M. F. Proença et al.
FULL PAPER
NMR (75 MHz, [D6]DMSO): δ = 152.4, 152.0, 151.0, 138.3, 118.8,
(253.31): calcd. C 66.38, H 5.97, N 27.65; found C 66.42, H 6.19,
47.5, 25.1 ppm. IR (nujol mull): ν = 1601, 1517 cm–1. C9H11N5 N 27.71.
˜
(189.22): calcd. C 57.13, H 5.86, N 37.01; found C 57.02, H 5.72,
N 37.28.
6-(Piperidin-1-yl)-9-(4-tolyl)-9H-purine (6m): Yield 0.45 mmol, 51%
from the reaction of imidazole 1f and amine, followed by addition
1
N,N,9-Trimethyladenine (6f): Yield: 0.93 mmol, 80% from the reac-
tion of imidazole 7d and acetal 2. M.p. 124 °C (dec.). 1H NMR
(300 MHz, [D6]DMSO): δ = 8.17 (s, 1 H), 8.05 (s, 1 H), 3.69 (s, 3
H), 3.41 (br. s, 6 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
154.2, 151.7, 150.6, 140.2, 119.1, 37.9, 29.4 ppm. IR (nujol mull):
of acetal 2. M.p. 126–127 °C. H NMR (300 MHz, [D6]DMSO): δ
= 8.49 (s, 1 H), 8.24 (s, 1 H), 7.69 (d, J = 8.1 Hz, 2 H), 7.37 (d, J
= 8.1 Hz, 2 H), 4.23 (br. s, 4 H) 2.37 (s, 3 H), 1.68 (m, 4 H), 1.60
(m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 153.3, 152.5,
150.2, 138.5, 137.2, 132.5, 129.8, 123.3, 119.4, 45.6, 25.7, 24.3,
ν = 1593, 1561 cm–1. C H N (177.21): calcd. C 54.22, H 6.26, N
20.6 ppm. IR (nujol mull): ν = 1592, 1579, 1554, 1524, 1507 cm–1.
˜
˜
8
11
5
39.52; found C 54.07, H 6.18, N 39.20.
HRMS: calcd. for C17H20N5 [M + H]+ 294.171871; found
294.171615.
9-(2-Hydroxyethyl)-N,N-dimethyladenine (6g): Yield: 1.40 mmol,
38%; m.p. 135–136 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.19
(s, 1 H), 8.08 (s, 1 H), 4.99 (t, J = 5.7 Hz, 1 H), 4.18 (t, J = 5.7 Hz,
2 H), 3.71 (q, J = 5.7 Hz, 2 H), 3.44 (br. s, 6 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 154.3, 151.6, 150.3, 140.3, 119.2, 59.2,
Acknowledgments
The authors gratefully acknowledge the financial support by the
University of Minho and Fundação para a Ciência e Tecnologia
(project PRAXIS/C/QUI/45391/2002).
45.7, 37.8 ppm. IR (nujol mull): ν = 1645, 1604, 1584, 1548,
˜
1498 cm–1. HRMS: calcd. for C9H14N5O [M + H]+ 208.119835;
found 208.120586.
9-(2-Hydroxyethyl)-6-(piperidin-1-yl)-9H-purine (6h): Yield:
1.10 mmol, 51% from the reaction of imidazole 7e and acetal 2.
M.p. 170 °C (dec.). H NMR (300 MHz, [D6]DMSO): δ = 8.19 (s,
[1] For a recent review, see: M. Legraverend, D. S. Grierson, Bi-
oorg. Med. Chem. 2006, 14, 3987–4006.
1
[2] J. Vara, G.-J. Perez, Biochemistry 1985, 24, 8074–8081.
1 H), 8.07 (s, 1 H), 4.99 (s, 1 H), 4.18 (t, J = 5.4 Hz, 6 H), 3.72 (s, [3] a) J. L. Kelley, E. W. McLean, R. M. Ferris, J. L. Howard, J.
2 H), 1.65 (m, 4 H), 1.56 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]-
Med. Chem. 1989, 32, 1020–1024; b) J. L. Kelley, E. W.
McLean, R. M. Ferris, J. L. Howard, J. Med. Chem. 1990, 33,
1910–1914; c) J. L. Kelley, E. W. McLean, J. A. Linn, M. P.
Krochmal, R. M. Ferris, J. L. Howard, J. Med. Chem. 1990,
33, 196–202.
DMSO): δ = 153.1, 151.7, 150.5, 140.1, 118.9, 59.2, 45.7, 43.6, 25.7,
24.3 ppm. IR (nujol mull): ν = 1637, 1589, 1557, 1528 cm–1
.
˜
C12H17N5O (247.30): calcd. C 58.28, H 6.93, N 28.32; found C
58.45, H 6.90, N 28.19.
[4] a) J. L. Kelley, J. A. Linn, J. W. T. Selway, J. Med. Chem. 1991,
34, 157–160; b) J. L. Kelley, J. A. Linn, J. W. T. Selway, J. Med.
Chem. 1989, 32, 218–224.
[5] a) J. L. Kelley, M. P. Krochmal, J. A. Linn, E. W. McLean,
F. E. Soroko, J. Med. Chem. 1988, 31, 606–612; b) J. L. Kelley,
M. P. Krochmal, J. A. Linn, E. W. McLean, F. E. Soroko, J.
Med. Chem. 1988, 31, 1005–1009.
9-(4-Chlorophenyl)-N,N-dimethyladenine (6i): Yield: 0.15 mmol,
77% from the reaction of imidazole 7f and acetal 2. M.p. 208–
1
209 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.60 (s, 1 H), 8.27
(s, 1 H), 7.93 (d, J = 8.7 Hz, 2 H), 7.66 (d, J = 8.7 Hz, 2 H), 3.50
(br. s, 6 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.5,
152.5, 149.9, 138.4, 133.9, 131.9, 129.5, 124.9, 119.7, 38.0 ppm. IR
[6] a) J. L. Kelley, R. M. Bullock, M. P. Krochmal, E. W. McLean,
J. A. Linn, J. Med. Chem. 1997, 40, 3207–3216.
(nujol mull): ν = 1604, 1586, 1560 cm–1. C13H12N5Cl·0.1H2O
˜
(275.53): calcd. C 56.67, H 4.46, N 25.42; found C 56.49, H 4.34,
N 25.16.
[7] H. Chapuis, P. Strazewski, Tetrahedron 2006, 62, 12108–12115.
[8] a) R. D. Thompson, S. Secunda, J. W. Daly, R. A. Olsson, J.
Med. Chem. 1991, 34, 2877–2882; b) K. A. Jacobson, X.-D. Ji,
A.-H. Li, N. Melman, M. A. Siddiqui, K.-J. Shin, V.-E. Mar-
quez, R. G. Ravi, J. Med. Chem. 2000, 43, 2196–2203.
[9] a) M. S. Wolf, R. T. Borchardt, J. Med. Chem. 1991, 34, 1521–
1530; b) S. W. Schneller, Curr. Top. Med. Chem. 2002, 2, 1087–
1092.
[10] a) W.-G. Friebe, M. Thiel, W. Winter, A. Roesch, W. Schaum-
ann (Boehringer Mannheim GmbH), USP 3996361, 1976; b)
H. Yuki, H. Sueoka, M. Yasumoto, M. Terasawa, T. Imayoshi
(Yoshitomi Pharmaceutical Industries Ltd), USP 4728644,
1988.
9-(4-Chlorophenyl)-6-(piperidin-1-yl)-9H-purine (6j): Yield:
0.39 mmol, 78% from the reaction of imidazole 7g and acetal 2.
1
M.p. 149–150 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.59 (s, 1
H), 8.27 (s, 1 H), 7.92 (d, J = 6.6 Hz, 2 H), 7.66 (d, J = 6.6 Hz, 4
H), 4.23 (br. s, 2 H), 1.68 (m, 2 H), 1.59 (m, 4 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 153.3, 152.6, 150.1, 138.3, 133.8, 131.8,
129.4, 124.9, 119.4, 45.8, 25.7, 24.3 ppm. IR (nujol mull): ν = 1660,
˜
1578, 1550, 1520, 1500 cm–1. C16H16ClN5 (313.79): calcd. C 61.24,
H 5.14, N 22.32; found C 61.12, H 5.19, N 22.29.
9-(4-Methoxyphenyl)-N,N-dimethyladenine (6k): Yield: 0.48 mmol,
74% from the reaction of imidazole 7h and acetal 2. M.p. 165 °C
(dec.). 1H NMR (300 MHz, [D6]DMSO): δ = 8.45 (s, 1 H), 8.23 (s,
1 H), 7.71 (d, J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 3.82 (s,
3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 158.6, 154.5,
152.3, 150.1, 138.7, 127.9, 125.1, 119.6, 114.6, 55.5, 38.0 ppm. IR
[11] a) D. B. R. Johnston, M. MacCross, S. Marburg, L. C. Meurer,
R. L. Tolman (Merck & Co., Inc.), USP 5057517, 1991; b)
D. A. Griffith (Pfizer, Inc.), USP 7129239, 2006.
[12] D. J. Cavalla, M. Chasin, P. Hofer, A. Gehriq, P. Winterqerst
(Euro-Celtique S.A), USP 6294541, 2001.
[13] For recent reviews, see: a) M. K. Lakshman, J. Organomet.
Chem. 2002, 653, 234–251; b) M. Hocek, Eur. J. Org. Chem.
2003, 245–254. For representative references, see: c) H. Zhang,
R. F. Schinazi, C. K. Chu, Bioorg. Med. Chem. 2006, 14, 8314–
8322; d) C. K. L. Gilbert, C. R. Lisek, R. L. White, G. Gum-
ina, Tetrahedron 2005, 61, 8339–8350; e) Y. Choi, C. George,
P. Strazewski, V. E. Marquez, Org. Lett. 2002, 4, 589–592; f)
O. Botta, E. Moyround, C. Lobato, P. Strazewski, Tetrahedron
1998, 54, 13529–13546; g) J. Barends, J. B. Linden, F. L. Delft,
G. J. Koomen, Nucleosides Nucleotides 1999, 18, 2121–2126.
[14] M. J. Alves, B. L. Booth, A. P. Freitas, M. F. Proença, J. Chem.
Soc. Perkin Trans. 1 1992, 913–917.
(nujol mull): ν = 1597, 1556, 1520, 1484 cm–1. C H N O (269.31):
˜
14 15
5
calcd. C 62.44, H 5.61, N 26.00; found C 62.47, H 5.62, N 25.98.
9-(4-Tolyl)-N,N-dimethyladenine (6l): Yield: 0.85 mmol, 84% from
the reaction of imidazole 7 and acetal 2. M.p. 162–163 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 8.52 (s, 1 H), 8.25 (s, 1 H), 7.72
(d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 3.50 (br. s, 6 H),
2.38 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.4,
152.3, 149.9, 138.5, 137.0, 132.5, 129.8, 123.1, 119.7, 37.9,
20.6 ppm. IR (nujol mull): ν = 1600, 1556, 1520 cm–1. C H N
˜
14 15
5
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