Synthesis of C6-azolyl purine nucleosides via C-N coupling reaction of unprotected 6-chloropurine nucleosides and N-heterocycles under catalyst- and solvent-free conditions

Article abstract of DOI:10.1039/c2gc35419e

C6-azolyl purine nucleoside products are prepared in high yields under solvent- and catalyst-free conditions via C-N coupling reaction of unprotected 6-chloropurine nucleosides and N-heterocycles, providing a unifying, simple and environmentally friendly complement to the available methods. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc35419e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 1877
www.rsc.org/greenchem
COMMUNICATION
Synthesis of C6-azolyl purine nucleosides via C–N coupling reaction of
unprotected 6-chloropurine nucleosides and N-heterocycles under catalyst-
and solvent-free conditions†
Gui-Rong Qu,*a Hong-Liang Zhang,a Hong-Ying Niu,b Zai-Kun Xue,a Xin-Xin Lva and Hai-Ming Guo*a
Received 21st March 2012, Accepted 14th May 2012
DOI: 10.1039/c2gc35419e
reaction between halopyridines and nitrogen nucleophiles cata-
lyzed by Cu2O was developed to synthesize N-heteroarylated
products in good yields.1a To further avoid the use of metal cata-
lyst, azolyl purine nucleosides were successfully synthesized
under reflux in different organic solvents without any metal cata-
lyst.9 However, different organic solvents were needed to give
satisfactory yields of N-heterocycles substituted purines at C6,
and no unifying solvent can be used for the synthesis of azolyl
purine derivatives. Due to the drawbacks of the above mentioned
methodologies, the ideal method for the preparation of C6-azolyl
purine nucleosides should be conducted under catalyst- and
ligand-free, and even solvent-free conditions. We herein report
our findings for the synthesis of C6-azolyl nucleosides under
catalyst-, ligand-, and solvent-free reaction conditions between
unprotected 6-chloropurine nucleosides with various N-nucleo-
philes, providing a unifying, simple and environmentally
friendly complement to the reported methods.
C6-azolyl purine nucleoside products are prepared in high
yields under solvent- and catalyst-free conditions via C–N
coupling reaction of unprotected 6-chloropurine nucleosides
and N-heterocycles, providing a unifying, simple and envir-
onmentally friendly complement to the available methods.
N-Heterocycles, including imidazoles, triazoles, pyrroles and
indoles, have become increasingly important building blocks in
biological, pharmaceutical and material sciences.1 Substituted
N-heterocycles, especially heterocyclic nucleosides by the
formation of C–N bonds, have broad applications in biological
and medical aspects due to their unique and valuable properties.2
For example, more and more C6-pyrrolyl purine compounds
have been found to have potential utility as antiarrhythmic
agents,3 and 6-heteroarylpurines are reported to have anti-HCV4
or antimycobacterial activity.5 Including their special biological
activities, C6-azolyl purine nucleosides are becoming more and
more meaningful in the synthesis of biologically relevant com-
pounds.6 For instance, heterocyclic nucleosides are often used as
intermediates for the synthesis of some useful purine nucleosides
by substitution reactions as some heterocycles are good protect-
ing and leaving groups.7
Palladium- or nickel-catalyzed cross-coupling reactions of
6-halopurines with heteroaryl organometallic reagents are among
the most efficient methods for the preparation of 6-heteroaryl-
purine derivatives by the formation of C–N bonds.8 However,
the popularity of this method is restricted by the fairly harsh
reaction conditions and the reduced stability/accessibility of
the corresponding organometallic species. Recently, the Pd-cata-
lyzed C–N (sp2) bond formation reactions with proper ligands
between halopurine nucleosides and different amines were also
found to be a general method for the synthesis of C6-azolyl
purine nucleosides.2 Recently, to avoid the use of ligand, a
microwave-assisted solvent- and ligand-free cross-coupling
Results and discussion
In order to obtain the most efficient reaction conditions, we
screened the temperature, the reaction time, and the molar ratio
of the substrates using solid unprotected 6-chloropurine nucleo-
sides (1a) and 1H-1,2,4-triazole (2a) as a model reaction. As
shown in Table 1, when the reaction was conducted below
120 °C, the yield was quite low (entries 1–2). When the reaction
temperature was 120 °C, excellent yield was obtained (entry 3).
