Synthesis and study of prototropic tautomerism of 2-(3-chromenyl)-1- hydroxyimidazoles

Article abstract of DOI:10.1016/j.tet.2013.02.039

A series of novel derivatives of imidazole containing a chromenyl moiety in position 2 of the ring has been synthesized. A characteristic response of the chromenyl ring H-2 proton to its environment allows the study of the prototropic tautomerism of novel 1-hydroxyimidazoles in solution using ¹H NMR spectroscopy. It has been shown that the predominance of one or another tautomer depends on the nature of the substituents of the imidazole ring, and the proton-donating/proton-withdrawing properties of a solvent. X-ray diffraction data for two of the compounds has revealed that in the solid state these 1-hydroxyimidazole derivatives exist as N-oxide tautomers.

Full text of DOI:10.1016/j.tet.2013.02.039

Accepted Manuscript
Synthesis and study of prototropic tautomerism of 2-(3-chromenyl)-1-
hydroxyimidazoles
Polina A. Nikitina, Ludmila G. Kuz’mina, Valery P. Perevalov, Iosif I. Tkach
PII:
S0040-4020(13)00250-0
10.1016/j.tet.2013.02.039
TET 24034
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 December 2012
Revised Date: 24 January 2013
Accepted Date: 11 February 2013
Please cite this article as: Nikitina PA, Kuz’mina LG, Perevalov VP, Tkach II, Synthesis and study of
prototropic tautomerism of 2-(3-chromenyl)-1-hydroxyimidazoles, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.02.039.
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Synthesis and Study of Prototropic
Tautomerism of 2-(3-Chromenyl)-1-
Hydroxyimidazoles
Leave this area blank for abstract info.
Polina A. Nikitinaa, Ludmila G. Kuzminab, Valery P. Perevalova, Iosif I. Tkacha,*
aD.Mendeleyev University of Chemical Technology of Russia, Miusskaya sq., 9, Moscow, 125047, Russia
bKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science, Leninskii pr., 31, Moscow, 117907, Russia

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1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis and study of prototropic tautomerism of 2-(3-chromenyl)-1-
hydroxyimidazoles
Polina A. Nikitinaa , Ludmila G. Kuz’minab, Valery P. Perevalova , and Iosif I. Tkacha,*
aDepartment of Fine Organic Synthesis and Chemistry of Dyes, D.Mendeleyev University of Chemical Technology of Russia, Miusskaya sq., 9, Moscow, 125047,
Russia
bKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Science, Leninskii pr., 31, Moscow, 117907, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of novel derivatives of imidazole containing a chromenyl moiety in position 2 of
the ring has been synthesized.
A characteristic response of the chromenyl ring H-2 proton to its environment allows the
1
study of the prototropic tautomerism of novel 1-hydroxyimidazoles in solution using H
Available online
NMR spectroscopy. It has been shown that the predominance of one or another tautomer
depends on the nature of the substituents of the imidazole ring, and the proton-
donating/proton-withdrawing properties of a solvent.
X-ray diffraction data for two of the compounds has revealed that in the solid state these 1-
hydroxyimidazole derivatives exist as N-oxide tautomers.
Keywords:
Prototropic tautomerism
1-Hydroxyimidazole
Imidazole N-oxide
2-(3-Chromenyl)imidazole
NMR spectroscopy
X-ray diffraction
1. Introduction
Prototropic
tautomerism
of
aryl-substituted
1-
1-Hydroxyimidazole derivatives exhibit various kinds of
biological activity. They display insecticidal1,2,3 and bacteriostatic
properties;4,5 antiviral6,7 and antihypertensive8 activities; they are
also considered as potent AMPA receptor agonists9 and so on. 1-
Hydroxyimidazoles are also valuable intermediates for the
synthesis of imidazole derivatives (see, e.g., reviews;10,11
papers12-16).
hydroxyimidazoles was discussed in a series of papers published
in 1960s17-21. In the paper of A.R. Katrizky,21 the results of
previous publications have been critically considered. For 2,4,5-
triphenylimidazole 3-oxide and benzimidazole 3-oxide, it has
been shown that these compounds exist predominantly in the N-
hydroxy- form in nonpolar solvents, the content of the NH-form
being increased as the polarity of a solvent increases. The main
conclusions were based on the similarity of the absorption
spectra of the compounds under consideration, and model
compounds (N- and O-methyl derivatives), and the comparison
of their pKa values in aqueous solution.
It is supposed that 1-hydroxyimidazole derivatives exist in
either N-hydroxy (a) or N-oxide (b) tautomeric form:
A few studies of the prototropic tautomerism of related
compounds (1-hydroxybenzimidazole derivatives) are also
known.22-25 The prototropic tautomerism of 6-nitro- and 6-
ethoxycarbonyl-1-hydroxybenzimidazol-2-carboxylic
acids
1
derivatives has been studied by H and 13C NMR spectroscopy,
Figure 1. Prototropic tautomerism of 1-hydroxyimidazoles.
———
* Corresponding author. Tel.: +7-499-978-8842; e-mail: iosif_tkach@mail.ru

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2
Tetrahedron
quantum-chemical calculations, and X-ray structural analysis.25
In order to compare properties of 1-hydroxyimidazoles with 1-
substituted imidazole 3-oxide, novel 2-chromenyl-substituted
imidazole 3-oxide 14 was synthesized. Condensation was carried
out in glacial acetic acid at room temperature, with benzylamine
15 being used as the amine constituent.
The main conclusion is that only the N-hydroxy form of these
compounds may exist in the solid state. In solution,
predominance of one of the tautomeric forms has been explained
by a trend of the solvent forming hydrogen bonds (hydrogen-
bond-donor HBD or hydrogen-bond-acceptor HBA) rather than
solvent polarity.
a
To the best of our knowledge, other papers concerning
prototropic tautomerism in 1-hydroxyimidazoles are lacking.
Apparently, it is explained by the use of these compounds mainly
as intermediates in the syntheses of imidazoles. Recently,
however, research interest in the biological activity of 1-
hydroxyimidazoles (see, e.g.,3,9
)
and their coordinating
Scheme 3. Synthesis of imidazole N-oxide 14.
properties26,27 has increased. From this point of view, it is
reasonable to return to the investigation of prototropic
tautomerism of 1-hydroxyimidazoles.
As is known, 1-hydroxyimidazoles may be easily reduced into
In our opinion, the study of 1-hydroxyimidazole derivatives
capable of intramolecular hydrogen-bond formation may be of
particular interest. In this work, we investigate 2-(3-chromenyl)-
substituted 1-hydroxyimidazoles containing (or not containing)
the carbonyl group in position 5 of the imidazole ring.
the
corresponding
imidazoles
by
refluxing
with
triphenylphosphine in glacial acetic acid. This was demonstrated
on 1-hydroxyimidazole 4:
2. Results and Discussion
2.1. Synthesis of 2-Chromenyl Substituted 1-Hydroxyimidazoles
One of the most convenient and wide-spread methods to
synthesise 1-hydroxyimidazoles is the cyclization of α-
hydroxyiminoketones with aldehydes and ammonium acetate
(see, e.g.,3, 27-29). The reaction is carried out either in alcohol or in
glacial acetic acid. The temperature of the reaction may vary.
Scheme 4. Reduction of 1-hydroxyimidazole 4.
All novel imidazole derivatives (1-4, 14) were characterized
by 1H and 13C NMR spectroscopy and mass spectrometry,
elemental analysis, and melting point data.
Novel 1-hydroxyimidazoles 1-4 were obtained by
condensation of 4-oxo-4H-chromenyl-3-carbaldehyde 5 with
ammonium acetate and the corresponding oxime 6-9 in glacial
acetic acid at room temperature.
2.2. Study of Prototropic Tautomerism of 2-Chromenyl
Substituted 1-Hydroximidazoles in Solution
Prototropic tautomerism of heterocyclic compounds in
solution is widely studied by means of NMR spectroscopy (see,
e.g.,25, 33, 34). This method may be useful and informative in the
case of 1-hydroxy-2-chromenylimidazoles 1 – 4. It will be shown
in the further discussion that chemical shifts of the proton at the
C-2 atom (НС2) of the chromenyl moiety are different for the N-
hydroxy- and N-oxide tautomers.
In order to escape the possible (though unlikely) influence of
the C-H-acidity at the C-2 atom (НС2) of the chromenyl ring and
following exchange processes, the NMR spectra of protonated
compounds 1 – 4 and 14 were recorded in CD3CN with the
addition of ~10 equivalents of trifluoromethanesulfonic acid, and
in trifluoroacetic acid. In both cases the НС2 signal appears as a
narrow singlet (Table 1), which precludes the exchange process.
Scheme 1. Synthesis of 2-chromenyl-substituted
1-hydroxyimidazoles
Starting aldehyde
5
was obtained by treatment of
hydroxyacetophenone 10 with phosphorous-oxychloride in
dimethyl formamide.30 Starting oximes 7-9 were obtained by
nitrosation of the corresponding diketones 11-13 by techniques
close to those described in literature.31,32 Butandione monoxime 6
is commercially available.
Table 1. Chemical shifts for the НС2 proton of protonated
forms of compounds 1-4 and 14.
Solvent
1
2
3
4
14
CD3CN + CF3SO3H
CF3COOH
9.29
9.44
9.36
9.59
9.47
9.70
9.40
9.57
8.82
8.40
In the 1H NMR spectra recorded in deuterated chloroform, the
НС2 signal is found either at 10.62 ppm (compound 1), or at 8.93
ppm (compound 3), or it appears as two signals in the 8.65 – 8.85
and 10.66 – 10.79 ppm ranges, that correspond to different
tautomeric forms (Table 2 and Figure 2). The low-field signals in
the 11.2 – 13.2 ppm range are attributed to the OH (NH) group
protons. A comparison of the positions of the signals for НС2 in
Scheme 2. Synthesis of starting compounds.

