Synthesis and NMR spectroscopic assignment of chlorinated benzimidazole-2-thione derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151078

The benzimidazole-2-thione scaffold is present in many drugs encompassing various therapeutic areas. Due to the broad spectrum of bioactivities it also represents an important starting point in drug discovery campaigns, especially those based on fragment-

Full text of DOI:10.1016/j.tetlet.2019.151078

Tetrahedron Letters 60 (2019) 151078
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and NMR spectroscopic assignment of chlorinated
benzimidazole-2-thione derivatives
⇑
ˇ
Matic Proj, Izidor Sosic, Stanislav Gobec
ˇ
University of Ljubljana, Faculty of Pharmacy, Chair of Pharmaceutical Chemistry, Aškerceva 7, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzimidazole-2-thione scaffold is present in many drugs encompassing various therapeutic areas.
Due to the broad spectrum of bioactivities it also represents an important starting point in drug discovery
campaigns, especially those based on fragment-based design. Despite simple structures the tautomerism
and regioisomerism of substituted benzimidazole-2-thiones makes unambiguous structural analysis dif-
ficult. Tautomeric duplicates are present in commercial libraries resulting in two tautomers being sold as
different products. To showcase an example of appropriate structural determination, we synthesized and
characterized a set of benzimidazole-2-thiones with different positions of a chlorine atom on the ring.
Using NOESY and 13C NMR spectroscopy, we determined that the thione tautomer predominates in the
thione-thiol equilibrium. Furthermore, NOESY and HMBC experiments confirmed the position of the sub-
stituents on the benzimidazole-2-thione ring.
Received 20 July 2019
Revised 20 August 2019
Accepted 22 August 2019
Available online 23 August 2019
Keywords:
Benzimidazole-2-thione
2-Mercaptobenzimidazole
Fragments in drug discovery
Regioisomerism
NOESY
Ó 2019 Elsevier Ltd. All rights reserved.
HMBC
Introduction
(Fig. 1). Benzimidazole-2-thiones are sulfur analogs of benzimida-
zolones that exhibit thione-thiol (i.e. thioamide-iminothiol) pro-
Benzimidazole-2-thione (commonly known as 2-mercaptoben-
zimidazole) is an important fragment, present in various com-
pounds with biological activity. It has been found in
progesterone receptor antagonists [1], luteinizing hormone-releas-
ing hormone antagonists [2,3], antiviral [4,5], antiprotozoal [6,7],
antimicrobial [8–10], analgesic [11], anti-inflammatory [11], anti-
convulsant [12], and antidiabetic [12] compounds. Furthermore,
an even wider range of biological activities has been reported for
compounds with the benzimidazole core, including clinically
approved drugs [13–15].
Tautomerism is a phenomenon involving the dynamic equilib-
rium between interconvertible structural isomers. The most wide-
spread form of tautomerism is relocation of a proton, called
prototropy. A subtype of prototropy, typical for heterocyclic aro-
matic compounds, such as benzimidazoles, is annular tau-
tomerism, where a proton migrates between cyclic nitrogen or
carbon atoms while retaining aromaticity [16]. Benzimidazole tau-
tomerism has also been the subject of various studies [16–20]. An
example of tautomeric equilibria is given for compounds 1, 2 and 3
totropy, which is analogous to the keto-enol type of
tautomerism. Furthermore, compounds with hydrogen at positions
1 and 3 exhibit annular tautomerism, resulting in two thiol forms
(1b and 1c). When a larger substituent is attached at position 1,
annular tautomerism is prevented and two distinct, isomeric com-
pounds exist (2 and 3, in this case).
A recent study evaluated tautomerism overlap in commercial
databases and it was shown that the presence of tautomeric dupli-
cates is not rare, meaning that the same chemicals are sold as dif-
ferent products [21]. In the case of compound 4 (Fig. 2), two
tautomers were sold under different supplier IDs for different
prices, despite having the same CAS number [22,23]. Furthermore,
nomenclature for this type of compounds is not well established
and different vendors use different tautomers (thiole or thione)
when naming compounds. Sometimes, the rule for assigning the
lowest substituent number is also neglected. According to IUPAC,
the numbering of benzimidazoles starts from the nitrogen atom
of the NH (or the N-methyl) in the direction of other heteroatoms
so that the substituents have the lowest possible numbers [24]. In
general practice, compounds for which the tautomerism is well
studied, are named by the tautomer that predominates at equilib-
rium. Therefore, the actual name for 2-mercaptobenzimidazole is
1,3-dihydro-2H-benzo[d]imidazole-2-thione.
Abbreviations: NOESY, nuclear overhauser effect spectroscopy; HSQC, heteronu-
clear single-quantum correlation spectroscopy; HMBC, heteronuclear multiple-
bond correlation spectroscopy.
⇑
Corresponding author.
E-mail address: stanislav.gobec@ffa.uni-lj.si (S. Gobec).
https://doi.org/10.1016/j.tetlet.2019.151078
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
M. Proj et al. / Tetrahedron Letters 60 (2019) 151078
Fig. 1. Tautomeric equilibria for benzimidazole-2-thione derivatives. Only compounds with hydrogen at position 1 exhibit annular tautomerism and have two thiol forms.
When N1 is methylated, two isomeric compounds, i.e. 2 and 3 exist.
Fig. 2. The six examined chlorobenzimidazole-2-thiones with the correct ring numbering, so that the substituents have the lowest possible numbers.
The most effective tool to study tautomerism is NMR spec-
troscopy. Interconversion of benzimidazole tautomers occurs
either through intermolecular transfer of a proton from one mole-
cule to another or through interaction with a protic solvent. The
interconversion has a low energy barrier which can result in
NMR spectra presenting average signals. To slow down the pro-
totropic rate in solution, either the temperature must be lowered
or the solvent (hexamethylphosphoramide-d18, for example) must
prevent formation of hydrogen bonds. Dynamic NMR studies have
further explored thermodynamic and kinetic aspects of the equilib-
rium [17–19]. 15N NMR spectroscopy is a powerful tool for deter-
mining the tautomerism of nitrogen containing heteroaromatic
compounds, because of the wide range of chemical shifts and high
sensitivity to structural and environmental changes [16]. Solid
state NMR experiments enable the study of tautomerism in solid
samples, as an alternative to X-ray crystallography [17]. Based on
crystallographic data available in the Cambridge Structural Data-
base for benzimidazole-2-thiones, an exocyclic CAS distance indi-
cates that the thione form is the predominant tautomer in the solid
state [25–28]. Furthermore, a 15N NMR study reported that the
thione form is also predominant in deuterated DMSO for benzimi-
dazole-2-thione and 1-methylbenzimidazole-2-thione [29]. There-
fore, we decided to name and represent the compounds only in the
thione form in this manuscript.
Herein, we report the synthesis and straightforward NMR
assignment of benzimidazole-2-thiones with varying positions of
the chlorine atom (Fig. 2). Such sets of compounds are useful as
starting points in fragment-based drug discovery campaigns to
explore the space around the binding site and determine the direc-
tion for further fragment evolution [30]. Due to the fact that benz-
imidazole-2-thione is present as a hit in fragment-based drug
design campaigns, we believe that it is important to unambigu-
ously demonstrate the position of substituents on the ring before
interpreting any biochemical results [31].
Results and discussion
4-Chloro-1,3-dihydro-2H-benzo[d]imidazole-2-thione (1) was
prepared from the corresponding o-phenylenediamine and potas-
sium ethyl xanthate (Scheme 1). In the next step, trityl chloride
was used as a thiol protective group to enable the selective methy-
lation of nitrogen. Due to annular tautomerism of thiol-protected
1, two positional isomers 4-chloro (2) and 7-chloro (3) were
formed after the methylation procedure. Both products were suc-
cessfully isolated using column chromatography. In the same man-
ner, positional isomers 5-chloro (5) and 6-chloro (6) were prepared
from commercially available 5-chloro-1,3-dihydro-2H-benzo[d]

M. Proj et al. / Tetrahedron Letters 60 (2019) 151078
3
step a, the ratio between the reagents was adjusted, the reaction
was carried out in an ice bath, and methyl iodide was diluted in
DMF before adding it dropwise to the reaction mixture. In step b,
the nitro group was reduced to the amine group in the presence
of iron metal and HCl. Finally, the benzimidazole-2-thione core
was formed using the same procedure as for compound 1; this
time leading to a single regioisomer 2. By this alternative synthetic
procedure, we could unambiguously confirm the position of the
methyl group relative to the chlorine atom (Scheme 1). For full
synthetic procedures, see the ESI. Three benzimidazole-2-thione
derivatives were also commercially available: 3 (Innovapharm
Ltd.), 4 (Fluorochem Ltd.) and 6 (Innovapharm Ltd.). Compounds
3 and 4 were used without further purification, while 6 was recrys-
tallized from EtOH. Notably, the analytical data for purchased com-
pounds 3 and 6 was the same as for the synthesized compounds
(compound 4 was not synthesized).
