Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

Abstract

Indole-3,4- and 4,5-fused carbo- and heterocycles are ubiquitous in bioactive natural products and pharmaceuticals, and hence, a variety of synthetic approaches toward such compounds have been developed. Among these, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an electrophilic aromatic substitution (SEAr) as the ring closure are particularly attractive, because they avoid the use of 3,4- or 4,5-difunctionalized indoles as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by summarizing recent relevant literature reports.

Synthesis of benzimidazole-fused 1,4-benzoxazepines and benzosultams spiro-connected to a 2-oxindole core via a tandem epoxide-opening/SNAr approach

“…The ring-opening of epoxides, whether in simple transformations or in cascade reactions, constitutes a powerful tool for the elaboration of a diverse class of acyclic and (poly)cyclic compounds—ranging from simple primary alcohols to complex natural products. 8 Nucleophilic aromatic substitution (S N Ar) is another hallmark reaction widely used for arene functionalization. 9 Notably, S N Ar is the second most frequently-used transformation after amide bond formation reaction in medicinal chemistry.…”

An epoxide-opening cyclization/double Smiles rearrangement cascade approach to N-aryl-1,4-benzoxazines and N-arylindolines

“…Epoxide-opening cyclization represents another highly useful reaction that enables the construction of stereogenic sp 3 -carbon-bearing carbo- and heterocycles, often under full regio- and stereo-control. 4 In conjunction with our program directed toward the development of new cyclization strategies making use of intramolecular epoxide-opening reactions, 5 in 2020, we disclosed a base-mediated exo -selective epoxide-opening cyclization/intramolecular S N Ar cascade of ortho -fluorobenzenesulfonamide-tethered epoxides (Scheme 1A). 6 In the same year, Ma and co-workers synthesized 1-(arylamino)propan-2-ols via the reaction of EWG-substituted arylsulfonyl amides with terminal epoxides (Scheme 1B).…”