Synthesis of bis(7-methyl-2- or 6-purinyl) disulfides

Article abstract of DOI:10.1080/10426500701542734

Substituted 7-methyl-2- or 6-purinethiones were obtained in series of reactions by nucleophilic substitution with oxygen, chloro, and sulfur nucleophiles. Oxidation of the sulfur atom at position 6 or 2 in purinethiones to corresponding disulfides depende

Full text of DOI:10.1080/10426500701542734

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Phosphorus, Sulfur, and Silicon
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Synthesis of Bis(7-Methyl-2- or
6-Purinyl) Disulfides
Alicja Kowalska a
a Department of Organic Chemistry , The Medical
University of Silesia , Sosnowiec, Poland
Published online: 03 Dec 2007.
To cite this article: Alicja Kowalska (2007) Synthesis of Bis(7-Methyl-2- or 6-Purinyl)
Disulfides, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:12,
2881-2890, DOI: 10.1080/10426500701542734
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Phosphorus, Sulfur, and Silicon, 182:2881–2890, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701542734
Synthesis of Bis(7-Methyl-2- or 6-Purinyl) Disulfides
Alicja Kowalska
Department of Organic Chemistry, The Medical University of Silesia,
Sosnowiec, Poland
Substituted 7-methyl-2- or 6-purinethiones were obtained in series of reactions by
nucleophilic substitution with oxygen, chloro, and sulfur nucleophiles. Oxidation
of the sulfur atom at position 6 or 2 in purinethiones to corresponding disulfides
depended on the conditions of the reaction and oxidizing agent.
Keywords 7-Methyl-2 or 6-purinethiones; bis(7-methyl-2- or 6-purinyl) disulfides;
oxidation reaction
INTRODUCTION
The purine ring system is a key structural element of substrates
and ligands of many biosynthetic, regulatory, and signal transduction
proteins including cellular kinases, G proteins and polymerases.1 6-
Mercaptopurine and 6-thioguanine are considered among the most ef-
fective drugs used in cancer chemotherapy for the treatment of a num-
ber of types of leukemia, non-Hodgkin’s lymphoma and other neoplastic
conditions.2–5 Azathioprine is an immunosuppressive agent, which is
widely used in clinical treatment of autoimmune disorders as well as in
organ and tissue transplantation.6,7 The sulfur containing purines are
metabolically activated by hepatic cytochrome P-450 systems to reac-
tive metabolites, and the oxidation reactions play an important role in
their metabolism. The biological activity of mercaptopurines has been
found to be related to its ease of oxidation to disulfides, sulfenic, and
sulfinic acids, resulting from reaction of thiol radicals with molecu-
lar oxygen.1,3 The reactive metabolites of mercaptopurines are capable
of binding to microsomal proteins largely through formation of mixed
disulfide with protein thiols.5,8 Protein disulfide isomerase (PDI) is a
Received January 29, 2007; accepted May 29, 2007.
Address correspondence to Alicja Kowalska, Department of Organic Chemistry,
The Medical University of Silesia, Jagiellonska 4, Sosnowiec, 41-200 Poland. E-mail:
kowalska@slam.katowice.pl
2881

2882
A. Kowalska
multifunctional protein catalyzing the formation, reduction and isomer-
ization of disulfide bonds, and their ability to bind to polypeptide chains.
Formation of the methyltransferases-DNA complexes via a disulfide co-
valent bond can repair a variety of premutagenic lesions arising from
exposure of DNA to alkylating agents.10 Some mixed disulfide deriva-
tives of purinethiones (mercaptopurine, thioguanine) and their nucleo-
sides have activity in experimental tumor systems (Leukemia L-1210,
Sarcoma – 180).5,11−13
RESULTS AND DISCUSSION
In order to find more effective substances, a series of symmetrical bis(7-
methyl-2- or 6-purinyl) disulfides were prepared by the oxidation of the
corresponding purinethiones.
6-Thiopurines 4 containing methoxy and methylthio groups in po-
sition 2 were prepared in three steps from 2,6-dimethoxy- or 2,6-
dimethylthio-7-methylpurines 1 by nucleophilic substitution at position
6 (Scheme 1).
SCHEME 1
Oxidation of 2-substituted 6-purinethiones 4 with iodine in phos-
phate buffer, pH 7.6, according to Doerr’s procedure,11 leads to 6,6ꢀ-
dipurinyl disulfides 5 (Scheme 2).
SCHEME 2
Symmetrical 7,7ꢀ-dimethyl-6,6ꢀ-dipurinyl disulfide 5d was obtained
by the N-methylation reaction of 6,6ꢀ-dipurinyl disulfide 5e. The lower
reactivity of position 2 in the purine ring, observed in the reaction of 2-
chloro-7-methyl-6-substituted purines 6 with thiourea, did not provide
the expected 6-substituted 2-purinethiones 7, but led to two products:

Bis(7-Methyl-2- or 6-Purinyl) Disulfides
2883
2-chroro-6-ethoxy-7-methylpurine 6c and 7-methyl-2-thioxanthine 8.
Yields of both compounds depended on the reaction time (Scheme 3).
Prolongated time (from 3 h to 12 h) discriminated in favor of formation
of 6c from 53% to 26% (see Experimental).
SCHEME 3
The formation of 6c and 8 was a result of the high reactivity
of position 6 in 2-chloro-6-methoxy- or 6-methylthio-7-methylpurines
(6a, 6b) to oxygen nucleophilic agents, observed previously in other
purine derivatives.14–16 This reaction probably proceeds through sub-
stitution with ethoxide anion generated from solvent followed by 0-6-
dealkylation.
On the other hand, the chlorine atom in position 2 smoothly
underwent nucleophilic substitution in the reaction of 7-methyl-2-
chloroxanthine 6d with sodium hydrosulfide in dimethylformamide.
Treatment of 7-methyl-2-thioxanthine 8 with phosphorus oxychlo-
ride gave the respective 6-chloro derivative 7c, which underwent
nucleophilic displacement of the halogen atom by the methoxide
and methanethiolate anions resulting in 7-methyl-6-substituted-2-
purinethiones 7a and 7b (Scheme 4).
SCHEME 4

2884
A. Kowalska
Failure of the oxidation of 6-substituted 2-purinethiones 7 under the
same conditions as the 6-isomers 4, was unexpected. Oxidation of com-
pounds 7, however, with hydrogen peroxide in 70% ethanol led to the
respective disulfides 9 in 73–80% yield (Scheme 5).
SCHEME 5
All disulfides were identified by their physical and spectroscopic
properties. Complete oxidation of purinethiones 4a–c and 7a–c was
assessed by TLC analysis. Whereas 6,6ꢀ-dipurinyl disulfides 5a–c were
isolated as insoluble solids from the alkaline buffer solution at the end
of the reaction, 2,2ꢀ-dipurinyl disulfides 9a–c were isolated after evap-
oration of the solvent. TLC analysis (silica gel, chloroform-methanol
9:1) showed that disulfides 5 and 9 were more mobile than the start-
1
ing purinethiones 4 and 7 by ꢀRf = 0.17–0.22. Analysis of H NMR
spectra of disulfides 5 and 9 revealed a characteristic downfield shift of
the H-8 proton signal by ꢀδ = 0.26–0.39 ppm and ꢀδ = 0.27–0.33 ppm,
respectively, in comparison with purinethiones 4 and 7. A lack of an
acidic NH proton signal which was found at δ = 13.48–14.54 ppm and
δ = 11.02–12.18 ppm in purinethiones 4 and 7, as well. Mass spec-
tra revealed easy cleavage of the S-S linkage. In model disulfide 5e,
the base peak was [M/2 +1]+ and molecular peak (M+) was not ob-
served. In disulfides 5 and 9, molecular peaks (M+) possess an inten-
sity of 12.3–18.5% and 15.2–21.2% in comparison with the base peak
of [M 1/2 + 1]+.
From above results, it appears that oxidation of the sulfur atom at po-
sition 6 in 6-purinethiones 4 to the corresponding disulfides proceeded
easier than at position 2 in 2-purinethiones 7 and depended on the
oxidizing agent.
Although 2,6-dithio-7-methylpurine was obtained from the 2,6-
dichloro analog by reaction with thiourea in ethanol in about 95%
yield,17 the 2-monochloro derivatives 6 did not react under the same
conditions. We report the synthesis of 13 new 2- and 6-thiopurines such
as purinethiones, methylthiopurines, and dipurinyl disulfides.

