A green synthesis of nitrones from diamino glyoxime using aldehydes and ketones

Article abstract of DOI:10.1007/s13738-013-0230-8

The reaction of diaminoglyoxime with aldehyde and ketone derivatives in the presence of p-toluene sulphonic acid in H₂O-MeOH mixture at room temperature afforded nitrone derivatives in high yields within 10-140 min. The applicability of ketones in this reaction for the preparation of novel nitrones has been verified. The effect of the temperature on the stability of the structural isomers of the products has been studied by NMR as well. The results showed that, at high temperatures only one product could be observed. The nature of solvent and catalyst were evaluated and found that the strong acids H ₂SO₄ and CF₃SO₃H in protic solvent CH₃OH work well while neither CH₃SO₃H in protic solvent nor p-toluene sulphonic acid in aprotic solvents toluene and THF perform the same reactions.

Full text of DOI:10.1007/s13738-013-0230-8

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0230-8
ORIGINAL PAPER
A green synthesis of nitrones from diamino glyoxime using
aldehydes and ketones
•
Abolghasem Moghimi Rahim Hosseinzadeh Khanmiri
•
•
Ahmad Shaabani Homayoon Hamadani
Received: 15 September 2012 / Accepted: 20 January 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract The reaction of diaminoglyoxime with alde-
hyde and ketone derivatives in the presence of p-toluene
sulphonic acid in H2O–MeOH mixture at room temperature
afforded nitrone derivatives in high yields within
10–140 min. The applicability of ketones in this reaction
for the preparation of novel nitrones has been verified. The
effect of the temperature on the stability of the structural
isomers of the products has been studied by NMR as well.
The results showed that, at high temperatures only one
product could be observed. The nature of solvent and
catalyst were evaluated and found that the strong acids
H2SO4 and CF3SO3H in protic solvent CH3OH work well
while neither CH3SO3H in protic solvent nor p-toluene
sulphonic acid in aprotic solvents toluene and THF perform
the same reactions.
membered ring systems [2–5]. On the other hand, they are
source of new heterocyclic compound via ring opening
reactions [6–8]. Under facial concerted [g4s ? 2s] cyclo-
g
addition reaction, nitrones react with acetylenes and olefins
to yield isoxazolines and isoxazolidines, respectively.
Furthermore, due to the stability of resulting nitroxide
radicals and ease of chemical modification [9], nitrones
have important biological activity [10–12]. Nitrones are not
only useful to understand age-related disease processes but
also serendipitously have proven to be candidate for ther-
apeutics in some cases [13]. A number of reports have
appeared on the chemistry of 1,3-dipolar species, with
special emphasis on their cycloaddition reaction with
multiple bonds [14]. The cycloadducts of di- and tri-ary-
limidazoline-3-oxides [15] with a variety of dipolarophiles
[16–21] give interesting biologically active heterocyclic
compounds [22]. The 1, 3-dipolar cycloaddition of imi-
dazolin-3-oxides was shown to proceed regio- and diaste-
roselectivity and interesting reactions of these adducts
under various conditions such as the double cis elimination
they undergo in the presence of dialkylamines was reported
[23, 24].
Keywords Nitrones Á Diaminoglyoxime Á Benzaldehyde Á
Cyclohexanone Á Condensation Á Acid catalyst
Introduction
Nitrones as the 1,3-dipolar species are valuable interme-
diates in organic synthesis [1]. Thermal cycloaddition
reactions of nitrones with multiple bond systems is an
efficient strategy for providing various heterocyclic five-
The most common procedures for the preparation of
nitrones include oxidation of secondary amines or N,N-
disubstituted hydroxylamine or condensation reaction
between aldehydes or ketones with N-monosubstituted
hydroxylamines [25, 26]. To the best of our knowledge,
there are two known cases in the literature reported by G-Q
Chen et al. [27, 28] in which 3,4-diaminoglyoxime, DAG,
has acted as amine source for the synthesis of nitrones. In
those cases the reaction of benzaldehyde derivatives and
DAG has been carried out in anhydrous ethanol in the
presence of p-toluene sulphonic acid (p-TSA) at 55–65 °C
within 6–28 h. Herein, we wish to extend the previously
published methodology for the preparation of novel
A. Moghimi (&) Á R. H. Khanmiri Á H. Hamadani
Department of Chemistry, Faculty of Science,
Imam Hossein University, Tehran, Iran
e-mail: samoghimi@yahoo.com
R. H. Khanmiri Á A. Shaabani
Department of Chemistry, Faculty of Science,
University of Shahid Beheshti,
Tehran, Iran
123

J IRAN CHEM SOC
nitrones from DAG and cyclic or acyclic ketones and
modify the reaction conditions for both ketones and alde-
hydes. Accordingly, a modified green method for the
reaction of DAG with both benzaldehydes and ketones is
reported in H2O/MeOH mixture at room temperature in the
presence of a strong acid for much shorter reaction times.
However, it was found that the nitrones are prepared in
the presence of p-TSA, as catalyst, under the reaction
conditions applied, as shown in Scheme 2.
The condensation reaction of DAG was initially per-
formed in the absence of p-TSA using benzaldehyde or
cyclohexanone in methanol–water (30:70) mixture at room
temperature and the progress of the reaction was monitored
by TLC. A slow condensation reaction was noticed. Then,
they were performed in the presence of p-TSA and, after
the completion of the reaction, the corresponding nitrones
were isolated as white precipitate within 10–140 min in 83
and 95 %, respectively. It became clear to us that the
anhydrous condition is not mandatory, as was applied
earlier, and the reaction works well in H2O/MeOH solvent
at room temperature. The same procedure was successfully
applied to the other aldehydes (2) and ketones (4) and the
expected nitrones 3a-i and 5a-e were isolated in good
yields (Table 1). It was found that higher yields could be
achieved for the aromatic aldehyde derivatives involving
electron donating group, as shown in Table 1.
Results and discussion
The chemistry of DAG is of great interest because of the
fact that it involves two different reactive functional
groups, amine and oxime, that have been repeated twice.
One or more functional groups in DAG may react, as
expected, with other appropriate functional groups such as
aldehydes in different manners and, therefore, totally dif-
ferent products may result. From the theoretical point of
view, DAG can perform condensation reaction with alde-
hyde and ketone in a number of ways. It can react, for
instance, (1) in 2:1 molar ratio to get a bis-Schiff bases
(I, IV), (2) in 1:1 molar ratio between two NH2 of DAG
and –COH to reach five-membered ring heterocycles
(II, V) and (3) in 1:1 molar ratio between NH2 and oxime
functional groups of DAG and –COH to obtain nitrones
(III, VI) as shown in Scheme 1.
Considering the proposed mechanism by G-Q Chen
et al. for the reaction of DAG and benzaldehyde deriva-
tives, we suggest a similar reaction mechanism for ketones
as shown in the scheme 3. Firstly, the protonated carbonyl
in ketone derivatives is attacked by the nitrogen atom of
one of the amino groups of 3,4-diaminoglyoxime 1, and the
C=N functional group is formed by deprotonation and
dehydration. Subsequently, the nitrogen in the newly
formed C=N bond is protonated, followed by the nucleo-
philic attach by the oxime nitrogen atom, and the five-
membered heterocyclic ring is formed. By deprotonation,
the final products 5(a-e) are obtained.
O
H
N
HON
HON
HON
HON
N
N
H2N
CHAr
CHAr
N
Ar
Ar
N
H
N
H
HON
(I)
(II)
(III)
R1
O
H2N
H
N
H
H
N
N
O
R1
R2
H
H
N
N
O
N
R1
R2
N
N
The structure of nitrones 3(a-i) and 5(a-e) were deter-
mined by IR, 1HNMR, 13CNMR and mass spectra. In the IR
spectra 3(a-i) strong absorption bands at 2,883–2,892 cm-1
can be observed which should be assigned to the C–H in
imidazole ring and 1,450–1,650 cm-1 for the benzene ring.
In addition, in the 13C spectra of nitrones 5(a-e) character-
istic peaks in the 80–100 ppm region can be observed, which
R2
R1
N
O
H N
O
N
H
H
O
R2
(v)
(IV)
(VI)
Scheme 1 Three logically expected products for each of the reaction
of DAG with aldehyde and ketone derivatives
O
O
O
O
,
p-TSA
,
H2N
H2N
NOH
NH2
R2
p-TSA
R1
H2N
H
R3
N
N
R1
R2
2
4
Y
H2O/MeOH (70/30)
rt
H2O/MeOH (70/30)
rt
HON
N
H
N
H
HON
HON
1
3a-i
5a-e
R3: 3-MeC6H4, C6H5, 4- MeOC6H4, 4-ClC6H4, 2- MeOC6H4, 5-Br-2-HOC6H4, 2-ClC6H4, 3- MeOC6H4, CH3
4: Cyclopentanone, Cyclohexanone, Cycloheptanone, 4-tert-butyl cyclohexanone, acetone
Scheme 2 Cyclic functionalized nitrones obtained in the reaction of DAG with aldehydes and ketones
123

J IRAN CHEM SOC
O
N
Table 1 Reaction conditions for the synthesis of nitrones 3a-i and
5a-e in H2O/MeOH(70/30) solvent at room temperature
O
N
H2N
HO
H2N
N
Solvent
Entry Comp. R3
Time
(min)
Yield
(%)a
N
H
N
H
N
OH
(E)
(5b)
(5b)
(Z)
1
3a
3b
3c
3d
3e
3f
3-MeC6H4
120
120
60
90
83
84
81
69
62
70
71
65
90
95
88
94
2
C6H5
3
4-MeOC6H4
4-ClC6H4
O
N
O
N
H2N
H2N
4
10
5
2-MeOC6H4
5-Br-2-HOC6H4
2-ClC6H4
15
O
N
H
N
H
N
N
O
6
110
60
7
3g
3h
3i
8
3-MeOC6H4
CH3
30
Scheme 4 A proposed Z–E isomerization pathway for HO–N=C–NH
segment in 5b
9
140
120
25
10
11
12
13
5a
5b
5c
5d
Cyclopentanone
Cyclohexanone
Cycloheptanone
cyclohexane resonated at 21.2, 22.4, 24.1, 24.3, 34.7,
35.8 ppm. Other carbons were observed at 135.5, 141.8,
143.7 and 150.5 ppm. As noticed for the nitrone products
obtained from aldehyde derivatives, the number of 13C
peak observed for the nitrones resulted from ketones are
almost double of those expected in the static 13C NMR
spectra. This might be due to the Z–E isomerization of
HO–N=C–NH segment via either tautomerization followed
by rotation or nitrogen inversion of the hydroxyimino
group shown for 5b. (Scheme 4) Similar isomerization
pathway could be considered for the other nitrone deriva-
tives 3 and 5.
100
90
4-tert-butyl
cyclohexanone
14
5e
Acetone
70
85
Reaction conditions: DAG (1.0 mmol), aldehyde or ketone
(1.2 mmol), p-TSA (3 mol %), MeOH/H2O (30/70) (3 mL), room
temperature
a
Isolated yield
confirms the presence of spiro carbon of the corresponding
nitrones.
1
The HNMR spectrum of 3b before heating at 100 °C
exhibited characteristic signals for CH imidazole ring at
5.62, 5.77 ppm, NH2 at 6.40, 6.49 ppm, NH at 7.57,
7.83 ppm, NOH at 10.02, 10.23 ppm and CH aryl hydro-
gens in the 7.30–7.56 ppm regions. In the 13CNMR spec-
tra, aromatic carbon atoms resonated at 126.9, 127.0,
127.2, 128.1, 128.9, 129.2, 129.4, 129.7, 129.9, 131.3 ppm.
Other carbons were observed at 140.1, 141.9 and 145.4 and
152.0 ppm. It is worth to note that the expected peak
numbers in 13CNMR spectra are almost double in most of
the cases.
The 1HNMR spectrum of 5b exhibited characteristic
CH2 signals for cyclohexane ring in the 1.19–1.67 ppm
region, NH2 at 5.47, 6.25 ppm, NH at 6.94, 7.76 ppm,
NOH at 9.91, 10.07 ppm. In the 13CNMR spectra, spiro
carbon appeared at 83.7, 97.6 ppm and carbons of cyclic
To investigate the unexpected number of NMR peaks in
the obtained nitrone derivatives, dynamic NMR studies
were undertaken. So, the effect of heat treatment on the 1H
1
NMR and 13C NMR spectra was monitored. The H– and
13C NMR spectra for 3b and 5b showed the presence of
1
two isomers of nitrones at room temperature. The H– and
13C NMR spectra were recorded again after heating the
samples at 100 °C for 1 h and cooling down the sample to
room temperature. As shown in Fig. 1 and 2, only one
isomer was noticed in each case, after heat treatment. This
is probably due to the thermal stability of the Z-isomer over
the E-isomer of nitrone [27, 28]. Based on the chemical
shifts of the observed peaks, after heat treatment, one can
specify which set of peaks in the NMR spectra of Z–E
mixtures are due to each of the isomers. This method has
Scheme 3 The plausible
mechanism for the formation of
2-amino-3-(hydroxyimino)-1,
4-diazaspiro [4.5]dec-1-ene
1-oxide from the reaction of
cyclohexanone and DAG
H2N
HO N
NH2
OH
NH2
N
N
NH2
H
N OH
NH2
-H
-H2O
+H
OH
O
HO N
N OH
HO
N
OH
OH
NH
OH
NH
HO
N
HO
N
H
H
N
N
H
N
H
N
NH2
N
-H
NH2
N
N
NH2
NH2
N
OH
HO
O
OH
123

J IRAN CHEM SOC
Fig. 1 1HNMR spectra of 3b before (a) and after (b) heat treatment
at 100 °C for 1 h
been followed to analyze the NMR spectral data in
‘‘Experimental’’ section.
The reaction of aldehyde 2c and DAG was performed in
the various protic and aprotic solvents to evaluate the role
of the solvent on the reaction. It was found that MeOH and
H2O showed good and low yields, respectively, and their
mixtures showed less yields than MeOH (Table 2), while
no progress was detected in THF or toluene even after
24 h.
In addition, the reaction of 2c and DAG in MeOH/H2O
solvent was investigated in the presence of other acids such
as H2SO4, CF3SO3H and CH3SO3H as the catalyst
(Table 3). It was found that the H2SO4 and CF3SO3H work
better than p-TSA in a much shorter period of time while
the weaker acid CH3SO3H was found to be unreactive.
