Propylphosphonic anhydride (T3P): an efficient reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.tet.2009.09.114

Propylphosphonic anhydride (T3P) has been demonstrated to be an efficient and mild reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles from carboxylic acids.

Full text of DOI:10.1016/j.tet.2009.09.114

Tetrahedron 65 (2009) 9989–9996
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Propylphosphonic anhydride (T3PÒ): an efficient reagent for the one-pot
synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles
*
John Kallikat Augustine , Veeramani Vairaperumal, Sharmila Narasimhan,
Padma Alagarsamy, Anbarasi Radhakrishnan
Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra-Jigani Road, Bangalore 560 099, India
a r t i c l e i n f o
a b s t r a c t
Propylphosphonic anhydride (T3PÒ) has been demonstrated to be an efficient and mild reagent for the
one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles from carboxylic acids.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 22 August 2009
Received in revised form
29 September 2009
Accepted 29 September 2009
Available online 1 October 2009
Keywords:
Propylphosphonic anhydride
1,2,4-Oxadiazole
1,3,4-Thiadiazole
Diacylhydrazide
Cyclodehydration
O
1. Introduction
R2
R1
O
Propylphosphonic anhydride (T3PÒ) is a highly reactive n-pro-
pyl phosphonic acid cyclic anhydride, generally used as a coupling
agent and water scavenger with low toxicity and low allergenic
potential.1 T3P offers several advantages over traditional reagents,
such as broad functional group tolerance, low epimerization ten-
dency, easy work up due to water-soluble by-products, and above
all it gives high yields and purity. Although T3P has been primarily
used as a mild coupling reagent in peptide synthesis, new appli-
cations have recently been developed for this reagent2 (Scheme 1).
For instance, T3P is well known for conversion of carboxylic acids
and amides into nitriles,3 formation of Weinreb amides,4 ester
synthesis,5 dehydrations,3,6 oxidation of alcohols,7 isonitrile syn-
thesis,3 synthesis of alkenes from alcohols,8 and C–C coupling re-
actions.9 Further, T3P has been found to promote the Biginelli
synthesis of 3,4-dihydropyrimidin-2(1H)-ones.10 The wide-ranging
applications and nontoxic nature of T3P show its prospective as
a reagent in organic synthesis.
O
R1
O
O
R2
R2
R1
R1COOH
R2OH
COOH
R1
R2
O
HO
R2
R1
O
O
P O O
RNHCHO
RCOOH or
RCONH2
O
P
RNC
RCN
P
O
O
R1R2CHOH
H2N
S
O
R1
R2
R1COOH
R2R3NH
N
H
R1
R1
O
N
Understanding five-membered heterocycles has been a long
standing objective because they are the primary skeletons of more
than half of the compounds produced by nature and they play vital
HN
S
R2
R2
O
R3
R1
N
R2
* Corresponding author. Tel.: þ91 80 2808 3131; fax: þ91 80 2808 3150.
E-mail address: john.kallikat@syngeneintl.com (J.K. Augustine).
Scheme 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.114

9990
J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
roles in biological activities.11 Five-membered heterocycles such as
1,2,4-oxadiazoles,12 1,3,4-oxadiazoles,13 and 1,3,4-thiadiazoles,14 are
commonly utilized pharmacophores due to their metabolic profile
and ability to engage in hydrogen bonding. The discovery of their
important pharmacological properties stimulated substantial in-
terest in the chemistry and synthesis of these important heterocy-
cles. Most synthetic efforts toward the preparation of these
heterocyclic systems are multi-step in nature and have focused on
a stepwise approach wherein the first step of the synthesis involves
the condensation of carboxylic acids with respective amidoximes or
hydrazides in the presence of a coupling reagent. The heterocycles
are subsequently formed by intramolecular cyclodehydration. Sev-
eral conditionsof cyclodehydration have beenreported, for instance,
1,2,4-oxadiazoles are formed by heating the O-acylated amidoximes
in solvents such as pyridine,15 DMF,16 in the presence or of additives
such as EDC,17 or CDI,16 while thionyl chloride,18 P2O5,19 H2SO4,20
POCl3,21 Burgess reagent,22 triphenylphospine,23 and triflic anhy-
dride24 are used for the cyclization of diacylhydrazide intermediate
to 1,3,4-oxadiazoles. However, despite their common use, most
reported methods to prepare these heterocycles suffer from harsh
conditions or stoichiometric formation of an intractable by-product.
Though, T3P has been identified as a mild water scavenger3,8 the
broad scope and synthetic utility of this reagent as a cyclo-
dehydration agent has not been explored. In precise, it has not been
studied and utilized extensively as a potentially routine reagent for
the synthesis of five-membered heterocycles such as 1,2,4-oxa-
diazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. Here, we report
a one-pot synthesis of 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, and
1,3,4-thiadiazoles directly from carboxylic acids using T3P, wherein,
T3P acts both as a coupling and cyclodehydration reagent.
Table 1
Screening optimal conditions
NHNH2
O
COOH
N
N
T3P
O
+
Base
Br
1a
Br
Entry
T3P (equiv)a
Basec
Temp (ꢀC)
Time (h)
Yield (%)e
1
2
3
4
5
6
7
8
9
1.5
2.5
4
TEA
60
80
80
110
80
80
80
110
25
4
3
3
0.5
3
4
3
0.5
6
65
94
94
93
89
71
92
91
TEA
TEAd
TEA
2.5b
2.5
2.5
2.5
2.5b
2.5
DIEA
DBU
Pyridine
Pyridine
TEA
Trace
a
50% solution in EtOAc.
50% solution in DMF.
3.0 equiv.
5.0 equiv.
Isolated yields.
b
c
d
e
In order to validate that the final ring closing dehydration was
mediated byT3Pand not just a thermal process, a control experiment
was undertaken. Thus, 4-bromo-N0-[(4-tert-butylphenyl)carbo-
nyl]benzohydrazide (Scheme 3) was prepared via a standard amide
coupling reaction. Subsequent heating at reflux in ethyl acetate for
12 h and monitoring by LC–MS showed no reaction. Addition of
1.1 equiv of T3P to the reaction and heating for an additional 3 h, gave
1a in 68% isolated yield. Further, it was observed that the yield of 1a
could be improved to 91% by adding TEA (1.5 equiv), thus indicating
the need of a base for superior results (Scheme 3). In precise, the
formation of 1,3,4-oxadiazole is not a thermal process, but could be
a chronological coupling and cyclodehydration process mediated by
T3P in one-pot.
2. Results and discussion
Our interest in T3P was aggravated during our investigation of
the diacylhydrazide synthesis from acylhydrazides. In the course of
this study, we observed significant amounts of cyclodehydration of
diacylhydrazide that gave rise to 1,3,4-oxadiazoles as major by-
products (Scheme 2). This led to subsequent studies and in the
process we have discovered a new route for the direct conversion of
carboxylic acids to 1,3,4-oxadiazoles.
O
H
N
EtOAc, reflux, 12 h
No reaction
O
N
H
N
N
O
1a
EtOAc, T3P (1.1 equiv)
reflux, 3 h, 68%
O
Br
1
R2 NHNH2
O
O
EtOAc, T3P (1.1 equiv)
R
O
N
N
Br
1
TEA (1.5 equiv), reflux, 3 h, 91%
2
R
R
+
1
2
R
R
T3P / TEA
60 °C
OH
O
NH
NH
Scheme 3.
