N -Oxide-Controlled Chemoselective Reduction of Nitrofuroxans

Article abstract of DOI:10.1055/s-0037-1611056

A facile and chemoselective SnCl ₂ -mediated mild reduction of regioisomeric 3- and 4-nitrofuroxans for the synthesis of aminofurazans and aminofuroxans in good yields is developed. Reduction of 4-nitrofuroxans results in the selective formation of 4-aminofuroxans, while analogous reduction of 3-nitrofuroxans affords 3-aminofurazans as a result of simultaneous reduction of the nitro group and exocyclic N-O bond.

Full text of DOI:10.1055/s-0037-1611056

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
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en
L. L. Fershtat et al.
Paper
Synthesis
N-Oxide-Controlled Chemoselective Reduction of Nitrofuroxans
Leonid L. Fershtat*a
Dmitry M. Bystrova,b
Egor S. Zhilina,b
0
0
0
0
0-
0
0
2
0-
2
0
3
1-
0
2
5
R
NOH
Nina N. Makhovaa
R
NH2
R
NO2
R
NO2
R
NH2
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, 119991 Moscow, Russian Federation
fershtat@bk.ru
b Department of Chemistry, Moscow State University, 119991 Moscow,
Leninskie Gory 1-3, Russian Federation
SnCl2
HCl
SnCl2
HCl
PhMe
N
N
N
N
O
N
N
N
N
D, 3 h
O
O
O
O
O
O
(60–81%)
(61–84%)
(95–99%)
(70–98%)
13 examples
13 examples
simultaneous reduction
of nitro group and N-oxide motif
chemoselective
nitro group reduction
Received: 07.07.2018
Accepted after revision: 31.08.2018
Published online: 21.09.2018
volve exhaustive multistep procedures. The main route to
aminofurazans is based on the cyclodehydration of vicinal
dioximes (glyoximes), which in turn are prepared through a
two-step sequence from the corresponding methylene-ac-
tive nitriles (Scheme 1).8a Also, a one-pot procedure for the
preparation of aminofurazans through the intermediate
formation of aminoglyoximes by cascade reactions of 1,3-
keto esters has been developed.9 However, the cyclodehy-
dration step is usually performed by refluxing the initial
glyoxime in a high boiling solvent (100–150 °C) in the pres-
ence of a strong base. Various activating reagents including
Ac2O,10 SOCl2,11 succinic anhydride12 and urea9 have been
reported to facilitate this cyclization, but temperatures
greater than 100 °C are typically required. Recently, 1,1′-
carbonyldiimidazole was utilized for the preparation of
aminofurazans from the corresponding pre-synthesized
aminoglyoximes at ambient temperature.13 Aminoglyoxim-
es can also be used for the synthesis of aminofuroxans via
oxidation reactions. Oxidation of aminoglyoximes with
DOI: 10.1055/s-0037-1611056; Art ID: ss-2018-t0462-op
Abstract A facile and chemoselective SnCl2-mediated mild reduction
of regioisomeric 3- and 4-nitrofuroxans for the synthesis of amino-
furazans and aminofuroxans in good yields is developed. Reduction of
4-nitrofuroxans results in the selective formation of 4-aminofuroxans,
while analogous reduction of 3-nitrofuroxans affords 3-aminofurazans
as a result of simultaneous reduction of the nitro group and exocyclic
N–O bond.
Key words furoxans, furazans, reduction, heterocycles, chemoselec-
tivity
1,2,5-Oxadiazoles (furazans) and their N-oxides (furoxans)
have found myriad applications in organic and medicinal
chemistry, materials science, etc.1 The 1,2,5-oxadiazole ring
is a valuable scaffold in the design of promising drug candi-
dates with antibacterial,2 antiparasitic3 and cytotoxic4
activities. In addition, furoxan derivatives possess antiplate-
let5 and cardiovascular6 properties due to their ability to
facilitate exogenous NO release. The special interest in
1,2,5-oxadiazole chemistry is also attributed to the con-
struction of high-energy systems incorporating additional
nitrogen–oxygen explosophoric fragments.7 This is con-
nected with the aromaticity and planarity of the 1,2,5-oxa-
diazole subunit resulting in high density of furazan- and
furoxan-containing derivatives. Moreover, in contrast to
other nitrogen-containing heterocycles, furazans and
furoxans possess ‘active’ oxygen atoms that are not bonded
to hydrogen or carbon atoms and these atoms are therefore
able to undergo oxidation in combustion or explosive de-
gradation processes.
14
14a
Br2 or K3Fe(CN)6 results in the regioselective formation
of 3-amino-4-arylfuroxans, which can be thermally isom-
erized into the corresponding 4-amino isomers on heating
in toluene.14a At the same time, the regioselective synthesis
of 4-aminofuroxans can be achieved through the Schmidt
rearrangement of acetylfuroxans15 and the Curtius rear-
rangement of azidocarbonylfuroxans.16 However, both
NOH
NH2
R
R
1. [NO+]
R
NH2
– H2O
2. NH2OH
N
N
CN
NOH
[O]
O
NH2
NH2
R
R
D
Aminofurazans and aminofuroxans are especially im-
portant precursors for the synthesis of various pharmaco-
logically oriented or high-energy systems.8 However, meth-
ods for the synthesis of amino-1,2,5-oxadiazoles usually in-
N
N
N
N
O
O
O
O
Scheme 1 Known methods for the synthesis of aminofurazans and
aminofuroxans
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
L. L. Fershtat et al.
Paper
Synthesis
Na
R
NO2
R
NO2
O
NaCH(NO2)2
(2 equiv)
HON
R
NOH
NOH
Cl
NOO Na
NO2
O
NaNO2
NCS
DMF
N
N
PhMe
R
N
N
N
N
AcOH/AcONa
NO2
R
– NaNO2
D, 3 h
O
O
O
O
R
NO2
1 (61–84%)
2 (95–99%)
R = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c), 4-EtOC6H4 (d), 3,4-(MeO)2C6H3 (e), 2-FC6H4 (f)
3-FC6H4 (g), 4-FC6H4 (h), 4-ClC6H4 (i), 2-BrC6H4 (j), 4-BrC6H4 (k), 4-F3CC6H4 (l), Me (m)
Scheme 2 Synthesis of the initial nitrofuroxans
these approaches suffer from a narrow substrate scope and
require preliminary multistep preparations of the corre-
sponding functionally substituted furoxans.
imes with dinitromethane sodium salt and subsequent ni-
trosation of the dinitromethyl derivatives and in situ intra-
molecular cyclization.18 3-Nitrofuroxans 1 are obtained in
high yields in one synthetic step, do not require additional
purification and can be quantitatively isomerized into the
4-nitrofuroxans 2. Following this method, we prepared a
series of 3- and 4-nitrofuroxans in good to high yields
(Scheme 2).
4-Nitro-3-phenylfuroxan (2a) was chosen as a model
substrate to optimize the reaction conditions. The reduc-
tion of the nitrofuroxan 2a to the aminofuroxan 3a by SnCl2
has a single literature precedent described by Wieland in
1903.19 Indeed, our attempt to reproduce this procedure re-
sulted in target aminofuroxan 3a, albeit in a low yield. In
addition, furoxanylhydroxylamine 4a as an intermediate
Herein, we report a chemoselective N-oxide-controlled
SnCl2-mediated mild reduction of nitrofuroxans for the
synthesis of aminofurazans and aminofuroxans. Reduction
of 4-nitrofuroxans with SnCl2/HCl results in the regio- and
chemoselective formation of 4-aminofuroxans, while anal-
ogous reactions of 3-nitrofuroxans afford 3-aminofurazans.
Recent achievements in the chemistry of furoxans have
enabled a direct access to 3- and 4-nitrofuroxans 1 and 2.17
For the synthesis of 3-nitrofuroxans, we used our recently
developed approach based on the cascade one-pot reac-
tions of aldoximes. This approach includes chlorination of
the initial aldoximes, acylation of the intermediate chlorox-
Table 1 Optimization of the Reaction Conditionsa
Ph
NHOH
Ph
NO2
Ph
NH2
Ph
NH2
reducing agent
+
+
N
N
N
N
N
N
solvent
temperature
HON
NOH
O
O
O
O
O
O
2a
3a
4a
5a
Entry
Reducing agent (equiv) Additive
Solvent
T ( °C)
Time (h)
Yield (%)b
3a
4a
5a
tracec
1
2
SnCl2 (5.0)
SnCl2 (5.0)
SnCl2 (5.0)
SnCl2 (6.0)
SnCl2 (8.0)
SnCl2 (10.0)
SnCl2 (13.0)
SnCl2 (5.0)
SnCl2 (2.5)
SnCl2 (10.0)
SnCl2 (10.0)
Zn (5.0)
HCl
–
50 → 20
5 → 20
20
1
2
12
26
45
62
84
98
95
–
5
HCl
–
20
10
17
6
–
3
HCl
–
1
–
4
HCl
–
20
1
–
5
HCl
–
20
1
–
6
HCl
–
20
1
–
–
7
HCl
–
20
1
–
–
8
–
EtOH
EtOH
–
40
0.5
1
–
81
20
–
9
HCl
20
35
–
17
67
10
11
12
13
50% H2SO4
CF3COOH
HCl
20
3
e
e
e
–
20
24
2
–
–
–
–
–
HFIP
20
7
39
–
Na2S2O4 (3.0)d
–
EtOH/H2O
20
4
tracec
a Reaction conditions: 4-nitrofuroxan 2a (1 mmol), reducing agent, concd HCl as an additive (7 mL), solvent (5 mL), stirring at the appropriate temperature.
b Yield of isolated products.
c According to 1H NMR spectroscopy.
d Total decomposition of 4-nitrofuroxan 2a was observed.
e No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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L. L. Fershtat et al.
Paper
Synthesis
product and aminoglyoxime 5a as a result of furoxan ring
reduction were also formed as side products (Table 1, entry
1). Performing an analogous reaction at lower temperature
afforded a mixture of amine 3a and hydroxylamine 4a in
nearly equimolar amount (Table 1, entry 2), while the reac-
tion at room temperature increased the 3a/4a ratio to 4.5:1
(Table 1, entry 3). A gradual increase of the amount of SnCl2
provided higher yields of 4-aminofuroxan 3a with 10
equivalents of SnCl2 being the best (Table 1, entries 4–7). In-
terestingly, replacing HCl with EtOH resulted in the selec-
tive formation of aminoglyoxime 5a in a good yield (Table 1,
entry 8), while the HCl/EtOH combination afforded a mix-
ture of all three products (Table 1, entry 9). Surprisingly, the
utilization of 50% H2SO4 afforded hydroxylamine 4a as the
sole product (Table 1, entry 10), while CF3COOH was inef-
fective (Table 1, entry 11). The use of either zinc20a or sodi-
um dithionite20b to reduce the nitro group to an amine led
to ring cleavage (Table 1, entries 12 and 13).
With optimized conditions in hand, we next investigat-
ed the substrate scope for the synthesis of 4-aminofurox-
ans. The target 4-aminofuroxans 3a–m were all formed
chemoselectively in good to high yields under very mild
conditions at 20 °C using SnCl2 (10 equiv) in concentrated
HCl. In all cases, the endocyclic and exocyclic N–O bonds of
the heterocyclic subunit were tolerated under these condi-
tions and the furoxan ring remained unchanged. The yields
of 4-aminofuroxans 3b–e bearing electron-donating groups
(alkyl, alkoxy) were higher (88–95%) than those of halogen-
substituted 4-aminofuroxans 3f–k (75–84%). Incorporation
of a strong electron-withdrawing CF3 group on the aromatic
ring afforded target aminofuroxan 3l in a good yield. To our
delight, the reduction of 4-nitrofuroxan 2m bearing an ali-
phatic substituent provided the corresponding aminofurox-
an 3m in 70% yield (Scheme 3).
Surprisingly, analogous reactions of the 3-nitrofuroxans
1a–m did not provide the expected 3-aminofuroxans, but
directly afforded aminofurazans 6a–m in good yields as a
result of the simultaneous reduction of the nitro group and
the N-oxide motif. The yields of aminofurazans 6b–e bear-
ing electron-donating groups (alkyl, alkoxy) were slightly
higher (75–81%) than those of halogen- and CF3-substituted
aminofurazans 6f–l (62–71%). 3-Amino-4-methylfurazan
(6m) was also formed in a good yield upon reduction of the
corresponding 3-nitrofuroxan 1m (Scheme 4). Arguably,
the difference in the chemoselectivity of the reduction of
regioisomeric 3- and 4-nitrofuroxans is attributed to the
position of the N-oxide fragment in the furoxan ring. In 3-
nitrofuroxans, the steric proximity of the nitro group and
the exocyclic oxygen atom enables effective chelation of
both oxygen motifs with SnCl2. However, when the reduc-
tion of the 3-nitrofuroxan 1a was stopped after 10 minutes,
the corresponding 3-aminofuroxan was detected according
1
to TLC and H NMR data. This fact may serve as evidence
that the reduction of the nitro group precedes the reduction
of the N-oxide moiety in 3-nitrofuroxans.
In summary, we have developed a chemoselective N-ox-
ide-controlled reduction of regioisomeric 3- and 4-nitrofu-
roxans under the action of SnCl2/HCl. The reduction of 4-ni-
trofuroxans results in the regio- and chemoselective forma-
tion of 4-aminofuroxans, while the same reaction of 3-
nitrofuroxans directly affords aminofurazans as a result of
the simultaneous reduction of the nitro group and exocyclic
R
NO2
R
NH2
SnCl2
HCl
N
N
N
N
O
O
O
O
2a–m
3a–m
Me
MeO
EtO
Ph
NH2
NH2
N
NH2
NH2
N
N
O
O
N
N
O
N
N
N
O
O
O
O
O
3a (98%)
3b (91%)
3c (88%)
3d (89%)
OMe
MeO
F
F
NH2
NH2
NH2
NH2
F
N
N
N
O
N
N
O
N
O
N
N
O
O
O
O
O
3e (95%)
3f (84%)
3g (81%)
3h (80%)
Cl
Br
F3C
Me
NH2
NH2
NH2
N
NH2
NH2
Br
N
N
N
N
O
O
O
O
N
N
N
N
N
O
O
O
O
O
O
3i (77%)
3j (75%)
3k (78%)
3l (71%)
3m (70%)
Scheme 3 Substrate scope for the reduction of 4-nitrofuroxans
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
L. L. Fershtat et al.
Paper
Synthesis
R
NO2
R
NH2
SnCl2
HCl
N
N
N
N
O
O
O
1a–m
6a–m
Me
MeO
EtO
Ph
NH2
NH2
NH2
NH2
N
N
O
N
N
N
O
N
N
N
O
O
6a (81%)
6b (76%)
6c (75%)
6d (76%)
F
OMe
MeO
F
NH2
NH2
NH2
NH2
F
N
O
N
N
O
N
N
N
N
N
O
O
6e (81%)
6f (71%)
6g (69%)
6h (70%)
Cl
F3C
Br
Me
N
NH2
NH2
NH2
Br
NH2
NH2
N
O
N
N
N
N
O
N
N
N
N
O
6m (60%)
O
O
6i (67%)
6j (68%)
6k (68%)
6l (62%)
Scheme 4 Substrate scope for the reduction of 3-nitrofuroxans
N–O bond. These conditions afford the target products in
good yields and high purities without the need for column
chromatography, thus providing a direct and general access
to amino-1,2,5-oxadiazoles.
