Divergent Synthesis of Five-Membered Nitrogen Heterocycles via Cascade Reactions of 4-Arylfuroxans

Article abstract of DOI:10.1055/s-0040-1707393

A novel method for the synthesis of a diverse series of functionally substituted five-membered heterocyclic compounds via atom-economic, regio-, and diastereoselective one-pot reaction cascade was developed. This approach involves a ring opening in 4-aryl

Full text of DOI:10.1055/s-0040-1707393

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–L
paper
A
en
D. A. Chaplygin et al.
Paper
Synthesis
Divergent Synthesis of Five-Membered Nitrogen Heterocycles via
Cascade Reactions of 4-Arylfuroxans
Daniil A. Chaplygina
Ivan V. Ananyevb,c
Leonid L. Fershtat*a
Nina N. Makhovaa
R2
R2
R2
R3
R3
R3
R1
R3
R2
R2
R3
R1
R1
R1
or
OH
OH
O
0
0
0
0-0
0
0
2-
0
2
0
3-1
0
2
5
EtOH–H2O
EtOH–H2O
20 °C
then KOH
N
N
N
N
O
N
N
N
N
20 °C
O
O
O
O
then KOH
a N. D. Zelinsky Institute of Organic Chemistry,
Russian Academy of Sciences, 119991 Leninsky
prosp., 47, Moscow, Russian Federation
fershtat@bk.ru
b A. N. Nesmeyanov Institute of Organoelement
Compounds, Russian Academy of Sciences,
119991, Vavilova str., 28, Moscow, Russian
Federation
c National Research University Higher School of
Economics, 101000, Moscow, Russian Federation
R3
R2
or
R3
R2
R2
N
- atom-economic and divergent protocol
- mild conditions, high yields (60–96%)
- additional functional groups are formed
R3
R1
N
- 28 examples of heterocycles synthesized
O
OH
Received: 17.03.2020
Accepted after revision: 07.04.2020
Published online: 05.05.2020
ole core is a common structural subunit in various
pharmaceuticals, such as flucloxacillin, valdecoxib, and le-
flunomide. Another structural derivatives of isoxazole fam-
ily – 1,2,5-oxadiazoles (furazans) – constitute an important
class of heterocycles that have found a myriad of applica-
tions in organic chemistry.6 Furazans possess a number of
useful properties to be part of organic solar cells7 and ex-
hibit various pharmacological activities.8 Recently, azofu-
razan derivative was recommended as a broad-spectrum
antibiotic with a desired pharmacological profile.9 On the
other hand, furazan subunit is an essential structural motif
in a number of modern energetic materials with excellent
performance and a high level of environmental compatibili-
ty.10
DOI: 10.1055/s-0040-1707393; Art ID: ss-2020-t0146-op
Abstract A novel method for the synthesis of a diverse series of func-
tionally substituted five-membered heterocyclic compounds via atom-
economic, regio-, and diastereoselective one-pot reaction cascade was
developed. This approach involves a ring opening in 4-arylfuroxans to
-oximinoarylacetonitrile oxides followed by [3+2] cycloaddition to var-
ious dipolarophiles to afford multisubstituted isoxazoles and isoxazo-
lines. Subsequent azole–azole rearrangement of (oximino)isoxazolines/-
isoxazoles, which can be conducted in a one-pot manner, results into
functionally substituted furazans formation. The developed protocol is
operationally simple, proceeds in mild conditions and with high yields of
target heterocyclic systems. Overall, this study represents a new mode
of isoxazole and 1,2,5-oxadiazole functionalization strategy, which is
useful in medicinal and materials chemistry.
Despite the structural similarity, synthetic routes to the
isoxazole (isoxazoline) and furazan scaffolds are different. A
construction of the isoxazole core is usually achieved
through a [3+2] cycloaddition of various dipolarophiles to
nitrile oxides, which are generated in situ from the corre-
sponding chloroximes,11 nitrolic acids,12 or aliphatic nitro
compounds13 (Scheme 1a). However, these methods for ni-
trile oxides generation have some limitations on functional
group tolerance and require an additional synthetic step for
the preparation of the corresponding dipolar precursors.13
An assembly of the 1,2,5-oxadiazole framework is usually
accomplished via a dehydrative cyclization of tailor-made
vicinal dioximes.14 This process usually entails refluxing the
precursor in a high-boiling solvent (100–150 °C) in the
presence of a strong base, such as NaOH or KOH (Scheme
1b). However, such a method requires a multi-step prepara-
tion of dioxime precursors and usually suffers from harsh
reaction conditions. These disadvantages preclude the pres-
ence of base-sensitive functional groups and stereocenters,
elsewhere in the molecule.
Key words nitrogen heterocycles, 1,2,5-oxadiazole, rearrangement,
cascade reactions, [3+2] cycloaddition
Nitrogen heterocycles are the most frequently occurring
structural motifs in various pharmaceuticals and promising
drug candidates.1 Recent analysis of a database of U.S. FDA
approved drugs revealed that 59% of clinically used small-
molecule medicines incorporate a nitrogen heterocycle
subunit.2 However, the construction of individual pharma-
ceutical scaffolds using known synthetic methodologies of-
ten involves multi-step and energy-consuming procedures
or suffers from a lack of reproducibility and scalability.
Therefore, a creation of novel step-economy protocols for
the assembly of various nitrogen-containing heterocyclic
scaffolds remains highly urgent.3
Among nitrogen heterocycles isoxazoles and their par-
tially hydrogenated analogues isoxazolines are of special in-
terest due to numerous pharmacological activities dis-
played by these heterocyclic systems.4,5 In addition, isoxaz-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. A. Chaplygin et al.
Paper
Synthesis
Initial 4-arylfuroxans 1a,b were synthesized by an oxi-
dation of the corresponding amphi-dioximes (Scheme 2).
Previous works
A) [3+2] Cycloaddition of nitrile oxides
R1
X
X = Cl, NO2
R
NOH
R
N2O4
– HX
R3
R2
R2
R2
N
N
N
OH
N
N
or
R3
Et2O, –10
20 °C
O
R3
O
OH
1a,b
R1
R1
N
O
a R = Ph
b R = 3-MeOC6H4
O
– H2O
NO2
Scheme 2 Synthesis of initial 4-arylfuroxans 1a,b
R1
B) Dehydration of vicinal dioximes
R1
R2
R1
R2
base
It is known, that 4-phenylfuroxan (1a) is capable to un-
dergo the heterocyclic ring cleavage under mild conditions
generating nitrile oxide 2a.18 We decided to use this furox-
an reactivity mode to perform tandem ring opening/[3+2]
cycloaddition sequence and to prepare a series of (oximi-
no)isoxazoles and -isoxazolines. The accessible 4-phenylfu-
roxan (1a)19 and acrylamide as dipolarophile were selected
as model substrates. To optimize the conditions for the ox-
ime 3a synthesis, molar ratios of reagents, solvents, tem-
perature, and reaction time were varied (Table 1). Reactions
of furoxan 1a and 2 equivalents of acrylamide in MeOH,
EtOH, or H2O either at 20 °C or under reflux were ineffec-
tive (entries 1–6).
100–150 °C
N
N
HON
NOH
O
- harsh reaction conditions
- pre-functionalized substrates
C) Azole–azole rearrangement
R1
OH
R1
A
N
B
base
A
HO
N
B
N
N
O
O
A, B = CH, N
- multi-step pre-functionalization
- only (Z)-oxime undergoes rearrangement
This work
D) Cascade reactions of 4-arylfuroxans
R2
N
R3
R1
R3
R2
OH
R1
then KOH
N
O
O
N
N
R2
O
R3
O
O
R2
R3
R1
Table 1 Optimization of the Reaction Conditionsa
1
then KOH
or
R3
- operationally simple protocol
R3
N
N
R2
R2
R2
Ph
CONH2
Ph
Ph
CONH2
N
O
N
N
O
N
HON
HON
O
O
3 - mild conditions, high yields (60–96%)
- additional functionalities are formed
R1
N
R
1a
2a
3a
O
N
Entry
Acrylamide Temp
Time
(h)
Solvent
Yield
OH
(equiv)
(°C)
(%)b
Scheme 1 Synthetic routes to isoxazoles and furazans
c
1
2
2
20
12
12
12
3
MeOH
EtOH
H2O
–
c
2
20
20
60
78
100
20
20
20
20
20
20
20
20
20
–
Another general approach for the synthesis of furazans
is based on transformations of other more accessible het-
erocycles through the so-called azole-to-azole interconver-
sion.15,16 To accomplish this rearrangement the initial azole
has to contain a ring-conjugated side chain reacting as a nu-
cleophile (e.g., oxime group) toward the pivotal annular ni-
trogen atom in the SNi-type reaction followed by a cleavage
of the adjacent bond to form a new azole.17 However, main
disadvantages of this method include a necessary step-by-
step synthesis of oximes and their carbonyl precursors
(Scheme 1c). In addition, this intramolecular process pro-
ceeds usually under considerably harsh conditions and,
thus, preclude high levels of chemoselectivity and function-
al group tolerance in the synthesis of functionally substi-
tuted furazans. Therefore, new step-economy routes to the
construction of both isoxazole and furazan derivatives from
the same available starting materials are desirable. Herein,
we describe a novel atom-economic and divergent ap-
proach to the assembly of isoxazole, isoxazoline, and fu-
razan subunits via cascade reactions of 4-arylfuroxans
(Scheme 1d).
c
3
2
–
d
4
2
MeOH
EtOH
H2O
–
d
5
2
3
–
d
6
2
3
–
7
2
1.5
4
MeOH–H2O (2:1)
MeOH–H2O (5:1)
77
75
73
74
78
86
83
85
83
8
2
9
2
6.5
3
MeOH–H2O (10:1)
EtOH–H2O (1:1)
EtOH–H2O (2:1)
EtOH–H2O (1:1)
EtOH–H2O (1:1)
EtOH–H2O (1:1)
EtOH–H2O (1:1)
10
11
12
13
14
15
1
1.5
2
2
1.5
1.5
1.5
1.5
2.5
3
4
a Reaction conditions: furoxan 1a (0.6 mmol), acrylamide, solvent (4 mL),
20 °C.
b Isolated yields.
c No reaction.
d Decomposition of starting material was observed.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

C
D. A. Chaplygin et al.
Paper
Synthesis
R2
N
R2
N
R1
R3
R3
R1
N
R1
N
dipolarophile
or
N
N
O
EtOH–H2O (1:1), 20 °C
O
O
O
OH
OH
3
1a,b
4
O
Ph
CO2Me
CO2Me
Ph
Ph
Ph
Ph
Ph
N
Ph
H
CO2Me
Ph
CONH2
N
N
N
N
N
O
N
N
N
O
N
O
N
N
O
N
O
O
H
OH
OH
OH
OH
3e (80%, 2 h)
OH
N
O
OH
3d (98%, 18 h)
3a (84%, 1.5 h)
3b (95%, 1.5 h)
3f (75%, 1.5 h)
dr = 5:1
3c (94%, 30 min)
OMe
OMe
OMe
OMe
OMe
OMe
O
Ph
CO2Me
CO2Me
N
H
N
Ph
CO2Me
CONH2
O
N
N
N
N
N
N
N
O
OH
H
N
N
O
O
N
O
N
N
O
O
OH
OH
OH
3k (92%, 4 h)
OH
OH
3l (95%, 2 h)
dr = 8:1
3g (80%, 4 h)
3h (90%, 1 h)
3i (70%, 4 h)
3j (96%, 24 h)
OMe
OMe
OMe
CO2Et
Ph
Ph
Ph
CO2Et
CO2Me
Ph
N
CO2Et
CO2Et
N
N
N
O
N
O
N
O
OH
4a (96%, 45 min)
OH
4b (70%, 25 min)
OH
4c (75%, 35 min)
Ph
CO2Me
N
N
N
N
N
O
N
O
O
OH
4f (72%, 2 h)
OH
OH
4e (60%, 2 h)
4d (95%, 2 h)
Scheme 3 Substrate scope for the synthesis of (oximino)isoxazolines 3 and (oximino)isoxazoles 4. Reagents and conditions: furoxan 1a,b (0.6 mmol),
dipolarophile (1.2 mmol), EtOH–H2O (1:1), 20 °C.
1
Target isoxazoline 3a was obtained in a mixture of
MeOH–H2O. A decrease of H2O amount did not affect the
yields of the product 3a, but reaction times increased (Table
1, entries 7–9). A replacement of MeOH with EtOH resulted
generally in a yield increase (entries 11–15). Therefore, the
optimal conditions were 2 equivalents of acrylamide in an
EtOH–H2O (1:1) mixture at 20 °C for 1.5 hours (entry 12).
The optimal conditions found were suitable for a repre-
sentative range of C=C and C≡C dipolarophiles. Target ben-
zoylisoxazoline oximes 3a–f and benzoylisoxazole oximes
4a–c were synthesized with complete regioselectivity and
in high yields. Similar results were obtained in a reaction of
3-methoxyphenylfuroxan (1b) with same dipolarophiles
(Scheme 3). The developed protocol tolerated well amide
and ester functionalities in a dipolarophile structure. How-
ever, reaction times of furoxans 1a,b with various dipolaro-
philes differed. In particular, reactions with acetylenes pro-
ceeded faster than with olefins and furoxan 1b underwent
tandem transformation slower than furoxan 1a. The reac-
tions with N-phenylmaleimide and dimethyl fumarate oc-
curred diastereoselectively. Isoxazolines 3d and 3j were iso-
lated as single diastereomers, while isoxazolines 3f and 3l
were formed as a mixture of two diastereomers in a ratio of
diffraction study (Figure 1). One signal of OH group in H
NMR spectra of compounds 3 and 4 along with the X-ray
data unambiguously confirmed the Z-configuration of ox-
ime groups.
1
5:1 for 3f and 8:1 for 3l according to H NMR spectra. Al-
though cycloaddition of internal olefins to nitrile oxides
proceeds usually with complete diastereoselectivity, in the
case of dimethyl fumarate a mixture of diastereoisomers
may be observed due to epimerization.13b–d The synthesized
Figure 1 The general view of molecules of compounds 3c (up) and 4a
(down). Atoms are represented by probability ellipsoids of atomic vibra-
tions (p = 0.5%).
1
compounds 3 and 4 were characterized by IR, H, and 13C
NMR spectroscopy and high-resolution mass spectrometry.
In addition, structures of isoxazoline 3c and isoxazole 4a
were unambiguously determined by single-crystal X-ray
Indeed, the O2N2C4C3 torsion angles in crystals of both,
3c and 4a, are small [0.3(2)° and 3.0(2)°, respectively]. The
oxime function is significantly rotated with respect to the
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

D
D. A. Chaplygin et al.
Paper
Synthesis
five-membered heterocycle: the N2C4C3N1 torsion angle
equals to 94.1(2)° and 128.4(1)° in 3c and 4a, correspond-
ingly. This, together with rather large C4–C3 bond lengths
[1.490(2) and 1.481(2) Å, respectively for 3c and 4a], indi-
cates the absence of meaningful -conjugation between ox-
ime and isoxazole (isoxazoline) fragments. By contrast, the
oxime groups are more co-planar with the phenyl rings
[the N2C4C10C11 and N2C4C5C6 torsion angles in 3c and
4a, respectively, equal to 24.4(3)° and 21.8(2)°]. The only
meaningful difference between heterocycles in 3c and 4a is
the expected non-planarity of isoxazoline fragment in 3c
resulting from the envelope conformation: the C1 atom out-
goes from the O1N1C2C3 mean-squared plane on 0.290(2)
Å.
According to the DFT calculations of isolated molecules
of 3c and 4a, the influence of crystal packing effects on mo-
lecular structures is substantial in both compounds (Figure
S1, see SI). The weighted root mean square deviations of the
crystal and equilibrium isolated structures are 0.68 and
0.31 Å, for 3c and 4a, respectively. The difference in devia-
tions can be rationalized not only by the presence of more
flexible isoxazoline cycle in 3c but also by effects of specific
solvation in crystals, which were analyzed using geometric
criteria (Figure 2). Particularly, there are strong intermolec-
ular OH···N hydrogen bonds between oxime and pyridine
moieties in 3c, which bound molecules into chains [the
O2···N3 distance is 2.701(2) Å, the O2–H2O···N3 angle is
172.5° with the O2–H2O distance being normalized on the
idealized value of 0.993 Å]. By contrast, the 4a molecules
are aggregated into centrosymmetric dimers by weaker and
less directional hydrogen bonds between oxime functions
[O2···N2 2.784(2) Å, O2–H2···N2 157.0°]. These interactions
clearly cannot cause significant changes of molecular con-
formation of 4a.
Nonetheless, the Z-configuration of oxime groups per-
sists in the isolated states: the O2N2C4C3 torsion angles are
4.3° and 1.5° in isolated molecules of 3c and 4a, respective-
ly. Moreover, the rotation of the O2N2C4C3 torsion angle is
substantially hindered according to the corresponding re-
laxed scans of potential energy surface for isolated species
(35 steps by 10°). The energy barriers of rotation estimated
at the least stable of available points for each compound
(115.7° and 118.5° for 3c and 4a, respectively) are 82.3 and
78.8 kcal·mol–1.
Figure 2 Fragments of crystal packing of 3c (up) and 4a (down) mole-
cules
Next, a search of optimal conditions for a rearrange-
ment of oximes 3 and 4 to the corresponding furazans was
performed. Oxime 3c was selected as a model substrate.
Solvents, temperature, various bases, and reaction times
were varied (Table 2). A thermal rearrangement of oxime 3c
by refluxing it in EtOH or CHCl3 was unsuccessful (entries 1,
2). Stirring of oxime 3c in a mixture of CHCl3–H2O in the
presence of NaHCO3 or K2CO3 in different molar ratios was
also ineffective (entries 3–6). Target furazan 6a was ob-
tained under the action of KOH in alcoholic media. In all
cases the reaction was accomplished within 30 minutes
and furazan 6a was formed almost quantitatively irrespec-
tive of the molar ratio 3c:KOH (entries 7–10). To our de-
light, the rearrangement of oxime 3c into furazan 6a also
efficiently occurred in EtOH–H2O mixture (entry 11), which
was used for the preparation of initial oxime 3с. Therefore,
this reaction medium could be suitable for the synthesis of
furazans 6 via one-pot cascade transformation of 4-arylfu-
roxans.
If a furoxan ring cleavage was performed in the absence
of a dipolarophile, the formed nitrile oxides 2a,b under-
went dimerization to bis(oximino)furoxans 5a,b in high
yields (Scheme 4).
Indeed, the found optimal reaction medium proved to
be suitable to perform a one-pot cascade transformation of
furoxans 1a,b under the action of alkenes. Target furazans
6a–h were prepared in high yields (Scheme 5). Reaction
times for the isoxazolines 3 formation were the same as in-
dicated on Scheme 3, while the rearrangement step was ac-
complished in 30 minutes after KOH addition in all cases. In
R
R
R
R
HON
NOH
N
O
N
N
EtOH–H2O–PhH
(1:1:1), 20 °C
O
HON
O
N
N
O
2a,b
1a,b
O
a R = Ph
b R = 3-MeOC6H4
5a,b (85–90%)
Scheme 4 Synthesis of bis(oximino)furoxans 5a,b
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

E
D. A. Chaplygin et al.
Paper
Synthesis
Table 2 Optimization of Rearrangement Conditionsa
R1
R1
O
R2
R1
N
R2
KOH
R2
N
N
30 min
O
EtOH–H2O, 20 °C
0.5–24 h
R1 = Ph, 3-MeOC6H4
N
N
Ph
O
O
OH
N
Ph
OH
3a–c,e,g–i,k
1a,b
base
6a–h
N
OH
N
N
solvent, T
N
N
O
Ph
Ph
Ph
Ph
OH
N
O
Ph
OH
CO2Me
CONH2
OH
3c
6a
N
N
N
N
O
N
OH
N
N
O
N
OH
N
O
O
Temp ( °C) Time (h) Yield (%)b
6b (96%, via 3b)
6d (80%, via 3e)
6a (94%, via 3a)
6c (90%, via 3c)
Entry Solvent
Base (equiv)
OMe
OMe
OMe
OMe
c
1
2
EtOH
–
78
61
20
20
20
20
20
20
20
20
20
4
4
–
–
–
–
–
–
c
c
c
c
d
CHCl3
–
CONH2
Ph
OH
CO2Me
N
N
N
N
N
3
CHCl3/H2O (1:1)
CHCl3/H2O (1:1)
CHCl3/H2O (1:1)
CHCl3/H2O (1:1)
EtOH
NaHCO3 (1.5)
NaHCO3 (3)
NaHCO3 (4)
K2CO3 (4)
KOH (2)
KOH (3)
KOH (4)
KOH (4)
KOH (2)
6
OH
6g (78%, via 3i)
CO2Me
N
N
O
OH
N
OH
N
O
O
O
4
6
6e (85%, via 3g)
6f (92%, via 3h)
6h (91%, via 3k)
MeO2C
R1
5
6
R1
R1
CO2Me
MeO2C
CO2Me
KOH
CO2Me
6
19
N
N
O
N
EtOH–H2O, 20 °C
N
N
O
O
OH
N
O
R1 = Ph, 3-MeOC6H4
OH
7
0.5
94
96
95
93
92
1a,b
6i,j
3f,l
8
EtOH
0.5
0.5
0.5
0.5
Scheme 5 Scope of the one-pot cascade transformation of 4-arylfu-
roxans 1a,b with alkenes. Reagents and conditions: 1a,b (0.6 mmol),
alkene (1.2 mmol), EtOH–H2O (1:1, 4 mL), 20 °C, then a 25% solution of
KOH (1.2 mmol) in EtOH.
9
EtOH
10
11
MeOH
EtOH–H2O (1:1)
a Reaction conditions: oxime 3c (0.6 mmol), base, solvent (4 mL).
b Isolated yields.
c No reaction.
Cascade reactions of 4-arylfuroxans 1a,b with acety-
lenes also afforded target furazans in good and high yields.
It is interesting to note that the reaction of furoxans 1a,b
with methyl propiolate resulted in enols 6k,m, while in the
case of phenylacetylene ketones 6l,n were formed. Analo-
gous interaction of furoxans 1a,b with diethyl acetylenedi-
carboxylate resulted in a mixture of cis- and trans-isomers
6o,p in a ratio of 1:2. Isomerization of trans-6o,p into cis-
forms is evidently proceeded via the keto form 7 (Scheme
6). The main advantage of the presented approach includes
a direct installation of several functional groups to the fu-
razan backbone.
A plausible mechanism for the developed one-pot cas-
cade transformation of 4-arylfuroxans 1a,b into furazans 6
is outlined in Scheme 7. Due to the strong electron-with-
drawing effect of the furoxan ring, C–H bond in 4-arylfu-
roxans 1 is readily dissociated in EtOH–H2O mixture fol-
lowed by ring cleavage to -oximinoarylacetonitrile oxide 2.
d Decomposition of starting material was observed.
addition, we studied a scalability of the presented approach
under the standard reaction conditions for the synthesis of
isoxazoline 6d. It was found that our protocol can be ap-
plied on a 0.5 g scale for the preparation of compound 6d in
the same yield. However, an introduction of dimethyl fuma-
rate in the studied one-pot cascade process resulted in a
1
complex mixture of products. Although H NMR spectra of
crude mixtures contained appropriate signals of furazans
6i,j, attempts to isolate target products by column chroma-
tography were unsuccessful. It seems that compounds 6i,j
underwent significant decomposition after their formation
in basic medium. Presumably, such instability of diesters
6i,j is caused by a high acidity of the proton of CH group
linked to a strongly electron-withdrawing furazan ring,
thus promoting anionic oligomerization.
R1
CO2Me
N
R2
R2 = CO2Me
R1
N
R1
N
R1
O
R1
CO2Et
O
CO2Et
OH
OH
N
O
EtO2C
CO2Et
R2
KOH
CO2Et
KOH
CO2Et
6k,m (60–80%)
O
N
N
30 min
(86–89%)
N
30 min
N
EtOH–H2O, 20 °C
EtOH–H2O, 20 °C
R1
O
N
O
N
OH
4b,c,e,f
OH
Ph
1a,b
trans-6o,p
R1 = Ph (6o), 3-MeOC6H4 (6p)
4a,d
R2 = Ph
N
O
N
O
6l,n (75%)
R1
R1
CO2Et
CO2Et
OMe
OMe
CO2Et
OH
Ph
Ph
N
N
N
O
CO2Et
cis-6o,p
CO2Me
OH
N
N
Ph
O
O
N
CO2Me
Ph
7
N
O
N
O
O
N
N
OH
6m (60%)
N
N
O
6k (75%)
6l (75%)
O
O
6n (75%)
Scheme 6 Scope of the one-pot cascade transformation of 4-arylfuroxans 1a,b with alkynes. Reagents and conditions: 1a,b (0.6 mmol), alkyne (1.2
mmol), EtOH–H2O (1:1, 4 mL), 20 °C, then a 25% solution of KOH (1.2 mmol) in EtOH.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

F
D. A. Chaplygin et al.
Paper
Synthesis
This reactivity pattern was previously shown to proceed in
various reaction media, including EtOH–H2O mixture.18
Arguably, the presence of water as a highly polarizable sol-
vent ( = 78.4 at 298 K) promoted dissociation, which was
not observed in less polar MeOH ( = 32.7 at 298 K) or EtOH
( = 24.3 at 298 K). At the same time, EtOH is required to
dissolve the substrate. Subsequent [3+2] cycloaddition of
intermediate 2 to a C=C or C≡C dipolarophile results in the
formation of isoxazoline 3 (isoxazole 4) incorporating Z-
configuration of an oxime group. Upon addition of KOH, ox-
ime group in compounds 3 and 4 is deprotonated promot-
ing the azole–azole rearrangement to final functionally
substituted furazans 6.
3000. External calibration of the mass spectrometer was performed
with Electrospray Calibrant Solution (Fluka). A direct syringe injec-
tion was used for all analyzed solutions in MeCN (flow rate: 3 L min–
1). N2 was used as nebulizer gas (0.4 bar) and dry gas (4.0 L min–1);
interface temperature was set at 180 °C. All spectra were processed
by using Bruker DataAnalysis 4.0 software package. The melting
points were determined on Stuart SMP20 apparatus and are uncor-
rected. Analytical TLC was carried out on Merck 25 TLC silica gel 60
F
254 aluminum sheets. The visualization of the TLC plates was accom-
plished with a UV light. Column chromatography was performed on
silica gel 60 Å (0.060–0.200 mm, Acros Organics). All solvents were
purified and dried using standard methods prior to use. All standard
reagents were purchased from Aldrich or Acros Organics and used
without further purification. 4-Phenylfuroxan (1a)19 was synthesized
according to a published procedure.
