An efficient and facile methodology for bromination of pyrimidine and purine nucleosides with sodium monobromoisocyanurate (SMBI)

Article abstract of DOI:10.3390/molecules181012740

An efficient and facile strategy has been developed for bromination of nucleosides using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides. Unprotected and also several protected nucleosides were brominated in moderate to high yields following this procedure.

Full text of DOI:10.3390/molecules181012740

Molecules 2013, 18, 12740-12750; doi:10.3390/molecules181012740
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
An Efficient and Facile Methodology for Bromination of
Pyrimidine and Purine Nucleosides with Sodium
Monobromoisocyanurate (SMBI)
Jyotirmoy Maity * and Roger Stromberg *
Department of Biosciences and Nutrition, Karolinska Institute (KI), Novum, Huddinge SE-141 83,
Sweden
* Authors to whom correspondence should be addressed; E-Mails: Jyotirmoy.Maity@ki.se (J.M.);
Roger.Stromberg@ki.se (R.S.); Tel.: +46-8-5248-1024 (R.S.); Fax: +46-8-5248-1034 (R.S.).
Received: 2 September 2013; in revised form: 2 October 2013 / Accepted: 9 October 2013 /
Published: 15 October 2013
Abstract: An efficient and facile strategy has been developed for bromination of nucleosides
using sodium monobromoisocyanurate (SMBI). Our methodology demonstrates bromination
at the C-5 position of pyrimidine nucleosides and the C-8 position of purine nucleosides.
Unprotected and also several protected nucleosides were brominated in moderate to high
yields following this procedure.
Keywords: bromination; sodium monobromoisocyanurate (SMBI); pyridine-based
nucleosides; purine-based nucleosides; bromonucleosides
1. Introduction
Over the past decades, 5-halopyrimidine nucleosides have been found to be of interest for their
antiviral [1–3] and antineoplastic [4,5] properties. 5-Bromo-2'-deoxyuridine has shown in vivo
antiviral activity through its incorporation into the DNA of replicating cells as a structural analogue of
thymidine [6]. Radiolabeled 5-bromo- and 5-iodo-pyrimidine nucleoside analogues have been tested
for their potential in diagnostic oncology [7]. In search of new potential agents with superior biological
activity, a variety of structural and functional moieties have been introduced into pyrimidine and
purine nucleoside analogues by palladium assisted routes [8]. Halonucleosides have been used
extensively as starting material for these reactions. 8-Bromopurine nucleosides have been used as key
intermediates for synthesizing fluorescently labeled nucleosides, which have promising applications in

Molecules 2013, 18
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the field of molecular biology [9,10]. In view of this relevance, development of efficient methodology
for the synthesis of 5-bromopyrimidine and 8-bromopurine nucleosides is always of immense interest.
Direct halogenation of nucleosides has been found to be a proficient approach for the synthesis of
5-halopyrimidine, 6-halopurine [11–13] and 8-halopurine nucleosides [14]. Unprotected and protected
nucleosides have been halogenated by direct reaction with halogens or halogenating agents. Bromination
at C-5 of pyrimidine moieties was achieved by reaction of Br2/water [15], Br2/DMF [16], Br2/CCl4 [17],
Br2/CCl4 in solvent mixture of anhydrous acetic acid and pyridine [18], N-bromosuccinimide (NBS) in
DMF [19], NBS/NaN3 in DME [20], NBS in ionic liquids [21], m-chloroperbenzoic acid (MCPBA)/HBr
in DMA or DMF [22], ceric ammonium nitrate (CAN)/LiBr in AcOH or MeCN [23], KBr/potassium
monoperoxysulfate under aqueous conditions [24]. Bromination of C-8 of purine moieties has been
attained by reaction of Br2 in glacial AcOH/NaOAc [25], NBS in DMF [19], Br2 in NaOAc
buffer/dioxane [10] and Br2 in NaOAc buffer [26,27]. A thorough study of the literature procedures for
bromination of nucleosides shows that most of these methods have some disadvantages, such as highly
acidic reaction condition, handling of toxic reagents, longer reaction time, complicated work up
procedure and low yield of the products. Noticeably, very few of these methods are general for
bromination of pyrimidine nucleosides as well as purine nucleosides.
In recent years, sodium monobromoisocyanurate (SMBI) has proven its capacity as an efficient
brominating agent. It has been used in various solvents to brominate a range of aromatic moieties with
both activating and deactivating substituents [28]. Bromination of azulene derivatives with SMBI was
achieved in DCM and DCM/water [29]. Unprotected aromatic amino acids were also brominated with
SMBI in aq. H2SO4 to produce mono-brominated products in good yield [30]. SMBI has also been
found to act as a catalyst for the synthesis of aryl thiocyanates [31]. Following the literature on SMBI,
we believed it to be an efficient brominating agent for nucleosides. In this report, we describe the
ability of SMBI to brominate the C-5 of pyrimidine nucleosides and C-8 of purine nucleosides. Along
with unprotected nucleosides of naturally occurring bases, we have also successfully brominated
nucleosides with alkyl, silyl, dimethoxytrityl (DMTr)/monomethoxytrityl (MMTr) protection on the
sugar moiety and/or acyl protection on the nucleobase. DMTr/ MMTr groups are among the most
frequently used protective groups in nucleoside chemistry. Due to their high sensitivity towards acidic
reaction conditions, there is no literature procedure available for bromination of DMTr/MMTr
protected nucleosides. Here we report for the first time in literature bromination of DMTr/MMTr
protected nucleosides.
2. Results and Discussion
Initially, we tried to brominate the C-5 position of uridine (1) and screened various reaction conditions
(Scheme 1, Table 1). Treatment of 1 with SMBI (1.05 equiv.) in a solvent mixture of 10% H2O-CH3CN
in presence of NaN3 (4.0 equiv.) at room temperature produced 5-bromouridine (2) [20,21,23,32] in
94% yield within 30 minutes. Next, we tried another reaction with 1, where we added 2.0 equiv. of
NaN3 keeping other conditions unaltered. Bromo nucleoside 2 was obtained in 88% yield in 2 h by this
reaction. However, when 1 was treated with SMBI (1.15 equiv.) in 10% H2O-CH3CN in the absence of
NaN3 at room temperature, the bromination reaction was slow and took a longer time (18 h) to afford 2
in only 40% yield.

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Scheme 1. Bromination of uridine and derivatives thereof.
O
O
Br
NH
NH
R1O
R1O
N
O
N
O
O
O
SMBI
10% H2O-CH3CN
NaN3/ rt
OR2
OR2
X
X
1, 2 R1= H; R2 = H, X = OH
3, 4 R1= H; R2 = H, X = H
5, 6 R1= H; R2 = H, X = OCH3
7, 8 R1= DMTr; R2 = H, X = OH
9, 10 R1, R2 = TIPDS, X = OH
11,12 R1= TBDPS; R2 = H, X = OH
Table 1. Screening for appropriate bromination condition of uridine and bromination of
uridine derivatives.
SMBI
(eq.)
1.05
1.05
1.15
1.15
1.05
1.15
1.1
NaN3
(eq.)
4.0
2.0
0
Reaction
time (h)
0.5
Yield (%)
Isolated
Entry
Substrate
Product
Solvent
(NMR/TLC)
yield (%)
1
2
3
4
5
6
7
8
9
1
1
2
2
10% H2O-CH3CN
10% H2O-CH3CN
10% H2O-CH3CN
20% H2O-DMF
94 a
88 a
40 c
15 c
90 a
-
86 a
94 a
-
79 b
1.5
-
1
2
18.0
18.0
1.2
-
1
2
0
-
3
4
4.0
4.0
4.0
4.0
4.0
10% H2O-CH3CN
10% H2O-CH3CN
10% H2O-CH3CN
10% H2O-CH3CN
10% H2O-CH3CN
86 d
93 d
81 d
91 d
92 d
5
6
1.5
7
8
1.0
9
10
1.1
1.5
11
12
1.1
1.2
a Yield calculated by 1H-NMR spectroscopy of the crude reaction mixture. b Isolated yield after crystallization.
c Yield judged by TLC. d Isolated yield after purification by column chromatography.
We also investigated bromination of 1 in 20% H2O-DMF without addition of NaN3. Even after a
prolonged reaction time (18 h) bromo-nucleoside 2 was only obtained in low yield. Analysis of these
reaction conditions applied for uridine (entry 1/entry 2/entry 3/entry 4, Table 1) verifies the crucial role
of NaN3 in the halogenation reactions (bromination reactions in our case) at the C-5 position of the
pyrimidine nucleosides. The azido group plays the role of an excellent leaving group from the C-6
position of the 5-halo-6-azido-5,6-dihydro intermediates to restore the 5,6-olefinic bond [20]. The
bromination reaction conditions optimized for uridine (1) were next successfully employed for other
uridine derivatives. Bromination of 2'-deoxyuridine (3) was carried out with SMBI (1.05 equiv.) and
NaN3 (4.0 equiv.) in 10% H2O-CH3CN which produced 5-bromo-2'-deoxyuridine (4) [20,21,23] in
90% yield (Table 1). 2'-O-Methyluridine (5) was treated under the same reaction conditions, followed
by addition of 0.1 equiv. of SMBI after 1 h. The reaction was stopped after 1.5 h and purification of
the product by column chromatography afforded 5-bromo-2'-O-methyluridine (6) in 93% yield.

Molecules 2013, 18
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Reaction of 5'-O-dimethoxytrityluridine (7) with 1.1 equiv. of SMBI in 10% H2O-CH3CN in the
presence of NaN3 (4.0 equiv.) produced bromo nucleoside 8 [33] in 86% yield. Similar treatment of
silyl protected nucleosides 3',5'-O-tetraisopropyldisilyl-uridine (9) and 5'-O-tert-butyldiphenylsilyl-
uridine (11) with 1.1 equivalent of SMBI afforded the corresponding bromonucleosides 10 [34] and 12
in 94% and 92% yields, respectively.
We then applied our methodology for the bromination of cytidine (13) (Scheme 2). Nucleoside 13
was treated with 1.05 equiv. of SMBI in presence of NaN3 (4.0 equiv.) in 10% H2O-CH3CN at rt. The
progress of the reaction was followed by TLC. Additional amounts of SMBI (0.2 equiv. each time)
were added into the reaction mixture after 1 h and 2 h. This reaction produced 5-bromocytidine (14) in
83% yield after 3 h (Table 2). In another reaction, 13 was dissolved in 20% H2O-DMF and treated with
1.2 equiv. of SMBI, followed by further additions of the reagent (0.3 equiv. each time) after 3 h and 6 h
stirring at rt. The reaction was stirred for 20 h, followed by the work up, which produced the brominated
nucleoside 14 in 73% yield. The reaction time and yield for bromination of 13 (entry 1/entry 2, Table 2)
were compared, which indicated the first conditions to be more efficient.
Scheme 2. Bromination of cytidine and derivatives thereof.
NHR3
N
NHR3
N
Br
R1O
R1O
N
O
N
O
O
O
SMBI
10% H2O-CH3CN
NaN3/ rt
OR2
OR2
X
X
13, 14 R1= H; R2 = H, X = OH, R3 = H
15, 16 R1= H; R2 = H, X = H, R3 = H
17, 18 R1= H; R2 = H, X = OCH3, R3 = H
19, 20 R1= MMTr; R2 = H, X = OH, R3 = COCH2CH3
Table 2. Comparison of suitable bromination condition for cytidine and bromination of
cytidine derivatives.
SMBI NaN3
Reaction Yield (%)
Isolated
yield (%)
69 b
Entry Substrate Product
Solvent
(eq.)
1.45
1.8
(eq.)
4.0
0
time (h)
3.0
(NMR)
1
2
3
4
5
13
13
15
17
19
14
14
16
18
20
10% H2O-CH3CN
20% H2O-DMF
83 a
73 a
73 a
-
20.0
3.5
-
1.6
4.0
4.0
4.0
10% H2O-CH3CN
10% H2O-CH3CN
10% H2O-CH3CN
66 c
1.25
2.0
78 c
1.25
2.5
-
59 c
Yield calculated by 1H-NMR spectroscopy of the crude reaction mixture.
Isolated yield after
a
b
crystallization. c Isolated yield after purification by column chromatography.
We then performed a reaction of nucleoside 15 with 1.2 equiv. of SMBI in 10% H2O-CH3CN and in
the presence of NaN3. Following the progress of the reaction on TLC, an excess amount of SMBI
(0.2 equiv. each time) was added after 1.5 h and 3 h. 5-Bromo-dC, 16, was obtained in 73% yield after

Molecules 2013, 18
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3.5 h stirring at rt. 2'-O-Methylcytidine (17) was treated with 1.25 equiv. of SMBI (entry 4, Table 3)
which produced nucleoside 18 in 78% yield after 2 h. When N4-propanoyl-5'-O-dimethoxytritylcytidine
(19) [35] was treated with 1.25 equiv. of SMBI, 5-bromo-N4-propanoyl-5'-O-dimethoxytritylcytidine
(20) was obtained in 59% yield in 2.5 h. (entry 5, Table 2).