Dinitromethane Sodium Salt22
CAUTION! Although we encountered no difficulties during the prepa-
ration and handling of dinitromethane sodium salt, it is a potentially
explosive energetic material which is sensitive to impact and friction.
Mechanical actions of this energetic material, involving scratching or
scraping, must be avoided. Any manipulations must be carried out by
using appropriate standard safety precautions.
All reactions were carried out in well-cleaned, oven-dried glassware
with magnetic stirring. The 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.
Analytical thin-layer chromatography (TLC) was carried out on Merck
25 TLC silica gel 60 F254 aluminum sheets. The visualization of the TLC
plates was accomplished with a UV light source. Melting points were
determined on a Stuart SMP20 apparatus and are uncorrected. IR
spectra were recorded on a Bruker ‘Alpha’ spectrophotometer in the
range 400–4000 cm–1 (resolution: 2 cm–1). 1H, 13C and 19F NMR spec-
tra were recorded on a Bruker AM-300 (300.13, 75.47 and 282.4 MHz,
respectively) spectrometer and referenced to the residual solvent
peak. 14N NMR spectra were measured on a Bruker AM-300 (21.69
MHz) spectrometer using MeNO2 (δ14N = 0.0) as an external standard.
15N NMR spectra were recorded on a Bruker DRX500 instrument (the
frequency for 15N was 50.7 MHz) at room temperature; experiment
times were determined as recommended.21 The chemical shifts are
reported in ppm (δ); multiplicities are indicated by s (singlet), d (dou-
blet), t (triplet), q (quartet), m (multiplet) and br (broad). Coupling
constants, J, are reported in Hertz. Elemental analysis was performed
using a Perkin-Elmer 2400 CHN Analyzer. 3-Nitrofuroxans 1a,b,f,i,k,l
and 4-nitrofuroxans 2a,b,f,i,k,l were prepared according to a de-
scribed procedure.18a
Tetranitromethane (60 mL, 0.5 mol) was added to a solution of nitro-
methane (27 mL, 0.5 mol) in MeOH (150 mL) at room temperature
and under mechanical stirring. The reaction mixture was cooled to –
5 °C (dry ice bath) and a cold solution of NaOH (40 g, 1.0 mol) in
MeOH (500 mL) was added dropwise. After the addition was com-
plete, the mixture was stirred for 1 h at 0 °C. The solid was filtered off
and washed with acetone (6 × 50 mL) and Et2O (2 × 50 mL). The prod-
uct was dried in air as a thin layer for 40 min and kept in a freezer.
The obtained dinitromethane sodium salt can be stored at –20 °C for
at least 4 months without decomposition.
Yield 49.3 g (77%).
3-Nitrofuroxans; General Procedure
NCS (0.29 g, 2.2 mmol) was added to a stirred solution of the corre-
sponding carbaldehyde oxime (22 mmol) in anhydrous DMF (30 mL)
at room temperature. The reaction mixture was heated to 35–40 °C
(to initiate the chlorination), further NCS (2.65 g, 19.9 mmol) was
added and the mixture was cooled to 30 °C. The resulting solution
was stirred at room temperature for 1 h (TLC monitoring), then cooled
to 0 °C and dinitromethane sodium salt (6.2 g, 48.4 mmol) was added.
The mixture was stirred for an additional 30 min and left to stand in a
refrigerator for 36 h. Next, anhydrous AcONa (5.7 g, 70 mmol) was
added portionwise to the reaction mixture at 0–5 °C. The resulting
mixture was stirred for 30 min and then AcOH (35 mL) was added
dropwise at 0–5 °C. NaNO2 (7.59 g, 110 mmol) was added portion-
wise, the reaction mixture was stirred for 30 min at 0–5 °C, then the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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L. L. Fershtat et al.
Paper
Synthesis
cooling bath was removed and stirring was continued at room tem-
perature for 3 h. The reaction mixture was poured into H2O (300 mL)
and stirred for 30 min. The obtained solid was filtered off, washed
with H2O and dried in air.
14N NMR (21.7 MHz, CDCl3): δ = –35.5 (s, NO2).
19F NMR (282.4 MHz, CDCl3): δ = –111.1 (s, F).
Anal. Calcd for C8H4FN3O4: C, 42.68; H, 1.79; N, 18.66. Found: C, 42.51;
H, 1.93; N, 18.79.
4-(4-Methoxyphenyl)-3-nitrofuroxan (1c)
4-(4-Fluorophenyl)-3-nitrofuroxan (1h)
Yield: 4.02 g (77%); yellow solid; mp 82–83 °C; Rf = 0.53 (CHCl3/CCl4,
1:1).
Yield: 4.16 g (84%); pale yellow solid; mp 61–62 °C; Rf = 0.59 (CHCl3/CCl4,
1:1).
IR (KBr): 2972, 2943, 1648, 1584, 1543, 1518, 1469, 1438, 1401, 1346,
IR (KBr): 2884, 2780, 1627, 1523, 1475, 1434, 1360, 1341, 1232, 1162,
1291, 1253, 1051, 1009, 878, 848, 773 cm–1
.
1105, 1012, 984, 848, 782 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.91 (s, 3 H, CH3), 7.07 (d, J = 8.9 Hz, 2
H, ArH), 7.67 (d, J = 8.9 Hz, 2 H, ArH).
13C NMR (75.5 MHz, CDCl3): δ = 55.6, 114.5, 115.8, 126.4, 130.6, 150.9,
1H NMR (300 MHz, CDCl3): δ = 7.26–7.31 (m, 2 H, ArH), 7.73–7.77 (m,
2 H, ArH).
13C NMR (75.5 MHz, CDCl3): δ = 116.5 (d, J = 22.4 Hz), 120.0 (d, J = 3.4
Hz), 126.6, 131.4 (d, J = 9.0 Hz), 150.4, 165.0 (d, J = 254.4 Hz).
14N NMR (21.7 MHz, CDCl3): δ = –35.1 (s, NO2).
19F NMR (282.4 MHz, CDCl3): δ = –107.0 (s, F).
162.7.
14N NMR (21.7 MHz, CDCl3): δ = –38.4 (s, NO2).
Anal. Calcd for C9H7N3O5: C, 45.58; H, 2.97; N, 17.72. Found: C, 45.49;
H, 3.09; N, 17.88.
Anal. Calcd for C8H4FN3O4: C, 42.68; H, 1.79; N, 18.66. Found: C, 42.59;
H, 1.63; N, 18.77.
4-(4-Ethoxyphenyl)-3-nitrofuroxan (1d)
Yield: 4.20 g (76%); yellow solid; mp 76–77 °C; Rf = 0.52 (CHCl3/CCl4,
1:1).
4-(2-Bromophenyl)-3-nitrofuroxan (1j)
Yield: 5.22 g (83%); pale yellow solid; mp 74–76 °C; Rf = 0.61 (CHCl3/CCl4,
1:1).
IR (KBr): 2980, 2945, 1652, 1580, 1545, 1520, 1472, 1432, 1400, 1348,
1296, 1250, 1050, 1015, 850, 775 cm–1
.