The mild and practical one-pot dehydrative cyclization of vari-
ous carboxylic acids with diverse alkyl and arylhydrazides was
examined under the conditions of entry 2 in Table 1. As shown in
Table 2, these reactions occurred in moderate to excellent isolated
yields. The reaction condition was compatible with halo, cyano,
hydroxy, methoxy, and N-Boc substituents. However, for com-
pounds bearing acid sensitive functional groups such as N-Boc
(Table 2, entries 3, 4, 8, and 11), an excess of base (5.0 equiv) was
used to avoid any complications arising out of acidic nature of T3P.
It is interesting to note that, azetidine-3-carboxylic acid, a fairly
strained molecule reacted smoothly under the standard reaction
conditions to provide the respective oxadiazoles in good yields
(Table 2, entries 3 and 4). Further, chromatographic isolation of the
products was not necessary and an aqueous work up was sufficient
to isolate the products with good purity.
Scheme 2.
The model reaction of 4-bromobenzoic acid (1.0 equiv) with 4-
tert-butylphenyl hydrazide (1.0 equiv) in the presence of T3P
(1.5 equiv, 50% solution in EtOAc) and TEA (3.0 equiv) in EtOAc at
60 ꢀC provided 1a25 (Table 1, entry 1) in 65% yield in addition to the
uncyclized diacylhydrazide (Scheme 2). After few reaction optimi-
zation such as performing the reaction at higher temperatures
using T3P in DMF (commercially offered as 50% solution) and use of
varying equivalents of T3P and different bases such as TEA, DBU,
DIEA, and pyridine, we were able to conclude that use of T3P
(2.5 equiv, 50% solution in EtOAc) and TEA (3.0 equiv) at 80 ꢀC in-
deed was the ideal method to achieve optimum yield (Table 1, entry
2). However, except DBU, all other bases were effective in pro-
moting the oxadiazole formation. Further, performing the reaction
in DMF using T3P (50% solution in DMF) at 110 ꢀC drastically re-
duced the reaction time, but with no significant increase in the
yield of oxadiazole (Table 1, entry 4). Similarly, at room temperature
the reaction did not proceed for cyclodehydration (Table 1, entry 9)
and we isolated the respective diacylhydrazide.
The 1,2,4-oxadiazole heterocycle has been utilized as a stable
ester or amide bioisostere and is found in several drugs and drug
leads. Having achieved the initial objective of one-pot synthesis of
1,3,4-oxadiazole using T3P, we proceeded to study the scope of this
method and subsequently, investigated the synthesis of 1,2,4-

J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
9991
Table 2
T3P mediated synthesis of 1,3,4-oxadiazoles
1
N
N
R
O
NHNH
T3P (2.5 equiv)
TEA (3 equiv)
2
+
1
2
R
R
2
O
OH
O
R
80 o
C
1
Entry
1
R1
R2
Product
Yielda (%)
N
N
4-tBu-Ph
94
O
4-Br-Ph
Br
1a
N
N
OMe
OH
O
2
3
4
5
4-Br-Ph
3-MeO–4-OH-Ph
2,4-Cl-Ph
86
Br
1b
N
N
Cl
N
85b
82b
91
O
N-Boc-azetidine-3-yl
N-Boc-azetidine-3-yl
5-Me-thiophen-2-yl
O
N
N
Cl
Br
1c
O
O
N
N
O
5-Br-pyridin-3-yl
tBu
O
1d
N
N
O
S
1e
N
N
Br
O
6
7
8
9
5-Br-pyridin-3-yl
1-Naphthyl
H
84
90
88b
92
N
1f
N
N
O
4-Br-Ph
Br
1g
O
N
N
N-Boc-aminoethyl
Cyclopentyl
4-Me-1,2,3-thiadiazol-5-yl
3-Me–4-NO2-Ph
S
O
N
H
N
N
1hO
N
N
O
O
NO2
NO2
1i
N
N
10
3-MeO-Ph
3-Me–4-NO2-Ph
3-F-Ph
88
1j
OMe
N
N
H
85b
O
N
F
11
N-Boc-aminomethyl
O
O
1k
a
Isolated yields.
TEA (5 equiv) was used.
b
oxadiazoles from carboxylic acids and amidoximes26 (Table 3).
Thus, the reaction of 4-bromobenzoic acid (1.0 equiv) and benza-
midoxime (1.0 equiv) with T3P (2.5 equiv) and TEA (3.0 equiv) at
80 ꢀC afforded 2a in 96% isolated yield (Table 3, entry 1). The
method was then extended to various carboxylic acids and ami-
doximes. To our delight, a variety of aromatic and aliphatic car-
boxylic acids bearing functional groups such as halo, methoxy,
alkyl, cyano, formyl, and N-Boc participated effectively in this re-
action and provided respective 1,2,4-oxadiazoles in good yields
(Table 3). As in the case of 1,3,4-oxadiazole synthesis, excess of TEA
(5.0 equiv) was used for substrates possessing an acid sensitive
functional group (Table 3, entries 2, 5, 7, 8, and 11). Although the
conversion of carboxylic acids to 1,2,4-oxadiazoles proceeded best
when the reaction was performed in EtOAc (as T3P is available as
a 50% solution in EtOAc), we found that with mixed solvents (1:1
mixture of EtOAc and DMF) the reaction could be performed at
elevated temperatures (110 ꢀC) to lessen the reaction time.
The potential scope of this method was evident when the protocol
was further extended to one-step synthesis of 1,3,4-thiadiazoles from
acid hydrazides (Table 4). To test the feasibility, 4-toluic acid and 3-
fluorophenyl hydrazide were reacted with P2S5 (2.0 equiv) in the
presence of T3P under the reaction conditions of entry 2 in Table 1.
After 4 h of heating at 80 ꢀC, 3a (Table 4, entry 1) was isolated in 92%
yield along with a minor amount of 1,3,4-oxadiazole 5 (3%) as by-
product. After few optimization reactions, we found that use of T3P
(1.2 equivas 50%solutioninEtOAc)andP2S5 (1.5 equiv)was optimalto
promote the reaction to completion. However, the formation of by-
product 1,3,4-oxadiazolecouldnotbeavoided inanyof theconditions.
The result was identical when Lawesson’s reagent was used inplace of
P2S5. However, the reaction failed to yield the desired thiadiazole
whenT3P in DMF was used. Upon further investigation, we found that
the thionation reagent (P2S5 or Lawesson’s reagent) was completely
consumed by DMF (reaction medium) to produce N,N-dimethylth-
ioformamide,27 thus unavailable for thiadiazole formation.

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J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
Table 3
Table 4
T3P mediated synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes
T3P mediated synthesis of 1,3,4-thiadiazoles from carboxylic acids
1
1
T3P (1.2 equiv)
TEA (2.5 equiv)
2
N
N
2
R
O
R
O
R
+
R
O
O
N
NOH
T3P (2.5 equiv)
+
1
2
1
R
2
R
R
R
S
3
OH
NHNH
Lawesson's Reagent
or
P2S5 (1.5 equiv)
OH
2
N
NH
TEA (3 equiv)
80 oC, 2-3 h
2
2
80 oC, 3-5 h
Entry R1
R2
Product
Yield
(%)
Entry R1
R2
Product
Yield
(%)a
O
N
N
1
2
4-Br-Ph
4-Br-Ph
4-CN-Ph
Ph
96
N
N
Br
2a
F
1
2
3
4-Me-Ph
4-CN-Ph
3-F-Ph
S
92
86
93
O
N
3a
N
N
NH
N-Boc-aminoethyl
88a
N
N
Br
O
O
Br
2b
S
5-Br-pyridin-3-yl
3-Me–4-NO2-Ph
NC
N
O
N
3b
N
N
N
3
6-Cl-pyridin-3-yl
89
NC
Cl
N
S
Cyclopentyl
Cyclobutyl
2c
3c
NO2
O
N
Br
N
N
4
5-Me-thiophen-2-yl 5-Br-pyridin-3-yl
92
tBu
S
N
87
85
S
4
5
N
2d
O
3d
N
N
Br
5
N-Boc-azetidine-3-yl 5-Br-pyridin-3-yl
87a
93
N
F
O
N
O
S
2-Me-propyl
4-NO2-Ph
3-F-Ph
N
2e
O
3e
N
N
O
N
6
7
tBu
Me
90
94
6
2-MeO-
b
-styryl
Me
S
N
N
2f
O2N
3f
O
N
N
91a
90a
94
N
NH
S
7
5-Br-thiophen-2-yl N-Boc-aminoethyl
N-Boc-aminomethyl 5-NO2-furan-2-yl
5-Br-furan-2-yl
S
Br
O
Br
O
O
2g
3g
O
N
N
N
H
N
O
O
NO2
8
N
S
3h
8
9
N-Boc-piperidin-4-yl 3-Me–4-NO2-Ph
87
O
O
N
NO2
2h
O
F
O
N
N
N
N
9
4-CHO-Ph
Me
Ph
S
OHC
4-CF3-
b
-styryl
H
F
F
88
93
2i
3i
O
N
N
N
Br
O
N
10
11
5-Br-furan-2-yl
89
S
3j
10
4-Cl–2-Me-Ph
Me
2j
Cl
O
N
O
a
Purified by crystallization or column chromatography.
N
2k
N-Boc-piperidin-4-yl 6-Cl-pyridin-3-yl
86a
O
N
N
Cl
O
O
NHNH2
F
O
H
4-toluic acid
O
N
N
N
H
F
NO2
N
12
2-Me-propyl
5-NO2-furan-2-yl
95
O
N
EtOAc, T3P (1.1 equiv)
TEA (2.2 equiv), 2 h
88%
2l
4
a
TEA (5 equiv) was used.
N
P2S5 (1.5 equiv)
3a
F
O
In order to verify if the final cyclodehydration was arbitrated by
T3P or by a thermal process, a sequential experiment was carried out
(Scheme 4). The benzohydrazide 4 prepared was treated with P2S5
(1.5 equiv) at reflux in ethyl acetate for 12 h and monitoring by LC–MS
showed the formation of 3a (37%) besides the by-product 1,3,4-oxa-
diazole 5 (3%), thus indicating the cyclodehydration to be a thermal
process. However, addition of 1.2 equiv of T3P to the reaction mass
and heating for 5 h provided 3a in 86% yield in addition to a small
amount of 5 (5%). In the next experiment, TEA (2.5 equiv) was in-
troduced and the reaction mixture was heated at reflux to obtain
a comparable result in 3 h. Interestingly, the one-pot reaction of 4-
toluic acid and 3-fluorophenyl hydrazide with P2S5 in the presence of
T3P (1.2 equiv) and TEA (2.5 equiv) also provided 3a in good yield
(Table 4, entry1). Basedonaboveresults, itmaypossiblybeconcluded
that unlike in the cases of 1,3,4-oxadiazole and 1,2,4-oxadiazole
synthesis, the formation of 1,3,4-thiadiazoles by cyclodehydration
+
EtOAc, reflux, 12h
37%
3%
5
P2S5 (1.5 equiv)
4
3a (86%)
(5%)
5
+
T3P (1.2 equiv),
EtOAc, reflux, 5h
P2S5 (1.5 equiv),
TEA (2.5 equiv)
3a
(89%)
(4%)
5
+
T3P (1.2 equiv),
EtOAc, reflux, 3h
Scheme 4.

J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
9993
could be a thermal process and the role of T3P might be limited to
initial coupling reaction. The use of merely 1.2 equiv of T3P in the case
of 1,3,4-thiadiazole formation also supports this assumption.
Using the optimized reaction conditions, the efficiency of this
protocol was studied for the synthesis of various thiadiazoles and
the results are summarized in Table 4. In most cases, the reaction
proceeded with high efficiency and broad functional group toler-
ance. Various acids reacted efficiently with hydrazides in presence
of T3P to yield respective thiadiazoles in a single step. However, the
products were contaminated with a small percentage of by-product
1,3,4-oxadiazole (3–5%) but could be easily purified by re-
crystallization or column chromatography to isolate pure products
from dark brown reaction mixture.
C18H17BrN2O requires C, 60.52; H, 4.80; N, 7.84%]; dH (400 MHz,
CDCl3) 8.06 (2H, dd, J 6.8, 1.8 Hz, Ph), 8.00 (2H, dd, J 6.8, 1.8 Hz, Ph),
7.68 (2H, dd, J 8.6, 1.8 Hz, Ph), 7.55 (2H, d, J 8.6 Hz, Ph), 1.38 (9H, s,
Ph-tBu); dC (100.6 MHz, CDCl3) 164.7,163.5,155.4,132.4,128.2,126.7,
126.1, 126.0, 122.9, 120.8, 35.0, 31.0; MS (ESI-APCI) 359 [Mþ2]þ.
4.2.2. 4-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-2-methoxyphenol
(1b). Off-white solid; mp 204.2–205.7 ꢀC; nmax (KBr) 3087, 1600,
1497, 1478, 1286, 730 cmꢂ1; [Found: C, 51.94; H, 3.24; N, 8.00.
C15H11BrN2O3 requires C, 51.90; H, 3.19; N, 8.07%]; dH (400 MHz,
DMSO-d6) 10.0 (1H, s, OH), 8.05 (2H, d, J 8.4 Hz, Ph), 7.83 (2H, d, J
8.4 Hz, Ph), 7.60–7.59 (2H, m, Ph), 6.97 (1H, d, J 8.8 Hz, Ph), 3.89 (3H,
s, Ph-OMe); dC (100.6 MHz, DMSO-d6) 164.9, 163.1, 151.0, 148.5,
132.8, 128.8, 125.8, 123.1, 121.1, 116.5, 114.5, 110.6, 56.3; MS (ESI-
APCI) 349 [Mþ2]þ.
3. Conclusion
A key feature of this reaction was its inherent simplicity in pro-
ducing 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, and 1,3,4-thiadiazoles
directly from carboxylic acids in excellent yields. There was no need
for rigorous exclusion of air or moisture in order to effect cyclo-
dehydration; however, the reactions continue to work even with
these precautions. As T3P produces only water-soluble by-products,
in most cases, an aqueous work up was sufficient to obtain pure
products. In summary, T3P has been demonstrated to be an efficient
reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxa-
diazoles, and 1,3,4-thiadiazoles from carboxylic acids. Further, as
T3P is less toxic and the method is very simple, this reaction rep-
resents a useful way to prepare such heterocycles and highlights the
synthetic utility of T3P as a versatile reagent in organic chemistry.
4.2.3. tert-Butyl
3-[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]-
azetidine-1-carboxylate (1c). Colorless liquid; nmax (liquid film)
1695, 1387, 1365, 1130, 810 cmꢂ1; [Found: C, 51.96; H, 4.67; N, 11.29.
