Synthesis and tautomerism of 2-phenacyl-1H-benzimidazoles and their hydrogen bromide salts

Article abstract of DOI:10.1007/s10593-011-0860-7

2-Phenacyl-1H-benzimidazoles were prepared by the acylation of 2-methylbenzimidazole using aroyl chlorides with subsequent alcoholysis or aminolysis of the N,C,O-triacylation products obtained. Treatment of the 2-phenacyl-1H-benzimidazoles with hydrobromic acid gave the corresponding salts. The structure of the products was supported by IR, ¹H and ¹³C NMR, and HMBC spectroscopy as well as by quantum-chemical calculations. 2-Phenacyl-1H-benzimidazoles in DMSO-d₆ solution were found to display predominantly imino-enamino tautomerism, while their salts were found to display predominantly keto-enol tautomerism.

Full text of DOI:10.1007/s10593-011-0860-7

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
SYNTHESIS AND TAUTOMERISM OF 2-PHENACYL-
1H-BENZIMIDAZOLES AND THEIR HYDROGEN
BROMIDE SALTS
I. B. Dzvinchuk1**, A. M. Nesterenko1, V. V. Polovinko2,
A. B. Ryabitskii1, and M. O. Lozinskii1*
2-Phenacyl-1H-benzimidazoles were prepared by the acylation of 2-methylbenzimidazole using aroyl
chlorides with subsequent alcoholysis or aminolysis of the N,C,O-triacylation products obtained.
Treatment of the 2-phenacyl-1H-benzimidazoles with hydrobromic acid gave the corresponding salts.
1
The structure of the products was supported by IR, H and 13C NMR, and HMBC spectroscopy as well
as by quantum-chemical calculations. 2-Phenacyl-1H-benzimidazoles in DMSO-d6 solution were found
to display predominantly imino-enamino tautomerism, while their salts were found to display
predominantly keto-enol tautomerism.
Keywords: benzimidazoles, acylation, deacylation, quantum-chemical study, spectroscopy, tautomerism.
Benzimidazole compounds are isoelectronic analogs of purine, which is one of the most biophoric
heterocycles. These compounds also display various biological activity and may serve as effective agents for
disease prevention in humans, animals, and plants. Furthermore, the 5,6-dimethylbenzimidazole fragment is
found in vitamin B12 [1, 2].
O
Ar
N
N
H
1a–j
1a Ar = Ph, b Ar = p-MeOC6H4, c Ar = p-MeC6H4, d Ar = m,p-(MeO)3C6H2, e Ar = p-ClC6H4,
f Ar = p-BrC6H4, g Ar = m-ClC6H4, h Ar = m-O2NC6H4, i Ar = p-O2NC6H4, j Ar = o,p-(HO)2C6H3
_______
*Deceased.
** To whom correspondence should be addressed, e-mail: Rostov@ioch.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094 ,
Ukraine.
2Ukrorgsintez, 29 Shchorsa St., Kyiv 02042, Ukraine; e-mail: nmr@mail.enamine.net.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1162-1174, August, 2011.
Original article submitted May 18, 2010, submitted after revision February 17, 2011.
0009-3122/11/4708-0953©2011 Springer Science+Business Media, Inc.
953