IR (KBr): 2895, 2835, 2797, 1645, 1592, 1540, 1513, 1445, 1413, 1346,
1H NMR (300 MHz, DMSO-d6): δ = 1.38 (t, J = 6.9 Hz, 3 H, CH3), 4.14 (q,
J = 6.9 Hz, 2 H, OCH2), 7.13 (d, J = 8.6 Hz, 2 H, ArH), 7.71 (d, J = 8.6 Hz,
2 H, ArH).
1268, 1202, 1058, 1027, 1004, 845, 790, 756 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.50–7.62 (m, 3 H, ArH), 7.75–7.81 (m,
1 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 15.0, 64.0, 115.0, 116.9, 128.4,
13C NMR (75.5 MHz, CDCl3): δ = 123.4 (2 C), 125.9, 128.0, 131.3, 133.3
131.5, 152.8, 161.6.
(2 C), 151.1.
14N NMR (21.7 MHz, CDCl3): δ = –39.3 (s, NO2).
14N NMR (21.7 MHz, DMSO-d6): δ = –36.2 (s, NO2).
Anal. Calcd for C10H9N3O5: C, 47.81; H, 3.61; N, 16.73. Found: C, 47.94;
H, 3.48; N, 16.59.
Anal. Calcd for C8H4BrN3O4: C, 33.59; H, 1.41; N, 14.69. Found: C,
33.73; H, 1.29; N, 14.82.
4-(3,4-Dimethoxyphenyl)-3-nitrofuroxan (1e)
4-Methyl-3-nitrofuroxan (1m)
Yield: 4.41 g (75%); orange solid; mp 103–104 °C; Rf = 0.22 (CHCl3/CCl4,
Yield: 1.95 g (61%); white solid; mp 41–42 °C; Rf = 0.44 (CHCl3/CCl4,
1:1).
1:1).
IR (KBr): 2972, 2910, 2870, 1672, 1603, 1540, 1498, 1463, 1430, 1362,
1250, 1190, 1156, 1023, 882, 870, 856, 778 cm–1
.
IR (KBr): 2889, 1637, 1523, 1414, 1387, 1354, 1266, 1129, 988, 852,
807, 716 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.94 (s, 3 H, CH3), 3.98 (s, 3 H, CH3),
7.02 (d, J = 8.4 Hz, 1 H, ArH), 7.23 (s, 1 H, ArH), 7.31 (d, J = 8.4 Hz, 1 H,
ArH).
13C NMR (75.5 MHz, CDCl3): δ = 56.1, 56.2, 111.2, 111.5, 115.9, 122.6,
126.7, 149.4, 150.9, 152.5.
1H NMR (300 MHz, CDCl3): δ = 2.73 (s, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): δ = 13.0, 126.9, 149.7.
14N NMR (21.7 MHz, CDCl3): δ = –37.3 (s, NO2).
Anal. Calcd for C3H3N3O4: C, 24.84; H, 2.08; N, 28.96. Found: C, 24.71;
H, 1.99; N, 29.09.
14N NMR (21.7 MHz, CDCl3): δ = –38.4 (s, NO2).
Anal. Calcd for C10H9N3O6: C, 44.95; H, 3.40; N, 15.73. Found: C, 45.09;
H, 3.27; N, 15.62.
4-Nitrofuroxans 2; General Procedure
A mixture of a 3-nitrofuroxan 1 (10 mmol) in PhMe (25 mL) was heat-
ed at reflux temperature for 3 h. Evaporation of the solvent afforded
the corresponding 4-nitrofuroxan 2 in nearly quantitative yield.
4-(3-Fluorophenyl)-3-nitrofuroxan (1g)
Yield: 4.06 g (82%); pale yellow solid; mp 76–77 °C; Rf = 0.63 (CHCl3/CCl4,
1:1).
3-(4-Methoxyphenyl)-4-nitrofuroxan (2c)18a
IR (KBr): 2873, 2798, 1644, 1627, 1542, 1519, 1462, 1402, 1352, 1242,
1153, 1004, 884, 868, 846, 793, 776 cm–1
.
Yield: 2.35 g (99%); yellow solid; mp 75–76 °C; Rf = 0.53 (CHCl3/CCl4,
1:1).
1H NMR (300 MHz, CDCl3): δ = 7.37 (t, J = 8.1 Hz, 1 H, ArH), 7.45–7.62
(m, 3 H, ArH).
1H NMR (300 MHz, CDCl3): δ = 3.90 (s, 3 H, OCH3), 7.06 (d, 3J = 8.7 Hz,
2 H, ArH), 7.57 (d, 3J = 8.7 Hz, 2 H, ArH).
13C NMR (75.5 MHz, CDCl3): δ = 116.3 (d, J = 24.4 Hz), 119.4 (d,
J = 21.0 Hz), 124.6, 124.9 (d, J = 3.2 Hz), 125.6 (d, J = 8.5 Hz), 130.9 (d,
J = 8.3 Hz), 150.2, 162.6 (d, J = 248.9 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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Synthesis
3-(4-Ethoxyphenyl)-4-nitrofuroxan (2d)18a
1H NMR (300 MHz, CDCl3): δ = 7.49–7.59 (m, 3 H, ArH), 7.77–7.80 (m,
1 H, ArH).
Yield: 2.48 g (99%); yellow solid; mp 87–88 °C; Rf = 0.50 (CHCl3/CCl4,
13C NMR (75.5 MHz, CDCl3): δ = 109.3, 121.8, 124.3, 128.3, 131.7,
1:1).
1H NMR (300 MHz, CDCl3): δ = 1.47 (t, 3J = 6.8 Hz, 3 H, CH3), 4.12 (q,
3J = 6.8 Hz, 2 H, CH2), 7.04 (d, 3J = 8.2 Hz, 2 H, ArH), 7.55 (d, 3J = 8.2 Hz,
2 H, ArH).
133.4, 133.5, 150.0.
14N NMR (21.7 MHz, CDCl3): δ = –35.3 (s, NO2).
Anal. Calcd for C8H4BrN3O4: C, 33.59; H, 1.41; N, 14.69. Found: C,
33.46; H, 1.31; N, 14.92.
3-(3,4-Dimethoxyphenyl)-4-nitrofuroxan (2e)
3-Methyl-4-nitrofuroxan (2m)17b
Yield: 2.59 g (97%); orange solid; mp 92–93 °C; Rf = 0.24 (CHCl3/CCl4,
1:1).
Yield: 1.39 g (96%); white solid; mp 68–69 °C; Rf = 0.48 (CHCl3/CCl4,
IR (KBr): 2965, 2941, 2840, 1614, 1574, 1529, 1494, 1457, 1435, 1368,
1:1).
1262, 1234, 1180, 1142, 1118, 1016, 866, 811, 781 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.50 (s, 3 H, CH3).
1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, CH3), 3.92 (s, 3 H, CH3),
6.98 (d, J = 8.5 Hz, 1 H, ArH), 7.10 (s, 1 H, ArH), 7.16 (d, J = 8.5 Hz, 1 H,
ArH).
Reduction of 3- and 4-Nitrofuroxans; General Procedure
SnCl2 (1.90 g, 10 mmol) was added to a vigorously stirred mixture of
the corresponding nitrofuroxan 1 or 2 (1 mmol) and concd HCl (7 mL)
in one portion at room temperature. The reaction mixture was stirred
for 1 h, then poured into H2O (15 mL) and extracted with EtOAc
(3 × 15 mL). The combined organic layers were washed with brine (30
mL) and dried over MgSO4. The drying agent was removed by filtra-
tion, the solvent was evaporated in vacuo and the residue was tritu-
rated with H2O. The solid product was filtered, washed with cold CH-
Cl3 (2 mL) and dried in air.
