The Convenient Synthesis of Unsaturated Nucleoside Analogues in Water under Microwave Irradiation

Article abstract of DOI:10.1080/15257770.2015.1114129

A convenient method for the regioselective synthesis of unsaturated nucleoside analogs in water under microwave irradiation was developed. All pyrimidine and purine nucleoside derivatives were exclusively alkylated at N1 and N9 respectively in good to excellent yields. In addition, this system could tolerate a broad range of functional groups, such as chloro, bromo, iodo, alkyl, amino, and hydroxyl groups. More importantly, the reaction scale could be enlarged to 50 mmol which made this route attractive for industrial application.

Full text of DOI:10.1080/15257770.2015.1114129

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
The Convenient Synthesis of Unsaturated
Nucleoside Analogues in Water under Microwave
Irradiation
Ran Xia & Li-Ping Sun
To cite this article: Ran Xia & Li-Ping Sun (2016): The Convenient Synthesis of Unsaturated
Nucleoside Analogues in Water under Microwave Irradiation, Nucleosides, Nucleotides and
Nucleic Acids, DOI: 10.1080/15257770.2015.1114129
To link to this article: http://dx.doi.org/10.1080/15257770.2015.1114129
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Date: 31 January 2016, At: 08:14

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
, VOL. , NO. , –
http://dx.doi.org/./..
The Convenient Synthesis of Unsaturated Nucleoside
Analogues in Water under Microwave Irradiation
Ran Xiaa and Li-Ping Sunb
aCollege of Chemistry and Chemical Engineering, Xinxiang City, Henan Province, P. R. China; bSchool of
Life Science and Technology, Xinxiang University, Xinxiang City, Henan Province, P. R. China
ABSTRACT
ARTICLE HISTORY
Received  June 
Accepted  October 
A convenient method for the regioselective synthesis of unsat-
urated nucleoside analogs in water under microwave irradiation
was developed. All pyrimidine and purine nucleoside derivatives
were exclusively alkylated at N1 and N9 respectively in good to
excellent yields. In addition, this system could tolerate a broad
range of functional groups, such as chloro, bromo, iodo, alkyl,
amino, and hydroxyl groups. More importantly, the reaction scale
could be enlarged to 50 mmol which made this route attractive
for industrial application.
KEYWORDS
Microwave irradiation;
convenient synthesis;
unsaturated nucleoside;
green solvent
GRAPHICAL ABSTRACT
In recent years, modified nucleoside analogues have become of great interest due to
their intriguing biological and pharmacological properties.[1–3] A number of nucleo-
side drugs exhibiting potent antiviral and antitumor activities have been prepared by
modification of the carbohydrate cycles.[4–6] Unsaturated bonds are widely prevalent
in carbohydrate cycles of many drugs and bioactive compounds such as neplanocin
A,[7] carbovir,[8] entecavir[9] and stavudine (Scheme 1).[10] Furthermore, because
the effective participation of arene moieties and p-bonds in biological systems, allyl
and arylmethyl nucleobases can be proved as vital synthons for the development of
new drug molecules.[11]
CONTACT Ran Xia
ing, Xinxiang, China.
ranxia@hotmail.com
Xinxiang University, College of Chemistry and Chemical Engineer-
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lncn.
©  Taylor & Francis Group, LLC

2
R. XIA AND L.-P. SUN
As a result, the development of methods for introducing unsaturated bonds into
nucleosides has been the subject of intense research. A variety of direct nucleophilic
substitution reactions have been developed for the synthesis of unsaturated nucle-
oside analogues in the presence of strong bases in organic solvents, such as DMF
(N,N-dimethyl-formamide), DCE (1,2-dichloroethane), and DMSO (dimethyl sul-
foxide) et al. (route 1, Scheme 2).[12,13] In addition, Mitsunobu reaction[14] and
palladium-catalyzed Tsuji–Trost reaction[15] were also available (routes 2–3,
Scheme 2). Iodine catalyzed coupling of 2,4-bis(trimethylsiloxy) pyrimidines with
allyl halides and arylmethyl halides was also employed to afford unsaturated nucle-
oside analogues.[16,17] Despite these extensive progresses, current methods have sig-
nificant limitations: some systems utilized strong basic conditions and organic sol-
vents. Others often required toxic and expensive transition metals. Therefore, a
green method with a broad substrate scope is highly desirable. Water is cheap, clean,
nontoxic, and nonflammable, which leads to easier workup and has attracted much
attention in synthetic chemistry recently.[18,19] In the context of ongoing projects on
the synthesis of nucleosides,[20–23,5] herein, we reported the synthesis of the simplest
unsaturated nucleoside analogs in water under microwave irradiation.
Scheme . The selected nucleoside drugs with unsaturated bonds.
Scheme . The routes to unsaturated nucleoside analogues.
Results and discussion
To initiate our study, we conducted the reaction of uracil and ally bromide in water
under microwave irradiation. The influence of various bases was examined to eval-
uate their activities as well as selectivities. The results are summarized in Table 1.
When DMF or acetonitrile was used as solvent, NaH or NaOH as base, the reac-
tion proceeded smoothly to give the product 3a in 36–56% yield (Table 1, entries
1–4). The base was necessary in water because no reaction happened without the

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Table . Optimization of reaction conditions.a
Entry
Solvent
Base
Reaction time/min
Yield/%b








DMF
DMF
CHCN
CHCN
HO
HO
HO
HO
HO
HO
HO
NaH
NaOH
NaH
NaOH
Free











10














80



EtN
DIPEA
DMAP
KCO
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH



12


 c
H2O
HO
HO
HO
aReaction conditions: 1a (. mmol), 2a (. mmol), base (. mmol), solvent ( mL), MW – W (°C);
bisolated yields;
cheated in oil bath at °C.
base (entry 5). However, lower yields were obtained when employing DMAP (4-
dimethylaminopyridine), Et3N or K2CO3 as the bases in water (entries 6–9). Chang-
ing reaction time had some influence on the yields (entries 11–14). When the reac-
tion time was shorter or longer than 10 minutes, lower yield was obtained. Therefore
10 minutes was the best choice. To verify the microwave effects, we conducted the
reaction in oil bath under the same reaction conditions. The reaction proceeded for
120 minutes and the product was isolated in lower yield of 68%, which showed the
positive effects of microwave irradiation.
After obtaining the optimized reaction conditions, we examined the scope of
pyrimidine derivatives using 2a as the alkylating donor (Scheme 3). The uracil and
cytosine derivatives could be alkylated in perfect regioselectivity to yield the desired
unsaturated nucleoside analogues 3a–3g in up to 91% yield. The pyrimidine bear-
ing different functional groups at C5 such as hydrogen, methyl, fluoro, chloro, and
bromo or iodo groups all furnished the target products in good yields (73–91%).
When H atom was substituted with methyl group in C5, the yield was enhanced
(3a versus 3b). When H atom at C5 was substituted with fluoro group, a slightly
reduced yield could be observed (3f versus 3g). The electron-withdrawing groups
at C5 had negative effects on the yields compared to electron-donating groups (3a
versus 3c–3e). The cytosine derivatives gave lower yields compared to the uracil
derivatives (3a versus 3f). To our delight, it is unnecessary to protect the exocyclic
amino group in cytosines (3f–3g), because the alkalinity of NH at N9 was stronger
than exocyclic amino group. More importantly, 3a and 3f could be got at 50 mmol
scales with maintained yields and the products could be purified by recrystallization
rather than time-consuming chromatography.
Next, we applied this procedure to a series of purine derivatives and the desired
products alkylated at N9 position were also obtained in moderate to good yields
(Scheme 4, 76–89%). Remarkably, several functional groups such as chloro, amino,
morpholinyl, and phenyl amine were tolerated well under the reaction conditions.

