| Abstract
| - SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides andnitrogen, oxygen, and sulfur nucleophiles were studied. Pseudo-first-order kinetics were measured with6-halopurine compounds, and comparative reactivities were determined versus a 6-(alkylsulfonyl)purinenucleoside. 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 autocatalyticand 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 nucleosideanalogue 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. Titrationof the 6-halopurine nucleosides in CDCl3 with TFA showed progressive downfield1H NMR chemical shiftsfor H8 (larger) and H2 (smaller). The major site of protonation as N7 for both the 6-fluoro and 6-bromoanalogues was confirmed by large upfield shifts (∼16 ppm) of the 15N NMR signal for N7 upon addition ofTFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented.
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