Sarkar Deeptanu, Deswal Shiksha, Chandra Das Rohan, Biju Akkattu T
Department of Organic Chemistry, Indian Institute of Science Bangalore-560012 India
Chem Sci. 2024 Sep 10;15(39):16243-9. doi: 10.1039/d4sc03893b.
Strain-release driven annulations with bicyclo[1.1.0]butanes (BCBs) have become an attractive area of research for the synthesis of bioisosteric bicyclohexane derivatives, which play a vital role in drug discovery. Interestingly, the utilization of the inherent strain in BCBs for the synthesis of functionalized amino-bicyclo[2.1.1]hexenes, which may spatially mimic substituted benzenes and anilines, has received only scant attention. Herein, we report the Sc(OTf)-catalyzed (3 + 2) annulation of BCBs with ynamides for the facile synthesis of 2-amino-bicyclo[2.1.1]hexenes in one step under mild conditions. The reaction likely proceeds nucleophilic addition facilitated by the nitrogen lone pair from the alkynyl group of the ynamides to the unsubstituted side of the BCBs, followed by the annulation of the resulting enolate with the keteniminium species. For the first time, the C-C triple bond of ynamides was utilized as the coupling partner for BCBs, resulting in products adorned with a functionalizable amino group and an integrated strained alkene moiety.
双环[1.1.0]丁烷（BCBs）的应变释放驱动环化反应已成为生物电子等排体双环己烷衍生物合成领域一个具有吸引力的研究方向，这类衍生物在药物发现中起着至关重要的作用。有趣的是，利用BCBs中固有的应变来合成官能化氨基双环[2.1.1]己烯，这类化合物在空间上可模拟取代苯和苯胺，但目前受到的关注却很少。在此，我们报道了在温和条件下，Sc(OTf)催化的BCBs与烯基酰胺的(3 + 2)环化反应，可一步简便地合成2-氨基双环[2.1.1]己烯。该反应可能通过烯基酰胺炔基的氮孤对促进亲核加成到BCBs的未取代侧，然后生成的烯醇盐与烯酮亚胺物种发生环化反应。烯基酰胺的碳-碳三键首次被用作BCBs的偶联伙伴，得到的产物带有可官能化的氨基和一个整合的应变烯烃部分。