Fig. 2 1HNMR and 13CNMR spectra of 5b before a and after b heat
treatment at 100 °C for 1 hour
Table 2 Solvent effect on the reaction yield for the condensation
reaction of DAG and 2c in the presence of p-TSA
Conclusions
Entry
Solvent
Time
Yield(%)a
In summary, the present procedure provides an example
of green chemistry methodology for the synthesis of
2,5-dihydro-1H-imidazole 3-oxides and 1,4-diazaspi-
ro[4.n]dec-1-ene 1-oxides (n = 4–6) involving an amine
and an oxime functional groups at 4 and 5 positions in
protic solvent MeOH or H2O/MeOH with high yields
within 1–2 h using p-TSA, H2SO4 or CF3SO3H as catalyst.
The resulting nitrones are highly potent for the preparation
of fused ring heterocyclic compounds by the application of
1,3-dipolar cycloaddition reactions. In addition, the amine
and oxime functional groups in the nitrone derivatives
can be applied for the generation of new fused ring
1
2
3
4
5
6
7
8
H2O
80 min
45 min
24 h
20
88
10
85
84
78
Trace
0
MeOH
EtOH
MeOH/H2O(50/50)
MeOH/H2O(30/70)
MeOH/H2O(20/80)
THF
40 min
60 min
60 min
24 h
Toluene
24 h
Reaction conditions: DAG (1.0 mmol), 4-MeOC6H4 (1.2 mmol),
p-TSA (3 mol %), room temperature
a
Isolated yield
123

J IRAN CHEM SOC
4-Amino-5-(hydroxyimino)-2-(4-methylphenyl)-2,5-
dihydro-1H-imidazole3-oxide(3a)
Table 3 The effect of various acids on the reaction time and yield
Entry
Acid
Time (min)
Yield (%)a
(90 %) white solid, mp 209–210 °C; IR (KBr, cm-1):
3,358, 3,242 (NH2), 3,158, 3,097 (OH), 2,883 (CH-Imid-
azole), 1,716, 1,683 (C=N), 1,602, 1,454 (benzene ring),
1,353 (N=O), 1,226 (C–N), 933,921 (N–O).
1
2
3
4
H2SO4
3
2
89
90
–
CF3SO3H
CH3SO3H
p-TSA
60
60
84
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 3.39
Reaction conditions: DAG (1.0 mmol), 4-MeOC6H4 (1.2 mmol), acid
(3 mol %), MeOH/H2O (30/70) (3 mL), room temperature
(s, 3H, CH3), 5.60, 5.71 (s, H, CH-Imidazole), 6.34, 6.51 (s,
H, NH2), 7.32-7.44 (m, H–Ar), 7.49, 7.76 (s, H, NH), 9.98,
10.20 (s, H, NOH) ppm; 13CNMR (62.5 MHz, DMSO-d6):
81.2, 93.8, 127.2, 128.0, 129.1, 129.3, 134.2, 137.1, 139.0,
141.9, 144.1, 152.0 ppm.
a
Isolated yield
heterocycles. Therefore, they are expected to find impor-
tant applications in the synthesis of novel fused ring sys-
tems. This proposal is under investigation and the results
will be published elsewhere.
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 3.39 (s, 3H,
CH3), 5.60 (s, H, CH-Imidazole), 6.35 (s, H, NH2),
7.33–7.47 (m, H–Ar), 7.47 (s, H, NH), 10.20 (s, H, NOH)
ppm; 13CNMR (62.5 MHz, DMSO-d6): 94.8, 127.8, 128.6,
129.3, 129.5, 137.6, 139.9, 142.9, 153.0 ppm.
In comparison to the previously reported methodology
for the preparation of the under-discussion nitrones there
are some advantages for the current modification including
(1) synthesis of a new class of nitrones with the ketones, (2)
application of a green procedure by the usage of H2O as
solvent, (3) improvement of the reaction yields, (4) appli-
cation of mild reaction conditions and (5) avoiding long
reaction times. Finally, the effect of the Heat treatment on
the stability of the structural isomers of the products has
been studied as well.
4-Amino-5-(hydroxyimino)-2-phenyl-2,5-dihydro-1H-
imidazole 3-oxide (3b)
(83 %) white solid, mp 202–203 °C; IR(KBr, cm-1):
3,355, 3,251 (NH2), 3,183, 3,097 (OH), 2,884 (imidazole
C–H), 1,716, 1,682 (C=N), 1,603, 1,458 (benzene ring),
1,360 (N=O), 1,226 (C–N), 933, 921 (N–O); MS: m/e (%)
206 (M?, 10), 189(M-NH3, 9), 161(20), 139(80), 105
(C6H5CHNH, base peak, 100), 77 (90), 69 (40), 65 (50).
1
Experimental
Z and E isomer: HNMR (250 MHz, DMSO-d6): 5.62,
5.77 (s, H, CH-Imidazole), 6.40, 6.49 (s, H, NH2), 7.30-
7.56 (m, H–Ar), 7.57, 7.83 (s, H, NH), 10.02, 10.23 (s, H,
NOH) ppm; 13C NMR (62.5 MHz, DMSO-d6): 80.2, 93.8,
126.9, 127.0, 127.2, 128.1, 128.9, 129.2, 129.4, 129.7,
129.9, 131.3, 140.1, 141.9, 145.4, 152 ppm.
