Lewis-Acid-Catalyzed Dearomative 4π + 2σ Cycloaddition of Bicyclobutanes with Isoquinolinium Methylides for the Synthesis of Ring-Fused Azabicyclo3.1.1heptanes

• Published in: Organic letters 2024-11, Vol.26 (43), p.9311
• Main Authors: Jiang, Qin, Dong, Jianyang, Zhou, Xuechen, Liao, Huijuan, Zhou, Juan, Xue, Dong
• Format: Article
• Language: English
• ISSN: 1523-7052; 1523-7052
• DOI: 10.1021/acs.orglett.4c03489

Dearomative cycloadditions are valuable for efficiently generating three-dimensional molecular complexity. However, despite recent reports of cycloadditions of bicyclobutanes (BCBs) for the synthesis of aza-bicyclo[3.1.1]heptanes (aza-BCHeps), which are bioisosteres of meta-substituted aza-arenes, dearomative cycloaddition of BCBs with N-heteroarenes for the synthesis of ring-fused aza-BCHeps has yet to be achieved. Herein, we disclose a method for Lewis acid-catalyzed [4π + 2σ] cycloaddition of isoquinolinium methylides with BCBs, which furnished a diverse array of previously inaccessible ring-fused 3-aza-BCHeps. We demonstrated the synthetic utility of the method by carrying out scaled-up reactions and transforming the products.Dearomative cycloadditions are valuable for efficiently generating three-dimensional molecular complexity. However, despite recent reports of cycloadditions of bicyclobutanes (BCBs) for the synthesis of aza-bicyclo[3.1.1]heptanes (aza-BCHeps), which are bioisosteres of meta-substituted aza-arenes, dearomative cycloaddition of BCBs with N-heteroarenes for the synthesis of ring-fused aza-BCHeps has yet to be achieved. Herein, we disclose a method for Lewis acid-catalyzed [4π + 2σ] cycloaddition of isoquinolinium methylides with BCBs, which furnished a diverse array of previously inaccessible ring-fused 3-aza-BCHeps. We demonstrated the synthetic utility of the method by carrying out scaled-up reactions and transforming the products.