Synthesis of 2-aroyl-1-hydroxy-4,5-dimethylimidazoles by reaction of 3-hydroxyamino-2-butanone oxime with arylglyoxals

Article abstract of DOI:10.1007/s10593-009-0329-0

Treatment of the acetate of 3-hydroxyamino-2-butanone oxime with arylglyoxals gives α-aroylnitrones which cyclize under acid catalyzed conditions to form principally 2-aroyl-1-hydroxy-4,5-dimethyl-imidazoles. An X-ray structural analysis of 2-benzoyl-1-hy

Full text of DOI:10.1007/s10593-009-0329-0

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
SYNTHESIS OF 2-AROYL-1-HYDROXY-
4,5-DIMETHYLIMIDAZOLES BY REACTION
OF 3-HYDROXYAMINO-2-BUTANONE OXIME
WITH ARYLGLYOXALS*
S. A. Amitina1, A. Ya. Tikhonov1**, I. A. Grigor'ev1,
Yu. V. Gatilov1, and B. A. Selivanov1
Treatment of the acetate of 3-hydroxyamino-2-butanone oxime with arylglyoxals gives α-aroylnitrones
which cyclize under acid catalyzed conditions to form principally 2-aroyl-1-hydroxy-4,5-dimethyl-
imidazoles. An X-ray structural analysis of 2-benzoyl-1-hydroxy-4,5-dimethylimidazole has been carried
out.
Keywords: arylglyoxals, 2-aroyl-1-hydroxyimidazoles, α-aroyl nitrones, hydroxylamino oxime,
pyrazine 1,4-dioxides, X-ray structural analysis.
Imidazoles are an important class of heterocyclic compounds with a broad spectrum of biological
activity and practical importance [1]. 1-Hydroxy-2-[(4-phenoxy)benzoyl]-4,5,6,7-tetrahydrobenzimidazole has
recently been shown to have antibacterial activity [2]. 2-Aroyl-1-hydroxy-4,5,6,7-tetrahydrobenzimidazoles
have previously been prepared by condensation of 2-hydroxyaminocyclohexanone oxime with aryl- and
hetarylglyoxals while use of phenylglyoxal gave significant amounts of 5,6,7,8-tetrahydroxyquinoxaline
1,4-dioxide [3]. It should be noted that 4,5-dialkyl-1-hydroxyimidazoles or their tautomeric imidazole N-oxides
were not formed upon oxidation of an imidazole ring [4].
In this work we report a study of the condensation of the acetate of the acyclic 3-hydroxyamino-
2-butanone oxime 1 with the arylglyoxals hydrates 2a-f in order to establish the cyclization route. In this case
predominant formation of imidazole derivatives rather than pyrazines would be expected because the absence of
a methylene bridge should have assisted cyclization of the intermediate nitrones to form the five-membered
heterocycle.
_______
* Dedicated to Academician Boris Aleksandrovich Trofimov on the occasion of his 70th jubilee.
** To whom correspondence should be addressed, e-mail: alyatikh@nioch.nsc.ru.
1N. N. Vorozhtsov Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
Novosibirsk 630090, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 868-874, June, 2009. Original
article submitted May 30, 2008.
0009-3122/09/4506-0691©2009 Springer Science+Business Media, Inc.
691

