Science of Synthesis

Liang, Y.; Wen, Z.; Cabrera, M.; Howlader, A. H.; Wnuk, S. F., Science of Synthesis Knowledge Updates, (2020) 1, 200.

Amide-controlled one-pot reaction of 4-(alkylamino)-5-amino-6-chloropyrimidines ‌34‌ with primary alcohols and N,N-dimethyl alkyl- or arylamides ‌35‌ in the presence of sodium hydride leads to the formation of 6,8,9-trisubstituted purines ‌36‌ and ‌37‌ (‌Scheme 7‌).[‌11‌] Purines ‌36‌ contain the R1 substituent derived from the amide used at C8, whereas the unexpected purines ‌37‌ have substituents at C8 originating from the alcohol used. The formation of alkoxyiminium ions in the absence of steric impediments leads to purine analogues ‌36‌. By contrast, oxidation of the alcohol in the presence of larger N,N-dimethyl amides gives rise to purines ‌37‌. The competition between alkoxyiminium ion formation versus oxidative alkoxide coupling decides whether ‌36‌ or ‌37‌ is obtained for various substrates. Purines ‌36‌ (R1 = H; R2 = Ph; R3 = iPr) and ‌37‌ (R2 = Et; R3 = iPr) reduce trypanosome viability with IC50 of 1 µM and 4.8 µM, respectively.

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References