Issue in Honor of Prof. Pierre Vogel ARKIVOC 2014 (iii) 154-169
Initial experiments using HCl.Et2O failed, resulting in rapid decomposition of the starting amine (entry 1). Protonation with trifluoromethanesulfonic acid (entries 2 and 3) yielded the desired compound 20, but also led to the formation of unidentified side products. Protonation with 0.9 or 2.0 equivalents of p-toluenesulfonic acid afforded the mono- and diprotonated compounds 22 and 23, respectively, in good yields (entries 4 and 5). Unfortunately, the resulting trifluoromethanesulfonate and p-toluenesulfonate salts proved to be highly sensitive to air and difficult to handle. Eventually, tetrafluoroboric acid diethyl etherate proved to be the optimal choice, affording 24 in 95% yield (entry 6). The resulting salt was found to be stable towards air and moisture, and the corresponding bisprotonated species was not detected even when two equivalents of acid were added (entry 7). In an analogous manner, the monoprotonated compounds 26 and 27 were cleanly obtained in 97% yield (Scheme 4).
Scheme 4. Protonation of 15 and 16. Methylation
With reliable procedures for the preparation of monoprotonated amino pyridines in hand, we studied the reaction of standard methylating agents such as methyl trifluoromethanesulfonate, trimethyloxonium tetrafluoroborate (Me3OBF4), dimethyl sulfate or methyl tosylate with ammonium salt 24. While treatment with MeOTos and Me2SO4 led to the formation of complex mixtures, the use of Me3OBF4 resulted in formation of the desired biscationic salt, albeit with low conversion. MeOTf gave more promising results and, therefore, further studies focused on this reagent. After some experimentation, we identified dioxane as ideal solvent for this transformation (Table 4).
Variation of the temperature revealed that an increase from rt to 50 ºC had a negative impact on conversion (entries 1 and 2). Because of the relatively low solubility of 24 in dioxane, solvent mixtures of dioxane and 10% DMF were tested to enhance solubility, but the reaction was slower in this case (entry 3). Notably, shorter reaction times led to higher conversion (entries 4-6), which is consistent with the observation that the resulting biscationic salts are unstable and probably decompose over extended reaction times. Lowering the concentration from 0.2 M to 0.1 M increased the conversion from 22% to 47% (entry 6), a trend that became even more obvious when the concentration was lowered to 0.02 M, resulting in an improved conversion of 70% (entry 8). As observed before higher temperatures led to lower yields (entry 9). At 0 ºC, the 1H NMR spectra showed no remaining starting material after 1 h, but the formation of almost
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