Synthesis of 2- and 6-(dialkylaminoalkylthio)- and 2,6- bis(dialkylaminoalkylthio)-7-methylpurines

Article abstract of DOI:10.3987/COM-12-12546

An efficient synthesis of 21 new thiopurines being 2-substituted 6-(dialkylaminoalkylthio)-7-methylpurines, 6-substituted 2- (dialkylaminoalkylthio)- 7-methylpurines, and 2,6-bis(dialkylaminoalkylthio)-7- methylpurines was reported. 2-Substituted 6-(dialkylaminoalkylthio) and 2,6-bis(dialkylaminoalkylthio) derivatives were obtained via direct S-dialkylaminoalkylation of the appro- priate purinethiones. The different reactivities of the dialkylaminalkylthio groups in positions 2 and 6 towards sodium alkoxides were the key processes in a few step synthesis of 2-(dialkylaminoalkylthio) derivatives from 2,6-bis(dialkylaminoalkylthio) derivatives.

Full text of DOI:10.3987/COM-12-12546

HETEROCYCLES, Vol. 85, No. 10, 2012
2473
HETEROCYCLES, Vol. 85, No. 10, 2012, pp. 2473 - 2483. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 11th July, 2012, Accepted, 2nd August, 2012, Published online, 8th August, 2012
DOI: 10.3987/COM-12-12546
SYNTHESIS OF 2- AND 6-(DIALKYLAMINOALKYLTHIO)- AND
2,6-BIS(DIALKYLAMINOALKYLTHIO)-7-METHYLPURINES
Alicja Kowalska* and Krystian Pluta
Department of Organic Chemistry, The Medical University of Silesia,
Jagiellońska 4, 41-200 Sosnowiec, Poland. E-mail: kowalska@sum.edu.pl
Abstract – An efficient synthesis of 21 new thiopurines being 2-substituted
6-(dialkylaminoalkylthio)-7-methylpurines, 6-substituted 2-(dialkylaminoalkyl-
thio)-7-methylpurines, and 2,6-bis(dialkylaminoalkylthio)-7-methylpurines was
reported. 2-Substituted 6-(dialkylaminoalkylthio) and 2,6-bis(dialkylamino-
alkylthio) derivatives were obtained via direct S-dialkylaminoalkylation of the
appro- priate purinethiones. The different reactivities of the dialkylaminalkylthio
groups in positions 2 and 6 towards sodium alkoxides were the key processes in a
few step synthesis of 2-(dialkylaminoalkylthio) derivatives from 2,6-bis(dialkyl-
aminoalkylthio) derivatives.
INTRODUCTION
The purine ring system is a key structural element of substrates and ligands of many biosynthetic,
regulatory, and signal transduction proteins, and polymerases.1 Thiopurine antimetabolites such as
6-mercaptopurine, 6-thioguanine and azathioprine form an important group of cytotoxic drugs used in
treating in several diseases including cancer. They have been used as immunosuppresants and
anti-inflammatory agents in organ transplantation and chemotherapy, exhibited antineoplastic,
antileukemic, antiviral, antibacterial and antifungal activities.2-8
6-Substituted mercaptopurine derivatives possessing the pyrimidyl, imidazolyl, quinolyl1 or aminoalkyl9
groups at the sulfur atom were very effective against Mycobacterium paratuberculosis,1,10 Leishmania
amazonensis and L. chagasi.9 Alkylaminoalkylthiopurines alone11 and with the phenyl or pyridyl
substituens12 showed antibacterial12 and antithrombotic activities.11 There was also described the
synthesis of the thiopurinyl piperazine derivatives usefull as cardiotonic and antiarrhythmic agents13 and
the quinoline,2 steroid, and triazole14 conjugates with 6-mercaptopurine possessing antimalarial and
antileishmanial activity.1,14

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HETEROCYCLES, Vol. 85, No. 10, 2012
Recently it has been revealed a new mechanism of action the thiopurine drugs by which they regulate
dendritic cells (DC) integrated functions, inducing a functionally less immunogenic phenotype.15
6-Thioguanine (6-TG) incorporated into the DNA of macrophages sensitizes them to killing by
endogenously produced reactive oxygen species. The findings suggests that the low oxidation potential of
DNA 6-TG may influence the immunomodulatory effects of thiopurines and suggests a potential new
therapeutic role for this long established class of drugs.16
In our previous papers,17,18 we reported the effective synthesis of the azathioprine analogs containing one
or two 1-methyl-4-nitroimidazol-5-yl groups at the sulfur atom in positions 2 or/and 6 of 7-methylpurines.
