Route to 1,2,4- and 1,2,5-oxadiazole ring assemblies via a one-pot condensation/oxidation protocol

Article abstract of DOI:10.1016/j.tetlet.2020.151678

A novel one-pot approach for the synthesis of 1,2,4- and 1,2,5-oxadiazole ring assemblies has been developed. The synthetic strategy involves the condensation of furoxanyl amidoximes with aldehydes and subsequent iodine-mediated oxidation of the intermedi

Full text of DOI:10.1016/j.tetlet.2020.151678

Journal Pre-proofs
Route to 1,2,4- and 1,2,5-oxadiazole ring assemblies via a one-pot condensation/
oxidation protocol
F.E. Teslenko, A.I. Churakov, A.A. Larin, I.V. Ananyev, L.L. Fershtat, N.N.
Makhova
PII:
S0040-4039(20)30097-6
DOI:
https://doi.org/10.1016/j.tetlet.2020.151678
TETL 151678
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 November 2019
16 January 2020
24 January 2020
Please cite this article as: Teslenko, F.E., Churakov, A.I., Larin, A.A., Ananyev, I.V., Fershtat, L.L., Makhova, N.N.,
Route to 1,2,4- and 1,2,5-oxadiazole ring assemblies via a one-pot condensation/oxidation protocol, Tetrahedron
Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151678
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Route to 1,2,4- and 1,2,5-oxadiazole ring assemblies via a one-pot condensation/oxidation
protocol
F. E. Teslenko,a,b A. I. Churakov,a A. A. Larin,a I. V. Ananyev,c,d L. L. Fershtat,a* N. N. Makhovaa
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
119991, Leninsky Prospect, 47, Moscow (Russia). E-mail: fershtat@bk.ru
b
Department of Chemistry, Moscow State University, 119991 Moscow, Leninskie Gory 1-3,
Russian Federation
c
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences
119991, Vavilova str., 28, Moscow (Russia)
d National Research University Higher School of Economics, 101000, Vavilova str., 7, Moscow,
Russian Federation
A novel one-pot approach for the synthesis of 1,2,4- and 1,2,5-oxadiazole ring assemblies
has been developed. The synthetic strategy involves the condensation of furoxanyl amidoximes
with aldehydes and subsequent iodine-mediated oxidation of the intermediate 1,2,4-
oxadiazolines. The analogous reaction of 4-aminofuroxanyl-3-carboxamidoxime results not only
in formation of the 1,2,4-oxadiazole subunit, but also rearrangement of the furoxan ring to the
furazan one, which is the first example of a Lewis acid-promoted rearrangement in a furoxan
series.
The 1,2,4-oxadiazole ring is a valuable heterocyclic scaffold incorporated in a number of
pharmaceutical compounds (Fig. 1): azilsartan (treatment of hypertension),1 prenoxdiazine
(cough suppressant)2 and ataluren (treatment of Duchenne muscular dystrophy).3 In addition,
various 1,2,4-oxadiazole derivatives exhibit a wide range of pharmacological activities: anti-
inflammatory,4 antimicrobial,5 neuroprotective6 and anticancer.7 The 1,2,4-oxadiazole motif is
also considered as a bioisostere for amide or ester functionalities thus enabling its wide
applicability in medicinal chemistry and drug design.8
F
N
N
N
N
COOH
O
O N
ataluren
prenoxdiazine
Figure 1. Representative drugs featuring a 1,2,4-oxadiazole motif.
Another type of oxadiazoles – 1,2,5-oxadiazoles (furazans) and their N-oxides (furoxans)
have been widely studied in recent years.9 Furazans and furoxans demonstrate diverse biological
activities, including antibacterial,10 antiparasitic11 and cytotoxic.12 Furthermore, furoxans
correspond to a widely studied subclass of exogenous nitric oxide donors and possess

