Ionic liquid mediated synthesis of 5-halouracil nucleosides: Key precursors for potential antiviral drugs

Article abstract of DOI:10.1080/15257770903170252

Synthesis of antiviral 5-halouracil nucleosides, also used as key precursors for the synthesis of other potential antiviral drugs, has been demonstrated using ionic liquids as convenient and efficient reaction medium.

Full text of DOI:10.1080/15257770903170252

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Ionic Liquid Mediated Synthesis of 5-
Halouracil Nucleosides: Key Precursors
for Potential Antiviral Drugs
Vineet Kumar a & Sanjay V. Malhotra a
a Laboratory of Synthetic Chemistry, SAIC-Frederick, NCI-Frederick ,
Frederick, Maryland, USA
Published online: 04 Sep 2009.
To cite this article: Vineet Kumar & Sanjay V. Malhotra (2009) Ionic Liquid Mediated Synthesis of 5-
Halouracil Nucleosides: Key Precursors for Potential Antiviral Drugs, Nucleosides, Nucleotides and
Nucleic Acids, 28:9, 821-834, DOI: 10.1080/15257770903170252
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Nucleosides, Nucleotides and Nucleic Acids, 28:821–834, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903170252
IONIC LIQUID MEDIATED SYNTHESIS OF 5-HALOURACIL
NUCLEOSIDES: KEY PRECURSORS FOR POTENTIAL ANTIVIRAL
DRUGS
Vineet Kumar and Sanjay V. Malhotra
Laboratory of Synthetic Chemistry, SAIC-Frederick, NCI-Frederick, Frederick, Maryland, USA
Synthesis of antiviral 5-halouracil nucleosides, also used as key precursors for the synthesis
2
of other potential antiviral drugs, has been demonstrated using ionic liquids as convenient and
efficient reaction medium.
Keywords Ionic liquids; antiviral; Idoxuridine; 5-halouracil nucleosides
INTRODUCTION
The rational variation at C-5 position of uracil nucleosides can enhance
their properties in terms of oral bioavailability, metabolic stability, pharma-
cokinetics, etc. 5-Halouracil nucleosides are of great pharmaceutical interest
and have been extensively investigated due to their anti-neoplastic and
anti-viral properties.[1] Idoxuridine, also known as 5-iodo-2ꢁ-deoxyuridine
and marketed as Herples and Stoxil, is one of the drugs used for conjunctival
and corneal disease associated with feline herpes virus. Some of the 5-
chlorouracil nucleoside derivatives have shown selective anti-HIV activity.[2]
5-Halouracil nucleosides are important intermediates for the synthesis of a
wide range of modified nucleosides showing activity, mainly against HSV-1
and HSV-2 (herpes simplex virus type 1 and 2) and VZV (varicella-zoster
virus).[3] Radioactive halogenated uracil nucleosides have been used as
Received 8 September 2008; accepted 30 June 2009.
This project has been funded in whole or in part with federal funds from the National Cancer
Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication
does not necessarily reflect the views or policies of the Department of Health and Human Services, nor
does mention of trade names, commercial products, or organizations imply endorsement by the U.S.
Government.
Address correspondence to Sanjay V. Malhotra, Laboratory of Synthetic Chemistry, SAIC-Frederick,
NCI-Frederick, 1050 Boyles Street, Frederick, Maryland, 21702, USA. E-mail: malhotrasa@mail.nih.gov
821

822
V. Kumar and S. V. Malhotra
mechanistic probes for DNA metabolism studies.[4] Therefore, new meth-
ods for the synthesis of 5-halouracil nucleosides are of great interest in
nucleoside chemistry.
One approach to synthesize 5-halouracil nucleosides is the coupling
of a protected chlorosugar and a halogenated base, but this method
requires multiple steps and often results in the mixture of α and β
anomers.[5] The other method is direct halogenation of protected or
unprotected nucleosides.[6] Prusoff et al. were the first to report iodi-
nation of uridine (U) and 2ꢁ-deoxyuridine (2ꢁ-dU) at the C-5 position
using I2/HNO3 or KI/H2SO4.[7] Later, Lipkin et al. carried out iodina-
tion of nucleosides with N-iodosuccinimide or iodine monochloride (ICl)
in DMSO or N-ethylacetamide using different catalysts.[8] In a similar
attempt, N-chlorosuccinimide has been used with an excess of pyridine
to obtain 5-chlorouracil nucleosides.[2] Dale et al. reported iodination of
5-mercurouridines in aqueous alcohol.[9] Chlorination of different nucle-
osides including uridine and 2ꢁ-deoxyuridine has been carried out using
an acyl chlorides/DMF/MCPBA system in moderate yields.[10] Recently,
Kumar et al. have reported halogenation of protected and unprotected
uracil nucleosides using N-halosuccinimides and ICl in the presence of
excess sodium azide, which required reaction times up to 48 hours.[11] All
the methods mentioned above have disadvantages, that is, harsh reaction
conditions, longer reaction time, use of toxic oxidizing agents or catalysts
(e.g., HNO3, H2SO4, sodium azide, etc.), highly toxic and high boiling
solvents (e.g., DMSO, DMF, pyridine, acetic acid, etc.), which are difficult to
remove and often get contaminated with product which makes the workup
procedure of these reactions more tedious. Asakura and Robins reported a
simple approach of 5-halogenation of U and dU with iodine and lithium
halides in the presence of ceric ammonium nitrate (CAN) using acetic
acid/acetonitrile as solvent.[12] This method required a highly acidic solvent
and lots of extraction steps in the workup. In this article, we have used the
same reagents in ionic liquids and observed superior results.
Over the last decade, ionic liquids (ILs) have emerged as effective
alternatives to conventional organic solvents due to their attractive proper-
ties viz. negligible vapor pressure, recyclability, high thermal stability and
their ability to dissolve a wide range of compounds.[13] The possibilities
of their structural variations help in designing ideal solvents suitable for
any particular process.[14] We have recently designed ILs that provide high
solubility for nucleosides and that were found to be efficient reaction
media for their selective modifications, giving high yields under ambient
conditions.[15] Herein we are reporting an improved, convenient, and safe
method for 5-halogenation of protected and unprotected U and dU using
lithium halides as halogenating agents in the presence of ceric ammonium
nitrate (CAN) with an ionic liquid as the reaction medium.

IL-Mediated Synthesis 5-Halouracil Nucleosides
823
FIGURE 1 Ionic liquids used for halogenation of U and 2ꢁdU.
RESULTS AND DISCUSSION
The ionic liquids utilized are 1-methoxyethyl-3-methylimidazolium
methanesulfonate ([MoeMIm][Ms]), 1-methoxyethyl-3-methylimidazolium
trifluoroacetate ([MoeMIm][TFA]), 1-butyl-3-methylimidazolium methane-
sulfonate ([BMIm][Ms]) and 1-butyl-3-methylimidazolium trifluoroacetate
([BMIm][TFA]) (Figure 1). The hydroxyl groups of 2ꢁ-deoxyuridine (2ꢁ-
dU) (1a) and uridine (U) (1b) were first acetylated to give 3ꢁ,5ꢁ-di-
O-acetyl-2ꢁ-deoxyuridine (2a) and 2ꢁ,3ꢁ,5ꢁ-tri-O-acetyluridine (2b), respec-
tively. Usually, these reactions are carried out in pyridine/DMAP[16] or
acetonitrile/Et3N/DMAP[17] with an excess of acetic anhydride, and the
reaction time varies from 2 to 12 hours. We carried out this reaction in ILs
[MoeMIm][Ms], [MoeMIm][TFA] and [BMIm][TFA] at room temperature
using DMAP as catalyst and a stoichiometric amount of acetic anhydride as
the acylating agent. The IL [BMIm][Ms] was not used for these reactions
as it is a solid at room temperature. The reactions with all three ILs were
completed in 20–25 minutes to give the acetylated derivative in high yields
as a single product (Scheme 1). Moreover, no purification was required and
the product was obtained by simple extraction. All three ILs were reused up
to four times for this reaction with no loss in product yield (Table 1).
All four ILs were then screened for 5-iodination of 2a under conditions
reported earlier in the literature i.e. using iodine or lithium iodide in
the presence of CAN at 80◦C (Table 2). In ILs [MoeMIm][TFA] and
[BMIm][TFA] having a trifluoroacetate anion, the reactions were slow.
Although, the conversion was relatively fast with iodine in both the ILs as
compared to that with lithium iodide, but the reactions were not 100%
complete and the deacetylated products started to form over time. At this
point the reactions were stopped and products were isolated (Table 2). In
IL [BMIm][Ms] also, the conversion was very slow and incomplete with
lithium iodide and the yield was only 10% but no deacetylation products
was observed on TLC (entry 6, Table 2), however, the reaction is fast in
the case of iodine and completed in 45 minutes to give the product in 80%

824
V. Kumar and S. V. Malhotra
SCHEME 1 Synthesis of 5-halouridines and 5-halo-2ꢁ-deoxyuridines.
yield (entry 7, Table 2). The best results were obtained in IL [MoeMIm][Ms]
where 100% conversion was observed in 20 minutes with lithium iodide and
in 1 hour with iodine to give the iodinated products in 96% (entry 1, Table
2) and 95% (entry 1, Table 2), respectively. The reaction time was less than
half as compared to the literature method in the case of lithium iodide and
yields were also better with both iodine and lithium iodide (Table 2).
TABLE 1 Recycling of ILs for acetylation reaction of U and 2ꢁ-dU
Reaction time (min)/yield (%)
[MoeMIm][Ms]
MoeMIm][TFA]
[BMIm][TFA]
Cycle
1a to 2a 1b to 2b 1a to 2a 1b to 2b 1a to 2a 1b to 2b
0
1
2
3
20/91
20/90
25/90
25/89
25/93
25/92
30/91
30/91
25/90
25/90
35/89
35/89
30/92
30/91
3091
25/90
30/89
30/89
35/85
30/93
30/92
35/90
35/89
35/90

IL-Mediated Synthesis 5-Halouracil Nucleosides
825
TABLE 2 5-Iodination of 2a (0.5 mmol) in different ILs at 80◦C
Entry
Solvent
MX (mol equiv.) CAN (mol equiv.) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
10
[MoeMIm][Ms]
[MoeMIm][Ms]
[MoeMIm][TFA]
[MoeMIm][TFA]
[BMIm][TFA]
[BMIm][TFA]
[BMIm][Ms]
[BMIm][Ms]
MeCN
LiI (1.2)
I2 (0.6)
I2 (0.6)
LiI (1.2)
I2 (0.6)
LiI (1.2)
I2 (0.6)
LiI (1.2)
I2 (0.6)
LiI (1.2)
2.0
0.5
0.5
2.0
0.5
2.0
0.5
2.0
0.5
2.0
20 min
96
95
1
3
12
3
12
45 min
12
1
1
70a
15a
65a
20a
80
10b
92c
93c
MeCN
aStarting material left and deacetylation starts after this time.
bStarting material left and no change in conversion was observed on TLC after this time.
cLiterature data from.[13]
The reaction proceeds through oxidation of halide salts by CAN result-
ing in the generation of electron deficient halogen species which attack at
C-5 position of the uracil moiety.[12b] It is also known that the kinetics of this
reaction depends on the concentration of CAN and the temperature.[12a] To
study these effects, we first carried out the iodination of 2a using iodine at
different concentration of CAN and at different temperatures. The results
show that the reaction rate increases with an increase in the concentration
of CAN (Table 3). Also, for the same concentration of CAN, the reaction
rate increased with an increase in temperature. It is important to note that
at higher temperatures the decomposition starts taking place over time, as
indicated by multiple spots on the TLC (entry 4, Table 3). The best results
were obtained with 1.0 equivalent of CAN where the reaction is completed
in 4 hours at room temperature to give 91% yield (entry 11, Table 3) and in
10 minutes at 100◦C to give 94% yield (entry 14, Table 3). Similar effects of
CAN concentration and temperature were also observed with iodination of
2a with lithium iodide (Table 4). No reactions were observed with 0.2 and
0.5 equivalents of lithium iodide at 80◦C (entry 1 and 2, Table 4), and the
conversion is incomplete (only 20%) with 1.0 equivalent of lithium iodide
(entry 3, Table 4). The best results with lithium iodide were obtained with
2.0 equivalent of CAN where the reaction is completed in 20 minutes at
80◦C and in 10 minutes at 100◦C to give the product in 96 and 94% yields,
respectively (entry 7 and 8, Table 4).
After thoroughly screening the reaction conditions, we carried out
halogenation of both protected and unprotected 2ꢁ-dU and U using lithium
halides (1.2 equiv.) and CAN (2.0 equiv.) at 80◦C. The results are sum-
marized in Table 5. The iodination and bromination of all the substrates
i.e. 2ꢁ-dU (1a) (entry 1 and 2, Table 5), U (1b) (entry 7 and 8, Table 5),
3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (2a) (entry 4 and 5, Table 5), 2ꢁ,3ꢁ,5ꢁ-tri-O-
acetyluridine (2b) (entry 10 and 11, Table 5) were achieved in comparable

826
V. Kumar and S. V. Malhotra
TABLE 3 Effect of CAN concentration and temperature on
5-iodination of 2a (0.5 mmol) using iodine (0.6 mol equiv.)
in IL [MoeMIm][Ms]
CAN (mol
equiv.)
Time
(h)
Entry
Temp (◦C)
Yield%
1
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.2
0.2
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
80
100
150
150
80
100
RT
50
4.0
1.0
1.0
3.0
1.5
45 min
4.0
1.2
1.0
30 min
4.0
82
90
75a
b
90
94
30c
93
93
95
91
94
95
94
9
80
10
11
12
13
14
100
RT
50
80
100
35 min
20 min
10 min
aStarting material left.
bDecomposition was observed on TLC indicated by multi-
ple spots.
cStarting material left and no change in conversion was
observed on TLC after this time.
yields in less time as compared to the reported method. The yields were
lower in the case of the chlorination reaction because of competitive
decomposition, which was also observed in the reported method. Moreover,
no product could be isolated for the chlorination of uridine (1b) using LiCl
in literature method, while our method afforded the desired product in 32%
isolated yields (entry 9, Table 5). The deacetylation reactions were carried
out using 0.5 M NaOMe/MeOH in quantitative yields. The overall yields of
TABLE 4 Effect of CAN concentration and temperature on 5-iodination of
2a (0.5 mmol) using lithium iodide (1.2 mol equiv.) in IL [MoeMIm][Ms]
Entry
CAN (mol equiv.)
Temp. (◦C) Time (h)
Yield%
1
2
3
8
4
5
6
7
8
0.2
0.5
1.0
1.5
1.5
1.5
2.0
2.0
2.0
80
80
80
50
80
100
50
80
24.0
24.0
2.0
no reactiona
no reactiona
20b
30b
95
94
90
6.0
40 min
30 min
4.0
20 min
10 min
96
94
100
aNo reaction.
bStarting material left and no change in conversion was observed on TLC
after this time.