Thus, new benzimidazole compounds hold promise in the search for compounds with useful
applications. We have developed a method for the synthesis of these compounds based on the conversion of
2-phenacyl-1H-benzimidazoles 1a-j [3-5]. A general convenient method for the preparation of such compounds
has not yet been reported.
Tajana et al. [6] have reported the synthesis of compound 1a by recyclization upon the acid hydrolysis of
2-(4-methylpiperazin-1-yl)-4-phenyl-1,5-benzodiazepine. Sakamoto et al. [7] have reported the synthesis of
compound 1i by the C-acylation of 2-methylbenzimidazole using 4-nitrobenzoyl cyanide. Khilya et al. [8, 9]
have reported the synthesis of compound 1j (Ar = o,p-(HO)2-m-R-C6H2, where R = H or Alk) from
2-benzimidazolylacetonitrile and resorcinols using the Hoesch reaction. The first two methods give low product
yields (9-28%), while the latter, despite high yields of 50-80%, has only limited application.
On the other hand, 2-phenacyl-1H-imidazoles, which are structural analogs of compound 1, were readily
obtained in 65-83% yield by the acid hydrolysis of products of the acylation of 2-methylimidazole using aroyl
chlorides [10, 11]. Similarly, we have synthesized compound 1a in 89% yield by subsequent mopholinolysis of
the benzoylation product [12].
The data on the tautomerism of compounds of type 1 are contradictory. According to Sakamoto [7],
compound 1i is found only in enamino-keto form B and not ketonic form A. According to Khilya [8, 9],
compound 1j exists in solution as an equilibrium mixture of ketone A and enol C, similar to its imidazole
analogs [10, 11].
O
H
O
H
O
Ar
N
N
Ar
N
N
Ar
N
N
R
A
R
R
B
C
1a–j R = H; 2 R= Me, Ar = Ph
In contrast, 1-methyl-2-phenacyl-1H-benzimidazole (2) exists in solution as a mixture of tautomers A
and B without a trace of enol C [13, 14]. In a later work, Khilya [9] described a keto-enol tautomerism for
derivatives 2 containing an o-hydroxyl group in the benzene ring. Indeed, form B for compounds of type 1 and 2
has less aromaticity than form C. Both forms, in all likelihood, readily interconvert as a result of concurrent
displacement of a proton between the nitrogen and oxygen atoms and of the bonds in the cyclic six-centered
conjugated system. The preference for form B or C is determined by the extent of bonding of this proton with
either the nitrogen or oxygen heteroatom.
In the present communication, we describe a preparative method for the synthesis of various 2-phenacyl-
1H-benzimidazoles and propose simple criteria for recognition of the structure of their tautomeric forms.
The above-mentioned two-step scheme for the preparation of compound 1a was found to be general and
suitable for the synthesis of a series of 2-phenacyl-1H-benzimidazoles 1a-i.
COAr
H
N
OCOAr
Ar
N
N
ArCOCl
Et3N
1-BuOH
1a–i
Me
C
or morpholine
H
N
The reaction of 2-methylbenzimidazole with aroyl chlorides using triethylamine as the base proceeds as
N,C,O-triacylation. The products of this reaction, which are shown in the above scheme in brackets, are readily
isolated in most cases as a precipitate. Upon heating with 1-butanol, the triacylated products undergo alcoholysis
leading to N,O-deacylation and formation of compounds 1b-i with rather high regioselectivity. The triacylation
product could not be isolated as a solid when anisoyl chloride was used though aminolysis of the reaction
mixture with excess morpholine proceeds smoothly, leading to compound 1b.
954

In order to study the tautomerism of compounds 1a-i, we used 1-methyl-2-phenacyl-1-benzimidazole (2)
synthesized from 1,2-dimethylbenzimidazole in 88% yield by our scheme for the preparation of compound 1
[15]. We should note that compound 2 was previously prepared by Huang and Wang [14] in 41% yield by
another procedure.
We also obtained the corresponding salts 3a,b,i, and 4 by the reaction of compounds 1a,b,i, and 2 with
hydrobromic acid. The existence of phenacyl (A'), enamino ketone (B'), and enol (C') forms may be proposed
for these salts.
H
H
O
–
O
H
H
O
–
Br
Br
Ar
Ar
N
Ar
N
N
HBr
+
1a,b,i
2
+
–
+
N
N Br
R
N
H
R
R
А'
B'
C'
3a,b,i, 4
3 R = H, a Ar = Ph, b Ar = p-MeOC6H4, i Ar = p-NO2C6H4; 4 R = Me, Ar = Ph
Our conclusions about the composition and structure of the products 1-4 were based on the results of
1
elemental analysis (Table 1), IR and H NMR spectroscopy (Table 2), and the HMBC two-dimensional
heteronuclear correlation spectrum of compound 1i (Fig. 1), as well as quantum-chemical calculations for the
tautomeric forms of compounds 1a and 3a (Tables 3-5).
TABLE 1. Characteristics of Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, С
С
Н
N
1a
1b
1c
1d
1e
1f
С15H12N2O
76.25
76.38
5.12
5.10
11.86
11.95
178–179
89
82
71
66
85
77
70
60
69
89
179 [6]
C16H14N2O2
72.31
72.16
5.18
5.30
10.60
10.52
208–209
C16H14N2O
76.37
76.78
5.45
5.64
10.97
11.19
195–196
155–157
226–228
244–246
218–220
266–268
C18H18N2O4·0.5 H2O
C15H11ClN2O
C15H11BrN2O
C15H11ClN2O
C15H11N3O3
64.05
64.47
5.82
5.71
8.20
8.35
66.64
66.55
4.06
4.10
10.22
10.35
57.08
57.16
3.27
3.52
25.28
8.89
1g
1h
1i
66.38
66.55
4.02
4.10
10.14
10.35
63.88
64.05
3.77
3.94
14.87
14.94
C15H11N3O3
64.18
64.05
3.81
3.94
14.98
14.94
296–297
165–166 [7]
3a
С15H12N2O·HBr
56.98
56.80
3.95
4.13
8.98
8.83
173–175
277–278 [20]
3b
3i
4
C16H14N2O2·HBr
C15H11N3O3·HBr
C16H14N2O·HBr
55.48
55.35
4.14
4.35
9.35
8.07
194–196
91
99
90
49.98
49.74
3.18
3.34
11.82
11.60
285–287 (dec.)
164–166
58.39
58.02
4.38
4.56
8.63
8.46
955

956

957

The signals for the protons of the individual groups in the 1H NMR spectra of compounds 1-4 in DMSO-d6
are doubled, which reflects the existence of these compounds in two tautomeric forms A (A' for salts 3a,b,i, 4) and B
or C (B' or C' for salts 3a,b,i, 4). There are no signals for traces of water, which indicates the active participation of
water in the exchange processes. The signals for the protons of the methylene group and vinyl fragment in the bases
appear at 4.6-4.9 and 6.0-6.3 ppm, respectively. These signals for the salts appear at 5.1-5.4 and 6.0-6.3 ppm,
respectively. It is important to note that these signals are not overlapped by other signals and, thus, the ratio of their
integral intensities could be used to determine the tautomeric composition for each compound. This approach
permitted us to elucidate the effect of substituent Ar on the tautomeric equilibrium and draw preliminary conclusions
regarding the structure of the most stable tautomers using the Kabachnik theory [16], according to which, any such
equilibrium is shifted toward the less dissociated (less acidic) product.
The stability of form A (or A') was found to drop from 50 to 2% in the series of bases 1b > 1c > 1d > 1a
> 2 > 1e > 1f > 1g > 1h > 1i and from 88 to 36% in the series of salts 3b > 4 > 3a > 3i, on the whole, with
increasing electron-withdrawing nature of substituents Ar as might have been expected in accord with their effect
on the acidity of the methylene group.
Form A is less stable for bases 1a, b, i, and 2 (20, 50, 2, and 14% content in the mixture, respectively)
than form A' obtained from the derived salts 3a, b, i, and 4 (68, 88, 30, and 73%, respectively). This finding, at
first glance, contradicts the theory, according to which, form A should be more stable since the 2-benzimidazole
fragment is a weaker electron-withdrawing substituent than its protonated form. The reason for this apparent
discrepancy likely lies in the different structure of the second, vinyl-containing tautomer of the bases and salts.
Thus, form B' is unlikely for salts due to the obvious breakdown in the aromaticity of the heterocycle, in which
the ammonium nitrogen atom lacks a free unshared electron pair, thereby preventing ring overlap of the
-orbitals. Enol form C' is energetically favored for the salts. In the case of the bases, on the other hand,
especially high stabilization of form B may result from the formation of an energetically favorable conjugation
chain, in which electron density is transferred from the nitrogen atoms of the heterocycle to the carbonyl group
through the vinyl fragment. The thermodynamic stability of form B of the bases was also indicated in quantum-
chemical calculations (see below).
TABLE 3. Enthalpies of Formation of Some Tautomeric Forms of
Compounds 1a and 3a in DMSO from PM3 Quantum-chemical
Calculations
Tautomers 1а
Strucrture
Tautomers 3а (cation part)
Structure ΔH, kcal/mol
ΔH, kcal/mol
O
O
H
H
Ph
Ph
Ph
N
N
N
N
25.64
137.19
138.35
+
H
H
H
H
H
B'
B
O
O
H
+
N
N
Ph
N
N
28.95
H
H
H
H
H
C1
B'1
H
H
O
O
Ph
N
Ph
N
N
29.92
126.35
+
N
C2
C'
958

