Mild and convenient one-pot synthesis of 1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2010.06.139

A mild, general, convenient, and efficient one-pot synthesis of 2-phenyl-5-substituted-1,3,4-oxadiazoles is described. Both (hetero)aryl and alkyl carboxylic acids were efficiently condensed with benzohydrazide in the presence of TBTU to give diacylhydrazine intermediates. The latter underwent a smooth TsCl-mediated cyclodehydration reaction to afford 2-phenyl-5-substituted- 1,3,4-oxadiazoles in good to very good yields.

Full text of DOI:10.1016/j.tetlet.2010.06.139

Tetrahedron Letters 51 (2010) 4801–4805
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Tetrahedron Letters
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Mild and convenient one-pot synthesis of 1,3,4-oxadiazoles
a
a
a
a
Paolo Stabile a, , Alessandro Lamonica , Arianna Ribecai , Damiano Castoldi , Giuseppe Guercio ,
*
Ornella Curcuruto b
a Chemical Development Department, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy
b Analytical Chemistry Department, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, general, convenient, and efficient one-pot synthesis of 2-phenyl-5-substituted-1,3,4-oxadiazoles
is described. Both (hetero)aryl and alkyl carboxylic acids were efficiently condensed with benzohydrazide
in the presence of TBTU to give diacylhydrazine intermediates. The latter underwent a smooth TsCl-med-
iated cyclodehydration reaction to afford 2-phenyl-5-substituted-1,3,4-oxadiazoles in good to very good
yields.
Received 12 May 2010
Revised 24 June 2010
Accepted 29 June 2010
Available online 14 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,3,4-Oxadiazoles
Cyclodehydration
Tosyl chloride
One-pot synthesis
The 1,3,4-oxadiazole motif has been extensively used for many
years by medicinal chemists as a bioisosteric replacement of acid,
ester, and amide functionalities in compounds exhibiting a wide
range of biological activities.1 Among the reported methodologies
for the synthesis of 1,3,4-oxadiazoles, the cyclodehydration reaction
of 1,2-diacylhydrazines is often found in the literature.2 In particu-
lar, dehydrating agents such as SOCl2 and highly toxic POCl3 are
widely employed.3 However, harsh reaction conditions, such as high
temperatures and large excess of the dehydrating reagent, are usu-
ally required. Milder cyclodehydration reactions have been medi-
ated by 2-chloro-1,3-dimethylimidazolinium chloride,4 PPh3/I2,
and PPh3/CX4 systems (X = Cl or Br)5 or the expensive Burgess
reagent.6 The readily available and relatively cheap 4-methyl-
benzenesulfonyl chloride has also been described to promote
1,3,4-oxadiazole formation from 1,2-diacylhydrazines.7 In addition,
microwave-mediated syntheses of 1,3,4-oxadiazoles have also been
reported.8
Very recently, a few efficient one-pot protocols appeared in the
literature. Dickson and Li prepared 2,5-disubstituted 1,3,4-oxadi-
azoles starting from benzohydrazide and a variety of carboxylic
acids.9 Nevertheless, quite expensive HATU, as an amide coupling
agent, and Burgess reagent, as dehydrating system, were utilized.
On the other hand, Augustine et al. described the use of T3PÒ acting
both as the coupling and the cyclodehydration agent in the synthe-
sis of 1,3,4-oxadiazoles from carboxylic acids and hydrazides.10
Despite the wide generality and the high efficiency of the above-
mentioned methodologies, some limitations still remain. As a
matter of fact, the high cost of the reagents and the need to store
the Burgess reagent at low temperatures do not make these proce-
dures appealing for large-scale preparations.
Table 1
TsCl-mediated cyclodehydration of 3a
O
H
N
O
N
TsCl, base
solvent,T
N
H
N
O
4a
3a
Entry
Solvent
Base
T (°C)
Yielda,b (%)
Yieldc,d (%)
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Acetone
Acetone
Acetone
Acetone
TEA
Pyridine
DBU
K2CO3
TEA
Pyridine
DBU
K2CO3
TEA
Pyridine
DBU
25
40
25
25
25
40
25
25
40
40
25
40
>99
0
85
>99
>99
0
95
—
—
95
95
—
—
—
96
—
—
69
>99
>99
0
86
>99
10
11
12
K2CO3
90
a
A mixture of 3a (1 mmol), the base (3 equiv) and TsCl (1.5 equiv) in the solvent
(4.8 ml) was stirred at the indicated temperature.
b
Yield determined in solution by HPLC, using a calibration curve.
Reactions were carried out with 3.3 mmol of 3a.
Isolated yield after chromatographic purification.
* Corresponding author. Tel.: +39 0458219648; fax: +39 0458218117.
E-mail addresses: paolo.stabile@aptuit.com, paostabile@googlemail.com (P.
Stabile).
c
d
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.139

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P. Stabile et al. / Tetrahedron Letters 51 (2010) 4801–4805
Table 2
Synthesis of 2-aryl-5-phenyl-1,3,4-oxadiazolesa
O
H
H
N
R
O
TBTU, DIPEA
DIPEA, TsCl
rt
R
N
RCOOH
+
N
H
NH2
N
N
MeCN, rt
O
O
1
4
3
2
Entry
1
Carboxylic acid
Product
Yieldb (%)
O
COOH
78
N
N
1a
4a
O
COOH
2
3
79
80
N
N
1b
4b
MeO
Me
MeO
Me
O
COOH
COOH
COOH
COOH
N
N
1c
4c
O
4
5
72
74
73
79
63
65
74
N
N
1d
1e
1f
4d
Cl
Cl
O
N
N
4e
O2N
O2N
O
6
N
N
4f
OMe
OMe
O
COOH
7
N
N
1g
4g
Me
Me
O
COOH
8
N
N
1h
4h
Cl
Cl
O
N
4i
COOH
9
N
1i
NMe2
NMe2
O
COOH
10
N
N
1j
4j

P. Stabile et al. / Tetrahedron Letters 51 (2010) 4801–4805
4803
Table 2 (continued)
Entry
Carboxylic acid
Product
Yieldb (%)
O
11
77
81
COOH
N
N
1k
4k
OMe
OMe
MeO
MeO
MeO
O
MeO
COOH
12
N
N
1l
4l
a
To a mixture of 1 (5 mmol), 2 (1 equiv), and DIPEA (3 equiv) in MeCN (60 ml) at room temperature was added TBTU (1.1 equiv). To the resulting mixture of the
intermediate 3 were then added DIPEA (2 equiv) and TsCl (3 equiv).
b
Isolated yield.
Table 3
Synthesis of 2-heteroaryl-5-phenyl-1,3,4-oxadiazoles and 2-alkyl-5-phenyl-1,3,4-oxadiazolesa
O
H
N
H
N
R
O
TBTU, DIPEA
MeCN, rt
DIPEA, TsCl
rt
R
RCOOH
+
N
H
NH2
N
N
O
O
1
4
3
2
Entry
1
Carboxylic acid
Product
Yieldb (%)
O
N
COOH
1m
N
84
N
N
4m
N
N
O
COOH
1n
2
68
79
N
N
4n
O
COOH
1o
S
S
3
4
N
N
4o
O
O
O
COOH
1p
79
84
N
N
4p
O
COOH
N
N
5
6
1q
COOH
1r
4q
O
N
N
75
4r
(continued on next page)

4804
P. Stabile et al. / Tetrahedron Letters 51 (2010) 4801–4805
Table 3 (continued)
Entry
Carboxylic acid
Product
Yieldb (%)
O
COOH
7
8
9
N
85
N
1s
4s
O
N
4t
COOH
76
N
1t
O
N
N
N
COOH
COOH
90
79
O
N
O
N
N
O
O
1u
4u
O
O
O
O
O
10
N
N
1v
4v
a
To a mixture of 1 (5 mmol), 2 (1 equiv), and DIPEA (3 equiv) in MeCN (60 ml) at room temperature was added TBTU (1.1 equiv). To the resulting mixture of the
intermediate 3 were then added DIPEA (2 equiv) and TsCl (3 equiv).
b
Isolated yield.