vasodilating and anticoagulant properties.13 Recent trends in the medicinal chemistry of these
systems has shifted toward the construction of 1,2,5-oxadiazole-based hybrids comprising of a
heterocyclic motif linked to a known pharmaceutical scaffold through an appropriate linker.14 In
addition, furazans and furoxans with high nitrogen and oxygen contents are of interest in the
design of next-generation high-energy density materials: primary and secondary explosives,
pyrotechnics and propellants.15 Therefore, we intended to develop a simple synthetic
methodology to access 1,2,4- and 1,2,5-oxadiazole ring assemblies.
Several methods for the synthesis of (1,2,4-oxadiazolyl)-1,2,5-oxadiazoles were
previously reported. In particular, a general route for the synthesis of (1,2,4-oxadiazolyl)furazans
involved the condensation of furazanyl amidoximes with various carboxylic acid derivatives
(chlorides,16 anhydrides,17 nitriles,18 amides19). However, such methods suffer from harsh
reaction conditions and have a limited substrate scope. Another approach for the synthesis of
1,2,4-oxadiazole rings is based on the condensation of amidoximes with carbonyl compounds.20
The synthesis of several representatives of (1,2,4-oxadiazolyl)furoxans under mild conditions
was previously accomplished by our research group.21 This method involved the acylation of
furoxanyl amidoximes with carboxylic acid chlorides followed by base-promoted
cyclodehydration of the formed intermediates. However, carboxylic acid chlorides are rather
labile substrates and require an additional synthetic step for their preparation. In this sense, a
direct one-pot protocol for the synthesis of (1,2,4-oxadiazolyl)-1,2,5-oxadiazoles from readily
available compounds would be highly desirable. (1,2,4-Oxadiazolyl)furazans are of interest
either as high-energy materials22 or antiproliferative agents.23 Herein, we disclose a tandem
condensation-oxidation approach to 1,2,4- and 1,2,5-oxadiazole ring assemblies based on the
reaction of furoxanyl amidoximes with aldehydes.
Our investigations began with optimization of the reaction conditions using furoxanyl
amidoxime 1a and 4-methoxybenzaldehyde 2a as model compounds. Molar ratios of reagents,
various additives, solvents and temperatures were varied (Table 1). The reaction in AcOH at
room temperature was ineffective (Table 1, entry 1) while at reflux decomposition of the starting
materials was observed (Entry 2). Catalytic amounts of Brønsted acids were also ineffective:
H2SO4 provided only trace amounts of 1,2,4-oxadiazoline 3 (Entry 3), while p-toluenesulfonic
acid (PTSA) promoted hydrolysis of the initial amidoxime 1a to the corresponding amide 4
(Entries 4, 5). Utilization of either organic or inorganic bases did not give the target product 3
(Entries 6, 7). The use of BF3·Et2O provided the target 1,2,4-oxadiazoline 3 albeit in a low yield
.
(Entries 9, 10). Ni(ClO4)2 6H2O and Yb(OTf)3 were ineffective (Entries 11, 12). Sc(OTf)3 was
found to be the most useful catalyst for this condensation (Entries 13-21) and the highest yield of
1,2,4-oxadiazoline 3 was achieved performing the reaction in neat aldehyde at 65 oC (Entry 19).
However, the yield of 1,2,4-oxadiazoline 3 was still moderate (56%) due to incomplete
1
conversion of the starting material according to TLC and H NMR data. Arguably, this fact is
attributed to the known reversibility of the condensation of amidoximes with carbonyl
compounds.24
Table 1. Optimization of the reaction conditions for the synthesis of 1,2,4-oxadiazoline 3.a
CHO
HON
O
N
Me
CONH2
Me
N
Me
OMe
NH2
additive
N
H
solvent,
temperature
N
N
N
N
O
O
N
O
O
O
O
OMe
4
1a
3
2a

