In conclusion, the use of piperidine as a base in direct C–H
arylation of purines makes it possible to decrease the reaction
temperature and apply this reaction for arylation of nucleosides.
Unprotected purine nucleosides can be easily arylated by diverse
aryl iodides or bromides at position 8 in ca. 30–70% yields using
this methodology. In arylation of adenosines N6,8-diarylated
minor side-products are also formed in ca. 10% yields. Though the
yields of the desired 8-arylated nucleosides are rather moderate
and lower than in most cross-coupling reactions of 8-bromopurine
nucleosides with arylstannanes or -boronic acids, this methodology
is applicable directly to purine nucleosides without the need to
halogenate them and makes use of easily available aryl iodides
rather than the more expensive arylboronic acids or toxic
arylstannanes and thus saves 1–2 steps of the synthesis. Also it
can be an attractive alternative in cases where the corresponding
organometallic reagent is inaccessible or unstable. It is the first
example of successful direct C–H arylation of purine nucleosides
and work on further applications of this methodology in the
synthesis of modified nucleosides or oligonucleotides is under way.
This work is a part of the research project Z4 055 0506. It was
supported by the ‘‘Centre for Chemical Genetics’’ (LC06077) and
by Gilead Sciences, Inc. (Foster City, CA, USA).
Scheme 3 C–H arylation of adenosines.
Table 2 C–H arylation of adenosines 5 and 6
Entry 5,6 Time/temperature Ar–X
Products (Yields)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
6
6
22 h/100 uC
20 h/125 uC
60 h/150 uC
5 h/150 uC
5 h/150 uC
5 h/150 uC
5 h/150 uC
5 h/125 uC
4-Tol–I
4-Tol–I
4-Tol–I
4-Tol–I
3-Tol–I
1-pyrenyl–Br 7c (62%)
4-Tol–I
4-Tol–I
7a (50%) 8a (12%)
7a (56%) 8a (18%)
decomposition
7a (68%) 8a (15%)
7b (55%) 8b (12%)
—
decomposition
9 (31%) 10 (8%)
somewhat less reactive, giving 4a in 30% yield. Iodobenzene,
3-tolyl iodide and 4-methoxyphenyl iodide reacted reasonably well,
giving the corresponding nucleosides 4b–4d in acceptable yields of
43–47%. The more sterically hindered 2-tolyl iodide gave nucleo-
side 4e in a lower 27% yield. 1-Bromopyrene was also less reactive
but still gave the 8-pyrenylpurine nucleoside 4f in 30% yield.
Having this straightforward methodology in hand, we further
explored the possibility of direct arylation of natural adenine
nucleosides 5 and 6. The first experiments were performed with the
more stable adenosine 5 (Scheme 3, Table 2). Its reaction with
4-tolyl iodide under analogous conditions at 100 uC for 22 h gave
8-tolyladenosine (7a) in a good yield of 50%. A side-product of this
reaction was the N6,8-diarylated nucleoside 8a (12%) as the
product of subsequent Cu-catalyzed N-arylation. TLC analysis
showed the presence of a significant amount of starting compound
which was not isolated due to its immobility on the chromato-
graphy column. When the reaction was performed at 125 uC, the
conversion was somewhat higher to give 56% of the desired 7a and
18% of diarylated nucleoside 8a. The same reaction at 150 uC for
60 h gave complete decomposition of the nucleosides. However,
when the reaction was performed at 150 uC for just 5 h, 7a was
isolated in 68% yield. This optimized procedure was then used for
arylation of 5 with other aryl halides. Its reaction with 3-tolyl
iodide gave the desired 8-aryladenosine 7b in 55% yield
accompanied by 12% of the diarylated 8b. Reaction of 5 with
1-bromopyrene gave the 8-(pyren-1-yl)adenosine 7c in a good yield
of 62% (no diarylated by-product was observed in this case).
Finally, labile 29-deoxyadenosine 6 was tested as a substrate for the
C–H arylation. Here, we had to use a lower temperature (125 uC)
for a shorter time (5 h) to prevent decomposition (entries 7,8).