In continuation of our studies on the thiopurine derivatives, we describe in this paper the synthesis of
a series of new 7-methylpurines with pharmacophoric dialkylaminoalkyl substituents: diethylaminoethyl,
dimethylaminopropyl, pyrrolidinylethyl, piperidinylethyl and morpholinylethyl groups at the sulfur atoms
in positions 2 and 6.
RESULTS AND DISCUSSION
We started our synthesis from the reactions of 2-substituted 7-methyl-6-purinethiones 1a-c, possessing
the chloro, methoxy and methylthio groups, with hydrochlorides of 2-diethylaminoethyl or 3-dimethyl-
aminopropyl chlorides in boiling ethanol in the presence of sodium hydroxide to give 2-substituted
6-(dialkylaminoalkylthio)-7-methylpurines 2a-f in very good yields (77.5-95%, Scheme 1).
(CH2)nNR2
S
N
S
N
Me
N
Me
N
NaOH
HN
N
+
R2N(CH2)nCl x HCl
N
N
X
X
2a X = Cl, n = 2, R = Et
1a
X = Cl
2b
X = OMe, n = 2, R = Et
1b X = OMe
1c X = SMe
2c
X = SMe, n = 2, R = Et
2d X = Cl, n = 3, R = Me
2e
X = OMe, n = 3, R = Me
2f X = SMe, n = 3, R = Me
Scheme 1
When the similar reactions were carried out using 7-methyl-2,6-dithioxanthine (3) and hydrochlorides of
dialkylaminoalkyl chlorides in refluxing ethanol, to obtain the double dialkylaminoalkylation products,
7-methyl-2,6-bis(dialkylaminoalkylthio)purines (4a-e), the yields were not quite satisfactory (48-56%).
Only the reactions carried out in refluxing dioxane in the presence of sodium hydroxide led to the desired
products 4 in high yields (80-95%) (Scheme 2). These conditions enabled to introduce the

HETEROCYCLES, Vol. 85, No. 10, 2012
2475
dialkylaminoalkyl substituent possessing not only acyclic but also cyclic amino groups (pyrrolidine,
piperidine and morpholine) at the sulfur atoms in both positions 2 and 6.
(CH2)nNR2
S
Me
N
S
N
Me
N
HN
NaOH
N
+
2 R2N(CH2)nCl x HCl
N
S
N
H
N
R2N(CH2)nS
n
NR2
3
4a 2 NEt2
4b 3 NMe2
4c 2 N
4d 2
4e 2
N
N
O
Scheme 2
Next step was synthesis of 2-(dialkylaminoalkylthio)-7-methylpurines, isomeric to compounds 2. The
isomeric substrates, 6-substituted 7-methylpurine-2(3H)thiones, are not available in a simple way but in
a few step synthesis from 2-chloro-7-methylpurin-6(1H)-one.19 As the substituents in position 6 are much
more susceptible for nucleophilic reagents than in position 2,17-19 2,6-disubstituted products 4 were used
as the substrates. Our previous regioselective results with 2,6-di[(alkyl/aryl)thio]-7-methylpurines with
nucleophilic reagents17-19 prompted us to carried out the reaction with boiling phosphorus oxychloride to
obtain the 6-chloro derivatives. Unfortunately, this reaction and the reactions with a mixture POCl3-DMF
o
or phenyl dichlorophosphate at 105-110 C led to S-de(dialkylaminoalkylation) products, 2,6-dithio
compound 3 (in 52–61% yield) and 2-(dialkylaminoalkylthio)-7-methylpurine-6(1H)thiones 5a and 5b in
low yields (5-17%, the details in Experimental) (Scheme 3). Unlike the 1-methyl-4-nitroimidazol-5-ylthio
group, the diethylaminoethylthio and dimethylaminopropylthio groups did not undergo the chlorination
with phosphorus oxychloride and its derivatives.
Next we carried out the reactions with sodium alkoxides in boiling alcohols (methyl and ethyl). This time
the reaction did not run as the dialkylaminoalkyl-sulfur bond cleavage process but as the monoalkoxy-
lation to give 2-(dialkylaminoalkylthio)-6-alkoxy-7-methylpurines (7a-d) in very good yields (74-85.5%).
The structural problem (which dialkylaminoalkylthio group was substituted by the alkoxy group) was
solved comparing the physical (mp), chromatographical (Rf) and spectroscopical (1H NMR spectra) data
of compounds 7a and 7c with compounds 2b and 2e, which turned out to be different.

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HETEROCYCLES, Vol. 85, No. 10, 2012
o
Compounds 7b and 7d treated with phenyl dichlorophosphate at 105-110 C gave 2-(dialkylamino-
alkylthio)-6-chloro compounds 8a and 8b (in 72% and 76% yields), and 6-chloro-2-purinethione 9 (in
15% and 12% yield, respectively) as S-de(dialkylaminoalkylation) product. The chloro derivatives 8 in
the reaction with thiourea gave the same thio compounds 5a and 5b (in 83% and 85.5% yields) directly
from compound 4. S-Methylation of compounds 5a and 5b with methyl iodide led to methylthio
compounds 6a and 6b in 82% and 83% yields (being isomeric to compounds 2c and 2f). The
dialkylaminoalkyl groups in position 6 in thiopurines 4a and 4b turned out to be quite good leaving
groups in the reactions with sodium alkoxides.
SMe
Me
N
N
N
N
R2N(CH2)nS
6a n = 2, R = Et
6b n = 3, R = Me
MeI
(CH2)nNR2
S
N
S
S
Me
N
Me
Me
N
N
POCl3, POCl3-DMF
or PhOPOCl2
HN
N
HN
+
N
N
N
N
S
N
H
R2N(CH2)nS
R2N(CH2)nS
5a n = 2, R = Et
5b n = 3, R = Me
4a, 4b
3
R'OH
R'ONa
(NH2)2CS
Cl
Cl
N
OR'
Me
N
Me
Me
N
N
N
N
PhOPOCl2
R' = Et
N
N
+
N
N
S
N
H
N
R2N(CH2)nS
R2N(CH2)nS
7a n = 2, R = Et, R' = Me
7b n = 2, R = Et, R' = Et
7c n = 3, R = Me, R' = Me
7d n = 3, R = Me, R' = Et
8a n = 2, R = Et
8b n = 3, R = Me
9
Scheme 3
All 2- and 6-(dialkylaminoalkylthio)-7-methylpurines (2, 5-8) and 2,6-bis(dialkylaminoalkylthio)-7-
methylpurines (4) exhibit promising potential antitumoral, antiaggregation, anti-inflammatory, cardio-
tonic, antiviral and nootropic activity, and could be useful as anticancer, and in particular as cardiopro-
tective agents.20

HETEROCYCLES, Vol. 85, No. 10, 2012
2477
CONCLUSION
Here, we report an efficient synthesis of 21 new thiopurines being 2-substituted 6-(dialkylaminoalkyl-
thio)-7-methylpurines, 6-substituted 2-(dialkylaminoalkylthio)-7-methylpurines, and 2,6-bis(dialkyl-
aminoalkylthio)-7-methylpurines. 2-Substituted 6-(dialkylaminoalkylthio) and 2,6-bis(dialkylamino-
alkylthio) derivatives were obtained via the direct S-dialkylaminoalkylation of the appropriate purine-
thiones. The different reactivities of the dialkylaminoalkylthio groups in positions 2 and 6 towards
sodium alkoxides were the key processes in a few step synthesis of 2-(dialkylaminoalkylthio) derivatives
from 2,6-bis(dialkylaminoalkylthio) derivatives.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Boetius melting point apparatus and were
1
uncorrected. The H NMR spectra were recorded on a Varian Unity-Inova 300 spectrometer (300 MHz)
in CDCl3 and DMSO-d6 with TMS as an internal standard. EI MS and FAB MS (in the m-nitrobenzyl
alcohol and glycerol matrix) were run on a Finnigan MAT 95 spectrometer at 70eV.
General synthesis of 2-substituted 6-(dialkylaminoalkylthio)-7-methylpurines (2)
A mixture of 6-purinethione 1a-c19 (1 mmol), 2-diethylaminoethyl or 3-dimethylaminopropyl chloride
hydrochloride (1.5 mmol), 10% aqueous NaOH solution (0.25 mL) and absolute EtOH (20 mL) was
refluxed for 2 h. After cooling the small amount of resulting solid was filtered off, and the ethanolic
filtrate was evaporated in vacuo. The residue was extracted with CHCl3 (3 x 10 mL), dried with anhy-
drous Na2SO4 and evaporated in vacuo. Crude products were purified by crystallization from EtOH and
column chromatography (aluminium oxide, CHCl3-EtOH, 9:1 v/v) to give the 6-(dialkylaminoalkylthio)
derivatives 2a–f:
1
2-Chloro-6-(2-diethylaminoethylthio)-7-methylpurine (2a) (0.284 g, 95%); mp 158-159 °C (EtOH). H
NMR (CDCl3), : 1.08 (t, J = 7.1 Hz, 6H, 2CCH3), 2.67 (q, J = 7.1 Hz, 4H, 2NCH2), 2.85 (t, J = 7.2 Hz,
2H, SCH2), 3.48 (t, J = 7.2 Hz, 2H, NCH2), 4.05 (s, 3H, NCH3), 7.94 (s, 1H, H-8), FAB MS m/z: 300
(M+1, 55), 201 (M+1-C2H3N(C2H5)2, 18), 100 (C2H4N(C2H5)2, 100). Anal. Calcd for C12H8ClN5S: C
48.07, H 6.05, N 23.36. Found C 48.33, H 5.98, N 23.58.
6-(2-Diethylaminoethylthio)-2-methoxy-7-methylpurine (2b) (0.255 g, 86.5%); mp 165-166 °C (EtOH).
1H NMR (CDCl3), : 1.04 (t, J = 7.1 Hz, 6H, 2CCH3), 2.57 (q, J = 7.1 Hz, 4H, 2NCH2), 2.75 (t, J = 7.2
Hz, 2H, SCH2), 3.14 (t, J = 7.1 Hz, 2H, NCH2), 4.05 (s, 3H, NCH3), 4.12 (s, 3H, OCH3), 7.87 (s, 1H,
H-8), FAB MS m/z: 296 (M+1, 100), 197 (M+1-C2H3N(C2H5)2, 16). Anal. Calcd for C13H21N5OS: C
52.86, H 7.17, N 23.71. Found C 52.62, H 7.12, N 23.98.
6-(2-Diethylaminoethylthio)-7-methyl-2-methylthiopurine (2c) (0.270 g, 87%); mp 143-144 °C (EtOH).
1H NMR (CDCl3), : 1.08 (t, J = 7.1 Hz, 6H, 2CCH3), 2.63 (s, 3H, SCH3), 2.67 (q, J = 7.1 Hz, 4H, 2
NCH2), 2.83 (t, J = 7.2 Hz, 2H, SCH2), 3.31 (t, J = 7.1 Hz, 2H, NCH2), 4.07 (s, 3H, NCH3), 7.88 (s, 1H,

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HETEROCYCLES, Vol. 85, No. 10, 2012
H-8), FAB MS m/z: 312 (M+1, 100), 213 (M+1-C2H3N(C2H5)2, 12). Anal. Calcd for C13H21N5S2: C
50.13, H 6.80, N 22.48.Found C 50.44, H 6.74, N 22.29.
2-Chloro-6-(3-dimethylaminopropylthio)-7-methylpurine (2d) (0.238 g, 83%); mp 186-187 °C (EtOH).
1H NMR (CDCl3), : 2.11 (m, 2H, CH2), 2.71 (s, 6H, 2NCH3), 3.40 (t, J = 7.1 Hz, 2H, SCH2), 3.70 (t, J =
7.1 Hz, 2H, NCH2), 4.03 (s, 3H, NCH3), 8.11 (s, 1H, H-8), FAB MS m/z: 286 (M+1, 100), 201
(M+1-C3H5N(CH3)2, 9). Anal. Calcd for C11H16ClN5S: C 46.23, H 5.64, N 24.50. Found C 46.48, H 5.78,
N 24.31.
6-(3-Dimethylaminopropylthio)-2-methoxy-7-methylpurine (2e) (0.223 g, 79%); mp 169-170 °C (EtOH).
1H NMR (CDCl3), : 2.01 (m, 2H, CH2), 2.36 (s, 6H, 2NCH3), 2.55 (t, J = 7.1 Hz, 2H, SCH2), 3.29 (t, J =
7.1 Hz, 2H, NCH2), 3.92 (s, 3H, OCH3), 4.01 (s, 3H, NCH3), 7.86 (s, 1H, H-8), FAB MS m/z: 282 (M+1,
100), 197 (M+1-C3H5N(CH3)2, 8). Anal. Calcd for C12H19N5OS: C 51.22, H 6.81, N 24.89. Found C
51.53, H 6.73, N 25.12.
6-(3-Dimethylaminopropylthio)-7-methyl-2-methylthiopurine (2f) (0.230 g, 77.5%); mp 147-148 °C
1
(EtOH). H NMR (CDCl3), : 2.10 (m, 2H, CH2), 2.61 (s, 3H, SCH3), 2.68 (s, 6H, 2NCH3), 2.93 (t, J =
7.1 Hz, 2H, SCH2), 3.55 (t, J = 7.1 Hz, 2H, NCH2), 4.06 (s, 3H, NCH3), 7.98 (s, 1H, H-8), FAB MS m/z:
298 (M+1, 100), 213 (M+1-C3H5N(CH3)2, 19). Anal. Calcd for C12H19N5S2: C 48.46, H 6.44, N 23.55.
Found C 48.22, H 6.52, N 23.86.
