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M. Hocek, P. Stepnicka et al.
FULL PAPER
a Bruker AMX-3 400 (400 MHz for 1H and 100.6 MHz for 13C nuclei) or
a Bruker DRX 500 (500 MHz for 1H and 125.8 MHz for 13C) spectrome-
ters. Tetramethylsilane was used as an internal standard. Mass spectra
were measured on a ZAB-EQ (VG Analytical) spectrometer using FAB
(ionization by Xe, accelerating voltage 8 kV, glycerol matrix). Cytostatic
activity tests were performed as described in ref. [8a].
(CH Fc), 85.69, 85.88 (CꢁC), 118.62 (C-5), 127.96, 128.45, 129.08 (CH-
arom.), 135.45 (C-i-arom.), 140.89 (CH-8), 147.20, 150.52, 155.26 (C-2, C-
4, C-6); IR (CHCl3): n˜ =2217, 1627, 1586, 1444, 1384, 1362 cmꢀ1; UV/Vis
(MeOH): lmax (e)=449 (500), 366 (1400), 308 (8500); 265 nm (19800); EI
MS: m/z (%): 433 (100) [M +], 342 (7), 91 (26); exact mass (EI HR MS):
calcd for C24H19FeN5: 433.0990; found: 433.0980; elemental analysis calcd
(%) for C24H19FeN5 (433.3): C 66.53, H 4.42, N 16.16; found: C 66.20, H
4.40, N 15.95.
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Et3N was degassed in vacuo and stored over molecular sieves under
argon. DMF was distilled from P2O5, degassed in vacuo and stored over
molecular sieves under argon. Starting compounds 1,[17] 2a[18] and 2b[19]
were prepared according to the literature procedures. Other chemicals
were purchased from commercial suppliers and used as received.
General procedure: Hydrogenation of alkynylpurines 3
Asolution of an ethynylpurine 3 (1 mmol) in a mixture of dioxane
(20 mL), ethanol (100 mL) and acetic acid (20 mL) was hydrogenated in
the presence of 10% Pd/C (150 mg) under atmospheric pressure for 36 h.
The catalyst was filtered off, the mixture evaporated, and the residue pu-
rified by chromatography on a silica gel column (150 g, ethyl acetate/light
petroleum 1:2, then ethyl acetate to ethyl acetate/MeOH 9:1).
2-Chloro-9-benzyladenine (2c): Amixture of 2-chloroadenine (10 g,
59 mmol), K2CO3 (26 g, 188 mmol) and DMF (150 mL) was stirred at
508C for 1 h under Ar. After cooling to RT, benzyl chloride (12 mL) was
added through a septum and the mixture was stirred at 908C for 18 h.
The solvent was evaporated and the residue was purified by chromatog-
raphy on a silica gel column (400 g, ethyl acetate/MeOH 10:0!8:2) to
give the title compound accompanied by a complex mixture of the start-
ing material and some side-products. The title compound was recrystal-
lized from MeOH/toluene to yield colourless crystals (3.76 g, 25%). M.p.
222 2258C; 1H NMR ([D6]DMSO, 500 MHz): d=5.32 (s, 2H, CH2Ph),
7.25 7.36 (m, 5H, H-arom.), 7.78 (s, 2H, NH2), 8.24 (s, 1H, H-2);
13C NMR ([D6]DMSO, 125.8 MHz): d=46.22 (CH2Ph), 117.71 (C-5),
127.32, 127.74, 128.68 (CH-arom.), 136.66 (C-i-arom.), 141.39 (CH-8),
150.52 (C-4), 153.09 (C-6), 156.76 (C-2); 1H,13C HMBC cross-peaks: CH2
to CH-8 and C-4; EI MS: m/z (%): 259 (21) [M +], 224 (6), 182 (8), 91
(100); exact mass (EI HR MS): calcd for C12H10ClN5: 259.0625; found:
259.0615; elemental analysis calcd (%) for C12H10ClN5 (259.7): C 55.50,
H 3.88, N 26.97, Cl 13.65; found: C 55.62, H 3.96, N 26.64, Cl 14.00.
9-Benzyl-6-(2-ferrocenylethyl)purine (4a): Yield 52%; brownish oil that
crystallized on standing; m.p. 1278C (decomp); 1H NMR (CDCl3,
400 MHz): d=2.96 (dd, 2H, J=8.4, 7.7 Hz, CH2CH2), 3.45 (dd, 2H, J=
8.4, 7.7 Hz, CH2CH2), 4.04 (s, 2H, H-Fc), 4.11 4.15 (s, 7H, H-Fc), 5.44 (s,
2H, CH2Ph), 7.29 7.36 (m, 5H, H-arom.), 8.00 (s, 2H, H-8), 8.94 (s, 1H,
H-2); 13C NMR (CDCl3, 100.6 MHz): d=28.14, 34.49 (CH2CH2), 47.24
(CH2Ph), 67.20, 68.04, 68.49 (CH Fc), 88.22 (C Fc), 127.81, 128.55,
129.11 (CH-arom.), 132.44, 135.18 (C-5, C-i-arom.), 143.55 (CH-8),
152.61 (CH-2); 150.87 (C-4), 162.09 (C-6); IR (CHCl3): n˜ =1596, 1499,
1456, 1406, 1332 cmꢀ1; EI MS: m/z (%): 422 (100) [M +], 357 (95), 279
(16), 224 (16), 91 (99); exact mass (EI HR MS): calcd for C24H22FeN4:
422.1194 found: 422.1200; elemental analysis calcd (%) for C24H22FeN4
(422.3): C 68.26, H 5.25, N 13.27; found: C 68.22, H 5.42, N 12.96.
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9-Benzyl-8-(2-ferrocenylethyl)adenine (4b): Yield 71%; yellow crystals
from MeOH/toluene/heptane; m.p. 1988C (decomp); 1H NMR (CDCl3,
500 MHz): d=2.75 (dd, 2H, J=8.5, 7.3 Hz, CH2CH2), 2.90 (dd, 2H, J=
General procedure: Cross-coupling of halopurines 2 with ethynylferro-
cene
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DMF (12 mL) and Et3N (4 mL) were added through a rubber septum to
an argon purged flask containing halopurine 2a c (2 mmol), ethynylfer-
rocene (1) (465 mg, 2.2 mmol), CuI (50 mg, 0.25 mmol), and [Pd(PPh3)4]
(100 mg, 0.087 mmol). After the mixture had been stirred at 1208C for
16 h, the solvents were evaporated in vacuo and the residue purified by
column chromatography on silica gel (150 g, ethyl acetate/light petroleum
1:2, and then ethyl acetate to ethyl acetate/MeOH 9:1).
8.5, 7.3 Hz, CH2CH2), 3.98 (s, 2H, H Fc), 4.04 (s, 5H, H Fc), 4.05 (m,
ꢀ
2H, H Fc), 5.26 (s, 2H, CH2Ph), 5.69 (s, 2H, NH2), 7.10 7.12 (m, 2H, H-
arom.), 7.27 7.33 (m, 3H, H-arom.), 8.37 (s, 1H, H-2); 13C NMR (CDCl3,
125.8 MHz): d=27.75, 29.87 (CH2CH2), 45.59 (CH2Ph), 67.58, 68.05,
68.52 (CH Fc), 86.98 (C-Fc), 118.54 (C-5), 126.81, 128.00, 128.96 (CH-
arom.), 135.97 (C-i-arom.), 152.51 (CH-2), 151.43, 152.83, 154.46 (C-4, C-
6, C-8); IR (CHCl3): n˜ =1633, 1608, 1498, 1456, 1385, 1327 cmꢀ1; EI MS:
m/z (%): 437 (70) [M +], 372 (85), 281 (21), 121 (45), 91 (100); exact
mass (EI HR MS): calcd for C24H23FeN5: 437.1303 found: 437.1307; ele-
mental analysis calcd (%) for C24H23FeN5 (437.3): C 65.91, H 5.30, N
16.01; found: C 65.70, H 5.33, N 15.92.
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9-Benzyl-6-(ferrocenylethynyl)purine (3a): Yield 86%; dark red crystals;
m.p. 158 1618C (CH2Cl2/heptane); 1H NMR (CDCl3, 400 MHz): d=4.29
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(s, 5H, H Fc), 4.38 (s, 2H, H Fc), 4.75 (s, 2H, H Fc), 5.48 (s, 2H,
CH2Ph), 7.28 7.39 (m, 5H, H-arom.), 8.12 (s, 1H, C-8), 8.96 (s, 1H, H-2);
13C NMR (CDCl3, 100.6 MHz): d=47.36 (CH2Ph), 62.43 (C-Fc), 70.08,
9-Benzyl-2-(2-ferrocenylethyl)adenine (4c): Yield 56%; orange crystals
from MeOH/toluene/heptane; slow decomp. above 808C; 1H NMR
(CDCl3, 400 MHz): d=2.89, 3.08 (2îbrt, 2î2H, J=7.6 Hz, CH2CH2),
4.03 4.15 (brm, 9H, H-Fc), 5.36 (s, 2H, CH2Ph), 5.70 (s, 2H, NH2), 7.20
7.40 (brm, 5H, H-arom.), 7.69 (s, 1H, H-8); 13C NMR (CDCl3,
100.6 MHz): d=28.52, 40.51 (CH2CH2), 47.05 (CH2Ph), 67.05, 68.10,
ꢀ
70.34, 72.72 (CH Fc), 81.59, 100.22 (CꢁC), 127.81, 128.66, 129.18 (CH-
arom.), 133.62, 135.00 (C-i-arom. and C-5), 142.45 (C-6), 144.57 (CH-8),
151.52 (C-4), 152.86 (CH-2); IR (CHCl3): n˜ =2207, 1578, 1498, 1432,
1400, 1327 cmꢀ1; EI MS: m/z (%): 418 (73) [M +], 353 (12), 327 (7), 121
(6), 91 (100); exact mass (EI HR MS): calcd for C24H18FeN4: 418.0881;
found: 418.0884; elemental analysis calcd (%) for C24H18FeN4 (418.3): C
68.92, H 4.34, N 13.39; found: C 68.71, H 4.40, N 13.38.
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68.46 (CH Fc), 88.82 (C-Fc), 117.76 (C-5), 127.95, 128.30, 128.97 (CH-
arom.), 135.90 (C-i-arom.), 139.95 (CH-8), 151.03, 155.17 (C-4, C-6),
165.43 (C-2); IR (CHCl3), n˜ =1626, 1592, 1498, 1456, 1391, 1339 cmꢀ1; EI
MS: m/z (%): 437 (100) [M +], 372 (62), 294 (29), 121 (36), 91 (80); exact
mass (EI HR MS); calcd for C24H23FeN5: 437.1303; found: 437.1306; ele-
mental analysis calcd (%) for C24H23FeN5 (437.3): C 65.91, H 5.30, N
16.01; found: C 65.84, H 5.48, N 15.73.
9-Benzyl-8-(ferrocenylethynyl)adenine (3b): Yield 92%; dark red crystals
from EtOH/toluene; m.p. >2158C (slow decomp.); 1H NMR
ꢀ
([D6]DMSO, 500 MHz): d=4.21 (s, 5H, H Fc), 4.43 (t, 2H, J=1.6 Hz,
ꢀ
H Fc), 4.68 (t, 2H, J=1.6 Hz, H-Fc), 5.44 (s, 2H, CH2Ph), 7.30 7.41 (m,
5H, H-arom.), 7.45 (s, 2H, NH2), 8.21 (s, 1H, H-2); 13C NMR
([D6]DMSO, 125.8 MHz): d=46.01 (CH2Ph), 61.34 (C-Fc), 69.95, 70.01,
71.68 (CH-Fc), 75.25, 95.27 (CꢁC),118.67 (C-5), 127.37, 127.78, 128.69
(CH-arom.), 133.69, 136.73 (C-i-arom. and C-8), 153.66 (CH-2), 149.30,
155.65 (C-4, C-6); IR (CHCl3): n˜ =2223, 1633, 1588, 1575, 1464,
1327 cmꢀ1; UV/Vis (MeOH): lmax (e)=449 (1300), 308 nm (24000); EI
MS: m/z (%): 433 (100) [M +], 368 (11), 342 (10), 121 (26), 91 (70); exact
mass (EI HR MS): calcd for C24H19FeN5: 433.0990; found: 433.1000; ele-
mental analysis calcd (%) for C24H19FeN5 (433.3): C 66.53, H 4.42, N
16.16; found: C 66.22, H 4.45, N 16.04.
X-Ray crystallography: Single-crystals were grown by crystallization
from dichloromethane/hexane (3a: ruby red prism, 0.27î0.32î0.40 mm3;
4a: orange-yellow block, 0.28î0.28î0.30 mm3; 3b: rusty orange block,
0.13î0.25î0.33 mm3). Repeated attempts at obtaining single crystals of
4b resulted only in thin, layered crystalline aggregates. Finally, a very
thin yellow plate (0.30î0.13î0.03 mm3) was selected after crystallizatiom
from MeOH/toluene and subjected to crystallographic analysis. Although
the obtained data and, consequently, the structure determination are of a
rather low precision (see R values and residual electron density in
Table 6), the overall chemical picture, and particularly the crystal pack-
ing, which shows interresting features very different from other studied
compounds, are unambiguous.
9-Benzyl-2-(ferrocenylethynyl)adenine (3c): Reaction time 36 h, yield
37% (40% of starting compound was recovered), red crystals from
EtOH/toluene; m.p. 1388C (decomp); 1H NMR (CDCl3, 400 MHz): d=
ꢀ
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4.28 (brs, 7H, CH Fc), 4.66 (brs, 2H, CH Fc), 5.40 (s, 2H, CH2Ph), 5.95
(s, 2H, NH2), 7.26 7.40 (m, 5H, H-arom.), 7.72 (s, 1H, H-8); 13C NMR
(CDCl3, 100.6 MHz): d=47.16 (CH2Ph), 63.26 (C-Fc), 69.38, 70.11, 72.35
Full-set diffraction data (ÆhÆkÆl) for all compounds were collected on
an Nonius KappaCCD diffractometer equipped with Cryostream Cooler
(Oxford Cryosystems) at 150(2) K using graphite monochromatized MoKa
2064
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2004, 10, 2058 2066