Synthesis of novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides under microwave irradiation in neat water

Article abstract of DOI:10.1039/b902025j

Novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides were prepared in one step by nucleophilic substitution reaction of 6-choloropurine nucleosides with diethanolamine. Shorter reaction times and higher yields were achieved under microwave irradiation

Full text of DOI:10.1039/b902025j

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Synthesis of novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleosides
under microwave irradiation in neat water†
Gui-Rong Qu, Jing Wu, Yan-Yan Wu, Feng Zhang and Hai-Ming Guo*
Received 2nd February 2009, Accepted 6th March 2009
First published as an Advance Article on the web 16th March 2009
DOI: 10.1039/b902025j
Novel 6-[N,N-bis(2-hydroxyethyl)amino]purine nucleo-
sides were prepared in one step by nucleophilic substi-
tution reaction of 6-choloropurine nucleosides with di-
ethanolamine. Shorter reaction times and higher yields were
achieved under microwave irradiation conditions in neat
water.
irradiation in neat water, aiming at providing an efficient route to
the synthesis of new nucleoside analogues which are important
candidates for biologically active compounds.
6-[N,N-Bis(2-hydroxyethyl)amino]purine nucleosides were
prepared from commercially available 6-chloropurine nucleo-
sides and various N9-substituted 6-chloropurine nucleosides
that can be synthesized by alkylation of 6-chloropurine with
nonsugar carbon chain, and then reacted with diethanolamine
under microwave irradiation (Scheme 1). The procedures for
synthesis of nucleosides analogues under microwave irradiation
were well developed in our laboratories. Products (3a–3m) were
purified by column chromatography in yields of 57–91%. Their
structures were confirmed by NMR spectra and high-resolution
mass spectrometry.
Nucleosides play important roles in many biological pro-
cesses. Many nucleoside analogues with modifications on the
heterocyclic bases have been investigated for their antiviral
and anticancer activities.1 There are extensive interests in the
study of purine derivatives with various substituents at C6
due to their broad spectrum of biological activities.2 N6-(2-
hydroxyethyl)adenosine (HEA) (1), which behaves as a Ca2+
antagonist and an inotropic agent, was isolated from cordy-
ceps and isaria species.3 6-[N,N-Bis (2-hydroxyethyl)amino]-9-
(2-b-C-methyl-b-D-ribofuranosyl)-purine (2)4 and 6-[N,N-bis-
(2-hydroxyethyl)aminomethyl]-9-(b-D-ribofuranosyl)purine (3)5
showed potency in inhibiting HCV RNA replication (Fig. 1).
Scheme 1 Microwave-promoted synthesis of 6-[N,N-bis(2-hydroxy-
ethyl)amino]purine nucleosides.
To initiate our study, the influence of reaction conditions was
examined. As shown in Table 1, when CH2Cl2 was used as the
solvent, no reaction was observed (entry 1), when CH3CH2OH
Fig. 1 Structures of some 6-hydroxyethylpurine nucleosides.
Table 1 Effect of solvent and the optimization of reaction conditionsa
However, there are few reports on the synthesis of such 6-
hydroxyethylpurine nucleosides6a,6b and no detailed study on
such compounds. Recently, we have reported the synthesis of
C6-modified purine nucleosides such as C6-cyclo secondary
amine substituted purine analogues, C6-phosphonated purine
nucleosides and 6-N-(2-hydroxyethyl)aminopurine nucleosides
under microwave irradiation.7 The results showed that the
microwave-promoted method was very successful for various
modifications of nucleoside analogues. Based on our preliminary
study, we carried out a rapid and convenient method for the
preparation of novel 6-[N,N-bis(2-hydroxyethyl)amino]purine
nucleosides in good to excellent isolated yields under microwave
Entry
Solvent
T/◦C
Time/min
Yieldb (%)
1
2
3
4
5
6
CH2Cl2
CH3CH2OH
DMF
H2O
H2O
40
80
60
80
100
120
10
10
10
15
10
8
No reaction
40
89
88
91
90
College of Chemistry and Environmental Science, Henan Normal
University, Xinxiang, Henan, 453007, China.
E-mail: guohm518@hotmail.com; Fax: 86-373-3329276
† Electronic supplementary information (ESI) available: General; syn-
thesis and characterization of compounds; NMR spectra. See DOI:
10.1039/b902025j
H2O
a Reaction conditions: 2,6-dichloropurine (1 mmol), diethanolamine
(1.5 mmol), H2O (5 mL), MWI 400 W (100 ◦C). b Isolated yields based
on nucleobases.
760 | Green Chem., 2009, 11, 760–762
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was used as the solvent, low yield was obtained (entry 2) (40%).
With increasing solvent polarity, the yields were improved.
When DMF was used as the solvent, the yields could reach
to 89% (entry 3), but many side products were produced in
this reaction medium. To overcome the disadvantages of these
organic solvent, we used neat water as the solvent, and product
3a was still formed in good yield (entry 5) (91%). It is noteworthy
that no side products were obtained in water and the product 3a
could crystallizefromthe reaction system and could be separated
easily by direct filtration. At room temperature, the yield was low.