Condensation of 3-hydroxyamino-2-butanone oxime 1 acetate with phenylglyoxal hydrate 2a at room
temperature in methanol or in water gave initially the α-benzoylnitrone 3a. Under the same conditions
(methanol) reaction of the 1·AcOH salt with the arylglyoxal hydrates 2b,c gave the corresponding α-aroyl
nitrones 3b,c. Chromatography of the reaction mixture after preparation of the benzoylnitrone 3b gave the
benzoylimidazole 4b and pyrazine 1,4-dioxide 5b.
O
R
OH
N
Me
R1
R
R1
N
Me
Me
+
Me
O
O
N
NHOH
O
OH
2a–f
1
6
R1
OH
Me
N
Me
Me
N
Me
N
R
O
O
N
O
OH
4a–f
R
R1
R
O
3a–c
R1
Me
N
N
3b,c
Me
O
5b,c
2–5 a–e R = H; a R1 = H, b R1 = Cl, c R1 = NO2, d R1 = OMe, e R1 = OEt, f R = R1 = OEt
Heating solutions of the nitrones 3a-c in methanol in the presence of acetic acid or nitrone 3a in acetic
acid led to formation of the 1-hydroxyimidazoles 4a-c while TLC showed that the reaction mixture contained
the pyrazine 1,4-dioxides 5a-c isomeric with the 1-hydroxyimidazoles 4a-c. The pyrazine 1,4-dioxide 5a was
identified by TLC comparison with a known sample which is quantitatively formed by condensation of the
E-isomer of 2-hydroxyamino-1-phenylethanone oxime with diacetyl [5]. As expected, carrying out the
condensation of salt 1·AcOH with the arylglyoxal hydrates 2d-f by heating in methanol in the presence of acetic
acid led to the 1-hydroxyimidazoles 4d-f. Typifying the 1H NMR spectra of compounds 4a-f is the presence of a
low field hydroxyl group proton signal at 13.7-14.4 ppm and for the pyrazine 1,4-dioxides 5b,c the signal for the
heteroaromatic proton at 8.1-8.7 ppm (Table 1) (cf. [4, 5]).
Formation of the 1-hydroxyimidazoles 4a-f evidently occurs via a ready dehydration reaction of the
intermediate 2-aroyl-1-hydroxy-3-imidazoline 3-oxides 6 (see [6]).
The structure and composition of all of the synthesized compounds were supported by their
spectroscopic charcteristics (Table 1) and by elemental analytical data (Table 2).
Through studying the structure of the 2-benzoyl-1-hydroxy-4,5-dimethylimidazole 4a by X-ray analysis
it was found that the N(1)–C(7) fragment and atoms O(1), O(2), C(13), and C(14) lie in a single plane in the
molecule within ± 0.080 Å. The benzene ring deviates from this plane, the dihedral angle being 14.58(5)º. There is
no information in the Cambridge structural database regarding the structure of 1-hydroxyimidazoles containing an
692

