New synthetic approach for the preparation of imidazole N3-oxide

Article abstract of DOI:10.1055/s-2004-831212

A new synthetic procedure of 1-alkyl(aryl)-1H-4-methylimidazole N ³-oxide derivatives by cyclocondensation of α-amineoximes and orthoesters was studied. Low yields in the cyclization process were the result of predominant Z-stereoisomer around the oxime moiety of α-amineoxime reactants. Different attempts to improve these yields were assayed, mild conditions being those that produce the best results. Also, the special acidity of hydrogen-2 in the imidazole N³-oxide system was studied in solution by NMR spectroscopy. This property provides a convenient intermediate to access 2-substituted analogues.

Full text of DOI:10.1055/s-2004-831212

2678
PAPER
New Synthetic Approach for the Preparation of Imidazole N3-Oxide
New
S
ynthetic Ap
u
proach for th
g
e
Preparationoof Imidazole 3
N
-OC
xide erecetto,*a Alejandra Gerpe,a Mercedes González,*a Yolanda Fernández Sainz,b Oscar E. Piro,c
Eduardo E. Castellanod
a
Department of Organic Chemistry, Faculty of Chemistry/Faculty of Sciences, University of the Republic, 11400 Montevideo, Uruguay
Fax +598(2)5250749; E-mail: hcerecet@fq.edu.uy; E-mail: megonzal@fq.edu.uy
b
c
d
Facultad de Ciencias, Pz/Misael Bañuelos s/n, Universidad de Burgos, Burgos, Spain
Department of Physic, University National of La Plata, 1900 La Plata, Argentina
Institute of Physics, University of São Paulo, 13560 São Carlos, Brazil
Received 30 April 2004; revised 2 July 2004
thetic routes from diacetyl monooxime or a-chloroace-
Abstract: A new synthetic procedure of 1-alkyl(aryl)-1H-4-meth-
ylimidazole N3-oxide derivatives by cyclocondensation of a-amine-
oximes and orthoesters was studied. Low yields in the cyclization
process were the result of predominant Z-stereoisomer around the
oxime moiety of a-amineoxime reactants. Different attempts to im-
prove these yields were assayed, mild conditions being those that
produce the best results. Also, the special acidity of hydrogen-2 in
the imidazole N3-oxide system was studied in solution by NMR
spectroscopy. This property provides a convenient intermediate to
access 2-substituted analogues.
tone are depicted in Schemes 1b and 1c, respectively.
a-Amineoximes were obtained by reductive amination of
diacetyl monooxime6 (1–5) or by nucleophilic substitu-
tion of a-chloroacetone with amines followed by oxime
formation with hydroxylamine (16). The first procedure
leads to the desired compounds in discrete yields
(Table 1) without reaction in the case of the weak nucleo-
phile p-nitroaniline (6). The substitution procedure pro-
ceeded with adequate yield only with p-toluidine
(Table 1). In the other cases polyalkylated products were
obtained (14, 15).
Keywords: imidazole N-oxide, cyclization, H-2 acidity
Cyclization of a-amineoximes was initially carried out
with orthoester as solvent in the presence of catalytic
amounts of p-TsOH6 (Method A). However, yields did not
overpass 30% (Table 1) and the reactions were not com-
plete (a-amineoximes were chromatographically ob-
served after 48 h of reflux, longer time of reaction
produced decomposition of the product). During the cy-
The synthesis and chemical reactivity of 1H-imidazole
N3-oxide have been little studied.1–4 Interesting synthetic
procedures were previously described. However, pharma-
cological aspects related with derivatives of this heterocy-
clic system were poorly reported.4 To our knowledge, we
were the first group that studied 1H-imidazole N3-oxide
derivatives as anti-parasitic agents.5
The synthetic routes described until now1,2 for the prepa-
ration of 1H-imidazole N3-oxide derivatives involucrate
electrophile-nucleophile and nucleophile-electrophile
synthons. The electrophile-nucleophile synthons de-
scribed included 1,2-diimines that contribute with the fi-
nal N-1, C-4 and C-5 heterocycle atoms, and a-
oximineketones that contribute with the final N-3, C-4,
and C-5 heterocycle atoms. Besides, the nucleophile-elec-
trophile synthons described were oximes that contribute
with the final C-2 and N-3 heterocycle atoms, and hexahy-
dro-1,3,5-triazines or formaldimines that contribute with
the final N-1 and C-2 heterocycle atoms (Scheme 1a). Ac-
cording to Lettau et al. the desired products were obtained
in low yields due to the low stability of this kind of hetero-
cycles.2a,b
In this work the synthesis of 1-alkyl(aryl)-1H-4-meth-
ylimidazole N3-oxide derivatives involving a bis-nucleo-
phile synthon (a-amineoximes that contribute with the
final N-1, N-3, C-4 and C-5 atoms of the heterocyclic
skeleton) and an electrophile synthon (orthoesters that
contribute with the C-2 portion) is reported. These syn-
SYNTHESIS 2004, No. 16, pp 2678–2684
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831212; Art ID: M03004SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4
Scheme 1 (i) R1NH2/ZnCl2/NaCNBH3/MeOH/r.t. (R1: see Table 1);
(ii) R2C(OR3)3 (R2 = H, CH3; R3 = CH3, CH2CH3)/H+; (iii) 1) R1NH2/
Na2CO3/KI/ acetone/reflux; 2) NH2OH/NaOAc/MeOH/r.t.

PAPER
New Synthetic Approach for the Preparation of Imidazole N3-Oxide
2679
Table 1 a-Amineoxime Intermediates and Imidazole N3-Oxide Developed by Method A
Compound R1
R3
Yield (%)a,b Compound R1
R2
R3
Yield
(%)a,c
1
2
n-butyl
CH3
CH3
CH3
CH3
CH3
CH3
H
24
7
8
CH2CH2Ph
CH2CH2Ph
CH2-furyl
CH2-furyl
Ph-p-OCH3
Ph-p-CH3
Ph-p-CH3
Ph-p-CH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
6
27
NR
21
10
8
CH2CH2Ph
CH2-furyl
Ph-p-OCH3
Ph-p-CH3
Ph-p-NO2
CH2CH2Ph
CH2-furyl
Ph-p-CH3
48
CH3
H
3
46
9
4
32
10
11
12
13
17
CH3
H
5
38
6
NRd
NPe
NP
58
H
14
15
16
CH3
H
10
15
H
H
a Chromatographically isolated products.
b Complete reactions.
c Incomplete reactions.
d NR: No reaction was observed.
e NP: No desired products but only polyalkylated products were obtained.
clization of 1 with methyl orthoformate a dimeric product Alternatively, derivative 12 was also obtained by a proce-
was obtained that was characterized by NMR-HETCOR dure described by Alcázar et al.1 and it was compared with
experiments. Two molecules of 1 were interconnected the product obtained by our method for which chromato-
through the aminic nitrogen of one molecule and the ox- graphic and spectroscopic results were identical.
imic carbon of the other, the free N-aminic and O-oximic
sites were blocked with orthoester units.
The cyclization reactions evolved with improved yields in
the synthesis of 2-methyl derivatives, when ethyl orthoac-
The imidazole N3-oxide formation (7, 8, 10–13 and 17) etate was used as solvent for the reaction (compare deriv-
was confirmed by spectroscopy. Clearly, the 13C NMR, atives 7 with 8, 9 with 10, and 12 with 13). These results
NMR-HETCOR experiments, i.e. HMQC, HMBC, and could indicate that the reflux temperature has an influence
MS permit to endorse the presence of the heterocycle. 13C on the product yield. This fact together with the non-com-
NMR spectra showed the signal that corresponds to C-2 of pleted reaction observation and with previous reports3
the imidazole N3-oxide. The presence of the N-oxide moi- conducted us to propose that the stereoisomeric form of
ety easily became evident from spectroscopic data;7 the the oxime in the a-amineoxime reactants was not ade-
N3-oxide shifts moved to higher fields with respect to the quate for the cyclization, since only the E-isomer is the
imidazole C-2 signals [dC-2 (imidazole) ca. 136 ppm, in spatial form that produced the desired heterocycle.
these derivatives dC-2 (2-non-substituted imidazole N3-ox-
In order to study the proportion of the isomeric forms of
ide) ca. 129–135 ppm and dC-2 (2-CH3 imidazole N3-ox-
the a-amineoxime in solution, we used 1H NMR and 13
C
ide) ca. 143–144 ppm]. The HMQC experiments
permitted an unequivocal assignment for C-2 in the 2-
non-substituted imidazole N3-oxide. HMBC experiments
allowed to confirm that the cyclization process took place.
Figure 1 shows the corresponding HMBC experiments for
derivatives 8 and 11. For derivative 11 it is possible to ob-
serve that H-2 correlates, in the HMBC experiment, with
C-4 and C-5 of the imidazole ring (Figure 1a). In the case
of derivative 8 it is possible to observe correlation be-
tween C-2 and C-5 of the imidazole ring with methylenic
hydrogens of the N1-lateral chain (Figure 1b). The frag-
mentation patterns found in the mass spectrum corrobo-
rated the spectroscopy results described above.