General synthesis of 2,6-bis(dialkylaminoalkyl or 2-pyrrolidinylethyl, piperidinylethyl and morpho-
linylethyl)thio-7-methylpurines (4)
To a mixture of 7-methylpurine-2(3H),6(1H)-dithione (3) (0.198 g, 1 mmol) and NaOH (0.4 g, 10 mmol)
in stirred (10 mL) dry dioxane at rt for 1 h, 2.5 mmol of 2-diethylaminoethyl, 3-dimethylaminopropyl,
2-pyrrolidinylethyl, 2-piperidinylethyl or 2-morpholinylethyl chloride hydrochloride was added and the
mixture was refluxed for 2 h. After cooling the solid was filtered off and the solvent removed in vacuo.
The residue was extracted with CHCl3 (3 x 10 mL), dried with anhydrous Na2SO4 and evaporated in
vacuo. Crude products were crystallized from EtOH and purified by column chromatography (aluminium
oxide, CHCl3-EtOH, 9:1 v/v) to give the bis(dialkylaminoalkylthio) derivatives 4a-e.
2,6-Bis(2-diethylaminoethylthio)-7-methylpurine (4a) (0.343 g, 86.5%); an oil. 1H NMR (CDCl3), : 1.07
(t, J = 7.2 Hz, 6H, 2CCH3), 1.12 (t, J = 7.2 Hz, 6H, 2CCH3), 2.63 (q, J = 7.2 Hz, 4H, 2NCH2), 2.70 (q, J
= 7.2 Hz, 4H, 2NCH2), 2.82 (t, J = 7.2 Hz, 2H, SCH2), 2.91 (t, J = 7.2 Hz, 2H, SCH2), 3.34 (t, J = 7.2 Hz,
2H, NCH2), 3.45 (t, J = 7.2 Hz, 2H, NCH2), 4.05 (s, 3H, NCH3), 7.84 (s, 1H, H-8), FAB MS m/z: 397
(M+1, 100), 298 (M+1-C2H3N(C2H5)2, 19). Anal. Calcd for C18H32N6S2: C 54.51, H 8.13, N 21.19.
Found C 54.81, H 8.04, N 20.96.
1
2,6-Bis(3-dimethylaminopropylthio)-7-methylpurine (4b) (0.296 g, 80.5%); mp 127-128 °C (EtOH). H
NMR (CDCl3), : 2.03 (m, 4H, 2CH2), 2.32 (s, 6H, 2NCH3), 2.37 (s, 6H, 2NCH3), 2.52 (t, J = 7.2 Hz, 2H,
SCH2), 2.67 (t, J = 7.2 Hz, 2H, SCH2), 3.27 (t, J = 7.2 Hz, 2H, NCH2), 3.39 (t, J = 7.2 Hz, 2H, NCH2),

HETEROCYCLES, Vol. 85, No. 10, 2012
2479
4.05 (s, 3H, NCH3), 7.86 (s, 1H, H-8), FAB MS m/z: 369 (M+1, 100), 284 (M+1-C3H5N(CH3)2, 15).
Anal. Calcd for C16H28N6S2: C 52.14, H 7.66, N 22.80. Found C 52.40, H 7.56, N 22.53.
1
2,6-Bis(2-pyrrolidinylethylthio)-7-methylpurine (4c) (0.364 g, 93%); mp 116-117 °C (EtOH). H NMR
(CDCl3), : 1.29 (m, 8H, 4CH2), 2.67 (m, 8H, 4CH2), 2.82 (t, J = 7.5 Hz, 2H, SCH2), 2.87 (t, J = 7.5 Hz,
2H, SCH2), 3.38 (t, J = 7.5 Hz, 2H, NCH2), 3.50 (t, J = 7.5 Hz, 2H, NCH2), 4.04 (s, 3H, NCH3), 7.84 (s,
1H, H-8), FAB MS m/z: 393 (M+1, 100), 296 (M+1-C2H3NC4H8, 18). Anal. Calcd for C18H28N6S2: C
55.07, H 7.19, N 21.41. Found C 55.35, H 7.14, N 21.65.
2,6-Bis(2-piperidinylethylthio)-7-methylpurine (4d) (0.400 g, 95%); an oil. 1H NMR (CDCl3), : 1.45 (m,
4H, 2CH2), 1.61 (m, 8H, 4 CH2), 2.55 (m, 8H, 4CH2), 2.69 (t, J = 7.5 Hz, 2H, SCH2), 2.78 (t, J = 7.5 Hz,
2H, SCH2), 3.39 (t, J = 7.5 Hz, 2H, NCH2), 3.51 (t, J = 7.5 Hz, 2H, NCH2), 4.05 (s, 3H, NCH3), 7.84 (s,
1H, H-8), FAB MS m/z: 421 (M+1, 19), 308 (M+1-C2H5NC5H10, 7), 112 (C2H4NC5H10, 100). Anal.
Calc for C20H32N6S2: C 57.11, H 7.67, N 19.98. Found C 56.82, H 7.60, N 20.21.
2,6-Bis(2-morpholinylethylthio)-7-methylpurine (4e) (0.385 g, 90.5%); an oil. 1H NMR (CDCl3), : 2.58
(m, 8H, 4CH2), 2.67 (m, 8H, 4CH2), 2.73 (t, J = 7.5 Hz, 2H, SCH2), 2.78 (t, J = 7.5 Hz, 2H, SCH2), 3.39
(t, J = 7.5 Hz, 2H, NCH2), 3.51 (t, J = 7.5 Hz, 2H, NCH2), 4.06 (s, 3H, NCH3), 7.86 (s, 1H, H-8), FAB
MS m/z: 425 (M+1, 44), 312 (M+1-C2H3NOC4H8, 14), 114 (C2H4NOC4H8, 100). Anal. Calcd for
C18H28N6O2S2: C 50.92, H 6.65, N 19.79. Found C 51.19, H 6.71, N 19.51.
Synthesis of 7-methyl-6-purinethiones (5a, 5b)
A. From 8a,b
A solution of the 6-chloro derivative 8a or 8 b (1 mmol) and thiourea (0.152 g, 2 mmol) in absolute EtOH
(10 mL) was refluxed for 1 h. The solvent was removed in vacuo and the residue was dissolved in 5%
aqueous NaOH solution. The reaction product was precipitated with 15% hydrochloric acid and the
process was repeated twice to give pure 6-purinethiones 5a or 5b in 83% and 85.5% yields, respectively.
B. From 4a,b
A solution of anhydrous substrates 4a (or 4b) (1 mmol) in POCl3 (5 mL) or in a mixture of POCl3-DMF
(1:2 v/v, 10 mL) or in phenyl dichlorophosphate (5 mL) was stirred on oil bath at 105-110 °C for 4 h.
After cooling the reaction mixture was poured into crushed ice (10 g), neutralized with concentrated
NH4OH solution at 0-5 °C up to pH = 4-5 and the resulted solid was filtered off to give the mixture of
products 3 and 5a (or 5b). The resulting mixture was separated by extraction with absolute EtOH (3 x 15
mL). The solvent was removed in vacuo and the residue was dissolved in 5% aqueous NaOH solution.
The product 5a (or 5b) was precipitated with 15% aqueous HCl. The residue after extraction with EtOH
was also dissolved in 5% aqueous NaOH solution and the product 3 was precipitated by acidification with
15% aqueous HCl to pH = 3.

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HETEROCYCLES, Vol. 85, No. 10, 2012
Substrate Reagent/solvent Products (yield, %)
4a
4a
4a
4b
4b
4b
POCl3
3 (56), 5a (7)
3 (54), 5a (10)
3 (52), 5a (17)
3 (61), 5b (6)
3 (53), 5b (12)
3 (57), 5b (17)
POCl3-DMF
PhOPOCl2
POCl3
POCl3-DMF
PhOPOCl2
2-(2-Diethylaminoethylthio)-7-methylpurine-6(1H)-thione (5a) (0.246 g, 83%); mp 177-178 °C (EtOH).
1H NMR (DMSO-d6), : 1.38 (t, J = 7.2 Hz, 6H, 2CCH3), 2.68 (t, J = 7.2 Hz, 2H, SCH2), 2.98 (q, J = 7.2
Hz, 4H, 2NCH2), 3.23 (t, J = 7.2 Hz, 2H, NCH2), 4.07 (s, 3H, NCH3), 8.05 (s, 1H, H-8), 9.44 (s, 1H, NH),
FAB MS m/z: 298 (M+1, 100), 255 (M+1-(C2H5)2NH, 6). Anal. Calcd for C12H19N5S2: C 48.46, H 6.44,
N 23.55. Found C 48.73, H 6.35, N 23.38.
2-(3-Dimethylaminopropylthio)-7-methylpurine-6(1H)-thione (5b) (0.242 g, 85.5%); mp 193-194 °C
(EtOH). 1H NMR (DMSO-d6), : 2.12 (m, 2H, CH2), 2.83 (s, 6H, 2NCH3), 3.47 (t, J = 7.2 Hz, 2H, SCH2),
3.75 (t, J = 7.2 Hz, 2H, NCH2), 4.08 (s, 3H, NCH3), 8.10 (s, 1H, H-8), 10.81 (s, 1H, NH), FAB MS m/z:
284 (M+1, 100), 239 (M+1-(CH3)2NH, 9). Anal. Calcd for C11H17N5S2: C 46.62, H 6.05, N 24.71.
Found C 46.89, H 6.08, N 24.52.
Synthesis of 2-(dialkylaminoalkylthio)-7-methyl-6-methylthiopurines (6a, b)
To a stirred solution of 6-purinethione 5a (or 5b) (1 mmol) in 4% aqueous KOH solution at rt, methyl
iodide (0.28 g, 2 mmol) was added. After 20 min the resulting solid was filtered off and washed with
water. The crude products were purified by column chromatography (aluminium oxide, CHCl3, and
CHCl3-EtOH, 9:1, v/v) to give compound 6a (or 6b).
2-(2-Diethylaminoethylthio)-7-methyl-6-methylthiopurine (6a) (0.256 g, 82%); mp 134-135 °C (EtOH).
1H NMR (CDCl3), : 1.10 (t, J = 7.1 Hz, 6H, 2CCH3), 2.68 (q, J = 7.1 Hz, 4H, 2NCH2), 2.72 (s, 3H,
SCH3), 2.91 (t, J = 7.1 Hz, 2H, SCH2), 3.41 (t, J = 7.1 Hz, 2H, NCH2), 4.05 (s, 3H, NCH3), 7.90 (s, 1H,
H-8), FAB MS m/z: 312 (M+1, 100), 239 (M+1-(C2H5)2NH, 16). Anal. Calcd for C13H21N5S2: C 50.13,
H 6.80, N 22.48. Found C 49.89, H 6.73, N 22.74.
2-(3-Dimethylaminopropylthio)-7-methyl-6-methylthiopurine (6b) (0.246 g, 83%); mp 139-140 °C
1
(EtOH). H NMR (CDCl3), : 2.08 (m, 2H, CH2), 2.45 (s, 6H, 2NCH3), 2.74 (s, 3H, SCH3), 3.03 (t, J =
7.1 Hz, 2H, SCH2), 3.81 (t, J = 7.1 Hz, 2H, NCH2), 4.07 (s, 3H, NCH3), 7.96 (s, 1H, H-8), FAB MS m/z:
298 (M+1, 100), 253 (M+1-(CH3)2NH, 12). Anal. Calcd for C12H19N5S2: C 48.46, H 6.44, N 23.55.
Found C 48.74, H 6.36, N 23.24.
Reaction of 2,6-bis(dialkylaminoalkylthio)-7-methylpurines (4a,b) with alcohols

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A solution of 4a or 4b (1 mmol) and sodium methoxide or ethoxide (1 mmol) in respective dry alcohol
(methanol or ethanol, 10 mL) was refluxed for 2 h. After cooling small amount of resulting solid was
filtered off and the alcoholic filtrate was evaporated to dryness in vacuo. The residue was crystallized
from EtOH and purified by column chromatography (aluminium oxide, CHCl3-EtOH, 9:1 v/v) to give
compouns 7a-d.
2-(2-Diethylaminoethylthio)-6-methoxy-7-methylpurine (7a) (0.220 g, 74.5%); mp 155-156 °C (EtOH).
1H NMR (CDCl3), : 1.11 (t, J = 7.2 Hz, 6H, 2CCH3), 2.68 (q, J = 7.2 Hz, 4H, 2NCH2), 2.90 (t, J = 7.1
Hz, 2H, SCH2), 3.44 (t, J = 7.1 Hz, 2H, NCH2), 3.67 (s, 3H, OCH3), 4.05 (s, 3H, NCH3), 7.85 (s, 1H,
H-8), FAB MS m/z: 296 (M+1, 100), 223 (M+1-(C2H5)2NH, 6). Anal. Calcd for C13H21N5OS: C 52.86,
H 7.17, N 23.71. Found C 52.59, H 7.23, N 23.89.
1
2-(2-Diethylaminoethylthio)-6-ethoxy-7-methylpurine (7b) (0.242 g, 78%); mp 124-125 °C (EtOH). H
NMR (CDCl3), : 1.13 (t, J = 7.1 Hz, 6H, 2CCH3), 1.45 (t, J = 7.2 Hz, 3H, CCH3), 2.69 (q, J = 7.1 Hz,
4H, 2NCH2), 2.98 (t, J = 7.1 Hz, 2H, SCH2), 3.51 (t, J = 7.1 Hz, 2H, NCH2), 3.99 (s, 3H, NCH3), 4.58 (q,
J = 7.2 Hz, 2H, OCH2), 7.84 (s, 1H, H-8), FAB MS m/z: 310 (M+1, 100), 237 (M+1-(C2H5)2NH, 20).
Anal. Calcd for C14H23N5OS: C 54.34, H 7.49, N 22.63. Found C 54.61, H 7.54, N 22.32.
2-(3-Dimethylaminopropylthio)-6-methoxy-7-methylpurine (7c) (0.223 g, 79%); mp 159-160 °C (EtOH).
1H NMR (CDCl3), : 1.97 (m, 2H, CH2), 2.29 (s, 6H, 2NCH3), 2.65 (t, J = 7.1 Hz, 2H, SCH2), 3.42 (t, J =
7.1 Hz, 2H, NCH2), 3.69 (s, 3H, OCH3), 4.04 (s, 3H, NCH3), 7.85 (s, 1H, H-8), FAB MS m/z: 282 (M+1,
100), 237 (M+1-(CH3)2NH,10). Anal. Calcd for C 12H19N5OS: C 51.22, H 6.81, N 24.89. Found C 50.94,
H 6.88, N 24.63.
2-(3-Dimethylaminopropylthio)-6-ethoxy-7-methylpurine (7d) (0.252 g, 85.5%); mp 130-131 °C (EtOH).
1H NMR (CDCl3), : 1.45 (t, J = 7.2 Hz, 3H, CCH3), 2.07 (m, 2H, CH2), 2.40 (s, 6H, 2NCH3), 2.67 (t, J =
7.1 Hz, 2H, SCH2), 3.26 (t, J = 7.1 Hz, 2H, NCH2), 3.97 (s, 3H, NCH3), 4.57 (q, J = 7.2 Hz, 2H, OCH2),
7.83 (s, 1H, H-8), FAB MS m/z: 296 (M+1, 100), 251 (M+1-(CH3)2NH, 19). Anal. Calcd for
C13H21N5OS: C 52.86, H 7.17, N 23.71. Found C 52.59, H 7.17, N 23.94.
Synthesis of 2-(dialkylaminoalkylthio)-6-chloro-7-methylpurines (8a,b)
A solution of 6-ethoxy derivatives 7b or 7d (1 mmol) in phenyl dichlorophosphate (5 mL) was stirred on
oil bath at 105-110 °C for 2 h. After cooling the reaction mixture was poured into crushed ice (20 g),
neutralized with concentrated NH4OH solution at 0-5 °C up to pH = 7 and extracted with CHCl3 (3 x 15
mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was evaporated in vacuo
and the residue was purified by column (Al2O3, CHCl3-EtOH, 9:1 v/v) and preparative thin layer
(aluminium oxide, CHCl3) chromatographies to give compounds 8a (0.216 g, 72%) or 8b (0.217 g 76%).
1
6-Chloro-2-(2-diethylaminoethylthio)-7-methylpurine (8a) (0.216 g, 72%); mp 146-147 °C (EtOH). H
NMR (CDCl3), : 1.45 (t, J = 7.1 Hz, 6H, 2CCH3), 3.12 (q, J = 7.1 Hz, 4H, 2NCH2), 3.22 (t, J = 7.1 Hz,

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2H, SCH2), 3.85 (t, J = 7.1 Hz, 2H, NCH2), 4.10 (s, 3H, NCH3), 8.05 (s, 1H, H-8), FAB MS m/z: 300
(M+1, 100), 227 (M+1-(C2H5)2NH, 9). Anal. Calcd for C12H18ClN5S: C 48.07, H 6.05, N 23.36. Found
C 48.35, H 5.97, N 23.17.
6-Chloro-2-(3-dimethylaminopropylthio)-7-methylpurine (8b) (0.217 g, 76%); mp 173-174 °C (EtOH).
1H NMR (CDCl3), : 2.14 (m, 2H, CH2), 2.62 (s, 6H, 2NCH3), 3.46 (t, J = 7.1 Hz, 2H, SCH2), 3.85 (t, J =
7.1 Hz, 2H, NCH2), 4.09 (s, 3H, NCH3), 8.15 (s, 1H, H-8), FAB MS m/z: 286 (M+1, 100), 241
(M+1-(CH3)2NH, 7). Anal. Calcd for C11H16ClN5S: C 46.23, H 5.64, N 24.50. Found C 46.44, H 5.70, N
24.26.
The aqueous solution (after extraction with CHCl3) was acidified with 15% aqueous HCl up to pH = 4-5
and the resulting solid was filtered off and crystallized from EtOH to give 6-chloro-7-methylpurine-
1
2(3H)-thione19 (9) (0.030 and 0.025 g, 15% and 12%); mp > 300 °C (EtOH). H NMR (DMSO-d6), :
4.15 (s, 3H, NCH3), 8.28 (s, 1H, H-8), 12.18 (s, 1H, NH).
ACKNOWLEDGEMENTS
This work was supported by The Medical University of Silesia (grant KNW-1-073/P/1/0).
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