13C NMR (75.5 MHz, CDCl3): δ = 56.0, 56.1, 109.2, 110.9, 111.0, 111.3,
122.5, 149.3, 151.9, 158.2.
14N NMR (21.7 MHz, CDCl3): δ = –33.9 (s, NO2).
Anal. Calcd for C10H9N3O6: C, 44.95; H, 3.40; N, 15.73. Found: C, 44.79;
H, 3.32; N, 15.92.
3-(3-Fluorophenyl)-4-nitrofuroxan (2g)
Yield: 2.23 g (99%); pale yellow solid; mp 58–59 °C; Rf = 0.58 (CHCl3/CCl4,
1:1).
4-Amino-3-phenylfuroxan (3a)14a
IR (KBr): 2910, 2726, 1612, 1572, 1509, 1484, 1459, 1367, 1294, 1218,
Yield: 173 mg (98%); beige solid; mp 137–138 °C.
1H NMR (300 MHz, DMSO-d6): δ = 6.39 (br s, 2 H, NH2), 7.52–7.59 (m,
3 H, ArH), 7.81 (d, J = 6.5 Hz, 2 H, ArH).
1110, 1072, 1007, 884, 841, 782 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.42 (m, 3 H, ArH), 7.54–7.62 (m,
1 H, ArH).
13C NMR (75.5 MHz, CDCl3): δ = 108.3, 116.1 (d, J = 24.8 Hz), 119.2 (d,
J = 21.1 Hz), 121.2 (d, J = 8.7 Hz), 124.7 (d, J = 3.4 Hz), 131.0 (d, J = 8.3
Hz), 149.7, 162.6 (d, J = 249.3 Hz).
14N NMR (21.7 MHz, CDCl3): δ = –34.9 (s, NO2).
19F NMR (282.4 MHz, CDCl3): δ = –110.5 (s, F).
4-Amino-3-(4-tolyl)furoxan (3b)14a
Yield: 174 mg (91%); white solid; mp 176–177 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.38 (s, 3 H, CH3), 6.35 (br s, 2 H,
NH2), 7.38 (d, J = 7.8 Hz, 2 H, ArH), 7.74 (d, J = 7.8 Hz, 2 H, ArH).
Anal. Calcd for C8H4FN3O4: C, 42.68; H, 1.79; N, 18.66. Found: C, 42.55;
H, 1.63; N, 18.82.
4-Amino-3-(4-methoxyphenyl)furoxan (3c)
Yield: 182 mg (88%); beige solid; mp 109–110 °C; Rf = 0.31 (CHCl3/EtOAc,
20:1).
3-(4-Fluorophenyl)-4-nitrofuroxan (2h)
IR (KBr): 3425, 3318, 3239, 2973, 2941, 2839, 1636, 1610, 1533, 1485,
1457, 1435, 1399, 1305, 1257, 1180, 1057, 1026, 979, 886, 830 cm–1
.
Yield: 2.21 g (98%); pale yellow solid; mp 69–70 °C; Rf = 0.57 (CHCl3/CCl4,
1:1).
1H NMR (300 MHz, DMSO-d6): δ = 3.83 (s, 3 H, CH3), 6.14 (br s, 2 H,
NH2), 7.10 (d, J = 8.8 Hz, 2 H, ArH), 7.72 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 55.8, 115.0, 118.2, 129.7, 147.0,
IR (KBr): 2926, 2735, 1624, 1567, 1523, 1492, 1439, 1409, 1365, 1298,
1273, 1237, 1162, 1121, 1071, 987, 837, 784 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.32 (m, 2 H, ArH), 7.63–7.66 (m,
155.7, 161.2.
2 H, ArH).
Anal. Calcd for C9H9N3O3: C, 52.17; H, 4.38; N, 20.28. Found: C, 52.04;
H, 4.22; N, 20.45.
13C NMR (75.5 MHz, CDCl3): δ = 108.7, 115.4 (d, J = 3.5 Hz), 116.8 (d,
J = 22.5 Hz), 131.3 (d, J = 8.1 Hz), 148.8, 164.4 (d, J = 255.0 Hz).
14N NMR (21.7 MHz, CDCl3): δ = –34.7 (s, NO2).
19F NMR (282.4 MHz, CDCl3): δ = –106.3 (s, F).
4-Amino-3-(4-ethoxyphenyl)furoxan (3d)
Yield: 197 mg (89%); beige solid; mp 118–119 °C; Rf = 0.24 (CHCl3/EtOAc,
20:1).
Anal. Calcd for C8H4FN3O4: C, 42.68; H, 1.79; N, 18.66. Found: C, 42.87;
H, 1.96; N, 18.52.
IR (KBr): 3398, 3326, 3238, 2978, 2930, 2884, 1638, 1592, 1512, 1464,
1411, 1255, 1186, 1162, 1117, 1046, 966, 840 cm–1
.
3-(2-Bromophenyl)-4-nitrofuroxan (2j)
1H NMR (300 MHz, DMSO-d6): δ = 1.35 (t, J = 7.0 Hz, 3 H, CH3), 4.10 (q,
J = 7.0 Hz, 2 H, OCH2), 6.32 (br s, 2 H, NH2), 7.10 (d, J = 8.8 Hz, 2 H,
ArH), 7.75 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 15.0, 63.9, 109.6, 115.0, 115.3,
129.6, 157.4, 160.2.
Yield: 2.72 g (95%); pale yellow solid; mp 70–71 °C; Rf = 0.60 (CHCl3/CCl4,
1:1).
IR (KBr): 2922, 2856, 1629, 1570, 1516, 1474, 1444, 1362, 1290, 1136,
1072, 1047, 985, 801, 770, 741 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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Synthesis
Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N, 19.00. Found: C,
54.42; H, 4.90; N, 18.84.
Anal. Calcd for C8H6FN3O2: C, 49.24; H, 3.10; N, 21.53. Found: C, 49.13;
H, 3.24; N, 21.66.
4-Amino-3-(3,4-dimethoxyphenyl)furoxan (3e)
4-Amino-3-(4-chlorophenyl)furoxan (3i)14a
Yield: 225 mg (95%); beige solid; mp 178–179 °C; Rf = 0.16 (CHCl3/EtOAc,
Yield: 163 mg (77%); white solid; mp 165–166 °C.
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.41 (br s, 2 H, NH2), 7.63 (d, J = 8.6
Hz, 2 H, ArH), 7.84 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 109.2, 122.2, 129.5, 129.9, 135.3,
IR (KBr): 3393, 3323, 3232, 2981, 2948, 2846, 1619, 1596, 1521, 1487,
1442, 1415, 1357, 1258, 1226, 1196, 1180, 1156, 1093, 1015, 977 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.83 (s, 3 H, CH3), 3.84 (s, 3 H, CH3),
6.36 (br s, 2 H, NH2), 7.15 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (s, 1 H, ArH),
7.40 (d, J = 8.4 Hz, 1 H, ArH).
157.2.
15N NMR (50.7 MHz, DMSO-d6): δ = –329.1 (t, J = 84.9 Hz, NH2), –52.0,
–33.7.
13C NMR (75.5 MHz, DMSO-d6): δ = 56.0, 56.1, 109.6, 111.1, 112.3,
115.2, 121.3, 149.2, 150.7, 157.4.
4-Amino-3-(2-bromophenyl)furoxan (3j)
Anal. Calcd for C10H11N3O4: C, 50.63; H, 4.67; N, 17.71. Found: C,
50.49; H, 4.83; N, 17.88.