All the reagent and solvents were obtained from Merck
(Germany) and were used without further purification.
DAG was prepared according to the literature proce-
dure17. Melting points were measured on an Electro-
thermal 9100 apparatus. Mass spectra were recorded on a
FINNIGAN-MAT 8430 mass spectrometer operating at
an ionization potential of 70 eV. 1H and 13C NMR
spectra were recorded on a Bruker DRX-300 Advance
spectrometer at 300.13 and 75.47 MHz, respectively.
NMR spectra were obtained in DMSO-d6 using TMS as
internal standard.
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 5.75 (s, H,
CH-Imidazole), 6.52 (s, H, NH2), 7.43-7.75 (m, H–Ar),
7.87 (s, H, NH), 10.25 (s, H, NOH) ppm. 13C NMR
(62.5 MHz, DMSO-d6): 92.6, 126.6, 127.2, 128.7, 129.1,
129.2, 129.5, 129.9, 132.3, 143.6, 152.3 ppm.
4-Amino-5-(hydroxyimino)-2-(4-methoxyphenyl)-2,5-
dihydro-1H-imidazole 3-oxide (3c)
General procedure for the preparation of nitrones
(84 %) white solid, mp 196-198 °C; IR(KBr, cm-1): 3,395,
3,311 (NH2), 3,167, 3,097 (OH), 2,891 (CH-Imidazole),
1,716, 1,694 (C=N), 1,613,1,515 (benzene ring), 1,372
(N=O), 1,248 (C–N), 937,923 (N–O).
3,4-Diaminoglyoxime (0.12 g, 1 mmol), benzaldehyde
derivatives(1.2 mmol) or ketones (1.2 mmol) and p-tolu-
ene sulphonic acid (p-TSA) (0.034 g, 0.2 mmol) were
added to a solution of water:methanol (70:30, 5 ml), and
the mixture was stirred at room temperature for appropriate
time. The progress of the reaction was monitored by TLC
(ethyl acetate/n-hexane 7:3). Then, the reaction mixture
was filtered off and the precipitate was washed with
methanol–water and dried.
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 3.75,
3.78 (s, 3H, CH3), 5.72, 6.03 (s, H, CH-Imidazole), 6.51, 6.64
(s, H, NH2), 6.96-7.38 (m, H–Ar), 7.38, 7.54 (s, H, NH), 9.94,
10.21 (s, H, NOH) ppm; 13CNMR (62.5 MHz, DMSO-d6):
55.94, 55.97, 78.9, 88.50, 111.58, 120.68, 127.13, 127.49,
130.81, 130.90, 142.00, 151.83, 153.5, 157.50 ppm.
123

J IRAN CHEM SOC
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 3.76 (s, 3H,
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 5.63,
5.97 (s, H, CH-Imidazole), 6.24, 6.36 (s, H, NH2),
7.94–8.72 (m, H–Ar, NH), 10.21, 10.35 (s, H, NOH),
12.94, 13.26 (s, 1H, OH) ppm; 13CNMR (62.5 MHz,
DMSO-d6): 56.50, 84.6, 93.7, 116.7, 118.51, 120.12,
121.42, 126.5, 128.7, 129.3, 130.7, 131.9, 142.0, 152.0,
159.4, 161.13 ppm.
CH3), 5.71 (s, H, CH-Imidazole), 6.65 (s, H, NH2),
6.94–7.29 (m, H–Ar), 7.40 (s, H, NH), 10.23 (s, H, NOH)
ppm; 13CNMR (62.5 MHz, DMSO-d6): 55.44, 88.53,
113.54, 121.48, 127.17, 128.49, 130.81, 131.90, 142.20,
152.83, 157.50 ppm.
1
4-Amino-5-(hydroxyimino)-2-(4-chlorophenyl)-2,5-
dihydro-1H-imidazole 3-oxide (3d)
Z-isomer: HNMR (250 MHz, DMSO-d6): 5.95 (s, H,
CH-Imidazole), 6.37 (s, H, NH2), 7.86–8.68 (m, H–Ar,
NH), 10.35 (s, H, NOH), 13.26 (s, 1H, OH) ppm; 13CNMR
(62.5 MHz, DMSO-d6): 56.61, 93.7, 128.7, 129.3, 131.9,
142.0, 152.0, 159.4 ppm.
(81 %) white solid, mp 206–207 °C; IR (KBr, cm-1):
3,365, 3,239 (NH2), 3,182 (OH), 2,883 (CH-Imidazole),
1,716, 1,684 (C=N), 1,599, 1,455 (benzene ring), 1,351
(N=O), 1,229 (C–N), 927 (N–O).