TABLE 1. Spectroscopic Characteristics for the Compounds Synthesized
UV spectrum,
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)*
λ
max, nm
ν, cm–1
(log ε)
3a
3318, 1649,
1520, 1242,
948
309 (4.14)
1.53 (3H, d, J = 6.5, СН3); 1.81 (3Н, s, СН3);
5.15 (1Н, q, J = 6.5, СН–СН3);
7.50-7.59 (3Н, m, H-3,4,5 Ar);
7.91 (2Н, m, H-2,6 Ar); 8.56 (1Н, s, =СН);
11.16 (1Н, s, 1-ОН)
3b
3245, 1651,
1529, 1247,
953
314 (4.21)
1.54 (3H, d, J = 6.5, СН3); 1.83 (3Н, s, СН3);
5.17 (1Н, q, J = 6.5, СН-СН3);
7.65 (2Н, m, H-3,5 Ar); 7.95 (2Н, m, H-2,6 Ar);
8.59 (1Н, s, =СН); 11.25 (1Н, br. s, ОН)
3с
1657, 1525,
1347, 1231,
953
271 (4.06),
316 (4.15)
1.52 (3H, d, J = 6.9, СН3); 1.80 (3Н, s, СН3);
5.18 (1Н, q, J = 6.9, СН–СН3);
8.09 (2Н, m, H-2,6 Ar); 8.34 (2Н, m, H-3,5 Ar);
8.63 (1Н, s, =СН); 11.21 (1Н, br. s, ОН)
4а
1640, 1467,
1292, 909
258 (3.90),
328 (4.06)
2.28 (6Н, s, 4,5-СН3); 7.40–7.60 (3Н, m, H-3,4,5Ar);
8.57 (2Н, m, H-2,6 Ar); 14.15 (1Н, s, 1-ОН)
4b
1637, 1587,
1463, 1298,
909
265 (3.88),
331 (3.97)
2.30 (6Н, s, 4,5-СН3); 7.49 (2Н, m, H-3,5 Ar);
8.60 (2Н, m, H-2,6 Ar); 14.06 (1Н, s, 1-ОН)
4c
1608, 1563,
1525, 1472,
1344, 1300,
918
268 (4.07),
340 (3.90)
2.26 (3Н, s, 4- or 5-СН3);
2.28 (3Н, s, 4- or 5-СН3); 8.30 (2Н, m, H-2,6 Ar);
8.74 (2Н, m, H-3,5 Ar); 13.71 (1Н, s, 1-ОН)
4d
4e
1603, 1456,
1296, 1259,
1170, 908
228 (3.84),
337 (4.45)
2.24 (6Н, s, 4,5-СН3); 3.86 (3Н, s, 4-OСН3);
6.97 (2Н, m, H-3,5 Ar); 8.66 (2Н, m, H-2,6 Ar);
14.39 (1Н, s, 1-ОН)
1606, 1451,
1293, 1254,
1164, 907
228 (3.80),
343 (4.18)
1.42 (3H, t, J = 6.9, 4-ОСН2СН3);
2.24 (6Н, s, 4,5-СН3);
4.09 (2Н, q, J = 6.9, 4-ОСН2СН3);
6.95 (2Н, m, H-3,5 Ar); 8.64 (2Н, m, H-2,6 Ar);
14.41 (1Н, s, 1-ОН)
4f
1598, 1464,
1274, 1259,
1145, 1041
241 (3.91),
357 (4.13)
1.47 (6H, t, J = 7.0, 3,4-ОСН2СН3);
2.24 (6Н, s, 4,5-СН3);
4.17 (4Н, q, J = 7.0, 3,4-ОСН2СН3);
6.93 (1Н, d, J = 8.4, H-5 Ar);
8.09 (1Н, d, J = 1.8, H-2 Ar);
8.50 (1Н, dd, J = 1.8, 8.4, H-6 Ar);
14.39 (1Н, s, 1-ОН)
5b
5c
1595, 1489,
1354, 1243,
1107, 1091
265 (4.37),
314 (4.24)
2.57 (6Н, s, 2,3-СН3); 7.46 (2Н, m, H-3,5 Ar);
7.69 (2Н, m, H-2,6 Ar); 8.18 (1Н, s, H-6)
1601, 1516,
1348, 1248,
1105
260 sh.
(3.15),
294 (4.32)
2.46 (3Н, s, 2- or 3-СН3);
2.47 (3Н, s, 2- or 3-СН3); 8.07 (2Н, m, H-2,6 Ar);
8.33 (2Н, m, H-3,5 Ar); 8.69 (1Н, s, H-6)
_______
1
* The H NMR spectra were recorded in DMSO-d6 (compounds 3a-c and
5c) or CDCl3 (compounds 4a-f and 5b).
aroyl or acetyl group at position 2 of the heterocycle. Table 3 shows selected bond lengths for the 4a molecule and
those calculated by the DFT/PBE/3z method for the isolated molecule 4a. The high uniformity of bond lengths for
the imidazole ring in the crystal with those calculated should be noted. The parameters for the intramolecular
hydrogen bond O(1)–H(1)···O(2) are: O–H 1.03(3), H···O 1.60(3), O···O 2.536(2) Å and O–H···O 150(2)º. In the
crystal of compound 4a stacs of the molecules are formed along the a axis thanks to π-stacking interaction
between the imidazole rings (intercentroid and interplanar distances 3.488(1) and 3.410 Å) and also between the
C=O group and the imidazole ring (distances centroid-C(6) 3.477, interplanar 3.356 Å).
693