The appropriate deuterated solvents for NMR spectroscopy, i.e.
pyridine-d5 and/or acetone-d6, were selected based on the solubil-
ity and peak separation for all analyzed compounds. An example of
peak separation for 3 in various solvents (acetone-d6, pyridine-d5,
DMSO-d6, TFA-d and CD3OD) is presented in the ESI (Fig. S1). The
complete assignment of 1H and 13C chemical shifts was straightfor-
ward following these steps: i) splitting pattern and coupling con-
stants of the trisubstituted benzene ring distinguished the 5- and
6-chloro derivatives from the 4- and 7-chloro derivatives; ii)
NOESY experiments further distinguished between the 5- and 6-
chloro, and between the 4- and 7-chloro analogs; iii) HSQC exper-
iments determined which hydrogens are connected to which car-
bons; iv) HMBC experiments and/or; v) comparison between
different isomers enabled the identification of the remaining car-
bons. It is important to state that with HMBC spectroscopy only
correlations through three covalent bonds (meta) were observed
for compounds 1–6. Tables 1 and 2 contain chemical shift data in
pyridine-d5 and acetone-d6. For graphical representations and
assigned spectra in other solvents see the ESI (Figs. S2–5).
Scheme 1. Synthesis of chlorinated benzimidazole-2-thione derivatives. Reagents
and conditions: (a) MeI, NaH, DMF, 0 °C, 1 h, 47% yield; (b) Fe, HCl (37%), EtOH,
80 °C, 6 h, 76% yield; (c) potassium ethyl xanthate, EtOH (96%), H2O, 80 °C,
overnight, 27% yield for 1, 16% yield for 2; (d) i) TrCl, TEA, anhydrous THF, Ar, rt,
overnight; ii) MeI, KOH, acetone, rt, 2–5 h; iii) 5% AcOH in MeOH, 65 °C, 30 min, 58%
yield for 2 and 3, 73% yield for 5 and 6.
For example, in the 1H NMR spectrum of compound 2 two dou-
blets of doublets and one triplet were present in the aromatic
region, which means that only 4-chloro or 7-chloro substitutions
were possible. NOESY experiment showed coupling between the
CH3 protons and the doublets of doublets of C7-H (Fig. 3a). There-
fore, compound 2 was determined to be 4-chloro substituted. The
first step in assigning the 13C NMR spectrum was to determine
which hydrogens are connected to which carbons using HSQC
experiments. The remaining signals were identified by observing
imidazole-2-thione (4) (Scheme 1). Compound 2 was also prepared
using an alternative procedure where the nitrogen atom was
methylated prior to cyclization. To increase the selectivity of
monomethylation vs. dimethylation for the aniline derivative in
Table 1
1H NMR chemical shifts in pyridine-d5 and acetone-d6 (d in ppm) of benzimidazole-2-thiones 1–6. Splitting patterns and ortho, meta and para coupling constants are given in
parentheses. See ESI (Figs. S2–3) for graphical representations.
Compound Solvent
NH
C4-H
C5-H
C6-H
C7-H
CH3
–
1
Pyridine-d5 14.88 (bs, 1H), –
14.59 (bs, 1H)
7.22 (1H) or 7.20 (1H)a
7.10 (t, J = 8.0 Hz, 1H)
7.22 (1H) or
7.20 (1H)a
Acetone-d6 11.77 (bs, 1H), –
11.59 (bs, 1H)
7.22–7.14 (multiplet, 3H)
–
2
3
4
Pyridine-d5 14.95 (bs, 1H)
Acetone-d6 11.88 (bs, 1H)
–
–
7.21 (1H)a
7.10 (t, J = 8.0 Hz, 1H)
7.32–7.20 (multiplet, 3H)
7.02 (dd, J = 8.0, 0.9 Hz, 1H) 3.70 (s, 3H)
3.71 (s, 3H)
Pyridine-d5 14.73 (bs, 1H) 7.19 (dd, J = 7.7, 1.1 Hz, 1H) 7.06 (t, J = 7.9 Hz, 1H)
Acetone-d6 11.75 (bs, 1H) 7.22 (dd, J = 7.1, 2.0 Hz, 1H)
7.13 (dd, J = 8.0, 1.1 Hz, 1H) –
7.21–7.15 (multiplet, 2H)
4.06 (s, 3H)
4.05 (s, 3H)
–
Pyridine-d5 14.54 (bs, 1H), 7.47 (dd, J = 1.7, 0.6 Hz, 1H) –
7.24 (dd, J = 8.4, 1.8 Hz, 1H) 7.28 (dd, J = 8.4, 0.6 Hz, 1H) –
14.50 (bs, 1H)
Acetone-d6 11.46 (bs, 2H) 7.25 (d, J = 1.9 Hz, 1H)
–
–
7.17 (dd, J = 8.5, 1.9 Hz, 1H) 7.23 (d, J = 8.5 Hz, 1H)
–
5
6
Pyridine-d5 14.65 (bs, 1H) 7.44 (d, J = 1.8 Hz, 1H)
Acetone-d6 11.59 (bs, 1H) 7.26 (dd, J = 1.9, 0.4 Hz, 1H) –
7.25 (dd, J = 8.5, 2.0 Hz, 2H) 7.06 (d, J = 8.5 Hz, 1H)
7.22 (dd, J = 8.5, 2.0 Hz, 1H) 7.31 (d, J = 8.5 Hz, 1H)
3.68 (s, 3H)
3.70 (s, 3H)
Pyridine-d5 14.60 (bs, 1H) 7.23 (1H)a
Acetone-d6 11.58 (bs, 1H) 7.25 (d, J = 8.1 Hz, 1H)
7.26 (dd, J = 8.4, 1.7 Hz, 1H) –
7.20 (dd, J = 8.4, 1.9 Hz, 1H) –
7.32 (dd, J = 1.6, 0.5 Hz, 1H) 3.73 (s, 3H)
7.41 (d, J = 1.3 Hz, 1H) 3.71 (s, 3H)
a
Signal overlaps with the solvent peak.

4
M. Proj et al. / Tetrahedron Letters 60 (2019) 151078
Table 2
13C NMR chemical shifts in pyridine-d5 and acetone-d6 (d in ppm) of benzimidazole-2-thiones 1–6. See ESI (Figs. S4–5) for graphical representations.
Compound
Solvent
C2
C3a
C4
C5
C6
C7
C7a
CH3
1
Acetone-d6
Pyridine-d5
171.78
172.46
131.24
132.25
114.78
114.79
123.15 or 109.01b
122.65 or 108.76b
124.46
123.77
123.15 or 109.01b
122.65 or 108.76b
134.63
135.40
–
–
2
3
Acetone-d6
Pyridine-d5
171.85
172.01
129.57
130.30
114.88
114.92
124.23 and 123.45a
108.79
108.25
135.80
135.74
30.92
30.98
123.10
123.62
Acetone-d6
Pyridine-d5
172.16
172.25
133.83
134.24
109.39
109.12
124.67 and 124.63a
115.87
115.75
130.33
130.29
33.36
33.35
124.12a
134.37 or 128.49b
132.58
4
5
6
Acetone-d6
Acetone-d6
Acetone-d6
171.80
171.78
172.00
134.37 or 128.49b
110.24
110.21
111.21
123.33
123.09
128.47
111.24
110.96
110.23
132.35
133.46
135.54
–
128.80
30.63
30.68
130.64
123.59
a
Unambiguous assignment is not possible, because the signals are too close.
Carbons show the same correlation with protons in the HMBC spectrum.
b
Fig. 3. 2D NMR spectra for compound 2. a) NOESY experiment, pyridine-d5. Circled cross-peaks indicate coupling between CH3 and C7-H. Solvent and residual water peaks
are unassigned. b) HMBC experiment, pyridine-d5. Circled peak indicates coupling between CH3 and C7a (overlapping with solvent peak). Only the cross peaks that correlate
protons and carbons, which are connected through three covalent bonds, are visible. Solvent and residual water peaks are unassigned.

M. Proj et al. / Tetrahedron Letters 60 (2019) 151078
5
meta correlations using HMBC experiments. Furthermore, correla-
Appendix A. Supplementary data
tions between CH3 and C2, C7a were confirmed using HMBC exper-
iments (Fig. 3b). Overall, both NOESY and HMBC experiments
confirmed the 4-chloro substitution for compound 2. NOESY and
HMBC spectra for all compounds are available in the ESI
(Figs. S6–17). The assignments and substitutions were determined
following the same steps as for the compound 2. However, some
missing signals in the 13C NMR were assigned only after comparing
different isomers.
Supplementary data (full experimental section, synthetic proce-
dures, 1H and 13C NMR spectroscopy data, 2D NMR spectra and
HPLC chromatograms) to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151078.
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dominates at equilibrium [34]. Additionally, our NOESY
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Acknowledgement
The authors acknowledge the support by the Slovenian
Research Agency: research core funding No. P1-0208, and grant
number N1-0068 (B) to S.G.