This might be explained by the experimental observation that
1H-1,2,4-triazole began to melt at 120 °C under solvent-free
conditions, and the molten 1H-1,2,4-triazole made a good
contact with 6-chloropurine nucleosides (1a) to speed up the
reaction. Screening of reaction time showed that 45 min was
the best choice (entries 3–5). The results also proved that
the optimal molar ratio of 6-chloropurine nucleosides to 1H-
1,2,4-triazole was 1 to 1.3 (entries 6–8), where 1H-1,2,4-triazole
was excess to be both reactant and solvent for this SN (nucleo-
philic substitution) reaction.
aCollege of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education,
Henan Normal University, Xinxiang 453007, Henan, China.
E-mail: quguir@sina.com, guohm518@hotmail.com;
With the optimized conditions in hand, we next studied the
generality of the reaction between N-nucleophiles and 6-chloro-
purine nucleosides, and the results are summarized in Table 2.
The yield of the product was slightly affected by the structure of
amine in the following sequence: triazole > 1H-imidazole ≈ 1H-
pyrazole > 2H-tetrazole (entries 1–4). When 1H-benzoimidazole
Fax: +86 373 3329276; Tel: +86 373 3329255
bSchool of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang 453003, China
†Electronic supplementary information (ESI) available: General infor-
mation, experimental procedures, and characterization data for the products
including spectroscopic information. See DOI: 10.1039/c2gc35419e
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1877–1879 | 1877

View Article Online
Table 1 Optimization of the reaction conditions
Table 2 The reaction of 6-chloropurine nucleosides (1) with various
N-nucleophilesa
Entry 1a (mmol) 2a (mmol) Ta (°C) Time (min) Yieldb (%)
Entry
1
N-Nucleophiles
Product
Yieldb (%)
99
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
1.5
1.3
1.2
90
60
60
60
45
30
45
45
45
Trace
38
99
99
76
110
120
120
120
120
120
120
99
99 (65)c
90
a The reaction was heated in oil bath. b Isolated yields based on
nucleosides. c Recrystallization yield in parentheses.
2
3
94
95
was used as the starting material, the reaction was performed at
150 °C to ensure the substrates melted well and make full
contact with each other (entries 5–6). 6-Chloro-2-aminopurine
nucleoside could also react with imidazole or triazole under the
same conditions, which were not much different to 6-chloro-
purine nucleoside in yield (entries 7–8). Generally, most of
N-nucleophiles proceeded smoothly to give high yields of the
corresponding product.
Intrigued by the above-described results, a variety of 6-chloro-
purines (nucleosides) were further explored under the optimized
reaction conditions. As shown in Table 3, protected 6-chloro-
purine nucleosides gave excellent yields without the cleavage of
the C–N glucosidic bond, providing a useful methodology for
the synthesis of nucleosides with potential medicinal applications
(entries 1–2). To our pleasure, the reaction selectivity was very
good because the coupling reaction exclusively occurred on C6
position of purine even when protected 2,6-dichloropurine
nucleosides were used as a substrate (entry 2). And various
6-chloro-9-alkylpurines could also give high yields of the corre-
sponding products (entries 3–9, up to 96%), indicating the gener-
ality of this simple and green process.
4
91
95
5c
6c
94
91
Conclusions
In conclusion, we have developed an operationally simple,
efficient and green method for the preparation of C6-azolyl
purines (nucleosides) which are very important in biological,
pharmaceutical and material sciences. Compared to previously
reported approaches, this process avoids the use of organic sol-
vents and metal catalysts, providing a valuable method for the
synthesis of these bioactive C6-azolyl purine compounds. The
simplicity, generally high yields, and the versatility of the reac-
tion make this methodology quite attractive and useful for
library synthesis in drug discovery efforts.
7
1878 | Green Chem., 2012, 14, 1877–1879
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 (Contd.)
Acknowledgements
Entry
8
N-Nucleophiles
Product
Yieldb (%)
89
We are grateful for financial support from the National Nature
Science Foundation of China (Grant Nos. 21072047, and
21172059), the Program for New Century Excellent Talents in
University of Ministry of Education (No. NCET-09-0122),
Excellent Youth Foundation of Henan Scientific Committee (No.
114100510012), the Program for Changjiang Scholars and Inno-
vative Research Team in University (IRT1061), the Program for
Innovative Research Team in University of Henan Province
(2012IRTSTHN006), the Excellent Youth Program of Henan
Normal University, and Foundation for University Key Teacher
by Henan Province (No. 2011GGJS-132).
a Reaction conditions: 6-chloropurine nucleosides (1) (1.0 mmol),
N-nucleophiles (1.3 mmol), 120 °C, 45 min. b Isolated yields based on
nucleosides. c Reaction performed at 150 °C.
