Next Article in Journal
The Effect of Molecular Crowding on the Stability of Human c-MYC Promoter Sequence I-Motif at Neutral pH
Next Article in Special Issue
Oligonucleotide Labelling Using a Fluorogenic “Click” Reaction with a Hemicarboxonium Salt
Previous Article in Journal
Microwave Assisted Synthesis, Antifungal Activity and DFT Theoretical Study of Some Novel 1,2,4-Triazole Derivatives Containing the 1,2,3-Thiadiazole Moiety
Previous Article in Special Issue
Enzymatic Synthesis of Highly Fluorescent 8-Azapurine Ribosides Using a Purine Nucleoside Phosphorylase Reverse Reaction: Variable Ribosylation Sites
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 18
Issue 10
10.3390/molecules181012740
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

An Efficient and Facile Methodology for Bromination of Pyrimidine and Purine Nucleosides with Sodium Monobromoisocyanurate (SMBI)

by
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.
Molecules 2013, 18(10), 12740-12750; https://doi.org/10.3390/molecules181012740
Submission received: 2 September 2013 / Revised: 2 October 2013 / Accepted: 9 October 2013 / Published: 15 October 2013
(This article belongs to the Special Issue Synthesis of Nucleosides, Nucleotides and Their Derivatives)
Browse Figures
Versions Notes

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.

Graphical Abstract

1. Introduction

Over the past decades, 5-halopyrimidine nucleosides have been found to be of interest for their antiviral [1,2,3] 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 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 [11,12,13] 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.
Molecules 18 12740 g001 550
Scheme 1. Bromination of uridine and derivatives thereof.
Scheme 1. Bromination of uridine and derivatives thereof.
Molecules 18 12740 g001
Table
Table 1. Screening for appropriate bromination condition of uridine and bromination of uridine derivatives.
Table 1. Screening for appropriate bromination condition of uridine and bromination of uridine derivatives.
EntrySubstrateProductSMBI (eq.)NaN3 (eq.)SolventReaction time (h)Yield (%) (NMR/TLC)Isolated yield (%)
1121.054.010% H2O-CH3CN0.594 a79 b
2121.052.010% H2O-CH3CN1.588 a-
3121.15010% H2O-CH3CN18.040 c-
4121.15020% H2O-DMF18.015 c-
5341.054.010% H2O-CH3CN1.290 a86 d
6561.154.010% H2O-CH3CN1.5-93 d
7781.14.010% H2O-CH3CN1.086 a81 d
89101.14.010% H2O-CH3CN1.594 a91 d
911121.14.010% H2O-CH3CN1.2-92 d
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. 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.
Molecules 18 12740 g002 550
Scheme 2. Bromination of cytidine and derivatives thereof.
Scheme 2. Bromination of cytidine and derivatives thereof.
Molecules 18 12740 g002
Table
Table 2. Comparison of suitable bromination condition for cytidine and bromination of cytidine derivatives.
Table 2. Comparison of suitable bromination condition for cytidine and bromination of cytidine derivatives.
EntrySubstrateProductSMBI (eq.)NaN3 (eq.)SolventReaction time (h)Yield (%) (NMR)Isolated yield (%)
113141.454.010% H2O-CH3CN3.083 a69 b
213141.8020% H2O-DMF20.073 a-
315161.64.010% H2O-CH3CN3.573 a66 c
417181.254.010% H2O-CH3CN2.0-78 c
519201.254.010% H2O-CH3CN2.5-59 c
a Yield calculated by 1H-NMR spectroscopy of the crude reaction mixture. b Isolated yield after 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 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
Table 3. Bromination conditions for purine nucleosides.
Table 3. Bromination conditions for purine nucleosides.
EntrySubstrateProductSMBI (eq.)SolventReaction time (h)Yield (%) (NMR/TLC)Isolated yield (%)
121221.420% H2O-DMF2.589 a73 b
223241.320% H2O-DMF2.093 a88 d
325261.4520% H2O-DMF2.078 a71 d
427281.220% H2O-DMF4.0<5 c-
529301.520% H2O-DMF4.015 c-
631321.520% H2O-DMF4.062 a57 d
733341.2520% H2O-DMF2.0-96 d
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.
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).
Molecules 18 12740 g003 550
Scheme 3. Bromination of adenosine and derivatives thereof.
Scheme 3. Bromination of adenosine and derivatives thereof.
Molecules 18 12740 g003
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.
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).
Molecules 18 12740 g004 550
Scheme 4. Bromination of guanosine and derivatives thereof.
Scheme 4. Bromination of guanosine and derivatives thereof.
Molecules 18 12740 g004
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 tetramethylsilane or the deuterated solvent as internal standard for 1H 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 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, C-1'H), 8.53 (s, 1H, C-6H), 11.82 (s, 1H, NH). 13C-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''', 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% methanol in dichloromethane); 1H-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: https://www.mdpi.com/1420-3049/18/10/12740/s1.

Acknowledgments

We gratefully acknowledge financial support from the Swedish Research Council.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Van Aershot, A.; Everaert, D.; Balzarini, J.; Augustyns, K.; Jie, L.; Janssen, G.; Peeters, O.; Blaton, N.; DeRanter, C.; DeClercq, E.; Herdewijn, P. Synthesis and anti-HIV evaluation of 2',3'-dideoxyribo-5-chloropyrimidine analogues: Reduced toxicity of 5-chlorinated 2',3'-dideoxynucleoside. J. Med. Chem. 1990, 33, 1833–1839. [Google Scholar] [CrossRef]
  2. Fox, L.; Dorbersen, M.J.; Greer, S. Incorporation of 5-substituted analogs of deoxycytidine into DNA of herpes simplex virus-infected or -transformed cells without deamination to the thymidine analog. Antimicrob. Agents Chemother. 1983, 23, 465–476. [Google Scholar] [CrossRef]
  3. Harki, D.A.; Graci, J.D.; Galarraga, J.E.; Chain, W.J. Synthesis and antiviral activity of 5-substituted cytidine analogues: Identification of a potent inhibitor of viral RNA-dependent RNA polymerases. J. Med. Chem. 2006, 49, 6166–6169. [Google Scholar] [CrossRef]
  4. Perigaud, C.; Gosselin, G.; Imbach, J.L. Nucleoside analogues as chemotherapeutic agents: A review. Nucleosides Nucleotides 1992, 11, 903–945. [Google Scholar] [CrossRef]
  5. Clercq, E.; Balzarini, J.; Torrence, P.F.; Mertes, M.P.; Schmidt, C.L.; Shugar, D.; Barr, P.J.; Jones, A.S.; Verhelst, G.; Walker, R.T. Thymidylate synthetase as target enzyme for the inhibitory activity of 5-substituted 2′-deoxyuridines on mouse leukemia L1210 cell growth. Mol. Pharmacol. 1981, 19, 321–330. [Google Scholar]
  6. Szybalski, W. X-ray sensitization by halopyrimidines. Cancer Chemother. Rep. 1974, 58, 539–557. [Google Scholar]
  7. Mercer, J.R.; Xu, L.H.; Knaus, E.E.; Wiebe, L.I. Synthesis and tumor uptake of 5-82Br- and 5-131I-labeled 5-halo-1-(2-fluoro-2-deoxy-β-d-ribofuranosyl)uracils. J. Med. Chem. 1989, 32, 1289–1294. [Google Scholar] [CrossRef]
  8. Agrofoglio, L.A.; Gillaizeau, I.; Saito, Y. Palladium-assisted routes to nucleosides. Chem. Rev. 2003, 103, 1875–1916. [Google Scholar] [CrossRef]
  9. Amann, N.; Wagenknecht, H.-A. Preparation of pyrenyl-modified nucleosides via Suzuki-Miyaura cross-coupling reactions. Synlett 2002, 5, 687–691. [Google Scholar] [CrossRef]
  10. Clima, L.; Bannwarth, W. Building-block approach for the straightforward incorporation of a new FRET (Fluorescence-Resonance-Energy Transfer) system into synthetic DNA. Helv. Chim. Acta 2008, 91, 165–175. [Google Scholar] [CrossRef]
  11. Veliz, E.A.; Beal, P.A. 6-Bromopurine nucleosides as reagents for nucleoside analogue synthesis. J. Org. Chem. 2001, 66, 8592–8598. [Google Scholar] [CrossRef]
  12. De Napoli, L.; Messere, A.; Montesarchio, D.; Piccialli, G.; Varra, M. 6-Chloroxanthosine, a useful intermediate for the efficient syntheses of [6-15N]-isoguanosine, isoinosine and other purine nucleoside analogues. Nucleosides Nucleotides 1997, 16, 183–191. [Google Scholar] [CrossRef]
  13. De Napoli, L.; Messere, A.; Montesarchio, D.; Piccialli, G.; Santacroce, C.; Varra, M. Reaction of 3',5'-di-O-acetyl-2'-deoxyinosine with the chlorinating agent PPh3-CCl4: Synthesis of the 6-chloroderivative and of a new base linked dimer, useful intermediate to 15N-1-labelled 2'-deoxxyinosine. J. Chem. Soc. Perkin Trans. 1 1994, 1994, 923–925. [Google Scholar]
  14. Ueda, T. Synthesis and Reaction of Pyrimidine Nucleosides. In Chemistry of Nucleosides and Nucleotides; Townsend, L.B., Ed.; Plenum Press: New York, NY, USA, 1988; Volume 1, pp. 1–95. [Google Scholar]
  15. Fukuhara, T.K.; Visser, D.W. Pyrimidine nucleoside antagonisty. J. Biol. Chem. 1951, 190, 95–101. [Google Scholar]
  16. Duval, J.; Ebel, J.P. Halogenation of nucleic acids: Action of bromine on bases and nucleosides in dimethylformamide medium. Bull. Soc. Chim. Biol. 1964, 46, 1059–1071. [Google Scholar]
  17. Fukuhara, T.K.; Visser, D.W. Cytidine derivatives. J. Am. Chem. Soc. 1955, 77, 2393–2395. [Google Scholar] [CrossRef]
  18. Frisch, D.M.; Visser, D.W. 5-Bromodeoxycytidine and 5-chlorodeoxycytidine. J. Am. Chem. Soc. 1959, 81, 1756–1758. [Google Scholar] [CrossRef]
  19. Srivastava, P.C.; Nagpal, K.L. Bromination of nucleosides. Experientia 1970, 26, 220. [Google Scholar] [CrossRef]
  20. Kumar, R.; Wiebe, L.I.; Eknaus, E. A mild and efficient methodology for the synthesis of 5-halogeno uracil nucleosides that occurs via a 5-halogeno-6-azido-5,6-dihydro intermediate. Can. J. Chem. 1994, 72, 2005–2010. [Google Scholar] [CrossRef]
  21. Kumar, V.; Yap, J.; Muroyama, A.; Malhotra, S. Highly efficient method for C-5 halogenation of pyrimidine-based nucleosides in ionic liquid. Synthesis 2009, 23, 3957–3962. [Google Scholar]
  22. Ryu, E.K.; MacCoss, M. New Procedure for the chlorination of pyrimidine and purine nucleosides. J. Org. Chem. 1981, 46, 2819–2923. [Google Scholar] [CrossRef]
  23. Asakura, J.; Robins, M.J. Cerium (IV) mediated halogenation at C-5 of uracil derivatives. J. Org. Chem. 1990, 55, 4928–4933. [Google Scholar] [CrossRef]
  24. Ross, S.A.; Burrows, C.J. Bromination of pyrimidines using bromide and monoperoxysulfate: A competition study between cytidine, uridine and thymidine. Tetrahedron Lett. 1997, 38, 2805–2808. [Google Scholar] [CrossRef]
  25. Holmes, R.E.; Robins, R.K. Purine nucleosides. VII. Direct bromination of adenosine, deoxyadenosine, guanosine, and related purine nucleosides. J. Am. Chem. Soc. 1964, 86, 1242–1245. [Google Scholar] [CrossRef]
  26. Ghanty, U.; Fostvedt, E.; Valenzuela, R.; Beal, P.A.; Burrows, C.J. Promiscuous 8-alkoxyadenosine in the guide strand of an SiRNA: Modulation of silencing efficacy and off-pathway protein binding. J. Am. Chem. Soc. 2012, 134, 17643–17652. [Google Scholar]
  27. Ohkubo, A.; Nishino, Y.; Yokouchi, A.; Ito, Y.; Noma, Y.; Kakishima, Y.; Masaki, Y.; Tsunoda, H.; Seio, K.; Sekine, M. Stable triplex formation using the strong stacking effect of consecutive thionucleoside moieties. Chem. Commun. 2011, 47, 12556–12558. [Google Scholar] [CrossRef]
  28. Okada, Y.; Yokozawa, M.; Akiba, M.; Oishi, K.; O-kawa, K.; Akeboshi, T.; Kawamura, Y.; Inokuma, S.; Nakamura, Y.; Nishimura, J. Bromination by means of sodium monobromoisocyanurate (SMBI). Org. Biomol. Chem 2003, 1, 2506–2511. [Google Scholar] [CrossRef]
  29. Sumida, T.; Kikuchi, S.; Imafuku, K. Bromination of azulene derivatives with sodium monobromoisocyanurate. Synthetic Commun. 2004, 34, 4273–4284. [Google Scholar]
  30. Yokoyama, Y.; Yamaguchi, T.; Sato, M.; Kobayashi, E.; Murakami, Y.; Okuno, H. Chemistry of unprotected amino acids in aqueous solution: Direct bromination of aromatic amino acids with bromoisocyanuric acid sodium salt under strong acidic condition. Chem. Pharm. Bull. 2006, 54, 1715–1719. [Google Scholar] [CrossRef]
  31. Kumar, J.A.; Srinivasan, N.; Shanmugham, C. Sodium monobromoisocyanurate: A new catalyst for direct synthesis of aryl thiocyanates. Int. J. Chem. 2011, 3, 95–98. [Google Scholar]
  32. Ebrahimi, M.; Rossi, P.; Rogers, C.; Harbison, G.S. Dependence of 13C-NMR chemical shifts on conformations of RNA nucleosides and nucleotides. J. Magn. Reson. 2001, 150, 1–9. [Google Scholar] [CrossRef]
  33. Shah, K.; Wu, H.; Rana, T.M. Synthesis of uridine phosphoramidite analogues: Reagents for site-specific incorporation of photoreactive sites into RNA sequence. Bioconjug. Chem. 1994, 5, 508–512. [Google Scholar] [CrossRef]
  34. Matsuda, A.; Takenuki, K.; Tanaka, M.; Sasaki, T.; Ueda, T. Nucleosides and Nucleotides. 97. Synthesis of new broad spectrum antineoplastic nucleosides, 2'-deoxy-2'-methylidenecytidine (DMDC) and its derivatives. J. Med. Chem. 1991, 34, 812–819. [Google Scholar] [CrossRef]
  35. Westman, E.; Stawinski, J.; Stromberg, R. RNA synthesis using H-Phosphonates. Synchronizing 2'-OH and N-protection. Collect. Czech. Chem. Commun. 1993, 58, 236–237. [Google Scholar]
  36. Mamos, P.; Van Aerschot, A.A.; Weyns, N.J.; Herdewijn, P.A. Straightforward C-8 alkylation of adenosine analogues with tetraalkyltin reagents. Tetrahedron Lett. 1992, 33, 2413–2416. [Google Scholar] [CrossRef]
  37. Wood, S.G.; Upadhya, K.G.; Dalley, N.K.; McKernan, P.A.; Canonico, P.G.; Robins, R.K.; Revankar, G.R. 8-Substituted guanosine and 2'-deoxyguanosine derivatives as potential inducers of the differentiation of friend erythroleukemia cells. J. Med. Chem. 1985, 28, 1194–1198. [Google Scholar] [CrossRef]
  • 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.

Share and Cite

MDPI and ACS Style

Maity, J.; Stromberg, R. An Efficient and Facile Methodology for Bromination of Pyrimidine and Purine Nucleosides with Sodium Monobromoisocyanurate (SMBI). Molecules 2013, 18, 12740-12750. https://doi.org/10.3390/molecules181012740

AMA Style

Maity J, Stromberg R. An Efficient and Facile Methodology for Bromination of Pyrimidine and Purine Nucleosides with Sodium Monobromoisocyanurate (SMBI). Molecules. 2013; 18(10):12740-12750. https://doi.org/10.3390/molecules181012740

Chicago/Turabian Style

Maity, Jyotirmoy, and Roger Stromberg. 2013. "An Efficient and Facile Methodology for Bromination of Pyrimidine and Purine Nucleosides with Sodium Monobromoisocyanurate (SMBI)" Molecules 18, no. 10: 12740-12750. https://doi.org/10.3390/molecules181012740

Article Metrics

Back to TopTop