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Gundersen et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 159−166
1H), 2.08 (m, 1H), 1.69 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
162.4, 152.8, 150.3, 143.3, 141.2, 135.3, 132.2, 129.1, 128.5, 128.4,
127.4, 126.1, 126.1, 47.2, 29.6, 24.7, 20.3; MS (EI) m/z (rel.%): 326
(Mϩ, 100), 236 (9), 235 (67), 224 (11), 208 (2), 181 (2), 115 (1), 91
(48); Anal: Found: C, 76.93; H, 5.60; N, 16.90. C21H18N4 requires
C, 77.28; H, 5.56; N, 17.17%.
6H, J 6.87 Hz, CH3 i-Pr); 13C NMR (75 MHz, CDCl3): δ 153.6,
152.1, 151.5, 141.7, 139.52, 139.49, 136.1, 131.4, 129.3, 128.7, 127.8,
122.4, 47.2, 22.5; MS (EI) m/z (rel.%): 264 (Mϩ, 58), 263 (100), 222
(19), 221 (70), 194 (6), 140 (8), 91(1), 77 (3); HRMS: Found
264.1357, calcd. for C16H16N4 264.1375.
9-[(Methylthio)methyl]-6-[(E)-2-phenylethen-1-yl]-9H-purine 7f
6-(cis-2-Phenylcycloprop-1-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-
purine 6
The compound was prepared by Stille coupling on 6-chloro-9-
[(methylthio)methyl]-9H-purine [25] (328 mg, 1.53 mmol) as de-
scribed for the synthesis of compound 7d above. The crude product
was purified by flash chromatography on silica gel eluting with
10Ϫ20% acetone in hexane; yield 352 mg (82%) colorless crystalline
solid, mp. 79Ϫ81°C. 1H NMR (300 MHz, CDCl3): δ 8.82 (s, 1H,
H-2), 8.31 (d, 1H, J 16.2 Hz, ϭCH), 8.15 (s, 1H, H-8), 7.60 (m, 3H,
Ph and ϭCH), 7.27 (m, 3H, Ph), 5.17 (s, 2H, CH2), 2.04 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3): δ 153.8, 152.5, 151.8, 143.5,
139.9, 135.8, 130.7, 129.3, 128.7, 127.7, 122.1, 46.0, 15.0; MS (EI)
m/z (rel.%): 282 (Mϩ, 63), 281 (100), 278 (7), 253 (7), 236 (32), 235
(26), 222 (14), 221 (69), 208 (5), 179 (4); HRMS (ESI): Found
283.1015, calcd. for C15H14N4C[Hϩ] 283.1011.
2-Bromo-1-phenylcyclopropane (cis/trans: 1.85/1, 300 mg, 1.53
mmol) [10] was dissolved in dry THF (2 mL) and cooled Ϫ89°C.
n-BuLi (960 μL, 1.53 mmol) was added and the mixture was stirred
for 1 h before a solution of ZnBr2 (1.50 mL, 1.50 mmol, 1.0 M in
THF) was added. After stirring for 1 h, the zinc reagent was reacted
with 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-purine 1a (239mg, 1.0
mmol) following the procedure described for the synthesis of 5a
above. The crude product was purified by flash chromatography on
silica gel eluting with 10%, 15%, 20%, 25%, and 30% acetone in
hexane; yield 80 mg, (16%) 6-(trans-2-phenylcycloprop-1-yl)-9-
(tetrahydro-2H-pyran-2-yl)-9H-purine 5a and 116 mg (24%) of the
title compound 6, colorless crystalline solid, mp. 138Ϫ142°C. 1H
NMR (500 MHz, CDCl3): δ 8.56 (s, 1/2H, H-2), 8.54 (s, 1/2H, H-
2), 8.18 (s, 1/2H, H-8), 8.17 (s, 1/2H, H-8), 7.13 (m, 2H, Ph), 7.03
(m, 2H, Ph), 6.97 (m, 1H, Ph), 5.68 (m, 1H, THP-2), 4.14 (m, 1H),
3.74 (m, 1H), 3.26 (m, 1H), 2.91 (m, 1H), 2.44 (m, 1H), 2.03 (m,
3H, THP), 1.67 (m, 3H, THP); 13C NMR (75 MHz, CDCl3): δ
159.6, 159.5, 151.5, 149.2, 149.1, 141.0, 140.9, 136.8, 136.7, 133.93,
133.88, 129.5, 129.4, 127.5, 127.4, 125.94, 125.88, 81.8, 81.7, 68.8,
68.7, 31.8, 31.6, 28.7, 28.6, 24.8, 22.80, 22.75, 21.7, 21.4, 11.2, 11.1
(Double set of signals were seen for several carbons in the dia-
stereomeric mixt.); MS (EI) m/z (rel.%): 320 (Mϩ, 3), 237 (19), 236
(100), 235 (42), 221 (6), 159 (8), 134 (20), 91(2), 85 (5), 77 (2), 65
(1), 41 (6), 29 (6); HRMS: Found 320.1638, calcd. for C19H20N4O
320.1637; Anal: Found: C, 70.77; H, 6.50; N, 17.23. C19H20N4O
requires C, 71.23; H, 6.29; N, 17.49.
9-Phenyl-6-[(E)-2-phenylethen-1-yl]-9H-purine 7g
The compound was prepared by Stille coupling on 6-chloro-9-
phenyl-9H-purine [26] (101 mg, 0.44 mmol), as described for the
synthesis of compound 7d above. The crude product was purified
by flash chromatography on silica gel eluting with EtOAc-hexane
(1:3) followed by (1:1); yield 116 mg, (89%) colorless crystalline
solid, mp. 155Ϫ158°C. 1H NMR (200 MHz, CDCl3): δ 8.96 (s, 1H,
H-2), 8.42 (d, 1H, J 16.2 Hz, ϭCH) 8.33 (s, 1H, H-8), 7.78 (d, 1H,
J 16.2 Hz, ϭCH), 7.73 (m, 3H, Ph), 7.55 (m, 2H, Ph), 7.39 (m, 5H,
Ph); 13C NMR (50 MHz, CDCl3): δ 154.3, 153.1, 151.6, 142.9,
140.0, 136.0, 134.4, 131.5, 129.9, 129.5, 128.8, 128.4, 127.9, 123.5,
122.1; MS (EI) m/z (rel.%): 298 (Mϩ, 41), 297 (100), 270 (3), 194
(2), 167 (2), 149 (2), 140 (3); HRMS (ESI): Found 299.1280, calcd.
for C19H14N4[Hϩ] 299.1291.
9-Methyl-6-[(E)-2-phenylethen-1-yl]-9H-purine 7d
2-Methyl-6-[(E)-2-phenylethen-1-yl]-9-phenylmethyl-9H-purine 7j
6-Chloro-9-methyl-9H-purine [22] (135 mg, 0.799 mmol), (E)-tri(n-
butyl)styryltin [23] (398 mg, 1.04 mmol) and Pd(PPh3)2Cl2 (28 mg,
0.004 mmol) was dissolved in dry DCE (6 mL) and refluxed for 22
h. Solvents were removed in vacuo, saturated KF in MeOH (10 mL)
was added and the residue was stirred for 20 h before evaporation
in vacuo together with a small amount of silica gel. The residue was
added on top of a flash chromatography column and the product
eluted with EtOAc-hexane (3:1) followed by 5% MeOH in EtOAc;
yield 134 mg (71%) colorless crystalline solid, mp. ca. 150°C (dec).
1H NMR (300 MHz, CD3OD): δ 8.82 (s, 1H, H-2), 8.42 (s, 1H, H-
8), 8.32 (d, 1H, J 16.2 Hz, vinyl), 7.69 (m, 2H, Ph), 7.66 (d, 1H, J
16.2 Hz, vinyl), 7.41 (m, 3H, Ph), 3.90 (s, 3H, CH3); 13C NMR (50
MHz, CDCl3): δ 153.4 152.2, 144.4, 139.5, 135.9, 131.7, 129.2,
128.7, 128.6, 127.6, 122.2, 29.5; MS (EI) m/z (rel.%): 236 (Mϩ, 35),
235 (100), 222 (1), 221 (70), 194 (2), 140 (5), 91(1), 77 (4); HRMS:
Found 236.1033, calcd. for C14H12N4 236.1062; Anal: Found: C,
70.95; H, 5.19. C14H12N4 requires C, 71.17; H, 5.12.
MeMgBr in THF (190 μL, 3 M, 0.577 mmol) dissolved in dry THF
(1.5 mL) was cooled to -78°C before ZnBr2 (580 μL, 1.0 M, 0.58
mmol) was added. The solution was stirred at -78°C for 1 h. In a
separate flask, 2-chloro-6-[(E)-2-phenylethen-1-yl]-9-phenylmethyl-
9H-purine 7i (100 mg, 0.288 mmol), (dba)3Pd2 (6.6 mg, 0.0072
mmol) and PPh3 (15 mg, 0.058 mmol) was dissolved in dry THF
(3 mL) and stirred until a clear yellow solution was formed. The
purine solution was transferred to the zinc reagent and refluxed for
22 h before evaporation. The crude product was purified by flash
chromatography on silica gel eluting with 10Ϫ50% EtOAc in hex-
ane; yield 42 mg (44%) yellow crystalline solid, mp. 109Ϫ112°C.
1H NMR (300 MHz, CDCl3): δ 8.44 (d, 1H, J 16.4 Hz, ϭCH), 7.95
(s, 1H, H-8), 7.71 (m, 2H, Ph), 7.65 (d, 1H, J 16.4 Hz, ϭCH), 7.35
(m, 8H, Ph), 5.43 (s, 2H, CH2), 2.05 (s, 3H, CH3); 13C NMR (75
MHz, CDCl3): δ 162.3, 153.6, 152.6, 143.4, 139.9, 136.3, 135.4,
129.2, 129.1, 128.8, 128.7, 128.5, 127.84, 127.83, 123.1, 46.9, 26.2;
MS (EI) m/z (rel.%): 326 (Mϩ, 100), 325 (25), 236 (15), 235 (93),
140 (8), 115 (6), 91 (29). HRMS: Found 326.1530, calcd. for
C21H18N4 326.1531.
9-(1-Methylethyl)-6-[(E)-2-phenylethen-1-yl]-9H-purine 7e
The compound was prepared by Stille coupling on 6-chloro-9-(1-
methylethyl)-9H-purine [24] (202 mg, 1.03 mmol), as described
above for the synthesis of compound 7d. The crude product was
purified by flash chromatography on silica gel eluting with 10Ϫ20%
acetone in hexane; yield 222 mg (82%) pale yellow oil. 1H NMR
(300 MHz, CDCl3): δ 8.90 (s, 1H, H-2), 8.39 (d, 1H, J 16.2 Hz, ϭ
CH), 8.12 (s, 1H, H-8), 7.71 (d, 1H, J 16.2 Hz, ϭCH), 7.70 (m, 2H,
Ph), 7.37 (m, 3H, Ph), 4.92 (m, 1H, J 6.97 Hz, CH i-Pr), 1.63 (d,
2-Methoxy-6-[(E)-2-phenylethen-1-yl]-9-phenylmethyl-9H-purine
7k
NaOMe (1.5 mL, 1.0 M in MeOH) was added to 2-chloro-6-[(E)-2-
phenylethen-1-yl]-9-phenylmethyl-9H-purine 7i (175 mg, 0.505
mmol) and the solution was heated at 50°C for 24 h. The reaction
mixture was cooled to ambient temperature and aqueous NaHCO3
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