Under such conditions, 8-tolyl-29-deoxyadenosine (9) was isolated
in an acceptable 31% yield along with diarylated compound 10
(8%).
Notes and references
1 (a) K. Kohda, H. Tsunomoto, T. Kasamatsu, F. Sawamura, I. Teashima
and S. Shibutani, Chem. Res. Toxicol., 1997, 10, 1351–1358; (b)
P. M. Ganett, J. H. Powell, R. Rao, X. Shi, T. Lawson, C. Kolar and
B. Toth, Chem. Res. Toxicol., 1999, 12, 297–304; (c) Q. Dai, D. Xu,
K. Lim and R. G. Harvey, J. Org. Chem., 2007, 72, 4856–4863.
2 (a) J. L. Sessler and J. Jayawickramarajah, Chem. Commun., 2005,
1939–1949; (b) J. L. Sessler, C. M. Lawrence and J. Jayawickramarajah,
Chem. Soc. Rev., 2007, 36, 314–325; (c) J. L. Sessler,
J. Jayawickramarajah, C. L. Sherman and J. S. Brodbeldt, J. Am.
Chem. Soc., 2004, 126, 11460–11461; (d) J. L. Sessler, M. Sathiosatham,
C. T. Brown, T. A. Rhosdes and G. Wiederrecht, J. Am. Chem. Soc.,
2001, 123, 3655–3660; (e) V. Gubala, J. E. Betancourt and J. M. Rivera,
Org. Lett., 2004, 6, 4735–4738.
3 (a) E. Mayer, L. Valis, R. Huber, N. Amann and H.-A. Wagenknecht,
Synthesis, 2003, 2335–2340; (b) L. Valis and H.-A. Wagenknecht, Synlett,
2005, 2281–2284; (c) L. Valis, E. Mayer-Enthart and H.-A. Wagenknecht,
Bioorg. Med. Chem. Lett., 2006, 16, 3184–3187.
4 For reviews on cross-coupling reactions of purines see: (a) M. Hocek,
Eur. J. Org. Chem., 2003, 245–254; (b) L. A. Agrofoglio, I. Gillaizeau and
Y. Saito, Chem. Rev., 2003, 103, 1875–1916.
5 (a) E. C. Western, J. R. Daft, E. M. Johnson, P. M. Gannett and
K. H. Shaughnessy, J. Org. Chem., 2003, 68, 6767–6774; (b) E. C. Western
ˇ
and K. H. Shaughnessy, J. Org. Chem., 2005, 70, 6378–6388; (c) P. Capek
ˇ
and M. Hocek, Synlett, 2005, 3005–3007; (d) P. Capek, R. Pohl and
M. Hocek, Org. Biomol. Chem., 2006, 4, 2278–2284; (e) M. Vra´bel,
ˇ
R. Pohl, B. Klepeta´rova´, I. Votruba and M. Hocek, Org. Biomol. Chem.,
2007, 5, 2849–2857.
6 Reviews: (a) J. A. Labinger and J. E. Bercaw, Nature, 2002, 417, 507–514;
(b) K. Godula and D. Sames, Science, 2006, 312, 67–72.
7 (a) F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi and S. Viel, J. Org.
Chem., 2005, 70, 3997–4005; (b) F. Bellina, S. Cauteruccio, L. Mannina,
R. Rossi and S. Viel, Eur. J. Org. Chem., 2005, 693–703; (c) F. Bellina,
S. Cauteruccio and R. Rossi, Eur. J. Org. Chem., 2006, 1379–1382; (d)
F. Bellina, C. Calandri, S. Cauteruccio and R. Rossi, Tetrahedron, 2007,
63, 1970–1980; (e) Review: I. V. Seregin and V. Gevorgyan, Chem. Soc.
Rev., 2007, 36, 1173–1193.
ˇ
8 I. Cernˇa, R. Pohl, B. Klepeta´rˇova´ and M. Hocek, Org. Lett., 2006, 8,
5389–5392.
4730 | Chem. Commun., 2007, 4729–4730
This journal is ß The Royal Society of Chemistry 2007