NMR spectroscopy at room temperature.8 As shown in the
examples in Table 2, the oxime reactants exist in solution
predominantly as Z-isomers, the non-reactive form. In all
cases, the proportions of E-isomers were in agreement
with the cyclization product yields. Therefore, this fact
could be the main reason for the low yields during the cy-
clization process.
In order to improve these yields some experimental mod-
ifications were carried out. First, we studied the use of mi-
crowaves as the cyclization energy.9 In this sense,
different experimental conditions were assayed for the
synthesis of derivative 11 (Table 3). The heterocycle was
generated only without any solid support, but in lower
Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York

2680
H. Cerecetto et al.
PAPER
mined by NMR spectroscopy. In addition, suitable
crystals were obtained for X-ray diffraction studies.
Figure 2 displays the ORTEP draw10a showing the label-
ing of the non-H atoms and their displacement ellipsoids
at 30% probability level.
Table 3 Microwave Irradiation Processes
Entrya Catalyst
Period of irradiation Totaltime Yield [%]c
[s]b
[min]
11/18
1
SiO2
30 (first 4 min) and 14
NPd
60 (last 10 min)
2
3
4
5
p-TsOH + SiO2
60
60
14
14
14
15
NP
K10e
NP
f
p-TsOH + Al2O3 60
p-TsOH 180
NP
4g/90
a Reagents: 4 (50 mg) and HC(OCH3)3 (0.5 mL).
b The reaction mixture was irradiated over the period of time indicat-
ed, each period was separated by 1–2 min of absence of irradiation.
c Isolated yield after chromatographic purification.
d NP: formation of imidazole N3-oxide was not chromatographically
observed.
e Montmorillonite K10.
f Neutral aluminum oxide.
g Entry 5 was repeated for the preparation of derivative 12 with 5% of
yield.
Figure 1 HMBC experiments of compounds 8 and 11
In an other attempt to increase the cyclization yields the
use of acetic acid as Z/E isomerization promoting agent
was employed. Our initial approach consisted in the use of
AcOH as the reaction solvent at reflux temperature. Under
these conditions the desired products were generated
(Table 4). However, the number of secondary products
was increased, generating very complex reaction mix-
tures. Mild conditions (room temperature) permitted to
obtain the 1-alkyl(aryl)-1H-4-methylimidazole N3-oxide
derivatives in best yields (Method B, Table 4).
Table 2 Selected a-Amineoximes and Signals Used for the Isomer-
ic Study
4
4′
1
1′
3
2
3′
2′
N
NH R1
N
R1
N
HO
H
O
H
Z
E
Compound
Proportion E:Z
5:95
Chemical shifts (ppm)
1
2
4
5
d
d
d
d
H-3¢ = 3.94, dH-3 = 3.38
H-3¢ = 4.20, dH-3 = 3.45a
H-3¢ = 4.90, dH-3 = 4.07
H-3¢ = 4.94, dH-3 = 4.13b
During the characterization of 2-non-substituted 1H-imi-
dazole N3-oxide (7, 11, 12, and 17) by 1H NMR spectros-
copy an interesting phenomenon was observed. The H-2
signal appeared as a broad singlet and its chemical shift
seemed to be highly dependent of the solvent. As it was al-
ready reported for N-protonated or N-alkylated imidazole
and thiazole these facts indicate that H-2 presents an un-
usual acidity.11 Furthermore, it was described recently
that this property could be used in the 2-functionalization
of azoles by reacting them with an adequate electrophile,
via azolium ylide11 (as hypothesized in Scheme 3 for our
system).
11:89
16:84
18:82
a dC-3¢ = 51.17, dC-3 = 57.34.
b dC-3¢ = 45.99, dC-3 = 53.41
yield than by using Method A (Table 1). Under these con-
ditions a main product, 18, was formed (Scheme 2). Com-
pound 18 could be seen as the result of a fragmentation
process of the cyclization intermediate mediated by mi-
crowaves. The structure of compound 18 has been deter-
Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York

PAPER
New Synthetic Approach for the Preparation of Imidazole N3-Oxide
2681
Scheme 2 Microwave formation and ORTEP diagram of 18
Table 4 Cyclization in Acetic Acid as Solvent
We also present herein the first approach to study the H-2
deprotonation conditions for 2-non-substituted imidazole
N3-oxides. The process was studied by 1H NMR spectros-
copy using isotopic H/D exchange12 at C-2 of the imida-
zolium species at different pHs. We evaluated the
variation on H-2 integration by the action of different
agents and at different times at room temperature (see
Table 5 for studies on derivative 12).
