Synthesis and study of prototropic tautomerism of 2-(2-hydroxyphenyl)-1-hydroxyimidazoles

Article abstract of DOI:10.1016/j.tet.2015.06.032

Novel 2-(2-hydroxyphenyl) substituted imidazoles have been synthesized. A prototropic tautomerism of the 1-hydroxyimidazole derivatives has been studied. X-ray diffraction analysis and IR-spectroscopy have revealed that in the solid state the title compounds exist as the N-hydroxy tautomers. The ¹H and ¹³C NMR spectra of the new imidazole derivatives are discussed. It has been shown that in chloroform solutions 5-carbonyl substituted 2-(2-hydroxyphenyl)-1-hydroxyimidazoles exist in the N-hydroxy tautomeric form. A transition to DMSO results in the existence of the 1-hydroxyimidazoles under study as the N-oxide tautomers.

Full text of DOI:10.1016/j.tet.2015.06.032

Accepted Manuscript
Synthesis and study of prototropic tautomerism of 2-(2-hydroxyphenyl)-1-
hydroxyimidazoles
Polina A. Nikitina, Aleksandr S. Peregudov, Tatiana Yu Koldaeva, Ludmila G.
Kuz’mina, Evgeniy I. Adiulin, Iosif I. Tkach, Valery P. Perevalov
PII:
S0040-4020(15)00901-1
10.1016/j.tet.2015.06.032
TET 26867
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 May 2015
Revised Date: 29 May 2015
Accepted Date: 9 June 2015
Please cite this article as: Nikitina PA, Peregudov AS, Koldaeva TY, Kuz’mina LG, Adiulin EI,
Tkach II, Perevalov VP, Synthesis and study of prototropic tautomerism of 2-(2-hydroxyphenyl)-1-
hydroxyimidazoles, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.032.
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Synthesis and study of prototropic
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hydroxyimidazoles
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a
b
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a
a
P.A.Nikitina , A.S. Peregudov , T.Yu.Koldaeva , L.G. Kuz’mina , E.I. Adiulin , I.I. Tkach and V.P. Perevalov
a
D.I. Mendeleev University of Chemical Technology of Russia, Miusskaya sq., 9, Moscow, 125047, Russia
A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Science, Vavilova str., 28, Moscow, 119991, Russia
b
c
N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science, Leninsky Av., 31, Moscow, 117907, Russia
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O
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1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis and study of prototropic tautomerism of 2-(2-hydroxyphenyl)-1-
hydroxyimidazoles
a,∗
b
a
c
Polina A. Nikitina ,Aleksandr S. Peregudov ,Tatiana Yu. Koldaeva ,Ludmila G. Kuz’mina ,Evgeniy I.
a
a
a
Adiulin , Iosif I. Tkach and Valery P. Perevalov
a
Department of Fine Organic Synthesis and Chemistry of Dyes, D.I. Mendeleev University of Chemical Technology of Russia, Miusskaya sq., 9, Moscow,
1
25047, Russia
b
A.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Science, Vavilova str., 28, Moscow, 119991, Russia
N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science,Leninsky Av., 31, Moscow, 117907, Russia
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Novel 2-(2-hydroxyphenyl) substituted imidazoles have been synthesized. A prototropic
tautomerism of the 1-hydroxyimidazole derivatives has been studied. X-ray diffraction analysis
and IR-spectroscopy have revealed that in the solid state the title compounds exist as the N-
hydroxy tautomers. The H and C NMR spectra of the new imidazole derivatives are
discussed. It has been shown that in chloroform solutions 5-carbonylsubstituted 2-(2-
hydroxyphenyl)-1-hydroxyimidazoles exist in the N-hydroxy tautomeric form. A transition to
DMSO results in the existence of the 1-hydroxyimidazoles under study as the N-oxide
tautomers.
1
13
Available online
Keywords:
Prototropic tautomerism
1
-Hydroxyimidazole
2
009 Elsevier Ltd. All rights reserved.
Imidazole N-oxide
X-ray diffraction
IR spectroscopy
NMR spectroscopy
—
——
∗
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
1
. Introduction
obtained from the X-ray structural analysis data (see, e.g.,
ACCEPTED MANUSCRIPT
19-25 24
papers).
In the report the X-ray data for 1-hydroxyimidazole
1
-Hydroxyimidazole derivatives are known not only as
derivatives were considered with regard to their tautomeric form
stabilization.
1
valuable intermediates in the syntheses of imidazoles but also as
biologically active compounds. For example, it has been shown
that 1-hydroxyimidazole derivatives display insecticidal and
The stabilization of a tautomer in the crystal state is achieved
due to inter- and intra-molecular interactions and depends on a
nature of imidazole ring substituents. Interestingly, it has been
reported that in the molecule of 1,1’-dihydroxy-2,2’-biimidazole
derivative one imidazole ring existed in the N-hydroxy form
while the second imidazole ring was found to occur in the N-
2
3,4
herbicidal properties, exhibit antiprotozoal activity.
It is supposed that 1-hydroxyimidazoles exist in either N-
hydroxy or N-oxide tautomeric form.
25
oxide form.
Previously we have studied the prototropic tautomerism of 2-
23
(3-chromenyl)-1-hydroxyimidazoles.
By X-ray diffraction
analysis it was shown that in the crystal state these compounds
1
exist in the N-oxide tautomeric form. According to the H NMR
spectroscopic data in relatively dilute solutions regardless of their
nature, 4,5-dimethyl-2-chromenyl-1-hydroxyimidazole existed as
the N-hydroxy tautomer. An introduction of the carbonyl group
in position 5 of 1-hydroxyimidazole shifts the equilibrium to the
N-oxide tautomer; in this case the proton-donor (proton-acceptor)
properties of the solvent have an impact on the equilibrium. The
weaker the proton-donor properties of the solvent are, the greater
is the shift of the tautomeric equilibrium in solution to the N-
oxide form.
Scheme 1. Prototropic tautomerism of 1-hydroxyimidazoles.
Studying the prototropic tautomerism for potentially
biologically active compounds constitutes an important part in
5
Drug Discovery. Recently some new studies dealing with
6-9
coordination properties of 1-hydroxyimidazoles have appeared.
Undoubtedly, the data concerning the tautomeric forms of the
compounds under consideration are also important for this line of
investigation.
The prototropic tautomerism of 1-hydroxyimidazoles and their
benzannelated analogues has not been much investigated.
In order to continue study of the 1-hydroxyimidazole
derivatives capable of formation of intramolecular hydrogen
bonds (IMHB) here we present an investigation of 2-(2-
hydroxyphenyl)-1-hydroxyimidazoles with a carbonyl-containing
substituent in position 5 of the heterocycle.
The tautomerism of these compounds was discussed in papers
1
0-15
published in the 1960s.
This discussion was summarized in
15
A.R. Katrizky’s paper in which the results of previous papers
have been considered. It has also been shown by the example of
2
. Results and Discussion
1
-hydroxy-2,4,5-triphenylimidazole and 1-hydroxybenzimidazole
that these compounds existed predominantly as N-
hydroxytautomers in non-polar solvents. An increase in the
solvent polarity resulted in an increase of the N-oxide form
content. The main conclusions were based on the similarity of the
absorption spectra of the compounds under consideration and
some model compounds (N- and O-methyl derivatives), and the
2
.1. Synthesis of compounds
One of the most widespread and convenient methods to
synthesize 1-hydroxyimidazoles is a cyclization of starting
aldehydes with α-hydroxyiminoketones and ammonium
acetate
1,2,4,7,23,24,26-30
in alcohols or glacial acetic acid.
15
comparison of their pKa values in aqueous solutions.
16,17
15
In later papers
the position of coalescent signal in the N
NMR spectra for 1-hydroxybenzimidazole and 2-phenyl-1-
hydroxybenzimidazole made it possible to determine the ratio of
the tautomeric forms in the equilibrium. It was shown that the
equilibrium shifted to the N-oxide tautomer with the decrease of
16
the solvent (DMSO, MeOH, CF CH OH) pKa,
corresponded to the Katrizky’s data.
which
3
2
15
18
However, in Castellano’s paper it was supposed that the
solvent polarity far not always significantly influences on the
1
tautomer ratio. By H NMR spectroscopy it was shown that the
predominance of one or another tautomeric form of 6-nitro- and
6
-ethoxycarbonyl-1-hydroxybenzimidazol-2-carboxylic
acids
derivatives was related to proton-donor (proton-acceptor)
properties of the solvent. The hydrogen-bond-acceptor (HBA)
solvents stabilized the N-hydroxy tautomer, while hydrogen-
bond-donor (HBD) solvents, the N-oxide one. In solvents that
could act as both, the stabilization of one or another form
depended on the acid-base properties. In less polar solvents (such
as chloroform) the predominance of one of the tautomers
18
depended on intramolecular interactions. The prototropic
tautomerism of 1-hydroxybenzimidazoles in the solid state was
also considered by means of IR-spectroscopy and X-ray analysis
Scheme 2. Synthesis of 1-hydroxyimidazoles 1-4.
18
data.
Novel 1-hydroxyimidazole derivatives 1-4 were synthesized
by condensation of salicylic aldehyde 5 with the corresponding
Unambiguous evidence for the occurence of the N-
hydroxyimidazole tautomeric form in the solid state may be

3
oximes 6-9 and ammonium acetate in glacial
A
ac
C
eti
C
c
E
ac
P
id
TED
0- MANUSCRIPT
a
t 4
4
5°C. Starting oximes 7-9 were obtained by nitrosation of the
Methoxyimidazoles were synthesized as model structures for
N-hydroxytautomer. Apparently, N-methoxysubstituted
2
3
corresponding diketones as described earlier. Butanedione
monoxime 6 is commercially available.
imidazoles 15-18 cannot be obtained by direct methylation due to
a possible methylation of the hydroxy group in the phenyl
substituent. Therefore, in order to obtain N-methoxyimidazoles
One of the methods to study prototropic tautomerism is to
compare the spectral data of the compounds under consideration
with a model molecule that has a structure corresponding to a
1
5-18 this group has been protected.
15-18,23,31
32
definite tautomer (see, e.g., papers
and also a review).
1
-Methylimidazole 3-oxides were chosen as model structures
for the N-oxide tautomer. Imidazole N-oxides 10-12 were
obtained by condensation of salicylic aldehyde with
5
corresponding oximes 6-8 and methyl amine (as a 40% aqueous
solution) in ethyl alcohol at room temperature.
Scheme 5. Protection of hydroxyl group.
The condensation of aldehyde 19 with oximes 6-9 and
ammonium acetate in glacial acetic acid led to 2-(2-
benzyloxyphenyl)-1-hydroxyimidazoles 20-23. Technically, in
molecules 20-23 the methylation can proceed either at hydroxyl
in position 1 or at the N(3) nitrogen atom of the imidazole ring. It
is known that the methylation of such structures goes selectively
1
5,18
at the hydroxy group in position 1 (see, e.g., Refs.).
The
methylation of compounds 20-23 was carried out by the
interaction with methyl iodide either in THF in the presence of
sodium hydride (synthesis of 24) or in DMF in the presence of
potassium hydroxide (syntheses of 25-27). N-Methoxyimidazoles
Scheme 3. Synthesis of imidazole N-oxides 10-12.
2
4-27 were the only products of this reaction.
N-Oxide 13 was obtained in two steps. Reaction of salicylic
aldehyde 5 with aqueous solution of methyl amine led to
azomethine 14. The condensation of the latter with oxime 9 in
glacial acetic acid at room temperature resulted in target
compound 13.
The benzyl group of 2-(2-benzyloxyphenyl)-1-
methoxyimidazoles 24-27 was removed by catalytic
hydrogenation with hydrogen on the palladium catalyst in
methanol at room temperature and small excessive pressure.
It should be mentioned that in the case of 5-methyl- and 5-
acetyl-1-methoxyimidazoles 24 and 25 the reduction reaction
resulted in mixture of target N-methoxy derivatives 15 or 16 and
imidazoles 28 or 29 without methoxy groups. A decrease in the
reaction time in the case of compounds 26 or 27 resulted in N-
methoxysubstituted imidazoles 17 and 18 with an admixture of
starting compounds 26 and 27.
Scheme 4. Synthesis of imidazole N-oxide 13.
Scheme 6. Synthesis of 1-methoxyimidazoles 15-18.
1,10-15,23-25
It is supposed (see, e.g., Refs.
hydroxyimidazoles may exist in the two tautomeric forms
Scheme 1). Taking into consideration possible hydrogen
)
that 1-
2
.2. Study of prototropic tautomerism in the solid state.
(