4-Amino-5-(hydroxyimino)-2-(2-cholorophenyl)-2,5-
dihydro-1H-imidazole 3-oxide (3 g)
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 5.60,
5.81 (s, H, CH-Imidazole), 6.40, 6.72 (s, H, NH2), 7.86-
8.28 (m, H–Ar), 8.14, 8.24 (s, H, NH), 10.41, 10.45 (s, H,
NOH) ppm; 13CNMR (62.5 MHz, DMSO-d6): 80.12, 92.9,
128.4, 128.7, 128.9, 129.0, 129.2, 131.7, 134.1, 134.2,
141.8, 147.5, 148.4, 151.9, 166.4 ppm.
(70 %) white solid, mp 205–207 °C; IR(KBr, cm-1):
3,364, 3,241 (NH2), 3,184 (OH), 2,883 (CH-Imidazole),
1,715, 1,682 (C=N), 1,600,1,458 (benzene ring), 1,353
(N=O), 1,231 (C–N), 931 (N–O).
1
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 5.63 (s, H,
Z-isomer: HNMR (250 MHz, DMSO-d6): 6.17 (s, H,
CH-Imidazole), 6.42 (s, H, NH2), 7.82–8.23 (m, H–Ar),
8.11 (s, H, NH), 10.36 (s, H, NOH) ppm; 13CNMR
(62.5 MHz, DMSO-d6): 92.9, 128.4, 128.7, 128.9, 129.0
129.4, 1,134.2, 134.5, 142.8, 148.4, 152.9, 167.4 ppm.
CH-Imidazole), 7.28 (s, H, NH2), 7.40–7.46 (m, H–Ar),
8.14 (s, H, NH), 10.24 (s, H, NOH) ppm; 13CNMR
(62.5 MHz, DMSO-d6): 78.1, 127.9, 130.2, 130.4, 131.4,
133.7, 134.0, 139.3, 145.2 ppm.
4-Amino-5-(hydroxyimino)-2-(2-methoxyphenyl)-2,5-
dihydro-1H-imidazole 3-oxide (3e)
4-Amino-5-(hydroxyimino)-2-(3-methoxyphenyl)-2,5-
dihydro-1H-imidazole 3-oxide(3 h)
(69 %) white solid, mp 196–198 °C; IR(KBr, cm-1):
3,400, 3,264 (NH2), 3,180 (OH), 2,892 (CH-Imidazole),
1,709, 1,687 (C=N), 1,687,1,469 (benzene ring), 1,348
(N=O), 1,220 (C–N), 931 (N–O).
(71 %) white solid, mp 197–199 °C; IR(KBr, cm-1):
3,400, 3,264 (NH2), 3,180 (OH), 2,892 (CH-Imidazole),
1,709, 1,687 (C=N), 1,687,1,469 (benzene ring), 1,348
(N=O), 1,220 (C–N), 931 (N–O).
1
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 3.77,
Z-isomer: HNMR (250 MHz, DMSO-d6): 3.78 (s, 3H,
3.79 (s, 3H, CH3), 5.49, 5.66 (s, H, CH-Imidazole), 6.04,
6.66 (s, H, NH2), 6.98–7.05 (m, H–Ar), 7.23, 7.31 (s, H,
NH), 10.13, 10.17 (s, H, NOH) ppm; 13CNMR (62.5 MHz,
DMSO-d6): 55.11, 79.1, 88.5, 111.6, 120.6, 127.2, 127.5,
130.8, 142.0, 151.8, 157.5 ppm.
CH3), 5.59 (s, H, CH-Imidazole), 6.38 (s, H, NH2),
6.90–7.06 (m, H–Ar), 7.53 (s, H, NH), 10.2 (s, H, NOH)
ppm; 13CNMR (62.5 MHz, DMSO-d6): 56.3, 93.6, 112.5,
114.9, 115.2, 120.1, 129.8, 130.0, 141.9, 158.8 ppm.
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 3.79 (s, 3H,
4-Amino-5-(hydroxyimino)-2-methyl-2,5-dihydro-1H-
imidazole 3-oxide (3i)
CH3), 5.51 (s, H, CH-Imidazole), 6.64 (s, H, NH2), 6.95-
7.04 (m, H–Ar), 7.33 (s, H, NH), 10.14 (s, H, NOH) ppm;
13CNMR (62.5 MHz, DMSO-d6): 55.11, 88.5, 111.6,
120.6, 125.3, 127.2, 127.5, 128.2, 130.8, 131.0, 142.0,
148.2, 151.8, 153.3, 157.5 ppm.
1
(65 %) yellow solid, mp 237–239 °C; HNMR (250 MHz,
DMSO-d6): 1.32–1.34 (d, 3H, CH3), 3.36 (q, H, CH-
Imidazole), 6.32 (s, H, NH2), 7.24 (s, H, NH), 9.91 (s, H,
NOH) ppm.
4-Amino-2-(5-bromo-2-hydroxyphenyl)-5-(hydroxyimino)-
2,5-dihydro-1H-imidazole 3-oxide (3f)
2-Amino-3-(hydroxyimino)-1,4-diazaspiro[4.4]non-1-ene
1-oxide(5a)
(62 %) white solid, mp 173–175 °C; IR(KBr, cm-1):
3,329, 3,285 (NH2), 3,188 (OH), 2,912 (CH-Imidazole),
1,715, 1,685 (C=N), 1,594, 1,495 (benzene ring), 1,354
(N=O), 1,226 (C–N), 934 (N–O).
(90 %) white solid, mp 216 °C; IR (KBr, cm-1): 3,443,
3,324, 3,185, 1,714, 1,684, 1,466, 1,330, 1,193, 1,036, 959.
746. Z and E isomer: 1HNMR (250 MHz, DMSO-d6):
123

J IRAN CHEM SOC
1.57–1.73 (m, 8H, Cyclopentane), 5.49, 6.38 (s, 2H, NH2),
7.14, 7.85 (s, H, NH), 9.92, 10.11 (s, H, NOH) ppm;
13CNMR (62.5 MHz, DMSO-d6): 23.4, 25.1, 36.9, 38.2,
91.0, 107.5, 136.4, 142.3, 144.4, 151.0 ppm.
Z-isomer: 1HNMR (250 MHz, DMSO-d6): 1.57–1.73
(m, 8H, Cyclopentane), 6.39 (s, 2H, NH2), 7.85 (s, H, NH),
9.92 (s, H, NOH), ppm; 13CNMR (62.5 MHz, DMSO-d6):
24.5, 36.3, 90.5, 136.0, 143.9 ppm.
27.58, 32.12, 36.04, 36.19, 36.70, 38.40, 81.04, 99.25,
136.02, 138.8, 146.01, 150.16 ppm.
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 0.88 (s, 9H,
m, Tert-butyl), 1.43 (p, 1H, cyclohexane), 1.39–2.11 (m,
8H, Cyclohexane), 6.43 (s, 2H, NH2), 8.03 (s, H, NH),
10.12 (s, H, NOH) ppm.
4-Amino-5-(hydroxyimino)-2,2-dimethyl-2,5-dihydro-1H-
imidazole 3- oxide(5e)
2-Amino-3-(hydroxyimino)-1,4-diazaspiro[4.5]dec-1-ene-
1-oxide(5b)
(85 %) white solid, mp 217 °C; IR(KBr, cm-1): 3,460,
3,357, 3,187, 2,765, 1,695, 1,636, 1,439, 1,315, 1,191, 947,
718. Z and E isomer: 1HNMR (250 MHz, DMSO-d6): 1.35
(s, 6H, CH3), 5.48, 6.24 (s, 2H, NH2), 6.96, 7.59 (s, H,
NH), 9.85, 10.12 (s, H, NOH) ppm; 13CNMR (62.5 MHz,
DMSO-d6): 25.9, 26.5, 81.0, 97.0, 135.0, 141.8, 143.9,
150.5 ppm.
(95 %) white solid, mp 208–210 °C; IR (KBr, cm-1):
3,318, 3,189, 2,933, 2,867, 2,796, 1,712, 1,695, 1,614,
1,455, 1,383, 1,315, 1,251, 1,167, 936, 753.
Z and E isomer: 1HNMR (250 MHz, DMSO-d6):
1.19–1.67 (m, 10H, Cyclohexane) 5.47, 6.25 (s, 2H, NH2),
6.94, 7.76 (s, H, NH), 9.91, 10.07 (s, H, NOH) ppm;
13CNMR (62.5 MHz, DMSO-d6): 21.2, 22.4, 24.1, 24.3,
34.7, 35.8, 83.2, 97.6, 135.5, 141.8, 143.7, 150.5 ppm.
Z-isomer: 1HNMR (250 MHz, DMSO-d6): 1.19-2.08
(m, 10H, cyclohexane) 5.47 (s, 2H, NH2), 6.94 (s, H, NH),
10.04 (s, H, NOH) ppm; 13CNMR (62.5 MHz, DMSO-d6):
22.4, 24.3, 35.8, 97.6, 141.8, 150.5 ppm.
1
Z-isomer: HNMR (250 MHz, DMSO-d6): 1.39 (s, 6H,
CH3), 6.34 (s, 2H, NH2), 7.64 (s, H, NH), 10.16 (s, H,
NOH) ppm; 13CNMR (62.5 MHz, DMSO-d6): 26.1, 97.3,
142.0, 150.8 ppm.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
2-Amino-3-(hydroxyimino)-1, 4-diazaspiro[4.6]undec-1-
ene-1-oxide (5c)
References
(88 %) white solid, mp 163 °C; IR (KBr, cm-1): 3,374,
3,152, 2,923, 1,684, 1,574, 1,459, 1,317, 1,273, 1,205, 945,
912, 746.