C16H17Cl2N3O3 requires C, 51.91; H, 4.63; N, 11.35%]; dH (400 MHz,
CDCl3) 7.89 (1H, d, J 8.4 Hz, Ph), 7.52 (1H, d, J 1.9 Hz, Ph), 7.36 (1H, dd,
J 8.4, 1.9 Hz, Ph), 4.36–4.32 (2H, m, CH2–CH–CH2), 4.27–4.23 (2H, m,
CH2–CH–CH2), 4.08–4.05 (1H, m, CH2–CH–CH2), 1.47 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 166.7, 162.9, 155.9, 138.2, 133.8,
131.8, 131.1, 127.6, 121.4, 80.2, 52.9, 28.3, 24.8; MS (ESI-APCI) 314
[Mꢂ56]þ.
4.2.4. tert-Butyl 3-[5-(5-bromopyridin-3-yl)-1,3,4-oxadiazol-2-yl]-
azetidine-1-carboxylate (1d). Off-white solid; mp 158.8–160.1 ꢀC;
nmax (KBr) 1687, 1401, 1137 cmꢂ1; [Found: C, 47.34; H, 4.54; N, 14.61.
C15H17BrN4O3 requires C, 47.26; H, 4.49; N, 14.70%]; dH (400 MHz,
CDCl3) 9.20 (1H, s, Ph), 8.86 (1H, s, Ph), 8.50 (1H, s, Ph), 4.42–4.38
(2H, m, CH2–CH–CH2), 4.33–4.30 (2H, m, CH2–CH–CH2), 4.14–4.08
(1H, m, CH2–CH–CH2), 1.48 (9H, s, COOtBu); dC (100.6 MHz, CDCl3)
166.9, 162.0, 155.8, 153.5, 145.6, 136.3, 121.3, 121.0, 80.2, 52.8, 28.2,
24.8; MS (ESI-APCI) 283 [Mꢂ100]þ.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on 400-MHz and 100-
MHz Bruker spectrometer, respectively, and elemental analysis was
performed on a Thermo Finnigan FLASH EA 1112 CHN analyzer.
Melting points were recorded (uncorrected) on Buchi Melting Point
B-545 instrument. Infrared spectra were recorded on a Thermo
Scientific Nicolet 6700 FT-IR spectrometer. Coupling constants
were reported wherever it was necessary in hertz (Hz). The mass
spectra were recorded on Agilent LC/MSD SL 1100 instrument.
Reactions were carried out in an oven dried three-necked round-
bottomed flask. Yields in table refer to isolated yields of compounds
with purity >95% as determined by 1H NMR and LC–MS analysis.
4.2.5. 2-tert-Butyl-5-(5-methylthiophen-2-yl)-1,3,4-oxadiazole
(1e). Viscous liquid; nmax (liquid film) 2971, 1594, 1557, 1519, 1457,
1149, 1067, 804 cmꢂ1
; [Found: C, 59.48; H, 6.39; N, 12.55.
C11H14N2OS requires C, 59.43; H, 6.35; N, 12.60%]; dH (400 MHz,
CDCl3) 7.49 (1H, d, J 3.6 Hz, Ph), 6.78 (1H, d, J 2.8 Hz, Ph), 2.52 (3H, s,
Ph-Me), 1.44 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 172.1, 160.7,
145.0, 129.4, 126.2, 122.9, 32.3, 28.1, 15.3; MS (ESI-APCI) 223
[MþH]þ.
4.2. General procedure for one-pot synthesis of
1,3,4-oxadiazoles (Table 2)
4.2.6. 3-Bromo-5-(1,3,4-oxadiazol-2-yl)pyridine (1f). Off-white solid;
mp 180.2–181.6 ꢀC; nmax (KBr) 1569, 1509, 1253, 1098, 949 cmꢂ1
;
[Found: C, 37.27; H, 1.82; N, 18.51. C7H4BrN3O requires C, 37.20; H,
1.78; N, 18.59%]; dH (400 MHz, CDCl3) 9.23 (1H, s, Ph), 8.87 (1H, s,
Ph), 8.56 (1H, s, Ph), 8.54 (1H, s, Ph); dC (100.6 MHz, CDCl3) 161.5,
153.7, 153.1, 145.8, 136.6, 121.2, 121.0; MS (ESI-APCI) 228 [Mþ2]þ.
To a mixture of carboxylic acid (0.01 mol)and hydrazide (0.01 mol)
in EtOAc (5 mL) was added triethylamine (0.03 mol, and for substrates
possessing acid sensitive functional groups, 0.05 mol)followed by T3P
(0.025 mol, 50% solution in EtOAc or DMF) in drops. The mixture was
heated to 80 ꢀC under nitrogen atmosphere for 3–5 h. The completion
of reaction was confirmed by TLC. The mixture was cooled to room
temperature, and poured onto ice-water. The product was extracted
with ethyl acetate (2ꢁ25 mL). The combined organic phase was
washed with saturated sodium hydrogen carbonate solution
(2ꢁ25 mL) and brine (25 mL). The organic phase was dried over an-
hydrous magnesium sulfate. The solvent was removed under reduced
pressure and the crude product was re-crystallized from hexane/
EtOAc to afford respective 1,3,4-oxadiazoles (1a–k).
4.2.7. 2-(4-Bromophenyl)-5-(naphthalen-1-yl)-1,3,4-oxadiazole
(1g)28. Off-white solid; mp 146.2–147.3 ꢀC; nmax (KBr) 1597, 1577,
1543, 1403, 1071, 769 cmꢂ1; [Found: C, 61.60; H, 3.20; N, 7.94.
C18H11BrN2O requires C, 61.56; H, 3.16; N, 7.98%]; dH (400 MHz,
CDCl3) 9.28 (1H, d, J 8.2 Hz, Ph), 8.29–8.26 (1H, dd, J 7.3, 1.0 Hz, Ph),
8.09–8.06 (3H, m, Ph), 7.96 (1H, d, J 8.2 Hz, Ph), 7.74–7.70 (3H, m,
Ph), 7.64–7.60 (2H, m, Ph); dC (100.6 MHz, CDCl3) 164.6,163.3,133.8,
132.6, 132.4, 130.0, 128.6, 128.3 (2C), 128.1, 126.7, 126.4, 126.1, 124.7,
122.7, 120.2; MS (ESI-APCI) 353 [Mþ2]þ.
4.2.1. 2-(4-Bromophenyl)-5-(4-tert-butylphenyl)-1,3,4-oxadiazole
4.2.8. tert-Butyl{2-[5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadi-
azol-2-yl]ethyl}carbamate (1h). Colorless liquid; nmax (liquid film)
3334,1696,1506, 1365,1163, 756 cmꢂ1; [Found: C, 46.33; H, 5.56; N,
(1a)25. Off-white solid; mp 137.8–139.1 ꢀC; nmax (KBr) 1601, 1475,
1070, 1026, 830 cmꢂ1
; [Found: C, 60.57; H, 4.83; N, 7.80.

9994
J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
22.41. C12H17N5O3S requires C, 46.29; H, 5.50; N, 22.49%]; dH
(400 MHz, CDCl3) 5.10 (1H, br, NH), 3.69–3.64 (2H, m, CH2–NH),
3.18–3.15 (2H, m, CH2–CH2–NH), 3.09 (3H, s, Ph-Me), 1.42 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 166.1, 159.4, 157.7, 156.6, 131.7, 79.7,
37.0, 28.2, 26.5, 14.1; MS (ESI-APCI) 312 [MþH]þ.
11.37. C15H18BrN3O3 requires C, 48.93; H, 4.93; N, 11.41%]; dH
(400 MHz, CDCl3) 7.99 (2H, d, J 7.5 Hz, Ph), 7.68 (2H, d, J 7.5 Hz, Ph),
5.00 (1H, br, NH), 3.62–3.60 (2H, m, CH2-NH), 3.02–2.99 (2H, m,
CH2–CH2–NH), 1.44 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 174.7,
169.4, 155.6, 132.4, 129.3, 127.7, 122.9, 79.4, 37.6, 28.2, 26.9; MS (ESI-
APCI) 270 [Mꢂ100]þ.
4.2.9. 2-Cyclopentyl-5-(3-methyl-4-nitrophenyl)-1,3,4-oxadiazole
(1i). Off-white solid; mp 65.2–66.9 ꢀC; nmax (KBr) 1588, 1514, 1334,
1307 cmꢂ1; [Found: C, 61.57; H, 5.58; N, 15.31. C14H15N3O3 requires
C, 61.53; H, 5.53; N, 15.38%]; dH (400 MHz, CDCl3) 8.08–8.04 (2H, m,
Ph), 7.99 (1H, dd, 1H, J 7.0, 1.5 Hz, Ph), 3.43–3.39 (1H, m, CH2–CH–
CH2), 2.68 (3H, s, Ph-Me), 2.22–2.17 (2H, m, CH2–CH–CH2), 2.16–
2.00 (2H, m, CH2–CH–CH2), 1.99–1.90 (2H, m, CH–CH2–CH2), 1.88–
1.79 (2H, m, CH–CH2–CH2); dC (100.6 MHz, CDCl3) 171.0, 162.8,
150.5, 134.5, 130.7, 127.9, 125.3, 125.0, 35.9, 31.1, 25.4, 20.2; MS (ESI-
APCI) 274 [MþH]þ.
4.3.3. 4-[3-(6-Chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl]benzonitrile
(2c). Off-white solid; mp 218.2–219.6 ꢀC; nmax (KBr) 2231 (CN),
1616,1597,1382,1138, 759 cmꢂ1; [Found: C, 59.53; H, 2.55; N,19.76.
C14H7ClN4O requires C, 59.48; H, 2.50; N, 19.82%]; dH (400 MHz,
CDCl3) 9.19–9.18 (1H, dd, J 3.2, 0.8 Hz, Ph), 8.42–8.34 (3H, m, Ph),
7.90–7.88 (2H, dd, J 9.2, 2.6 Hz, Ph), 7.53–7.50 (1H, dd, J 11.0, 0.8 Hz,
Ph); dC (100.6 MHz, CDCl3) 174.5, 166.5, 154.3, 148.7, 137.1, 132.9,
128.6, 127.3, 124.6, 121.6, 117.5, 116.6; MS (ESI-APCI) 283 [MþH]þ.
4.3.4. 3-Bromo-5-[5-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl]-
pyridine (2d). Off-white solid; mp 116.5–118.1 ꢀC; nmax (KBr) 1595,
4.2.10. 2-(3-Methoxyphenyl)-5-(3-methyl-4-nitrophenyl)-1,3,4-
oxadiazole (1j). Off-white solid; mp 153.7–154.7 ꢀC; nmax (KBr)
1589, 1518, 1339, 1220, 732 cmꢂ1; [Found: C, 61.79; H, 4.28; N, 13.44.
C16H13N3O4 requires C, 61.73; H, 4.21; N, 13.50%]; dH (400 MHz,
DMSO-d6) 8.28 (1H, s, Ph), 8.18 (2H, br, Ph), 7.74 (1H, d, J 8.0 Hz, Ph),
7.65 (1H, d, J 1.9 Hz, Ph), 7.55 (1H, t, J 8.0 Hz), 7.24 (1H, dd, J 7.8, 1.9 Hz,
Ph), 3.87 (3H, s, Ph-OMe), 2.49 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3)
165.3, 162.9, 160.0, 150.7, 134.7, 131.0, 130.3, 127.7, 125.5, 125.2, 124.4,
119.4, 118.5, 111.8, 55.5, 20.4; MS (ESI-APCI) 312 [MþH]þ.
1511, 1442, 749 cmꢂ1
; [Found: C, 44.79; H, 2.53; N, 12.96.
C12H8NBrN3OS requires C, 44.74; H, 2.50; N, 13.04%]; dH (400 MHz,
CDCl3) 9.27 (1H, d, J 1.6 Hz, Ph), 8.82 (1H, d, J 2.4 Hz, Ph), 8.57 (1H, t,
J 2.4 Hz, Ph), 7.80 (1H, d, J 3.7 Hz, Ph), 6.91–6.90 (1H, dd, J 3.7, 1.0 Hz,
Ph), 2.61 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3) 171.9, 165.6, 152.9,
148.5, 146.5, 137.1, 132.7, 127.1, 124.5, 122.5, 120.8, 15.6; MS (ESI-
APCI) 324 [Mþ2]þ.
4.3.5. tert-Butyl 3-[3-(5-bromopyridin-3-yl)-1,2,4-oxadiazol-5-yl]-
azetidine-1-carboxylate (2e). Off-white solid; mp 120.4–121.9 ꢀC;
nmax (KBr) 1685, 1586, 1370, 1139, 771 cmꢂ1; [Found: C, 47.30; H,
4.53; N,14.66. C15H17BrN4O3 requires C, 47.26; H, 4.49; N,14.70%]; dH
(400 MHz, CDCl3) 9.23 (1H, d, J 1.3 Hz, Ph), 8.82 (1H, d, J 2.0 Hz, Ph),
8.52 (1H, t, J 2.0 Hz, Ph), 4.43–4.38 (2H, m, CH2–CH–CH2), 4.33–4.30
(2H, m, CH2–CH–CH2), 4.11–4.05 (1H, m, CH2–CH–CH2), 1.47 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 179.8, 165.5, 155.7, 153.1, 146.4,
137.0,124.0, 120.9, 80.2, 53.0, 28.2, 25.6; MS (ESI-APCI) 383 [Mþ2]þ.
4.2.11. tert-Butyl {[5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-
carbamate (1k). Off-white solid; mp 69.2–70.9 ꢀC; nmax (KBr) 1712,
1509, 1250, 1164, 753 cmꢂ1; [Found: C, 57.39; H, 5.56; N, 14.27.
C14H16FN3O3 requires C, 57.33; H, 5.50; N, 14.33%]; dH (400 MHz,
CDCl3) 7.84 (1H, d, J 8.0 Hz, Ph), 7.74 (1H, d, J 9.0 Hz), 7.50 (1H, dd, J
13.7, 8.0 Hz, Ph), 7.27–7.23 (1H, m, Ph), 5.22 (1H, br, NH), 4.64 (2H, d,
J 4.9 Hz, CH2–NH),1.48 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 164.3,
164.1, 161.0, 155.3, 130.7 (d), 125.3 (d), 122.5 (d), 118.7 (d), 113.8 (d),
80.5, 35.8, 28.1; MS (ESI-APCI) 294 [MþH]þ.
4.3.6. 5-[2-(2-Methoxyphenyl)ethenyl]-3-methyl-1,2,4-oxadiazole
(2f). Off-white solid; mp 61.2–62.8 ꢀC; nmax (KBr) 1637, 1604, 1295,
1044, 772 cmꢂ1; [Found: C, 66.69; H, 5.64; N, 12.89. C12H12N2O2
requires C, 66.65; H, 5.59; N, 12.95%]; dH (400 MHz, CDCl3) 7.75 (1H,
d, J 16.4 Hz, olefinic), 7.33 (1H, t, J 7.6 Hz, Ph), 7.17 (1H, d, J 7.6 Hz,
Ph), 7.08 (1H, d, J 1.8 Hz, Ph), 6.97–6.93 (2H, m, Ph, olefinic), 3.85
(3H, s, Ph-OMe), 2.43 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3) 174.8,
167.4, 159.9, 142.2, 135.6, 129.9, 120.4, 116.1, 112.7, 110.3, 55.2, 11.5;
MS (ESI-APCI) 217 [MþH]þ.
4.3. General procedure for one-pot synthesis of
1,2,4-oxadiazoles (Table 3)
To a mixture of carboxylic acid (0.01 mol) and amidoxime26
(0.01 mol) in EtOAc (5 mL) was added triethylamine (0.03 mol and
for substrates possessing acid sensitive functional groups, 0.05 mol)
followed by T3P (0.025 mol, 50% solution in EtOAc or DMF) in
drops. The mixture was heated to 80 ꢀC under nitrogen atmosphere
for 2–3 h. The completion of reaction was confirmed by TLC. The
mixture was cooled to room temperature, and poured onto ice-
water. The product was extracted with ethyl acetate (2ꢁ25 mL). The
combined organic phase was washed with saturated sodium hy-
drogen carbonate solution (2ꢁ25 mL) and brine (25 mL). The or-
ganic phase was dried over anhydrous magnesium sulfate. The
solvent was removed under reduced pressure. The crude product
was re-crystallized from hexane/EtOAc to afford respective 1,2,4-
oxadiazoles (2a–l).
4.3.7. tert-Butyl
{2-[5-(5-bromothiophen-2-yl)-1,2,4-oxadiazol-3-
yl]ethyl}carbamate (2g). Off-white solid; mp 69.6–70.5 ꢀC; nmax
(KBr) 3342, 1693, 1596, 1523, 1164 cmꢂ1; [Found: C, 41.80; H, 4.37;
N, 11.16. C13H16BrN3O3S requires C, 41.72; H, 4.31; N, 11.23%]; dH
(400 MHz, CDCl3) 7.61 (1H, d, J 4.0 Hz, Ph), 7.16 (1H, d, J 4.0 Hz, Ph),
5.0 (1H, br, NH), 3.58–3.57 (2H, m, CH2–NH), 2.98–2.95 (2H, m,
CH2–CH2–NH), 1.43 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 170.0,
169.2, 155.7, 132.0, 131.5, 126.9, 120.2, 79.5, 37.6, 28.3, 26.9; MS (ESI-
APCI) 274 [Mꢂ100]þ.
4.3.1. 5-(4-Bromophenyl)-3-phenyl-1,2,4-oxadiazole (2a)12. Off-white
4.3.8. tert-Butyl
{[3-(5-nitrofuran-2-yl)-1,2,4-oxadiazol-5-yl]-
methyl}carbamate (2h). Off-white solid; mp 128.5–130.0 ꢀC; nmax
(KBr) 3316, 1655, 1514, 1300, 1159 cmꢂ1; [Found: C, 46.50; H, 4.59;
N, 17.99. C12H14N4O6 requires C, 46.45; H, 4.55; N, 18.06%]; dH
(400 MHz, CDCl3) 7.44 (1H, d, J 3.8 Hz, Ph), 7.28 (1H, d, J 3.8 Hz, Ph),
5.30 (1H, br, NH), 4.67 (2H, d, J 5.8 Hz, CH2-NH),1.47 (9H, s, COOtBu);
dC (100.6 MHz, CDCl3) 178.0, 159.9, 155.3, 152.7, 143.3, 115.3, 112.1,
80.9, 37.0, 28.1; MS (ESI-APCI) 309 [MꢂH]þ.
solid; mp 115.8–117.2 ꢀC; nmax (KBr) 1602,1551,1410, 1358, 736 cmꢂ1
;
[Found: C, 55.89; H, 3.06; N, 9.26. C14H9BrN2O requires C, 55.84; H,
3.01; N, 9.30%]; dH (400 MHz, CDCl3) 8.16 (2H, dd, J 7.0, 2.4 Hz, Ph),
8.09 (2H, d, J 11.3 Hz, Ph), 7.72 (2H, d, J 11.3 Hz, Ph), 7.54–7.51 (3H, m,
Ph); dC (100.6 MHz, CDCl3) 174.8, 169.0, 132.4, 131.2, 129.4, 128.8,
127.6, 127.4, 126.6, 123.1; MS (ESI-APCI) 303 [Mþ2]þ.
4.3.2. tert-Butyl {2-[5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-
carbamate (2b). Off-white solid; mp 119.2–120.6 ꢀC; nmax (KBr)
3371, 1688, 1605, 1519, 1162 cmꢂ1; [Found: C, 48.96; H, 4.96; N,
4.3.9. 4-(3-Methyl-1,2,4-oxadiazol-5-yl)benzaldehyde (2i). White
solid; mp 135.4–136.5 ꢀC; nmax (KBr) 1699, 1584, 1557, 1335, 1202,

J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
9995
835 cmꢂ1; [Found: C, 63.90; H, 4.34; N, 14.81. C10H8N2O2 requires C,
63.83; H, 4.28; N, 14.89%]; dH (400 MHz, CDCl3) 10.12 (1H, s, Ph-
CHO), 8.30 (2H, d, J 8.4 Hz, Ph), 8.05 (2H, d, J 8.4 Hz, Ph), 2.51 (3H, s,
Ph-Me); dC (100.6 MHz, CDCl3) 181.0, 174.1, 168.0, 138.7, 130.0, 128.9,
128.5, 11.5; MS (ESI-APCI) 189 [MþH]þ.
dH (400 MHz, CDCl3) 9.10 (1H, s, Ph), 8.83 (1H, s, Ph), 8.56 (1H, t, J
2.0 Hz, Ph), 8.15 (2H, d, J 8.4 Hz, Ph), 7.84 (2H, d, J 8.4 Hz, Ph); dC
(100.6 MHz, CDCl3) 167.0, 164.3, 153.2, 146.7, 137.1, 133.4, 133.1,
128.5, 117.8, 115.0; MS (ESI-APCI) 345 [Mþ2]þ.
4.4.3. 2-Cyclopentyl-5-(3-methyl-4-nitrophenyl)-1,3,4-thiadiazole
(3c). Off-white solid; mp 83.5–85.1 ꢀC; Rf (10% EtOAc/hexane) 0.75;
nmax (KBr) 2946, 1515, 1391, 1347 cmꢂ1; [Found: C, 58.17; H, 5.30; N,
14.45. C14H15N3O2S requires C, 58.11; H, 5.23; N, 14.52%]; dH
(400 MHz, CDCl3) 8.06 (1H, d, 1H, J 8.5 Hz, Ph), 7.95 (1H, s, Ph), 7.88
(1H, dd, J 8.5, 1.8 Hz, Ph), 3.65–3.61 (1H, m, CH2–CH–CH2), 2.67 (3H,
s, Ph-Me), 2.33–2.26 (2H, m, cyclopentyl), 1.91–1.74 (6H, m, cyclo-
pentyl); dC (100.6 MHz, CDCl3) 176.7,165.5,149.9,134.6,134.3,131.6,
126.0, 125.4, 41.2, 34.5, 25.3, 20.4; MS (ESI-APCI) 290 [MþH]þ.