4
Tetrahedron
bonding in the molecules under study, the
A
fo
C
llo
C
w
of
E
ingPTut
E
mo
D
st MAarran
NU
ge
S
m
C
en
R
t (
I
Figure 2). The stacks are running along the a-axis.
P
T
forms of the prototropic tautomers
hydroxyphenyl)substituted 1-hydroxyimidazoles 2-4 could be
proposed:
2-(2-
In a stack the molecules are linked by π-π stacking interactions.
All other intermolecular contacts in crystal packing of 2
correspond to van der Waals interactions.
Scheme 7. Utmost forms of prototropic tautomers of 5-
carbonylsubstituted 2-(2-hydroxyphenyl)-1-
hydroxyimidazoles.
The structure of 5-acetyl substituted 1-hydroxyimidazole 2
was determined by an X-ray diffraction study (Figure 1).The
planar molecule involves two intramolecular hydrogen bonds
O1-H…O2 and O3-H…N2 closing 6-membered cycles. The
O…H and N…H distances correspond to a hydrogen bond of
medium strength.
Figure 2. Fragments of crystal packing of compound 2 in
different projections.
Figure 1. Compound 2. Structure of formula units: thermal
displacement ellipsoids are drawn at the level of 50%
probability.
A confirmation of the presence or absence of intramolecular
hydrogen bonding may also be found in the IR spectra of
compounds 1-4, 10-13, 15-18, 29 (Table 1).
In the crystal the molecules are combined in
centrosymmetrically related stacks with the “head-to-tail” mutual
-1
a
Table 1. Frequencies (cm ) of characteristic absorption bands in IR-spectra of 5-carbonylsubstituted 2-(2-
hydroxyphenyl)imidazoles.
1
1
2
2×H
2
O
16
29
12
3
17
13
4
18
С=O
1670
1662
1672
1662
1648
1730
1709
1708
1678
1666
1662
N-O
1304
-
1304
-
-
1300
-
-
1304
-
(N-oxide)
OCH
OH/NH
N-OH)
3
-
-
-
2942
-
-
-
2939
-
-
2870
3023
(OH)
3116
(NH)
3089
(NH)
2981
(OH)
3132
(
a
For complete IR spectra see Supplementary Information.
Figure 3. IR spectrum of 1-hydroxyimidazole 2.

5
ACCEPTED MAba
N
nd
U
s
S
fo
C
r t
R
heIPse
T
ries 2, 11, 16 and 4, 13, 18. Secondly, in all
these three series the position of the absorption band for the
carbonyl group in 1-hydroxyimidazoles is closer to that in N-
methoxyimidazoles and is shifted to lower frequencies with
respect to imidazole N-oxides (Table 1).
Obviously, these relative positions of the carbonyl group
bands allow us to estimate the total electronic effect of the
differently N-substituted imidazole ring with respect to the
electron-withdrawing substituent in position 5. Thus,
a
heterocycle containing the N-oxide moiety appears to be more
electron-withdrawing than the N-hydroxy- or N-methoxy-
substituted one.
Figure 4. IR spectrum of 1-methoxyimidazole 16.
According to the IR-spectroscopic data it may be supposed
that in the solid state 1-hydroxyimidazoles 2, 3 and 4 exist in the
N-hydroxy tautomeric form stabilized by two intramolecular
hydrogen bonds (IMHB).
In order to verify the assumption of H-bond lability in N-
hydroxyimidazole 2 an infrared spectrum of its hydrate (see
Experimental) has been recorded.
Figure 5. IR spectrum of imidazole N-oxide 11.
The intramolecular hydrogen bond between the hydroxy group
of the phenyl substituent and the “pyridine type” nitrogen atom
of the imidazole ring may be clearly observed in the IR spectra of
N-methoxy substituted compounds 15-18. A broad band of a
-
1
medium intensity at 2500-2800 cm can be attributed to the H-
bonded hydroxy group.
A band corresponding to this kind of intramolecular hydrogen
bond (IMHB) is lacking in the spectra of imidazole N-oxides 10-
Figure 6. IR spectrum of hydrate of 1-hydroxyimidazole 2.
1
3. In these compounds the band for the OH-group vibrations
probably H-bonded with the oxygen atom of the N-oxide
moiety) apparently has a lower intensity and is observed at 2500-
In contrast to the band for H O adsorbed by KBr (a broad
2
(
-1
band of medium intensity at 3450 cm ), the band for bound
-
1
water of hydrate 2 appears as a strong broad band at approx. 3380
2
650 cm .
-1
cm .
As for N-hydroxyimidazoles 2, 3 and 4, a broad band of a
-
1
-1
Interestingly, the band for the carbonyl group of hydrate 2 is
medium intensity appears at 2500-2800 cm (2), 2300-2500 cm
-1
-1
-
1
10 cm shifted to higher frequencies (1672 cm ). At the same
time the intensity of the absorption band for the “N-
(
3); 2550-2700 cm (4). This band is similar to the one for the
hydroxy group of the phenyl substituent in the spectra of N-
methoxyimidazoles 15-18.
-1
hydroxygroup” at 3000-3100 cm increases, whereas the
intensity of the absorption band for the OH-group of the phenyl
substituent decreases. It seems that N-hydroxyimidazole 2
containing bound water exists in the N-oxide tautomeric form
The shapes of the absorption bands corresponding to the two
fragments of the second hydrogen bond are also worth
discussing. The H-bonded hydroxy group of imidazole appears as
-
1
and the band at 3000-3100 cm corresponds to the NH-group
vibrations. By the way, the band for the NH-group in imidazole
-
1
broad strong band with maximum absorption at 3023 cm for 5-
-
1
-1
acetylimidazole 2, at 2981 cm for 5-ethoxycarbonylimidazole 3
29 is intense and it is situated at 3089 cm like the band in
-
1
and at 3132 cm for benzimidazole 4. A significant shift of the
band towards higher energies may be explained by a stronger
IMHB in compound 4 with the fixed carbonyl group.
hydrate 2 (See Supplementary).
The fact that hydrate 2 exists as the N-oxide is also confirmed
-1
by the band at 1304 cm which may be attributed to the N->O
It should be noted that in the IR-spectra of N-
methoxyderivatives 16-18 and N-oxides 11-13 the C=O group
stretching vibrations appear as strong narrow bands. Unlike that
in the IR-spectra of N-hydroxyimidazoles 3 and 4 this band is
evidently broadened. Broadening of the band may be explained
by its involvement in hydrogen bonding. It is interesting that in
the case of N-hydroxyimidazole 2 this band is not significantly
broadened which may be attributed to a higher lability of this H-
bond because of rotational flexibility of acetyl group.
stretch. A similar band is also present in the IR-spectrum of N-
oxide 11 but it is lacking in the spectra of N-methoxyimidazole
16 and anhydrous 1-hydroxyimidazole 2.
It is worth mentioning that one should regard the assignment
of the N->O stretch with great caution. Different authors note
that depending on the N-oxide structure the band for the N->O
-1
-1 33
group may appear between 1200 and 1320 cm : 1205 cm ,
-1 34
-1 18
-1
-1
-1 35
1
215 cm , 1223 cm , 1249 cm , 1310 cm , 1320 cm .
We may only suppose that in the case under consideration this
Relative positions of the bands corresponding to the carbonyl
groups in the series of compounds 2, 11, 16; 3, 12, 17 and 4, 13,
8 are also noteworthy. First of all, according to the electronic
-1
band appears at 1304 cm for N-oxides 11 and 13, and at 1300
-1
cm for N-oxide 12. The unambiguous assignment is precluded
1
by a large number of bands in this region.
effect of the electron-donating ethoxy group the bands for C=O
-
1
in the series 3, 12, 17 are shifted (ꢀ≈40-60 cm ) to higher
Thus, according to the analysis of IR spectra it may be
concluded that in the solid state anhydrous 5-carbonyl substituted
frequencies (lower wavelengths) with respect to the position of

6
Tetrahedron
EDN- MA2,
2
-(2-hydroxyphenyl)-1-hydroxyimidazoles e
A
xi
C
st
C
a
E
s
P
th
T
e
N
w
U
hic
S
h
C
re
R
ve
I
als cross-peaks of these protons not only with water
P
T
hydroxy tautomers, which corresponds to the X-ray diffraction
data. The presence of the bound water in the molecule of 1-
hydroxyimidazole (hydrate) leads to a transition into the N-oxide
tautomer.
([13.96, 1.66]; [12.43, 1.66]) but also with each other ([13.96,
12.43]) (see Supplementary).
It should be noted that OH proton of the phenyl substituent in
imidazole N-oxide 11 is observed as a rather narrow signal at
1
2.60 ppm (ν ≈ 15 Hz). For 1-methoxyimidazole 16 the OH
½
signal is very broadened (ν ≈ 360 Hz) and is observed at 12.45
½
ppm.
It should be also noted that the position of the signal of the
CH protons of the acetyl group for N-hydroxyimidazole 2 (2.57
3
ppm) is closer to the position of the signal of methoxyderivative
1
6 (2.59 ppm) than to the one of N-oxide 11 (2.81 ppm). It is of
1
interest that in the H NMR spectrum one can observe the overlap
of signals for two methyl groups (2.574 ppm and 2.571 ppm). At
the same time the C NMR spectrum reveals two signals (28.1
ppm and 16.8 ppm) that correspond to cross-peaks in 2D HMQC
spectrum: [2.57, 28.1] for COCH and [2.57, 16.8] for CH in
13
3
3
position 4, respectively (see Supplementary).
1
Scheme 8. Stabilization of prototropic tautomers of anhydrous
A comparison of the H NMR spectra of the model
compounds (i.e., imidazole N-oxide 11 and 1-methoxyimidazole
16) reveals a difference in the chemical shifts of protons in
position 6 of the hydroxyphenyl substituent (H6’). For imidazole
N-oxide 11 this signal appears at 7.20 ppm. Being a part of ABC
spin system, it is observed as a doublet of doublets with the
5
-carbonylsubstituted 2-(2-hydroxyphenyl)-1-
hydroxyimidazoles by IMHB.
2
2
.3. Study of prototropic tautomerism in solution.
3
4
.3.1. Solutions in deuterated chloroform.
ortho- and meta- coupling constants ( J = 7.9 Hz, J = 1.7 Hz). In
the case of N-methoxyimidazole 16 the H6’ signal is shifted to
lower field (8.17 ppm), being a doublet of doublets, too ( J = 8.1
Hz, J = 1.6 Hz). This kind of deshielding occurs due to the effect
of the neighbouring anisotropic imidazole moiety.
Prototropic tautomerism of N-hydroxyimidazoles and their
3
benzannulated analogues in solution may be efficiently studied
1
6-18,23,32
4
by means of NMR spectroscopy.
It was possible to record
1
the H NMR spectra in DMSO-d for all of the compounds.
6
Unfortunately, not all of the imidazole derivatives under
consideration are soluble in chloroform, so only the spectra of
compounds 2, 4, 11, 13, 16 and 18 were recorded in CDCl3.
It may be supposed that such deshielding is a consequence of
the IMHB formation between the 2-hydroxy group of the phenyl
substituent and the “pyridine-type” nitrogen atom of imidazole,
which results in a stabilization of a planar structure of the
molecule (see X-ray data). In model imidazole N-oxide 11 such
type of bonding is impossible. IMHB between the phenyl OH-
group and the N-oxide moiety oxygen atom leads to the
formation of the non-planar seven-numbered cycle and the
corresponding shift of the H6’ proton to a higher field. Similarly
in the spectra of compounds 21 (hydroxyimidazole) and 25
(methoxyimidazole) bearing bulky benzyloxy substituents (that
prevent the planarity of the structures) the signals of the H6’
protons are observed at 7.76 ppm (21) and 7.27-7.47 ppm (25).
First we consider NMR spectra of 5-acetyl substituted
imidazole derivatives in CDCl (Table 2).
3
1
a
Table 2. H NMR spectra in CDCl (δ, ppm) .
3
1
6
2
11
18
4
13
N-OH
-
13.93
-
-
-
OH
H-3'
12.46
7.07
12.40
7.03 (dd)
12.60
7.10
(dd)
12.55
7.07
(d)
12.50
7.16
(d)
7.06
(d)
(dd)
H-4'
H-5'
H-6'
7.35 (t)
6.95 (t)
8.17
7.33 (t)
6.94 (t)
7.43 (t)
7.36 (t)
7.36
7.46 (t)
(
t)
6.96
t)
1
6.94 (t)
6.95 (t)
6.96 (t)
In the H NMR spectra of 2-(2-hydroxyphenyl)substituted 1-
(
hydroxyimidazole 2 the H6’ proton is observed as a broadened
8.32
(br.s)
-
7.20
(dd)
3.62
8.20
(d)
4.14
8.27
(d)
-
7.20
(d)
3.66
signal at 8.32 ppm (ν ≈ 19 Hz).
(dd)
½
OCH
NCH
COCH
-CH
3
/
3
4.00
1
The H NMR spectra at different temperatures (293 K, 273 K,
2
63 K, 253 K, 243 K) were also recorded (Table 3).
3
2.59
2.56
2.57
2.57
2.81
2.60
-
-
-
-
-
-
4
3
1
Table 3.Chemical shifts of characteristic protons in H NMR
CH
CH
2
-
-
-
-
-
-
-
-
-
2.75
2.47
1.16
2.75
2.48
1.19
2.77
2.46
1.21
spectra of compound 2 in CDCl at different temperatures (δ,
3
2
a
ppm) .
2
CH
3
2
93 K
273 K
13.98
(br s;
263 K
14.01
(s;
253 K
14.04
(s)
243 K
14.06
(s)
ꢀδ
0.13
a
For coupling constants or widths at half height see
N-
OH
13.93
(br)
Experimental.
ν
½
≈40Hz)
12.54
(br s;
ν
ν
ν
½
≈16Hz)
12.56
(br s;
In CDCl3 two OH protons of compound 2 appear as
OH
12.41
(br)
12.64
(s)
12.70
(s)
0.30
0.06
broadened singlets at 13.93 ppm (N-OH; width at half height ν ≈
½
1
5 Hz) and at 12.40 ppm (ν ≈ 62 Hz). At the same time the
½
ν
½
≈56Hz)
8.34
(br. s;
½
≈28Hz)
8.36
signal of water from the solvent is observed at 1.64 ppm (ν ≈ 67
½
H-6'
8.32
8.37 (d;
J =
8.38
(d;
Hz).
(br. s;
(br. s;
ν
½
≈19Hz)
ν
½
≈30Hz)
8.1Hz)
J =
Apparently, the reason of OH signal broadening may be
connected with the processes of an intermolecular hydrogen
exchange. This exchange is evident from the EXSY spectrum of
½
≈20Hz)
8.1Hz)
a
For complete spectral data see Supplementary Information.

