3316
T. Ostrowski et al. / European Journal of Medicinal Chemistry 44 (2009) 3313–3317
0 0
(C-4a), 139.27 (C-2), 129.96, 124.19 (C-6, C-2 ), 128.10 (C-4 ), 126.99,
the internal standard; the chemical shifts are reported in ppm (
scale). Thin-layer chromatography (TLC) was performed on Merck
precoated 60 F254 gel plates. Column chromatography was carried
d
0 0 00
125.96 (C-3 , C-5 ), 115.29 (C-9a), 102.24 (C-7), 60.84, 60.65 (C1 –
0
0
00
00
CH
2
–OH, C2 –CH
2
–OH), 47.74 (C1 –CH
2
–N), 26.82 (C-1 ), 24.44
S$0.25 H O: C 54.32,
0
0
00
out on Merck silica gel 60H (40–63
mm).
(C-2 ), 13.94 (C-3 ). Anal. Calcd for C17
H
17
N
5
O
3
2
H 4.69, N 18.63, S 8.53; found: C 54.50, H 4.69, N 18.56, S 8.45.
5.1.1. 2-(2-Bromoacetyl)thiophene
Purified by silica gel column chromatography using toluene for
5.1.7. 6-(5-Bromothien-2-yl)-3,9-dihydro-3-[(2-
elution, followed by rechromatography using hexane–EtOAc 9:1 to
hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (5c)
Product isolated by chromatography (138 mg, 67% yield) was
subjected to crystallization from MeOH–EtOAc 4:1 to afford
yellowish material. It was next recrystallized from MeOH at room
1
0
give colorless oil in 73% yield. H NMR (CDCl
3
)
d
7.84 (dd, 1H, 3 -H,
0
0
J ¼ 4.0, 1.2 Hz), 7.75 (dd, 1H, 5 -H, J ¼ 5.2, 1.2 Hz), 7.20 (dd, 1H, 4 -H,
J ¼ 5.2, 4.0 Hz), 4.39 (s, 2H, CH
2
Br).
ꢀ
temperature resulting in white crystals: mp 226–227 C (dec).
1
5.1.2. 2-(2-Bromoacetyl)-5-bromothiophene
Fluorescence emission (H
(DMSO-d
H), 7.44, 7.32 (2ꢃd, 2H, 3 -H, 4 -H, J ¼ 3.9, 3.9 Hz), 5.50 (s, 2H,
2
O):
l
max 414 nm;
f
F
¼ 0.007. H NMR
Chromatographed on silica gel column using toluene to obtain
6
) d 13.24 (br s, 1H, NH), 8.06 (s, 1H, C2–H), 8.04 (s, 1H, C7–
1
0
0
0
white foam in 79% yield. H NMR (CDCl
3
)
d
7.55 (d, 1H, 3 -H,
Br).
0
13
J ¼ 3.9 Hz), 7.14 (d, 1H, 4 -H, J ¼ 3.9 Hz), 4.28 (s, 2H, CH
2
N–CH
2
–O), 4.68 (t, 1H, OH), 3.44–3.56 (m, 4H, CH
2 2
–CH ). C NMR
(
DMSO-d ) d
6
151.11 (C-9), 150.38 (C-3a), 146.15 (C-4a), 139.43 (C-2),
0
0
0
5
.1.3. 2-(2-Bromoacetyl)furan
Purified by silica gel column chromatography using toluene–
MeOH 99:1 / 98:2 for elution to obtain colorless oil in 75% yield.
131.72, 123.22 (C-6, C-2 ), 131.38 (C-4 ), 126.54 (C-3 ), 115.48 (C-9a),
0
112.19 (C-5 ), 103.26 (C-7), 72.37 (N–CH
2
–O), 70.61 (HO–CH
SBr$0.25 H O: C 40.54,
H 3.04, N 16.89, S 7.73; found: C 40.68, H 3.20, N 16.58, S 7.78.
2 2
–CH ),
59.91 (HO–CH
2
). Anal. Calcd for C14
H
12
N
5
O
3
2
1
0
0
H NMR (CDCl
3
)
d
7.64 (dd, 1H, 5 -H, J ¼ 1.8, 0.6 Hz), 7.34 (dd, 1H, 3 -
0
H, J ¼ 3.6, 0.6 Hz), 6.60 (dd, 1H, 4 -H, J ¼ 3.6, 1.8 Hz), 4.32 (s, 2H,
0
0
0
CH
2
Br).
5.1.8. 3-{[cis-1 ,2 -Bis(hydroxymethyl)cycloprop-1 -yl]methyl}-6-
5-bromothien-2-yl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-a]
purine (5d)
(
5.1.4. General procedure for the alkylation–condensation reactions
To a suspension of 1a or 3a (0.5 mmol) in anhydrous DMF
10 ml) was added sodium hydride as 60% suspension in oil (1.5 eq).
After being stirred with exclusion of moisture for 1–2 h at room
temperature, the resulting solution was treated with bromoketone
Crude isolated product (99 mg, 44% yield) was dissolved in
ꢀ
(
EtOAc–MeOH 3:1, concentrated and kept at þ5 C to give
ꢀ
a yellowish crystalline precipitate: mp 261–263 C (dec). Fluores-
1
cence emission (H
2
O):
l
max 412 nm;
f
F
¼ 0.002. H NMR (DMSO-d
6
)
(
1.2 eq). The reaction mixture was stirred at room temperature for
the next 2 h, made alkaline by addition of 25% aqueous ammonia
10 ml) and left overnight. The volatiles were evaporated and the
oily residue was chromatographed on silica gel column using
CH Cl –MeOH (8:1 / 7:1 or 8:1 / 6:1). Fractions containing the
d 13.15 (br s, 1H, NH), 8.01 (s, 1H, C7–H), 7.98 (s, 1H, C2–H), 7.44, 7.31
0
0
(2ꢃd, 3 -H, 4 -H, J ¼ 3.9, 3.9 Hz), 4.69 (t, 1H, OH), 4.59 (t, 1H, OH),
0
0
00
(
4.14 (d, 1H, N–CHH–C1 , J ¼ 13.8 Hz), 4.00 (d, 1H, N–CHH–C1 ,
0
0
00
J ¼ 14.1 Hz), 3.61 (m, 1H, C2 –CHH–OH), 3.46 (dd, 1H, C2 –CHH–
0
0
2
2
OH, J ¼ 11.7, 5.1 Hz), 3.29–3.42 (m, 2H, C1 –CHH–OH), 1.31 (m, 1H,
0
0
00
00
main product were evaporated, whereas the residual solid was
subjected to further work-up.
C2 –H), 0.92 (dd, 1H, C3 –HH, J ¼ 8.7, 4.8 Hz), 0.43 (t, 1H, C3 –HH,
13
J ¼ 5.4 Hz). C NMR (DMSO-d
6
) d 151.13 (C-9), 150.52 (C-3a), 145.99
0
0
(
C-4a), 139.32 (C-2), 131.89, 123.17 (C-6, C-2 ), 131.38 (C-4 ), 126.44
0
0
0
0
5
.1.5. 3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-(thien-2-
yl)-5H-imidazo[1,2-a]purine (5a)
(C-3 ), 115.28 (C-9a), 112.06 (C-5 ), 103.10 (C-7), 60.85, 60.65 (C1 –
0
0
00
00
CH
2
–OH, C2 –CH
2
–OH), 47.76 (C1 –CH
2
–N), 26.84 (C-1 ), 24.45
SBr$1.25 H O: C
0
0
00
Crude product after chromatography (94 mg, 57% yield) was
(C-2 ), 13.94 (C-3 ). Anal. Calcd for C17
H
16
N
5
O
3
2
ꢀ
recrystallized from MeOH at þ5 C to afford colorless crystalline
43.18, H 3.94, N 14.81, S 6.78; found: C 43.42, H 4.05, N 14.40, S 6.96.
ꢀ
material: mp 240–242 C (dec). Fluorescence emission (H
2
O):
l
max
1
3
(
7
93 nm;
f
F
¼ 0.075. H NMR (DMSO-d
6
)
d
13.21 (br s, 1H, NH), 8.06
5.1.9. 3,9-Dihydro-3-[(2-hydroxyethoxy)methyl]-6-(furan-2-yl)-9-
oxo-5H-imidazo[1,2-a]purine (5e)
0
s, 1H, C2–H), 7.94 (s, 1H, C7–H), 7.67 (dd, 1H, 5 -H, J ¼ 5.1, 1.2 Hz),
0
0
.62 (dd, 1H, 3 -H, J ¼ 3.6, 1.2 Hz), 7.18 (dd, 1H, 4 -H, J ¼ 5.1, 3.6 Hz),
Chromatographically purified product (117 mg, 74% yield) was
ꢀ
5
.51 (s, 2H, N–CH
2
–O), 4.69 (t, 1H, OH), 3.45–3.56 (m, 4H, CH
C NMR (DMSO-d 151.12 (C-9), 150.34 (C-3a), 146.14 (C-4a),
39.36 (C-2), 129.87, 124.32 (C-6, C-2 ), 128.09 (C-4 ), 127.08, 126.02
2
–CH
2
).
recrystallized from MeOH at þ5 C to afford colorless crystals: mp
1
3
ꢀ
6
)
d
219–221 C (dec). Fluorescence emission (H
2
O):
l
max 388 nm;
0
0
1
1
(
(
5
f
F
¼ 0.026. H NMR (DMSO-d
6
) d 13.22 (br s, 1H, NH), 8.07 (s, 1H,
0
0
0
C-3 , C-5 ), 115.47 (C-9a), 102.38 (C-7), 72.36 (N–CH
HO–CH –CH ), 59.90 (HO–CH ). Anal. Calcd for C14
0.75, H 3.95, N 21.14, S 9.68; found: C 50.52, H 4.15, N 20.97, S 9.35.
2
–O), 70.59
C2–H), 7.86 (d, 1H, 5 -H, J ¼ 1.5 Hz), 7.83 (s, 1H, C7–H), 7.00 (d, 1H,
0
0
2
2
2
H
13
N
5
O
3
S: C
3 -H, J ¼ 3.3 Hz), 6.68 (dd, 1H, 4 -H, J ¼ 3.6, 1.8 Hz), 5.51 (s, 2H,
13
N–CH
2
–O), 4.69 (t, 1H, OH), 3.44–3.56 (m, 4H, CH
2
–CH
2
). C NMR
0
(
DMSO-d
6
)
d
0
151.17 (C-9), 150.39 (C-3a), 146.08 (C-4a), 144.04 (C-5 ),
0
0
0
0
5
.1.6. 3-{[cis-1 ,2 -Bis(hydroxymethyl)cycloprop-1 -yl]methyl}-3,9-
143.04 (C-2 ), 139.42 (C-2), 121.24 (C-6), 115.48 (C-9a), 112.02 (C-4 ),
0
dihydro-9-oxo-6-(thien-2-yl)-5H-imidazo[1,2-a]purine (5b)
108.60 (C-3 ), 101.73 (C-7), 72.35 (N–CH
2
–O), 70.61 (HO–CH
$1.25 H O: C 49.78, H
4.63, N 20.73; found: C 50.16, H 4.84, N 20.31.
2 2
–CH ),
Crude solid (104 mg, 56% yield) was recrystallized from MeOH at
59.90 (HO–CH
2
). Anal. Calcd for C14
H
13
N
5
O
4
2
ꢀ
room temperature to obtain colorless spangles: mp 295–298 C
1
(
dec). Fluorescence emission (H
2
O):
l
max 410 nm;
f
F
¼ 0.030.
H
0
0
0
NMR (DMSO-d
6
)
d
13.12 (br s, 1H, NH), 7.98 (s, 1H, C2–H), 7.91 (s, 1H,
5.1.10. 3-{[cis-1 ,2 -Bis(hydroxymethyl)cycloprop-1 -yl]methyl}-
3,9-dihydro-6-(furan-2-yl)-9-oxo-5H-imidazo[1,2-a]purine (5f)
Crude isolated product (91 mg, 51% yield) was subjected to
0
0
C7–H), 7.66 (dd, 1H, 5 -H, J ¼ 5.1, 1.2 Hz), 7.62 (dd, 1H, 3 -H, J ¼ 3.6,
0
1
.2 Hz), 7.17 (dd, 1H, 4 -H, J ¼ 5.1, 3.6 Hz), 4.69 (t,1H, OH), 4.59 (t,1H,
00
00
ꢀ
OH), 4.15 (d, 1H, N–CHH–C1 , J ¼ 14.1 Hz), 4.01 (d, 1H, N–CHH–C1 ,
crystallization from EtOAc–MeOH 3:1 at þ5 C to obtain colorless
00
00
ꢀ
J ¼ 14.4 Hz), 3.61 (m, 1H, C2 –CHH–OH), 3.47 (dd, 1H, C2 –CHH–
crystals: mp 260–261 C (dec). Fluorescence emission (H
2
O):
l
max
00
1
OH, J ¼ 12.0, 6.0 Hz), 3.28–3.42 (m, 2H, C1 –CHH–OH), 1.32 (m, 1H,
381 nm;
f
F
¼ 0.026. H NMR (DMSO-d
6
) d 13.12 (br s, 1H, NH), 7.98
0
0
00
00
0
C2 –H), 0.93 (dd, 1H, C3 –HH, J ¼ 8.7, 5.1 Hz), 0.44 (t, 1H, C3 –HH,
(s, 1H, C2–H), 7.85 (d, 1H, 5 -H, J ¼ 1.8 Hz), 7.80 (s, 1H, C7–H), 7.00 (d,
13
0
0
J ¼ 5.1 Hz). C NMR (DMSO-d
6
)
d
151.14 (C-9), 150.50 (C-3a), 145.95
1H, 3 -H, J ¼ 3.3 Hz), 6.67 (dd, 1H, 4 -H, J ¼ 3.3, 1.8 Hz), 4.69 (t, 1H,