# Fast Access to 5-Hydroxymethyl Derivatives of 2'-Deoxyuridine Promoted by Acidic Amberlyst 15 Resin

D. Liu, O. Monfret, Y. Bourdreux, D. Urban, D. Guianvarc'h, G. Doisneau

► To cite this version:

D. Liu, O. Monfret, Y. Bourdreux, D. Urban, D. Guianvarc'h, et al.. Fast Access to 5-Hydroxymethyl Derivatives of 2'-Deoxyuridine Promoted by Acidic Amberlyst 15 Resin. SYNLETT, In press, 34 (02), pp.137-142. 10.1055/a-1961-7251. hal-04047031

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Submitted on 13 Nov 2023

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Fast Access to 5-Hydroxymethyl Derivatives of 2'-Deoxyuridine Promoted by Acidic
Amberlyst 15 Resin

D. Liu, O. Monfret Y. Bourdreux, D. Urban, D. Guianvarc'h,* G. Doisneau*

Université Paris-Saclay, CNRS, Institut de Chimie Moléculaire et des Matériaux d'Orsay, UMR
8182, 91405, Orsay, France

**Abstract:** 5-Hydroxymethyl derivatives of pyrimidine nucleosides are an important class of biologically relevant compounds. In addition, such derivatives and related compounds can be functionalized for various applications. To enable fast, economical, and efficient access to 5-hydroxymethylated derivatives of 2'-deoxyuridine, we report a method for the O-5 chemoselective transformation of unprotected 5-(hydroxymethyl)-2'-deoxyuridine through selective etherification in the presence of an alcohol promoted by acidic Amberlyst 15 resin at room temperature. These mild conditions constitute a significant improvement compared with the harsh conditions previously described. Applied to various primary or secondary alcohols, the reaction showed a broad substrate scope, and 24 C(5)-modified derivatives of 5hmdU were synthesized with good isolated yields. Notably, this efficient procedure represents a straightforward method for preparing (i) several useful building blocks for subsequent chemical ligation by using CuAAC reactions; (ii) natural hypermodified thymidines and analogues, including glycosylated derivatives; and (iii) cyanoethyl-protected 5hmdU, useful for solid-phase oligonucleotide syntheses

C(5)-Modified pyrimidine nucleosides have been extensively studied due to their
antiviral, antibacterial, and anti-tumoral activities. ¹⁻⁶ Furthermore, the discovery of
oxidative lesions⁷ or enzymatically catalyzed modifications at the C(5) position of
pyrimidines within DNA⁸⁻¹² have prompted the development of efficient routes to the
corresponding nucleoside building blocks for subsequent incorporation into
oligonucleotides. ¹³⁻¹⁶ Moreover, the C(5) position is a popular site for the internal
introduction of various labels and reactive groups into either synthetic oligonucleotides or
natural nucleic acids, with applications in detection and quantification. ¹⁷ These various fields
of investigation related to C(5)-modified pyrimidines explain the many synthetic approaches
that have been developed to provide access to 5-substituted pyrimidine nucleosides and for
their functionalization. ²,¹⁸ Most of these methods rely on easily accessible 5-iodo-2'-
deoxyuridine (5IdU)¹⁹ which has been extensively used in Sonogashira, Heck, Stille, Suzuki-
Miyaura, and Buchwald–Hartwig–Migita cross-coupling reactions. ²⁰ Interestingly, in recent
years, a repertoire of Pd-catalyzed reactions that proceed in water under mild conditions
have been developed for applications in the functionalization of nucleobases and have
revealed a potential for the biorthogonal labeling of nucleic acids. ²¹⁻²⁵ 5- Bromomethyl-2'-
deoxyuridine (5BrmdU) has also often been used as key intermediate for the preparation of
5- modified derivatives of deoxyuridine; ²⁶,²⁷ nucleophilic substitutions of the bromine atom
with alcohols or amines gives rapid access to such products. However, the preparation of the
5BrmdU requires radical bromination at the 5- methyl position of thymidine by using N-
bromosuccinimide in benzene or CCl4, and strict control of this reaction is necessary to avoid
the formation of secondary products through dibromination. ²⁸ Other drawbacks are its
modest yields, the need to work with the fully protected thymidine, and the requirement to
engage the product in subsequent reactions without purification to avoid its degradation. 5-
(Hydroxymethyl)-2'-deoxyuridine (5hmdU, 1) is also an interesting precursor for the introduction of functionalization at the C(5) position, as exemplified by esterification or glycosylation reactions with appropriately activated sugar derivatives.²⁸⁻³⁰ However, the preparation of 5',3'-protected 5-hydroxymethyl derivatives requires the aforementioned 5BrmdU. In the present study, we focused our attention on the unprotected 5hmdU (1) as a precursor providing rapid and selective access to 5-modified 2'-deoxyuridine compounds. 5hmdU is a chemically stable compound, easily prepared from 2'-deoxyuridine by using a scalable single-step reaction without protecting groups. Indeed, hydroxymethylation of 2'-deoxyuridine can be accomplished in aqueous formaldehyde or paraformaldehyde solutions with potassium hydroxide or triethylamine as a base.³¹ The resulting 5hmdU (1) can be isolated by silica gel column chromatography in 60-80% yield. Further selective reactions of the 5-hydroxy group are limited due to the presence of the second 5' primary alcohol group on the deoxyribose unit. However, the pseudobenzylic position makes it possible to envisage selective transformations.

