Synthesis of 2,4-disubstituted 6-phenyl-7H-pyrrolo[3,2-d]-pyrimidin-7-one 5-oxides

Article abstract of DOI:10.1002/jhet.5570450610

(Chemical Equation Presented) A relatively short and efficient method for the utilization of 4,6-dichloro-2-methylthio-5-nitropyrimidine (1) in the synthesis of the polysubstituted pyrrolo[3,2-d]pyrimidin-7-one 5-oxides (6a-g) is reported. Some new 4-subs

Full text of DOI:10.1002/jhet.5570450610

Nov-Dec 2008
1615
Synthesis of 2,4-Disubstituted 6-Phenyl-7H-pyrrolo[3,2-d]-
pyrimidin-7-one 5-Oxides
Inga Cikotiene*, Erika Pudziuvelyte and Algirdas Brukstus
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, LT – 03225,
Vilnius, Lithuania, e-mail: inga.cikotiene@chf.vu.lt
Received February 25, 2008
R1
N
R
N
N
O-
N+
Cl
N
NO2
Cl
4-5 steps
N
R2
N
S
O
R3
A relatively short and efficient method for the utilization of 4,6-dichloro-2-methylthio-5-nitropyrimidine (1)
in the synthesis of the polysubstituted pyrrolo[3,2-d]pyrimidin-7-one 5-oxides (6a-g) is reported. Some new 4-
substituted 6-chloro-2-methylthio-5-nitropyrimidines (2a-e) were prepared by reaction of 4,6-dichloro-2-
methylthio-5-nitropyrimidine (1) with amines. 4-Substituted 2-methylthio-5-nitro-6-phenylethynylpyrimidines
(3a-e), obtained from 4-substituted 6-chloro-2-methylthio-5-nitropyrimidines (2a-e) via palladium-catalyzed
Sonagashira coupling reaction with 1-phenylacetylene, underwent smooth cyclization reaction in boiling 2-
propanol in the presence of catalytic amount of pyridine to give 4-substituted 2-methylthio-6-phenyl-7H-
pyrrolo[3,2-d]pyrimidin-7-one 5-oxides (4a-e). The methylthio group of the latter compounds can be easily and
selectively oxidized by m-chloroperbenzoic acid and replaced with different amines.
J. Heterocyclic Chem., 45, 1615 (2008).
INTRODUCTION
good yields. The latter compounds could be converted to
the 2-methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-7-one
5-oxides (4a-e) during refluxing in dry pyridine (using the
method which we described earlier [10]). This way was
simple and rapid, but purification of the obtained products
was complicated in some cases. To avoid that difficulty
and to increase the yields of the compounds 4a-e, we
decided to develop a new method for the cyclization of 5-
nitro-6-phenylethynylpyrimidines into pyrrolo[3,2-d]-
pyrimidin-7-one 5-oxides. For this purpose the cyclization
reaction of 3a was studied under different conditions.
Various initiators: nitrosobenzene in different solvents,
pyridine, concentrated sulphuric acid, tetrabutyl-
ammonium fluoride (TBAF) and UV light (the latter five
Pyrrolo[3,2-d]pyrimidin-7-one 5-oxides, being aza-
analogues of isatogens, attract our attention as potential
free radical traps in biological milieu [1-3]. Moreover, the
pyrrolo[3,2-d]pyrimidine heterosystem is an important
class of compounds, possessing notable biological
activities, in particular purine nucleoside phosphorylase
[4,5] and thymidylate synthase [6,7] inhibitory,
neuropeptide Y5 receptor [8] and A1,A2-adenoside
receptor [9] antagonistic properties. Recently we have
reported that 4-amino-6-arylethynyl-5-nitropyrimidines in
dry pyridine undergo smooth intramolecular cyclization to
give pyrrolo[3,2-d]pyrimidin-7-one 5-oxides [10–12]. As
a continuation of our study aimed at the synthesis of the
pyrimidine moiety containing heterocycles [13-15] with a
potential biological activity, we report herein a novel
method for the utilization of 4,6-dichloro-2-methylthio-5-
nitropyrimidine (1) in the synthesis of the polysubstituted
pyrrolo[3,2-d]pyrimidin-7-one 5-oxides (6a-g).
Table 1
Formation of 4-amino-2-methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-7-
one 5-oxide (4a) from 4-amino-2-methylthio-5-nitro-6-phenylethynyl-
pyrimidine (3a) under different conditions.
Entry
Initiator
Solvent
Time,
hours
0.5
18 - 20
4
Yield, %
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
-
Pyridine [a]
CH2Cl2 [a]
CH3OH [a]
C2H5OH [a]
2-C3H7OH [a]
1-C4H9OH [a]
C6H5CH3 [a]
o-xylene [a]
2-C3H7OH [a]
CHCl3 [b]
75
50
40
80
91
75
70
52
95
0
PhNO
PhNO
PhNO
PhNO
PhNO
PhNO
PhNO
Pyridine
UV
Our optimized procedure is exemplified in the synthesis
of 2,4-disubstituted 6-phenylpyrrolo[3,2-d]pyrimidin-7-
one 5-oxides according to the conditions set forth in
Schemes 1 and 2. Reaction of easily available 4,6-
dichloro-2-methylthio-5-nitropyrimidine (1) [16] with
different amines in methanol – diethylether mixture at 0
°C temperature provided the mono-substituted compounds
2a-e. Palladium-catalyzed Sonagashira coupling reaction
of 2a-e with 1-phenylacetylene gave the corresponding 4-
substituted 5-nitro-6-phenylethynylpyrimidines (3a-e) in
2
0.5
0.5
0.7
2
0.5
48
9
10
11
12
TBAF
-
THF[b]
H2SO4(concd.) [c]
24
4
0
0
[a] Reactions were performed at reflux temperature; [b] Reaction was
performed at room temperature; [c] Reaction was performed at 0 °C.

1616
I. Cikotiene, E. Pudziuvelyte, A. Brukstus
Vol 45
methods were employed for cyclization of o-(alkynyl)-
nitrobenzenes into isatogens [17,18]) were used (Table 1).
The data obtained indicated that only pyridine and
nitrosobezene initiated the transformations of 3a into 4-
amino-2-methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-7-
one 5-oxide (4a). UV light, TBAF and cold
concentrated sulphuric acid (entries 10 - 12) had no
success. In these cases after the work-up of the
reaction mixtures the initial compound 3a was
recovered. Cyclization of 3a occured using a catalytic
amount of freshly-prepared nitroso-benzene in
different solvents at reflux. It was found that the
fastest cyclization and the highest yield of 4a were
performed in boiling 2-propanol during 30 minutes
(Scheme 1).
The next step of synthetic approach to polysubstituted
pyrrolo[3,2-d]pyrimidin-7-one 5-oxides was modification of
the 2-position of the pyrrolo[3,2-d]pyrimidine system.
Substitution of methylthio moiety at the 2nd position of
pyrrolo[3,2-d]pyrimidin-7-one 5-oxides by nitrogen nucleo-
philes was exceedingly difficult. No reaction took place when
compound 4a was treated with secondary amine piperidine in
dimethylsulfoxide at an elevated temperature for 24 hours. To
avoid such difficulties the synthetic route was redesigned to
employ another method, which is based on oxidation of the
methylthio moiety followed by nucleophilic substitution
Scheme 1
R1
N
R
R1
N
R
R1
N
R
Cl
N
N
O-
N+
N
N
NO2
Cl
NO2
NO2
Cl
i
N
ii
iii
S
N
S
N
S
N
S
O
3a-e
1
2a-e
4a-e
(90 - 95%)
(67 - 71%)
(79 - 86%)
2-4 NRR1
a
b
c
d
e
NH2
NHCH2CH2N(CH2)4O
NHCH2C6H5
N(CH2)4
N(CH3)C6H5
Reagents and conditions: i) amine (2 equivalents), methanol, 0oC; ii) 1-phenylacetylene (1.2 equivalents), PdCl2(PPh3)2 (2 mol %), CuI (1 mol %),
Et3N, Ar, 40oC, 2 hours; iii) pyridine (1 drop), 2-propanol, reflux, 30 minutes.
Scheme 2
R1
N
R
R1
N
R
NH2
O-
N+
O-
N+
N
N
N
N
O-
N+
ii
N
i
Ph
R2
4a
S
N
N
S
O
O
O
O
R3
5
6a-g
(70 - 83%)
4a,c,d
(85%)
iii
4a,c,d
Reagents and conditions: i) m-CPBA (1.5 equivalents), CH2Cl2, r.t., 1 h; ii) amine (2 equivalents), dimethylsulfoxide, r.t.,
3 hours; iii) m-CPBA (1.5 equivalents), CH2Cl2, r.t., 1 hour, then amine (3 equivalents), r.t., 3 hours.
achieved in boiling 2-propanol (entry 5). Moreover, it
reaction. Performing an oxidation of compound 4a by a slight
excess of m-chloroperbenzoic acid (mCPBA) in dichloro-
methane at room temperature for 1 hour led to formation of 2-
methylsulfinyl derivative 5. Nucleophilic substitution of the 2-
methylsulfinyl group by various amines underwent easily and
rapidly, so it could be achieved at room temperature in
dimethylsulfoxide solution within 3 hours. On the other hand,
the synthetic route could be realized in a one-pot method.