IL-Mediated Synthesis 5-Halouracil Nucleosides
827
TABLE 5 5-Halogenation of acetylated and unacetylated
2ꢁ-dU and U in IL [MoeMIm][Ms] using lithium halides (1.2
mol equiv.)
Substrate
Product (%
Entry (0.5 mmol)
MX
LiI
Time (h)
Yield)
1
2
1a
1a
10 min
30 mina
20 min
30 mina
5.0
4a (82)
4b (73)a
LiBr
4b (86)
4b (81)a
3
4
1a
2a
LiCl
LiI
4c (30)b
20 min
3a (95) 4a (90)c
3a (93)a
1.0a
5
2a
2a
1b
1b
1b
2b
2b
2b
LiBr
LiCl
LiI
30 min
1.5a
3b (94) 4b (88)c
3b (90)a
6
2.5
3c (58)d 4c (55)c
3c (95)a
6.0a
7
20 min
30 mina
20 min
30 mina
5.0
4d (80)
4d (78)a
8
LiBr
LiCl
LiI
4e (80)
4e (82)a
9
4f (32)b
4.0a
Decompositiona
3d (92) 4d (76)c
3d (96)a
10
11
12
20 min
1.0a
LiBr
LiCl
30 min
1.5a
3e (93) 4e (76)c
3e (91)a
2.0
3f (32)d 4f (30)c
3f (90)a
24.0a
aLiterature data from ref[13] using acetic acid/MeCN as
solvent.
bStarting material left and decomposition of product was
also observed as indicated by multiple spots on TLC.
cOverall yield from 2a or 2b.
dDecomposition was taking place simultaniously.
compounds 4a, 4b, 4c from 2a and that of compounds 4d, 4e and 4f from
2b are given in Table 5 (entry 4, 5, 6, 10, 11, and 12). It is also important
to note that all the reported methods for halogenation of nucleosides
require 10–15 ml of highly polar and high boiling solvents (viz. DMSO, DMF,
acetic acid, etc) to dissolve 1 mmol of substrate.[7–13] But in our reactions
only 1 ml of IL was required to dissolve the same amount of substrate
because of their highly solubilizing nature. This 10-fold decrease in the
solvent requirement makes this protocol more benign. In comparison to the
multiple extraction and chromatography steps required in earlier reports,
the workup procedure of our method is very simple. The reaction mixture,
being very low in the volume, was directly loaded on silica gel column and
the products were isolated by using methanol/dichloromethane as eluents

828
V. Kumar and S. V. Malhotra
in increasing order of polarity, however the ionic liquids could not be
recovered in this process.
CONCLUSION
In summary, we have successfully synthesized 5-halo derivatives of both
protected and unprotected U and 2ꢁdU using ionic liquids as reaction
medium. The acetyl protection of hydroxyl groups of U and 2ꢁdU was
also carried out in ILs and all the ILs were successfully recovered and
reused for up-to 4 cycles without any loss in yields. The lower reac-
tion volume of IL mediated reactions makes the workup procedure very
convenient.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Varian 400MR
spectrometer at 400 and at 101 MHz, respectively using TMS as internal stan-
dard. The LC-MS were done on Agilent 1200 series system equipped with Ag-
ilent 6210 Time-Of-Flight mass detector. All chemicals used were purchased
either from Sigma-Aldrich Corp. (St. Louis, MO, USA) and used without
further purification. Analytical thin layer chromatography (TLC) was per-
formed on precoated Merck silica gel 60F254 plates; the spots were de-
tected under ultraviolet (UV) light or by charring with 5% H2SO4/ethanol
solution. Purification of all the products was done on Teledyne ISCO
Combiflash Companion flash chromatography system. Ionic liquid 1-butyl-
3-methylimidazolium methanesulfonate ([BMIm][Ms]) was purchased
from Sigma-Aldrich Ionic liquids 1-methoxyethyl-3-methylimidazolium
methanesulfonate ([MoeMIm][Ms]), 1-methoxyethyl-3-methylimidazolium
triflruoroacetate ([MoeMIm][TFA]) and 1-butyl-3-methylimidazolium tri-
flruoroacetate ([BMIm][TFA]) were prepared following the literature
protocol.[5b]
General procedure for acetylation of 1a and 1b in ionic liquids: 1a (1g,
4.38 mmol) or 1b (1g, 4.09 mmol) was dissolved in IL (3 ml) at 50◦C and
the mixture was then cooled down to room temperature (substrate does not
precipitate at room temperature once it is dissolved) followed by addition
of 4-dimethylaminopyridine (DMAP) (100 mg) and acetic anhydride (9.20
mmol for 1a and 13.09 mmol for 2a). The reaction mixture was stirred at
room temperature. After completion (TLC), water (15 ml) was added to
reaction mixture and product was extracted with ethyl acetate (5 × 25 ml).
The water layer was concentrated on rotary evaporator to recover the IL
which was dried in vacuum oven overnight and was further used for the
same reaction. The combined organic layers were first washed with saturated