4.3.10. 5-(5-Bromofuran-2-yl)-3-phenyl-1,2,4-oxadiazole (2j). Off-
white solid; mp 98.1–99.5 ꢀC; nmax (KBr) 1624, 1544, 1457, 1358,
732 cmꢂ1; [Found: C, 49.55; H, 2.46; N, 9.55. C12H7BrN2O2 requires
C, 49.51; H, 2.42; N, 9.62%]; dH (400 MHz, CDCl3) 8.16–8.13 (2H, m,
Ph), 7.53–7.47 (3H, m, Ph), 7.31 (1H, d, J 4.8 Hz, Ph), 6.58 (1H, d, J
4.8 Hz, Ph); dC (100.6 MHz, CDCl3) 168.6, 166.4, 141.7, 131.3, 128.7,
128.1, 127.5, 126.2, 118.5, 114.4; MS (ESI-APCI) 293 [Mþ2]þ.
4.3.11. tert-Butyl 4-[3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl]-
piperidine-1-carboxylate (2k). Off-white solid; mp 114.9–116.0 ꢀC;
nmax (KBr) 2967, 1686, 1594, 1382, 1231, 1110 cmꢂ1; [Found: C,
56.03; H, 5.86; N, 15.29. C17H21ClN4O3 requires C, 55.97; H, 5.80; N,
15.36%]; dH (400 MHz, CDCl3) 9.07 (1H, d, J 3.6 Hz, Ph), 8.31–8.28
(1H, dd, J 8.3, 2.2 Hz, Ph), 7.45 (1H, d, J 8.3 Hz, Ph), 4.15–4.12 (2H, m,
CH2–N(BOC)–CH2), 3.22–3.18 (1H, m, CH2–CH–CH2), 3.16–3.14 (2H,
m, CH2–N(BOC)–CH2), 2.14–2.10 (2H, m, CH2–CH–CH2), 1.93–1.83
(2H, m, CH2–CH–CH2), 1.49 (9H, s, COOtBu); dC (100.6 MHz, CDCl3)
182.0, 165.4, 154.4, 153.8, 148.5, 137.1, 124.4, 122.0, 79.8, 42.7, 34.4,
29.0, 28.3; MS (ESI-APCI) 265 [Mꢂ100]þ.
4.4.4. 2-tert-Butyl-5-cyclobutyl-1,3,4-thiadiazole (3d). Yellow liq-
uid; Rf (10% EtOAc/hexane) 0.80; nmax (liquid film) 2962, 1482, 1081,
760 cmꢂ1; [Found: C, 61.22; H, 8.25; N, 14.21. C10H16N2S requires C,
61.18; H, 8.22; N, 14.27%]; dH (400 MHz, CDCl3) 3.95–3.91 (1H, m,
CH2–CH–CH2), 2.53–2.46 (2H, m, CH2–CH–CH2), 2.39–2.33 (2H, m,
CH2–CH–CH2), 2.13–2.05 (1H, m, cyclobutyl), 2.03–1.98 (1H, m,
cyclobutyl), 1.46 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 179.7, 174.3,
36.1, 35.4, 31.0, 30.1, 18.5; MS (ESI-APCI) 197 [MþH]þ.
4.4.5. 2-(3-Fluorophenyl)-5-(2-methylpropyl)-1,3,4-thiadiazole
(3e). Colorless liquid; Rf (10% EtOAc/hexane) 0.70; nmax (liquid film)
2958, 1587, 1462, 1293, 855, 783, 681 cmꢂ1; [Found: C, 61.03; H,
5.60; N, 11.79. C12H13FN2S requires C, 60.99; H, 5.55; N, 11.85%]; dH
(400 MHz, CDCl3) 7.68–7.65 (2H, m, Ph), 7.44–7.40 (1H, m, Ph), 7.17–
7.12 (1H, m, Ph), 3.0 (2H, d, J 7.2 Hz, CH–CH2), 2.15–2.08 (1H, m, CH–
(Me)2),1.02 (6H, d, J 6.6 Hz, CH–(Me)2); dC (100.6 MHz, CDCl3) 169.5,
167.1 (d), 162.8 (d), 132.2 (d), 130.7 (d), 123.6 (d), 117.7 (d), 114.5 (d),
38.9, 29.7, 22.1; MS (ESI-APCI) 237 [MþH]þ.
4.3.12. 5-(2-Methylpropyl)-3-(5-nitrofuran-2-yl)-1,2,4-oxadiazole
(2l). Off-white solid; mp 72.7–74.0 ꢀC; nmax (KBr) 2960, 1566, 1509,
1351,1021, 741 cmꢂ1; [Found: C, 50.69; H, 4.73; N,17.68. C10H11N3O4
requires C, 50.63; H, 4.67; N, 17.71%]; dH (400 MHz, CDCl3) 7.44 (1H,
d, J 3.8 Hz, Ph), 7.28 (1H, d, J 3.8 Hz, Ph), 2.87 (2H, d, J 7.2 Hz, CH–
CH2), 2.32–2.26 (1H, m, CH–(Me)2), 1.05 (6H, d, J 6.7 Hz, CH–(Me)2);
dC (100.6 MHz, CDCl3) 180.5, 159.8, 152.6, 143.9, 114.8, 112.0, 35.1,
27.3, 22.1; MS (ESI-APCI) Not ionized.
4.4.6. 2-tert-Butyl-5-(4-nitrophenyl)-1,3,4-thiadiazole (3f). Off-white
solid; mp 227.3–228.9 ꢀC; Rf (10% EtOAc/hexane) 0.75; nmax (KBr)
2969,1510, 1367,1090, 851 cmꢂ1; [Found: C, 54.80; H, 5.01; N,15.91.
C12H13N3O2S requires C, 54.74; H, 4.98; N, 15.96%]; dH (400 MHz,
CDCl3) 8.34 (2H, dd, J 7.0, 1.6 Hz, Ph), 8.14 (2H, dd, J 7.0, 1.6 Hz, Ph),
1.56 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 181.7, 165.5, 148.9, 136.0,
128.4, 124.3, 36.5, 31.0; MS (ESI-APCI) 264 [MþH]þ.
4.4. General procedure for one-pot synthesis of
1,3,4-thiadiazoles (Table 4)
To a mixture of carboxylic acid (0.01 mol), hydrazide (0.01 mol),
and P2S5 (0.015 mol) in EtOAc (12 mL) was added triethylamine
(0.025 mol) followed by T3P (0.012 mol, 50% solution in EtOAc) in
drops. The mixture was then heated to 80 ꢀC under nitrogen at-
mosphere for 3–5 h. The completion of reaction was confirmed by
TLC. The brown reaction mass was cooled to room temperature, and
poured onto ice-water. The product was extracted with ethyl acetate
(2ꢁ25 mL). The combined organic phase was washed with satu-
rated sodium hydrogen carbonate solution (2ꢁ25 mL) and brine
(25 mL). The organic phase was dried over anhydrous magnesium
sulfate. The solvent was removed under reduced pressure and the
crude product was passed through a small plug of silica using
hexane/EtOAc (9:1) to afford respective 1,3,4-thiadiazoles (3a–j).
4.4.7. 2-(5-Bromofuran-2-yl)-5-methyl-1,3,4-thiadiazole (3g). Off-
white solid; mp 142.6–143.9 ꢀC; Rf (10% EtOAc/hexane) 0.65; nmax
(KBr) 3102, 1487, 1423, 1245, 1014, 798 cmꢂ1; [Found: C, 34.37; H,
2.13; N, 11.35. C7H5BrN2OS requires C, 34.30; H, 2.06; N, 11.43%]; dH
(400 MHz, CDCl3) 7.10 (1H, d, J 3.5 Hz, Ph), 6.50 (1H, d, J 3.5 Hz, Ph),
2.82 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3) 164.0, 157.7, 147.3, 125.0,
114.1, 113.1, 15.4; MS (ESI-APCI) 247 [Mþ2]þ.
