Synthesis and Highly Selective Bromination of Azacalix[4]pyrimidine Macrocycles

A number of N-substituted azacalix[4]pyrimidines were synthesized by two methods. While straightforward condensation reaction between 4,6-dichloropyrimidine and 4,6-bis(alkylamino)pyrimidines gave identically N-substituted azacalix[4]pyrimidines in low yields, a general and moderate-to-high yielding 1 + 3 macrocyclic fragment coupling reaction afforded azacalix[4]pyrimidines that contained either the same or different N-substituents. Upon treatment with N-bromosuccinimide (NBS) under controlled conditions, methylazacalix[4]pyrimidine was selectively brominated at lower rim to produce mono-, di-, and tribrominated azacalix[4]pyrimidines in good yields. While azacalix[4]pyrimidine derivatives adopted 1,3-alternate conformation in the solid state, the synthesized macrocycles were fluxional in solution, and the interconversion of various conformational structures was rapid relative to the NMR time scale.

研究通过两种方法合成了多种N-取代氮杂杯[4]嘧啶（azacalix[4]pyrimidines）。4,6-二氯嘧啶与4,6-二(烷基氨基)嘧啶间的直接缩合反应虽可得到N取代基完全一致的氮杂杯[4]嘧啶，但产率偏低；而通过一种通用且产率中等至高的1+3大环片段偶联反应，则可制备得到带有相同或不同N取代基的氮杂杯[4]嘧啶。在受控条件下以N-溴代琥珀酰亚胺（N-bromosuccinimide, NBS）处理甲基氮杂杯[4]嘧啶时，可在其下缘实现选择性溴代，以良好产率获得单溴代、双溴代及三溴代氮杂杯[4]嘧啶。固态下，氮杂杯[4]嘧啶衍生物采取1,3-交替构象；而所合成的大环化合物在溶液中具有构象动态性，各类构象结构间的互变速率远快于NMR时间尺度。