7
A decrease in temperature leads to a change
signal. At 253 K and 243 K it is observed as a doublet with the
coupling constant 8.1 Hz.
A
in
C
th
C
e
E
H6
P
’
T
pr
E
ot
D
on MAN
T
U
he
S
H
C
6
R
’ p
I
roton in diluted solution is observed as a doublet
P
T
3
( J = 8.0 Hz). The OH signals are narrowed. The chemical shift
for water is shifted from 1.66 ppm in the starting solution to 1.56
ppm in a diluted one (which corresponds to the chemical shift for
At lower temperatures the rotation processes including both
the rotation around phenyl-imidazole bond and the rotation of
acetyl group are slowed down. As a result the most energetically
favorable structure is achieved. Most likely it is an N-hydroxy
tautomeric form stabilized by the two hydrogen bonds (Scheme
36
water in pure chloroform ), its ν decreasing from 60 Hz to 3 Hz.
½
Narrowing of the signals under consideration is an evidence of
decrease of the intermolecular proton exchange between the
hydroxyl groups and water molecules due to the decrease of the
concentration.
8
) fixing the planarity of the molecule.
Thus in a diluted solution the influence of the neighbouring
molecules (including water) on the violation of the molecule
planarity reduces. As a result, the acetyl moiety is not withdrawn
from the phenyl-imidazole plane. It leads to narrowing of the H-
A possibility of the intermolecular proton exchange between
the two OH-groups and the water molecules required an
investigation of an influence of a concentration on inter- and
intramolecular interactions in 1-hydroxyimidazole 2 solution to
be carried out. The existence of intermolecular exchange is
confirmed by the presence of three cross-peaks in the NOESY
6
’ and N-OH proton signals due to the fact that hindrances for the
formation of a planar six-membered cycle are eliminated.
(
(
EXSY) spectrum ([13.96, 1.66], [12.43, 1.66], [13.96, 12.43])
see Supplementary). The intensity of the cross-peak
The lower effect of dilution on the phenyl-OH proton signal
pattern probably evidences that the IMHB C H -OH – N is
6
4
corresponding to the N-OH – H O interaction is higher than the
stronger and less dependent on external factors than IMHB N-
OH – O=C. This corresponds to the assumptions made on the
basis of the IR-spectra analysis.
2
intensity of that corresponding to the C H -OH – H O interaction,
6
4
2
which evidences a higher rate of the intermolecular exchange in
the former case. Apparently, it is explained by a higher acidity of
the N-OH proton. For reference, pKa of phenol is 10.0, whereas
1
As a whole, the H NMR spectra of 1-hydroxyimidazole 4
15
with fixed carbonyl group in position 5 of imidazole and its
model compounds 13 and 18 are similar to the ones considered
above.
pKa of 1-hydroxy-2,4,5-trimethylimidazole is 8.39 (in water).
On dilution the chemical shifts of protons remain practically
unchanged, but the character of the H6’ proton signal and both
OH-groups is altered (Table 4).
The “reference” H6’ proton signal in CDCl is observed at
3
3
1
8.27 ppm ( J = 8.2 Hz) for compound 4. The similar signal for
model N-oxide 13 is observed at 7.20 ppm ( J = 7.9 Hz, J = 1.4
Hz). For N-methoxyimidazole 18 it is observed at 8.20 ppm ( J =
Table 4. Chemical shifts of characteristic protons in H NMR
3
4
spectra of solutions with differing concentrations of compound 2
3
a
in CDCl3(δ, ppm) .
8
.1 Hz). The observed deshielding of the H6’ protons for
Starting
solution
.067 mol/L
13.93
Dilution 1
0.034
mol/L
13.94
(br. s;
Dilution 2
0.017
mol/L
Dilution 3
0.007
mol/L
compounds 4 and 18 is due to a fixation of the benzimidazole
moiety in the plane of the hydroxyphenyl substituent by IMHB
between the OH-group of the substituent in position 2 and
0
N-OH
OH
13.95 (s)
13. 95 (s)
“
pyridine-type” nitrogen atom of the imidazole ring.
(
br;
≈45Hz)
12.41
br;
ν
½
½
ν ≈19Hz)
2
.3.2. Solutions in DMSO-d6 .
12.40
(br. s;
12.40
(br. s;
12.40
(br. s;
(
A solubility of 1-hydroxyimidazoles 1-4 and their model N-
ν
½
≈60Hz)
8.32
ν
½
≈35Hz)
8.34
(br. d;
ν
½
≈20Hz)
8.35
(br. d;
ν
½
≈18Hz)
8.35
(d;
oxides 10-13 and N-methoxyimidazoles 15-18 in DMSO-d6
allowed to record the NMR spectra for all the compounds under
consideration (Table 5).
H-6'
(br. s;
ν
½
≈20Hz)
J=7.9Hz)
J=8.0Hz)
J=8.0Hz)
Signal of
1.66
1.56
1.56
1.56
H
2
O
ν
½
≈60Hz
ν
½
≈18Hz
ν
½
≈9Hz
½
ν ≈3Hz
a
For complete spectral data see Supplementary Information.
1
a
Table 5.Chemical shifts of characteristic protons in H NMR spectra in DMSO-d (δ, ppm) .
6
1
-
5
1
14.66
(br)
12.54
(br)
10
-
16
2
11
-
17
-
3
12
18
4
13
N-
OH
OH
-
13.79
(br)
13.59
(br)
-
-
-
12.95 (br.
s)
13.78 (br.
s)
12.16
(s)
12.62
(br. s)
12.18
(s)
12.89
(br)
13.04 (br.
s)
12.14
(s)
12.75
(br)
12.86
(br)
H-6'
8.00 (dd)
7.47 (br.
d)
7.45 (d)
8.02 (d)
7.55
(br.s)
7.42-7.52
(m)
8.03 (d)
8.00
(br.s)
7.42-7.53
(m)
8.04
(dd)
8.11
(br.s)
7.56 (d)
a
For complete spectral data see Experimental.
The electronic effect of a substituent in heterocycle position 5 on
the proton shielding is typical for the H NMR spectra of N-
range in accordance with the 2-hydroxygroup effect. Therefore,
there is an IMHB between the OH-proton and the “pyridine-type”
nitrogen atom in solutions of N-methoxy derivatives 15-18 in
1
methoxysubstituted 15-18 in DMSO-d . One can observe a
6
downfield shift when passing from the electron-donating
substituent (methyl group) to the electron-withdrawing ones.
DMSO-d . This IMHB stabilizes the planar structure of their
molecules.
6
Thus, maximum differences in the spectra are observed for
compounds 15 and 18. The low field shift of the H6’ proton
signal for all methoxy derivatives should be particularly
mentioned together with the differences in signals for the protons
of the phenyl moiety (H4’) and the OH-group. As a comparison,
As a result, the H6’ proton is deshielded due to anisotropic
and –M effects of the heterocycle. The H4’ proton is also
sensitive to the effect of the imidazole ring substituent variability.
The differences in chemical shifts of the OH-group proton for
compound 15 (12.95 ppm) and 5-carbonylsubstituted derivatives
16-18 (12.14 – 12.18 ppm) should also be mentioned. This shift
to lower field indicates an increase of IMHB strength in
compound 15. It seems that the strength of this IMHB depends
1
in the H NMR spectra of model N-methylimidazole oxides 10-
1
3 (where a planarity of imidazole and phenyl fragments is
violated) the phenyl protons are observed in a rather narrow