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3
compounds 1 – 4 with that in compound 14 makes it possible to
1
conclude that the signals in the ranges 10.62 – 10.79 and 11.22 –
12.16 ppm correspond to the НС2 and ОH-group protons of the N-
hydroxy tautomer (а), whereas the signals in the 8.65 – 8.93 and
12.73 – 13.15 ppm ranges refer to the НС2 and NH protons of the
N-oxide form of imidazole (b). Thus, in deuterochloroform 4,5-
dimethylimidazole 1 exists exclusively as the N-hydroxytautomer
(a), whereas 5-carbonyl-substituted imidazoles (2 – 4) exist either
as the N-oxide tautomer (b) (compound 3) or as an equilibrium
mixture of the tautomers (compounds 2 and 4) where the N-
hydroxy- form (а) prevails (integration of signals in the NMR
spectra allows a rough estimation of the tautomer ratio to make,
viz, (а) : (b) ≈ 2 : 1). For compound 4, a transition of one
tautomer into another one proceeds rather quickly, which is
indicated by a broad НС2 signal in the range 9.0 – 9.3 ppm
(coalescence point). Lowering the temperature to 242K allows us
to observe the signals of both tautomers of this compound. It
should be noted that, for compound 3 in chloroform, the
integrated intensity of the НС2 signal is slightly understated.
0.02
0.01
H-2
OH
0.780.83
13
12
11
10
9
Chemic al Shift (ppm)
2
H-2
NH
0.2
0.1
H-2
OH
0.26
13
0.67
0.67
0.24
9
12
11
10
Chemical Shift (ppm)
3
0.050
1
However, the H NMR spectrum at decreased temperatures does
not reveal any “new” signals that could be attributed to another
tautomeric form (a).
NH
H-2
0.025
Table 2. Chemical shiftsa of characteristic protons in various
solvents.
0.77
13
0.66
9
12
11
10
Chemical Shift (ppm)
CDCl3
OH
[D6]DMSO
CD3CN
H-2
CD3OD
H-2
4
H-2
H-2
OH
(NH)
(NH)
0.075
H-2
OH
1
2
10.79
8.85
11.22
(OH)
12.88
(NH)
11.79
(OH)
12.73
(NH)
13.15b
(NH)
12.16b
(OH)
-
10.62
8.74
11.89
(OH)
11.94
(NH)
10.48
10.15
0.050
0.025
NH
H-2
non
non
0.36
13
0.58
12
0.59
11
0.31
soluble
soluble
10
9
10.79
8.93
Chemical Shift (ppm)
14
3
4
8.76
8.73
11.60
(NH)
11.92
(NH)
9.23 (br)
9.25 (br)
9.57 (br)
9.60 (br)
0.4
0.3
0.2
0.1
H-2
8.65b
10.66b
8.70
0.82
13
12
11
10
9
Chemical Shift (ppm)
14
a δ, ppm
8.69
-
8.41
8.40
Figure 2. 8.5 – 13.5 range of 1H NMR spectra of compounds
1-4, 14 registered in CDCl3.
b The spectrum was recorded at 242К.
In more polar aprotic ([D6]DMSO and CD3CN) and protic
(CD3OD) solvents, the situation is roughly similar. Thus,
according to the agreement of the chemical shifts for НС2 of
compounds 2 – 4 and N-oxide 14, it may be established that, in
strongly polar aprotic [D6]DMSO, 5-carbonyl-substituted
imidazoles (2 - 4) exist as N-oxide tautomers (b), while, in the
case of 4,5-dimethylimidazole 1, the signal of the similar proton
is shifted downfield by near 2 ppm (hydroxytautomer (а)). In less
polar acetonitrile, the signal of НС2 for compound 1 appears at
10.48 ppm, which qualitatively coincides with the position of this
signal in СDCl3 and [D6]DMSO (hydroxytautomer (а)). For
compounds 3 and 4, the НС2 signals are broadened and they
appear in the range 9.2 – 9.3 ppm (an intermediate between
positions for compounds 1 and 14, see Table 2), which indicates
the existence of the tautomeric equilibria.
In polar protic CD3OD, the situation is quite similar to that
observed in acetonitrile. Unfortunately, it was impossible to
record the NMR spectra of compounds 3, 4 in CD3CN and
CD3OD at a lower temperature because of their poor solubility in
these solvents.

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4
Tetrahedron
So, 4,5-dimethylimidazole 1 exists in solution as the N-
hydroxytautomer regardless of the nature of the solvent. In a
hydrogen-bond acceptor, [D6]DMSO, 5-carbonyl substituted
imidazoles 2 – 4 exist in the N-oxide form. In a weak hydrogen-
bond donor, CDCl3, compound 3 containing a fixed carbonyl
group in 5 position also exists as a N-oxide tautomer. Evidently,
it can be explained by the favourable conditions for conjugation
in enaminone moiety, that is additionally stabilized by the
intramolecular hydrogen bond between N-H proton and carbonyl
oxygen in the chromenyl part of the molecule.
Figure 4. Compound 1. Molecular structure thermal atomic
displacement parameter are given at the 50% probability
level.
Selected bond lengths are listed in Table 3.
Figure 3. Enaminone structure.
Table 3. Selected bond lengths (Å) in molecules.
Compound 1 Compound 3
The weakening of conjugation due to the possibility of
carbonyl group rotation in compounds 2 and 4 in СDCl3, and also
the increase in proton-donating ability of a solvent (CD3CN and
CD3OD), that loosens the intramolecular hydrogen bond
(compounds 2 and 4), favours the occurence of the second (N-
hydroxy) tautomer (a). This leads to the mixture of tautomers in
solution.
1.238(4)
1.362(4)
1.382(4)
1.349(4)
-
1.230(2)
1.343(2)
1.367(2)
1.321(2)
1.219(2)
1.339(2)
1.393(2)
1.354(2)
1.364(2)
1.463
O1−C1
O2-C3
O2-C4
O3-N1
O4-C13
N1-C10
N1-C12
N2-C11
N2-C10
C1-C2
C1-C5
C2-C3
C2-C10
C4-C5
C4-C9
C5-C6
C6-C7
C7-C8
C8-C9
1.346(5)
1.399(5)
1.373(5)
1.371(5)
1.469(5)
1.467(5)
1.366(5)
1.446(5)
1.388(5)
1.398(2)
1.405(5)
1.373(5)
1.414(6)
1.379(6)
Thus, for this series of compounds, the N-oxide form prevails
only in molecules stabilized by conjugation in the enaminone
structure in the absence of strong proton-donating solvent
properties.
It should be mentioned that a high sensitivity of the НС2 proton
of the chromenyl ring towards the influence of atom environment
is typical not only for 1-hydroxyimidazole derivatives but also
for imidazoles themselves.
1.474(2)
1.350(2)
1.454(2)
1.383(2)
1.398(2)
1.406(2)
1.372(3)
1.396(3)
1.363(3)
1.372(2)
-
In the 1H NMR spectrum of compound 16, recorded in
deuterated chloroform, the НС2 proton signal appears as two
singlets at 9.19 and 9.09 ppm (the ratio of integrated intensities is
1 : 1.2). The signals of aliphatic protons are also doubled.
Specifically, the methyl group in the 4(5) position of the
imidazole ring reveals two singlets at 2.64 and 2.56 ppm (the
ratio of integrated intensities is 1 : 1.2). Obviously, it is related to
the migration of the proton between the nitrogen atoms of
imidazole ring, rather than possible conformers obtained as a
result of the rotation around the bond between two heterocycles,
otherwise in the latter case the signal of the methyl group protons
should not be split.
C11-C12 1.363(5)
C11-C14 1.504(5)
C11-C16
-
1.479(2)
1.450(2)
1.509(2)
1.537(3)
1.540(2)
C12-C13 1.482(5)
2.3. Study of Prototropic Tautomerism of 2-Chromenyl
Substituted 1-Hydroxyimidazoles in Solid State
C13-C14
C14-C15
C15-C16
-
-
-
X-ray analysis data have been obtained for compounds 1 and
3.
The structures of formula units are shown in Figures 4 and 7.
Molecules of 1 are packed in infinite chains through hydrogen
bonds of the type O3…H2−N2 (see Figures 4 and 5). Geometric
parameters of these bonds are as follows: O3…H2 2.312 Å, angle
at H2 atom 130°, angle at O3 atom 134.1°. These parameters
correspond to a rather weak interaction.

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5
Figure 5. Fragment of crystal packing for compound 1.
Figure 8. Fragment of crystal packing of compound 3.
It is seen from the projection of the crystal packing that
solvate methanol molecules are situated in the cavities between
the main molecules in the vicinity of the O3 atom of the main
molecules. In all orientations of the disordered solvent molecules,
their hydroxyl groups (O1S) are turned towards the O3 atoms.
This means that solvent molecules are involved in crystal
packing due to hydrogen bonds. The distances between the
oxygen atoms of disordered methanol and the O3 atom lies
within the range 2.535 – 2.887 Å, typical for hydrogen bonds
O−H…O.
Figure 6. System of hydrogen bonds in crystals of compound
1; labels A, B, C and D in atom denotation indicate different
molecules.
Figure 9 shows the system of hydrogen bonds within the
crystal. The molecules are combined in endless chains due to
hydrogen bonding O4…H2A−N2. The distances O4…N2 and
O4…H2A (2.915(2) 2.21 Å, respectively) correspond to
N−H…O hydrogen bond, although the angle at H2A hydrogen
atom is equal to 139°. This indicates that the location of the
hydrogen atom is not optimal, and this hydrogen bond should be
rather weak. In the chain, the molecules that have labels C and D,
as well A and B in atom denotation are related by translation
along the c-axis. Pairs of molecules with labels A and C, as well
as D and B are related via 21 axes.
Figure 7. Compound 3. Structure of formula units; thermal
atomic displacement parameters are given at the level of 30%
probabililty.
As a whole, compound 3 is planar, with the exception of
saturated fragment C13…C18. The C13-C12-C11-C16 fragment
is planar, whereas atoms C14 and C15 are displaced from the
plane of the planar fragment by 0.243 and -0.466 Å, respectively.
Methyl groups at C17 and C18 have equatorial and axial
orientations, respectively.
Some bond length alternation is observed in the C4…C9
benzene ring. In the crystal, the molecules are linked by
hydrogen bonds (Figure 8).

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6
Tetrahedron
Figure 9. System of hydrogen bonds in crystal of compound
A mixture of aldehyde 5 (4.0 g, 0.023 mol), oxime 6 (2.3 g,
0.023 mol) and ammonium acetate (2.5 g, 0.032 mol) in glacial
acetic acid (30 mL) was stirred at room temperature for 12 hours
and left to stand overnight. The precipitate was filtered off and
washed with ether. The filtrate was poured into water (100 mL),
and the precipitate filtered off and dried. The precipitates were
combined (5.8 g) and recrystallized from toluene yielding 4.7 g
(80%) of product 1 as yellow solid as the mono-hydrate; m.p.
178-180°С. After drying under reduced pressure over P2O5 m.p.
is 203-204°С.
1H NMR (300 MHz, CDCl3, 299K): δ = 11.20 (br. s, 1H, OH);
10.79 (br. s, 1H, HAr-2); 8.30 (dd J = 8.07 Hz, 1H, HAr-5); 7.73 -
7.82 (m, 1H, HAr-7); 7.60 (d, J = 8.07 Hz, 1H, HAr-8); 7.45 - 7.53
(m, 1H, HAr-6); 2.28 (s, 3H, CH3); 2.25 (s, 3H, CH3) ppm.
1H NMR (300 MHz, [D6]DMSO, 302K): δ = 11.89 (br. s,
0.7H, OH); 10.62 (br. s, 0.7H, HAr-2); 8.10 - 8.25 (m, 1H, H-Ar);
7.67 - 7.92 (m, 2H, H-Ar); 7.50 - 7.60 (m, 1H, H-Ar); 2.18 (s,
3H, CH3); 2.06 (s, 3H, CH3) ppm.
1H NMR (300 MHz, CF3COOH, 296K): δ = 9.44 (s, 1H, HAr-
2); 8.12 - 8.21 (m, 1H, H-Ar); 7.80 - 7.90 (m, 1H, H-Ar); 7.50 -
7.68 (m, 2H, H-Ar); 2.29 (s, 3H, CH3); 2.26 (s, 3H, CH3) ppm.
1H NMR (300 MHz, CD3CN, 300K): δ = 10.48 (s, 1H, HAr-
2); 8.23 (d, J = 8.07 Hz, 1H, H-Ar); 7.75 - 7.85 (m, 1H, H-Ar);
7.50 - 7.66 (m, 2H, H-Ar); 2.22 (s, 3H, CH3); 2.11 (s, 3H, CH3)
ppm.
1H NMR (300 MHz, CD3CN+CF3SO3H, 301K): δ = 9.29 (s,
1H, HAr-2); 8.27 - 8.35 (m, 1H, H-Ar); 7.92 - 8.04 (m, 1H, H-Ar);
7.62 - 7.82 (m, 2H, H-Ar); 2.34 (s, 3H, CH3); 2.30 (s, 3H, CH3)
ppm.
1H NMR (300 MHz, CD3OD, 300K): δ = 10.15 (s, 1H, HAr-
2); 8.24 - 8.31 (m, 1H, H-Ar); 7.80 - 7.89 (m, 1H, H-Ar); 7.64 -
7.71 (m, 1H, H-Ar); 7.50 - 7.58 (m, 1H, H-Ar); 2.29 (s, 3H,
CH3); 2.20 (s, 3H, CH3) ppm.
13C NMR (75.48 MHz, [D6]DMSO): δ = 173.8, 155.3, 155.3,
155.2, 134.6, 125.9, 125.2, 124.2, 123.0, 121.5, 120.9, 118.6,
10.4, 6.9 ppm.
3; labels A, B, C and D in atom denotation indicate different
molecules.
According to the X-ray analysis data, both compounds 1 and
3, in the solid state exist as N-oxide tautomers, the difference in
topology of the intermolecular bonds in these molecules being
rather interesting.
Thus, in the crystal form, molecules of compound 1 are bound
into long chains via hydrogen bonds between the oxygen atom of
the N-oxide group and the NH-moiety of the adjacent molecule
(that is, they are ordered by imidazole fragments).
As for compound 3, its NH-moiety is bound by hydrogen
bonds with the carbonyl in the 5 position of the imidazole ring of
the adjacent molecule, the N-oxide oxygen atom being excluded
from formation of the H-bond.
In both cases the carbonyl oxygen atom of the chromenyl
moiety does not participate in the formation of chains.
3. Conclusion
In the crystal state, substituted imidazoles 1 and 3 exist in the
N-oxide tautomeric form. However, the crystal packing of these
two compounds is different.
A rather close packing of the molecules in the crystal, and the
presence of long chains for 4,5-dimethylimidazole derivative 1
are caused by hydrogen bonds between the imidazole N-oxide
moieties of the molecules.
The presence of a bulky annulated ring in the 4,5 positions of
the imidazole moiety of compound 3 prevents the formation of an
ordered chain structure.
In relatively dilute solution, regardless of the polarity and
proton-donor (proton-acceptor) properties of the solvent, in the
case of 4,5-dimethyl-2-chromenyl-1-hydroxyimidazole 1 the
tautomeric equilibrium between N-hydroxy- (a) and N-oxide (b)
forms is shifted to the N-hydroxy tautomer that is apparently
more thermodynamically favourable. The introduction of a
carbonyl group in position 5 of the 1-hydroxyimidazole shifts the
equilibrium to the N-oxide tautomer (b), that becomes more
energetically favorable due to the conjugation between the
endocyclic amino group of the imidazole moiety and the carbonyl
group (an enaminone chain). The more effective this conjugation
is (fixed carbonyl group, absence or very weak proton-donating
properties of the solvent), the more the tautomeric equilibrium is
shifted to the N-oxide form (b).
MS (EI): m/z = 256 [M]+.
Anal. C14H12N2O3 ·H2O (274): calcd. C 61.31, H 5.11, N
10.22; found C 61.11, H 5.07, N 9.89.
Anal. C14H12N2O3 (256): calcd. C 65.63, H 4.69, N 10.94;
found C 65.78, H 4.73, N 10.90.
IR νmax (KBr) 3400-3000 (br), 2924, 1650, 1637, 1613, 1572,
1463, 1372, 1300, 1261, 1225, 1208, 1163, 1086, 849, 794, 757,
703, 675, 591, 519 cm-1.
4. Experimental Section
4.1. General
νmax (film) 3400-3000 (br), 2924, 1650, 1633, 1614, 1572,
1464, 1373, 1300, 1263, 1227, 1209, 1163, 1087, 849, 789, 758,
704, 675, 638, 590, 518 cm-1.
Chemicals were purchased from commercial sources and were
1
used without further purification. H and 13C NMR spectra were
recorded with Bruker VP-200 or Bruker AvanceTM-300
spectrometers with the residual solvents as internal standards.
4.2.2. 3-(5-Acetyl-1-hydroxy-4-methyl-1H-imidazol-2-yl)-4H-
chromen-4-one (2).
Mass-spectra were recorded with
a
LKB-2000 mass
spectrometer. Infrared spectra of solids were recorded with
Shimadzu IRAffinity-1 FTIR spectrophotometer as film obtained
from chloroform solution or with Nicolet Magna 750 IR
spectrophotometer in a KBr matrix.
A mixture of aldehyde 5 (4.0 g, 0.023 mol), oxime 7 (3.0 g,
0.023 mol) and ammonium acetate (2.5 g, 0.032 mol) in glacial
acetic acid (30 mL) was stirred at room temperature for 11 hours
and left to stand for 3 days. The precipitate was filtered off and
washed with ether yielding 5.6 g (86%) of chromatographically
pure product 2 as a white solid. After recrystallization from
glacial acetic acid and drying under reduced pressure over alkali
m.p. is 214-216°С.
4.2. The detailed experimental procedures and
characterization data.
4.2.1.
3-(1-Hydroxy-4,5-dimethyl-1H-imidazol-2-yl)-4H-
chromen-4-one (1).

ACCEPTED MANUSCRIPT
7
1H NMR (300 MHz, CDCl3, 296K): δ = 12.88 (s, 0.3H, NH);
11.79 (s, 0.7H, OH); 10.79 (s, 0.7H, H-2); 8.85 (s, 0.3H, H-2);
8.20 - 8.45 (m, 1H, H-Ar); 7.72 - 7.90 (m, 1H, H-Ar); 7.54 - 7.67
(m, 2H, H-Ar); 2.86 (s, 3H, CH3); 2.60 (s, 3H, CH3) ppm.
1H NMR (300 MHz, CD3OD, 296K): δ = 9.57 (br. s, 1H,
HAr-2); 8.22 - 8.30 (m, 1H, H-Ar); 7.82 - 7.90 (m, 1H, H-Ar);
7.50 - 7.72 (m, 2H, H-Ar); 2.83 (s, 2H, CH3); 2.46 (s, 2H, CH3);
1.15 (s, 6H, 2CH3) ppm.
1H NMR (300 MHz, [D6]DMSO, 301K): δ = 11.94 (br. s, 0.5
H, NH); 8.74 (br. s, 0.5 H, HAr-2); 8.10 - 8.22 (m, 1H, H-Ar);
7.85 - 7.95 (m, 1H, H-Ar); 7.72 - 7.80 (m, 1H, H-Ar); 7.55 - 7.63
(m, 1H, H-Ar); 2.56 (s, 3H, CH3); 2.42 (s, 3H, CH3) ppm.
1H NMR (300 MHz, CF3COOH, 296K): δ = 9.59 (s, 1H, HAr-
2); 8.12 - 8.22 (m, 1H, H-Ar); 7.85 - 7.94 (m, 1H, H-Ar); 7.56 -
7.72 (m, 2H, H-Ar); 2.80 (s, 3H, CH3); 2.69 (s, 3H, CH3) ppm.
13C NMR (75.48 MHz, [D6]DMSO): δ = 185.7, 173.5, 158.2,
155.5, 134.9, 126.3, 125.3, 124.8, 123.4, 122.9, 119.3, 118.6,
114.3, 52.4, 38.3, 35.3, 28.0 ppm.
MS (EI): m/z = 324 [M]+.
Anal. C18H16N2O4 (324): calcd. C 66.67; H 4.94; N 8.64;
found C 66.68; H 5.06; N 8.48.
IR νmax (KBr) 3104, 2954, 2859, 2600-2200 (br), 1662, 1613,
1557, 1464, 1405, 1312, 1291, 1173, 1142, 1073, 912, 861, 768,
652 cm-1.
1H NMR (300 MHz, CD3CN+CF3SO3H, 296K): δ = 9.36 (s,
1H, HAr-2); 8.25 - 8.34 (m, 1H, H-Ar); 7.92 - 8.02 (m, 1H, H-Ar);
7.62 - 7.80 (m, 2H, H-Ar); 2.71 (s, 3H, CH3); 2.67 (s, 3H, CH3)
ppm.
13C NMR (75.48 MHz, [D6]DMSO): δ = 188.6, 173.9, 157.6,
156.2, 155.5, 135.0, 126.3, 126.1, 125.3, 123.8, 123.2, 123.0,
118.7, 29.8, 14.5 ppm.
νmax (film) 3300-3100 (br), 2959, 2700-2400 (br), 1665, 1616,
1570, 1464, 1370, 1310, 1219, 1176, 1140, 1076, 914, 855, 760,
640 cm-1.
4.2.4. Ethyl 1-hydroxy-4-methyl-2-(4-oxo-4H-chromen-3-yl)-
1H-imidazole-5-carboxylate (4).
MS (EI): m/z = 284 [M]+.
A mixture of aldehyde 5 (2.1 g, 0.012 mol), oxime 9 (1.91 g,
0.012 mol) and ammonium acetate (1.85 g, 0.024 mol) in glacial
acetic acid (20 mL) was stirred at 40-50°С for 3 hours and left to
stand overnight. The reaction mixture was poured into water (60
mL), the product was extracted with chloroform (15 mL × 2), the
extract was dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure. The obtained oil was
treated with ether yielding 3.0 g (80%) of product 4 as a
yellowish solid. M.p. 172-173°С (toluene).
Anal. C15H12N2O4 (284): calcd. C 63.38, H 4.23, N 9.86;
found C 63.49, H 4.29, N 9.58.
IR νmax (film) 3267, 1659, 1639, 1613, 1565, 1559, 1497,
1464, 1410, 1302, 1275, 1224, 1204, 1171, 1146, 957, 916, 855,
802, 760, 687, 605, 530 cm-1.
4.2.3.
1-Hydroxy-5,5-dimethyl-2-(4-oxo-4H-chromen-3-yl)-
4,5,6,7-tetrahydro-1H-benzo[d]imidazol-7(4H)-one (3).
A mixture of aldehyde 5 (4.5 g, 0.026 mol), oxime 8 (4.4 g,
0.026 mol) and ammonium acetate (2.2 g, 0.029 mol) in glacial
acetic acid (35 mL) was stirred at room temperature for 11 hours
and left to stand for 3 days. The precipitate was filtered off and
washed with ether yielding 5.0 g (60%) of product 3 as a yellow
solid. After recrystallization from toluene and drying under
reduced pressure over paraffin m.p. is 205-206°С.
1H NMR (300 MHz, CDCl3, 302K): δ = 12.73 (br. s, 1H, NH);
8.93 (br. s, 1H, HAr-2); 8.25 - 8.42 (m, 1H, H-Ar); 7.74 - 7.87 (m,
1H, H-Ar); 7.45 - 7.67 (m, 2H, H-Ar); 2.69 (s, 2H, CH2); 2.42 (s,
2H, CH2); 1.12 (s, 6H, 2CH3) ppm.
1H NMR (300 MHz, CDCl3, 262K): δ = 12. 96 (br. s, 1H,
NH); 8.97 (br. s, 1H, HAr-2); 8.28 - 8.36 (m, 1H, H-Ar); 7.78 -
7.86 (m, 1H, H-Ar); 7.50 - 7.66 (m, 2H, H-Ar); 2.69 (s, 2H,
CH2); 2.42 (s, 2H, CH2); 1.11 (s, 6H, 2CH3).
1H NMR (300 MHz, [D6]DMSO, 300K): δ = 11.63 ( br. s,
0.8H, NH); 8.76 (br. s, 0.8H, HAr-2); 8.10 - 8.17 (m, 1H, H-Ar);
7.84 - 7.94 (m, 1H, H-Ar); 7.71 - 7.76 (m, 1H, H-Ar); 7.53 - 7.62
(m, 1H, H-Ar); 2.67 (s, 2H, CH2); 2.36 (s, 2H, CH2); 1.08 (s, 6H,
2CH3) ppm.
1H NMR (300 MHz, CF3COOH, 296K): δ = 9.70 (s, 1H, HAr-
2); 8.15 - 8.24 (m, 1H, H-Ar); 7.85 - 7.96 (m, 1H, H-Ar); 7.55 -
7.72 (m, 2H, H-Ar); 3.00 (s, 2H, CH2); 2.64 (s, 2H, CH2); 1.15 (s,
6H, 2CH3) ppm.
1H NMR (300 MHz, CD3CN, 300K): δ = 9.23 (br. s, 1H, HAr-
2); 8.25 - 8.36 (m, 1H, H-Ar); 7.85 - 7.98 (m, 1H, H-Ar); 7.53 -
7.76 (m, 2H, H-Ar); 2.70 (s, 2H, CH2); 2.37 (s, 2H, CH2); 1.10 (s,
6H, 2CH3) ppm.
1H NMR (300 MHz, CD3CN+CF3SO3H, 301K): δ = 9.47 (s,
1H, HAr-2); 8.26 - 8.33 (m, 1H, H-Ar); 7.92 - 8.03 (m, 1H, H-Ar);
7.62 - 7.81 (m, 2H, H-Ar); 2.98 (s, 2H, CH2); 2.56 (s, 2H, CH2);
1.18 (s, 6H, 2CH3) ppm.
1H NMR (300 MHz, CDCl3, 242K): δ = 13.15 (br. s, 0.4H,
NH); 12.16 (br. s, 0.6H, OH); 10.66 (br. s, 0.6H, HAr-2); 8.65 (br.
s, 0.3H, HAr-2); 8.19 (d, J = 7,34 Hz, 1H, H-Ar); 7.70 - 7.83 (m,
1H, H-Ar); 7.42 - 7.60 (m, 2H, H-Ar); 4.18 - 4.40 (m, 2H,
OCH2CH3); 2.49 (s, 3H, CH3); 1.30 (t, 3H, OCH2CH3) ppm.
1H NMR (300 MHz, CDCl3, 299K): δ = 12.19 (br. s, 0.7 H,
OH); 8.27 (d, J = 8.1 Hz, 1H, H-Ar); 7.70 - 7.83(m, 1H, H-Ar);
7.42 - 7.60 (m, 2H, H-Ar); 4.35 (q, 2H, OCH2CH3); 2.47 (s, 3H,
CH3); 1.36 (t, 3H, OCH2CH3) ppm.
1H NMR (300 MHz, [D6]DMSO, 301K): δ = 11.92 (br. s,
0.8H, NH); 8.73 (s, 1H, HAr-2); 8.05 - 8.20 (m, 1H, H-Ar); 7.80 -
7.92 (m, 1H, H-Ar); 7.64 - 7.75 (m, 1H, H-Ar); 7.49 - 7.60 (m,
1H, H-Ar); 4.20 - 4.40 (m, 2H, OCH2CH3); 2.33 (s, 3H, CH3);
1.20 - 1.35 (m, 3H, CH2CH3) ppm.
1H NMR (300 MHz, CF3COOH, 296K): δ = 9.57 (s, 1H, HAr-
2); 8.13 - 8.20 (m, 1H, H-Ar); 7.82 - 7.93 (m, 1H, H-Ar); 7.54 -
7.71 (m, 2H, H-Ar); 4.55 (q, 2H, OCH2CH3); 2.68 (s, 3H, CH3);
1.39 (t, 3H, OCH2CH3) ppm.
1H NMR (300 MHz, CD3CN, 298K): δ = 9.25 (br. s, 1H, HAr-
2); 8.22 - 8.30 (m, 1H, H-Ar); 7.84 - 7.93 (m, 1H, H-Ar); 7.54 -
7.73 (m, 2H, H-Ar); 4.25 - 4.36 (m, 2H, OCH2CH3); 2.40 (s, 3H,
CH3); 1.29 - 1.38 (m, 3H, CH2CH3) ppm.
1H NMR (300 MHz, CD3CN+CF3SO3H, 301K): δ = 9.40 (s,
1H, HAr-2); 8.25 - 8.32 (m, 1H, H-Ar); 7.91 - 8.01 (m, 1H, H-Ar);
7.60 - 7.78 (m, 2H, H-Ar); 4.47 (q, 2H, OCH2CH3); 2.65 (s, 3H,
CH3); 1.35 - 1.45 (m, 3H, CH2CH3) ppm.
1H NMR (300 MHz, CD3OD, 300K): δ = 9.61 (s, 1H, HAr-2);
8.21 - 8.29 (m, 1H, H-Ar); 7.81 - 7.89 (m, 1H, H-Ar); 7.64 - 7.70
(m, 1H, H-Ar); 7.52 - 7.59 (m, 1H, H-Ar); 4.38 (q, 2H,
OCH2CH3); 2.52 (s, 3H, CH3); 1.39 (t, 3H, CH2CH3) ppm.

