ZnCl2 catalyzed efficient synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole

Article abstract of DOI:10.1016/j.tetlet.2014.04.046

New methods for the synthesis of 1,3,4-oxadiazole and 1,3,4-thiadiazole have been described. No cyclizations took place in the absence of ZnCl ₂. 1,3,4-Thiadiazoles are formed in the presence of ZnCl₂ alone, whereas oxadiazoles are produced when a base such as Et₃N or KOH was used along with ZnCl₂. % Yields are optimized.

Full text of DOI:10.1016/j.tetlet.2014.04.046

Accepted Manuscript
ZnCl2 Catalyzed Efficient Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole
Md.A. Rahman, Mohammad R. Karim, Md. Arifuzzaman, Tasneem A.
Siddiquee, Aminul H. Mirza
PII:
S0040-4039(14)00658-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.046
TETL 44508
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 January 2014
10 April 2014
14 April 2014
Please cite this article as: Rahman, Md.A., Karim, M.R., Arifuzzaman, Md., Siddiquee, T.A., Mirza, A.H., ZnCl2
Catalyzed Efficient Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.04.046
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ZnCl2 Catalyzed Efficient Synthesis of 1,3,4-
Oxadiazole and 1,3,4-Thiadiazole.
Md. A. Rahman1, Mohammad R. Karim1*,
Md. Arifuzzaman,2 Tasneem A. Siddiquee1,
Aminul H. Mirza3.
*For correspondence, Tel: 615-963-5344, Fax: 615-963-5326, Email: mkarim@tnstate.edu
1Department of Chemistry, Tennessee State University, 3500 John Merritt Blvd, Nashville, TN 37209
2Department of Chemisry, Iowa State University, Ames, IA 50011
3Chemistry, faculty of Science, University of Brunei Darussalam, Jalan Tungku Link, Gadong, BE 1410

1
Tetrahedron Letters
journal homepage: www.elsevier.com
ZnCl2 Catalyzed Efficient Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole.
Md. A. Rahman1, Mohammad R. Karim1*, Md. Arifuzzaman2, Tasneem A. Siddiquee*, Aminul H.
Mirza3
*For all correspondance
1Department of Chemistry, Tennessee State University, 3500 John Merritt Blvd., Nashville, TN 37209
2Department of Chemistry, Iowa State University, Ames, IA 50011
3Faculty of Science, Universiti of Brunei Darussalam, Jalan Tungku Link, Gadong, BE 1410
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
New methods for the synthesis of 1,3,4-oxadiazole and 1,3,4-
thiadiazole have been described. No cyclizations took place in the
absence of ZnCl2. 1,3,4-thiadiazoles are formed in the presence of
ZnCl2 alone, whereas oxadiazoles are produced when a base such
as Et3N or KOH was used along with ZnCl2. % Yields are optimized.
Available online
Keywords:
Phenanthroline,
2009 Elsevier Ltd. All rights reserved.
1,3,4-oxadiazole,
1,3,4-thisadiazole,
cyclization using oxidant such as KMnO410, acetic
anhydride11, chloramin T12, CAN13, HgO/I2 or via
Cu(OTf)2 catalyzed14, PbO2, hypervalent iodines,
1. Introduction:
Heterocyclic
compounds
containing
five
15
Br2 and I2/K2CO3
etc. Besides these some
membered rings are commonly used as platform
in pharmaceuticals to provide potent and selective
drugs1. In this family, Oxadiazoles and
thiadiazoles are important classes of heterocyclic
compounds and have created greater interest in
synthetic organic, agriculture and medicinal
chemistry due to their versatile medicinal
potential2. Both 1,3,4-oxa and thiadiazole ring
containing compounds display a remarkable broad
spectrum of biological activity.2 Therefore, these
heterocyclic rings have attracted researchers from
all over the world to synthesize these classes of
compounds by employing traditional methods,
introducing new innovative methods and
techniques, and studying their biological
applications.
desulfurating agents such as p-TsCl16, EDC.HCl17,
methyl iodide18, ethyl bromoactate19 and mercury
oxides20 are also used to synthesis this
compound.
The conventional method of
synthesizing 1,3,4-oxadiazole-2-thione from acid
21
hydrazide is by using KOH in ethanol/CS2 or
22
pyridine/CS2
.
Generally acidic reagents are
used to synthesize 1,3,4-thiadiazole such as
23
24
POCl3
,
H3PO4
,
methylsulphonic
acid25,
HClO426, and strong mineral acid27. Recently a
number of publications have been reported some
milder cyclization methods for the synthesis of
1,3,4-thiadiazole using TMSCl28, (PhO)2P(O)Cl,
Ph3P29, Laesson’s reagent30 and p-TsCl/TEA31. A
number reports are published on multi-step
synthesis of thiadiazoles32, however, one-pot or
one step synthesis are rare. 1,3,4-thiadiazoles are
A number of methods have been reported to
synthesized
from
acid
hydrazides
and
synthesize
1,3,4-oxadiazoles
and
1,3,4-
thioethylorthoalkanoates using P4S10/Al2O333, from
thiosemicarbazone using FeCl3 in EtOH/H2O34 and
from dithiocarbamate and acid hydrazide in
presence of triethylamine or pyridine in water35.
thiadiazoles. 1,3,4-oxadiazole is synthesized by
3
using cyclodehydrating agents such as SOCl27,
4
5
POCl3 , PPA, H2SO4 , Burgess reagent6, P2O5 ,
Ph3P8 and T3P9 etc. and also by oxidative

2
Tetrahedron Letters
Several methods have been developed for the
Scheme 1: Formation of 1,3,4-Oxa and
Thiadiazole from methyl 2-(1,10-phenanthroline-2-
carbonyl)hydrazinecarbodithioate.
synthesis of 1,3,4-oxadiazoles and thiadiazoles,
however still there are some limitations associated
with these methods, such as hazardous materials,
harsh reaction conditions, limited substrate scope,
and scalability. Besides this, most of the synthetic
methods are involved forcing reaction conditions
such as high temperature, long reaction time, and
purification problems. Therefore for the synthesis
of 1,3,4-oxadiazole and 1,3,4-thiadiazole from
easily available starting materials by more general
and environmental friendly procedures are still
highly desirable. We have developed a facile and
a regioselective synthesis of 1,3,4-oxadiazole and
1,3,4-thiadiazole derivatives from reagent based
cyclization of the acyldithiocarbazates.
.
2. Results and Discussion:
In an attempt to make Zn2+ salt of the methyl
2-(1,10-phenanthroline-2-carbonyl)hydrazinecarbo
dithioate 1, ZnCl2 solution (0.42 mmol in 5mL
THF) was added in a solution of 1 (0.21 mmol in
25mL THF) in the presence of Et3N (0.3 mL) or
KOH (0.2 mmol) and stirred at reflux for 2 hours. A
single solid product was obtained in high yield
(Y:97%).37 Spectroscopic analysis of the product
revealed that it was, indeed, 1,3,4-oxadiazole ring
containing product 1a as shown in Scheme 1
(Path A). The structure has been confirmed by
spectral as well as X-Ray crystallographic data.36
In the absence of ZnCl2, only unreacted starting
material was recovered. However when the
reaction was carried out using ZnCl2 in the
absence of Et3N or KOH, the product formed was
1,3,4-thiadiazole ring containing compound 1b
(Path B, Scheme 1). 1:2 ratio of the
substarte:ZnCl2 ratio and refluxing for 2 hours
was found to produce the best yield (95%).38
ZnBr2 also produced the desired product in high
yield. ZnI2 was found to be less effective in
catalyzing the reactions, producing albeit in low
yield (Y: 67%). Other Zn-salts with different
counter ions were utilized in the same reaction
under the same conditions. However, no other
Zn2+ salts were effective. Only unreacted starting
materials were recovered. This suggests that the
counter ion of Zn2+ may have an important impact
on the catalyzing ability of Zn2+ in the reaction.
A possible explanation of the impact of Zn2+
Since Zn2+ plays an important role in the
formation of either of the products, possibly in the
presence of a base, Zn2+ coordinates with Sulfur
and Nitrogen as shown in Scheme 2 forming
oxadiazole. In the absence of the base, Zn+2
coordinates with Oxygen and Nitrogen as shown
in Scheme 3 forming 1,3,4-thiadiazole ring. In
Scheme 2 in the presence of Et3N or KOH, an
iminolate ion may have been formed and involved
in the formation of the bicyclic transition state
facilitating nucleophilic attack of the oxygen to
thione carbon followed by elimination of thiomethyl
(CH3S-) group forming 1,3,4-oxadiazole ring. In the
absence of Et3N, the Zn2+ may have coordinated
with nitrogen and oxygen atoms as shown in
Scheme 3, where sulfur of the thione group acts
as
a
nucleophile followed by dehydration
producing thiadiazole. Experiments are underway
to determine the detailed mechanism of the
reactions.

3
Scheme 2: Possible Coordination by Zn2+ Ion
produced both thiadiazole and oxadiazole rings
towards the formation of Oxadiazole
in low yield. The precursor containing a methyl
group on the keto side did not produce any of the
desired diazole compounds. The yields for all
other entries are moderate to high (60-97%) for
phenanthroline or pyridinyl rings. The exact nature
of the nitrogen of the phenanthroline or pyridinyl
ring is not clear. Studies are in progress to
investigate the mechanistic detail of this reaction.
When reactions are carried out under basic
conditions (in the presence of Et3N or KOH), the
corresponding 1,3,4-oxadiazole-2-thiones are
produced through the elimination of a thioalkyl
group. A general mechanism for the formation of
both rings is shown in the Scheme 4.
Scheme 4: General mechanism for the formation
of 13,4-oxa and 1,3,4-thiadiazole
Scheme 3:
Possible Coordination by Zn2+ Ion towards the
formation of Thiadiazole
3. Conclusion
In conclusion, new methods for the
formation of very important 1,3,4-oxadiazole-2-
thione and 1,3,4-thiadiazole-2-thioalkyl rings have
been developed. 1:2 ratio of the substrate:ZnCl2
and refluxing for 2 hours was found to produce the
highest yield. The nitrogen atoms in the
phenanthroline ring may have an additional impact
enhancing the formation of both oxadiazole and
thiadiazole rings. Investigation will continue to
explore the role of Zn2+ in ZnCl2 and
phenanthroline ring in the formation of these rings
as well as mechanistic detail of these reactions.
To explore the scope of the catalytic
activity, several precursors (Entries 3-12, Table 1)
have been synthesized using previously
established conditions. Entries 3-12 gave the best
result by refluxing in dioxane, whereas entries 1-2
were found to produce highest yield in THF.
Therefore, a solution of the substrates in entries 3,
5, 7, 9 and 11 (0.2 mmol in 5 mL dioxane) were
added into with ZnCl2 solution (0.4 mmol solution
in dioxane) and refluxed (approx. 110oC) for 2
hours. Yields are shown on Table 1. Each product
was purified by crystallization, and characterized
by
spectroscopic
methods
and
mass
spectrometry, and are found to produce 1,3,4-
thiadiazoe rings. Similarly, substrates in entries 2,
4, 6, 10 and 12 (0.2 mmol) were refluxed with
ZnCl2 (0.4 mmol) in dioxane in the presence of
KOH or Et3N (0.2 mmol) for 2 hours. The products
were found to produce 1,3,4-oxadiazole rings.
Entries 3 and 4, containing phenyl group,
Acknowledgment.
We thank the Department of Chemistry at
Tennessee State University for providing the
necessary support to carry out the research. We
also thank the Department of Education, Title III
funds for providing instrumental support.

4
Tetrahedron Letters
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37. General Procedure for Synthesis of 1,10-
Phenanthroline-2,9-bis-1,3,4-Oxadiazole:
S-methylhydrazinecarbodithioate 1 (0.100g,
0.21 mmol) was dissolved in THF (25mL) with
heat followed by the addition of KOH(15 mg,
0.26 mmol) or Et3N (0.3 mL, 0.21 mmol). Then
a solution of ZnCl2 (0.058g, 0.42mmol) in THF
(5mL) was added drop-wise to the
carbodithioate solution and refluxed for 2 hrs
(at 66oC). The reaction mixture was cooled to
room temp; solvent was evaporated, washed
with ether and dried under vacuum. The
product was further purified by recrystallization
from DMSO to obtain white crystals (0.076g,
95 %Y). Note: Dioxane was used as solvent
for all other substrates.
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Phenanthroline-2,9-bis-1,3,4-thiadiazole-2-S-
methylthiol: S-methylhydrazinecarbodithioate
1 (0.100g, 0.21 mmol) was dissolved in THF
(25mL) with heat until a clear solution was
formed. Then a solution of ZnCl2 (0.058g,
0.42mmol) in THF (5mL) was added drop-wise
to the carbodithioate solution. The resulting
mixture was refluxed (66oC) for 2 hrs., cooled
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(0.078g, 97 %Y). Note: Dioxane was used as
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Table 1: Formation of Oxadiazole and Thiadiazoles (All %Yields are optimized).
Entry
Precursor
Reagent(s)
Product
% Y
ZnCl2
97
1
ZnCl2/ Et3N
95
2
ZnCl2
18
20
3
4
ZnCl2/ KOH
ZnCl2
47
5
ZnCl2/ KOH
ZnCl2
53
64
6
7
ZnCl2/ KOH
70
8

ZnCl2
84
9
ZnCl2/ KOH
93
10
ZnCl2
77
72
11
12
ZnCl2/ KOH

Table 2: Spectroscopic Data (All MS data were taken with Varian LC-MS with ESI
technique)
For some compounds high resolution MS data is given in parenthesis as M+1
Compounds
1HNMR
13CNMR
MS (m/z)
IR ν( cm-1)
(DMSO-d6,
400MHz)
δH= 8.80 (d,
J=8.36 Hz, 2H),
8.55(d, J= 8.36
Hz, 2H), 8.24 (s,
(DMSO-d6,
400MHz)
δC = 170.2, 169.9,
147.9, 144.4,
138.3, 129.7,
127.6, 119.6,
S
N
441(M+ H) 100%
3059 (Aromatic C-
S
HRMS (Q-TOF-ESI) H), 2920(C-H),
Calcd for 1600-1500 (C=C),
C18H12N6S4 (MNa+): 1666(C=N), 1024
N
N
N
2H), 2.88 (s, 6H). 16.5.
462.9904, found
462.9859
(C-S).
N
N
S
S
S
δH = 8.80 (d, J=
8.4Hz, 2H),
8.43(d, J=8.4Hz,
δC = 178.2, 159.9, 381(M+ H) 100%
144.9, 141.9,
138.4, 130.1,
3500-3230 (N-H),
1180 (C-O), 3100-
3000(C-H), 1600-
1500 (Aromatic
C=C), 1621(C=N),
971 (C=S).
C
O
NH
N
N
2H), 8.25 (s, 2H). 128.3, 121.8.
N
N
NH
S
O
SCH3
δH = 8.3 (d, J=
7.4Hz, 2H), 8.2
(t,J=7.1Hz, 1H),
2.85 (s, 6H).
δC = 170.4, 167.8, 340(M+H+) 100%
148.3,140.0,
121.8, 16.5.
3131 (Aromatic
HRMS (Q-TOF-ESI) C-H). 2929 (C-H),
Calcd for C11H9N5S4 1605,1580 (C=C),
N
N
S
(MNa+): calcd
361.9638, found
361.9636)
1054(C-S).
N
N
N
S
C
SCH3
δH = 8.03 (t, J=7.6 δC = 181.6, 160.9, 280(M+H+) 5%
3377(NH),
S
Hz, 1H), 7.90(d,
J=7.5 Hz, 2H).
144.7, 138.9,
121.1.
3060(aromatic C-
H), 1153(C-O),
2930 (C-H), 1095
(N-N), 949 (C=S).
O
NH
N
N
N
O
NH
C
S
δH = 8.58 (d, J=
δC = 170, 169,
260 (M+ H+) 100%
3057(Aromatic C-
8.6 Hz, 1H), 8.25 148, 147, 138,
(d, J=8.6 Hz, 1H), 130.8, 129.3,
HRMS (Q-TOF-ESI) H) , 2909(C-H),
Calcd for C12H9N3S2 1610,1582(C=C)
S
S
N
8.1(d, J=8.6 Hz,
128.7, 128.4,
(MH+): calcd ,
260.0316, found
260.0311)
1063 (N-N), 958
(C-S).
N
N
1H), 8.05(d, J=8.6 127.9, 117.5,
Hz, 1H), 7.8(t,
J=7.0Hz 1H),
7.7(t, J=7.0Hz
16.6.

