Reactions of 2-carbonyl- And 2-hydroxy(or methoxy)alkylsubstituted benzimidazoles with arenes in the superacid CF3SO3H. NMR and DFT studies of dicationic electrophilic species

Article abstract of DOI:10.3762/bjoc.15.191

Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkylbenzimidazoles with arenes in the Br?nsted superacid TfOH resulted in the formation of the corresponding Friedel-Crafts reaction products, 2-diarylmethyl and 2-arylmethyl-substituted benzimidazoles, in yields up to 90%. The reaction intermediates, protonated species derived from starting benzimidazoles in TfOH, were thoroughly studied by means of NMR and DFT calculations and plausible reaction mechanisms are discussed.

Full text of DOI:10.3762/bjoc.15.191

Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkyl-
substituted benzimidazoles with arenes in the superacid
CF3SO3H. NMR and DFT studies of dicationic
electrophilic species
Dmitry S. Ryabukhin1, Alexey N. Turdakov1, Natalia S. Soldatova2,
Mikhail O. Kompanets3,4, Alexander Yu. Ivanov5, Irina A. Boyarskaya6
and Aleksander V. Vasilyev*1,6
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1962–1973.
1Department of Chemistry, Saint Petersburg State Forest Technical
University, Institutsky per., 5, Saint Petersburg, 194021, Russian
Federation, 2National Research Tomsk Polytechnic University, Lenin
Avenue 30, Tomsk, 634050, Russian Federation, 3Litvinenko Institute
of Physico-Organic and Coal Chemistry, NAS of Ukraine, Kharkivske
Hgw, 50, Kyiv, 02160, Ukraine, 4National Technical University of
Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, Prosp. Peremohy,
37, Kyiv, 03056, Ukraine, 5Center for Magnetic Resonance, Research
Park, Saint Petersburg State University, Universitetskiy pr., 26, Saint
Petersburg, Petrodvoretz, 198504, Russian Federation and
6Department of Organic Chemistry, Institute of Chemistry, Saint
Petersburg State University, Universitetskaya nab., 7/9, Saint
Petersburg, 199034, Russian Federation
doi:10.3762/bjoc.15.191
Received: 13 April 2019
Accepted: 06 August 2019
Published: 19 August 2019
Associate Editor: J. A. Murphy
© 2019 Ryabukhin et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Aleksander V. Vasilyev* - aleksvasil@mail.ru
* Corresponding author
Keywords:
benzimidazoles; cations; Friedel–Crafts reaction; triflic acid
Abstract
Reactions of 2-carbonyl- and 2-hydroxy(or methoxy)alkylbenzimidazoles with arenes in the Brønsted superacid TfOH resulted in
the formation of the corresponding Friedel–Crafts reaction products, 2-diarylmethyl and 2-arylmethyl-substituted benzimidazoles,
in yields up to 90%. The reaction intermediates, protonated species derived from starting benzimidazoles in TfOH, were thor-
oughly studied by means of NMR and DFT calculations and plausible reaction mechanisms are discussed.
1962