Notes and references
1 (a) Z. J. Liu, J. P. Vors, E. R. F. Gesing and C. Bolm, Green Chem., 2011,
13, 42; (b) T. T. Denton, X. Zhang and J. R. Cashman, J. Med. Chem.,
2005, 48, 224; (c) H.-C. Zhang, C. K. Derian, D. F. McComsey,
K. B. White, H. Ye, L. R. Hecker, J. Li, M. F. Addo, D. Croll,
A. J. Eckardt, C. E. Smith, Q. Li, W.-M. Cheung, B. R. Conway,
S. Emanuel, K. T. Demarest, P. Andrade-Gordon, B. P. Damiano and B.
E. Maryanoff, J. Med. Chem., 2005, 48, 1725; (d) J. Roppe, N. D. Smith,
D. Huang, L. Tehrani, B. Wang, J. Anderson, J. Brodkin, J. Chung,
X. Jiang, C. King, B. Munoz, M. A. Varney, P. Prasit and N. D. P. Cosford,
J. Med. Chem., 2004, 47, 4645; (e) Y. Wang, Y. Li and B. Wang,
Int. J. Mol. Sci., 2007, 8, 166; (f) N. P. Buu-Hoi, R. Rips and R. Cavier,
J. Med. Chem., 1960, 2, 335; (g) A. M. Crider, R. Lamey, H. G. Floss and
J. M. Cassady, J. Med. Chem., 1980, 23, 848; (h) L. He, L. Duan, J. Qiao,
R. Wang, P. Wei, L. Wang and Y. Qiu, Adv. Funct. Mater., 2008, 18, 2123.
2 P. Lagisetty, L. M. Russon and M. K. Lakshman, Angew. Chem., Int. Ed.,
2006, 45, 3660.
Table 3 The reactions of 1-H-triazole (2a) with various 6-
chloropurinesa
Entry
1
R
R′
Product
Yieldb (%)
92
H
4a
3 K. G. Estep, K. A. Josef, E. R. Bacon, P. M. Carabateas, S. Rumney IV,
G. M. Pilling, D. S. Krafte, W. A. Volberg, K. Dillon, N. Dugrenier,
G. M. Briggs, P. C. Canniff, W. P. Gorczyca, G. P. Stankus and A.
M. Ezrin, J. Med. Chem., 1995, 38, 2582.
2
3
Cl
4b
90
H
4c
92
4 M. Hocek, P. Naus, R. Pohl, I. Votruba, P. A. Furman, P. M. Tharnish and
M. J. Otto, J. Med. Chem., 2005, 48, 5869.
5 M. Brændvang and L. L. Gundersen, Bioorg. Med. Chem., 2005, 13,
6360.
4
5
H
H
4d
4e
96
93
6
H
4f
94
6 (a) S. Bae and M. K. Lakshman, J. Org. Chem., 2008, 73, 1311;
(b) M. K. Lakshman, Curr. Org. Synth., 2005, 2, 83; (c) H. M. Guo,
P. Y. Xin, H. Y. Niu, D. C. Wang, Y. Jiang and G. R. Qu, Green Chem.,
2010, 12, 2131; (d) G. R. Qu, J. Wu, Y. Y. Wu, F. Zhang and H. M. Guo,
Green Chem., 2009, 11, 760; (e) G. R. Qu, L. Zhao, D. C. Wang, J. Wu
and H. M. Guo, Green Chem., 2008, 10, 287.
7
8
H
H
4g
4h
93
94
7 (a) I. Nowak and M. J. Robins, Org. Lett., 2003, 5, 3345; (b) V. Samano,
R. W. Miles and M. J. Robins, J. Am. Chem. Soc., 1994, 116, 9331.
8 (a) M. Hocek, P. Nauš, R. Pohl, I. Votruba, P. A. Furman, P. M. Tharnish
and M. J. Otto, J. Med. Chem., 2005, 48, 5869; (b) J. Liu and
M. J. Robins, Org. Lett., 2004, 6, 3421; (c) E. A. Véliz and P. A. Beal,
J. Org. Chem., 2001, 66, 8592; (d) M. Zhong, I. Nowak and M. J. Robins,
Org. Lett., 2005, 7, 4601.
9
H
4i
93
a Reaction conditions: 6-chloropurine (1.0 mmol), 1-H-triazole (2a)
(1.3 mmol), 120 °C, 45 min. b Isolated yields based on nucleobases.
9 M. Zhong, I. Nowak, J. F. Cannon and M. J. Robins, J. Org. Chem., 2006,
71, 4216.
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1877–1879 | 1879