Yield 3
Yield 4
Entry 2a (eq.)
Additive (mol%)
Solvent T (oC) Time (h)
(%)b
(%)b
c
c
1
2
1.1
1.1
1.1
1.1
10.0
10.0
10.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
3.0
5.0
1.1
1.1
10.0
1.1
1.1
-
-
AcOH
AcOH
MeCN
PhMef
20
118
60
110
65
80
80
20
65
80
80
80
65
80
65
65
40
100
65
80
80
24
24
24
10
24
24
24
48
24
24
30
24
24
24
24
24
24
24
24
10
24
-
-
-
-
d
d
3
4
5
6
7
8
9
98% H2SO4 (20)
PTSA (50)
PTSA (50)
DABCO (100)
Cs2CO3 (100)
BF3·Et2O (20)
BF3·Et2O (20)
BF3·Et2O (20)
Tracee
-
-
19
37
g
-
Tracee
g
c
c
-
-
-
g
-
-
Tracee
29
26
Tracee
12
MeCN
MeCN
MeCN
10
11
12
13
14
15
16
17
18
19
20
21
24
19
c
c
Ni(ClO4)2·6H2O (10) MeCN
-
-
Yb(OTf)3 (10)
Sc(OTf)3 (5)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (5)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (100)
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeNO2
11
26
35
37
45
9
7
13
14
16
c
-
Tracee
Tracee
16
15
12
c
-
g
-
56
21
28
PhHf
MeCN
a Reagents and conditions: amidoxime 1a (1 mmol), 4-methoxybenzaldehyde 2a, additive,
solvent (4 mL), stirring at the appropriate temperature.
b Isolated yield.
c No reaction.
d Decomposition of the starting material was observed.
e Determined by 1H NMR spectroscopy.
f Azeotropic distillation was used.
g Neat.
We assumed that the one-pot oxidation of 1,2,4-oxadiazoline 3 to the corresponding
1,2,4-oxadiazole may result in full conversion of the starting material. Optimization of a tandem
reaction process was then performed using the same model compounds 1a and 2a. Molar ratios
of reagents, various oxidants, solvents and temperatures were varied (Table 2). Sc(OTf)3 was
used in all experiments as a catalyst for the first reaction step since it was the most effective one.
o
o
The utilization of DDQ in MeCN at 20 C or MnO2 in AcOH at 80 C (Table 2, entries 1, 2)
resulted in decomposition of the starting materials. Various amounts of MnO2 in different
solvents provided low yields of the target 1,2,4-oxadiazole 5a along with partial hydrolysis of
the initial amidoxime 1a to amide 4 (Entries 3-5). Utilization of KMnO4 as an oxidant was
ineffective since oxidation of the aldehyde proceeded rapidly and full conversion of 1,2,4-
oxadiazoline 3 was not achieved, while a significant amount of 4-methoxybenzoic acid was also
produced (Entry 6). Similar results were obtained upon oxidation with hypervalent iodine
reagents (Entries 7-9). Molecular iodine proved to be the best oxidant since it tolerated the oxime
functionality (Entries 10-14) and provided the highest yield of the target 1,2,4-oxadiazole 5a
(Entry 12).

Table 2. Optimization of the reaction conditions for the one-pot synthesis of 1,2,4-oxadiazole
5a.a
CHO
HON
O
O
N
N
N
Me
N
Me
N
Me
CONH2
Me
OMe
OMe
NH2
Sc(OTf)3 (10 mol.%)
oxidant
N
H
solvent,
temperature
N
N
N
N
O
O
N
N
O
O
O
O
O
O
OMe
3
5a
4
1a
2a
Yield 5a, Yield 4,
Entry 2a (eq.)
Oxidant (eq.)
Solvent T (oC) Time (h)
(%)b
(%)b
c
c
1
2
1.1
1.1
1.1
1.1
5.0
5.0
1.1
5.0
5.0
1.1
5.0
8.0
10.0
8.0
DDQ (1.0)
MnO2 (2.0)
MnO2 (3.5)
MnO2 (3.5)
MnO2 (5.0)
KMnO4 (3.0)
MeCN
AcOH
MeCN
dioxane
MeCN
MeCN
MeCN
MeCN
20
80
65
65
65
65
80
80
80
80
80
65
65
20
4
4
4
4
4
4
6
6
-
-
c
c
-
-
3
4
5
6
20
13
12
5
30
13
42
58
22
26
15
23
17
16
53
-
7
8
9
PhI(OAc)2 (1.1)
PhI(OAc)2 (1.1)
PhI(OCOCF3)2 (1.1) MeCN
4
10
11
12
13
14
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.0)
I2 (1.5)
MeCN
MeCN
24
24
24
24
48
37
-
d
-
63
-
d
-
35
-
-
d
-
Tracee
a
Reagents and conditions: amidoxime 1a (1 mmol), 4-methoxybenzaldehyde 2a, Sc(OTf)3 (49
mg, 0.1 mmol), oxidant, solvent (4 mL), stirring at the appropriate temperature.
b Isolated yield.
c Decomposition of the starting material was observed.
d Neat.
e Determined by 1H NMR spectroscopy.
To demonstrate the efficiency of this tandem condensation-oxidation protocol, a series of
aldehydes were reacted with furoxanyl amidoxime 1a under the optimized conditions (Table 3).
Benzaldehyde and aromatic aldehydes bearing a halogen atom (fluoro-, bromo-) located ortho-,
meta- or para- to the formyl moiety were compatible with our conditions, as exemplified by the
formation of (1,2,4-oxadiazolyl)furoxans 5b-f in good yields. The reaction of furoxanyl
amidoxime 1a with 4-(trifluoromethyl)benzaldehyde incorporating a strong electron-
withdrawing CF3-group at the para-position of the benzene ring also proceeded smoothly. The
developed protocol was also suitable for heterocyclic aldehydes, as was demonstrated by the
formation of 1,2,4-oxadiazole 5h bearing 5-nitrofuryl moiety. However, the utilisation of
isobutyraldehyde or 2-thiophenecarboxaldehyde was unsuccessful due to their rapid
decomposition under the reaction conditions. Also, aromatic aldehydes with melting points
exceeding 65 oC cannot be employed in this protocol.
Table 3. Substrate scope for the synthesis of (1,2,4-oxadiazolyl)furoxans 5a-h.

O
O
HON
R
R
N
N
N
Me
NH2
RCH
Me
NH
O, I2
Me
N
Sc(OTf)3 (10 mol%), 65 o
C
N
N
O
N
N
N
O
O
O
O
O
1a
3
5a-h
OMe
O
O
O
O
N
N
N
N
F
N
N
Me
Me
Me
N
Me
N
F
N
N
N
N
O
N
N
N
O
N
O
O
O
O
O
O
5a
5b
(60%)
5d (88%)
(63%)
5c
(71%)
CF3
F
O
O
O
N
O
N
N
NO2
N
N
O
Me
N
Me
N
Me
Me
N
Br
N
O
N
N
N
N
N
N
N
O
O
O
O
O
O
O
5e
(81%)
5f
5g
(58%)
(60%)
5h
(52%)
Subsequently, we investigated the scope of this transformation with furoxanyl amidoxime
1b bearing an amino group at the C(4) carbon of the furoxan ring. Surprisingly, the reaction of
amidoxime 1b with aldehydes under the same conditions not only resulted in 1,2,4-oxadiazole
ring formation, but also in transformation of the aminofuroxan motif into the (carbamoyl)furazan
one. Furazans 6a-e were also formed in moderate to good yields (Table 4).
Table 4. Substrate scope for the synthesis of (1,2,4-oxadiazolyl)furazans 6a-e.
O
R
N
HON
R
N
H2N
NH
N
NH2
RCHO, I2
Sc(OTf)3 (10 mol%), 65 o
O
C
N
N
N
O
O
O
1b
6a-e
MeO
OMe
O
F
O
O
N
N
N
N
N
F
NH
N
N
NH
N
N
NH
N
N
F
F
O
O
O
N
O
O
O
6a
6c
(42%)
(46%)
CF3
6b
(45%)
F3C
F
F
O
O
N
N
NH
N
NH
N
O
O
N
N
N
N
O
O
6d
(52%)
6e
(61%)
All compounds were fully characterized by IR, 1H and 13C NMR spectroscopy as well as
high-resolution mass spectrometry. The structure of (1,2,4-oxadiazolyl)furazan 6e was
additionally confirmed by X-ray diffraction study (Fig. 2, CCDC 1965628).