4.4.8. tert-Butyl-4-[5-(3-methyl-4-nitrophenyl)-1,3,4-thiadiazol-2-yl]-
piperidine-1-carboxylate (3h). Off-white solid; mp 156.1–156.9 ꢀC;
Rf (10% EtOAc/hexane) 0.75; nmax (KBr) 2971, 1678, 1514, 1421, 1165,
1140 cmꢂ1; [Found: C, 56.49; H, 6.05; N, 13.78. C19H24N4O4S re-
quires C, 56.42; H, 5.98; N,13.85%]; dH (400 MHz, CDCl3) 8.08 (1H, d,
J 8.4 Hz, Ph), 7.97 (1H, s, Ph), 7.90 (1H, dd, J 8.4, 1.8 Hz, Ph), 4.25–
4.22 (2H, m, CH2–N(BOC)–CH2), 3.42–3.36 (1H, m, CH2–CH–CH2),
2.98–2.91 (2H, m, CH2–N(BOC)–CH2), 2.69 (3H, s, Ph-Me), 2.20–2.17
(2H, m, CH2–CH–CH2), 1.86–1.76 (2H, m, CH2–CH–CH2), 1.49 (9H, s,
COOtBu); dC (100.6 MHz, CDCl3) 175.0, 165.7, 154.5, 150.1, 134.6,
134.0, 131.7, 126.1, 125.5, 79.8, 43.3, 38.2, 32.5, 28.3, 20.3; MS (ESI-
APCI) 403 [MꢂH]þ.
4.4.1. 2-(4-Methylphenyl)-5-(3-fluorophenyl)-1,3,4-thiadiazole
(3a). Off-white solid; mp 127.5–128.7 ꢀC; Rf (10% EtOAc/hexane)
0.75; nmax (KBr) 2917, 1583, 1438, 1291, 781 cmꢂ1; [Found: C, 66.69;
H, 4.16; N,10.31. C15H11FN2S requires C, 66.65; H, 4.10; N,10.36%]; dH
(400 MHz, CDCl3) 7.91 (2H, d, J 7.8 Hz, Ph), 7.76 (2H, d, J 7.8 Hz, Ph),
7.50–7.45 (1H, m, Ph), 7.32–7.19 (3H, m, Ph), 2.44 (3H, s, Ph-Me); dC
(100.6 MHz, CDCl3) 168.7, 166.3, 164.1, 161.7, 141.8, 132.2 (d), 130.8
(d), 129.9, 127.9 (d), 123.7 (d), 117.9 (d), 114.6 (d), 21.5; MS (ESI-APCI)
271 [MþH]þ.
4.4.2. 4-[5-(5-Bromopyridin-3-yl)-1,3,4-thiadiazol-2-yl]benzonitrile
(3b). Off-white solid; mp 267.1–268.5 ꢀC; Rf (10% EtOAc/hexane)
0.60; nmax (KBr) 2957, 2236, 1434, 1399, 831 cmꢂ1; [Found: C, 49.05;
H, 2.11; N, 16.27. C14H17BrN4S requires C, 49.00; H, 2.06; N, 16.32%];
4.4.9. 2-{2-[4-(Trifluoromethyl)phenyl]ethenyl}-1,3,4-thiadiazole
(3i). White solid; mp 155.9–157.5 ꢀC; Rf (10% EtOAc/hexane) 0.70;
nmax (KBr) 3108, 1321, 1104, 1063, 815 cmꢂ1; [Found: C, 51.61; H,

9996
J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996
11. Bird, C. W.; Cheeseman, B. W. H. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, NY,1984; Vol. 4, Chapter 1.
12. For examples of 1,2,4-oxadiazole synthesis, see: (a) Evans, M. D.; Ring, J.;
Schoen, A.; Bell, A.; Edwards, P.; Berthelot, D.; Micewonger, R.; Baldino, C. R.
Tetrahedron Lett. 2003, 44, 9337; (b) Liang, G.; Feng, D. D. Tetrahedron Lett. 1996,
37, 6627; (c) Romdhane, A.; Gharbi, R.; Mighri, Z. Heterocycl. Commun. 2004,
10, 151.
2.79; N, 10.87. C11H7F3N2S requires C, 51.56; H, 2.75; N, 10.93%]; dH
(400 MHz, CDCl3) 9.08 (1H, s, Ph), 7.67 (4H, m, Ph), 7.58 (1H, d, J
16.0 Hz, olefinic), 7.46 (1H, d, J 16.0 Hz, olefinic); dC (100.6 MHz,
CDCl3) 166.6, 150.6, 138.3, 137.5, 131.1 (q), 127.6 (d), 125.9 (dd), 123.8
(d), 119.9; MS (ESI-APCI) 257 [MþH]þ.
13. For examples of 1,3,4-oxadiazole synthesis, see: (a) Weaver, G. W. In Science of
Synthesis; Storr, R. C., Gilchrist, T. L., Eds.; Thieme: Stuttgart, 2004; Vol. 13,
p 219; (b) Hill, J. In Comprehensive Heterocyclic Chemistry II; Storr, R. C., Ed.;
Pergamon: Oxford, 1996; Vol. 4, pp 267 and 905.; (c) Dobrota, C.; Codruta, C.;
Ioana, D. P.; Matache, M.; Baciu, I.; Ruta, L. L. Tetrahedron Lett. 2009, 50, 1886
and the references cited therein.
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Soos, T.; Roman Dembinski, R. Org. Lett. 2006, 8, 1625; (b) Kilburn, J. P.; Lau, J.;
Jones, R. C. F. Tetrahedron Lett. 2003, 44, 7825; (c) Polshettiwar, V.; Varma, S. R.
Tetrahedron Lett. 2008, 49, 879.
15. (a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoregh, I.; Hesselink, W.; Hacksell,
U. J. Org. Chem. 1995, 60, 3112; (b) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem.1999, 42, 4331; (c) Buchanan, J.; Bohacek, R.;
Vu, C. B.; Luke, G. P.; Ariad Pharmaceuticals, WO 99/47529 A1, 23 Sept. 1999.
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4.4.10. 2-Methyl-5-(4-chloro-2-methylphenyl)-1,3,4-thiadiazole
(3j). Off-white solid; mp 52.1–53.9 ꢀC; Rf (10% EtOAc/hexane) 0.75;
nmax (KBr) 2923, 1592, 1441, 1196, 971, 867, 816 cmꢂ1; [Found: C,
53.51; H, 4.11; N, 12.42. C10H9ClN2S requires C, 53.45; H, 4.04; N,
12.47%]; dH (400 MHz, CDCl3) 7.59 (1H, d, J 8.2 Hz, Ph), 7.33 (1H, s,
Ph), 7.28–7.26 (1H, m, Ph), 2.84 (3H, s, Ph-Me), 2.55 (3H, s, Ph-Me);
dC (100.6 MHz, CDCl3) 166.7, 165.4, 238.8, 136.0, 131.7, 131.3, 127.8,
126.3, 21.2, 15.4; MS (ESI-APCI) 225 [MþH]þ.
Acknowledgements
We thank Dr. Ashis Baran Mandal and gratefully acknowledge
Dr. Goutam Das, COO, Syngene International Ltd for his invaluable
support.
17. Durette, P. L.; Hagmann, W. K.; Kopka, I. E.; MacCoss, M.; Merck, WO 00/71572
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