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H. Hrebabecky et al. / Tetrahedron 68 (2012) 1286e1298
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4.15.2. 9-[(1R*,4R*,5S*)-2-Azabicyclo[2.2.1]hept-5-yl]-6-chloro-9H-
purine trifluoroacetic acid salt (9b). Yield 140 mg (77%) of white
powder after crystallization from ethanol. Mp 181.5e183 ꢁC,
decomp. IR (KBr): 3117, 3017 (br), 2791 (w, br), 2721 (w, br), 2547
(w, br), 1695, 1685, 1590, 1565, 1486 (w), 1443, 1418, 1392, 1345,
1200, 1181, 1125, 835, 789, 723 cmꢂ1. 1H NMR: 9.12 (br s, 1H) and
8.75 (br s,1H, NH); 8.87 (s, 1H, H-8); 8.79 (s, 1H, H-2); 4.86 (ddd, 1H,
J¼8.4, 4.2, 1.0, H-5); 4.23 (m, 1H, H-10); 3.17e3.25 (m, 2H, H-30); 3.12
(br d, 1H, J¼3.6H, H-40); 2.55 (ddd, 1H, J¼15.1, 8.4, 2.7, H-60endo);
2.44 (br dt, 1H, J¼15.1, 3.7, H-60exo); 2.17 (dm, 1H, J¼11.8, H-70b);
1.76 (dm, 1H, J¼11.8, H-70a). 13C NMR: 158.75 (q, J¼31.4, C]O);
152.17 (C-4); 151.61 (C-2); 149.32 (C-6); 145.85 (C-8); 131.56 (C-5);
117.41 (q, J¼298.9, CF3); 56.80 (C-10); 55.77 (C-50); 47.21 (C-30);
40.97 (C-40); 34.31 (C-70); 34.10 (C-60). ESI MS, m/z (%): 252.2/250.2
(30/100) [MꢂCF3COOHþ1]. For C13H13ClF3N5O2 (363.73) calcu-
lated: 42.93% C, 3.60% H, 9.75% Cl, 19.25% N; found: 42.72% C, 3.73%
H, 9.85% Cl, 18.99% N.
1177, 1138 (br), 828, 799, 722 cmꢂ1. 1H NMR: 9.73 (br s, 1H), 9.48
(br s, 1H) and 8.67 (br s, 1H, NH); 8.36 (br s, 1H, H-2); 8.26 (s, 1H,
H-8); 4.99 (br dd, 1H, J¼9.0, 4.6, H-20); 4.60 (br d, 1H, J¼4.6, H-10);
4.46 (br t, 1H, J¼4.5, H-40); 2.98 (br s, 1H, CH of cyclopropyl); 2.48
(dd, 1H, J¼14.0, 9.2, H-30endo); 2.28 (dm, 1H, J¼14.0, H-30exo);
1.71e2.00 (m, 4H, H-50, H-60); 0.78 (m, 2H) and 0.66 (m, 2H, CH2 of
cyclopropyl); 13C NMR: 158.55 (q, J¼34.1, COO); 154.80 (C-6);
150.51 (C-2); 147.50 (C-4); 141.07 (C-8); 119.90 (C-5); 116.49 (q,
J¼294.9, CF3); 62.14 (C-10); 57.87 (C-40); 56.40 (C-20); 36.49 (C-30);
25.61 (C-50); 24.57 (C-60); 6.54 (CH2 of cyclopropyl). ESI MS, m/z
(%): 272.3 (27) [Mþ2H], 271.3 (100) [MþH]. For C18H20F6N6O4
(498.39) calculated: 43.38% C, 4.05% H, 16.86% N; found: 43.21% C,
3.92% H, 16.66% N.
4.15.6. 9-[(1R*,2R*,4S*)-7-Azabicyclo[2.2.1]hept-2-yl]-N-cyclopropyl-
9H-purin-6-amine bis trifloroacetic acid salt (20). Yield 204 mg
(82%) of a white powder after crystallization from ethanol/ether.
Mp 183e185 ꢁC. IR (KBr): 3222, 3182 (br), 3012 (br), 3103, 2903 (br),
2719 (br), 2582 (br), 1978 (w, br), 1930 (w, br), 1690 (br),1672e1654
(br), 1592, 1522, 1433, 1412, 1359, 1128 (br), 837, 800, 721 cmꢂ1. 1H
NMR: 9.47 (br s, 1H), 9.40 (br s, 1H) and 8.95 (br s, 1H, NH); 8.58 (s,
1H, H-8); 8.41 (br s, 1H, H-2); 5.14 (m, 1H, H-20); 4.59 (t, 1H, J¼4.7,
H-10); 4.39 (m, 1H, H-40); 2.95 (br s, 1H, CH of cyclopropyl);
2.50e2.54 (m, 2H, H-30); 2.04 (ddd, 1H, J¼12.7, 9.7, 4.6, H-50endo);
1.92 (m, 1H, H-50exo); 1.74 (m, 1H, H-60exo); 1.35 ddd, 1H, J¼13.8,
9.6, 4.7, (H-60endo); 0.81 (m, 2H) and 0.69 (m, 2H, CH2 of cyclo-
propyl). 13C NMR: 158.70 (q, J¼34.0, COO); 153.6 (C-6); 150.02 (C-
2); 149.1 (C-4); 140.9 (C-8); 119.55 (C-5); 116.24 (q, J¼295.2, CF3);
59.69 (C-10); 58.51 (C-40); 53.19 (C-20); 29.96 (C-30); 26.45 (C-50);
23.6 (CH of cyclopropyl); 20.48 (C-60); 6.79 (CH2 of cyclopropyl). ESI
MS, m/z (%): 272.2 (18) [Mþ2H], 271.2 (100) [MþH]. For
C18H20F6N6O4 (498.39) calculated: 43.38% C, 4.05% H, 16.86% N;
found: 43.09% C, 3.92% H, 16.59% N.
4.15.3. 9-[(1R*,4S*,6R*)-2-Azabicyclo[2.2.1]hept-6-yl]-N-cyclopropyl-
9H-purin-6-amine bis trifluoroacetic acid salt (13a). Yield 215 mg
(86%) of a white powder after crystallization from ethanol/ether.
Mp 192e193.5 ꢁC, decomp. IR (KBr): 3228 (sh), 3114, 3011e2965
(br), 2913 (br), 2749 (br), 2547 (br), 2472 (br), 1700, 1684, 1665,
1592, 1527, 1428, 1410, 1359, 1344, 1202, 1189 (sh), 1179 (sh), 1130,
834, 799, 722 cmꢂ1. 1H NMR: 9.54 (br s, 1H) and 9.03 (br s, 2H, NH);
8.50 (s, 1H, H-8); 8.43 (br s, 1H, H-2); 5.02 (ddd, 1H, J¼8.3, 5.3, 1.3,
H-60); 4.28 (m, 1H, H-10); 3.13 (m, 1H, H-30exo); 3.02 (m, 1H, H-
30endo); 2.93 (br s, 1H, CH of cyclopropyl); 2.84 (br s, 1H, H-40); 2.33
(m, 1H, H-50exo); 2.27 (ddd, 1H, J¼13.3, 8.5, 1.8, H-50endo); 2.15 (dm,
1H, J¼11.8, H-70b); 1.74 (dm, 1H, J¼11.9, H-70a); 0.82 (m, 2H) and
0.68 (m, 2H, CH2 of cyclopropyl); 13C NMR: 158.85 (q, J¼31.2, C]O);
153.37 (C-6); 149.49 (C-2); 148.44 (C-4); 140.30 (C-8); 119.34 (C-5);
116.73 (q, J¼295.5, CF3); 59.73 (C-10); 53.20 (C-60); 48.93 (C-30);
35.23 (C-40); 35.08 (C-50); 34.40 (C-70); 23.89 (CH of cyclopropyl);
6.87 (CH2 of cyclopropyl). ESI MS, m/z (%): 271.1 (100) [MþH], 176.2
(26) [6-(cyclopropylamino)purineþH]. For C18H20F6N6O4 (498.39)
calculated: 43.38% C, 4.05% H, 16.86% N; found: 43.20% C, 4.09% H,
16.73% N.
4.15.7. (1R*,2S*,4S*)-2-[(5-Amino-6-chloropyrimidin-4-yl)amino]-7-
azabicyclo[2.2.1]heptane trifluoroacetic acid salt (24b). Yield 161 mg
(91%) of a white powder after crystallization from ethanol/ether.
Mp 166.5e168 ꢁC. IR (KBr): 3417, 3343, 3253, 2972 (br), 2868, 2690,
2569, 1671 (br), 1604, 1580 (br), 1495, 1462, 1434, 1420, 1381, 1211,
1187, 1174, 1148, 1129, 838, 834, 801, 722 cmꢂ1. 1H NMR: 9.00 (br s,
1H) and 8.76 (br s,1H, NH); 7.81 (s,1H, H-2); 6.81 (br d,1H, J¼5.2, 4-
NH); 5.11 (br s, 2H, NH2); 4.22 (m, 1H, H-40); 4.17 (m, 1H, H-10); 4.10
(m, 1H, H-20); 2.21 (dd, 1H, J¼13.6, 8.5, H-30endo); 1.93 (dm, 1H,
J¼13.5, H-30exo); 1.78e1.88 (m, 2H, H-50exo, H-60exo); 1.71 (m, 1H,
H-60endo); 1.62 (m, 1H, H-50endo). 13C NMR: 158.82 (q, J¼31.3,
COO); 151.31 (C-4); 145.64 (C-2); 137.56 (C-6); 124.49 (C-5); 117.30
(q, J¼298.8, CF3); 62.18 (C-10); 57.06 (C-40); 53.02 (C-20); 35.63 (C-
30); 25.77 (C-50); 23.71 (C-60). ESI MS, m/z (%): 242.1/240.1 (35/100)
[MþH]. For C12H15ClF3N5O2 (353.73) calculated: 40.75% C, 4.27% H,
10.02% Cl, 19.80% N; found: 40.77% C, 4.32% H, 10.05% Cl, 19.64% N.
4.15.4. 9-[(1R*,4R*,5S*)-2-Azabicyclo[2.2.1]hept-5-yl]-N-cyclopropyl-
9H-purin-6-amine bis trifluoroacetic acid salt (13b). Yield 214 mg
(86%) of a white powder after crystallization from ethanol/ether.
Mp 190e191.5 ꢁC, decomp. IR (KBr): 3223 (br), 3111, 2967 (br), 2760
(br), 2552, 1984 (w, br), 1926 (w), 1875 (w), 1697, 1677, 1654, 1593,
1522, 1432, 1417, 1408, 1362, 1343, 1203, 1185, 1175, 1133, 836, 828,
799, 721 cmꢂ1. 1H NMR: 9.19 (br s, 2H) and 8.79 (br s, 1H, NH); 8.51
(s, 1H, H-8); 8.41 (br s, 1H, H-2); 4.77 (br dd, 1H, J¼8.4, 4.2, H-50);
4.21 (br s, 1H, H-10); 3.14e3.24 (m, 2H, H-30); 3.01 (m, 1H, H-40);
2.92 (br s, 1H, CH of cyclopropyl); 2.52 (ddd, 1H, J¼15.1, 8.7, 2.6, H-
60endo); 2.38 (dm, 1H, J¼15.1, H-60exo); 2.13 (dm, 1H, J¼11.8, H-70b);
1.74 (dm, 1H, J¼11.8, H-70a); 0.82 (m, 2H) and 0.69 (m, 2H, CH2 of
cyclopropyl). 13C NMR: 158.80 (q, J¼33.5, COO); 153.2 (C-6); 149.23
(C-2); 148.48 (C-4); 140.51 (C-8); 119.47 (C-5); 116.78 (q, J¼296.0,
CF3); 56.80 (C-10); 55.18 (C-50); 47.23 (C-30); 41.23 (C-40); 34.18 (C-
60, C-70); 23.69 (CH of cyclopropyl); 6.91 (CH2 of cyclopropyl). ESI
MS, m/z (%): 272.2 (17) [Mꢂ2 CF3COOHþ2H], 271.2 (100) [Mꢂ2
CF3COOHþH], 176.2 (9) [6-(cyclopropylamino)purine]. For
C18H20F6N6O4 (498.39) calculated: 43.38% C, 4.05% H, 16.86% N;
found: 43.27% C, 3.96% H, 16.68% N.
4.15.8. 9-[(1R*,2S*,4S*)-7-Azabicyclo[2.2.1]hept-2-yl]-6-chloro-9H-
purine trifluoroacetic acid salt (26). Yield 164 mg (90%) of a white
powder after crystallization from ethanol. Mp 153e156 ꢁC decomp. IR
(KBr): 3105, 3071, 2972, 2901 (br), 2725, 2674, 2542 (br), 1691, 1640,
1632 (sh), 1595, 1566, 1558, 1496 (w), 1428, 1417, 1400, 1343, 1203,
1181, 1123, 834, 794, 722 cmꢂ1. 1H NMR: 9.34 (br s, 2H, NH); 8.83 (s,
1H, H-8); 8.82 (s,1H, H-2); 5.06 (br dd,1H, J¼9.0, 4.9, H-20); 4.82 (br d,
1H, J¼4.8, H-10); 4.41 (br t, 1H, J¼4.5, H-40); 2.55 (dd, 1H, J¼14.1, 9.0,
H-30endo); 2.45 (m, 1H, H-30exo); 1.73e2.03 (m, 4H, H-50, H-60). 13C
NMR: 151.86 (C-4); 151.36 (C-2); 149.41 (C-6); 146.60 (C-8); 131.77
(C-5); 61.62 (C-10); 57.76 (C-40); 56.53 (C-20); 36.08 (C-30); 25.42 (C-
50); 24.77 (C-60). ESI MS, m/z (%): 252.1/250.1 (38/100) [MþH], 157.0/
155.0 (11/33) [6-chloropurineþH]. For C13H13ClF3N5O2 (363.73) cal-
culated: 42.93% C, 3.60% H, 9.75% Cl,19.25% N; found: 43.02% C, 3.64%
H, 9.61% Cl, 19.27% N.
4.15.5. 9-[(1R*,2S*,4S*)-7-Azabicyclo[2.2.1]hept-2-yl]-N-cyclopropyl-
9H-purin-6-amine bis trifluoroacetic acid salt (19). Yield 184 mg
(74%) of a white powder after crystallization from ethanol/ether.
Mp 167e169 ꢁC. IR (KBr): 3233 (br), 3097, 3017 (br), 2892 (br),
2861 (br), 2735 (br), 2559, 1998 (w, br), 1930 (w, br), 1886 (w, br),
1702, 1684 (br), 1602 (sh), 1559, 1516, 1430, 1411, 1362, 1200 (br),