Synthesis of 2-unsubstituted 1-arylimidazoles

Article abstract of DOI:10.1007/s10593-013-1210-8

A method has been developed for the synthesis of 1-arylimidazoles lacking a substituent at position 2, featuring the preparation of 1-arylimidazole N-oxides stabilized as boron trifluoride derivatives, with subsequent reduction to the desired imidazoles. This method permits broad variation of the substituents in the aryl part of these molecules.

Full text of DOI:10.1007/s10593-013-1210-8

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS OF 2-UNSUBSTITUTED 1-ARYLIMIDAZOLES
V. S. Mityanov1*, V. P. Perevalov1, and I. I. Tkach1
A method has been developed for the synthesis of 1-arylimidazoles lacking a substituent at position 2,
featuring the preparation of 1-arylimidazole N-oxides stabilized as boron trifluoride derivatives, with
subsequent reduction to the desired imidazoles. This method permits broad variation of the substituents
in the aryl part of these molecules.
Keywords: 1-arylimidazoles, boron trifluoride, imidazole N-oxides, heterocyclization, N-oxide
reduction.
1-Arylimidazole derivatives display a broad spectrum of biological activity, such as antitumor and
immunodepressant activity [1]. These compounds hold interest in the treatment of many neurological conditions
such as obesity, motion disorders, and schizophrenia [1]. Thus, such imidazole derivatives undoubtedly hold
pharmacological potential [2-5]. Particular attention is given to 1-arylimdiazoles lacking a substituent at
position 2. However, the difficulty in preparing many such compounds has hindered the study of their
properties. Thus, considerable interest is found in the development of an effective method for the synthesis of
1-arylimidazoles unsubstituted at position 2.
Two fundamentally different approaches are known for the synthesis of 1-arylimidazoles. The first
method involves the direct introduction of the aryl fragment by means of aromatic nucleophilic substitution
reactions [6] or cross coupling [7]. However, these methods place serious restrictions on the nature and position
of the substituents in the aryl fragment. Furthermore, in the case of different substituents at positions 4 and 5 in
the imidazole, a mixture of products is formed with predominance of the less sterically hindered compound. The
second approach entails the preparation of 1-arylimidazoles from acyclic precursors using various
cyclocondensation reactions. However, the methods described in the literature [8-11], though providing
imidazoles with the desired set of substituents, involve many steps, proceed with low overall yield, and are
suitable for only a limited number of compounds.
This work has been focussed on a scheme that combines the preparation of 1-arylimidazole N-oxides
with free position 2 and subsequent reduction of the N-oxide function.
The first attempts to synthesize 2-unsubstituted 1-arylimidazole N-oxides [12-14] involved the acid-
catalyzed condensation of α-diketone monooximes either with aromatic amines and formaldehyde or with
previously obtained N-arylmethylenamines. In the former case, 1-arylimidazole N-oxides could not be isolated,
_______
*To whom correspondence should be addressed, e-mail: mityanovvs@yandex.ru.
1D. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Sq., Moscow 125047, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1916-1923, December, 2012.
Original article submitted May 22, 2012.
0009-3122/13/4812-1793©2013 Springer Science+Business Media New York
1793

apparently, due to very rapid isomerization of these compounds to 2-imidazolones [14]. In the latter case, a few
compounds were synthesized in low yields by minimizing the amount of water generated during the
condensation. In recent years, attempts were undertaken to develop alternative methods for the synthesis of
these compounds entailing the condensation of α-amino oximes with ethyl orthoformate [15] or the
condensation of α-diimines with aldoximes [16], but the yields of 1-arylimidazoles were also low in these cases,
while the starting α-diimines and α-amino oximes often proved not readily available.
We assumed that 2-unsubstituted imidazole N-oxides could be stabilized by binding them in some
complex. Indeed, the condensation of aromatic amines 1a-h with formaldehyde and the butane-2,3-dione
monooxime (2), similar to the condensation of N-arylmethylenamines 3a,c,f with oxime 2 in the presence of
boron trifluoride etherate in acetic acid or chloroform led to the 1-aryl-3-[(difluoroboryl)oxy]-4,5-dimethyl-
1H-imidazolium fluorides 4a-h in high yield.
F2B
F
O
N+
Me
Me
Me
N
Me
O
BF3·Et2O
ArNH2
+
CH2O
+
AcOH
N
HO
1a–h
2
Ar
4a–h
BF3·Et2O
4a,c,f
Ar
N
CH2
+
2
CHCl3
3a,c,f
a Ar = Ph, b Ar = 2,4,6-Me3C6H2, c Ar = 4-MeOC6H4, d Ar = 3-FC6H4,
e Ar = 2,4,6-(MeO)3C6H2, f Ar = 3-ClC6H4, g Ar = 4-O2NC6H4, h Ar = 3-Py
The use of boron trifluoride etherate is very convenient. This complex not only stabilizes imidazole
N-oxides but also acts as an acid catalyst facilitating the reaction, such that it may proceed under mild
conditions. Even such weakly basic amines as 4-nitroaniline (1g) and 3-aminopyridine (1h) readily take part in
this reaction. It is interesting that 4-nitroaniline (1g) undergoes the reaction even when using aqueous
formaldehyde in water-immiscible solvent (chloroform). We selected chloroform and acetic acid as the standard
solvents in our study of this condensation, but the reaction can also be carried out in other solvents such as
alcohols and dichloroethane.
In the case of mesidine 1b and 2,4,6-trimethoxyaniline 1e, we showed that even very sterically hindered
arylamines readily undergo this reaction. We should note that imidazole derivatives with sterically hindered
2,6-diaryl fragments at the position N-1 have not been described in the literature.
Table 1 shows that the yields in the condensation of α-diketone monooxime with formaldehyde and an
arylamine are independent of both the nature of the substituents in the aryl fragment and the steric hindrance,
but rather are a function of the ease of the pure product isolation. Carrying out this condensation using
previously obtained N-arylmethylenamines 3a,c,f is preparatively more convenient and permits the use of mild
conditions. The product isolation in this case does not pose difficulties, and the yields range from 54 to 85%.
Imidazolium salt 4h was obtained as a complex with two equivalents of BF3 as indicated by the
elemental analysis. The second equivalent of BF3 apparently forms a donor-acceptor bond with the pyridine
nitrogen atom.
The starting N-arylmethylenamines 3a,c,f were obtained by the reaction of arylamines with
formaldehyde in ethanol [17]. According to the spectral data, azomethines 3a,c,f exist in equilibrium with the
cyclic form, namely, 1,3,5-trisubstituted hexahydro-1,3,5-triazines. The cyclic form predominates in the case of
aromatic amines [13].
1794

TABLE 1. Physicochemical Characteristics of Compounds 4a-h, 6a-f,h and 7
Found, %
Calculated, %
H
Yield*2, %
(Method)
——————
Com-
pound
Empirical
formula
Mp*, °С
C
N
C11H12BF3N2O
C14H18BF3N2O
C12H14BF3N2O2
C11H11BF4N2O
C14H18BF3N2O4
C11H11BClF3N2O
C11H11BF3N3O3
C10H11B2F6N3O
C11H12N2
51.30
51.60
56.35
56.41
50.35
50.39
48.15
48.22
48.50
48.58
45.38
45.48
43.84
43.89
36.87
36.98
76.65
76.71
78.39
78.46
71.30
71.26
69.40
69.46
64.04
64.11
63.89
63.93
4.52
4.72
5.97
6.09
4.90
4.93
3.98
4.05
5.20
5.24
3.79
3.82
3.60
3.68
3.47
3.41
6.95
7.02
8.67
8.47
7.16
6.98
5.80
5.83
6.87
6.92
5.31
5.36
10.79
10.94
9.37
9.40
9.73
9.79
10.18
10.22
8.01
8.09
9.60
9.64
13.92
13.96
12.86
12.94
16.19
16.26
12.91
13.07
13.59
13.85
14.69
14.73
10.61
10.68
13.49
13.55
80-82
174-176
165-166
108-110
156-158
189-190
203-205
165-167
Oil
73 (A)
54 (B)
44 (A)
4a
4b
4c
4d
4e
4f
44 (A)
67 (B)
45 (A)
81 (A)
55 (A)
85 (B)
58 (A)
61 (B)
4g
4h
6a
6b
6c
6d
6e
6f
65 (A)
80
C14H18N2
110-112
48-50
93
C12H14N2O
71
C11H11FN2
Oil
71
C14H18N2O3
C11H11ClN2
138-140
Oil
84
90
C10H11N3
69.28
69.34
70.50
70.56
6.23
6.40
6.89
7.00
24.21
24.26
22.39
22.44
>165
65
6h
7
(decomp.)
