Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles via the cyclopropyliminium rearrangement of substituted 2-cyclopropylbenzimidazoles

Article abstract of DOI:10.1016/j.tet.2013.02.021

2-Cyclopropylbenzimidazole derivatives with various substituents in the small ring undergo cyclopropyliminium rearrangement into 2,3- dihydropyrrolobenzimidazoles substituted at positions 1, 2 or 3. The substrates containing a functional group in position 1 of the cyclopropane ring form products substituted at position 3. Substituents at position 2 in most cases lead to the formation of a mixture of isomers. The reaction can be directed to yield one of the isomers predominantly by varying the solvent polarity.

Full text of DOI:10.1016/j.tet.2013.02.021

Accepted Manuscript
Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles via the cyclopropyliminium
rearrangement of substituted 2-cyclopropylbenzimidazoles
Rinat F. Salikov, Dmitry N. Platonov, Aleksandr E. Frumkin, Dmitry L. Lipilin, Yury V.
Tomilov
PII:
S0040-4020(13)00213-5
10.1016/j.tet.2013.02.021
TET 24016
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 November 2012
Revised Date: 15 January 2013
Accepted Date: 4 February 2013
Please cite this article as: Salikov RF, Platonov DN, Frumkin AE, Lipilin DL, Tomilov YV, Synthesis of
2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles via the cyclopropyliminium rearrangement of substituted 2-
cyclopropylbenzimidazoles, Tetrahedron (2013), doi: 10.1016/j.tet.2013.02.021.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-
a]benzimidazoles via the cyclopropyliminium
rearrangement of substituted 2-
cyclopropylbenzimidazoles
Rinat F. Salikov, Dmitry N. Platonov, Aleksandr E. Frumkin, Dmitry L. Lipilin, and Yury V. Tomilov
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prospect, 119991 Moscow Russian Federation

ACCEPTED MANUSCRIPT
Synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles via the
cyclopropyliminium rearrangement of substituted 2-
cyclopropylbenzimidazoles
Rinat F. Salikov, Dmitry N. Platonov, Aleksandr E. Frumkin, Dmitry L. Lipilin,
and Yury V. Tomilov*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., 119991 Moscow, Russian Federation
A B S T R A C T
2-Cyclopropylbenzimidazole derivatives with various substituents in the small ring undergo
cyclopropyliminium rearrangement into 2,3-dihydropyrrolobenzimidazoles substituted at positions 1, 2 or
3.. The substrates containing a functional group in position 1 of the cyclopropane ring form products
substituted at position 3. Substituents at position 2 in most cases lead to the formation of a mixture of
isomers. The reaction can be directed to yield one of the isomers predominantly by varying the solvent
polarity.
© 2012 Elsevier Ltd. All rights reserved.
Keywords: Cyclopropyliminium rearrangement, cyclopropylbenzimidazoles,
dihydropyrrolobenzimidazoles, cyclopropane ring-opening.
1. Introduction
Benzimidazole derivatives play an important role in the medical field because of their varied
pharmacological activities.1 Research interest in the benzimidazole fragment has grown partly
because of the fact that it is a structural component of the vitamin B122, but this does not mean
that its derivatives are expected to exhibit vitamin-like activities. Benzimidazoles are, for
instance, used as anthelmintics;3 at the same time they seem to be promising compounds in the
field of small-molecule RNA targeting.4 Here we concentrated our efforts at the synthesis of 2,3-
dihydropyrrolo[1,2-a]benzimidazoles which are interesting as the precursors of mitomycin-like
antitumor drugs.5,6
There are several methods for the synthesis of these annulated benzimidazoles. Most of them7-
11
are appropriate for the synthesis of 2,3-dihydropyrrolo[1,2-a]benzimidazole itself, and its
derivatives substituted at the aromatic ring, while introducing substituents at positions 1, 2 and 3
is strongly restricted by the availability of starting materials. Recently, Bergman and Ellman12
developed a catalytic approach to dihydropyrrolobenzimidazoles substituted at the pyrroline ring
starting from allyl- and β-allyl-substituted benzimidazoles. The authors reported the synthesis of
* Corresponding author. Tel./fax: +7 499 135 6390. E-mail address: tom@ioc.ac.ru (Y.V. Tomilov).
1

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dihydropyrrolobenzimidazoles containing one alkyl or aryl group at positions 2 and/or 3 with no
example of reactions in systems containing a reactive functional group.
The cyclopropyliminium rearrangement has been found to be a versatile pathway for the
synthesis of several types of heterocyclic compounds. Since Cloke13 reported this type of
transformation using only one example of cyclopropylketimine that rearranged into the
corresponding pyrroline under acid-nucleophilic catalysis, many authors have subsequently
applied it towards the synthesis of natural products and their analogs.14,15 The rearrangement has
been found to proceed in the case of other types of compounds as well, e.g. cyclopropane
thiomethylimidates.16 We have recently17,18 shown that cyclopropylazoles are also capable of the
rearrangement and thus essentially extended the reaction scope and discovered a new synthetic
pathway to the aforementioned 2,3-dihydropyrrolo[1,2-a]benzimidazole derivatives.
Scheme 1. The rearrangement of 2-cyclopropylbenzimidazoles substituted at the aromatic ring
In the previous paper17 we reported the general principles of the cyclopropyliminium
rearrangement, including, among others, the influence of substituents at the aromatic ring, so
here we present a detailed investigation of the rearrangement of 2-cyclopropylbenzimidazoles
substituted on the small ring.
2. Results and discussion
2.1. Synthesis of starting cyclopropylbenzimidazoles.
We synthesized the previously unknown (with one exception, see Table 1) 2-cyclopropyl-1H-
benzimidazoles with various substituents at different positions of the small ring, most of them
being obtained using the corresponding cyclopropanecarboxylic acids 1a–i as the starting
materials. The acids were first transformed into either acyl chlorides or mixed anhydrides using
standard procedures19, which were further subjected to reaction with phenylenediamine without
prior purification to give monoamides 2 (or mixtures with diamides 3, monoamides being
obtained by transformation into water-soluble salts). The monoacylated derivatives were
transformed into 2-cyclopropylbenzimidazoles 4–12 under acid catalysis (Table 1).
Table 1. Synthesis of substituted cyclopropanecarbamides 2a–i and 2-cyclopropylbenzimidazoles 4–12
2

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Reaction conditions: i: SOCl2, Py, ether or ClCO2Et, NEt3, CH2Cl2 (entry 2), or
dicyclohexylcarbodiimide (DCC), CH2Cl2 (entry 3); ii: 1,2-diaminobenzene, MeCN, –20°C (CH2Cl2 in
entries 2–3); iii: AcOH, reflux for 3 h.
Yield of acylated
products (%)
Yield
(%)
entry
Starting acid
i
iii
Product
2
3
1
2
3
SOCl2
ClCO2Et
DCC
52
12
AcOH
AcOH
98
1a
1b
1c
4
5
6
24 a
82
–
–
0
HCO2H b
56
7 c
4
5
6
SOCl2
SOCl2
SOCl2
54
49
40
0
–
AcOH
AcOH
AcOH
74
99
91
1d
1e
1f
8
21
9
7
8
9
SOCl2
SOCl2
SOCl2
45
50
42
18
0
AcOH
AcOH
AcOH
94
92
90
1g
1h
1i
10
11
12
20
a
Synthesis was carried out without purification of monoacylated product 2b; the yield of imidazole 5 is
given for the three steps.
b Reflux in 95% HCO2H for 45 min.
c Synthesis of compound 7 was carried out according to the previously described procedure.20
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It is worth noting that the cyclization of monoamide 2b, which was synthesized from 1-(tert-
butoxycarbonylamino)cyclopropanecarboxylic acid in acetic acid, was accompanied by the
amino group deprotection and its subsequent acetylation to form benzimidazole 5 (Table 1, entry
2). At the same time, for cyclization of more reactive amide 2c (entry 3) into corresponding
cyclopropylbenzimidazole 6 boiling formic acid was used. In this condition compound 6 was
obtained in a very good yield, although we observed a side process, namely, the formation of 2-
(3,4-dihydro-2H-pyrrol-4-yl)-1H-benzimidazole (13). Presumably, this product results from the
cyclopropane ring-opening of 6 under the action of formic acid through intermediate 14 with
subsequent cyclization at the nitrogen atom of the cyano group, which is evident from the
increased yield of compound 13 over longer reaction times.
O
CN
N
HCO2H
N
NH
6
+
∆
N
H
NH2
2c
13
H
N
O
N
H
CN
O
14
Scheme 2. Transformations of N-(2-aminophenyl)-1-cyanocyclopropanecarbamide (2c).
2-(1-Methylcyclopropyl)-1H-benzimidazole (15) was synthesized in two steps from
commercially available 1-methylcyclopropanecarbonitrile (16). The starting nitrile 16 was
transformed into the iminoester using ethanol in dry ether. The subsequent reaction with 1,2-
diaminobenzene gave product 15 (Scheme 3).
1) EtOH, HCl
N
abs. ether
Me
CN
2) 1,2-C6H4(NH2)2
abs. EtOH
N
Me
H
15, 58%
16
Scheme 3. Synthesis of 2-(1-methylcyclopropyl)-1H-benzimidazole (15).
To fully investigate the rearrangement we synthesized cyclopropylbenzimidazole containing
an ester group at the vicinal position of the small ring relative to the junction with the
heterocyclic part (Scheme 4). Initially, 2-vinylbenzimidazole was benzylated to give 17. The
next step – the carbene cyclopropanation of the vinyl group – was performed using the thermal
decomposition of methyl diazoacetate in the presence of unsaturated compound 17 and p-xylene.
Thus we obtained a mixture of E- and Z-18, which was further debenzylated by catalytic
4

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hydrogenation (Pd/methanol), which required fairly strong conditions (100°C, 100 bar).
Hydrogenation resulted in the more stable E-isomer 19 and a set of side products, which were
not identified. Also, no debenzylated Z-isomer was obtained. Probably, Z-isomer did not tolerate
the harsh reaction conditions and could undergo cyclopropane ring-opening and other side
processes.
N
N
N
N
N
N2CHCO2Me
+
p-xylene, reflux
N
CO2Me
CO2Me
Ph
Ph
Ph
E-18 (56%)
17
Z-18 (11%)
N
H2/Pd(C)
mixture of
E- and Z-18
AcOH, MeOH
100°C, 100 bar
N
H
CO2Me
19 (30%)
Scheme 4. Synthesis of E-methyl 2-(1H-benzimidazol-2-yl)cyclopropanecarboxylate (19).
2.2. Rearrangement of 2-cyclopropylbenzimidazoles.
The rearrangement of 2-cyclopropylbenzimidazoles containing a substituent at position 1 of
the cyclopropane ring (compounds 4–6 and 15) leads to the formation of 2,3-dihydropyrrolo[1,2-
a]benzimidazoles 20–23 substituted at position 3 (Table 2). It is important that we successfully
used substrates not only with alkyl (15) and aryl (4) groups in the cyclopropane ring but also
cyclopropylbenzimidazoles functionalized with acetamino (5) and cyano (6) groups, which
expands the scope of this method to a great extent, and allows the synthesis of
dihydropyrrolobenzimidazoles with various functional groups at position 3.
Table 2. Rearrangement of 2-(1-R-cyclopropyl)benzimidazoles.
N
N
N
i
R
N
H
R
4–6, 15
20–23
Starting
material
Product (isolated
yield, %)
entry
R
Reaction conditionsa
1
2
3
4
Me
HI, 1,2-dichlorobenzene, reflux
HBr, 200°C
20 (82)
15
Ph
21 (65)
22 (87)
22 (60)
4
5
6
NHAc
CN
NH4I, 1,2-dichlorobenzene, reflux
NH4I, 150°C
a
Hydrohalides were synthesized in a separate step; the rearrangement product was obtained in basic
form after the treatment with an alkali solution.
5

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Comparison of the NMR-followed conversions of 4–6, 15 and 2-cyclopropylbenzimidazole
with no substituent in the small ring in the same reaction conditions (1.1 equivalent of NH4I,
150°C, 30 min) allowed us to conclude that the electron-withdrawing groups at position 1 of the
cyclopropane ring accelerate the ring-opening, as it happened with the substrates with electron-
withdrawing
groups
at
the
aromatic
ring17.
Thus,
the
conversion
of
cyanocyclopropylbenzimidazole 6 into product 23 was over 96%, whereas the conversion of 2-
cyclopropylbenzimidazole and its phenyl derivative 4 were 17 and 35% respectively. Derivatives
5 and 15 did not rearrange in this conditions, presumably due to their higher melting points in a
mixture with NH4I (over 150°С). The accelerating action of the cyano and phenyl groups is
apparently due to easier formation of conjugated intermediates 24, which in turn may undergo
side processes, e.g. dehydrohalogenation and subsequent polymerization. This accounts for
lower yields of products 21 and 23 in contrast with the yields of 20 and 22 at complete
conversion (Table 2).
H
R
N
Hal
N
H
24 (R = CN, Ph)
Substituents at position 2 of the cyclopropane ring do not prevent the rearrangement;
however, in this case the ring-opening can proceed by the cleavage of either the more or the less
substituted bonds of the cyclopropane ring. Thus, the rearrangement of alkyl substituted 2-
cyclopropylbenzimidazole hydroiodides 8–10 leads to the formation of isomeric
dihydropyrrolobenzimidazoles 26–28 and 31–33 (Table 3). The ratio of the isomers is modulated
by the solvent polarity change. It was found that the reaction in rather polar N-methylpyrrolidone
is accompanied by the prevalent cleavage of the more substituted bond to form 1-substituted
products 26–28 while weakly polar dichlorobenzene promotes the cleavage of the less
substituted bond to form 2-substituted compounds 31–33 as major products.
Table 3. Rearrangement of 2-cyclopropylbenzimidazoles substituted at position 2 of the cyclopropane
ring. Reversal of regioselectivity by the change of solvent polarity. The prevalent isomers are shaded
grey.
N
N
N
N
HI
+
N
∆
R2
R2
R1
N
H
R1
R1
R2
7–11, 19
25–29
30–34
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Starting
R1
R2
H
Solvent
T (°C) Time (h)
Products (yield, %)
compound
1,2-dichlorobenzene
N-methylpyrrolidone
1,2-dichlorobenzene
N-methylpyrrolidone
1,2-dichlorobenzene
N-methylpyrrolidone
1,2-dichlorobenzene
N-methylpyrrolidone
1,2-dichlorobenzene
N-methylpyrrolidone
1,2-dichlorobenzene
180
1
25 (40)
30 (13)
30 (47)
31 (80)
31 (30)
32 (58)
32 (traces)
33 (61)
33 (8)
Ph
7
202 0.5
25 (13)
26 (6)
26 (56)
27 (12)
27(64)
28 (traces)
28 (48)
–
180
202
4
2
Me
Me
H
8
180 1.5
202
180 14
202
Me
9
1
(CH2)5
10
6
180 0.7
202 0.7
180 0.5
34 (74)
34 (76)
–
(CH2)2
CO2Me
11
19
–
H
29 (19)
The selectivity in this case can be explained by the competition of two different mechanisms
(Scheme 5). The first one, which is analogous to that of the previously described rearrangement
of ketimines into pyrrolines21, includes the nucleophilic attack of the halide anion on the
cyclopropane ring involving the ring-opening to form halide 36, tautomerization, driven by the
restoration of aromaticity in the heterocycle, and intramolecular alkylation. The second
mechanism includes the monomolecular ring-opening to give carbocation 36, which undergoes
subsequent tautomerization and cyclization analogous to 35.
H
R2
R2
I
I
N
H
N
H
N
R1
R1
I
nonpolar
medium
H
N
N
I
N
H
N
R2
R1
31–33
35
R2
N
H
R1
H
N
Solv
8–10
Solv
I
R1
R2
R1
Solv
R2
H
H
N
polar
medium
N
N
Solv
N
N
H
I
Solv
I
R1
R2
36
26–28
Scheme 5. The mechanisms of 2-alkyl substituted 2-cyclopropylbenzimidazoles rearrangement in either
polar or non-polar solvents.
The quaternary carbon in the cyclopropane ring must be less attractive to a nucleophile, so the
first mechanism is most likely to occur in the case of the less substituted bond cleavage. Since
intermediate 35 is a neutral compound, the first mechanism should be prevalent in less polar
solvents. The formation of 1-substituted products 26–28 is in turn most likely to proceed via
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cation 36, which is stabilized by both the electron-donating alkyl groups and the solvation by the
polar solvent molecules.
Intrinsically, the selectivity regulation of the rearrangement depends on the substituent nature.
For instance, the rearrangement of 2-(2-phenylcyclopropyl)benzimidazole 7, in contrast to its
methyl analog 8, is subject to inversed selectivity in terms of the solvent nature: the major
product in dichlorobenzene is 1-phenyldihydropyrrolobenzimidazole 25, while in polar N-
methylpyrrolidone, 2-substituted product 30 prevails (Table 3). In this case, a mixed mechanism
may take place, since the phenyl substituent probably stabilizes the transition states of both
mono- and bimolecular ring-opening. So, the observed isomer ratio is due to a more intricate
dependence of the reaction rate on the solvent nature and temperature.
In contrast to 2-cyclopropylbenzimidazoles 7–10, the rearrangement of 2-
spiropentylbenzimidazole (11) gives product 34, containing a spiro-cyclopropane fragment at
position 2 of dihydropyrrolobenzimidazole regioselectively in both solvents in the same yields
(Scheme 6). Therefore, the ring-opening in this case proceeds on the less substituted bond
regardless of the solvent polarity, indicating the pathway involving an iodide-anion attack to
form intermediate 37 preferred over the formation of cation 38 (Scheme 6).
I
N
N
NH4I
Solv
N
H
N
H
11
37
Solv
N
N
N
Solv
N
H
38
34
76%
74%
Solv = 1,2-dichlorobenzene
N-methylpyrrolidone
Scheme 6. Rearrangement of 2-spiropentylbenzimidazole (11).
The introduction of an electron withdrawing ester group in the vicinal position of the
cyclopropane ring (compound 19) leads to more complicated transformations. Only 1 hour is
required to complete conversion of 19 in dichlorobenzene at 180°С, however the yield of the
product (methyl 2,3-dihydro-1H-pyrrolo[1,2-a] benzimidazole-1-carboxylate (29)) is only 19%
(Scheme 7). The presence of the electron withdrawing group apparently leads to deprotonation
of the corresponding intermediates regardless of the character of the cyclopropane ring-opening
to form conjugated dienes, which easily oligomerize in the reaction conditions.
8

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N
N
N
NH4I
C6H4Cl2,
reflux
N
H
MeO2C
CO2Me
19
29, 19%
Scheme 7. Rearrangement of methyl E-2-(1H-benzimidazol-2-yl)cyclopropanecarboxylate (19).
The presence of four methyl groups at the cyclopropane ring essentially decreases the reaction
rate. Thus, compound 12 hydrobromide completely transforms at 200°C in the absence of
solvent in 4.5 h while nonsubstituted 2-cyclopropylbenzimidazole hydrobromide completely
rearranges in the same conditions in 10 min17. Despite the stringent reaction conditions, product
39 was obtained in a fair yield (Scheme 7) due to symmetrical substitution of the cyclopropane
ring and the stabilization of the cation center in the intermediate.
N
Me
1) HBr/MeOH
2) 200°C
Me
Me
N
N
3) NaOH/H2O
Me
Me
N
H
Me
Me
Me
12
39, 63%
Scheme 7. Rearrangement of 2-(2,2,3,3-tetramethylcyclopropyl)benzimidazole (12).
3. Conclusion
We have reported the study of the cyclopropyliminium rearrangement of 2-
cyclopropylbenzimidazoles with substitutuents at the cyclopropane ring as a method for the
synthesis of 2,3-dihydropyrrolobenzimidazoles substituted at positions 1, 2 or 3. The substituents
at position 1 of the cyclopropane ring that stabilize the forming double bond accelerate the
reaction. Electron-donating groups at positions 2 and 3 were found to slow down the
rearrangement and vice versa. In the case of 2-substituted substrates with no substituents at
position 3, a method for the ring-opening control varying the solvent polarity was found. In
conclusion, we have revealed the reaction scope, the influence of the substituent nature and the
solvent polarity on the reaction rate and regioselectivity. In comparison to the previously known
methods for the synthesis of 2,3-dihydropyrrolobenzimidazoles our approach allows the
construction of the target molecules with various substituents in the pyrroline ring, namely, one
substituent at position 3 and one or two substituents at positions 1 and 2.
4. Experimental section
4.1. General
All reagents and solvents used were commercial grade chemicals unless noted otherwise. 1-
Methylcyclopropanecarbonitrile19, methyl 1-cyanocyclopropanecarboxylate22, ethyl spiro[2.5]octane-1-
9

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carboxylate23, 2-methylcyclopropanecarboxylic acid24, 1-phenylcyclopropanecarboxylic acid25,
spiro[2.2]pentane-1-carboxylic acid26, 2-vinyl-1H-benzimidazole27 and 2-(2-phenylcyclopropyl)-1H-
benzimidazole20 were prepared using procedures reported previously. Several starting compounds were
synthesized by improved procedures (see Supplementary data in the online version at doi: ). The TLC
analysis was performed on Silufol chromatographic plates (Merck). For preparative chromatography,
1
silica gel 60 (0.040–0.063 mm; Merck) was used. H and 13C NMR spectra were recorded on «Bruker
AM-200” and «Bruker AVANCE II 300» spectrometers in CDCl3, (CD3)2SO, CD3OD or CD3CN all
containing 0.05% Me4Si as an internal standard. Mass spectra were recorded using ESI mode MS (70
eV). The elemental compositions were determined on a Perkin–Elmer Series II 2400 CHN Analyzer. All
the compounds containing a chiral center were racemic mixtures.
4.2. Procedures for the synthesis of substutited N-(2-aminophenyl)cyclopropanecarboxamides (2).
4.2.1. General method for the synthesis of compounds 2 via cyclopropanecarbonyl chlorides formation
Thionyl chloride (1.35 g, 10 mmol) was slowly added to a solution of cyclopropanecarboxylic
acid (10 mmol) and pyridine (10 mmol) in ether (50 mL) at temperatures not above 20°C. The
mixture was stirred for 1 h and the two layers were separated. The lower layer was slowly added
to a solution of 1,2-diaminobenzene (2.18 g, 20 mmol) and triethylamine (1.01 g, 10 mmol) in
acetonitrile (30 mL) at –25 to –15°C, and the reaction mixture was stirred for 1 h at low
temperature and then 1 h at room temperature. After that, the mixture was diluted with water
(100 mL) and filtered. The residue was treated with a 0.5 M solution of HCl for 30 min, filtered
off and dried to give bisacylated phenylenediamine 3. The filtrate was then basified until pH 9
and the precipitate formed was filtered and dried in vacuo to give monoacylated
phenylenediamine 2 (see Table 1).
4.2.1.1. N-(2-Aminophenyl)-1-phenylcyclopropanecarboxamide (2a). Yield of 52%, colorless crystals,
m.p. 115–117°C. IR (KBr) 3440, 3346, 3280, 3027, 3004, 2928, 1653, 1622, 1503, 1492 cm–1; EI-MS
(m/z, %) 252 (42, M+), 135 (60, M+–C9H9), 117 (100, C9H9 ). 1H NMR (200 MHz, DMSO-d6) δ 8.09 (br
+
s, 1H, NH), 7.52 and 7.33 (both m, 2+3H, Ph), 7.14 (dd, 4J = 1.6, 3J = 7.6 Hz, 1H, H(6´)), 6.89 (dt, 4J =
1.6, 3J = 7.6 Hz, 1H, H(4´)), 6.71 (dd, 4J = 1.5, 3J = 7.6 Hz, 1H, H(3´)), 6.55 (dt, 4J = 1.5, 3J = 7.6 Hz, 1H,
H(5´)), 4.55 (br s, 2H, NH2), 1.47 and 1.09 (both m, 2×2H, CH2CH2); 13C NMR (50 MHz, DMSO-d6) δ
171.3 (C=O), 141.9 (C(2´)), 140.1 (i-C), 129.9 (m-C), 128.7 (o-C), 127.3 (p-C), 125.9 and 125.3 (C(4´),
C(6´)), 124.2 (C(1´)), 116.9 and 116.5 (C(3´), C(5´)), 31.0 (C(1), 15.0 (CH2CH2). HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H17N2O 253.1335; found 253.1336.
1,2-bis(1-Phenylcyclopropyl-1-carbonylamino)benzene (3a). Yield of 12%, colorless crystals, m.p. 124–
127°C. IR (KBr) 3296, 3057, 3023, 3013, 2929, 2853, 1661, 1599, 1513, 1467 cm–1; EI-MS (m/z, %) 396
+
(26, M+), 117 (100, C9H9 ). 1H NMR (200 MHz, DMSO-d6) δ 8.30 (br s, 2H, 2 NH), 7.38 (m, 12H, 2 Ph
and H(3,6)), 7.04 (m, 2H, H(4,5)), 1.34 and 1.05 (both m, 2×4H, CH2CH2); 13C NMR (50 MHz, DMSO-
10

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d6) δ 171.9 (C=O), 139.2 (i-C)), 131.3 (C(1,2)), 130.3 (m-C), 128.8 (o-C), 127.6 (p-C), 125.5 and 125.2
(C(3,6), C(4,5)), 30.6 (C(1´), 15.6 (CH2CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H25N2O2
397.1911; found 397.1907.
4.2.1.2. N-(2-Aminophenyl)-2-methylcyclopropanecarboxamide (2e). Yield of 49%, E-isomer (~95%),
colorless crystals, m.p. 142–143°C. IR (KBr) 3414, 3272, 3038, 3002, 2957, 2929, 1639, 1536,
1458 cm–1; EI-MS (m/z, %) 190 (52, M+), 108 (97), 82 (100, C5H6O+). 1H NMR (200 MHz, DMSO-d6) δ
9.37 (br s, 1H, NH), 7.19 (dd, 4J = 1.6, 3J = 7.5 Hz, 1H, H(6´)), 6.89 (dt, 4J = 1.6, 3J = 7.5 Hz, 1H, H(4´)),
6.71 (dd, 4J = 1.6, 3J = 7.5 Hz, 1H, H(3´)), 6.53 (dt, 4J = 1.6, 3J = 7.5 Hz, 1H, H(5´)), 4.84 (br s, 2H, NH2),
1.58 (m, 1H, H(1)), 1.32–0.88 (m, 5H, CH3, H2C(3)), 0.58 (m, 1H, H(2)). 13C NMR (50 MHz, DMSO-d6)
δ 171.1 (C=O), 141.5 (C(2´)), 125.5 (C(6´)), 124.8 (C(4´)), 123.9 (C(1´)), 116.3 and 116.0 (C(3´), C(5´)),
22.6 (C(1)), 17.6 (C(2)), 15.2 (CH3), 15.1 (C(3)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H15N2O
191.1179; found 191.1178.
4.2.1.3. N-(2-Aminophenyl)-2,2-dimethylcyclopropanecarboxamide (2f). Yield of 40%, colorless crystals,
m.p. 145–147°C. IR (KBr) 3429, 3344, 3218, 3037, 1941, 2919, 2865, 1672, 1610, 1590, 1508 cm–1; EI-
MS (m/z, %) 204 (28, M+), 108 (100); 1H NMR (200 MHz, DMSO-d6) δ 9.09 (br s, 1H, NH), 7.19 (dd, 4J
= 1.7, 3J = 7.6 Hz, 1H, H(6´)), 6.89 (dt, 4J = 1.7, 3J = 7.6 Hz, 1H, H(4´)), 6.73 (dd, 4J = 1.5, 3J = 7.6 Hz,
1H, H(3´)), 6.55 (dt, 4J = 1.5, 3J = 7.6 Hz, 1H, H(5´)), 4.70 (br s, 2H, NH2), 1.68 (m, 1H, H(1)), 1.18 and
1.15 (both s, 2×3H, 2 CH3), 0.98 (dd, 2J = 4.5, 3J = 4.6 Hz, 1H, Ha(3)), 0.73 (dd, 2J = 4.5, 3J = 7.9 Hz, 1H,
Hb(3)). 13C NMR (50 MHz, DMSO-d6) δ 163.0 (C=O), 141.3 (C(2´)), 125.2 and 124.7 (C(4´), C(6´)),
123.9 (C(1´)), 116.1 and 115.7 (C(3´), C(5´)), 28.0, 26.5, 20.6, 19.4, 18.3. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C12H17N2O 205.1335; found 205.1332.
1,2-bis(2,2-Dimethylcyclopropyl-1-carbonylamino)benzene (3f). Yield of 21% (mixture of
diastereomers), colorless crystals, m.p. 146–149°C. IR (KBr) 3274, 3227, 2960, 2951, 2924, 2871, 1664,
1649, 1600, 1527 cm–1; EI-MS (m/z, %) 300 (19, M+), 204 (61), 108 (100); 1H NMR (300 MHz, CDCl3) δ
8.42 (br s, 2H, NH), 7.30 and 7.11 (both m, 2×2H, C6H4), 1.38 (dd, 3J = 7.9 and 4.6 Hz, 2H, H(1´)), 1.25
2
3
and 1.19 (both s, 4×3H, 2 CH3), 1.21 (m, 2H, Ha(3´)), 0.82 (dd, J = 4.5, J = 7.9 Hz, 2H, Hb(3´)). 13C
NMR (75 MHz, CDCl3) δ 171.2 (C=O), 130.9 (C(1,2)), 125.7 and 125.5 (C(3,6), C(4,5)), 29.5 (C(1´)),
27.2 (CH3), 22.8 (C(2´)), 20.9 (C(3´), 18.7 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H25N2O2
301.1911; found 301.1912.
4.2.1.4. N-(2-Aminophenyl)spiro[2,5]octane-1-carboxamide (2g). Yield of 45%, colorless crystals, m.p.
119–121°C. IR (KBr) 3392, 3336, 3276, 2924, 2848, 1648, 1500 cm–1; EI-MS (m/z, %) 244 (17, M+), 108
(100); 1H NMR (200 MHz, DMSO-d6) δ 9.30 (br s, 1H, NH), 7.15 (dd, 4J = 1.6, 3J = 7.7 Hz, 1H, H(6´)),
6.88 (dt, 4J = 1.6, 3J = 7.7 Hz, 1H, H(4´)), 6.72 (dd, 4J = 1.5, 3J = 7.7 Hz, 1H, H(3´)), 6.54 (dt, 4J = 1.5, 3J
= 7.7 Hz, 1H, H(5´)), 4.77 (br s, 2H, NH2), 1.15–1.76 (m, 11H, (CH2)5 and H(1)), 0.96 (dd, 2J = 4.2, 3J =
2
3
4.4 Hz, 1H, Ha(2)), 0.72 (dd, J = 4.2, J = 7.8 Hz, 1H, Hb(2)). 13C NMR (50 MHz, DMSO-d6) δ 169.9
11

ACCEPTED MANUSCRIPT
(C=O), 142.2 (C(2´)), 126.0 and 125,6 (C(4´), C(6´)), 124.6 (C(1´)), 116.8 and 116.5 (C(3´), C(5´)), 37.5
(C(4)), 29.4 (C(3)), 28.7 (C(8)), 27.9 (C(1)), 26.4, 25.9 and 25.8 (C(5), C(6), C(7)), 19,0 (C(2)). HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C15H21N2O, 245.1648; found 245.1651.
1,2-bis(Spiro[2,5]octyl-1-carbonylamino)benzene (3g). Yield of 18% (mixture of two diastereomers in
ratio 2.4:1), colorless crystals, m.p. 98–101°C. IR (KBr) 3246, 2924, 2850, 1653, 1601, 1533, 1447 cm–1;
1
EI-MS (m/z, %) 380 (3, M+), 286 (1), 255 (36), 108 (100); H NMR (200 MHz, DMSO-d6) δ 9.70 and
9.60 (both br s, 2H, NH in two isomers), 7.44 and 7.10 (both m, 2×2H, C6H4), 1.10–1.70 (m, 22H, H(1´),
(CH2)5), 0.99 and 0.97 (both dd, 2J = 4.1, 3J = 5.1 Hz, 2H, Ha(2´) in two isomers), 0.75 and 0.74 (both dd,
3
2J = 4.1, J = 7.6 Hz, 2H, Ha(2´) in two isomers). 13C NMR (50 MHz, DMSO-d6) δ 169.4 (C=O), 130.3
and 130.4 (C(1,2) in two isomers), 124.3 and 124.1 (C(3,6), C(4,5) both isomers), 36.6 (C(4´)), 28.99 and
29.92 (C((3´)), 27.86 and 27.73 (C(8´)), 27.46 and 27.37 (C(1´)), 25.3, 24.8 and 24.7 (C(5´), C(6´),
C(7´)), 18.23 and 18.18 (C(2´)). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H32N2O2Na 403.2356;
found 403.2350.
4.2.1.5. N-(2-Aminophenyl)spiro[2.2]pentane-1-carboxamide (2h). Yield of 50%, colorless crystals, m.p.
176–176.5°C. IR (KBr) 3439, 3362, 3267, 3171, 3061, 2986, 1643, 1590, 1541, 1526, 1456 cm–1; EI-MS
(m/z, %) 202 (55, M+), 185 (9, M+–NH3), 135 (9, M+–C5H7), 108 (100); 1H NMR (200 MHz, DMSO-d6) δ
3
4
9.25 (s, 1H, NH), 7.18 (dd, 4J = 1.5, J = 7.7 Hz, 1H, H(6´)), 6.88 (dt, J = 1.5, 3J = 7.6 Hz, 1H, H(4´)),
6.71 (dd, 4J = 1.4, 3J = 7.6 Hz, 1H, H(3´)), 6.53 (dt, 4J = 1.4, 3J = 7.7 Hz, 1H, H(5´)), 4.80 (br s, 2H, NH2),
3
2.16 (dd, J = 4.5 and 7.8 Hz, 1H, H(1)), 1.25–1.40 (m, 2H, H2C(2)), 0.72–0.95 (m, 4H, CH2CH2). 13C
NMR (50 MHz, DMSO-d6) δ 170.3 (C=O), 141.6 (C(2´)), 125.5 and 124.9 (C(4´), C(6´)), 123.9 (C(1´)),
116.3 and 116.1 (C(3´), C(5´)), 21.4 (C(1)), 17.5 (C(3)), 13.0 (C(2)), 6.0 and 4.8 (C(4), C(5)). Anal. Calcd
for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C, 71.17; H, 7.03; N, 13.79.
4.2.1.6. N-(2-Aminophenyl)-2,2,3,3-tetramethylcyclopropanecarboxamide (2i). Yield of 42% colorless
crystals, m.p. 129–132°C. IR (KBr) 3360, 3318, 3274, 2991, 2944, 2922, 2869, 1671, 1648 cm–1; EI-MS
(m/z, %) 232 (26, M+), 217 (20, M+–Me), 125 (61), 108 (100). 1H NMR (200 MHz, DMSO-d6) δ 9.12 (s,
1H, NH), 7.17 (dd, 4J = 1.5, 3J = 7.8 Hz, 1H, H(6´)), 6.86 (dt, 4J = 1.5, 3J = 7.7 Hz, 1H, H(4´)), 6.70 (dd,
4J = 1.4, 3J = 7.7 Hz, 1H, H(3´)), 6.52 (dt, 4J = 1.4, 3J = 7.8 Hz, 1H, H(5´)), 4.78 (br s, 2H, NH2), 1.34 (s,
1H, H(1)), 1.24 and 1.18 (both s, 2×6H, 4 CH3). 13C NMR (50 MHz, DMSO-d6) δ 169.7 (C=O), 141.5
(C(2´)), 125.3 and 124.9 (C(4´), C(6´)), 124.2 (C(1´)), 116.3 and 116.0 (C(3´), C(5´)), 36.3 (C(1)), 27.7
(C(2), C(3)), 23.6 and 16.6 (2×2 CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H21N2O 233.1648;
found 233.1652.
1,2-bis(2,2,3,3-Tetramethylcyclopropyl-1-carbonylamino)benzene (3i). Yield of 20%, colorless crystals,
m.p. 178–179°C. IR (KBr) 3427, 3303, 2988, 2946, 2922, 2868, 1654, 1601, 1535, 1522, 1475,
1
1445 cm–1; EI-MS (m/z, %) 356 (8, M+), 341 (7, M+–CH3), 259 (10), 125 (100); H NMR (200 MHz,
DMSO-d6) δ 9.38 (br s, 2H, NH), 7.45 and 7.10 (both m, 2×2H, C6H4), 3.32 (s, 2H, H(1´)), 1.25 and 1.19
12

ACCEPTED MANUSCRIPT
(both s, 4×6H, 8 CH3). 13C NMR (75 MHz, DMSO-d6) δ 170.0 (C=O), 130.8 (C(1,2)), 124.7 and 124.5
(C(3,6), C(4,5)), 37.0 (C(1´)), 28.2 (C(2´), C(3´)), 23.5 and 16.6 (2×2 CH3). Anal. Calcd for C22H32N2O2:
C, 74.12; H, 9.05; N, 7.86. Found: C, 74.27; H, 9.02; N, 7.73.
4.2.2. Synthesis of N-(2-aminophenyl)-1-cyanocyclopropanecarboxamide (2c)
Dicyclohexylcarbodiimide (3.00 g, 14.6 mmol) was added to a solution of 1-cyanocyclopropane-
carboxylic acid (1.60 g, 14.4 mmol) and 1,2-diaminobenzene (1.74 g, 16.1 mmol) in dichloromethane (10
mL). The reaction mixture was stirred for 1 h and left overnight. Then the mixture was filtered, the
mother liquid was evaporated, dissolved in a 4% solution of HCl (40 mL), filtered, basified with a
solution of NaOH till pH = 13 and filtered once more. The residue formed was further dried in vacuo to
give compound 2c (1.63 g, 56%), colorless crystals, m.p. 132–134°C. IR (KBr) 3405, 3336, 3213, 3008,
2242, 2237, 1515, 1501 cm–1; EI-MS (m/z, %) 201 (52, M+), 135 (100, M+–C3H4CN), 107 (67). 1H NMR
4
3
4
(200 MHz, DMSO-d6) δ 9.22 ((br s, 1H, NH), 7.01 (dd, J = 1.5, J = 7.6 Hz, 1H, H(6´)), 6.95 (dt, J =
1.5, 3J = 7.6 Hz, 1H, H(4´)), 6.72 (dd, 4J = 1.4, 3J = 7.6 Hz, 1H, H(3´)), 6.54 (dt, 4J = 1.4, 3J = 7.6 Hz, 1H,
H(5´)), 4.88 (br s, 2H, NH2), 1.64 (m, 4H, CH2CH2). 13C NMR (50 MHz, DMSO-d6) δ 164.5 (C=O),
143.5 (C(2´)), 127.2 and 127.0 (C(4´), C(6´)), 122.3 (C(1´)), 120.3 (CN), 116.1 and 116.0 (C(3´), C(5´)),
17.1 (C(2), C(3)), 14.5 (C(1)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H12N3O 202.0975; found
202.0980.
4.3. Procedures for the synthesis of substituted 2-cyclopropylbenzimidazoles
4.3.1. Preparation of 2-(1-acetamidocyclopropyl)-1H-benzimidazole (5)
Ethyl chloroformate (0.54 g, 5 mmol) was added to a solution of 1-(tert-butoxycarbonylamino)-
cyclopropanecarboxylic acid (1b) (1.0 g, 5 mmol) and Et3N (0.51 g, 5 mmol) in CH2Cl2 (50 mL) at –5–
0°C and the mixture was stirred for 30 min. A solution of 1,2-diaminobenzene (0.58 g, 5.4 mmol) in
CH2Cl2 (50 mL) was subsequently added to the mixture at 0°C in 15 min. The mixture was stirred for 1 h
at room temperature, washed with water, dried over anhydrous MgSO4 and the solvent was evaporated.
The residue was dissolved in acetic acid (10 mL) and heated to reflux for 8 h. Then the mixture was
treated with a saturated solution of NaHCO3, extracted with EtOAc, dried over anhydrous MgSO4 and
evaporated to give the desired product 5 in a yield of 24%, colorless crystals, m.p. 197–190°C. IR (KBr)
3270, 3053, 3026, 1658, 1538, 1456, 1421 cm–1; EI-MS (m/z, %) 215 (46, M+), 172 (100, M+–Ac), 155
1
(26), 144 (44). H NMR (300 MHz, CD3OD) δ 7.45 and 7.13 (both m, 2×2H, C6H4), 5.00 (br s, 2H, 2
NH), 2.06 (s, 3H, CH3), 1.65 (dd, 3J = 7.9, 2J = 4.9 Hz, 2H, HC–CH), 1.35 (dd, 3J = 7.9, 2J = 4.9 Hz, 2H,
HC–CH). 13C NMR (75 MHz, CD3OD) δ 175.0 (C=O), 158.1 (C(2)), 123.1 (C(4), C(5), C(6), C(7)),
115.2 (C(3a), C(7a)), 31.9 (C(1´)), 22.9 (CH3), 19.3 (CH2CH2). Anal. Calcd. for C12H13N3O: C, 66.96; H,
6.09; N, 19.52. Found: C, 66.99; H, 6.11; N, 19.39.
4.3.2. Synthesis of 2-(1-cyanocyclopropyl)benzimidazole (6)
13

ACCEPTED MANUSCRIPT
A solution of N-(2-aminophenyl)-1-cyanocyclopropanecarboxamide (2c) (1.63 g, 8 mmol) in formic
acid (4 mL) was heated to reflux for 45 min, evaporated in vacuo and treated with a saturated solution of
NaHCO3. The mixture obtained was filtered, evaporated in vacuo and separated by column
chromatography (chloroform–AcOEt, 1:1) to give 2-(1-cyanocyclopropyl)benzimidazole (6) (Rf = 0.39)
and 2-(3,4-dihydro-2H-pyrrol-4-yl)-1H-benzimidazole (14) (Rf = 0.22) in yields of 82 and 10%
respectively which were both additionally recrystallized from chloroform.
Compound 6, colorless crystals, m.p. 178–183°C IR (KBr) 3095, 2983, 2936, 2841, 2242, 1543,
1
1454, 1422 cm–1; EI-MS (m/z, %) 183 (93, M+), 182 (81, M+–H), 155 (20), 143 (100). H NMR (200
MHz, (CD3)2CO) δ 11.6 (br s, 1H, NH), 7.53 and 7.19 (both m, 2×2H, C6H4), 1.80–2.00 (m, 4H,
CH2CH2). 13C NMR (50 MHz, (CD3)2CO) δ 150.5 (C(2)), 139.2 and 133.3 (broad, C(3a), C(7a)), 123.2
(C(5), C(6)), 121.0 (CN), 119.1 and 113.2 (broad, C(4), C(7)), 19.2 (CH2CH2), 10.4 (C(1´)). Anal. Calcd.
for C11H9N3: C, 72.11; H, 4.95; N, 22.94. Found: C, 72.03; H, 5.00; N, 22.83.
1
Compound 14. IR (KBr) 3383, 3170, 3056, 2801, 2744, 1723, 1619 cm–1. H NMR (300 MHz,
CD3CN) δ 8.04 (br s, 1H, =CH), 7.62 and 7.30 (both m, 2×2H, C6H4), 5.41 (br s, 1H, NH), 4.58 (m, 1H,
H(3´)), 4.32 (m, 2H, H2C(5´)), 2.54 (m, 2H, H(4´)). 13C NMR (75 MHz, CD3CN) δ 162.1 (C(2)), 138.77
(C(2´)), 124.1 (C(5) and C(6)), 116.2 (C(4) and C(7)), 61.2 (C(5´)), 32.0 (C(4´), 29.8 (C(3´). HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C11H12N3 186.1026; found 186.1027.
4.3.3. Synthesis of substituted cyclopropylbenzimidazoles from mono-N-acylated phenylenediamines
A solution of the corresponding N-(2-aminophenyl)cyclopropanecarboxamide 2 (10 mmol) in acetic
(15 mL) was heated to reflux for 3 h. Then acid was subsequently evaporated, and the mixture was treated
with a saturated solution of NaHCO3 and filtered. The residue was dried in vacuo to form the desired
product.
4.3.3.1. 2-(1-Phenylcyclopropyl)-1H-benzimidazole (4). Yield of 98%, colorless crystals, m.p. 196–
199°C. IR (KBr) 3437, 2077, 3056, 2979, 2926, 2652, 1533, 1455, 1410, 1327 cm–1; EI-MS (m/z, %) 234
(82, M+), 233 (100, M+–H), 219 (9, M+–CH3), 157 (8), 132 (13). 1H NMR (200 MHz, DMSO-d6) δ 11.8
(br s, 1H, NH), 7.35–7.92 (m, 7H, H(4), H(7) and Ph), 7.12 (m, 2H, H(5), H(6)), 1.58 and 1.34 (both m,
2×2H). 13C NMR (50 MHz, DMSO-d6) δ 157.0 (C(2)), 141.4 (i-C), 140.3 and 137.0 (broad, C(3a),
C(7a)), 128.6 and 128.1 (o-C, m-C), 126.4 (p-C), 120.8 (C(5), C(6)), 114.8 and 114.0 (broad, C(4), C(7)),
24.7 (C(1´)), 15.7 (CH2CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H15N2 235.1230; found: m/z
235.1234.
4.3.3.2. 2-(2-Methylcyclopropyl)-1H-benzimidazole (8). Yield of 99%, colorless crystals, m.p. 217–
220°C. IR (KBr) 3420, 2051, 2960, 2926, 1548, 1455, 1425 cm–1; EI-MS (m/z, %) 172 (92, M+), 171
1
(100, M+–H), 157 (43, M+–Me), 156 (45), 132 (11). H NMR (300 MHz, DMSO-d6) δ 12.1 (br s, 1H,
NH), 7.38 and 7.02 (both m, 2×2H, C6H4), 1.79 (m, 1H, H(1´)), 1.39 and 0.82 (both m, 2×1H, H2C(3´)),
3
1.22 (m, 1H, H(2´)), 1.14 (br d, J = 5.9 Hz, 3H, CH3). 13C NMR (75 MHz, DMSO-d6) δ 156.7 (C(2)),
14

ACCEPTED MANUSCRIPT
143.3 and 134.1 (broad, C(3a), C(7a)), 120.8 (C(5), C(6)), 117.6 and 110.3 (broad, C(4), C(7)), 18.1
(CH3), 17.6 and 17.1 (C(1´), C(2´)), 16.5 (C(3´)). Anal. Calcd. for C11H12N2: C, 76.71; H, 7.02; N, 16.27.
Found: C, 76.88; H, 7.02; N, 16.18.
4.3.3.3. 2-(2,2-Dimethylcyclopropyl)-1H-benzimidazole (9). Yield of 91%, colorless crystals, m.p. 210–
213°C; IR (KBr) 3052, 2984, 2944, 2912, 2872, 2792, 1548, 1456, 1416 cm–1; EI-MS (m/z, %) 186 (88,
M+), 185 (55, M+–H), 171 (64, M+–CH3), 145 (100, M+–C3H5). 1H NMR (200 MHz, DMSO-d6) δ 9.80 (br
s, 1H, NH), 7.52 and 7.20 (both m, 2×2H, C6H4), 1.97 (dd, 3J = 8.5 and 5.4 Hz, 1H, H(1´)), 1.38 (dd, 2J =
3
2
3
4.9, J = 5.4 Hz, 1H, Ha(3´)), 1.23 and 1.05 (both s, 2×3H, 2 CH3), 1.03 (dd, J = 4.9, J = 8.5 Hz, 1H,
Ha(3´)). 13C NMR (50 MHz, DMSO-d6) δ 153.8 (C(2)), 139.3 and 136.5 (broad, C(3a), C(7a)), 120.4
(C(5), C(6)), 113.9 (broad, C(4), C(7)), 26.1 (C(1´)), 22.7 and 20.4 (2 CH3), 19.4 (C(2´)), 19.0 (C(3´)).
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H15N2 187.1230; found 187.1228.
4.3.3.4. 2-(Spiro[2,5]oct-1-yl)-1H-benzimidazole (10). Yield of 94%, colorless crystals, m.p. 236–237°C;
IR (KBr) 3442, 3052, 2996, 2920, 2848, 1540, 1456, 1420, 1272, 736 cm–1; EI-MS (m/z, %) 226 (100,
M+), 225 (60, M+–H), 211 (37, M+–CH3), 197 (48), 183 (40), 169 (36), 145 (98), 132 (98). 1H NMR (200
3
MHz, DMSO-d6) δ 12.2 (br s, 1H, NH), 7.40 and 7.03 (both m, 2×2H, C6H4), 1.94 (dd, J = 8.3 and 5.3
Hz, 1H, H(1´)), 1.12–1.68 (m, 10H, (CH2)5), 1.07 and 0.91 (both m, 2×1H, H2C(3´)). 13C NMR (50 MHz,
DMSO-d6) δ 153.8 (C(2)), 142.5 and 135.0 (broad, C(3a), C(7a)), 120.6 (C(5), C(6)), 117.0 and 112.2
(broad, C(4), C(7)), 36.3 (C(4)), 28.7 (C(8)), 28.3 (C(3)), 25.6 (C(1)), 25.0, 24.7 and 21.9 (C(5), C(6),
C(7)), 18.0 (C(2)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19N2 227.1543; found 227.1542.
4.3.3.5. 2-(Spiropent-1-yl)-1H-benzimidazole (11). Yield of 92%; the product obtained was additionally
recrystallized from acetone, colorless crystals, m.p. 200–201°C; IR (KBr) 3053, 2993, 2898, 2747, 2666,
2645, 1550, 1531, 1454, 1427 cm–1; EI-MS (m/z, %) 184 (37, M+), 183 (100, M+–H), 156 (21, M+–C2H4),
1
143 (10). H NMR (300 MHz, DMSO-d6) δ 11.9 (br s, 1H, NH), 7.46 and 7.37 (both m, 2×1H, H(4),
H(7)), 7.02 (m, 2H, H(5), H(6)), 1.54 (m, 2H, H(1´) and Ha(2´)), 0.93 (m, 4H, CH2CH2), 0.70 (m, 1H,
Hb(2´)). 13C NMR (75 MHz, DMSO-d6) δ 155.7 (C(2)), 143.4 and 134.3 (broad, C(3a), C(7a)), 121.0 and
120.7 (C(5), C(6)), 117.7 and 110.4 (broad, C(4), C(7)), 18.3 (C(3´)), 16.6 (C(1´)), 14.4 (C(2´)), 6.6 and
4.8 (CH2CH2). Anal. Calcd. for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C, 78.04; H, 6.50; N,
15.12.
4.3.3.6. 2-(2,2,3,3-Tetramethylcyclopropyl)-1H-benzimidazole (12). Yield of 90%, colorless crystals, m.p.
198–199°C; IR (KBr) 3084, 3052, 2984, 2816, 2772, 2656, 1536, 1416 cm–1; EI-MS (m/z, %) 214 (23,
M+), 199 (100, M+–Me), 173 (24). 1H NMR (200 MHz, DMSO-d6) δ 11.5 (br s, 1H, NH), 7.49 and 7.35
(both m, 2×1H, H(4), H(7)), 7.07 (m, 2H, H(5), H(6)), 1.62 (s, 1H, H(1´)), 1.26 and 1.22 (both s, 2×6H).
13C NMR (50 MHz, DMSO-d6) δ 153.5 (C(2)), 143.6 and 133.7 (broad, C(3a), C(7a)), 120.7 (C(5), C(6)),
118.1 and 110.1 (broad, C(4), C(7)), 31.7 (C(1´)), 26.3 (C(2´), C(3´)), 23.4 and 17.8 (4 CH3). Anal. Calcd.
for C14H18N2: C, 78.46; H, 8.47; N, 13.07. Found: C, 78.20; H, 8.50; N, 13.14.
15

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4.3.4. Synthesis of 2-(1-methylcyclopropyl)-1H-benzimidazole (15)
1-Methylcyclopropanecarbonitrile (16) (3.24 g, 40 mmol) was added to a solution of HCl (1.6 g, 44
mmol) in a mixture of absolute ethanol (2.02 g, 44 mmol) and dry ether (20 mL) at 0°C and the reaction
mixture was kept in a refrigerator for 48 h. The precipitate formed was filtered, washed with absolute
ether and dried in vacuo to give ethyl 1-methylcyclopropanecarbimidate (2.1 g), which was further used
without additional purification. The product obtained was added to a solution of 1,2-diaminobenzene
(1.27 g, 13 mmol) in absolute ethanol (19 mL) and the mixture was heated to reflux for 1 h, allowed to
cool to room temperature and evaporated. The residue was dissolved in water (19 mL) and a concentrated
ammonia solution (2 mL) was added to the mixture. The precipitate formed was filtered, washed with
cool water and dried in vacuo to give 2-(1-methylcyclopropyl)-1H-benzimidazole (15) (1.27 g, 58%). To
additionally purify the product was recrystallized from a mixture of ethyl acetate and methanol (1:1),
colorless crystals, m.p. 240–244°C; IR (KBr) 3001, 2970, 2931, 2887, 2844, 2794, 1543, 1460, 1408
1
cm–1; EI-MS (m/z, %) 172 (62, M+), 171 (100, M+–H), 157 (44, M+–Me), 156 (36), 132 (18). H NMR
(200 MHz, DMSO-d6) δ 12.0 (br s, 1H, NH), 7.44 and 7.08 (both m, 2×2H, C6H4), 1.53 (s, 3H, CH3), 1.20
and 0.88 (both m, 2×2H, CH2CH2). 13C NMR (50 MHz, DMSO-d6) δ 159.1 (C(2)), 137.4 and 133.0
(broad, C(3a), C(7a)), 121.0 (C(5), C(6)), 115.9 and 114.4 (broad, C(4), C(7)), 21.1 (CH3), 16.6
(CH2CH2), 15.0 (C(1´)). Anal. Calcd. for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.57; H,
7.09; N, 16.14.
4.3.5. Preparation of methyl E-2-(1H-benzimidazol-2-yl)cyclopropanecarboxylate (E-19)
4.3.5.1. 1-Benzyl-2-ethenyl-1H-benzimidazole (17). A suspension (60% in oil) of sodium hydride (2.63 g,
65 mmol) was added in portions to a solution of 2-ethenyl-1H-benzimidazole (9.00 g, 65 mmol) in dry
dimethylformamide (60 mL) and the reaction mixture was stirred for 30 min at room temperature. Then
benzyl chloride (9.7 g, 68.7 mmol) was added and the mixture was additionally stirred for 12 h. After that
the mixture was treated with water and extracted with ether. The combined organic layer was washed
with water, dried over anhydrous MgSO4 and evaporated. Column chromatography on SiO2 (EtOAc–
hexane, 1:5) gave the desired product (11.4 g, 78%) as a brownish oil. The product is inclined to
polymerize, so it should be used in next steps as fast as possible. IR (KBr) 2976, 1497, 1455, 1427, 1047
1
cm–1; EI-MS (m/z, %) 234 (58, M+), 233 (28, M+–H), 219 (20, M+–CH3), 91 (100, Bn+). H NMR (300
MHz, CDCl3) δ 7.79 (m, 1H, H(4)), 7.20–7.42 (m, 6H, H(5), H(6), H(7), m-H, p-H)), 7.10 (m, 2H, o-H),
6.72 (dd, 3J = 17.2 and 11.0 Hz, 1H, =CH), 6.58 (dd, 3J = 17.2, 2J = 1.4 Hz, 1H, Ha), 5.67 (dd, 3J = 11.0,
2J = 1.4 Hz, 1H, Hb), 5.40 (CH2). 13C NMR (75 MHz, CDCl3) δ 150.8 (C(2)), 143.1 (C(3a)), 136.1 and
135.6 (i-C, C(7a)), 129.1 (m-C), 128.0 (p-C), 126.2 (o-C), 123.7 (=CH2), 123.1, 122.9 and 119.9 (C(4),
C(5), C(6)), 109.8 (C(7)), 47.0 (CH2).
4.3.5.2. Methyl E- and Z-2-(1-benzyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (E- and Z-18). A
mixture of 1-benzyl-2-ethenyl-1H-benzimidazole (8.07 g, 34 mmol), methyl diazoacetate (6.90 g, 69
16

ACCEPTED MANUSCRIPT
mmol) and 30 mL of p-xylene was heated to reflux for 3 h. The solvent was removed under reduced
pressure and the reaction mixture was separated by column chromatography on SiO2 (CHCl3–EtOAc,
1:1). The first product was recrystallized from a mixture of EtOAc–hexanes (5:1) to give 1.16 g (11%) Z-
18 as colorless crystals, m.p. 168–168.5°C; IR (KBr) 3074, 3066, 3027, 3003, 2953, 1727, 1462, 1411,
1388 cm−1; EI-MS (m/z, %) 306 (29, M+), 275 (8, M+–MeO), 247 (21, M+–CO2Me), 233 (19), 215 (26),
183 (20), 156 (28), 155 (30), 91 (100, Bn+). 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 1H, H(4´)), 7.15–7.41
(m, 6H, H(5´), H(6´), H(7´), m-H, p-H)), 7.08 (m, 2H, o-H), 5.38 (s, 2H, CH2), 3.42 (s, 3H, OCH3), 2.37
(ddd, 3J = 8.9, 8.8 and 6.9 Hz, 1H, H(1)), 2.10–2.23 (m, 2H, H(2), Ha(3)), 1.50 (ddd, 3J = 8.9 and 7.0, 2J =
3.3 Hz, 1H, Hb(3)). 13C NMR (75 MHz, CDCl3) δ 170.7 (COO), 150.7 (C(2´)), 142.5 (C(3´a)), 135.9 and
135.7 (i-C, C(7´a)), 128.9 (m-C), 127.8 (p-C), 126.3 (o-C), 122.6 and 122.0 (C(5´), C(6´)), 119.9 (C(4´)),
109.5 (C(7´)), 51.9 (OCH3), 46.9 (CH2), 20.7 (C(2)), 17.3 (C(1)), 11.8 (C(3)). Anal. Calcd. for
C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.68; H, 5.94; N, 9.18. The second product was
additionally purified by column chromatography (CHCl3–EtOAc, 4:1) to give 5.92g (56%) isomer E-18
as colorless oil; IR 3063, 3032, 2951, 1729, 1523, 1497, 1462, 1454 cm−1; EI-MS (m/z, %) 306 (41, M+),
275 (9, M+–MeO), 247 (24, M+–CO2Me), 233 (21, M+–CH2CO2Me), 215 (31, M+–Bn), 183 (22), 156
(30), 155 (33), 91 (100, Bn+). 1H NMR (300 MHz, CDCl3) δ 7.71 (dd, 3J = 6.3, 4J = 1.8 Hz, 1H, H(4´)),
2
7.18–7.34 (m, 6H, H(5´), H(6´), H(7´), m-H, p-H)), 7.07 (m, 2H, o-H), 5.46 and 5.42 (both d, J = 16.7
Hz, 2×1H, CH2)), 3.67 (s, 3H, OCH3), 2.57 (ddd, 3J = 9.0, 6.1 and 4.1 Hz, 1H, H(1)), 2.31 (ddd, 3J = 8.7,
3
2
3
5.6 and 4.1 Hz, 1H, H(2)), 1.82 (ddd, J = 8.7 and 6.1, J = 4.3 Hz, 1H, H(3a)), 1.62 (ddd, J = 9.0 and
2
5.6, J = 4.3 Hz, 1H, H(3b)). 13C NMR (75 MHz, CDCl3) δ 172.9 (COO), 153.2 (C(2´)), 142.2 (C(3´a)),
135.8 and 135.7 (i-C, C(7´a)), 129.0 (m-C), 127.9 (p-C), 126.4 (o-C), 122.6 and 122.4 (C(5´), C(6´)),
119.3 (C(4´)), 109.4 (C(7´)), 52.1 (OCH3), 47.0 (CH2), 23.1 (C(1)), 17.9 (C(2)), 16.0 (C(3)). HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C19H19N2O2 307.1447; found 307.1442.
4.3.5.3. Methyl E-2-(1H-benzimidazol-2-yl)cyclopropanecarboxylate (E-19). A solution of a mixture of
compounds E- and Z-18 (1.31 g, 4.3 mmol) in MeOH (40 mL) was hydrogenated using 5% Pd/C and
acetic acid (43 mg, 8.5 mmol) at 100°C and 100 bar of H2 for 7 h. The solution obtained was evaporated,
residue was separated by column chromatography (eluent — CHCl3) and necessary fraction was
recrystallized from a mixture of EtOAc–hexanes (3:1) to give only the isomer E-19 (0.28 g, 30%), m.p.
166–170°C; IR (KBr) 3065, 2999, 2853, 1734, 1550, 1441, 1428 cm–1; EI-MS (m/z, %) 216 (34, M+), 185
1
(39, M+–OCH3), 157 (100, M+–CO2CH3), 156 (59, M+–HCO2Me). H NMR (300 MHz, CD3OD) δ 7.47
3
(m, 2H, H(4´), H(7´)), 7. 19 (m, 2H, H(5´), H(6´)), 3.74 (s, 3H, OCH3), 2.68 (ddd, J = 9.2, 6.2 and 4.1
3
3
2
Hz, 1H, H(1)), 2.32 (ddd, J = 8.5, 5.9 and 4.1 Hz, 1H, H(2)), 1.69 (ddd, J = 8.5, 6.2, J = 4.4 Hz, 1H,
3
2
H(3a)), 1.65 (ddd, J = 9.2, 5.9, J = 4.4 Hz, 1H, H(3b)). 13C NMR (50 MHz, CD3OD) δ 174.2 (COO),
154.9 (C(2´)), 141.8 and 136.4 (C(3a), C(7a)), 123.5 (C(5), C(6)), 115.3 (broad, C(4), C(7)), 52.7
(OCH3), 23.9 (C(2)), 20.1 (C(1)), 16.5 (C(3)). Anal. Calcd. for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96.
Found: C, 66.43; H, 6.60; N, 13.00.
17

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4.4. Procedures for the synthesis of substituted 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles
4.4.1. General procedure for the synthesis of 2-cyclopropyl-1H-benzimidazolium halogenides
A solution of hydrobromic (48%) or hydriodic (57%) acid (7.2 mmol HHal) was added to a solution of
applicable benzimidazole (6.0 mmol) in methanol (15 mL) and the reaction mixture was stirred for 5 min.
The solvent was evaporated and the residue was dried in vacuo. The hydrohalides formed this way were
further used without additional purification. In some cases the generation of 2-cyclopropyl-1H-
benzimidazole hydroiodides was carried out in situ by using ammonium iodide.
4.4.2. 3-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (20). A suspension of hydriodide 15 (0.87
g, 2.9 mmol) in 1,2-dichlorobenzene (10 mL) was refluxed for 1.5 h. Then the solvent was evaporated,
and the residue was treated with a 5% aqueous solution of NaOH (10 mL) and extracted with ethyl
acetate. The product was further purified by column chromatography (AcOEt–chloroform, 1:1) to give
compound 20 (0.41 g, 82%), m.p. 39–40°C; IR (KBr) 3052, 2968, 2931, 2875, 1620, 1529, 1452 cm–1;
EI-MS (m/z, %) 172 (92, M+), 157 (100, M+–CH3), 156 (55). HRMS calcd for C11H13N2: M+H, 173,1073.
Found: m/z 173,1071. The NMR spectroscopic data match those reported in literature.28
4.4.3. 3-Phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (21). Hydrobromide 4 (0.42 g, 1.3 mmol)
was heated at 200°C for 10 min. The reaction mixture was treated with a 5% aqueous solution of NaOH
(5 mL) and subsequently extracted with ethyl acetate. The organic layer was dried over anhydrous
MgSO4, filtered and evaporated. The product was purified by column chromatography (AcOEt–
chloroform, 1:1) to give compound 21 (0.20 g, 65%), EI-MS (m/z, %) 234 (98, M+), 233 (100, M+–H),
219 (20) 157 (44, M+–Ph), 132 (6). 1H NMR (200 MHz, CDCl3) δ 7.72 (m, 1H, H(5)), 7.18–7.45 (m, 8H,
3
H(6), H(7), H(8) and Ph), 4.52 (dd, J = 6.8 and 7.0 Hz, 1H, H(3)), 4.28 and 4.13 (both m, 2×1H,
H2C(1)), 3.20 and 2.74 (both m, 2×1H, H2C(2)). 13C NMR (50 MHz, CDCl3) δ 162.3 (C(3a)), 148.9
(C(4a)), 140.4 (i-C), 132.4 (C(8a)), 129.0 and 127.7 (o-C, m-C), 127.3 (p-C), 122.2 and 122.0 (C(6),
C(7)), 120.2 (C(5)), 109.8 (C(8)), 42.13 and 42.09 (C(1), C(3)), 36.9 (C(2)). The other data match those
available in the literature.29
4.4.4. N-(2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl)acetamide (22). A mixture of acetamide 5
(0.14 g, 0.66 mmol), ammonium iodide (0.11 g, 0.79 mmol) in 1,2-dichlorobenzene (6 mL) was refluxed
for 1 h. The solvent was removed in vacuo, and the residue was treated with a 5% aqueous solution of
NaOH (10 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4,
filtered and evaporated. The crude product was purified by column chromatography (EtOAc–chloroform,
4:1) and recrystallized from acetone to give the desired product 22 in a yield of 87%, colorless crystals,
m.p. 189.5–190.4°C; IR (KBr) 3257, 3058, 2993, 2936, 2399, 2373, 1662, 1637, 1558, 1523 cm–1; EI-MS
1
(m/z, %) 215 (35, M+), 172 (100, M+–Ac), 157 (7), 144 (10). H NMR (200 MHz, CD3OD) δ 7.62 and
7.42 (both m, 2×1H, H(5), H(8)), 7.26 (m, 2H, H(6), H(7)), 5.42 (dd, 1H, 3J = 8.6 and 6.3 Hz, H(3)), 5.00
18

ACCEPTED MANUSCRIPT
(br s, 1H, NH), 4.26 and 4.07 (both m, 2×1H, H2C(1)), 3.09 and 2.52 (both m, 2×1H, H2C(2)), 2.02 (s,
3H, COCH3). 13C NMR (50 MHz, CD3OD) δ 175.6 (C=O), 163.1 (C(3a)), 151.4 (C(4a)), 136.0 (C(8a)),
126.4 and 126.1 (C(6), C(7)), 122.6 (C(5)), 114.1 (C(8)), 49.6 (C(3)), 45.2 C(1)), 38.2 (C(2)), 25.3 (CH3).
Anal. Calcd. for C12H13N3O: C, 66.96; H, 6.09; N, 19.52. Found: C, 67.13; H, 6.12; N, 19.69.
4.4.5. 3-Cyano-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (23). A ground mixture of compound 6
(0.183 g, 1.0 mmol) and ammonium iodide (0.160 g, 1.1 mmol) was heated at 150°C for 30 min. The melt
was allowed to cool to room temperature, treated with a solution of K2CO3 (0.41 g, 3.3 mmol) in 15 mL
of water and extracted with ethyl acetate. The product was then purified by column chromatography
(EtOAc–MeOH, 9:1) to give cyano derivative 23 (0.11 g, 60%) as colorless crystals, m.p. 133–136°C; IR
(KBr) 3265, 3006, 2891, 2249, 2237, 1680, 1660 cm–1; EI-MS (m/z, %) 183 (100, M+), 182 (56, M+–H),
155 (13). 1H NMR (300 MHz, CD3CN) δ 7.65 and 7.40 (both m, 2×1H, H(5), H(8)), 7.23 (m, 2H, H(6),
3
H(7)), 4.44 (dd, J = 9.0 and 7.4 Hz, 1H, H(3)), 4.23 and 4.07(both m, 2×1H, H2C(1)), 3.13 and 2.92
(both m, 2×1H, H2C(2)). 13C NMR (75 MHz, CD3CN) δ 155.5 (C(3a)), 149.4 (C(4a)), 133.7 (C(8a)),
123.5 and 122.9 (C(6), C(7)), 120.7 (C(5)), 119.0 (CN), 111.5 (C(8)), 42.7 (C(1)), 32.9 (C(2)), 27.3
(C(3)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H10N3 184.0869; found 184.0872.
4.4.6. Rearrangement of asymmetrically substituted benzimidazoles (General procedure). A solution of
applicable 2-cyclopropyl-1H-benzimidazol hydriodide (1.5 mmol) in 5 mL of either 1,2-dichlorobenzene
or N-methylpyrrolidone was refluxed for the time indicated in Table 3. The mixture was subsequently
evaporated, treated with a 5% aqueous solution of NaOH (15 mL) and extracted with ethyl acetate. The
organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude mixture of
regioisomers was separated by column chromatography with the solvents indicated below to give
corresponding 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazoles 25–34 (yields are given in Table 3).
4.4.6.1. 1-Phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (25). Eluent, AcOEt–chloroform, 1:1;
colorless crystals, m.p. 133–136°C; IR (KBr) 3077, 3061, 3031, 2970, 2931, 1618, 1525, 1451, 1451,
1
1399 cm–1; EI-MS (m/z, %) 234 (96, M+), 233 (41, M+–H), 157 (20, M+–Ph), 132 (100). H NMR (200
MHz, CDCl3) δ 7.71 (dd, 3J = 8.0, 4J = 1.3 Hz, 1H, H(5)), 7.14–7.39 (m, 6H, H(6) and Ph), 7.04 (dt, 4J =
1.3, 3J = 8.0 Hz, 1H, H(7)), 6.80 (dd, 3J = 8.1, 4J = 1.2 Hz, 1H, H(8)), 5.41 (dd, 3J = 8.1 and 7.5 Hz, 1H,
H(1)), 3.00–3.35 (m, 3H, H2C(3), Ha(2)), 2.58 (m, 1H, Hb(2)). 13C NMR (50 MHz, CDCl3) δ 161.1
(C(3a)), 149.0 (C(4a)), 139.6 (i-C), 131.9 (C(8a)), 129.1 (m-C), 128.4 (p-C), 126.2 (o-C), 121.8 (C(6),
C(7)), 119.7 (C(5)), 110.3 (C(8)), 60.0 (C(1)), 37.5 (C(2)), 23.6 (C(3)). HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C16H15N2 235.1230; found 235.1229.
4.4.6.2. 2-Phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (30). Eluent, AcOEt–chloroform, 1:1;
colorless crystals, m.p. 116–118°C; IR (KBr) 3059, 3028, 2885, 1524, 1454, 1410 cm−1; EI-MS (m/z, %)
234 (100, M+), 233 (30, M+–H), 219 (13), 157 (4, M+–Ph), 130 (98). 1H NMR (200 MHz, CDCl3) δ 7.73
(dd, 3J = 7.8, 4J = 1.3 Hz, 1H, H(5)), 7.15–7.42 (m, 8H, H(6), H(7), H(8) and Ph), 4.51 (dd, 2J = 9.8, 3J =
19

ACCEPTED MANUSCRIPT
8.0 Hz, 1H, Ha(1)), 4.24 (m, 1H, H(2)), 4.08 (dd, 2J = 9.8, 3J = 6.9 Hz, 1H, Hb(1)), 3.51 (dd, 2J = 16.9, 3J
2
3
= 8.6 Hz, 1H, Ha(3)), 3.18 (dd, J = 16.9, J = 7.6 Hz, 1H, Ha(3)). 13C NMR (50 MHz, CDCl3) δ 160.0
(C(3a)), 148.8 (C(4a)), 142.0 (i-C), 132.6 (C(8a)), 129.2 (o-C), 127.6 (p-C), 126.9 (m-C), 122.1 and 121.9
(C(6), C(7)), 120.0 (C(5)), 109.5 (C(8)), 50.4 (C(1)), 46.3 (C(2)), 32.4 (C(3)). HRMS calcd for C16H15N2:
M+H, 235.1235. Found: m/z 235.1230. The data match those in literature.30
4.4.6.3. 1-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (26). Eluent, AcOEt–chloroform, 1:1;
colorless crystals, m.p. 69–70°C; IR (KBr) 2970, 2932, 2874, 2856, 1621, 1525, 1455 cm−1; EI-MS (m/z,
%) 172 (50, M+), 171 (7, M+–H), 157 (100, M+–Me).1H NMR (200 MHz, CDCl3) δ 7.67 (m, 1H, H(5)),
7.31 (m, 1H, H(8)), 7.14 (m, 2H, H(6), H(7)), 4.48 (m, 1H, H(1)), 2.98 (m, 2H, H2C(3)), 2.79 and 2.20
(both m, 2×1H, H2C(2)), 1.52 (d, J = 6.6, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 160.0 (C(3a)), 149.0
(C(4a)), 131.9 (C(8a)), 121.7 and 121.6 (C(6), C(7)), 119.7 (C(5)), 109.6 (C(8)), 52.1 (C(1)), 34.7 (C(2)),
23.2 (C(3)), 20.4 (CH3). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H13N2 173,1073; found 173,1071.
4.4.6.4. 2-Methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (31). Eluent, AcOEt–chloroform, 1:1, the
product was recrystallized from AcOEt–hexane, 1:2 to give colorless crystals, m.p. 86–88°C; IR (KBr)
3446, 3051, 2960, 1616, 1524, 1454 cm−1; EI-MS (m/z, %) 172 (100, M+), 171 (37, M+–H), 157 (46, M+–
Me). 1H NMR (300 MHz, CDCl3) δ 7.67 (m, 1H, H(5)), 7.12–7.31 (m, 3H, H(6), H(7), H(8)), 4.16 (dd, 2J
3
2
3
= 10.0, J = 7.8 Hz, 1H, Ha(1)), 3.56 (dd, J = 10.0, J = 6.3 Hz, 1H, Hb(1)), 2.98–3.25 (m, 2H, H(2),
Ha(3)), 2.61 (m, 1H, Hb(3)), 1.28 (d, J = 6.7, 3H, CH3). 13C NMR (50 MHz, CDCl3) δ 160.5 (C(3a)),
148.2 (C(4a)), 132.2 (C(8a)), 121.7 and 121.5 (C(6), C(7)), 119.4 (C(5)), 109.4 (C(8)), 49.9 (C(1)), 35.6
(C(2)), 32.0 (C(3)), 19.8 (CH3). Anal. Calcd. for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.79;
H, 7.05; N, 16.32.
4.4.6.5. 1,1-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (27). Eluent – EtOAc; colorless
crystals; m.p. 88.5–90°C; IR (KBr) 3046, 2967, 2929, 2875, 1617, 1525, 1453, 1395 cm−1; EI-MS (m/z,
1
%) 186 (46, M+), 185 (19, M+–H), 171 (100, M+–CH3). H NMR (200 MHz, CDCl3) δ 7.70 (m, 1H,
H(5)), 7.41 (m, 1H, H(8)), 7.19 (m, 2H, H(6), H(7)), 3.09 (t, 2H, J = 7.8, H2C(3)), 2.52 (t, 2H, J = 7.8,
H2C(2)), 1.64 (s, 6H, 2 CH3). 13C NMR (50 MHz, CDCl3) δ 159.8 (C(3a)), 149.1 (C(4a)), 131.1 (C(8a)),
122.1 (C(6), C(7)), 119.8 (C(5)), 109.5 (C(8)), 60.5 (C(1)), 41.8 (C(2)), 27.2 (CH3), 23.1 (C(3)). Anal.
Calcd. for C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.30; H, 7.55; N, 14.99.
4.4.6.6. 2,2-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (32). Eluent – AcOEt; colorless
crystals, m.p. 58–59°C; IR (KBr) 2964, 2939, 2905, 2872, 1619, 1528, 1454, 1407 cm−1; EI-MS (m/z, %)
1
186 (100, M+), 185 (75, M+–H), 171 (65, M+–CH3). H NMR (200 MHz, CDCl3) δ 7.70 (m, 1H, H(5)),
7.16–7.31 (m, 3H, H(6), H(7), H(8)), 3.83 (s, 2H, H2C(1)), 2.89 (s, 2H, H2C(3)), 1.36 (s, 6H, 2 CH3). 13C
NMR (50 MHz, CDCl3) δ 160.3 (C(3a)), 148.2 (C(4a)), 132.6 (C(8a)), 121.9 and 121.7 (C(6), C(7)),
119.6 (C(5)), 109.5 (C(8)), 56.2 (C(1)), 43.3 (C(2)), 39.3 (C(3)), 28.3 (CH3). Anal. Calcd. for C12H14N2:
20

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1
C, 77.38; H, 7.58; N, 15.04. Found: C, 77.20; H, 7.61; N, 14.98. The H NMR data match those
previously reported.31
4.4.6.7. 1-Azaspiro[4,5]deca[1,2-a]benzimidazole (28). Eluent – AcOEt; colorless crystals, m.p. 148–
151°C; IR (KBr) 3052, 2928, 2856, 1616, 1532, 1448, 1396 cm−1; EI-MS (m/z, %) 226 (71, M+), 225 (20,
1
M+–H), 211 (16, M+–CH3), 197 (20), 183 (100), 170 (29), 145 (13), 132 (44). H NMR (300 MHz,
CDCl3) δ 7.69 (dd, 3J = 6.7, 4J = 2.1 Hz, 1H, H(5)), 7.44 (dd, 3J = 6.8, 2.0 Hz, 1H, H(8)), 7.10–7.26 (m,
2H, H(6), H(7)), 3.04 (t, J = 7.7 Hz, 2H, H2C(3), 2.52 (t, J = 7.7 Hz, 2H, H2C(2)), 2.20, 1.80 and 1.21–
1.59 (all m, 2+4+4H, (CH2)5). 13C NMR (75 MHz, CDCl3) δ 159.4 (C(3a)), 149.2 (C(4a)), 131.0 (C(8a)),
121.8 and 121.4 (C(6), C(7)), 119.7 (C(5)), 109.9 (C(8)), 63.9 (C(1)), 36.3 (C(2)), 35.8 (C(2´), C(6´)),
25.2 (C(4´)), 23.4 (C(3´), C(5´)), 22.7 (C(3)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19N2
227.1543; found 227.1545.
4.4.6.8. 2-Azaspiro[4,5]deca[2,3-a]benzimidazole (33). Eluent – AcOEt; colorless crystals, m.p. 105–
108°C; IR (KBr) 3050, 2928, 2850, 1523, 1454, 1416 cm−1; EI-MS (m/z, %) 226 (100, M+), 225 (42, M+–
1
H), 211 (12, M+–CH3), 197 (17), 183 (23), 169 (23), 144 (23), 132 (26). H NMR (300 MHz, CDCl3) δ
7.69 (m, 1H, H(5)), 7.15–7.30 (m, 3H, H(6), H(7), H(8)), 3.86 (s, 2H, H2C(1)), 2.90 (s, 2H, H2C(3)),
1.42–1.71 (m, 10H, (CH2)5). 13C NMR (75 MHz, CDCl3) δ 160.0 (C(3a)), 148.3 (C(4a)), 132.5 (C(8a)),
121.7 and 121.5 (C(6), C(7)), 119.5 (C(5)), 109.4 (C(8)), 54.2 (C(1)), 47.1 (C(2)), 37.2 (C(2´), C(6´)),
36.9 (C(3)), 25.5 (C(4´)), 23.1 (C(3´), C(5´)). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19N2
227.1543 found 227.1544.
4.4.6.9. Methyl 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-1-carboxylate (29). A mixture of compound
19 (0.132 g, 0.61 mmol), ammonium iodide (0.107 g, 0.74 mmol) in 1,2-dichlorobenzene (6 mL) was
refluxed for 1 h. The solvent was removed in vacuo, and the residue was treated with a 5% aqueous
solution of NaHCO3 (10 mL) and extracted with AcOEt. The organic layer was dried over anhydrous
MgSO4, filtered and evaporated. The crude product was purified by column chromatography (EtOH–
chloroform, 1:4) and recrystallized from acetone to give the desired product in a yield of 19%. 1H NMR
(200 MHz, CD3OD) δ 7.89 – 7.78 (m, 1H, H(5)), 7.78 – 7.68 (m, 1H, H(8)), 7.66 – 7.52 (m, 2H, H(6),
H(7)), 5.16 (dd, J = 9.0, 4.8 Hz, 1H, H(1)), 4.01 (s, 3H, OCH3), 3.52 – 3.36 (m, 2H, H(3)), 3.28 – 3.11
(m, 1H, H(2a)), 3.01 – 2.80 (m, 1H, H(2b)).
4.4.6.10. 5-Azaspiro[2.4]hepta[5,6-a]benzimidazole (34). A mixture of 2-(spiro[2.2]pentan-1-yl)-1H-
benzimidazole (0.176 g, 0.96 mmol), NH4I (0.174 g, 1.2 mmol) in 10 mL of either 1,2-dichlorobenzene or
N-methylpyrrolidone was heated to reflux for 40 min. The solvent was removed in vacuo, and the residue
was treated with a solution of NaOH (0.71 g, 18 mmol) in 20 mL of water and extracted with methylene
chloride. The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude product
was purified by column chromatography (AcOEt–chloroform, 1:1) and recrystallized from acetone to
give the only one regioisomer 34 in yield of 76% in 1,2-dichlorobenzene or 74% in N-methylpyrrolidone,
21

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colorless crystals, m.p. 119–121°C IR (KBr) 3053, 2991, 2958, 1619, 1523, 1454, 1412 cm−1; EI-MS
1
(m/z, %) 184 (100, M+), 183 (54, M+–H), 169 (26, M+–CH3), 156 (48, M+–C2H4). H NMR (200 MHz,
CDCl3) δ 7.72 (m, 1H, H(5)), 7.18–7.32 (m, 3H, H(6), H(7), H(8)), 4.01 (s, 2H, H2C(1)), 3.07 (s, 2H,
H2C(3)), 0.89 (m, 4H, CH2CH2). 13C NMR (50 MHz, CDCl3) δ 160.0 (C(3a)), 148.0 (C(4a)), 132.3
(C(8a)), 121.8 and 121.7 (C(6), C(7)), 119.6 (C(5)), 109.4 (C(8)), 51.5 (C(1)), 33.6 (C(3)), 22.4 (C(2)),
13.2 (CH2CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H13N2 185.1073; found 185.1080.
4.4.7. 1,1,2,2-Tetramethyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole (39). 2-(2,2,3,3-Tetrame-
thylcyclopropyl)-1H-benzimidazolium bromide (0.37 g, 1.3 mmol), prepared from compound 12, was
heated at 200°C for 4.5 h. Then the mixture was allowed to cool to room temperature, treated with an 3%
aqueous solution of NaOH (15 mL) and extracted twice with dichloromethane (25 mL). The organic layer
was dried over anhydrous MgSO4, filtered and evaporated. The product was additionally purified by
column chromatography (AcOEt–chloroform, 1:1) to give compound 39 in a yield of 63% as colorless
crystals, m.p. 72.5–74°C; IR (KBr) 2977, 2955, 2935, 2875, 1616, 1530, 1451 cm−1; EI-MS (m/z, %) 214
1
(42, M+), 199 (100, M+–Me). H NMR (200 MHz, CDCl3) δ 7.70 and 7.40 (both m, 2×1H, H(5), H(8)),
7.19 (m, 2H, H(6), H(7)), 2.88 (s, 1H, H(3)), 1.50 and 1.18 (both s, 2×6H, 4 CH3). 13C NMR (126 MHz,
CDCl3) δ 158.3 (C(3a)), 148.3 (C(4a)), 132.0 (C(8a)), 121.5 and 121.4 (C(6), C(7)), 119.7 (C(5)), 109.4
(C(8)), 65.2 (C(1)), 48.1 (C(2)), 38.5 (C(3)), 24.0 and 22.6 (2×2 CH3). Anal. Calcd. for C14H18N2: C,
78.46; H, 8.47; N, 13.07. Found: C, 78.45; H, 8.50; N, 12.92.
Acknowledgements
The project was financially supported by the Presidium of the Russian Academy of Sciences (Program for
the Development of Methods for the Synthesis of Chemical Compounds and the Creation of New
Materials) and the Division of Chemistry and Materials Science of the Russian Academy of Sciences
(Program for Basic research “Biomolecular and Medical Chemistry”). We also thank our colleague
Evgeny V. Shulishov for invaluable help in NMR spectroscopy.
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