Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves

Váňa, Lubomír; Vrzal, Lukáš; Dvořáková, Hana; Himl, Michal; Linhart, Igor

doi:10.1080/00397911.2013.831902

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…Thus, solvents for the reactions of these compounds are limited to dimethyl sulfoxide (DMSO) and DMF. The direct alkylation of adenine using an alkyl halide in the presence of a base (such as NaH, NaOH, KOH, or K 2 CO 3 ) is a common reaction carried out in these two solvents to achieve N9‐alkylated adenine derivatives [2–6], which have an important biological activity such as potent cyclic nucleotide phosphodiesterase inhibition, antiinflammatory activity, and antiviral activity [7–11]; however, this reaction has long presented the problem of complex mixtures (N9‐, N3‐, and N7‐alkylated adenine regioisomers) and low yields [2–4, 6, 12–16].…”

Section: Introductionmentioning

confidence: 99%

Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

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Pilcher

2023

Journal of Heterocyclic Chem

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The alkylation of adenine using alkyl halides under basic conditions in dimethyl sulfoxide (DMSO), a common reaction to achieve N9‐alkylated adenine derivatives, is often low yielding with unreacted adenine and complicated reaction mixtures. Herein, we report the reaction monitoring of the alkylation of adenine in DMSO in the presence of NaH using benzylic halides via real‐time 1H NMR spectroscopy. NMR analysis revealed that under these generally used reaction conditions, the adeninate anion starting material is protonated as the anionic nucleophile abstracts a labile proton from an alkoxy sulfonium ion intermediate formed via the Kornblum oxidation reaction. To prevent the protonation of the adeninate anion, the reaction was performed in the presence of a mop‐up base DBU. Simultaneously increasing the concentration of the alkyl halide and the mop‐up base in a 1:1 ratio resulted in a complete reaction; however, increasing the temperature of the reaction promoted depletion of the starting material by protonation and hence reduced conversion to products. This result implies that heating of such electrophiles in DMSO should be avoided. The addition of a mop‐up base can help resolve the complication of protonation arising from the Kornblum oxidation reaction in alkylation reactions under similar conditions.

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Section: Introductionmentioning

confidence: 99%

Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

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Pilcher

2023

Journal of Heterocyclic Chem

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“…This step is followed by the direct alkylation of the adeninate anion [4,[10][11][12][13][14][15][16][17]. The direct alkylation, conducted under different experimental conditions, leads to various mixtures of regio-isomers, having the N9-alkylated adenine reported as the main isomer in polar aprotic solvents [12,[14][15][16][18][19][20]. The occurrence of mixtures of regio-isomers has sparked investigations to understand how the free anion governs alkylation at its four reactive nitrogen atoms, the N1, N3, N7, and N9 [15,18,19,21,22].…”

Section: Introductionmentioning

confidence: 99%

Coordination Sites for Sodium and Potassium Ions in Nucleophilic Adeninate Contact ion-Pairs: A Molecular-Wide and Electron Density-Based (MOWED) Perspective

2022

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The adeninate anion (Ade−) is a useful nucleophile used in the synthesis of many prodrugs (including those for HIV AIDS treatment). It exists as a contact ion-pair (CIP) with Na+ and K+ (M+) but the site of coordination is not obvious from spectroscopic data. Herein, a molecular-wide and electron density-based (MOWED) computational approach implemented in the implicit solvation model showed a strong preference for bidentate ion coordination at the N3 and N9 atoms. The N3N9-CIP has (i) the strongest inter-ionic interaction, by −30 kcal mol−1, with a significant (10–15%) covalent contribution, (ii) the most stabilized bonding framework for Ade−, and (iii) displays the largest ion-induced polarization of Ade−, rendering the N3 and N9 the most negative and, hence, most nucleophilic atoms. Alkylation of the adeninate anion at these two positions can therefore be readily explained when the metal coordinated complex is considered as the nucleophile. The addition of explicit DMSO solvent molecules did not change the trend in most nucleophilic N-atoms of Ade− for the in-plane M-Ade complexes in M-Ade-(DMSO)4 molecular systems. MOWED-based studies of the strength and nature of interactions between DMSO solvent molecules and counter ions and Ade− revealed an interesting and unexpected chemistry of intermolecular chemical bonding.

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Identification of New DNA Adducts of Phenylnitrenium

Králík

Linhart

Váňa

et al. 2015

Chem. Res. Toxicol.

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Phenylnitrenium ion (PhNH(+)) may bind to nucleophiles through nitrogen as well as through C2 or C4 carbons. However, only adducts of the former type have been hitherto reported after its reaction with purine nucleosides. In this study, reactions of N-acetoxyaniline (PhNHOAc), a precursor to PhNH(+), with 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), and with DNA in vitro at physiological conditions are described. The reaction of PhNHOAc with dA followed by a hydrolytic deribosylation afforded 8-phenylaminoadenine (C8-PhNHA) together with a smaller amount of N(6)-(4-aminophenyl)adenine (N(6)-4APA). A similar reaction with dG afforded 8-phenylaminoguanine (C8-PhNHG) together with traces of 7-(4-aminophenyl)guanine (N7-4APG). The same adducts were found also in the DNA treated with PhNHOAc, and all of them were identified by comparison of their HPLC retention times and MS(2) spectra with a set of synthesized authentic adenine adducts at C2, C8, N7, and N(6) positions and guanine adducts at C8, N7, and N(2) positions. The newly identified minor adduct, N7-4APG, represents the first proof of arylnitrenium adduction at the N7 position of dG, which is the prominent site of attack by most C-electrophiles.

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Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves

Cited by 3 publications

References 22 publications

Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Coordination Sites for Sodium and Potassium Ions in Nucleophilic Adeninate Contact ion-Pairs: A Molecular-Wide and Electron Density-Based (MOWED) Perspective

Identification of New DNA Adducts of Phenylnitrenium

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Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves

Cited by 3 publications

References 22 publications

Migrating 1H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Migrating 1H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Coordination Sites for Sodium and Potassium Ions in Nucleophilic Adeninate Contact ion-Pairs: A Molecular-Wide and Electron Density-Based (MOWED) Perspective

Identification of New DNA Adducts of Phenylnitrenium

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Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

Migrating ¹H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO