Facilitation of addition–elimination reactions in pyrimidines and purines using trifluoroacetic acid in trifluoroethanol

Abstract

SNAr displacement reactions of 6-cyclohexylmethoxy-2-fluoropurine, 6-amino-2-butylsulfonyl-4-cyclohexylmethoxypyrimidine and 2-amino-6-chloropurine with substituted anilines (e.g. the weakly nucleophilic 4-aminobenzenesulfonamide) are dramaticallyaccelerated in the presence of trifluoroacetic acid and occur especially efficiently in 2,2,2-trifluoroethanol solvent.

Trifluoroacetic Acid in 2,2,2‐Trifluoroethanol Facilitates SNAr Reactions of Heterocycles with Arylamines

“…[2,8,29] In earlier studies we focused on the use of TFA-TFE with conventional heating. [7] We have now found that the more difficult substitutions can be facilitated by microwave heating. [15,30] Furthermore, it is sometimes convenient to use an aniline hydrochloride as reactant, with the hydrogen chloride liberated providing acidic catalysis.…”

“…The syntheses of heterocyclic substrates used in this study, when not commercially available, have either been described [5,[7][8][9] or utilised standard methods (see the Experimental Section and the Supporting Information). Table 1 and Table 2 summarise the panel of heterocycles and anilines that have been examined (further examples are given in the Supporting Information, Table S1).…”

“…Initially, we employed classical S N Ar conditions whereby a 2-fluoropurine was heated with an aniline in 2-butanol. [7,8] Whereas this procedure was satisfactory with relatively basic/ nucleophilic anilines, it failed with weakly nucleophilic anilines, such as 4-nitroaniline. Although the desired products might have been accessible by treating the aniline with a 2-iodopurine in the presence of a palladium/phosphine catalyst, we explored alternative S N Ar conditions, resulting in the discovery of the versatile and reliable protocol described herein.…”

“…In earlier studies we found that the treatment of 2-fluoro-6-cyclohexyl- [a] Dr. B. Carbain, Dr. C. R. Coxon, H. Lebraud methoxypurine with aniline appeared to accelerate at later reaction times. [7] This was ascribed to the formation of hydrofluoric acid, which autocatalysed the reaction, presumably by activation of the purine by N-protonation. An investigation, in which various acid catalysts and solvents were explored, led to the identification of trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) as a convenient and efficacious combination for effecting S N Ar reactions with purines and pyrimidines.…”

Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media

“…This is supported by the observation that reactions of 2-fluoroimidazole, a model analog of 8-fluoropurines with nucleophiles, follow an addition-elimination mechanism [20]. Interestingly, reactions of certain substituted chloropurines have also been reasoned to occur via S N Ar mechanisms [21]. Thus, in the S N Ar reaction shown in Scheme 4 the addition of NH 3 to the 8-fluoropurines 2, a likely ratedetermining step [22], would lead to the formation of the Meisenheimer complex [23] 15 which could collapse to the corresponding 8-amino derivatives 8.…”