Tetrahedron 65 (2009) 9989–9996

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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

Article history: Propylphosphonic anhydride (T3PÒ) has been demonstrated to be an efficient and mild reagent for the
Received 22 August 2009 one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles from carboxylic acids.
Received in revised form Ó 2009 Elsevier Ltd. All rights reserved.
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

1. Introduction O

1 R2
R O
Propylphosphonic anhydride (T3PÒ) is a highly reactive n-pro- O O R1
R2
pyl phosphonic acid cyclic anhydride, generally used as a coupling 2
R
agent and water scavenger with low toxicity and low allergenic R1 R1 COOH O
potential.1 T3P offers several advantages over traditional reagents, R2 OH
COOH
such as broad functional group tolerance, low epimerization ten- R1 O
HO
dency, easy work up due to water-soluble by-products, and above R2
all it gives high yields and purity. Although T3P has been primarily R2 R1 O

used as a mild coupling reagent in peptide synthesis, new appli-

cations have recently been developed for this reagent2 (Scheme 1).
RCOOH or O P O O RNHCHO
For instance, T3P is well known for conversion of carboxylic acids O P
RCN RNC
and amides into nitriles,3 formation of Weinreb amides,4 ester RCONH2 P O
synthesis,5 dehydrations,3,6 oxidation of alcohols,7 isonitrile syn- O

thesis,3 synthesis of alkenes from alcohols,8 and C–C coupling re-

actions.9 Further, T3P has been found to promote the Biginelli O
H2N S R1R2CHOH
synthesis of 3,4-dihydropyrimidin-2(1H)-ones.10 The wide-ranging R1 N R2 R1COOH
applications and nontoxic nature of T3P show its prospective as H
R1
a reagent in organic synthesis. R2R3NH
N R1 O
Understanding five-membered heterocycles has been a long HN S
standing objective because they are the primary skeletons of more R2
than half of the compounds produced by nature and they play vital 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 Table 1

1,2,4-oxadiazoles,12 1,3,4-oxadiazoles,13 and 1,3,4-thiadiazoles,14 are Screening optimal conditions

commonly utilized pharmacophores due to their metabolic profile COOH O NHNH2

N N
and ability to engage in hydrogen bonding. The discovery of their T3P
+ O
important pharmacological properties stimulated substantial in-
Base Br
terest in the chemistry and synthesis of these important heterocy-
Br 1a
cles. Most synthetic efforts toward the preparation of these
heterocyclic systems are multi-step in nature and have focused on
Entry T3P (equiv)a Basec Temp ( C) Time (h) Yield (%)e
a stepwise approach wherein the first step of the synthesis involves
1 1.5 TEA 60 4 65
the condensation of carboxylic acids with respective amidoximes or
2 2.5 TEA 80 3 94
hydrazides in the presence of a coupling reagent. The heterocycles 3 4 TEAd 80 3 94
are subsequently formed by intramolecular cyclodehydration. Sev- 4 2.5b TEA 110 0.5 93
eral conditions of cyclodehydration have been reported, for instance, 5 2.5 DIEA 80 3 89
1,2,4-oxadiazoles are formed by heating the O-acylated amidoximes 6 2.5 DBU 80 4 71
7 2.5 Pyridine 80 3 92
in solvents such as pyridine,15 DMF,16 in the presence or of additives
8 2.5b Pyridine 110 0.5 91
such as EDC,17 or CDI,16 while thionyl chloride,18 P2O5,19 H2SO4,20 9 2.5 TEA 25 6 Trace
POCl3,21 Burgess reagent,22 triphenylphospine,23 and triflic anhy- a
50% solution in EtOAc.
dride24 are used for the cyclization of diacylhydrazide intermediate b
50% solution in DMF.
to 1,3,4-oxadiazoles. However, despite their common use, most c
3.0 equiv.
d
reported methods to prepare these heterocycles suffer from harsh 5.0 equiv.
e
conditions or stoichiometric formation of an intractable by-product. Isolated yields.

Though, T3P has been identified as a mild water scavenger3,8 the

In order to validate that the final ring closing dehydration was
broad scope and synthetic utility of this reagent as a cyclo-
mediated by T3P and not just a thermal process, a control experiment
dehydration agent has not been explored. In precise, it has not been
was undertaken. Thus, 4-bromo-N0 -[(4-tert-butylphenyl)carbo-
studied and utilized extensively as a potentially routine reagent for
nyl]benzohydrazide (Scheme 3) was prepared via a standard amide
the synthesis of five-membered heterocycles such as 1,2,4-oxa-
coupling reaction. Subsequent heating at reflux in ethyl acetate for
diazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles. Here, we report
12 h and monitoring by LC–MS showed no reaction. Addition of
a one-pot synthesis of 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, and
1.1 equiv of T3P to the reaction and heating for an additional 3 h, gave
1,3,4-thiadiazoles directly from carboxylic acids using T3P, wherein,
1a in 68% isolated yield. Further, it was observed that the yield of 1a
T3P acts both as a coupling and cyclodehydration reagent.
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
2. Results and discussion formation of 1,3,4-oxadiazole is not a thermal process, but could be
a chronological coupling and cyclodehydration process mediated by
Our interest in T3P was aggravated during our investigation of T3P in one-pot.
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-
H O EtOAc, reflux, 12 h
products (Scheme 2). This led to subsequent studies and in the O N
N No reaction
process we have discovered a new route for the direct conversion of N
H O
carboxylic acids to 1,3,4-oxadiazoles. 1a
EtOAc, T3P (1.1 equiv) N
O reflux, 3 h, 68%
Br
R1 O R2 NHNH2 O O N N EtOAc, T3P (1.1 equiv)
TEA (1.5 equiv), reflux, 3 h, 91% Br
R1 R2 +
OH R1 R2
T3P / TEA NH NH O Scheme 3.
60 °C

Scheme 2. The mild and practical one-pot dehydrative cyclization of vari-

ous carboxylic acids with diverse alkyl and arylhydrazides was
The model reaction of 4-bromobenzoic acid (1.0 equiv) with 4- examined under the conditions of entry 2 in Table 1. As shown in
tert-butylphenyl hydrazide (1.0 equiv) in the presence of T3P Table 2, these reactions occurred in moderate to excellent isolated
(1.5 equiv, 50% solution in EtOAc) and TEA (3.0 equiv) in EtOAc at yields. The reaction condition was compatible with halo, cyano,
60  C provided 1a25 (Table 1, entry 1) in 65% yield in addition to the hydroxy, methoxy, and N-Boc substituents. However, for com-
uncyclized diacylhydrazide (Scheme 2). After few reaction optimi- pounds bearing acid sensitive functional groups such as N-Boc
zation such as performing the reaction at higher temperatures (Table 2, entries 3, 4, 8, and 11), an excess of base (5.0 equiv) was
using T3P in DMF (commercially offered as 50% solution) and use of used to avoid any complications arising out of acidic nature of T3P.
varying equivalents of T3P and different bases such as TEA, DBU, It is interesting to note that, azetidine-3-carboxylic acid, a fairly
DIEA, and pyridine, we were able to conclude that use of T3P strained molecule reacted smoothly under the standard reaction
(2.5 equiv, 50% solution in EtOAc) and TEA (3.0 equiv) at 80  C in- conditions to provide the respective oxadiazoles in good yields
deed was the ideal method to achieve optimum yield (Table 1, entry (Table 2, entries 3 and 4). Further, chromatographic isolation of the
2). However, except DBU, all other bases were effective in pro- products was not necessary and an aqueous work up was sufficient
moting the oxadiazole formation. Further, performing the reaction to isolate the products with good purity.
in DMF using T3P (50% solution in DMF) at 110  C drastically re- The 1,2,4-oxadiazole heterocycle has been utilized as a stable
duced the reaction time, but with no significant increase in the ester or amide bioisostere and is found in several drugs and drug
yield of oxadiazole (Table 1, entry 4). Similarly, at room temperature leads. Having achieved the initial objective of one-pot synthesis of
the reaction did not proceed for cyclodehydration (Table 1, entry 9) 1,3,4-oxadiazole using T3P, we proceeded to study the scope of this
and we isolated the respective diacylhydrazide. 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

R1 O NHNH2 T3P (2.5 equiv) N N

+ R1 R2
TEA (3 equiv) O
OH O R2 1
80 oC

Entry R1 R2 Product Yielda (%)

N N

1 4-Br-Ph 4-tBu-Ph O 94
Br
1a
N N
OMe
2 4-Br-Ph 3-MeO–4-OH-Ph O 86
Br OH
1b
N N Cl

3 N-Boc-azetidine-3-yl 2,4-Cl-Ph O 85b

O N
1c Cl
O
N N
Br
4 N-Boc-azetidine-3-yl 5-Br-pyridin-3-yl O 82b
O N
1d N
O

N N

5 5-Me-thiophen-2-yl t
Bu O 91
S
1e
N N
Br
6 5-Br-pyridin-3-yl H O 84
N
1f
N N
7 1-Naphthyl 4-Br-Ph O 90
Br
1g

O N N
8 N-Boc-aminoethyl 4-Me-1,2,3-thiadiazol-5-yl S
88b
O N O N
H 1h N
N N

9 Cyclopentyl 3-Me–4-NO2-Ph O 92
NO2
1i
N N
O
10 3-MeO-Ph 3-Me–4-NO2-Ph 88
NO2
OMe
1j

H N N
11 N-Boc-aminomethyl 3-F-Ph O N F 85b
O
O 1k
a
Isolated yields.
b
TEA (5 equiv) was used.

oxadiazoles from carboxylic acids and amidoximes26 (Table 3). The potential scope of this method was evident when the protocol
Thus, the reaction of 4-bromobenzoic acid (1.0 equiv) and benza- was further extended to one-step synthesis of 1,3,4-thiadiazoles from
midoxime (1.0 equiv) with T3P (2.5 equiv) and TEA (3.0 equiv) at acid hydrazides (Table 4). To test the feasibility, 4-toluic acid and 3-
80  C afforded 2a in 96% isolated yield (Table 3, entry 1). The fluorophenyl hydrazide were reacted with P2S5 (2.0 equiv) in the
method was then extended to various carboxylic acids and ami- presence of T3P under the reaction conditions of entry 2 in Table 1.
doximes. To our delight, a variety of aromatic and aliphatic car- After 4 h of heating at 80  C, 3a (Table 4, entry 1) was isolated in 92%
boxylic acids bearing functional groups such as halo, methoxy, yield along with a minor amount of 1,3,4-oxadiazole 5 (3%) as by-
alkyl, cyano, formyl, and N-Boc participated effectively in this re- product. After few optimization reactions, we found that use of T3P
action and provided respective 1,2,4-oxadiazoles in good yields (1.2 equiv as 50% solution in EtOAc) and P2S5 (1.5 equiv) was optimal to
(Table 3). As in the case of 1,3,4-oxadiazole synthesis, excess of TEA promote the reaction to completion. However, the formation of by-
(5.0 equiv) was used for substrates possessing an acid sensitive product 1,3,4-oxadiazole could not be avoided in any of the conditions.
functional group (Table 3, entries 2, 5, 7, 8, and 11). Although the The result was identical when Lawesson’s reagent was used in place of
conversion of carboxylic acids to 1,2,4-oxadiazoles proceeded best P2S5. However, the reaction failed to yield the desired thiadiazole
when the reaction was performed in EtOAc (as T3P is available as when T3P in DMF was used. Upon further investigation, we found that
a 50% solution in EtOAc), we found that with mixed solvents (1:1 the thionation reagent (P2S5 or Lawesson’s reagent) was completely
mixture of EtOAc and DMF) the reaction could be performed at consumed by DMF (reaction medium) to produce N,N-dimethylth-
elevated temperatures (110  C) to lessen the reaction time. ioformamide,27 thus unavailable for thiadiazole formation.
9992 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

R1 O R2 NOH O N R1 O R2 O T3P (1.2 equiv) N N

T3P (2.5 equiv) TEA (2.5 equiv)
+ R1
+ R1 R2 OH S R2
OH NH2 TEA (3 equiv) N NHNH2 Lawesson's Reagent
2 or 3
80 oC, 2-3 h
P2S5 (1.5 equiv)
80 oC, 3-5 h
Entry R1 R2 Product Yield
(%)
Entry R1 R2 Product Yield
O N
(%)a
1 4-Br-Ph Ph N 96
N N
Br 2a F
1 4-Me-Ph 3-F-Ph S 92
O N
3a
N NH
2 4-Br-Ph N-Boc-aminoethyl 88a N N
Br O O Br
2b 2 4-CN-Ph 5-Br-pyridin-3-yl S 86
O N NC 3b N