X-ray diffraction studies of the 3c crystal were performed using a
Bruker APEX II Duo CCD diffractometer (MoK-radiation, graphite
monochromator, -scans), whereas the X-ray diffraction for 4a was
measured using a Bruker Quest D8 diffractometer equipped with a
Photon-III area-detector (MoK-radiation, graphite monochromator,
shutterless ϕ- and -scan techniques). The intensity data were inte-
grated by the SAINT program20 and were corrected for absorption and
decay using SADABS.21 Both structures were solved by direct methods
using SHELXS22 and refined on F2 using SHELXL-2018.23 All non-hy-
drogen atoms were refined with individual anisotropic displacement
parameters. The locations of H2O and H2 atoms in 3c and 4a, respec-
tively, were found from the electron density-difference map; these at-
oms were refined with an individual isotropic displacement parame-
ter. All other H2 atoms were placed in ideal calculated positions and
refined as riding atoms with relative isotropic displacement parame-
ters. The main crystallographic data and refinement parameters are
given in Table S1 of Supporting Information.24
R2
R1
N
R1
H
R3
R1
N
R2
or
R3
R3
N
O
OH
N
N
– H2O
O
O
O
N
OH
2
1a,b
OH
3,4
R2
KOH
R2
R2
R1
R3
R1
N
R3
OH
H
N
O
N
N
O
O
6
K
Scheme 7 A plausible reaction mechanism for the formation of fu-
razans 6
In summary, we have developed an efficient divergent
approach for the preparation of functionally substituted
isoxazoles, isoxazolines, and furazans. This process is atom-
economic, proceeds in mild conditions via generation of in-
termediate Z-oximes with high regio- and diastereoselec-
tivity and in high yields of final heterocyclic systems. It is
important to note that a wide range of (oximino)dihy-
droisoxazoles underwent azole–azole rearrangement for
the first time. Thus, the developed functionalization proto-
col provides a direct access to a diverse series of 5-mem-
bered nitrogen heterocycles incorporating hydroxy, carbon-
yl, ester, and amide functionalities or their combination at
the azole backbone, which enables the potential use of
these molecular systems in medicinal and materials chem-
istry.
The DFT calculations of isolated molecules of 3c and 4a were per-
formed using the Gaussian 09 program25 (rev. D01) at the PBE026,27/6-
311++G(d,p) level with the Grimme’s D3 dispersion corrections and
Becke–Jonson damping.28 Standard convergence criteria were used for
the optimization procedures and relaxed scans. Equilibrium struc-
tures of both compounds correspond to minimums on potential ener-
gy surface according to the calculations of Hessian of electronic ener-
gy (ultrafine grids, no imaginary modes were found).
4-(3-Methoxyphenyl)furoxan (1b)
A cooled solution of N2O4 (12.5 mmol, 0.8 mL) in anhyd Et2O (4 mL)
was added dropwise to a magnetically stirred solution of amphi-2-
(hydroxyimino)-2-(3-methoxyphenyl)acetaldehyde oxime (1.94 g, 10
mmol) in Et2O (20 mL) at –10 °C. The reaction mixture was allowed to
stir and warm up to 20 °C for 1.5 h. Then the solvent was evaporated
under reduced pressure, the crude product was crystallized from a
mixture of MeOH and concd HCl (5:1) and washed with cold MeOH (4
mL) to afford 1b as a white solid; yield: 1.50 g (78%); mp 85–86 °C;
Rf = 0.67 (CHCl3–EtOAc 3:1).
All reactions were carried out in well-cleaned oven-dried glassware
with magnetic stirring. 1H and 13C NMR spectra were recorded on a
Bruker AM-300 (300.13 and 75.47 MHz, respectively) spectrometer
and referenced to residual solvent peak. The chemical shifts are re-
ported in ppm (); multiplicities are indicated by standard abbrevia-
tions. Coupling constants, J, are reported in hertz (Hz). The IR spectra
were recorded on a Bruker ‘Alpha’ spectrometer in the range 400–
4000 cm–1 (resolution 2 cm–1). High-resolution mass spectra were re-
corded on a Bruker microTOF spectrometer with electrospray ioniza-
tion (ESI). All measurements were performed in a positive (+MS) ion
mode (interface capillary voltage: 4500 V) with scan range m/z: 50–
IR (KBr): 3127, 1608, 1586, 1481, 1440, 1392, 1287, 1271, 1214, 1188,
1040, 996, 943, 773 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.89 (s, 3 H, OCH3), 7.09 (d, J = 8.5 Hz, 1
H, Ar), 7.25–7.31 (m, 3 H, Ar + Het), 7.43 (t, J = 7.9 Hz, 1 H, Ar).
13C NMR (75.5 MHz, CDCl3):  = 55.5, 102.4, 111.5, 117.5, 119.0, 127.2,
130.5, 156.3, 160.3.
Anal. Calcd for C9H8N2O3: C, 56.25; H, 4.20; N, 14.58. Found: C, 56.42;
H, 4.29; N, 14.31.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
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Synthesis
4,5-Dihydroisoxazoles 3 and Isoxazoles 4; General Procedure
1H NMR (300 MHz, DMSO-d6):  = 5.15 (d, J = 9.5 Hz, 1 H), 5.90 (d, J =
9.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 2 H), 7.46–7.61 (m, 8 H), 12.51 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 57.6, 80.9, 126.5, 127.2, 129.4,
129.6, 130.4, 132.0, 133.3, 135.1, 145.1, 149.7, 170.5, 172.8;
HRMS (ESI): m/z [M + H]+ calcd for C18H14N3O4: 336.0979; found:
A solution of 4-arylfuroxan 1a/b (0.6 mmol) in EtOH (2 mL) was add-
ed dropwise to a magnetically stirred mixture of the respective dipol-
arophile (1.2 mmol) in H2O (2 mL) at 20 °C. The reaction mixture was
stirred at 20 °C for 0.5–24 h (TLC monitoring until consumption of
initial furoxan 1) and then extracted with CHCl3 (5 × 2 mL). The com-
bined organic layers were dried (anhyd MgSO4), filtered, and the sol-
vent was evaporated under reduced pressure. The crude product was
purified by gradient flash-column chromatography on SiO2 using
CHCl3–EtOAc as eluent to afford the pure target product.
336.0976.
Phenyl(5-phenyl-4,5-dihydroisoxazol-3-yl)methanone Oxime (3e)
White solid; yield: 128 mg (80%); mp 103–104 °C; Rf = 0.64 (CHCl3–
EtOAc 3:1).
IR (KBr): 3239, 2963, 1727, 1566, 1494, 1427, 1413, 1260, 998, 771
3-[(Hydroxyimino)(phenyl)methyl]-4,5-dihydroisoxazole-5-car-
boxamide (3a)
cm–1
.
White solid; yield: 117 mg (84%); mp 127–128 °C; Rf = 0.34 (EtOAc).
1H NMR (300 MHz, DMSO-d6):  = 3.43 (dd, J = 8.2, 11.0 Hz, 1 H), 3.90
(dd, J = 6.5, 11.0 Hz, 1 H), 5.77 (dd, J = 6.5, 8.2 Hz, 1 H), 7.34–7.44 (m, 8
H), 7.61 (br s, 2 H), 12.19 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 44.8, 82.4, 126.7, 127.6, 128.7,
128.9, 129.2, 129.8, 134.7, 141.1, 147.5, 153.1.
IR (KBr): 3415, 3228, 3157, 2987, 1692, 1653, 1602, 1558, 1496, 1436,
1422, 1083, 905, 879 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.49–3.57 (m, 1 H), 3.64–3.74 (m, 1
H), 5.05–5.11 (m, 1 H), 7.42 (br s, 4 H), 7.57 (br s, 2 H), 7.68 (br s, 1 H),
12.19 (br s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O2: 267.1128; found:
267.1129.
13C NMR (75.5 MHz, DMSO-d6):  = 41.1, 78.9, 127.5, 128.9, 129.9,
134.6, 147.0, 153.1, 172.3.
HRMS (ESI): m/z [M + H]+ calcd for C11H12N3O3: 234.0873; found:
234.0875.
Dimethyl 3-[(Hydroxyimino)(phenyl)methyl]-4,5-dihydroisoxaz-
ole-4,5-dicarboxylate (3f)
A mixture of two diastereomers in 5:1 ratio; pale brown solid; yield:
138 mg (75%); mp 108–109 °C; Rf = 0.41 (CHCl3–EtOAc 3:1).
Methyl 3-[(Hydroxyimino)(phenyl)methyl]-4,5-dihydroisoxazole-
5-carboxylate (3b)
IR (KBr): 3252, 2988, 1750, 1732, 1616, 1316, 1246, 1195, 1174, 1103,
1048, 981, 929, 775, 764 cm–1
.
Yellow oil; yield: 141 mg (95%); Rf = 0.38 (CHCl3–EtOAc 3:1).
1H NMR (300 MHz, DMSO-d6):  (major diastereoisomer) = 3.60 (s, 3
H), 3.77 (s, 3 H), 5.11 (d, J = 5.9 Hz, 1 H), 5.60 (d, J = 5.9 Hz, 1 H), 7.44
(br s, 3 H), 7.54 (br s, 2 H), 12.39 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  (major diastereoisomer) = 53.3,
58.2, 58.5, 81.0, 127.4, 128.9, 130.0, 134.4, 145.8, 150.0, 168.0, 169.1.
IR (neat): 3361, 2972, 2800, 1725, 1430, 1415, 1337, 1255, 1237,
1019, 1006, 839 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.51 (dd, J = 6.6, 6.7 Hz, 1 H), 3.62–
3.68 (m, 1 H), 3.73 (s, 3 H), 5.25 (dd, J = 6.6, 6.7 Hz, 1 H), 7.34–7.43 (m,
5 H), 12.15 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 38.4, 52.9, 78.3, 128.2, 129.2,
129.4, 131.1, 149.3, 157.2, 170.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H15N2O6: 307.0925; found:
307.0928.
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O4: 249.0870; found:
249.0876.
3-[(Hydroxyimino)(3-methoxyphenyl)methyl]-4,5-dihydroisoxaz-
ole-5-carboxamide (3g)
White solid; yield: 126 mg (80%); mp 114–115 °C; Rf = 0.22 (EtOAc).
Phenyl[5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl]methanone Ox-
IR (KBr): 3405, 3188, 1661, 1599, 1585, 1470, 1291, 1253, 1217, 1096,
ime (3с)
1032, 1013, 879, 786 cm–1
.
Pale pink solid; yield: 151 mg (94%); mp 135–136 °C; Rf = 0.18
(CHCl3–EtOAc 3:1).
1H NMR (300 MHz, DMSO-d6):  = 3.48 (dd, J = 6.1, 6.2 Hz, 1 H), 3.62–
3.83 (m, 4 H), 5.05–5.11 (m, 1 H), 6.98–7.00 (m, 1 H), 7.09–7.15 (m, 2
H), 7.32 (t, J = 8.0 Hz, 1 H), 7.44 (br s, 1 H), 7.69 (br s, 1 H), 12.20 (s, 1
H).
13C NMR (75.5 MHz, DMSO-d6):  = 40.6, 55.1, 78.3, 112.1, 115.1,
119.3, 129.5, 135.3, 146.4, 152.5, 159.1, 171.8.
IR (KBr): 3345, 2980, 2709, 1610, 1598, 1497, 1436, 1021, 1005, 938,
854, 769 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.73 (dd, J = 7.2, 11.0 Hz, 1 H), 3.89
(dd, J = 7.3, 11.0 Hz, 1 H), 5.83 (dd, J = 7.2, 11.0 Hz, 1 H), 7.39–7.43 (m,
4 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.60–7.63 (m, 2 H), 7.88 (t, J = 7.6 Hz, 1
H), 8.63 (d, J = 4.9 Hz, 1 H), 12.16 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H14N3O4: 264.0978; found:
264.0987.
13C NMR (75.5 MHz, DMSO-d6):  = 42.8, 82.6, 122.0, 124.0, 127.6,
128.8, 129.8, 134.8, 137.7, 147.4, 149.9, 153.3, 159.1;
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O2: 268.1081; found:
268.1088.
Methyl 3-[(Hydroxyimino)(3-methoxyphenyl)methyl]-4,5-dihy-
droisoxazole-5-carboxylate (3h)
Yellow oil; yield: 150 mg (90%); Rf = 0.58 (CHCl3–EtOAc 3:1).
IR (neat): 3356, 3007, 2957, 2840, 1744, 1601, 1579, 1490, 1435,
3-[(Hydroxyimino)(phenyl)methyl]-5-phenyl-3aH-pyrrolo[3,4-
d]isoxazole-4,6(5H,6aH)-dione (3d)
1289, 1230, 1185, 1162, 962, 880, 811, 790 cm–1
.
White solid; yield: 197 mg (98%); mp 129–130 °C; Rf = 0.28 (CHCl3–
EtOAc 3:1).
1H NMR (300 MHz, DMSO-d6):  = 3.55–3.61 (m, 2 H), 3.73 (s, 3 H),
3.77 (s, 3 H), 5.32 (dd, J = 5.6, 6.0 Hz, 1 H), 6.99–7.02 (m, 1 H), 7.10–
7.14 (m, 2 H), 7.31–7.36 (m, 1 H), 12.25 (s, 1 H).
IR (KBr): 3421, 1710, 1597, 1502, 1449, 1393, 1204, 1104, 997 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
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Synthesis
13C NMR (75.5 MHz, DMSO-d6):  = 40.5, 52.9, 55.6, 77.7, 112.8, 115.5,
119.9, 130.0, 130.9, 135.8, 146.6, 152.9, 170.8.
IR (neat): 3376, 3008, 2958, 1744, 1601, 1580, 1491, 1438, 1290,
1257, 1212, 1017, 962, 889, 814, 789 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C13H15N2O5: 279.0975; found:
279.0972.
1H NMR (300 MHz, DMSO-d6):  (major diastereoisomer) = 3.59 (s, 3
H), 3.76 (s, 3 H), 3.77 (s, 3 H), 5.08 (d, J = 6.0 Hz, 1 H), 5.59 (d, J = 6.0
Hz, 1 H), 6.99–7.03 (m, 1 H), 7.08–7.11 (m, 2 H), 7.34 (t, J = 9.0 Hz, 1
H), 12.40 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  (major diastereoisomer) = 52.9 (2
C), 55.1, 57.8, 80.6, 112.2, 115.2, 119.4, 129.6, 133.0, 145.2, 149.5,
159.2, 167.5, 168.7.
(3-Methoxyphenyl)[5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-
yl]methanone Oxime (3i)
Pale pink solid; yield: 125 mg (70%); mp 117–118 °C; Rf = 0.14
(CHCl3–EtOAc 3:1).
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O7: 337.1030; found:
337.1029.
IR (KBr): 2959, 2938, 2794, 1595, 1491, 1469, 1334, 1317, 1283, 1232,
1164, 1043, 1002, 969, 900, 853, 813, 787 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.75–3.85 (m, 5 H), 5.82 (br s, 1 H),
6.99 (br s, 1 H), 7.14–7.19 (m, 2 H), 7.31–7.38 (m, 2 H), 7.51 (br s, 1 H),
7.85 (br s, 1 H), 8.60 (br s, 1 H), 12.15 (s, 1 H).
Diethyl 3-[(Hydroxyimino)(phenyl)methyl]isoxazole-4,5-dicar-
boxylate (4a)
Yellow oil; yield: 191 mg (96%); Rf = 0.54 (CHCl3–EtOAc 3:1).
13C NMR (75.5 MHz, DMSO-d6):  = 42.3, 55.1, 81.9, 112.3, 115.0,
119.5, 121.5, 123.5, 129.5, 135.5, 137.2, 146.8, 149.4, 152.7, 158.6,
159.1.
IR (neat): 3265, 2948, 2840, 1753, 1738, 1626, 1496, 1437, 1428,
1375, 1329, 1238, 1228, 1202, 1028, 890, 771, 752 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O3: 298.1186; found:
298.1180.
1H NMR (300 MHz, DMSO-d6):  = 1.13 (t, J = 7.2 Hz, 3 H), 1.34 (t, J =
7.2 Hz, 3 H), 4.18 (q, J = 7.2 Hz, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 7.42–7.45
(m, 3 H), 7.53–7.56 (m, 2 H), 12.34 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 13.5, 13.7, 61.6, 63.0, 116.1, 126.2,
128.7, 129.8, 133.4, 144.1, 155.5, 156.2, 159.0, 159.6.
3-[(Hydroxyimino)(3-methoxyphenyl)methyl]-5-phenyl-3aH-pyr-
rolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (3j)
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2O6: 333.1079; found:
333.1081.
White solid; yield: 210 mg (96%); mp 185–186 °C; Rf = 0.36 (CHCl3–
EtOAc 3:1).
IR (KBr): 3329, 2997, 2970, 1709, 1600, 1582, 1492, 1468, 1431, 1395,
1332, 1255, 1205, 1155, 1044, 1025, 963, 869, 813, 700 cm–1
.
Methyl 3-[(Hydroxyimino)(phenyl)methyl]isoxazole-5-carboxyl-
ate (4b)
1H NMR (300 MHz, DMSO-d6):  = 3.79 (s, 3 H), 5.13 (d, J = 9.4 Hz, 1
H), 5.91 (d, J = 9.4 Hz, 1 H), 7.06 (d, J = 7.0 Hz, 1 H), 7.11–7.14 (m, 2 H),
7.26 (d, J = 7.5 Hz, 2 H), 7.39 (t, J = 8.1 Hz, 1 H), 7.46–7.55 (m, 3 H),
12.54 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 55.7, 57.6, 80.9, 111.4, 116.1,
119.1, 127.1, 129.4, 129.6, 130.6, 132.0, 134.6, 144.9, 149.6, 159.9,
170.5, 172.9.
Pale yellow solid; yield: 103 mg (70%); mp 127–128 °C; Rf = 0.57
(CHCl3–EtOAc 3:1).
IR (KBr): 3388, 3177, 3147, 1733, 1585, 1573, 1498, 1445, 1403, 1329,
1319, 1268, 1268, 1211, 1106, 1029, 1000, 968, 919, 771, 701 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.93 (s, 3 H), 7.43 (br s, 3 H), 7.53
(br s, 2 H), 7.60 (s, 1 H), 12.41 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 53.0, 111.7, 127.0, 128.5, 129.6,
133.9, 145.0, 156.5, 156.7, 159.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H16N3O5: 366.1084; found:
366.1086.
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O4: 247.0713; found:
247.0722.
(3-Methoxyphenyl)(5-phenyl-4,5-dihydroisoxazol-3-yl)metha-
none Oxime (3k)
White solid; yield: 163 mg (92%); mp 104–105 °C; Rf = 0.60 (CHCl3–
EtOAc 3:1).
Phenyl(5-phenylisoxazol-3-yl)methanone Oxime (4c)
White solid; yield: 119 mg (75%); mp 129–130 °C (Lit.29 mp 129–
130 °C); Rf = 0.67 (CHCl3–EtOAc 3:1).
IR (KBr): 3355, 2943, 2842, 1608, 1576, 1489, 1453, 1430, 1355, 1292,
1261, 1231, 1156, 1136, 1050, 1009, 960, 875, 809 cm–1
.
IR (KBr): 3027, 2876, 1570, 1442, 1429, 1270, 1057, 1044, 976, 957,
1H NMR (300 MHz, DMSO-d6):  = 3.38–3.43 (m, 1 H), 3.76 (s, 3 H),
3.82–3.92 (m, 1 H), 5.77 (dd, J = 2.9, 8.2 Hz, 1 H), 6.99–7.03 (m, 1 H),
7.11–7.17 (m, 2 H), 7.31–7.43 (m, 6 H), 12.19 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 44.8, 55.6, 82.3, 112.7, 115.5,
120.0, 126.7, 128.7, 129.1, 130.0, 136.0, 141.2, 147.3, 153.0, 159.6.
817, 764 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 7.39–7.44 (m, 4 H), 7.55–7.59 (m, 5
H), 7.95 (d, J = 6.9 Hz, 2 H), 12.25 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 102.7, 126.2, 127.1, 127.5, 129.0,
129.8, 129.9, 131.1, 134.9, 146.5, 157.2, 169.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H13N2O2: 265.0972; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O3: 297.1234; found:
297.1238.
265.0962.
Dimethyl 3-[(Hydroxyimino)(3-methoxyphenyl)methyl]-4,5-dihy-
droisoxazole-4,5-dicarboxylate (3l)
Diethyl 3-[(Hydroxyimino)(3-methoxyphenyl)methyl]isoxazole-
4,5-dicarboxylate (4d)
A mixture of two diastereomers in 8:1 ratio; pale brown oil; yield:
192 mg (95%); Rf = 0.37 (CHCl3–EtOAc 3:1).
Yellow oil; yield: 206 mg (95%); Rf = 0.45 (CHCl3–EtOAc 3:1).
IR (neat): 3390, 2985, 2940, 1747, 1604, 1579, 1468, 1391, 1370,
1319, 1217, 1192, 1106, 1055, 1013, 861, 822, 789 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
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Synthesis
1H NMR (300 MHz, DMSO-d6):  = 1.15 (t, J = 7.1 Hz, 3 H), 1.35 (t, J =
7.1 Hz, 3 H), 3.78 (s, 3 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.44 (q, J = 7.1 Hz, 2
H), 7.02–7.08 (m, 2 H), 7.12–7.14 (m, 1 H), 7.35 (t, J = 8.0 Hz, 1 H),
12.36 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 14.0, 14.2, 55.6, 62.1, 63.5, 111.7,
115.9, 116.6, 119.4, 130.3, 135.2, 144.4, 156.0, 156.6, 159.5, 159.8,
160.0.
Furazans 6; General Procedure
A solution of 4-arylfuroxan 1a/b (0.6 mmol) in EtOH (2 mL) was add-
ed dropwise to a magnetically stirred mixture of the respective dipol-
arophile (1.2 mmol) in H2O (2 mL) at 20 °C. The resulting solution was
stirred at 20 °C for 0.5–24 h (TLC monitoring until consumption of
initial furoxan 1) and then a solution of KOH (0.28 g, 1.2 mmol) in
EtOH (190 L) was added. The reaction mixture was stirred for 30 min
at 20 °C, then concd HCl was added till pH 7. The resulting mixture
was poured into H2O (15 mL) and extracted with CHCl3 (5 × 3 mL). The
combined organic layers were dried (anhyd MgSO4), filtered, and the
solvent was evaporated under reduced pressure. The residue was pu-
rified by column chromatography on SiO2 using CHCl3–EtOAc as elu-
ent to afford the target product.
HRMS (ESI): m/z [M + H]+ calcd for C17H19N2O7: 363.1187; found:
363.1189.
Methyl 3-[(Hydroxyimino)(3-methoxyphenyl)methyl]isoxazole-5-
carboxylate (4e)
White solid; yield: 99 mg (60%); mp 100–101 °C; Rf = 0.64 (CHCl3–
EtOAc 3:1).
2-(4-Phenyl-1,2,5-oxadiazol-3-yl)-1-(pyridin-2-yl)ethanol (6a)
IR (KBr): 3526, 3173, 3143, 1733, 1600, 1583, 1492, 1441, 1316, 1293,
Pale yellow solid; yield: 151 mg (94%); mp 83–84 °C; Rf = 0.22 (CHCl3–
EtOAc 3:1).
1230, 1200, 1167, 1099, 1050, 1035, 978, 957, 893, 815, 799, 703 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.76 (s, 3 H), 3.93 (s, 3 H), 7.01–
7.10 (m, 3 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.58 (s, 1 H), 12.43 (s, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 53.5, 55.6, 112.1, 112.6, 115.7,
120.1, 130.1, 131.0, 135.7, 145.3, 157.0, 159.7, 159.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H13N2O5: 277.0740; found:
IR (KBr): 3065, 2940, 2847, 1593, 1573, 1451, 1438, 1385, 1072, 1002,
993, 896, 773, 753 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.21–3.28 (m, 1 H), 3.51–3.57 (m, 1
H), 4.94–4.99 (m, 1 H), 5.86 (br s, 1 H), 7.22–7.26 (m, 1 H), 7.48 (d, J =
7.8 Hz, 1 H), 7.58 (br s, 3 H), 7.77–7.81 (m, 3 H), 8.45 (d, J = 6.0 Hz, 1
H).
277.0738.
13C NMR (75.5 MHz, DMSO-d6):  = 31.4, 71.7, 120.2, 122.4, 125.6,
128.4, 129.1, 130.4, 136.7, 148.4, 151.8, 154.5, 162.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O2: 268.1081; found:
268.1088.
(3-Methoxyphenyl)(5-phenylisoxazol-3-yl)methanone Oxime (4f)
Yellow oil; yield: 127 mg (72%); Rf = 0.85 (CHCl3–EtOAc 3:1).
IR (neat): 3066, 2936, 2838, 1690, 1597, 1471, 1450, 1334, 1289,
1216, 1003, 843 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.76 (s, 3 H), 7.02 (d, J = 8.1 Hz, 1
H), 7.09 (d, J = 7.7 Hz, 1 H), 7.15 (s, 1 H), 7.31–7.37 (m, 2 H), 7.54–7.56
(m, 3 H), 7.95 (d, J = 7.1 Hz, 2 H), 12.26 (s, 1 H).
Methyl 2-Hydroxy-3-(4-phenyl-1,2,5-oxadiazol-3-yl)propanoate
(6b)
Brown oil; yield: 143 mg (96%); Rf = 0.48 (CHCl3–EtOAc 3:1).
13C NMR (75.5 MHz, DMSO-d6):  = 55.1, 102.2, 112.0, 115.1, 119.6,
125.7, 126.6, 129.3, 129.6, 130.6, 135.7, 145.8, 156.6, 159.2, 168.9.
IR (neat): 3469, 2956, 1746, 1452, 1441, 1387, 1346, 1228, 1106,
1025, 1002, 993, 896, 773, 735 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O3: 295.1077; found:
295.1074.
1H NMR (300 MHz, DMSO-d6):  = 3.24 (dd, J = 5.3, 10.0 Hz, 1 H), 3.38
(dd, J = 5.3, 10.0 Hz, 1 H), 3.61 (s, 3 H), 4.45 (q, J = 6.0 Hz, 1 H), 5.96 (d,
J = 6.0 Hz, 1 H), 7.58–7.60 (m, 3 H), 7.78–7.82 (m, 2 H).
13C NMR (75.5 MHz, DMSO-d6):  = 28.2, 51.7, 68.4, 125.3, 128.4,
Bis(hydroxyimino)furoxans 5a,b; General Procedure
129.2, 130.6, 151.0, 154.4, 172.7.
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O4: 249.0870; found:
249.0876.
A solution of 4-arylfuroxan 1a/b (0.6 mmol) in a mixture of EtOH–
H2O–benzene (1:1:1, total volume 6 mL) was stirred for 30 min at
20 °C. Then the product was extracted with CHCl3 (5 × 2 mL). The
combined organic layers were dried (anhyd MgSO4), filtered, and the
solvent was evaporated under reduced pressure to afford crude prod-
ucts, which were additionally washed with n-pentane.
2-Hydroxy-3-(4-phenyl-1,2,5-oxadiazol-3-yl)propanamide (6c)
Yellow solid; yield: 126 mg (90%); mp 109–110 °C; Rf = 0.24 (EtOAc).
IR (KBr): 3415, 3228, 2987, 1692, 1653, 1602, 1572, 1558, 1450, 1422,
Synthesis and spectral characteristics of the furoxan 5a were reported
previously.30
1312, 1270, 1252, 1008, 905, 766 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.03–3.11 (m, 1 H), 3.40–3.42 (m, 1
H), 4.18 (br s, 1 H), 5.89 (br s, 1 H), 7.28 (br s, 1 H), 7.35 (br s, 1 H),
7.59–7.62 (m, 3 H), 7.79–7.83 (m, 2 H).
13C NMR (75.5 MHz, DMSO-d6):  = 29.2, 70.1, 126.0, 129.0, 129.6,
131.0, 152.2, 155.0, 175.1.
[3,4-Bis(hydroxyimino)(3-methoxyphenyl)methyl]furoxan (5b)
White solid; yield: 98 mg (85%); mp 118–119 °C; Rf = 0.73 (CHCl3–
EtOAc 3:1).
IR (KBr): 3002, 1610, 1481, 1455, 1289, 1267, 1027, 978, 815, 774 cm–1
1H NMR (300 MHz, DMSO-d6):  = 3.79 (s, 6 H), 7.05 (d, J = 8.5 Hz, 2
.
HRMS (ESI): m/z [M + H]+ calcd for C11H12N3O3: 234.0873; found:
234.0875.
H), 7.21–7.27 (m, 4 H), 7.36–7.41 (m, 2 H), 13.41 (br s, 2 H).
13C NMR (75.5 MHz, DMSO-d6):  = 55.6, 55.7, 111.0, 111.7, 112.5,
116.8, 118.5, 118.7, 118.9, 120.3, 126.2, 129.8, 130.1, 130.7, 131.0,
132.7, 157.9, 160.0.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N4O6: 385.1064; found:
385.1060.
1-Phenyl-2-(4-phenyl-1,2,5-oxadiazol-3-yl)ethanol (6d)
White solid; yield: 128 mg (80%); mp 96–97 °C; Rf = 0.70 (CHCl3–EtOAc
3:1).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
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Synthesis
IR (KBr): 3443, 3064, 1604, 1585, 1494, 1454, 1386, 1056, 1028, 896,
771 cm–1
IR (neat): 3454, 3031, 1587, 1470, 1383, 1324, 1290, 1224, 1180,
.
1040, 847, 790, 716 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.26–3.37 (m, 2 H), 4.88–4.92 (m, 1
H), 5.68 (br s, 1 H), 7.23–7.31 (m, 5 H), 7.59–7.61 (m, 3 H), 7.77–7.80
(m, 2 H).
1H NMR (300 MHz, DMSO-d6):  = 3.17–3.33 (m, 2 H), 3.84 (s, 3 H),
4.85–4.89 (m, 1 H), 7.15–7.37 (m, 8 H), 7.50 (t, J = 7.9 Hz, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 33.7, 55.8, 71.4, 114.3, 116.7,
13C NMR (75.5 MHz, DMSO-d6):  = 33.8, 71.3, 126.0, 126.1, 127.8,
121.1, 126.1, 127.2, 127.8, 128.6, 130.9, 144.8, 152.3, 154.9, 160.0.
128.6, 128.9, 129.6, 131.0, 144.8, 152.3, 155.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O2: 267.1128; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O3: 297.1234; found:
297.1238.
267.1129.
Methyl 2-Hydroxy-3-(4-phenyl-1,2,5-oxadiazol-3-yl)acrylate (6k)
2-[4-(3-Methoxyphenyl)-1,2,5-oxadiazol-3-yl]-1-(pyridin-2-
yl)ethanol (6e)
White solid; yield: 111 mg (75%); mp 239–240 °C; Rf = 0.57 (CHCl3–
EtOAc 3:1).
Yellow solid; yield: 151 mg (85%); mp 96–97 °C; Rf = 0.19 (CHCl3–EtOAc
3:1).
IR (KBr): 2958, 1707, 1576, 1534, 1483, 1426, 1223, 1141, 988, 779
cm–1
.
IR (KBr): 3189, 3008, 2934, 1593, 1572, 1474, 1437, 1339, 1323, 1246,
1H NMR (300 MHz, DMSO-d6):  = 3.17 (s, 1 H), 3.58 (s, 3 H), 5.41 (br s,
1 H), 7.55–7.61 (m, 5 H).
1213, 1175, 1107, 1077, 1031, 1003, 874, 794, 752 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.26 (dd, J = 6.2, 8.7 Hz, 1 H), 3.56
(dd, J = 4.6, 10.3 Hz, 1 H), 3.85 (s, 3 H), 4.96–5.02 (m, 1 H), 5.90 (d, J =
5.1 Hz, 1 H), 7.15 (dd, J = 2.6, 5.6 Hz, 1 H), 7.23–7.27 (m, 1 H), 7.35–
7.40 (m, 2 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.78 (dt, J = 2.9, 7.7 Hz, 1 H),
8.45–8.48 (m, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 51.4, 77.4, 127.5, 128.7, 129.2,
130.0, 151.8, 153.2, 162.7, 168.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O4: 247.0713; found:
247.0722.
13C NMR (75.5 MHz, DMSO-d6):  = 31.9, 55.8, 72.3, 114.2, 116.8,
120.7, 121.2, 122.9, 127.2, 130.8, 137.2, 148.9, 152.4, 154.9, 160.0,
163.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O3: 298.1186; found:
298.1180.
1-Phenyl-2-(4-phenyl-1,2,5-oxadiazol-3-yl)ethanone (6l)
Pale yellow solid; yield: 119 mg (75%); mp 64–65 °C; Rf = 0.67 (CHCl3–
EtOAc 3:1).
IR (KBr): 3150, 3027, 2875, 1687, 1457, 1429, 1269, 1216, 1056, 976,
930, 817, 765, 671 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 5.11 (s, 2 H), 7.49–7.60 (m, 5 H),
7.68–7.74 (m, 3 H), 8.03 (d, J = 7.7 Hz, 2 H).
13C NMR (75.5 MHz, DMSO-d6):  = 33.8, 125.4, 127.7, 128.3, 128.8,
Methyl 2-Hydroxy-3-[4-(3-methoxyphenyl)-1,2,5-oxadiazol-3-
yl]propanoate (6f)
Red oil; yield: 163 mg (92%); Rf = 0.60 (CHCl3–EtOAc 3:1).
129.1, 130.6, 134.0, 135.4, 149.6, 154.6, 194.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H13N2O2: 265.0972; found:
IR (neat): 3468, 2956, 1744, 1606, 1588, 1471, 1440, 1290, 1225,
1182, 1107, 1040, 1003, 843, 791 cm–1
.
265.0962.
1H NMR (300 MHz, DMSO-d6):  = 3.23 (dd, J = 7.9, 7.4 Hz, 1 H), 3.37–
3.41 (m, 1 H), 3.62 (s, 3 H), 3.84 (s, 3 H), 4.40–4.46 (m, 1 H), 5.98 (d, J =
5.8 Hz, 1 H), 7.16–7.20 (m, 1 H), 7.33–7.36 (m, 2 H), 7.51 (t, J = 8.1 Hz,
1 H).
Methyl 2-Hydroxy-3-[4-(3-methoxyphenyl)-1,2,5-oxadiazol-3-
yl]acrylate (6m)
White solid; yield: 99 mg (60%); mp 236–237 °C; Rf = 0.65 (CHCl3–
EtOAc 3:1).
13C NMR (75.5 MHz, DMSO-d6):  = 28.7, 52.3, 55.8, 68.9, 114.3, 116.8,
121.1, 126.9, 130.9, 151.6, 154.8, 160.0, 173.2.
IR (KBr): 3424, 2979, 2961, 1698, 1591, 1547, 1492, 1434, 1364, 1323,
HRMS (ESI): m/z [M + H]+ calcd for C13H15N2O5: 279.0975; found:
279.0972.
1240, 1214, 1188, 1144, 1034, 1001, 862, 789 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.62 (s, 3 H), 3.82 (s, 3 H), 5.50 (s, 1
H), 7.11–7.22 (m, 3 H), 7.49 (t, J = 7.9 Hz, 1 H).