TABLE 4. Thermodynamic Characteristics of Some Tautomeric Forms of
Compound 1a from Semiempirical Quantum-chemical Calculations
H
O
H
H O
O
Ph
N
Ph
N
N
Ph
HN
N
N
H
H
TS (B–C)
H
B
B
ΔН B,
kcal/mol
ΔН TS(B-C)
kcal/mol
ΔН C,
kcal/mol
Еа,
cal/mol
Е(C)–Е(B),
kcal/mol
Method \ Model
АМ1* (in vacuum)
РМ3* (in vacuum)
РМ3*2 (in DMSO)
РМ3*3 (in DMSO)
_______
57.63
34.24
25.64
-19.34
83.58
59.15
51.38
2.41
61.23
36.90
28.95
-24.30
25.95
24.91
25.74
21.75
3.60
2.66
3.31
-4.97
*Enthalpy of formation (H) and activation energy (Ea).
*2Values of H and Ea calculated taking account the solvent in the
COSMO model.
*3Energies given for the complex of B (or C) with one DMSO molecule
taking account the DMSO solvent in the COSMO model.
TABLE 5. Thermodynamic Characteristics of Tautomeric Forms of
Compound 1a from Nonempirical DFT Quantum-chemical Calculations
(B3LYP in the 6-31+G(d,p) Basis)
Е(C)–Е(B),
Model
Еа, kcal/mol
B
TS(B-C)
C
kcal/mol
0.002903
a.u. = 1.82
Еtot
-763.622239
-763.616755
-763.624041
-0.00141
а.u. = -0.88
(in vakuum)*
ZPE
0.237113
0.233137
0.237520
Еtot
-763.640701
-763.629692
-763.635803
0.011
а.u = 6.91
0.0049
а.u. = 3.08
(in DMSO)*2
_______
*Total energies (Etot) given in a.u. (1 a.u. = 627.51 kcal/mol), zero point
energy (ZPE) in Hartree/particle.
*2Tomasi IPCM model used.
1
Comparison of the H NMR spectral data for compound 1a and its N-methyl analog 2 as well as
compounds 1b,c,e (Table 2) and their previously described N-methyl derivatives [14] shows that the
introduction of a methyl substituent at a nitrogen atom leads to a reduction in the content of tautomer A by a
factor of 1.4-2.6. This finding is probably related to an increase in the basicity of the nitrogen atom, which
enhances its tendency to transmit an electron-donor effect to the carbonyl group in form B. On the other hand,
the spectra of salts 3a and 4 show that the same structural change leads to an increase in the amount of form A'
by a factor of ~1.1. This effect may be attributed to diminished acidity of the methylene group due to a drop in
the electron-withdrawing properties of the heterocyclic fragment.
1
The signals of the protons bound to the benzimidazole nitrogen atoms in the H NMR spectra of
compounds 1a-i in most cases appear as three singlets. We assigned the first and second singlets to protons of
form A and the proton removed from the C=O group in form B. These signals overlap or coalesce into a single
959