In the course of our studies aiming at the optimization of the
synthesis of new biologically active chemical entities, we were
interested in establishing a convenient, practical, and general
methodology for preparing a variety of 2,5-disubstituted-1,3,
4-oxadiazoles. The commercial availability of a wide range of
carboxylic acids prompted us to investigate the synthesis of 2-phe-
nyl-5-substituted-1,3,4-oxadiazoles via their condensation
reaction with benzohydrazide and successive cyclodehydration of
the resulting diacylhydrazine intermediates.
As a first instance, we focused on the cyclodehydration reaction
of diacylhydrazines. Among the variety of available dehydrating
agents, we turned our attention toward 4-methylbenzenesulfonyl
chloride (TsCl) because it is a non-toxic and cheap reagent. Thus,
benzoic acid, 1a, was condensed with benzohydrazide, 2, by using
propylphosphonic anhydride (T3PÒ) as coupling agent to afford the
model substrate N0-(phenylcarbonyl)benzohydrazide 3a. Succes-
sively, the TsCl-mediated intramolecular cyclocondensation of 3a
was investigated and a solvent/base screening was carried out (Ta-
ble 1). Both triethylamine (TEA) and K2CO3 gave compound 4a in
excellent yield in all the solvents tested (Table 1, entries 1, 5, and
9 and entries 4, 8, and 12, respectively). However, no reaction oc-
curred in the presence of pyridine (Table 1, entries 2, 6, and 10),
whilst DBU provided compound 4a in lower yields (Table 1, entries
3, 7, and 11). Worthy of note is the formation of a by-product iden-
tified as N,N-diethyl-4-methylbenzenesulfonamide, when using
TEA as base.
With these satisfactory results in our hands, we started inves-
tigating the synthesis of diacylhydrazine derivatives 3 and, in par-
ticular, the condensation reaction of a few model carboxylic acids
(namely, compounds 1a, 1b, 1c, and 1q) with benzohydrazide, 2.
Thus, a screening of amide coupling agents, that is, T3PÒ, N,
N0-dicyclohexylcarbodiimide (DCC), and O-(benzotriazol-1-yl)-
N,N,N0,N0-tetramethyluronium tetrafluoroborate (TBTU), and bases
(diisopropylethylamine and triethylamine) in different solvents
(dichloromethane, tetrahydrofuran, and acetonitrile) was
performed at room temperature. In spite of the fact that T3PÒ
and TBTU provided fast and efficient condensation reactions of
1a-c1a–c and 1q with 2, isolation of the corresponding diacylhydr-
azines 3a–c and 3q was not always straightforward due to their
poor solubility in common solvents. Nonetheless, we speculated
that the addition of TsCl to the crude mixtures of compounds 3
could result in the formation of the desired 2-phenyl-5-substi-
tuted-1,3,4-oxadiazoles 4, thus skipping the isolation step of the
intermediate diacylhydrazines. We were pleased to find that when
using TBTU as the coupling agent, the one-pot protocol furnished
very encouraging results. In particular, the best performances were
observed when using diisopropylethylamine (DIPEA) as the base in
acetonitrile at room temperature, affording the desired compounds
4a–c (Table 2, entries 1–3) and 4q (Table 3, entry 5) in satisfactory
yields after chromatographic purification.
With this piece of information in our hands, we wished to ex-
tend our methodology to a variety of aryl acids 1 (Table 2). Thus,
compounds 1 (5 mmol), 2 (1 equiv), and DIPEA (3 equiv) were
mixed in MeCN (60 ml) at room temperature and TBTU (1.1 equiv)
was added. Once the formation of intermediates 3 reached com-
pleteness, more DIPEA (2 equiv) and TsCl (3 equiv) were charged
to afford the 2-aryl-5-phenyl-1,3,4-oxadiazoles 4 (Table 2). It
should be noted that 1H-1,2,3-benzotriazol-1-ol formed during
the amide coupling step as a by-product, consumed 1 equiv of TsCl
and therefore an excess (3 equiv) of the latter was required to per-
form efficiently the cyclodehydration step. The crude reaction mix-
tures were then treated with an aqueous solution of ammonia to
transform the excess of TsCl in 4-methylbenzenesulfonamide, thus
allowing easier chromatographic purification in the majority of
cases (Table 2). However, in a few instances, 4-methylbenzenesulf-
onamide had to be completely removed prior to the chromato-
graphic purification to obtain pure 1,3,4-oxadiazoles 4. This was
accomplished by treating the crude compounds 4 with a 2 N aque-
ous solution of NaOH.
