A convenient synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles from corresponding acylthiosemicarbazides using iodine and Oxone

Article abstract of DOI:10.3184/174751912X13551638283701

A convenient methodology has been developed for the synthesis of substituted 2-amino-1,3,4-oxadiazoles from corresponding acylthiosemicarbazides using catalytic amount of iodine/KI in the presence of Oxone as a bulk oxidant. This offers the adv

Full text of DOI:10.3184/174751912X13551638283701

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 53
JANUARY, 53–54
A convenient synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles from
corresponding acylthiosemicarbazides using iodine and Oxone®
Vikas N. Shinde, Bheemarao G. Ugarkar and Sandeep R. Ghorpade*
AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, Karnataka, India
A convenient methodology has been developed for the synthesis of substituted 2-amino-1,3,4-oxadiazoles from cor-
responding acylthiosemicarbazides using catalytic amount of iodine/KI in the presence of Oxone® as a bulk oxidant.
This offers the advantage of short reaction times and substrate variability which is suitable for the rapid production
of analogues required for lead optimisation programmes. The method could also be useful for large-scale synthesis
because of the mild reaction conditions and the use commercially inexpensive and safe reagents.
Keywords: oxone, oxadiazole, acylthiosemicarbazides
1,3,4-Oxadiazoles are a commonly found pharmacophore in a
variety of biologically-active molecules and are often utilised
as ester and amide bioisosteres in drug discovery programmes.1
This may be attributed to their ability to engage in hydrogen
bonding with the added benefit of a stable metabolic profile.
As a part of our drug research programme we needed a conve-
nient general method for the synthesis of various 5-substituted
2-amino-1,3,4-oxadiazoles. The oxidative cyclisation of acy-
thiosemicarbazide is an attractive method for the synthesis of
1,3,4-oxadiazoles due to the ease of synthesis of these interme-
diates.2 Rivera et al.3 have screened several oxidising agents
for the purpose of finding a better alternative to previously
reported iodine as a reagent and they found that 1,3-dibromo-
5,5-dimethylhydantoin in the presence of potassium iodide
and sodium hydroxide was a more convenient reagent for
large-scale applications. Recently hypervalent iodine reagents
have been reported to bring about oxidative cyclisation of acyl-
thiosemicarbazides efficiently using equimolar quantities of
IBX4 or alternatively using excess of iodobenzene and oxone
to form the hypervalent iodine reagent in situ.5 We now report
the observation that a catalytic amount of iodine or potassium
iodide in the presence of Oxone® as the bulk oxidant are as
effective as the hypervalent iodine reagents in bringing about
the oxidative cyclisation of substituted acylthiosemicarbazides
to 5-substituted 2-amino-1,3,4-oxadiazoles.We found that this
method is suitable for the rapid production of analogues and is
also convenient for the scale-up.
could be used as an effective replacement for iodine (Table 1,
entry 6).
To explore the generality of the method, we subjected differ-
ent acylthiosemicarbazides to oxidative cyclisation using cata-
lytic amount of iodine in the presence of Oxone® and base
(Table 2). The acylthiosemicarbazides were synthesised in
good to excellent yields by using a standard procedure of treat-
ing the appropriate acid chlorides with thiosemicarbazide in
THF.6 Acylthiosemicarbazides with different acyl substitutions
such as aryl, heteroaryl, benzyl, cycloalkyl and alkyl were
cyclised rapidly under these conditions to afford the corre-
sponding aminooxadiazoles in good to excellent yields within
a short reaction period of 10–20 minutes. A variety of substi-
tutents on the aryl ring were tolerated including alkyl, halogen,
nitrile, dimethylamino and methoxy groups (Table 2, entries 2
to 12). Heterocycles like furan, thiophene as well as cinammoyl
groups were found to be stable under the oxidative reaction
conditions and gave the corresponding substituted oxadiazoles
in good yields (Table 2, entries 14, 16 and 17). Also, N-substi-
tuted semicarbazides were cyclised efficiently to provide the
corresponding oxadiazoles (Table 2, entries 18 and 19). All the
products were isolated in good purity either by extraction with
ethyl acetate or by filtration of the reaction media, thus avoid-
ing column chromatography which can be a bottle-neck during
the scale-up of the reaction. This reaction could easily be
scaled up to a gram quantity with good isolated yield (Table 2,
entry 12).
This reaction may proceed via an iodine mediated elimina-
tion of sulfur in the presence of a base as proposed by other
investigators.3,4 Oxone® can act as a bulk oxidant to regenerate
iodine from the iodide formed in the reaction cycle.20 Hence a
catalytic amount of iodine or KI is sufficient to drive the reac-
tion in presence of Oxone®. The high rate of reaction could be
attributed to Oxone® mediated oxidation of iodine to a more
Results and discussion
Oxone® which is an inexpensive, commercially available
stable ternary composite of KHSO5, KHSO4 and K2SO4 in a
2:1:1 molar ratio, has proved to be a mild and safe oxidising
agent with wide range of applications in synthetic organic
chemistry. We decided to explore the use of Oxone® in the
oxidative cyclisation of acylthiosemicarbazides with catalytic
amounts of iodine. In preliminary experiments, benzoylthios-
emicarbazide was treated with 1 equivalent of Oxone® in the
presence of I2 (10 mol%), NaOH as a base and isopropyl alco-
hol as the solvent at room temperature. This effectively gave
the desired 5-phenyl-2-aminooxadiazole in good yield (80% in
15 min, Table 1, entry 3). Reaction without Oxone® required
at least 1 equiv. of iodine and took several hours for comple-
tion with typical yields of 40% (Table 1, entry 1 and 2). Con-
versely, the reaction without iodine was very slow and <10%
conversion was observed after 12 h (Table 1, entry 5). In the
presence of 1 equiv. of Oxone®, the stoichiometry of iodine
could be reduced to 5 mol% although the reaction took longer
duration (1h) for completion and a lower yield (60%) was
obtained (Table 1, entry 4). Alternatively potassium iodide
Table 1 Oxidative cyclisation of phenylthiosemicarbazidea
Entry
Iodine source
/equv.
Oxone®
/equv.
Time
/h
Yield
/%b
1
2
3
4
5
6
I2 (1)
I2 (0.1)
I2 (0.1)
I2 (0.05)
none
0
0
1
1
1
1
6
40
22
80
60
20
0.25
1
12
0.25
c
–
KI (0.1)
70
a All the reactions were carried out at room temperature.
b isolated yields.
* Correspondent. E-mail: Sandeep.ghorpade@astrazeneca.com
c Less than 10% conversion.

54 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 Synthesis of 2-amino-1,3,4-oxadiazolesa
was added to the reaction mixture at room temperature. The solution
was then cooled to 0 °C and 5 N NaOH solution (1.5 mL, 7.50 mmol)
was added. The reaction mixture was then warmed to room tempera-
ture and an aqueous solution of Oxone® (3.3 g, 5.37 mmol) was added
drop-wise over 10 minutes. Once the addition was complete, the
reaction mixture turned brown and a solid precipitated. The reaction
mixture was stirred at room temperature for 30 minutes and was then
quenched with NaHSO3 solution (60 mL) It was extracted with ethyl
acetate (three times). The ethyl acetate layers were combined and
were successively washed with water and brine, dried over Na2SO4
and evaporated under vacuum. The solid which was obtained was
triturated with methanol and filtered to provide the corresponding
5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-amine (0.625 g, 67%) as a
Entry
R
R’
Yieldb M.p./°C Lit. m.p./°C
/%
1.
2.
Ph
2-Cl–Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
80 241–244 240–2417
80 165–167 164–1668
76 225–227 224–2279
3.
3-Cl–Ph
4.
4-Cl–Ph
80 272–275
27410
60 126–128 125–12711
61 255–258 256–2588
77 165–167 16612
1
white powder; m/z (ES+) = 192.25 (MH+) for C9H9N3O2; H NMR
5.
2-Me–Ph
4-tert.bu–Ph
2-F–Ph
6.
(400 MHz, DMSO-d6): δ 7.43–7.48 (m, 1H) 7.36–7.40 (m, 1H) 7.30
(dd, 1H) 7.27 (s, 2H) 7.07–7.11 (m, 1H) 3.82 (s, 3H); m.p. 65 °C (lit.9
66 °C).
7.
8.
4-CF3–Ph
3-CF3–Ph
4-CN–Ph
4-(CH3)2N–Ph
3-OCH3–Ph
Benzyl
66 260–263
59 217–219 215–21711
90 69–70
69–7113
–
9.
2-Amino-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazole: The pro-
cedure was similar to that described for the representative example.
Yield = 66% as a grey crystalline powder. HRMS: m/z (ES+) =
10.
11
12.
13.
14.
15.
16.
17.
18.
19.
70 219–220 218–22014
67
65
62
65–67
158
669
159–16015
184–18616
–
1
230.0533 (MH+) for C9H6F3N3O; H NMR (300 MHz, DMSO-d6)
δ ppm 8.01–8.50 (d, 2H) 7.86–7.90 (d, 2H) 7.34 (s, 2H); m.p. 260–
263 °C.
Cinnamoyl
2-Cyclopentylethyl
2-Furyl
185
77 200–204
77 224–226 225–22611
81 237–240 237–24017
74 152–155
2-Amino-5-(2-cyclopentylethyl)-1,3,4-oxadiazole: The procedure
was similar to that described for the representative example. Yield =
77% as a white crystalline powder. HRMS: m/z (ES+) = 182.1284
(MH+) for C9H15N3O; 1H NMR (300 MHz, DMSO-d6) δ 6.80 (s, 2H)
2.65 (t, 2H) 1.66–1.85 (m, 3H) 1.42–1.65 (m, 6H) 1.0–1.30 (m, 2H);
m.p. 200–204 °C.
2-Thiophenyl
Ph
15318
20519
Ph
1-piper- 75 203–205
dinyl
a Reactions were carried out at RT in isopropanol using 1.1 equiv.
of Oxone®, 0.1 equiv. of iodine and 1.5 equiv. 5N NaOH.
b Isolated yield.
We thank Mr Vijaykamal Ahuja, AstraZeneca, India for per-
forming the mass spectroscopy experiments. The authors also
thank Dr Eknath Bellale, AstraZeneca, India and Dr Subra-
manyam Tantry, AstraZeneca, India for scientific discussions
during the preparation of the manuscript.
reactive electrophilic species. Sureshbabu et al.4 reported very
rapid reaction rates for this reaction using strongly electro-
philic hypervalent iodine reagent which may support this
hypothesis.
Received 9 October 2012; accepted 1 December 2012
Paper 1201562 doi: 10.3184/174751912X13551638283701
Published online: 15 January 2013
Conclusion
In summary, we have demonstrated the effectiveness of
Oxone® in mediating iodine catalysed cyclisation of easily
accessible acylthiosemicarbazides to the corresponding 2-
amino-5-substituted-1,3,4-oxadiazoles which is otherwise a a
sluggish reaction. This methodology offers the advantage of
short reaction times and tolerates to a variety of functional
groups which facilitates the rapid lead optimisation in drug
discovery programmes. This method could also be useful for
large-scale synthesis due to the mild reaction conditions which
employ commercially inexpensive and safe reagents.
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