By increasing the temperature to 80 ◦C, the reaction completed
within 15 min with a yield of 88% (entry 4). By increasing the
temperature to 100 ◦C, the reaction completed within 10 min
with a yield of 91% (entry 5). By increasing the temperature
to 120 ◦C, no significant change in yield was observed (entry 6)
(90%). Therefore, 100 ◦C and 10 min were the optimized reaction
conditions. Further screening of irradiation power confirmed
that 400 W was the best condition.
products were prepared in good to excellent yields by using this
one-step reaction.
Intrigued by the above-described results, more electron-rich 2-
amino-6-chloropurine nucleosides were chosen as the substrates
to probe whether the nucleophilic substitution could be easily
accessed. As shown in Table 3, under microwave irradiation,
2-amino-6-chloropurine 1k reacted with diethanolamine to
afford 3k with 83% yield (entry 3) and 2-amino-6-chloropurine
nucleoside 1l gave the corresponding product 3l with 80%
yield (entry 6), which indicated that 2-amino-6-chloropurine
nucleosides can also react with this nucleophile smoothly in
good yields. Our synthetic method using microwave irradiation
is definitely valuable for the rapid access of these bioactive
heterocyclic bases. The results in Table 3 also show that
the relative activity of heterocyclic substrates for the nucle-
ophilic substitution is in the order: 2,6-dichloropurine > 6-
chloropurine > 2-amino-6-chloropurine, which indicated that
The substrate scope of 6-chloropurine nucleosides is sum-
marized in Table 2, a group of different substituents at N9 were
subjected to the optimized reaction conditions, including ribofu-
ranosyl, n-butyl, allyl, benzyl, etc. The kinds of substituents had
some impact on the yields. When R1 was H, the yield was much
higher (entry 1) (90%), ribofuranosyl-substituted substrates also
give high yield (entry 2) (82%), and allyl-substituted substrates
gave product 3f with 78% (entry 3). With all these substrates, the
Table 3 Reaction of diethanolamine with various 6-chloropurines, 2,6-
dichloropurines and 2-amino-6-choloropurinesa
Table 2 Reaction of diethanolamine with various 6-chloropurinesa
Entry
Product
R1
R2
Yieldb (%)
1
2
3
4
3e
3a
3k
3f
H
H
H
H
Cl
NH2
H
90
91
83
82
R1
H
Yieldb (%)
5
6
3b
3l
Cl
85
80
Entry
Product
1
2
3e
3f
90
82
NH2
3
4
3g
3h
78
75
7
8
9
3g
3c
3h
H
Cl
H
78
79
68
5
6
3i
3j
68
61
10
3d
Cl
72
a Reaction conditions: 6-chloropurine nucleosides (1◦ mmol), di-
ethanolamine (1.5 mmol), H2O (5 mL), MWI 400 W (100 C). b Isolated
yields based on nucleobases.
a Reaction conditions: 6-chloropurines (2,6-dichloropurines or 2-amino-
6-chloropurines) nucleosides (1 mmol), diethanolamine (1.5 mmol), H2O
(5 mL), MWI 400 W (100 ◦C). b Isolated yields based on nucleobases.
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the electron-donating effects on C2 could lead to decrease of the
yields.
hydroxyethyl)amino]purine nucleosides which are important
candidates for biologically active compounds. The synthetic
method using microwave irradiation is definitely valuable for
the rapid access of these bioactive heterocyclic bases, and the
pharmacological evaluation of these compounds is underway in
our laboratories.
In order to compare the efficiency of microwave irradia-
tion with conventional heating, 2-amino-6-chloropurine was
heated with 1.5 equiv of diethanolamine at 100 ◦C in an
oil bath for 10 min to give 30% of 2-amino-6-[N,N-bis(2-
hydroxyethyl)amino]purine, far less than the 85% under mi-
crowave irradiation. This clearly indicated that the microwave-
assisted reaction exhibited significant advantages over the
conventional heating by not only reducing the reaction time
but also improving the reaction yield.
The use of microwave irradiation to generate 6-hydroxy-
ethylpurine nucleosides was also tested on other 6-chloropurine
derivatives. For example, 9-allyl-2-(N,N-diallyl)-6-[N,N-bis-(2-
hydroxyethyl)amino]purine could also be synthesized from
the corresponding 9-allyl-2-(N,N-diallyl)-6-chloropurine with
an isolated yield of 57% using the same reaction conditions
(Scheme 2).
Acknowledgements
We are grateful for financial support from the National Nature
Science Foundation of China (grants 20772024 and 20802016).
Notes and references
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It was found that the reaction of 6-chloropurine nucleoside
and its analogues with diethanolamine could occur efficiently
under microwave irradiation within 10 min. It is very easy to
handle because most of the products can crystallize from the
solution and the pure samples can be obtained in excellent
yields after simple filtration and washing. And using water as
solvent makes this method environmentally benign. This will
be a highly useful method for the synthesis of 6-[N,N-bis(2-
hydroxyethyl)amino]purine nucleosides.
In conclusion, we have developed a rapid and operationally
simple method for the preparation of various 6-[N,N-bis(2-
762 | Green Chem., 2009, 11, 760–762
This journal is
The Royal Society of Chemistry 2009
©