Yield: 192 mg (75%); white solid; mp 125–126 °C; Rf = 0.34 (CHCl3/EtOAc,
20:1).
IR (KBr): 3404, 3323, 3232, 2928, 2769, 1636, 1609, 1588, 1492, 1450,
1427, 1355, 1170, 957, 856 cm–1
.
4-Amino-3-(2-fluorophenyl)furoxan (3f)
Yield: 164 mg (84%); white solid; mp 133–134 °C; Rf = 0.40 (CHCl3/EtOAc,
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.35 (br s, 2 H, NH2), 7.51–7.59 (m,
3 H, ArH), 7.84 (d, J = 6.9 Hz, 1 H, ArH).
IR (KBr): 3336, 3241, 3206, 2879, 2814, 1648, 1638, 1578, 1533, 1474,
13C NMR (75.5 MHz, DMSO-d6): δ = 110.8, 124.3, 124.6, 128.8, 133.3,
133.4, 133.5, 157.4.
1457, 1408, 1316, 1208, 1112, 985, 880, 819, 764, 745 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 6.21 (br s, 2 H, NH2), 7.36–7.46 (m,
2 H, ArH), 7.61–7.68 (m, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 113.8 (d, J = 14.6 Hz), 116.9 (d,
J = 20.6 Hz), 125.5 (d, J = 3.3 Hz), 131.6 (d, J = 2.2 Hz), 133.2 (d, J = 8.3
Hz), 143.7, 156.3, 160.3 (d, J = 249.9 Hz).
Anal. Calcd for C8H6BrN3O2: C, 37.53; H, 2.36; N, 16.41. Found: C,
37.39; H, 2.52; N, 16.58.
4-Amino-3-(4-bromophenyl)furoxan (3k)
Yield: 200 mg (78%); white solid; mp 174–175 °C; Rf = 0.31 (CHCl3/EtOAc,
20:1).
19F NMR (282.4 MHz, DMSO-d6): δ = –113.5 (s, F).
Anal. Calcd for C8H6FN3O2: C, 49.24; H, 3.10; N, 21.53. Found: C, 49.40;
H, 3.22; N, 21.29.
IR (KBr): 3384, 3320, 3232, 2873, 1638, 1586, 1491, 1460, 1392, 1305,
1158, 1114, 1072, 1010, 965, 874, 830 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 6.42 (br s, 2 H, NH2), 7.74–7.81 (m,
4 H, ArH).
4-Amino-3-(3-fluorophenyl)furoxan (3g)
Yield: 158 mg (81%); white solid; mp 153–154 °C; Rf = 0.32 (CHCl3/EtOAc,
20:1).
13C NMR (75.5 MHz, DMSO-d6): δ = 109.3, 122.6, 124.0, 130.1, 132.4,
157.2.
IR (KBr): 3423, 3332, 3238, 2729, 1639, 1590, 1499, 1463, 1432, 1276,
Anal. Calcd for C8H6BrN3O2: C, 37.53; H, 2.36; N, 16.41. Found: C,
37.41; H, 2.23; N, 16.60.
1216, 1155, 1097, 987, 884, 784, 684 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 6.45 (br s, 2 H, NH2), 7.40 (t, J = 7.8
Hz, 1 H, ArH), 7.59–7.69 (m, 3 H, ArH).
4-Amino-3-[4-(trifluoromethyl)phenyl]furoxan (3l)
13C NMR (75.5 MHz, DMSO-d6): δ = 109.1, 115.0 (d, J = 24.2 Hz), 117.6
(d, J = 20.9 Hz), 124.2 (d, J = 2.8 Hz), 125.3 (d, J = 9.2 Hz), 131.5 (d,
J = 8.5 Hz), 157.2, 162.4 (d, J = 244.3 Hz).
Yield: 174 mg (71%); white solid; mp 160–161 °C; Rf = 0.41 (CHCl3/EtOAc,
20:1).
IR (KBr): 3388, 3328, 3246, 2943, 2751, 1641, 1593, 1515, 1465, 1403,
19F NMR (282.4 MHz, DMSO-d6): δ = –112.4 (s, F).
1328, 1144, 1113, 1067, 967, 848 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 6.49 (br s, 2 H, NH2), 7.93 (d, J = 8.3
Hz, 2 H, ArH), 8.04 (d, J = 8.3 Hz, 2 H, ArH).
Anal. Calcd for C8H6FN3O2: C, 49.24; H, 3.10; N, 21.53. Found: C, 49.11;
H, 2.92; N, 21.74.
13C NMR (75.5 MHz, DMSO-d6): δ = 109.1, 126.1 (q, J = 3.6 Hz), 127.9
(q, J = 274.5 Hz), 129.0, 129.9 (q, J = 32.1 Hz), 157.2, 160.2.
4-Amino-3-(4-fluorophenyl)furoxan (3h)
Yield: 156 mg (80%); white solid; mp 170–171 °C; Rf = 0.24 (CHCl3/EtOAc,
20:1).
19F NMR (282.4 MHz, DMSO-d6): δ = –62.4 (s, CF3).
Anal. Calcd for C9H6F3N3O2: C, 44.09; H, 2.47; N, 17.14. Found: C,
43.95; H, 2.33; N, 17.38.
IR (KBr): 3425, 3331, 3237, 2927, 2856, 2737, 1638, 1589, 1519, 1467,
1407, 1314, 1251, 1162, 1102, 964, 867, 835 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 6.40 (br s, 2 H, NH2), 7.40–7.46 (m,
2 H, ArH), 7.85–7.90 (m, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 109.3, 116.6 (d, J = 22.2 Hz), 119.7
(d, J = 3.0 Hz), 130.7 (d, J = 8.8 Hz), 157.3, 163.2 (d, J = 248.9 Hz).
19F NMR (282.4 MHz, DMSO-d6): δ = –110.2 (s, F).
4-Amino-3-methylfuroxan (3m)16
Yield: 81 mg (70%); white solid; mp 132–133 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.01 (s, 3 H, CH3), 6.26 (br s, 2 H,
NH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

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Synthesis
3-Amino-4-phenylfurazan (6a)13
19F NMR (282.4 MHz, DMSO-d6): δ = –113.5 (s, F).
Yield: 130 mg (81%); beige solid; mp 96–97 °C.
3-Amino-4-(3-fluorophenyl)furazan (6g)
1H NMR (300 MHz, DMSO-d6): δ = 6.17 (br s, 2 H, NH2), 7.56 (br s, 3 H,
Yield: 124 mg (69%); white solid; mp 110–111 °C; Rf = 0.38 (CHCl3/EtOAc,
ArH), 7.77 (br s, 2 H, ArH).
20:1).
3-Amino-4-(4-tolyl)furazan (6b)9b
IR (KBr): 3450, 3328, 3241, 3071, 2874, 2757, 1637, 1588, 1524, 1475,
1450, 1405, 1307, 1198, 991, 887, 855, 798 cm–1
.
Yield: 133 mg (76%); white solid; mp 142–143 °C; Rf = 0.51 (CHCl3/EtOAc,
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.28 (br s, 2 H, NH2), 7.37–7.46 (m,
1H NMR (300 MHz, DMSO-d6): δ = 2.38 (s, 3 H, CH3), 6.16 (br s, 2 H,
NH2), 7.36 (d, J = 7.4 Hz, 2 H, ArH), 7.67 (d, J = 7.4 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 21.4, 123.1, 128.0, 130.1, 140.5,
1 H, ArH), 7.57–7.65 (m, 3 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 115.1 (d, J = 23.4 Hz), 117.6 (d,
J = 21.0 Hz), 124.5 (d, J = 2.9 Hz), 128.1 (d, J = 8.6 Hz), 131.7 (d, J = 8.4
Hz), 146.4 (d, J = 2.6 Hz), 155.7, 162.7 (d, J = 245.0 Hz).