IL-Mediated Synthesis 5-Halouracil Nucleosides
829
sodium bicarbonate solution followed by water and then dried over sodium
sulfate and finally concentrated on rotary evaporator and dried overnight
under vacuum to get the desired acetoxy derivatives 2a and 2b as off-white
solids.
General procedure for iodination of 2a using iodine in ionic liquids: 2a
(0.5 mmol) was taken in a vial and dissolved in ionic liquid (1 ml) at 50◦C.
The mixture was then cooled down to room temperature (no precipitation
of substrate was observed at room temperature) followed by the addition
of CAN and iodine. The reaction mixture was then stirred at the desired
temperature. To check the reaction progress, a small amount of reaction
mixture was taken out by capillary tube and dissolved in methanol and this
solution was used to check the TLC (5% MeOH/CH2Cl2). After completion,
the reaction mixture was diluted by CH2Cl2 (5 ml), loaded on a silica
gel column, which was eluted with MeOH/CH2Cl2 in increasing order of
polarity. The fractions containing the pure product were mixed together
and concentrated under vacuum to get the desired product 3a. The reaction
temperature, different ionic liquids used, and amount of CAN and iodine
(with respect to the substrate) for different reactions along with the isolated
yields are given in Tables 2 and 3.
General procedure for halogenation of nucleosides using lithium
halides in ionic liquids: Compound 1a, 1b, 2a, or 2b (0.5 mmol) was
dissolved in IL (1 ml) at 50◦C and the mixture was then cooled down to
room temperature followed by addition of CAN and lithium halides. The
reaction mixture was then stirred at the desired temperature. To check
the reaction progress, a small amount of reaction mixture was taken out
by capillary tube and dissolved in methanol, and this solution was used to
check the TLC for reactions of 1a, 1b (20% MeOH/CH2Cl2), and 2a, 2b
(5% MeOH/CH2Cl2). After completion, the reaction mixture was diluted
by CH2Cl2 (5 ml), loaded on silica gel column which was eluted with
MeOH/CH2Cl2 in increasing order of polarity. The fractions containing
the pure product were mixed together and concentrated under vacuum to
get the desired products. The reaction temperature, different ionic liquids
used, and amount of CAN and lithium halides used (with respect to the
substrate) for different reactions alongwith the isolated yields are given in
Tables 2, 4, and 5.
General procedure for deacetylation reactions: The deacetylation was
carried out by base-catalyzed de-esterification. Compounds 3a-d (0.25
mmol) were dissolved in the 0.5 M solution of NaOMe in methanol (2 ml)
and the reaction mixture was stirred at room temperature. The reaction
was completed in one h and checked by TLC (10% MeOH/CH2Cl2). The
reaction mixture was then concentrated under vacuum and the residue was
purified by silica gel flash chromatography using MeOH/CH2Cl2 as solvent
system in increasing order of polarity to get the products 4a-d. The overall
yields of 4a-d from 2a-b are given in Table 5.

830
V. Kumar and S. V. Malhotra