C11H13N3
128-130
40
_______
*Recrystallization solvents: 2-propanol (compounds 4a,b,d,e), ethyl acetate
(compounds 4c,f), acetone (compounds 4g,h), heptane (compounds 6b,c,e,h),
and toluene–heptane (compound 7).
*2The yields of the reduction reactions are given for compounds 6a-f,h and 7.
Sprung [17] reported that heating 4-nitroaniline (1g) with formaldehyde in ethanol at reflux under
neutral conditions proceeds somewhat unusually to give N,N'-bis(4-nitrophenyl)methanediamine (5). It is
interesting that diamine 5, similar to arylamines 1a-h and N-arylmethylenamines 3a,c,f, undergoes condensation
with butane-2,3-dione monooxime (2) to give the corresponding derivative 4g.
Ar
N
3 Ar–N=CH2
3 ArNH2
+
3 CH2O
N
N
1a,c,f
Ar
Ar
3a,c,f
O2N
NO2
2 1g
+
CH2O
N
N
H
H
5
1795

The desired 1-aryl-4,5-dimethylimidazoles 6a-f,h were obtained by the reduction of 1-aryl-3-[(difluoro-
boryl)oxy]-4,5-dimethyl-1H-imidazolium fluorides 4a-f, h by using iron in acetic acid. In the case of nitro
derivative 4g, reduction of the nitro group also occurs under these conditions to give the amino derivative 7.
Me
N
N
Me
Me
Me
N
N
Fe
4a–h
+
AcOH
Ar
6a–f,h
H2N
7 (from 4g)
a Ar = Ph, b Ar = 2,4,6-Me3C6H2, c Ar = 4-MeOC6H4, d Ar = 3-FC6H4,
e Ar = 2,4,6-(MeO)3C6H2, f Ar = 3-ClC6H4, h Ar = 3-Py
The thermal stability of derivatives 4c,f,g was studied. Upon heating in a polar solvent (DMF) on a
steam bath for 0.5 h, salts 4c,f did not undergo any change. After prolonged heating at reflux in DMF, the
fluoride 4c decomposed completely. Heating the 4-nitrophenyl derivative 4g in DMF on a steam bath for 10 min
gave quantitative conversion to the corresponding N-oxide 8.
Heating 1-arylimidazole N-oxides in the weakly polar solvent bromobenzene led to a rearrangement
giving 2-imidazolones [13]. However, the fluorides 4c,g were not altered under these conditions.
O
SnCl2, HCl, EtOH
N+
Me
(for 4с)
4c,g
or
N
Me
DMF, 100°C, 10 min
Ar
(for 4g)
8, 9
8 Ar = 4-O2NC6H4, 9 Ar = 4-MeOC6H4
Imidazole N-oxides are also known to undergo facile reduction to give imidazoles by the action of
triphenylphosphine in acetic acid [18]. However, only the starting compounds were detected after prolonged
heating of 3-[(difluoroboryl)oxy]-1-phenyl-1H-imidazolium fluoride 4a with excess triphenylphosphine at
reflux both in acetic acid and propionic acid. The presence of the difluoroboryl group at the N-oxide oxygen
atom apparently hindered the coordination of the bulky triphenylphosphine molecule at this atom and the
subsequent deoxygenation reaction.
