Construction of <i>N</i>-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products

Abstract

This account summarizes the development of a benzyne-mediated cyclization/functionalization protocol for the versatile construction of highly substituted benzene derivatives fused with an N-heterocyclic ring such as indolines, indoles, and related nitrogen-containing heterocycles. The protocol comprises sequential reactions initiated by generating a benzyne species and subsequent cyclization via addition of magnesium amide to the benzyne, followed by trapping of the resultant magnesium compound in situ with various electrophiles. The substituent scope was expanded by conducting a transmetalation on a copper species to introduce alkyl, aryl, and alkenyl substituents. The utility of the sequential reaction was demonstrated in the synthesis of a carbazole natural product (heptaphylline), pyrrolo[4,3,2-de]quinoline alkaloids (batzellines), and pyrrolo[2,3-c]carbazole alkaloids (dictyodendrines).

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes

“…Tokuyama and colleagues used Mg(TMP) 2 •2LiCl for aryne generation. [21][22][23] In our method, Mg(TMP) 2 •2LiCl was used in the selective deprotonation step without noticeable aryne generation. The precursor 1 was obtained in 88% yield by treating C-silylated phenol 4 with Tf 2 O in the presence of (i-Pr) 2 NEt.…”