3 4-CN-Ph 6-Cl-pyridin-3-yl N 89 N N
NC N Cl 3 Cyclopentyl 3-Me–4-NO2-Ph S 93
2c
3c NO2
O N
Br N N
4 5-Me-thiophen-2-yl 5-Br-pyridin-3-yl N 92
S 4 Cyclobutyl t
Bu S 87
2d N
3d
O N
Br N N
5 N-Boc-azetidine-3-yl 5-Br-pyridin-3-yl N 87a F
O N 5 2-Me-propyl 3-F-Ph S 85
2e N
O 3e
O O N N N
6 2-MeO-b-styryl Me N 93 6 4-NO2-Ph t
Bu S 90
2f O2N 3f
O N N N
7 5-Br-thiophen-2-yl N-Boc-aminoethyl N NH 91a S
S 7 5-Br-furan-2-yl Me 94
O O O
Br 2g Br 3g
H O N N N
O N O NO2
8 N-Boc-aminomethyl 5-NO2-furan-2-yl N 90a S
O 8 N-Boc-piperidin-4-yl 3-Me–4-NO2-Ph O N
87
2h 3h NO2
O
O N
N N
9 4-CHO-Ph Me N 94
S
OHC 9 4-CF3-b-styryl H F 88
2i F
3i
O N F
Br O N N
10 5-Br-furan-2-yl Ph N 89
10 4-Cl–2-Me-Ph Me S 93
2j
Cl 3j
O N
a
N Purified by crystallization or column chromatography.
11 N-Boc-piperidin-4-yl 6-Cl-pyridin-3-yl O N
86a
2k N Cl
O
O NHNH2
O H
O N 4-toluic acid N
O NO2
N F
12 2-Me-propyl 5-NO2-furan-2-yl N 95 H O
F EtOAc, T3P (1.1 equiv)
2l 4 88%
TEA (2.2 equiv), 2 h
a
TEA (5 equiv) was used.

N N
P2S5 (1.5 equiv)
F
3a O
In order to verify if the final cyclodehydration was arbitrated by +
T3P or by a thermal process, a sequential experiment was carried out EtOAc, reflux, 12h 37%
3% 5
(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 P2S5 (1.5 equiv)
process. However, addition of 1.2 equiv of T3P to the reaction mass 4
T3P (1.2 equiv),
3a (86%) + 5 (5%)
and heating for 5 h provided 3a in 86% yield in addition to a small EtOAc, reflux, 5h
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- P2S5 (1.5 equiv),
toluic acid and 3-fluorophenyl hydrazide with P2S5 in the presence of TEA (2.5 equiv)
T3P (1.2 equiv) and TEA (2.5 equiv) also provided 3a in good yield 3a (89%) + 5 (4%)
(Table 4, entry 1). Based on above results, it may possibly be concluded T3P (1.2 equiv),
EtOAc, reflux, 3h
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 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 C18H17BrN2O requires C, 60.52; H, 4.80; N, 7.84%]; dH (400 MHz,
initial coupling reaction. The use of merely 1.2 equiv of T3P in the case CDCl3) 8.06 (2H, dd, J 6.8, 1.8 Hz, Ph), 8.00 (2H, dd, J 6.8, 1.8 Hz, Ph),
of 1,3,4-thiadiazole formation also supports this assumption. 7.68 (2H, dd, J 8.6, 1.8 Hz, Ph), 7.55 (2H, d, J 8.6 Hz, Ph), 1.38 (9H, s,
Using the optimized reaction conditions, the efficiency of this Ph-tBu); dC (100.6 MHz, CDCl3) 164.7, 163.5, 155.4, 132.4, 128.2, 126.7,
protocol was studied for the synthesis of various thiadiazoles and 126.1, 126.0, 122.9, 120.8, 35.0, 31.0; MS (ESI-APCI) 359 [Mþ2]þ.
the results are summarized in Table 4. In most cases, the reaction
proceeded with high efficiency and broad functional group toler- 4.2.2. 4-[5-(4-Bromophenyl)-1,3,4-oxadiazol-2-yl]-2-methoxyphenol
ance. Various acids reacted efficiently with hydrazides in presence (1b). Off-white solid; mp 204.2–205.7  C; nmax (KBr) 3087, 1600,
of T3P to yield respective thiadiazoles in a single step. However, the 1497, 1478, 1286, 730 cm1; [Found: C, 51.94; H, 3.24; N, 8.00.
products were contaminated with a small percentage of by-product C15H11BrN2O3 requires C, 51.90; H, 3.19; N, 8.07%]; dH (400 MHz,
1,3,4-oxadiazole (3–5%) but could be easily purified by re- DMSO-d6) 10.0 (1H, s, OH), 8.05 (2H, d, J 8.4 Hz, Ph), 7.83 (2H, d, J
crystallization or column chromatography to isolate pure products 8.4 Hz, Ph), 7.60–7.59 (2H, m, Ph), 6.97 (1H, d, J 8.8 Hz, Ph), 3.89 (3H,
from dark brown reaction mixture. 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-
3. Conclusion APCI) 349 [Mþ2]þ.

