Ye Zhishi, Adhikari Sarju, Xia Yu, Dai Mingji
Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
Nat Commun. 2018 Feb 19;9(1):721. doi: 10.1038/s41467-018-03085-3.
Saturated 1,4-diazo heterocycles including piperazines, 1,4-diazepanes, and 1,4-diazocanes, are highly important for therapeutic development, but their syntheses are often tedious. We describe here an amphoteric diamination strategy to unite readily available 1,2-, 1,3- or 1,4-diamine derivatives with electron-deficient allenes via a formal [n + 2] (n = 4, 5, 6) cyclization mode to produce the corresponding 1,4-diazo heterocycles in just one step. This strategy features mild reaction conditions, high functional group tolerance, and scalability (gram scale). The reagents used are cheap and readily available and no transition metal catalysts are needed. More sophisticated products containing trifluoromethyl group or bicyclic ring systems can be accessed via a one-pot procedure as well. Our mechanistic studies support that formation of mono-iodinated or chlorinated diamine intermediates is important for the desired transformation and the commonly proposed chloride-iodide exchange process and a radical N-C bond formation is unlikely when the combination of NCS/KI is used.
包括哌嗪、1,4 - 二氮杂环庚烷和1,4 - 二氮杂环辛烷在内的饱和1,4 - 重氮杂环化合物对于药物研发非常重要，但其合成过程往往很繁琐。我们在此描述了一种两性双胺化策略，通过形式上的[n + 2]（n = 4、5、6）环化模式，将易于获得的1,2 -、1,3 - 或1,4 - 二胺衍生物与缺电子的丙二烯结合，一步生成相应的1,4 - 重氮杂环化合物。该策略具有反应条件温和、官能团耐受性高和可扩展性（克级规模）的特点。所使用的试剂便宜且易于获得，无需过渡金属催化剂。含有三氟甲基或双环体系的更复杂产物也可以通过一锅法制备。我们的机理研究表明，单碘化或氯化二胺中间体的形成对于所需转化很重要，当使用NCS/KI组合时，通常提出的氯 - 碘交换过程和自由基N - C键形成不太可能发生。
