Microwave irradiated C6-functionalization of 6-chloropurine nucleosides with various mild nucleophiles under solvent-free conditions

Article abstract of DOI:10.1039/c0gc00517g

An efficient method for the synthesis of C6-functionalized purine nucleosides was developed via the direct nucleophilic substitution reaction of 6-chloropurine derivatives with various mild nucleophiles. The eco-friendly solvent-free process gave good to

Full text of DOI:10.1039/c0gc00517g

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Microwave irradiated C6-functionalization of 6-chloropurine nucleosides
with various mild nucleophiles under solvent-free conditions†
Hai-Ming Guo,*a Peng-Yang Xin,a Hong-Ying Niu,b Dong-Chao Wang,a Yi Jianga and Gui-Rong Qu*a
Received 5th September 2010, Accepted 20th October 2010
DOI: 10.1039/c0gc00517g
An efficient method for the synthesis of C6-functionalized
purine nucleosides was developed via the direct nucleophilic
substitution reaction of 6-chloropurine derivatives with
various mild nucleophiles. The eco-friendly solvent-free
process gave good to high isolated yields within a short re-
action time (5 min) under microwave irradiated conditions.
Over the past few decades, purine bases and nucleosides have
been reported to possess a wide scope of bioactivities.1 Purine
derivatives with various substituents (such as C-, N-, O-,
S-substituents) at C6 constitute one of the largest classes of
these bioactive compounds.2 The method commonly used for
the construction of theses C6-substituted purine bases and
nucleosides is based on the classical nucleophilic substitution
reaction. One route is through the direct nucleophilic
substitution reaction of 6-halopurine analogues and strong
nucleophilic agents such as MeONa, PhONa, MeSNa, and
PhSNa etc. (route A, Scheme 1).3 Another route proceeds
via the introduction of an efficient leaving group4 (such as
1-hydroxybenzotriazole (HOBT),4a,4b,4c pyridine,4d imidazole,4e
1,4-diazabicyclo-[2.2.2]octane (DABCO),4f triazole,4g 1-
methylpyrrolidine,4h trimethylamine4i) at C6 position, followed
by the nucleophilic displacement (route B, Scheme 1). In both
routes, either strong alkaline nucleophiles or efficient leaving
groups are needed with long reaction times.4 It is known that the
SN (nucleophilic substitution) reaction depends on the activities
of nucleophiles and leaving groups. Chlorine is a relatively poor
leaving group compared to HOBT, pyridine, etc. At the same
time, the nucleophilic abilities of PhOH, PhSH or PhNH2 are
much poorer than their corresponding alkaline compounds.
Up to now, however, there is no report on the process between
6-chloropurine analogues and mild nucleophilic agents such as
PhOH, PhSH, PhNH2 and naphthol.
Scheme 1 Different routes for the synthesis of C6-functionalized purine
analogues.
Table 1 Optimization of the reaction conditionsa
Reactions under solvent-free conditions are especially
appealing as they provide the opportunity to avoid the use
of toxic solvents.5 Based on our preliminary work on the
synthesis of various nucleoside analogues,6 herein a green and
efficient protocol for the synthesis of C6-functionalized purine
Entry
T/◦C
Time/min
Yieldb(%)
1
2
3
4
5
6
50
70
90
110
90
90
10
10
10
10
3
54
76
85
87
62
83
aCollege of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions of Ministry of Education, Henan
Normal University, Xinxiang, 453007, China.
E-mail: guohm518@hotmail.com, quguir@sina.com;
Fax: +86-3733329276
5
bSchool of Chemistry and Chemical Engineering, Henan Institute of
Science and Technology, Xinxiang, 453003, China
a Reaction conditions: 6-chloroguanosine (1 mmol), phenol (1.5 mmol),
K2CO3 (2 mmol), MWI 400 W. b Isolated yields based on 6-
chloroguanosine.
† Electronic supplementary information (ESI) available: Experimental
details, NMR data of all compounds and full characterization of novel
compounds. See DOI: 10.1039/c0gc00517g
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Table 2 Reaction of phenol with various 6-chloropurinesa
Table 3 Reaction of 9-allyl-2,6-dichloro-9H-purine with various mild
nucleophilesa
Entry
1
Nucleophile
Product
Yieldb(%)
95
Entry
Product
R
Yieldb(%)
1
2
3
3a
3b
3c
H
CH3
87
95
84
4
5
3d
3e
89
91
2
3
4
89
89
87
6
3f
79
7
8
3g
3h
H
86
87
9
3i
3j
91
75
10
5
6
90
81
11
3k
81
a Reaction conditions: 6-chloropurines (1 mmol), phenol (1.5 mmol),
K2CO3 (2 mmol), MWI 400 W (90 ◦C). b Isolated yields based on
nucleobases.
nucleosides was described via the direct nucleophilic substitution
reaction of 6-chloropurine derivatives and mild nucleophiles like
PhOH, PhSH, PhNH2 under microwave irradiated conditions
without solvent (route C, Scheme 1).
7
8
93
97
To initiate our study, we examined the microwave promoted
nucleophilic substitution reaction between 6-chloroguanosine
and phenol. As shown in Table 1, at 50 ◦C the yield was low
(entry 1, 54%). With the increase of the reaction temperature,
the yields were improved. When the reaction temperature was at
90 ◦C, the yield reached up to 85% (entry 3). By increasing the
reaction temperature to 110 ◦C, no significant change in the yield
was observed (entry 4, 87%). Next, we investigated the effect of
reaction time. When the reaction time was 3 min, the yield was
low (entry 5, 62%). By increasing the reaction time to 5 min,
the yield reached 83% (entry 6). When the reaction time was
10 min, no significant change in the yield was observed (entry 3,
85%). Therefore, 90 ◦C and 5 min were the optimized reaction
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Table 3 (Contd.)
exhibited significant advantages over the conventional heating
by not only reducing the reaction time, but also improving the
reaction yield.
In conclusion, we have developed a general, rapid and solvent-
free protocol for the synthesis of C6-funtionalized purine nucle-
osides between 6-halopurine analogues and mild nucleophiles,
which avoids the use of strong alkaline nucleophiles or the
introduction of efficient leaving groups. This method also has
several advantages such as mild reaction conditions, ease of
manipulation and a short reaction time. Furthermore, most of
the reactions involved are efficient, giving the desired compound
in higher purity and yield. Moreover, our eco-friendly solvent-
free method avoids the use of toxic solvents such as DMF,
DMSO, CH3CN and toluene. This environmentally friendly
procedure represents a promising green route for the syn-
thesis of these important C6-functionalized purine nucleoside
compounds.
Entry
9
Nucleophile
Product
Yieldb(%)
0
10
11
91
Acknowledgements
We are grateful for financial support from the National Nature
Science Foundation of China (grants 20772024, 20802016, and
21072047), the Program for New Century Excellent Talents
in University of Ministry of Education (NCET-09-0122), the
Program for Innovative Research Team in University of Henan
Province (2008IRTSTHN002), and the Henan National Nature
Science Foundation (092300410225).
78c
a Reaction conditions: 9-allyl-2,6-dichloro-9H-purine (1 mmol), nucle-
ophile (1.5 mmol), K2CO3 (2 mmol), MWI 400 W (90 ◦C). b Isolated
yields based on nucleobases. c Reaction time, 10 min.
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400 W was the best choice.
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chloropurine derivatives with various substituents, including a
sugar carbon substituent at N9, were subjected to the optimized
reaction conditions, affording the desired 6-phenoxypurine
derivatives in good to excellent isolated yields (75–95%)
(Table 2). The type of substituent at N9 had a slight impact
on the yield of the products: the alkyl-substituted substrates
gave higher yields, while the sugar-substituted substrates gave
slightly lower yields.
Intrigued by the results described above, other substrates, such
as phenol, naphthol, thiophenol and aniline derivatives, were
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substitution reactions could be easily accessed. The results are
shown in Table 3. As expected, these reactions also proceeded
smoothly to give the corresponding 6-substituted purines in
good to high yields (78–97%) except that the desired product
4i could not be obtained even after 0.5 h, which might be due to
the strong steric hindrance of tert-butyl.
In order to compare the efficiency of microwave irradiation
with conventional heating, the formation of 4c was carried out
in an oil bath under the same conditions. It turned out that the
reaction afforded only 45% yield even after 24 h, far less than
the yield of 89% afforded under microwave irradiation within
5 min. This clearly indicated that the microwave-assisted reaction
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