However, only a few selective O(5) chemical transformations of 5hmdU (1) have been reported. Following the initial works of Cline et al. in 1959 on 5-substituted pyrimidines³² and that of Scheit in 1966³³ on uridine derivatives, Sowers and Beardsley accomplished an O(5)-selective reaction of 1 in refluxing glacial acetic acid in the presence of trifluoroacetic acid to furnish the corresponding acetylated derivative in a good yield under S<sub>N</sub>1 conditions.³⁴ Later, the Sowers group selectively prepared a 5-cyanoethyl derivative by trifluoroacetic acid-catalyzed etherification in refluxing 2-cyanoethanol (Scheme 1A).³⁵ It has also been reported by Sekine and co-workers³⁶ that the 5-hydroxy group of 5hmdU reacts selectively with sodium azide in chloro(trimethyl)silane with the incorporation of an azido group through the formation of a chloromethyl intermediate.³⁰,³⁷ As shown in Scheme 1B, these selective 5hmdU transformations take advantage of the allylic position of the alcohol functionality allowing the formation of stable cat- ionic intermediates that react with nucleophiles to give either the ester 2 or the ether 3. These reactions were found to be fully selective, as proven by NMR analysis and comparison of the chemical shift of the respective C(5) methylene protons.
A

<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

B

<figure><img src="image_4.png" /><figcaption>**Scheme 1** (A) Previous works and our approach to the selective transformation of 5hmdU. (B) Proposed mechanism for the acid-catalyzed selective transformation.</figcaption></figure>

Because of our interest in preparing ether derivatives of 5hmdU, we (and others) observed that these harsh conditions of etherification give rise to moderate yields¹³,¹⁴,¹⁶ and, in our hands, subsequent cleavage of the glycosidic bond occurred. To identify milder conditions for forming the allylic cation intermediate suitable for the O(5)-selective etherification of 5hmdU by an S<sub>N</sub>1-type reaction, we then considered the use of a polystyrene sulfonic resin as a catalyst at room temperature. Acidic resins are widely used as catalysts in organic reactions, and they have been found to be useful for the activation of hydroxy groups to access ester, alkene, or ether functionalities.³⁸⁻⁴⁰ Use of such resins facilitates the workup of reactions, as simple filtration can be used to remove the acidic reagent. Allylic and benzylic alcohols form stable electrophilic intermediates that react readily with nucleophiles to form ether products, even at room temperature, and for this purpose, Amberlyst 15 proved to be very efficient.⁴¹,⁴² Amberlyst 15 has even been used to induce the selective iodination of primary alcohols with sodium iodide, further demonstrating its usefulness in promoting the formation of electrophilic intermediates.⁴³

Here, we report a selective transformation of unprotected 5hmdU (1) by using acidic Amberlyst 15 resin as a promoter for the formation of the intermediate allylic cation and its reaction with several alcohols. This procedure permits rapid and efficient syntheses of several 5-(alkoxymethyl)-2'-deoxyuridines (including some that are useful as building blocks for subsequent functionalization), as well as natural hypermodified thymidines and their analogues, such as glycosylated derivatives, or cyanoethyl-protected 5hmdU, useful in solid-phase oligonucleotide syntheses.

Initially, we tested the selective etherification of 5hmdU (1) at room temperature by using Amberlyst 15 resin as a catalyst in the presence of several primary alcohols, which also served as solvents (Table 1). Due to the large excess of alcohol used in these preliminary reactions, low-boiling methanol, ethanol, and propan-1-ol were initially selected as reactants
to facilitate the purification of the final products. Under these reaction conditions, total conversion of the starting material was observed within 24 hours. After removal of the residual alcohol, the resulting products were purified by flash column chromatography on silica gel, and the C(5) methyl ethers **4a-c** were isolated in yields of 80–88% (Table 1, entries 1, 3, and 4). Interestingly, by using these mild conditions, we did not observe any glycosidic bond cleavage. Switching from Amberlyst 15 to acidic Dowex 50W resin did not improve either the time required for the reaction or the yield of the isolated products (entry 2). Because of these encouraging results, we then attempted to perform the reaction in acetonitrile as the solvent to decrease the amount of alcohol required. Interestingly, we found that reactions in such conditions were also efficient and allowed the amount of the alcohol to be reduced to just five equivalents with no significant difference in yield (entries 5–7).

<figure><img src="image_5.png" /><figcaption>**Table 1** Optimizations of the conditions for the etherification reaction</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Resin H<sup>+</sup></th><th>Solvent</th><th>Alcohol</th><th>R</th><th>Product</th><th>Yield <sup>c</sup> (%)</th></tr></thead><tbody><tr><td>1<sup>a</sup></td><td>Amberlyst 15</td><td></td><td>MeOH</td><td>Me</td><td><b>4a</b></td><td>87</td></tr><tr><td>2<sup>a</sup></td><td>Dowex 50W</td><td></td><td>MeOH</td><td>Me</td><td><b>4a</b></td><td>76</td></tr><tr><td>3<sup>a</sup></td><td>Amberlyst 15</td><td></td><td>EtOH</td><td>Et</td><td><b>4b</b></td><td>88</td></tr><tr><td>4<sup>a</sup></td><td>Amberlyst 15</td><td></td><td>PrOH</td><td>Pr</td><td><b>4c</b></td><td>87</td></tr><tr><td>5<sup>b</sup></td><td>Amberlyst 15</td><td>CH<sub>3</sub>CN</td><td>MeOH</td><td>Me</td><td><b>4a</b></td><td>76</td></tr><tr><td>6<sup>b</sup></td><td>Amberlyst 15</td><td>CH<sub>3</sub>CN</td><td>EtOH</td><td>Et</td><td><b>4b</b></td><td>83</td></tr><tr><td>7<sup>b</sup></td><td>Amberlyst 15</td><td>CH<sub>3</sub>CN</td><td>PrOH</td><td>Pr</td><td><b>4c</b></td><td>80</td></tr></tbody></table>

Etherification reactions with various alcohols were then examined. A range of 2-substituted ethanols, including several derivatizable alcohols (2-bromo-, 2-chloro-, and 2-azidoethanol) were then used in etherification reaction (Scheme 2).44 Moreover, 2-cyanoethanol, commonly used to attach a protecting group to 5-(hydroxymethyl)pyrimidines for solid-phase oligonucleotide syntheses,35 was assayed. The ether products **4d-i** were obtained in good yields and with similar efficiencies, except for the reactions with 2-bromoethanol and ethane-1,2-diol, which gave **4e** and **4g**, respectively, in yields of only 36 and 57%. Interestingly, the introduction of the azido group in **4i** and **4j** provided two useful building blocks for subsequent chemical ligation with alkynes through copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reactions. Importantly, the cyanoethyl-protected 5hmdU **4h** was obtained in an excellent 90% yield. The synthesis of the cyanoethyl ether from unprotected 5hmdU previously required the use of harsh conditions involving the

<footnote><sup>a</sup> Carried out at r.t. for 12–24 h.</footnote>

<footnote><sup>b</sup> Carried out with ROH (5 equiv) at r.t. for 12–24 h.</footnote>

<footnote><sup>c</sup> Isolated yield after flash chromatography (silica gel).</footnote>
presence of TFA at 100 °C, and gave only a 50% yield.13,14,16 The present procedure therefore provides easy access to a valuable starting precursor for the preparation of phosphoramidite building blocks for the synthesis of DNA containing 5hmdU or 5hmdC residues, as cyanoethyl ether-protected pyrimidines are widely used in automated DNA synthesis.

The procedure was then tested with several unsaturated ethenyl or propargyl alcohols (Scheme 2). We found an excellent reactivity, as 5hmdU was efficiently converted into the ethenyl derivatives **4k–m** in yields from 87 to 97% in the case of pent-4-en-1-ol; the propargyl and homopropargyl ethers **4n** and **4o**, respectively, were also obtained in yields of 90 and 89%. These two propargyl derivatives are also potential versatile building blocks for further derivatization of nucleoside analogues by using CuAAC reactions.