3ꢁ,5ꢁ-Di-O-acetyl-2ꢁ-deoxyuridine (2a):[18] Obtained as white solid with
m.p. 106–107◦C (lit m.p. 104–108◦C[18]); 1H NMR (400 MHz, CDCl3, δ) 9.82
(s, 1H, NH), 7.51 (d, 1H, J = 8.2 Hz, H6), 6.29 (dd, 1H, J = 5.9 and 7.9 Hz,
H1ꢁ), 5.80 (d, 1H, J = 8.1 Hz, H5), 5.22 (d, 1H, J = 6.4 Hz, H3ꢁ), 4.42–4.22
4ꢁ
(m, 3H, H5ꢁ and H ), 2.54 (dd, 1H, J = 4.3 and 14.2 Hz, H2 ), 2.26–1.97
ꢁ
b
(m, 7H, H2ꢁ and 2 × CH3CO); 13C NMR (101 MHz, CDCl3, δ) 170.53
a
(CH3CO), 170.37 (CH3CO), 163.50 (C4), 150.49 (C2), 139.02 (C6), 103.10
(C5), 85.45 (C1ꢁ), 82.49 (C3ꢁ), 74.22 (C4ꢁ), 63.95 (C5ꢁ), 37.97 (C2ꢁ), 21.03
(CH3CO), 20.94 (CH3CO); LC-MS (ESI-TOF): m/z 313.12259 ([M+H]+,
C13H17N2O7Na calcd. 313.10303).
2ꢁ,3ꢁ,5ꢁ-Tri-O-acetyluridine (2b):[19] Obtained as white solid with m.p.
127–128◦C (lit. m.p. 128.3–129.7◦C[19]); H NMR (400 MHz, CDCl3, δ)
1
9.75 (s, 1H, NH), 7.42 (d, 1H, J = 8.2 Hz, H6), 6.06 (d, 1H, J = 4.9
Hz, H1ꢁ), 5.81 (d, 1H, J = 8.1 Hz, H5), 5.41–5.30 (m, 2H, H2ꢁ and H3ꢁ),
4.42–4.30 (m, 3H, H5ꢁ and H4ꢁ), 2.15 (s, 3H, CH3CO), 2.14 (s, 3H, CH3CO),
2.11 (s, 3H, CH3CO).13C NMR (101 MHz, CDCl3, δ) 170.19 (CH3CO),
169.68 (CH3CO), 169.67 (CH3CO), 163.10 (C4), 150.40 (C2), 139.39 (C6),
103.45 (C5), 87.45 (C1ꢁ), 79.92 (C3ꢁ), 72.72 (C2ꢁ), 70.21 (C4ꢁ), 63.20 (C5ꢁ),
20.79 (CH3CO), 20.53 (CH3CO), 20.43 (CH3CO); LC-MS (ESI-TOF): m/z
371.13206 ([M+H]+, C15H19N2O9 calcd. 371.10851).
5-Iodo-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (3a):[11] Obtained as white solid
with m.p. 156–158◦C (lit. m.p. 157–158◦C[11]); 1H NMR (400 MHz, CDCl3,
δ) 9.76 (s, 1H, NH), 7.98 (s, 1H, H6), 6.30 (dd, 1H, J = 5.8 and 8.1 Hz,
H1ꢁ), 5.25 (dt, 1H, J = 1.9 and 6.3 Hz, H3ꢁ), 4.45–4.28 (m, 3H, H5ꢁ and H4ꢁ),
2.61–2.52 (m, 1H, bH2ꢁ), 2.26–2.19 (m, 4H, aH2ꢁ and CH3CO), 2.13 (s, 3H,
CH3CO). 13C NMR (101 MHz,) 170.43 (CH3CO), 170.21 (CH3CO), 159.94
(C4), 150.08 (C2), 143.81 (C6), 85.50 (C1ꢁ), 82.66 (C3ꢁ), 74.13 (C4ꢁ), 69.10
(C5), 63.88 (C5ꢁ), 38.26 (C2ꢁ), 21.14 (CH3CO), 20.92 (CH3CO); LC-MS
(ESI-TOF): m/z 439.02593 ([M+H]+, C13H16IN2O7 calcd. 438.99967).
5-Bromo-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (3b):[11] Obtained as white
solid with m.p. 153–154◦C (lit. m.p. 15205–153◦C[11]); 1H NMR (400 MHz,
CDCl3, δ) 9.37 (s, 1H, NH), 7.91 (s, 1H, H6), 6.31 (dd, 1H, J = 5.8
and 8.0 Hz, H1ꢁ), 5.24 (d, 1H, J = 6.6 Hz, H3ꢁ), 4.47–4.27 (m, 3H, H5ꢁ
and H4ꢁ), 2.56 (ddd, 1H, J = 2.2, 5.8 and 14.3 Hz, bH2ꢁ), 2.27–2.16
(m, 4H, H2ꢁ and CH3CO), 2.13 (s, 3H, CH3CO). 13C NMR (101 MHz,)
a
170.39 (CH3CO), 170.13 (CH3CO), 158.70 (C4), 149.54 (C2), 138.58 (C6),
97.46 (C5), 85.56 (C1ꢁ), 82.69 (C-3ꢁ), 73.98 (C4ꢁ), 63.81 (C5ꢁ), 38.26
(C2ꢁ), 20.93(CH3CO), 20.89 (CH3CO); LC-MS (ESI-TOF): m/z 391.04328
([M+H]+, C13H16BrN2O7 calcd. 391.01345).
5-Chloro-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (3c):[11] Obtained as white
1
solid with m.p. 174–175◦C (lit. m.p. 174.5–175◦C[11]); H NMR (400 MHz,
CDCl3, δ) 9.07 (s, 1H, NH), 7.81 (s, 1H, H6), 6.31 (dd, 1H, J = 5.7 and 8.0
Hz, H1ꢁ), 5.24 (dt, 1H, J = 2.4 and 6.4 Hz, H3ꢁ), 4.45–4.27 (m, 3H, H5ꢁ and

