Synthesis of 4-alkyl- or 4-phenyl-7-methyl-1,2-dihydro-7H-imidazo[1,2,3-cd]purine-6,8-diones

Article abstract of DOI:10.1135/cccc19980407

New 4-alkyl- or 4-phenyl-7-methyl-1,2-dihydro-7H-imidazo[1,2,3-cd]purine-6,8-diones 1 were obtained by intramolecular alkylation of 8-alkyl-or 8-phenyl-9-(2-mesyloxyethyl)-1-methyl-9H-purine-2,6(1H,3H)-diones 5. The necessary compounds 5 were prepared fro

Full text of DOI:10.1135/cccc19980407

Synthesis of Imidazo[1,2,3-cd]purines
407
SYNTHESIS OF 4-ALKYL- OR 4-PHENYL-7-METHYL-1,2-DIHYDRO-7H-
IMIDAZO[1,2,3-cd]PURINE-6,8-DIONES
1
2,
3
Ondrej SIMO , Alfonz RYBAR * and Juraj ALFOLDI
Institute of Chemistry, Slovak Academy of Sciences, SK-842 38 Bratislava, Slovak Republic;
e-mail: 1 chemsimo@savba.sk, 2 chemryba@savba.sk, 3 chempaty@savba.sk
Received September 1, 1997
Accepted February 5, 1998
Dedicated to Professor Wolfgang Pfleiderer on the occasion of his 70th birthday.
New 4-alkyl- or 4-phenyl-7-methyl-1,2-dihydro-7H-imidazo[1,2,3-cd]purine-6,8-diones 1 were ob-
tained by intramolecular alkylation of 8-alkyl- or 8-phenyl-9-(2-mesyloxyethyl)-1-methyl-9H-purine-
2,6(1H,3H)-diones 5. The necessary compounds 5 were prepared from 6-[(2-hydroxyethyl)-
amino]-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione (2), which was hydrogenated to 5-amino-6-
[(2-hydroxyethyl)amino]-3-methyl derivative 3; consecutive reactions of the latter with an orthocar-
boxylate and mesyl chloride afforded 8-alkyl- or 8-phenyl-9-(2-hydroxyethyl)-1-methyl-9H-purine-
2,6(1H,3H)-diones 4 and compounds 5, respectively.
Key words: Imidazo[1,2,3-cd]purines; 3,9-Annelated purines; Xanthine derivatives; Acyclic nucleo-
side analogues.
Our recent studies on fused purine derivatives1,2 concerned compounds in which a he-
terocycle was peri-fused to a purine ring system3. The present paper dealing with the
synthesis of alkyl and phenyl derivatives of the hitherto not described imidazo[cd]pu-
rinedione skeleton is to be regarded as a continuation of our research programme. Some
of these derivatives, after functionalization of their alkyl groups, are aimed to serve as
precursors for preparation of potentionally hypocholesterolemic effective 3-hydroxy-3-
methylglutaryl CoA reductase inhibitors4 and potentionally effective A2 receptor anta-
gonists5,6
.
The synthesis of tricyclic 4-alkyl- and 4-phenyl-7-methyl-1,2-dihydro-7H-imi-
dazo[1,2,3-cd]purine-6,8-diones 1 was attempted in two ways. The first one started
from the known 6-[(2-hydroxyethyl)amino]-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-
dione (2) (refs7,8), and continued by its hydrogenation to the corresponding diamino
derivative 3 and cyclization with orthocarboxylates to 8-alkyl- or 8-phenyl-9-(2-hydroxy-
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

408
Simo, Rybar, Alfoldi:
ethyl)-1-methyl-9H-purine-2,6(1H,3H)-diones 4. Mesylation of 9-(2-hydroxyethyl)
derivatives 4 produced 8-alkyl- or 8-phenyl-9-(2-mesyloxyethyl)-1-methyl-9H-purine-
2,6(1H,3H)-diones 5 affording the final compounds 1 on intramolecular alkylation
(Scheme 1).
O
4
O
O
6
3
N
1
N
7
H C
3
5
6
NO
NH
H C
3
NH
NH
H C
3
2
H
R-C(OR’)
3
2
N
N
5
8
2
3
N
H
Pd/C
1
N
H
4
O
O
N
H
O
N
R
2
9
(CH ) OH
2 2
(CH ) OH
(CH ) OH
2 2
2 2
2
3
4
O
O
6
5
N
7
N
H C
3
H C
3
5a
N
N
K CO
2
3
9
N
3
N
DMF
4
R
O
N
H
N
R
O
8
(CH ) OMs
2 2
1
2
5
1
MsCl
Et N
3
1, 4-6
R
O
N
H
Me
Et
Pr
Bu
Ph
a
b
c
d
e
f
H C
3
N
N
MsO
N
R
(CH ) OMs
2 2
6
SCHEME 1
The starting nitroso derivative 2 was hydrogenated8 according to a modified proce-
dure (palladium on charcoal in ethanol) which afforded very pure 5-amino-6-[(2-
hydroxyethyl)amino]-3-methylpyrimidine-2,4(1H,3H)-dione (3).
Curiously enough, 1-substituted 8-alkyl- or 8-phenyl-9-(2-hydroxyethyl)purine-
diones 4 were not described as yet. To obtain them from diamine 3 possessing an
N-hydroxyalkyl group, an acid-catalyzed reaction with orthocarboxylates was con-
sidered most suitable for the synthesis of the imidazole ring embodied in compound 4.
Hydrochloric acid-catalyzed condensation of diamine 3 with an excess of orthocarboxy-
lates at room temperature required a long reaction time (cf., e.g., ref.9). The p-toluene-
sulfonic acid-catalyzed reaction in dimethylformamide at 100 °C made it possible to
shorten the reaction time to 2–4 h. Substantially more problematic appeared to be the
mesylation of compounds 4. In contrast to that of 8-alkyl- or 8-phenyl-9-(3-hydroxy-
propyl) derivatives described in our preceding paper3, compounds 4 formed double
mesylated products, i.e. 8-alkyl- or 8-phenyl-2-mesyloxy-9-(2-mesyloxyethyl)-1-
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Synthesis of Imidazo[1,2,3-cd]purines
409
methyl-9H-purine-6(1H)-ones 6, in addition to the expected 8-alkyl- or 8-phenyl-9-(2-
mesyloxyethyl) derivatives 5. Structure of compound 6 was supported by both the IR
spectra (absence of absorption bands associated with the second C=O and R–SO2N
groups, presence of an R–SO2–O group) and easy elimination of the second mesyl
group. It was therefore necessary to optimize the reaction conditions leading to com-
pound 5, namely to ensure a full consumption of the starting 9-(2-hydroxyethyl) deriva-
tive 4 and minimize the formation of double-mesylated derivatives 6. The
TLC-monitored 4–24 h reaction revealed that at a molar ratio intermediate 4 : mesyl
chloride : triethylamine (1 : 1.1–1.5 : 1.1–1.5) in dichloromethane at 0–25 °C, both
compound 6 and the triethylammonium salt of compound 5 (5 Et3N) were formed in
virtually the same relative amounts, but accompanied by a great amount of unreacted
starting intermediate 4. To ensure a complete reaction of intermediate 4, the reactant
ratio must be increased up to 1 : 3 : 8. Such a great excess of triethylamine had a
positive impact on the ratio of compounds 6 and 5. Triethylamine, namely, minimizes
successively the content of compound 6 in the mixture during a relatively short reaction
time. Thus, not only the starting material was consumed during 1 h, but also compound 6
appeared in trace amounts. A thorough acidification of the triethylammonium salts re-
maining in the filtrate led to the required compounds 5.
To evidence the mesylation course as monitored by TLC, i.e., that compounds 6 were
converted into triethylammonium salt of mesyloxyethyl derivatives 5 with triethylam-
monium chloride and the already mentioned great excess of triethylamine in dichloro-
methane, we prepared pure 8-ethyl derivative 6c and converted it into the
corresponding 5c under the already given conditions.