Bis(7-Methyl-2- or 6-Purinyl) Disulfides
2885
EXPERIMENTAL
Melting points were determined on a Boetius melting point apparatus
1
and are uncorrected. The H NMR spectra were recorded on a Varian
Unity-Inova-300 spectrometer at 300 MHz in deuteriochloroform and
dimethyl sulphoxide-d6 with tetramethylsilane as the internal stan-
dard. Electron impact mass spectra (EI MS) were run on a LKB 9000S
at 70eV. Thin layer chromatography (TLC) was performed on silica gel
60254F plates (Merck) using a solution of chloroform-methanol (9:1) as
the developing system. Chromatograms were visualized in UV light or
by iodine vapor.
2-Methoxy- and 2-methylthio-7-methyl-6-oxo-1,6-dihydropurines 2
were prepared from symmetrical 2,6-dimethoxy- or 2,6-dimethylthio-
7-methylpurines 1a, 1b with sodium hydroxide solution according to
known procedures.14,20
Reactions of Xanthines 2a, 2b, and 8 with Phosphorus
Oxychloride
Dry 2-methoxy-, 2-methylthio-7-methylhypoxanthines 2a, 2b or 7-
methyl-2-thioxanthine 8 (10 mmol) were refluxed with 35 mL of phos-
phorus oxychloride for 4 h. The excess phosphorus oxychloride was re-
moved under reduced pressure and the residue was added to 35 g of
crushed ice. Reactions were then neutralized with conc. ammonia at
0–5◦C up to pH ∼7. The solid was filtered off or the mixture was ex-
tracted with chloroform (3 × 15 mL). The extracts were combined and
dried over anhydrous sodium sulfate. The solvent was evaporated un-
der vacuum, and the residue was recrystallized from ethanol or purified
by column chromatography (silica gel 60, chloroform) to obtain:
1. 6-Chloro-2-methoxy-7-methylpurine 3a, (yield 74%), m.p. 156-
157◦C, lit.18 m.p. 156-158◦C.
2. 6-Chloro-2-methylthio-7-methylpurine 3b, (yield 88%), m.p.
1
176–177◦C. H NMR (CDCl3)δ: 8.05 (s, 1H, H-8), 4.10 (s, 3H, N-
CH3), 2.65 (s, 3H, S-CH3), EI MS (70 eV) m/z: 214 (M+, 100). Anal.
Calcd. for C7H7ClN4S (214.67): C, 39.17; H, 3.29; N, 26.10. Found:
C, 39.50; H, 3.22; N, 25.91.
3. 6-Chloro-7-methyl-2-thioxanthine 7c, (yield 79%), m.p. >300◦C.
1H NMR (DMSO-d6)δ: 12.18 (s, 1H, N-H), 8.28 (s, 1H, H-8), 4.15 (s,
3H, N-CH3), EI MS (70 eV) m/z: 200 (M+, 100), TLC R f = 0.20. Anal.
Calcd. for C6H5ClN4S (200.64): C, 35.92; H, 2.51; N, 27.92. Found:
C, 35.61; H, 2.65; N, 28.12.

2886
A. Kowalska
Synthesis of 6-Purinethiones 4
6-Chloropurines 3a,3b (5 mmol) were heated under reflux in 75 mL of
absolute ethanol with 0.76 g (10 mmol) of thiourea for 1.5 h. The solvent
was removed in vacuo, and the residue was dissolved in dilute sodium
hydroxide. Product was precipitated with dilute hydrochloric acid, and
the process was repeated twice to give pure 6-purinethiones 4a and4b
in 74% and 87% yields, respectively.
1. 2-Methoxy-7-methyl-6-purinethione 4a, (yield 74%), m.p. 239–
1
240◦C. H NMR (DMSO-d6)δ: 13.48 (s, 1H, N-H), 8.26 (s, 1H, H-8),
4.13 (s, 3H, O-CH3), 3.94 (s, 3H, N-CH3), EI MS (70 eV) m/z: 196
(M+, 100), TLC R f = 0.19. Anal. Calcd. for C7H8N4OS (196.22): C,
42.85; H, 4.11; N, 28.55. Found: C, 42.67; H, 4.02; N, 28.82.
2. 2-Methylthio-7-methyl-6-purinethione 4b, (yield 87%) m.p.
1
216–217◦C. H NMR (DMSO-d6)δ: 13.81 (s, 1H, N-H), 8.32 (s, 1H,
H-8), 4.13 (s, 3H, N-CH3), 2.54 (s, 3H, S-CH3), EI MS (70 eV) m/z:
212 (M+, 100), TLC R f = 0.22. Anal. Calcd. for C7H8N4S2 (212.28):
C, 39.61; H, 3.80; N, 26.39. Found: C, 39.85; H, 3.69; N, 26.16.
3. 2-Chloro-7-methyl-6-purinethione 4c, (yield 95%), m.p. >300◦C,
lit.17 m.p. > 300◦C was prepared by reaction of 2,6-dichloro-7-
methylpurine with sodium sulfide (Na2S × 9H2O) by a described
method.17 1H NMR (DMSO-d6)δ: 14.54 (s, 1H, N-H), 8.38 (s, 1H,
H-8), 4.16 (s, 3H, N-CH3), TLC R f = 0.18.
Synthesis of 2-Purinethiones 7
6-Chloro-7-methyl-2-thioxanthine 7c (1 g, 5 mmol) was added to a solu-
tion of sodium (0.14 g, 6 mmol) in 50 mL of absolute methanol or sodium
methanethiolate (0.52 g, 7.5 mmol) in 150 mL of absolute ethanol. The
mixture was boiled for 3 h and an insoluble solid (up to 10% of the total
amount of product) was separated by hot filtration from the reaction
mixture. The filtrate was evaporated to dryness. The residue was dis-
solved in dilute sodium hydroxide and precipitated by neutralization
with dilute hydrochloric acid to pH∼5. The crude product was crystal-
lized from ethanol to give compounds 7a or 7b.
1. 6-Methoxy-7-methyl-2-purinethione 7a, (yield 79%), m.p. 246–
◦
1
248 C. H NMR (DMSO-d6)δ: 11.02 (s, 1H, N-H), 8.19 (s, 1H, H-8),
4.06 (s, 3H, O-CH3), 3.95 (s, 3H, N-CH3), EI MS (70eV) m/z: 196 (M+,
100), TLC R f = 0.21. Anal. Calcd. for C7H8N4OS (196.22): C, 42.85;
H, 4.11; N, 28.55. Found: C, 42.76; H, 4.20; N, 28.79.

Bis(7-Methyl-2- or 6-Purinyl) Disulfides
2887
2. 6-Methylthio-7-methyl-2-purinethione 7b, (yield 82%), m.p.
1
200–202◦C. H NMR (DMSO-d6)δ: 11.42 (s, 1H, N-H), 8.21 (s, 1H,
H-8), 4.12 (s, 3H, N-CH3), 2.65 (s, 3H, S-CH3), EI MS (70eV) m/z:
212 (M+, 100), TLC R f = 0.23. Anal. Calcd. for C7H8N4S2 (212.28):
C, 39.61; H, 3.80; N, 26.39. Found: C, 39.47; H, 3.65; N, 26.61.
Reactions of Chloropurines 6a and 6b with Thiourea
2-Chloropurines 6a and 6b (5 mmol) were heated under reflux in 75
mL of absolute ethanol with 0.76 g (10 mmol) of thiourea for 3 or 12
h. The solvent was removed in vacuo, and the residue was extracted
with chloroform (3 × 10 mL) to give 2-chloro-6-ethoxy-7-methylpurine
6c.19 The residue was dissolved in dilute sodium hydroxide solution
and next was acidified with dilute hydrochloric acid to give 7-methyl-2-
thioxanthine 8.17 Yields of both products depended on the reaction time.
TABLE I
Products (%)
Reaction
Substrate
time [h]
6c
8
6a
6a
6b
6b
3
12
3
51
26
53
32
30
65
29
52
12
7-Methyl-2-thioxanthine 8, m.p. >300◦C.
1H NMR (DMSO-d6)δ: 13.23 (s, 1H, N1-H), 12.18 (s, 1H, N3-H), 8.03 (s,
1H, H-8), 4.03 (s, 3H, N-CH3), EI MS (70eV) m/z: 182 (M+, 100).
Synthesis of 7-Methyl-2-Thioxanthine 8, (Yield 88%).
To a suspension of 2-chloro-7-methyl-6-oxo-1,6-dihydropurine 6d (1.84
g, 10 mmol) in 200 mL of dimethylformamide (DMF), (0.99 g, 12 mmol)
sodium hydrosulfide (NaSH × 1.5 H2O) was added. The mixture was
refluxed for 2 h, cooled to room temperature, and the DMF was evapo-
rated in vacuo. The resulting solid was dissolved in 5% aqueous sodium
hydroxide and product was precipitated by dilute hydrochloric acid. The
compound was identical with the product described above.
Oxidation Reaction of 6- and 2-Purinethiones 4 and 7
A. 6-Purinetlhiones 4a–c (1 mmol) were dissolved in 100 mL of warm
phosphate buffer, pH 7.6, the solution was filtered and cooled to room

2888
A. Kowalska
temperature. To the stirred solution, 1 mL (0,5 mmol) of aqueous 1N
iodine solution (containing sodium iodide in the proportion of 2 parts of
sodium iodide to 1 part iodine by weight) was added over a period of 10
min. The precipitate was filtered and washed with water and ethanol.
The crude products were recrystallized from 85% ethanol or purified by
column chromatography (silica gel 60, chloroform, ethanol) to give:
1. Bis (7-methyl-2-methoxy-6-purinyl) disulfide 5a, (yield 80%),
1
m.p. 228–229◦C. H NMR (CDCl3)δ: 8.52 (s, 2H, H-8), 4.17 (s, 6H,
O-CH3), 4.14 (s, 6H, N-CH3), EI MS (70 eV) m/z: 390 (M+, 15.7), 195
(1/2 M, 59.5), 196 (1/2 M + 1, 100), TLC Rf = 0.36. Anal. Calcd. for
C14H14N8O2S2 (390.43): C, 43.07; H, 3.61; N, 28.70. Found: C, 43.34;
H, 3.43; N, 28.41.
2. Bis (7-methyl-2-methylthio-6-purinyl) disulfide 5b, (yield
1
75%), m.p. 205–206◦C. H NMR (CDCl3)δ: 8.61 (s, 2H, H-8), 4.27
(s, 6H, N-CH3), 2.56 (s, 6H, S-CH3), EI MS (70 eV) m/z: 422 (M+,
18.5), 211 (1/2 M, 76.7), 212 (1/2 M + 1, 100), TLC Rf = 0.43. Anal.
Calcd. for C14H14N8S4 (422.55): C, 39.79; H, 3.34; N, 26.52. Found:
C, 40.16; H, 3.20; N, 26.26.
3. Bis (7-methyl-2-chloro-6-purinyl) disulfide 5c, (yield 96%), m.p.
223–224◦C. 1H NMR (CDCl3)δ: 8.77 (s, 2H, H-8), 4.24 (s, 6H, N-CH3),
EI MS (70 eV) m/z: 399 (M+, 12.3), 199 (1/2 M, 79.3), 200 (1/2 M +
1, 100), TLC Rf = 0.40. Anal. Calcd. for C12H8Cl2N8S2 (399.27): C,
36.10; H, 2.02; N, 28.06. Found: C, 35.72; H, 2.24; N, 27.77.
B. To a stirred suspension of 2-purinethiones 7a–c in 10 mL of 70%
ethanol, 0.5 mL of 10% hydrogen peroxide was added. The reaction ran
with gradual solubilization of purine substrate 7a–c up to full disso-
lution. After 10 min stirring at room temperature, the solution was
evaporated to dryness. The residue was dissolved in chloroform and
purified by column chromatography on silica gel (200–300 mesh) using
chloroform as eluent to give:
1. Bis (7-methyl-6-methoxy-2-purinyl) disulfide 9a (yield 73%),
1
m.p. 238–239◦C. H NMR (CDCl3) δ: 8.46 (s, 2H, H-8), 4.10 (s, 6H,
O-CH3), 4.08 (s, 6H, N-CH3), EI MS (70 eV) m/z: 390 (M+, 21.2), 195
(1/2 M+, 62.8), 196 (1/2 M + 1, 100), TLC Rf = 0.42. Anal. Calcd. for
C14H14N8O2S2 (390.43): C, 43.07; H, 3.61; N, 28.70. Found: C, 42.83;
H, 3.47; N, 28.45.
2. Bis (7-methyl-6-methylthio-2-purinyl) disulfide 9b (yield 72%),
1
m.p. 209–210◦C. H NMR (CDCl3) δ: 8.49 (s, 2H, H-8), 4.29 (s, 6H,
N-CH3), 2.68 (s, 6H, S-CH3), EI MS (70 eV) m/z: 422 (M+, 19.7), 211
(1/2 M+, 75.4), 212 (1/2 M + 1, 100), TLC Rf = 0.38. Anal. Calcd. for

Bis(7-Methyl-2- or 6-Purinyl) Disulfides
2889
C14H14N8S4 (422.55): C, 39.79; H, 3.34; N, 26.52. Found: C, 39.52; H,
3.16; N, 26.20.
3. Bis (7-methyl-6-chloro-2-purinyl) disulfide 9c (yield 80%), m.p. 232–
1
233◦C. H NMR (CDCl3) δ: 8.61 (s, 2H, H-8), 4.22 (s, 6H, N-CH3),
EI MS (70 eV) m/z: 399 (M+, 15.2), 199 (1/2 M, 72.8), 200 (1/2 M+
1, 100), TLC Rf = 0.37. Anal. Calcd. for C12H8Cl2N8S2 (399.27): C,
36.10; H, 2.02; N, 28.06. Found: C, 35.89; H, 2.14; N, 28.17.
Synthesis of Bis(7-Methyl-6-purinyl) Disulfide 5d (yield 68%),
m.p. 219–220◦C
To a stirred solution of 6,6ꢀ-dipurinyl disulfide 5e (0.3g, 1 mmol) in a
mixture of sodium methoxide (0.54 g, 1 mmol) and 40 mL dry methanol,
at 20◦C, methyl iodide (0.14 g, 1 mmol) was added. After 1 h, the result-
ing solid was collected by filtration and washed with water. The crude
product was purified by column chromatography (silica gel 200–300
mesh, chloroform) to give disulfide 5d.
1H NMR (CDCl3)δ: 8.68 (s, 2H, H-8), 8.33 (s, 2H, H-2), 3.74 (s, 6H,
N-CH3), EI MS (70 eV) m/z: 332 (M+, 7.9), 166 (1/2 M, 82.5), 167 (1/2
M + 1, 100), TLC Rf = 0.44. Anal. Calcd. for C12H10N8S2 (330.38): C,
43.63; H, 3.05; N, 33.92. Found: C, 43.36; H, 3.27; N, 33.60.
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