Novel Acyclic Nucleoside Phosphonates
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General Procedure for the Synthesis of Diisopropyl 2-(6-Chloropurin-
9-yl)ethoxyphenylphosphonates 4 by the Mitsunobu Reaction: Di-
isopropyl azadicarboxylate (DIAD, 1.6 mL, 8.4 mmol) was added
slowly to a solution of triphenyphosphane (2.36 g, 9 mmol) in dry
THF (30 mL) cooled to –20 °C under argon. The mixture was
stirred for 30 min and this preformed complex was added to the
reaction mixture containing 6-chloropurine (1.02 g, 6.6 mmol), dry
THF (20 mL) and diisopropyl [(2-hydroxyethoxy)phenyl]phos-
phonate 3 (3 mmol) at –40 °C under argon. The resulting mixture
was slowly warmed to room temperature and stirred overnight. The
solvent was evaporated and the crude mixture was purified by
chromatography on silica gel (0–5% MeOH in CHCl3).
ylphosphonate (o-3), yield 0.67 g, 49%. H NMR ([D6]DMSO): δ
= 8.35 (s, 1 H, 8-H), 7.84 (m, 1 H, Ar), 7.71 (s, 1 H, Ar), 7.13 (s,
1 H, Ar), 7.07 (m, 1 H, Ar), 6.93 (s, 2 H, NH2), 4.52 (m, 2 H, iPr),
4.43 (t, J = 5.3 Hz, 2 H, 1Ј-H), 4.42 (t, J = 5.0 Hz, 2 H, 2Ј-H), 1.24
(d, J = 6.1 Hz, 6 H, iPr), 1.10 (d, J = 6.1 Hz, 6 H, iPr) ppm. 13C
NMR ([D6]DMSO): δ = 159.58 (C-2), 159.27 [d, J(P,C) = 2.2 Hz,
O-Ar], 153.89 (C-4), 149.13 (C-6), 143.73 (C-8), 132.62 [d, J(P,C)
= 9.6 Hz, Ar], 128.48 [d, J(P,C) = 12.0 Hz, Ar], 123.03 (C-5), 120.54
[d, J(P,C) = 14.0 Hz, Ar], 117.68 [d, J(P,C) = 184.6 Hz, P-Ar],
112.43 [d, J(P,C) = 8.8 Hz, Ar], 69.77 [d, J(P,C) = 5.5 Hz, 2 C, iPr],
66.03 (C-2Ј), 42.27 (C-1Ј), 23.38 [dd, J(P,C) = 32.7, 4.0 Hz, 4 C,
iPr] ppm. MS (ESI): m/z = 454 [M + H]+.
Diisopropyl 2-[2-(6-Chloropurin-9-yl)ethoxy]phenylphosphonate (o-
4): Starting from diisopropyl 2-[(2-hydroxyethoxy)phenyl]phos-
phonate (o-3), yield 0.64 g, 49%. H NMR ([D6]DMSO): δ = 8.93
Diisopropyl
3-[2-(2-Amino-6-chloropurin-9-yl)ethoxy]phenylphos-
phonate (m-5): Starting from diisopropyl 3-(2-hydroxyethoxy)phen-
ylphosphonate (m-3), yield 0.69 g, 51%. H NMR ([D6]DMSO): δ
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(s, 1 H, 2-H), 8.81 (s, 1 H, 8-H), 7.69 (m, 1 H, Ar), 7.56 (m, 1 H,
Ar), 7.14 (m, 1 H, Ar), 7.06 (m, 1 H, Ar), 4.71 (t, J = 4.9 Hz, 2 H,
1Ј-H), 4.50 (m, 4 H, iPr, 2Ј-H), 1.21 (d, J = 6.2 Hz, 6 H, iPr), 1.06
(d, J = 6.2 Hz, 6 H, iPr) ppm. 13C NMR ([D6]DMSO): δ = 159.18
[d, J(P,C) = 2.3 Hz, O-Ar], 151.82 (C-4), 151.31 (C-2), 148.75 (C-
6), 148.01 (C-8), 134.20 (m, 2 C, Ar), 130.55 (C-5), 120.61 [d, J(P,C)
= 14.0 Hz, Ar], 117.62 [d, J(P,C) = 184.2 Hz, P-Ar], 112.43 [d,
J(P,C) = 8.9 Hz, Ar], 69.74 [d, J(P,C) = 5.5 Hz, 2 C, iPr), 65.95 (C-
2Ј), 43.05 (C-1Ј), 23.35 [dd, J(P,C) = 35.1, 4.4 Hz, 4 C, iPr] ppm.
MS (ESI): m/z = 439 [M + H]+.
= 8.20 (s, 1 H, 8-H), 7.43 (m, 1 H, Ar), 7.23 (s, 1 H, Ar), 7.21 (m,
2 H, Ar), 6.97 (s, 2 H, NH2), 4.52 (m, 2 H, iPr), 4.45 (t, J = 5.3 Hz,
2 H, 1Ј-H), 4.38 (t, J = 5.0 Hz, 2 H, 2Ј-H), 1.26 (d, J = 6.2 Hz, 6
H, iPr), 1.14 (d, J = 6.2 Hz, 6 H, iPr) ppm. 13C NMR ([D6]DMSO):
δ = 159.67 (C-2), 157.53 [d, J(P,C) = 1.9 Hz, O-Ar], 154.02 (C-4),
149.21 (C-6), 143.31 (C-8), 131.21 [d, J(P,C) = 185.0 Hz, P-Ar],
129.98 [d, J(P,C) = 16.8 Hz, Ar], 123.66 [d, J(P,C) = 8.9 Hz, Ar],
123.08 (C-5), 118.42 [d, J(P,C) = 3.0 Hz, Ar], 116.83 [d, J(P,C) =
11.2 Hz, Ar], 70.10 [d, J(P,C) = 5.5 Hz, 2 C, iPr], 65.43 (C-2Ј),
42.23 (C-1Ј), 23.48 [dd, J(P,C) = 17.2, 4.0 Hz, 4 C, iPr] ppm. MS
(ESI): m/z = 454 [M + H]+.
Diisopropyl 3-[2-(6-Chloropurin-9-yl)ethoxy]phenylphosphonate (m-
4): Starting from diisopropyl 3-(2-hydroxyethoxy)phenylphos-
phonate (m-3), yield 1.16 g, 88%. 1H NMR ([D6]DMSO): δ = 8.80
(s, 1 H, 2-H), 8.79 (s, 1 H, 8-H), 7.40 (m, 1 H, Ar), 7.24 (m, 1 H,
Ar), 7.14 (m, 2 H, Ar), 4.72 (t, J = 5.1 Hz, 2 H, 1Ј-H), 4.48 (m, 4
H, iPr, 2Ј-H), 1.25 (d, J = 6.2 Hz, 6 H, iPr), 1.13 (d, J = 6.2 Hz, 6
H, iPr) ppm. 13C NMR ([D6]DMSO): δ = 157.46 [d, J(P,C) =
18.8 Hz, O-Ar], 151.93 (C-4), 151.38 (C-2), 148.84 (C-6), 147.68
(C-8), 131.19 [d, J(P,C) = 185.0 Hz, P-Ar], 130.60 (C-5), 129.92 [d,
J(P,C) = 16.9 Hz, Ar], 123.66 [d, J(P,C) = 8.9 Hz, Ar], 118.21 [d,
J(P,C) = 3.0 Hz, Ar], 116.93 [d, J(P,C) = 11.0 Hz, Ar], 70.06 [d,
J(P,C) = 5.5 Hz, 2 C, iPr], 65.60 (C-2Ј), 43.16 (C-1Ј), 23.47 [dd,
J(P,C) = 17.5, 3.9 Hz, 4 C, iPr] ppm. MS (ESI): m/z = 439 [M +
H]+.
Diisopropyl
4-[2-(2-Amino-6-chloropurin-9-yl)ethoxy]phenylphos-
phonate (p-5): Starting from diisopropyl 4-(2-hydroxyethoxy)phen-
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ylphosphonate (p-3), yield 0.61 g, 45%. H NMR ([D6]DMSO): δ
= 8.18 (s, 1 H, 8-H), 7.60 (dd, J = 12.6, 8.8 Hz, 2 H, Ar), 7.05 (dd,
J = 8.8, 3.2 Hz, 2 H, Ar), 6.95 (s, 2 H, NH2), 4.46 (m, 4 H, iPr, 1Ј-
H), 4.40 (t, J = 5.0 Hz, 2 H, 2Ј-H), 1.25 (d, J = 6.2 Hz, 6 H, iPr),
1.13 (d, J = 6.2 Hz, 6 H, iPr) ppm. 13C NMR ([D6]DMSO): δ =
160.64 [d, J(P,C) = 3.4 Hz, O-Ar], 159.64 (C-2), 153.99 (C-4),
149.21 (C-6), 143.25 (C-8), 133.08 [d, 2 C, J(P,C) = 11.1 Hz, Ar],
123.08 (C-5), 121.54 [d, J(P,C) = 192.3 Hz, P-Ar], 114.45 [d, J(P,C)
= 15.5 Hz, 2 C, Ar], 69.65 [d, J(P,C) = 5.5 Hz, 2 C, iPr], 65.31 (C-
2Ј), 42.24 (C-1Ј), 23.48 [dd, J(P,C) = 16.4, 3.9 Hz, 4 C, iPr] ppm.
MS (ESI): m/z = 454 [M + H]+.
Diisopropyl 4-[2-(6-Chloropurin-9-yl)ethoxy]phenylphosphonate (p-
4): Starting from diisopropyl 4-(2-hydroxyethoxy)phenylphos-
General Procedure for the Synthesis of 2-(6-Chloropurin-9-yl)-
ethoxyphenylphosphonic Acids 6a–8a: A mixture of diisopropyl es-
ter 4 (440 mg, 1 mmol), acetonitrile (10 mL), BrSiMe3 (0.5 mL) and
2,6-lutidine (0.4 mL) was stirred overnight at room temperature.
After evaporation and co-distillation with acetonitrile (5ϫ), the res-
idue was treated with aqueous methanol (2:1, 20 mL) for 0.5 h,
evaporated and co-distilled with water. The residue was purified by
preparative HPLC (water/methanol) and the product was obtained
as a white solid.
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phonate (p-3), yield 1.06 g, 81%. H NMR ([D6]DMSO): δ = 8.80
(s, 1 H, 2-H), 8.77 (s, 1 H, 8-H), 7.58 (dd, 2 H, Ar), 7.02 (dd, 2 H,
Ar), 4.73 (t, J = 5.1 Hz, 2 H, 1Ј-H), 4.49 (t, J = 5.4 Hz, 2 H, 2Ј-
H), 4.46 (m, 2 H, iPr), 1.24 (d, J = 6.2 Hz, 6 H, iPr), 1.12 (d, J = 6.2
Hz, 6 H, iPr) ppm. 13C NMR ([D6]DMSO): δ = 160.61 [d, J(P,C) =
3.3 Hz, O-Ar], 151.96 (C-4), 151.44 (C-2), 148.90 (C-6), 147.65 (C-
8), 133.08 [d, J(P,C) = 11.2 Hz, 2 C, Ar], 130.65 (C-5), 121.61 [d,
J(P,C) = 192.2 Hz, P-Ar], 114.51 [d, J(P,C) = 15.5 Hz, 2 C, Ar],
69.70 [d, J(P,C) = 5.5 Hz, 2 C, iPr], 65.46 (C-2Ј), 43.14 (C-1Ј), 23.52
[dd, J(P,C) = 16.9, 3.9 Hz, 4 C, iPr] ppm. MS (ESI): m/z = 439 [M
+ H]+.
2-[2-(6-Chloropurin-9-yl)ethoxy]phenylphosphonic Acid (6a): Start-
ing from diisopropyl 2-[2-(6-chloropurin-9-yl)ethoxy]phenylphos-
phonate (o-4), yield 236 mg, 65%. 1H NMR ([D6]DMSO): δ = 9.07
(s, 1 H, 2-H), 8.80 (s, 1 H, 8-H), 7.65 (m, 1 H, Ar), 7.44 (m, 1 H,
Ar), 7.01 (m, 2 H, Ar), 4.73 (t, J = 4.8 Hz, 2 H, 1Ј-H), 4.38 (t, J =
4.8 Hz, 2 H, 2Ј-H) ppm. 13C NMR ([D6]DMSO): δ = 158.93 [d,
J(P,C) = 2.1 Hz, O-Ar], 151.75 (C-4), 151.19 (C-2), 148.60 (C-6),
148.52 (C-8), 133.02 [d, J(P,C) = 6.8 Hz, Ar], 132.71 [d, J(P,C) =
1.7 Hz, Ar], 130.46 (C-5), 121.87 [d, J(P,C) = 178.8 Hz, P-Ar],
120.22 [d, J(P,C) = 13.5 Hz, Ar], 111.96 [d, J(P,C) = 8.3 Hz, Ar],
66.23 (C-2Ј), 42.91 (C-1Ј) ppm. MS (ESI–): m/z = 353 [M – H]–.
C13H12ClN4O4P·½H2O (363.69): calcd. C 42.93, H 3.60, N 15.40;
found C 43.04, H 3.63, N 15.32.
General Procedure for the Synthesis of Diisopropyl 2-(2-Amino-6-
chloropurin-9-yl)ethoxyphenylphosphonates 5 by the Mitsunobu Re-
action: Starting from 2-amino-6-chloropurine, the procedure used
was identical to that described above for 6-chloropurine, except that
after stirring the reaction mixture overnight, water (20 mL) was
added and the mixture was heated at 60 °C for 20 h. The solvent
was then evaporated and the crude mixture was purified by
chromatography on silica gel (0–7% MeOH in CHCl3).
Diisopropyl
2-[2-(2-Amino-6-chloropurin-9-yl)ethoxy]phenylphos-
phonate (o-5): Starting from diisopropyl 2-(2-hydroxyethoxy)phen-
Eur. J. Org. Chem. 2010, 2885–2892
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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