TABLE 2. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield∗2, %
C
H
N
3а
3b
3c
4a
C12H14N2O3
61.72
61.52
6.06
6.02
11.80
11.96
153-154
(decomp.)
62
(60)
C12H13ClN2O3*3
C12H13N3O5
54.10
53.64
4.85
4.88
10.68
10.43
132
(decomp.)
41
72
51.65
51.61
4.75
4.69
14.83
15.05
149
(decomp.)
C12H12N2O2
66.65
66.65
5.84
5.59
12.97
12.96
62-64
84
(84)
76
4b
4c
4d
4e
4f
C12H11ClN2O2*4
C12H11N3O4
57.40
57.49
4.34
4.42
11.43
11.18
111-112
149-150
103-104
92-93
54.94
55.17
4.03
4.24
16.03
16.09
55
57
46
63
8
C13H14N2O3
63.58
63.40
5.73
5.73
11.33
11.38
C14H16N2O3
64.52
64.60
6.21
6.20
10.73
10.76
C16H20N2O4
63.48
63.14
6.72
6.62
9.16
9.21
116-117
192-193
5b
5c
C12H11ClN2O2*4
C12H11N3O4
57.94
57.49
4.27
4.42
10.99
11.18
55.36
55.17
4.45
4.24
16.19
16.09
249
(decomp.)
12
_______
* Solvent for crystallization: MeOH (compounds 3c, 4c,f, 5b,c), hexane
(compounds 4a,b) or ether (compounds 4d,e).
*2 Yield in brackets given for method B.
*3 Found, %: Cl 13.19. Calculated, %: Cl 13.20.
*4 Found, %: Cl 14.15. Calculated, %: Cl 14.15.
Fig. 1. Molecular structure and atomic numbering for compound 4a. The
thermal ellipsoids are shown at the 30% probability level.
According to the DFT/PBE/3z calculated for the gaseous phase the possible tautomer of compound 4a
as 2-benzoyl-4,5-dimethyl-1H-imidazole 3-oxide is 8.0 kcal/mol less stable and the alternative tautomer 2-(1-
hydroxy-1-phenylmethylidene)-4,5-dimethyl-2H-imidazole 1-oxide is not a local minimum and crosses to 4a
without a barrier.
694

TABLE 3. Selected Bond Lengths (l) in the Compound 4a Molecule
Bond
l, Å
DFT/PBE/3z
Bond
l, Å
DFT/PBE/3z
N(1)–C(2)
C(2)–N(3)
N(3)–C(4)
C(4)–C(5)
C(5)–N(1)
1.374(2)
1.338(2)
1.353(2)
1.387(2)
1.344(2)
1.391
1.353
1.353
1.416
1.354
N(1)–O(1)
C(2)–C(6)
C(6)–O(2)
C(6)–C(7)
1.376(2)
1.442(2)
1.249(2)
1.484(2)
1.370
1.443
1.272
1.485
Hence the α-benzoylnitrones formed by condensation of the acyclic 1,2-hydroxylamino oxime with
arylglyoxals undergo cyclization to form principally the 2-aroyl-1-hydroxyimidazoles and these can be prepared
in a single stage without separation of the α-benzoylnitrones.
EXPERIMENTAL
IR spectra for KBr tablets were recorded on a Bruker Vector 22 spectrophotometer and UV spectra on a
1
Hewlett Packard 8453 spectrophotometer using ethanol. H NMR spectra were taken on a Bruker AC-300
instrument (300 MHz) with residual solvent as internal standard (CDCl3 at 7.24 ppm and DMSO-d6 at 2.50
ppm). Monitoring of the reaction course and the purity of the compounds obtained was carried out by TLC on
Silufol UV-254 plates with chloroform–methanol (10:1) as eluent.
The acetate of the hydroxylamino oxime 1 was obtained by method [8] and the arylglyoxals via the
Riley reaction [9]. The melting points of the arylglyoxal hydrates 2a-f agreed with those given in the literature
[10–12].
N-(2-Hydroxyimino-1-methylpropyl)-α-aroyl nitrones 3a-c. (General Method) A. The acetate of
hydroxylamino oxime 1 (5 mmol) was dissolved with heating in MeOH (7 ml) and cooled to room temperature.
The arylglyoxals 2a-c (5 mmol) were added with stirring and full solubility occurred. The solution turned
yellow after 5-10 min, a precipitate was formed, and the mixture was allowed to stand overnight. The
precipitated aroyl nitrones 3a-c filtered off, washed with MeOH, and dried.
The filtrate after separation of the benzoyl nitrone 3b was evaporated and the residue was treated with
water and then NaHCO3 to neutrality and extracted with chloroform. The chloroform solution was washed with
water, dried over MgSO4, solvent was evaporated, and the residue was chromatographed on a silica gel column
(eluent chloroform) to give the aroylimidazole 4b (0.45 g, 36%). Elution with chloroform–MeOH (10:1) then
gave the pyrazine 5b (0.1 g, 8%).
N-Benzoylmethylidene-N-(2-hydroxyimino-1-methylpropyl)amine N-Oxide (3a). B. The phenyl-
glyoxal 2a (1.6 g, 10.5 mmol) was added portionwise, as solubility allowed, to a solution of the hydroxylamino
oxime acetate (1.78 g, 10 mmol) in water (7 ml). After 5-7 min the solution became turbid and a yellow
precipitate began to form. The reaction mixture was left overnight at room temperature and then cooled to 5ºC.
The precipitate formed was filtered off, washed on the filter with water, and dried in air to give compound 3a
(1.4 g, 60%).
2-Aroyl-1-hydroxy-4,5-dimethylimidazoles 4a-c. (General Method). A. The aroyl nitrones 3a-c
(5 mmol) were heated at 80-90ºC in a mixture of MeOH (10 ml) and glacial AcOH (3 ml). The solution was
evaporated and the residue was mixed with water, neutralized with NaHCO3, and extracted with chloroform.
The chloroform solution was washed with water, dried over MgSO4, and the solvent was evaporated.
Crystallization of the residue from hexane gave the imidazoles 4a,b. In the case of cyclization of aroylnitrone 3c
cooling of the reaction mixture gave the pyrazine 5c and the filtrate after dilution with water gave the imidazole
4c.
695

