The first direct C-H arylation of purine nucleosides

Article abstract of DOI:10.1039/b714253f

Pd-catalyzed direct C-H arylation of unprotected purine nucleosides with aryl iodides at position 8 was developed to allow a straightforward single-step introduction of diverse aryl groups. The Royal Society of Chemistry.

Full text of DOI:10.1039/b714253f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The first direct C–H arylation of purine nucleosides{
ˇ
Igor Cerna, Radek Pohl and Michal Hocek*
ˇ
Received (in Cambridge, UK) 14th September 2007, Accepted 17th October 2007
First published as an Advance Article on the web 25th October 2007
DOI: 10.1039/b714253f
Pd-catalyzed direct C–H arylation of unprotected purine
nucleosides with aryl iodides at position 8 was developed to
allow a straightforward single-step introduction of diverse aryl
groups.
8-Arylpurine nucleosides are metabolites1 of DNA damage by
Scheme 1 Model C–H arylation of 9-benzyl-6-phenylpurine.
arylhydrazines and they find a wide range of applications in self-
assembly2 and as optical probes3 for oligonucleotide hybridization.
They are usually prepared by cross-coupling reactions4 of
arylstannanes or arylboronic acids with protected 8-bromopurine
nucleosides in organic solvents. Recently, aqueous-phase Suzuki–
Miyaura reactions of unprotected 8-bromopurine nucleosides with
boronic acids have been developed,5 allowing a straightforward
synthesis of the 8-arylpurine nucleosides. However, there is still a
need for new alternative efficient methodologies for the synthesis
of these important compounds, especially for aryl groups where
the corresponding organometallic reagent is not readily accessible
or sufficiently stable or reactive.
Under such conditions purine nucleosides should be reasonably
stable and therefore we have used the reaction for model C–H
arylation of an unprotected 6-(4-methoxyphenyl)purine ribonu-
cleoside (3, Scheme 2, Table 1). In the first experiment (entry 1),
nucleoside 3 reacted with 4-tolyl iodide (2 equiv.) in the presence of
Pd(OAc)2 (5 mol%), CuI (3 equiv.) and piperidine (5 equiv.) in
DMF at 125 uC for 20 h. The desired 8-tolylpurine nucleoside 4a
was isolated in 39% yield along with unreacted starting compound
(ca. 30%) and some unidentified by-products of decomposition.
When the same reaction was performed for 49 h, the isolated yield
of 4a was improved to 50% (entry 2). Further prolongation of
reaction time led to a higher degree of decomposition and did not
bring any improvement in the yield of 4a. Therefore, further
experiments with other aryl halides were performed under the
above-mentioned conditions for 49 h. 4-Tolyl bromide was
Direct C–H arylation is one of the most efficient and useful
methods of C–H activation6 and, as an alternative to classical
cross-coupling reactions, it was applied to many carbo- and
heterocycles.7 Recently, we have developed8 a new efficient Pd-
catalyzed direct C–H arylation of 9-benzylpurines at position 8
with aryl iodides in the presence of CuI and Cs2CO3 in DMF and
used8 it in combination with cross-couplings for regioselective
consecutive synthesis of 6,8-di- and 2,6,8-trisubstituted purines.
Here we report on the extension of this methodology to arylation
of unprotected purine nucleosides.
Our previously reported protocol8 for direct C–H arylation of
purines used rather harsh conditions (160 uC) and long reaction
times (60 h) to achieve efficient conversions. Such conditions are
not compatible with rather labile nucleosides and therefore, for
such applications, the procedure must be further optimized to
lower the temperature. Based on the assumption that the long-
term heating of DMF generates some dimethylamine which may
influence the rate of the reaction, we have used piperidine (4 equiv.)
as a higher-boiling secondary amine in the model reaction of
9-benzyl-6-phenylpurine (1) with 4-tolyl iodide (Scheme 1). Indeed,
we have found that it accelerates the reaction and even at 120 uC
the 8-arylpurine product 2 was formed in a good yield of 77% after
60 h.
Scheme 2 C–H arylation of 6-(4-methoxyphenyl)purine ribonucleoside.
Table 1 C–H arylations of nucleoside 3
Entry
Ar–X
Product
Yield (%)
1
2
3
4
5
6
7
8
a
4-Tol–I
4-Tol–I
4-Tol–Br
Ph–I
3-Tol–I
4-MeOPh–I
2-Tol–I
1-pyrenyl–Br
4a
4a
4a
4b
4c
4d
4e
4f
39a
50
30
43
47
45
27
30
Institute of Organic Chemistry and Biochemistry, Academy of Sciences
of the Czech Republic, Gilead & IOCB Research Center, Flemingovo
nam. 2, CZ-16610 Prague 6, Czech Republic.
E-mail: hocek@uochb.cas.cz; Fax: +420 220183559;
Tel: +420 220183324
{ Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b714253f
Reaction time 20 h.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 4729–4730 | 4729

View Article Online
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