Greener and rapid access to bio-active heterocycles: one-pot solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.tetlet.2007.11.165

A novel one-pot solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles by condensation of acid hydrazide and triethyl orthoalkanates under microwave irradiations is reported. This green protocol was catalyzed efficiently by solid supported NafionNR50 and phosphorus pentasulfide in alumina (P₄S₁₀/Al₂O₃) with excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.11.165

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 879–883
Greener and rapid access to bio-active heterocycles: one-pot
solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles
Vivek Polshettiwar, Rajender S. Varma *
Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency,
26 West Martin Luther King Drive, MS 443, Cincinnati, OH 45268, USA
Received 10 October 2007; revised 26 November 2007; accepted 27 November 2007
Available online 4 December 2007
Abstract
A novel one-pot solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles by condensation of acid hydrazide and triethyl
orthoalkanates under microwave irradiations is reported. This green protocol was catalyzed efficiently by solid supported NafionÒNR50
and phosphorus pentasulfide in alumina (P4S10/Al2O3) with excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 1,3,4-Oxadiazole; 1,3,4-Thiadiazole; Nafion; P4S10/Al2O3; Solvent-free reaction; Microwave irradiation
1,3,4-Oxadiazoles and 1,3,4-thiadiazoles are a class of
heterocycles which have attracted significant interest in
medicinal chemistry and they have a wide range of pharma-
ceutical and biological activities including antimicrobial,
anti-fungal, anti-inflammatory, and antihypertensive.1–5
The widespread use of 1,3,4-oxadiazoles as a scaffold in
medicinal chemistry establishes this moiety as an important
bio-active class of heterocycles. These molecules are also
utilized as pharmacophores due to their favorable meta-
bolic profile and ability to engage in hydrogen bonding.
In particular, marketed antihypertensive agents such as tio-
dazosin6 and nesapidil7 as well as antibiotics such as
furamizole8 contain the oxadiazole nucleus. They are also
useful as HIV integrase inhibitors and the angiogenesis
inhibitors.8,9
a few efficient examples have been reported for the synthe-
sis of 1,3,4-oxadiazoles, especially from readily available
carboxylic acids and acid hydrazides. However, these pro-
tocols use expensive catalysts, and require longer times for
the completion of the reactions.20
Ainsworth in 1954 reported a one-step synthesis of these
1,3,4-oxadiazoles from corresponding acid hydrazides.21
However, despite its common use, this protocol suffers
from harsh conditions, such as use of excess orthoformates
and longer reaction time. In view of the emerging interest
in sustainable chemistry,22 and in keeping with our empha-
sis on the development of green synthetic methods,23 we
revisited this Ainsworth protocol and herein report Nafion
catalyzed synthesis of 1,3,4-oxadiazoles under microwave
(MW) irradiation (Scheme 1).
Several methods have been reported in the literature for
the synthesis of 1,3,4-oxadiazoles.10–19 Most of these proto-
cols are multi-step in nature, and generally involve the
cyclization of acid hydrazides with a variety of reagents,
such as thionyl chloride, phosphorus oxychloride or sulfu-
ric acid, usually under harsh reaction conditions. Recently,
After screening a range of usual inorganic and organic
acids and exploring the scope of various solvents, we found
that the solid supported NafionÒNR5024 was the most effi-
cient catalyst for this protocol in the absence of any sol-
vent.25 The efficiency of this protocol was then studied
for the synthesis of various 1,3,4-oxadiazoles and the
results are summarized in Table 1.
Various hydrazides reacted efficiently with triethyl
orthoformate, triethyl orthoproponate and triethyl ortho-
benzoate to afford the desired 1,3,4-oxadiazoles in good
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569 7677.
E-mail address: varma.rajender@epa.gov (R. S. Varma).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.165

880
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 879–883
O
R1
R2
O
Nafion®NR50
MW
R2
O
NHNH2
O
N
N
O
R1
R1 = H, F, OMe, 2-furyl, 2-thienyl, 4-pyridyl
R2 = H, Et, Ph
Scheme 1. Nafion catalyzed 1,3,4-oxadiazoles synthesis.
Table 1
NafionÒNR50-catalyzed synthesis of 1,3,4-oxadiazoles under MW irradiationa
Entry
1
Hydrazide
Product
Yield (%)
80
O
NHNH2
N
N
N
N
O
O
NHNH2
NHNH2
2
3
80
81
N
O
O
O
N
O
O
O
O
4
5
85
88
88
90
90
90
90
90
90
NHNH2
NHNH2
N
N
N
N
O
N
O
6
NHNH2
O
N
F
F
O
7
NHNH2
N
N
N
N
F
O
O
O
8
NHNH2
N
F
F
O
9
NHNH2
O
N
F
MeO
O
10
11
NHNH2
N
N
MeO
MeO
MeO
O
O
MeO
MeO
O
NHNH2
NHNH2
N
N
O
12
N
N
a
Reaction temperature 80 °C, time 10 min, and no solvent.

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 879–883
881
Table 2
It is noteworthy to mention that these reactions pro-
ceeded efficiently without any solvent, even though they
involved the use of heterogeneous solid supported catalyst.
This is due to selective absorption of microwaves by reac-
tants, polar intermediates and Nafion, which accelerate
the reaction rate.26 Also the catalyst NafionÒNR50 is very
easy to handle, as it involves simply the addition of Nafion
bead (like a glass bead) in a reaction vessel, which can be
physically removed by forceps after the completion of
reaction.
In view of the exceptional biological properties of
heterocyclic hydrazides and to further define the scope of
this reaction, a wide variety of heterocyclic hydrazides were
evaluated for this cyclization reaction and the results are
summarized in Table 2. Various heterocyclic hydrazides
such as 2-furyl hydrazides (entries 1–3), 2-thiophenyl
hydrazides (entries 4–6), and 4-pyridyl hydrazides (entries
7–9) reacted efficiently to afford corresponding 1,3,4-oxadi-
azoles in good yields.
Finally, this protocol was also extended for one-step
synthesis of 1,3,4-thiadiazoles from acid hydrazides. One
of us has previously used phosphorus pentasulfide in alu-
mina (P4S10/Al2O3) as an efficient thionating agent for
various carbonyl compounds.27 We used this reagent for
one-pot synthesis of 1,3,4-thiadiazoles under MW irradia-
tion conditions (Scheme 2) and to the best of our knowl-
edge this is the first report on one-step one-pot synthesis
of 1,3,4-thiadiazoles from acid hydrazides.
NafionÒNR50-catalyzed 1,3,4-oxadiazoles synthesis using heterocyclic
hydrazidesa
Entry
Hydrazide
Product
Yield (%)
O
O
68
1
O
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
N
N
N
O
O
O
2
3
4
5
6
7
8
70
72
78
78
80
78
80
80
O
N
O
O
O
O
S
N
N
N
O
O
O
N
S
O
O
S
N
N
S
O
O
S
N
N
O
N
S
O
Using the optimized reaction conditions,25 the efficiency
of this protocol was studied for the synthesis of various thi-
adiazoles. The results are summarized in Table 3. Various
aromatic and heterocyclic hydrazides reacted efficiently
with P4S10/Al2O3 to yield thiadiazoles in a single step.
The reaction proceeds efficiently without any solvent, with
moderate to good yields of 1,3,4-thiadiazole.
N
N
N
N
N
N
N
O
O
N
N
O
N
O
9
For practical applications of the catalyst NafionÒNR50,
the lifetime of the catalyst and its level of reusability are
important factors. The catalyst showed excellent recyclabil-
ity in the synthesis of 1,3,4-oxadiazoles from benzoic
hydrazide and triethylorthoformate. The reactions were
carried out under similar conditions (80 °C/10 min) with-
out any solvent. After the completion of the first reaction
to afford the corresponding 1,3,4-oxadiazoles in 85% yield,
the catalyst was recovered by forceps, washed with dichlo-
romethane, dried and a new reaction was then performed
with fresh reactants under the same conditions; Naf-
ionÒNR50 could be used for at least five times without
any change in activity.
N
a
Reaction temperature 130 °C, time 25 min, and no solvent.
yields (entries 1–12). This approach establishes a conve-
nient and flexible method for the synthesis of 1,3,4-oxadi-
azoles having functional arms at the 2 and 5 positions,
which can be further elaborated. The reactions also pro-
ceed without catalyst, but require higher temperature
(135 °C) with longer reaction time (1.5 h) under MW irra-
diation. This reaction also gets completed under conven-
tional heating in an oil bath at the reflux temperature but
requires an extended period of time, 16–18 h.
O
R1
R2
P4S10/Al2O3
S
R2
O
NHNH2
º
120 C, MW
O
N
N
O
R1
R1 = H, F, OMe, 2-furyl, 2-thienyl, 4-pyridyl
R2 = H, Et, Ph
Scheme 2. P4S10/Al2O3 mediated synthesis of 1,3,4-thiadiazoles.

882
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 879–883
Table 3
P4S10/Al2O3 mediated synthesis of 1,3,4-thiadiazolesa
Entry
1
Hydrazide
Product
Yield (%)
65
O
S
NHNH2
N
N
N
O
S
2
3
4
70
70
70
NHNH2
O
N
MeO
MeO
F
S
NHNH2
N
N
MeO
MeO
O
S
NHNH2
N
N
O
S
5
65
NHNH2
N
N
F
O
S
6
7
8
9
70
72
68
70
70
S
S
NHNH2
NHNH2
NHNH2
NHNH2
NHNH2
N
N
S
O
S
S
N
N
N
S
O
O
N
N
S
O
O
N
N
N
N
O
N
S
10
N
N
a
Reaction temperature 120 °C, time 10 min, and no solvent.
In conclusion, we have demonstrated a new and efficient
approach for the synthesis of 1,3,4-oxadiazoles and 1,3,4-
thiadiazoles, which may find useful application in drug
discovery. Also the use of solid supported, relatively low
toxic, and inexpensive NafionÒNR50 and P4S10/Al2O3 as
a catalyst and the solvent-free reaction conditions are addi-
tional eco-friendly attributes of this synthetic protocol.
Institute for Science and Education through an interagency
agreement between the US Department of Energy and the
US EPA.
References and notes
1. Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J. Med.
Chem. 1991, 34, 2060–2067.
2. Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1994, 59, 3738–3741.
3. Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35,
267–271.
4. Crimmin, M. J.; O’Hanlon, P. J.; Rogers, N. H.; Walker, G. J. Chem.
Soc., Perkin Trans. 1 1989, 2047–2056.
Acknowledgment
Vivek Polshettiwar was supported, in part, by the Post-
graduate Research Program at the National Risk Manage-
ment Research Laboratory administered by the Oak Ridge

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 879–883
883
5. Laddi, U. V.; Desai, S. R.; Bennur, R. S.; Bennur, S. C. Ind. J.
Heterocycl. Chem. 2002, 11, 319–322.
6. Vardan, S.; Mookherjee, S.; Eich, R. Clin. Pharm. Ther. 1983, 34,
290–296.
7. Schlecker, R.; Thieme, P. C. Tetrahedron 1988, 44, 3289–3294.
8. Ogata, M.; Atobe, H.; Kushida, H.; Yamamoto, K. J. Antibiot. 1971,
24, 443–451.
9. Johns, B. A. PCT Int Appl. WO 101512, 2004.
10. Piatnitski, E.; Kiselyov, A.; Doody, J.; Hadari, Y.; Ouyang, S.; Chen,
X. PCT Int Appl. WO 052280, 2004.
11. Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61,
5323–5349.
R. S. Tetrahedron Lett. 2007, 48, 8735–8738; (f) Polshettiwar, V.;
Varma, R. S. Tetrahedron Lett. 2007, doi:10.1016/j.tetlet.2007.11.017;
(g) Gawande, M. B.; Polshettiwar, V.; Varma, R. S. Tetrahedron Lett.
2007, 48, 8170–8173; (h) Namboodiri, V. V.; Polshettiwar, V.; Varma,
R. S. Tetrahedron Lett. 2007, 48, 8839–8842; (i) Ju, Y.; Kumar, D.;
Varma, R. S. J. Org. Chem. 2006, 71, 6697–6700; (j) Ju, Y.; Varma, R.
S. J. Org. Chem. 2006, 71, 135–141; (k) Ju, Y.; Varma, R. S. Org. Lett.
2005, 7, 2409–2411; (l) Kumar, D.; Chandra Sekhar, K. V. G.;
Dhillon, H.; Rao, V. S.; Varma, R. S. Green Chem. 2004, 6, 156–157;
(m) Kumar, D.; Reddy, V. B.; Mishra, B. G.; Rana, R. K.;
Nadagouda, M. N.; Varma, R. S. Tetrahedron 2007, 63, 3093–3097;
(n) Strauss, C. R.; Varma, R. S. Top. Curr. Chem. 2006, 266, 199–231.
´
12. Brown, B. J.; Clemens, I. R.; Neesom, J. K. Synlett 2000, 1, 131–133.
13. Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G. Tetrahedron
Lett. 2004, 45, 3257–3260.
14. Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett.
1999, 40, 3275–3278.
15. Brain, C. T.; Brunton, S. A. Synlett 2001, 3, 382–384.
16. Tandon, V. K.; Chhor, R. B. Synth. Commun. 2001, 31, 1727–1732.
17. Mashraqui, S. H.; Ghadigaonkar, S. G.; Kenny, R. S. Synth.
Commun. 2003, 33, 2541–2545.
18. Bentiss, F.; Lagrenee, M.; Barbry, D. Synth. Commun. 2001, 31, 935–
938.
24. (a) Lopez, D. E.; Goodwin, J. G., Jr.; Bruce, D. A. J. Catal. 2007, 245,
381–391; (b) Stanescu, M. A.; Varma, R. S. Tetrahedron Lett. 2002,
43, 7307–7309; (c) Olah, G. A.; Shamma, T.; Surya Prakash, G. K.
Catal. Lett. 1997, 46, 1–4; (d) Yamato, T.; Hideshima, C.; Tashiro,
M.; Surya Prakash, G. K.; Olah, G. A. Catal. Lett. 1990, 6, 341–
344.
25. Experimental procedure for the synthesis of 2-phenyl-1, 3, 4-oxadiazole:
Phenyl hydrazide (0.13 g, 1 mmol) and triethylorthoformate (0.17 g,
1.2 mmol) were placed in 10 mL crimp-sealed thick-walled glass tube
equipped with a pressure sensor and a magnetic stirrer. To this, 20 mg
(in general one small bead) of catalyst NafionÒNR50 was added and
the reaction tube was placed inside the cavity of a CEM Discover
focused microwave synthesis system, operated at 80 5 °C (temper-
ature monitored by a built-in infrared sensor), power 40–140 W, and
pressure 20–40 psi for 10 min. After completion of the reaction, the
solid catalyst was physically removed by forceps, to isolate crude
1,3,4-oxadiazoles, which were further purified by column chromatog-
raphy, 85% yield. 1H NMR (CDCl3): d 8.5 (s, 1H), 8.1 (m, 2H), 7.5 (d,
3H); 13C NMR (CDCl3): d 164, 152, 133, 129, 127, 123; MS: 146
(M+), 118, 105, 90, 77, 63, 51.
19. Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
105–108.
20. (a) Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org.
Chem. 2006, 71, 9548–9551; (b) Jakopin, Z.; Roskar, R.; Dolenc, M.
S. Tetrahedron Lett. 2007, 48, 1468; (c) Souldozi, A.; Ramazani, A.
Tetrahedron Lett. 2007, 48, 1549–1551; (d) Dabiri, M.; Salehi, P.;
Baghbanzadeha, M.; Bahramnejada, M. Tetrahedron Lett. 2006, 47,
6983–6986; (e) Rajapakse, H. A.; Zhu, H.; Young, M. B.; Mott, B. T.
Tetrahedron Lett. 2006, 47, 4827–4830.
21. Ainsworth, C. J. Am. Chem. Soc. 1954, 77, 1148–1150.
22. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–2591; (b)
Varma, R. S. Org. Chem. Highlights 2007, Clean Chemical Synthesis in
Water, URL: http://www.organic-chemistry.org/Highlights/2007/
01February.shtm; (c) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 5,
68–82; (d) Varma, R. S. In Green Chemistry: Challenging Perspectives;
Tundo, P., Anastas, P. T., Eds.; Oxford University Press: Oxford,
2000; p 221; (e) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory
and Practice; Oxford University Press: Oxford, 2000.
23. (a) Polshettiwar, V.; Varma, R. S. Curr. Opin. Drug Discov. Develop.
2007, 10, 723–737; (b) Polshettiwar, V.; Varma, R. S. J. Org. Chem.
2007, 72, 7420–7422; (c) Polshettiwar, V.; Varma, R. S. Tetrahedron
Lett. 2007, 48, 5649–5652; (d) Polshettiwar, V.; Varma, R. S.
Tetrahedron Lett. 2007, 48, 7343–7346; (e) Polshettiwar, V.; Varma,
For the synthesis of oxadiazole from heterocyclic hydrazide, the
reaction conditions were, temperature, 130 °C; reaction time – 25 min;
and NafionÒNR50 – 40 mg.
Typical experimental procedure for thiadiazole synthesis: The acid
hydrazides (1 mmol), triethylorthoformate or triethylorthoproponate
or triethylorthobenzoate (1.1 mmol) and 0.2 g of P4S10/Al2O3 were
placed in a 10 mL crimp-sealed thick-walled glass tube equipped with
a pressure sensor and a magnetic stirrer and the experimental
procedure described above was followed, at temperature, 120 °C.
26. Loupy, A.; Varma, R. S. Chim. Oggi 2006, 24, 36–40.
27. (a) Polshettiwar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 2315–
2317; (b) Polshettiwar, V.; Kaushik, M. P. Tetrahedron Lett. 2004, 45,
6255–6257; (c) Polshettiwar, V.; Kaushik, M. P. J. Sulfur Chem. 2006,
27, 353–386.