1. E. Colacino, P. Nun, F.M. Colacino, J. Martinez, Tetrahedron 64,
5569 (2008)
2. D. St. C. Black, R. F. Crozier, V. C. Davis, Synthesis 205 (1975)
3. A. Padwa, Angew. Chem., Int Ed Engl 15, 123 (1976)
4. W. Oppolzer, Angew Chem Int Ed Engl 16, 10 (1977)
5. C.P. Dell, J Chem Soc Perkin Trans 1, 3873 (1998)
6. N. Coskun, Turk J Chem 25, 267 (2001)
7. N. Coskun, F.T. Tat, Phosphorus Sulfur 178, 881 (2003)
8. N. Coskun, F.T. Tat, Turk J Chem 28, 1 (2004)
9. L.-C. Li, D.-Z. Liao, L.-J. Bai, Z.-H. Jiang, S.-P. Yan, J Mol
Struct 569, 179 (2004)
10. M.A. Voinov, I.A. Grigorev, L.B.T. Volodarsky, Tetrahedron 56,
4071 (2000)
11. A.R. Green, T. Ashwood, T. Odergren, D.M. Jackson, Pharmacol
Ther 100, 195 (2003)
Z and E isomer: 1HNMR (250 MHz, DMSO-d6):
1.52–2.16 (m, 12H, Cycloheptane), 5.45, 6.23 (s, 2H,
NH2), 7.06, 7.77 (s, H, NH), 9.87, 10.05 (s, H, NOH) ppm.
13CNMR (62.5 MHz, DMSO-d6): 21.3, 21.8, 29.0, 29.7,
39.5, 39.6, 80.5, 101.8, 125.5, 141.9, 144.6, 150.4 ppm.
Z-isomer: 1HNMR (250 MHz, DMSO-d6): 1.61–2.32
(m, 12H, Cycloheptane), 6.26(s, 2H, NH2), 7.79 (s, H, NH),
10.06 (s, H, NOH) ppm. 13CNMR (62.5 MHz, DMSO-d6):
21.8, 29.7, 39.5, 101.8, 141.9, 150.4 ppm.
12. N. Coskun, H. Mert, N. Arikan, Tetrahedron 62, 1351 (2006)
13. R.A. Floyd, Dieases Aging Cell 5, 51 (2006)
14. A. Banerji, A. Sahu, J Sci Ind Res 45, 355 (1986)
15. N. Coskun, D. Su Mengen, Synth Commun 23, 1699 (1993)
16. N. Coskun, Tetrahedron Lett 38, 2299 (1997)
17. N. Coskun, Tetrahedron 53, 13873 (1997)
18. N. Coskun, M. Ay, Heterocycles 48, 537 (1998)
19. N. Coskun, F.T. Tat, O.O. Gu-ven, D. lku, C. Arıcı, Tetrahedron
Lett 41, 5407 (2000)
20. N. Coskun, F.T. Tat, O.O. Gu¨ven, Tetrahedron 57, 3413 (2001)
21. N. Coskun, F.T. Tat, O.O. Gu¨ven, Tetrahedron Asymmetry 12,
1463 (2001)
22. N. Coskun, H. Mert, N. Arikan, Tetrahedron 62, 1351 (2006)
23. N. Coskun, F.T. Tat, O.O. Gu¨ven, D. lku¨, C. Arıcı, Tetrahedron
Lett 41, 5407 (2000)
2-Amino-8-tert-butyl-3-(hydroxyimino)-1,
4-diazaspiro[4.5]dec-1-ene 1-oxide(5d)
(92 %) white solid, mp 220 °C; IR (KBr, cm-1): 3,585,
3,257, 2,954, 2,867, 1,690, 1,478, 1,368, 1,304, 1,249,
1,194, 1,133, 946, 748.
1
Z and E isomer: HNMR (250 MHz, DMSO-d6): 0.84,
0.86 (s, 9H, m, Tert-butyl), 1.28 (p, 1H,CH-cyclohexane),
1.32–2.00 (m, 8H, Cyclohexane), 5.84, 6.27 (s, 2H, NH2),
7.35, 7.96 (s, H, NH), 9.86, 10.03 (s, H, NOH) ppm;
13CNMR (62.5 MHz, DMSO-d6): 18.11, 23.28, 27.43,
123

J IRAN CHEM SOC
24. N. Coskun, F.T. Tat, O.O. Gu¨ven, Tetrahedron 57, 3413 (2001)
25. S.A. Popov, R.V. Andreev, G.V. Romanenko, V.I. Ovcharenko,
V.A. Reznikov, J Mol Struct 49, 697 (2004)
26. Y.B. Han, B. Tuccio, R. Lauricella, A. Rockenbauer, J.L. Zweier,
F.A. Villamena, J Org Chem 73, 2533 (2008)
27. X.-Q. Cao, Z.-X. Li, G.-Q. Chen, D.-C. Zhang, Acta Cryst 63,
671 (2007)
28. X.-Q. Cao, Z.-X. Li, W.-X. Zhong, L.-H. Qiu, G.-Q. Chen,
Heterocycles 78, 1445 (2009)
123