In conclusion, this method enables a facile preparation of 4-alkyl- or 4-phenyl-7-
methyl-1,2-dihydro-7H-imidazo[1,2,3-cd]purine-6,8-diones (1) in 4 steps with overall
yields 13–36%. Further application of this methodology is a facile preparation of 8-alkyl-
or 8-phenyl-9-(2-hydroxyethyl)-1-methyl-9H-purine-2,6(1H,3H)-diones (4) in 2 steps
with overall yields 39–55%.
EXPERIMENTAL
Melting points were determined on Kofler apparatus and are uncorrected. Samples for analysis were
dried over P4O10 at 60 °C and 30 Pa for 8–10 h. The 1H (300 MHz) and 13C (75.45 MHz) NMR
spectra were obtained on a Bruker AM-300 spectrometer. Chemical shifts (δ) are reported in ppm,
using TMS as internal reference. Mass spectra were obtained on a Finnigan MAT SSQ 710 instru-
ment using the electron impact ionization technique (100–210 °C, 70 eV). The reaction progress and
purity of all prepared compounds was followed by TLC (SILUFOL UV254, Kavalier, Votice, Czech
Republic) in the system chloroform–methanol 9 : 1 using UV detection.
5-Amino-6-[(2-hydroxyethyl)amino]-3-methylpyrimidine-2,4(1H,3H)-dione (3)
Compound 2 (21.4 g, 0.1 mol) was suspended in ethanol (300 ml) and hydrogenated over 10% pal-
ladium on carbon (1.0 g) at room temperature for 3 h. The orange colour of the starting material 2
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

410
Simo, Rybar, Alfoldi:
TABLE I
Yields and physicochemical properties of compounds 1, 4 and 5
Calculated/Found
Yield
%
M.p., °C
Solvent
Formula
M.w.
Compound
% C
% H
% N
% S
–
1a
1b
1c
1d
1e
1f
52
73
62
68
72
60
65
80
72
68
65
60
52
295–297
ethanol
C8H8N4O2
192.2
50.00
50.29
4.20
4.41
29.15
29.04
251–253
acetone
C9H10N4O2
206.2
52.42
52.49
4.89
5.15
27.17
27.04
–
–
–
–
–
–
–
–
–
–
–
161–163
C10H12N4O2
220.2
54.54
54.75
5.49
5.71
25.44
25.20
propan-2-ol
186–188
hexane
C11H14N4O2
234.3
56.40
56.66
6.02
6.00
23.92
23.66
128–130
C12H16N4O2
248.3
58.05
57.89
6.50
6.58
22.57
22.41
hexane–propan-2-ol
320–323
ethanol
C14H12N4O2
268.3
62.68
62.39
4.51
4.63
20.88
21.09
4a
4b
4c
4d
4e
4f
278–280
water
C8H10N4O3
210.2
45.71
45.58
4.80
4.99
26.66
26.52
301–303
water
C9H12N4O3
224.2
48.21
48.10
5.39
5.65
24.99
24.84
330–333
water
C10H14N4O3
238.3
50.41
50.23
5.92
6.11
23.52
23.50
288–290
ethanol
C11H16N4O3
252.3
52.37
52.49
6.39
6.51
22.21
22.00
257–259
ethanol
C12H18N4O3
266.3
54.12
54.38
6.81
6.96
21.04
20.93
317–318
water
C14H14N4O3
286.3
58.74
58.68
4.93
5.01
19.57
19.41
5a
283–285
C9H12N4O5S
288.3
37.50
37.43
4.20
4.51
19.43
19.30
11.12
11.34
methanol–water
5b
5c
83
68
238–240
water
C10H14N4O5S
302.3
39.73
39.34
4.67
4.96
18.53
18.49
10.61
10.58
206–208
41.77
41.89
5.10
5.12
17.71
17.90
10.13
10.09
C11H16N4O5S
316.3
ethanol–acetone
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Synthesis of Imidazo[1,2,3-cd]purines
411
TABLE I
(Continued)
Calculated/Found
Yield
%
M.p., °C
Solvent
Formula
M.w.
Compound
% C
% H
% N
% S
5d
5e
5f
92
71
88
238–240
C12H18N4O5S
330.4
43.63
43.40
5.49
5.68
16.96
17.21
9.70
water–acetone
10.10
220–222
C13H20N4O5S
344.4
45.34
45.52
5.85
5.67
16.27
16.24
9.31
9.20
ethanol–water
211–213
water
C15H16N4O5S
364.4
49.44
49.15
4.43
4.63
15.38
15.49
8.80
9.03
disappeared, a grey powdery product was filtered off together with the catalyst, and crystallized from
water. Yield 15.0 g (75%) of light yellow crystals with no characteristic m.p. (decomposition around
220 °C; ref.8 reports 220 °C slow decomposition). The diamine 3 is light- and air-instable and, there-
1
fore, it has to be consumed within 2 weeks. H NMR spectrum (DMSO-d6): 3.19 s, 3 H ( N-3-CH3);
3.40 q, 2 H (NH-CH2); 3.48 bs, 1 H (OH); 3.60 t, 2 H (CH2OH); 6.18 t, 1 H (6-NH). 13C NMR
spectrum (DMSO-d6): 26.9 (N-3-CH3); 44.2 (NH-CH2); 60.7 (CH2OH); 94.5 (C-5); 145.0 (C-6);
149.7 (C-2); 160.3 (C-4).
8-Alkyl- or 8-Phenyl-9-(2-hydroxyethyl)-1-methyl-9H-purine-2,6(1H,3H)-diones 4
A stirred mixture of compound 3 (2.0 g, 10 mmol), dimethylformamide (25 ml), trimethyl or triethyl
orthocarboxylate (15 mmol) and p-toluenesulfonic acid (10–12 mg) was heated to 100 °C (2 h for 4e
and 4f; 3 h for 4a, 4c and 4d; 4 h for 4b). The catalytic amount of p-toluenesulfonic acid was neu-
tralized with ethanolic ammonia and the volatile portion was distilled off under diminished pressure. The
crude dry residue was crystallized from a suitable solvent with addition of charcoal.
8-Alkyl- or 8-Phenyl-9-(2-mesyloxyethyl)-1-methyl-9H-purine-2,6(1H,3H)-diones 5
Mesyl chloride (0.69 g, 0.45 ml, 6.0 mmol) in dichloromethane (10 ml) was added gradually (15
min) to a stirred solution of intermediate 4 (2.0 mmol) in dichloromethane (30 ml) and triethylamine
(1.62 g, 2.23 ml, 16 mmol) at 20–25 °C. The mixture was stirred for 1 h at the same temperature,
the volatile components were removed under reduced pressure, the residue was dissolved in water,
the light turbidity being filtered off, and pH of the clear filtrate was adjusted with acetic acid to 6–7
under cooling. Compounds 5a–5c, 5f and 5d, 5e were separated from filtrate within 10–5 min and
2–4 h, respectively. The resulting mixture was left standing in refrigerator overnight, product was
filtered off and re-crystallized from a suitable solvent with addition of charcoal.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

412
Simo, Rybar, Alfoldi:
TABLE II
1H NMR spectra of compounds 1, 4 and 5
Compound
1H NMR (CDCl3/TMS), δ (ppm)
1a
1b
1c
3.24 s, 3 H (N-7-CH3); 4.67 m, 2 H (H-2); 4.83 m, 2 H (H-1); 7.78 s, 1 H (H-4)
2.41 s, 3 H (4-CH3); 3.31 s, 3 H (N-7-CH3); 4.54 m, 2 H (H-2); 4.87 m, 2 H (H-1)
1.30 t, 3 H (CH2CH3); 2.76 q, 2 H (CH2CH3); 3.21 s. 3 H (N-7-CH3); 4.62 m, 2 H
(H-2); 4.81 m, 2 H (H-1)
1d
1e
1.03 t, 3 H (CH2CH3); 1.75 sextet, 2 H (CH2CH3); 2.71 t, 2 H (C-4-CH2); 3.22 s, 3 H
(N-7-CH3); 4.61 m, 2 H (H-2); 4.82 m, 2 H (H-1)
0.94 t, 3 H (CH2CH3); 1.40 sextet, 2 H (CH2CH3); 1.70 quintet, 2 H (C-4-CH2CH2);
2.69 t, 2 H (C-4-CH2); 3.30 s, 3 H (N-7-CH3); 4.56 t, 2 H (H-2); 4.87 t, 2 H (H-1)
1f
4a
4b
4c
3.27 s, 3 H (N-7-CH3); 4.94 m, 4 H (H-2, H-1); 7.92–7.96 m, 5 H (C6H5)
3.28 s, 3 H (N-1-CH3); 3.73 t, 2 H (N-9-CH2); 4.19 t, 2 H (OCH2); 7.73 s, 1 H (H-8)
2.41 s, 3 H (8-CH3); 3.25 s, 3 H (N-1-CH3); 3.69 t, 2 H (N-9-CH2); 4.10 t, 2 H (OCH2)
1.30 t, 3 H (CH2CH3); 2.78 q, 2 H (CH2CH3); 3.27 s, 3 H (N-1-CH3); 3.69 t, 2 H
(N-9-CH2); 4.11 t, 2 H (OCH2)
4d
4e
1.00 t, 3 H (CH2CH3); 1.77 sextet, 2 H (CH2CH3); 2.71 t, 2 H (C-8-CH2); 3.25 s, 3 H
(N-1-CH3), 3.70 t, 2 H (N-9-CH2); 4.11 t, 2 H (OCH2)
0.90 s, 3 H (CH2CH3); 1.42 sextet, 2 H (CH2CH3); 1.75 quintet, 2 H (C-8-CH2CH2);
2.75 t, 2 H (C-8-CH2); 3.25 s, 3 H (N-1-CH3); 3.68 t, 2 H (N-9-CH2); 4.10 t, 2 H
(OCH2)
4f
5a
5b
5c
5d
5e
3.30 s, 3 H (N-1-CH3); 3.65 t, 2 H (N-9-CH2); 4.27 t, 2 H (OCH2); 7.50–7.80 m, 5 H
(C6H5)
3.29 s, 3 H (N-1-CH3); 3.22 s, 3 H (CH3SO2); 4.53 m, 4 H (N-9-CH2,OCH2)a; 7.78 s,
1 H (H-8)
2.44 s, 3 H (8-CH3); 3.23 s, 3 H (CH3SO2); 3.27 s, 3 H (N-1-CH3); 4.48 m, 4 H
(N-9-CH2, OCH2)a
1.32 t, 3 H (CH2CH3); 2.80 q, 2 H (CH2CH3); 3.23 s, 3 H (CH3SO2); 3.28 s, 3 H
(N-1-CH3); 4.48 m, 4 H (N-9-CH2, OCH2)a
1.07 t, 3 H (CH2CH3); 1.83 sextet, 2 H (CH2CH3); 2.75 t, 2 H (C-8-CH2); 3.21 s, 3 H
(CH3SO2); 3.28 s, 3 H (N-1-CH3); 4.48 bs, 4 H (N-9-CH2, OCH2)a
1.01 t, 3 H (CH2CH3); 1.48 sextet, 2 H (CH2CH3); 1.78 quintet, 2 H (C-8-CH2CH2);
2.76 t, 2 H (C-8-CH2); 3.21 s, 3 H (CH3SO2); 3.28 s, 3 H (N-1-CH3); 4.48 bs, 4 H
(C-9-CH2, OCH2)a
5f
3.05 s, 3 H (CH3SO2); 3.32 s, 3 H (N-1-CH3); 4.39 t, 2 H (OCH2); 4.59 t, 2 H
(N-9-CH2); 7.58–7.69 m, 5 H (C6H5)
a Determined by single-frequency decoupling.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Synthesis of Imidazo[1,2,3-cd]purines
413
TABLE III
13C NMR spectra of compounds 1, 4 and 5
Compound
13C NMR (CDCl3/TMS), δ (ppm)
1a
1b
1c
1d
1e
28.0 (N-7-CH3); 47.7 (C-2); 54.0 (C-1); 108.3 (C-5a); 133.6 (C-4); 149.8 (C-9a);
151.8 (C-8); 157.8 (C-6)
13.9 (4-CH3); 28.6 (N-7-CH3); 46.5 (C-2); 53.9 (C-1); 107.7 (C-5a); 142.5 (C-4);
149.9 (C-9a); 151.5 (C-8); 157.6 (C-6)
11.2 (CH2CH3); 20.8 (CH2CH3); 27.9 (N-7-CH3); 47.0 (C-2); 54.0 (C-1); 106.4 (C-5a);
147.1 (C-4); 149.7 (C-9a); 152.2 (C-8); 157.5 (C-6)
13.4 (CH2CH3); 20.1 (CH2CH3); 27.9 (N-7-CH3); 29.2 (C-4-CH2); 47.0 (C-2); 54.1
(C-1); 106.4 (C-5a); 146.0 (C-4); 149.8 (C-9a); 152.2 (C-8); 157.5 (C-6)
13.5 (CH2CH3); 22.0 (CH2CH3); 27.8 (N-7-CH3); 28.3 (C-4-CH2CH2); 29.2
(C-4-CH2); 46.8 (C-2); 53.8 (C-1); 107.2 (C-5a); 146.4 (C-4); 149.6 (C-9a); 151.3
(C-8); 157.6 (C-6)
1f
4a
4b
4c
4d
4e
28.1 (N-1-CH3); 49.7 (C-2); 54.0 (C-1); 108.2 (C-5a); 125.5, 128.1, 129.0, 129.3
(C6H5); 153.1 (C-8); 157.6 (C-6)
27.0 (N-1-CH3); 46.5 (N-9-CH2); 59.5 (OCH2); 114.8 (C-5); 137.5 (C-8); 138.8 (C-4);
150.7 (C-2); 157.5 (C-6)
13.6 (2-CH3); 27.5 (N-1-CH3); 46.2 (N-9-CH2); 59.9 (OCH2); 113.1 (C-5); 140.2 (C-8);
146.0 (C-4); 151.3 (C-2); 157.9 (C-6)
11.5 (CH2CH3); 19.9 (CH2CH3); 27.4 (N-1-CH3); 45.7 (N-9-CH2); 59.8 (OCH2);
113.2 (C-5); 140.1 (C-8); 149.9 (C-4); 151.3 (C-2); 157.8 (C-6)
14.1 (CH2CH3); 20.4 (CH2CH3); 27.5 (N-1-CH3); 28.4 (C-8-CH2); 45.8 (N-9-CH2);
59.9 (OCH2); 113.4 (C-5); 140.0 (C-8); 149.0 (C-4); 151.2 (C-2); 157.9 (C-6)
14.2 (CH2CH3); 22.2(CH2CH3); 26.2 (C-8-CH2CH2); 27.6 (N-1-CH3); 29.1 (C-8-CH2);
45.8 (N-9-CH2); 59.9 (OCH2); 113.4 (C-5); 140.0 (C-8); 149.1 (C-4); 151.3 (C-2);
157.9 (C-6)
4f
5a
5b
5c
5d
27.7 (N-1-CH3); 47.0 (N-9-CH2); 59.4 (OCH2); 114.7 (C-5); 129.5, 2 × 129.8, 130.0
(C6H5); 141.0 (C-8); 147.3 (C-4); 151.3 (C-2); 158.2 (C-6)
27.0 (N-1-CH3); 36.7 (CH3SO2); 43.1 (N-9-CH2); 67.9 (OCH2); 114.4 (C-5); 137.2
(C-8); 138.8 (C-4); 150.7 (C-2); 157.4 (C-6)
13.1 (8-CH3); 27.0 (N-1-CH3); 36.6 (CH3SO2); 42.3 (N-9-CH2); 68.0 (OCH2); 113.0
(C-5); 139.4 (C-8); 144.3 (C-4); 150.6 (C-2); 157.1 (C-6)
10.9 (CH2CH3); 19.4 (CH2CH3); 26.9 (N-1-CH3); 36.7 (CH3SO2); 41.9 (N-9-CH2);
68.0 (OCH2); 113.1 (C-5); 139.4 (C-8); 148.6 (C-4); 150.6 (C-2); 157.2 (C-6)
13.7 (CH2CH3); 19.7 (CH2CH3); 26.9 (N-1-CH3); 27.7 (C-8-CH2); 38.6 (CH3SO2);
41.9 (N-9-CH2); 68.0 (OCH2); 113.5 (C-5); 139.3 (C-8); 147.5 (C-4); 150.7 (C-2);
157.2 (C-6)
5e
5f
13.7 (CH2CH3); 21.8 (CH2CH3); 25.5 (C-8-CH2CH2); 27.0 (N-1-CH3); 28.4
(C-8-CH2); 36.7 (CH3SO2); 41.9 (N-9-CH2); 68.0 (OCH2); 113.2 (C-5); 139.3 (C-8);
147.7 (C-4); 150.7 (C-2); 157.2 (C-6)
27.1 (N-1-CH3); 36.6 (CH3SO2); 43.1 (N-9-CH2); 67.1 (OCH2); 113.0 (C-5); 128.7,
129.0, 129.3, 129.5 (C6H5); 140.2 (C-8); 146.2 (C-4); 150.6 (C-2); 157.4 (C-6)
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

414
Simo, Rybar, Alfoldi:
4-Alkyl- or 4-Phenyl-7-methyl-1,2-dihydro-7H-imidazo[1,2,3-cd]purine-6,8-diones 1
Compound 5 (2.0 mmol), potassium carbonate (0.33 g, 2.4 mmol) and dimethylformamide (30 ml)
were heated at 120 °C (30 min for 1b–1d and 1f; 45 min for 1e; 60 min for 1a). Dimethylformamide
was distilled off under reduced pressure, the dry residue was extracted with chloroform (3 × 50 ml)
and the solvent was removed. The dry residue was crystallized from a suitable solvent with addition
of charcoal. For all prepared compounds 1, 4 and 5 melting points, yields and elemental analyses are
1
summarized in Table I, H NMR spectra in Table II, 13C NMR spectra in Table III, and mass spectra
in Table IV.
8-Ethyl-2-mesyloxy-9-(2-mesyloxyethyl)-1-methyl-9H-purin-6(1H)-one (6c)
Mesyl chloride (0.48 g, 0.33 ml, 4.2 mmol) in dichloromethane (5 ml) was added gradually (10 min)
to a stirred suspension of 4c (0.63 g, 2.0 mmol) in dichloromethane (10 ml) and triethylamine (0.51 g,
0.70 ml, 5.0 mmol) at 20 °C. After 1 h the content dissolved at the same temperature; the volatile
components were distilled off under diminished pressure and water (5 ml) was added to the residue.
The white precipitate was filtered off, dried and dissolved in acetone (20 ml) at room temperature.
TABLE IV
Mass spectra of compounds 1, 4 and 5
Compound
EI MSa, m/z (rel. int.%)
1a
1b
1c
1d
1e
1f
192 (M+, 34), 135 (100), 108 (33), 81 (14)
206 (M+, 36), 149 (100), 121 (26), 107 (4), 81 (11)
220 (M+, 51), 163 (100), 134 (21), 120 (2), 107 (8), 83 (64), 81 (10)
234 (M+, 30), 177 (100), 149 (14), 121 (25), 107 (4), 97 (30)
248 (M+, 47), 206 (68), 191 (98), 149 (100), 134 (9), 121 (38)
268 (M+, 65), 211 (100), 182 (18), 131 (56), 103 (74)
4a
4b
4c
4d
4e
4f
210 (M+, 75), 180 (9), 153 (23), 123 (19), 109 (100)
224 (M+, 89), 193 (27), 167 (18), 137 (18), 123 (100), 109 (9)
238 (M+, 100), 207 (58), 153 (19), 150 (25), 137 (85), 109 (62)
252 (M+, 47), 224 (32), 221 (21), 208 (17), 180 (100), 151 (10), 136 (10), 123 (76)
266 (M+, 56), 237 (14), 224 (48), 209 (10), 194 (17), 180 (100), 123 (26)
286 (M+, 100), 255 (40), 185 (46), 157 (16), 104 (89)
5a
5b
5c
5d
5e
5f
192 (M+ – MsOH, 32), 166 (3), 134 (4), 108 (22), 96 (75), 81 (52), 79 (100)
206 (M+ – MsOH, 16), 180 (5), 149 (3), 108 (8), 96 (89), 81 (58), 79 (100)
220 (M+ – MsOH, 32), 180 (7), 163 (100), 134 (13), 83 (42), 79 (8)
234 (M+ – MsOH, 23), 206 (7), 177 (84), 149 (15), 121 (22), 96 (87), 79 (100)
248 (M+ – MsOH, 11), 224 (14), 206 (38), 191 (48), 149 (59), 96 (100), 79 (83)
268 (M+ – MsOH, 100), 242 (49), 236 (17), 185 (11), 108 (18), 104 (59), 79 (50)
a MsOH = CH3SO3H.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Synthesis of Imidazo[1,2,3-cd]purines
415
The filtered solution was concentrated to one half of its original volume and the product was precipi-
tated with diethyl ether. Yield 0.51 g (65%). Analytical sample was purified by crystallization from
water, m.p. 138–140 °C. For C12H18N4O7S2 (394.4) calculated: 36.54% C, 4.60% H, 14.20% N,
1
16.26% S; found: 36.40% C, 4.82% H, 14.32% N, 16.41% S. H NMR spectrum (DMSO-d6): 1.39 t,
3 H (CH2CH3); 2.49 s, 3 H (C-2-OSO2-CH3); 2.95 q, 2 H (CH2CH3); 3.26 s, 3 H (CH2-OSO2-CH3);
3.30 s, 3 H (N-1-CH3); 4.52–4.58 overlapped m, 4 H (N-9-CH2CH2). 13C NMR spectrum (DMSO-d6):
10.8 (CH2CH3); 19.0 (CH2CH3); 27.1 (N-1-CH3); 36.7 (CH2-OSO2-CH3); 39.7 (C-2-OSO2-CH3);
42.7 (N-9-CH2); 67.5 (CH2O); 109.8 (C-5); 139.1 (C-8); 149.8 (C-4); 150.7 (C-2); 155.7 (C-6).
8-Ethyl-9-(2-mesyloxyethyl)-1-methyl-9H-purine-2,6(1H,3H)-dione (5c)
Suspension of 6c (0.79 g, 2 mmol) and triethylamine hydrochloride (0.28 g, 2 mmol) in triethylamine
(1.42 g, 1.95 ml, 14 mmol) and dichloromethane (20 ml) was stirred at room temperature for 1 h
during which compound 6c dissolved. Stirring was continued for another 1 h, the volatile compo-
nents were removed under diminished pressure, the residue was dissolved in water (5 ml) and the
solution was neutralized to pH 7 with aqueous acetic acid (1 : 1). The product separated on standing
in refrigerator was filtered off and crystallized from water. Yield 0.39 g (62%). Product 5c obtained
1
in this way proved to be identical (mixed m.p., EI MS, H NMR) with that prepared according to the
above-mentioned general procedure for compounds 5.
Financial support from the Slovak Grant Agency (project No. 2/568/96) is gratefully acknowledged.
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Collect. Czech. Chem. Commun. (Vol. 63) (1998)