signal if the content of form A is less than 10%. The third singlet at low field is highly broadened (it was not
observed in the spectrum of compound 1i) and its integral intensity could not be determined due to considerable
error. This singlet may be assigned to the second proton of form B located close to the C=O group since its
chemical shift is similar to the corresponding shift of the proton in compound 2 in form B (13.92 ppm). It is
precisely this proton, which can form a reversible hydrogen bond with the carbonyl oxygen atom and also
directly participate in the interconversion of tautomers A and B. The signals for the NH group, CH2 group, and
vinyl fragment disappear in the NMR spectrum of compound 1a after treatment of its solution with D2O.
We should note that the 1H NMR spectra of structural analogs of 1a-i and 2 such as 1j given by Khilya
[8, 9] contain an even more downfield signal for a chelate proton at ~15 ppm, which is seen as evidence for a
tautomeric equilibrium of phenacyl form A and enol form C. We assume, however, that this proton should be
seen as chelated in form B. The chelated state is characteristic for a proton in the field of two heteroatoms in a
state of rapid dynamic oscillation not bound by either a covalent or hydrogen bond with either heteroatom. This
is usually seen for a proton located between heteroatoms of the same type, for example, between the oxygen
atoms in 1,3-diketones [17] or between the nitrogen atoms in hydrazohydrazone products obtained in azo
coupling of aryldiazonium chlorides at the active methylene group of 2-benzimidazolylacetonitrile [18, 19].
Benzimidazole 1j in phenacylidene form B (as in compounds 1a-i and 2 in form B) undergoes a strong
electron-donor effect of the nitrogen atoms of the cyclic fragment on the carbonyl group, which may reflect by
boundary structure B1. Thus, the carbonyl oxygen atom should have enhanced electron density, which would
attract the proton of the adjacent phenol hydroxyl group. Such an interaction is probably sufficient to place this
proton located between two oxygen atoms into a chelated state (oscillation between forms B1 and B2).
HO
HO
HO
H
H
O
O
H
H
H
O
OH
N
N
N
N
N
N
A
C
1j
B
–
H
O
H
–
O
H
H
O
H
H
O
N
N
+
+
N
N
B2
B1
8H.09
H 8.28
7.58
H
124.1
O
1.71.1
127.4
H
145.1
123.1
7.19 H
114.2 N
NO2
124.1
148.2
127.4
111.1
80.3
153.5
111.1
114.2 N
H
H
H8.28
7.19H
123.1
8.09
6.11
H
H
12.39
7.58
Fig. 1. Assignment of signals in the HMBC spectrum of compound 1i and structurally-significant correlations.
The appearance of a downfield signal for the C=O group carbon atom in the 13C NMR spectrum of
compound 1i is evidence for the strong effect of the benzimidazole fragment on the carbonyl group in form B
(Table 2). For example, the carbonyl carbon atom in amides appears in the near vicinity [17]. The reliability of
the assignment of the signals for compound 1i was indicated by the HMBC spectrum (Fig. 1).
960