A key feature of this reaction was its inherent simplicity in pro- 4.2.3. tert-Butyl 3-[5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]-
ducing 1,3,4-oxadiazoles, 1,2,4-oxadiazoles, and 1,3,4-thiadiazoles azetidine-1-carboxylate (1c). Colorless liquid; nmax (liquid film)
directly from carboxylic acids in excellent yields. There was no need 1695, 1387, 1365, 1130, 810 cm1; [Found: C, 51.96; H, 4.67; N, 11.29.
for rigorous exclusion of air or moisture in order to effect cyclo- C16H17Cl2N3O3 requires C, 51.91; H, 4.63; N, 11.35%]; dH (400 MHz,
dehydration; however, the reactions continue to work even with CDCl3) 7.89 (1H, d, J 8.4 Hz, Ph), 7.52 (1H, d, J 1.9 Hz, Ph), 7.36 (1H, dd,
these precautions. As T3P produces only water-soluble by-products, J 8.4, 1.9 Hz, Ph), 4.36–4.32 (2H, m, CH2–CH–CH2), 4.27–4.23 (2H, m,
in most cases, an aqueous work up was sufficient to obtain pure CH2–CH–CH2), 4.08–4.05 (1H, m, CH2–CH–CH2), 1.47 (9H, s,
products. In summary, T3P has been demonstrated to be an efficient COOtBu); dC (100.6 MHz, CDCl3) 166.7, 162.9, 155.9, 138.2, 133.8,
reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxa- 131.8, 131.1, 127.6, 121.4, 80.2, 52.9, 28.3, 24.8; MS (ESI-APCI) 314
diazoles, and 1,3,4-thiadiazoles from carboxylic acids. Further, as [M56]þ.
T3P is less toxic and the method is very simple, this reaction rep-
resents a useful way to prepare such heterocycles and highlights the 4.2.4. tert-Butyl 3-[5-(5-bromopyridin-3-yl)-1,3,4-oxadiazol-2-yl]-
synthetic utility of T3P as a versatile reagent in organic chemistry. azetidine-1-carboxylate (1d). Off-white solid; mp 158.8–160.1  C;
nmax (KBr) 1687, 1401, 1137 cm1; [Found: C, 47.34; H, 4.54; N, 14.61.
4. Experimental 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
4.1. General (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)
1
H and 13C NMR spectra were recorded on 400-MHz and 100- 166.9, 162.0, 155.8, 153.5, 145.6, 136.3, 121.3, 121.0, 80.2, 52.8, 28.2,
MHz Bruker spectrometer, respectively, and elemental analysis was 24.8; MS (ESI-APCI) 283 [M100]þ.
performed on a Thermo Finnigan FLASH EA 1112 CHN analyzer.
Melting points were recorded (uncorrected) on Buchi Melting Point 4.2.5. 2-tert-Butyl-5-(5-methylthiophen-2-yl)-1,3,4-oxadiazole
B-545 instrument. Infrared spectra were recorded on a Thermo (1e). Viscous liquid; nmax (liquid film) 2971, 1594, 1557, 1519, 1457,
Scientific Nicolet 6700 FT-IR spectrometer. Coupling constants 1149, 1067, 804 cm1; [Found: C, 59.48; H, 6.39; N, 12.55.
were reported wherever it was necessary in hertz (Hz). The mass C11H14N2OS requires C, 59.43; H, 6.35; N, 12.60%]; dH (400 MHz,
spectra were recorded on Agilent LC/MSD SL 1100 instrument. CDCl3) 7.49 (1H, d, J 3.6 Hz, Ph), 6.78 (1H, d, J 2.8 Hz, Ph), 2.52 (3H, s,
Reactions were carried out in an oven dried three-necked round- Ph-Me), 1.44 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 172.1, 160.7,
bottomed flask. Yields in table refer to isolated yields of compounds 145.0, 129.4, 126.2, 122.9, 32.3, 28.1, 15.3; MS (ESI-APCI) 223
with purity >95% as determined by 1H NMR and LC–MS analysis. [MþH]þ.

4.2. General procedure for one-pot synthesis of 4.2.6. 3-Bromo-5-(1,3,4-oxadiazol-2-yl)pyridine (1f). Off-white solid;
1,3,4-oxadiazoles (Table 2) mp 180.2–181.6  C; nmax (KBr) 1569, 1509, 1253, 1098, 949 cm1;
[Found: C, 37.27; H, 1.82; N, 18.51. C7H4BrN3O requires C, 37.20; H,
To a mixture of carboxylic acid (0.01 mol) and hydrazide (0.01 mol) 1.78; N, 18.59%]; dH (400 MHz, CDCl3) 9.23 (1H, s, Ph), 8.87 (1H, s,
in EtOAc (5 mL) was added triethylamine (0.03 mol, and for substrates Ph), 8.56 (1H, s, Ph), 8.54 (1H, s, Ph); dC (100.6 MHz, CDCl3) 161.5,
possessing acid sensitive functional groups, 0.05 mol) followed by T3P 153.7, 153.1, 145.8, 136.6, 121.2, 121.0; MS (ESI-APCI) 228 [Mþ2]þ.
(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 4.2.7. 2-(4-Bromophenyl)-5-(naphthalen-1-yl)-1,3,4-oxadiazole
of reaction was confirmed by TLC. The mixture was cooled to room (1g)28. Off-white solid; mp 146.2–147.3  C; nmax (KBr) 1597, 1577,
temperature, and poured onto ice-water. The product was extracted 1543, 1403, 1071, 769 cm1; [Found: C, 61.60; H, 3.20; N, 7.94.
with ethyl acetate (225 mL). The combined organic phase was C18H11BrN2O requires C, 61.56; H, 3.16; N, 7.98%]; dH (400 MHz,
washed with saturated sodium hydrogen carbonate solution CDCl3) 9.28 (1H, d, J 8.2 Hz, Ph), 8.29–8.26 (1H, dd, J 7.3, 1.0 Hz, Ph),
(225 mL) and brine (25 mL). The organic phase was dried over an- 8.09–8.06 (3H, m, Ph), 7.96 (1H, d, J 8.2 Hz, Ph), 7.74–7.70 (3H, m,
hydrous magnesium sulfate. The solvent was removed under reduced Ph), 7.64–7.60 (2H, m, Ph); dC (100.6 MHz, CDCl3) 164.6, 163.3, 133.8,
pressure and the crude product was re-crystallized from hexane/ 132.6, 132.4, 130.0, 128.6, 128.3 (2C), 128.1, 126.7, 126.4, 126.1, 124.7,
EtOAc to afford respective 1,3,4-oxadiazoles (1a–k). 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-

