Formation of unsymmetrical 2-(diacylmethylene)-2,3-dihydro-1H-benzimidazoles during acidolysis of 1-benzoyl-2-(β-benzoyloxy-β-phenylvinyl)-1H-benzimidazole

Article abstract of DOI:10.1023/A:1011696219717

The reaction of 1-benzoyl-2-(β-benzoyloxy-β-phenylvinyl)-1H-benzimidazole with carboxylic acids was investigated. A convenient method was developed for the synthesis of unsymmetrical 2-(diacylmethylene)-2,3-dihydro-1H-benzimidazoles. 2-(4-Pyrazolyl)-1H-benzimidazoles were obtained by the reaction of 2-(benzoylformylmethylene)-2,3-dihydro-1H-benzimidazole with hydrazine.

Full text of DOI:10.1023/A:1011696219717

Chemistry of Heterocyclic Compounds, Vol. 37, No. 5, 2001
FORMATION OF UNSYMMETRICAL
2-(DIACYLMETHYLENE)-2,3-DIHYDRO-
1H-BENZIMIDAZOLES DURING
ACIDOLYSIS OF 1-BENZOYL-
2-(β-BENZOYLOXY-
β-PHENYLVINYL)-1H-BENZIMIDAZOLE
I. B. Dzvinchuk and M. O. Lozinskii
The reaction of 1-benzoyl-2-(β-benzoyloxy-β-phenylvinyl)-1H-benzimidazole with carboxylic acids was
investigated.
A
convenient method was developed for the synthesis of unsymmetrical
2-(diacylmethylene)-2,3-dihydro-1H-benzimidazoles. 2-(4-Pyrazolyl)-1H-benzimidazoles were obtained
by the reaction of 2-(benzoylformylmethylene)-2,3-dihydro-1H-benzimidazole with hydrazine.
Keywords: benzimidazoles, pyrazoles, acidolysis, C-acylation.
The acylation of 2-methyl-1H-benzimidazole (1) with the Vilsmeier reagent [1] and phthalic anhydride
[2] takes place at the methyl group with the formation of symmetrical 2-(diacylmethylene)-2,3-dihydro-1H-
benzimidazoles. Acylation with benzoyl chloride in the presence of triethylamine leads with a quantitative yield
to the product of N,C,O-tribenzoylation 1-benzoyl-2-(β-benzoyloxy-β-phenylvinyl)-1H-benzimidazole (
2),
which when heated with benzoic acid 3a forms 2-(dibenzoylmethylene)-2,3-dihydro-1H-benzimidazole 4 [3].
The mechanism of the transformation can probably be represented as acidolysis with the intermediate formation
of 2-phenacyl-1H-benzimidazole (4) and benzoic anhydride 5a, the reaction of which leads to the formation of
the symmetrical diketone 6a. On the basis of these ideas in the present work we investigated the reaction of
compound 2 with carboxylic acids in order to obtain the previously unknown unsymmetrical
2-(diacylmethylene)-2,3-dihydro-1H-benzimidazoles.
We investigated the acidolysis of p-nitrobenzoic, phenoxyacetic, acetic, trifluoroacetic, and formic acids
3b-f. This secured selective acylation of the investigated compound by the mixed anhydrides of benzoic and
other employed acids formed intermediately in the reaction. Optimum conditions were found for the formation
of the desired compounds 6b-f (molar ratio of reagents 1:1 or a larger amount of the acid, solvent dioxane or an
excess of the acid, temperature 95-105°C, reaction time 1-4 h, yields 59-85%). The choice of reagent ratio can
be determined by the solubility of the initial acid, which is important for facilitating the isolation of the final
product in the individual state. With the reagents in a molar ratio of 1.1 the reaction is complete in 3-4 h and
with an excess of the acid in 1 h.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 606-611, May,
2001. Original article submitted June 22, 1999.
554
0009-3122/01/3705-0554$25.00©2001 Plenum Publishing Corporation

COPh
H
N
RCOOH
3a–f
Ph
N
PhCOCl
NEt3
Me
C
H
N
N
OCOPh
1
2
O
O
O
H
O
Ph
R
N
N
Ph
CH2
+
4
5a–f
O
O
Ph
H
N
H2NNHR'
H
N
Ph
R
R'
7a–c
N
N
N
H
6a–f
N
R = H
R
8a–c
3, 5, 6 a R = Ph, b p-C6H4NO2, c PhOCH2, d Me, e CF3, f H;
7, 8 a R' = H, b Ph, c p-C6H4NO2
The yields of the desired compounds can be increased. It was established, for example, that during the
acidolysis of compound 2 with acetic acid in the presence of acetic anhydride the yield of the C-acetyl
derivative 6d is increased from 85 to 96%.
HCOOH Ac2O
86%
HOAc Ac2O
96%
HOAc Ac2O
96%
6f
6d
4
2
Compound 6d is formed with a 96% yield during the C-acetylation of compound 4 [obtained by the
morpholinolysis of compound 2 [3]] with a mixture of acetic acid and its anhydride. The C-formyl derivative 6f
was obtained similarly with an 86% yield from compound 4 and a mixture of formic acid and acetic anhydride.
The obtained results partly confirm the presented acidolysis scheme, but the two-stage mechanism must
be considered over-simplified. The sequence of the acidolysis of the nonequivalent O- and N-acyl bonds has not
been explained. Besides, the reaction details are not significant enough for a final result. The motivating force
for the transformations of the initial and intermediate compounds with labile O- and N-acyl bonds is probably
the formation of thermodynamically compounds containing stronger carbon-acyl bonds.
2-Cyanomethyl-1H-benzimidazole is acylated by acid anhydrides at the methylene group [4], and the
discussed C-acylation of compound 4 is therefore a normal phenomenon. However, the advantage of our method
is the fact that more readily available initial substances are used in place of compound 4 and the anhydrides. A
limitation of the reaction is that it only makes it possible to introduce a benzoyl or more electrophilic acyl
group. The obtained products (β-carbonyl compounds) can provide a source of previously unobtainable
heteroarylbenzimidazoles. We found that compound 6f reacts with the hydrazines 7a-c to form 2-(4-pyrazolyl)-
1H-benzimidazoles 8a-c.
The obtained new compounds 6b-f and 8a-c are stable crystalline substances. Compound 6b like its
dibenzoyl analog 6a is yellow. Compounds 6d,f are pale-yellow, and 6c,e and 8a-c are colorless substances.
Compounds 6b-d,f are poorly soluble in organic solvents, and their trifluoromethyl analog 6e reacts with boiling
2-propanol to form a homogeneous solution. The pyrazole 8a is readily soluble in alcohols, and its derivatives
8b,c are less soluble compounds.
555

1
The structure of the synthesized new compounds was confirmed by the data from IR and H NMR
spectroscopy (see the experimental section and Table 1). The extremely informative proton spectra, which make
it possible to reveal the stereochemical details, are examined in greater detail. Thus, the spectral characteristics
of the unsymmetrical β-dicarbonyl compounds
6b-f and their symmetrical dibenzoyl structural analog 6a [3]
have common features. In the new diketones the symmetry of distribution of electron density in the
benzimidazole ring is retained. The narrow multiplet signal of 5- and 6-H appears at 7.24-7.31 ppm, and that of
4- and 7-H at 7.67-7.75 ppm; the protons at positions 1 and 3 are equivalent and resonate in the form of a
common singlet at 12.94-13.20 ppm. This confirms the enaminocarbonyl structure of the compounds stabilized
by two intramolecular hydrogen bonds.
The phenyl rings in the acetyl and formyl derivatives 6d,f appear as a narrow multiplet at 7.47 and
7.48 ppm (as in toluene [5]), i.e., they are turned from the plane of the molecule so much that they hardly
make any contact with the adjacent carbonyl group. In these compounds the substituents CH3 and H at the
second carbonyl group are probably in the field of the screening effect of the phenyl ring and resonate at
1.64 and 9.31 ppm, i.e., upfield from the position expected for the methyl ketone and aldehyde (2.10 and
9.96 ppm [5]). On the other hand in the dibenzoyl compound 6a and its p-nitrobenzoyl, phenoxybenzoyl, and
trifluoroacetyl analogs 6b,c,e the phenyl rings appear in a broad region with resolution of the individual
multiplet signals for the protons at the ortho, meta, and para positions. In these compounds between the
substituents at the carbonyl groups there is probably mutual repulsion, due to unfavorable overlap of the orbitals
of the aromatic rings and the electronegative atoms. This removes the dicarbonylmethylenebenzimidazole
fragment of the molecule from the coplanar state and secures partial conjugation of the phenyl ring with the
adjacent C=O group.
1
According to data from the H NMR spectra, the pyrazole 8a is characterized by tautomerism due to
proton migration between the nitrogen atoms of the pyrazole ring. This agrees with previously obtained data on
the tautomerism of 2-(4-pyrazolyl)benzimidazoles [6]. We note that in the hydrochloride of the compound the
tautomeric interconversions are accelerated so much that the tautomeric forms do not appear individually. In the
base, however, the singlet signals of the protons of the amino groups and also of the pyrazole ring are doubled.
The ratio of the integral intensities is 1:1, demonstrating the energy equivalence of the tautomeric forms. At first
sight this conclusion contradicts data on the tautomerism of 3(5)-methyl-5(3)-phenylpyrazole, which indicate
that the proton of the N–H bond is removed preferentially from the phenyl ring [7, 8]. Substitution of the methyl
group by the hydrogen atom having less steric hindrances should probably demonstrate even more strongly the
energy nonequivalence of the tautomeric forms, but the benzimidazole ring probably has a substantial effect on
the tautomerism of compound 8a. As acceptor it must enter into conjugation with the electron-donating pyrazole
ring. Thus, there is a tendency to bring both heterocycles into one plane. As a result the phenyl ring experiences
disturbances on the part of the benzimidazole and is forced to turn away from the plane of the pyrazole ring,
losing here the electronic influence on the whole molecule and the steric influence on the nearest environment,
thereby securing the equivalence of the pyrazole nitrogen atoms. The phenyl ring retains its conjugation with the
adjacent π-electron-deficient carbon atom of the pyrazole ring, and its
ortho, meta, and para protons appear
separately in the spectrum.
In pyrazoles 8b,c the C-phenyl ring experiences hindrances on the part of the benzimidazolyl and
N-aryl substituent and is turned fully away from the plane of the pyrazole ring, appearing in the H NMR
1
spectrum in the form of a narrow multiplet at 7.36 and 7.45 ppm respectively (like the phenyl group of toluene).
It is thus confirmed that the 5-phenyl-substituted pyrazoles and not the 3-phenyl-substituted isomers are
obtained. Thus, previously unknown unsymmetrical 2-(diacylmethylene)-2,3-dihydro-1H-benzimidazoles, which
are prospective reagents for the synthesis of 2-heterylbenzimidazoles, can be obtained by a simple procedure
from readily obtainable reagents, 1-benzoyl-2-(β-benzoyloxy-β-phenylvinyl)-1H-benzimidazole, and carboxylic
acids.
556

1
TABLE 1. The Characteristics of the H NMR Spectra of Compounds 6a-f
and 8a-c
Com-
δ, ppm (DMSO-d6), J (Hz)
pound
7.04 (6Н, m, p- + m-С6Н5); 7.27 (6Н, m, о-С6Н5 + 5-, 6-Н); 7.70 (2Н, m, 4-, 7-Н);
13.09 (2Н, s, NH)
6а
6b
6c
7.07 (3H, m, p- + m-С6Н5); 7.32 (4H, m, о-С6Н5 + 5-, 6-Н); 7.50 (2H, m, m-C6H4NO2,
J = 8.7); 7.75 (2H, m, 4-, 7-Н); 7.88 (2H, m, o-C6H4NO2, J = 8.7); 13.10 (2Н, s, NH)
4.17 (2Н, s, СН2); 6.60 (2Н, d, о-ОС6Н5); 6.83 (1Н, m, p-ОС6Н5);
7.16 (2Н, m, m-ОС6Н5); 7.27 (2H, m, 5-, 6-Н); 7.46 (3H, m, p- + m-С6Н5);
7.63 (2H, d, о-С6Н5, J = 7.7 ); 13.07 (2Н, s, NH)
1.64 (3Н, s, СН3); 7.24 (2H, m, 5-, 6-Н); 7.47 (5Н, m, С6Н5); 7.67 (2Н, m, 4, 7-Н);
6d
6e
6f
13.09 (2Н, s, NH)
7.31 (2H, m, 5-, 6-Н); 7.49 (2H, m, m-С6Н5); 7.59 (1Н, m, p-С6Н5); 7.67 (2Н, m, 4-, 7-Н);
7.73 (2H, m, о-С6Н5, J = 7.4); 12.94 (2Н, s, NH)
7.30 (2H, m, 5-, 6-Н); 7.48 (5Н, m, С6Н5); 7.74 (2Н, m, 4-, 7-Н); 9.31 (1Н, s, СНО);
13.20 (2Н, s, NH)
7.15 (2H, m, 5-, 6-Н); 7.38 (2H, m, m-С6Н5); 7.46 (2Н, m, 4-, 7-Н); 7.56 (1H, m, p-С6Н5);
7.86 (2H, d, о-С6Н5, J = 7.5); 8.07 and 8.30 (1Н, 2s, 3'-H); 12.33 and 12.38 (1Н, 2s, 1-H);
13.34 and 13.50 (1Н, 2s, 1'-H); hydrochloride: 7.50 (3Н, m, p- + m-С6Н5);
7.54 (2H, m, 5-, 6-Н); 7.62 (2H, m, о-С6Н5); 7.75 (2Н, m, 4-, 7-Н); 8.57 (1Н, s, 3'-H);
NH not appears
8а
7.13 (2H, m, 5-, 6-Н); 7.25 (2H, m, о-С6Н5N); 7.37 (8Н, m, p- + m-С6Н5N+С6Н5);
8b
8c
7.48 (2Н, m, 4-, 7-Н); 8.35 (1Н, s, 3'-H); 12.40 (1Н, s, 1-H)
7.14 (2H, m, 5-, 6-Н); 7.45 (7Н, m, 4-, 7-Н + С6Н5); 7.49 (2H, d, o-C6H4NO2, J = 9.8);
8.23 (2H, d, m-C6H4NO2, J = 9.8); 8.47 (1Н, s, 3'-H); 12.46 (1Н, s, 1-H)
EXPERIMENTAL
The IR spectra were recorded on a UR-20 instrument for tablets with potassium bromide. The 1H NMR
spectra were obtained on a Varian VXR-300 spectrometer at 300 MHz with DMSO-d6 as solvent and TMS as
internal standard. The reactions and the individuality of the synthesized compounds were monitored by TLC on
Silufol UV-254 plates in the 9:1 benzene–ethanol solvent system (development in UV light).
p
A mixture of compound
2-(Benzoyl- -nitrobenzoylmethylene)-2,3-dihydro-1H-benzimidazole (6b).
2 (8.88 g, 20 mmol) and acid 3b (3.34 g, 20 mmol) in anhydrous dioxane (10 ml) was boiled for 4 h. After
cooling the mixture was mixed with water (50 ml). The aqueous layer was decanted. The residue was boiled
with 2-propanol (30 ml) until crystallization began. After cooling the precipitate was filtered off and washed
with 2-propanol. Yield 6.51 g (84%); mp 248.5-250°C (n-butanol–DMF, 3:1). IR spectrum, , cm-1: 1350, 1540
ν
(NO2), 1595, 1615 (C=C and C=O), 3275 (NH). Found, %: C 68.7; H 4.0; N 10.8. C22H15N3O4. Calculated, %:
C 68.6; H 3.9; N 10.9.
2-(Benzoylphenoxyacetylmethylene)-2,3-dihydro-1H-benzimidazole (6c). A mixture of compound 2
(0.44 g, 1 mmol), acid 3c (0.23 g, 1.5 mmol), and anhydrous dioxane (1 ml) was boiled for 3 h. To the boiling
solution we added water (0.5 ml). After cooling the precipitate was filtered off and washed with 2-propanol.
Yield 0.22 g (59%); mp 216.5-218°C (aqueous dioxane, 1:2). IR spectrum, , cm-1: 1595, 1615 (C=C and C=O),
ν
3255 (NH). Found, %: C 74.7; H 4.8; N 7.6. C22H15N3O4. Calculated, %: C 74.6; H 4.9; N 7.6.
2-(Acetylbenzoylmethylene)-2,3-dihydro-1H-benzimidazole (6d). A. A mixture of compound 2
(2.22 g, 5 mmol) and acid 3d (4.2 ml, 70 mmol) was kept at 95-100°C for 45 min. After cooling the mixture was
stirred with 2-propanol (4.0 ml). The precipitate was filtered off and washed with 2-propanol. Yield 1.18 g
(85%); mp 273.5-275°C (o-xylene). IR spectrum, , cm-1: 1600, 1615 (C=C and C=O), 3215 (NH). Found, %:
ν
C 73.5; H 5.1; N 10.0. C22H15N3O4. Calculated, %: C 73.4; H 5.1; N 10.0.
557

B. A mixture of compound 2 (1.11 g, 2.5 mmol), acetic anhydride (1.89 ml, 20 mmol), and acid 3d
(1.8 ml, 30 mmol) was boiled for 20 min. After cooling the precipitate was filtered off and washed with
2-propanol. Yield 0.67 g (96%).
C. A mixture of compound 6 (1.18 g, 5 mmol), acetic anhydride (1.89 g, 20 mmol), and acid 3d (1.8 ml,
30 mmol) was kept at 95-100°C for 1 h. After cooling the precipitate was filtered off and washed with
2-propanol. Yield 1.33 (96%).
A mixed melting test with samples obtained by methods A-C did not give a melting point depression.
2-(Benzoyltrifluoroacetylmethylene)-2,3-dihydro-1H-benzimidazole (6e). A mixture of compound 2
(4.44 g, 10 mmol), anhydrous dioxane (5 ml), and acid 3e (1.53 ml, 20 mmol) was boiled for 1 h. Dioxane was
evaporated under the vacuum of a water-jet pump at 95-100°C. The residue was dissolved in boiling toluene
(10 ml). The solution was cooled with running water and left at 15-20°C for 1.5 h. The precipitate was filtered
off and washed with toluene. Yield 2.47 g (74%); mp 207.5-209°C (toluene). IR spectrum, , cm-1: 1605, 1625
ν
(C=C and C=O), 3250 (NH). Found, %: C 61.8; H 3.5; N 8.7. C17H11F3N2O2. Calculated, %: C 61.5; H 3.3;
N 8.4.
2-(Benzoylformylmethylene)-2,3-dihydro-1H-benzimidazole (6e). A. A mixture of compound 2
(4.44 g, 10 mmol), anhydrous dioxane (10 ml), and 90% acid 3f (0.85 ml, 20 mmol) was boiled for 1 h. To the
hot mixture while stirring we added water (5 ml). After cooling the precipitate was filtered off and washed with
2-propanol. Yield 2.02 g (77%); mp 283.5-285.5°C (aqueous acetic acid, 1:4). IR spectrum, , cm-1: 1615, 1630
ν
(C=C and C=O), 3240 (NH). Found, %: C 72.6; H 4.5; N 10.5. C16H12N2O2. Calculated, %: C 72.7; H 4.6;
N 10.6.
B. To a mixture of compound 4 (4.72 g, 20 mmol) and anhydrous dioxane (20 ml) we added a mixture
of 90% acid 3f (1.68 ml, 40 mmol) and acetic anhydride (8 ml, 80 mmol). The mixture was heated to boiling. At
the end of the exothermic reaction the mixture was boiled for 5 min, and water (30 ml) was then cautiously
added drop by drop over 3 min with shaking. After cooling the precipitate was filtered off and washed with
2-propanol. Yield 4.43 g (84%). A mixed melting test with a sample obtained by method A did not give a
melting point depression.
2-[3(5)-Phenyl-4-pyrazolyl]-1H-benzimidazole (8a). A mixture of compound 6f (3.0 g, 11.4 mmol)
and hydrazine (3.0 ml, 60 mmol) hydrate in ethanol (15 ml) was boiled with a reflux condenser for 3 h. The
solution was evaporated under the vacuum of a water-jet pump at 95-100°C. The residue was mixed with water
(30 ml) and concentrated hydrochloric acid (3 ml) and heated to boiling. After cooling the precipitate was
filtered off, washed with iced water and with acetone, and dried at 95-100°C. We obtained 2.60 g of
hydrochloride of compound 8a (0.6 g of the sample was recrystallized from water for the 1H NMR spectrum). A
mixture of the obtained salt (2.0 g), acetone (10 ml), and 20% ammonia (2.0 ml) was boiled for 1 min and was
then diluted with water (20 ml). The boiling was continued with evaporation of the acetone until the product had
fully crystallized. The precipitate was filtered off and washed with water. Yield 1.43 g (63%); mp 188-189.5°C
(aqueous 2-propanol, 1:2). Found, %: C 73.7; H 4.6; N 21.5. C16H12N4. Calculated, %: C 73.8; H 4.7; N 21.5.
2-(1,5-Diphenyl-4-pyrazolyl)-1H-benzimidazole (8b). A mixture of compound 6f (0.26 g, 1 mmol),
phenylhydrazine (0.15 ml, 1.5 mmol), and DMF (1.5 ml) was boiled for 3 h. Water was added cautiously drop
by drop with stirring until crystallization began. After cooling the precipitate was filtered off and washed with
2-propanol. Yield 0.16 g (48%); mp 291-292°C (aqueous pyridine, 1:4). Found, %: C 78.7; H 4.6; N 16.6.
C22H16N4. Calculated, %: C 78.5; H 4.8; N 16.7.
2-[1-(4-Nitrophenyl)-5-phenyl-4-pyrazolyl]-1H-benzimidazole (8b). A mixture of compound 6f
(0.26 g, 1 mmol), p-nitrophenylhydrazine (0.18 g, 1.2 mmol), DMF (2.5 ml), and concentrated hydrochloric acid
(0.12 ml, 1.2 mmol) was boiled for 2 h. After cooling 20% ammonia (0.24 ml) was added, and the mixture was
heated to boiling with stirring. Water was added cautiously drop by drop with stirring until crystallization
began. After cooling the precipitate was filtered off and washed with 2-propanol. Yield 0.23 g (60%);
mp 259-260.5°C (aqueous DMF, 1:3). Found, %: C 69.4; H 4.2; N 18.5. C22H15N5O2. Calculated, %: C 69.3;
H 4.0; N 18.4.
558

REFERENCES
1.
2.
3.
4.
H. A. Naik, V. Purnaprajna, and S. Seshadri, Indian J. Chem., 15B, 338 (1977).
J. van Alpen, Rec. Trav. Chim., 59, 289 (1940).
I. B. Dzvinchuk, M. O. Lozinskii, and A. V. Vypirailenko, Zh. Org. Khim., 30, 909 (1994).
F. S. Babich and Yu. M. Volovenko, Eighth Ukrainian Republican Conference on Organic Chemistry.
Abstracts [in Russian], Donetsk (1978), p. 38.
5.
6.
R. Gordon and R. Ford, The Chemist's Companion, Wiley-Interscience (1973).
I. B. Dzvinchuk, A. V. Vypirailenko, V. V. Pirozhenko, and M. O. Lozinskii, Khim. Geterotsikl.
Soedin., 1512 (1999).
7.
8.
J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, The Tautomerism of Heterocycles. Adv.
Heterocycl. Chem. Suppl. 1, Academic Press, New York, etc. (1976), pp. 34, 41, 48, 269.
L. G. Tensmeyer and C. Ainsworth, J. Org. Chem., 31, 1878 (1966).
559