Synthesis of the azathiopurine analogs

Article abstract of DOI:10.3987/COM-07-11232

The effective synthesis of the azathioprine analogs - 2-subsituted derivatives of 7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)purines 5 has been achieved by the reaction of 2-subsituted 6-purinethiones 4 with 5-chloro-l-methyl-4-nitroimidazole in ethano

Full text of DOI:10.3987/COM-07-11232

HETEROCYCLES, Vol. 75, No. 3, 2008
555
HETEROCYCLES, Vol. ,75, No. 3, 2008, pp. 555 - 569. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd October, 2007, Accepted, 13th November, 2007, Published online, 16th November, 2007. COM-07-11232
SYNTHESIS OF THE AZATHIOPURINE ANALOGS
Alicja Kowalska* and Krystian Pluta
Department of Organic Chemistry, The Medical University of Silesia,
Jagiellońska 4, 41-200 Sosnowiec, Poland
E-mail: kowalska@slam.katowice.pl
Abstract – The effective synthesis of the azathioprine analogs - 2-subsituted
derivatives of 7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)purines 5 has been
achieved by the reaction of 2-subsituted 6-purinethiones 4 with 5-chloro-1-me-
thyl-4-nitroimidazole in ethanol. In the case of 7-methyl-2,6-dithioxanthine 4j,
reaction in DMF gave di(imidazolyl) product 5l. The key step in this synthesis
was preparation of the appropriate 2-substituted 6-purinones 2 and 6-chloropu-
rines 3 which were further converted to 6-purinethione 4.
INTRODUCTION
Azathioprine, 6-(1-methyl-4-nitroimidazol-5-ylthio)purine, is one of the oldest immunosuppressive
agents available today.1,2 Now rarely used for chemotherapy but more for immunosuppresion in solid
organ transplantation and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease,
hematologic malignancies, dermatologic afflictions, ulcerative colitis or Crohn’s disease.1,3-5 Azathioprine
is a prodrug that is converted in the liver to imidazole derivatives and 6-mercaptopurine. The metabolites
of both substances have independent immunosuppressive properties. The accepted mechanism of its
action is at the level of DNA.4 Azathioprine interferes with DNA and RNA synthesis and has numerous
non-specific effects on immune system. The active metabolite of 6-mercaptopurine, thioquanine, is
incorporated into ribonucleotides, thereby exerting an antiproliferative effect on mitotically active
lymphocyte populations.1,3,4 Azathioprine also possesses direct antiinflammatory properties by inhibiting
cytotoxic T cell and natural killer cell function.4,6-8 The unique and unexpected role for azathioprine and
its metabolites is the control of T cell apoptosis by modulation of GTP-binding protein – Rac 1 upon
CD28 costimmulation.7-9 Searching for prodrugs with potential biological activity, the synthesis of new
analogs of azathioprine as 7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)purines has been described.
RESULTS AND DISCUSSION
The key step in the synthesis of the azathioprine analogs 5 was a preparation of appropriate 2-substituted
7-methyl-6-purinethiones 2 and 2-substituted 6-chloro-7-methylpurines 3 which were further transformed
into appropriate 6-purinethiones 4. Problems with the synthesis of the chloro substrates 3 were overcome

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HETEROCYCLES, Vol. 75, No. 3, 2008
exploiting regioselective reactions of identical substituted 2,6-dialkoxy- and 2,6-dialkylthio-7-
methylpurines 1 with the hydroxide ion to give the hypoxanthine analogs 2. This alkaline hydrolysis of
compounds 1 proceeded in aqueous sodium hydroxide solution in position 6 and was effective for
compounds with the methoxy, ethoxy, allyloxy, methylthio and ethylthio substituents in position 2 (2a-c,
2e, 2f, 85-98% yield, Scheme 1). The yields of hydrolysis of compounds 1 with other substituents, i.e.
benzyloxy, allylthio and benzylthio were unsatisfactory (10-21% yields) in these conditions, probably for
O
Me
N
H
N
A
N
RX
N
2a-h
XR
N
O
OEt
N
Me
N
Me
N
Me
N
H
N
N
N
B
+
N
N
N
RX
RX
N
RX
1a-h
1i, 1j
2d, 2g, 2h
O
Me
N
H
O
N
C
N
A
. 8% NaOH/H2O
N
H
2i
B
C
. 8% NaOH/H2O-EtOH (1:2)
. 5% NaOH/H2O-DMSO (1:2)
Substrate 1
Products
R
Method
No
a
b
c
d
X
O
O
O
O
R
Me
Et
allyl
Bn
No
X
Yield (%)
A
A
A
A
B
C
2a
2b
2c
2d
2d
2i
O
O
O
O
O
Me
Et
allyl
Bn
Bn
85
97
95
21
94
92
e
f
g
S
S
S
Me
Et
allyl
A
A
A
B
2e
2f
2g
2g
1i
2h
2h
1j
S
S
S
S
S
S
S
S
Me
Et
allyl
allyl
allyl
Bn
98
90
19
88
8
10
87
12
90
h
S
Bn
A
B
Bn
Bn
C
2i
Scheme 1
the reason of weak solubility of the 2,6-dibenzyloxy-, 2,6-diallylthio- and 2,6-dibenzylthio-7-methyl-
purines 1d, 1g, 1h in water. When the alkaline hydrolysis was carried out in aqueous ethanol solution
(water-ethanol 1:2 v/v) 6-purinones 2d, 2g and 2h were obtained in good yields (87-94%) but 2-allylthio-