(1a)25. Off-white solid; mp 137.8–139.1  C; nmax (KBr) 1601, 1475, azol-2-yl]ethyl}carbamate (1h). Colorless liquid; nmax (liquid film)
1070, 1026, 830 cm1; [Found: C, 60.57; H, 4.83; N, 7.80. 3334, 1696, 1506, 1365, 1163, 756 cm1; [Found: C, 46.33; H, 5.56; N,
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 11.37. C15H18BrN3O3 requires C, 48.93; H, 4.93; N, 11.41%]; dH
(400 MHz, CDCl3) 5.10 (1H, br, NH), 3.69–3.64 (2H, m, CH2–NH), (400 MHz, CDCl3) 7.99 (2H, d, J 7.5 Hz, Ph), 7.68 (2H, d, J 7.5 Hz, Ph),
3.18–3.15 (2H, m, CH2–CH2–NH), 3.09 (3H, s, Ph-Me), 1.42 (9H, s, 5.00 (1H, br, NH), 3.62–3.60 (2H, m, CH2-NH), 3.02–2.99 (2H, m,
COOtBu); dC (100.6 MHz, CDCl3) 166.1, 159.4, 157.7, 156.6, 131.7, 79.7, CH2–CH2–NH), 1.44 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 174.7,
37.0, 28.2, 26.5, 14.1; MS (ESI-APCI) 312 [MþH]þ. 169.4, 155.6, 132.4, 129.3, 127.7, 122.9, 79.4, 37.6, 28.2, 26.9; MS (ESI-
APCI) 270 [M100]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, 4.3.3. 4-[3-(6-Chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl]benzonitrile
1307 cm1; [Found: C, 61.57; H, 5.58; N, 15.31. C14H15N3O3 requires (2c). Off-white solid; mp 218.2–219.6  C; nmax (KBr) 2231 (CN),
C, 61.53; H, 5.53; N, 15.38%]; dH (400 MHz, CDCl3) 8.08–8.04 (2H, m, 1616, 1597, 1382, 1138, 759 cm1; [Found: C, 59.53; H, 2.55; N, 19.76.
Ph), 7.99 (1H, dd, 1H, J 7.0, 1.5 Hz, Ph), 3.43–3.39 (1H, m, CH2–CH– C14H7ClN4O requires C, 59.48; H, 2.50; N, 19.82%]; dH (400 MHz,
CH2), 2.68 (3H, s, Ph-Me), 2.22–2.17 (2H, m, CH2–CH–CH2), 2.16– CDCl3) 9.19–9.18 (1H, dd, J 3.2, 0.8 Hz, Ph), 8.42–8.34 (3H, m, Ph),
2.00 (2H, m, CH2–CH–CH2), 1.99–1.90 (2H, m, CH–CH2–CH2), 1.88– 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,
1.79 (2H, m, CH–CH2–CH2); dC (100.6 MHz, CDCl3) 171.0, 162.8, Ph); dC (100.6 MHz, CDCl3) 174.5, 166.5, 154.3, 148.7, 137.1, 132.9,
150.5, 134.5, 130.7, 127.9, 125.3, 125.0, 35.9, 31.1, 25.4, 20.2; MS (ESI- 128.6, 127.3, 124.6, 121.6, 117.5, 116.6; MS (ESI-APCI) 283 [MþH]þ.
APCI) 274 [MþH]þ.
4.3.4. 3-Bromo-5-[5-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-3-yl]-
4.2.10. 2-(3-Methoxyphenyl)-5-(3-methyl-4-nitrophenyl)-1,3,4- pyridine (2d). Off-white solid; mp 116.5–118.1  C; nmax (KBr) 1595,
oxadiazole (1j). Off-white solid; mp 153.7–154.7  C; nmax (KBr) 1511, 1442, 749 cm1; [Found: C, 44.79; H, 2.53; N, 12.96.
1589, 1518, 1339, 1220, 732 cm1; [Found: C, 61.79; H, 4.28; N, 13.44. C12H8NBrN3OS requires C, 44.74; H, 2.50; N, 13.04%]; dH (400 MHz,
C16H13N3O4 requires C, 61.73; H, 4.21; N, 13.50%]; 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,
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), 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-
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, APCI) 324 [Mþ2]þ.
119.4, 118.5, 111.8, 55.5, 20.4; MS (ESI-APCI) 312 [MþH]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;
4.2.11. tert-Butyl {[5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-
nmax (KBr) 1685, 1586, 1370, 1139, 771 cm1; [Found: C, 47.30; H,
carbamate (1k). Off-white solid; mp 69.2–70.9  C; nmax (KBr) 1712,
4.53; N, 14.66. C15H17BrN4O3 requires C, 47.26; H, 4.49; N, 14.70%]; dH
1509, 1250, 1164, 753 cm1; [Found: C, 57.39; H, 5.56; N, 14.27.
(400 MHz, CDCl3) 9.23 (1H, d, J 1.3 Hz, Ph), 8.82 (1H, d, J 2.0 Hz, Ph),
C14H16FN3O3 requires C, 57.33; H, 5.50; N, 14.33%]; dH (400 MHz,
8.52 (1H, t, J 2.0 Hz, Ph), 4.43–4.38 (2H, m, CH2–CH–CH2), 4.33–4.30
CDCl3) 7.84 (1H, d, J 8.0 Hz, Ph), 7.74 (1H, d, J 9.0 Hz), 7.50 (1H, dd, J
(2H, m, CH2–CH–CH2), 4.11–4.05 (1H, m, CH2–CH–CH2), 1.47 (9H, s,
13.7, 8.0 Hz, Ph), 7.27–7.23 (1H, m, Ph), 5.22 (1H, br, NH), 4.64 (2H, d,
COOtBu); dC (100.6 MHz, CDCl3) 179.8, 165.5, 155.7, 153.1, 146.4,
J 4.9 Hz, CH2–NH), 1.48 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 164.3,
137.0, 124.0, 120.9, 80.2, 53.0, 28.2, 25.6; MS (ESI-APCI) 383 [Mþ2]þ.
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,
4.3. General procedure for one-pot synthesis of 1044, 772 cm1; [Found: C, 66.69; H, 5.64; N, 12.89. C12H12N2O2
1,2,4-oxadiazoles (Table 3) 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,
To a mixture of carboxylic acid (0.01 mol) and amidoxime26 Ph), 7.08 (1H, d, J 1.8 Hz, Ph), 6.97–6.93 (2H, m, Ph, olefinic), 3.85
(0.01 mol) in EtOAc (5 mL) was added triethylamine (0.03 mol and (3H, s, Ph-OMe), 2.43 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3) 174.8,
for substrates possessing acid sensitive functional groups, 0.05 mol) 167.4, 159.9, 142.2, 135.6, 129.9, 120.4, 116.1, 112.7, 110.3, 55.2, 11.5;
followed by T3P (0.025 mol, 50% solution in EtOAc or DMF) in MS (ESI-APCI) 217 [MþH]þ.
drops. The mixture was heated to 80  C under nitrogen atmosphere
for 2–3 h. The completion of reaction was confirmed by TLC. The 4.3.7. tert-Butyl {2-[5-(5-bromothiophen-2-yl)-1,2,4-oxadiazol-3-
mixture was cooled to room temperature, and poured onto ice- yl]ethyl}carbamate (2g). Off-white solid; mp 69.6–70.5  C; nmax
water. The product was extracted with ethyl acetate (225 mL). The (KBr) 3342, 1693, 1596, 1523, 1164 cm1; [Found: C, 41.80; H, 4.37;
combined organic phase was washed with saturated sodium hy- N, 11.16. C13H16BrN3O3S requires C, 41.72; H, 4.31; N, 11.23%]; dH
drogen carbonate solution (225 mL) and brine (25 mL). The or- (400 MHz, CDCl3) 7.61 (1H, d, J 4.0 Hz, Ph), 7.16 (1H, d, J 4.0 Hz, Ph),
ganic phase was dried over anhydrous magnesium sulfate. The 5.0 (1H, br, NH), 3.58–3.57 (2H, m, CH2–NH), 2.98–2.95 (2H, m,
solvent was removed under reduced pressure. The crude product CH2–CH2–NH), 1.43 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 170.0,
was re-crystallized from hexane/EtOAc to afford respective 1,2,4- 169.2, 155.7, 132.0, 131.5, 126.9, 120.2, 79.5, 37.6, 28.3, 26.9; MS (ESI-
oxadiazoles (2a–l). APCI) 274 [M100]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]-