8
Tetrahedron
15 MAN
on the N(3) atom basicity, that is the larges
A
t in
C
c
C
om
E
p
P
ou
T
n
E
d
D
F
U
or
S
th
C
e
R
m
I
olecule of compound 1 it is possible if hydroxy-
P
T
due to the position 5 methyl substituent electron-donating
properties. It is noteworthy that the signal of the OH-proton is
slightly broadened especially in the case of compounds 15 and 16
oxide tautomerism is taken into consideration. Then in the oxide
(the “open” form of N-oxide) the signal at 12.54 ppm can be
1
attributed to the NH-proton (in H NMR spectrum of 2-(2-
(
ν½ ≈ 9-20 Hz). It may be explained by intermolecular exchange
hydroxyphenyl)-4,5-dimethylimidazole 28 the NH-proton is
observed at 12.50 ppm while the OH proton of 2-hydroxyphenyl
substituent is observed at 12.88 ppm). In the series of 1-
hydroxyimidazoles a replacement of the CH3 group by the
with water which is confirmed by the presence of corresponding
cross-peak in the NOESY (EXSY) spectrum of compound 16
(see Supplementary).
COCH one in position 5 along with the remaining non-planarity
of the molecules results in the converging of signals of protons at
3
In the molecules of imidazole N-oxides 10-13 the phenyl and
imidazole moieties do not lie in the same plane. As a result, the
H6’ proton deshielding is not observed. The shift of the OH-
proton to a lower field also attracts attention, especially for
compound 10. This shift cannot be explained by only a specific
interaction with a bipolar solvent. From our point of view, it is
possible that the structures of imidazole N-oxides 10-13 are
stabilized by IMHB between the OH-group and the N-oxide
moiety oxygen atom. This IMHB results in the formation of non-
planar seven-membered cycle. The maximum shift to lower field
of the OH proton of compound 10 is explained by the maximum
electron-donating effect of the N-oxide oxygen atom in 4,5-
dimethylsubstituted derivative 10. It should be mentioned that the
the heteroatoms (12.54 ppm and 14.66 ppm for compound 1;
1
3.59 ppm and 13.79 ppm for compound 2). This regularity is a
result of the varying electronic effect of the methyl and acetyl
groups on the N-oxide oxygen atom and the “pyrrole-type”
nitrogen atom of the “open” form of NH-imidazole N-oxide. For
the planar “closed” forms of N-oxides (compounds 3 and 4) the
signals of “mobile” protons are observed as one signal (12.89
ppm for 3 and 12.75 ppm for 4, respectively).
signal of the OH-group proton is broadened (ν ≈ 8-90 Hz) and
½
that in the NOESY (EXSY) spectrum of compound 11 one can
observe a cross-peak corresponding to the intermolecular
exchange of this proton with water (see Supplementary).
1
The analysis of the H NMR spectra of 1-hydroxyimidazoles
1
-4 in DMSO-d makes it possible to separate these compounds
6
Scheme 9. Two forms of N-oxide tautomer in DMSO
solutions.
into two groups. The first group contains compounds 3 and 4
with low-field signals for the H6’ protons, i.e. a broadened (ν ≈
½
3
2
0 Hz) signal at 8.00 ppm for compound 3 and a broadened (ν ≈
0 Hz) signal at 8.11 ppm for N-hydroxyimidazole 4. The second
½
The NMR spectra of 5-acetylsubstituted 1-hydroxyimidazole
group consists of compounds 1 and 2 with the H6' proton signal
in higher field (7.47 ppm for 1 and 7.55 ppm for 2) evidencing a
non-planar structure.
2
recorded in mixture of solvents (CDCl -DMSO-d 1:1) are
3 6
similar to those in DMSO-d6 and testify the “open” NH-
imidazole N-oxide tautomeric form (See Supplementary).
Apparently, for compounds 3 and 4 the shift of the H6’ proton
signals to a lower field indicates that the 2-hydroxyphenyl and
imidazole moieties of the molecules are near coplanar. Whereas,
in the low-field area (12.00 – 15.00 ppm) only one signal at
1 3
2
.3.3. C NMR spectra.
1
The preliminary conclusion based on the analysis of H NMR
spectra is confirmed by C NMR data (Table 7).
13
13
1
2.75 ppm (ν ≈ 95 Hz) is observed for compound 4, with the
Table 6. C NMR of 5-acetylsubstituted imidazole derivatives
(δ, ppm).
½
integrated intensity corresponding to two protons. This signal is
shifted to a lower field as compared with that of the OH-proton
of N-methoxyimidazole 18 (12.14 ppm) where the IMHB with
the “pyridine-type” nitrogen atom exists. This may be interpreted
as an evidence of a certain difference in the IMHB formation in
planar molecules of 4 and 18.
in CDCl
3
in CDCl
DMSO-d
3
–
6
in DMSO-d
6
(1:1)
1
6
2
11
2
16
2
11
C-2
C-4
C-5
141.7 139.4 137.5
141.6 142.2 134.3
123.6 120.6 127.3
135.7
134.3
127.2
190.0
30.9
12.7
--
141.3 136.0 136.9
141.2 134.7 135.7
124.0 127.2 126.5
187.2 190.0 190.3
As it was already mentioned, the IMHB occurs between the
OH group and the “pyridine-type” nitrogen atom in compound
СOCH3 186.9 192.0 190.9
1
8. However, this kind of the IMHB does not explain the
COCH3
4-CH3
NCH3/
30.0
16.7
66.5
28.1
16.8
--
31.0
10.6
32.9
30.3
16.8
67.4
30.6
12.7
--
31.0
10.7
33.5
downfield shift of the “acidic” proton in compound 4. In order to
explain this we assumed that the NH-imidazole N-oxide is
formed in this case. The corresponding proton should display a
rather high acidity under the influence of the “pyridine-type”
nitrogen atom and the cyclic carbonyl substituent. In this case
one may expect the formation of IMHB between the NH group
and the oxygen atom in position 2 of the phenyl substituent (the
OCH
C-1'
3
110.7 110.8 111.2
158.8 158.4 159.8
118.0 117.6 121.3
132.0 131.9 132.8
119.4 119.2 119.0
125.9 127.4 129.0
112.7
158.7
118.9
132.8
120.7
128.6
111.6 112.5 112.0
158.1 158.7 159.5
117.7 119.2 120.7
132.4 132.9 133.0
119.9 120.0 119.3
127.2 128.7 130.6
C-2'
C-3'
C-4'
C-5'
C-6'
“
closed” form of N-oxide).
1
In the H NMR spectrum of non-planar compound 1 the
signals of the OH-protons are observed at 12.54 ppm and 14.66
ppm. The second signal is shifted to a lower field compared to
that for the OH-proton of N-oxide 10. The corresponding
hydrogen atom can interact with the oxygen atom of the N-oxide
moiety via IMHB in the non-planar structure.
The imidazole ring C-atoms are most sensitive to the definite
tautomeric form existence. Changes in the nature of the
heterocycle nitrogen atoms cause a shift of the signals of these
atoms in positions 4 and 5 of the imidazole ring. For the sake of
convenience we find it possible to numerate the C-atoms in the

9
cycle of imidazole N-oxides in the same way as
hydroxy)derivatives:
A
in
C
N
C
-m
E
et
P
ho
T
x
E
y(
D
N- MAfro
N
m
U
th
S
e
C
ph
R
en
I
yl-imidazole plane. It is also supposed that due to
P
T
the acceptor properties of DMSO N-hydroxyimidazoles 3 and 4
containing bulky ethoxycarbonyl substituent (3) or fixed
carbonyl group (4) in position 5 of imidazole ring transfer to the
N-oxide tautomeric form either. The planar structure of this form
is stabilized by IMHB between the hydrogen atom at the
“
pyrrole-type” nitrogen atom and the oxygen atom of the
hydroxy group of the phenyl substituent.
4
. Experimental
Scheme 10. Numeration of carbon atoms in imidazole ring.
It is noteworthy that the change of a solvent has practically no
impact on the position of C nuclei signals of heterocycle for the
model structures.
4.1. General
Chemicals were purchased from commercial sources and were
used without further purification. The NMR experiments were
carried out using a Bruker Avance 300 spectrometer operating
13
TM
1
13
at 300.13 MHz for H and 75.47 MHz for C or using a Bruker
TM
1
1
3
Avance 600 spectrometer operating at 600.22 MHz for H and
In the C NMR spectrum of 1-hydroxyimidazole 2 in CDCl
3
13
13
150.93 MHz for C. The spectrometers were equipped with
unverse gradient probe-head. Chemical shifts are given relative to
the residual proton signal of solvent (7.27 ppm for CDCl or 2.50
ppm for DMSO-d ) for H and relative to CDCl (77.0 ppm) or to
the signals for C nuclei of imidazole ring atoms are observed at
39.4 ppm (C-2), 142.2 ppm (C-4) and 120.6 ppm (C-5). These
1
3
values are closer to the ones in the spectrum of N-
methoxyimidazole 16, so we may conclude that N-
hydroxyimidazole 2 exists in the N-hydroxy tautomeric form in
chloroform.
1
6
3
13
1
13
DMSO-d (35.9 ppm) for C. All 1D H and C experiments as
6
well as 2D experiments (COSY, HSQC, HMBC, EXSY) were
performed using standard pulse sequences from the Bruker
library. The assignment of the signals in H and С NMR spectra
has been performed by use of 2D COSY, HMQC and HMBC
techniques. The mixing time in EXSY experiment is equal to 0.5
s. Mass-spectra were recorded with a LKB-2000 mass
spectrometer. Infrared spectra of solids were recorded with
Shimadzu IRAffinity-1 FTIR spectrophotometer in a KBr matrix.
13
1
13
On the contrary, in DMSO-d the chemical shifts of C nuclei
6
attributed to imidazole ring (135.7 ppm (C-2), 134.7 ppm (C-4),
1
27.2 ppm (C-5)) are close to those of imidazole N-oxide 11.
This result evidences the existence of N-hydroxyimidazole 2 as
the N-oxide tautomer in this solvent.
Signals with practically the same chemical shifts are observed
13
in the C NMR spectrum of 1-hydroxyimidazole 2 recorded in a
mixture of solvents (CDCl – DMSO-d 1:1). So, under these
4.2. Detailed experimental procedure and characterization data
3
6
4
.2.1. 2-(2-Hydroxyphenyl)-4,5-dimethyl-1H-
conditions compound 2 also exists as the N-oxide tautomer.
imidazol-1-ol (1).
13
The same regularity is observed for the signals of the
C
A mixture of aldehyde 5 (3.00 g, 0.0245 mol), oxime 6 (2.50
g, 0.0245 mol) and ammonium acetate (2.30 g, 0.0300 mol) in
glacial acetic acid (30 mL) was stirred at 40-45°C for 4 h, cooled
to room temperature and left to stand overnight. The solvent was
removed under reduced pressure. The residue was treated with
ether. The obtained solid was heated at reflux in acetonitrile and
filtered off warm yielding 4.00 g (80%) of product 1 as white
solid. M.p. 251-253 °C.
nuclei of substituents in positions 4 and 5 of the imidazole ring.
This is especially clear in the case of the 4-CH group directly
3
13
bonded to the imidazole ring. In the C NMR spectrum of N-
hydroxyimidazole 2 in CDCl this signal (16.8 ppm) corresponds
3
to the one in the spectrum of N-methoxyimidazole 16 (16.7 ppm)
rather than the one of imidazole N-oxide 11 (10.6 ppm). As for
13
the spectra recorded in DMSO-d , the chemical shift of C nuclei
6
of 4-CH group of N-hydroxyimidazole 2 (12.7 ppm) is closer to
3
1
that in imidazole N-oxide 11 (10.7 ppm) and differs from the
H NMR (300 MHz, DMSO-d ): δ= 14.66 (br. s, 1H, OH),
6
13
chemical shift of
C
nuclei of 4-CH3 group of N-
12.54 (br. s, 1H, OH), 7.47 (br. d, J = 8.0 Hz, 1H, H6’), 7.30 (t,
1H, H4’), 6.80-6.90 (m, 2H, H3’ and H5’), 2.21 (s, 3H, 5-CH ),
.11 (s, 3H, 4-CH ) ppm.
methoxyimidazole 16 (16.8 ppm).
3
2
3
3
2
. Conclusions
13
C NMR (75.47 Hz, DMSO-d ): δ= 158.2 (C2’), 134.0 (C2),
6
In the solid state 5-carbonylsubstituted 1-hydroxyimidazoles
-4 exist in the N-hydroxy tautomeric form stabilized by two
131.4 (C6’), 127.4 (C4’), 123.9 (C4), 122.2 (C5), 119.4 (C5’),
118.1 (C3’), 112.9 (C1’), 9.6 (4-CH ), 6.9 (5-CH ) ppm.
3
3
hydrogen bonds. The presence of hydrate water in the sample of
-acetylsubstituted 1-hydroxyimidazole 2 leads to the N-oxide
tautomeric form.
+
MS(EI): m/z=204[M] . Anal. C H N O (204): calcd. C
11
12
2
2
5
6
4.71, H 5.88, N 13.73; found C 64.37, H 5.93, N 13.55.
4
1
.2.2. 1-(1-Hydroxy-2-(2-hydroxyphenyl)-4-methyl-
H-imidazol-5-yl)ethanone (2)
A mixture of aldehyde 5 (2.50 g, 0.0205 mol), oxime 7 (3.00
In CDCl 1-hydroxyimidazoles 2 and 4 also exist as the N-
3
hydroxy tautomers stabilized by two hydrogen bonds. The
presence of water affects the hydrogen bonding but has no impact
on the transition from one tautomeric form into another.
g, 0.0233 mol) and ammonium acetate (2.00 g, 0.0260 mol) in
glacial acetic acid (30 mL) was stirred at 45-55°C for 60 h.
Reaction mixture was poured into water (100 mL), triturated, and
the precipitate was filtered off and recrystallized from water
yielding 1.91 g (41%) of product 2 as a beige solid; m.p. 172-173
°C.
In polar aprotic DMSO-d (strong hydrogen bond acceptor) 1-
6
hydroxyimidazoles 1-4 exist as the N-oxide tautomers of the
different nature. It is supposed that 5-methyl- and 5-acetyl
substituted N-hydroxyimidazoles 1 and 2 exist as the N-oxide
tautomers stabilized by IMHB between the hydroxy group of the
phenyl substituent and the oxygen atom of the N-oxide moiety.
This kind of hydrogen bond withdraws the phenyl substituent
1
H NMR (600 MHz, CDCl , 293 K, [0.067 mol/l]): δ= 13.93
3
(br. s, ν = 47 Hz, 1H, N-OH), 12.40 (br. s, ν = 62 Hz, 1H, OH),
½
½

