Synthesis of annulated benzimidazoles via amidine cyclization

Article abstract of DOI:10.1016/j.tet.2012.02.027

Structurally diverse annulated benzimidazoles were synthesized via two copper(I)-catalyzed cyclocondensation reactions. In the first case the title compounds were prepared from lactams and o-bromoaniline. An alternative route consisted of an intramolecular cyclization of o-bromoarylamidines.

Full text of DOI:10.1016/j.tet.2012.02.027

Tetrahedron 68 (2012) 2993e3000
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Synthesis of annulated benzimidazoles via amidine cyclization
,
a
b
Kostiantyn Liubchak a , Kostiantyn Nazarenko , Andrey Tolmachev
*
a Institute of Organic Chemistry of NAS of Ukraine, 5 Murmanska str., Kyiv 02094, Ukraine
b Research and Development Center for Chemistry and Biology, National Taras Shevchenko University of Kyiv, 62 Volodymyrska str., Kyiv 01033, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2011
Received in revised form 27 January 2012
Accepted 13 February 2012
Available online 17 February 2012
Structurally diverse annulated benzimidazoles were synthesized via two copper(I)-catalyzed cyclo-
condensation reactions. In the first case the title compounds were prepared from lactams and o-bro-
moaniline. An alternative route consisted of an intramolecular cyclization of o-bromoarylamidines.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
of annulated benzimidazoles carried out as multi-step procedures
with limited number of starting compounds.5 Therefore it is of
Annulated benzimidazoles play an important role in drug dis-
covery and can be regarded as key structures in pharmaceutical
research. Investigation of biological activity of annulated benz-
imidazoles started from the middle of the recent century when
analgesic activity of numerous pyrido-1 (I) and pyrrolobenzimida-
zoles2 (II) was found (Fig. 1). In the 1990s Skibo et al. designed a set
of pyrrolo[1,2-c]benzimidazolequinones (PBIs) having high-grade
antitumor activity.3 The most recent studies of the annulated
benzimidazoles showed the ring-size influence on their toxicity
toward the Fanconi anemia skin cells (III).4 Unfortunately, synthesis
importance to develop methods for the preparation of functional-
ized annulated benzimidazoles.
We have recently described a novel non-catalytic approach to
annulated benzimidazoles of type 2 via an intramolecular arylation
of cyclic amidines 1 (Scheme 1).6 The method combined the ease of
a one-pot procedure with the availability of the cyclic amidines. A
major obstacle of our published method was a low reactivity of the
CeHal bond requiring quite harsh reaction conditions and acti-
vating substituents in the aromatic ring. For instance, amidines 1
(Scheme 1, X¼F) undergo cyclocondensation at 150 ꢀC to give 2 only
when activated with strong electron-withdrawing groups (R), such
as F and NO2.
Scheme 1. Annulated benzimidazole synthesis.
Nowadays the synthesis of annulated nitrogen heterocycles
largely relies on metal-mediated reactions for the CeN bond for-
mation.7 For example, intramolecular Ullmann-type copper-cata-
lyzed cyclocondensations resulting in the CeN bond formation
were employed in the synthesis of many heterocycles, such as in-
doles8 and imidazoles.9 The preparation of 1,2-disubstituted
benzimidazoles was carried out in some pathways: (i) a cyclo-
condensation of o-haloanilides;10 (ii) an arylation of amides with
o-haloanilines;11 (iii) a cyclization of arylamidines and related
Fig. 1. Biological active benzimidazoles.
* Corresponding author. Tel.: þ380 50 707 12 10; e-mail address: kliubchak@
gmail.com (K. Liubchak).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.027

2994
K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
compounds;12 (iv) an arylation of amidines with 1,2-dihalobenzene
derivatives;13 (v) cascade addition/cyclization amines with o-hal-
oarylisocyanides14 and o-haloarylcarbodiimides.15 Some of these
procedures were also employed for the synthesis of annulated
benzimidazoles. Thus, a copper/DMEDA-mediated arylation of
2-iminopiperidine with 1,2-diiodobenzene led to compound 2
(n¼2, R¼H) with an isolated yield of 52%.13 Moreover, a few
aminopiperidine-fused benzimidazoles were obtained through
a Cu-catalyzed condensation of substituted valerolactams with
o-bromo- or iodoanilines and 2-aminopyridines.16
In this contribution we describe the synthesis of structurally
diverse annulated benzimidazoles through two copper(I)-mediated
cyclocondensation reactions. In the first case the title compounds
were prepared from lactams and o-bromoaniline. An alternative
route consisted of cyclization of amidines of type 1 (Scheme 1,
X¼Br).
Table 2
Preparation of amidines 1
Amidine
R1, R2
R3
Method
Yield, %
1a
1b
1c
1d
1e
1f
1g
1h
1i
e(CH2)3e
e(CH2)4e
e(CH2)5e
e(CH2)6e
o-C6H4e(CH2)2e
o-C6H4e(CH2)3e
Me, Me
H
H
H
H
H
H
H
H
H
F
F
F
F
F
F
F
A
A
A
A
B
B
B
B
B
A
A
A
A
B
B
B
93
80
72
93
94
71
83
80
70
80
54
65
58
79
83
83
Et, Me
Ph, Me
1k
1l
e(CH2)3e
e(CH2)4e
e(CH2)5e
e(CH2)6e
Me, Me
1m
1n
1o
1p
1r
2. Results and discussion
The reaction of lactams with o-bromoaniline was carried out as
described by Buchwald et al.17 in boiling toluene in the presence of
5 mol % CuI, 10 mol % DMEDA, and 2 mol % K2SP3 (Table 1). 1H NMR
and LC/MS analyses of crude reaction products revealed that in the
case of n¼2e4 the yields of benzimidazoles 2 were in the range
7e19%. At the same time no N-arylated intermediates 4 were
detected. In the case of V¼1 the crude product contained ca. 50% of
1-(2-aminophenyl)pyrrolidine-2-one 4. All attempts at the cycli-
zation of the latter compound into the corresponding benzimid-
azole under the given conditions were unsuccessful. Variation of
solvents, temperature, and reagents (e.g., the use of o-iodoaniline
instead of o-bromoaniline) did not influence the yields of benz-
imidazoles 2.
Et, Me
Ph, Me
Reaction conditions: Method A: 2 mol amide, 1 mol o-bromoaniline, 1 mol POCl3 in
toluene. Method B: 1 mol o-bromoaniline, 1.07 mol amide, 1.17 mol PCl5 in benzene.
As shown previously, this is due to the presence of reversible Z,E-
isomerization about the exocyclic C]N bond in amidines.18 The
assignment of the signals of the isomers is easily accomplished by
the different shielding of the 3-CH2 group. In the 19F NMR spectra of
amidines 1ker the ratio of Z/E isomers is rather evident and well
correlated with 1H NMR spectra.
To find the most suited procedure for the catalytic cyclo-
condensation of amidines 1 we have carried out a condition in-
volved solvent, base, and the copper(I) ligand. Our tests were
performed on model cyclization amidine 1a into benzimidazole 2a.
Copper(I) iodide was choused among other copper catalysts (e.g.,
Cu2O, CuCl) through its air stability and ample availability. Aceto-
nitrile was found to be a good solvent for the reaction; the reaction
rate in toluene or dioxane was considerably slower, whereas the
use of DMF complicated the product isolation. In contrast to
1,10-phenanthroline and proline, the use of DMEDA as a chelating
ligand resulted in nearly quantitative conversions (Table 3, entries
8, 12, and 13). Potassium carbonate was used as a base to promote
the arylation reaction resulting in better yields compared with
those obtained with cesium carbonate, sodium hydrogen carbon-
ate, and potassium fluoride on aluminum oxide. High conversions
were also observed in the case of sodium hydride in DMF. The
latter system was not used further because of the above solvent
limitation.
We have found that the CuI-promoted cyclocondensation of 1a
proceeds smoothly in refluxing acetonitrile in the presence of po-
tassium carbonate and 10 mol % of DMEDA as the base and the
copper complexing ligand, respectively. Under given conditions the
conversion of 1a to 2a was complete within 1 h.
The ease of the copper-catalyzed cyclocondensation of 1a can
possibly be explained by the presence of the aliphatic chain in its
ring. Further investigation revealed that cyclization of 1b bearing
six-membered saturated ring went identical to the amidine 1a.
Next expansion of the amidine ring slows down the cyclization
rate. For example, the conversion of 1c and 1d to the corresponding
benzimidazoles was complete only after 4 h. Cyclization of six-
membered cyclic compound 1b and its benzannulated analog 1e
did not reveal any differences in their reactivity under the given
reaction conditions. However, this was not the case with seven-
membered analogous amidines 1c and 1f. The latter amidine
Table 1
Copper-catalyzed reaction of lactams with o-bromoanilinea
n
Conversionb GS/MS, %
Product 4
Product 2
1
2
3
4
47.1
d
d
18.7
17.0
7.4
d
d
a
Reaction conditions: 1 mol lactam, 1 mol o-bromoaniline, 10 mol % DMEDA,
5 mol % CuI, toluene, stirring and reflux, 16 h.
b
Conversion given as an average of three independent measurements.
The unsatisfactory yields of bezimidazoles in this reaction
prompted us to search for an alternative synthetic approach to the
title compounds. As a promising option we suggested an intra-
molecular cyclization of o-bromoarylamidines 1. The literature
analysis showed that a metal-mediated intramolecular N-arylation
proceeded under milder conditions and with higher yields com-
pared to an intermolecular N-arylation.17
Starting amidines 1aer were synthesized from o-bromoaniline
and appropriate amides in the presence of POCl3 (for compounds
1aed, ken) or PCl5 (for compounds 1eei, oer) (Table 2). In the 1H
NMR spectra of cyclic amidines 1aed, ken there are two sets of
signals whose ratio depends on the size of the saturated ring, the
presence of substituents in the aromatic ring and the solvent.

K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
2995
Table 3
Optimization of the copper-catalyzed cyclizationa
Table 4
Reaction time and yields of cyclocondensations of amidines 1 to benzimidazoles 2
Entry
Ligand
Base
Solvent
Conversionb (%)
1
2
3
4
4
5
6
7
8
9
10
11
12
13
No ligand
No ligand
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
K2CO3
NaH
KOH
Acetonitrile
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
Toluene
DMF
DMF
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
16
25
d
Amidine
Timea
1
h
Benzimidazole
Yieldb
93
%
K2CO3
K2CO3
K2CO3
K2CO3
NaH
K2CO3
Cs2CO3
NaHCO3
KF/Al2O3
K2CO3
K2CO3
12
7
a
50c
95
99
>99
72
59
79
68
55
1
4
4
96
91
94
b
c
L-Proline
1,10-Phenanthroline
a
Reaction conditions: 1 mol amidine, 0.05 mol CuI, 0.1 mol ligand, 2 mol base,
stirring, 80 ꢀC, 1 h.
b
The conversion was measured by LC/MS analysis of the crude product. The value
is an average of three independent measurements.
c
Heating temperature 110 ꢀC.
d
reacted as fast as compounds 1a,b,e (Table 4) showing that the
presence of the annulated benzene ring enhances the reactivity.
Acetamidines 1gei reacted considerably slower than their cyclic
congeners. For example, acetamidines 1g,h bearing alkyl groups at
their nitrogen atoms underwent complete conversion to the cor-
responding benzimidazoles after 6 h of refluxing in acetonitrile.
Interestingly, non-cyclic amidine 1i with two aromatic groups on
its nitrogen atoms reacted within 2 h. Most likely, the latter case is
similar to that of compound 1f in which the presence of aromatic
substituent at its nitrogen atom increases the reactivity. Finally, the
presence of heteroaromatic unit in amidine 1j make it least re-
active compound among 1aej. Nevertheless, pyrido[1,2-a]benz-
imidazole 2j was isolated after 24 h in a yield of 98%. This
constitutes a considerable improvement compared with the pub-
lished preparation of 2j via Pd-catalyzed cyclization of 1j (59% after
67 h).19
1
1
90
93
e
f
Amidines 1ker having in their structures aromatic rings with
both bromine and fluorine functional groups give an interesting
opportunity to investigate the selectivity of the cyclocondensation
under different conditions. It was expected that, depending on the
reaction conditions, these compounds would undergo either an
intramolecular SNAr substitution reaction (CeF bond) or copper-
catalyzed N-arylation (CeBr bond). The data collected in Table 4
show that carrying out the copper-catalyzed reaction (Method A)
resulted in a clean substitution of the bromine yielding benz-
imidazoles 2ker. LC/MS analysis of the latter benzimidazoles did
not reveal any byproducts of the fluorine substitution under given
conditions. Refluxing compounds 1ker in DMF in the presence of
potassium carbonate (Table 5, Method B) gave rise to benzimid-
azoles 3ler. LC/MS and 19F NMR analysis of the latter compounds
showed a selective substitution of the fluorine in the aromatic
ring.
Cyclocondensations of amidines 1o and 1p bearing alkyl sub-
stituents proceeded similarly to those of 1ker but required more
time to yield benzimidazoles 2o,p and 3o,p under conditions of
Method A and Method B, respectively (Table 5).
However, Method B failed in the case of preparation of benz-
imidazole 3k from 1k. This seem to take place due to an excessive
steric load in the transition state (Meisenheimer-type sigma com-
plex) of the intramolecular arylation. Given the different reaction
6
6
95
92
g
h
i
2
96
98
24
j
a
Time required for complete conversion. The conversion was estimated by LC/MS
analysis of the reaction mixture. The value is an average of three independent
measurements.
b
Isolated yields are given.

2996
K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
Table 5
AVANCE spectrometer at 500 MHz and Varian VXR-300 spec-
trometer at 300 MHz. 13C NMR spectra were recorded on the
Bruker AVANCE spectrometer at 125 MHz. 19F NMR spectra
were recorded on Varian VXR-300 spectrometer at 282 MHz.
Chemical shifts are reported in parts per million downfield from
TMS or C6F6 as internal standard. Coupling constant values were
extracted assuming first-order coupling. The multiplicities are
abbreviated as follows: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad. LC/MS spectra were recorded using
chromatography/mass spectrometric system that consists of high-
performance liquid chromatograph ‘Agilent 1100 Series’ equipped
with diode-matrix and mass-selective detector ‘Aligent LC/MSD
SL’. The parameters of chromatographyemass analysis: Column:
Zorbax SB-C18, 1.8 mm.4.6 mm.15 mm. Solvents: A acetonitrile/
water (95:5), 0.1% TFA, B water (0.1% of TFA). Eluent flow: 3 mL/s.
The volume of injected sample: 1 mL. UV-detectors operate at 215,
254, and 265 nm. Ionization method: chemical ionization under
atmospheric pressure (APCI). Ionization mode: simultaneous
scanning of positive and negative ions in the mass range of m/z
80e1000. IR spectra were recorded on PerkineElmer FTIR spec-
trometer. All values are given as cmꢁ1. The Microanalytical Labo-
ratory of Institute of Organic Chemistry of NASU produced
quantitative analysis. All values are given as percentages.
Synthesis of benzimidazoles 2,3 with selective F or Br substitution in amidines 1a
Amidine
R1, R2
Method A product
Method B product
2 yields, %
3 yields, %
1k
1l
e(CH2)3e
e(CH2)4e
e(CH2)5e
e(CH2)6e
Me, Me
87
88
83
95
89
87
91
d
85
87
92
91b
89b
95
1m
1n
1o
1p
1r
Et, Me
Ph, Me
a
MethodA:CuI, DMEDA, K2CO3, CH3CN, reflux4 h. Method B:DMF, K2CO3, reflux, 4 h.
The reaction time was 24 h.
b
4.3. General procedure for amidines 1aed, 1ken
mechanism, the use of Method A on 1k successfully affords the
cyclization product 2k.
Amide (25 mmol) was dissolved in dry toluene (100 mL) and
POCl3 (1.93 g, 12.5 mmol) was added dropwise at 0 ꢀC. The reaction
solution was kept at the ice-bath with stirring for 2 h. After that
aniline (12.5 mmol) was added in one portion and the result mix-
ture was refluxed under stirring for 4 h. The organic layer was re-
moved and the residue was dissolved in 50 mL of water. The
mixture was stirred with coal for 30 min and after filtration 2 M
NaOH was added to a pH¼10. Precipitate was filtered, dried, and
crystallized from a mixture of EtOAc/hexane (1:1).
The present results show that in spite of the high selectivity of
the amidine cyclization by either SNAr-mechanism (Method B) or
copper-catalyzed coupling (Method A), there are at least two main
factors favoring the ring closure. First, the presence of a saturated
ring in amidines seems to stabilize transition states in both cases
(with the exception of 1k in Method B). The second factor is the
increased acidity of arylamidines. The deprotonated arylamidines
react as efficient N-anionic nucleophiles that is reflected in high
cyclization rates.
4.3.1. 2-Bromo-N-[pyrrolidin-2-ylidene]aniline
from hexane; yield 2.76 g (93%); mp 143e144 ꢀC; 1H NMR
(500 MHz, CDCl3):
(1a). Crystallized
3. Conclusions
d
7.54 (d, J¼7.3 Hz, 1H), 7.23e7.00 (m, 2H), 6.89
(t, J¼7.1 Hz, 1H), 6.56e5.77 and 4.90e4.26 (br, 1H), 3.71e3.26 (br,
2H), 2.83e2.22 (m, 2H), 2.15e1.95 (m, 2H). IR (KBr) nmax: 2923,1631,
1578, 1255, 1225. Anal. Calcd for C10H11BrN2: C 50.23; H 4.64; N
11.72. Found C 50.28; H 4.68; N 11.69.
We have described an efficient synthetic approach to structur-
ally diverse annulated benzimidazoles. The method consists of
intramolecular copper-catalyzed N-arylation of readily available
cyclic amidines. The reaction occurs under mild conditions with
nearly quantitative yields. The described method can also be
employed in the synthesis of 1,2-disubstituted benzimidazoles.
4.3.2. 2-Bromo-N-[piperidin-2-ylidene]aniline (1b). Yield 1.89
(60%); mp 75e77 ꢀC; 1H NMR (500 MHz, CDCl3):
g
d
7.53 (d, J¼7.0 Hz,
1H), 7.25e7.14 (m, 1H), 7.03e6.88 (m, 1H), 6.84 (t, J¼7.0 Hz, 2H),
5.91e5.00(br, NH(E)) and 4.56e4.30 (br, 1H, NH(Z)), 3.40e3.08 (s,
2H), 2.70e2.01 (m, 2H), 1.92e1.58 (m, 4H). IR (KBr) nmax: 2946,
1633, 1576, 1472,1218. Anal. Calcd for C11H13BrN2: C 52.19; H 5.18; N
11.07. Found C 52.22; H 5.21; N 11.05.
4. Experimental section
4.1. General methods
Commercial reagents of high purity were purchased from ei-
ther Aldrich or Acros and used without further purification. 1,4-
Dioxane, dimethylformamide (DMF), and acetonitrile (CH3CN)
were freshly distilled and dried by standard methods. All solvents
for crystallization and flash-column chromatography were used
without additional purification. Reactions were monitored by
thin layer chromatography (TLC) carried out on 0.25 mm Merck
silica gel plates (60 F254) using UV light as a visualizing agent.
Merck silica gel 60 (230e400 mesh) was used for flash-column
chromatography.
4.3.3. N-[-Azepan-2-ylidene]-2-bromoaniline (1c). Yield 2.40
g
(72%); mp 106e107 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.55 (d,
J¼7.8 Hz, 1H), 7.23 (t, J¼7.3 Hz, 1H), 6.95e6.72 (m, 2H), 5.66e5.50
(m, NH(E)) and 4.67e4.50 (m, 1H, NH(Z)), 3.35e3.22 (m, NCH2(E))
and 3.22e3.05 (m, 2H, NCH2(Z)), 2.68e2.54 (m, CCH2(Z)) and
2.32e2.18 (m, 2H, CCH2(E)), 2.09e1.92 (m) and 1.92e1.80 (m, 2H),
1.80e1.66 (m, 2H), 1.66e1.46 (m, 2H). IR (KBr) nmax: 2932, 1635,
1576, 1218. Anal. Calcd for C12H15BrN2: C 53.95; H 5.66; N 10.49.
Found C 53.91; H 5.63; N 10.52.
4.2. Instrumentation
4.3.4. N-[2-Azocan-2-ylidene]-2-bromoaniline (1d). Yield 3.26
g
(93%); mp 125e126 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.56 (d,
Melting points were determined using a Fisher-Jones melting
point apparatus. 1H NMR spectra were recorded on the Bruker
J¼8.1 Hz, 1H), 7.23 (t, J¼7.8 Hz, 1H), 6.92e6.77 (m, 2H), 5.66e5.19
(br, NH(E)) and 4.38e4.20 (br, 1H, NH (Z)), 3.44e3.32 (m,

K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
2997
NCH2(E)) and 3.32e3.18 (m, 2H, NCH2 (Z)), 2.62e2.47 (m,
CCH2(Z)) and 2.38e2.21 (m, 2H, CCH2(E)), 2.00e1.85 (br, 2H),
1.71e1.54 (m, 4H), 1.54e1.38 (m, 2H). IR (KBr) nmax: 1632, 1577,
1218. Anal. Calcd for C13H17BrN2: C 55.53; H 6.09; N 9.96. Found C
55.52; H 6.08; N 9.96.
(d, J¼8.1 Hz, 1H), 2.99 (t, J¼8.1 Hz, 1H), 2.91e2.80 (m, 2H), 2.46 (t,
J¼7.3 Hz, 1H). IR (KBr) nmax: 1657, 1384, 1253, 1228, 753. Anal. Calcd
for C15H13BrN2: C 59.82; H 4.35; N 9.30. Found C 59.86; H 4.32;
N 9.28.
4.4.2. 2-Bromo-N-[1,3,4,5-tetrahydro-2H-1-benzazepin-2-ylidene]
4.3.5. (2-Bromo-4,6-difluorophenyl)-pyrrolidin-2-ylideneamine
(1k). Yield 2.75 g (80%); mp 114e115 ꢀC; 1H NMR (500 MHz,
aniline (1f). Yield 3.34 g (71%); mp 124e125 ꢀC; 1H NMR (500 MHz,
CDCl3):
d
7.62 (d, J¼8.2 Hz) and 7.56 (d, J¼8.1 Hz, 1H), 7.35e7.25 (m,
CDCl3):
d
7.17e7.03 (m, 1H), 6.87e6.72 (m, 1H), 6.14e6.00 (m,
1H), 7.25e7.11 (m, 2H), 7.11e6.85 (m, 3H), 6.76 (d, J¼8.1 Hz) and
6.10e5.86 (m, 1H), 2.91 (t, J¼7.1 Hz, 1H), 2.84e2.70 (m, 1H), 2.53 (t,
J¼6.8 Hz, 1H), 2.33e2.09 (m, 3H). IR (KBr) nmax: 1640, 1576, 1383,
1262. Anal. Calcd for C16H15BrN2: C 60.97; H 4.80; N 8.89. Found C
60.96; H 4.82; N. 8.85.
NH(E)) and 4.68e4.54 (m, 1H, NH(Z)), 3.53e3.35 (2H, m, NCH2),
2.70 (t, J¼7.5 Hz, 1H), 2.21e2.00 (m, 3H). 19F NMR (282 MHz, CDCl3,
C6F6):
d
ꢁ118.5 (d, J¼10.1 Hz), ꢁ119.4 (m), ꢁ119.7 (d, J¼8.1 Hz),
ꢁ120.0 (m). IR (KBr) nmax: 2853, 1650, 1579, 1220. Anal. Calcd for
C10H9BrF2N2: C 43.66; H 3.30; N 10.18. Found C 43.67; H 3.28; N
10.20.
4.4.3. N0-(2-Bromophenyl)-N-methylethanimidamide
2.83 g (83%); mp 35e37 ꢀC; 1H NMR (500 MHz, CDCl3):
J¼7.8 Hz, 1H), 7.18 (t, J¼7.6 Hz, 1H), 6.82 (t, J¼8.1 Hz, 2H), 4.51 (s,
1H), 2.95 (s, 3H), 1.71 (s, 3H). 13C NMR (125 MHz, CDCl3):
157.2,
150.2, 132.6, 127.9, 123.7, 123.1, 117.6, 28.5, 17.9. IR (KBr) nmax:
(1g). Yield
7.51 (d,
d
4.3.6. (2-Bromo-4,6-difluorophenyl)-piperidin-2-ylideneamine
(1l). Yield 1.95 g (54%); mp 109e110 ꢀC; 1H NMR (500 MHz, CDCl3):
d
d
7.21e7.03 (m, 1H), 6.90e6.70 (m, 1H), 6.10e5.71 (m, NH(E)) and
4.67e4.38 (m, 1H, NH(Z)), 3.42e3.27 (m, NCH2(E)) and 3.27e3.10
1623, 1560, 1466, 1234. Anal. Calcd for C9H11BrN2: C 47.60; H 4.88;
N 12.33. Found C 47.61; H 4.87; N 12.35.
(m, 2H, NCH2 (Z)), 2.74e2.49 (m, 1H), 2.30e1.61 (m, 6H); 19F NMR
(282 MHz, CDCl3, C6F6):
d
ꢁ118.4 (d, J¼8.2 Hz), ꢁ119.3, ꢁ119.4 (d,
J¼10.0 Hz), ꢁ120.3. IR (KBr) nmax: 2932, 1636, 1576, 1508, 1271, 1211.
Anal. Calcd for C11H11BrF2N2: C 45.70; H 3.83; N 9.69. Found C
45.71; H 3.85; N 9.71.
4.4.4. N0-(2-Bromophenyl)-N-ethylethanimidamide
2.89 g (80%); mp 38e40 ꢀC; 1H NMR (500 MHz, CDCl3):
(1h). Yield
7.51 (d,
d
J¼7.8 Hz, 1H), 7.18 (t, J¼7.3 Hz, 1H), 6.90e6.73 (m, 2H), 4.51e4.26
(br, NH(E)) and 4.20e3.97 (br, 1H, NH(Z)), 3.48e3.33 (m, (E)) and
3.26e3.08 (m, 2H, CH2(Z)), 1.80e1.65 (s, 3H), 1.26 (t, J¼7.3 Hz, (E))
4.3.7. N-[-Azepan-2-ylidene]-2-bromo-4,6-difluoroaniline
(1m). Yield 2.46 g (65%); mp 92e94 ꢀC; 1H NMR (500 MHz, CDCl3):
and 1.17e1.04 (m, 3H, (Z)). 13C NMR (125 MHz, CDCl3):
d 156.1,150.3,
d
7.18e7.03 (m, 1H), 6.88e6.70 (m, 1H), 5.87e5.68 (m, NH(E)) and
132.5, 127.8, 123.6, 123.0, 117.7, 36.2, 18.1, 14.7. IR (KBr) nmax: 1620,
1570. Anal. Calcd for C10H13BrN2: C 49.81; H 5.43; N 11.62. Found C
49.85; H 5.40; N 11.65.
4.77e4.52 (m, 1H, NH(Z)), 3.29e3.24 (m, NCH2(E)) and 3.24e3.17
(m, 2H, NCH2(Z)), 2.68e2.52 (m, CCH2(Z)) and 2.23e2.12 (m, 2H,
CCH2(E)), 1.90e1.59 (m, 6H). 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ118.64, ꢁ119,12, ꢁ119.4, ꢁ120.12. IR (KBr) nmax: 2853, 1600, 1211.
4.4.5. N0-(2-Bromophenyl)-N-phenylethanimidamide
3.03 g (70%); mp 110e112 ꢀC; 1H NMR (500 MHz, CDCl3):
(1i). Yield
7.58 (d,
Anal. Calcd for C12H13BrF2N2: C 47.55; H 4.32; N 9.24. Found C 47.52;
H 4.30; N 9.26.
d
J¼8.0 Hz, 2H), 7.41e7.31 (m, 3H), 7.31e7.22 (m, 1H), 7.14e7.03 (m,
1H), 7.03e6.80 (m, 1H), 6.80e6.30 (br, 1H), 2.36e2.10 (s) and
2.10e1.80 (s, 3H, CH3). IR (KBr) nmax: 2923, 1546, 1218. Anal. Calcd
for C14H13BrN2: C 58.15; H 4.53; N 9.69. Found C 58.17; H 4.50;
N 9.68.
4.3.8. N-[-Azocan-2-ylidene]-2-bromo-4,6-difluoroaniline
(1n). Yield 2.29 g (58%); mp 116e117 ꢀC; 1H NMR (300 MHz,
CDCl3):
d 7.23e7.08 (m, 1H), 6.91e6.72 (m, 1H), 5.65e5.50 (br,
NH(E)) and 4.44e4.24 (br, 1H, NH(Z)), 3.43e3.25 (m, 2H),
2.66e2.17 (m, 2H), 2.01e1.87 (m, 1H), 1.75e1.42 (m, 7H). 19F NMR
4.4.6. N0-(2-Bromo-4,6-difluorophenyl)-N-methylacetimidamide
(1o). Yield 3.11 g (79%); mp 83e85 ꢀC; 1H NMR (500 MHz, CDCl3):
(282 MHz, CDCl3, C6F6):
d
ꢁ118.3 (d, J¼8.1 Hz), ꢁ120.4 (m), ꢁ119.4
(m). IR (KBr) nmax: 2853, 1633, 1579, 1244, 1200. Anal. Calcd for
C13H15BrF2N2: C 49.23; H 4.77; N 8.83. Found C 49.26; H 4.80;
N 8.79.
d
7.12 (dt, J¼2.8, 7.9 Hz, 1H), 6.81 (dt, J¼2.7, 9.0 Hz, 1H), 4.69 (br,
1H), 2.97 (d, J¼4.4 Hz, 3H), 1.72 (s, 3H). 13C NMR (125 MHz,
CDCl3):
d
159.2, 157.2 (dd, J¼12.8, 245.0 Hz), 154.1 (dd, J¼12.4,
245.5 Hz), 135.4 (d, J¼15.9 Hz), 118.5 (dd, J¼3.1, 12.4 Hz), 115.0 (dd,
4.4. General procedure for amidines 1eei, 1oer
J¼3.1, 24.3 Hz), 103.5 (t, J¼26.1 Hz), 28.5, 18.3. 19F NMR (282 MHz,
CDCl3, C6F6):
d
ꢁ117.8 (m), ꢁ118.4 (m), ꢁ120.0 (d, J¼8.1 Hz),
To solution PCl5 (0.0165 mol) in 100 mL of dry benzene was
added 0.015 mol amide at ꢁ5 ꢀC. The solution was stirred for 15 min
and 0.014 mol aniline was added at the same temperature. The
result mixture was stirred for 20 min at the room temperature and
then stirred and refluxed for 4 h. The separation procedure was
different in each case: (i) for oily reaction mixture the solvent was
removed under reduced pressure. (ii) The precipitate was filtered
where it was possible. In any case the residue was dissolved in
75 mL water. Then 5 M NaOH was added to pH¼10. The formed oil
was solidified during 1e4 h and precipitate was filtered. The
product was purified by crystallization from a mixture of EtOAc/
hexane (1:1).
ꢁ120.3 (m). IR (KBr) nmax: 1619, 1574, 1472, 1223. Anal. Calcd for
C9H9BrF2N2: C 41.09; H 3.45; N 10.65. Found C 41.11; H 3.47;
N 10.69.
4.4.7. N0-(2-Bromo-4,6-difluorophenyl)-N-ethylacetimidamide
(1p). Yield 3.44 g (83%); mp 80e81 ꢀC; 1H NMR (500 MHz,
CDCl3):
d
7.13 (dt, J¼2.8, 7.9 Hz, 1H), 6.81 (dt, J¼2.8, 8.6 Hz, 1H),
4.61 (br, 1H), 3.44 (m, 2H), 1.71 (s, 3H), 1.26 (t, J¼7.6 Hz, 3H). 13C
NMR (125 MHz, CDCl3):
d
158.0, 156.8 (dd, J¼12.4, 245.0 Hz), 154.1
(dd, J¼12.8, 245.9 Hz), 135.4 (dd, J¼15.9 Hz), 118.6 (dd, J¼3.5,
12.4 Hz), 115.0 (dd, J¼3.5, 24.3 Hz), 103.4 (t, J¼25.8 Hz), 36.4, 18.5,
14.5. 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ120.1 (d, J¼8.1 Hz),
ꢁ120.4. IR (KBr) nmax: 2969, 1616, 1217, 836. Anal. Calcd for
C10H11BrF2N2: C 43.34; H 4.00; N 10.11. Found C 43.35; H 3.98;
N 10.13.
4.4.1. 2-Bromo-N-[3,4-dihydroquinolin-2(1H)-ylidene]aniline
(1e). Yield 4.24 g (94%); mp 138e140 ꢀC; 1H NMR (500 MHz,
CDCl3):
d
8.43e7.95 and 6.44e6.32 (br, 1H, NH), 7.63 (d, J¼8.3 Hz)
and 7.58 (d, J¼7.8 Hz 1H), 7.34e7.26 (m, 1H), 7.14 (d, J¼7.3 Hz, 1H),
7.08 (d, J¼7.1 Hz, 1H), 7.00e6.85 (m, 3H), 6.66 (d, J¼6.5 Hz) and 6.54
4.4.8. N0-(2-Bromo-4,6-difluorophenyl)-N-phenylacetimidamide
(1r). After the general procedure the precipitate was filtered and

2998
K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
75 mL of water was added to it. A large excess of 5 M NaOH was
added to the mixture. The resulting mixture was stirred for 4 h and
filtered. After crystallization from hexane a white solid was iso-
lated; yield 4.03 g (83%); mp 182e183 ꢀC; 1H NMR (500 MHz,
110.0, 30.2, 30.0, 25.2. IR (KBr) nmax: 1602, 1583, 1452, 1248.
Anal. Calcd for C16H14N2: C 82.02; H 6.02; N 11.96. Found C 82.04;
H 6.00; N 11.96.
DMSO-d6):
d
9.31 (s, 1H, NH), 7.80 (d, J¼8.1 Hz, 2H), 7.46 (d,
4.5.7. 1,2-Dimethyl-1H-benzo[d]imidazole (2g). Yield 116 mg (95%);
mp 104e105 ꢀC (lit.21 101e103 ꢀC). The spectroscopic data were
identical to the reported.21
J¼8.8 Hz, 1H), 7.39e7.29 (m, 1H), 7.31 (t, J¼7.8 Hz, 2H), 6.99 (t,
J¼7.6 Hz, 1H), 1.84 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
d 156.9
(dd, J¼13.3, 243.2 Hz), 156.8, 153.4 (dd, J¼13.7, 245.0 Hz), 152.5,
140.8, 136.5 (dd, J¼4.0, 15.5 Hz), 122.7, 120.3, 117.8 (dd, J¼4.0,
12.4 Hz), 115.6 (dd, J¼4.0, 24.8 Hz), 104.6, 104.4, 104.2, 19.1. 19F NMR
4.5.8. 1-Ethyl-2-methyl-1H-benzo[d]imidazole (2h). Yield 123 mg
(92%); oil. The spectroscopic data were identical to the reported.22
(282 MHz, DMSO-d6, C6F6):
d
ꢁ119.4. IR (KBr) nmax: 1607, 1588,
1468, 1207. Anal. Calcd for C14H11BrF2N2: C 51.71; H 3.41; N 8.62.
Found C 51.71; H 3.42; N 8.61.
4.5.9. 2-Methyl-1-phenyl-1H-benzo[d]imidazole (2i). Yield 167 mg
(96%); mp 47e48 ꢀC (lit.21 46e48 ꢀC). The spectroscopic data were
identical to the reported.21
4.4.9. 2-(2-Bromoimino)pyridine (1j). Compound 1j was obtained
from 2-iminopyridine and 1-bromo-2-iodobenzene according to
published procedure.19
4.5.10. Pyrido[1,2-a]benzimidazole (2j). For the purification the
crude pyrido[1,2-a]benzimidazole was dissolved in 5 mL of MeOH
and 1 mL of concentrated HCl was added. The solvent was evaporated
to dryness and the solid was triturated with acetone. The precipitate
was filtered and dissolved in water. 1 N NaOH was added to adjust to
pH¼10. The mixture was extracted by 50 mL Et2O twice, dried over
Na2SO4, and evaporated. Yield 138 mg (98%); mp 179e180 ꢀC (lit.19
4.5. General procedure for copper-catalyzed amidines
cyclization
To a solution 0.84 mmol of amidine in 5 mL dry acetonitrile
were added powdered 234 mg (0.84 mmol) K2CO3, 0.72 mg
179e182 ꢀC); 1H NMR (500 MHz, CDCl3):
d
8.44 (d, J¼6.8 Hz, 1H),
(0.084 mmol) DMEDA, and
8
mg (0.042 mmol) powdered
7.93 (d, J¼8.1 Hz,1H), 7.88 (d, J¼8.3 Hz,1H), 7.68 (d, J¼9.4 Hz,1H), 7.53
(t, J¼7.5 Hz, 1H), 7.42 (t, J¼7.5 Hz, 1H), 7.36 (t, J¼7.7 Hz, 1H), 6.84 (t,
CuI. The result mixture was stirred and refluxed for 4 h under
Ar atmosphere. After cooling 5 mL of CH2Cl2 was added and
solution was filtered and solvent was evaporated. The residue
was purified by flash-column chromatography (CH2Cl2/
MeOH¼1:9).
J¼6.7 Hz,1H); 13C NMR (125 MHz, CDCl3):
d 148.5,144.5,129.3,128.7,
125.7,121.0,119.9,118.0,110.4,110.3. Anal. Calcd for C11H8N2: C 78.55;
H 4.79; N 16.66. Found C 78.53; H 4.80; N 16.67.
4.5.11. 5,7-Difluoro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole
(2k). Yield 141 mg (87%); mp 103e105 ꢀC; 1H NMR (300 MHz,
4.5.1. 2,3-Dihydro-1H-pyrrolo[1,2-a]benzimidazole
(2a). Yield
123 mg (93%); mp 106e107 ꢀC (lit.20 105e107 ꢀC). The spectro-
CDCl3):
d
6.80 (dd, J¼2.2, 8 Hz, 1H), 6.72 (dt, J¼2.2, 10.3 Hz, 1H), 4.08
scopic data were identical to the reported.20
(t, J¼7.1 Hz, 2H), 3.06 (t, J¼7.6 Hz, 2H), 2.85e2.45 (m, 2H). 13C NMR
(125 MHz, CDCl3):
d
162.01, 158.4 (dd, J¼11.0, 240.6 Hz), 152.6 (dd,
4.5.2. 1,2,3,4-Tetrahydropyrido[1,2-a]benzimidazole
(2b). Yield
J¼15.0, 253.9 Hz), 134.1, 133.5, 97.2 (dd, J¼22.7, 28.7 Hz), 92.7 (dd,
138 mg (96%); mp 98e101 ꢀC (lit.20 99e100 ꢀC). The spectroscopic
J¼4.4, 27.4 Hz), 42.9, 26.2, 23.4. 19F NMR (282 MHz, CDCl3, C6F6):
data were identical to the reported.20
d
ꢁ118.8 (m), ꢁ126.12 (d, J¼10.1 Hz). IR (KBr) nmax: 2853, 1745, 1590,
1447. Anal. Calcd for C10H8F2N2: C 61.85; H 4.15; N 14.43. Found C
61.83; H 4.13; N 14.42.
4.5.3. 7,8,9,10-Tetrahydro-6H-azepino[1,2-a]benzimidazole
(2c). Yield 142 mg (91%); mp 123e125 ꢀC (lit.20 124e125 ꢀC). The
spectroscopic data were identical to the reported.20
4.5.12. 6,8-Difluoro-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole
(2l). Yield 153 mg (88%); mp 111e112 ꢀC; 1H NMR (300 MHz,
4.5.4. 6,7,8,9,10,11-Hexahydroazocino[1,2-a]benzimidazole
CDCl3):
4.03 (t, J¼6 Hz, 2H), 3.08 (t, J¼6.4 Hz, 2H), 2.25e2.10 (m, 2H),
2.10e1.95 (m, 2H). 13C NMR (125 MHz, CDCl3):
d
6.79 (dd, J¼2.2, 8.2 Hz, 1H), 6.72 (dd, J¼2.2, 10.9 Hz, 1H),
(2d). Yield 157 mg (94%); mp 76e77 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.71 (m, 1H), 7.26 (m, 1H), 7.22 (m, 2H), 4.23 (m, 2H), 3.02 (m, 2H),
1.91 (m, 2H), 1.83 (m, 2H), 1.49 (m, 2H), 1.24 (m, 2H). 13C NMR
(125 MHz, CDCl3): 156.6, 142.9, 134.5, 121.9, 121.8, 119.2, 109.0,
d
158.5 (dd, J¼11.1,
240.6 Hz), 152.6 (dd, J¼14.2, 253.9 Hz), 152.5, 136.7 (dd, J¼10.2,
14.2 Hz), 127.7 (d, J¼15.9 Hz), 97.6 (dd, J¼22.1, 28.7 Hz), 91.9 (dd,
J¼4.4, 27.4 Hz), 42.9, 25.4, 22.4, 20.5. 19F NMR (282 MHz, CDCl3,
d
41.5, 31.1, 29.7, 27.1, 25.6, 24.0. IR (KBr) nmax: 2927, 1507, 1459, 1446,
1255. Anal. Calcd for C13H16N2: C 77.96; H 8.05; N 13.99. Found C
77.97; H 8.00; N 14.03.
C6F6):
d
ꢁ118.8 (m), ꢁ126.8 (m). IR (KBr) nmax: 1637, 1223, 1118.
Anal. Calcd for C11H10F2N2: C 63.45; H 4.84; N 13.45. Found C 63.46;
H 4.82; N 13.46.
4.5.5. 5,6-Dihydrobenzimidazo[1,2-a]quinoline (2e). Yield 166 mg
(90%); yellow oil; 1H NMR (500 MHz, CDCl3):
d
7.95e7.76 (m, 3H),
4.5.13. 2,4-Difluoro-7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimid-
azole (2m). Yield 154 mg (83%); mp 128e129 ꢀC; 1H NMR
7.48e7.15 (m, 5H), 3.26 (t, J¼7.5 Hz, 2H), 3.05 (t, J¼7.8 Hz, 2H). 13C
NMR (125 MHz, CDCl3):
d
152.8, 143.6, 135.7, 131.9, 129.1, 128.6,
(300 MHz, CDCl3):
11.2 Hz, 1H), 4.15e4.00 (m, 2H), 3.15e3.00 (m, 2H), 2.12e1.90 (m,
2H), 1.90e1.70 (m, 4H). 13C NMR (125 MHz, CDCl3):
158.7 (dd,
d
6.77 (dd, J¼2.0, 8.6 Hz, 1H), 6.71 (dt, J¼2.2,
127.9, 125.2, 123.2, 122.9, 119.9, 116.6, 111.3, 26.5, 24.6. Anal. Calcd
for C15H12N2: C 81.79; H 5.49; N 12.72. Found C 81.78; H 5.52; N
12.70.
d
J¼11.1, 240.2 Hz), 158.3, 152.9 (dd, J¼14.6, 254.3 Hz), 137.8 (dd,
J¼10.6 Hz), 127.4 (d, J¼16.8 Hz), 97.0 (dd, J¼21.0, 28.7 Hz), 91.9 (dd,
J¼4.4, 27.4 Hz), 45.2, 30.7, 29.9, 28.6, 25.4. 19F NMR (282 MHz,
4.5.6. 6,7-Dihydro-5H-benzimidazo[1,2-a][1]benzazepine (2f). Yield
182 mg (93%); yellow oil; 1H NMR (500 MHz, CDCl3):
d
7.79 (d,
CDCl3, C6F6):
d
ꢁ118.6 (m), ꢁ126.6 (d, J¼8.2 Hz). IR (KBr) nmax: 2853,
J¼6.8 Hz, 1H), 7.59 (d, J¼7.6 Hz, 1H), 7.50 (d, J¼8.1 Hz, 1H), 7.46 (t,
J¼7.3 Hz, 1H), 7.42 (d, J¼7.3 Hz, 1H), 7.39e7.34 (m, 1H), 7.32e7.23
(m, 2H), 3.28e3.05 (m, 2H), 2.88e2.53 (m, 3H), 2.54e2.38 (m,
1597, 1234, 1220. Anal. Calcd for C12H12F2N2: C 64.86; H 5.44; N
12.61. Found C 64.81; H 5.48; N 12.66.
1H), 2.38e2.21 (m, 1H). 13C NMR (125 MHz, CDCl3):
d
154.6,
4.5.14. 2,4-Difluoro-6,7,8,9,10,11-hexahydroazocino[1,2-a]benzimid-
azole (2n). Yield 188 mg (95%); mp 96e97 ꢀC; 1H NMR (500 MHz,
143.0, 136.1, 135.4, 130.6, 127.7, 127.6, 123.0, 122.8, 122.6, 119.6,

K. Liubchak et al. / Tetrahedron 68 (2012) 2993e3000
2999
CDCl3):
d
6.80 (d, J¼8.3 Hz, 1H), 6.73 (d, J¼10.3 Hz, 1H), 4.21 (t,
1H), 4.20e4.00 (m, 2H), 3.25e3.00 (m, 2H), 2.07e1.90 (m, 2H),
1.90e1.66 (m, 4H). 13C NMR (125 MHz, CDCl3):
158.9, 158.7 (d,
J¼5.9 Hz, 2H), 3.06e2.98 (m, 2H), 1.96e1.88 (m, 2H), 1.88e1.80 (m,
d
2H), 1.57e1.47 (m, 2H), 1.32e1.20 (m, 2H). 13C NMR (125 MHz,
J¼242.2 Hz), 137.6, 135.5 (d, J¼12.0 Hz), 113.0 (d, J¼28.3 Hz), 112.2
CDCl3):
d
158.7 (dd, J¼11.1, 240.2 Hz), 157.3 (d, J¼2.2 Hz), 153.1 (dd,
(d, J¼12.4 Hz), 95.2 (d, J¼30.0 Hz), 45.3, 30.7, 29.9, 28.6, 25.3. 19F
J¼14.6, 254.3 Hz), 136.6 (dd, J¼11.5, 14.6 Hz), 128.1 (d, J¼18.1 Hz),
97.4 (dd, J¼22.1, 28.7 Hz), 92.1 (dd, J¼4.4 Hz, 27.9 Hz), 42.0, 31.0,
NMR (282 MHz, CDCl3, C6F6):
2930,1583,1470,1212,1188. Anal. Calcd for C12H12BrFN2: C 50.90; H
4.27; N 11.72. Found C 50.88; H 4.30; N 11.69.
d
ꢁ120.0 (t, J¼8.1 Hz). IR (KBr) nmax
:
29.5, 27.1, 25.5, 23.7. 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ118.7,
ꢁ126.4. IR (KBr) nmax: 2853, 1595, 1221. Anal. Calcd for C13H14F2N2:
C 66.09; H 5.97 N 11.86. Found C 66.11; H 5.93; N 11.82.
4.6.3. 4-Bromo-2-fluoro-6,7,8,9,10,11-hexahydroazocino[1,2-a]-
benzimidazole (3n). Yield 229 mg (92%); mp 107e108 ꢀC; 1H NMR
4.5.15. 4,6-Difluoro-1,2-dimethyl-1H-benzimidazole
(2o). Yield
6.77 (d,
(500 MHz, CDCl3):
d
7.20 (d, J¼9.3 Hz, 1H), 6.93 (d, J¼8.3 Hz, 1H),
136 mg (89%); mp 77e76 ꢀC; 1H NMR (500 MHz, CDCl3):
d
4.24e4.10 (m, 2H), 3.10e2.94 (m, 2H), 1.98e1.88 (m, 2H), 1.88e1.71
J¼8.5 Hz, 1H), 6.72 (t, J¼10.0 Hz, 1H), 3.68 (s, 1H), 2.59 (s, 3H); 13C
(m, 2H), 1.57e1.45 (m, 2H), 1.33e1.15 (m, 2H). 13C NMR (125 MHz,
NMR (125 MHz, CDCl3):
d
158.6 (dd, J¼11.1, 240.4 Hz), 152.8 (dd,
CDCl3):
113.3 (d, J¼27.9 Hz), 112.3 (d, J¼11.9 Hz), 96.4 (d, J¼27.0 Hz), 45.1,
31.0, 29.5, 27.1, 25.5, 23.9. 19F NMR (282 MHz, CDCl3, C6F6):
d
158.7 (d, J¼247.2 Hz), 157.9, 138.3, 134.4 (d, J¼13.2 Hz),
J¼14.6, 254.3 Hz), 152.6, 137.9 (dd, J¼11.1, 15.4 Hz), 127.5 (d,
J¼16.8 Hz), 97.3 (dd, J¼21.7, 28.7 Hz), 92.1 (dd, J¼4.4, 27.4 Hz), 30.3,
d
ꢁ119.9.
13.8. 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ118.3, ꢁ126.6. IR (KBr)
IR (KBr) nmax: 2857, 1579, 1472, 1251. Anal. Calcd for C13H14BrFN2: C
52.54; H 4.75; N 9.43. Found C 52.52; H 4.81; N 9.41.
nmax: 2853, 1595, 1221. Anal. Calcd for C9H8F2N2: C 59.34; H 4.43; N
15.38. Found C 59.38; H 4.39; N 15.41.
4.6.4. 4-Bromo-6-fluoro-1,2-dimethyl-1H-benzimidazole (3o). The
reaction time was 24 h. Yield 208 mg (91%); mp 115e116 ꢀC; 1H
4.5.16. 1-Ethyl-4,6-difluoro-2-methyl-1H-benzimidazole (2p). Yield
143 mg (87%); mp 81e82 ꢀC; 1H NMR (500 MHz, CDCl3):
d
6.81 (d,
NMR (500 MHz, CDCl3):
d
7.20 (dd, J¼2.3, 9.4 Hz, 1H), 6.93 (dd,
J¼8.1 Hz, 1H), 6.72 (t, J¼10.0 Hz, 1H), 4.11 (q, J¼7.1 Hz, 2H), 2.61 (s,
J¼2.2, 8.3 Hz, 1H), 3.67 (s, 3H), 2.61 (s, 3H); 13C NMR (125 MHz,
3H), 1.40 (t, J¼7.6 Hz, 3H). 13C NMR (125 MHz, CDCl3):
d
158.6 (dd,
CDCl3):
d
158.8 (d, J¼243 Hz), 153.27, 153.25; 137.9, 135.6 (d,
J¼10.2, 230.4 Hz), 152.8 (dd, J¼13.7, 255.6 Hz), 152.0, 136.9 (dd,
J¼10.6, 15.5 Hz), 127.7 (d, J¼16.4 Hz), 97.3 (dd, J¼22.6, 29.2 Hz), 92.1
(d, J¼27.0 Hz), 39.1, 14.6, 13.7. 19F NMR (282 MHz, CDCl3, C6F6):
J¼14 Hz), 134.5, 113.2 (d, J¼27 Hz), 112.2 (d, J¼12 Hz), 95.4 (d,
J¼27 Hz), 30.4, 13.9; 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ119.0. IR
(KBr) nmax: 1381, 1261, 1201, 830. Anal. Calcd for C9H8BrFN2: C
d
ꢁ118.5, ꢁ126.5. IR (KBr) nmax: 3034, 1641, 1598, 1495, 1226, 1109.
44.47; H 3.32; N 11.52. Found: C 44.49; H 3.30; N 11.50.
Anal. Calcd for C10H10F2N2: C 61.22; H 5.14; N 14.28. Found C 61.25;
H 5.11; N 14.25.
4.6.5. 4-Bromo-6-fluoro-2-methyl-1-ethyl-1H-benzimidazole
(3p). The reaction time was 24 h. Yield 192 mg (89%); mp
4.5.17. 4,6-Difluoro-2-methyl-1-phenyl-1H-benzimidazole
(2r). Yield 186 mg (91%); mp 111e112 ꢀC; 1H NMR (500 MHz,
134e138 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.23 (dd, J¼2.2, 9.8 Hz,
1H), 6.98 (dd, J¼2.1, 8.6 Hz, 1H), 4.13 (q, J¼7.3 Hz, 2H), 2.66 (s, 3H),
CDCl3):
d
7.60e7.53 (m, 2H), 7.53e7.46 (m, 1H), 7.29 (d, J¼7.1 Hz,
1.42 (t, J¼7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 158.8 (d,
2H), 6.69 (t, J¼10.0 Hz, 1H), 6.56 (d, J¼7.3 Hz, 1H), 2.44 (s, 3H); 13C
J¼241.8 Hz), 152.61, 152.59, 138.0, 134.7, 134.6, 113.2 (d, J¼28 Hz),
NMR (125 MHz, CDCl3):
d
159.0 (dd, J¼10.6, 241.0 Hz), 152.6 (dd,
112.2 (d, J¼12 Hz), 95.3 (d, J¼27 Hz), 39.1, 14.7, 13.8; 19F NMR
J¼14.6, 254.8 Hz), 152.4, 138.5 (dd, J¼10.2, 15.0 Hz), 135.3, 130.1,
(282 MHz, CDCl3, C6F6):
Anal. Calcd for C10H10BrFN2: C 46.72; H 3.92; N 10.90. Found: C
46.73; H 3.95; N 10.85.
d
ꢁ118.9. IR (KBr) nmax: 3033, 1598, 1226.
129.4, 127.7 (d, J¼17.2 Hz), 126.8, 97.7 (dd, J¼21.7, 28.7 Hz), 93.1 (dd,
J¼4.9, 27.9 Hz), 14.3; 19F NMR (282 MHz, CDCl3, C6F6):
d
ꢁ117.7,
ꢁ126.5. IR (KBr) nmax: 3032, 1499, 1220. Anal. Calcd for C14H10F2N2:
C 68.85; H 4.13; N 11.47. Found C 68.81; H 4.18; N 11.49.
4.6.6. 4-Bromo-6-fluoro-2-methyl-1-phenyl-1H-benzimidazole
(3r). Yield 243 mg (95%); mp 146e147 ꢀC; 1H NMR (500 MHz,
4.6. General procedure for the non-catalytic cyclization
amidines
DMSO-d6):
d
7.71e7.50 (m, 5H), 7.43 (dd, J¼1.3, 9.5 Hz,1H), 6.96 (dd,
J¼1.2, 8.6 Hz, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 159.2
(d, J¼243.3 Hz), 153.10, 153.08, 137.9, 136.5, 136.4, 135.4, 130.2,
Amidine 3 (0.084 mmol) and 0.168 mol of K2CO3 in 5 mL DMF
were heated under stirring for 4e24 h. The reaction was monitored
by 19F NMR. After that the solvent was evaporated to dryness and
the residue was diluted with water and then extracted with 50 mL
dichloromethane twice. The crude product was purified by crys-
tallization from a mixture of EtOAc/hexane (1:1).
129.5, 126.9, 114.0 (d, J¼27.9 Hz), 112.1 (d, J¼12.4 Hz), 96.4 (d,
J¼27.4 Hz), 14.4. 19F NMR (282 MHz, CDCl3, C6F6):
ꢁ119.9. IR (KBr)
d
nmax: 3034, 1597, 1500, 1232. Anal. Calcd for C14H10BrFN2: C 55.10; H
3.30; N 9.18. Found C 55.13; H 3.27; N 9.16.
Acknowledgements
4.6.1. 6-Bromo-8-fluoro-1,2,3,4-tetrahydropyrido[1,2-a]benzimid-
azole (3l). Yield 192 mg (85%); mp 123e124 ꢀC; 1H NMR (500 MHz,
This work was financially supported by Enamine Ltd.
Supplementary data
CDCl3):
J¼5.9 Hz, 2H), 3.12 (t, J¼6.1 Hz, 2H), 2.19e2.08 (m, 2H), 2.08e1.95
(m, 2H). 13C NMR (125 MHz, CDCl3):
d
7.22 (d, J¼2.2 Hz, 1H), 6.95 (d, J¼2.2 Hz, 1H), 4.03 (t,
Copies of 1H, 13C, and 19F NMR spectra. Supplementary data
related to this article can be found online at doi:10.1016/
j.tet.2012.02.027.
d
158.5 (d, J¼242.2 Hz), 153.1
(d, J¼2.2 Hz), 138.2, 134.4 (d, J¼13.7 Hz), 113.5 (d, J¼27.4 Hz), 112.0
(d, J¼12.8 Hz), 95.2 (d, J¼27.4 Hz), 43.0, 25.6, 22.5, 20.6. 19F NMR
(282 MHz, CDCl3, C6F6):
d
ꢁ119.7 (t, J¼8.1 Hz). IR (KBr) nmax: 2853,
1620, 1581, 1473. Anal. Calcd for C11H10BrFN2: C 49.09; H 3.75; N
10.41. Found C 49.13; H 3.76; N 10.44.
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