Thus, reaction of 2-methylthiopyrrolo[3,2-d]pyrimidin-7-one
5-oxides (4a,c,d) with mCPBA in dichloromethane at room
temperature, followed after 1 hour by treatment of the reaction
was established that cyclization of 3a also proceeded
using a catalytic amount of pyridine in boiling 2-
propanol (entry 9). The latter method of cyclization of
5-nitro-6-phenylethynylpyrimidines into pyrrolo[3,2-
d]pyrimidin-7-one 5-oxides seemed to be the shortest
and the most efficient.
So, the 4-substituted 2-methylthio-6-phenylpyrrolo[3,2-
d]pyrimidin-7-one 5-oxides (4a-e) were prepared via
pyridine initiated cyclization of 4-substituted 5-nitro-6-
phenylethynylpyrimidines (3a-e). Reactions were

Nov-Dec 2008
Synthesis of 2,4-Disubstituted 6-Phenyl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-Oxides
1617
Table 2
Synthesized 2,4-disubstituted pyrrolo[3,2-d]pyrimidin-7-one 5-oxides (6a-g) prepared according to the presented methods.
Entry
Compound
NRR1
NH2
NH2
NH2
NH2
NH2
NHCH2C6H5
N(CH2)4
NR2R3
Yield, %
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
NHCH2CH2CH3
NHCH2CH2N(CH2)4O
NHCH2C6H5
N(CH2)5
N(CH2)4O
NHCH2C6H5
N(CH2)4O
71 [a], 80 [b]
72 [a], 75 [b]
74 [a], 78 [b]
75 [a], 79 [b]
70 [a], 83 [b]
71 [b]
6g
78 [b]
[a] Synthesis was performed by nucleophilic substitution reaction of compound 5 with amines;
[b] Synthesis was performed by one-pot reaction based on oxidation/substitution steps.
8.57 (br s, 1H, NH); 13C nmr (deuteriochloroform): ꢀ = 14.9,
38.5, 53.4, 55.9, 67.2, 123.7, 155.1, 155.8, 176.5. Anal. Calcd
for C11H16ClN5O3S: C, 39.58; H, 4.83; N, 20.98. Found: C,
39.41; H, 4.99; N, 20.67.
4-N-Benzylamino-6-chloro-2-methylthio-5-nitropyrimidine
(2c). This compound was obtained as yellow solid, mp 92 – 93
°C (from 2-propanol); yield: 82%; ir (KBr): 3371 (NH) cm-1; 1H
nmr (dimethylsulfoxide-d6): ꢀ = 2.49 (s, 3H, SCH3), 4.71 (d, J =
6 Hz, 2H, NHCH2), 7.28 – 7.38 (m, 5H, ArH), 9.20 (t, J = 6 Hz,
1H, NH); 13C nmr (dimethylsulfoxide-d6): ꢀ = 13.1, 44.9, 112.8,
127.0, 127.1, 128.4, 138.7, 146.1, 155.3, 165.1. Anal. Calcd for
C12H11ClN4O2S: C, 46.38; H, 3.57; N, 18.03. Found: C, 46.49;
H, 3.58; N, 17.86.
mixture with 3 equivalents of different amines for 3 hours
provided the corresponding 2,4-disubstituted pyrrolo[3,2-
d]pyrimidin-7-one 5-oxides (6a-g) in good yields (Scheme 2).
Table 2 shows representative compounds which were prepared
using the method described above.
In conclusion, we have developed a relatively short and
efficient synthetic method of preparing 2,4-disubstituted
6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides through
palladium-catalyzed coupling reaction of 4-substituted 6-
chloro-5-nitropyrimidines with 1-phenylacetylene, subse-
quent cyclization of the obtained 4-substituted 2-
methylthio-5-nitro-6-phenylethynyl-pyrimidines and one-
pot oxidation/substitution of methylthio group at the 2nd
6-Chloro-2-methylthio-4-pyrrolidino-5-nitropyrimidine
(2d). This compound was obtained as yellow solid, mp 141 –
1
.
position of the pyrrolo[3,2-d]pyrimidine heterosystem
143 °C (from 2-propanol); yield: 86%; H nmr (deutériochloro-
form): ꢀ = 1.98 – 2.03 (m, 4H, (CH2)2), 2.53 (s, 3H, SCH3), 3.50
– 3.55 (m, 4H, N(CH2)2); 13C NMR (deutériochloroform): ꢀ =
14.7, 25.4, 48.7, 126.7, 151.5, 151.7, 171.6. Anal. Calcd for
C9H11ClN4O2S: C, 39.35; H, 4.04; N, 20.39. Found: C, 39.61; H,
4.02; N, 20.49.
4-(N-Methyl)anilino-6-chloro-2-methylthio-5-nitropyrimi-
dine (2e). This compound was obtained as yellow solid, mp 87 –
89 °C (from 2-propanol); yield: 75%; 1H nmr (dimethyl-
sulfoxide-d6): ꢀ = 2.60 (s, 3H, SCH3), 3.56 (s, 3H, NCH3), 7.35
– 7.40 (m, 5H, ArH); 13C nmr (dimethylsulfoxide-d6): ꢀ = 14.8,
42.2, 125.3, 126.5, 128.7, 130.5, 143.0, 151.9, 153.9, 171.9.
Anal. Calcd for C12H11ClN4O2S: C, 46.38; H, 3.57; N, 18.03.
Found: C, 46.47; H, 3.55; N, 17.84.
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. IR spectra were run in Nujol mulls or in KBr discs
on a Perkin-Elmer FT spectrophotometer Spectrum BX II. H
1
and 13C NMR spectra were recorded with a Varian Unity
INOVA spectrometer (300 MHz) using tetramethylsilane as
internal standard. Mass spectra were performed using direct
insertion probe on a Kratos MS-30 spectrometer (30 eV).
Elemental analysis (C, H, N) results were found to be in good
agreement (±0.4%) with the calculated values. All reactions and
purity of the synthesized compounds were monitored by TLC
using Silica gel 60 F254 aluminium plates (Merck). Visualization
was accomplished by UV light.
General Procedure for the Synthesis of 4-substituted 2-
methylthio-5-nitro-6-phenylethynylpyrimidines (3a-e).
A
mixture of the corresponding compound 2a-e (1.15 mmoles),
PdCl2(PPh3)2 (0.016 g, 0.023 mmole), CuI (0.0022 g, 0.0115
mmole) and dry triethylamine (10 mL) was stirred under argon
atmosphere for 3 minutes. Then the 1-phenylacetylene (0.14 g,
1.38 mmoles) was added, the mixture was flushed with argon
and heated under stirring at 40 °C for 2 hours. After cooling to
r.t. the precipitate was collected by filtration and recrystallized
to give compounds 3a-e. Data for compound 3a have been
published in the previous paper [12].
2-Methylthio-4-[N-(2-morpholin-4-ylethyl)-amino]-5-nitro-
6-phenylethynylpyrimidine (3b). This compound was obtained
as yellow solid, mp 219 – 222 °C (from 2-propanol); yield: 67%;
ir (KBr): 3225 (NH), 2205 (CꢀC) cm-1; 1H nmr (dimethyl–
sulfoxide-d6): ꢀ = 2.47 (br s, 2H, NCH2), 2.55 (s, 3H, SCH3), 2.59
(t, J = 6 Hz, 4H, N(CH2)2), 3.65 (br s, 2H, NHCH2), 3.67 (t, J = 6
Hz, 4H, O(CH2)2), 7.50 – 7.54 (m, 3H, ArH), 7.64 – 7.67 (m, 2H,
ArH), 8.97 (br s, 1H, NH); 13C nmr (dimethylsulfoxide-d6): ꢀ =
Compound 2a was prepared according to the method
published in the literature [19].
General Procedure for the Synthesis of 4-substituted 6-
chloro-2-methylthio-5-nitropyrimidines (2b-e). To a cooled to
5 °C solution of 4,6-dichloro-2-methylthio-5-nitro-pyrimidine (1)
(5 g, 20.8 mmoles) in methanol (15 mL) and diethylether (10 mL)
mixture a solution of the corresponding amine (41.6 mmoles) in
methanol (10 mL) was added dropwise. The reaction mixture was
stirred at 5 °C for 30 minutes. The precipitate was collected by
filtration and recrystallized to give compounds 2b-e.
6-Chloro-2-methylthio-4-[N-(2-morpholin-4-ylethyl)-amino]-
5-nitropyrimidine (2b). This compound was obtained as yellow
solid, mp 150 – 151 °C (from 2-propanol); yield: 79%; ir (KBr):
3265 (NH) cm-1; 1H nmr (deuteriochloroform): ꢀ = 2.54 (t, J = 3
Hz, NCH2), 2.57 (s, 3H, SCH3), 2.67 (t, J = 6 Hz, 4H, N(CH2)2),
3.69 (q, J = 3 Hz, 2H, NHCH2), 3.77 (t, J = 6 Hz, 4H, O(CH2)2),

1618
I. Cikotiene, E. Pudziuvelyte, A. Brukstus
Vol 45
14.8, 38.6, 53.7, 56.4, 66.9, 87.0, 98.3, 121.0, 126.7, 129.8, 131.6,
133.1, 145.7, 154.4, 174.6. Anal. Calcd for C19H21N5O3S: C,
57.12; H, 5.30; N, 17.53. Found: C, 56.92; H, 5.28; N, 17.45.
4-Benzylamino-2-methylthio-5-nitro-6-phenylethynylpyrim-
idine (3c). This compound was obtained as yellow solid, mp 154
– 156 °C (from methanol); yield: 71%; ir (KBr): 3377 (NH),
heated to reflux for 30 minutes. After cooling to room
temperature, the precipitate was collected by filtration and
recrystallized to give compounds 4b-e.
2-Methylthio-4-[N-(2-morpholin-4-ylethyl)amino]-6-phenyl-
pyrrolo[3,2-d]pyrimidin-7-one 5-oxide (4b). This compound
was obtained as dark violet solid, mp 183 – 185 °C (from 2-
propanol); yield: 90%; ir (KBr): 3369 (NH), 1720 (C=O) cm-1;
1H nmr (dimethylsulfoxide-d6): ꢀ = 2.51 (br s, 2H, NCH2), 2.54
(s, 3H, SCH3), 2.63 (t, J = 3 Hz, 4H, N(CH2)2), 3.43 (br s, 2H,
NHCH2), 3.64 (t, J = 3 Hz, 4H, O(CH2)2), 7.48 – 7.56 (m, 3H,
1
2209 (CꢀC) cm-1; H nmr (dimethylsulfoxide-d6): ꢀ = 2.56 (s,
3H, SCH3), 4.46 (d, J = 3 Hz, 2H, NHCH2), 7.28 – 7.40 (m,
10H, ArH), 9.28 (t,
J = 3
Hz, 1H, NH); 13C NMR
(dimethylsulfoxide-d6): ꢀ = 14.3, 43.8, 87.1, 98.8, 120.9, 123.4,
126.1, 126.4, 127.7, 128.7, 129.0, 139.0, 141.8, 158.3, 160.1,
175.1. Anal. Calcd for C20H16N4O2S: C, 63.81; H, 4.28; N,
14.88. Found: C, 64.00; H, 4.30; N, 15.00.
ArH), 7.98 (t, J = 1 Hz, 1H, NH), 8.33 – 8.35 (m, 2H, ArH); 13
C
nmr (dimethylsulfoxide-d6): ꢀ = 14.9, 37.4, 53.7, 57.0, 66.8,
120.6, 126.3, 127.5, 128.2, 129.2, 130.7, 149.6, 150.2, 174.9,
186.8. Anal. Calcd for C19H21N5O3S: C, 57.12; H, 5.30; N,
17.53. Found: C, 56.96; H, 5.44; N, 17.59.
2-Methylthio-5-nitro-6-phenylethynyl-4-pyrrolidinopyrim-
idine (3d). This compound was obtained as yellow solid, mp
180 – 182 °C (from 2-propanol); yield: 70%; ir (KBr): 2217
4-Benzylamino-2-methylthio-6-phenylpyrrolo[3,2-d]pyrim-
idin-7-one 5-oxide (4c). This compound was obtained as dark
violet solid, mp 170 - 172 °C (from 2-propanol); yield: 91%;
ir (KBr): 3368 (NH), 1716 (C=O) cm-1; 1H nmr
(dimethylsulfoxide-d6): ꢀ = 2.45 (s, 3H, SCH3), 4.73 (d, J = 6.3
Hz, 2H, NHCH2), 7.23 – 7.41 (m, 5H, ArH), 7.50 – 7.56 (m, 3H,
ArH), 8.34 – 8.37 (m, 2H, ArH), 8.60 (t, J = 6.3 Hz, 1H, NH);
13C nmr (dimethylsulfoxide-d6): ꢀ = 14.2, 43.4, 119.9, 125.6,
126.9, 127.4, 127.5, 128.3, 128.5, 129.9, 135.6, 138.9, 149.2,
149.3, 173.9, 180.0. Anal. Calcd for C20H16N4O2S: C, 63.81; H,
4.28; N, 14.88. Found: C, 63.77; H, 4.45; N, 14.99.
1
(CꢀC) cm-1; H nmr (dimethylsulfoxide-d6): ꢀ = 1.91 (br s, 2H,
(CH2)2), 2.52 (s, 3H, SCH3), 3.42 (br s, 4H, N(CH2)2), 7.50 –
7.61 (m, 5H, ArH); 13C nmr (dimethylsulfoxide-d6): ꢀ = 14.6,
26.2, 49.3, 83.6, 97.6, 120.5, 129.8, 130.8, 131.6, 132.9, 143.1,
151.2, 171.9. Anal. Calcd for C17H16N4O2S: C, 59.98; H, 4.74;
N, 16.46. Found: C, 60.07; H, 4.69; N, 16.69.
4-(N-Methyl)anilino-2-methylthio-5-nitro-6-phenylethynyl-
pyrimidine (3e). This compound was obtained as yellow solid,
mp 138 – 140 °C (from methanol); yield: 67%; ir (KBr): 2215
1
(CꢀC) cm-1; H nmr (dimethylsulfoxide-d6): ꢀ = 2.59 (s, 3H,
SCH3), 3.56 (s, 3H, NCH3), 7.31 – 7.36 (m, 5H, ArH), 7.47 –
7.55 (m, 5H, ArH); 13C nmr (dimethylsulfoxide-d6): ꢀ = 14.0,
40.8, 82.9, 97.3, 119.6, 124.9, 127.5, 129.1, 129.5, 130.9, 131.5,
132.1, 143.0, 143.1, 152.7, 171.8. Anal. Calcd for C20H16N4O2S:
C, 63.81; H, 4.28; N, 14.88. Found: C, 63.99; H, 4.25; N, 14.79.
2-Methylthio-6-phenyl-4-pyrrolidinopyrrolo[3,2-d]pyrim-
idin-7-one 5-oxide (4d). This compound was obtained as dark
violet solid, mp 207 – 209 °C (from 2-propanol); yield: 95%; ir
1
(KBr): 1702 (C=O) cm-1; H nmr (deuterio-chloroform): ꢀ =
2.02 (br s, 2H, (CH2)2), 2.59 (s, 3H, SCH3), 3.49 (br s, 4H,
N(CH2)2), 7.44 – 7.49 (m, 3H, ArH), 8.43 – 8.46 (m, 2H, ArH);
13C nmr (deuteriochloroform): ꢀ = 15.1, 26.6, 52.7, 121.3, 125.9,
127.7, 128.8, 130.3, 131.7, 148.2, 151.1, 174.2, 186.9. Anal.
Calcd for C17H16N4O2S: C, 59.98; H, 4.74; N, 16.46. Found: C,
60.12; H, 4.76; N, 16.41.
4-(N-Methylanilino)-2-methylthio-6-phenylpyrrolo[3,2-d]-
pyrimidin-7-one 5-oxide (4e). This compound was obtained as
dark violet solid, mp 218 – 220 °C (from 2-propanol); yield:
94%; ir (KBr): 1697 (C=O) cm-1; 1H nmr (dimethylsulfoxide-d6):
ꢀ = 2.58 (s, 3H, SCH3), 3.62 (s, 3H, NCH3), 7.33 – 7.45 (m, 8H,
ArH), 8.04 – 8.06 (m, 2H, ArH); 13C nmr (dimethylsulfoxide-
d6): ꢀ = 15.0, 41.3, 123.5, 124.2, 126.3, 127.4, 129.1, 129.8,
130.0, 130.5, 140.6, 147.8, 150.0, 153.4, 173.8, 186.3. Anal.
Calcd for C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88. Found: C,
63.77; H, 4.45; N, 14.97.
Synthesis of 4-amino-2-methylthio-6-phenyl-pyrrolo[3,2-d]-
pyrimidin-7-one 5-oxide (4a).
Method A. A solution of 4-amino-2-methylthio-5-nitro-6-
phenylethynylpyrimidine (3a) (0.29 g, 1 mmole) in dry
pyridine (3 mL) was refluxed for 30 minutes. The solution
was concentrated under the reduced pressure. The solid
residue was washed with water, dried and recrystallized to
give compound 4a.
Method B. To a solution of 4-amino-2-methylthio-5-nitro-6-
phenylethynylpyrimidine (3a) (0.29 g, 1 mmole) in 2-propanol
(3 mL) 1 drop of pyridine was added and the reaction mixture
was heated to reflux for 30 minutes. After cooling to room
temperature, the precipitate was collected by filtration and
recrystallized to give compound 4a.
Method C. To a solution of 4-amino-2-methylthio-5-nitro-6-
phenylethynylpyrimidine (3a) (0.29 g, 1 mmole) in 2-propanol
(3 mL) catalytic amount of freshly prepared nitrosobenzene was
added and the reaction mixture was heated to reflux for 30
minutes. After cooling to room temperature, the precipitate was
collected by filtration and recrystallized to give compound 4a.
Yield: 75% (method A), Yield: 95% (method B), Yield: 91%
(method C).
Data for compound 4a have been published in the previous
paper [12].
General Procedure for the Synthesis of 4-substituted 2-
methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides
Synthesis of 4-amino-2-methylsulfinyl-6-phenylpyrrolo-
[3,2-d]pyrimidin-7-one 5-oxide (5). To a solution of the 4-
amino-2-methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-
oxide 4a (0.5 g, 1.6 mmoles) in dichloromethane (25 mL) m-
chloroperbenzoic acid was added (0.41 g, 2.4 mmoles) in
portions. The resulting solution was stirred for 1 hour at room
temperature. The precipitate was collected by filtration, washed
with saturated aqueous sodium bicarbonate solution and dried to
give compound 5, which can be used in the next steps without
purification. This compound was obtained as dark blue solid, mp
265 – 267 °C; yield: 0.41 g, 85%; ir (KBr): 3432, 3229 (NH2),
1
1719 (C=O) cm-1; H nmr (dimethylsulfoxide-d6): ꢀ = 2.90 (s,
(4b-e). To
a solution of the corresponding 5-nitro-6-
3H, SOCH3), 7.52 – 7.57 (m, 3H, ArH), 7.91 (br s, 1H, NH),
8.37 – 8.40 (m, 2H, ArH), 8.83 (br s, 1H, NH); 13C nmr
(dimethylsulfoxide-d6): ꢀ = 34.3, 122.6, 125.4, 127.0, 127.5,
phenylethynylpyrimidine (3b-e) (1 mmole) in 2-propanol (3 mL)
1 drop of pyridine was added and the reaction mixture was

Nov-Dec 2008
Synthesis of 2,4-Disubstituted 6-Phenyl-7H-pyrrolo[3,2-d]pyrimidin-7-one 5-Oxides
1619
128.6, 130.4, 149.9, 152.1, 179.6, 185.4; ms: m/z 302 (M+), 287
(M+ - CH3). Anal. Calcd for C13H10N4O3S: C, 51.65; H, 3.33; N,
18.53. Found: C, 52.00; H, 3.43; N, 18.72.
4-Amino-2-piperidino-6-phenylpyrrolo[3,2-d]pyrimidin-7-
one 5-oxide (6d). This compound was obtained as dark blue
solid, mp 200 – 201.5 °C (from octane); yield: 75% (method A),
79% (method B); ir (KBr): 3469, 3328 (NH), 1715 (C=O) cm-1;
1H nmr (dimethylsulfoxide-d6): ꢁ = 1.54 – 1.66 (m, 6H, (CH2)3),
3.82 (br s, 4H, N(CH2)2), 7.01 (br s, 1H, NH), 7.42 – 7.53 (m,
3H, ArH), 7.65 (br s, 1H, NH), 8.28 – 8.31 (m, 2H, ArH); 13C
nmr (dimethylsulfoxide-d6): ꢁ = 24.2, 25.5, 44.9, 113.3, 126.3,
128.0, 128.2, 128.4, 138.9, 151.4, 152.6, 161.7, 186.9. Anal.
Calcd for C17H17N5O2: C, 63.15; H, 5.30; N, 21.66. Found: C,
63.55; H, 5.55; N, 21.45.
General Procedure for the Synthesis of 2,4-disubstituted 6-
phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides (6a-g).
Method A. To a solution of the 4-amino-2-methylsulfinyl-6-
phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxide (5) (0.4 g, 1.3
mmoles) in dimethylsulfoxide (10 mL) the corresponding amine
(4 mmoles) was added. The resulting green solution was stirred
for 3 hours at room temperature, then added to 1.0 M
hydrochloric acid (75 mL) and extracted with dichloromethane
(2 ꢀ 30 mL). The organic phases were combined and washed
with brine (3 ꢀ 30 mL), dried over anhydrous sodium sulfate,
filtered and concentrated in vacuo to give compounds 6a-e.
Method B. To a solution of the corresponding 2-methylthio-
6-phenylpyrrolo[3,2-d]pyrimidin-7-one 5-oxides (4a,c,d) (1.6
mmoles) in dichloromethane (25 mL) m-chloro-perbenzoic acid
was added (0.41 g, 2.4 mmoles) in portions. The resulting
solution was stirred for 1 hour at room temperature then the
corresponding amine (4.8 mmoles) was added. The reaction
mixture was stirred for 3 hours at room temperature, then
washed with 1.0 M hydrochloric acid (75 mL), brine (3 ꢀ 30
mL), dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo to give compounds 6a-g.
4-Amino-2-morfolino-6-phenylpyrrolo[3,2-d]pyrimidin-7-
one 5-oxide (6e). This compound was obtained as dark blue
solid, mp 159 – 160 °C (from 2-propanol); yield: 70% (method
A), 83% (method B); ir (KBr): 3459, 3333 (NH2), 1709 (C=O)
1
cm-1; H nmr (dimethylsulfoxide-d6): ꢁ = 3.66 (t, J = 3 Hz, 4H,
N(CH2)2), 3.78 (t, J = 3 Hz, 4H, O(CH2)2), 7.03 (br s, 1H, NH),
7.42 – 7.52 (m, 3H, ArH), 7.67 (br s, 1H, NH), 8.28 – 8.30 (m,
2H, ArH); 13C nmr (dimethylsulfoxide-d6): ꢁ = 45.1, 66.7, 114.8,
126.8, 126.9, 127.0, 129.1, 129.9, 152.1, 152.9, 162.7, 187.4.
Anal. Calcd for C16H15N5O3: C, 59.07; H, 4.65; N, 21.53. Found:
C, 59.44; H, 4.93; N, 21.55.
2,4-Dibenzylamino-6-phenylpyrrolo[3,2-d]pyrimidin-7-one
5-oxide (6f). This compound was obtained as dark blue solid,
mp 238 - 240 °C (from 2-propanol); yield: 71% (method B); ir
(KBr): 3379 (NH), 3368 (NH), 1715 (C=O) cm-1; 1H nmr
(deuteriochloroform): ꢁ = 4.68 (d, J = 6 Hz, 2H, NHCH2), 4.72
(d, J = 6 Hz, 2H, NHCH2), 6.47 (br s, 1H, NH), 7.20 (br s, 1H,
NH), 7.30 – 7.48 (m, 8H, ArH), 8.42 – 8.45 (m, 2H, ArH); 13C
nmr (dimethylsulfoxide-d6): ꢁ = 42.7, 43.4, 120.7, 125.0, 126.2,
126.6, 127.0, 127.4, 128.0 (2C), 128.3, 128.5 (2C), 129.9, 138.5,
140.3, 158.4, 163.3, 170.1, 184.1. Anal. Calcd for C26H21N5O2:
C, 71.71; H, 4.86; N, 16.08. Found: C, 71.92; H, 5.02; N, 15.91.
2-Morfolino-6-phenyl-4-pyrrolidinopyrrolo[3,2-d]pyrimi-
din-7-one 5-oxide (6g). This compound was obtained as dark
blue solid, mp 221 – 223 °C (from 2-propanol); yield: 78%
(method B); ir (KBr): 1707 (C=O) cm-1; 1H nmr (deutériochloro-
form): ꢁ = 1.99 (br s, 4H, (CH2)2), 3.77 – 3.94 (m, 12H,
N(CH2)2, N(CH2)4O), 7.40 – 7.48 (m, 3H, ArH), 8.39 – 8.42 (m,
2H, ArH); 13C nmr (deuteriochloroform): ꢁ = 26.0, 44.9, 53.5,
66.8, 116.4, 126.2, 127.4, 128.4, 129.4, 149.2, 153.7, 161.1,
165.4, 187.0. Anal. Calcd for C20H21N5O3: C, 63.31; H, 5.58; N,
18.46. Found: C, 63.67; H, 5.60; N, 18.55.
4-Amino-6-phenyl-2-propylaminopyrrolo[3,2-d]pyrimidin-
7-one 5-oxide (6a). This compound was obtained as dark blue
solid, mp 173 – 175 °C (from 2-propanol); yield: 71% (method
A), 80% (method B); ir (KBr): 3450, 3391, 3329 (NH, NH2),
1
1712 (C=O) cm-1; H nmr (dimethylsulfoxide-d6): ꢁ = 0.91 (t, J
= 7.2 Hz, 3H, CH2CH2CH3), 1.54 – 1.5 (m, 2H, CH2CH2CH3),
3.30 (q, J = 7.2 Hz, 2H, NHCH2CH2CH3), 6.98 (br s, 1H, NH),
7.41 – 7.50 (m, 3H, ArH), 7.65 (br s, 1H, NH), 8.02 (br s, NH),
8.28 – 8.31 (m, 2H, ArH); 13C nmr (dimethylsulfoxide-d6): ꢁ =
11.4, 21.9, 43.2, 112.6, 125.8, 126.2, 128.3, 128.9, 135.5, 151.5,
153.2, 163.4, 184.2. Anal. Calcd for C15H15N5O2: C, 60.60; H,
5.09; N, 23.56. Found: C, 60.54; H, 4.99; N, 23.55.
4-Amino-2-[N-(2-morpholin-4-ylethyl)amino]-6-phenyl-
pyrrolo[3,2-d]pyrimidin-7-one 5-oxide (6b). This compound
was obtained as dark blue solid, mp 250 – 252 °C (from 2-
propanol); yield: 72% (method A), 75% (method B); ir (KBr):
3390, 3345, 3333, (NH, NH2), 1709 (C=O) cm-1; 1H nmr
(deuteriochloroform): ꢁ = 2.53 – 2.54 (m, 4H, N(CH2)2), 2.63 (t,
J = 4.8 Hz, 2H, NCH2), 3.54 – 3.56 (m, 2H, NHCH2), 3.75 –
3.77 (m, 4H, O(CH2)2), 5.45 (br s, 1H, NH), 6.36 (br s, 1H, NH),
6.75 (br s, 1H, NH), 7.46 – 7.52 (m, 3H, ArH), 8.44 – 8.47 (m,
2H, ArH); 13C nmr (deuteriochloroform): ꢁ = 35.0, 50.9, 55.2,
66.0, 119.8, 125.7, 126.3, 128.5, 129.0, 134.0, 152.2, 155.2,
170.4, 182.6. Anal. Calcd for C18H20N5O3: C, 58.69; H, 5.47; N,
22.81. Found: C, 58.58; H, 5.76; N, 22.86.
Acnowledgement. We express our gratitude to M.
Kreneviciene and A. Karosiene for the recording of NMR and
IR spectra and to E. Kersuliene and M. Gavrilova for the
elemental analysis data.
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4-Amino-2-benzylamino-6-phenylpyrrolo[3,2-d]pyrimidin-
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solid, mp 240 - 242 °C (from 2-propanol); Yield: 74% (method
A), 78% (method B); ir (KBr): 3435, 3393, 3334 (NH, NH2),
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