1
0
Tetrahedron
8
.32 (br. s, ν = 19 Hz, 1H, H6’), 7.33 (t, 1H
A
, H
C
4
C
’),
E
7.
P
03
T
(dd
E
D
, J MA(C
N
6’
U
),
S
11
C
8.
R
8
I
(C5’), 117.8 (C3’), 111.6 (C1’), 52.4 (CH ), 37.1
2
P
T
½
=
8.3, 1.2 Hz, 1H, H3’), 6.94 (t, 1H, H5’), 2.57 (s, 6H, 2CH )
(C(CH ) ), 35.3 (CH ), 27.8 (2CH ) ppm.
3
3 2
2
3
ppm.
+
MS(EI): m/z=272[M] . Anal. C H N O (272): calcd. C
15
16
2
3
13
C NMR (150.94 MHz, CDCl ): δ= 192.0 (C=O), 158.4 (C-
66.18, H 5.88, N 10.29; found C 66.09, H 5.94, N 10.23.
3
2
’), 142.2 (C-4), 139.4 (C-2), 131.8 (C-4’), 127.4 (C-6’), 120.6
4
.2.5. 2-(2-Hydroxyphenyl)-1,4,5-trimethyl-1H-
(C-5), 119.2 (C-5’), 117.6 (C-3’), 110.8 (C-1’), 28.1 (COCH3),
imidazole 3-oxide (10).
1
6.8 (4-CH ) ppm.
3
4
0% Aqueous solution of methyl amine (2.50 g), containing
1
H NMR (600 MHz, DMSO-d ): δ= 13.79 (br. s, 1H, N-OH),
1.0 g (0.033 mol) of methyl amine was added dropwise to a
mixture of aldehyde 5 (3.60 g, 0.0295 mol) and oxime 6 (3.6 g,
0.0295 mol) in ethanol (15 mL). The resulting mixture was
stirred at room temperature for 1 h and left to stand overnight.
The precipitate was filtered off, washed with ethanol and
recrystallized from toluene, yielding 3.80 g (60%) of product 10
as a light-yellow solid. M.p. 218-220 °C.
6
1
1
3.59 (br. s, 1H, OH), 7.55 (br. s, ν = 68 Hz, 1H, H6’), 7.41 (t,
½
H, H4’), 6.96 (t, 1H, H5’), 6.93 (d, J = 8.3 Hz, 1H, H3’), 2.66
(s, 3H, COCH ), 2.48 (s, 3H, CH ) ppm.
3
3
13
C NMR (150.94 MHz, DMSO-d ): δ= 190.0 (C=O), 158.7
6
(
1
(
C-2’), 136.0 (C-2), 134.7 (C-4), 132.9 (C-4’), 128.7 (C-6’),
27.2 (C-5), 120.0 (C-5’), 119.2 (C-3’), 112.5 (C-1’), 30.6
COCH ), 12.7 (4-CH ) ppm.
1
3
3
H NMR (300 MHz, DMSO-d ): δ= 13.78 (br.s, ν = 50 Hz,
6
½
+
1H, OH), 7.45 (d, J = 7.5 Hz, 1H, H6’), 7.39 (t, 1H, H4’), 6.90-
.00 (m, 2H, H3’ and H5’), 3.61 (s, 3H, NCH ), 2.27 (s, 3H, 5-
MS(EI): m/z=232[M] . Anal. C H N O ×0.25H O (236.5):
12
12
2
3
2
7
3
calcd. C 60.89, H 5.28, N 11.84; found C 61.15, H 5.22, N 11.88.
CH ), 2.16 (s, 3H, 4-CH ) ppm.
3
3
4
.2.3. Ethyl 1-hydroxy-2-(2-hydroxyphenyl)-4-
1
3
C NMR (75.47 Hz, DMSO-d ): δ= 159.3 (C2’), 134.8 (C2),
6
methyl-1H-imidazole-5-carboxylate (3).
1
1
31.5 (C6’), 129.2 (C4’), 124.3 (C4), 123.1 (C5), 120.1 (C5’),
18.0 (C3’), 112.4 (C1’), 32.6 (NCH ), 8.8 (4-CH ), 6.9 (5-CH )
ppm.
A mixture of aldehyde 5 (3.10 g, 0.0254 mol), oxime 8 (4.00
g, 0.0252 mol) and ammonium acetate (2.00 g, 0.0260 mol) in
glacial acetic acid (30 mL) was stirred at room temperature for 5
h and left to stand for 3 d. The reaction mixture was poured into
water (100 mL), the precipitate was filtered off and washed with
ether. The obtained solid was heated at reflux in acetonitrile,
cooled to room temperature, and filtered off, yielding 1.3 g (20%)
of chromatographically pure product 3 as white solid. M.p. 236-
3
3
3
+
MS(EI): m/z=218[M] . Anal. C H N O (218): calcd. C
66.06, H 6.42, N 12.84; found C 66.15, H 6.53, N 12.82.
12
14
2
2
4
1
.2.6. 4-Acetyl-2-(2-hydroxyphenyl)-1,5-dimethyl-
H-imidazole 3-oxide (11).
Similarly to 10 from aldehyde 5 (2.80 g, 0.0230 mol), oxime 7
3.00 g, 0.0230 mol) and 40% aq. CH NH (2.00 g) product 11
(2.70 g; 48%) was obtained. Yellowish solid, m.p. 216-218 °C
(methanol).
2
37 °C.
(
3 2
1
H NMR (300 MHz, DMSO-d ): δ= 12.89 (br. s, 2H, 2OH),
6
8
.00 (br. s, ν = 32 Hz, 1H, H-6’), 7.35 (t, 1H, H4’), 6.89-6.97
½
(m, 2H, H3’ and H5’), 4.21 (q, 2H, OCH CH ), 2.45 (s, 3H, 4-
2 3
1
H NMR (600 MHz, CDCl , 293 K): δ= 12.60 (br. s, ν = 14.5
3
½
CH ), 1.32 (t, 3H, OCH CH ) ppm.
3
2
3
Hz, 1H, OH), 7.43 (t, 1H, H4’), 7.20 (dd, J = 7.9, 1.7 Hz, 1H,
H6’), 7.10 (dd, J = 8.4 Hz, 1.1 Hz, 1H, H3’), 6.94 (t, 1H, H5’),
3.62 (s, 3H, NCH ), 2.81 (s, 3H, COCH ), 2.60 (s, 3H, 4-CH )
13
C NMR (75.47 Hz, DMSO-d ): δ= 158.5 (C=O), 157.9
6
(C2’), 137.5 (C2), 135.5 (C4), 131.7 (C4’), 127.3 (C6’), 118.6
3
3
3
(C5’), 118.1 (C3’), 117.9 (C5), 111.8 (C1’), 60.3 (OCH CH ),
ppm.
2
3
1
4.2 (OCH CH ), 11.5 (4-CH ) ppm.
2 3 3
13
C NMR (150.94 MHz, CDCl ): δ= 190.9 (C=O), 159.8 (C-
3
+
MS(EI): m/z=262[M] . Anal. C H N O (262): calcd. C
2’), 137.5 (C-2), 134.3 (C-4), 132.8 (C-4’), 129.0 (C-6’), 127.3
(C-5), 121.3 (C-3’), 119.0 (C-5’), 111.2 (C-1’), 32.9 (NCH3),
13
14
2
4
5
9.54, H 5.34, N 10.69; found C 59.44, H 5.26, N 10.65.
3
1.0 (COCH ), 10.6 (4-CH ) ppm.
3 3
4
4
.2.4. 1-Hydroxy-2-(2-hydroxyphenyl)-5,5-dimethyl-
,5,6,7-tetrahydro-1H-benzo[d] imidazole-7(4H)-one
1
H NMR (600 MHz, DMSO-d , 293 K): δ= 12.62 (s, 1H, OH),
6
(
4).
7
.42-7.52 (m, 2H, H6’ and H4’), 6.95-7.05 (m, 2H, H3’ and
A mixture of aldehyde 5 (2.30 g, 0.0184 mol), oxime 9 (3.10
H5’), 3.65 (s, 3H, NCH ), 2.74 (s, 3H, COCH ), 2.56 (s, 3H, 4-
3
3
g, 0.0184 mol) and ammonium acetate (1.50 g, 0.0190 mol) in
glacial acetic acid (30 mL) was stirred at 40-45°C for 4 h, cooled
to room temperature and left to stand overnight. The precipitate
was filtered off and then heated at reflux in acetonitrile (40 mL)
CH ) ppm.
3
13
C NMR (150.94 MHz, DMSO-d ): δ= 190.3 (C=O), 159.5
6
(
1
(
C-2’), 136.9 (C-2), 135.7 (C-4), 133.0 (C-4’), 130.6 (C-6’),
26.5 (C-5), 120.7 (C-3’), 119.3 (C-5’), 112.0 (C-1’), 33.5
NCH ), 31.0 (COCH ), 10.7 (4-CH ) ppm.
and filtered off warm, yielding 2.50
g
(50%) of
3
3
3
chromatographically pure product 4 as a yellow solid. M.p. 262-
+
2
64 °C.
MS(EI): m/z=246[M] . Anal. C H N O (246): calcd. C
1
3
14
2
3
1
63.41, H 5.69, N 11.38; found C 63.35, H 5.65, N 11.19.
H NMR (300 MHz, CDCl ): δ= 8.27 (d, J = 8.2 Hz, 1H, H6’),
3
7
2
.36 (t, 1H, H4’), 7.06 (d, J = 8.1 Hz, 1H, H3’), 6.96 (t, 1H, H5’),
4.2.7. 4-(Ethoxycarbonyl)-2-(2-hydroxyphenyl)-1,5-
dimethyl-1H-imidazole 3-oxide (12).
.75 (s, 2H, CH ), 2.48 (s, 2H, CH ), 1.16 (s, 6H, 2CH ) ppm.
2
2
3
1
40% aqueous solution of methyl amine (1.08 g), containing
H NMR (300 MHz, DMSO-d ): δ= 12.75 (br. s, 2H, 2OH),
6
0
.43 g (0.0139 mol) of methyl amine was added dropwise to a
mixture of aldehyde 5 (1.53 g, 0.0126 mol) and oxime 8 (2.00 g,
.0126 mol) in ethanol (5 mL). The resulting mixture was stirred
at room temperature for 1 h and left to stand for 3 d. The solvent
was removed under reduced pressure and the obtained oil was
treated with small amount of ether. Thus obtained precipitate was
8
2
6
.11 (br. s, ν = 24 Hz; 1H, H6’), 7.36 (t, 1H, H4’), 6.90-7.00 (m,
H, H3’ and H5’), 2.74 (s, 2H, CH ), 2.41 (s, 2H, CH ), 1.08 (s,
H, 2CH ) ppm.
½
2
2
0
3
13
C NMR (75.47 Hz, DMSO-d ): δ= 185.6 (C=O), 157.9
6
(
C2’), 145.6 (C2), 142.3 (C4), 131.9 (C5), 127.2 (C4’), 122.2

