ACS Combinatorial Science
RESEARCH ARTICLE
Scheme 4. Preparation of N9-Unsubstituted Compoundsa
project CZ.1.07/2.3.00/20.0009 coming from European Social
Fund. Infrastructural part of this project (Institute of Molecular
and Translational Medicine) was supported from the Opera-
tional Program Research and Development for Innovations
(Project CZ.1.05/2.1.00/01.0030). The work was supported
by the Department of Chemistry and Biochemistry at the
University of Notre Dame.
a Reagents and conditions: (i) aryl iodide, CuI, Pd(OAc)2, piperidine,
anhydrous DMF, 135 °C, 48 h; (ii) 50% TFA in DCM, 1 h.
’ ACKNOWLEDGMENT
We gratefully appreciate the use of the NMR facility at the
University of Notre Dame.
longer reaction time for aryl bromides, versus aryl iodides, all
preparative reactions in this study were performed with aryl
iodides (method A).
’ REFERENCES
Direct C8ꢀH Arylation of 2,6-Disubstituted Purines. We
also tested C8ꢀH arylation of N9-unsubstituted purines (Scheme 4),
which can be subsequently converted to a C8-modified purine
nucleosides. Unfortunately, the presence of the acidic hydrogen
on purine N9 decreased reactivity toward arylation. A very low
conversion (about 10%, HPLC-UV traces) was observed under
the previously described conditions. Increasing the concentra-
tion of aryl iodide or piperidine or both did not improve the
conversion (only 10% to 20%).
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When higher temperature was used (135 °C), the arylation
proceeded significantly better. However, we did not observe quanti-
tative reaction; the best purity (71%) was achieved for derivative
5(2,3,1,3) (HPLC-UV traces). For this reason N9-unsubstituted
purines were isolated after HPLC purification in 14 to 21% yield.
’ CONCLUSION
We developed a solid-phase synthesis for direct C8ꢀH aryla-
tion of purine derivatives. The versatility of the method was
documented by the preparation, isolation and characterization of
fourteen 2,6,8,9-tetrasubstituted purines. An optimized reaction
sequence provided target compounds in very good purity. The
conditions were evaluated for aryl iodides as reactants, but aryl
bromides were also found to be applicable as reactants though
reaction times were prolonged. The method was applied, also, for
the synthesis of 2,6,8-trisubstituted compounds (three examples
are given). Although the isolated yields of individual chemical
entities are not quantitative, the, method is suitable for high-
throughput synthesis of chemical libraries from commercially
available synthons to afford, rapidly, a set of compounds for
biological screening. The, method thus represents an additional
tool for systematic biological study of purine derivatives using
combinatorial chemistry.
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’ ASSOCIATED CONTENT
S
Supporting Information. General information, analyti-
b
cal data, and 1H and 13C NMR spectra. This material is available
(13) Ibrahim, N.; Legraverend, M. High-Yielding Two-Step Synth-
esis of 6,8-Disubstituted N-9-Unprotected Purines. J. Comb. Chem.
2009, 11 (4), 658–666.
’ AUTHOR INFORMATION
(14) Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.; Matsukura,
M.; Kabasawa, Y.; Niijima, J.; Kotake, Y.; Watanabe, N.; Kawata, T.;
Inoue, T.; Horizoe, T.; Yasuda, N.; Minami, H.; Nagata, K.; Murakami,
M.; Nagaoka, J.; Kobayashi, S.; Tanaka, I.; Abe, S. 2-Alkynyl-8-aryl-9-
methyladenines as Novel Adenosine Receptor Antagonists: Their
Synthesis and StructureꢀActivity Relationships toward Hepatic Glu-
cose Production Induced via Agonism of the A2B Receptor. J. Med.
Chem. 2001, 44 (2), 170–179.
Corresponding Author
*Phone: +420 585634405. Fax: +420 585634465. E-mail: hlavac@
orgchem.upol.cz.
Funding Sources
The authors are grateful to the Ministry of Education, Youth and
Sport of the Czech Republic, for the grant ME09057 and for
499
dx.doi.org/10.1021/co200075r |ACS Comb. Sci. 2011, 13, 496–500