Cleavage of the oxygen–boron bond with retention of the N-oxide function was found upon the
reduction of fluoride 4c using SnCl2 in ethanol in the presence of hydrochloric acid both at room temperature
and at reflux. The corresponding N-oxide 9 was obtained in 92% yield.
Table 2 shows that the 1H NMR spectra of 1-aryl-3-[(difluoroboryl)oxy]-1H-imidazolium fluorides 4a-h
displayed a narrow signal at 9.16-9.58 ppm for the proton at the imidazole ring C-2 atom. This signal was
shifted downfield by approximately 1 ppm in comparison with the corresponding N-oxides (compare
compounds 4g with 8 and 4c with 9).
1796

TABLE 2. 1H NMR Spectra of Compounds 4a-h, 6a-f,h and 7
Chemical shifts*, δ, ppm (J, Hz)
Com-
pound
4,5-СН3
H-2 (1H, s)
Aromatic protons
Other signals
—
(3H, s) and (3Н, s)
4a
4b
9.42
9.29
2.25; 2.12
2.33; 2.28
7.70-7.50 (5H, m)
7.15 (2H, s)
1.95 (6Н, s, 2',6'-СН3);
1.90 (3Н, s, 4'-СН3)
4c
9.37
2.24; 2.09
7.51 (2H, d, J = 9.2);
7.14 (2H, d, J = 9.2)
3.84 (3Н, s, ОСН3)
4d
4e
9.48
9.13
2.25; 2.15
2.22; 1.90
7.70-7.47 (4H, m)
6.46 (2H, s)
—
3.87 (3H, s, 4'-OCH3);
3.79 (6H, s, 2',6'-OCH3)
4f
9.47
9.58
2.25; 2.14
2.27; 2.18
7.82 (1H, s); 7.78-7.55 (3H, m)
—
—
4g
8.45 (2Н, d, J = 9.0);
7.93 (2Н, d, J = 9.0)
4h
9.50
2.26; 2.16
8.93-8.85 (2H, m);
8.31-8.25 (1H, m);
7.83-7.77 (1H, m)
—
—
6a
6b
6c
6d
6e
7.49-7.40*2
7.23
2.23; 2.09
2.32; 2.23
2.19; 2.02
2.23; 2.12
2.20; 1.85
7.49-7.40 (4H, m, H-2, H Ar);
7.26-7.23 (2H, m)
6.95 (2H, s)
1.91 (6Н, s, 2',6'-СН3);
1.83 (3Н, s, 4'-СН3)
3.82 (3Н, s, ОСН3)
7.41
7.16 (2H, d, J = 8.8);
6.95 (2H, d, J = 8.8)
7.51
7.50-7.42 (2H, m);
7.16-6.98 (2H, m)
—
7.23
6.18 (2H, s)
3.84 (3H, s, 4'-OCH3);
3.71 (6H, s, 2',6'-OCH3)
6f
7.45
2.19; 2.08
2.90; 2.73
7.40-7.12 (4H, m)
—
—
3
6h
*
9.88 (1H, s);
9.75-9.60 (1H, m);
9.43-9.30 (1H, m);
8.95-8.80 (1H, m)
7
7.39
2.19; 2.01
6.98 (2Н, d, J = 8.8);
6.68 (2Н, d, J = 8,8)
3.97 (2H, s, NH2)
_______
*The spectra of fluorides 4a-h were recorded in DMSO-d6, while the spectra of
imidazoles 6a-f and 7 were recorded in CDCl3, and the spectrum of 6h was
recorded in trifluoroacetic acid.
*2Superposition onto the multiplet of the phenyl ring proton signals.
*3Found within the multiplet of the pyridine ring protons.
The 13C NMR spectra of fluorides 4a-h did not provide much useful information. The signals of all the
aromatic ring carbon atoms are located in an extremely narrow range. Additional study is required for the
assignment of these signals.
The mass spectra of fluorides 4a-h given in Table 3 show signals corresponding to the 1-aryl-3-[(di-
fluoroboryl)oxy]-1H-imidazolium molecular cation and signals for the [M-BR2]+· radical cation, as well as a
+
rather strong signal for the fragment with m/z 49, corresponding to the BF2 cation. This suggests that
compounds 4a-h were indeed 1-aryl-3-[(difluoroboryl)oxy]-1H-imidazolium fluorides with a covalent bond
between oxygen and boron, and not BF3 complexes of 1-arylimidazole N-oxides.