147.3, 155.7.
19F NMR (282.4 MHz, DMSO-d6): δ = –112.5 (s, F).
3-Amino-4-(4-methoxyphenyl)furazan (6c)9b
Anal. Calcd for C8H6FN3O: C, 53.63; H, 3.38; N, 23.46. Found: C, 53.79;
H, 3.16; N, 23.29.
Yield: 143 mg (75%); beige solid; mp 103–104 °C; Rf = 0.29 (CHCl3/EtOAc,
20:1).
3-Amino-4-(4-fluorophenyl)furazan (6h)9b
1H NMR (300 MHz, DMSO-d6): δ = 3.83 (s, 3 H, CH3), 6.14 (br s, 2 H,
NH2), 7.10 (d, J = 8.9 Hz, 2 H, ArH), 7.72 (d, J = 8.9 Hz, 2 H, ArH).
Yield: 125 mg (70%); white solid; mp 133–134 °C; Rf = 0.42 (CHCl3/EtOAc,
13C NMR (75.5 MHz, DMSO-d6): δ = 55.8, 115.0, 118.2, 129.7, 147.0,
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.22 (br s, 2 H, NH2), 7.36–7.44 (m,
155.7, 161.2.
2 H, ArH), 7.80–7.86 (m, 2 H, ArH).
19F NMR (282.4 MHz, DMSO-d6): δ = –111.1 (s, F).
3-Amino-4-(4-ethoxyphenyl)furazan (6d)
Yield: 156 mg (76%); beige solid; mp 102–103 °C; Rf = 0.36 (CHCl3/EtOAc,
3-Amino-4-(4-chlorophenyl)furazan (6i)9b
20:1).
IR (KBr): 3392, 3336, 3230, 2972, 2924, 2892, 1645, 1588, 1503, 1452,
Yield: 131 mg (67%); beige solid; mp 137–138 °C; Rf = 0.40 (CHCl3/EtOAc,
20:1).
1400, 1274, 1193, 1151, 1105, 1022, 977, 848 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 1.35 (t, J = 6.9 Hz, 3 H, CH3), 4.10 (q,
J = 6.9 Hz, 2 H, OCH2), 6.13 (br s, 2 H, NH2), 7.08 (d, J = 8.6 Hz, 2 H,
ArH), 7.71 (d, J = 8.6 Hz, 2 H, ArH).
1H NMR (300 MHz, DMSO-d6): δ = 6.24 (br s, 2 H, NH2), 7.61 (d, J = 7.4
Hz, 2 H, ArH), 7.79 (d, J = 7.4 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 15.0, 63.8, 115.5, 118.0, 129.7,
3-Amino-4-(2-bromophenyl)furazan (6j)
147.0, 155.7, 160.5.
Yield: 163 mg (68%); white solid; mp 102–103 °C; Rf = 0.32 (CHCl3/EtOAc,
20:1).
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.71; H, 5.28; N, 20.31.
IR (KBr): 3402, 3315, 3220, 2932, 2788, 1621, 1592, 1480, 1438, 1411,
1360, 1188, 942, 832 cm–1
.
3-Amino-4-(3,4-dimethoxyphenyl)furazan (6e)
1H NMR (300 MHz, DMSO-d6): δ = 6.27 (br s, 2 H, NH2), 7.45–7.54 (m,
3 H, ArH), 7.77 (d, J = 7.0 Hz, 1 H, ArH).
Yield: 179 mg (81%); white solid; mp 146–147 °C; Rf = 0.23 (CHCl3/EtOAc,
20:1).
13C NMR (75.5 MHz, DMSO-d6): δ = 124.1, 124.5, 129.2, 133.1, 133.2,
IR (KBr): 3419, 3340, 3083, 3002, 2980, 2944, 2841, 1624, 1596, 1537,
1495, 1462, 1433, 1407, 1303, 1252, 1224, 1175, 1144, 1026, 981,
133.3, 146.2, 155.9.
Anal. Calcd for C8H6BrN3O: C, 40.03; H, 2.52; N, 17.50. Found: C,
39.89; H, 2.69; N, 17.36.
850, 818 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 3.83 (s, 3 H, CH3), 3.85 (s, 3 H, CH3),
6.16 (br s, 2 H, NH2), 7.11 (d, J = 8.4 Hz, 1 H, ArH), 7.28 (s, 1 H, ArH),
7.33 (d, J = 8.4 Hz, 1 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 56.0, 56.1, 111.3, 112.4, 118.2,
121.1, 147.2, 149.4, 150.9, 155.7.
3-Amino-4-(4-bromophenyl)furazan (6k)9b
Yield: 163 mg (68%); white solid; mp 145–146 °C; Rf = 0.40 (CHCl3/EtOAc,
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.24 (br s, 2 H, NH2), 7.71 (d, J = 8.6
Hz, 2 H, ArH), 7.76 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 124.3, 125.2, 130.3, 132.6, 146.7,
Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N, 19.00. Found: C,
54.43; H, 4.89; N, 18.83.
155.7.
3-Amino-4-(2-fluorophenyl)furazan (6f)9b
Yield: 127 mg (71%); white solid; mp 115–116 °C; Rf = 0.47 (CHCl3/EtOAc,
20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.21 (br s, 2 H, NH2), 7.36–7.46 (m,
2 H, ArH), 7.61–7.68 (m, 2 H, ArH).
13C NMR (75.5 MHz, DMSO-d6): δ = 113.8 (d, J = 14.6 Hz), 116.9 (d,
J = 20.6 Hz), 125.4 (d, J = 3.3 Hz), 131.6, 133.1 (d, J = 8.3 Hz), 143.7,
156.3, 160.3 (d, J = 249.9 Hz).
3-Amino-4-[4-(Trifluoromethyl)phenyl]furazan (6l)13
Yield: 143 mg (62%); pale yellow solid; mp 108–109 °C; Rf = 0.36
(CHCl3/EtOAc, 20:1).
1H NMR (300 MHz, DMSO-d6): δ = 6.32 (br s, 2 H, NH2), 7.91 (d, J = 8.3
Hz, 2 H, ArH), 8.00 (d, J = 8.3 Hz, 2 H, ArH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
L. L. Fershtat et al.
Paper
Synthesis
3-Amino-4-methylfurazan (6m)9a
1,2,5-Oxadiazoles, In Comprehensive Heterocyclic Chemistry III;
5
V
o.
l
Katritzky, A. R.; Ramsden, C. A. V.; Scriven, E. F.; Taylor, R. J. K.,
Eds.; Elsevier: Amsterdam, 2008, 316–393. (c) Fershtat, L. L.;
Makhova, N. N. Russ. Chem. Rev. 2016, 85, 1097. (d) Fershtat, L.
L.; Makhova, N. N. ChemMedChem 2017, 12, 622.
Yield: 59 mg (60%); white solid; mp 72–73 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.27 (s, 3 H, CH3), 6.11 (br s, 2 H,
NH2).
(2) Segretti, N. D.; Serafim, R. A. M.; Segretti, M. C. F.; Miyata, M.;
Coelho, F. R.; Augusto, O.; Ferreira, E. I. Bioorg. Med. Chem. Lett.
2016, 26, 3988.
(3) Guglielmo, S.; Cortese, D.; Vottero, F.; Rolando, B.; Kommer, V.
P.; Williams, D. L.; Fruttero, R.; Gasco, A. Eur. J. Med. Chem. 2014,
84, 135.