2-Benzoyl-1-hydroxy-4,5-dimethylimidazole (4a). B. The benzoyl nitrone 3a (1.03 g, 4.4 mmol) was
dissolved with heating in AcOH (12 ml) and held overnight at room temperature. Solvent was evaporated and
the residue was dissolved in EtOAc. The solution was washed with a 3% solution of sodium bicarbonate and
water, dried over MgSO4, and the solvent was evaporated. Chromatography of the residue on a silica gel column
with pentane–ether as eluent gave compound 4a (0.8 g, 84%).
2-Aroyl-1-hydroxy-4,5-dimethylimidazoles (4d-f) (General Method). The arylglyoxal 2d-f
(10 mmol) was added to a solution of the hydroxylamino oxime 1 acetate (10.5 mmol) in a mixture of MeOH
(20 ml) and glacial AcOH (3 ml). The solution obtained was heated for 2 h at 80-90ºC. Solvent was evaporated
and the residue was washed with water, neutralized with NaHCO3, and extracted with chloroform. The extract
was washed with water, dried over MgSO4, and the solvent was evaporated. Treatment of the crystalline residue
with ether gave the imidazoles 4d-f in 30-60% yield. The ether solution was evaporated and the residue was
chromatographed on a silica gel column using chloroform eluent to give additional amounts of the imidazoles
4d-f.
X-ray Structural Investigation. Single crystals of compound 4a (hexane). The size of the crystal in the
X-ray diffraction experiment was 0.56×0.44×0.32 mm and the work was carried out on a Bruker P4
diffractometer (graphite monochromator, λ(MoKα) = 0.71073 Å, temperature 296 K, θ/2θ scanning to
–
2θmax = 55º). Crystallographic data for compound 4a: C H N O , triclinic crystal system, space group P ,
1
12 12
2
2
a = 7.4321(5), b = 8.0943(6), c = 9.6860(7) Å, α = 90.999(6), β = 107.164(5), γ = 98.264(6)º, V = 549.85(7) Å3,
Z = 2, Mr = 216.24, Dx = 1.306 g/cm3, µ = 0.091 mm-1. Calculation of the absorption was carried out from the
azimuthal scanning experimental curve (Tmin/Tmax = 0.9262/0.9693). The structure was solved by a direct
method. The positions and thermal parameters for the atoms were calculated in the anisotropic-isotropic (for H
atoms) approximation using full matrix least squares analysis. The hydrogen atoms were localized from
difference synthesis. The refinement parameters were: wR2 = 0.1400, S = 1.041 for all 2535 independent
reflections, R = 0.0463 for 1895 observed reflections with I > 2σ(I). All of the calculations were carried out
using the SHELX-97 program package [13]. The data obtained was deposited in the Cambridge structural data
bank (deposit No CCDC 688298).
DFT/PBE/3z quantum-chemical calculations were carried out using the PRIRODA program [14].
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