T3P as an efficient cyclodehydration reagent for the one-pot synthesis of 2-amino-1,3,4-oxadiazoles

Article abstract of DOI:10.1007/s12039-015-0834-x

Abstract A scalable and environmentally friendly one-pot method for the synthesis of 2-amino-1,3,4-oxadiazoles from acylhydrazides and isocyanates has been achieved with propane phosponic anhydride (T3P) acting as cyclodehydrating reagent. [Figure not ava

Full text of DOI:10.1007/s12039-015-0834-x

c
J. Chem. Sci. Vol. 127, No. 5, May 2015, pp. 797–801. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-0834-x
T3P as an efficient cyclodehydration reagent for the one-pot synthesis
of 2-amino-1,3,4-oxadiazoles
ANDIVELU ILANGOVANa,∗, SHANMUGASUNDAR SARAVANAKUMARa,b and
SIDDAPPA UMESHb
aSchool of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India
bSyngene International Ltd., Bangalore 560 099, India
e-mail: ilangovanbdu@yahoo.com
MS received 10 August 2014; revised 20 January 2015; accepted 30 April 2015
Abstract. A scalable and environmentally friendly one-pot method for the synthesis of 2-amino-1,3,4-
oxadiazoles from acylhydrazides and isocyanates has been achieved with propane phosponic anhydride (T3P)
acting as cyclodehydrating reagent.
Keywords. Cyclizations; 2-amino-1,3,4-oxadiazoles; propane phosponic anhydride; heterocycles; one-pot
synthesis
with the aid of polymer supported reagents.8 The prob-
lems associated with these methods are the use of toxic
reagents and the formation of significant byproducts
such as 1,3,4-thiadiazoles.
1. Introduction
1,3,4-Oxadiazoles constitute the core structure of a
number of pharmacologically and biologically impor-
tant compounds.1 Drugs such as tiodazosin, nesapidil,
furamizole and raltegravir and Zibotentan, which is
in the late clinical development stage, have the hete-
rocyclic oxadiazole nucleus. Also, a large number of
patent applications containing the oxadiazole nucleus
substantiate its importance (figure 1).5,6a Further, the
utility of the sub-class 2-amino-1,3,4-oxadiazoles was
demonstrated through numerous biological activities
such as anti-microbial,2a anti-convulsant,2b anti-cancer,2c
anti-mitotic,2d and muscle relaxants.2e In addition, they
find application in agricultural chemistry as active
scaffolds3a and in material science as photosensitizers.3b
An elaborate survey of the literature revealed that
the methods used for the preparation of 2-amino-1,3,4-
oxadiazoles can be classified into a few categories. The
widely used approach is cyclodesulfurization of acyl
thiosemicarbazides and a number of reagents such as
carodiimides,4 tosyl chloride/pyridine,5 2-iodoxyben-
zoic acid (IBX),6a I2/NaOH6b and mercury salts7 have
been employed for this purpose. These reagents promote
the cyclization by selectively activating the sulphur
moiety. Carbodiimides acted as H2S scavengers while
iodine reagents shifted the equilibrium to the right side
by precipitating elemental sulphur. This method has
been successfully exploited in solid phase synthesis
The next important approach is cyclodehydration
of acylsemicarbazides. Although this method appeared
to be most clear-cut, harsh reagents such as H2SO4,9a
POCl3,9b SOCl2 and PPh3/CCl4 were used. Burgess
reagent,11 polymer supported N,N’-dicyclohexylcarbo-
diimide (DCC)12 and polymer supported phosphazine
base12 effected this conversion only under microwave
irradiation. It seems this method is less preferred as it
employed unfavorable reagents and suited only for solid
phase synthesis. In line with the cyclodesulfurization
approach, selenosemicarbazides were converted into
2-amino-1,3,4-oxadiazoles without any deselenizing
reagent.15 The other important approach includes SNAr
substitution of oxadiazol-2-ones by activation using the
phosphonium reagent (benzotriazol-1-yloxy)tris(dime-
thylamino)phosphonium hexafluorophosphate (BOP).13
A variety of peptide coupling reagents such as DCC12,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),4
O-(benzotriazol-1-yl)-N,N,Nꢁ,Nꢁ-tetramethyluronium
tetrafluoroborate (TBTU)14 have been engaged as the
cyclodesufurizers, however their role in cyclodehydra-
tion is very limited and only an example of using DCC
under microwave irradiation is known.12 The disadvan-
tages of using coupling reagents are the need for large
excess (at least 3 equiv.) of reagents, purification to
remove residues of some of the coupling reagents, diffi-
culty in the availability of resin-bound coupling agents
and lower yields. Thus, identification of an efficient
9b
10
∗For correspondence
797

