Stereoselective Convergent Synthesis of Tetrahydro‑5H‑benzo[c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition

• Published in: Journal of organic chemistry 2019-05, Vol.84 (9), p.5277-5291
• Main Authors: Lekky, Anek, Ruengsatra, Tanachote, Ruchirawat, Somsak, Ploypradith, Poonsakdi
• Format: Article
• Language: English
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b00263

The diene methyl ethers or acetates, constructed from the Li–Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)­bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda–Grubbs II as a catalyst to provide the corresponding benzannulated (Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5H-benzo­[c]­fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5–C6) and trans at the site of nucleophilic attack (C6–C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5H-benzo­[c]­fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.