solid; mp 115.8–117.2  C; nmax (KBr) 1602, 1551, 1410, 1358, 736 cm1; methyl}carbamate (2h). Off-white solid; mp 128.5–130.0  C; nmax
[Found: C, 55.89; H, 3.06; N, 9.26. C14H9BrN2O requires C, 55.84; H, (KBr) 3316, 1655, 1514, 1300, 1159 cm1; [Found: C, 46.50; H, 4.59;
3.01; N, 9.30%]; dH (400 MHz, CDCl3) 8.16 (2H, dd, J 7.0, 2.4 Hz, Ph), N, 17.99. C12H14N4O6 requires C, 46.45; H, 4.55; N, 18.06%]; dH
8.09 (2H, d, J 11.3 Hz, Ph), 7.72 (2H, d, J 11.3 Hz, Ph), 7.54–7.51 (3H, m, (400 MHz, CDCl3) 7.44 (1H, d, J 3.8 Hz, Ph), 7.28 (1H, d, J 3.8 Hz, Ph),
Ph); dC (100.6 MHz, CDCl3) 174.8, 169.0, 132.4, 131.2, 129.4, 128.8, 5.30 (1H, br, NH), 4.67 (2H, d, J 5.8 Hz, CH2-NH), 1.47 (9H, s, COOtBu);
127.6, 127.4, 126.6, 123.1; MS (ESI-APCI) 303 [Mþ2]þ. 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 [MH]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) 4.3.9. 4-(3-Methyl-1,2,4-oxadiazol-5-yl)benzaldehyde (2i). White
3371, 1688, 1605, 1519, 1162 cm1; [Found: C, 48.96; H, 4.96; N, 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 cm1; [Found: C, 63.90; H, 4.34; N, 14.81. C10H8N2O2 requires C, dH (400 MHz, CDCl3) 9.10 (1H, s, Ph), 8.83 (1H, s, Ph), 8.56 (1H, t, J
63.83; H, 4.28; N, 14.89%]; dH (400 MHz, CDCl3) 10.12 (1H, s, Ph- 2.0 Hz, Ph), 8.15 (2H, d, J 8.4 Hz, Ph), 7.84 (2H, d, J 8.4 Hz, Ph); dC
CHO), 8.30 (2H, d, J 8.4 Hz, Ph), 8.05 (2H, d, J 8.4 Hz, Ph), 2.51 (3H, s, (100.6 MHz, CDCl3) 167.0, 164.3, 153.2, 146.7, 137.1, 133.4, 133.1,
Ph-Me); dC (100.6 MHz, CDCl3) 181.0, 174.1, 168.0, 138.7, 130.0, 128.9, 128.5, 117.8, 115.0; MS (ESI-APCI) 345 [Mþ2]þ.
128.5, 11.5; MS (ESI-APCI) 189 [MþH]þ.
4.4.3. 2-Cyclopentyl-5-(3-methyl-4-nitrophenyl)-1,3,4-thiadiazole
4.3.10. 5-(5-Bromofuran-2-yl)-3-phenyl-1,2,4-oxadiazole (2j). Off- (3c). Off-white solid; mp 83.5–85.1  C; Rf (10% EtOAc/hexane) 0.75;
white solid; mp 98.1–99.5  C; nmax (KBr) 1624, 1544, 1457, 1358, nmax (KBr) 2946, 1515, 1391, 1347 cm1; [Found: C, 58.17; H, 5.30; N,
732 cm1; [Found: C, 49.55; H, 2.46; N, 9.55. C12H7BrN2O2 requires 14.45. C14H15N3O2S requires C, 58.11; H, 5.23; N, 14.52%]; dH
C, 49.51; H, 2.42; N, 9.62%]; dH (400 MHz, CDCl3) 8.16–8.13 (2H, m, (400 MHz, CDCl3) 8.06 (1H, d, 1H, J 8.5 Hz, Ph), 7.95 (1H, s, Ph), 7.88
Ph), 7.53–7.47 (3H, m, Ph), 7.31 (1H, d, J 4.8 Hz, Ph), 6.58 (1H, d, J (1H, dd, J 8.5, 1.8 Hz, Ph), 3.65–3.61 (1H, m, CH2–CH–CH2), 2.67 (3H,
4.8 Hz, Ph); dC (100.6 MHz, CDCl3) 168.6, 166.4, 141.7, 131.3, 128.7, s, Ph-Me), 2.33–2.26 (2H, m, cyclopentyl), 1.91–1.74 (6H, m, cyclo-
128.1, 127.5, 126.2, 118.5, 114.4; MS (ESI-APCI) 293 [Mþ2]þ. 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.
4.3.11. 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; 4.4.4. 2-tert-Butyl-5-cyclobutyl-1,3,4-thiadiazole (3d). Yellow liq-
nmax (KBr) 2967, 1686, 1594, 1382, 1231, 1110 cm1; [Found: C, uid; Rf (10% EtOAc/hexane) 0.80; nmax (liquid film) 2962, 1482, 1081,
56.03; H, 5.86; N, 15.29. C17H21ClN4O3 requires C, 55.97; H, 5.80; N, 760 cm1; [Found: C, 61.22; H, 8.25; N, 14.21. C10H16N2S requires C,
15.36%]; dH (400 MHz, CDCl3) 9.07 (1H, d, J 3.6 Hz, Ph), 8.31–8.28 61.18; H, 8.22; N, 14.27%]; dH (400 MHz, CDCl3) 3.95–3.91 (1H, m,
(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–CH–CH2), 2.53–2.46 (2H, m, CH2–CH–CH2), 2.39–2.33 (2H, m,
CH2–N(BOC)–CH2), 3.22–3.18 (1H, m, CH2–CH–CH2), 3.16–3.14 (2H, CH2–CH–CH2), 2.13–2.05 (1H, m, cyclobutyl), 2.03–1.98 (1H, m,
m, CH2–N(BOC)–CH2), 2.14–2.10 (2H, m, CH2–CH–CH2), 1.93–1.83 cyclobutyl), 1.46 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 179.7, 174.3,
(2H, m, CH2–CH–CH2), 1.49 (9H, s, COOtBu); dC (100.6 MHz, CDCl3) 36.1, 35.4, 31.0, 30.1, 18.5; MS (ESI-APCI) 197 [MþH]þ.
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 [M100]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)
4.3.12. 5-(2-Methylpropyl)-3-(5-nitrofuran-2-yl)-1,2,4-oxadiazole 2958, 1587, 1462, 1293, 855, 783, 681 cm1; [Found: C, 61.03; H,
(2l). Off-white solid; mp 72.7–74.0  C; nmax (KBr) 2960, 1566, 1509, 5.60; N, 11.79. C12H13FN2S requires C, 60.99; H, 5.55; N, 11.85%]; dH
1351, 1021, 741 cm1; [Found: C, 50.69; H, 4.73; N, 17.68. C10H11N3O4 (400 MHz, CDCl3) 7.68–7.65 (2H, m, Ph), 7.44–7.40 (1H, m, Ph), 7.17–