798
Andivelu Ilangovan et al
O
N
N
OH
N
S
O
NH
O
H
NH
N
N
N
N
O
O
N
O
O
N
O
F
N
Raltegravir
(Anti-retroviral agent)
Zibotentan (In late clinical
development as anti-cancer agent)
O
NH2
N
N
MeO
NH2
N
N
N
OH
N
O
O
O
N
MeO
N
N
O
O2N
O
N
O
SMe
N
N
Nesapidil
(Anti-hypertensive agent)
Furamizole
(Anti-bacterial)
Tiodazosin
(Anti-hypertensive agent)
Figure 1. Important bioactive oxadiazoles.
coupling reagent for cyclodehydration of acyl semicar- 2. Experimental
bazides is still a challenge (figure 2).
2.1 Materials and Instrumentation
Propane phosponic anhydride (T3P) is a preferred
peptide coupling reagent due to the advantages such as
low toxicity, broad functional group tolerance, low
epimerization and solubility of by-products in water.16
In the past, T3P has been used for the synthesis of hete-
rocycles such as indoles,17a quinolines,17b 1,3-benza-
zoles,17c thieno [2,3-d]pyrimidin-4-ol17d and oxadiaoles17e
besides used in various other transformations such as
carboxylic acids and amides to nitriles,18a acylations,18b
and Perkin rearrangement18c apart from peptide coup-
ling. Considering various important applications of 2-
amino-1,3,4-oxadiazoles, developing a new and mild
method overcoming the aforesaid problems, would be
highly desirable. In this direction, we examined differ-
ent peptide coupling reagents for the cyclodehydration
reaction of acylsemicarbazides to get 2-amino-1,3,4-
oxadiazoles.
Proton (1H NMR) and carbon (13C NMR) nuclear mag-
netic resonance spectra were recorded on Bruker 300
& 400 MHz instruments. Chemical shifts are reported
in ppm (δ) relative to internal standard tetramethylsi-
lane (TMS, δ 0.00 ppm). Carbon chemical shifts are
reported in ppm with respect to solvent resonance as
the internal standard (CDCl3 at 77.0 ppm and DMSO-
d6at 39.5 ppm). Data are reported as follows: chemi-
cal shift (multiplicity [singlet (s), doublet (d), triplet (t),
quartet (q), pentet (p), multiplet (m), broad (br)], cou-
pling constants [Hz], integration). All the NMR spectra
were acquired at ambient temperature. Infrared (FT-IR)
spectra were recorded on a Perkin-Elmer spectrometer.
Analytical thin-layer chromatography (TLC) was per-
formed using Silica Gel 60 Å F254 pre-coated plates
F
F
F
F
F
P-
N
F
N
C
N
O
P+
N
N
N
N
N
N,N'-Dicyclohexylcarbodiimide
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate
F
F
B-
N
N
C
F
N
+F
N
N
O
N
N
N
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate
O
P
O
P
O
P
O
O
O
Propane phosponic anhydride
Figure 2. Few cyclodehydrating agents.

2-amino-1,3,4-oxadiazoles
799
(0.25 mm thickness). Visualization was accomplished 3. Results and Discussion
by irradiation with a UV lamp and staining with I2
5-(4-Methoxybenzoyl)-N-(p-tolyl)hydrazine-1-carboxa-
mide 3a, prepared from 4-methoxybenzohydrazide,
was taken as the model compound for the screening ex-
periments with different coupling reagents for the
cyclodehydration reaction. The reaction was carried out
at 100◦C in different solvents and the results are sum-
marized in table 1.
While BOP and DPPA gave 5% and 3% of the
desired product respectively, other reagents such as
CDI, EDCI, TBTU and Mukaiyama reagent failed to
cause any conversion. However, T3P, a mild water scav-
enger and a low epimerization coupling reagent, deliv-
ered the product 4a in 60% yield in acetonitrile as the
on silica gel. Flash column chromatography was per-
formed using Silica Gel 60-120 Å (32–63 micron).
The elemental analysis was done with vario MICRO
V1.3.2 Elemental Analyser system, GmbH instruments.
Reactions that required atmosphere and moisture con-
trol were carried out in argon atmosphere employing
flame-dried glassware. All solvents and chemicals were
purchased from commercial sources.
2.2 General method: Typical experimental procedure
for the preparation of 2-amino-1,3,4-oxadiazoles (4)
Hydrazide 1 (0.5 mmol) was added slowly to a solution solvent (table 1, entry 8). The best result was obtained
of isocyanate 2 (0.5 mmol) in toluene (3 mL) at room with 1.5 equiv. of T3P in toluene at 100◦C (table 1, entry
temperature and the mixture was stirred for 30 min. 11, 88%). Other solvents such as dioxane, DMF, ace-
Completion of the reaction was checked by TLC, then tonitrile only lowered the yield. Interestingly, increas-
T3P (1.5 mmol, 50% in EtOAc) was added under stir- ing the quantity of T3P lowered the yield (table 1, entry
ring. The resulting suspension was heated at 100◦C for 14). When the reaction was carried out at reflux tem-
2–4 hours. The clear solution was cooled to ambient perature (table 1, entry 12), there was no change in
temperature and carefully quenched with 10% NaHCO3 the yield. This result shows that the maximum yield
solution. The organic layer was separated, washed with can be obtained with 100◦C itself and also there was
water (2 x 2 mL), brine (2 mL), dried over Na2SO4 no reaction in the absence of T3P (table 1, entry 15).
and evaporated under reduced pressure to get the crude The results clearly demonstrated that T3P played a vital
product which was purified by column chromatography. role in the reaction and found to be the most suitable
Table 1. Optimisation of peptide coupling reagents in the synthesis of 2-amino-1,3,4-oxadiazoles.
Entry
Reagent
Equiv.
Solvent
Temp (◦C)
Time (h)
Yield (%)b
1.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CDI
EDCI.HCl
BOP
TBTU
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.05
3
1,4-Dioxane
1,4-Dioxane
Acetonitrile
DMF
Toluene
Toluene
Acetonitrile
Acetonitrile
Dioxane
DMF
Toluene
Toluene
100
100
100
100
100
100
80
6
6
6
6
6
6
6
6
6
6
2
2
4
2
6
NR
Traces
5
NR
NR
3
Traces
60
52
40
88
88
65
Mukaiyama reagent
DPPA
T3Pa
T3P
T3P
T3P
T3P
T3P
T3P
T3P
-
80
100
100
100
110
100
100
100
Toluene
Toluene
Toluene
55
NR
-
a with 3 equiv. of triethylamine; b isolated yield: NR = no reaction.

