Chemoselective Trimerization of Isocyanides: De Novo Synthesis of 2-Indole-Substituted Quinolines and Pyridines

Abstract

A catalyst-free chemoselective trimerization reaction of readily available isocyanides is described. This domino reaction provides facile access to a wide range of 2-(indol-2-yl)-quinolines and 2-(indol-2-yl)-pyridines in moderate to excellent yields. A “head to head” heterodimerization of two isocyanides is proposed as the key step of this reaction.

Reactions Involving Multiple Isocyanide Insertions

“…published the first report of chemoselective trimerization of isocyanides 275 with 304 and 309 for the synthesis of 2‐(indol‐2‐yl)‐quinolines 308 and 2‐(indol‐2‐yl)‐pyridines 310 in DME at 150 °C (Scheme 41). [19] Under these catalyst‐free conditions, two molecules of isocyanides 275 react with one molecule of isocyanides 304 to produce 2‐(indol‐2‐yl)‐quinolines 308 in moderate to excellent yields (60–96%). However, the reaction of the two isocyanides 275 molecules with isocyanides 309 instead, affords 2‐(indol‐2‐yl)‐pyridines 310 in good to excellent yields (78–98%) under the same circumstances.…”

“…Compared to the popularity of single isocyanide reactions, few examples of reactions involving two/multiple isocyanides have been reported in literature. Two molecules of isocyanide carry out reactions such as double isocyanide insertions, [16,17] isocyanide‐based MCR [18] and oligomerization [19] /polymerization [15] . However, few reports have been disclosed on double isocyanide insertions because isocyanides are readily polymerized under metal‐catalyzed conditions.…”

Indole frameworks via transition-metal-free annulation: a current perspective

“…A fascinating chemoselective trimerization reaction of isocyanides for synthesis of 2-(indol-2-yl)quinolines and 2-(indol-2-yl)-pyridines was accomplished by Dong, Xu and co-workers. 112 The authors found that the reaction of aryl isocyanides 172 and o -alkenyl arylisocyanides 173 in 1,2-dimethoxyethane (DME) at 150 °C selectively produced 2-(indol-2-yl)quinolines 174 . On the other hand, the assembly of aryl isocyanides 172 and 1,3-dienyl isocyanides 175 yielded trimerized product 2-(indol-2-yl)-pyridines 176 under similar reaction conditions.…”

Tandem ring-opening and formal [3 + 2] cycloaddition of furo[2,3-d]pyrimidine-2,4-diones

“…4 In recent years, many domino and multicomponent reactions based on the nucleophilic addition of alkyl isocyanides have been successfully developed. 5…”