4
R. XIA AND L.-P. SUN
Scheme . Alkylation of ally bromide with pyrimidine derivatives.
It is also worthy of mentioning that the exocyclic amino groups in 5a–5b were not
alkylated (5a–5b). When the hydrogen at C2 was replaced by a chloride, the yield
increased slightly (5a versus 5b, 5d versus 5e, and 5f versus 5g). Furthermore, we
synthesized 5f and 5g at 50 mmol scales through easy workup process and the yields
were maintained.
Scheme . Alkylation of various purine derivatives with allyl bromide.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
In order to check the generality of our method, other alkylation donors were
investigated. Treatment of 6-chloropurine with allyl chloride, benzyl bromide, and
o-chloro-benzyl bromide under the optimized conditions as mentioned above gave
the corresponding products 6a–6b and 5f in good yields and good regioselectivity.
The results are summarized in Scheme 5. The alkylation donors containing bromide
usually gave the desired products in good yields (6a, 6b, and 5f) whereas the bro-
mide alkylation donors were more costly.
Scheme . Alkylation of -chloropurine with alkyl halides.
Conclusion
In conclusion, we developed a convenient method for the synthesis of unsaturated
nucleoside analogues in water under microwave irradiation. All of the products were
obtained in good to excellent yields. Pyrimidine and purine derivatives were exclu-
sively alkylated at N1 and N9, respectively. This method also had the practical advan-
tage that the protection of hydroxyl and amino groups was unnecessary. Extension
of this strategy to a new class of drugs and tools for chemical biology is currently in
progress in our laboratories.
Experimental
General
Melting points were recorded with a micro melting point apparatus and uncor-
1
rected. NMR spectra were recorded with a 400 MHz spectrometer for H NMR,

6
R. XIA AND L.-P. SUN
100 MHz for 13C NMR. Chemical shifts δ are given in ppm relative to tetram-
ethylsilane as internal standard, residual CHCl3 (DMSO) for 1H or 13C NMR spec-
troscopy. Multiplicities are reported as follows: singlet (s), doublet (d), doublet of
doublets (dd), triplet (t), quartet (q), and multiplet (m). High resolution mass spec-
tra were taken with a 3000 mass spectrometer, using Waters Q-TofMS/MS system.
The reaction was carried out in the single-mode MAS-II microwave reactor (real-
time monitoring and control of the reaction temperature by infrared temperature
measurement, accuracy 1°C) produced by Sineo Microwave Chemical Technol-
ogy Co. Ltd. For column chromatography silica gel (200–300 mesh) was used as the
stationary phase. All reactions were monitored by thin-layer chromatography. All
reagents and solvents were purchased from commercial sources and purified com-
monly before used.
General procedures
The procedure for uracil with ally bromide at 0.5 mmol scale (3a). To a mix-
ture of uracil (0.056 g, 0.5 mmol) and NaOH (0.014 g, 0.6 mmol) in neat H2O (2
mL), allyl bromide (0.052 mL, 0.6 mmol) was added. Then the mixture was put into
the microwave reactor and irradiated at 0–400 W (internal temperature: 100°C) for
10 minutes. After completion of the reaction, the mixture was concentrated under
reduced pressure and the residue was purified by column chromatography using
EtOAc-cyclohexane (9:1) as the eluent to afford 3a, yield 82%.
The procedure for uracil with ally bromide at 50 mmol scale (3a). To a mix-
ture of uracil (5.6 g, 50 mmol) and NaOH (1.44 g, 60 mmol) in neat H2O (200
mL), allyl bromide (5.2 mL, 60 mmol) was added. Then the mixture was put into
the microwave reactor and irradiated at 0–400 W (internal temperature: 100°C) for
10 minutes. After completion of the reaction, the mixture was concentrated under
reduced pressure and the residue was recrystallized from ethanol to afford 3a, yield
80%.
Characterization of Compounds, see the supporting information.
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