Halogen-Containing 2-methylpyrimido[1,2-a]-benzimidazol-4(10H)-ones

Article abstract of DOI:10.1007/s10593-014-1556-6

We have synthesized a series of 3-halo-substituted pyrimidobenzimidazolones and studied the alkylation reaction of the obtained derivatives.

Full text of DOI:10.1007/s10593-014-1556-6

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Chemistry of Heterocyclic Compounds, Vol. 50, No. 7, October, 2014 (Russian Original Vol. 50, No. 7, July, 2014)
HALOGEN-CONTAINING 2-METHYLPYRIMIDO[1,2-a]-
BENZIMIDAZOL-4(10Н)-ONES*
1
1
1
1**
E. N. Ulomskiy , O. S. El'tsov , S. S. Borisov , K. V. Savateev ,
E. K. Voinkov1, V. V. Fedotov1, and V. L. Rusinov1
We have synthesized a series of 3-halo-substituted pyrimidobenzimidazolones and studied the alkylation
reaction of the obtained derivatives.
Keywords: azolopyrimidines, nitrogen heterocycles, pyrimido[1,2-a]benzimidazol-4(10Н)-one, alkylation,
halogenation.
Aminobenzimidazoles and their structural analogs belong to an important group of compounds, many
representatives of which show a wide spectrum of biological activity, including antiviral effects. One of the
leading antiviral agents among 2-aminobenzimidazoles is maribavir (1) [1, 2].
Cl
Pr
-i
N
N
O
Ar
H
N
O
OH
N
H
O
H
N
OH
N
Cl
R
O
N
N
N
N
O
N
H
Me
OH OH
1
2
3
Condensed tricyclic derivatives of aminobenzimidazoles, pyrimidobenzimidazoles 2, 3, also exhibit
high activity with respect to respiratory syncytial virus, herpes virus, and HIV [3, 4]. The biological activity of
halogenated benzimidazoles and pyrimidobenzimidazoles is explained by their ability to bind with proteins
[5, 6] and DNA [7], which is not surprising, taking into account the obvious structural similarity with
4-quinolones, which often exhibit antimicrobial and antiviral activity due to inhibition of DNA gyrase [8, 9].
Thus, halogen-containing 2-methylpyrimido[1,2-a]benzimidazol-4(10H)-ones are a perspective group of
compounds that deserves attention. In this work, we present the results regarding the synthesis of halogen-
containing pyrimido[1,2-a]benzimidazol-4(10H)-ones and their alkylation.
_______
*Dedicated to Academician O. N. Chupakhin on the occasion of his 80th birthday.
**To whom correspondence should be addressed, e-mail: ulomsky@yandex.ru.
1Ural Federal University named after the First President of Russia B. N. Yeltsin, 19 Mira St., Yekaterinburg
620002, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1090-1099, July, 2014. Original
article submitted April 8, 2014.
0009-3122/14/5007-1005©2014 Springer Science+Business Media New York
1005

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It is known that heating of 2-aminobenzimidazole (4а) with acetoacetic ester in polyphosphoric acid
[10] or ethanol [11] results in the formation of 2-methylpyrimido[1,2-a]benzimidazol-4(10H)-one (5а). We have
established that compound 5а and its difluoro-substituted analog 5b easily form in higher than 80% yields when
this reaction is performed in refluxing pyridine. The use of fluoroacetoacetate in a reaction with 2-amino-
benzimidazoles 4a,b under the same conditions allowed to obtain 3-fluoro-2-methylpyrimido[1,2-a]benz-
imidazol-4(10H)-ones 6а,b with 78 and 71% yields, respectively.
O
O
O
R
F
Me
OEt
R
R
N
F
N
NH2
R
Me
Py, , 6 h
N
H
N
N
H
4a,b
6a,b
O
O
Py, , 4 h
Me
OEt
6
O
O
(For 7а, R = H):
R
R
X
4
7
3
HCl, KClO3, 50°C, 2 h
5
N
N
8
(For 8а,b):
Br2, CF3COOH, room temp., 2 h
R
R
Me
Me
2
N
10
N
9
N
N
H
1
H
(For 9а, R = H):
ICl, H2O, , 4 h
5a,b
7a, 8a,b, 9a
a R = H, b R = F; 7 X = Cl, 8 X = Br, 9 X = I
The structure of fluorinated derivatives 6а,b was established based on NMR spectroscopy and elemental
analysis data (Tables 1-3). The 19F NMR spectrum contained one signal (δ -168.2 ppm, Table 2), which pointed
to the presence of fluorine in the molecular structure of compound 6а, which was in a good agreement with the
spectral data for close structural analogs, 6-fluoro-1,2,4-triazolo[1,5-a]pyrimidin-7-ones (δ -169...-170 ppm)
[12]. The 13С NMR spectra also confirmed the presence of one fluorine atom in the pyrimidobenzimidazolone
6а. Thus, the resonance signals of four carbon atoms of the pyrimidine fragment (С-2,3,4 and СН3) appeared in
the 13С NMR spectra as doublets, due to the coupling with fluorine atom (δ, ppm / J, Hz, respectively:
126.2/26.0, 139.9/228.8, 151.9/28.1, 17.4/4.0, Table 3). In addition, the 1Н NMR signal of the methyl group was
a doublet (δ 2.30 ppm, J = 3.7 Hz, Table 2), which also confirmed the presence of fluorine atom in the
pyrimidine fragment.
Separate synthetic methods were developed for other 3-halo-substituted 2-methylpyrimido[1,2-a]benz-
imidazol-4(10H)-ones containing chlorine, bromine, and iodine atoms in the pyrimidine ring. Thus, the
chlorinated derivative 7а was obtained in 59% yield by the action of potassium chlorate in hydrochloric acid on
the pyrimidobenzimidazolone 5а. The previously published method for the synthesis of compound 7а by
condensation of 2-aminobenzimidazole (4a) with ethyl 2-chloroacetoacetate in methanol [13] was highly
effective (the preparative yield was 88%), but chloroacetoacetate ester was capable of aminoazole alkylation
side reactions, therefore our proposed method was more generally applicable to the synthesis of chloroazolo-
[1,5-a]pyrimidinones.
The synthesis of 3-bromo-2-methylpyrimido[1,2-a]benzimidazol-4(10H)-ones 8а,b was accomplished
1
by the action of bromine in trifluoroacetic acid on the pyrimidobenzimidazol-4(10H)-ones 5а,b. The Н NMR
spectra of brominated derivatives 8a,b contained one three-proton singlet at 2.47-2.49 ppm and multiplets at
7.34-8.38 ppm, corresponding to the methyl group and benzene ring protons (Table 2). The 13С NMR spectrum
of compound 8а featured a methyl group signal at 25.9 ppm, as well as the signals of ten carbon atoms forming
the heterocyclic system in the region of 89.7-161.3 ppm (Table 3).
1006

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TABLE 1. Physicochemical Characteristics of Compounds 5-21
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Mp,°С
Yield, %
C
H
N
C11H9N3O
66.29
66.32
4.60
4.55
21.11
21.09
287-290
>300
85
88
78
71
59
75
72
69
92
93
91
94
90
40
42
39
44
41
20
17
23
25
22
5a
C11H7F2N3O
C11H8FN3O
56.15
2.95
17.82
5b
56.18
3.00
17.87
60.79
60.83
3.73
3.71
19.37
19.35
>300
6a
C11H6F3N3O
C11H8ClN3O
C11H8BrN3O
C11H6BrF2N3O
C11H8IN3O
52.22
2.42
16.55
>300
6b
52.18
2.39
16.60
56.60
56.55
3.41
3.45
17.97
17.98
>300
7a
47.45
2.97
15.10
>300
8a
47.51
2.90
15.11
42.13
42.07
1.99
1.93
13.44
13.38
>300
8b
40.61
2.52
12.91
>300
9a
40.64
2.48
12.92
C11H7FN3NaO
C11H7ClN3NaO
C11H7BrN3NaO
C11H5BrF2N3NaO
C11H7IN3NaO
C12H10FN3O
C12H10ClN3O
C12H10BrN3O
C12H8BrF2N3O
C12H10IN3O
55.28
55.24
2.97
2.95
17.50
17.57
>300
10a
11a
12a
12b
13a
14a
15a
16a
16b
17a
18a
19a
20a
20b
21a
51.66
2.79
16.43
>300
51.68
2.76
16.44
44.00
44.03
2.40
2.35
13.98
14.00
>300
39.36
1.57
12.57
>300
39.31
1.50
12.50
38.09
38.07
2.05
2.03
12.05
12.11
>300
62.38
4.32
18.15
155-157
160-162
153-156
155-157
161-163
200-203
205-207
201-204
204-206
199-202
62.33
4.36
18.17
58.13
58.19
4.11
4.07
17.00
16.97
49.29
3.43
14.45
49.34
3.45
14.38
43.99
43.93
2.52
2.46
12.88
12.81
42.46
3.03
12.37
42.50
2.97
12.39
C12H10FN3O
C12H10ClN3O
C12H10BrN3O
C12H8BrF2N3O
C12H10IN3O
62.43
62.33
4.34
4.36
18.23
18.17
58.22
4.16
17.09
58.19
4.07
16.97
49.37
49.34
3.49
3.45
14.48
14.38
44.01
2.55
12.92
43.93
2.46
12.81
42.56
42.50
3.06
2.97
12.44
12.39
Finally, the synthesis of iodinated derivative 9а was accomplished in 69% yield by the action of
aqueous iodine chloride on pyrimidobenzimidazolone 5а. A common spectral feature of the halogenated
1
derivatives 6-9 was the increase of chemical shift of methyl group signals in Н NMR spectra from the
fluorinated derivative 6a (2.30 ppm) to the iodinated derivative 9а (2.57 ppm).
The halogenated derivatives 6-9 showed the properties of NH acids, forming stable salts 10-13 with
aqueous sodium carbonate. The 1Н NMR spectra of the sodium salts 10-13 contained one three-proton singlet at
2.30-2.57 ppm (Table 2). The 13С NMR spectra of sodium salts 10-13 contained a methyl group signal at
17.4-29.8 ppm and ten carbon signals of the heterocyclic system in the region of 89.7-164.9 ppm (Table 3).
Thus, the spectral characteristics of compounds 10-13 were in general agreement with the spectra of the
corresponding 3-halo-2-methylpyrimido[1,2-a]benzimidazol-4(10H)-ones 6-9.
1007

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