Table 3. Bromination conditions for purine nucleosides.
SMBI
(eq.)
1.4
Reaction
time (h)
2.5
Yield (%)
(NMR/TLC)
89 a
Isolated
Entry
Substrate
Product
Solvent
yield (%)
1
2
3
4
5
6
21
23
25
27
29
31
33
22
24
26
28
30
32
34
20% H2O-DMF
20% H2O-DMF
20% H2O-DMF
20% H2O-DMF
20% H2O-DMF
20% H2O-DMF
20% H2O-DMF
73 b
88 d
71 d
-
1.3
2.0
93 a
1.45
1.2
2.0
78 a
4.0
<5 c
1.5
4.0
15 c
-
1.5
4.0
62 a
57 d
96 d
7
1.25
2.0
-
a
b
Yield calculated by 1H-NMR spectroscopy of the crude reaction mixture.
Isolated yield after
crystallization. c Yield judged by TLC. d Isolated yield after purification by column chromatography.
Unlike the pyrimidine nucleosides, purine nucleosides were not completely soluble in 10%
H2O-CH3CN. This observation led us to carry out the reactions in 20% H2O-DMF. Adenosine (21) was
treated with SMBI (1.1 equiv.) in 20% H2O-DMF at rt and the reaction was monitored by TLC
(Scheme 3). Additional amounts of the reagent were added (0.2 equiv. after 1 h and 0.1 equiv. after 2
h) to drive the reaction towards completion. Reaction was stopped after 2.5 h to afford the brominated
nucleoside 22 [26,32,36] in 89% yield (entry 1, Table 3).
Scheme 3. Bromination of adenosine and derivatives thereof.
NHR3
N
NHR3
N
N
N
N
N
Br
R1O
R1O
N
N
O
O
SMBI
20% H2O-DMF
rt
OR2
X
OR2
X
21, 22 R1= H; R2 = H, X = OH, R3 = H
23, 24 R1= H; R2 = H, X = H, R3 = H
25, 26 R1= H; R2 = H, X = OCH3, R3 = H
27, 28 R1= MMTr; R2 = H, X = OH, R3 = COCH2CH2CH3
Deoxyadenosine, 23, was stirred with 1.25 equiv. of SMBI for 1 h followed by addition of 0.5 equiv
of the reagent. Reaction was stopped after stirring for another 1 h when compound 24 [10] was obtained
in 93% yield. Similarly, 2'-O-Methyladenosine (25) was treated with SMBI (1.25 equiv.), and the
reaction mixture was stirred for 1 h, followed by addition of 0.2 equiv. of the reagent. Reaction was
worked up after 2 h, and the bromonucleoside 26 [27] was obtained in 78% yield. However, the 5'-O-
and base protected nucleoside 27 [35] was found to be unsuitable for bromination under these reaction
conditions. We could trace the product by ESI-TOF mass spectroscopy, but it was difficult to isolate
from the reaction mixture as most of the starting material remained unreacted.

Molecules 2013, 18
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Next, we extended the application of the SMBI reagent for guanine-based nucleosides. Guanosine
(29) was treated with SMBI (1.25 equiv.) in 20% H2O-DMF at rt, followed by addition of another
lot of SMBI (0.25 equiv.) after 2 h (Scheme 4). Reaction was stopped after 4 h to produce
8-bromo-guanosine (30) [37], albeit in low yield (entry 5, Table 3).
Scheme 4. Bromination of guanosine and derivatives thereof.
O
N
O
N
N
N
N
N
NH
NH
Br
R1O
R1O
NHR3
NHR3
O
O
SMBI
20% H2O-DMF
rt
OR2
X
OR2
X
29, 30 R1= H; R2 = H, X = OH, R3 = H
31, 32 R1= H; R2 = H, X = H, R3 = H
33, 34 R1= MMTr; R2 = H, X = OH, R3 = COCH2OPh
Similar treatment of deoxyguanosine, 31, with SMBI (starting the reaction with 1.25 equiv. of
reagent and then addition of 0.25 equiv. of the reagent after 2 h stirring) produced 62% of bromo
nucleoside 32 [37] in 4 h. We did not get a very high yield for bromination of 29, so we explored these
reaction conditions for a protected guanosine derivative. N2-Phenyloxyacetyl-5'-O-monomethoxytrityl-
guanosine (33) [35] was treated with 1.1 equiv. of SMBI and stirred at rt. After 1.5 h, a supplementary
amount (0.15 equiv.) of the reagent was added to drive forward the reaction. Bromonucleoside 34 was
obtained from the reaction in 96% yield after 2 h.
3. Experimental
3.1. General
All solvents were of commercial analytical grade and reagents were of commercial reagent grade
and used without further purification. Anhydrous reactions were carried out under nitrogen
atmosphere. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were recorded in D2O, DMSO-d6,
CD3OD or CDCl3 on a Bruker DRX 400. Chemical shifts are reported in ppm relative to
1
tetramethylsilane or the deuterated solvent as internal standard for H and 13C-NMR. Coupling
constants (J values) are given in Hz. Structural assignments are based on DEPT-135 and COSY
experiments. HRMS-ESI was recorded on a Micromass LCT in negative ion mode. TLC was run on
analytical TLC plates (silica gel 60 F254), purchased from Merck (Stockholm, Sweden). Spots were
visualized by UV light.
3.2. Typical Procedure for the Bromination of Pyrimidine Nucleosides and Their Derivatives
2'-O-Methyluridine (5, 0.103 g, 0.4 mmol) was dissolved in aqueous acetonitrile solution
(H2O:CH3CN 1:9, 5 mL) under stirring. NaN3 (0.104 g, 1.6 mmol) was added, followed by addition of

Molecules 2013, 18
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SMBI (0.101 g, 0.44 mmol) at r.t. and the mixture was stirred. Progress of the reaction was followed
by TLC. On completion of the reaction after 1.5 h, the reaction mixture was filtered, evaporated to
dryness under reduced pressure and coevaporated with acetonitrile (2 × 2 mL). The crude reaction
mixture was purified by column chromatography (4%–6% MeOH in DCM, v/v) to afford bromo
nucleoside 6 (0.117 g, 93%) in pure form as a white solid.
5-Bromo-2'-O-methyluridine (6). M.p. Turns brown above 200 °C; Rf = 0.42 (20% methanol in
dichloromethane); 1H-NMR (DMSO-d6): δ = 3.39 (s, 3H, OCH3), 3.57–3.60 (m, 1H, C-5'Ha), 3.69–3.73
(m, 1H, C-5'Hb), 3.81 (t, J = 4.4 Hz, 1H, C-2'H), 3.86–3.87 (m, 1H, C-4'H), 4.12 (q, J = 5.6 Hz, 1H,
C-3'H), 5.12 (d, J = 6.4 Hz, 1H, C-3'OH), 5.32 (t, J = 4.4 Hz, 1H, C-5'OH), 5.80 (d, J = 3.6 Hz, 1H,
13
C-1'H), 8.53 (s, 1H, C-6H), 11.82 (s, 1H, NH). C-NMR (DMSO-d6): δ = 57.5 (OCH3), 59.5 (C-5'),
67.6 (C-3'), 82.9 (C-2'), 84.7 (C-4'), 86.6 (C-1'), 95.6 (C-5), 140.0 (C-6), 149.6 (C-2), 159.0 (C-4).
HRMS-ESI (m/z): calcd. for C10H12BrN2O6 [M−H]−, 334.9884; found 334.9881.
5-Bromo-5'-O-tert-butyldiphenylsilyluridine (12). White solid (0.103 g, 92%), M.p. Turns black above
185 °C; Rf = 0.35 (5% methanol in dichloromethane); 1H-NMR (CD3OD): δ = 1.11 (s, 9H, (C(CH3)3),
3.84 (dd, J = 11.6, 3.2 Hz, 1H, C-5'Ha), 3.98 (dd, J = 11.6, 2.4 Hz, 1H, C-5'Hb), 4.07–4.09 (m, 1H,
C-4'H), 4.23–4.28 (m, 2H, C-2'H and C-3'H), 6.02 (d, J = 5.6 Hz, 1H, C-1'H), 7.40–7.48 (m, 6H,
C-3''H, C-4''H, C-5''H, C-3'''H, C-4'''H and C-5'''H), 7.72 (d, J = 7.2 Hz, 4H, C-2''H, C-6''H, C-2'''H and
C-6'''H), 7.97 (s, 1H, C-6H). 13C-NMR (CD3OD): δ = 20.2 (C(CH3)3), 27.7 (C(CH3)3), 65.1 (C-5'),
71.7 (C-2'), 76.1 (C-3'), 86.6 (C-4'), 90.2 (C-1'), 99.3 (C-5), 129.0 (C-3'', C-5'', C-3''' and C-5'''), 131.1 ,
131.2 (C-4'' and C-4'''), 133.8 , 134.1 (C-1'' and C-1'''), 136.7 , 136.8 (C-2'', C-6'', C-2''' and C-6'''),
140.0 (C-6), 156.8 (C-2), 167.4 (C-4). HRMS-ESI (m/z): calcd. for C25H28BrN2O6 [M−H]−, 559.0905;
found 559.0927.
5-Bromo-2'-O-methylcytidine (18). White solid (0.052 g, 78%), M.p. 86–89°C; Rf = 0.36 (2.5%
methanol in dichloromethane); 1H-NMR (D2O): δ = 3.49 (s, 3H, OCH3), 3.77 (dd, J = 9.0, 3.6 Hz, 1H,
C-5'Ha), 3.88–3.91 (m, 1.6H, C-5'Hb(1) and C-2'H), 3.94 (d, J = 2.4 Hz, 0.4H, C-5'Hb(2)), 4.01–4.04 (m,
1H, C-4'H), 4.22 (dd, J = 7.2, 5.2 Hz, 1H, C-3'H), 5.85 (d, J = 2.8 Hz, 1H, C-1'H), 8.27 (s, 1H, C-6H).
13C-NMR (D2O): δ = 58.7 (OCH3), 60.1 (C-5'), 68.0 (C-3'), 83.7 (C-2'), 84.1 (C-4'), 88.9 (C-1'), 89.2
(C-5), 142.5 (C-6), 156.5 (C-2), 163.3 (C-4). HRMS-ESI (m/z): calcd. for C10H13BrN3O5 [M−H]−,
334.0044; found 334.0049.
5-Bromo-5'-O-monomethoxytrityl-N4-propanoyl-2'-deoxycytidine (20). White solid (0.037 g, 59%),
M.p. 96–101 °C; Rf = 0.59 (25% methanol in dichloromethane); 1H-NMR (CDCl3): δ = 1.12 (t, J = 7.2 Hz,
3H, COCH2CH3), 2.18–2.27 (m, 1H, C-2'Ha), 2.43 (br s, 1H, C-3'OH), 2.68–2.71 (m, 1H, C-2'Hb),
3.03–3.08 (m, 2H, COCH2CH3) , 3.32 (dd, J = 10.6, 3.2 Hz, 1H, C-5'Ha), 3.36 (dd, J = 10.6, 3.2 Hz,
1H, C-5'Hb), 3.73 (s, 3H, OCH3), 4.09–4.10 (m, 1H, C-4'H), 4.49 (brs, 1H, C-3'H), 6.19 (t, J = 6.4 Hz,
1H, C-1'H), 6.77 (d, J = 9.2 Hz, 2H, C-3''H and C-5''H), 7.15–7.24 (m, 8H, C-2''H, C-6''H, C-3'''H,
C-4'''H, C-5'''H, C-3''''H, C-4''''H and C-5''''H), 7.33 (d, J = 7.6 Hz, 4H, C-2'''H, C-6'''H, C-2''''H and
C-6''''H), 7.78 (s, 1H, NHCO), 8.25 (s, 1H, C-6H). 13C-NMR (CDCl3): δ = 8.5 (COCH2CH3), 32.0
(COCH2CH3), 42.4 (C-2'), 55.4 (OCH3), 63.4 (C-5'), 72.2 (C-3'), 87.0 (C-4'), 87.5 (OC(Ar)3), 87.8
(C-1'), 88.2 (C-5), 113.5 (C-3'' and C-5''), 127.4 (C-4''' and C-4''''), 128.4 (C-2'', C-6'', C-3''', C-5''',

Molecules 2013, 18
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C-3'''' and C-5''''), 130.5 (C-2''', C-6''', C-2'''' and C-6''''), 135.0 (C-1''), 143.5 (C-1'''), 143.9 (C-1''''),
144.0 (C-6), 153.5 (C-2), 157.2 (C-4''), 159.0 (C-4), 175.7 (NHCOCH2). HRMS-ESI (m/z): calcd. for
C32H31BrN3O6 [M−H]−, 632.1402; found 632.1411.
3.3. Typical Procedure for Bromination of Purine Nucleosides and Their Derivatives
5'-O-Monomethoxytrityl-N2-phenoxyacetylguanosine (33, 0.138 g, 0.2 mmol) was dissolved in
aqueous DMF solution (H2O:DMF 1:4, 5 mL) under stirring. SMBI (1.1 equiv., 0.051 g, 0.22 mmol)
was added at r.t. and the mixture stirred. Progress of the reaction was followed by TLC. An additional
amount of the reagent (0.15 equiv., 0.007 g) was added into the reaction mixture after 1.5 h. On
completion of the reaction by 2 h, the reaction mixture was filtered, evaporated to dryness under
reduced pressure and coevaporated with water (2 × 2 mL). The crude reaction mixture was purified by
column chromatography (4%–5% MeOH in DCM, v/v) to afford nucleoside 34 (0.148 g, 96%) in pure
form as a white solid.
8-Bromo-5'-O-monomethoxytrityl-N2-phenoxyacetylguanosine (34). M.p. 136–139 °C; Rf = 0.60 (10%
1
methanol in dichloromethane); H-NMR (CD3OD): δ = 3.18 (d, J = 2.4 Hz, 0.5H, C-5'Ha), 3.33 (dd,
J = 10.0, 6.4 Hz, 1H, C-5'Hb), 3.59 (s, 3H, OCH3), 4.04–4.09 (m, 1H, C-4'H), 4.44 (t, J = 5.6 Hz, 1H,
C-3'H), 4.58 (d, J = 15.2 Hz, 1H, COCH2(a)O), 4.64 (d, J = 15.2 Hz, 1H, COCH2(b)O), 5.14 (t, J = 4.8 Hz,
1H, C-2'H), 5.91 (d, J = 4.4 Hz, 1H, C-1'H), 6.58 (d, J = 8.8 Hz, 2H, C-3'''H and C-5'''H), 6.86–6.91
(m, 3H, C-2''H, C-4''H and C-6''H), 7.01–7.06 (m, 6H, C-3''''H, C-4''''H, C-5''''H, C-3'''''H, C-4'''''H and
C-5'''''H), 7.10 (d, J = 8.8 Hz, 2H, C-2'''H and C-6'''H), 7.18 (t, J = 8.0 Hz, 2H, C-3''H and C-5''H),
7.23–7.25 (m, 4H, C-2''''H, C-6''''H, C-2'''''H and C-6'''''H). 13C-NMR (CD3OD): δ = 55.7 (OCH3), 65.6
(C-5'), 68.3 (COCH2O), 72.0 (C-2'), 72.8 (C-3'), 85.7 (C-4'), 87.6 (OC(Ar)3), 92.9 (C-1'), 113.9 (C-3'''
and C-5'''), 116.1 (C-2'' and C-6''), 122.9 (C-5), 123.3 (C-4''), 127.4 (C-8), 127.9, 128.0, 129.6, 129.7,
130.8, 131.6 (C-2'', C-3'', C-5'', C-6'', C-2''', C-6''', C-2'''', C-3'''', C-4'''', C-5'''', C-6'''', C-2''''', C-3''''', C-4''''',
C-5''''' and C-6'''''), 136.6 (C-1'''), 145.8, 146.0 (C-1'''' and C-1'''''), 148.3 (C-2), 151.1 (C-4), 156.3 (C-6),
159.0 (C-4'''), 160.1 (C-1''), 172.5 (NHCOCH2). HRMS-ESI (m/z): calcd. for C38H33BrN5O8 [M−H]−,
766.1518; found 766.1553.
4. Conclusions
In summary, we report here the development of an efficient and facile methodology for the
bromination of nucleosides. We have applied this process successfully for both purine and pyrimidine
nucleosides. Our process presents an efficient methodology of bromination for ribonucleosides,
2'-deoxynucleosides, silyl protected and DMTr/MMTr protected nucleosides. We believe this
methodology may be applied for the bromination of a wide range of nucleoside derivatives.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/10/12740/s1.

Molecules 2013, 18
12748
Acknowledgments
We gratefully acknowledge financial support from the Swedish Research Council.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 32 and 34
are available from the authors.
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