Figure 2. Structure of 6e in the crystal (probability ellipsoids for non-hydrogen atoms at
p = 0.5 level).
Plausible mechanisms for the formation of (1,2,4-oxadiazolyl)furazans and –furoxans are
outlined in Scheme 1. Initial condensation of furoxanyl amidoxime 1a with the Lewis acid-
activated aldehyde affords intermediate 7 which undergoes dehydration to the 1,2,4-oxadiazoline
3. Subsequent iodine-mediated oxidation of compound 3 results in the formation of (1,2,4-
oxadiazolyl)furoxan 5. Recently, a combination of Sc(OTf)3 and iodine was successfully
employed in the preparation of phenanthridines via a condensation/cyclization protocol from o-
biaryl ketones.25 Presumably, in the case of furoxanyl amidoxime 1b the formation of a 1,2,4-
oxadiazole motif proceeds similarly. On heating, thus generated 4-amino-3-(1,2,4-
oxadiazolyl)furoxan 8 isomerizes to the corresponding 3-aminofuroxan 8’. This tendency of
aminofuroxans to undergo rapid interconversion between two N-oxide forms at elevated
temperatures is well-known.26 Subsequent condensation of 3-aminofuroxan isomer 8’ with the
aldehyde affords vicinal aminoalcohol 9. Previously, it was shown that the 3-amino group in
isomeric aminofuroxans is more reactive than the corresponding 4-amino one.13c,27 Next, Lewis
acid-promoted intramolecular 5-exo-tet cyclization results in the formation of bicyclic structure
10. Since according to Baldwin’s rules28 5-exo-tet cyclization is favored while 5-endo-trig
process is disfavored, the possibility of imine formation may be ruled out. Subsequent thermal
degradation of the 1,2,4-oxadiazoline ring in intermediate 10 affords (carbamoyl)furazan 6.
Thermal cleavage of the annulated 2,5-dihydro-1,2,4-oxadiazole ring also has literature
precedent.29
RCHO
Sc(OTf)3
Sc(OTf)3
R
O
O
O
O
R
R
OH
N
N
Me
N
N
HO
NH2
Me
N
Me
NH
I2
R
Me
Sc(OTf)3
O
N
O
NH2
-H2O
-Sc(OTf)3
N
N
N
N
N
N
N
O
O
O
O
O
O
1a
5
7
3
O
N
O
O
O
HON
R
R
R
N
N
N
R
N
R
H
H2N
NH2
O
R
H
NH
N
R
H2N
N
N
N
H2N

N
N
RCHO

R
HO
N
-
NH
N
N
N
O
Sc(OTf)3
-Sc(OH)(OTf)3
O
N
N
N
N
N
N
N
O
-H
O
O
O
O
O
O
O
O
1b
Sc(OTf)3
N
9
10
8'
8
O
6
Scheme 1. Plausible reaction mechanisms.

In summary, we have developed a direct one-pot method for the synthesis of 1,2,4- and
1,2,5-oxadiazole ring assemblies based on the condensation of furoxanyl amidoximes with
aldehydes followed by iodine-mediated oxidation of the formed 1,2,4-oxadiazolines.30 In the
case of an amidoxime bearing an aminofuroxan motif the reaction proceeds further enabling
rearrangement of the furoxan ring to the furazan one. To the best of our knowledge, it is the first
example of a Lewis acid-promoted rearrangement in a furoxan series. Overall, a facile synthesis
of (1,2,4-oxadiazolyl)furazans and furoxans potentially enables the wider application of these
derivatives in medicine and related fields.
This work was supported by the Russian Foundation for Basic Research (grant # 18-33-20030).
I.V. Ananyev is thankful to the Russian President’s Council for Grants (project МК-
3372.2019.3) for the support of X-ray diffraction studies and theoretical calculations. Generous
allotment of computational time from Computational Center of Novosibirsk State University
(www.nusc.ru) is gratefully acknowledged.
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30. General procedure. A mixture of amidoxime 1a,b (1 mmol), aldehyde (8 mmol), I2 (0.4
o
g, 1.57 mmol) and Sc(OTf)3 (0.1 mmol) was stirred at 65 C for 24 h. Then the reaction
mixture was cooled to room temperature and EtOAc (20 mL) was added. The resulted
solution was washed with 1M Na2S2O3 (1x20 mL) to remove the excess iodine. The
organic layer was separated and the solvent was removed under reduced pressure. The
residue was dissolved in acetone (25 mL) and a solution of KMnO4 (1.42 g, 8 mmol) in
H2O (20 mL) was added. The resulted mixture was heated at reflux for 2 h to oxidize the
excess aldehyde. Oxalic acid was added until the complete dissolution of the formed
MnO2. Then NaHCO3 (4.7 g, 56 mmol) was added. The final mixture was extracted with
EtOAc (3x30 mL), the organic extracts were combined, washed with brine (2x30 mL)
and dried over MgSO4. Filtration of the drying agent and evaporation of the solvent
afforded a crude product which was purified by flash chromatography on SiO2.
Highlights
 A new method for the synthesis of (1,2,4-oxadiazolyl)-1,2,5-oxadiazoles was developed.
 The process involves a one-pot condensation/oxidation sequence.
 Previously unknown rearrangement in a furoxan series was found.
Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: