Synthesis and physicochemical properties of imidazo[1,2-f]xanthine derivatives

Article abstract of DOI:10.1007/s10600-014-0871-6

A simple preparative method for the synthesis of imidazo[1,2-f]xanthine derivatives, promising synthons for further modification of the xanthine molecule, was developed. The spectral characteristics of the synthesized compounds were studied.

Full text of DOI:10.1007/s10600-014-0871-6

Chemistry of Natural Compounds, Vol. 50, No. 1, March, 2014 [Russian original No. 1, January–February, 2014]
SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES
OF IMIDAZO[1,2-f]XANTHINE DERIVATIVES
1*
2
1
N. I. Romanenko, T. N. Rak, O. A. Pakhomova,
1
1
D. G. Ivanchenko, and A. A. Mylova
A simple preparative method for the synthesis of imidazo[1,2-f]xanthine derivatives, promising synthons for
further modification of the xanthine molecule, was developed. The spectral characteristics of the synthesized
compounds were studied.
Keywords: xanthine, synthesis, amines.
Xanthine derivatives that are variously condensed along the “f” edge exhibit a broad spectrum of biological activity
[1–4]. Imidazo[1,2-f]xanthines are the most studied of these with respect to both chemistry [5–7] and biology [8–11]. The
development of simple laboratory synthetic methods for new derivatives of this heteroaromatic system is of great practical and
theoretical interest because the xanthine molecule could be substantially modified at the uracil and annelated imidazole cores.
Therefore, the library of potential biologically active chemical compounds would be expanded.
Hence, we synthesized previously unknown imidazo[1,2-f]xanthine derivatives 3–16 by reacting 8-bromo-7-(2-
oxopropyl)xanthines (1 and 2) [12] with primary aliphatic amines in aqueous dioxane.
O
13
CH
12
O
O
C
3
4
6
1
N
3
N
5
N
R
7
R
5
6
N
CH
2
11
R CH NH
2
1
2
O
N3
N
Br
O
N1
N
N
12CH
2
7 CH
3
9
9
11
CH
CH
3
3
10
10
R
1
1, 2
1: R = H; 2: R = CH ; 3: R = H, R = CH(CH ) ; 4: R = H, R = n-C H ; 5: R = H, R = n-C H
5 11
3 - 16
3
1
3 2
1
4
9
1
6: R = H, R = (CH ) -morpholine-4; 7: R = CH , R = H; 8: R = CH , R = C H ; 9: R = CH ; R = n-C H
1
2 2
3
1
3
1
2
5
3
1
3 7
10: R = CH , R = CH(CH ) ; 11: R = CH , R = n-C H ; 12: R = CH , R = n-C H ; 13: R = CH , R = C H
3
1
3 2
3
1
4
9
3
1
5
11
3
1
6 5
14: R = CH , R = CH C H ; 15: R = CH , R = n-C H ; 16: R = CH , R = (CH ) OCH
3
1
2
6
5
3
1
5
11
3
1
2 2
3
The synthetic method for imidazo[1,2-f]xanthines that was proposed by us had important advantages over previously
published methods [13, 14]. Water was used as the solvent (dioxane was added for homogenization of the solution). The
reaction occurred at 100°C in 1.5-2.0 h. Therefore, this method had more favorable economic factors.
PMR spectra of 3–16 (Table 1) had characteristic singlets in the range 7.34–7.24 ppm (1H) and 2.32–1.96 ppm (3H)
that were due to resonance of the aromatic proton in the 6-position and methyl protons in the 7-position, respectively, and
confirmed unambiguously that an external imidazole ring was present. Methylene proton resonances (2H) of the appropriate
shape in the range 4.22–3.78 ppm proved that the alkyl substituent was present in the 8-position.
The benzyl methylene protons were found in the spectrum of 13 as a singlet at weak field of 5.30 ppm. Proton
resonances of other substituents in the 8-position of the imidazoxanthine were clearly resolved at the appropriate field with the
appropriate shape and intensity (Table 1). The uracil part of 3–6 was characterized by singlets in the ranges 10.86–10.69 (1H,
N H) and 3.40–3.35 ppm (3H, N CH ). Theophylline derivatives 7–16 were characterized by two strong singlets in the range
3
1
3
3.45–3.20 ppm that were due to resonance of N-methyl protons. These data confirmed convincingly the structures of the
synthesized compounds.
1) Zaporozhe State Medical University, Ukraine, 69035, Zaporozhꢀe, Ul. Mayakovskogo, 26,
e-mail: olya-martynyuk@rambler.ru; 2) S. I. Georgievskii Crimea State Medical University, Ukraine, 95006, Simferopolꢀ,
Blvr. Lenina, 5/7, Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2014, pp. 74–75. Original
article submitted September 13, 2013.
©
80
0009-3130/14/5001-0080 2014 Springer Science+Business Media New York

TABLE 1. PMR Spectra of compounds 3–16 (ꢁ, ppm)
NH
(1H, s)
N8CH2
(2H)
N1CH3, N3CH3
(3H, s)
CH3-7
(3H, s)
Compound
H-6 (1H, s)
Other resonances
10.86
10.69
7.34
7.24
3.8 d
4.0 t
3.35
3.40
2.29
2.32
2.24 (1Í, m, Í-13); 0.88 (6Í, d, Í-14, 15)
1.79 (2Í, m, Í-13); 1.36 (4Í, m, Í-14, 15);
0.91 (3Í, t, Í-16)
3
4
10.85
10.78
7.31
7.26
3.99 t
4.05 t
3.36
3.36
2.3
1.76 (2Í, m, Í-13); 1.28 (6Í, m, Í-14–16);
0.85 (3Í, t, Í-17)
3.53 (4Í, br.s, Í-17, 18);
2.29 (6Í, m, Í-14–16); 1.95 (2Í, m, Í-13)
–
1.79 (2Í, m, Í-14); 0.88 (3Í, t, Í-15)
1.77 (2Í, m, Í-14); 1.34 (2Í, m, Í-15);
0.95 (3Í, t, Í-16)
5
6
2.32
–
–
–
7.26
7.31
7.29
–
3.58*; 3.41; 3.24
3.41; 3.21
2.29
2.3
2.32
7
8
9
3.96 t
4.01 t
3.45; 3.24
–
–
7.31
7.3
3.78 d
3.97 t
3.39; 3.2
3.40; 3.2
2.29
2.3
2.21 (1Í, m, Í-14); 0.88 (6Í, d, Í-15, 16)
1.80 (2Í, m, Í-14); 1.27 (4Í, m, Í-15, 16);
0.85 (3Í, t, Í-17)
10
11
–
–
–
–
–
7.28
4.0 t
5.3 s
3.44; 3.24
3.42; 3.21
3.43; 3.22
3.44; 3.22
3.41; 3.21
2.32
2.23
1.96
2.31
2.29
1.79 (2Í, m, Í-14); 1.28 (6Í, m, Í-15–17);
0.86 (3Í, t, Í-18)
–
12
13
14
15
16
7.41–7.22
(6H, m, Í-6, 15–19)
7.23–7.1
(6H, m, Í-6, 16–20)
7.32
4.22 t
4.06 t
4.05 t
3.08 (2Í, t, Í-14)
4.66 (1Í, t, ÎÍ); 3.44 (2Í, m, Í-15);
1.92 (2Í, m, Í-14)
3.32 (2Í, t, ÎÑÍ2-15);
7.32
3.23 (3Í, s, ÎÑÍ3-16); 2.0 (2Í, m, Í-14)
______
*Chemical shift of resonances for protons N –, N –, and N –CH .
1
3
8
3
TABLE 2. Physicochemical Data and Yields of compounds 3–16
Compound
Empirical formula
Yield, %
Compound
Empirical formula
Yield, %
mp, ꢂÑ
mp, ꢂÑ
260–262
223–224
208–209
219–220
229–230
206–207
188–189
C13H17N5O2
C14H19N5O2
C15H21N5O2
C16H22N6O3
C11H13N5O3
C13H17N5O2
C14H19N5O2
65.5
90.0
81.8
54.6
40.4
78.5
62.3
167–168
181–182
176–177
219–220
223–224
248–249
178–179
C14H19N5O2
C15H21N5O2
C16H23N5O2
C17H17N5O2
C18H19N5O2
C13H17N5O3
C14H19N5O3
65.7
85.8
83.6
57.3
56.4
51.5
62.3
3
4
5
6
7
8
9
10
11
12
13
14
15
16
EXPERIMENTAL
Melting points were determined in open capillaries on a PTP (M) apparatus. PMR spectra were recorded in DMSO-d
6
or DMSO-d + CDCl with TMS internal standard on a Bruker SF-400 spectrometer. Elemental analyses were carried out on
6
3
an Elementar vario EL cube instrument and agreed with those calculated. Tables 1 and 2 present the physicochemical properties
of the compounds.
Synthesis of 3,8-Disubstituted 1,7-Dimethylimidazo[1,2-f]xanthines (3-16). A mixture of bromoxanthine (1 or 2,
0.01 mol), the appropriate primary amine (0.03 mol; for the syntheses of 7 and 8, 0.1 mol of 40% methylamine or propylamine
was used), H O (30 mL), and dioxane (5–10 mL) was refluxed for 1.5–2.0 h and cooled. The precipitate was filtered off,
2
washed with H O, and crystallized from aqueous i-PrOH (3–12 and 15), aqueous dioxane (13 and 14), or H O (16).
2
2
81

REFERENCES
1.
2.
V. M. Dianov, Vopr. Biol. Med. Farm. Khim., 3, 55 (2009).
N. I. Romanenko, B. A. Samura, I. V. Fedulova, B. A. Priimenko, A. Yu. Chervinskii, and S. N. Garmash, Khim.-farm.
Zh., 187 (1986).
3.
4.
N. I. Romanenko, I. V. Fedulova, B. A. Priimenko, B. A. Samura, L. M. Kapkan, A. Yu. Chervinskii, T. M. Pekhtereva,
and S. N. Garmash, Khim.-farm. Zh., 427 (1986).
N. I. Romanenko, I. V. Fedulova, B. A. Priimenko, N. A. Klyuev, T. A. Pereverzeva, B. A. Samura,
and E. V. Aleksandrova, Khim.-farm. Zh., 49 (1996).
5.
6.
7.
Yu. V. Strokin, B. A. Priimenko, A. K. Sheikman, and N. A. Klyuev, Khim. Geterotsikl. Soedin., 1404 (1979).
B. A. Priimenko, B. A. Samura, S. N. Garmash, N. A. Klyuev, and N. I. Romanenko, Khim.-farm. Zh., 32 (1983).
S. N. Garmash, B. A. Priimenko, N. A. Klyuev, N. I. Romanenko, and A. K. Sheikman, Khim. Geterotsikl. Soedin.,
407 (1984).
8.
9.
10.
V. I. Kornienko, B. A. Samura, M. I. Romanenko, and M. V. Glushchenko, Visn. Farm., 57 (1), 67 (2009).
B. A. Samura, N. I. Romanenko, and M. V. Glushchenko, Zaporozh. Med. Zh., 52 (1), 89 (2009).
V. I. Kornienko, B. A. Samura, N. I. Romanenko, and M. V. Glushchenko, Probl. Ecol. Med. Genet. Clin. Immunol.,
90 (3), 180 (2009).
11.
12.
I. V. Kireev, Visn. SumDU, Ser. Med., 1, 22 (2009).
M. I. Romanenko, T. M. Rak, O. O. Martinyuk, B. A. Samura, V. I. Kornienko, and B. O. Priimenko, Visn. Farm.,
65 (1), 67 (2011).
13.
14.
P. M. Kochergin, V. I. Linenko, A. A. Tkachenko, B. A. Samura, and M. V. Povstyanoi, Khim.-farm. Zh., 22 (1971).
A. A. Tkachenko, P. M. Kochergin, and F. A. Zubkov, Khim. Geterotsikl. Soedin., 682 (1971).
82