requires C, 50.63; H, 4.67; N, 17.71%]; dH (400 MHz, CDCl3) 7.44 (1H, 7.12 (1H, m, Ph), 3.0 (2H, d, J 7.2 Hz, CH–CH2), 2.15–2.08 (1H, m, CH–
d, J 3.8 Hz, Ph), 7.28 (1H, d, J 3.8 Hz, Ph), 2.87 (2H, d, J 7.2 Hz, CH– (Me)2), 1.02 (6H, d, J 6.6 Hz, CH–(Me)2); dC (100.6 MHz, CDCl3) 169.5,
CH2), 2.32–2.26 (1H, m, CH–(Me)2), 1.05 (6H, d, J 6.7 Hz, CH–(Me)2); 167.1 (d), 162.8 (d), 132.2 (d), 130.7 (d), 123.6 (d), 117.7 (d), 114.5 (d),
dC (100.6 MHz, CDCl3) 180.5, 159.8, 152.6, 143.9, 114.8, 112.0, 35.1, 38.9, 29.7, 22.1; MS (ESI-APCI) 237 [MþH]þ.
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
4.4. General procedure for one-pot synthesis of solid; mp 227.3–228.9  C; Rf (10% EtOAc/hexane) 0.75; nmax (KBr)
1,3,4-thiadiazoles (Table 4) 2969, 1510, 1367, 1090, 851 cm1; [Found: C, 54.80; H, 5.01; N, 15.91.
C12H13N3O2S requires C, 54.74; H, 4.98; N, 15.96%]; dH (400 MHz,
To a mixture of carboxylic acid (0.01 mol), hydrazide (0.01 mol), CDCl3) 8.34 (2H, dd, J 7.0, 1.6 Hz, Ph), 8.14 (2H, dd, J 7.0, 1.6 Hz, Ph),
and P2S5 (0.015 mol) in EtOAc (12 mL) was added triethylamine 1.56 (9H, s, Ph-tBu); dC (100.6 MHz, CDCl3) 181.7, 165.5, 148.9, 136.0,
(0.025 mol) followed by T3P (0.012 mol, 50% solution in EtOAc) in 128.4, 124.3, 36.5, 31.0; MS (ESI-APCI) 264 [MþH]þ.
drops. The mixture was then heated to 80  C under nitrogen at-
mosphere for 3–5 h. The completion of reaction was confirmed by 4.4.7. 2-(5-Bromofuran-2-yl)-5-methyl-1,3,4-thiadiazole (3g). Off-
TLC. The brown reaction mass was cooled to room temperature, and white solid; mp 142.6–143.9  C; Rf (10% EtOAc/hexane) 0.65; nmax
poured onto ice-water. The product was extracted with ethyl acetate (KBr) 3102, 1487, 1423, 1245, 1014, 798 cm1; [Found: C, 34.37; H,
(225 mL). The combined organic phase was washed with satu- 2.13; N, 11.35. C7H5BrN2OS requires C, 34.30; H, 2.06; N, 11.43%]; dH
rated sodium hydrogen carbonate solution (225 mL) and brine (400 MHz, CDCl3) 7.10 (1H, d, J 3.5 Hz, Ph), 6.50 (1H, d, J 3.5 Hz, Ph),
(25 mL). The organic phase was dried over anhydrous magnesium 2.82 (3H, s, Ph-Me); dC (100.6 MHz, CDCl3) 164.0, 157.7, 147.3, 125.0,
sulfate. The solvent was removed under reduced pressure and the 114.1, 113.1, 15.4; MS (ESI-APCI) 247 [Mþ2]þ.
crude product was passed through a small plug of silica using
hexane/EtOAc (9:1) to afford respective 1,3,4-thiadiazoles (3a–j). 4.4.8. 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;
4.4.1. 2-(4-Methylphenyl)-5-(3-fluorophenyl)-1,3,4-thiadiazole Rf (10% EtOAc/hexane) 0.75; nmax (KBr) 2971, 1678, 1514, 1421, 1165,
(3a). Off-white solid; mp 127.5–128.7  C; Rf (10% EtOAc/hexane) 1140 cm1; [Found: C, 56.49; H, 6.05; N, 13.78. C19H24N4O4S re-
0.75; nmax (KBr) 2917, 1583, 1438, 1291, 781 cm1; [Found: C, 66.69; quires C, 56.42; H, 5.98; N, 13.85%]; dH (400 MHz, CDCl3) 8.08 (1H, d,
H, 4.16; N, 10.31. C15H11FN2S requires C, 66.65; H, 4.10; N, 10.36%]; dH J 8.4 Hz, Ph), 7.97 (1H, s, Ph), 7.90 (1H, dd, J 8.4, 1.8 Hz, Ph), 4.25–
(400 MHz, CDCl3) 7.91 (2H, d, J 7.8 Hz, Ph), 7.76 (2H, d, J 7.8 Hz, Ph), 4.22 (2H, m, CH2–N(BOC)–CH2), 3.42–3.36 (1H, m, CH2–CH–CH2),
7.50–7.45 (1H, m, Ph), 7.32–7.19 (3H, m, Ph), 2.44 (3H, s, Ph-Me); dC 2.98–2.91 (2H, m, CH2–N(BOC)–CH2), 2.69 (3H, s, Ph-Me), 2.20–2.17
(100.6 MHz, CDCl3) 168.7, 166.3, 164.1, 161.7, 141.8, 132.2 (d), 130.8 (2H, m, CH2–CH–CH2), 1.86–1.76 (2H, m, CH2–CH–CH2), 1.49 (9H, s,
(d), 129.9, 127.9 (d), 123.7 (d), 117.9 (d), 114.6 (d), 21.5; MS (ESI-APCI) COOtBu); dC (100.6 MHz, CDCl3) 175.0, 165.7, 154.5, 150.1, 134.6,
271 [MþH]þ. 134.0, 131.7, 126.1, 125.5, 79.8, 43.3, 38.2, 32.5, 28.3, 20.3; MS (ESI-
APCI) 403 [MH]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) 4.4.9. 2-{2-[4-(Trifluoromethyl)phenyl]ethenyl}-1,3,4-thiadiazole
0.60; nmax (KBr) 2957, 2236, 1434, 1399, 831 cm1; [Found: C, 49.05; (3i). White solid; mp 155.9–157.5  C; Rf (10% EtOAc/hexane) 0.70;
H, 2.11; N, 16.27. C14H17BrN4S requires C, 49.00; H, 2.06; N, 16.32%]; nmax (KBr) 3108, 1321, 1104, 1063, 815 cm1; [Found: C, 51.61; H,
9996 J.K. Augustine et al. / Tetrahedron 65 (2009) 9989–9996

