SNAr displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides: Synthesis, kinetics, and mechanism

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作者：
Liu, Jiangqiong [1 ]
Robins, Morris J. [1 ]
机构：
[1] Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, United States
来源：
Journal of the American Chemical Society | 2007年 / 129卷 / 18期
关键词：
SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides and nitrogen, oxygen, and sulfur nucleophiles were studied. Pseudo-first-order kinetics were measured with 6-halopurine compounds, and comparative reactivities were determined versus a 6-(alkylsulfonyl)purine nucleoside. The displacement reactivity order was: F > Br > Cl > I (with BuNH2/MeCN), F > Cl Br > I (with MeOH/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)/MeCN), and F > Br > I > Cl [with K+ -SCOCH3/dimethyl sulfoxide (DMSO)]. The order of reactivity with a weakly basic arylamine (aniline) was: I > Br > Cl F (with 5 equiv of aniline in MeCN at 70°C). However, those reactions with aniline were autocatalytic and had significant induction periods (∼50 min for the iodo compound and ∼6 h for the fluoro analogue). Addition of trifluoroacetic acid (TFA) eliminated the induction period, and the order then was F > I > Br > Cl (with 5 equiv of aniline and 2 equiv of TFA in MeCN at 50°C). The 6-(alkylsulfonyl)purine nucleoside analogue was more reactive than the 6-fluoropurine compound with both MeOH/DBU/MeCN and iPentSH/DBU/MeCN and was more reactive than the Cl, Br, and I compounds with BuNH2 and aniline/TFA. Titration of the 6-halopurine nucleosides in CDCl3 with TFA showed progressive downfield 1H NMR chemical shifts for H8 (larger) and H2 (smaller). The major site of protonation as N7 for both the 6-fluoro and 6-bromo analogues was confirmed by large upfield shifts (∼16 ppm) of the 15N NMR signal for N7 upon addition of TFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented. © 2007 American Chemical Society;
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页码：5962 / 5968
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