Compound R1
R2
H
Conditions Time
Method A
Yield [%]a
6
5
Clearly it was possible to observe that the H-2 on 2-non-
substituted imidazole N3-oxides was slightly exchange-
able in acidic and neutral aqueous solution at room tem-
perature and exposure during 24 h. If the solution was
slightly basic the H/D exchange increased (Table 5, com-
pare entries 1–3). Increasing the amount of base lead to an
increase of the exchange rate , when the time of exposure
was longer (Table 5, compare entries 4 and 5). However,
if one mole of NaOD per mole of compound 12 was used
the H/D exchange was completed within 5 min at room
temperature (Table 5, entry 6).
7
8
CH2CH2Ph
Reflux
r.t.b
20 h
7 dc
89
27
10
40
8
Method A
Reflux
r.t.b
CH2CH2Ph CH3
20 h
7 dc
Method A
r.t.b
12
13
Ph-p-CH3
Ph-p-CH3
H
20 dc
20 dc
30
10
35
Method A
r.t.b
Table 5 Selected Experiments on H/D Exchange at H-2 of 2-Non-
Substituted Imidazole N3-Oxides
CH3
a Chromatographically isolated products.
b Method B.
Conditionsa
Entry Reagent/Volume [mL]
Time
24 h
H/D exchange [%]
c Incomplete reactions.
1
2
3
4
5
6
DCl (1 M, pH = 1.0)/ 0.1
D2O/0.1
10
20
24 h
K2CO3 (0.05 M)b/0.1c
K2CO3 (0.15 M)b/0.1d
NaOD (0.25 M)b/0.1e
NaOD (0.50 M)b/0.1f
24 h
35
30 min
5 min
5 min
80
15
>98
a Derivative 12 in acetone-d6, standard concentrations were 10 mg/0.5
mL.
b Solution prepared with D2O.
Scheme 3 Acidity of H-2 of 1-alkyl(aryl)-1H-4-methylimidazole
N3-oxide
c Corresponding to 0.1 mole of K2CO3 per mole of 12.
d Corresponding to 0.3 mole of K2CO3 per mole of 12.
e Corresponding to 0.5 mole of NaOD per mole of 12.
f Corresponding to 1.0 mole of NaOD per mole of 12.
Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York

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H. Cerecetto et al.
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1H NMR (CDCl3): d = 1.21 (d, 3 H, J = 6.8 Hz, 4-H both isomers),
1.84 (s, 3 H, 1-H both isomers), 3.43 (q, 1 H, J = 6.8Hz, 3-H Z), 3.68
(dd, 1 H, J1 = 14.5 Hz J2 = 2.5 Hz, HNCH2 both isomers), 3.73 (dd,
1 H, J1 = 14.5 Hz J2 = 2.4 Hz, HNCH2 both isomers), 4.12 (q, 1 H,
J = 7.1Hz, 3-H E), 5.74 (br s, 2 H, OH, NH both isomers), 6.17 (m,
1 H, furyl both isomers), 6.29 (m, 1 H, furyl both isomers), 7.34 (m,
1 H, furyl both isomers).
A new synthetic approach of 1-alkyl(aryl)-1H-imidazole
N3-oxide derivatives involving a-amineoximes as nucleo-
philic synthons and orthoesters as electrophiles was stud-
ied. The heterocycle was obtained in acetic acid at room
temperature. The H-2 acidity of 2-non-substituted 1H-im-
idazole N3-oxide derivatives was studied using H/D ex-
change.
MS (EI, 70 eV): m/z (%) = 182 (M+·, 1), 165 (M+· – 17, 21), 96 (33),
115 (28), 81 (100).
1H NMR, 13C NMR spectra and HETCOR experiments were re-
corded on a BRUKER DPX-400 (400 MHz) spectrometer using the
solvent indicated. Standard concentration of the samples was 20
mg/mL. Chemical shifts are reported in ppm (d) relative to TMS as
an internal standard. MS (EI) were recorded with a GC-MS SHI-
MADZU QP 1100 EX spectrometer operating at 70 eV. IR spectra
were recorded with a SHIMADZU DR-8031 spectrometer as KBr
pellets. Melting points were determined using a Leitz Microscope
Heating Stage Model 350 apparatus and are uncorrected. Elemental
analyses were obtained from vacuum-dried samples (over phospho-
rous pentoxide at 3–4 mm Hg, 24 h at r.t.) and performed on a
Fisons EA 1108 CHNS-O analyzer, and were within 0.4% of the-
oretical values. TLC analyses were carried out on aluminum sheets
silica gel 60 F254. Column chromatography was performed on silica
gel 60 (Merck, 60–230 mesh) with typically 30–50 g of stationary
phase per gram substance.
3-[(p-Methoxyphenyl)amino]butan-2-one Oxime (4)
Yellow oil.
