A new route for the synthesis of substituted 5-amino-4-cyanoimidazol-2-ones - Precursors for the preparation of 3,6,7,9-tetrahydro-8H-purin-8-ones derivatives

Article abstract of DOI:10.1007/s10593-011-0762-8

5-Alkyl(aryl)amino-4-cyanoimidazol-2-ones were obtained on the basis of 2-alkoxycarbonylamino-3,3-dichloroacrylonitriles. They were then used for the synthesis of derivatives of 3,6,7,9-tetrahydro-8H-purin-8-ones.

Full text of DOI:10.1007/s10593-011-0762-8

Chemistry of Heterocyclic Compounds, Vol. 47, No. 3, June, 2011 (Russian Original Vol. 47, No. 3, March, 2011)
A NEW ROUTE FOR THE SYNTHESIS OF SUBSTITUTED
5-AMINO-4-CYANOIMIDAZOL-2-ONES – PRECURSORS
FOR THE PREPARATION OF 3,6,7,9-TETRAHYDRO-
8H-PURIN-8-ONES DERIVATIVES
S. A. Chumachenko1, O. V. Shablykin1, A. P. Kozachenko,
T. V. Osadchuk, and V. S. Brovarets1*
5-Alkyl(aryl)amino-4-cyanoimidazol-2-ones were obtained on the basis of 2-alkoxycarbonylamino-
3,3-dichloroacrylonitriles. They were then used for the synthesis of derivatives of 3,6,7,9-tetrahydro-
8H-purin-8-ones.
Keywords: 5-alkyl(aryl)amino-2-oxoimidazole-4-thioamides, 5-alkyl(aryl)amino-4-cyanoimidazol-
2-ones, 2-alkoxycarbonylamino-3,3-dichloroacrylonitriles, 3,6,7,9-tetrahydro-8H-purin-8-ones, triethyl
orthoformate, heterocyclization.
It was shown previously [1,2] that compounds 1 [3-6] react readily with primary amines to form the
aminals 2.
Using method [2] we have obtained a series of compounds 2 containing aliphatic amine groups (2a-d, i),
aromatic amine groups (2e,f), and also cyclic amines (2g,h), with the object of synthesizing heterocyclic
compounds based on them.
Thus, we first showed that heating the aminals 2a-f in dilute alkali was accompanied by intramolecular
cyclization into the imidazol-2-ones 3a-f (cf. [7-9]. The possible mechanism, shown below, consists of
consecutive reactions: deprotonation (A) and cyclization (A→B→C) into an imidazolone with loss of a
molecule of an alcohol. Further protonation of the intermediate C leads to products 3.
For successful conversion of reagents 2a-f to compounds 3a-f the leaving group (RO) should possess
notable nucleophilicity, therefore introduction of the benzyloxycarbonyl derivative 2i (R = Bn) should facilitate
cyclization. However, apparently because of the steric effect of the benzyl group, the cyclization did not occur
and compound 2i decomposed under the reaction conditions. Similar instability under alkaline conditions
occurred with the cyclic aminals 2g,h.
The proposed approach gives the possibility of preparing a series of imidazolones 3a-f. Compound 3a
had been synthesized previously by other methods [10-12]. The presence of some functional groups in the
_______
* To whom correspondence should be addressed, e-mail: brovarets@bpci.kiev.ua
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanskaya St., Kyiv 02660, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, 410-416, March, 2011. Original article
submitted October 5, 2010
336
0009-3122/11/4703-0316©2011 Springer Science+Business Media, Inc.

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, ºС*
Yield, %
C
H
N
S
C7H12N4O2
C11H20N4O2
C19H20N4O2
C21H24N4O2
C17H16N4O2
C19H20N4O2
C7H10N4O2
C8H12N4O2
C25H24N4O2
C6H8N4O
45.70
45.65
54.87
54.98
67.80
67.84
69.18
69.21
66.18
66.22
67.80
67.84
46.02
46.15
48.88
48.97
72.73
72.80
47.28
47.36
57.63
57.67
71.00
71.04
72.21
72.27
69.47
69.55
71.01
71.04
71.62
71.68
72.78
72.81
70.31
70.33
63.81
63.88
65.56
65.55
61.87
61.92
63.81
63.88
65.44
65.50
66.94
67.00
6.62
6.57
8.31
8.39
5.87
5.99
6.53
6.64
5.18
5.23
5.89
5.99
5.50
5.53
6.08
6.16
5.78
5.86
5.23
5.30
7.68
7.74
5.23
5.30
6.01
6.06
4.31
4.38
5.21
5.30
5.63
5.70
6.32
6.40
4.82
4.86
5.29
5.36
6.04
6.05
4.51
4.55
5.29
5.36
4.57
4.63
5.31
5.35
30.43
30.42
23.26
23.31
16.59
16.65
15.29
15.37
18.12
18.17
16.59
16.65
30.71
30.75
28.47
28.55
13.49
13.58
36.77
36.82
26.85
26.90
18.37
18.41
16.78
16.85
20.22
20.28
18.36
18.41
17.53
17.16
16.11
16.17
19.26
19.30
16.48
16.55
15.26
15.29
17.98
18.05
16.48
16.55
16.02
16.08
14.81
14.88
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
160-161
35
40
73
65
75
75
40
38
64
45
50
85
80
85
75
78
74
75
56
25
45
45
80
75
82
85
2a
2b
2c
2d
2e
2f
113-115
152-153
136-137
150-152
181-183
193-195
2g
2h
2i
177-179
108-110
240-241
3a
3b
3c
3d
3e
3f
C10H16N4O
C18H16N4O
C20H20N4O
C16H12N4O
C18H16N4O
C19H18N4O
C21H22N4O
C17H14N4O
C18H18N4OS
C20H22N4OS
C16H14N4OS
C18H18N4OS
C19H16N4OS
C21H20N4OS
C17H12N4OS
C19H16N4OS
145-147
137-138
135-136
113-115
186-189
118-119
4c
4d
4e
5c
5d
5e
5f
90-92
185-186
9.49
9.47
8.77
8.75
10.27
10.33
9.49
9.47
9.25
9.20
8.57
8.52
10.10
10.01
9.25
9.20
173-175 (dec.)
120-122 (dec.)
130-131 (dec.)
140-142 (dec.)
236-237
6c
6d
6e
6f
120-122
63.68
63.73
65.44
65.50
3.71
3.78
4.57
4.63
17.42
17.49
16.02
16.08
282-283
310-312
_______
*Recrystallization solvents: ethyl acetate (compounds 2a-i), benzene
(compounds 3a-f, 4c-e), acetone (compounds 6c-f). Compounds 5c-f were
used for further conversions without further purification. The mp of
compounds 2a,c,d corresponded to those cited in [2], and compound 3a to that
in [10-12].
337

H
H
N
H
N
CN
RO
N
CN
Cl
RO
CN
R1NH2
1. KOH
2. HCl
Me2SO4/NaOH
O
O
O
N
Cl
HN
NH
R1
NHR1
R1
R1
2a–i
1a, b
Me
3a–f
CN
N
H2S/Py
O
N
NHR1
S
S
R1
H
N
H
HC(OEt)3
N
NH2
NHR1
N
4c–e
O
O
N
N
N
R1
R1
R1
5c–f
6c–f
1a, 2a–h R = Me, 1b, 2i R = Bn; 2,3 a R1 = Me, b R1 = Pr; 2c,i, 3c–6с R1 = Bn,
2, 3–6 d R1 = PhCH2CH2, 2, 3–6 e R1 = Ph, 2, 3, 5, 6 f R1 = 4-MeC6H4;
2g R1+R1 = (CH2)2, 2h R1+R1 = (CH2)3
TABLE 2. IR and Mass Spectra of Synthesized Compounds
Com-
pound
Mass spectrum,
IR spectrum, ν, cm-1
m/z [M]+
1747* (C=O), 2189 (CN), 3007-3327 (NH)
1716 (C=O), 2147 (CN), 2963-3378 (NH)
1716 (C=O), 2147 (CN), 2949-3342 (NH)
1710 (C=O), 2175 (CN), 3022-3360 (NH)
1726* (C=O), 2182 (CN), 3289-3376 (NH)
1697 (C=O), 2183 (CN), 3024-3327 (NH)
1730 (C=O), 2149 (CN), 3292-3411 (NH)
1702* (C=O), 2142 (CN), 3254-3551 (NH)
1719* (C=O), 2154 (CN), 3029-3350 (NH)
1749* (C=O), 2190 (CN), 3005-3326 (NH)
1721* (C=O), 2187 (CN), 2967-3330 (NH)
1692* (C=O), 2198 (CN), 3201-3325 (NH)
1710* (C=O), 2175 (CN), 3025-3360 (NH)
1694* (C=O), 2206 (CN), 3279-3383 (NH)
1704 (C=O), 2203 (CN), 3158-3397 (NH)
1711 (C=O), 2186 (CN), 3070-3565 (NH)
1707 (C=O), 2171 (CN), 3274-3505 (NH)
1702 (C=O), 2211 (CN), 3036-3218 (NH)
1719* (C=O), 3215-3583 (NH, NH2)
1721* (C=O), 3184-3553 (NH, NH2)
1719* (C=O), 3202-3353 (NH, NH2)
1695* (C=O), 3146-3380 (NH, NH2)
1710 (C=O), 3134 (NH)
184
240
336
364
308
336
182
196
412
152
208
304
332
276
304
318
346
290
338
366
310
338
348
376
320
348
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
4c
4d
4e
5c
5d
5e
5f
6c
6d
6e
6f
1715 (C=O), 3120 (NH)
1721 (C=O), 3130 (NH)
1717 (C=O), 3030 (NH)
_______
* Band with shoulder.
338

H
N
–
N
–
RO
CN
H
N
CN
CN
O
NaOH
HCl
2a–f
O
RO
–
N
R1
3a–f
O
–ROH
NH
R1
N
NHR1
N
NHR1
R1
R1
1
C
A
B
structure of the 5-alkyl(aryl)amino-4-cyanoimidazol-2-ones prepared (3a-f) allows their use as starting materials
for the synthesis of other examples of the imidazole series. Thus, in aqueous alkali compounds 3c-e were
alkylated with dimethyl sulfate to form 1-alkyl(aryl)-3-methylimidazol-2-ones 4c-e. The regioselective
alkylation of imidazolones is confirmed by a number of literature analogs [13-15] and also by 1H NMR spectral
data: the signals of the protons of the NMe group are found in the 3.03-3.23 ppm region. The thioamides 5c-f
were formed by the reactions of compounds 3c-f with hydrogen sulfide. We used the presence of the vicinal
thioamide and alkylamino groups in compounds 5c-f to obtain the purine analogs 6c-f, which are potential
biologically active compounds (cf. [16-18]).
Preliminary investigations of compounds 3 as inhibitors of furin showed that they had inhibitory effects
in the experimental conditions at 28.0-31.7%, which shows that these compounds have prospects for the creation
of modern medicinal preparations [19-22]. It should be noted that the N-methyl derivatives 4 show practically
no inhibition of furin under analogous conditions.
EXPERIMENTAL
IR spectra of KBr disks were recorded with a Vertx-70 spectrometer. 1H NMR spectra were obtained on
a Varian-300 (300 MHz) instrument with TMS as the internal standard. Chromato-mass spectra were obtained
using liquid chromato-mass spectrometer system based on an Agilent 1100 Series high efficiency liquid
chromatograph equipped with a diode matrix with an Agilent LC/MSD SL mass-selective detector. Parameters
of the chromato-mass analysis: Zorbax SB-C18 column, 1.8μm, 4.615 mm (PN 821975-932); solvents: A –
acetonitrile–water, 95:5, 0.1% trifluoroacetic acid, B – 0.1% aqueous trifluoroacetic acid, flow of eluent
3 ml/min, injection volume 1 μl; UV detectors – 215, 254, 285 nm; method of ionization – chemical ionization
at atmospheric pressure (APCI), scanning range m/z 80-1000. Melting points were measured with a Fisher-Johns
apparatus.
2-Alkyloxycarbonylamino-3,3-di[alkyl(aryl)amino]acrylonitriles 2a-i. To a suspension of compound
1a,b (0.05 mol) in tetrahydrofuran (100 ml), triethylamine (0.11 mol) was added with stirring and cooling
(10-15°C), followed by the corresponding amine (0.11 mol). The mixture was stirred for 12 h, the solvent was
evaporated in vacuum, the precipitate was washed with water and purified by recrystallization.
1-Alkyl(aryl)-5-alkyl(aryl)amino-2-oxo-2,3-dihydro-1H-imidazole-4-carbonitriles 3a-f. Potassium
hydroxide (0.015 mol) in water (2 ml) was added to a suspension of one of compounds 2a-f (0.005 mol) in
ethanol (10 ml) and the mixture was boiled for 10 min. The solution was cooled and water (5 ml) and 10%
hydrochloric acid (5.5 ml) were added. The precipitate was filtered off, washed with water and purified by
recrystallization.
1-Alkyl(aryl)-5-alkyl(aryl)amino-3-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carbonitriles
4c-e.
Dimethyl sulfate (0.015 mol) was added dropwise with stirring to a solution of one of the compounds 3c-e
(0.005 mol) in 5% aqueous sodium hydroxide solution (15 ml), the reaction mixture was stirred for a further 4 h
at 20-25°C, the precipitate formed was filtered off, washed with water and purified by recrystallization.
1-Alkyl(aryl)-5-alkyl(aryl)amino-2-oxo-2,3-dihydro-1H-imidazole-4-thioamides 5c-f. One of com-
pounds 3c-f (0.005 mol) was dissolved in a mixture of pyridine (10 ml) and triethylamine (1ml). A rapid flow
339

TABLE 3. 1H NMR Spectra of Synthesized Compounds
Com-
pound
Chemical shifts (DMSO-d6), δ, ppm (J, Hz)
2.83 (3Н, s, СН3); 3.05 (3Н, s, СН3); 3.34 (3Н, s, СН3); 6.07 (2Н, br. s, 2NH);
7.81 (1Н, br. s, NH)
2a
2b
2c
0.74-0.85 (6Н, m, 2СН3); 1.35-1.60 (4Н, m, 2СН2); 2.85-2.92 (2Н, m, СН2);
3.05-3.16 (2Н, m, СН2); 3.54 (3Н, s, СН3); 5.40-5.60 (2Н, br. s, 2NH); 7.55 (1Н, s, NH)
3.55 (3Н, s, СН3); 4.27 (2Н, d, J = 5.9, СН2); 4.32 (2Н, d, J = 5.9, СН2);
6.23 (1Н, br. s, NH); 6.33 (1Н, br. s, NH); 7.08-7.32 (10Н, m, Н arom);
7.72 (1Н, s, NH)
2.63 (2Н, m, СН2); 2.82 (2Н, m, СН2); 3.15-3.25 (2Н, m, СН2);
3.40-3.52 (2Н, m, СН2); 3.56 (3Н, s, СН3); 5.61 (1Н, br. s, NH); 5.77 (1Н, br. s, NH);
10.07-10.21 (10Н, m, Н arom); 7.61 (1Н, s, NH)
2d
3.50 (3Н, s, СН3); 6.95-7.22 (10Н, m, Н arom); 8.03 (1Н, s, NH); 8.57 (1Н, s, NH);
8.72 (1Н, s, NH)
2e
2f
2.18 (6Н, s, 2СН3); 3.57 (3Н, s, СН3); 6.92-7.05 (8Н, m, Н arom); 7.95 (1Н, s, NH);
8.43 (1Н, s, NH); 8.49 (1Н, s, NH)
3.37-3.49 (4Н, m, 2СН2); 3.55 (3Н, s, СН3); 6.48 (1Н, br. s, NH); 6.64 (1Н, br. s, NH);
7.42 (1Н, s, NH)
2g
2h
2i
1.73 (2Н, m, СН2); 3.07-3.17 (4Н, m, 2СН2); 3.55 (3Н, s, СН3); 6.23 (1Н, br. s, NH);
6.42 (1Н, br. s, NH); 7.32 (1Н, s, NH)
4.18 (2Н, d, J = 5.4, СН2); 4.28 (2Н, d, J = 4.7, СН2); 5.05 (2Н, s, СН2);
6.25 (1Н, br. s, NH); 7.11 (1Н, br. s, NH); 7.21-7.33 (15Н, m, Н arom);
7.82 (1Н, s, NH)
2.87 (3Н, d, J = 3.5, СН3); 2.97 (3Н, s, СН3); 6.52 (1Н, br. s, NH); 9.77 (1Н, s, NH)
3a
3b
0.85-0.92 (6Н, m, 2СН3); 1.50-1.60 (4Н, m, 2СН2); 3.10-3.16 (2Н, m, СН2);
3.43-3.47 (2Н, m, СН2); 6.46 (1Н, br. s, NH); 9.72 (1Н, s, NH)
3c
4.36 (2Н, d, J = 4.4, СН2); 4.83 (2Н, s, СН2); 7.25-7.38 (10Н, m, Н arom);
7.43 (1Н, br. s, NH); 10.02 (1Н, s, NH)
3d
2.73 (2Н, m, СН2); 2.85 (2Н, m, СН2); 3.39 (2Н, m, СН2); 3.74 (2Н, m, СН2);
6.72 (1Н, br. s, NH); 7.27-7.43 (10Н, m, Н arom); 9.90 (1Н, s, NH)
6.65-7.58 (10Н, m, Н arom); 8.30 (1Н, s, NH); 11.02 (1Н, s, NH)
3e
3f
2.18 (3Н, s, СН3); 2.31 (3Н, s, СН3); 6.77 and 6.98 (4Н, two d, J = 7.5, С6Н4);
7.23 (4Н, s, С6Н4); 8.08 (1Н, s, NH); 10.88 (1Н, s, NH)
3.07 (3Н, s, СН3); 4.45 (2Н, d, J = 6.1, СН2); 4.92 (2Н, s, СН2);
7.23-7.52 (10Н, m, Н arom); 8.35 (1Н, br. s, NH)
4c
4d
2.73 (2Н, m, СН2); 2.88 (2Н, t, J = 7.2, СН2); 3.03 (3Н, s, СН3); 3.39 (2Н, m, СН2);
3.75 (2Н, t, J = 7.2, СН2); 7.91 (1Н, s, NH); 7.25-7.33 (10Н, m, Н arom)
3.23 (3Н, s, СН3); 6.75-7.47 (10Н, m, Н arom); 8.38 (1Н, s, NH)
4e
5c
4.37 (2Н, d, J = 6.1, СН2); 4.95 (2Н, s, СН2); 7.23-7.33 (10Н, m, Н arom);
7.46 (1Н, br. s, NH); 7.78 (1Н, br. s, NH); 9.83 (1Н, br. s, NH); 10.15 (1Н, br. s, NH)
5d
2.76 (2Н, m, СН2); 2.91 (2Н, t, J = 6.9, СН2); 3.42-3.49 (2Н, m, СН2);
3.75 (2Н, t, J = 6.9, СН2); 7.09-7.51 (10Н, m, Н arom); 7.53 (1Н, br. s, NH);
7.83 (1Н, br. s, NH); 9.86 (1Н, br. s, NH); 10.22 (1Н, br. s, NH)
9.02-9.62 (10Н, m, Н arom); 7.95 (1Н, br. s, NH); 8.87 (1Н, br. s, NH);
10.13 (1Н, br. s, NH); 10.42 (1Н, br. s, NH)
5e
5f
2.09 (3Н, s, СН3); 2.19 (3Н, s, СН3); 6.63 and 6.82 (4Н, two d, J = 6.5, С6Н4);
7.04 and 7.15 (4Н, two d, J = 6.0, С6Н4); 7.93 (1Н, br. s, NH); 8.82 (1Н, br. s, NH);
10.18 (1Н, br. s, NH); 10.28 (1Н, br. s, NH)
4.83 (2Н, s, СН2); 5.43 (2Н, s, СН2); 6.96-7.42 (10Н, m, Н arom); 8.23 (1Н, s, NH);
11.73 (1Н, s, CH)
6c
2.94 (2Н, t, J = 7.4, СН2); 3.18 (2Н, t, J = 7.1, СН2); 4.08 (2Н, t, J = 7.4, СН2);
6d
4.35 (2Н, t, J = 7.1, СН2); 6.85-7.40 (10Н, m, Н arom); 7.84 (1Н, s, NH);
11.43 (1Н, s, CH)
7.08-7.40 (10Н, m, Н arom); 8.23 (1Н, s, NH); 11.63 (1Н, s, CH)
6e
6f
2.20 (6Н, s, 2СН3); 6.88 (4Н, s, С6Н4); 6.92 and 7.14 (4Н, two d, J = 7.5, С6Н4);
8.16 (1Н, s, NH); 11.57 (1Н, s, CH)
340

of hydrogen sulfide was passed through this solution for 1 h, it was stirred for a further 2 h at 20-25°C, water
(50 ml) was added, the precipitate was filtered off, and compounds 5c-f were used in further reactions without
additional purification.
3,9-Dialkyl(aryl)-6-thioxo-3,6,7,9-tetrahydro-8H-purin-8-ones 6c-f. A solution of the corresponding
imidazolone 5c-f in ethyl orthoformate (15 ml) was boiled for 4 h, the precipitate formed was filtered off,
washed with ether, and recrystallized.
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