1
1
filtered off and recrystallized from ethyl aceta
A
te
C
yi
C
eld
E
in
P
g
T
0.
E
45
D
g
MAof
N
pu
U
re
S
p
C
ro
R
du
I
c
P
t 15 (m.p. 95-97 °C) and 0.11 g (23%) of pure
T
(13%) of product 12 as a beige solid. M.p. 162-164 °C.
by-product 28 (m.p. 220-222 °C).
1
1
H NMR (300 MHz, DMSO-d ): δ= 13.04 (br. s, ν = 90 Hz,
H NMR (300 MHz, DMSO-d ): δ= 12.95 (br. s, ν = 20 Hz,
6 ½
6
½
1
H, OH), 7.42-7.53 (m, 2H, H4’ and H6’), 6.95-7.03 (m, 2H, H3’
1H, OH), 8.00 (dd, J = 8.3, 1.7 Hz, 1H, H6’), 7.25 (t, 1H, H4’),
and H5’), 4.33 (q, 2H, OCH CH ), 3.64 (s, 3H, NCH ), 2.55 (s,
6.90-6.97 (m, 2H, H3’ and H5’), 3.99 (s, 3H, OCH ), 2.26 (s, 3H,
2
3
3
3
3
H, 4-CH ), 1.32 (t, 3H, OCH CH ) ppm.
5-CH ), 2.13 (s, 3H, 4-CH ) ppm.
3
2
3
3
3
13
13
C NMR (75.47 Hz, DMSO-d ): δ= 159.4 (C=O), 158.2
C NMR (75.47 Hz, DMSO-d ): δ= 156.5 (C2’), 136.3 (C2),
6
6
(
C2’), 137.5 (C2), 135.3 (C4), 132.4 (C4’), 129.9 (C6’), 120.2
129.7 (C4’), 126.4 (C4), 124.1 (C6’), 120.6 (C5), 119.0 (C3’),
116.8 (C5’), 111.8 (C1’), 66.0 (OCH ), 12.3 (4-CH ), 6.9 (5-CH )
(C3’), 118.6 (C5), 118.5 (C5’), 111.5 (C1’), 60.6 (OCH CH ),
2
3
3
3
3
3
3.3 (NCH ), 14.1 (OCH CH ), 10.4 (4-CH ) ppm.
ppm.
3
2
3
3
+
+
MS(EI): m/z=276[M] . Anal. C H N O ·0.5H O (285):
MS(EI): m/z=218[M] . Anal. C H N O (218): calcd. C
14
16
2
4
2
12 14
2
2
calcd. C 58.95, H 5.96, N 9.82; found C 58.51, H 5.25, N 9.68.
66.06, H 6.42, N 12.84; found C 66.23, H 6.62, N 12.95.
1
4
4
.2.8. 2-(2-Hydroxyphenyl)-1,6,6-trimethyl-4-oxo-
,5,6,7-tetrahydro-1H-benzo[d] imidazole 3-oxide
By-product: (2-(4,5-dimethyl-1H-imidazol-2-yl)phenol (28). H
NMR (300 MHz, DMSO-d ): δ= 7.71 (d, J = 7.3 Hz, 1H, H-Ar),
7.11-7.20 (m, 1H, H-Ar), 6.82-6.92 (m, 2H, H-Ar), 2.15 (s, 6H,
6
(
13).
A mixture of azomethine 14 (1.60 g, 0.0118 mol) and oxime 9
2.00 g, 0.0118 mol) in glacial acetic acid (50 mL) was stirred at
+
2CH
) ppm. MS(EI): m/z=188[M] .
3
(
4
1
.2.11. 1-(2-(2-hydroxyphenyl)-1-methoxy-4-methyl-
room temperature for 4 h. The reaction mixture was poured into
water (50 mL), the product was extracted with chloroform (15
mL×2), the extract was sequentially washed with potassium
carbonate solution (3%) and water, then dried over anhydrous
magnesium sulfate. The solvent was removed under reduced
pressure. The obtained oil was treated with ether yielding 0.9 g
H-imidazol-5-yl)ethanone (16).
Similarly to 15 from imidazole 25 (0.40 g, 0.0012 mol) 0.17 g
58%) of product 16 (m.p. 116-117 °C) and 0.10 g (39%) of by-
(
product 29 (m.p. 264-266 °C) were obtained.
1
H NMR (600 MHz, CDCl , 293 K): δ= 12.46 (br. s, 1H, OH),
3
(26%) of product 13 as a beige solid. M.p. 230-232 °C.
8
.17 (dd, J = 8.1, 1.6 Hz, 1H, H6’), 7.35 (t, 1H, H4’), 7.07 (dd, J
= 8.4, 1.2 Hz, 1H, H3’), 6.95 (t, 1H, H5’), 4.00 (s, 3H, OCH3),
.59 (s, 3H, COCH ), 2.56 (s, 3H, 4-CH ) ppm.
1
H NMR (300 MHz, CDCl ): δ= 12.50 (br. s, ν = 30 Hz, 1H,
3
½
2
3
3
OH), 7.46 (t, 1H, H4’), 7.20 (dd, J = 7.9, 1.4 Hz, 1H, H6’), 7.16
13
(
d, J = 8.3 Hz, 1H, H3’), 6.96 (t, 1H, H5’), 3.66 (s, 3H, NCH3),
C NMR (150.94 MHz, CDCl ): δ= 186.9 (C=O), 158.8 (C-
2’), 141.7 (C-2), 141.6 (C-4), 132.0 (C-4’), 125.9 (C-6’), 123.6
(C-5), 119.4 (C-5’), 118.0 (C-3’), 110.7 (C-1’), 66.5 (OCH3),
3
2
.77 (s, 2H, CH ), 2.46 (s, 2H, CH ), 1.21 (s, 6H, 2CH ) ppm.
2 2 3
1
H NMR (300 MHz, DMSO-d ): δ= 12.86 (br. s, 1H, OH),
6
3
0.0 (COCH ), 16.7 (4-CH ) ppm.
3 3
7
2
2
.56 (d, J = 7.2 Hz, 1H, H6’), 7.48 (t, 1H, H4’), 6.96-7.04 (m,
H, H3’ and H5’), 3.66 (s, 3H, NCH ), 2.89 (s, 2H, CH ), 2.43 (s,
1
3
2
H NMR (600 MHz, DMSO-d , 293 K): δ= 12.16 (s, 1H, OH),
6
8.02 (dd, J = 8.0, 1.6 Hz, 1H, H6’), 7.39 (t, 1H, H4’), 6.98-7.04
H, CH ), 1.12 (s, 6H, 2CH ) ppm.
2
3
1
3
(m, 2H, H3’ and H5’), 3.98 (s, 3H, OCH ), 2.54 (s, 3H, COCH ),
3
3
C NMR (75.47 Hz, DMSO-d ): δ= 184.9 (C=O), 159.4
6
2
.49 (s, 3H, 4-CH ) ppm.
3
(
(
(
C2’), 141.9 (C2), 138.8 (C4), 132.6 (C4’), 129.8 (C6’), 121.9
C5), 120.3 (C3’), 118.6 (C5’), 111.2 (C1’), 52.0 (CH ), 34.4
C(CH ) ), 33.8 (CH ), 33.5 (NCH ), 27.9 (2CH ) ppm.
13
2
C NMR (150.94 MHz, DMSO-d ): δ= 187.2 (C=O), 158.1
6
3
2
2
3
3
(C-2’), 141.3 (C-2), 141.2 (C-4), 132.4 (C-4’), 127.2 (C-6’),
124.0 (C-5), 120.0 (C-5’), 117.8 (C-3’), 111.6 (C-1’), 67.4
+
MS(EI): m/z=286[M] . Anal. C H N O (286): calcd. C
7.13, H 6.29, N 9.79; found C 66.98, H 6.26, N 9.68.
16
18
2
3
(
OCH ), 30.3 (COCH ), 16.8 (4-CH ) ppm.
3 3 3
6
+
MS(EI): m/z=246[M] . Anal. C H N O (246): calcd. C
13
14
2
3
4
.2.9. 2-((Methylimino)methyl)phenol (14).
6
3.41, H 5.69, N 11.38; found C 62.95, H 5.99, N 11.38.
To aldehyde 5 (12.20 g, 0.10 mol) while stirring at room
temperature 40% aqueous solution of methyl amine (13.00 g)
containing 5.20 g (0.17 mol) was added dropwise. The mixture
was stirred at room temperature for 6 h, then sodium chloride
By-product: (1-(2-(2-hydroxyphenyl)-4-methyl-1H-imidazol-5-
1
yl)ethanone (29) H NMR (300 MHz, DMSO-d ): δ= 13.15 (br. s,
6
1H, NH), 12.30 (br. s, 1H, OH), 7.83 (d, J = 7.3 Hz, 1H, H-Ar),
(
3.6 g) was added. The product was extracted with ether (20
7.24-7.34 (m, 1H, H-Ar), 6.90-7.00 (m, 2H, H-Ar), 2.54 (s, 3H,
+
mL×2), the extract was dried over anhydrous potassium
carbonate. The solvent was removed under reduced pressure,
yielding 11.00 g (82%) of product 14 as a yellow liquid which
was used without further purification. H NMR (300 MHz,
CDCl ): δ= 13.48 (br. s, 1H, OH), 8.27 (s, 1H, NCH), 7.15-7.35
COCH ), 2.45 (s, 3H, CH ) ppm. MS(EI): m/z=216[M] .
3
3
4
.2.12. Ethyl 2-(2-hydroxyphenyl)-1-methoxy-4-
1
methyl-1H-imidazole-5-carboxylate(17).
To imidazole 26 (1.00 g, 0.0027 mol) dissolved in methanol
3
(20 mL) was added 10% palladium on carbon (0.10 g) and the
(m, 2H, H-Ar), 6.77-7.00 (m, 2H, H-Ar), 3.42 (s, 3H, CH ) ppm.
3
mixture was hydrogenated at room temperature and 1.3 atm for 4
h. The catalyst was filtered off and washed with methanol. The
solvent was removed from the filtrate under reduced pressure and
the residue was subjected to column chromatography (silica gel,
chloroform), yielding 0.15 g (20%) of pure product 17 (m.p. 119-
121 °C) and 0.55 g of starting imidazole 26.
4
.2.10. 2-(1-Methoxy-4,5-dimethyl-1H-imidazol-2-
yl)phenol (15).
To imidazole 24 (0.80 g, 0.0026 mol) dissolved in methanol
(20 mL) was added 10% palladium on carbon (0.1 g) and the
reaction mixture was hydrogenated at room temperature and 1.3
atm for 8 h. The catalyst was filtered off and washed with
methanol. The solvent was removed from the filtrate under
reduced pressure and the residue was subjected to column
chromatography (silica gel, chloroform), yielding 0.34 g (60%)
1
H NMR (300 MHz, DMSO-d ): δ= 12.18 (s, 1H, OH), 8.03
6
(d, J = 8.2 Hz, 1H, H6’), 7.38 (t, 1H, H4’), 6.95-7.03 (m, 2H, H3’
and H5’), 4.34 (q, 2H, OCH CH ), 4.03 (s, 3H, OCH ), 2.44 (s,
2
3
3
3
H, 4-CH ), 1.35 (s, 3H, OCH CH ) ppm.
3 2 3

