酸催化1,3-环二酮的选择性C-,O-异戊烯基化反应

doi:10.1016/S1872-2067(20)63575-6

摘要/Abstract

摘要： 5-色烯酮类衍生物广泛分布于自然界中，特别是各种天然药材中.例如，传统药材桃金娘和大麻的活性成分都含有这类骨架.因此，发展高效的策略来合成5-色烯酮一直受到科研工作者的关注.传统的方法主要是以1，3-环己二酮与异戊烯基溴或卤代苄溴为原料，经过取代和分子内环化两步反应合成得到.最近，1，3-环己二酮与不饱和分子的形式[3+3]环加成反应，由于其独特的原子和步骤经济性，已被用于构建色烯酮骨架.但这类不饱和分子仅限于α，β-不饱和醛与炔丙基醇.因此，发展新的、简单易得的合成子仍具有很大的吸引力.
本文采用廉价易得的工业化学品异戊二烯作为简单高效的合成子，用于构建5-色烯酮骨架.首先，以5-苯基-1，3-环己二酮和异戊二烯为模板底物，通过对固体酸催化剂、溶剂及反应温度等筛选发现，在固体酸Nafion（10 wt%）催化下，以DCE为溶剂，110℃反应24h，5-苯基-1，3-环己二酮会经过C-异戊烯基化和分子内环化的串联过程，一步生成[3+3]产物5-色烯酮，分离收率达到82%.该反应具有高的区域和化学选择性，以及原子经济性.若以异戊烯基醇为原料，在最优条件下，也可以顺利得到5-色烯酮产物.令人意外的是，当温度降低到70℃时，除了主产物5-色烯酮，还可以检测到少量O-异戊烯基化产物.由于1，3-环己二酮的直接O-异戊烯基化反应至今未有报道，我们对该选择性进行了优化.通过对酸催化剂种类、溶剂和温度等调控发现，以Lewis酸AlCl₃为催化剂，在DCE中，70℃反应24h，5-苯基-1，3-环己二酮可以只发生O-异戊烯基化反应，具有专一的选择性.
随后，对两种催化体系分别进行了底物普适性考察.在固体酸Nafion催化体系下，未取代和5-取代的1，3-环己二酮都能很好地参与反应.4，4-二甲基-1，3-环己二酮由于其非对称的结构，可以得到两种环化产物.2，2，4，4-四甲基-1，3，5-环己三酮（syncarpic acid）是很多天然产物分子的前体，其也可以和异戊二烯发生环化反应，所得产物结构得到了单晶衍射的确定.此外，该反应还适用于1，3-环戊二酮、1，3-环庚二酮以及巴比妥酸等底物.对于AlCl₃催化体系，五元、六元和七元环状二酮都能顺利地发生O-异戊烯基化反应.特别是，在该体系中，非对称的4，4-二甲基-1，3-环己二酮也只得到一种O-异戊烯基化产物，具有优异的区域选择性.
最后，在两种催化体系下，1，3-环己二酮的C-和O-异戊烯基化反应能够很容易放大到克级规模，并且所得到的两类产物在LiHMDS/TsCl作用下会发生芳构化过程，得到异戊烯基化的间苯二酚，该结构也是很多具有药理活性分子的核心单元.
因此，通过对催化剂种类和异戊烯基源的调节，首次实现了1，3-环二酮的选择性C-、O-异戊烯基化反应.在固体酸Nafion催化下，1，3-环己二酮和异戊二烯经过C-异戊烯基化和分子内环化的串联过程，生成[3+3]产物5-色烯酮.而以异戊烯基醇为原料时，在AlCl₃催化下，1，3-环己二酮可以专一地进行O-异戊烯基化反应.这种利用廉价易得的原材料合成具有高附加值的结构骨架在有机合成及工业生产中具有潜在的应用价值.

关键词: 5-色烯酮, 1,3-环己二酮, O-异戊烯基化, [3+3]环化反应, 异戊二烯, 异戊烯基醇

Abstract: The chemoselective C- and O-prenylation of cyclic 1,3-diketones was achieved by tuning the prenyl source and catalyst. In the presence of the solid acid Nafion, the coupling of 1,3-cyclohexanediones with isoprene gave C-prenylated 5-chromenones. Alternatively, using prenol as the substrate with the Lewis acid AlCl₃ as the catalyst resulted in the exclusive O-prenylation of 1,3-cyclohexanediones. Notably, the resulting products could easily undergo aromatization to deliver prenylated resorcinols that are otherwise difficult to prepare. Our methodology is highly selective, atom-economical, operationally simple, easily scalable, and has potential applications throughout organic synthesis.

Key words: 5-Chromenones, 1,3-Cyclohexanediones, O-Prenylation, [3+3] Annulation, Isoprene, Prenol

李莹, 呼延成, 季定纬, 何固城, 张炜松, 丛玉凤, 陈庆安. 酸催化1,3-环二酮的选择性C-,O-异戊烯基化反应[J]. 催化学报, 2020, 41(9): 1401-1409.

Ying Li, Yan-Cheng Hu, Ding-Wei Ji, Wei-Song Zhang, Gu-Cheng He, Yu-Feng Cong, Qing-An Chen. Acid-catalyzed chemoselective C- and O-prenylation of cyclic 1,3-diketones[J]. Chinese Journal of Catalysis, 2020, 41(9): 1401-1409.

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