1-Amino-2-phenylglyoxime (5a)14a
A suspension of the 4-nitrofuroxan 2a (207 mg, 1 mmol) in 95% EtOH
(5 mL) was heated to 40 °C and stirred until complete dissolution of
the starting material had occurred. SnCl2 (0.95 g, 5 mmol) was added
and the mixture was stirred for 15 min, then poured into H2O (100
mL) and extracted with EtOAc (3 × 25 mL). The combined organic lay-
ers were washed with H2O and dried over MgSO4.
(4) (a) Kulikov, A. S.; Larin, A. A.; Fershtat, L. L.; Anikina, L. V.;
Pukhov, S. A.; Klochkov, S. G.; Struchkova, M. I.; Romanova, A.
A.; Ananyev, I. V.; Makhova, N. N. ARKIVOC 2017, (iii), 250.
(b) Stepanov, A. I.; Astrat’ev, A. A.; Sheremetev, A. B.; Lagutina,
N. K.; Palysaeva, N. V.; Tyurin, A. Yu.; Aleksandrova, N. S.;
Sadchikova, N. P.; Suponitsky, K. Yu.; Atamanenko, O. P.;
Konyushkin, L. D.; Semenov, R. V.; Firgang, S. I.; Kiselyov, A. S.;
Semenova, M. N.; Semenov, V. V. Eur. J. Med. Chem. 2015, 94,
237.
(5) (a) Ustyuzhanina, N. E.; Fershtat, L. L.; Gening, M. L.; Nifantiev,
N. E.; Makhova, N. N. Mendeleev Commun. 2016, 26, 513.
(b) Ustyuzhanina, N. E.; Fershtat, L. L.; Gening, M. L.; Nifantiev,
N. E.; Makhova, N. N. Mendeleev Commun. 2018, 28, 49.
(6) (a) Ferioli, R.; Folco, G. C.; Ferretti, C.; Gasco, A. M.; Medana, C.;
Fruttero, R.; Civelli, M.; Gasco, A. Br. J. Pharmacol. 1995, 114,
816. (b) Bohn, H.; Brendel, J.; Martorana, P. A.; Schönafinger, K.
Br. J. Pharmacol. 1995, 114, 1605.
Yield 145 mg (81%); white solid; mp 152–153 °C.
1H NMR (300 MHz, DMSO-d6): δ = 5.38 (br s, 2 H, NH2), 7.22–7.29 (m,
2 H, Ph), 7.33–7.38 (m, 3 H, Ph), 10.06 (s, 1 H, OH), 11.42 (s, 1 H, OH).
4-(Hydroxyamino)-3-phenylfuroxan (4a)
SnCl2 (1.90 g, 10 mmol) was added to a vigorously stirred mixture of
4-nitrofuroxan 2a (207 mg, 1 mmol) and 50% H2SO4 (7 mL) in one
portion at room temperature. The reaction mixture was stirred for 3 h
then poured into H2O (30 mL) and extracted with EtOAc (3 × 15 mL).
The combined organic layers were washed with brine (30 mL) and
dried over MgSO4. The drying agent was removed by filtration, the
solvent was evaporated in vacuo and the residue was triturated with
H2O. The solid product was filtered, washed with cold CHCl3 (2 mL)
and dried in air.
(7) For selected examples, see: (a) Zhang, J.; Shreeve, J. M. J. Am.
Chem. Soc. 2014, 136, 4437. (b) He, C.; Shreeve, J. M. Angew.
Chem. Int. Ed. 2016, 55, 772. (c) Zhang, J.; Mitchell, L. A.; Parrish,
D. A.; Shreeve, J. M. J. Am. Chem. Soc. 2015, 137, 10532.
(d) Lempert, D. B.; Sheremetev, A. B. Chem. Heterocycl. Compd.
2016, 52, 1070. (e) Pagoria, P. F.; Zhang, M.-X.; Zuckerman, N. B.;
DeHope, A. J.; Parrish, D. A. Chem. Heterocycl. Compd. 2017, 53,
760. (f) Fershtat, L. L.; Ovchinnikov, I. V.; Epishina, M. A.;
Romanova, A. A.; Lempert, D. B.; Muravyev, N. V.; Makhova, N.
N. ChemPlusChem 2017, 82, 1315. (g) Fershtat, L. L.; Epishina, M.
A.; Kulikov, A. S.; Ovchinnikov, I. V.; Ananyev, I. V.; Makhova, N.
N. Tetrahedron 2015, 71, 6764.
Yield: 129 mg (67%); white solid; mp 113–114 °C; Rf = 0.14 (CH-
Cl3/EtOAc, 20:1).
1H NMR (300 MHz, DMSO-d6): δ = 7.55–7.62 (m, 3 H, ArH), 7.86 (d,
J = 6.8 Hz, 2 H, ArH), 9.05 (br s, 1 H, OH), 9.50 (br s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): δ = 109.9, 123.0, 127.8, 128.1, 129.4,
130.7, 157.4.
Anal. Calcd for C8H7N3O3: C, 49.74; H, 3.65; N, 21.75. Found: C, 49.59;
H, 3.78; N, 21.92.
Funding Information
(8) (a) Makhova, N. N.; Kulikov, A. S. Russ. Chem. Rev. 2013, 82,
1007. (b) Fischer, D.; Klapoetke, T. M.; Stierstorfer, J. Eur. J. Inorg.
Chem. 2014, 5808. (c) Wei, H.; He, C.; Zhang, J.; Shreeve, J. M.
Angew. Chem. Int. Ed. 2015, 54, 9367. (d) He, C.; Gao, H.; Imler,
G. H.; Parrish, D. A.; Shreeve, J. M. J. Mater. Chem. A 2018, 6,
9391. (e) Fershtat, L. L.; Radzhabov, M. R.; Romanova, A. A.;
Ananyev, I. V.; Makhova, N. N. ARKIVOC 2017, (iii), 140. (f) Shin,
D.-S.; Masciocchi, D.; Gelain, A.; Villa, S.; Barlocco, D.;
Meneghetti, F.; Pedretti, A.; Han, Y.-M.; Han, D. C.; Kwon, B.-M.;
Legnani, L.; Toma, L. Med. Chem. Commun. 2010, 1, 156.
(g) Masciocchi, D.; Villa, S.; Meneghetti, F.; Pedretti, A.;
Barlocco, D.; Legnani, L.; Toma, L.; Kwon, B.-M.; Nakano, S.; Asai,
A.; Gelain, A. Med. Chem. Commun. 2012, 3, 592.
This work was supported by the Russian Foundation for Basic Re-
search (project 18-03-00332) and the Russian President’s Council for
Grants (project MK-1302.2017.3).
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Acknowlegdment
NMR spectra were recorded in the Department of Structural Studies
of Zelinsky Institute of Organic Chemistry, Moscow.
Supporting Information
(9) (a) Sheremetev, A. B.; Shamshina, Yu. L.; Dmitriev, D. E. Russ.
Chem. Bull., Int. Ed. 2005, 54, 1032. (b) Sheremetev, A. B. Russ.
Chem. Bull., Int. Ed. 2005, 54, 1057.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611056.
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(10) (a) Shaposhnikov, S. D.; Pirogov, S. V.; Mel’nikova, S. F.;
Tselinsky, I. V.; Näther, C.; Graening, T.; Traulsen, T.;
Friedrichsen, W. Tetrahedron 2003, 59, 1059. (b) Samsonov, V.
A.; Sal’nikov, G. E.; Genayev, A. M. Russ. Chem. Bull., Int. Ed.
2009, 58, 2369.
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