1
2
Tetrahedron
1
3
C NMR (75.47 Hz, DMSO-d ): δ= 15
A
8.
C
1 (
C
C
E
=O
P
),
T
157
E
D
.5 MA4.
N
2.
U
16
S
.
C
1-
R
(2IP-(
T
2-(Benzyloxy)phenyl)-1-hydroxy-4-
6
(
(
(
C2’), 141.1 (C2), 140.9 (C4), 131.7 (C4’), 126.4 (C6’), 119.3
C5’), 117.2 (C3’), 115.1 (C5), 111.2 (C1’), 66.7 (OCH ), 60.4
OCH CH ), 15.3 (4-CH ), 14.0 (OCH CH ) ppm.
methyl-1H-imidazol-5-yl)ethanone (21).
3
A mixture of aldehyde 19 (5.00 g, 0.0236 mol), oxime 7 (3.0
g, 0.0236 mol) and ammonium acetate (2.7 g, 0.0351 mol) in
glacial acetic acid (45 mL) was stirred at 45-50 °C for 16 h. The
reaction mixture is then poured into water (150 mL), triturated
and the obtained precipitate is filtered off yielding 6.6 g (88%) of
2
3
3
2
3
+
MS(EI): m/z=276[M] . Anal. C H N O (276): calcd. C
14
16
2
4
6
0.87, H 5.80, N 10.14; found C 60.46, H 5.78, N 9.85.
1
4
.2.13. 2-(2-Hydroxyphenyl)-1-methoxy-5,5-
product 21 as beige solid. M.p. 180-182 °C. H NMR (300 MHz,
dimethyl-4,5,6,7-tetrahydro-1H-benzo[d] imidazole-
CDCl ): δ= 12.79 (br. s, 1H, OH), 7.76 (br. s, 1H, H-Ar), 7.25-
7.50 (m, 6H, H-Ar), 6.95-7.10 (m, 2H, H-Ar), 5.14 (s, 2H,
3
7
(4H)-one (18).
To imidazole 27 (1.00 g, 0.0027 mol) dissolved in methanol
20 mL) was added 10% palladium on carbon (0.10 g) and the
CH
Ph), 2.54 (s, 3H, COCH ), 2.49 (s, 3H, CH ) ppm. MS (EI):
2 3 3
+
(
m/z=322[M] .
mixture was hydrogenated at room temperature and 1.3 atm for 4
h. The obtained precipitate was filtered off together with the
catalyst and suspended in chloroform. The catalyst was filtered
off and solvent was removed from the filtrate under reduced
pressure yielding 0.27 g of product 18 as a white solid; m.p. 169-
4
.2.17. Ethyl 2-(2-(benzyloxy)phenyl)-1-hydroxy-4-
methyl-1H-imidazole-5-carboxylate(22).
A mixture of aldehyde 19 (5.30 g, 0.0250 mol), oxime 8 (4.0
g, 0.0252 mol) and ammonium acetate (2.6 g, 0.0338 mol) in
glacial acetic acid (40 mL) was stirred at room temperature for 9
h and left to stand for 4 d. The reaction mixture was poured into
water (150 mL), the product was extracted with chloroform (40
mL×2), the extract was washed with 2% solution of potassium
carbonate and with water and then dried over anhydrous
magnesium sulfate. The solvent was removed under reduced
pressure, the residue was subjected to column chromatography
(silica gel, eluent – chloroform, chloroform-methanol 100:1 –
1
70 °C. In order to obtain additional amount of 18, the solvent
from the filtrate after the reaction was removed under reduced
pressure and the residue was subjected to column
chromatography (silica gel, chloroform), yielding 0.15 g of
product 18, m.p. 169-170 °C and 0.22 g of starting material 27.
Total yield of product 18 0.42 g (55%).
1
H NMR (300 MHz, CDCl ): δ= 12.55 (br. s, ν = 24 Hz, 1H,
3
½
1
OH), 8.20 (d, J = 8.1 Hz, 1H, H6’), 7.36 (t, 1H, H4’), 7.07 (d, J =
10:1) to yield 3.0 g (34%) of product 22 as yellow oil. H NMR
8
2
.3 Hz, 1H, H3’), 6.95 (t, 1H, H5’), 4.14 (s, 3H, OCH ), 2.75 (s,
(300 MHz, CDCl ): δ= 11.03 (br. s, 1H, OH), 7.52-7.66 (m, 1H,
H-Ar), 7.28-7.45 (m, 6H, H-Ar), 7.00-7.11 (m, 2H, H-Ar), 5.17
3
3
H, CH ), 2.47 (s, 2H, CH ), 1.16 (s, 6H, 2CH ) ppm.
2
2
3
1
(s, 2H, CH
2
Ph), 4.43 (q, J=7.34 Hz, 2H, CH CH ), 2.50 (s, 3H,
2
3
H NMR (300 MHz, DMSO-d ): δ= 12.14 (s, 1H, OH), 8.04
6
CH ), 1.42 (t, J=6.97 Hz, 3H, CH CH ) ppm. MS (EI):
3
2
3
(
2
2
dd, J = 8.0, 1.6 Hz, 1H, H6’), 7.40 (t, 1H, H4’), 6.96-7.05 (m,
H, H3’ and H5’), 4.09 (s, 3H, OCH ), 2.74 (s, 2H, CH ), 2.45 (s,
H, CH ), 1.09 (s, 6H, 2CH ) ppm.
+
m/z=352[M] .
3
2
2
3
4.2.18. 2-(2-Benzyloxy)phenyl)-1-hydroxy-5,5-
dimethyl-4,5,6,7-tetrhydro-1H-benzo[d] imidazole-
13
C NMR (75.47 Hz, DMSO-d ): δ= 185.4 (C=O), 157.6
6
7
(4H)-one (23).
(
(
(
C2’), 148.2 (C2), 142.9 (C4), 132.1 (C4’), 126.6 (C6’), 120.4
C5), 119.4 (C5’), 117.2 (C3’), 111.1 (C1’), 66.6 (OCH ), 52.1
CH ), 37.7 (CH ), 35.3 (C(CH ) ), 27.8 (2CH ) ppm.
A mixture of aldehyde 19 (6.36 g, 0.0300 mol), oxime 9 (5.07
3
g, 0.0300 mol) and ammonium acetate (3.33 g, 0.0432 mol) in
glacial acetic acid (50 mL) was stirred at room temperature for 3
h and left to stand for 3 d. Then the reaction mixture was poured
into water (150 mL), the obtained precipitate was filtered off,
heated at reflux in acetonitrile and filtered off without cooling to
yield 6.64 g of chromatographically pure product 23 as a
yellowish solid; m.p. 218-220 °C. Cooling of the filtrate led to
the formation of precipitate which was also filtered off yielding
2
2
3 2
3
+
MS(EI): m/z=286[M] . Anal. C H N O (286): calcd. C
7.13, H 6.29, N 9.79; found C 66.96, H 6.19, N 9.61.
16
18
2
3
6
4
.2.14. 2-(Benzyloxy)benzaldehyde (19).
To a solution of aldehyde 5 (12.2 g, 0.10 mol) in ethanol (40
mL) a solution of benzyl chloride (13.9 g, 0.11 mol) in ethanol
50 mL) was added. The reaction mixture was stirred at reflux for
.5 h and filtered without cooling. From the filtrate the solvent
was removed under reduced pressure. The residue was dissolved
in sodium hydroxide solution (0.5 M, 60 mL), refluxed for 20
min, cooled to room temperature and filtered off, yielding 16.2 g
(
1
1
2
.74 g of product 23 as a yellowish crystalline solid; m.p. 221-
22 °C. Total yield 8.38 g (77%). H NMR (300 MHz, DMSO-
1
d6): δ= 11.74 (br.s, 1H, OH), 7.36-7.49 (m, 4H, H-Ar), 7.22-7.35
m, 3H, H-Ar), 7.11-7.19 (m, 1H, H-Ar), 6.98-7.09 (m, 1H, H-
Ar), 5.18 (s, 2H, CH Ph), 2.68 (s, 2H, CH ), 2.37 (s, 2H, CH ),
(
2
2
2
(
77%) of product 19 as a beige solid. M.p. 38-40 °C.
+
1
.08 (s, 6H, 2CH ) ppm. MS (EI): m/z=362[M] .
3
4
.2.15. 2-(2-(Benzyloxy)phenyl)-4,5-dimethyl-1H-
4
.2.19. 2-(2-(Benzyloxy)phenyl)-1-methoxy-4,5-
imidazol-1-ol (20).
dimethyl-1H-imidazole (24).
A mixture of aldehyde 19 (5.00 g, 0.0236 mol), oxime 6 (2.40
g, 0.0238 mol) and ammonium acetate (2.70 g, 0.0351 mol) in
glacial acetic acid (45 mL) was stirred at 45-50 °C for 5.5 h then
cooled to room temperature. The reaction mixture was poured
into water (140 mL), the product was extracted with chloroform
To a mixture of hydroxyimidazole 20 (1.50 g, 0.0050 mol)
and sodium hydride (0.12 g, 0.0050 mol) in THF (20 mL) at 0°C
methyl iodide (0.71 g, 0.0050 mol) was added dropwise while
stirring. Then the ice-bath was removed and the reaction mixture
was stirred at room temperature for 1 h and poured into water (40
mL). The product was extracted by ethyl acetate (25 mL), the
extract was washed with water and dried over anhydrous
magnesium sulfate. The solvent was removed under reduced
pressure and the residue was subjected to column
(
30 mL×2), the extract was sequentially washed with water and
sodium bicarbonate solution (2%, 50 mL). The obtained
precipitate was filtered off, yielding 6.5 (94%) of
chromatographically pure product 20 as a white solid. M.p. 160-
g
1
1
62 °C. H NMR (300 MHz, DMSO-d ): δ= 11.73 (br. s, 1H,
6
chromatography (silica gel, chloroform) to yield 0.40 g (26%) of
OH), 7.20-7.60 (m, 7H, H-Ar), 6.86-7.20 (m, 2H, H-Ar), 5.18 (s,
H, CH Ph), 2.08 (s, 3H, CH ), 2.00 (s, 3H, CH ) ppm. MS (EI):
1
product 24 as light-yellow thick oil. H NMR (300 MHz, CDCl ):
3
2
2
3
3
δ= 7.49 (dd, J 7.7 Hz, 1.8 Hz, 1H, H-Ar), 7.22-7.40 (m, 6H, H-
+
m/z=294[M] .
Ar), 6.95-7.06 (m, 2H, H-Ar), 5.12 (s, 2H, CH Ph), 3.69 (s, 3H,
2

1
3
OCH ), 2.22 (s, 3H, CH ), 2.20 (s, 3H, CH ) pp
3
m/z=308[M] .
A
C
C
m.
E
M
P
S
TE(E
D
I): MAN
T
U
he
S
e
C
xp
R
eri
I
mental data for structure 2 were deposited with
P
T
3
3
+
the Cambridge Crystallographic Data Centre (CCDC registration
number is 1056064). Copies of data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2, EZ, UK (fax: +44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
4
.2.20. 1-(2-(2-(Benzyloxy)phenyl)-1-methoxy-4-
methyl-1H-imidazol-5-yl)ethanone (25).
To a mixture of hydroxyimidazole 21 (1.50 g, 0.0046 mol)
and powdered potassium hydroxide (0.31 g, 0.0055 mol) in DMF
(10 mL) at 0°C methyl iodide (1.60 g, 0.0115 mol) was added
Table 7. Crystal data and structure refinement for compound
dropwise while stirring. Then the ice-bath was removed and the
reaction mixture was stirred at room temperature for 2 h and
poured into water (30 mL). The product was extracted by
tetrachloromethane (10 mL×3), the combined extracts were
washed with water and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
subjected to column chromatography (silica gel, chloroform) to
2
.
Empirical formula
Formula weight
12 12 2 3
C H N O
232.24
Temperature/K
Crystal system
Space group
a/Å
b/Å
c/Å
α/°
β/°
γ/°
Volume/Å
Z
ρ
173.15
monoclinic
P2 /n
1
7.9232(6)
11.0300(8)
12.3616(9)
90.00
91.3900(10)
90.00
1080.00(14)
4
1.428
1
yield 1.00 g (65%) of product 25 as yellow oil. H NMR (300
MHz, CDCl ): δ= 7.49-7.55 (m, 1H, H-Ar), 7.27-7.47 (m, 6H, H-
3
Ar), 7.00-7.10 (m, 2H, H-Ar), 5.14 (s, 2H, CH Ph), 3.76 (s, 3H,
2
OCH ), 2.57 (s, 3H, COCH ), 2.54 (s, 3H, CH ) ppm. MS (EI):
3
3
3
+
m/z=336[M] .
3
4
.2.21. Ethyl 2-(2-(benzyloxy)phenyl)-1-methoxy-4-
3
methyl-1H-imidazole-5-carboxylate (26).
calcg/cm


1
Similarly to 25 from hydroxyimidazole 22 (2.00 g, 0.0057
ꢁ/mm
0.105
mol) 1.00 g (48%) of product 26 was obtained as yellow
F(000)
Crystal size/mm
Radiation
2Θ range for data collection/° 4.96 to 61.08
Index ranges
Reflections collected
Independent reflections
Data/restraints/parameters
488.0
0.38 × 0.3 × 0.28
MoKα (λ = 0.71073)
1
3
crystallizing oil. H NMR (300 MHz; CDCl ): δ= 7.29-7.53 (m,
3
7
H, H-Ar), 6.97-7.10 (m, 2H, H-Ar), 5.15 (s, 2H, CH Ph),4.40
2
(
3
q, 2H, OCH CH ), 3.85 (s, 3H, OCH ), 2.55 (s, 3H, CH ),1.42 (t,
2
3
3
3
+
H, OCH CH ) ppm. MS (EI): m/z=366[M] .
-11 ≤ h ≤ 11, -15 ≤ k ≤ 15, -17 ≤ l ≤ 17
12523
3276 [Rint = 0.0220, Rsigma = 0.0191]
3276/0/158
1.046
2
3
4
.2.22. 2-(2-(Benzyloxy)phenyl)-1-methoxy-5,5-
dimethyl-4,5,6,7-tetrahydro-1H-benzo[d] imidazole-
7
(4H)-one (27).
2
Goodness-of-fit on F
To a mixture of hydroxyimidazole 23 (3.62 g, 0.0100 mol)
and powdered potassium hydroxide (0.65 g, 0.0116 mol) in DMF
15 mL) at 0°C methyl iodide (1.50 g, 0.0106 mol) was added
Final R indexes [I>=2σ (I)]
Final R indexes [all data]
Largest diff. peak/hole / e Å
R
R
1
= 0.0414, wR
= 0.0519, wR
2
2
= 0.1120
= 0.1209
1
-
3
(
0.33/-0.24
dropwise while stirring. Then the ice-bath was removed and the
reaction mixture was stirred at room temperature for 1.5 h and
poured into water (60 mL). The product was extracted by
tetrachloromethane (40 mL×2), the combined extracts were
washed with water and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure and the residue
Acknowledgements
This work was supported by the Ministry of Education and
Science of Russia under a state contract.
was triturated with ether yielding 2.27
g
(60%) of
chromatographically pure product 27 as white solid. M.p. 117-
1
1
18 °C. H NMR (300 MHz; CDCl ): δ= 7.40-7.54 (m, 2H, H-
3
Ar), 7.22-7.37 (m, 5H, H-Ar), 7.00-7.10 (m, 2H, H-Ar), 5.16 (s,
H, CH Ph), 3.93 (s, 3H, OCH ), 2.79 (s, 2H, CH ), 2.46 (s, 2H,
5. References
2
2
3
2
+
CH ), 1.17 (s, 6H, 2CH ) ppm. MS (EI): m/z=376[M] .
1. G.V. Nikitina, M.S. Pevzner, Chem. Heterocyl. Compd., 1993,
2
3
2
9(2), 127-151.
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3
.
.
M. Witschel, Bioorg. Med. Chem., 2009, 17(12), 4221-4229.
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Escario, Arch. Pharm. Pharm. Med. Chem., 2004, 337(5), 259-
270.
4
.3. X-Ray Determination
Crystals of C H N O (compound 2) were grown from a
12
12
2
3
toluene solution. A suitable single crystal was subjected to X-ray
measurements on aCCD area SMART-APEX-II diffractometer
under a stream of cooled nitrogen using graphite-monochramated
4. R.B. da Silva, U.B. Loback, K. Salomão, S.L. de Castro, J.L.
Wardell, S.M.S.V. Wardell, T.E.M.M. Costa, C. Penido,
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Molecules, 2013, 18(3), 3445-3457.
Mo-K radiation. The crystal was kept at 173.15 K during data
α
5
.
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Comput. Aided Mol. Des., 2010, 24(6-7), 475-484.
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21
refined in anisotropic approximation using Olex2 software.
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Positions of hydrogen atoms were calculated geometrically with
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determined objectively. The hydrogen atoms were refined using
4
580.
7
8
.
.
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“
riding” model.
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M.I. Rakhmanova, L.A. Sheludyakova, A.Ya. Tikhonov, S.V.
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M.B. Bushuev, B.A. Selivanov, N.V. Pervukhina, D.Ya. Naumov,
L.A. Sheludyakova, M.I. Rakhmanova, A.Ya. Tikhonov, S.V.
Larionov, J. Coord. Chem., 2014, 67(4), 611-622.
A summary of the crystallographic data and structure
determination parameters is provided in Table 8.
9
.

