1-substituted 2′-deoxyinosine analogues

Article abstract of DOI:10.1039/a700987i

The base 2-carbon of 2′,3′-di-O-acetyl-2′-deoxyinosine is strongly activated towards nucleophilic attack when either the 4-nitrophenyl or 2,4-dinitrophenyl group is attached to its N-1 position (product 1 or 2). 1-(ω-Aminoalkyl)- and 1-(ω-hydroxyalkyl)-2′

Full text of DOI:10.1039/a700987i

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1-Substituted 2Ј-deoxyinosine analogues
Lorenzo De Napoli, Anna Messere, Daniela Montesarchio, Gennaro Piccialli*
and Michela Varra
Dipartimento di Chimica Organica e Biologica, Università di Napoli ‘Federico II’,
Via Mezzocannone 16, I-80134 Napoli, Italy
The base 2-carbon of 2Ј,3Ј-di-O-acetyl-2Ј-deoxyinosine is strongly activated towards nucleophilic attack
when either the 4-nitrophenyl or 2,4-dinitrophenyl group is attached to its N -1 position (product 1 or 2).
1-(ù-Aminoalkyl)- and 1-(ù-hydroxyalkyl)-2Ј-deoxyinosine derivatives 5, 8–10 have been efficiently
synthesized by a rearrangement of the purine ring upon treatment of compound 1 or 2 with the
appropriate á,ù-diamine or á,ù-hydroxyamine. M oreover 1-amino-2Ј-deoxyinosine 11 and
1-hydroxy-2Ј-deoxyinosine 13 have been easily prepared in high yields by reaction of substrate
1 or 2, respectively, with hydrazine or hydroxylamine.
Introduction
O2N
R
N
O2N
R
O
N
O
N
It is well known that alkaline treatment of 1-substituted
hypoxanthine nucleosides causes a ring-opening reaction at
the 2-carbon to give 5-aminoimidazole-4-carboxamide ribo-
side (AICAR)1 or 2Ј-deoxyriboside (AICA-2ЈdR, 7).2 Our
previous studies3 showed that when a strongly electron-
withdrawing group (such as 4-nitrophenyl) was attached to the
1-nitrogen atom of the hypoxanthine ring, the 2-carbon
became electrophilic enough to react with aminic nucleophiles
(XNH2, Scheme 1) leading to a fast ring reclosure of the
formamidine intermediate 3, favoured by the loss of 4-
nitroaniline as the leaving group, to give the inosine derivative
4. Following this route 2Ј-deoxy-[1-15N]inosine and some 1-alkyl
derivatives of 2Ј-deoxyinosine3,4 were efficiently synthesized
by reaction of 3Ј,5Ј-di-O-acetyl-2Ј-deoxy-1-(4-nitrophenyl)-
inosine 1 respectively with 15NH4OH and amines. We reasoned
that this strategy could provide an easy and profitable two-
step access to 1-(ω-hydroxyalkyl)purine nucleosides5 and
particularly to 1-(ω-aminoalkyl) derivatives, the preparation
of which is otherwise not obvious. Among their possible
applications in nucleoside chemistry, such substrates,
incorporated into an oligonucleotide chain, can be used for a
specific post-synthetic conjugation with labels (for example
intercalators, photoreactive or cleaving agents). Several
methods are available in the literature to derivatize pyrimidine
nucleotides with such linker arms.6 On the other hand, few
syntheses concerning this kind of modification of purine
nucleosides (i.e., essentially alkylations of exocyclic amino
functions) have been described;6 this is probably due both to
the limited nucleophilicity of the exocyclic amino groups of
adenine and guanine and to the reduced stability of the N-
glycosidic bond in N-alkylated purines. With the aim of intro-
ducing linker units easily and in high yields at the 1-position
of purines, we herein explore the reactivity of 1-(4-nitro-
phenyl)- and 1-(2,4-dinitrophenyl)-2Ј-deoxyinosine derivatives
1, 2 towards a number of binucleophilic amino compounds
(a–f, Table 1).
H
N
N
N
N
N
HN
X
C
H
R1
R1
XNH2
1, 2
3
NO2
O
X
N
N
N
R
N
R1
NH2
4
1 R = H
2 R = NO2
R1 = 3,5-di-O-acetyl-2-deoxy-β--ribofuranosyl
Scheme 1
sponding 1-substituted compounds 8–10, Scheme 2) in high
yields. In the case of ethylenediamine a, different results were
obtained depending on whether compounds 1 or 2 were used
as the starting material. Compound 1, with ethylenediamine,
furnished a mixture of the target compound 5 (70%) and 5-
amino-1-(2Ј-deoxy-β--ribofuranosyl)imidazole-4-[N-(4-nitro-
phenyl)]carboxamide 63 (21%) as side product. The formation
of compound 6 can be ascribed to the degradation of the form-
amidine group of intermediate 3 by aminolysis. On the other
hand, treatment of compound 2 with ethylenediamine under
the same conditions gave AICA-2ЈdR 7 in almost quantitative
yield and with only traces of the cyclization product 5. A simi-
lar result was observed even when compound 2 was treated with
an equimolar amount of ethylenediamine in DMF solution
giving a mixture of mono- and di-acetyl derivatives of com-
pound 7. Such behaviour for substrate 2 could be explained
by hypothesizing in intermediate 3 (X = CH2CH2NH2) a fast
intramolecular nucleophilic attack of the primary amino func-
tion on the more reactive 1-carbon of the 2,4-dinitrophenyl
ring. This hypothetical reaction mechanism, involving an 11-
membered ring intermediate, seemed plausible also in the light
of the different behaviour shown by 1,6-diaminohexane b,
which with substrate 1, as well as with dinitro derivative 2,
yielded only the cyclization product 8.
The starting substrates 1 and 2 were obtained by treatment of
3Ј,5Ј-di-O-acetyl-2Ј-deoxyinosine (4; X = H) with 2.5 mol equiv.
of 4-nitrofluorobenzene or 2,4-dinitrochlorobenzene, respect-
ively, together with K2CO3 (2.5 mol equiv.) in dimethylform-
amide (DMF). Purification by silica gel chromatography
afforded the desired compounds in 92 and 91% yield, respect-
ively. Product 2 was obtained as a 1:1 mixture of atropisomers.7
The reactions of compounds 1 and 2 with α,ω-diamines a, b
and with α,ω-hydroxyamines c, d are summarized in Table 1.
Particularly, treatment with 1,6-diaminohexane b, ethanol-
amine c or 5-aminopentan-1-ol d gave the expected corre-
It is to be noted that this is a more convenient synthesis of
AICA-2ЈdR (overall yield 78% starting from 2Ј-deoxyinosine)
with respect to that already reported in the literature.2
J. Chem. Soc., Perkin Trans. 1, 1997
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Table 1 Reactions of substrates 1 and 2 with nucleophiles a–f
Nucleophiles
Substrates
Products
Yield (%)
Reaction conditions
a NH2[CH2]2NH2
b NH2[CH2]6NH2
c NH2[CH2]2OH
d NH2[CH2]5OH
e NH2NH2
1
2
1
2
1
2
1
2
1
2
1
2
5 and 6
7
8
8
9
9
10
10
11 and 12
11 and 12
6
13
70 and 21
94
92
80
90
88
92
90
a neat, 4 h, 50 ЊC
a neat, 2 h, 50 ЊC
b (10 mol equiv.), DMF, 4 h, 50 ЊC
b (10 mol equiv.), DMF, 3 h, 50 ЊC
c neat, 4 h, 50 ЊC
c neat, 2 h, room temp.
d neat, 4 h, 50 ЊC
d neat, 4 h, 50 ЊC
e (50% aq.), 14 h, 50 ЊC
e (50% aq.), 4 h, 50 ЊC
75 and 23
75 and 23
25
f NH2OH
f (10 mol equiv.), DMF–EtOH, KOH (10 mol equiv.), 4 h, 80 ЊC
f (10 mol equiv.), DMF–EtOH, KOH (10 mol equiv.), 4 h, 80 ЊC
75
O2N
O
O
O
H2N[CH2]2
N
N
N
N
N
N
H
H2N
N
N
N
H2N
H2N
R2
R2
R2
5
6
7
i
ii
O
N
O
O
N
H2N[CH2]6
Ar
N
HO[CH2]n
N
iii
N
N
iv
N
N
N
N
N
N
R2
R1
R2
1, 2
8
9 n = 2
10 n = 5
vi
v
O
N
O
NH2NH
H2N
O
H2N
HO
N
N
N
N
N
N
N
N
N
R2
R2
R2
11
12
13
1 Ar = 4-nitrophenyl
2 Ar = 2,4-dinitrophenyl
R2 = 2-deoxy-β--ribofuranosyl
R1 = 3,5-di-O-acetyl-2-deoxy-β--ribofuranosyl
Scheme 2 Reagents: i, a on 1; ii, a on 2; iii, b; iv, c or d; v, e; vi, f on 2
The reactivity of compounds 1 and 2 with hydrazine e and
hydroxylamine f was investigated in the expectation of the
formation of 1-amino and 1-hydroxy derivatives, respectively.
With hydrazine (50% aq.), substrate 1 or 2 gave in both cases
a mixture of 1-amino-2Ј-deoxyinosine 11 (75%) and the
hydrazide derivative 12 (23%). For product 11 we excluded the
other possible structure containing a seven-membered ring on
the basis of literature data, which reported a higher stability for
the 1-aminohypoxanthine ring,8 and spectroscopic evidence. In
the 1H NMR spectrum ([2H6]DMSO) the presence of a singlet
at δ 5.82 (2 H, exchangeable in D2O) is diagnostic for the exo-
cyclic 1-amino function. The formation of compound 12 as a
by-product can be explained by hydrazinolysis8 of amide 6 (or
its 2,4-dinitrophenyl analogue) or of carboxamide 7. Treatment
of compound 2 with hydroxylamine hydrochloride f dissolved
in EtOH–DMF in the presence of KOH produced a mixture of
2Ј-deoxy-1-hydroxyinosine 13 and its 3Ј,5Ј-di-O-acetyl and
monoacetyl derivatives, which were then converted into com-
pound 13 by deprotection with NH4OH (75% overall yield). On
the other hand, the same reaction, when performed on mono-
nitrophenyl substrate 1, led to a complex mixture in which the
main product was identified as 6 (25 %).
It is noteworthy that this route to 11 and 13 is a valuable
alternative to that already reported for 1-amino-9 and 1-hydroxy-
derivatives10 of hypoxanthine nucleosides.
In all the above reactions leading to 1-substituted purine
nucleosides, 4-nitroaniline (or 2,4-dinitroaniline) was isolated in
an equimolar ratio with respect to the cyclization product, con-
firming the proposed purinic rearrangement pathway.
Experimental
General
TLC plates (Merck, silica gel 60, F254) were developed in one
of several solvent systems: A [CHCl3–MeOH (95:5, v/v)]; B
[CHCl3–MeOH (7:3, v/v)]; C [ethyl acetate–acetone–water
2080
J. Chem. Soc., Perkin Trans. 1, 1997

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(5:10:1, v/v)]; D [butan-1-ol–acetic acid–water (60:15:25,
v/v)]. Column chromatography was performed on silica gel
(Merck, Kieselgel 60, 0.063–0.200 mm). The 1H and 13C NMR
spectra were recorded on a Bruker WM 270 instrument (270
MHz); J-Values are given in Hz. Fast-atom bombardment
(FAB) mass spectra (positive) were determined on a ZAB 2SE
spectrometer. UV spectra were taken on a Perkin-Elmer
lambda 7 spectrophotometer. Mps were determined on a
Reichert Thermovar apparatus and are uncorrected. Optical
rotations were measured with a Perkin-Elmer 141 polarimeter at
1-(6-Aminohexyl)-2Ј-deoxyinosine 8
Compound 1 (200 mg, 0.44 mmol) [or 2 (200 mg, 0.40 mmol)]
was treated in DMF (3 cm3) with 1,6-diaminohexane (510 mg,
4.4 mmol) and the mixture was heated at 50 ЊC for 4 h (3 h for
compound 2). The solution, dried in vacuo, was chromato-
graphed on a silica gel column (3 × 50 cm) eluted with increas-
ing amounts of MeOH in CHCl3 (from 0 to 25%) to give pure
title compound 8 (150 mg, 92%; or 80% starting from 2); Rf 0.15
(system B); mp 112–118 ЊC (amorphous solid) (Found: C,
54.81; H, 7.26; N, 20.05. C16H25N5O4 requires C, 54.69; H, 7.17;
N, 19.93%); λmax(MeOH)/nm 251 (12 900) and 267 (11 400);
m/z (FAB) 352 (MHϩ); [α]D Ϫ8.0 (c 0.04, MeOH); δH (CD3OD)
8.31 (2 H, br s, 2- and 8-H), 6.42 (1 H, dd, J 7.2 and 7.2, 1Ј-H),
4.56 (1 H, m, 3Ј-H), 4.10 (2 H, t, J 7.6, 1-CH2), 4.03 (1 H, m, 4Ј-
H), 3.76 (2 H, m, 5Ј-H2), 2.72 (1 H, m, 2Ј-Ha), 2.61 (2 H, t, J 6.7,
CH2NH2), 2.47 (1 H, m, 2Ј-Hb) and 1.55–1.30 (8 H, complex
signal, 4 × CH2); δC(CD3OD) 158.6 (C-6), 149.8 (C-2), 148.9
(C-4), 141.3 (C-8), 125.2 (C-5), 89.9 (C-4Ј), 86.7 (C-1Ј), 73.0
(C-3Ј), 63.6 (C-5Ј), (1-CH2, submerged by the solvent signal),
42.7 and 42.1 (C-2Ј and CH2NH2) and 34.0, 31.0, 27.8 and
27.7 (4 × CH2).
25 ЊC and are quoted in units of 10Ϫ1 deg cm2 gϪ1
.
3Ј,5Ј-Di-O-acetyl-2Ј-deoxy-1-(2,4-dinitrophenyl)inosine 2
A mixture of 3Ј,5Ј-di-O-acetyl-2Ј-deoxyinosine (336 mg, 1
mmol), 2,4-dinitrochlorobenzene (577 mg, 2.5 mmol) and
K2CO3 (345 mg, 2.5 mmol) was suspended in stirred, anhydrous
DMF (5 cm3) at 80 ЊC for 2.5 h. After cooling, the mixture was
filtered and the solid was washed with CHCl3. The filtrates and
washings, evaporated to dryness in vacuo, were purified on a
silica gel column (3 × 50 cm) eluted with increasing amounts of
MeOH in CHCl3 (from 0 to 4%) to give title compound 2 as a
diastereoisomeric mixture (456 mg, 91%); Rf 0.5 (system A);
mp 192–194 ЊC (from MeOH) (Found: C, 47.95; H, 3.71; N,
2Ј-Deoxy-1-(2-hydroxyethyl)inosine 9
16.70. C20H18N6O10 requires C, 47.81; H, 3.61; N, 16.73%); λmax
-
Compound 1 (200 mg, 0.44 mmol) [or 2 (200 mg, 0.40 mmol)]
was treated with 2 cm3 of ethanolamine and the mixture was
heated at 50 ЊC for 4 h (2 h at room temp. for compound 2).
The solution, dried in vacuo, was purified on silica gel plates
(20 × 20 cm, 0.5 mm), developed in eluent system B. The band
at Rf 0.40, scratched from the plates and eluted with CHCl3–
MeOH (1:1, v/v), afforded pure title compound 9 (117 mg,
90%; or 88% starting from 2), mp 172–175 ЊC (from MeOH)
(Found: C, 48.70; H, 5.59; N, 19.06. C12H16N4O5 requires C,
48.65; H, 5.44; N, 18.91%); λmax(water)/nm 247 (10 400) and
267sh (5300); m/z (FAB) 297 (MHϩ); [α]D Ϫ16.2 (c 0.07, water);
δH (D2O) 8.32 and 8.28 (1 H each, ss, 2- and 8-H), 6.44 (1 H,
dd, J 6.5 and 6.5, 1Ј-H), 4.64 (1 H, m, 3Ј-H), 2.25 (2 H, t, J 5.1,
1-CH2), 4.15 (1 H, m, 4Ј-H), 3.89 (2 H, t, J 5.1, CH2OH), 3.80 (2
H, m, 5Ј-H2), 2.82 (1 H, m, 2Ј-Ha) and 2.58 (1 H, m, 2Ј-Hb); δC-
([2H6]DMSO) 156.0 (C-6), 149.0 (C-2), 147.3 (C-4), 139.0 (C-8),
123.8 (C-5), 88.0 (C-4Ј), 83.7 (C-1Ј), 70.8 (C-3Ј), 61.7 (C-5Ј),
58.5 (CH2OH) and 48.0 (1-CH2) (signal for C-2Ј submerged by
the solvent signal).
(CHCl3)/nm 248 (ε/dm3 molϪ1 cmϪ1 20 100); m/z (FAB) 503
(MHϩ); [α]D 2.8 (c 0.05, CHCl3); δH (CDCl3) 9.06 (1 H, ss, 3-H
phenyl), 8.68 (1 H, ds, 5-H nitrophenyl), 8.03, 8.04, 8.04 and
8.05 (2 H, ss, 2- and 8-H), 7.72 (1 H, ss, 6-H nitrophenyl), 6.40
(1 H, m, 1Ј-H), 5.42 (1 H, m, 3Ј-H), 4.40 (3 H, m, 4Ј-H and 5Ј-
H2), 3.07–2.63 (2 H, ms, 2Ј-H2) and 2.16 and 2.11 (3 H each, ss,
Ac); δC(CDCl3) 170.3 and 170.2 (CH3CO), 155.0 (C-6), 148.1,
147.1, 146.2 and 135.5 (quaternary carbons of dinitrophenyl
and C-4), 144.9 (C-2), 139.0 and 138.4 (C-8), 131.8, 128.8,
121.3 (CH dinitrophenyl), 124.2 and 124.3 (C-5), 85.1 and 84.6
(C-4Ј), 82.8 (C-1Ј), 74.2 (C-3Ј), 63.6 (C-5Ј) and 38.0 and 37.6
(C-2Ј).
Reaction of compound 1 with ethylenediamine: 1-(2-amino-
ethyl)-2Ј-deoxyinosine 5 and 63 5-amino-N-(4-nitrophenyl)-
imidazole-4-carboxamide
Compound 1 (250 mg, 0.55 mmol) was treated with 3 cm3 of
ethylenediamine and the mixture was heated at 50 ЊC for 4 h
and stirred. The resulting solution, dried in vacuo, was purified
on silica gel plates (20 × 20 cm, 0.5 mm), developed in eluent
system B. The bands at Rf 0.15 and 0.85, scratched from the
plates and eluted with CHCl3–MeOH (1:1, v/v) afforded com-
pounds 5 (162 mg, 70%) and 6 (42 mg, 21%), respectively.
Compound 5: mp 113–116 ЊC (amorphous solid) (Found: C,
48.73; H, 5.90; N, 23.85. C12H17N5O4 requires C, 48.81; H, 5.80;
N, 23.72%); λmax(MeOH)/nm 246 (7600), 251 (7700) and 256sh
(4300); m/z (FAB) 296 (MHϩ); [α]D Ϫ8.6 (c 0.06, water); δH -
(CD3OD) 8.32 and 8.30 (2 H, s, 2- and 8-H), 6.43 (1 H, dd, J 6.5
and 6.5, 1Ј-H), 4.58 (1 H, m, 3Ј-H), 4.17 (2 H, t, J 6.3, 1-CH2),
4.04 (1 H, m, 4Ј-H), 3.77 (2 H, m, 5Ј-H2), 3.01 (2 H, t, J 6.3,
CH2NH2), 2.75 (1 H, m, 2Ј-Ha) and 2.44 (1 H, m, 2Ј-Hb);
δC(D2O) 158.2 (C-6), 149.7 (C-2), 148.2 (C-4), 141.1 (C-8), 122.3
(C-5), 88.3 (C-4Ј), 85.4 (C-1Ј), 71.9 (C-3Ј), 62.4 (C-5Ј), 50.2
(1-CH2), 42.1 (C-2Ј) and 39.9 (CH2NH2).
2Ј-Deoxy-1-(5-hydroxypentyl)inosine 10
Compound 1 (200 mg, 0.44 mmol) [or 2 (150 mg, 0.30 mmol)]
was treated in DMF (3 cm3) with 5-aminopentan-1-ol (903 mg,
8.8 mmol) and the mixture was heated at 50 ЊC for 4 h (2 h at
room temp. for compound 2). The solution, dried in vacuo, was
purified on silica gel plates (20 × 20 cm, 0.5 mm), developed in
eluent system B. The band at Rf 0.35, scratched from the plates
and eluted with CHCl3–MeOH (1:1, v/v), afforded pure title
compound 10 (137 mg, 92%; or 88% starting from 2) which
could not be induced to crystallize (Found: C, 53.30; H, 6.60; N,
16.64. C15H22N4O5 requires C, 53.25; H, 6.55; N, 16.56%); λmax
-
(MeOH)/nm 246 (10 800), 250 (11 000) and 268sh (6300); m/z
(FAB) 339 (MHϩ); [α]D Ϫ11.3 (c 0.06, MeOH); δH (CD3OD)
8.32 (2 H, br s, 2- and 8-H), 6.42 (1 H, dd, J 6.6 and 6.6, 1Ј-H),
4.54 (1 H, m, 3Ј-H), 4.11 (2 H, t, J 5.5, 1-CH2), 4.02 (1 H, m,
4Ј-H), 3.77 (2 H, m, 5Ј-H2), 3.55 (2 H, t, J 5.5, CH2OH), 2.73
(1 H, m, 2Ј-Ha), 2.44 (1 H, m, 2Ј-Hb) and 1.89–1.38 (6 H, ms,
3 × CH2); δC(CD3OD) 159.2 (C-6), 150.4 (C-2), 149.8 (C-4),
141.9 (C-8), 126.3 (C-5), 90.5 (C-4Ј), 87.3 (C-1Ј), 73.6 (C-3Ј),
64.2 and 63.5 (C-5Ј and CH2OH), 48.6 (1-CH2), 42.6 (C-2Ј) and
34.0, 31.4 and 24.8 (3 × CH2).
Reaction of compound 2 with ethylenediamine
5-Amino-1-(2Ј-deoxy-â-D-ribofuranosyl)imidazole-4-
carboxamide 7 (AICA-2ЈdR). Compound 2 (250 mg, 0.50
mmol) was treated with ethylene diamine (2 cm3) and the mix-
ture was heated at 50 ЊC for 4 h. The mixture was dried in vacuo
and then chromatographed on a silica gel column (3 × 50 cm)
eluted with increasing amounts of MeOH in CHCl3 (from 10 to
30%) to give pure compound 7 (115 mg, 94%); Rf 0.45 (system
Reaction of substrate 1 or 2 with hydrazine; products 11 and 12
Compound 1 (150 mg, 0.33 mmol) [or 2 (150 mg, 0.30 mmol)]
was treated with 4 cm3 of hydrazine (50%, w/w) and the mixture
was heated at 50 ЊC for 14 h (4 h at room temp. for compound
2). The mixture, dried in vacuo, was purified on silica gel plates
B); mp 175–177 ЊC (MeOH–CHCl3; lit.,2a 177–178 ЊC); λmax
-
(water)/nm 267 (11 500); m/z (FAB) 243 (MHϩ); 1H NMR data
in agreement with lit. values.2a
J. Chem. Soc., Perkin Trans. 1, 1997
2081

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(20 × 20 cm, 0.5 mm), developed in eluent system B. The bands
at Rf 0.33 and 0.45, scratched from the plates and eluted with
CHCl3–MeOH (1:1, v/v), afforded pure products 11 (66 mg,
75%) and 12 (19 mg, 23%), respectively.
Acknowledgements
We are grateful to CNF and MURST for grants in support
of these investigations and to the ‘Centro di Metodologie
Chimico-Fisiche dell’ Universita’ di Napoli Federico II’ for
NMR facilities and to Istituto P.I.T.A.G.O.R.A., Napoli for the
stimulating cultural support. A. M. thanks ‘Istituto Superiore
di Sanita’ for a fellowship ‘Borse di Studio AIDS-Italia.’ We
are also indebted to Miss Rita Carolla for competent technical
assistance.
1-amino-2Ј-deoxyinosine 11, mp 189–191 ЊC (from MeOH)
(Found: C, 45.09; H, 4.97; N, 26.35. C10H13N5O4 requires C,
44.94; H, 4.90; N, 26.21%); λmax(MeOH)/nm 247 (8400) and
254sh (4800); m/z (FAB) 268 (MHϩ); [α]D Ϫ8.2 (c (0.03,
MeOH); δH ([2H6]DMSO) 8.38 and 8.31 (1 H each, ss, 2- and 8-
H), 6.30 (1 H, dd, J 6.0 and 6.0, 1Ј-H), 5.82 (2 H, s, exchange-
able in D2O, 1-NH2), 5.31 (1 H, d, exchangeable in D2O, 3Ј-
OH), 4.92 (1 H, t, exchangeable in D2O, 5Ј-OH), 4.39 (1 H, m,
3Ј-H), 3.88 (1 H, m, 4Ј-H), 3.56 (2 H, m, 5Ј-H2), 2.62 (1 H, m,
2Ј-Ha) and 2.31 (1 H, m, 2Ј-Hb); δC(CD3OD) 158.8 (C-6), 150.2
(C-2), 148.6 (C-4), 141.5 (C-8), 125.2 (C-5), 89.9 (C-4Ј), 86.6
(C-1Ј), 72.9 (C-3Ј), 63.5 (C-5Ј) and 42.0 (C-2Ј).
References
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5-Amino-1-(2Ј-deoxy-β--ribofuranosyl)imidazole-4-carb-
oxylic acid hydrazide 12, amorphous solid which could not be
induced to crystallize (Found: C, 42.15; H, 5.98; N, 27.30.
C9H15N5O4 requires C, 42.02; H, 5.88; N, 27.22%); λmax
-
(MeOH)/nm 268 (9500); m/z (FAB) 258 (MHϩ); [α]D Ϫ13.1
(c 0.065, MeOH); δH (CD3OD) 7.34 (1 H, s, 2-H), 6.00 (1 H, dd,
J 6.4 and 6.1, 1Ј-H), 4.50 (1 H, m, 3Ј-H), 3.95 (1 H, m, 4Ј-H),
3.74 (2 H, m, 5Ј-H2), 2.62 (1 H, m, 2Ј-Ha) and 2.26 (1 H, m, 2Ј-
Hb); δC(D2O) 166.7 (CO), 143.8 (C-5), 131.0 (C-2), 130.4 (C-4),
87.6 (C-4Ј), 84.8 (C-1Ј), 71.5 (C-3Ј), 62.1 (C-5Ј) and 39.1 (C-2Ј).
5 1-(ω-Hydroxyalkyl)hypoxanthine derivatives can be prepared from
1-(ω-hydroxyalkyl)adenine derivatives by a deamination process
(a) T. Fujii, T. Saito and N. Terahara, Chem. Pharm. Bull., 1986,
34, 1094; or by
hypoxanthines (b) A. Montgomery and H. J. Thomas, J. Org. Chem.,
1963, 28, 2304).
a 1-alkylation procedure for 9-substituted
Reaction of substrate 1 or 2 with hydroxylamine hydrochloride
2Ј-Deoxy-1-hydroxyinosine 13. To hydroxylamine hydro-
chloride (208 mg, 4.0 mmol), dissolved in EtOH (5 cm3) at
reflux, was added a solution of KOH (224 mg, 4 mmol) in
EtOH (2 cm3) and the mixture was kept at room temp. After 10
min a solution of compound 2 (200 mg, 0.4 mmol) in DMF
(5 cm3) was added and the mixture was heated at 80 ЊC for 4 h.
The mixture was dried in vacuo and then was treated with conc.
NH4OH (5 cm3) at room temperature. After 5 h the mixture was
dried, and purified on a silica gel column (3 × 60 cm) eluted
with increasing amounts of MeOH in CHCl3. The fractions
eluted with 40–50% of MeOH contained product 13 (Rf 0.25
system D) which was further purified by HPLC on a reversed-
phase C-18 column eluted with MeOH–water (2:3, v/v). The
appropriate fractions, dried in vacuo, afforded pure compound
13 (80 mg, 75%). The same reaction performed on substrate 1
furnished product 6 (36 mg, 25%), mp (MeOH) >170 ЊC
(decomp.). For compound 13 (Found: C, 44.60; H, 4.70; N,
6 J. L. Ruth, Oligonucleotides and Analogues; a Practical Approach,
ed. F. Eckstein, IRL Press, Oxford, 1991, pp. 255–281.
7 Molecular mechanics calculations confirmed the presence of an
energy barrier created by the interactions of the 2-nitro group with
the 6-O and 2-H atoms of the purine ring, hindering the complete
rotation of the 2,4-dinitrophenyl ring. The same results were
obtained when the corresponding 2-nitrophenyl derivative was
synthesized (data not shown).
8 P. Scheiner, S. Arwin, M. Eliacin and J. Tu, J. Heterocycl. Chem.,
1985, 22, 1435.
9 For example see: (a) A. D. Broom and R. K. Robins, J. Org. Chem.,
1969, 34, 1025; (b) G.-F. Huang, M. Maeda, T. Akamoto and
Y. Kawazoe, Tetrahedron, 1975, 31, 1363; (c) J. A. Montgomery and
H. J. Thomas, J. Med. Chem., 1972, 15, 1334.
10 For example see: (a) A. R. Katritzky and J. M. Lagowsky, Chemistry
of Heterocyclic N-Oxides, Academic Press, London, 1971; (b)
E. C. Taylor, C. C. Cheng and O. Vogl, J. Org. Chem., 1959, 24,
2019; (c) H. Siegel, Helv. Chim. Acta, 1965, 48, 433; (d)
J. C. Parham, J. Fissekis and G. B. Brown, J. Org. Chem., 1966, 31,
966; (e) Ref. 9c.
21.07. C10H12N4O5 requires C, 44.78; H, 4.51; N, 20.89%); λmax
-
(water)/nm 226 (8200), 252 (2000) and 289 (950); m/z FAB 269
(MHϩ); [α]D Ϫ113 (c 0.019, water); δH (D2O) 8.49 and 8.30 (1 H
each, ss, 2- and 8-H), 6.45 (1 H, dd, J 6.6 and 6.6, 1Ј-H), 4.69
(1 H, m, 3Ј-H), 4.20 (1 H, m, 4Ј-H), 3.83 (2 H, m, 5Ј-H2), 2.86
(1 H, m, 2Ј-Ha) and 2.61 (1 H, m, 2Ј-Hb); δC(water) 160.4 (C-6),
145.8 (C-2), 144.9 (C-4), 141.8 (C-8), 123.8 (C-5), 88.0 (C-4Ј),
85.2 (C-1Ј), 71.9 (C-3Ј), 62.3 (C-5Ј) and 39.6 (C-2Ј).
Paper 7/00987I
Received 11th February 1997
Accepted 27th March 1997
2082
J. Chem. Soc., Perkin Trans. 1, 1997