1H NMR (CDCl3): d = 1.37 (d, 3 H, J = 6.8 Hz, 4-H E), 1.38 (d, 3
H, J = 6.8 Hz, 4-H Z), 1.74 (s, 3 H, 1-H E), 1.84 (s, 3 H, 1-H Z), 3.75
(s, 3 H, OCH3 both isomers), 4.07 (q, 1 H, J = 6.8 Hz, 3-H Z), 4.90
(q, 1 H, J = 6.8 Hz, 3-H E), 6.68 (m, 2 H, Ph both isomers), 6.77 (m,
2 H, Ph both isomers), 9.92 (br s, 1 H, NH both isomers), 10.88 (br
s, 1 H, OH both isomers).
MS (EI, 70 eV): m/z (%) = 208 (M+·, 4), 192 (M+· – 17, 1), 107 (100),
101 (20).
3-[(p-Methylphenyl)amino]butan-2-one Oxime (5)
Yellow oil.
1H NMR (CDCl3): d = 1.38 (d, 3 H, J = 6.8 Hz, 4-H E), 1.39 (d, 3
H, J = 6.8 Hz, 4-H Z), 1.76 (s, 3 H, 1-H E), 1.86 (s, 3 H, 1-H Z), 2.25
(s, 3 H, PhCH3 both isomers), 3.65 (br s, 1 H, NH both isomers),
4.13 (q, 1 H, J = 6.8 Hz, 3-H Z), 4.94 (q, 1 H, J = 6.8 Hz, 3-H E),
6.58 (d, 2 H, J = 8.2 Hz, Ph both isomers), 6.98 (d, 2 H, J = 8.2 Hz,
Ph both isomers), 8.07 (br s, 1 H, OH both isomers).
13C NMR (CDCl3): d (both isomers) = 9.71, 15.03, 18.13, 20.19,
20.75, 45.99, 53.41, 113.10, 113.92, 115.78, 127.41, 130.13,
130.30, 145.05, 160.96, 163.00.
Synthesis of a-Aminooximes 1–5; General Procedure
A mixture of butane-2,3-dione oxime (1.00 g, 9.9 mmol), the corre-
sponding amine (14.9 mmol), catalytic amounts of ZnCl2, MeOH
(10 mL) and molecular sieves (4 Å) was stirred at r.t. for 24 h.
NaCNBH3 (0.62 g, 9.9 mmol) was added and the mixture was
stirred at r.t. for 48 h (complete consumption of carbonyl com-
pound). The solvent was removed in vacuo. The residue was dis-
solved in EtOAc (30 mL) and washed with an aq soln of sat.
NaHCO3 (3 × 10 mL). The organic layer was dried (Na2SO4) and
evaporated in vacuo. The residue was purified by column chroma-
tography (petroleum ether–EtOAc, 1:1).
MS (EI, 70 eV): m/z (%) = 192 (M+·, 35), 177 (19), 134 (100), 118
(23), 91 (28).
Synthesis of 1-Alkyl(aryl)-1H-4-methylimidazole N3-Oxides 7,
8, 10–13, 17; General Procedure
3-(Butylamino)butan-2-one Oxime (1)
Colorless oil.
Method A: A mixture of the corresponding a-aminooxime (1.9
mmol), catalytic amounts of p-TsOH and the corresponding ortho-
ester (methyl orthoformate or ethyl orthoacetate) (10 mL) was heat-
ed at reflux for 24 h. Then the solvent was removed in vacuo and the
residue was purified by column chromatography (EtOAc–MeOH,
6:4).
1H NMR (CDCl3): d = 0.92 (t, 3 H, J = 7.2 Hz, CH2CH3 both iso-
mers), 1.22 (d, 3 H, J = 6.7 Hz, 4-H both isomers), 1.35 (m, 2 H,
CH2CH2 both isomers), 1.46 (m, 2 H, CH2CH2 both isomers), 1.85
(s, 3 H, 1-H both isomers), 2.50 (m, 2 H, HNCH2 both isomers),
3.38 (q, 1 H, J = 6.7 Hz, 3-H Z-isomer), 3.94 (q, 1 H, J = 6.9 Hz, 3-
H E-isomer), 7.20 (br s, 2 H, NH, OH both isomers).
Method B: A mixture of the corresponding a-aminooxime (1.9
mmol), the corresponding orthoester (methyl orthoformate or ethyl
orthoacetate) (5.7 mmol) and AcOH (10 mL) was stirred at r.t. for
the time indicated in Table 4. Then the solvent was removed in vac-
uo and the residue was purified by column chromatography
(EtOAc–MeOH, 6:4).
13C NMR (CDCl3): d (Z-isomer) = 9.21, 14.34, 19.80, 20.83, 32.70,
47.62, 57.60, 161.37.
3-[(2-Phenylethyl)amino]butan-2-one Oxime (2)
Yellow oil.
4,5-Dimethyl-1-(2-phenylethyl)-1H-imidazole N3-Oxide (7)
Brown oil.
IR (KBr): 2984, 2870, 1651, 1472, 1235, 1045, 723 cm–1.
1H NMR (methanol-d4): d = 2.04 (s, 3 H, C5CH3), 2.18 (s, 3 H,
C4CH3), 3.00 (t, 2 H, J = 7.3Hz, CH2Ph), 4.05 (t, 2 H, J = 7.3Hz,
NCH2), 7.28 (m, 5 H, Ph), 7.36 (br s, 1 H, 2-H).
13C NMR (methanol-d4): d = 8.56, 12.60, 37.95, 56.14, 122.50,
127.44, 129.04, 129.07, 132.50, 134.81, 137.70.
1H NMR (CDCl3): d = 1.20 (d, 3 H, J = 6.7Hz, 4-H E), 1.22 (d, 3 H,
J = 6.7Hz, 4-H Z), 1.76 (s, 3 H, 1-H E), 1.78 (s, 3 H, 1-H Z), 2.80
(m, 4 H, HNCH2CH2Ph, both isomers), 3.45 (q, 1 H, J = 6.7Hz, 3-
H Z), 4.20 (q, 1 H, J = 6.7Hz, 3-H E), 5.40 (br s, 1 H, NH both iso-
mers), 6.40 (br s, 1 H, OH both isomers), 7.22 (m, 3 H, Ph both iso-
mers), 7.28 (m, 2 H, Ph both isomers).
13C NMR (CDCl3): d (both isomers) = 9.27, 16.14, 18.00, 19.61,
36.47, 48.90, 49.39, 51.17, 57.34, 126.67, 128.84, 129.12, 140.26,
160.14, 160.35.
MS (EI, 70 eV): m/z (%) = 200 (M+· – 16, 100), 138 (28), 111 (42),
105 (47).
MS (EI, 70 eV): m/z (%) = 206 (M+·, 2), 189 (M+· – 17, 1), 132 (10),
115 (28), 91 (9), 56 (100).
Anal. Calcd for C13H16N2O×H2O: C, 66.64; H, 7.74; N, 11.96.
Found: C, 66.80; H, 7.59; N, 11.92.
3-[(2-Furfuryl)amino]butan-2-one Oxime (3)
Yellow oil.
Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York

PAPER
New Synthetic Approach for the Preparation of Imidazole N3-Oxide
2683
2,4,5-Trimethyl-1-(2-phenylethyl)-1H-imidazole N3-Oxide (8)
Brown oil.
13C NMR (methanol-d4): d = 13.26, 21.20, 21.46, 24.85, 118.00,
120.40, 128.00, 129.83, 137.00, 139.50, 144.00.
IR (KBr): 2984, 2870, 1653, 1472, 1258, 1044, 723 cm–1.
MS (EI, 70 eV): m/z (%) = 216 (M+·, 29), 200 (M+· – 16, 100), 144
(40), 91 (40).
1H NMR (methanol-d4): d = 2.00 (s, 3 H, C5CH3), 2.10 (br s, 6 H,
C2CH3, C4CH3), 2.87 (t, 2 H, J = 8.0 Hz, CH2Ph), 3.91 (t, 2 H,
J = 8.0 Hz, NCH2), 7.03 (d, 2 H, J = 7.4 Hz, Ph), 7.26 (m, 3 H, Ph).
Anal. Calcd for C13H16N2O×0.5H2O: C, 69.33; H, 7.56; N, 12.44.
Found: C, 68.99; H, 7.33; N, 12.57.
13C NMR (methanol-d4): d = 9.10, 12.71, 13.26, 37.33, 45.80,
Synthesis of 4-Methyl-1-(p-methylphenyl)-1H-imidazole N3-
Oxide (17)
1-[(p-Methylphenyl)amino]acetone Oxime (16)
121.78, 127.30, 129.13, 129.19, 131.50, 138.07, 142.59.
MS (EI, 70 eV): m/z (%) = 214 (M+· – 16, 98), 123 (100), 104 (31),
82 (21).
A mixture of chloroacetone (2.00 g, 21.0 mmol), p-toluidine (2.30
g, 21.0 mmol), K2CO3 (2.89 g, 21.0 mmol), KI (catalytic amounts)
and acetone (50 mL) was heated at reflux for 10 h. Then the solvent
was removed in vacuo. The residue was dissolved in EtOAc (30
mL) and washed with brine (3 × 10 mL). The organic layer was
dried (Na2SO4) and evaporated in vacuo. The residue (1.40 g, 40%)
was used in the next step without further purification.
1H NMR (CDCl3): d = 2.20 (s, 6 H, PhCH3, COCH3), 2.40 (br s, 1
H, NH), 3.90 (s, 2 H, HNCH2), 6.50 (d, 2 H, J = 8.3 Hz, Ph), 6.90
(d, 2 H, J = 8.3 Hz, Ph).
Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C,
72.66; H, 7.57; N, 11.95.
1-(2-Furylmethyl)-2,4,5-trimethyl-1H-imidazole N3-Oxide (10)
Orange oil.
IR (KBr): 2975, 2870, 1651, 1472, 1208, 1148 cm–1.
1H NMR (methanol-d4): d = 2.11 (s, 3 H, C5CH3), 2.13 (s, 3 H,
C4CH3), 2.39 (s, 3 H, C2CH3), 4.87 (s, 2 H, CH2), 6.10 (d, 1 H,
J = 3.4 Hz, Furyl), 6.29 (d, 1 H, J = 3.4 Hz, Furyl), 7.33 (t, 1 H,
J = 3.4 Hz, Furyl).
13C NMR (methanol-d4): d = 9.17, 12.71, 13.52, 41.07, 107.99,
110.78, 122.23, 131.58, 142.96, 143.03, 150.17.
13C NMR (CDCl3): d = 20.70, 27.80, 55.10, 113.40, 127.50, 130.20,
145.00, 204.80.
MS (EI, 70 eV): m/z (%) = 163 (M+·, 15), 120 (100).
MS (EI, 70 eV): m/z (%) = 190 (M+· – 16, 18), 109 (6), 81 (100).
A mixture of the a-aminocarbonyl compound (0.16 g, 1.0 mmol),
hydroxylamine hydrochloride (0.07 g, 1.0 mmol), NaOAc·3H2O
(0.13 g, 1.0 mmol) and MeOH (5 mL) was stirred at reflux for 1 h
and then at r.t. for 12 h. The solid residue (0.12 g, 67%) was used in
the next step without further purification. Infrared spectroscopy
confirmed the oxime formation.
Anal. Calcd for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C,
63.70; H, 6.90; N, 13.22.
1-(p-Methoxyphenyl)-4,5-dimethyl-1H-imidazole N3-Oxide (11)
Beige oil.
IR (KBr): 2984, 2870, 1647, 1516, 1472, 1256, 1042, 826 cm–1.
4-Methyl-1-(p-methylphenyl)-1H-imidazole N3-Oxide (17)
Beige solid; mp 202.0–203.0 °C (Lit.1b 197.0–199.0 °C).
1H NMR (methanol-d4): d = 2.11 (s, 3 H, C5CH3), 2.24 (s, 3 H,
C4CH3), 3.88 (s, 3 H, OCH3), 7.11 (d, 2 H, J = 6.8 Hz, Ph), 7.36 (d,
2 H, J = 6.8 Hz, Ph), 8.32 (s, 1 H, 2-H).
13C NMR (methanol-d4): d = 6.13, 8.04, 55.18, 115.03, 123.70,
126.30, 127.57, 127.74, 129.09, 161.08.
MS (EI, 70 eV): m/z (%) = 218 (M+·, 100), 202 (M+· – 16, 49), 148
(72), 107 (15).
1H NMR (CDCl3): d = 2.32 (s, 3 H, C4CH3), 2.40 (s, 3 H, PhCH3),
6.89 (s, 1 H, 5-H), 7.20 (d, 2 H, J = 8.5 Hz, Ph), 7.29 (d, 2 H, J = 8.5
Hz, Ph), 8.17 (br s, 1 H, 2-H).
13C NMR (CDCl3): d = 8.50, 21.34, 112.76, 121.04, 124.44, 131.12,
132.26, 135.00, 138.78.
MS (EI, 70 eV): m/z (%) = 188 (M+·, 40), 172 (M+· – 16, 8).
Anal. Calcd for C12H14N2O2×H2O: C, 61.00; H, 6.83; N, 11.86.
Found: C, 60.89; H, 6.64; N, 11.57.
Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.02; H, 6.27; N, 14.48.
4,5-Dimethyl-1-(p-methylphenyl)-1H-imidazole N3-Oxide (12)1c
Crystallographic Study
IR (KBr): 2919, 2849, 1682, 1516, 1456, 1210, 1111, 818 cm–1.
The diffraction pattern of compound 18, C8H9NO2, was collected at
120K on an Enraf-Nonius KappaCCD diffractometer employing
graphite mono-chromate MoKa radiation and j and w scans to ex-
plore the reciprocal space. Data were collected with the program
COLLECT10b and reduced with DENZO and SCALEPACK.10c
Compound 18 crystallizes in the orthorhombic space group Pna21
with a = 10.606(2), b = 7.669(2), c = 9.244(1) Å, and Z = 4. The
structure was solved by direct10d and Fourier10e methods from 1012
reflections with I>2s(I) and refined by full-matrix least-squares10e
to an agreement factor R1 = 0.0534. The H atoms were positioned
stereochemically and refined with the riding model. Phenyl C–C
bond lengths are in the range from 1.375(5) Å to 1.398(4) Å. Single
C(Ph)–N and C(Ph)–O bond distances are 1.414(4) Å and 1.357(4)
Å, respectively. The remaining single N–C and O–C(Me) bond
lengths are 1.330(4) Å and 1.439(4) Å, respectively, and the double
C=O bond distance is 1.229(4) Å. C(Ph)–O–C(Me) and C(Ph)–N–
C bond angles are 116.8(3)° and 126.9(3)°, respectively. Listings of
atomic coordinates and equivalent isotropic displacement parame-
ters, full intra-molecular bond distances and angles, hydrogen coor-
dinates and anisotropic displacement parameters were deposited in
1H NMR (CDCl3): d = 2.08 (s, 3 H, C5CH3), 2.26 (s, 3 H, C4CH3),
2.43 (s, 3 H, PhCH3), 7.13 (d, 2 H, J = 8.2 Hz, Ph), 7.29 (d, 2 H,
J = 8.2 Hz, Ph), 7.89 (br s, 1 H, 2-H).
13C NMR (methanol-d4): d = 7.74, 9.75, 21.49, 122.08, 124.84,
126.09, 127.77, 130.82, 132.88, 139.91.
MS (EI, 70 eV): m/z (%) = 202 (M+·, 30), 186 (M+· – 16, 100), 144
(38), 91 (44).
Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C,
70.95; H, 6.64; N, 13.52.
2,4,5-Trimethyl-1-(p-methylphenyl)-1H-imidazole N3-Oxide
(13)1b
Colorless oil.
IR (KBr): 2920, 2850, 1680, 1515, 1456, 1209, 1110, 810 cm–1.
1H NMR (methanol-d4): d = 1.96 (s, 3 H, C5CH3), 2.16 (s, 3 H,
C4CH3), 2.35 (s, 3 H, PhCH3), 2.44 (s, 3 H, C2CH3), 7.13 (d, 2 H,
J = 8.2 Hz, Ph), 7.39 (d, 2 H, J = 8.2 Hz, Ph).
Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York

2684
H. Cerecetto et al.
PAPER
the Cambridge Crystallographic Data Centre, reference number
CCDC-237524.
López de Ceráin, A.; Ezpeleta, O.; Monge, A. Med. Chem.
Res. 2001, 10, 328.
(7) Alcázar, J.; de la Hoz, A.; Begtrup, M. Magn. Reson. Chem.
1998, 36, 296.
Acknowledgments
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A. Spectrosc.–Int. J. 1988, 6, 33. (b) Wimmer, Z.; Saman,
D. Liebigs Ann. Chem. 1988, 11091. (c) Glaser, R.;
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(d) Fruttero, R.; Ferrarotti, B.; Serafino, A.; Gasco, A.
Liebigs Ann. Chem. 1990, 335.
(9) (a) Louërat, F. Heterocycles 1998, 48, 161. (b) Kidwai, M.;
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26, 289. (c) Cerecetto, H.; González, M.; Onetto, S.; Saenz,
P.; Ezpeleta, O.; López de Ceráin, A.; Monge, A. Arch.
Pharm. (Weinheim, Ger.) 2004, 337, 247.
(10) (a) Johnson, C. K. ORTEP-II. A Fortran Thermal-Ellipsoid
Plot Program Report ORNL-5138; Oak Ridge National
Laboratory: Tennessee USA, 1976. (b) Enraf-Nonius
(1997-2000). COLLECT. Nonius B. V., Delft, The
Netherlands. (c) Otwinowski, Z.; Minor, W. In Methods in
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Academic Press: New York, 1997, 307–326. (d) Sheldrick,
G. M. SHELXS-97. Program for Crystal Structure
Resolution; University of Göttingen: Göttingen Germany,
1997. (e) Sheldrick, G. M. SHELXL-97. Program for
Crystal Structures Analysis; University of Göttingen:
Göttingen Germany, 1997.
(11) (a) Breslow, R.; McNelis, E. J. Am. Chem. Soc. 1959, 81,
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Financial support came from Fondo Clemente Estable (Uruguay).
YFS thanks the ICI-AECI (Spain) for an InterCampus fellowship.
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Synthesis 2004, No. 16, 2678–2684 © Thieme Stuttgart · New York