14
Tetrahedron
1
0. F.J. Allan, G.G. Allan, Chem. Ind. (London), 1964(11), 1837.
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Muicheartaigh, J.B. Thomson, J. Bull. Chem. Soc. Jpn., 1969,
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2(11), 3204-3207.
4. K. Volkammer, H.W. Zimmermann, Chem. Ber., 1969, 102(12),
177-4187.
5. S.O. Chua, M.J. Cook, A.R. Katrizky J. Chem. Soc. B, 1971,
350-2355.
6. W. Schilf, L. Stefaniak, M. Witanowski, G.A. Webb, J. Mol.
Structure, 1986, 140(3-4), 311-315.
7. M. Witanowski, L. Stefaniak, Bull. Pol. Acad. Sci., Chem., 1987,
1
1
1
1
1
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2
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5(7-8), 305-320.
8. M. Boiani, H. Cerecetto, M. González, O.E. Piro, E.E. Castellano,
J. Phys. Chem. A, 2004, 108(51), 11241-11248.
9. V.L. Rusinov, M.N. Kushnir, O.N. Chupakhin, G.G. Alexandrov,
Mendeleev Commun., 1993, 3(5), 213-214.
0. S.A. Amitina, A.Ya. Tikhonov, I.A. Grigor’ev, Yu.V. Gatilov,
B.A. Selivanov, Chem. Heterocycl. Compd., 2009, 45(6), 691-697.
1. G. Laus, V. Kahlenberg, Crystals, 2012, 2, 1492-1501.
2. E.B. Nikolaenkova, A.Ya. Tikhonov, S.A. Amitina, Yu. V.
Gatilov, Chem. Heterocycl. Compd., 2014, 50(5), 699-706.
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Tetrahedron, 2013, 69(15), 3249-3256.
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2
2
2
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S.M.S.V. Wardell, J.L. Wardell, Z. Kristallogr., 2014, 229(10),
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2
6. Ya. Kamitori, Heterocycles, 2000, 53(1), 107-113.
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5(21), 4695-4705.
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8. R.B. Sparks, A.P. Combs, Org. Lett., 2004, 6(14), 2473-2475.
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993, 34(49), 7961-7964.
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Supplementary Data
1
13
Copies of IR; H and C spectra.

ACCEPTED MANUSCRIPT
SupplementaryꢀInformation.ꢀ
. CopiesꢀofꢀIRꢀspectraꢀofꢀcompoundsꢀ
1
2
3
4
5
. CopiesꢀofꢀNMRꢀspectraꢀofꢀcompoundsꢀ
. NMRꢀspectraꢀofꢀcompoundꢀ2ꢀatꢀdifferentꢀtemperatures.ꢀ
. NMRꢀspectraꢀofꢀcompoundꢀ2ꢀatꢀdifferentꢀconcentrations.ꢀ
. NMRꢀspectraꢀofꢀcompoundꢀ2ꢀinꢀmixtureꢀofꢀsolvents.ꢀ
ꢀ
1
. CopiesꢀofꢀIRꢀspectraꢀofꢀcompoundsꢀ(KBr).ꢀ
ꢀ
2-(2-Hydroxyphenyl)-4,5-dimethyl-1H-imidazol-1-olꢀ(1).ꢀ
ꢀ
120
112
104
9
6
8
0
2
4
6
8
0
2
4
6
8
8
7
6
5
4
4
3
2
1
3431.36
H-bonded
OH-groups
3
045.6
2987.74
922.16
CH3
2
8
1649.14
Ph
754.17
1269.16
0
736.81
500
1305.81
4000
3500
3000
2500
2000
1500
1000
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
1
-(1-Hydroxy-2-(2-hydroxyphenyl)-4-methyl-1H-imidazol-5-yl)ethanoneꢀ(2).ꢀ
ꢀ
ꢀ
104
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded OH groups
8
7
6
5
4
4
3
2
1
N
O
H
N-OH
3025.48
2635.84
2738.07
C=O
1661.75
Ph
8
764.81
1
250.89
0
1465.96
1500
4000
3500
3000
2500
2000
1000
500
Wavenumber (cm-1)
ꢀ
IRꢀspectrumꢀofꢀhydrateꢀ(KBr):ꢀ
120
112
104
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded
OH
8
7
6
5
4
4
3
2
1
2792.93
3381.21
2908.65
NH
3116.97
3045.6
1303.88
N-O
C=O
Ph
1676.14
763.81
8
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
Ethylꢀ1-hydroxy-2-(2-hydroxyphenyl)-4-methyl-1H-imidazole-5-carboxylateꢀ(3).ꢀ
ꢀ
120
112
104
9
6
8
0
2
4
6
8
0
2
4
6
H-bonded OH groups
8
8
7
6
5
4
4
3
2
1
N
O H
2372.44
2571.11
2773.64
N-OH
2899.01
2981.95
Ph
8
C=O
1
485.19
7
67.67
0
1
708.93
2000
Wavenumber (cm-1)
1184.29
4000
3500
3000
2500
1500
1000
500
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
1
-Hydroxy-2-(2-hydroxyphenyl)-5,5-dimethyl-4,5,6,7-tetrahydro-1H-
benzo[d]imidazole-7(4H)-oneꢀ(4).ꢀ
ꢀ
1
12
04
1
9
6
8
0
2
4
6
8
0
2
4
6
H-bonded OH groups
8
8
7
6
5
4
4
3
2
1
N
O H
2
598.12
2694.56
2652.12
N-OH
CH2
3
132.4
3084.18
2956.88
Ph
8
C=O
756.1
0
1666.5
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
2
-(2-Hydroxyphenyl)-1,4,5-trimethyl-1H-imidazoleꢀ3-oxideꢀ(10).ꢀ
ꢀ
1
12
04
1
OH
9
6
8
0
2
4
6
8
0
2
4
6
CH3
8
8
7
6
5
4
4
3
2
1
2
2
364.73
345.44
3
016.67
951.09
924.09
2
2
1
643.35
581.63
388.75
1
1284.59
1
1330.88
Ph
8
775.38
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
4
-Acetyl-2-(2-hydroxyphenyl)-1,5-dimethyl-1H-imidazoleꢀ3-oxideꢀ(11).ꢀ
ꢀ
1
12
04
1
9
6
8
0
2
4
6
8
0
2
4
6
OH
8
8
7
6
5
4
4
3
2
1
2576.9
2916.37
3028.24
1
303.88
Ph
8
N-O
C=O
767.67
0
1670.35
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
4
-(Ethoxycarbonyl)-2-(2-hydroxyphenyl)-1,5-dimethyl-1H-imidazoleꢀ3-oxideꢀ(12).ꢀ
ꢀ
120
112
104
OH
9
6
8
0
2
4
6
8
0
2
4
6
2
534.46
8
8
7
6
5
4
4
3
2
1
2980.02
Ph
1579.7
756.1
1300.02
N-O
C=O
8
1730.15
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
2
-(2-Hydroxyphenyl)-1,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-
benzo[d]imidazoleꢀ3-oxideꢀ(13).ꢀ
ꢀ
1
12
04
1
OH
9
6
8
0
2
4
6
8
0
2
4
6
8
2588.47
8
7
6
5
4
4
3
2
1
CH2
2
2
989.66
962.66
1303.88
N-O
Ph
1381.03
756.1
1489.05
C=O
1678.07
8
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
2
-(1-Methoxy-4,5-dimethyl-1H-imidazol-2-yl)phenolꢀ(15).ꢀ
ꢀ
120
112
104
9
6
8
0
2
4
6
8
0
2
4
6
8
8
7
6
5
4
4
3
2
1
H-bonded
OH
N
O H
2577.01
OCH3
CH3
8
Ph
2855.73
2
950.25
0
1
261.5
2
921.32
1479.47
1500
758.06
4000
3500
3000
2500
2000
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
1
-(2-(2-hydroxyphenyl)-1-methoxy-4-methyl-1H-imidazol-5-yl)ethanoneꢀ(16).ꢀ
ꢀ
1
12
04
1
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded
OH
8
7
6
5
4
4
3
2
1
N
O H
2718.78
OCH3
2942.53
Ph
7
64.81
8
C=O
1
250.89
0
1
662.71 1373.38
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
Ethylꢀ2-(2-hydroxyphenyl)-1-methoxy-4-methyl-1H-imidazole-5-carboxylateꢀ(17).ꢀ
ꢀ
1
12
04
1
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded
8
7
6
5
4
4
3
2
1
OH
N
O H
2632.83
2702.27
CH2
OCH3
939.52
2
2
981.95
Ph
8
C=O
0
765.74
1000
1
708.93
4000
3500
3000
2500
2000
1500
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
2
-(2-Hydroxyphenyl)-1-methoxy-5,5-dimethyl-4,5,6,7-tetrahydro-1H-
benzo[d]imidazole-7(4H)-oneꢀ(18).ꢀ
ꢀ
104
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded
OH
8
7
6
5
4
4
3
2
1
N
O H
2611.62
2708.06
OCH3
2870.08
CH2
2954.95
2962.66
8
C=O
Ph
0
1257.59
1500
1662.64
759.95
1000
4000
3500
3000
2500
2000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
(
1-(2-(2-hydroxyphenyl)-4-methyl-1H-imidazol-5-yl)ethanoneꢀ(29)ꢀ
ꢀ
104
9
6
8
0
2
4
6
8
0
2
4
6
8
H-bonded
OH
8
7
6
5
4
4
3
2
1
N
O
H
2715.89
2961.82
NH
3092.99
Ph
763.84
C=O
8
1653.07
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm-1)
ꢀ
ꢀ
ꢀ

ACCEPTED MANUSCRIPT
2
. CopiesꢀofꢀNMRꢀspectraꢀofꢀcompounds.ꢀ
2
-(2-Hydroxyphenyl)-4,5-dimethyl-1H-imidazol-1-olꢀ(1).ꢀ
1
HꢀNMRꢀinꢀDMSO-d ꢀ(300ꢀMHz)ꢀ
6
13CꢀNMRꢀinꢀDMSO-d
ꢀ(75.48ꢀMHz)ꢀ
6
ꢀ
ꢀ
ꢀ
ꢀ