13C NMR (75.5 MHz, DMSO-d6):  = 51.3, 55.3, 77.2, 113.9, 115.5,
2-Hydroxy-3-[4-(3-methoxyphenyl)-1,2,5-oxadiazol-3-yl]propan-
amide (6g)
120.6, 128.5, 130.2, 151.5, 152.7, 159.4, 162.5, 168.4.
White solid; yield: 123 mg (78%); mp 118–120 °C; Rf = 0.24 (EtOAc).
HRMS (ESI): m/z [M + H]+ calcd for C13H13N2O5: 277.0740; found:
277.0735.
IR (KBr): 3394, 3180, 1660, 1636, 1585, 1559, 1469, 1291, 1255, 1217,
1175, 1096, 1050, 1000, 906, 839, 787, 714 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.07 (dd, J = 6.2, 8.9 Hz, 1 H), 3.35–
3.43 (m, 1 H), 3.84 (s, 3 H), 4.19 (br s, 1 H), 5.94 (br s, 1 H), 7.14–7.18
(m, 1 H), 7.29 (br s, 1 H), 7.34–7.37 (m, 3 H), 7.50 (t, J = 8.1 Hz, 1 H).
2-[4-(3-Methoxyphenyl)-1,2,5-oxadiazol-3-yl]-1-phenylethanone
(6n)
Brown oil; yield: 132 mg (75%); Rf = 0.60 (CHCl3–EtOAc 3:1).
13C NMR (75.5 MHz, DMSO-d6):  = 29.1, 55.8, 70.1, 114.2, 116.9,
121.2, 127.1, 130.9, 152.2, 154.8, 160.0, 175.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H14N3O4: 264.0978; found:
IR (neat): 3454, 3031, 1587, 1470, 1383, 1324, 1290, 1224, 1180,
1040, 847, 790, 716 cm–1
.
264.0987.
1H NMR (300 MHz, DMSO-d6):  = 3.68 (s, 3 H), 5.11 (s, 2 H), 7.05–
7.09 (m, 1 H), 7.20 (br s, 1 H), 7.26 (d, J = 8.1 Hz, 1 H), 7.40 (t, J = 8.0
Hz, 1 H), 7.56 (t, J = 7.5 Hz, 2 H), 7.70 (t, J = 7.5 Hz, 1 H), 8.02 (d, J = 8.1
Hz, 2 H).
2-[4-(3-Methoxyphenyl)-1,2,5-oxadiazol-3-yl]-1-phenylethanol
(6h)
Brown oil; yield: 162 mg (91%); Rf = 0.60 (CHCl3–EtOAc 3:1).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
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Synthesis
13C NMR (75.5 MHz, DMSO-d6):  = 33.8, 55.1, 112.9, 116.4, 120.0,
126.6, 128.3, 128.8, 130.4, 134.0, 135.4, 149.6, 154.5, 159.5, 194.6.
Acknowledgment
Crystal structure determination of 3c was performed with the finan-
cial support from Ministry of Science and Higher Education of the
Russian Federation using the equipment of Center for molecular com-
position studies of INEOS RAS. Crystal structure determination of 4a
was performed in the Department of Structural Studies of Zelinsky
Institute of Organic Chemistry, Moscow.
HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O3: 295.0999; found:
295.1002.
Diethyl 2-Hydroxy-3-(4-phenyl-1,2,5-oxadiazol-3-yl)maleate (6o)
A mixture of cis- and trans-isomers; pale yellow solid; yield: 177 mg
(89%); mp 138–139 °C; Rf = 0.78 (EtOAc–EtOH 3:1).
IR (KBr): 3434, 2986, 1734, 1670, 1450, 1372, 1267, 1105, 1031, 966,
862, 776 cm–1
.
Supporting Information
1H NMR (300 MHz, DMSO-d6):  = 0.58 (t, J = 7.1 Hz, 3 H), 0.75 (t, J =
7.0 Hz, 1.5 H), 0.93 (t, J = 7.0 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 1.5 H), 3.64 (q,
J = 7.1 Hz, 1 H), 3.73 (q, J = 7.0 Hz, 2 H), 3.94 (q, J = 7.0 Hz, 2 H), 4.08 (q,
J = 7.1 Hz, 1 H), 7.45–7.51 (m, 4.5 H), 7.75 (d, J = 6.5 Hz, 3 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707393.
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13C NMR (75.5 MHz, DMSO-d6):  = 13.5 (2 C), 14.1, 14.4, 57.0, 59.2,
59.7, 60.6, 82.5, 126.9, 127.3, 127.4, 127.6, 128.0, 128.6, 129.0, 129.4,
129.9, 130.4, 151.6, 154.5, 165.8, 166.9, 169.4.
References
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Chem. 2019, 62, 2256. (b) Krska, S. W.; DiRocco, D. A.; Dreher, S.
D.; Shevlin, M. Acc. Chem. Res. 2017, 50, 2976. (c) Liu, Y.-J.; Xu,
H.; Kong, W.-J.; Shang, M.; Dai, H.-X.; Yu, J.-Q. Nature 2014, 515,
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(e) Hilton, M. C.; Zhang, X.; Boyle, B. T.; Alegre-Requena, J. V.;
Paton, R. S.; McNally, A. Science 2018, 362, 6416, 799.
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2O6: 333.1079; found:
333.1081.
Diethyl 2-Hydroxy-3-[4-(3-methoxyphenyl)-1,2,5-oxadiazol-3-
yl]maleate (6p)
A mixture of cis- and trans-isomers; pale yellow solid; yield: 187 mg
(86%); mp 101–102 °C; Rf = 0.74 (EtOAc–EtOH 3:1).
(2) (a) Das, P.; Delost, M. D.; Qureshi, M. H.; Smith, D. T.;
Njardarson, J. T. J. Med. Chem. 2019, 62, 4265. (b) Vitaku, E.;
Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257.
(3) For recent examples, see: (a) Kawamata, Y.; Vantourout, J. C.;
Hickey, D. P.; Bai, P.; Chen, L.; Hou, Q.; Qiao, W.; Barman, K.;
Edwards, M. A.; Garrido-Castro, A. F.; deGruyter, J. N.;
Nakamura, H.; Knouse, K.; Qin, C.; Clay, K. J.; Bao, D.; Li, C.; Starr,
J. T.; Garcia-Irizarry, C.; Sach, N.; White, H. S.; Neurock, M.;
Minteer, S. D.; Baran, P. S. J. Am. Chem. Soc. 2019, 141, 6392.
(b) Zhang, X.; McNally, A. ACS Catal. 2019, 9, 4862. (c) Boddy, A.
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N. N.; Belen’kii, L. I.; Gazieva, G. A.; Dalinger, I. L.; Konstantinova,
IR (KBr): 3434, 2986, 1726, 1660, 1535, 1468, 1368, 1257, 1002, 1035,
863, 781 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 0.85 (t, J = 7.1 Hz, 3 H), 1.00 (t, J =
7.1 Hz, 1.5 H), 1.23–1.29 (m, 4 H), 3.79 (s, 3 H), 3.82 (s, 1.5 H), 3.85 (q,
J = 7.1 Hz, 2 H), 3.98 (q, J = 6.9 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.22 (q,
J = 6.9 Hz, 1 H), 7.08–7.17 (m, 1.5 H), 7.26–7.33 (m, 2.5 H), 7.44 (t, J =
7.8 Hz, 1.5 H).
13C NMR (75.5 MHz, DMSO-d6):  = 13.5, 13.7, 13.8,,13.9, 55.2, 55.4,
59.4, 61.1, 111.9, 112.9, 113.2, 116.1, 116.6, 116.8, 119.6, 120.2, 127.3,
130.3, 130.5, 148.5, 148.9, 154.2, 159.5, 164.8, 165.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H19N2O7: 363.1187; found:
363.1189.
Scale-Up Experiment for 1-Phenyl-2-(4-phenyl-1,2,5-oxadiazol-3-
yl)ethanol (6d)
A solution of 4-phenylfuroxan (1a; 0.486 g, 3 mmol) in EtOH (10 mL)
was added dropwise to a magnetically stirred solution of styrene
(0.707 mL, 6 mmol) in H2O (10 mL) at 20 °C. The resulting solution
was stirred for 4 h at 20 °C and then a solution of KOH (0.34 g, 6
mmol) in EtOH (0.85 mL) was added. The reaction mixture was stirred
for 40 min at 20 °C and concd HCl was added till pH 7. The resulting
mixture was poured into H2O (40 mL) and extracted with CHCl3 (5 ×
10 mL). The combined organic layers were dried (anhyd MgSO4) and
the solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on SiO2 to afford 6d; yield: 638
mg (80%).
Funding Information
This work was supported by the Russian Foundation for Basic Re-
search (grant 18-03-00332). The structure analysis and DFT calcula-
tions were supported by the Russian Science Foundation (project 18-
73-10131).
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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D. A. Chaplygin et al.
Paper
Synthesis
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L