2.79; N, 10.87. C11H7F3N2S requires C, 51.56; H, 2.75; N, 10.93%]; dH 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.
(400 MHz, CDCl3) 9.08 (1H, s, Ph), 7.67 (4H, m, Ph), 7.58 (1H, d, J
12. For examples of 1,2,4-oxadiazole synthesis, see: (a) Evans, M. D.; Ring, J.;
16.0 Hz, olefinic), 7.46 (1H, d, J 16.0 Hz, olefinic); dC (100.6 MHz, Schoen, A.; Bell, A.; Edwards, P.; Berthelot, D.; Micewonger, R.; Baldino, C. R.
CDCl3) 166.6, 150.6, 138.3, 137.5, 131.1 (q), 127.6 (d), 125.9 (dd), 123.8 Tetrahedron Lett. 2003, 44, 9337; (b) Liang, G.; Feng, D. D. Tetrahedron Lett. 1996,
(d), 119.9; MS (ESI-APCI) 257 [MþH]þ. 37, 6627; (c) Romdhane, A.; Gharbi, R.; Mighri, Z. Heterocycl. Commun. 2004,
10, 151.
13. For examples of 1,3,4-oxadiazole synthesis, see: (a) Weaver, G. W. In Science of
4.4.10. 2-Methyl-5-(4-chloro-2-methylphenyl)-1,3,4-thiadiazole Synthesis; Storr, R. C., Gilchrist, T. L., Eds.; Thieme: Stuttgart, 2004; Vol. 13,
(3j). Off-white solid; mp 52.1–53.9  C; Rf (10% EtOAc/hexane) 0.75; 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.;
nmax (KBr) 2923, 1592, 1441, 1196, 971, 867, 816 cm1; [Found: C, Ioana, D. P.; Matache, M.; Baciu, I.; Ruta, L. L. Tetrahedron Lett. 2009, 50, 1886
53.51; H, 4.11; N, 12.42. C10H9ClN2S requires C, 53.45; H, 4.04; N, and the references cited therein.
12.47%]; dH (400 MHz, CDCl3) 7.59 (1H, d, J 8.2 Hz, Ph), 7.33 (1H, s, 14. For examples of 1,3,4-thiadiazole synthesis, see: (a) Kaleta, Z.; Makowski, B. T.;
Soos, T.; Roman Dembinski, R. Org. Lett. 2006, 8, 1625; (b) Kilburn, J. P.; Lau, J.;
Ph), 7.28–7.26 (1H, m, Ph), 2.84 (3H, s, Ph-Me), 2.55 (3H, s, Ph-Me); Jones, R. C. F. Tetrahedron Lett. 2003, 44, 7825; (c) Polshettiwar, V.; Varma, S. R.
dC (100.6 MHz, CDCl3) 166.7, 165.4, 238.8, 136.0, 131.7, 131.3, 127.8, Tetrahedron Lett. 2008, 49, 879.
126.3, 21.2, 15.4; MS (ESI-APCI) 225 [MþH]þ. 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.;
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