As shown in Table 2, both electron-rich and electron-poor aryl
carboxylic acids 1a–l afforded the corresponding 1,3,4-oxadiazoles
4a–l in good to very good yields. In particular, 4-substituted
derivatives 1c–e reacted more efficiently than the corresponding
2-substituted regioisomers 1g–i, likely because of the steric hin-
drance of the ortho substituent (Table 2, compare entries 3–5 with
entries 7–9).

P. Stabile et al. / Tetrahedron Letters 51 (2010) 4801–4805
4805
S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.;
Williamson, D. W.; Hargreaves, R. J. J. Med. Chem. 1996, 39, 2907–2914; (d)
Warmus, J. S.; Flamme, C.; Zhang, L. Y.; Barrett, S.; Bridges, A.; Chen, H.; Gowan,
R.; Kaufman, M.; Sebolt-Leopold, J.; Leopold, W.; Merriman, R.; Ohren, J.;
Pavlovsky, A.; Przybranowski, S.; Tecle, H.; Valik, H.; Whitehead, C.; Zhang, E.
Bioorg. Med. Chem. Lett. 2008, 18, 6171–6174; (e) Omar, F. A.; Mahfouz, N. M.;
Rahman, M. A. Eur. J. Med. Chem. 1996, 31, 819–825.
To further demonstrate the generality of our methodology, we
decided to extend it to substrates bearing heteroaryl and alkyl
functionalities. Both electron-rich and electron-poor heteroaryl
derivatives 1m–p reacted efficiently under our conditions and
the corresponding 2-heteroaryl-5-phenyl-1,3,4-oxadiazoles 4m–p
were prepared in 68–84% yield (Table 3, entries 1–4). Alkanoic
acids 1q–t proved to be excellent substrates as well, affording
1,3,4-oxadiazoles 4q–t in very good yields (Table 3, entries 5–8).
Finally, N-Boc-protected a- and b-aminoacids 1u and 1v furnished
the desired 4u and 4v in 90 and 79% yield, respectively (Table 3,
entries 9 and 10).
In conclusion, we have developed a mild and efficient one-pot
methodology to synthesize a variety of 2-aryl-, 2-heteroaryl-, and
2-alkyl-5-phenyl-1,3,4-oxadiazoles from commercially available
carboxylic acids and benzohydrazide. Non-toxic and cheap 4-meth-
ylbenzenesulfonyl chloride was employed to convert the 1,2-diacy-
lhydrazine intermediates to the desired 1,3,4-oxadiazoles.
2. (a) Hill, J. In Comprehensive Heterocyclic Chemistry II; Storr, R. C., Ed.; Pergamon:
Oxford, 1996; Vol. 4, pp 267–287; (b) Weaver, G. W. In Science of Synthesis;
Storr, R. C., Gilchrist, T. L., Eds.; Thieme: Stuttgart, 2004; Vol. 13, pp 219–251;
ˇ
ˇ
(c) Dobrota, C.; Paraschivescu, C. C.; Dumitru, I.; Matache, M.; Baciu, I.; Rußta, L.
L. Tetrahedron Lett. 2009, 50, 1886–1888; (d) Dabiri, M.; Salehi, P.;
Baghbanzadeh, M.; Zolfigol, M. A.; Bahramnejad, M. Synth. Commun. 2007, 37,
1201–1209; (e) Kangani, C. O.; Day, B. W. Tetrahedron Lett. 2009, 50, 5332–
5335; (f) Reddy, C. K.; Reddy, P. S. N.; Ratnam, C. V. Synthesis 1983, 842–844; (g)
Rauf, A.; Sharma, S.; Gangal, S. Chin. Chem. Lett. 2008, 19, 5–8.
3. (a) Padmavathi, V.; Reddy, G. S.; Padmaja, A.; Kondaiah, P.; Ali-Shazia Eur. J.
Med. Chem. 2009, 44, 2106–2112; (b) Hamad, A.-S. S.; Hashem, A. I. J.
Heterocycl. Chem. 2002, 39, 1325–1328; (c) Kerr, V. N.; Ott, D. G.; Hayes, F. N. J.
Am. Chem. Soc. 1960, 82, 186–189; (d) Da, Y.-X.; Yang, Z.; Quan, Z.-J.; Zhang, Z.;
Wang, X.-C. J. Heterocycl. Chem. 2009, 46, 737–741; (e) Rebek, J.; Gu, S.; Biros, S.
U.S. Pat. Appl. 2006/0205728, 2006.; (f) Borg, S.; Vollinga, R. C.; Labarre, M.;
Payza, K.; Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42, 4331–4342.
4. (a) Barrow, J. C.; Harrison, S.; Mulhearn, J.; Sur, C.; Williams, D. L.; Wolkenberg,
S. PCT Int. Appl. WO 2009/146343, 2009.; (b) Isobe, T.; Ishikawa, T. J. Org. Chem.
1999, 64, 6989–6992.
Acknowledgments
5. (a) Shchekotikhin, A. E.; Shevtsova, E. K.; Traven, V. F. Russ. J. Org. Chem. 2007,
43, 1686–1695; (b) Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.;
Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. Bioorg. Med. Chem. Lett.
2009, 19, 1807–1810; (c) Rajapakse, H. A.; Zhu, H.; Young, M. B.; Mott, B. T.
Tetrahedron Lett. 2006, 47, 4827–4830.
We gratefully thank Dr. Zadeo Cimarosti and Dr. Pieter Wester-
duin (GlaxoSmithKline, Verona) for the useful discussions and
valuable contributions.
6. (a) Bethel, P. A.; Gerhardt, S.; Jones, E. V.; Kenny, P. W.; Karoutchi, G. I.; Morley,
A. D.; Oldham, K.; Rankine, N.; Augustin, M.; Krapp, S.; Simader, H.;
Steinbacher, S. Bioorg. Med. Chem. Lett. 2009, 19, 4622–4625; (b) Aquino, C. J.;
Dickson, H.; Peat, A. J. PCT Int. Appl. WO 2008/157330, 2008.; (c) Lee, S. H.; Seo,
H. J.; Kim, M. J.; Kang, S. Y.; Song, K.-S.; Lee, S.-H.; Jung, M. E.; Kim, J.; Lee, J.
Bioorg. Med. Chem. Lett. 2009, 19, 1899–1902.
7. (a) Garfunkle, J.; Ezzili, C.; Rayl, T. J.; Hochstatter, D. G.; Hwang, I.; Boger, D. L. J.
Med. Chem. 2008, 51, 4392–4403; (b) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li,
Y.; Boger, D. L. Angew. Chem., Int. Ed. 2006, 45, 620–622; (c) Yuan, Z. Q.;
Ishikawa, H.; Boger, D. L. Org. Lett. 2005, 7, 741–744.
Supplementary data
Supplementary data (experimental procedures and characteriza-
tion data for all substrates 4a–v) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.06.139.
References and notes
8. (a) Saeed, A.; Mumtaz, A. Chin. Chem. Lett. 2008, 19, 423–427; (b) Wang, Y.;
Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 105–108; (c) Brain, C. T.;
Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999, 40, 3275–3278.
9. Li, C.; Dickson, H. D. Tetrahedron Lett. 2009, 50, 6435–6439.
10. Augustine, J. K.; Vairaperumal, V.; Narasimhan, S.; Alagarsamy, P.;
Radhakrishnan, A. Tetrahedron 2009, 65, 9989–9996.
1. For some examples see: (a) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.;
Hadley, M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.;
Wyman, P. J. Med. Chem. 1991, 34, 2726–2735; (b) Tully, W. R.; Gardner, C. R.;
Gillespie, R. J.; Westwood, R. J. Med. Chem. 1991, 34, 2060–2067; (c)
Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.;
Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski,