(dd, J 5 5.4, 4.6 Hz, 1H), 5.82 (br s, 2H), 5.93 (dd, J 5 5.4, 5.3 Hz, 1H),
6.18 (d, J 5 5.3 Hz, 1H), 7.97 (s, 1H), 8.37 (d, J 5 15.2 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): d 20.4, 20.5, 20.7, 63.1, 70.6, 73.2, 80.3, 86.2, 120.1 (d,
J 5 2.5 Hz), 138.9, 149.8 (d, J 5 3.0 Hz), 152.9 (d, J 5 2.0 Hz), 155.3 (d,
J 5 5.4 Hz), 169.4, 169.6, 170.3. 15N NMR (CDCl3, 30 MHz): d 2175.4
(10 M H15NO3 as the external reference). HRMS (FAB): calc. for
C16H20N415NO7 (M + H)+ 395.1333, found 395.1333.
§ General procedure for the preparation of 1-alkyladenosines: In a two-
necked flask, inosine 2a (1.00 mmol) was solved in CH3CN (12 mL). Then,
a solution of the alkylamine (1.00 mmol) in CH3CN (12 mL) was added via
cannula at 230 uC and stirring was continued until the starting nucleoside
was consumed, as determined by TLC analysis (typically 30 min).
Afterwards, water (8 mL) was added and the reaction mixture was heated
at reflux. When the consumption of the intermediate (around 40 min) was
completed, the resulting yellow solution was allowed to cool to room
temperature and concentrated in vacuo. The 1-alkyladenosine 4 was
isolated by flash chromatography (CH2Cl2–MeOH from 99:1 to 95:5).
Spectral data for 4a: 1H NMR (CDCl3, 400 MHz): d 2.09 (s, 3H), 2.12 (s,
6H), 4.30–4.43 (m, 3H), 5.26 (s, 2H), 5.61 (dd, J 5 5.5, 4.8 Hz, 1H), 5.86
(dd, J 5 5.5, 5.0 Hz, 1H), 6.00 (d, J 5 5.0 Hz, 1H), 7.30–7.36 (m, 5H), 7.73
(s, 1H), 7.74 (s, 1H). 13C NMR (CDCl3, 100 MHz): d 20.4, 20.5, 20.7, 49.9,
63.0, 70.4, 73.2, 80.1, 86.5, 124.4, 127.8, 128.0, 128.9, 136.0, 136.9, 141.3,
147.7, 154.5, 169.3, 169.5, 170.3. HRMS (FAB): calc. for C23H26N5O7
(M + H)+ 484.1832, found 484.1833.
1 S. R. Rajski and R. M. Williams, Chem. Rev., 1998, 98, 2723.
2 Chemistry of Nucleosides and Nucleotides, ed. L. B. Townsend, Plenum
Press, New York, 1988.
Scheme 7 Mechanism of formation of 1-alkyladenosine 4.
3 M. Roovers, J. Wouters, J. M. Bujnicki, C. Tricot, V. Stalon,
H. Grosjean and L. Droogmans, Nucleic Acids Res., 2004, 32, 465.
4 X. Ariza, V. Bou and J. Vilarrasa, J. Am. Chem. Soc., 1995, 117, 3665.
5 L. DeNapoli, A. Messere, D. Montesarchio, G. Piccialli and M. Varra,
J. Chem. Soc., Perkin Trans. 1, 1997, 2079.
6 Under these conditions the isomeric 6-O-sulfonylated product was not
observed.
7 Full assignment of 13C NMR signals was achieved by 2D NMR
experiments; particularly helpful was a HMBC correlation between C1
and the dinitrophenyl hydrogens.
8 M. Kainosho, Nat. Struct. Biol., 1997, 4, 858.
9 B. Catalanotti, L. De Napoli, A. Galeone, L. Mayol, G. Oliviero,
G. Piccialli and M. Varra, Eur. J. Org. Chem., 1999, 2235; L. De Napoli,
A. Messere, D. Montesarchio and G. Piccialli, J. Org. Chem., 1995, 60,
2251; L. De Napoli, A. Messere, D. Montesarchio, G. Piccialli,
C. Santacroce and M. Varra, J. Chem. Soc., Perkin Trans. 1, 1994, 923.
10 Compound 3a was compared to a sample prepared by acetylation of
adenosine: H. Bredereck, Chem. Ber., 1947, 80, 401.
11 The main byproduct is the desulfonylated inosine 1a (50% yield).
12 For an alternative preparation of [1-15N]adenosines using
[15N]benzylamine, see: X. Gao and R. A. Jones, J. Am. Chem. Soc.,
1995, 109, 1275; S. R. Sarfati and V. K. Kansal, Tetrahedron, 1988, 44,
6367.
Scheme 8 Synthesis of 1-alkylinosines.
In conclusion, the 2,4-dinitrobenzenesulfonyl group appears to
be a very interesting activating group since it allows an easy
transformation of inosines into 1-alkylinosines or into 1-alkylade-
nosines and [1-15N]adenosines (by a unique ANRORC rearrange-
ment). Currently, this method is being applied to the preparation
of novel 1-alkyladenosines that might be pharmacologically active
through their interaction with purine receptors.21
13 Direct formation of 1ar might arise from direct desulfonylation.
14 In the absence of H2O the cyclisation occurred in lower yields.
15 Compound 4a was chromatographically and spectroscopically identical
to a sample prepared by reaction of adenosine 3a with benzyl bromide
according to: P. Brookes, A. Dipple and P. D. Lawley, J. Chem. Soc.,
1968, 2026.
We are grateful to the Spanish MCYT (BQU2000-0647 and
BQU2003-04919) and to the Generalitat de Catalunya
(2001SGR051) for financial support.
16 T. Fujii and T. Itaya, Heterocycles, 1998, 48, 359.
17 Only when the reaction mixture was heated for a long time, small
amounts of 5a were formed.
Notes and references
{ General procedure for the preparation of [1-15N]adenosines: 15NH4Cl
(1.16 mmol) and KOH (1.05 mmol) were placed in a round-bottomed flask
sealed with a septum. Then, water (5 mL), CH3CN (14 mL), Et3N
(1.05 mmol), and a solution of inosine 2a or deoxyinosine 2b (1.00 mmol)
in CH3CN (2 mL) were added sequentially via syringe. After vigorous
stirring for 13 h, the reaction mixture was heated at reflux for 3 h. The
resulting yellow solution was cooled to room temperature and the volatile
materials were removed by rotatory evaporation. [1-15N]Adenosines 3a*
were isolated by flash chromatography (CH2Cl2–MeOH from 98:2 to 95:5).
Spectral data for 3a*: 1H NMR (CDCl3, 400 MHz): d 2.09 (s, 3H), 2.13 (s,
3H), 2.15 (s, 3H), 4.38 (dd, J 5 5.4, 11.2 Hz, 1H), 4.43–4.47 (m, 2H), 5.67
18 Compound 5a was compared with a sample prepared by addition of
benzylamine to 6-chloro-9-(29,39,59-tri-O-acetyl-ß-D-
ribofuranosyl)-9H-purine: A. P. Henderson, J. Riseborough,
C. Bleasdale, W. Clegg, M. R. J. Elsegood and B. T. Golding,
J. Chem. Soc., Perkin Trans. 1, 1997, 3407.
19 Compound 2ae was prepared from 6-bromo-9-(29,39,59-tri-O-acetyl-b-
D-ribofuranosyl)-9H-purine and Na18OH (from Na and H218O).
20 See for example: C. R. Allerson, S. L. Chen and G. L. Verdine, J. Am.
Chem. Soc., 1997, 119, 7423.
21 H. Rosemeyer, Chem. Biodiversity, 2004, 1, 361.
3970 | Chem. Commun., 2005, 3968–3970
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