The dark-green color reaction observed upon mixing compounds of type 1j with ethanolic ferric
chloride was given previously as additional proof for keto-enol tautomerism [8, 9]. As we have found,
compounds 1a-i and 2 also give a blue-green color with ferric chloride. However, this is insufficient to draw
conclusions about the keto-enol tautomerism of compounds if we assume that reactions between forms B and C
readily occur upon heating, catalysis, or change of the solvent. This is more true since in fact this color is a
property not of the starting compound but rather of the complex formed with the metal.
The NMR spectral data on the tautomeric equilibrium of compounds 1-4 are in accord with the results of
quantum-chemical calculations. Semiempirical calculations show that tautomeric form B is thermodynamically
more stable for base 1a, while form C' is more stable for salt 3a (Tables 3 and 4). The loss of aromaticity of the
benzimidazole system in form B is probably compensated by the formation of an energetically favorable
conjugation chain between the heterocycle nitrogen atoms and the carbonyl group. However, form C is favored
in the model entailing an adduct of a molecule 1a with a molecule of DMSO in the solvent. All the
semiempirical calculations showed that the activation barrier for the conversion of B to C through a transition
state (TS) is rather high. For a more reliable examination, we carried out a calculation for this transition by the
B3LYP density matrix functional method in the 6-31+G(d,p) basis (Table 5). These results show that, in contrast
to the semiempirical calculations, the DFT calculation indicates preference for tautomer C in a vacuum, while
the low activation energy suggests a rapid B  C interconversions.
The behavior in DMSO, however, is fundamentally different. Form B is much more thermodynamically
favored and the activation barrier is much higher.
Thus, the nature of the solvent is a factor determining the predominance of a particular tautomer in
solution, while an increase in polarity of the medium enhances the stability of tautomer B and the activation
barrier. By the way, the latter need not hinder tautomer interconversions although form C is not observed in the
1H NMR spectrum due to low concentration.
In the crystalline state, compounds 1d, 3a,b, and 4 exist in the phenacyl form A (or A'), while 1a-c, e-i, and
2 exist in phenacylidene form B and 3i exists in enol form C'. These conclusions are based on the IR spectra
(Table 2): compound 1d, 3a,b, and 4 appear as aryl ketones, 1a-c, e-i, and 2 appear as aminovinyl ketones, and 3c
appears as a compound with a hydroxyl group. Products 1a-c, e-h, and 2 are yellow, while 1i is red, which is in
accord with the presence of the typical N–C(–N)=CH–C(=O)Ar chromophor fragment. Product 3i has a yellowish
color, possibly due to the presence of a nitro group and chromophor chain transmitting the electron-donor effect
from the hydroxyl group to the benzimidazolium fragment. Products 1d, 3a,b, and 4 are colorless due to the lack of
chromophors. Product 1d would appear to fall outside the series 1a-i probably due to its high solubility and
crystallization under different conditions to give a stable crystal hydrate 1d·0.5H2O.
Hence, doubt arises concerning the structure of the product of the addition of o-phenylenediamine to
2-benzoyl-1-bromoacetylene, which was reported by Nakhmanovich et al. [20] as salt 3a in nonaromatic
tautomeric form B' [20]. The product of this reaction differs sharply in its color, melting point, IR and 1H NMR
spectra from salt 3a obtained in this work (Tables 1 and 2). Although we isolated salt 3a in the more stable
tautomeric form A', we should have expected at least identical NMR spectra due to establishment of a
tautomeric equilibrium in solution.
We should note that other 2-phenacylazaheterocycles [21] and other enamino-iminoenol tautomeric
systems [22] as bases also show a tendency for preference of an enamino ketone tautomeric form in DMSO-d6
solution. In deuterochloroform, the stability of phenacyl form A for compound 2 and its derivatives containing
OMe, Me, or Cl substituents in the para position of the phenyl fragment is known to depend only slightly on the
nature of these substituents and the content of form A is 36-41% at 25°C and 16-19% at 50°C [14]. Thus, our
conclusions concerning this tautomerism should be extended only to solutions in highly polar solvents at 20-25°C.
Therefore, the acylation of 2-methylbenzimidazole by aroyl chlorides with subsequent deacylation of
the resultant N,C,O-triacylation products is a convenient and general preparative method for the synthesis of
2-phenacyl-1H-benzimidazoles. In DMSO-d6 solution, 2-phenacyl-1H-benzimidazoles form an equilibrium
mixture with phenacylidene tautomers (enamino-ketone tautomerism), while their hydrogen bromide salts form
an equilibrium mixture of enolic tautomers.
961