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Introduction
Imidazoles and benzimidazoles are important heterocyclic scaf- lowed by alkylation of arenes have been reported involving
folds in pharmaceuticals and agrochemicals [1-10]. They also heterocycle-based superelectrophiles: pyridines, thiazoles,
have applications in the fields of dyes, chemo-sensing, and fluo- quinolines, isoquinolines, pyrazines, pyrazoles, imidazole and
rescent materials [3]. (Benz)imidazoles are a common motif furans, bearing a formyl (carbonyl) group [15-23]. These car-
present in some components of human organisms, histidine, bonyl-substituted heteroarenes possess basic sites (nitrogen or
vitamin B12, purines, histamine, biotin, and in natural com- oxygen atoms of the heterocyclic system), which are fully
pounds such as lepidiline A and B [6].
protonated in acid, so that upon subsequent protonation of the
carbonyl oxygen, more reactive dicationic electrophiles can be
Over the years of active research, benzimidazole derivatives generated.
have been involved in medicinal chemistry covering a wide
range of biological activities including antiparasitic (albenda- Previously, superelectrophilic activation of the carbonyl group
zole, mebendazole), antiulcer (omeprazole), antihypertensive was achieved for 5-formyl and 5-acetylimidazoles in triflic acid
(candesartan, telmisartan, azilsartan, medoxomil, mebefradil), CF3SO3H (TfOH) by Klumpp [19]. It was proposed that the
anticancer (bendamustine), antiemetic/antipsychotic (droperi- triflic acid initially protonated the imidazole ring and an equi-
dole), antihistaminic (astemizole, emedastine) and many others librium was established with the O-protosolvated form or the
(Figure 1) [1-10]. Benzimidazole fungicides (carbendazim, dicationic superelectrophile. These two kinds of species may
benomyl, thiabendazole and fuberidazole) have been widely react with benzene leading to products of the transformation of
used to fight against destructive plant pathogens (Figure 1) [7]. the carbonyl group into a diphenylmethyl one (Figure 2) [19].
Interestingly, most of the above listed drugs are 2- or 1,2-disub-
stituted benzimidazole derivatives [2].
To the best of our knowledge, no data on the generation of
superelectrophilic species from carbonyl-substituted benzimida-
Thus, the development of further syntheses of benzimidazole zoles and their reactions exist. Based on our previous studies on
derivatives and the study of their properties are important goals the chemistry of heterocycles under superelectrophilic activa-
for chemistry, medicine and materials science.
tion [22-24], we undertook this research on reactions of benz-
imidazole derivatives in (super)acids.
Since George Olah proposed the concept of generating super-
electrophilic intermediates through the protonation by Brønsted The main goal of this work was the study of reactions of substi-
superacids or coordination by a Lewis superacid to produce a tuted benzimidazoles 1–8 (Figure 3) with arenes under the
di- (tri- or higher) cationic species, the study of superelec- action of Brønsted (super)acids CF3SO3H (TfOH, triflic acid),
trophilic activation became a very active area of research [11- H2SO4 and strong Lewis acids AlX3 (X = Cl, Br). One would
13]. The acid-catalyzed condensation of ketones and aldehydes expect the electrophilic activation of carbonyl or 2-hydroxy-
with aromatic compounds is known as the hydroxyalkylation alkyl groups of these benzimidazoles in hydroxyalkylation and
reaction [14]. Recently, several hydroxyalkylation reactions fol- alkylation of arenes.
Figure 1: Examples of some commercially available pharmaceuticals and agrochemicals containing the benzimidazole scaffold.
1963