Thus, the proposed synthetic method provides a pathway to the preparation of 1-arylimidazoles, which
are difficult to obtain by other methods. The products obtained, which we have identified as 1-aryl-3-[(difluoro-
boryl)oxy]-1H-imidazolium fluorides, have not yet been described in the literature and may hold interest in
themselves.
1797

TABLE 3. Mass Spectra of Compounds 4a-h, 6a-f,h and 7
Com-
pound
m/z (Irel, %)*
M, g/mol
[М]+
[М-BF2]+•
[M-BF2-O]+
[M-BF2-OH]+
256
298
286
274
346
290
301
324
172
214
202
190
262
206
173
187
237 (20)
279 (4)
188 (100)
230 (52)
218 (100)
206 (100)
278 (61)
222 (100)
233 (93)
189 (100)
—
172 (27)
214 (100)
202 (19)
190 (25)
262 (100)
206 (21)
217 (100)
173 (31)
—
171 (49)
213 (25)
201 (43)
189 (65)
261 (33)
205 (63)
216 (87)
172 (57)
—
4a
4b
4c
267 (16)
255 (30)
327 (3)
4d
4e
4f*2
4g
4h
6a
6b
6c
271 (14)
282 (13)
238 (22)
172 (43)
214 (100)
202 (100)
190 (100)
262 (100)
206 (100)
173 (96)
187 (80)
—
—
—
—
—
—
—
—
—
6d
6e
6f*2
6h
7
—
—
—
—
—
—
—
—
—
—
—
—
_______
*For fluorides 4a-h, [M] is the 1-aryl-3-[(difluoroboryl)oxy]-1H-imidazolium cation.
*2For isotope 35Cl.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker AM-300 spectrometer (300 and 75 MHz,
respectively) with TMS as internal standard. The mass spectra were recorded on an LKB-2000 mass
spectrometer equipped with a system for direct sample inlet. The ionizing electron energy was 70 eV. The
elemental analysis was carried out on a Carlo Erba Model 1106 CHN analyzer manufactured in Italy. The
melting points were determined on a Kofler hot stage apparatus. The reaction course and purity of the products
were monitored by thin-layer chromatography on Silufol UV-254 plates.
Anilines 1a-d,f-h and oxime 2 are commercially available. The 2,4,6-trimethoxyaniline (1e) was obtained
according to the procedure of Fukui et al. [19]. N-Phenylmethylenamine (3a), N-(4-methoxyphenyl)methylenamine
(3c), and N,N'-bis(4-nitrophenyl)methanediamine (5) were obtained using standard procedures [17].
N-(3-Chlorophenyl)methylenamine (3f). 30% Formalin (22.0 ml, 24.0 g, 24 mmol) was added to a
solution of 3-chloroaniline (25.5 ml, 30.6 g, 24 mmol) in ethanol (100 ml). The reaction mixture was stirred at
reflux for 2.5 h and then cooled. The precipitate formed was filtered off and washed with ethanol (20 ml) to give
methylenamine 3f. Yield 19.3 g (58%). White powder; mp 172-174°C.
1-Aryl-3-[(difluoroboryl)oxy]-4,5-dimethyl-1H-imidazolium Fluorides 4a-h (General Method). A.
BF3·Et2O (1.4 ml, 1.6 g, 11 mmol) (in the case of 3-aminopyridine (1h), 3.1 ml, 3.6 g, 25 mmol), 40% formalin
(0.7 ml, 0.8 g, 10 mmol), and then amine 1a-h (10 mmol) were added to a solution of butane-2,3-dione
monooxime (2) (1.0 g, 10 mmol) in glacial acetic acid (10 ml). The mixture was stirred at 50-55°C for 4 h.
Acetic acid was evaporated under reduced pressure, and the product was obtained from the residue by
chromatography on a silica gel column using 100:1 chloroform–methanol as the eluent.
