermined by HPLC analysis (area%).
Merrifield resin according to our previously reported method.31a The acylhydrazine resin 1
was reacted with excessive aryl/alkyl isothiocyanates in ethanol to give the corresponding
resin-bound thiosemicarbazides 2. After acid-catalyzed ring closures of the corresponding
aroylthiosemicarbazides resin 2, the resin 3 was obtained. The desired 2-arylamino-5-(4-
hydroxyphenyl)-1,3,4-thiadiazole derivatives 4 were released at TFA/DCM cleavage for 4
h in high yield and purity, and were characterized by spectroscopic methods. The results
are summarized in Table I.
The successful formation of resin 2 was supported by comparison of its FT-IR
spectrum (KBr pellet) with resin 1. The N-H stretching bands at 3429, 3318 cm−1 shifted to
3298 and 3247 cm−1 and a strong C O stretching band at 1676 cm−1 for aroylsemicarbazide
resin 2 appeared, which is different from the C O signal of acylhydrazine resins at 1630
cm−1. When the resin 2 was converted into the resin 3, the strong carbonyl peak at 1676
cm−1 disappeared, and the signal of N-H shifted to 3240 cm−1. When the resin 3 was
cleaved by TFA/DCM, the product 4 was obtained in good yields and high purity.
Using this methodology, we have synthesized a representative set of 2-arylamino-
5-(4-hydroxyphenyl)-1,3,4-thiadiazole derivatives 4 (Table I) in 79–89% overall yield,
indicating a good yield for each step of the reaction.
In summary, we have studied and developed a new strategy for the preparation
of 2-arylamino-5-(4-hydroxyphenyl)-1,3,4-thiadiazole derivatives on solid support. The
use of resin-bound acylhydrazines in the reaction benefits the solid-phase synthetic route
because it not only provides a short synthetic route to the desired products but its chemical
versatility also adds to the diversity of the library. The 2-arylamino-5-(4-hydroxyphenyl)-
1,3,4-thiadiazole derivatives were synthesized in several steps providing 79–88% overall
yields and excellent purity. This synthetic methodology is ideally suitable for the high
throughput synthesis of drug libraries for potential drug discovery because all the reactions
were carried out under mild conditions. Further work is in progress on the solid-phase
synthesis of heterocyclic compounds via the resin-bound acylhydrazines.
EXPERIMENTAL
Starting materials were obtained from commercial suppliers and were used with-
out further purification. Solvents were distilled before use; CH2Cl2 was distilled from
CaH2. Merrifield resin (100–200 mesh, cross-linked with 1% divinylbenzene, loading

2378
Z. LIU ET AL.
1.95 mmol/g Cl) was purchased from commercial sources (Nankai University). Acylhy-
drazine resin 1 was prepared from the Merrifield resin according to our previously reported
method.31a
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker
Avance (400 MHz) spectrometer, using DMSO-d6 as the solvent and TMS as internal stan-
dard. MS spectra (EI, 70 eV) were recorded on a HP5989B mass spectrometer. IR spectra
were recorded on a Bruck Vector 22 spectrophotometer. Elemental analyses were per-
formed on a Flash EA1112 instrument. High-performance liquid chromatography (HPLC)
was performed on an Agilent 1100 [column, Eclipse XDB-C18 5 µm, 4.6–150 mm; mobile
phase, MeOH/H2O, 80/20 (v/v); flow rate, 1.0 mL/min; detector, UV 254 nm]. The samples
were further purified by preparative thin-layer chromatography (PTLC) for 13C NMR and
microanalyses.
General Procedure for the Synthesis of 2-Arylamino-5-
(4-hydroxyphenyl)-1,3,4-thiadiazole Derivatives
To the mixture of the acylhydrazine resin 1 (0.5 g, loading 1.59 mmol/g, based on N
microanalysis) in absolute EtOH (5 mL), phenyl isothiocyanate (0.324 g, 2.4 mmol) was
added. Then the mixture was stirred and refluxed for 6 h. The resin was filtered and washed
with EtOH (3 × 5 mL) and CH2Cl2 (3 × 5 mL) to remove contaminated species and then
dried to afford the resin 2.
Resin 2 was added to 3 mL concentrated H2SO4 (98%). The mixture was stirred at
room temperature for 4 h. Then it was poured into ice-water and filtered, and the resin was
washed with H2O (3 × 10 mL), EtOH (3 × 5 mL), and CH2Cl2 (3 × 5 mL) and dried to
afford the resin 3.
The resin 3 was well swollen in 3 mL CH2Cl2, and then 0.5 mL TFA was added. The
mixture was stirred at room temperature for 4 h and then filtered. The resin was washed
completely with EtOH (3 × 5 mL) and acetone (3 × 5 mL). The filtrate was combined to
afford the crude product 4 by evaporation.
All compounds gave satisfactory 1H NMR (400 MHz), 13CNMR (100 MHz), IR, and
MS spectra.
5-(4-Hydroxyphenyl)-2-(4-methoxyphenylamino)-1,3,4-thiadiazole (4a)
1
Mp 208–210◦C. H NMR: δ 3.73 (s, 3H), 6.86 (d, 2H, J = 8.8 Hz), 6.93 (d, 2H, J
= 8.8 Hz), 7.53 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.8 Hz), 10.01 (s, 1H), 10.20 (s,
1H). 13C NMR: δ 59.73, 118.80, 120.43, 123.69, 125.98, 132.83, 138.72, 159.00, 161.62,
163.73, 168.23. MS (m/e%): 299 (100), 284 (25), 165 (17). IR: 3186, 3063, 2947, 1606,
1574, 1511, 1464, 1435, 1280, 1247 cm−1. Calcd. for C15H13N3O2S: C, 60.18; H, 4.38; N,
14.04; S, 10.71; Found: C, 60.45; H, 4.51; N, 13.73.
5-(4-Hydroxyphenyl)-2-phenylamino-1,3,4-thiadiazole (4b)
1
Mp 246–248◦C. H NMR: δ 6.85 (d, 2H, J = 8.0Hz), 7.14 (d, 2H, J = 8.0Hz),
7.52 (m, 3H), 7.88 (m, 2H), 10.05 (s, 1H), 10.45 (s, 1H). 13C NMR: δ 120.50, 120.93,
125.64, 131.14, 133.02, 145.27, 145.97, 162.67, 164.01, 167.50. MS (m/e%): 269 (100),

SOLID-PHASE SYNTHESIS WITH RESIN-BOUND ACYLHYDRAZINES
2379
150 (53), 134 (59), 91 (44). IR: 3252, 3132, 3065, 1602, 1555, 1500, 1484 cm−1. Calcd. for
C14H11N3OS: C, 62.43; H, 4.12; N, 15.60; S, 11.91; Found: C, 62.71; H, 4.36; N, 15.78.
5-(4-Hydroxyphenyl)-2-(4-methylphenylamino)-1,3,4-thiadiazole (4c)
1
Mp 168–170◦C. H NMR: δ 2.27 (s, 3H), 6.86 (d, 2H, J = 7.6 Hz), 7.14 (d, 2H,
J = 7.6 Hz), 7.50 (d, 2H, J = 8.0Hz), 7.65 (d, 2H, J = 8.0Hz), 9.97(s, 2H), 10.302 (s,
1H). 13C NMR: δ 24.85, 120.45, 122.02, 125.88, 132.87, 133.98, 135.33, 142.78, 161.98,
163.80, 167.84. MS (m/e%): 283 (63), 164 (38), 134 (100). IR: 3250, 3210, 1620, 685
cm−1. Calcd. for C15H13N3OS:, C, 63.58; H, 4.62; N, 14.83; S, 11.32; Found: C, 63.39; H,
4.54; N, 14.67.