ACCEPTED MANUSCRIPT
8
Tetrahedron
13C NMR (75.48 MHz, [D6]DMSO): δ = 188.6, 173.7, 158.9,
A mixture of aldehyde 5 (2.0 g, 0.011 mol), oxime 6 (1.2 g,
0.011 mol) and benzylamine 15 (1.2 g, 0.011 mol) in glacial
acetic acid (15 mL) was stirred at room temperature for 3 hours
and left to stand for 10 days. The reaction mixture was poured
into water (100 mL), the precipitate was filtered off, washed with
water and dried giving 3.6 g of a pale yellow solid. The product
was sequentially refluxed first in toluene then in acetonitrile
yielding 2.0 g (53%) of chromatographically pure 14 as an off-
white solid. M.p. 209-210°С.
1H NMR (300 MHz, CDCl3, 300K): δ = 8.69 (s, 1H, HAr-2);
8.18 - 8.28 (m, 1H, H-Ar); 7.63 - 7.75 (m, 1H, H-Ar); 7.38 - 7.53
(m, 2H, H-Ar); 7.13 - 7.25 (m, 3H, H-Ar); 6.80 - 6.90 (m, 2H, H-
Ar); 5.16 (s, 2H, CH2Ph); 2.26 (s, 3H, CH3); 2.11 (s, 3H, CH3).
1H NMR (300 MHz, [D6]DMSO, 303K): δ = 8.69 (s, 1H, HAr-
2); 8.09 - 8.17 (m, 1H, H-Ar); 7.81 - 7.90 (m, 1H, H-Ar); 7.65 -
7.72 (m, 1H, H-Ar); 7.18 - 7.30 (m, 3H, H-Ar); 7.00 - 7.08 (m,
2H, H-Ar); 5.13 (s, 2H, CH2Ph); 2.10 (s, 6H, 2CH3).
1H NMR (300 MHz, CF3COOH, 300K): δ = 8.40 (s, 1H, HAr-
2); 8.17 - 8.36 (m, 1H, H-Ar); 7.87 - 7.98 (m, 1H, H-Ar); 7.57 -
7.70 (m, 2H, H-Ar); 7.21 - 7.30 (m, 3H, H-Ar); 6.90 - 7.00 (m,
2H, H-Ar); 5.29 (s, 2H, CH2Ph); 2.38 (s, 3H, CH3); 2.26 (s, 3H,
CH3) ppm.
1H NMR (300 MHz, CD3CN, 300K): δ = 8.41 (s, 1H, HAr-2);
8.10 - 8.18 (m, 1H, H-Ar); 7.76 - 7.84 (m, 1H, H-Ar); 7.48 - 7.62
(m, 2H, H-Ar); 7.19 - 7.31 (m, 3H, H-Ar); 6.97 - 7.05 (m, 2H, H-
Ar); 5.11 (s, 2H, CH2Ph); 2.13 (s, 3H, CH3); 2.09 (s, 3H, CH3)
ppm.
1H NMR (300 MHz, CD3CN+CF3SO3H, 301K): δ = 8.82 (s,
1H, HAr-2); 8.32 - 8.39 (m, 1H, H-Ar); 8.12 - 8.21 (m, 1H, H-Ar);
7.77 - 7.96 (m, 2H, H-Ar); 7.26 - 7.38 (m, 3H, H-Ar); 7.08 - 7.17
(m, 2H, H-Ar); 5.31 (s, 2H, CH2Ph); 2.36 (s, 3H, CH3); 2.22 (s,
3H, CH3) ppm.
1H NMR (300 MHz, CD3OD, 300K): δ = 8.40 (s, 1H, HAr-2);
8.16 - 8.21 (m, 1H, H-Ar); 7.80 - 7.89 (m, 1H, H-Ar); 7.51 - 7.68
(m, 2H, H-Ar); 7.20 - 7.31 (m, 3H, H-Ar); 7.01 - 7.08 (m, 2H, H-
Ar); 5.18 (s, 2H, CH2Ph); 2.25 (s, 3H, CH3); 2.18 (s, 3H, CH3)
ppm.
13C NMR (75.48 MHz, [D6]DMSO): δ = 174.3, 160.9, 155.5,
136.4, 134.9, 128.6, 128.4, 127.5, 127.3, 126.4, 126.2, 125.6,
125.3, 123.6, 122.6, 121.9, 118.6, 110.5, 47.9, 8.7, 7.4 ppm.
158.0, 155.6, 134.8, 134.7, 128.1, 126.2, 125.3, 125.0, 123.4,
118.6, 59.9, 15.4, 14.2 ppm.
MS (EI): m/z = 314 [M]+.
Anal. C16H14N2O5 (314): calcd. C 61.15; H 4.46; N 8.92;
found C 61.18; H 4.54; N 8.76.
IR νmax (film) 3300-3150 (br), 2982, 2700-2400 (br), 1717,
1655, 1616, 1576, 1463, 1314, 1260, 1219, 1180, 1165, 1148,
1101, 1059, 1018, 923, 852, 762, 708, 664, 610, 523 cm-1.
4.2.5. 4-Oxo-4H-chromene-3-carbaldehyde (5).30
Freshly distilled phosphorous-oxychloride (27.5 mL, 46.06 g,
0.30 mol) was added dropwise to DMF (60 mL) at 5-10°С and
stirring. The mixture was stirred for 15 minutes and then the
solution of o-hydroxyacetophenone 10 (13.60 g, 0.1 mol) in
DMF (40 mL) was added dropwise at 0-5°. The reaction mixture
was stirred at low temperature for 30 minutes and then heated
and stirred at 50-55°С for 4 hours. The mixture was cooled to
room temperature, poured into ice-water (approx. 400 mL) and
stirred for 1.5 hour. The precipitate was filtered off, washed with
water and cooled ethanol (100 mL) yielding 13.8 g (79%) of
product 5 as yellowish solid. M.p. 152-154°С (toluene). Lit. m.p.
152-153°С.30
4.2.6. Pentan-2,3,4-trione 3-oxime (7).31
Pentane-2,4-dione 11 (25.0 g, 0.25 mol) was dissolved in 7%
sulfuric acid (250 mL) at 15°C. Then a solution of sodium nitrite
(17.3 g, 0.25 mole) in water (75 mL) was added dropwise. The
reaction mixture was stirred at room temperature for 2 hours, the
product was extracted with ethyl acetate(50 mL × 3), the extract
was washed with water and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure yielding 29.3 g
(91%) of 7 as a pale yellow oil which crystallizes if left to stand
undisturbed. M.p. 73-75°С. Lit. m.p. 75°С.31 7 was used without
further purification.
4.2.7. 5,5-Dimethyl-1,2,3-trione 2-oxime (8).32
5,5-Dimethyl-1,3-cyclohexanedione 12 (50.0 g, 0.357 mol)
was suspended in a 15% solution of potassium hydroxide (118
mL) and sodium nitrite (24.6 g, 0.357 mol) was added. The
suspension obtained was diluted with water (20 mL) and cooled
to 0°C. Then 15% sulfuric acid (212 mL) was added dropwise at
0-10°C. The mixture was stirred at a low temperature for 30
minutes and then the precipitate was filtered off and dried under
reduced pressure over alkali to yield 58.8 g (97.5%) of 8 as
yellow solid; m.p. 85-88°C. Lit. m.p. 87°C.32 8 was used without
further purification.
MS (EI): m/z = 346 [M]+.
Anal. C21H18N2O3 ·0,5H2O (355): calcd. C 71.00; H 5.35; N
7.89; found C 71.45; H 5.13; N 7.84
IR νmax (film) 3400-3100 (br), 2959, 2926, 2363, 1643, 1609,
1576, 1508, 1464, 1379, 1339, 1289, 1221, 1186, 1115, 1096,
849, 772, 748, 706, 669, 588 cm-1.
4.2.8. Ethyl 2-(hydroxyimino)-3-butanoate (9).32
A solution of ethyl acetoacetate 13 (40 mL, 41.0 g, 0.315 mol)
in glacial acetic acid (52 mL) was cooled to 5°C and a solution of
sodium nitrite (32 g, 0.462 mol) in water (70 mL) was added
dropwise at 5-10°C. The mixture was stirred for 1 hour at 8±2°C
then a 18% solution of sodium chloride (150 mL) was added and
the mixture was stirred for 20 minutes more. Then it was
extracted with chloroform (75 mL × 2), the extract was
sequentially washed with 18% solution of sodium chloride, 10%
solution of sodium hydrocarbonate, 18% solution of sodium
chloride and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to yield 45.0 g (90%) of 9
as yellow oil. 9 was used without further purification.
4.2.10.
Ethyl
5-methyl-2(4-oxo-4H-chromen-3-yl)-1H-
imidazole -4-carboxylate (16).
A mixture of 1-hydroxyimidazole 4 (15.0 g, 0.0476 mol) and
triphenylphosphine (20.0 g, 0.0762 mol) was refluxed with
stirring in glacial acetic acid (64 mL) for 4 hours. The reaction
mixture was cooled on an ice bath, the precipitate was filtered off
and twice refluxed in ether (70 mL) yielding 8.1 g (57%) of
chromatographically pure 16 as a white solid. M.p. 152-154°C.
1H NMR (200 MHz, CDCl3, 293K): δ = 11.73 (br. s, 0.5H,
NH); 11.62 (br. s, 0.5 H, NH); 9.19 (s, 0.5H, HAr-2); 9.09 (s;
0.5H, HAr-2); 8.26 - 8.37 (m, 1H, H-Ar); 7.71 - 7.85 (m, 1H, H-
Ar); 7.45 - 7.62 (m, 2H, H-Ar); 4.30 - 4.50 (m, 2H, OCH2CH3);
4.2.9. 1-Benzyl-4,5-dimethyl-2-(4-oxo-4H-chromen-3-yl)-1H-
imidazole 3-oxide (14).

ACCEPTED MANUSCRIPT
9
µ [mm-1]
0.106
0.099
2.64 (s, 1.5H, CH3); 2.56 (s, 1.5H, CH3); 1.37 - 1.49 (m, 3H,
OCH2CH3) ppm.
F(000)
T [K]
536
776
13C NMR (75.48 MHz, [D6]DMSO): δ = 174.5, 163.2, 157.2,
156.1, 155.5, 145.3, 137.8, 136.3, 134.9, 134.7, 127.4, 126.3,
126.1, 125.2, 123.3, 118.7, 114.5, 109.5, 60.1, 59.2, 14.4, 14.3,
11.1 ppm.
123(2)
1.96 - 28.99
273(2)
2.19 - 28.00
θ
range [sec]
Limiting indices
-27 ≤ h ≤ 28, -6 ≤k ≤ -9 ≤ h ≤ 9, -24 ≤k ≤
5, -16 ≤ l ≤16
24, -18 ≤ l ≤18
17854/ 4221
[0.0356]
99.7
MS (EI): m/z = 298 [M]+.
Reflections / collected /
8359/ 3012 [0.1387]
Anal. C16H14N2O4 (298): calcd. C 64.43; H 4.70; N 9.40;
found C 64.10; H 4.58; N 9.37
unique [Rint
]
Completeness deg [%]
Reflections with I >
2σ(I)
99.9
IR νmax (film) 3358, 2980, 1705, 1643, 1618, 1574, 1466,
1425, 1380, 1341, 1314, 1265, 1248, 1169, 1146, 1107, 1094,
1020, 991, 849, 760, 704, 636 cm-1.
1673
2777
Data / parameters
GOF on F2
3012 / 172
4221 / 249
4.3. X-ray determination
1.019
1.043
Compound 1. Crystals suitable for X-ray structure analysis
were grown from an acetonitrile-benzene solution. A single
crystal of dimensions 0.09 × 0.03 × 0.02 was subjected to X-ray
measurements on a Bruker SMART-1K diffractometer using
graphite monochromatized MoKα radiation (0.71073 Å) and ω
scan mode at 123K. Data reduction was performed using the
SAINT program.35 The structure was solved by direct methods
and refined on F2 by full-matrix least-squares in anisotropic
approximation for non-hydrogen atoms. Hydrogen atoms were
refined using the “riding” model.
0.0757 / 0.1267
0.1615 / 0.1459
0.262 and -0.255
0.0488 / 0.1397
0.0769 / 0.1528
0.307 and -0.175
R1 / wR2 [I > 2σ(I)]
R1 / wR2 (all data)
Max/min residuals
[e/A3]
CCDC-905069 contains the supplementary crystallographic
data for compound 1. CCDC-905068 contains the supplementary
crystallographic data for compound 3. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Compound 3. Crystals suitable for X-ray structure analysis
were grown from methanol solution. A single crystal of
dimensions 0.24 × 0.22
measurements on
×
0.22 was subjected to X-ray
Supplementary Data
Copies of the 1H NMR and 13C NMR spectra of compounds 1-
4, 14, 16.
a
Bruker CCD SMART-APEX-II
diffractometer using graphite monochromatized MoKα radiation
(0.71073 Å) and ω scan mode at room temperature. Data
reduction was performed using the SAINT program.35 The
structure was solved by direct methods and refined on F2 by full-
matrix least-squares in anisotropic approximation for non-
hydrogen atoms. Hydrogen atoms were refined using the “riding”
model. In difference Fourier synthesis, several peaks of electron
density corresponding to a methanol solvate molecule were
located. The methanol molecule is disordered over four close
positions with equal occupations. The refinement of solvent
molecule was carried out in isotropic approximation.
5. References
1.
G.G. Allan, C.S. Chopra, T. Mattila, Pestic. Sci. 1972, 3(2), 153–
159 (Chem. Abstr. 1972, 77, 57559h).
2.
3.
4.
5.
6.
DE 2254474, 1973 (Chem. Abstr. 1973, 79, 42507g).
M. Witschel, Bioorg. Med. Chem. 2009, 17(12), 4221-4229.
US 3886180, 1975.
US 4006160, 1977 (Chem. Abstr., 1977, 86, 189707).
M.R. Harnden, L.J. Jennings, C.M.D. Mckie, A. Parkin, Synthesis
All of the calculations were performed using SHELXLT-Plus
software.36 A summary of the crystallographic data and structure
determination parameters is provided in Table 4.
1990, (10), 893-895.
7.
8.
9.
WO 2005002002576, 2005.
Table 4. Crystal Data and Structure Refinement for
compounds 1 and 3.
US 4232029, 1980 (Chem. Abstr. 1981, 94, 103377).
compound 1
C14H12N2O3
256.26
compound 3
C19H26N2O5
362.42
T.B. Stensbøl, P. Uhlmann, S. Morel, B.L. Eriksen, J. Felding, H.
empirical formula
formula weight
Color, habit
Crystal system
Space group
a [Å]
Kromann, M.B. Hermit, J.R. Greenwood, H. Bräuner-Osborne, U. Madsen, F.
Junager, P. Krogsgaard-Larsen, M. Begtrup, P. Vedsø, J. Med. Chem. 2002,
45, 19-31.
colourless, block
orthorhombic
Pca21
colourless, prism
monoclinic
P21/c
10.
G.V. Nikitina, M.S. Pevzner, Chemistry of Heterocyclic
Compounds 1993, 29, 127-151.
20.8148(15)
4.4300(4)
12.4420(10)
90.0
6.862(3)
18.604(8)
13.772(6)
91.468(7)
1757.5(13)
4
11.
12.
13.
M.R. Grimmett, Science of Synthesis 2002, (12), 325-528.
b [Å]
B.H. Lipshutz, M.C. Morey, Tetrahedron Lett. 1984, 25, 1319.
c [Å]
E.S. Kritschewskii, L.M. Alekseewa, O.S. Anisimova, W.G.
β
[°]
Granik, Khim.-farm. zh. 1995, 29(9), 50-53.
V [Å3]
1147.27(16)
4
14.
B.L. Eriksen, P. Vedsø, S. Morel, M. Begtrup, J. Org. Chem.
Z
1998, 63, 12-16.
Dcalc g cm-3
1.484
1.370
15.
B.L. Eriksen, P. Vedsø, M. Begtrup, J. Org. Chem. 2001, 66,
8344-8349.