800
Andivelu Ilangovan et al
reagent among the coupling reagents for the conversion suspension itself could be taken for the cyclodehydra-
of semicarbazides to 2-amino-1,3,4-oxadiazoles. tion. This hypothesis was tested by carrying out an
Having the optimized conditions in hand, next we experiment with equimolar amounts of hydrazide 1a
wanted to test the one-pot synthesis of 2-amino-1,3,4- and isocyanate 2a under the optimized reaction con-
oxadiazoles. Since the acylsemicarbazides are formed ditions. Gratifyingly, the reaction produced the same
rapidly in almost pure form from acylhydrazides and yield as that of the isolated acylsemicarbazide experi-
isocyanates, its isolation is not necessary and the crude ment. This result prompted us to test the scope of the
Table 2. One-pot synthesis of 2-amino-1, 3, 4-oxadiazolesa.
Hydrazide Isocyanate
(1)R1 (2) R2
Product (4) &
Hydrazide
Isocyanate
Product (4) &
Entry
Yield (%)b
Entry
(1) R1
(2) R2
Yield (%)b
1
2
4-MeO-Ph 4-CH3-Ph
12 2,4,6-(CH3)3-Ph
t-Butyl
4-F-Ph
4-CH3-Ph
13
14
4-CF3-Ph
2,6-(CH3)2-Ph
3
4
5
CH3
H
4-CH3-Ph
4-CH3-Ph
Ethyl
4-MeO-Ph
2,6-(CH3)2-Ph
15 3-Br-pyridi-4-yl Cyclopentyl
4-F-Ph
16 2,4,6-(CH3)3-Ph Cyclopentyl
17
18
4-MeO-Ph
4-MeO-Ph
p-Tosyl
6
7
3-NO2-Ph
4-MeO-Ph
Ethyl
3-Cl-Ph
Benzyl
8
9
3-NO2-Ph
4-MeO-Ph
Benzyl
t-Butyl
19 Indole-3-butyric
4-NO2-Ph
10
11
3-NO2-Ph
CH3
t-Butyl
t-Butyl
a Reaction conditions: Acylhydrazide (1 eq), isocyanate (1 eq), Toluene (2 mL), T3P (1.5 eq), 100◦C, 2–3 h; b Isolated yield.

2-amino-1,3,4-oxadiazoles
801
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yield with electron donating hydrazides giving slightly
higher yields than the electron withdrawing counter-
parts. Study of the steric effect showed that hindered
substrates (table 2, entry 12 and 16) reacted slowly even
though good yields were obtained in such cases. The
mild conditions are tolerable to different heterocyclic
ring systems including isonicotinic and indole rings
(table 2, entry 15 and 19). The steric factor played a
negligent role with respect to isocyanates since primary,
secondary and tertiary isocyanates produced similar
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We have described an efficient procedure for the prepa-
ration of 2-amino-1,3,4-oxadiazoles from acylhydra-
zides and isocyanates under one-pot conditions using
T3P. Unlike other coupling reagents, T3P has effec-
tively activated one of the oxygens in acylsemicar-
bazides to produce the cyclic compound. The conditions
are simple, mild, non-toxic, environmentally benign,
scalable and thus it is one of the robust methods avail-
able for the preparation of 2-amino-1,3,4-oxadiazoles.
12. Baxendale I R, Ley S V and Martinelli M M 2005
Tetrahedron 61 5323
Supplementary Information
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Rominger F and Bijanzadeh H R 2013 Tetrahedron 69
2075
15. Xie Y, Liu J, Yang P, Shi X and Li J 2011 Tetrahedron
67 5369
All additional information pertaining to characteriza-
tion of all new compounds are given the supplementary
information along with copies of 1H and 13C spectra and
are available at www.ias.ac.in/chemsci.
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Acknowledgements
SS & SU are thankful to Dr. G.Manickam for his valu-
able advice and Syngene International Ltd. for pro-
viding facilities to carry out the research work.
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