HETEROCYCLES, Vol. 75, No. 3, 2008
557
and 2-benzylthio-6-ethoxy-7-methylpurines 1i and 1j were also obtained (in 8 and 12% yields) as a result
of high reactivity of the position 6 in identical substituted purines towards the oxygen nucleophilic agents,
as observed previously in other purine derivatives.10 Hydrolysis in alkaline DMSO solution led to only
one product, 7-methylxanthine 2i, as the result of the double substitution (Scheme 1).
Next we wanted to convert 6-purinones 2 into corresponding 6-purinethiones 4 by the described earlier
procedure of chlorination of 2-substituted 7-methyl-6-purinones 2 with phosphorus oxychloride followed
by reaction with thiourea in ethanol.10a It appeared that only 2-methoxy-, 2-methylthio- and 2-ethylthio-7-
methyl-6-purinones 2a, 2e and 2f reacted smoothly with phosphorus oxychloride to give 6-chloroderivati-
ves 3a, 3e and 3f. The other 6-purinones with the ethoxy, benzyloxy, allylthio or benzylthio groups
underwent O- and S-dealkylation in position 2 during reaction with phosphorus oxychloride giving
6-chloro-7- methyl-2- purinone 3i or 2-purinethione 3j (Scheme 2). The last compound was used later for
the synthesis of the 2-allylthio- and 2-benzylthio derivatives 3g and 3h by S-alkylation.
Cl
Me
N
N
N
RX
N
O
N
Me
N
3a, 3e, 3f
H
N
POCl3
N
RX
Cl
N
Cl
Me
N
Me
2a-h
N
N
N
RX
N
N
RS
X
N
H
3g, 3h
3i, 3j
Substrate
Product
No
2a
2b
2c
2d
2e
2f
2g
2h
3j
X
O
O
O
O
S
S
S
S
S
R
Me
Et
allyl
Bn
Me
Et
allyl
Bn
No
3a
3i
3i
3i
3e
3f
3j
3j
3g
X
R
Me
Yield (%)
O
O
O
O
S
S
S
S
S
75
82
81
95
87
89
78
85
91
Me
Et
allyl
Bn
3j
S
3h
S
85
Scheme 2
In order to obtain 6-purinethiones 4 with the alkoxy and alkylthio groups in position 2 two routes were
used. In the first one 6-chloroderivatives 3 were refluxed with thiourea in ethanol and in the second one
6-purinones 2 were heated with phosphorus pentasulfide in pyridine. Treatment of 6-chloro-7-methyl-2-
purinone 3i or 2-purinethione 3j with thiourea led to 7-methyl-6-thioxanthine 4i and 7-methyl-2,6-dithio-

558
HETEROCYCLES, Vol. 75, No. 3, 2008
xanthine 4j (Scheme 3).
Cl
O
N
S
Me
N
Me
N
Me
N
H
H
B
A
N
N
N
N
N
N
N
RX
N
RX
RX
N
S
3a, 3e, 3f
4a-h
2b-d, 2g, 2h
Cl
Me
N
Me
N
H
X
A
N
N
N
N
N
H
X
4i, 4j
3i, 3j
H
A.
B.
NH2CSNH2, EtOH
P2S5, pyridine
Substrate
Method
R
Product
R
No
X
O
O
O
O
S
S
S
S
S
No
4a
4b
4c
4d
4e
4f
4g
4h
4g
4h
X
O
O
O
O
S
S
S
S
S
Yield (%)
3a
2b
2c
2d
3e
3f
3g
3h
2g
2h
Me
A
B
B
B
A
A
A
A
B
B
Me
Et
allyl
Bn
Me
Et
allyl
Bn
allyl
Bn
73
76
56
62
86
84
73
78
63
66
Et
allyl
Bn
Me
Et
allyl
Bn
allyl
Bz
S
S
3i
3j
O
S
A
A
4i
4j
O
S
95
98
Scheme 3
Reactions of 2-substituted (with the alkoxy, alkylthio and chloro groups) 7-methyl-6-purinethiones 4a-4h
and 4k with 5-chloro-1-methyl-4-nitroimidazole in 70% ethanol gave 2-substituted 7-methyl-6-(1-me-
thyl-4-nitroimidazol-5-ylthio)purines 5a-5h and 5k in good yields (71-98%, Scheme 4). In the case of the
2-allylthio and 2-benzylthio compounds 4g and 4h a process of S-dealkylation was also observed to give
derivative 5j (in 12% and 18% yield). Whereas reaction of 7-methyl-6-thioxanthine 4i with 5-chloro-1-
methyl-4-nitroimidazole in ethanol gave only expected imidazolylthio derivative 5i (in 68% yield),
7-methyldithioxanthine 4j gave 3 products: expected imidazolylthio derivative 5j (in low yield of 9%),
di(imidazolylthio) product 5l (in 62% yield) and a product being the result of an action of ethanol, ethoxy
derivative 5m (in 24%). Only di(imidazolylthio) product 5l in high yield of 91% was observed when the
reaction was carried out in DMF (Scheme 5). Unexpected ethoxy compound 5m was considered as a
result of the subsequent reaction of the formed di(imidazolylthio) product 5l rather than the substrate 4j
with ethanol. The separate reaction of compound 5l with boiling ethanol for 2 h showed the

HETEROCYCLES, Vol. 75, No. 3, 2008
559
imidazolylthio group in position 6 to be a quite good leaving group to give ethoxy derivative 5m in 82%
yield (Scheme 6).
N
N
S
N
Me N
NO2
Me N
NO2
Me
N
Me
N
H
70% EtOH
N
S
N
S
Me
N
Me
N
+
Cl
O2N
+
N
N
X
N
X
N
S
4a-h, 4k
N
N
N
H
5j
5a-h, 5k
Substrate
Products
No
4a
4b
4c
4d
4e
4f
X
OMe
OEt
Oallyl
OBn
SMe
SEt
No
5a
5b
5c
5d
5e
5f
5g
5j
5h
5j
X
OMe
OEt
Oallyl
OBn
SMe
SEt
Yield (%)
94
78
72
71
83
77
72
12
75
18
98
4g
Sallyl
Sallyl
4h
4k
SBn
Cl
SBn
Cl
5k
Scheme 4
N
N
OEt
N
Me
N
Me N
NO2
Me N
NO2
N
A
NO2
N
S
S
N
Me
N
Me
N
+
+ / or
NO2
N
S
S
Me
Me
N
N
N
N
H
N
N
5m
+
Cl
N
N
X
N
H
S
Me
N
N
X
N
H
N
5l
5i, 5j
4i, 4j
O2N
N
B
Me
5l
A. 70% EtOH
B
. DMF
Substrate
Products
No
4i
4j
X
O
S
Method
No
5i
5j
5l
5m
5l
X
O
S
-
-
-
Yield (%)
A
A
68
9
62
24
91
4j
S
B
Scheme 5

560
HETEROCYCLES, Vol. 75, No. 3, 2008
N
Me N
NO2
S
N
OEt
N
Me
Me
N
N
N
N
EtOH
NO2
NO2
N
N
S
S
N
N
5l
N
Me
5m
N
Me
Scheme 6
Conclusion
We report here an efficient synthesis of 13 new azathioprine analogs being of 2-subsituted derivatives of
7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)purines 5 in the series of transformations starting from
2,6-dialkoxy- and 2-dialkylthio-7-methylpurines 1.
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Boetius melting point apparatus and are
uncorrected. The 1H 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 standard.
Electron impact (EI MS) and chemical ionization mass spectra (CI MS) were run on Finnigan MAT 95
spectrometer at 70eV. Column chromatography was performed on silica gel 60 (Merck) using a mixture
of chloroform-methanol (10:1, v/v) as an eluent. 2,6-Dialkoxy-7-methylpurines 1a-d with identical alkyl
groups were prepared from 2,6-dichloro-7-methylpurine and corresponding sodium alkoxide in alcohol
solution according to known procedure.10c,11
1. 2,6-Dimethoxy-7-methylpurine (1a), mp 197-198 oC (EtOH), lit.,10c mp 198-199 oC.
2. 2,6-Diethoxy-7-methylpurine (1b), mp 147-148 oC (EtOH), lit.,10c mp 146-148 oC.
3. 2,6-Diallyloxy-7-methylpurine (1c), mp 109-110 oC (Et2O), lit.,11b mp 111-112 oC.
4. 2,6-Dibenzyloxy-7-methylpurine (1d), (2.57g, 75%), mp 103-105 oC (Et2O).
1H NMR (CDCl3) δ: 3.94 (s, 3H, NMe), 5.52 (s, 2H, O2CH2), 5.58 (s, 2H, O6CH2), 7.36 (m, 6H, 2
m-C6H5, 2 p-C6H5), 7.45 (d, J = 7.5 Hz, 2H, o-C6H5), 7.54 (d, J = 7.5Hz, 2H, o-C6H5), 7.83 (s, 1H, H8),
+
EI MS m/z: 346 (M+, 23), 255 (M-CH2C6H5, 33), C6H5 (100). Anal. Calcd for C20H18N4O2: C 69.35, H
5.24, N 16.17. Found C 69.07, H 5.29, N 15.96.
2,6-Dialkylthio-7-methylpurines 1e-h with identical alkyl groups were prepared from 2,6-dichloro-7-me-
thylpurine and thiourea in EtOH followed S-alkylation with 2 equivalents of alkyl halides (methyl iodide,
ethyl iodide, allyl bromide and benzyl chloride) in 4% KOH solution at room temperature.12
1. 2,6-Dimethylthio-7-methylpurine (1e), mp 176-177 oC (EtOH), lit.,12 mp 176-178 oC.

HETEROCYCLES, Vol. 75, No. 3, 2008
561
2. 2,6-Diethylthio-7-methylpurine (1f), (2.18g, 85%), mp 132-133 oC (EtOH).
1H NMR (CDCl3) δ: 1.41 (t, J = 7.3 Hz, 3H, Me), 1.45 (t, J = 7.3 Hz, 3H, Me), 3.24 (q, J = 7.3 Hz , 2H,
S2CH2), 3.38 (q, J = 7.3 Hz, 2H, CH2), 4.06 (s, 3H, NMe), 7.86 (s, 1H, H-8), EI MS m/z: 254 (M+, 100),
225 (M-C2H5, 89). Anal. Calcd for C10H14N4S2: C 47.22, H 5.55, N 22.03. Found C 47.06, H 5.59, N
21.76.
3. 2,6-Diallylthio-7-methylpurine (1g) (2.81g, 78%); mp 94-95 oC (Et2O).
1H NMR (CDCl3) δ: 3.91 (d, J = 6.9 Hz, 2H, S2CH2), 4.04 (d, J = 6.9 Hz, 2H, S6CH2), 4.08 (s, 3H, NMe),
5.12 (d, J = 10.1 Hz, 1H, =CH2), 5.20 (d, J = 10.1 Hz, 1H, =CH2), 5.33 (d, J = 13.5 Hz, 1H, =CH2), 5.39
(d, J = 13.5 Hz, 1H, =CH2), 6.01 (m, 2H, =CH), 8.00 (s, 1H, H8), EI MS m/z: 278 (M+, 27), 237 (M-C3H5,
100). Anal. Calcd for C12H14N4S2: C 51.77, H 5.07, N 20.13. Found C 51.55, H 5.17, N 19.88.
4. 2,6-Dibenzylthio-7-methylpurine (1h) (3.48g, 91%); mp 131-132 oC (EtOH).
1H NMR (CDCl3) δ: 4.01 (s, 3H, NMe), 4.52 (s, 2H, S2CH2), 4.57 (s, 2H, S6CH2), 7.27 (m, 6H, 2 m-C6H5,
2 p-C6H5), 7.41 (d, J = 6.9Hz, 2H, o-C6H5), 7.47 (d, J = 6.9Hz, 2H, o-C6H5), 7.88 (s, 1H, H8), EI MS
m/z: 378 (M+, 86), 287 (M-CH2C6H5, 100). Anal. Calcd for C20H18N4S2: C 63.46, H 4.79, N 14.80. Found
C 63.21, H 4.86, N 14.51.
Hydrolysis of dialkoxy- and dialkylthio-7-methylpurines 1 to 2-substituted 7-methyl-6-purinones 2 -
general procedure.
To the substrates 1 (10 mmol) in 8-10% aqueous NaOH solution (100 mL, method A) or a mixture of 8%
NaOH-EtOH solution (1:2 v/v, 120 mL, method B) or 5% NaOH-DMSO solution (1:2 v/v, 40 mL,
method C) was added. The mixture was boiled (until all the material had gone into solution) for 1-4 h up
to full clarification of a suspension. In 5% NaOH-DMSO solution, the suspension of the substrates 1d or
1h was stirred on an oil bath at 100 oC for 1.5 h. After cooling the clear solution was brought to pH = 6 by
addition of glacial acetic acid. The resulting solid was filtered off, air-dried and crystallized from EtOH to
give 6-purinones 2a-h. When the reaction was carried out in NaOH-EtOH solution, a mixture of two
products was obtained. After cooling, EtOH was evaporated in vaccuo and the residue was neutralized
with diluted hydrochloric acid. The resulting solid was filtered off to give crude products which were
purified by column chromatography (silica gel, CHCl3) to give 6-purinones 2d, 2g and 2h. The filtrate
was extracted with CHCl3 (3 x 10 mL), the extracts were dried with anhydrous sodium sulfate and
evaporated in vacuo to dryness. The residue was purified by column chromatography (silica gel, CHCl3)
to give 2-allylthio- 6-ethoxy-7-methylpurine 1i or 2-benzylthio-6-ethoxy-7-methylpurine 1j.
o
1. 2-Methoxy-7-methyl-6-oxo-1,6-dihydropurine (2a) (1.53g, 85%); mp 219-220 C (EtOH-water), lit.,13
mp 220 oC.

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HETEROCYCLES, Vol. 75, No. 3, 2008
2. 2-Ethoxy-7-methyl-6-oxo-1,6-dihydropurine (2b) (1.89g, 97%); mp 214-215 oC (EtOH-water).
1H NMR (DMSO-d6) δ: 1.29 (t, J = 6.9 Hz, 3H, Me), 3.88 (s, 3H, NMe), 4.30 (q, J = 6.9 Hz, 2H, OCH2),
7.92 (s, 1H, C8), 10.02 (s, 1H, NH), EI MS m/z: 194 (M+, 76), 166 (M-C2H4, 100). Anal. Calcd for
C8H10N4O2: C 49.48, H 5.19, N 28.85. Found C 49.18, H 5.25, N 28.54.
3. 2-Allyloxy-7-methyl-6-oxo-1,6-dihydropurine (2c) (1.95g, 95%); mp 199-200 oC (EtOH-water).
1H NMR (DMSO-d6) δ: 3.89 (s, 3H, NMe), 4.80 (d, J = 6.4 Hz, 2H, OCH2), 5.25 (d, J = 11.1 Hz, 1H,
=CH2), 5.40 (d, J = 18.0 Hz, 1H, =CH2), 6.04 (m, 1H, =CH), 7.94 (s, 1H, H8), 10.04 (s, 1H, NH), EI MS
m/z: 206 (M+, 23), 165 (M-C3H5, 100). Anal. Calcd for C9H10N4O2: C 52.42, H 4.89, N 27.17. Found C
52.18, H 4.96, N 26.88.
4. 2-Benzyloxy-7-methyl-6-oxo-1,6-dihydropurine (2d) (method A: 0.54g, 21%, method B: 2.41g, 94%);
mp 191-192 oC (EtOH).
1H NMR (DMSO-d6) δ: 3.87 (s, 3H, NMe), 5.32 (s, 2H, CH2) 7.32 (t, J = 7.4 Hz, 1H, p-C6H5), 7.38 (t, J =
7.4 Hz, 2H, m-C6H5), 7.44 (d, J = 7.4 Hz, 2H, o-C6H5), 7.89 (s, 1H, H8), 10.12 (s, 1H, NH), EI MS m/z:
+
256 (M+, 30), 165 (M-CH2C6H5, 13), C6H5CH2 (100). Anal. Calcd for C13H12N4O2: C 60.93, H 4.72, N
21.86. Found C 60.81, H 4.77, N 21.49.
o
5. 2-Methylthio-7-methyl-6-oxo-1,6-dihydropurine (2e) (1.92g, 98%); mp 303-305 C (water), lit.,10b mp
> 300 oC.
6. 2-Ethylthio-7-methyl-6-oxo-1,6-dihydropurine (2f) (1.89g, 90%); mp 275-276 oC (EtOH-water).
1H NMR (DMSO-d6) δ: 1.27 (t, J = 7.2 Hz, 3H, Me), 3.03 (q, J = 7.2 Hz, 2H, CH2), 3.88 (s, 3H, NMe),
7.82 (s, 1H, H8), 10.19 (s, 1H, NH), EI MS m/z: 210 (M+, 100), 182 (M-C2H4, 43). Anal. Calcd for
C8H10N4OS: C 45.70, H 4.79, N 26.65. Found C 45.49, H 4.69, N 26.39.
7. 2-Allylthio-7-methyl-6-oxo-1,6-dihydropurine (2g) (method A: 0.42 g, 19%, method B: 1.05g, 88%);
mp 216-218 oC (EtOH-water).
1H NMR (DMSO-d6) δ: 3.83 (d, J = 6.9 Hz, 2H, SCH2), 3.91 (s, 3H, NMe), 5.12 (d, J = 10.5 Hz, 1H,
=CH2), 5.31 (d, J = 17.4 Hz, 1H, =CH2), 5.95 (m, 1H, =CH), 8.07 (s, 1H, H8), 10.38 (s, 1H, NH), EI MS
m/z: 222 (M+, 100), 181 (M-C3H5, 55). Anal. Calcd for C9H10N4OS: C 48.64, H 4.53, N 25.21. Found C
48.41, H 4.55, N 24.92.
In the case of method B an additional product was isolated: 2-allylthio-6-ethoxy-7-methylpurine (1i)
(0,20g, 8%); mp 165-166 oC (EtOH).
1H NMR (CDCl3) δ: 1.47 (t, J = 7.2 Hz, 3H, Me), 3.90 (d, J = 6.9 Hz, 2H, SCH2), 4.02 (s, 3H, NMe),
4.60 (q, J = 7.2 Hz, 2H, OCH2), 5.11 (d, J = 10.2 Hz, 1H, =CH2), 5.34 (d, J = 17.3 Hz, 1H, =CH2), 6.04
(m, 1H, =CH), 8.03 (s, 1H, H8), EI MS m/z: 250 (M+, 39), 209 (M-C3H5, 65), 222 (M-C2H4, 100). Anal.
Calcd for C11H14N4OS: C 52.78, H 5.64, N 22.38. Found C 52.52, H 5.74, N 22.09.

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8. 2-Benzylthio-7-methyl-6-oxo-1,6-dihydropurine (2h) (method A: 0.27 g, 10%, 2.37g, 87%); mp
246-248 oC (EtOH).
1H NMR (DMSO-d6) δ: 3.91 (s, 3H, NMe), 4.44 (s, 2H, CH2), 7.32 (m, 3H, m-C6H5, p-C6H5), 7.43 (d, J =
6.9 Hz, 2H, o-C6H5), 8.10 (s, 1H, H8), 12.28 (s, 1H, NH), EI MS m/z: 272 (M+, 100), 181 (M-CH2C6H5,
+
22), C6H5CH2 (78). Anal. Calcd for C13H12N4OS: C 57.34, H 4.44, N 20.57. Found C 57.07, H 4.49, N
20.28.
In the case of method B an additional product was isolated: 2-benzylthio-6-ethoxy-7-methylpurine (1j)
(0.36g, 12%), mp 142-143 oC (EtOH).
1H NMR (CDCl3) δ: 1.39 (t, J = 6.9 Hz, 3H, Me), 3.96 (s, 3H, NMe), 4.51 (s, 2H, SCH2), 4.53 (q, J = 6.9
Hz, 2H, OCH2), 7.25 (m, 3H, m-C6H5, p-C6H5), 7.42 (d, J = 6.9 Hz, 2H, o-C6H5), 8.04 (s, 1H, H8), EI MS
m/z: 300 (M+, 32), 209 (M-CH2C6H5, 19), 272 (M-C2H4, 100). Anal. Calcd for C15H16N4OS: C 59.98, H
5.37, N 18.65. Found C 59.66, H 5.41, N 18.39.
9. 7-Methylxanthine (2i) (1.53 g, 92% from 1d, 1.49 g, 90% from 1h), mp > 300 oC (EtOH), lit.,14 mp >
300 oC.
Synthesis of 2-subsituted 6-chloro-7-methylpurines 3
2-Subsituted 6-chloro-7-methylpurines 3a, 3b and 3f were obtained by boiling appropriate 6-purinones 2
with phosphorus oxychloride, as described previously.10a When in position 2 in derivatives 2 the ethoxy,
allyloxy, benzyloxy 2b-d or allythio 2g and benzylthio 2h groups were present, O- or S-dealkylation took
place and the products were identified as 6-chloro-7-methyl-2-purinone 3i or 2-purinethione 3j.
6-Chloroderivatives 3g and 3h were prepared by S-alkylation with allyl bromide or benzyl chloride of
2-purinethione 3j according to earlier described procedure.12
1. 2-Methoxy-6-chloro-7-methylpurine (3a) (1.49g, 75%); mp 156-157 oC (EtOH), lit.,15 mp 156-158 oC.
o
2. 2-Methylthio-6-chloro-7-methylpurine (3e) (1.86g, 87%); mp 178-179 C (EtOH), lit.,10a mp 176-177
oC.
3. 2-Ethylthio-6-chloro-7-methylpurine (3f) (2.03g, 89%); mp 174-175 oC (EtOH).
1H NMR (CDCl3) δ: 1.43 (t, J = 7.2Hz, 3H, Me), 3.32 (q, J = 7.2 Hz, 2H, CH2), 4.06 (s, 3H, NMe), 7.75
(s, 1H, C8), EI MS m/z: 228 (M+, 100), 200 (M-C2H4, 23). Anal. Calcd for C8H9ClN4S: C 42.02, H 3.97,
N 24.50. Found C 41.84, H 3.91, N 24.18.
4. 2-Allylthio-6-chloro-7-methylpurine (3g) (2.18g, 91%); mp 206-207o C (EtOH).
1H NMR (CDCl3) δ: 3.97 (d, J = 6.9 Hz, 2H, SCH2), 4.06 (s, 3H, NMe), 5.17 (d, J = 10.3 Hz, 1H, =CH2),
5.36 (d, J = 17.2 Hz, 1H, =CH2), 5.97 (m, 2H, =CH), 7.75 (s, 1H, H8), EI MS m/z: 240 (M+, 100), 199
(M-C3H5, 83). Anal. Calcd for C9H9ClN4S: C 44.91, H 3.77, N 23.28. Found C 44.63, H 3.79, N 23.01.

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5. 2-Benzylthio-6-chloro-7-methylpurine (3h) (2.47g, 85%); mp 163-164 oC (EtOH).
1H NMR (CDCl3) δ: 4.02 (s, 3H, NMe), 4.45 (s, 2H, CH2), 7.31 (m, 3H, m-C6H5, p-C6H5), 7.45 (d, J =
+
6.9 Hz, 2H, o-C6H5), 8.66 (s, 1H, H8), EI MS m/z: 290 (M+, 100), 199 (M-CH2C6H5, 28), C6H5CH2 (96).
Anal. Calcd for C13H11ClN4S: C 53.70, H 3.81, N 19.27. Found C 53.49, H 3.86, N 19.02.
6. 6-Chloro-7-methyl-2-oxo-2,3-dihydropurine (3i); mp 290-292 oC (water).
1H NMR (DMSO-d6) δ: 3.82 (s, 3H, NMe), 7.90 (s, 1H, H8), 11.52 (s, 1H, NH), EI MS m/z: 184 (M+,
100). Anal. Calcd for C6H5ClN4O: C 39.04, H 2.73, N 30.35. Found C 38.82, H 2.79, N 30.03.
7. 6-Chloro-7-methyl-2-tioxo-2,3-dihydropurine (3j); mp > 300oC (water), lit.,10a mp > 300 oC.
Synthesis of 6-purinethiones 4a-h
A. Reaction with thiourea.
A solution of 6-chloroderivative 3a and 3e-h (5 mmol) and thiourea (0.76 g, 10 mmol) in absolute EtOH
(75 mL) was refluxed for 1-2 h. The solvent was removed in vaccuo and the residue was dissolved in 5%
NaOH solution. The reaction product was precipitated with 15% hydrochloric acid and the process was
repeated twice to give 6-purinethiones 4a and 4e-h in 73-86% yields, and 4i, 4j in 95% and 98% yields,
respectively.
1. 2-Methoxy-7-methyl-6-thioxo-1,6-dihydropurine (4a) (0.72g, 73%); mp 238-240 oC (EtOH), lit.,10a mp.
239-240 oC.
o
2. 2-Methylthio-7-methyl-6-thioxo-1,6-dihydropurine (4e) (0.91g, 86%); mp 176-177 C (EtOH), lit.,10a
mp 176-177 oC.
3. 2-Ethylthio-7-methyl-6-thioxo-1,6-dihydropurine (4f) (0.95g, 84%); mp 194-196 oC (EtOH).
1H NMR (DMSO-d6) δ: 1.29 (t, J = 7.1 Hz, 3H, Me), 3.06 (q, J = 7.1Hz, 2H, CH2), 3.91 (s, 3H, NMe),
7.97 (s, 1H, H8), 13.82 (s, 1H, N1), EI MS m/z: 226 (M+, 100), 198 (M-C2H4, 12). Anal. Calcd for
C8H10N4S2: C 42.46, H 4.45, N 24.76. Found C 42.16, H 4.49, N 24.49.
4. 2-Allylthio-7-methyl-6-thioxo-1,6-dihydropurine (4g) (0.87 g, 73%); mp 186-188 oC (EtOH).
1H NMR (DMSO-d6) δ: 3.85 (d, J = 6.9 Hz, 2H, SCH2), 3.93 (s, 3H, NMe), 5.13 (d, J =10.2 Hz, 1H,
=CH2), 5.32 (d, J = 17.1 Hz, 1H, =CH2), 5.96 (m, 1H, =CH), 8.10 (s, 1H, H8), 13.92 (s, 1H, N1), EI MS
m/z: 238 (M+, 100), 197 (M-C3H5, 42). Anal. Calcd for C9H10N4S2: C 45.36, H 4.23, N 23.51. Found C
45.23, H 4.29, N 23.32.
5. 2-Benzylthio-7-methyl-6-thioxo-1,6-dihydropurine (4h) (1.12g, 78%); mp 201-203 oC (EtOH).
1H NMR (DMSO-d6) δ: 4.15 (s, 3H, NMe), 4.41 (s, 2H, CH2), 7.29 (m, 3H, m-C6H5, p-C6H5), 7.44 (d, J =
6.9 Hz, 2H, o-C6H5), 8.18 (s, 1H, H8), 13.59 (s, 1H, N1), EI MS m/z: 288 (M+, 100), 197 (M-CH2C6H5,
87). Anal. Calcd for C13H12N4S2: C 54.14, H 4.19, N 19.43. Found C 53.91, H 4.11, N 19.21.

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5. 7-Methyl-2-oxo-6-thioxo-1,2,3,6-tetrahydropurine (4i) (0.87g, 95%); mp 342-344 oC (water), lit.,12 mp
343-344 oC.
6. 7-Methyl-2,6-dithioxo-1,2,3,6-tetrahydropurine (4j) (0.97g, 98%); mp >300 oC (EtOH), lit.,12, mp >300
oC.
B. Reaction with phosphorus pentasulfide
A mixture of 2-alkoxy- or 2-alkylthio-7-methyl-6-purinone 2b-d, 2g and 2h (1 mmol) and phosphorus
pentasulfide (0.67g, 3 mmol) in dry pyridine (30 mL) was stirred on oil bath at boiling temperature for
3.5 h. After cooling, the pyridine was removed in vaccuo and the residue was treated with boiling water
(15 mL) for 15 min. The insoluble portion was dissolved in 25% NH4OH solution and the products were
precipitated by acidification with glacial acetic acid to pH = 5. The resulting solid was filtered off and
air-dried to give 6-purinethiones 4b-d, 4g and 4h in 56-76% yields.
1. 2-Ethoxy-7-methyl-6-thioxo-1,6-dihydropurine (4b) (0.16g, 76%); mp 206-208 oC (EtOH).
1H NMR (DMSO-d6) δ: 1.29 (t, J = 7.1 Hz, 3H, Me), 3.68 (s, 3H, NMe), 4.33 (q, J = 7.1 Hz, 2H, OCH2),
7.98 (s, 1H, C8), 12.05 (s, 1H, NH), EI MS m/z: 210 (M+, 83), 182 (M-C2H4, 100). Anal. Calcd for
C8H10N4OS: C 45.70, H 4.79, N 26.65. Found C 45.41, H 4.69, N 26.37.
2. 2-Allyloxy-7-methyl-6-thioxo-1,6-dihydropurine (4c) (0.12g, 56%); mp 187-189 oC (EtOH).
1H NMR (DMSO-d6) δ: 3.77 (s, 3H, NMe), 4.81 (d, J = 6.9 Hz, 2H, OCH2), 5.25 (d, J = 10.1 Hz, 1H,
=CH2), 5.42 (d, J = 17.4 Hz, 1H, =CH2), 6.02 (m, 1H, =CH), 8.05 (s, 1H, H8), 12.15 (s, 1H, NH), EI MS
m/z: 222 (M+, 19), 181 (M-C3H5, 100). Anal. Calcd for C9H10N4OS: C 48.64, H 4.53, N 25.21. Found C
48.39, H 4.56, N 24.92.
3. 2-Benzyloxy-7-methyl-6-thioxo-1,6-dihydropurine (4d) (0.17g, 62%); mp 228-230 oC (EtOH).
1H NMR (DMSO-d6) δ: 4.01 (s, 3H, NMe), 5.80 (s, 2H, CH2), 7.24 (t, J = 7.2 Hz, 1H, p-C6H5), 7.44 (t, J
= 7.2 Hz, 2H, m-C6H5), 7.56 (d, J = 7.2 Hz, 2H, o-C6H5), 8.10 (s, 1H, H8), 12.27 (s, 1H, NH), EI MS
+
m/z: 272 (M+, 26), 181 (M-CH2C6H5, 18), C6H5CH2 (100). Anal. Calcd for C13H12N4OS: C 57.34, H
4.44, N 20.57. Found C 57.38, H 4.48, N 20.32.
4. 2-Allylthio-7-methyl-6-thioxo-1,6-dihydropurine (4g) (0.15g, 63%); mp 186-188 oC (EtOH).
5. 2-Benzylthio-7-methyl-6-thioxo-1,6-dihydropurine (4h) (0.19g, 66%); mp 201-203 oC (EtOH).
Synthesis of 2-substituted 7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)purines 5 - general
procedure
A. A mixture of 6-purinethione 4a-k (1 mmol), 5-chloro-1-methyl-4-nitroimidazole (0.16g, 1 mmol),
10% NaOH (0.4 mL) and 70% EtOH (10 mL) was refluxed for 2 h. After cooling the resulting solid was
filtered off, washed with water, air dried and recrystallized or purified by column chromatography (silica

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gel, CHCl3-EtOH, 10:1) to give 5a-k. The ethanolic filtrate was concentrated in vaccuo to 5 mL to give
an additional amount of products 5a-h and 5k or 7-methyl-6-(1-methyl-4-nitroimidazol-5-ylthio)-
2-purinone 5i and 2-purinethione 5j. Compounds 5l and 5m were separated by column chromatography
(silica gel, CHCl3).
o
1. 2-Methoxy-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5a) (0.3g, 94%); mp 218-219 C
(EtOH).
1H NMR (DMSO-d6) δ: 3.68 (s, 3H, OMe), 3.74 (s, 3H, N7Me), 4.14 (s, 3H, NMe), 8.27 (s, 1H, C8), 8.53
(s, 1H, CH), CI MS m/z: 322 (M+1, 100). Anal. Calcd for C11H11N7O3S: C 41.12, H 3.45, N 30.51.
Found C 41.01, H 3.40, N 30.22.
o
2. 2-Ethoxy-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5b) (0.26g, 78%); mp 182-183 C
(EtOH).
1H NMR (DMSO-d6) δ: 1.15 (t, J = 7.1 Hz, 3H, Me), 3.72 (s, 3H, N7Me), 4.06 (q, J = 7.1 Hz, 2H, OCH2),
4.12 (s, 3H, NMe), 8.26 (s, 1H, C8), 8.50 (s, 1H, CH), CI MS m/z: 336 (M+1, 60), 307 (M-C2H5 +1, 100).
Anal. Calcd for C12H13N7O3S: C 42.98, H 3.91, N 29.24. Found C 42.69, H 3.95, N 29.01.
3. 2-Allyloxy-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5c) (0.25g, 72%); mp 177-178 o C
(EtOH).
1H NMR (DMSO-d6) δ: 3.70 (s, 3H, N7Me), 4.11 (s, 3H, NMe), 4.85 (d, J = 6.9 Hz, 2H, OCH2), 5.18 (d,
J = 11.2 Hz, 1H, =CH2), 5.32 (d, J = 18.2 Hz, 1H, =CH2), 5.93 (m, 1H, =CH), 8.23 (s, 1H, H8), 8.45 (s,
1H, CH), CI MS m/z: 348 (M+1, 16), 307 M-C3H5 +1, 100). Anal. Calcd for C13H13N7O3S: C 44.95, H
3.77, N 28.23. Found C 44.66, H 3.79, N 27.94.
4. 2-Benzyloxy-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5d) (0.28g, 71%); mp 192-193
oC (EtOH).
1H NMR (DMSO-d6) δ: 3.74 (s, 3H, N7Me), 3.85 (s, 3H, NMe), 5.15 (s, 2H, CH2), 7.26 (m, 3H, m-C6H5,
p-C6H5), 7.41 (d, J = 7.2Hz, 2H, o-C6H5), 7.46 (s, 1H, H8), 7.88 (s, 1H, CH), CI MS m/z: 398 (M+1, 14),
307 (M-CH2C6H5+1, 100). Anal. Calcd for C17H15N7O3S: C 51.38, H 3.80, N 24.67. Found C 51.19, H
3.89, N 24.38.
5. 2-Methylthio-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5e) (0.28g, 83%); mp 224-225
oC (DMF/water).
1H NMR (DMSO-d6) δ: 2.17 (s, 3H, SMe), 3.73 (s, 3H, N7Me), 4.15 (s, 3H, NMe), 8.28 (s, 1H, H8), 8.58
(s, 1H, NH), CI MS m/z: 338 (M+1, 100). Anal. Calcd for C11H11N7O2S2: C 39.16, H 3.29, N 29.06.
Found C 38.87, H 3.35, N 28.82.
6. 2-Ethylthio-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5f) (0.27g, 77%); mp 238-239 oC
(EtOH).

HETEROCYCLES, Vol. 75, No. 3, 2008
567
1H NMR (DMSO-d6) δ: 1.24 (t, J = 7.5 Hz, 3H, Me), 2.95 (q, J = 7.5 Hz, 2H, SCH2), 3.06 (s, 3H, N7Me),
3.85 (s, 3H, NMe), 6.99 (s, 1H, H8), 7.64 (s, 1H, CH), CI MS m/z: 352 (M+1, 100), 323 (M-C2H5 +1, 66).
Anal. Calcd for C12H13N7O2S2: C 41.02, H 3.73, N 27.90. Found C 40.82, H 3.77, N 27.57.
7. 2-Allylthio-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5g) (0.26g, 72%); mp 174-175 oC
(EtOH).
1H NMR (DMSO-d6) δ: 3.54 (s, 3H, N7Me), 3.88 (d, J = 6.9 Hz, 2H, SCH2), 3.96 (s, 3H, NMe), 5.05 (d, J
= 10.1 Hz, 1H, =CH2), 5.22 (d, J = 16.9 Hz, 1H, =CH2), 5.82 (m, 1H, =CH), 7.11 (s, 1H, C8), 7.83 (s, 1H,
CH), CI MS m/z: 364 (M+1, 100), 323 (M-C3H5 +1, 83). Anal. Calcd for C13H13N7O2S2: C 42.97, H 3.61,
N 26.98. Found C 42.71, H 3.51, N 26.66.
8. 2-Benzylthio-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5h) (0.31g, 75%); mp 234-235
oC (EtOH).
1H NMR (DMSO-d6) δ: 3.77 (s, 3H, N7Me), 3.87 (s, 3H, NMe), 4.27 (s, 2H, CH2), 7.19 (t, J = 7.2 Hz, 1H,
p-C6H5), 7.27 (t, J = 7.2Hz, 2H, m-C6H5), 7.39 (d, J = 7.2Hz, 2H, o-C6H5), 7.65 (s, 1H, H8), 8.09 (s, 1H,
CH), CI MS m/z: 414 (M+1, 100), 323 (M-CH2C6H5 +1, 88). Anal. Calcd for C17H15N7O2S2: C 49.38, H
3.66, N 23.71. Found C 49.21, H 3.56, N 23.48.
9. 7-Methyl-2-oxo-2,3-dihydro-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5i) (0.21g, 68%); mp
216-218 oC (EtOH-water).
1H NMR (DMSO-d6): δ: 3.77 (s, 3H, N7Me), 3.99 (s, 3H, NMe), 7.99 (s, 1H, H8), 8.09 (s, 1H, CH),
12.24 (s, 1H, N3H), CI MS m/z: 308 (M+1, 100). Anal. Calcd for C10H9N7O3S: C 39.09, H 2.95, N 31.91.
Found C 39.01, H 2.90, N 31.66.
10. 7-Methyl-2-thioxo-2,3-dihydro-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5j) (0.04g, 12% from
4g, 0.06g, 18% from 4h, 0.03g, 9% from 4j); mp 223-225 oC (EtOH-water).
1H NMR (DMSO-d6): δ: 3.78 (s, 3H, N7Me), 4.12 (s, 3H, NMe), 8.12 (s, 1H, H8), 8.66 (s, 1H, CH),
12.35 (s, 1H, N1H), CI MS m/z: 324 (M+1, 100). Anal. Calcd for C10H9N7O2S2: C 37.15, H 2.81, N
30.32. Found C 36.91, H 2.88, N 30.02.
o
11. 2-Chloro-7-methyl-6-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5k) (0.32g, 98%); mp 257-258 C
(EtOH), lit.,16 mp 254-255 oC.
1H NMR (DMSO-d6) δ: 3.76 (s, 3H, N7Me), 4.19 (s, 3H, NMe), 8.74 (s, 1H, H8), 8.29 (s, 1H, CH), CI
MS m/z: 326 (M+1, 100).
o
12. 7-Methyl-2,6-bis(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5l) (0.28g, 62%); mp 165-166 C
(EtOH).
1H NMR (DMSO-d6): δ: 3.68 (s, 3H, N7Me), 3.76 (s, 3H, NMe), 3.89 (s, 3H, NMe), 8.07 (s, 1H, H8),
8.21 (s, 1H, CH), 8.36 (s, 1H, CH), CI MS m/z: 449 (M+1, 100). Anal. Calcd for C14H12N10O4S2: C 37.50,

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H 2.70, N 31.23. Found C 37.23, H 2.77, N 30.99.
13. 6-Ethoxy-7-methyl-2-(1-methyl-4-nitroimidazolyl-5-ylthio)purine (5m) (0.08g, 24%); mp 154-156 oC
(EtOH).
1H NMR (DMSO-d6) δ: 1.28 (t, J = 6.9 Hz, 3H, Me), 3.69 (s, 3H, N7Me), 3.90 (s, 3H, NMe), 4.31 (q, J =
6.9 Hz, 2H, CH2), 8.03 (s, 1H, H8), 8.35 (s, 1H, CH), CI MS m/z: 336 (M+1, 12), 307 (M-C2H5+1, 100).
Anal. Calcd for C12H13N7O3S: C 42.98, H 3.91, N 29.24. Found C 42.71, H 3.81, N 29.01.
B. A mixture of 7-methyl-2,6-thioxanthine 4j (0.20 g, 1 mmol) and NaH (0.072 g, 3 mmol, washed out
with hexane from mineral oil) in dry DMF (6 mL) was stirred at rt for 1 h. 5-Chloro-1-methyl-4-nitroimi-
dazole (0.48 g, 3 mmol) was added and the stirring was continued for 24 h. The reaction mixture was
poured into water (15 mL) and extracted with CHCl3 (3 x 5 mL). The extracts were dried with anhydrous
Na2SO4, and evaporated in vaccuo. The residue was recrystallized from EtOH to give compound 5l (0.41g,
91%);
Reaction of di(imidazolylthio) compound 5l with boiling ethanol
A solution of di(imidazolylthio) compound 5l (0.224 g, 0.5 mmol) in dry EtOH (5 mL) was refluxed for 2
h. After cooling a resulted small amount of solid was filtered off and the ethanolic filtrate was was
evaporated to dryness in vaccuo. The residue was crystallized from 70% EtOH to give compound 5m
(0.14 g, 82%), mp 154-156 oC.
REFERENCES
1. C. Rumbo, Pediatr. Transplantation, 2004, 8, 606.
2. C. Menor, M. D. Fernandez-Moreno, J. A. Fueyo, O. Escribano, T. Olleros, E. Arriaza, C. Cara, M.
Lorusso, M. Di Paola, I. D. Roman, and L. G. Guijarro, J. Pharmacol. Exp. Ther., 2004, 311, 668.
3. A. V. Anstey, S. Wakelin, and N. J. Reynolds, Br. J. Dermatol., 2004, 15, 1123.
4. J. S. Maltzman and G. A. Koretzky, J. Clin. Invest., 2003, 111, 1122.
5. L. Helpman, D. Pauzner, J. B. Lessing, M. J. Kupferminc, and G. Gutman, J. Med. Microbiol., 2005,
54, 803.
6. M. Hoffmann, J. Rychlewski, M. Chrzanowska, and T. Hermann, J. Am. Chem. Soc., 2001, 123,
6404.
7. J. Mudter and M. F. Neurath, Gut., 2007, 56, 293.
8. D. Poppe, I. Tiede, G. Fritz, C. Becker, B. Bartsch, S. Wirtz, D. Strand, S. Tanaka, P. R. Galle, X. R.
Bustelo, and M. F. Neurath, J. Immunol., 2006, 176, 640.
9. C. A. Siegel and B. E. Sands, Aliment. Pharmacol, Ther., 2005, 22, 1.
10. a) A. Kowalska, Phosphorus, Sulfur, Silicon, 2007, in press. b) U. Reichman, F. Bergman, D.

HETEROCYCLES, Vol. 75, No. 3, 2008
569
Lichtengberg, and Z. Neiman, J. Org, Chem., 1973, 38, 2066. c) A. Kowalska, A. Maślankiewicz, B.
Syrek, and P. Ciepliński, Monats. Chem., 1985, 116, 341.
11. a) E. Bergman and H. Heimhold, J. Chem. Soc., 1935, 955. b) E. Bergman and H. Heimhold, J. Chem.
Soc., 1935, 1365.
12. R. N. Prasad and R. K. Robins, J. Am. Chem. Soc., 1957, 79, 6401.
13. H. Bredereck and G. Kupsch, Chem. Ber., 1959, 92, 566.
14. J. Sarasin and E. Wegmann, Helv. Chim. Acta, 1924, 7, 713.
15. A. Kowalska and A. Maślankiewicz, Polish J. Chem., 2001, 75, 1327.
16. E. V. Aleksandrova, P. M. Kochergin, L. V. Persanova, V. S. Korsunskii, and V. S. Shlikhunova,
Khim. Geterotsikl. Soedin., 2001, 538.