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer for KBr pellets. The 1H NMR spectra were taken at
20°C and the HMBC two-dimensional heteronuclear correlation spectrum was taken at 40°C on a Bruker
Avance DRX 500 spectrometer at 500 and 125 MHz for solutions in DMSO-d6 with the signal of the residual
solvent protons as the internal standard. The semiempirical quantum-chemical calculations were carried out
using the MOPAC program [23] with consideration of the effect of the medium using the COSMO model [24].
The nonempirical calculations were carried out using the Gaussian03 program package [25] with consideration
of the polarity of the medium using the Tomasi IPCM model [26]. The course of the reactions and purity of the
compounds synthesized were monitored by thin-layer chromatography on Silufol UV-254 plates using
9:1 benzene–ethanol as the eluent and development by UV light.
Synthesis of 2-Phenacyl-1H-benzimidazoles 1a,c,e-i (General Method). A mixture of 2-methyl-
benzimidazole (0.1 mol), triethylamine (0.33 mol), anhydrous dioxane or acetonitrile (40 ml), and aroyl chloride
(0.33 mol) was stirred until the onset of reflux and periodically cooled using a water bath until the exothermal
reaction was completed. The thickening mass was maintained on the bath at 100°C for 1 h, diluted with - water
(40 ml), and stirred until crystallization began. The cooled reaction mixture was filtered and the precipitate was
washed on the filter with 1:1 2-propanol–water, water, and then 2-propanol. After drying, the triaroylation
product was stirred with 2-propanol (2 ml solvent per 1 g product) and heated with stirring at reflux for 2.5 h (in
the preparation of 1h,i, 1:1 1-butanol–dimethyl formamide was used and reflux was shortened to only 0.5 h).
The cooled mass was filtered. The precipitate was washed with cold 2-propanol and then hexane to give an
analytically pure product.
2-(4-Methoxyphenacyl)-1H-benzimidazole (1b). A mixture of 2-methylbenzimidazole (0.1 mol),
triethylamine (0.33 mol), anhydrous dioxane (40 ml), and 4-anisoyl chloride (0.33 mol) was stirred until
completion of the exothermal reaction, maintained on the bath for 3 h at 100°C, and carefully diluted by adding
water (40 ml) and morpholine (0.66 mol). Heating was then continued with stirring for an additional 15 min.
The cooled mass was filtered and the precipitate was recrystallized from 5:1 ethanol–pyridine to give
benzimidazole 1b.
2-(3,4,5-Trimethoxyphenacyl)-1H-benzimidazole (1d) was obtained analogously to compounds
1a,c,e-i from 2-methylbenzimidazole and 3,4,5-trimethoxybenzoyl chloride. In order to separate the product
from the reaction mixture, 1-butanol was distilled off at 100°C under reduced pressure. The residue was
dissolved in 80 ml hot toluene. The cooled mass was filtered and the precipitate of product 1d was recrystallized
from toluene with hot filtration to remove insoluble impurities.
2-Phenacyl-3H-benzimidazolium Bromide (3a) [20]. A mixture of compound 1a (1 mmol), methanol
(0.5 ml), water (2 ml), and 48% hydrobromic acid (0.2 ml) was stirred for about 5 min. After 16 h, the colorless
precipitate of product 3a was filtered off and washed with cold water.
Salts 3b and 4 were obtained analogously from compounds 1b and 2, respectively.
2-(4-Nitrophenacyl)-3H-benzimidazolium Bromide (3i). A mixture of compound 1i (1 mmol),
48% hydrobromic acid (0.4 ml), methanol (2 ml), and water (2 ml) was heated with stirring until a homogeneous
solution was obtained. After cooling, the precipitate of product 3i was filtered off and washed with cold
2-propanol.
The authors used the facilities of the Kyiv firm, Enamine, for which they are sincerely grateful to the
firm's director, Andrei Alekseevich Tolmachev.
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