B. BF3·Et2O (1.4 ml, 1.6 g, 11 mmol) and then N-arylmethylenamine 3a,c,f (10 mmol) were added to a
solution of butane-2,3-dione monooxime (2) (1.0 g, 10 mmol) in chloroform (10 ml). The mixture was stirred at
room temperature for 4 h. Chloroform was evaporated at reduced pressure. The product was isolated by
chromatography on a silica gel column using 100:1 chloroform–methanol as the eluent.
1798

13
Fluoride 4a. С NMR spectrum (DMSO-d6), δ, ppm: 133.4; 130.8; 130.2; 129.9; 126.3; 125.7; 123.8;
8.7 (СН3); 6.9 (СН3).
13
Fluoride 4c. С NMR spectrum (DMSO-d6), δ, ppm: 160.2; 130.8; 127.7; 126.1; 125.3; 124.0; 114.8;
55.6 (ОСН3); 8.54 (СН3); 6.92 (СН3).
1-Aryl-4,5-dimethylimidazoles 6a-f,h, 7 (General Method). Iron powder (8.4 g, 150 mmol) was
added to a solution of fluoride 4a-h (10 mmol) in glacial acetic acid (35 ml). The reaction mixture was stirred at
reflux for 2 h, cooled, and poured into water (70 ml). The iron sludge was filtered off. The filtrate was extracted
with chloroform (50 ml). The extract was washed with 5% aqueous potassium carbonate until the wash water
was slightly basic. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over
sodium sulfate, and then filtered. Chloroform was distilled off at reduced pressure. The residue was subjected to
chromatography on a silica gel column using 100:1 chloroform–methanol as the eluent.
4,5-Dimethyl-1-(4-nitrophenyl)imidazole N-Oxide (8). A solution of fluoride 4g (1.0 g, 3.3 mmol) in DMF
(5 ml) was heated at 100°C for 25 min and then cooled. The precipitated product was filtered off, washed with
water, and dried to give the N-oxide 8. Yield 0.5 g (61%). Light-yellow powder; mp 172-174°С (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm: (J, Hz): 8.65 (1Н, s, Н-2); 8.37 (2Н, d, J = 8.8, H Ar); 7.78 (2Н, d,
J = 8.8, H Ar); 2.19 (3Н, s, СН3); 2.08 (3Н, s, СН3). Mass spectrum, m/z (Irel, %): 233 [М]+· (93), 217 [M-O]+·,
(100), 216 [M-OH]+ (89). Found, %: C 56.59; H 4.71; N 17.55. C11H11N3O3. Calculated, %: C 56.65; H 4.75;
N 18.02.
4,5-Dimethyl-1-(4-methoxyphenyl)imidazole N-Oxide (9). A solution of fluoride 4c (1.0 g,
3.5 mmol) in ethanol (25 ml) was added to a solution of SnCl2·2H2O (4.7 g, 21 mmol) in concentrated
hydrochloric acid (25 ml). The reaction mixture was stirred at reflux for 7 h, cooled, and brought to pH 9-10 by
adding concentrated aqueous potassium hydroxide. The precipitate formed was filtered off, and the product in
the filtrate was extracted with chloroform (100 ml). The extract was evaporated and traces of water and ethanol
were removed by azeotropic distillation with benzene (10 ml) to give N-oxide 9. Yield 0.7 g (92%). White
1
powder; mp 90-94°С. H NMR spectrum (DMSO-d6), δ, ppm, (J, Hz): 8.35 (1Н, s, Н-2); 7.38 (2Н, d, J = 8.8,
H Ar); 7.14 (2Н, d, J = 8.8, H Ar); 3.81 (3Н, s, ОСН3); 2.05 (3Н, s, СН3); 2.04 (3Н, s, СН3). Mass spectrum,
m/z (Irel, %): 218 [М]+· (100), 202 [M-O]+· (18), 201 [M-OH]+ (26). Found, %: C 66.00; H 6.40; N 12.79.
C12H14N2O2. Calculated, %: C 66.04; H 6.47; N 12.84.
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