<figure><img src="image_6.png" /></figure>

**Scheme 2** Scope of the etherification reaction promoted by Amberlyst 15 acidic resin. Reagents and conditions: nucleoside 1, Amberlyst 15 (1 g/mmol **1**), ROH (5 equiv), MeCN, r.t., 12–24 h. Isolated yields after flash chromatography (silica gel)

Secondary alcohols were also high-yielding substrates, giving products **4r–u** in yields of 63–81%. Finally, as expected, the bulky tertiary alcohol tert-butanol did not give the corresponding ether; likewise, adamantan-1-ol gave only the 5-N-(acetamido)methyl
derivative product, due to a Ritter's reaction of the cationic intermediate with acetoni-
trile.⁴⁵,⁴⁶

By using benzylic alcohols in acetonitrile, ethers 4p and 4q were obtained in lower yields of 71 and 28% respectively. Unfortunately, we observed that a 4-methoxy substituent dramatically influenced the efficiency of the reaction. Interestingly, the transformation leading to the benzyl ether 4p can be seen as a selective masking reaction for the O(5) hydroxy group of 5hmdU. The alcohol functionality can then be easily recovered by a previously described protocol using anhydrous FeCl3 in dichloromethane.⁴⁷,⁴⁸

Next, to further investigate the scope of this protocol, we considered the synthesis of several C(5)-modified 2'-deoxyuridine derivatives of biological interest. Because oligonucleotide glycosylation has been shown to enhance cellular uptake,⁴⁹ we attempted to apply this method to the introduction of glycopyranosyl alcohol derivatives (Figure 1). Unfortunately, reactions of **1** with five equivalents of such derivatives were much less efficient, as exemplified by the low yields of **4v** (17%) and **4w** (33%) obtained by reactions with tri-O-benzyl-α-methylglucoside and diisopropylgalactoside respectively,⁵⁰ presumably due to the increased steric bulk of these reactants. We were, however, pleased to isolate the thioglycopyranoside **4x** in 74% yield,⁵¹ from a reaction conducted in the presence of five equivalents of β-2,3,4,6-tetra-O-acetylthioglycopyranose.⁵² Product **4x** is a thio analogue of β-D-glucopyranosyl-5-hydroxymethyl-2'-deoxyuridine (glc-5hmdU) or the base J motif, a rare DNA modification identified in Trypanosoma brucei in 1993.¹¹

<figure><img src="image_7.png" /><figcaption>**Figure 1** Structures of O- and S-glycoside derivatives</figcaption></figure>

As an example to demonstrate the usefulness of this etherification protocol for the synthesis of other natural hypermodified thymidines, we applied our approach to a rapid preparation of 5-(2-aminoethoxy)methyl-2'-deoxyuridine (5; 5-NeOmdU), a 5hmdU derivative reported as a thymidine hypermodification, replacing 40% of thymidine nucleotides in the Salmonella phage Vil.¹²,⁵³ Reaction of 2-azidoethanol (easily prepared in 92% yield from 2-chloroethanol) with 5hmdU in acetonitrile in the presence of Amberlyst 15 for 24 hours at room temperature gave the (2-azido-ethoxy)methyl derivative **4k** in 81% yield. The final conversion of the azide group into a primary amine by the Staudinger reaction with 1.1 equivalents of triphenyl-phosphine in 1:1 water-methanol at 50 °C for three hours gave
product 5 in 83% isolated yield (Scheme 3). We also prepared the aminopropoxy derivative 6 by a similar two-step transformation (Scheme 3). The previously reported synthesis of 5-NeOmdU (5) involved nucleophilic substitution of the bromine atom of the 5-bromomethyl derivative of 3',5'-di-O-acetyldeoxyuridine with an N-protected 2-aminoethanol as a nucleophile.⁵³ By using our protocol, the target compound 5 was obtained in only two steps from 5hmdU, without any protection steps, in 67% overall yield (Scheme 3).