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Figure 2: Formation of cationic species by protonation of 5-formyl-4-methylimidazole in TfOH and their reaction with benzene (data from ref. [19]).
Figure 3: Benzimidazoles 1–8 used in this study.
Results and Discussion
The calculation of electrophilic properties of these cations show
The protonation of formyl and acetylbenzimadazoles 1 and 2 that species I and II have higher values of electrophilicity
gave N,O-diprotonated species I and II, respectively (see indices ω of 4.4 and 4.9 eV, respectively, compared to cations
Table 1). Protonation of the hydroxy group of benzimidazoles III, V, VII, and VIII with ω values of 2.1–2.2 eV. Among all
3–8 in strong acids gave dicationic species III, V, VII, and studied species, the heteroaromatic benzyl dication IV, VI, IX
VIII, the dehydration of the latter resulted in the formation of have the highest electrophilicity indices ω = 5.6–6.1 eV
heteroaromatic benzyl-type dications IV, VI, and IX, respec- (Table 1).
tively. Electronic characteristics, energies of HOMO/LUMO,
electrophilicity indices ω [25,26], charge distribution, and In the dications I and II, the carbon Cα bears a large positive
contribution of atomic orbital into the LUMO of species I–IX charge (0.47 and 0.65 e) and gives a big contribution into the
were calculated by DFT method to estimate their electrophilic- LUMO (22.1 and 35.4%, Table 1). It points out that this partic-
ity and electronic properties (Table 1). Apart from that, ΔG298 ular carbon should be an electrophilic reactive center by both
of the formations of cations I–IX from parent benzimidazoles charge and orbital factors. For comparison, the carbon C2 in I
1–8 were calculated to estimate a thermodynamic possibility of and II has a less positive charge (0.33 and 0.35 e) and a much
the species formation (Table 1). The calculations were carried less contribution in the LUMO (2.3 and 4.7%).
out for the solution phase in water.
In hydroxonium type species III, V, VII, and VIII, the charge
According to DFT calculations, protonation of the benz- on the carbon Cα is from −0.06 to 0.11 e (Table 1). However,
imidazole nitrogen N3 and the oxygen of the carbonyl or this carbon provides a big contribution into the LUMO,
hydroxymethyl group in 1–8 leading to dicationic species I–III, 13.9–22%. This reveals that electrophilic properties of this car-
V, VII, and VIII is thermodynamically favorable (−18.6 to bon are mainly ruled by orbital factors. Despite the carbon C2
−25.8 kcal/mol, Table 1). On the other hand, the dehydration of in these species has a large positive charge (0.46–0.48 e) and a
species III, V, VII, VIII is rather unfavorable, since ΔG298 great orbital coefficient (17.3–26.3%), reactions of nucleo-
values for the formation of dications IV, VI, and IX are philes with this atom are less probable, since it leads to a loss of
7.2–15.8 kcal/mol (Table 1). These data reveal that, in the case aromaticity of the benzimidazole system. The same applies to
of carbonyl-substituted benzimidazoles 1 and 2, the formation the reactivity of the carbon C2 in dications I and II.
of dications I and II is very likely, and these species should be
reactive electrophiles. While, in the case of hydroxyalkylbenz- Then we studied the protonation of benzimidazoles in the super-
imidazoles 3–8, N,O-diprotonated species III, V, VII, VIII, the acid TfOH by means of NMR. Selected 1H, 13C and 15N NMR
most probably, may be reactive intermediates.
data for starting neutral benzimidazoles 1, 3a, and 7 (in CDCl3,
1964

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 1: Selected calculated [DFT, 6-311+G(2d,2p) basis set] electronic characteristics of the protonated forms of benzimidazoles.
Species
EHOMO, ELUMO, ωa
q(Cα)b q(C2)b q(N1)b q(N3)b
k(Cα)LUMOс
%
k(C2)LUMOс
%
∆Gd
kcal/mol
eV
eV
eV
e
e
e
e
−9.53
−6.39
4.9
0.47
0.65
0.33
−0.29
−0.44
22.1
2.3
−18.6
I
−9.38
−9.11
−4.16
−2.02
4.4
0.35
0.46
−0.30
−0.47
−0.44
−0.48
35.4
17.3
4.7
−21
II
2.2 −0.06
6.1 −0.06
26.3
−21.5
III
−10.07
−5.23
0.31
−0.42
−0.42
28.2
0.6
15.8
IV
V
−9.03
−9.77
−1.85
−4.92
2.1
5.6
0.11
0.14
0.48
0.33
−0.34
−0.28
−0.49
−0.43
13.9
30.5
20.4
1.4
−25.6
7.6
VI
−9.09
−1.90
2.1 −0.06
0.47
−0.48
−0.47
16.3
22.6
−25.8
VII
1965

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 1: Selected calculated [DFT, 6-311+G(2d,2p) basis set] electronic characteristics of the protonated forms of benzimidazoles. (continued)
−9.04
−9.96
−2.01
−5.14
2.2 −0.06
5.9 −0.08
0.47
0.33
−0.34
−0.29
−0.48
−0.43
22.1
26.5
17.3
0.6
−23.7
VIII
IX
14.4
aGlobal electrophilicity index ω = (EHOMO + ELUMO)2/8(ELUMO − EHOMO). bNatural charges. cContribution of atomic orbital into the molecular orbital.
dGibbs energy of the species formation reaction.
(CD3)2CO, CD3OD) and their corresponding protonated forms appear in the range of 11.37–12.12 ppm (Table 2, see
I', III', and VIII', respectively, in TfOH are presented in also the spectra given in Supporting Information File 1).
Table 2.
However, the signals of the proton bound to the oxygen of
the formyl or the hydroxy groups is not observed due to
the fast proton exchange for these groups in TfOH at room tem-
perature.
The signals of the proton attached to the nitrogen N3
in 1H NMR spectra of all species I', III', and VIII' in TfOH
Table 2: 1H, 13C and 15N NMR data of benzimidazoles 1, 3a, 7 in the corresponding deuterated solvent and species I', III', VIII' in TfOH at room tem-
perature.
Compound or cation
Solvent
NMR, δ, ppm
1H
13C
15N
Hα
N3H
–
C2
Cα
N1
N3
CDCl3
TfOH
10.09
146.1
137.4
185.0
268.4
142.2
1
10.28
12.12
176.8
158.9
151.6
I‘
∆δa
0.19
4.86
−8.7
−8.2
109.5
–b
9.4
–b
(CD3)2CO
TfOH
–
155.8
59.2
3a
5.64
0.78
11.53
149.5
57.5
148.7
–
148.7
–
III‘
∆δa
−6.3
−1.7
1966

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 2: 1H, 13C and 15N NMR data of benzimidazoles 1, 3a, 7 in the corresponding deuterated solvent and species I', III', VIII' in TfOH at room tem-
perature. (continued)
CD3OD
TfOH
4.85
–
142.5
57.7
no data
no data
7
5.57
0.72
11.37
148.4
5.9
56.9
152.5
–b
149.1
–b
VIII‘
∆δa
−0.8
a∆δ = δcation − δinitial. bNo correlation was observed in HSQC and HMBC N–H spectra.
The obtained NMR data demonstrate the formation of N-proto- 2-formyl-1-methylbenzimidazole (1) with various arenes
nated-O-protosolvated species I', III', and VIII' from benzimi- (benzene, and its methyl, methoxy or chloro-substituted deriva-
dazoles 1, 3a, and 7, respectively, in the superacid TfOH. How- tives) are given in Table 3. These reactions proceed on the
ever, it could not be excluded that the N,O-diprotonated species formyl group of 1 and give rise to the corresponding 2-diaryl-
was formed in low concentration as a result of complete proton- methylbenzimidazoles 9a–l. The best results were obtained in
ation of oxygen. These dicationic species may participate in neat TfOH, which gave high yields of reaction products
further reactions with arenes.
(54–86%) at room temperature after 2–3 h. Other acids were not
so efficient. Thus, reactions under the action of sulfuric acid
Signals of Hα protons for species I', III', and VIII' in TfOH are H2SO4 or AlCl3 and AlBr3 took longer time (24–27 h, Table 3,
downfield shifted relatively to the same signals in their neutral entries 1, 2, and 4). In some cases, the use of H2SO4 resulted in
precursors 1, 3a, and 7 (in CDCl3, (CD3)2CO, CD3OD), respec- the formation of oligomeric reaction products in the reaction of
tively (see ∆δ values in Table 2). This reveals substantial 1 with electron donating p-xylene (Table 3, entry 10). Apart
solvatation of the formyl or the hydroxy oxygen of benzimida- from that, the acidity of H2SO4 was not high enough to activate
zoles 1, 3a, 7 in TfOH.
1 in the reaction with poor π-nucleophilic 1,2-dichlorobenzene
(Table 3, entry 13).
In the 13C NMR spectra, the signal of carbon Cα in species I',
III', and VIII' in TfOH is slightly upfield shifted due to posi- 2-Acetylbenzimidazole (2) reacted with benzene in TfOH in the
tive charge delocalization into the benzimidazole ring. Apart same way, which gave two reaction products 10 and 11
from that, the chemical shift of Cα in hydroxonium-type species (Scheme 1). Compound 10 was obtained as a result of the addi-
III' and VIII' at 57.5 and 56.9 ppm, which are close to the tion of two benzene molecules to the carbonyl group of 2.
shifts in starting neutral precursors 3a and 7, proves unambigu- Alkenyl-substituted benzimidazole 11 was formed in an alterna-
ously that no dehydration of these species leading to heteroaro- tive way of transformation of intermediate cations (see reaction
matic benzyl-type cations take place.
mechanism below in Scheme 3). It should be noted, that com-
pound 11 in the reaction with benzene in TfOH at room temper-
Based on HSQC and HMBC N–H correlations, we were able to ature for 24 h afforded benzimidazole 10.
measure 15N chemical shifts of nitrogen atoms for cations I',
III', and VIII' in TfOH (Table 2). The peaks of the nitrogen Then, we studied reactions of 2-hydroxyalkylbenzimidazoles
atoms N1 and N3 appear in a rather narrow range of 3a–c, 4, 7, and 8. It was found that these reactions needed
148.7–158.9 ppm due to charge delocalization between these extremely harsh reaction conditions, heating in neat TfOH at
two nitrogen atoms for the corresponding resonance forms.
140 °C in glass high pressure tubes (Table 4, Scheme 2). Only
at this high temperature the formation of Friedel–Crafts reac-
Then, we carried out Friedel–Crafts reactions of benzimida- tion products 12a–h, 13, and 14 was achieved. No reactions
zoles 1–8 with arenes under the action of Brønsted acids took place at lower temperature or under the action of Lewis
(H2SO4, TfOH) or Lewis acids (AlX3, X = Cl, Br). Reactions of acids AlX3 (X = Cl, Br). For these 2-hydroxyalkylbenzimida-
1967

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 3: Reactions of 2-formyl-1-methylbenzimidazole (1) with arenes under the action of various acids at room temperature.
Entry
1
Arene (equiv)
Reaction conditionsa
Reaction products 9, yield (%)
Acid (equiv)
Time, h
benzene
(18)
H2SO4
(120)
24
9a (69%)
9a (61%)
benzene
(18)
benzene
(100)
benzene
(100)
TfOH
(35)
AlCl3
(5)
AlBr3
(5)
2
3
4
2
25
27
9a (54%)b
9a (80%)
toluene
(2.2)
TfOH
(35)
5
6
7
8
2
2
2
3
ratio 9b/9c 6:1
ratio 9d/9e 5:1
ratio 9f/9g 3:1
9h (75%)
anisole
(2.2)
TfOH
(35)
chlorobenzene
(2.2)
TfOH
(35)
o-xylene
(2.2)
TfOH
(35)
1968

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 3: Reactions of 2-formyl-1-methylbenzimidazole (1) with arenes under the action of various acids at room temperature. (continued)
m-xylene
(2.2)
TfOH
(35)
9
3
9i (63%)
p-xylene
H2SO4
(120)
10
11
24
3
oligomeric materials
(2.2)
p-xylene
(2.2)
TfOH
(35)
9j (86%)
1,2-dichlorobenzene
(2.2)
TfOH
(35)
12
13
14
3
24
3
9k (61%)
1,2-dichlorobenzene
(2.2)
H2SO4
(120)
–c
1,2,4-tremethylbenzene
(2.2)
TfOH
(35)
9l (78%)
aAll reactions were carried out at room temperature. b26% of the starting benzimidazole 1 was recovered. c72% of the starting benzimidazole 1 was
recovered.
Scheme 1: Reaction of 2-acetylbenzimidazole (2) with TfOH and benzene.
zoles 3a–c, 4, 7, and 8, we were able to receive compounds complex mixtures of oligomeric materials. The same interac-
12–14 only in reactions with benzene, 1,2-dichlorobenzene and tions of 2-methoxyalkylbenzimidazoles 5a–c, and 6 with
1,3-dibromobenzene (Table 4). Transformations with methyl- benzene in TfOH at 140 °C resulted in the formation of com-
substituted benzenes (xylenes) at these harsh conditions gave pounds 12a,f–h (Table 5).
1969