IL-Mediated Synthesis 5-Halouracil Nucleosides
831
H4ꢁ), 2.56 (ddd, 1H, J = 2.3, 5.8 and 14.3 Hz, bH2ꢁ), 2.25–2.15 (m, 4H, aH2ꢁ
and CH3CO), 2.13 (s, 3H, CH3CO). 13C NMR (101 MHz, CDCl3, δ) 170.36
(CH3CO), 170.08 (CH3CO), 158.47 (C4), 149.16 (C2), 135.92 (C6), 109.67
(C5), 85.52 (C1ꢁ), 82.65 (C-3ꢁ), 73.88 (C4ꢁ), 63.76 (C5ꢁ), 38.20 (C2ꢁ), 20.87
(CH3CO), 20.84 (CH3CO); LC-MS (ESI-TOF): m/z 347.07952 ([M+H]+,
C13H16ClN2O7 calcd. 347.06406).
[19]
5-Iodo-2ꢁ,3ꢁ,5ꢁ-tri-O-acetyluridine (3d):
Obtained as white solid with
1
m.p. 177–178◦C (lit. m.p. 177.8–179.3◦C[19]); H NMR (400 MHz, CDCl3,
δ) 7.90 (s, 1H, H6), 6.08 (d, 1H, J = 5.0 Hz, H1ꢁ), 5.31– 5.35 (m, 2H, H2ꢁ
and H3ꢁ), 4.43–4.32 (m, 3H, H4ꢁ and H5ꢁ), 2.25 (s, 3H, CH3CO), 2.14 (s,
3H, CH3CO), 2.11 (s, 3H, CH3CO). 13C NMR (101 MHz, CDCl3, δ) 170.30
(CH3CO), 169.86 (CH3CO), 169.83 (CH3CO), 159.68 (C4), 150.06 (C2),
143.92 (C6), 87.37 (C1ꢁ), 80.54 (C3ꢁ), 73.30 (C2ꢁ), 70.41 (C4ꢁ), 69.83 (C5),
63.25 (C5ꢁ), 21.35 (CH3CO), 20.74 (CH3CO), 20.64 (CH3CO); LC-MS (ESI-
TOF): m/z 497.03674 ([M+H]+, C15H18IN2O9 calcd. 497.00515).
5-Bromo-2ꢁ,3ꢁ,5ꢁ-tri-O-acetyluridine (3e):[12b] Obtained as colorless
highly viscous material that solidify on scratching to give a white solid
1
with m.p. 50–55◦C (m.p not reported in lit.); H NMR (400 MHz, CDCl3,
δ) 9.24 (brs, 1H, NH), 7.85 (s, 1H, H6), 6.10 (d, 1H, J = 4.1 Hz, H1ꢁ),
5.37–5.29 (m, 2H, H2ꢁ and H3ꢁ), 4.46–4.31 (m, 3H, H4ꢁ and H5ꢁ), 2.23 (s, 3H,
CH3CO), 2.14 (s, 3H, CH3CO), 2.12 (s, 3H, CH3CO). 13C NMR (101 MHz,
CDCl3, δ) 170.08 (CH3CO), 169.66 (CH3CO), 169.61 (CH3CO), 158.49
(C4), 149.55 (C2), 138.54 (C6), 97.97 (C5), 87.29 (C1ꢁ), 80.28 (C3ꢁ), 73.10
(C2ꢁ), 70.07 (C4ꢁ), 62.96 (C5ꢁ), 20.94 (CH3CO), 20.53 (CH3CO), 20.41
(CH3CO); LC-MS (ESI-TOF): m/z 449.04934 ([M+H]+, C15H18BrN2O9
calcd. 449.01902).
5-Chloro-2ꢁ,3ꢁ,5ꢁ-tri-O-acetyluridine (3f):[12b] Obtained as colorless highly
viscous material that solidify on scratching to give a white solid with m.p.
1
46–50◦C (m.p not reported in lit.); H NMR (400 MHz, CDCl3, δ) 8.98 (s,
1H, NH), 7.75 (s, 1H, H6), 6.09 (d, 1H, J = 3.9 Hz, H1ꢁ), 5.37–5.30 (m, 2H,
H2ꢁ and H3ꢁ), 4.45–4.31 (m, 3H, H4ꢁ and H5ꢁ), 2.21 (s, 3H, CH3CO), 2.13 (s,
3H, CH3CO), 2.12 (s, 3H, CH3CO). 13C NMR (101 MHz, CDCl3, δ) 170.01
(CH3CO), 169.62 (CH3CO), 169.57 (CH3CO), 158.27 (C4), 149.20 (C2),
135.87 (C6), 110.12 (C5), 87.30 (C1ꢁ), 80.26 (C3ꢁ), 73.06 (C2ꢁ), 70.02 (C4ꢁ),
62.91 (C5ꢁ), 20.83 (CH3CO), 20.50 (CH3CO), 20.41 (CH3CO); LC-MS (ESI-
TOF): m/z 405.09464 ([M+H]+, C15H18ClN2O9 calcd. 405.06953).
5-Iodo-2ꢁ-deoxyuridine (4a):[11] Obtained as white solid with m.p.
1
172–180◦C (dec) (lit. m.p. 170–180◦C (dec)[11]); H NMR (400 MHz,
DMSO-d6, δ) 11.66 (s, 1H, NH), 8.40 (s, 1H, H6), 6.10 (t, 1H, J = 6.5
Hz, H1ꢁ), 5.24 (d, 1H, J = 4.2 Hz, OH3ꢁ), 5.14 (t, 1H, J = 4.8 Hz, OH5ꢁ),
4.21–4.26 (m, 1H, H3ꢁ), 3.79 (dd, 1H, J = 3.2 and 6.4 Hz, H4ꢁ), 3.67–3.51
(m, 2H, H5ꢁ), 2.20–2.04 (m, 2H, H2ꢁ). 13C NMR (101 MHz, DMSO-d6, δ)
160.48 (C4), 150.09 (C2), 145.03 (C6), 87.50 (C1ꢁ), 84.63 (C3ꢁ), 69.99 (C5),