<figure><img src="image_8.png" /></figure>

**Scheme 3** Rapid preparation of 5-(2-aminoethoxy)methyl-2'-deoxyuridine (5) and 5-(2-aminopropoxy)methyl-2'-deoxyuridine (6). Reagents and conditions: (a) Azido alcohol (5 equiv), Amberlyst 15, MeCN, (b) Ph₃P (1.1 equiv), 1:1 MeOH-H₂O, 50 °C, 3 h

Finally, we were pleased to find that the Amberlyst 15-based procedure was highly efficient for the preparation of the 5-iodomethyl derivative **7** by reaction of 1 with one equivalent of sodium iodide in acetonitrile. Under these conditions, the formation of a new product and the total disappearance of the 5hmdU starting material was observed within one hour. After filtration of the resin, evaporation of the acetonitrile, and flash chromatography on silica gel, we obtained the iodide intermediate 7, which was found to be stable enough for ¹H and ¹³C NMR analysis.⁵⁴ Interestingly, compound 7 is a valuable intermediate for the rapid syntheses of various derivatives with different groups at the C(5)-position of the pyrimidine nucleoside, as exemplified with the synthesis of 5-{[(2-hydroxyethyl)amino]- methyl}-2'-deoxyuridine (5-heNmdU; 8)¹² in two steps and 70% overall yield (Scheme 4).

<figure><img src="image_9.png" /></figure>

**Scheme 4** Reagents and conditions: (a) NaI (1.0 equiv), Amberlyst 15, MeCN, r.t., 1 h; (b) 2-aminoethanol, KOH, r.t. 70% (two steps); (c) **9** (1.7 equiv), Et₃N, MeCN, r.t., 4 h, 59% (two steps)
The intermediate **7** was also used in a preparation of the base J analogue **4x** by nucleophilic substitution using 1.7 equivalents of the isothiourea derivative **9**.<sup>55-58</sup> Reaction for four hours at room temperature in acetonitrile in the presence of triethylamine gave the β-linked thioglucoside **4x** in 59% isolated yield (Scheme 4).

In conclusion, a selective reaction of unprotected 5- (hydroxymethyl)-2'-deoxyuridine with various alcohols promoted by acidic Amberlyst 15 resin at room temperature was successfully developed for the preparation of a large number of 5-modified 2'-deoxyuridine derivatives in high yields. This procedure is an important improvement on the previous method, which required harsh conditions, and gave lower yields due to substantial cleavage of the glycosidic bond. Under our mild conditions for etherification, a broad scope of functionalities, including alkene, alkyne, alcohol, amino, and azido groups, can be easily and selectively introduced at the C(5) position of pyrimidine bases, thereby permitting further transformations by click reactions. By using this procedure, we also succeeded in preparing 5-(iodomethyl)-2'-deoxyuridine, useful in nucleophilic substitutions, as exemplified by the rapid preparation of the thio analogue of the base J nucleoside **4x**. Work is in progress to extend this procedure to access more elaborate structures of biological relevance.

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(44) **5-[(2-Azidoethoxy)methyl]-2'-deoxyuridine (4i)**; **Typical Procedure**
5hmdU (1; 50 mg, 0.193 mmol) was suspended in MeCN (1.5 mL), and 2-azidoethanol (84 µL, 5 equiv) and Amberlyst 15 (193 mg) were successively added. The mixture was stirred overnight at r.t. until TLC showed that no starting material remained. The mixture was then filtered and concentrated to dryness. The residue was purified by column chromatography [silica gel, CH₂Cl₂-MeOH (50:1 to 20:1)] to give a colorless oil; yield: 51 mg (81%).
¹H NMR (360 MHz, CD₃OD): δ = 8.06 (t, J = 1.0 Hz, 1 H, H-6), 6.30 (t, J=6.6Hz,1H,H-1'),4.40(dt, J=6.0,3.5Hz,1H,H-3'),4.32(dd, J=1.0,12.1Hz,1H,H7a),4.27(dd, J=1.0,12.1Hz,1H, H7b), 3.94 (dt, J = 3.4, 3.5 Hz, 1 H, H-4'), 3.81 (dd, J = 3.5, 12.0 Hz, 1 H, H-5a'), 3.74 (dd, J = 3.5, 11.8
Hz, 1 H, H-5b'), 3.69 (m, 2 H, CH₂O), 3.40 (m, 2 H, CH₂N₃), 2.27 (m, 2 H, H2'). ¹³C NMR (100 MHz, CD₃OD): δ = 165.2 (C4), 152.2 (C2), 141.1 (C6), 112.3 (C5), 89.0 (C1'), 86.6 (C4'), 72.3 (C3'), 70.5 (C1''), 66.5 (C7), 62.9 (C5'), 51.8 (C2''), 41.4 (C2'). HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₇N₅NaO₆: 350.1077; found: 350.1065.

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(46) Das, B.; Majhi, A.; Banerjee, J.; Chowdhury, N. J. Mol. Catal. A: Chem. 2006, 260, 32.

(47) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett. 1987, 28, 3823.

(48) Padrón, J. I.; Vázquez, J. T. Tetrahedron: Asymmetry 1995, 6, 857.

(49) Yan, H.; Tram, K. Glycoconjugate J. 2007, 24, 107.

(50) Tri-O-benzyl-β-methylglucopyranoside was prepared according to Lin G.-M., Sun H. G., Liu H.-w: Org. Lett. 2016, 18, 3438; Diiso-propylgalactopyranoside was purchased from Acros Organics BVBA (Geel, Belgium).

### (51) Thioglucopyranoside 4x

Isolated as a white solid; yield: 74%. ¹H NMR (360 MHz, CD₃OD): δ = 8.05 (s, 1H, H-6), 6.28 (t, J=6.6Hz, 1H, H-1'), 5.27 (t, J=9.0 Hz, 1H, H-3''), 5.04 (t, J=9.6Hz, 1H, H-4''), 4.92 (t, J=9.0Hz, 1H, H-2''), 4.80 (d, J=9.0 Hz, 1H, H-1''), 4.45 (m, 1H, H-3'), 4.25 (dt, J=4.2, 12.6Hz, 1H, H-6a'), 4.11(dd, J=2.4, 12.6Hz, 1H, H-6b'), 3.95 (dt, J=3.4, 3.4 Hz, 1H, H-4'), 3.87 (m, 1H, H-5''), 3.84 (dd, J=3.4, 12Hz, 1H, H-5a'), 3.78(dd, J=3.4, 12.0Hz, 1H, H-5b'), 3.65 (d, J=14.1Hz, 1H, H-7a), 3.58 (d, J=14.1Hz, 1H, H-7b), 2.29 (m, 2H, H-2'), 2.06, 2.01, 2.01, 1.98 (s, 12H, 4Ac). ¹³C NMR (75 MHz, CD₃OD): δ = 170.9 (CO), 170.2 (CO), 169.8 (CO), 169.7 (CO), 163.5 (C4), 138.3 (C6), 111.9 (C5), 87.5 (C4'), 85.2 (C1'), 83.6 (C1''), 75.3 (C5'), 73.9 (C3''), 70.6 (C3'), 70.1 (C2''), 68.2 (C4''), 61.6 (C6''), 61.2 (C5''), 40.1 (C2'), 26.5 (C7), 19.2 (2Ac), 19.1 (2Ac). HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₄H₃₂N₂NaO₁₄S: 627.1466; found: 627.1459.

(52) β-2,3,4,6-Tetra-O-acetylthioglucopyranose was purchased from Acros Organics BVBA (Geel, Belgium).

(53) Levina, A. S.; Tabatadse, D. R.; Khalimskaya, L. M.; Prichodko, T. A.; Shishkin, G. V.; Alexandrova, L. A.; Zarytova, V. P. Bioconju-gate Chem. 1993, 4, 319.

### (54) 5-(Iodomethyl)-2'-deoxyuridine (7)

¹H NMR (300 MHz, CD₃OD): δ = 8.08 (t, J=0.9 Hz, 1H, H-6), 6.29 (t, J=6.8Hz, 1H, H-1'), 4.42(dt, J=6.0, 3.4Hz, 1H, H-3'), 4.20 (dd, J=0.9, 11.9Hz, 1H, H-7a), 4.16(dd, J=0.9, 11.9Hz, 1H, H-7b), 3.93 (dt, J=3.4, 3.4 Hz, 1H, H-4'), 3.82 (dd, J=3.4, 12.0 Hz, 1H, H-5a'), 3.73 (dd, J=3.7, 12.0 Hz, 1H, H-5b'), 2.27 (m, 2H, H-2').

¹³C NMR (75 MHz, CD₃OD): δ = 165.2 (C4), 152.3 (C2), 141.2 (C6), 112.1 (C5), 89.0 (C1'), 86.6 (C4'), 72.1 (C3'), 67.8 (C7), 62.8 (C5'), 41.4 (C2').

(55) Ibatullin, F. M.; Selivanov, S. I.; Shavva, A. G. Synthesis 2001, 419.

(56) Ibatullin, F. M.; Shabalin, K. A.; Jänis, J. V.; Shavva, A. G. Tetrahedron Lett. 2003, 44, 7961.

(57) Gan, Z.; Roy, R. Tetrahedron Lett. 2000, 41, 1155.

(58) Cagnoni, A. J.; Varela, O.; Gouin, S. G.; Kovensky, J.; Uhrig, M. L. J. Org. Chem. 2011, 76, 3064.