1H), 2.8 (s, 3H).
δH = 8.5 (d,
J=8.0Hz, 1H), 8.1 147.1, 142.9,
(d, J=8.0Hz, 1H), 137.5, 130.6,
8.0 (d, J=8.0Hz,
1H), 7.9(d,
J=8.0Hz, 1H),
7.8(t, J=6.98Hz,
1H), 7.7(t,
δC = 180.8, 161.3, 229(M+ H+) 7%
3450-3200(N-H),
3079 (aromatic C -
H), 1616, 1540
(C=C),
1631(C=N),
934(C=S).
S
O
N
N
NH
129.3, 129.1,
128.1, 127.8,
118.6.
J=6.98Hz, 1H).
δH = 7.9(d, J=
δC = 167.4, 167.1,
SCH3
S
N
Hz,1H), 7.6(d, J= 131, 129, 128,
Hz, 1H), 7.5(t, J= 126, 16.
Hz, 1H), 2.8 (s,
N
3H).
δH = 7.8 (d, J=
6.9Hz, 2H), 7.5 (t, 131, 129, 127,
J= 7.4Hz, 2H),
7.4 (t, J=
δC = 171, 161,
S
O
N
NH
126.
7.4Hz,1H).
δH = 9.1(s, 1H),
8.8 (dd, J=1.52,
4.88Hz, 1H),
8.3(dt, J= 1.5,
7.9Hz, 1H),
δC = 168, 164,
151, 147,135,
124, 119, 16.62.
210 (M+ H+) 100%
3051(Aromatic C-
H), 2924(C-H),
1032(C-S), 1455
(C-N).
SCH3
S
N
N
N
7.6(m, 1H), 2.8
(s, 3H)
δH = 9.1(s, 1H),
8.8 (dd, J=1.52,
4.88Hz, 1H),
8.3(dt, J= 1.5,
7.9Hz, 1H),
δC 178, 159, 152,
146, 133, 124,
119.
3225(N-H), 3045
(Aromatic C-H),
1216 (C-O),
1044(N-N).
933(C=S)
S
O
NH
N
N
7.6(m, 1H).
δH = 8.7 (d, J=
5.3Hz, 2H), 7.9(d, 150, 136, 121,
δC =169, 163,
210 (M+ H+) 100%
3060(Aromatic C-
H), 1030(C-S),
2995 (C-H),
SCH3
S
N
N
N
J= 5.3Hz, 2H),
2.8 (s, 3H).
16.66.
S
δH = 8.7 (d, J=
5.8Hz, 2H), 7.7(d, 150, 138, 119.
J= 5.8Hz, 2H).
δC =178, 159,
3378 (N-H),
1617(C=N),
931(C=S), 1205
(C-O).
O
N
NH
N