One-pot Synthesis of Benzo[4,5]imidazo[1,2-a]pyridine Derivatives in Aqueous Conditions

Article abstract of DOI:10.1002/jhet.2617

One-pot reaction of cyclic 1,3-diketones, dimethylformamide dimethylacetal (DMFDMA) and 2-(1H-benzo[d]imidaz-2-yl)acetonitrile was found to be a highly selective process leading to 4-oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinolin-6-yl cyanides. Op

Full text of DOI:10.1002/jhet.2617

Month 2016
One-pot Synthesis of Benzo[4,5]imidazo[1,2-a]pyridine Derivatives in
Aqueous Conditions
a
a
a
a,b
Maria A. Vodolazhenko, Anastasiia E. Mykhailenko, Nikolay Yu. Gorobets, * and Sergey M. Desenko
a
Department of Chemistry of Heterocyclic Compounds, SSI “Institute for Single Crystals” of National Academy of
Sciences of Ukraine, Nauky Avenue 60, Kharkiv 61001, Ukraine
Faculty of Chemistry, V.N. Karazin Kharkiv National University, Svobody Sq. 4, Kharkiv 61077, Ukraine
b
*
E-mail: gorobets@isc.kharkov.com
Additional Supporting Information may be found in the online version of this article.
Received November 12, 2015
DOI 10.1002/jhet.2617
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
One-pot reaction of cyclic 1,3-diketones, dimethylformamide dimethylacetal (DMFDMA) and 2-(1H-benzo[d]
imidaz-2-yl)acetonitrile was found to be a highly selective process leading to 4-oxo-1,2,3,4-tetrahydrobenzo[4,5]
imidazo[1,2-a]quinolin-6-yl cyanides. Optimized reaction conditions using water as solvent at room temperature
or under microwave heating allowed high yields of the target products required no additional purification.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
transformations [12–14], for example, with aromatic amines
way D). This enolates are readily soluble in water, and as
(
The concept of green chemistry is widely applied today not
only in the industrial scale of organic chemistry but also in the
research and educational laboratories to instill this chemical
philosophy and to expand the boundaries of the classical
methods oforganicchemistry[1].Thelimited solubilityofor-
ganic reactants in water used to be considered as the main dis-
advantage of thismedia. However, a great variety of chemical
processinlivingorganismsandinnatureproceedsinwaterme-
dium. Water as solvent has advantages over organic solvents
becauseitmeetsseveralgreenchemistryprinciples,beingnon-
toxic, nonflammable, odorless, andavailableat low cost;also,
one can see from Scheme 1, the additives of water to the clas-
sic organic solvents were previously used in the reaction pro-
tocols for ways B and C.
On the other hand, the synthesis of benzimidazole deriv-
atives fused with different heterocycles is a topic of numer-
ous modern publications due to many biologically active
compounds found within this class of heterocycles [16–
19]. Thus, we were intrigued by a possibility to apply
2-(1H-benzo[d]imidaz-2-yl)acetonitrile (9) as an active
methylene nitrile building block in reaction with enamines
2 within the general approach represented in Scheme 1.
“organic-free” water can be recovered for further use. More-
over, forreactions“onwater,”thelimitedsolubilityofstarting
compounds favors the process, and for reactions “in water,”
wherestartingmaterialsaresoluble, theisolationandpurifica-
tionoftheproductareoftenfacilitatedbecauseoftheirlowsol-
ubilityintheaqueousmedia[2].Thatiswhyorganicreactions
in aqueous media attract more and more attention [3–8].
Our research during last years was devoted to elabora-
tion of selectivity control methods for the synthesis of dif-
ferent heterocycles based on one-pot reaction of α-CH2-
carbonyl compounds, dimethylformamide dimethylacetal
RESULTS AND DISCUSSION
Synthesis of a model enamine 2a was carried out as
described previously by stirring of a neat equimolar mix-
ture of dimedone (1a) and DMFDMA during 5 min at
room temperature (Scheme 2). The obtained product was
used in further transformations without isolation. The reac-
tion of this enamine with 2-benzoimidazylacetonitrile (9)
under conditions of way A (Scheme 1) led to formation
of the condensation product 10a as described previously
[9]. A wide variation of reaction conditions, including the
reaction at 0°C or evaluated temperature (conventional or
microwave heating, including conditions applied in way
B) in the presence or absence of piperidine and in different
solvents always led to the formation of 10a as the main
(DMFDMA), and active methylene nitrile compounds [9–
15]. In particular, we have shown that this interaction using
cyclic 1,6-dicarbonyl compounds 1 and cyanoacetamides 3
have different outcome [9–11] depending on reaction condi-
tions (ways A–C, Scheme 1). Moreover, the isolation of the
polyfunctional intermediate enolates 4 allows their other
©
2016 Wiley Periodicals, Inc.

M. A. Vodolazhenko, A. E. Mykhailenko, N. Yu. Gorobets, and S. M. Desenko
Vol 000
Scheme 1. Reaction conditions for way A: i-PrOH, piperidine (cat.), microwave irradiation (MW) 100°C, 5 min [9]; way B: i-PrOH, piperidine (2.0
equiv), H
, ArNH
2
O, MW 120°C, 10 min [10]; way C: MeCN, piperidine (2.0 equiv), HCl (aqueous, 18%, 8.0 equiv), rt, 30 min [11]; way D: isolated enolate
(1.1 equiv), AcOH, rt [13]. DMFDMA-dimethylformamide dimethylacetal.
4
2
Scheme 2. Reaction of enamine 2a with 2-benzoimidazylacetonitrile (9).
product, and we were not able to isolate or even detect any
products of other reaction pathways that could be expected
based on the previously obtained results as illustrated in
Scheme 1.
83%. It should be noted that this product was obtained ear-
lier in isopropanol in the presence of piperidine under mi-
crowave irradiation at 100°C during 5 min with a yield of
78% (the conditions from way A, Scheme 1). Thus, further,
we aimed to apply the found aqueous conditions for the
synthesis of different benzo[4,5]imidazo[1,2-a]pyridine
derivatives 10 from available 1,3-cyclohexandiones
(1b–е).
In an attempt to trap the intermediate enolate, we used p-
toluidine in reactions with 2a and 9 (by analogy with way
D in Scheme 1); only enamine 11 or its mixture with 10a
were isolated after the reaction in acetic acid or in ethanol, re-
spectively. Application of strong acidic conditions (by anal-
ogy with way C in Scheme 1) led to formation of
unidentified reaction products. This data indicate the high se-
lectivity of the studied transformation and higher reactivity
of NH-nucleophile in benzimidazol fragment in the cycliza-
tion comparing with amide fragment in enolates 4 and thus
leading to the formation of only one product 10a under dif-
ferent reaction conditions.
In the course of further screening reaction conditions for
the consecutive one-pot interaction of dimedone (1a),
DMFDMA, and 2-cyanomethylbenzimidazole (9), applica-
tion of water as solvent without catalyst at room temperature
during 1h was found to give the highest yield (86%) of pure
product 10a easily separated from the reaction mixture by fil-
tration. Application of microwave heating at 120°C during
The reaction with 1,3-cyclohexandione (1b) at room
temperature or thermal heating in water or in isopropanol
without catalyst led to a mixture of cyanide 10b and initial
2-cyanomethylbenzimidazole (9). Pure product 10b in
good yield was obtained under microwave irradiation at
120°C during 5min in water without catalyst. These
conditions were also successfully used to obtain deriva-
tives 10c and 10d (Table 1). In the case of initial diketone
1е, an additional optimization step was required. In the first
stage, the reaction of 1e with DMFDMA required 1h at
room temperature for the completion, and for the second
stage, isopropanol has to be used because of the law
solubility of the intermediate enamine in water.
1
According to H NMR spectra of the isolated products,
all the obtained compounds did not require additional
5
min for this process gave a comparable product yield of
purification. Purity of compounds 10b and 10c over 99%
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
One-pot Synthesis of Benzo[4,5]imidazo[1,2-a]pyridine Derivatives in Aqueous
Conditions Aqueous Synthesis
Table 1
Synthesis of compounds 10а–е.
1
2
Product
R
R
Stage 1
Stage 2
O, rt, 1 h
O, MW, 120°С, 5 min
O, MW, 120°С, 5 min
O, MW, 120°С, 5 min
Yield
a
10a
10b
10c
10d
10e
Me
H
H
H
H
Me
H
2-Furyl
rt, 5 min
rt, 5 min
rt, 5 min
rt, 5 min
rt, 1 h
H
2
86 (83 )
67
H
2
H
2
H
2
74
64
50
3,4-di-OMe-С
4-OMe-С
6
Н
3
6
Н
4
i-PrOH, MW, 120°С, 5 min
a
The yield was obtained using H
2
O, MW, 120°С, 5 min in Stage 2.
was additionally determined by LC-MS. The characteriza-
(PerkinElmer, Inc., Shelton, CT) (pellets with potassium
bromide KBr). The mass spectra were recorded on a
Varian 1200 L GC-MS instrument with the use of direct
exposure probe method with EI at 70eV. LC-MS analyses
were carried out with the use of chromatographic/mass-
spectrometric system, which consist of HPLC
chromatograph equipped with diode matrix and mass-
selective detector, in the atmospheric pressure chemical
ionization (negative or positive APCI) mode, simultaneous
scanning of positive ions in mass 80–1,000m/z. Elemental
analysis was performed on a EuroVector EA-3000
instrument. All microwave experiments were carried out
using the EmrysTM Creator EXP from Biotage (Uppsala,
Sweden). All experiments were performed in sealed
microwave process vials (for maximum 2.5 mL of the
reaction mixture) utilizing the “High” absorbance level
1
13
tion data obtained by H NMR, C NMR, and IR spectros-
copy, mass-spectrometry, and elemental analysis can be
found in the Supporting Information.
CONCLUSION
Application of 2-cyanobenzimidazole in consecutive
one-pot interaction with cyclic 1,3-diketones and
DMFDMA under various conditions proceeds selectively
leading to formation of 4-oxo-1,2,3,4-tetrahydrobenzo[4,5]
imidazo[1,2-a]quinolin-6-yl cyanides (10). Water was
found to be the optimal medium for the majority of the
cases allowing facial synthesis and isolation of the pure
products.
(150W maximum power). Reaction times under
microwave conditions reflect the time the reaction mixture
was kept at the designated temperature (fixed hold time).
EXPERIMENTAL
2
-Cyanomethylbenzimidazole (9), dimedone (1а), and
General information.
acquired. Melting points were measured in open capillary
tubes and are uncorrected. NMR spectra were recorded on
a Bruker Avance drx 500 MHz (126 MHz for C NMR;
Bruker Spectrospin Ltd., Coventry, United Kingdom),
Varian MR 400MHz spectrometer (100MHz for
All solvents were used as
1,3-cyclohexadione (1b) are commercially available com-
pounds. Other substituted 1,3-cyclohexadiones 1с–е were
obtained using the known method [11]. The product 10a
was previously described [9].
General procedure for the synthesis of 4-oxo-1,2,3,4-
tetrahydrobenzo[4,5]imidazo[1,2-a]quinoline-6-yl cyanides
(10a–d). Enamines 2a–d were obtained by a reaction
of neat 1,3-cyclohexanediones (1a–d) (1.43 mmol) with
DMFDMA (170 mg, 1.43 mmol) stirred at room
temperature during 5 min in microwave process vial. To
the obtained mixture, 2-cyanomethylbenzimidazole (9,
225 mg, 1.43 mmol) and 1.0 mL of water were added.
The vial was encapsulated, and the reaction mixture
13
13
C
NMR), and Varian Mercury VX 200 MHz (Varian Inc.,
Palo Alto, CA) using DMSO-d as solvent and residual
6
solvent signal as the reference (TMS scale). Copies of
NMR spectra were prepared with the help of ACD/NMR
Processor (academic edition) program and are presented in
the Supporting Information. IR spectra were recorded on a
Perkin Elmer Spectrum One FTIR spectrometer
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Vodolazhenko, A. E. Mykhailenko, N. Yu. Gorobets, and S. M. Desenko
Vol 000
was heated under microwave irradiation at 120°С during
min in «High» mode (starting power is 150 W). After
cooling, the precipitate obtained was filtered off and
washed with water and small amount of isopropanol,
then dried on air.
was obtained as yellow crystals with the yield 64%, mp:
5
274–275°С; IR (potassium bromide): 1513, 1563, 1591,
À1
1
1625, 1678, 2230, 3070cm
;
H NMR (500MHz,
DMSO-d ): δ 8.52 (s, 1H), 8.17–8.33 (m, 1H), 7.90–8.06
6
(m, 1H), 7.60–7.72 (m, 1H), 7.43–7.55 (m, 1H), 7.14 (br.
s., 1H), 6.89–7.05 (m, 2H), 4.00–4.12 (m, 1H), 3.89–3.99
(m, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.58–3.71 (m, 1H),
Procedure for the synthesis of 2,2-dimethyl-4-oxo-1,2,3,4-
tetrahydrobenzo[4,5]imidazo[1,2-a]quinoline-6-yl cyanide (10a)
13
at room temperature.
Enamine 2a was obtained by a
3.15 (s, 1H), 2.72–2.88 (m, 1H); C NMR (126MHz,
DMSO) δ: 193.2, 154.9, 149.0, 148.1, 146.2, 145.0,
135.0, 134.2, 130.1, 127.1, 123.3, 120.1, 119.0, 116.9,
116.5, 115.2, 112.1, 111.4, 98.7, 55.65, 55.68, 43.0, 37.8,
reaction of neat dimedone (1a) (200mg, 1.43 mmol) with
DMFDMA (170mg, 1.43 mmol) stirred at room
temperature during 5 min. To the obtained mixture, 2-
cyanomethylbenzimidazole (9, 225mg, 1.43 mmol) and
+
35.3; MS: (70eV, electron impact) m/z 397 (M ); Anal.
1.0mL of water were added. The obtained reaction mixture
Calcd (C H N O ): C, 72.53; H, 4.82; N, 10.57. Found:
2
4 19 3 3
was stirred at room temperature during 1h. The precipitate
obtained was filtered off and washed with water and small
amount of isopropanol, then dried on air. Yield: 355 mg
C, 73.4; H, 5.0; N, 10.7.
Procedure for the synthesis of 2-(4′-methoxyphenyl)-4-
oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinoline-6-yl
cyanide (10е). Enamine 2e was obtained by a reaction
of neat 5-(4′-methoxyphenyl)-1,3-cyclohexanedione (1e,
312 mg, 1.43 mmol) with DMFDMA (170mg,
1.43 mmol) stirred at room temperature during 1h. To
obtained the solution, 2-cyanomethylbenzimidazole (9)
and 1.0 mL of isopropanol were added. The vial was
encapsulated, and obtained reaction mixture was heated
under microwave irradiation at 120°С during 5 min in
«High» mode (starting power is 150W). After cooling,
the precipitate obtained was filtered off and washed
with water and small amount of isopropanol, then dried
on air. Yield: 169mg (50%).
(86%).
2,2-Dimethyl-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]
quinoline-6-yl cyanide (10a). This compound was obtained
as light-yellow crystals with the yield 86%, mp: 310–315°С
1
(
mp 330–333°С [9]); H NMR (200MHz, DMSO-d ): δ
6
8.48 (s, 1H), 8.44 (d, J= 8.5 Hz, 1H), 7.98 (d, J=8.3Hz,
1H), 7.67 (t, J= 7.5 Hz, 1H), 7.52 (t, J= 7.7 Hz, 1H), 3.71
(s, 2H), 2.61 (s, 2H), 1.18 (s, 6H).
4
-Oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]quinoline-
6
-yl cyanide (10b). This compound was obtained as light-
yellow crystals with the yield 67%, mp: 241–242°С
(
1
decomp.); IR (potassium bromide): 756, 1513, 1561,
591, 1622, 1684, 2235, 3059 cm ; H NMR (500MHz,
À1
1
2-(4′-Methoxyphenyl)-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]
imidazo[1,2-a]quinoline-6-yl cyanide (10е). This compound
was obtained as light-yellow crystals, mp: 244°С; IR
(potassium bromide): 1511, 1559, 1588, 1621, 1684,
DMSO-d ): δ 8.46 (s, 1H), 8.31–8.42 (m, 1H), 7.90–8.01
6
(
3
m, 1H), 7.58–7.70 (m, 1H), 7.42–7.55 (m, 1H), 3.69–
13
.83 (m, 1H), 2.61–2.74 (m, 2H), 2.19–2.37 (m, 1H);
C
À1
1
NMR (126 MHz, DMSO-d ) δ: 193.6, 155.8, 146.0,
2235, 3056 cm
;
H NMR (200 MHz, DMSO-d ): δ
6
6
1
1
45.0, 134.3, 130.1, 126.9, 123.0, 119.9, 116.8, 116.7,
8.41–8.63 (m, 1H), 8.12–8.35 (m, 1H), 7.83–8.10 (m,
1H), 7.56–7.71 (m, 1H), 7.33–7.54 (m, 3H), 6.84–7.09
(m, 2H), 3.80–4.16 (m, 2H), 3.75 (s, 3H), 3.51–3.71 (m,
15.2, 98.3, 35.8, 27.8, 20.2; LC-MS, purity >99%, m/z
+
(APCI, pos.): 262.2 (M+H ), Anal. Calcd (C H N O):
1
6 11 3
13
C, 73.55; H, 4.24; N, 16.08. Found: C, 73.1; H, 4.2; N,
5.7.
1H), 2.97–3.19 (m, 1H), 2.64–2.86 (m, 1H); C NMR
1
(100 MHz, DMSO-d ) δ: 35.6, 37.6, 43.4, 55.5, 99.0,
6
2
-Furyl-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]
114.5, 115.5, 116.9, 117.2, 120.4, 123.6, 127.4, 128.6,
quinoline-6-yl cyanide (10с). This compound was obtained
as light-yellow crystals with the yield 74%, mp: 286–
130.5, 134.6, 134.8, 145.3, 146.5, 155.3, 158.8, 193.5;
MS (EI, 70 eV), m/z: 367 (M ); Anal. Calcd
+
2
1
8
8
6
2
1
1
9
3
4
88°С; IR (potassium bromide): 1512, 1563, 1592, 1624,
(C H N O ): C, 75.19; H, 4.66; N, 11.44. Found: C,
75.2; H, 4.8; N, 11.4.
23 17 3 2
À1 1
682, 2236, 3068cm ; H NMR (500MHz, DMSO-d ): δ
6
.53 (s, 1H), 8.42–8.56 (m, 1H), 8.34–8.40 (m, 1H), 7.94–
.01 (m, 1H), 7.61–7.70 (m, 2H), 7.49–7.57 (m, 1H),
.37–6.46 (m, 2H), 4.16–4.26 (m, 1H), 3.88–4.02 (m, 2H),
Acknowledgement. Authors are thankful to Enamine LTD, Kyiv,
and personally to Mr. Maxim Nechayev for their help with
1
3
.94–3.08 (m, 2H); C NMR (126MHz, DMSO) δ: 192.2,
86.3, 155.1, 153.9, 146.1, 145.0, 142.4, 134.1, 130.1,
27.1, 123.3, 120.1, 116.8, 116.5, 115.1, 110.6, 105.9,
8.8, 32.1, 31.6; LC-MS: purity >99%, m/z (APCI, pos.)
13
measurement of LC-MS and C NMR spectra.
REFERENCES AND NOTES
+
28.2 (M+H ); Anal. Calcd. (C H N O ): C, 73.38; H,
2
0 13 3 2
[1] Green Techniques for Organic Synthesis and Medicinal Chem-
.00; N, 12.84. Found: C, 72.6; H, 4.1; N, 12.6.
istry; Zhang, W.; Cue, B. Eds.; John Wiley & Sons: Weinheim, Germany,
2012; 768 p.
2
-(3′,4′-Dimethoxyphenyl)-4-oxo-1,2,3,4-tetrahydrobenzo[4,5]
[2] Chanda, A.; Fokin, V. V. Chem Rev 2009, 109, 725.
imidazo[1,2-a]quinoline-6-yl cyanide (10d). This compound
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
One-pot Synthesis of Benzo[4,5]imidazo[1,2-a]pyridine Derivatives in Aqueous
Conditions Aqueous Synthesis
[
[
[
[
[
[
[
3] Butler, R. N.; Coyne, A. G. Chem Rev 2010, 110, 6302.
4] Dallinger, D.; Kappe, C. O. Chem Rev 2007, 107, 2563.
5] Dicks, A. P. Green Chem Lett Rev 2009, 2, 9.
6] Kumaravel, K.; Vasuki, G. Curr Org Chem 2009, 13, 1820.
7] Raj, M.; Singh, V. K. Chem Commun 2009 6687.
8] Simon, M.-O.; Li, C.-J. Chem Soc Rev 2012, 41, 1415.
9] Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahe-
[13] Yermolayev, S. A.; Gorobets, N. Y.; Lukinova, E. V.;
Shishkin, O. V.; Shishkina, S. V.; Desenko, S. M. Tetrahedron 2008,
64, 4649.
[14] Yermolayev, S. A.; Gorobets, N. Y.; Shishkin, O. V.;
Shishkina, S. V.; Leadbeater, N. E. Tetrahedron 2011, 67, 2934.
[15] Gorobets, N. Y.; Sedash, Y. V.; Shishkina, S. V.; Shishkin, O.
V.; Yermolayev, S. A.; Desenko, S. M. ARKIVOC 2009 23.
[16] Dawood, K. M.; Abdel-Wahabb, B. F. ARKIVOC 2010, 1,
dron 2004, 60, 8633.
10] Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J Comb
Chem 2009, 11, 44.
333.
[
[17] Dawood, K. M.; Elwan, N. M.; Farahat, A. A.; Abdel-Wahab,
B. F. J Heterocyclic Chem 2010, 47, 243.
[18] Dawood, K. M.; Elwan, N. M.; Abdel-Wahab, B. F.
ARKIVOC 2011, 111.
[
11] Vodolazhenko, M. A.; Gorobets, N. Y.; Yermolayev, S. A.;
Musatov, V. V.; Chebanov, V. A.; Desenko, S. M. RSC Adv 2012, 2, 1106.
[12] Dzhavakhishvili, S. G.; Gorobets, N. Y.; Chernenko, V. N.;
[19] Bansal, Y.; Silakari, O. Bioorg Med Chem 2012, 20, 6208.
Musatov, V. I.; Desenko, S. M. Russ Chem Bull 2008, 57, 422.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet