Synthesis, Transformations, and Physicochemical Properties of 3-(4′-Methylphenyl)-8-Methylxanthine Derivatives

Article abstract of DOI:10.1007/s10600-014-0830-2

A preparative method for producing of 3-(4′-methylphenyl)-8- methylxanthine, its 7-substituted derivatives, 3-(4′-methylphenyl)-8- methylxanthinyl-7-acetic acid, its ester, amide, hydrazide, ylidenehydrazides, and N-phenylhydrazinocarbothiamide was developed. The structure of the cyclization product of the last, 3-(4′-methylphenyl)-7-[2-(4″- phenyl-5″-thio-4″H-[1″,2″,4″]triazol-3″-yl) methyl]xanthine, was confirmed by elemental analysis and PMR spectroscopy.

Full text of DOI:10.1007/s10600-014-0830-2

Chemistry of Natural Compounds, Vol. 49, No. 6, January, 2014 [Russian original No. 6, November–December, 2013]
SYNTHESIS, TRANSFORMATIONS, AND PHYSICOCHEMICAL
PROPERTIES OF 3-(4ꢀ-METHYLPHENYL)-
8-METHYLXANTHINE DERIVATIVES
*
E. V. Aleksandrova, S. V. Levich, N. I. Romanenko,
UDC 547.857.4ꢀ211.024.03/.04.057
A. S. Shkoda, and E. K. Mikhalꢀchenko
A preparative method for producing of 3-(4ꢀ-methylphenyl)-8-methylxanthine, its 7-substituted derivatives,
3-(4ꢀ-methylphenyl)-8-methylxanthinyl-7-acetic acid, its ester, amide, hydrazide, ylidenehydrazides, and
N-phenylhydrazinocarbothiamide was developed. The structure of the cyclization product of the last,
3-(4ꢀ-methylphenyl)-7-[2-(4ꢀꢀ-phenyl-5ꢀꢀ-thio-4ꢀꢀH-[1ꢀꢀ,2ꢀꢀ,4ꢀꢀ]triazol-3ꢀꢀ-yl)methyl]xanthine, was confirmed
by elemental analysis and PMR spectroscopy.
Keywords: xanthines, synthesis, PMR spectroscopy.
3-Methylxanthine derivatives are known to possess various types of pharmacological activity [1–7] that are responsible
for their wide range of medical application [8–10]. However, their structural analogs with different substituents in the
3-position of the bicyclic xanthine are insufficiently studied.
The goal of the present work was to elaborate synthetic approaches to the production of previously undescribed
3-(4ꢀ-methylphenyl)-8-methylxanthine derivatives and to study their physicochemical properties.
We used the known method of Traube xanthine synthesis to synthesize starting 3-(4ꢀ-methylphenyl)-8-methylxanthine
(2) [11] from 1-(4ꢀ-methylphenyl)-5,6-diamino-(1H,3H)pyrimidine-2,4-dione (1) [12], heating of which in an excess of glacial
acetic acid with subsequent cyclization of the intermediate in aqueous NaOH produced 2.
The PMR spectrum of 2 (Table 1) lacked resonances for the amines that were characteristic of 1. Instead, singlets for
NH groups at 13.39 ppm and methyl at 2.35 ppm of the corresponding intensities were observed and proved that the imidazole
ring had formed.
We showed earlier [13, 14] that alkylation of 3-arylxanthines in DMF in the presence of an equimolar amount of
NaHCO occurred at the N atom in the 7-position. We used this feature to produce 7-substituted 3–6 by reaction of 2 with
3
halocarbonyl compounds (ꢁ-bromoacetophenone, chloroacetic acid, n-propyl chloroacetate, or chloroacetamide). PMR spectra
of synthesized 3–6 (Table 1) lacked resonances for imidazole NH groups, which confirmed the substitution, and exhibited 2H
singlets for methylenes in the range 5.92–4.91 ppm. Resonances for xanthine protons and substituents in the 3-, 7-, and
8-positions of the bicyclic core were found at the appropriate fields with the corresponding shapes and intensities and proved
the structures of 3–6.
3-(4ꢀ-Methylphenyl)-8-methylxanthinyl-7-acetic acid (5) was produced in high final yield as a result of alkaline
hydrolysis of ester 6 or amide 4. Ester 6 was also synthesized by refluxing 5 in propanol-1 in the presence of dioxane and a
catalytic amount of conc. H SO . Samples of 5 and 6 that were produced by the different methods did not show melting-point
2
4
depression. Their PMR spectra were identical.
Considering that acid hydrazides are convenient synthons for further structural modification of the acetohydrazide
motif, including for the synthesis of various benzylidenehydrazides, potential antioxidants and antimicrobial compounds, 6
was reacted with an excess of hydrazine hydrate in EtOH to produce hydrazide 7 as a precipitate from the reaction mixture
after a few minutes of heating. Compound 7 was used in further reactions without additional purification.
Zaporozhe State Medical University, 69035, Ukraine, Zaporozhe, Prosp. Mayakovskogo, 26, e-mail:
rshlevas@gmail.com. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2013, pp. 950–953.
Original article submitted September 4, 2013.
©
0009-3130/14/4906-1105 2014 Springer Science+Business Media New York
1105

23
21
7
25
O
O
19
H
O
18
3
HN
1
5
5
NH
NH
2
2
N 7
O
17
CH
HN
1
5
N
3
17
3
HN
1
N
CH
3
O
N
O
N
7
9
3
10
N
O
N
9
11
15
10
11
15
11
9
13
16 CH
CH
13
3
3
3
1
CH
3
2
22
CH
OH
20
3
NH
2
3
19
19
O
18
21
18
O
19
O
18
N
7
O
N
7
17
17
CH
3
N
7
CH
3
17
CH
N
N
9
9
5
N
4
23
9
6
20
R
NH
2
HN
21
N
25
19
HN
18
7
19
O
18
7
N
N
O
17
CH
3
17
N
CH
3
9
N
31
7
9
8-12
O
29
25
25
H
S
20
SH
S
27
N
21
25
33
21 20
N
21 20
N
23
23
23
NH
N
N
HN
O
19
19
18
O
O
18
18
N
N
19
O
1
HN
5
N
1
1
5
5
N
7
N 7
7
17
CH
17
CH
HN
HN
CH
3
3
3
3
17
3
N
3
N
N
O
N
N
N
9
9
O
O
9
10
10
10
11
15
11
11
15
15
13
16CH
13
13
13
14
15
3
CH
CH
16
3
3
16
8: R = H; 9: R = Cl; 10: R = N(CH ) ; 11: R = OH; 12: R = OCH
3 2
3
The PMR spectrum of 7 (Table 1) contained resonances for protons of the acetohydrazide radical as broad singlets at
9.37 (1H, NH) and 4.31 ppm (2H, NH ). Resonances for methyl and methylene protons of the ester group were missing.
2
Brief heating of 7 with aromatic aldehydes in aqueous dioxane in the presence of AcOH produced
benzylidenehydrazides 8–12. Reaction with phenylisothiocyanate gave N-phenylhydrazinocarbothiamide 13.
PMR spectra of 8–12 (Table 1), in contrast with that of starting 7, showed singlets in the range 8.06–7.89 ppm for
resonances of the azomethine protons of the aldehyde group. Resonances for the hydrazide NH protons were shifted to weak
field in the range 11.84–11.52 ppm. This was explained by the electron-accepting effect of the N atom. Resonances of other
protons corresponded with the structure of the ylidenehydrazine substituents in the 7-position and proved unambiguously their
structures (Table 1).
The PMR spectrum of N-phenylhydrazinocarbothiamide 13 (Table 1) showed singlets for four NH protons at weak
field of 11.36, 10.51, 9.82, and 9.76 ppm. The intensity of the multiplet for the aromatic protons increased to nine units
compared with starting hydrazide 7.
Because 1,2,4-triazoles exhibit broad spectra of biological activity [15] and combination into a single structure of
triazole and natural heterocycles is advantageous [16], we synthesized 3-(4ꢀ-methylphenyl)-7-[2-(4ꢂ-phenyl-5ꢂ-thio-4ꢂH-
[1ꢂ,2ꢂ,4ꢂ]triazol-3ꢂ-yl)methyl]-8-methylxanthine (14) by heating 13 in basic solution. The PMR spectrum of 14 (Table 1) had
a singlet at 13.98 ppm that was due to the resonance of the SH proton and lacked resonances for NH protons of the
hydrazinocarbothioamide moiety.
1106

TABLE 1. PMR Spectra of Synthesized compounds 2–15 (400 MHz, CDCl , ꢃ, ppm, J/Hz)
3
Í-1
(1Í, s)
3H-17
(3Í, s)
3H-16
(3Í, s) (2Í, s)
2H-18
Compound
Harom.
Other resonances
11.22
11.18
7.31–7.12 (4Í, m, Í-11, 12, 14, 15)
8.22–7.92 (2Í, d, Í-14, 15);
2.35
2.32
2.18
2.20
–
5.92
13.39 (1Í, s, Í-7)
–
2
3
7.78–7.42 (5Í, m, Í-21-26);
7.40–7.19 (2Í, d, Í-11, 12)
11.12
11.20
11.21
7.36–7.17 (4Í, m, Í-11, 12, 14, 15)
7.34–7.19 (4Í, m, Í-11, 12, 14, 15)
7.32–7.16 (4Í, m, Í-11, 12, 14, 15)
2.36
2.38
2.31
2.19
2.22
2.19
4.91
5.01
5.14
7.69 (2Í, s, NH2-19)
12.61 (1H, s, OH-19)
4.13 (2Í, t, OCH2-20),
1.54 (2H, m, CH2-21),
0.82 (3Í, t, CH3-22)
9.37 (1Í, s, NH-19),
4.31 (2Í, s, NH2)
11.82 (1Í, s, NH-19),
8.02 (1Í, s, CH-20),
11.84 (1Í, s, NH-19),
8.06 (1Í, s, CH-20)
4
5
6
11.17
11.23
11.24
7.30–7.13 (4Í, m, Í-11, 12, 14, 15)
2.34
2.37
2.34
2.12
2.21
2.21
4.93
5.50
5.52
7
8
9
7.71–7.19 (9Í, m, Í-11, 12, 14, 15, 22–26)
7.80–7.62 (2Í, d, Í-22, 23);
7.53–7.39 (2Í, d, Í-25, 26);
7.32–7.12 (4Í, m, Í-11, 12, 14, 15)
7.52–7.39 (2Í, d, Í-22, 23);
7.33–7.18 (4Í, m, Í-11, 12, 14, 15);
6.79–6.64 (2Í, d, Í-25, 26)
7.59–7.42 (2Í, d, Í-22, 23);
7.36–7.22 (4Í, m, Í-11, 12, 14, 15);
6.92–6.75 (2Í, d, Í-25, 26)
7.71–7.52 (2Í, d, Í-22, 23);
7.52–7.22 (4Í, m, Í-11, 12, 14, 15);
7.03–6.89 (2Í, d, Í-25, 26)
11.17
11.19
11.22
11.36
2.35
2.39
2.36
2.38
2.20
2.21
2.24
2.24
5.43
4.99
5.54
5.06
11.52 (1Í, s, NH-19),
7.89 (1Í, s, CH-20),
2.98 (6H, s, CH3-27, 28)
11.60 (1Í, s, NH-19),
9.91 (1Í, s, ÎH-24),
7.92 (1Í, s, CH-20)
11.71 (1Í, s, NH-19),
7.98 (1Í, s, CH-20),
3.75 (3Í, s, ÎÑH3-27)
10.51 (1Í, s, NH-19),
9.82 (1Í, s, NHNH),
9.76 (1Í, s, NH-20)
13.98 (1Í, s, SH)
10
11
12
13
7.58–7.06 (9Í, m, Í-11, 12, 14, 15, 22-26)
11.19
11.12
7.62–7.31 (5H, m, Í-22–26)
7.11 (4Í, m, Í-11, 12, 14, 15)
7.99–7.04 (14Í, m, Í-11, 12, 14, 15, 22–26, 30–34)
2.38
2.36
2.21
2.23
5.38
5.54
14
15
4.84 (2Í, s, CH2
-27)
TABLE 2. Physicochemical Characteristics of Synthesized compounds 2–15
Empirical
formula
Empirical
formula
Compound
Yield, %
Compound
Yield, %
mp, ꢄÑ
mp, ꢄÑ
> 300
> 300
> 300
> 300
210–211
> 300
C13H12N4O2
C21H18N4O3
C15H15N5O3
C15H14N4O4
C18H20N4O4
C15H16N6O3
C22H20N6O3
76.9
75.3
82.7
*
**
83.7
98.4
> 300
297–299
> 300
> 300
234–236
> 300
C22H19N6O3Cl
C24H25N7O3
C22H20N6O4
C23H22N6O4
C22H21N7O3S
C22H19N7O2S
C30H25N7O3S
83.8
80.4
72.8
97.1
84.1
86.7
64.8
2
3
4
5
6
7
8
9
10
11
12
13
14
15
> 300
160–161
_______
*By method A, yield 35.2%; by method B, 84.8 and 80.2%, respectively; **by method A, yield 75.0%; by method B, 78.3%.
We found that brief heating of 14 with ꢁ-bromoacetophenone in basic aqueous EtOH formed 3-(4ꢀ-methylphenyl)-
7-[5ꢂ-(2ꢀꢂ-oxo-2ꢀꢂ-phenylethylthio)-4ꢂ-phenyl-4ꢂH-[1ꢂ,2ꢂ,4ꢂ]triazol-3ꢂ-ylmethyl]-8-methylxanthine (15). The resonance of
the triazole SH group disappeared in the PMR spectrum of S-substituted 15 (Table 1). However, a singlet for methylene
protons appeared and the intensity of the multiplet for the aromatic protons increased. This reaction opens possibilities for
further modification of the molecule by adding pharmacophores.
1107

EXPERIMENTAL
Melting points were determined in open capillaries on a PTP apparatus (M). PMR spectra were recorded in
DMSO-d or DMSO-d :CDCl with TMS internal standard on a Bruker SF-400 instrument. Elemental analyses were performed
6
6
3
on an Elementar Vario L cube instrument and agreed with those calculated for all compounds. Tables 1 and 2 present the
physicochemical properties of the synthesized compounds.
Synthesis of 3-(4ꢀ-Methylphenyl)-8-methylxanthine (2). Compound 1 (23.2 g, 0.1 mol) was dissolved in AcOH
(60 mL), refluxed for 3 h, cooled, and poured into H O. The resulting precipitate was filtered off, washed with H O, dried at
2
2
80°C, dissolved in NaOH solution (1 N, 200 mL), refluxed for 2.5 h, and filtered hot. The pH was adjusted to 4 using H SO
2
4
solution. The resulting precipitate was filtered off and dried at 100°C.
Synthesis of 3-(4ꢀ-Methylphenyl)-8-methylxanthinyl-7-acetic Acid (5). Method A. Compound 2 (2.56 g,
0.01 mol) was treated with DMF (15 mL) and NaHCO (1.84 g, 0.022 mol), heated for 15 min, treated with chloroacetic acid
3
(1.04 g, 0.011 mol), refluxed for 2 h, and filtered hot. The filtrate was cooled and poured into H O (50 mL). The pH was
2
adjusted to 2. The resulting precipitate was filtered off, washed with H O, dried at 70°C, and reprecipitated from aqueous
2
NaHCO .
3
Method B. Ester 6 (3.56 g, 0.01 mol) or amide 4 (3.13 g, 0.01 mol) was dissolved in aqueous NaOH (90 mL, 0.5 N),
refluxed for 2 h, and filtered hot. The filtrate was cooled and neutralized with H SO solution (0.1 N) until the pH was 2. The
2
4
resulting precipitate was filtered off, washed with H O, dried at 70°C, and reprecipitated from aqueous NaHCO .
2
3
Synthesis of n-Propyl Ester of 3-(4ꢀ-Methylphenyl)-8-methylxanthinyl-7-aceticAcid (6). Method A. Compound
2 (2.56 g, 0.01 mol) was treated with DMF (15 mL) and NaHCO (0.92 g, 0.011 mol), heated for 15 min, treated with n-propyl
3
chloroacetate (1.5 g, 0.011 mol), refluxed for 2 h, and filtered hot. The filtrate was cooled and treated with H O (50 mL). The
2
resulting precipitate was filtered off, washed with H O, dried at 70°C, and recrystallized from propanol-1.
2
Method B. A mixture of acid 5 (3.14 g, 0.01 mol), propanol-1 (80 mL), and conc. H SO (6 mL) was heated and
2
4
treated with dioxane until the acid dissolved completely. The resulting true solution was refluxed for 5 h, cooled, and poured
into H O (300 mL). The resulting precipitate was filtered off, washed with H O, dried at 70°C, and recrystallized from
2
2
propanol-1.
3-(4ꢀ-Methylphenyl)-7-(2ꢂ-phenyl-2ꢂ-oxoethyl)-8-methylxanthine (3) and the amide of 3-(4ꢀ-methylphenyl)-
8-methylxanthinyl-7-acetic acid (4) [using ꢁ-bromoacetophenone (2.19 g, 0.011 mol) and chloroacetamide (1.02 g,
0.011 mol) as the alkylating agent, respectively] were synthesized by method A.
Synthesis of the Hydrazide of 3-(4ꢀ-Methylphenyl)-8-methylxanthinyl-7-acetic Acid (7). A suspension of 6
(3.56 g, 0.01 mol) in EtOH (30 mL) was heated for 10 min and treated with hydrazine hydrate (5 mL). The resulting true
solution was refluxed for 30 min and cooled. Hydrazide 7 precipitated as crystals that were filtered off, washed with H O, and
2
dried at 80–85°C.
Synthesis of Benzylidenehydrazides of 3-(4ꢀ-Methylphenyl)-8-methylxanthinyl-7-acetic Acid (8–12). Asolution
of 7 (3.28 g, 0.01 mol) in aqueous dioxane (70 mL, 1:1) was heated to 50°C, treated with glacial AcOH (3 mL) and the
appropriate benzaldehyde (0.011 mol), refluxed for 15–25 min, and cooled. The corresponding ylidenehydrazides precipitated
and were filtered off, washed with H O and Et O, dried at 80–85°C, and recrystallized from aqueous dioxane.
2
2
Synthesis of 2-[3-(4ꢀ-Methylphenyl)-8-methylxanthin-7-yl]-N-[(phenylcarbamothioyl)amino]acetamide (13).
Compound 7 (3.28 g, 0.01 mol) was dissolved in dioxane–H O (100 mL, 2:1) with heating, treated with phenylisothiocyanate
2
(3 mL), refluxed for 15 min, and cooled. The resulting precipitate was filtered off, washed with H O, dried at 80–85°C, and
2
recrystallized from aqueous dioxane.
Synthesis of 3-(4ꢀ-Methylphenyl)-8-methyl-7-[2-(4ꢂ-phenyl-5ꢂ-thio-4ꢂH-[1ꢂ,2ꢂ,4ꢂ]triazol-3ꢂ-yl)methyl]xanthine
(14). Compound 13 (2.31 g, 0.005 mol) was dissolved in NaOH solution (25 mL, 0.25 N), refluxed for 1 h, and filtered hot.
The filtrate was cooled and neutralized with H SO to pH 4. The resulting precipitate was filtered off, washed with H O, dried
2
4
2
at 80°C, and recrystallized from aqueous dioxane.
Synthesis of 3-(4ꢀ-Methylphenyl)-7-[5ꢂ-(2ꢀꢂ-oxo-2ꢀꢂ-phenylethylthio)-4ꢂ-phenyl-4ꢂH-[1ꢂ,2ꢂ,4ꢂ]triazol-
3ꢂ-ylmethyl]-8-methylxanthine (15). A mixture of 14 (4.45 g, 0.01 mol) and aqueous NaOH (45 mL, 0.25 N) was heated,
treated with a mixture of ꢁ-bromoacetophenone (2.19 g, 0.011 mol) and propanol-2 (45 mL), refluxed for 1 h, and filtered hot.
The filtrate was cooled and poured into H O. The resulting precipitate was filtered off, washed with H O, dried at 80°C, and
2
2
recrystallized from EtOH.
1108

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1109