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
following reaction mechanisms are proposed (Scheme 3 and
Scheme 4).
2-Carbonyl-substituted benzimidazoles 1 and 2 give rise to
N-protonated-O-protosolvated forms I' and II'. These species in
reactions with arenes furnish hydroxyalkylation products X,
which are further transformed into cations XI. These species
consequently react with arenes forming the target compounds 9
and 10 after final hydrolysis of superacidic reaction mixtures.
There is another possible reaction pathway for 2-acetylbenzimi-
dazole (2) on the stage of the formation of cation XI. The latter
may undergo deprotonation at the methyl group, which results
in the formation of alkenyl benzimidazole 11. Compound 11
Scheme 2: Reactions of hydroxymethyl-substituted benzimidazole 7
and 8 with TfOH and benzene.
Summarizing all data obtained by DFT calculations (Table 1)
and NMR studies (Table 2) of intermediate cations generated
from benzimidazoles 1–8 in TfOH, and their reactions
with arenes (Tables 3–5, Scheme 1, and Scheme 2), the
Table 4: Reactions of 2-hydroxyalkylbenzimidazoles 3a–c and 4 with arenes in TfOH at 140 °C.
Entry
1
Starting benzimidazole
Starting arene (equiv)
Reaction products 12, yield (%)
benzene
(18)
3a
3a
12a (87%)
1,2-dichlorobenzene
(4)
2
ratio 12b/12c 1:0.5
1,3-dibromobenzene
(4)
3
4
3a
ratio 12d/12e 1:0.25
12f (82%)
benzene
(18)
3b
benzene
(18)
5
6
3c
4
12g (88%)
12h (90%)
benzene
(18)
1970

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Table 5: Reactions of 2-methoxyalkylbenzimidazoles 5a–c, and 6 with benzene in TfOH at 140 °C.
Entry
1
Strarting benzimidazole
Reaction products 12, yield (%)
5a
5b
12a (79%)
2
12f (79%)
3
4
5c
6
12g (52%)
12h (84%)
Scheme 3: Reaction mechanism of the formation of compounds 9–11.
may be also transformed into compound 10 by reaction with species react with arenes, the most probably, in SN2 way to give
arenes in TfOH (see Scheme 2 and the corresponding discus- benzimidazoles 12 (Scheme 4).
sion).
However, once again, in these reactions (Scheme 3 and
Hydroxy(or methoxy)alkyl-substituted benzimidazoles 3–8 Scheme 4) the formation of the corresponding N,O-diproto-
form cations III', V', VII', and VIII', respectively. These nated species I', II', III', V', VII', and VIII' in low concentra-
1971

Beilstein J. Org. Chem. 2019, 15, 1962–1973.
Scheme 4: Reaction mechanism of the formation of compounds 12.
Preprint
tion, which are not detected by NMR, could not be excluded.
And these dications may react with arenes, as well.
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.6.v1
It should be specially emphasized that 2-diarylmethyl and
2-arylmethyl-substituted benzimidazoles 9–12 are synthetically
hardly available compounds [27,28]. For instance, they were in-
vestigated as AMP-activated protein kinase activators [27].
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Supporting Information
Supporting Information File 1
Experimental details, compound characterization data,
copies of 1H and 13C NMR spectra, and details of DFT
calculations.
doi:10.1016/j.ejmech.2016.08.029
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ORCID® iDs
Dmitry S. Ryabukhin - https://orcid.org/0000-0001-5345-0038
Natalia S. Soldatova - https://orcid.org/0000-0002-1738-4747
Alexander Yu. Ivanov - https://orcid.org/0000-0002-4228-1248
Aleksander V. Vasilyev - https://orcid.org/0000-0003-3628-1492
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