832
V. Kumar and S. V. Malhotra
69.25 (C4ꢁ), 60.80 (C5ꢁ), 40.13 (C2ꢁ); LC-MS (ESI-TOF): m/z 354.995241
([M+H]+, C9H12IN2O5 calcd. 354.97854).
5-Bromo-2ꢁ-deoxyuridine (4b):[11] Obtained as white solid with m.p.
1
174–176◦C (dec) (lit. m.p. 175–179◦C (dec)[11]); H NMR (400 MHz,
DMSO-d6, δ) δ 11.76 (s, 1H, NH), 8.36 (s, 1H, H6), 6.07 (t, 1H, J = 6.5
Hz, H1ꢁ), 5.22 (brs, 1H, OH3ꢁ), 5.14 (brs, 1H, OH5ꢁ), 4.21 (d, 1H, J =
3.3 Hz, H3ꢁ), 3.77 (q, 1H, J = 3.2 Hz, H4ꢁ), 3.57 (dd, 2H, J = 11.7 and
25.3 Hz, H5ꢁ), 2.19–2.01 (m, 2H, H2ꢁ). 13C NMR (101 MHz, DMSO-d6, δ)
159.17 (C4), 149.74 (C2), 140.27 (C6), 95.66 (C5), 87.57 (C1ꢁ), 84.86 (C3ꢁ),
69.96 (C4ꢁ), 60.79 (C5ꢁ), 40.13 (C2ꢁ); LC-MS (ESI-TOF): m/z 307.00631
([M+H]+, C9H12BrN2O5 calcd. 306.99241).
5-Chloro-2ꢁ-deoxyuridine (4c):[11] Obtained as white solid with m.p.
1
174–178◦C (dec) (lit. m.p. 173–176◦C (dec)[11]); H NMR (400 MHz,
DMSO-d6, δ) 11.80 (brs, 1H, NH), 8.28 (s, 1H, H6), 6.08 (t, 1H, J = 6.5
Hz, H1ꢁ), 5.22 (d, 1H, J = 3.8 Hz, OH3ꢁ), 5.14 (brs, 1H, OH5ꢁ), 4.21 (brs,
1H, H3ꢁ), 3.77 (q, 1H, J = 3.2 Hz, H4ꢁ), 3.52–3.62 (m, 2H, H5ꢁ), 2.15–2.03
(m, 2H, H2ꢁ). 13C NMR (101 MHz, DMSO-d6, δ) 160.09 (C4), 150.40 (C2),
137.39 (C6), 107.27 (C5), 87.45 (C1ꢁ), 84.76 (C3ꢁ), 70.02 (C4ꢁ), 60.89 (C5ꢁ),
40.09 (C2ꢁ); LC-MS (ESI-TOF): m/z 263.05489 ([M+H]+, C9H12ClN2O6
calcd. 263.04293).
5-Iodouridine (4d):[11] Obtained as white solid with m.p. 205–210◦C
1
(dec) (lit. m.p. 207–209◦C (dec)[11]); H NMR (400 MHz, DMSO-d6, δ)
11.68 (s, 1H, NH), 8.48 (s, 1H, H6), 5.72 (d, 1H, J = 4.6 Hz, H1ꢁ), 5.41 (d,
1H, J = 5.0 Hz, OH3ꢁ), 5.26 (t, 1H, J = 4.5 Hz, OH5ꢁ), 5.07 (d, 1H, J = 5.0
Hz, OH2ꢁ), 4.01 (dq, 2H, J = 4.6 and 21.6 Hz, H3ꢁ and H2ꢁ), 3.87 (dt, 1H, J =
2.6 and 4.9 Hz, H4ꢁ), 3.73–3.64 (m, 1H,a H5ꢁ), 3.62–3.53 (m, 1H,b H5ꢁ). 13
C
NMR (101 MHz, DMSO-d6, δ) 160.48 (C4), 150.35 (C2), 145.11 (C6), 96.17
(C5), 88.27 (C1ꢁ), 84.73 (C3ꢁ), 73.95 (C2ꢁ), 69.31 (C4ꢁ), 60.18 (C5ꢁ); LC-MS
(ESI-TOF): m/z 370.99221 ([M+H]+, C9H12IN2O6 calcd. 370.97346).
5-Bromouridine (4e):[11] Obtained as white solid with m.p. 190–95◦C
1
(dec) (lit. m.p. 190–198◦C (dec)[11]); H NMR (400 MHz, DMSO-d6, δ)
δ11.78 (s, 1H, NH), 8.45 (s, 1H, H6), 5.70 (d, 1H, J = 4.5 Hz, H1ꢁ), 5.40
(d, 1H, J = 5.2 Hz, OH3ꢁ), 5.25 (t, 1H, J = 4.7 Hz, OH5ꢁ), 5.04 (d, 1H,
J = 4.6 Hz, OH2ꢁ), 4.01 (dd, 1H, J = 4.7 and 9.4 Hz, H3ꢁ), 3.96 (d, 1H, J
= 4.2 Hz, H2ꢁ), 3.84 (dt, 1H, J = 2.7 and 4.9 Hz), 3.67 (dd, 1H, J = 6.7
and 9.8 Hz), 3.59–3.50 (m, 1H). 13C NMR (101 MHz, DMSO-d6, δ)159.14
(C4), 149.97 (C2), 140.35 (C6), 95.69 (C5), 88.49 (C1ꢁ), 84.67 (C3ꢁ), 73.94
(C2ꢁ), 69.25 (C4ꢁ), 60.11 (C5ꢁ); LC-MS (ESI-TOF): m/z 323.0019 ([M+H]+,
C9H12BrN2O6 calcd. 322.98733).
5-Chlorouridine (4f):[11] Obtained as white solid with m.p. 210–216◦C
1
(dec) (lit. m.p. 215–220◦C (dec)[11]); H NMR (400 MHz, DMSO-d6, δ)
11.85 (s, 1H, NH), 8.41 (s, 1H, H6), 5.73 (d, 1H, J = 4.5 Hz, H1ꢁ), 5.43
(d, 1H, J = 5.3 Hz, OH3ꢁ), 5.28 (t, 1H, J = 4.7 Hz, OH5ꢁ), 5.08 (d, 1H, J =

IL-Mediated Synthesis 5-Halouracil Nucleosides
833
5.4 Hz, OH2ꢁ), 4.05 (dd, 1H, J = 4.8 and 9.6 Hz, H3ꢁ), 3.99 (dd, 1H, J = 4.9
and 9.8 Hz, H2ꢁ), 3.87 (dt, 1H, J = 2.7 and 5.0 Hz, H4ꢁ), 3.74–3.64 (m, 1H,
bH5ꢁ), 3.64–3.54 (m, 1H, H5ꢁ). 13C NMR (101 MHz, DMSO-d6, δ) 160.49
a
(C4), 150.99 (C2), 137.43 (C6), 107.35 (C5), 88.56 (C1ꢁ), 84.55 (C3ꢁ),
73.88 (C2ꢁ), 69.30 (C4ꢁ), 60.24 (C5ꢁ); LC-MS (ESI-TOF): m/z 279.04976
([M+H]+, C9H12ClN2O6 calcd. 279.03784).
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