ACCEPTED MANUSCRIPT
10
Tetrahedron
L.F.V. Pinto, G.C. Justino, A.J.S.C. Vieira, S. Prabhakar, A.M.
16.
Lobo, ARKIVOC 2010, (v), 17-23.
17.
18.
19.
F.J. Allan, G.G. Allan, Chem. Ind. 1964, 1837.
A.R. Katrizky, Chem. Ind. 1965, 331.
K. Akagane, F.J. Allan, G.G. Allan, T. Friberg, S.
Ó
Muicheartaigh, J.B. Thomson, Bull. Chem. Soc. Jpn. 1969, 42, 3204-3207.
20.
4187.
K. Volkamer, H.W. Zimmermann, Chem. Ber. 1969, 102, 4177-
S.O. Chua, M.J. Cook, A.R. Katrizky, J. Chem. Soc. B 1971,
S. Takahashi, H. Kano, Chem. and Pharm. Bull. 1963, 11, 1375-
21.
2350-2355.
22.
1381.
23.
24.
D.J. Neadle, R.J. Pollitt, J. Chem. Soc. C 1967, 1764-1766.
G.W. Stacy, T.E. Wollner, T.R. Oakes, J. Heterocycl. Chem.
1966, 3, 51-54.
25.
M. Boiani, H. Cerecetto, M. González, O.E. Piro, E.E. Castellano,
J. Phys. Chem. A, 2004, 108, 11241-11248.
26.
S. Abuskhuna, M. McCann, J. Briody, M. Devereux, K.
Kavanagh, N. Kayal, V. McKee, Polyhedron 2007, 26, 4573-4580.
27.
A.K. Padhy, B. Chetia, S. Mishra, A. Pati, P.K. Iger, Tetrahedron
Lett. 2010, 51, 2751-2753.
28.
29.
Y. Kamitori, Heterocycles 2000, 53(1), 107-113.
R.B. Sparks, A.P. Combs, Org. Lett. 2004, 6(14), 2473-2475.
A. Nohara, T. Umetani, Y. Sanno, Tetrahedron 1974, 30(19),
30.
3553-3561.
31.
32.
33.
L. Wolff, Justus Liebigs Ann. Chem. 1902, 325(2), 129-195.
J. Lifschitz, Chem. Ber. 1913, 46, 3233-3250.
M. Witanowski, L. Stefaniak, Bull. Pol. Acad. Sci., Chem. 1987,
35, 305-320.
34.
V.I. Minkin, A.D. Garnovskii, J. Elguero, A.R. Katrizky, O.V.
Denisenko, Adv. Heterocycl. Chem. 2000, 76, 157-323.
35.
SAINT. Version 6.02A. Bruker AXS Inc. Madison, Wisconsin,
USA, 2001.
36.
SHELXTL-Plus. Version 5.10. Bruker AXS Inc. Madison,
Wisconsin, USA, 1997.

ACCEPTED MANUSCRIPT
Supplementary Data
1Н and 13C NMR spectra
CH3
CH3
O
O
N
N
OH
1
0.78 0.83
1.00
3.15
6.00
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
300.13 MHz, CDCl3 (299K)
DMSO-d6
200
180
160
140
120
100
80
60
40
20
0
Chemical Shift (ppm)
75.48 MHz, [D6]DMSO (298K)

ACCEPTED MANUSCRIPT
Chloroform-d
CH3
CH3
O
O
N
N
OH
O
2
0.26
0.67
0.67
0.24
1.00
3.08
6.51
13.0
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Chemical Shift (ppm)
300.13 MHz, CDCl3 (296K)
DMSO-d6
220
200
180
160
140
120
100
80
60
40
20
0
Chemical Shift (ppm)
75.48 MHz, [D6]DMSO (299K)

ACCEPTED MANUSCRIPT
Chloroform-d
CH3
CH3
O
O
HN
N
O
O
3
0.77
0.66 1.00
3.11
2.18
2.5
6.61
1.0
13.0
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.0
1.5
Chemical Shift (ppm)
300.13 MHz, CDCl3 (302K)
DMSO-d6
200
180
160
140
120
100
80
60
40
20
0
Chemical Shift (ppm)
75.48 MHz, [D6]DMSO (299K)

ACCEPTED MANUSCRIPT
Chloroform-d
CH3
O
O
O
N
C2H5
N
O
OH
4
0.36
0.58
0.59
0.31 1.00
3.01
7.5
2.04
2.79
2.5
2.95
13.5
13.0
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
300.13 MHz, CDCl3 (242K)
DMSO-d6
220
200
180
160
140
120
100
80
60
40
20
0
Chemical Shift (ppm)
75.48 MHz; [D6]DMSO (298K)

ACCEPTED MANUSCRIPT
Chloroform-d
CH3
CH3
O
O
N
N
O
14
0.75 0.91
8.5
0.98 2.90 1.78
2.05
7.36
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
300.13 MHz, CDCl3 (300K)
DMSO-d6
180
160
140
120
100
80
60
40
20
Chemical Shift (ppm)
75.48 MHz, [D6]DMSO (299K)

ACCEPTED MANUSCRIPT
CH3
O
O
O
N
C2H5
N
H
O
16
0.83
0.87
0.98
3.05
7.5
2.00
2.98
2.5
2.91
1.5
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.0
1.0
0.5
Chemical Shift (ppm)
200.13 MHz, CDCl3 (293K)
DMSO-d6
200
180
160
140
120
100
80
60
40
20
0
Chemical Shift (ppm)
75.48 MHz, [D6]DMSO (298K)