5-(4-Hydroxyphenyl)-2-(4-trifluoromethoxyphenylamino)-1,3,4-thia-
diazole (4d)
Mp 206–208◦C. 1H NMR: δ 6.88 (d, 2H, J = 8.0Hz), 7.36 (d, 2H, J = 8.0Hz), 7.65
(d, 2H, J = 8.0Hz), 7.81(d, 2H, J = 8.0Hz), 10.34 (s, 2H), 11.0 (s, 1H). 13C NMR: δ 120.54,
122.96, 123.45, 125.66, 125.99, 126.45, 132.93, 144.53, 146.80, 162.94, 164.15, 167.20.
MS (m/e%): 353 (100). IR: 3421, 3216, 2925, 1610, 1546, 1510, 1461, 1433, 1384, 1264
cm−1. Calcd. for C15H10F3N3O2S: C, 50.99; H, 2.85; F, 16.13; N, 11.89; S, 9.08; Found:
C, 50.78; H, 2.66; N, 11.83.
5-(4-Hydroxyphenyl)-2-(2,4-difluorophenylamino)-1,3,4-thiadiazole (4e)
Mp 214–216◦C. 1H NMR: δ 6.86 (d, 2H, J = 8.0 Hz), 7.14 (m, 1H), 7.32 (m, 1H),
7.63 (d, 2H, J = 8.0 Hz), 8.32 (m, 1H), 9.89(s, 1H), 10.29 (s, 1H). 13C NMR: 108.26,
108.50, 115.50, 115.74, 120.51, 125.49, 126.07, 130.05, 132.80, 163.37, 164.29, 167.85.
MS (m/e%): 305 (100), 286 (32), 246 (17), 134 (53). IR: 3419, 3250, 2925, 1607, 1544,
1510, 1466, 1383, 1308 cm−1. Calcd. for C14H9F2N3OS: C, 55.08; H, 2.97; N, 13.76; S,
10.50; Found: C, 54.82; H, 3.12; N, 13.65.
5-(4-Hydroxyphenyl)-2-(2-methylphenylamino)-1,3,4-thiadiazole (4f)
Mp 232–234◦C. 1H NMR: δ 2.28 (s, 3H), 6.85 (d, 2H, J = 8.4 Hz), 7.02 (m, 1H), 7.21
(m, 1H), 7.61 (d, 2H, J = 8.4Hz), 7.86 (m, 2H, J = 7.6Hz), 9.59 (s, 1H), 10.31 (s, 1H). 13C
NMR: δ 22.69, 120.49, 125.76, 125.87, 128.35, 131.14, 132.75, 133.59, 135.19, 143.82,
162.34, 164.00, 169.71. MS (m/e%): 283 (69), 164 (100), 149 (78), 131 (54), 121 (60). IR:
3188, 3065, 2952, 1607, 1586, 1558, 1413, 1382, 1278 cm−1. Calcd. for C15H13N3OS: C,
63.58; H, 4.62; N, 14.83; S, 11.32; Found: C, 63.76; H, 4.53; N, 14.70.
5-(4-Hydroxyphenyl)-2-benzylamino-1,3,4-thiadiazole (4g)
1
Mp 238–240◦C. H NMR: δ 3.27 (s, 2H), 6.84 (d, 2H, J = 8.4Hz), 6.93 (m, 1H),
7.55 (m, 2H), 7.62 (d, 2H, J = 8.4Hz), 7.86 (m, 2H), 9.59 (s, 1H), 10.31 (s, 1H). 13C NMR:
δ 20.32, 117.71, 120.49, 125.76, 129.45, 130.86, 131.14, 132.75, 138.23, 162.34, 164.00,
169.71. MS (m/e%): 283 (M+, 100), 192 (60), 121 (40). IR: 3186, 3058, 2953, 1606, 1588,

2380
Z. LIU ET AL.
1382, 1278 cm−1. Calcd. for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83; S, 11.32; Found:
C, 63.42; H, 4.73; N, 14.88.
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