Synthesis of methyl 6-aryl-5-(1H-benzimidazol-2-yl)-2-methylnicotinates

Article abstract of DOI:10.1007/s10593-009-0370-z

A three-component cyclocondensation of 4-(dimethylamino)benzaldehyde, 2-phenacyl-1H-benz-imidazoles, and methyl 3-aminobut-2-enoate in refluxing acetic acid occurs via a Hantzsch type reaction and is accompanied by the loss of N,N-dimethylaniline to give

Full text of DOI:10.1007/s10593-009-0370-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
SYNTHESIS OF METHYL
6-ARYL-5-(1H-BENZIMIDAZOL-
2-YL)-2-METHYLNICOTINATES
I. B. Dzvinchuk1* and M. O. Lozinskii1
A three-component cyclocondensation of 4-(dimethylamino)benzaldehyde, 2-phenacyl-1H-benz-
imidazoles, and methyl 3-aminobut-2-enoate in refluxing acetic acid occurs via a Hantzsch type
reaction and is accompanied by the loss of N,N-dimethylaniline to give the previously unknown methyl
6-aryl-5-(1H-benzimidazol-2-yl)-2-methylnicotinates.
Keywords: benzimidazoles, pyridines, aromatization, dearylation, Hantzsch reaction.
We have previously found [1] that a Hantzsch type three component cyclocondensation reaction using
4-(dimethylamino)benzaldehyde (1) as the aldehyde component occurs uniquely in refluxing acetic acid. It does
not remain as the 1,4-dihydropyridine structure product but readily undergoes aromatization via desarylation
(loss of N,N-dimethylaniline). On this basis we have proposed a convenient single-stage method for the
CHO
Ar
H2N
Me
H
N
O
AcOH
+
+
O
120°C, 1 h
N
OMe
NMe2
3
1
2a–e
Ar
H
Ar
H
H
N
N
N
N
Me
CO2Me
Me
CO2Me
N
N
– PhNMe2
H
·AcOH
5a–e
Me2N
4a–e
2, 4, 5 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = MeC6H4, d Ar = ClC6H4, e Ar = 4-BrC6H4
_______
* To whom correspondence should be addressed, e-mail: Rostov@bpci.kiev.ua.
1Institute of Organic Chemistry National Academy of Sciences of Ukraine, Kiev 02094, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1186-1192, August, 2009. Original
article submitted December 24, 2008.
942
0009-3122/09/4508-0942©2009 Springer Science+Business Media, Inc.

synthesis of γ-unsubstituted pyridines condensed with other rings leading to a series of quinoline [2], acridine
[3], pyrazolo[3,4-b]pyridine [4], and pyrido[2,3-d]pyrimidine [5] derivatives. In this work the method is
extended to the synthesis of previously unknown functionalized pyridines.
We have found that a three component reaction of aldehyde 1, 2-phenacyl-1H-benzimidazoles 2a-e, and
methyl 3-aminobut-2-enoate (3) also occurs in refluxing acetic acid via a Hantzsch reaction scheme through the
1,4-dihydropyridines 4. Loss of N,N-dimethylaniline gives methyl 6-aryl-5-(1H-benzimidazol-2-yl)-2-methyl-
nicotinates which readily crystallize as 1:1 molar ratio solvates 5a-e with the indicated solvent.
In contrast to the examples listed above [1-5] the reaction occurs with low selectivity. Use of the starting
reactants 1, 2, 3 in the molar ratio 1:1:1 gives the target products with difficulty but with a 1:1:2.2 ratio (method
A) the products 5 can readily be crystallized from the reaction mixture in 39-49% yields.
The yield of compound 5a cannot be increased by splitting the process into two stages (method B), i.e. 1)
Knoevenagel type condensation of aldehyde 1 with active methylene compound 2a (as reported by us
previously [6]) and 2) introduction of the chalcone 6 obtained into the cyclocondensation with reagent 3.
The yield in the first stage is 75 and in the second 52% and this corresponds to an overall yield of 39%.
The three component variant of the synthesis gives compound 5a in 49% yield.
Ph
H
O
N
3
N
5a
1 + 2a
AcOH,
120 °C
6
Me2N
The crystal solvates 5a-e are stable at 20-40ºC. When held at 120ºC for 5 h they can be freed from acetic
acid by 93-95% (1H NMR spectroscopic data). As found by us, compound 5a can be readily converted to the
free base 7 by precipitation from a refluxing solution in pyridine by addition of water. Its structure was
confirmed by its chemical reactions, i.e. with DMF dimethylacetal to give the N-methyl derivative 8 and via
hydrazinolysis to give the hydrazide 9, the latter giving the amine 10 by the Curtius method.
The composition and structure of the compounds synthesized were confirmed by elemental analysis
(Table 1) and by IR and 1H NMR spectroscopic data (Table 2).
Py–H2O
5a
–AcOH
Ph
Ph
H
N
N
N
N
N
Me2NCH(OMe)2
Me
Me
N
CO2Me
CO2Me
Me
7
8
.
N2H4 H2O
Ph
Ph
H
N
H
N
N
N
HNO2
AcOH – conc. HCl
Me
NHNH2
Me
N
N
NH2
10
9
O
943

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp.*, °С
Yield*2, %
С
Н
N
5a
5b
5c
5d
5e
7
C21H17N3O2 •HOCOMe
C22H19N3O3 •HOCOMe
C22H19N3O2 •HOCOMe
C21H16ClN3O2•HOCOMe
C21H16BrN3O2 •HOCOMe
C21H17N3O2
68.72
68.47
5.16
5.25
10.63
10.42
268.0-269.5
221.0-222.5
236.0-237.5
260.5-262.0
246.5-248.0
268.0-269.5
175.0-176.5
283.0-284.5
222.0-223.5
49
46
48
46
39
98
78
85
88
66.76
66.50
5.23
5.35
9.72
9.69
69.34
69.05
5.27
5.55
10.23
10.07
63.31
63.09
4.48
4.60
9.77
9.60
57.43
57.27
3.88
4.18
8.85
8.71
73.34
73.45
5.07
4.99
12.18
12.24
8
C22H19N3O2
73.78
73.93
5.20
5.36
11.54
11.76
9
C20H17N5O
69.81
69.96
5.12
4.99
20.18
20.39
10
C19H16N4
75.77
75.98
5.42
5.37
18.43
18.65
_______
* On heating the adducts 5a-e lose acetic acid and melt as the free bases.
*2 Yields of compounds 5a-e using method A; yield of compound 5a by
method B = 52%.
Comparison of the IR spectra of adducts 5a-e with the free base 7 shows that the carbonyl group of the
acetic acid in the adducts occurs at 1700-1705 cm-1. It is known [7] that the νC=O absorption of carboxyl groups
as a free monomer occurs at 1750-1765 cm-1, as H-bonded dimers at 1710-1720 cm-1, and for a carboxylate ion
at 1550-1610 cm-1. Hence it is very likely that the adducts 5 occur in the crystalline state not as salts but as
solvates in which the hydrogen atom of the carboxyl group is bound by an intermolecular bond, presumable with
the nitrogen atom of the benzimidazole since it is somewhat more basic than the pyridine (the pKa values of the
corresponding unsubstituted heterocycles are 5.53 and 5.23 [8])
In the 1H NMR spectra of the adducts 5 in DMSO-d6 the H-7', H-4', the OH group of the acetic acid, and
the H-1' proton appear as separate signals at 7.39-7.43, 7.62-7.64, 11.94-11.96, and 12.38-12.48 ppm
respectively.
Due to the symmetry of the heterocycle and the presence of the positive charge in benzimidazolium salts
the spectroscopic picture is basically different, e.g. according to data in [9] the H-4 and H-7 protons in 2-(2,5-
diaryl-3-furyl)-3-benzimidazol-1-ium chlorides show equivalent resonances to lower field at 7.75-7.90 ppm and
the protons H-1 and H-3 are involved in rapid exchange processes and do not show a clearly defined signal. It
was notable that, in DMSO-d6, the CH3 group of acetic acid in the pure state and in compounds 5 are almost
identical at 1.91 [10] and 1.89-1.90 ppm. Moreover, if the acetic acid signal of adduct 5a is disregarded it is
virtually identical to the spectrum of the free base 7 isolated from it. It therefore follows that the adducts also do
not have a salt like nature in DMSO-d6. We have recently reported a similar structure for the adducts in a series
of 2-(3,6-diarylpyridazin-4-yl)-1H-benzimidazoles [11].
Hence the method of synthesis of compounds with a γ-unsubstituted pyridine ring based on a Hantzsch
reaction of 4-(dimethylamino)benzaldehyde is suitable for the preparation of the previously unknown methyl
6-aryl-5-(1H-benzimidazol-2-yl)-2-methylnicotinates.
944

TABLE 2. IR and 1H NMR Spectra of the Compounds Synthesized
IR spectrum
Com-
1Н NMR spectrum, δ, ppm (J, Hz)
(С=О, N-H),
pound
ν, cm-1
5a
5b
5c
5d
5e
7
1700, 1720
1705, 1720
1700, 1720
1700, 1725
1705, 1725
1720
1.90 (3Н, s, CH3CO2); 2.86 (3H, s, 2-CH3); 3.89 (3H, s, 3-CO2CH3);
7.16-7.20 (2H, m, H-5',6'); 7.30 (2H, t, J = 7.0, H-3,5 Ph);
7.35 (1H, t, J = 7.0, H-4 Ph); 7.38-7.40 (1H, m, H-7');
7.41 (2H, d, J = 7.0, H-2,6 Ph); 7.60-7.64 (1H, m, H-4');
8.51 (1H, s, H-4); 11.96 (1H, s, HOAc); 12.40 (1H, br. s, NH)
1.90 (3Н, s, CH3CO2); 2.84 (3H, s, 2-CH3); 3.72 (3H, s, OCH3);
3.88 (3H, s, 3-CO2CH3); 6.85 (2H, d, J = 8.5, Н Ar);
7.38 (2Н, d, J = 8.5, Н Ar); 7.17-7.21 (2H, m, H-5',6');
7.40-7.44 (1H, m, H-7'); 7.62-7.66 (1H, m, H-4'); 8.46 (1H, s, H-4);
11.96 (1H, s, HOAc); 12.38 (1H, br. s, NH)
1.90 (3Н, s, CH3CO2); 2.26 (3H, s, CH3Ar); 2.84 (3H, s, 2-CH3);
3.89 (3H, s, 3-CO2CH3); 7.09 (2Н, d, J = 8.0, Н Ar);
7.31 (2Н, d, J = 8.0, Н Ar); 7.16-7.20 (2H, m, H-5',6');
7.38-7.42 (1H, m, H-7'); 7.60-7.64 (1H, m, H-4'); 8.48 (1H, s, H-4);
11.94 (1H, s, HOAc); 12.38 (1H, br. s, NH)
1.89 (3Н, s, CH3CO2); 2.84 (3H, s, 2-CH3); 3.90 (3H, s, 3-CO2CH3);
7.18-7.20 (2H, m, H-5',6'); 7.37 (2Н, d, J = 8.0, Н Ar);
7.41 (2Н, d, J = 8.0, Н Ar); 7.41-7.45 (1H, m, H-7');
7.60-7.64 (1H, m, H-4'); 8.54 (1H, s, H-4); 11.96 (1H, s, HOAc);
12.44 (1H, br. s, NH)
1.90 (3Н, s, CH3CO2); 2.85 (3H, s, 2-CH3); 3.90 (3H, s, 3-CO2CH3);
7.17-7.21 (2H, m, H-5',6'); 7.34 (2Н, d, J = 8.0, Н Ar);
7.41-7.45 (1H, m, H-7'); 7.51 (2Н, d, J = 8.0, Н Ar);
7.60-7.64 (1H, m, H-4'); 8.54 (1H, s, H-4); 11.96 (1H, s, HOAc);
12.48 (1H, br. s, NH)
2.86 (3H, s, 2-CH3); 3.89 (3H, s, 3-CO2CH3);
7.17-7.19 (2H, m, H-5',6'); 7.30 (2H, t, J = 7.0, H-3,5 Ph);
7.35 (1H, t, J = 7.0, H-4 Ph); 7.39-7.43 (1H, m, H-7');
7.42 (2H, d, J = 7.0, H-2,6 Ph); 7.60-7.64 (1H, m, H-4');
8.51 (1H, s, H-4); 12.38 (1H, br. s, NH)
8
9
1720
2.89 (3H, s, 2-CH3); 3.08 (3H, s, 1'-CH3); 3.89 (3H, s, CO2CH3);
7.24-7.29 (4H, m, H-5',6', H-3,5 Ph); 7.33-7.37 (3H, m, H-2,4,6 Ph);
7.42-7.46 (1H, m, H-7'); 7.67-7.71 (1H, m, H-4'); 8.44 (1H, s, H-4)
1665, 3240,
3330
2.66 (3Н, s, 2-CH3); 4.57 (2H, s, NH2); 7.15-7.17 (2H, m, H-5',6');
7.27-7.33 (3H, m, H-3,4,5 Ph); 7.36-7.40 (3H, m, H-2,6 Ph, H-7');
7.59-7.63 (1H, m, H-4'); 8.02 (1H, s, H-4); 9.73 (1H, s, NHCO);
12.31 (1H, s, NH)
10
3375, 3455
2.41 (3Н, s, 2-CH3); 5.41 (2H, s, NH2);
7.13-7.18 (5H, m, H-3,4,5 Ph, H-5',6',); 7.22 (1H, s, H-4);
7.24-7.26 (2H, m, H-2,6 Ph); 7.32-7.36 (1H, m, H-7');
7.58-7.62 (1H, m, H-4'); 12.09 (1H, s, NH)
EXPERIMENTAL
1
IR spectra were taken on a UR-20 instrument for KBr tablets and H NMR spectra on a Bruker Avance
DRX 500 spectrometer (500 MHz) using DMSO-d6 and with TMS as internal standard. The course of the
reaction and purity of the compounds synthesized were monitored by TLC on Silufol UV-254 plates in the
system benzene–ethanol (9:1) and revealed using UV light. Compounds 5a-e were dried for 2 h at 40ºC and
compounds 8-10 for 5 h at 120ºC before determining the yield or carrying out elemental analysis or the
spectroscopic investigations.
Adduct of Methyl 5-(1H-benzimidazol-2-yl)-2-methyl-6-phenylnicotinate with Acetic Acid (5a).
A. A mixture of compound 1 (0.149 g, 1 mmol), compound 2a (0.236 g, 1 mmol), and compound 3
(0.252 g, 2.2 mmol) in glacial acetic acid (1 ml) was held at 120ºC for 1 h. The hot reaction mixture was diluted
945

with ethanol (1 ml), left to cool, and then further for 30 min at 20ºC and 30 min at 8ºC. The cooled product was
filtered and the residue on the filter was washed with cold ethanol to give analytically pure product 5a (0.186 g).
Compounds 5b-e were prepared similarly from compounds 1, 2b-e, and 3. In the preparation of
compound 5e 2 ml of acetic acid was used and the reaction mixture was held at a temperature not below 20ºC in
order to avoid crystallization of side products.
B. A mixture of compound 3 (0.126 g, 1.1 mmol) and compound 6 (0.184 g, 0.5 mmol) in glacial acetic
acid (1ml) was held for 30 min at 120ºC. The hot reaction mixture was diluted with ethanol (1 ml) and then
worked up as in method A to give analytically pure product 5a (0.105 g).
Methyl 5-(1H-Benzimidazol-2-yl)-2-methyl-6-phenylnicotinate (7). A mixture of compound 5a
(0.403 g, 1 mmol) and pyridine (1 ml) was refluxed with stirring to the formation of a homogenous solution and
then water (1.5 ml) was added slowly dropwise. The cooled product was filtered and the precipitate was washed
with water to give analytically pure product 7 (0.336 g).
Methyl 2-Methyl-5-(1-methyl-1H-benzimidazol-2-yl)-6-phenylnicotinate (8). A mixture of compound
7 (0.343 g, 1 mmol), DMF dimethyl acetal (1 ml), and anhydrous pyridine (1 ml) was held at 105ºC for 3.5 h.
The hot reaction mixture was diluted with water (3ml) with stirring. The cooled product was filtered and the
precipitate was washed with cold ethanol to give analytically pure product 8 (0.279 g).
5-(1H-Benzimidazol-2-yl)-2-methyl-6-phenylnicotinohydrazide (9). A mixture of compound 8
(0.343 g, 1 mmol), hydrazine hydrate (80%, 0.4 ml), and pyridine (1 ml) was held at 100ºC for 1.5 h. The hot
solution was diluted with water (3 ml) and stirred to the beginning of crystallization. The cooled product was
filtered and the precipitate was washed with water to give analytically pure product 9 (0.293 g).
3-Amino-5-(1H-benzimidazol-2-yl)-2-methyl-6-phenylpyridine (10). A solution of sodium nitrite
(0.076 g, 1.1 mmol) in water (1 ml) was added dropwise with stirring over 5 min to a solution of compound 9
(0.343 g, 1 mmol) in a mixture of glacial acetic acid (1 ml) and conc. HCl (0.5 ml) at 15ºC. The solution was
held for 30 min at 15ºC and then heated for 1.5 h at 100ºC. The product was diluted with water (2 ml), diethyl
ether (3 ml), and basified with 20% aqueous ammonia solution (3 ml). The mixture was heated with stirring to
evaporation of the ether and the oil produced crystallized. The hot mixture was filtered and the precipitate on the
filter was washed with water to give analytically pure product 10 (0.265 g).
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