Isocyanides in the Synthesis of Nitrogen Heterocycles

Abstract

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition-metal-catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.

Mechanistic Study of Stepwise Methylisocyanide Coupling and C–H Activation Mediated by a Low-Valent Main Group Molecule

“…5 Groundbreaking work by Passerini 6 and Ugi [7][8][9] led to a dramatic expansion of the study of cyanide and isocyanide coupling chemistry, most notably their metal catalyzed oligomerization and polymerization reactions. [10][11][12] However, knowledge of their mechanistic details remains limited. Some of the earliest coupling reactions were shown to be mediated by Grignard reagents 13 and other main group metal halides, [14][15] but most of the work on the mechanism of catalytic coupling of isocyanides has involved transition metal complexes either of the group 10 noble metals or various first row transition metal complexes.…”

Synthesis of 6‐Alkylated Phenanthridine Derivatives Using Photoredox Neutral Somophilic Isocyanide Insertion

“…[7][8][9][10] The radical 5 adds to 1 to produce the imidoyl radical intermediate 6, which undergoes intramolecular homolytic aromatic substitution to give the radical intermediate 7. [14] The 3 ]. Ultimately deprotonation assisted by base yields 6-alkylated phenanthridines.…”

“…[1] Isocyanides are isoelectronic with carbon monoxide, and thus it is not surprising that isocyanides can undergo insertion reactions (also named imidoylative reactions) [2] to provide N-containing heterocycles which are ubiquitous in pharmaceuticals and biologically active molecules. [2][3][4] As depicted in Scheme 1 a, palladium-catalyzed isocyanide insertion and somophilic isocyanide insertion represent two typical strategies currently reported for isocyanide insertion reactions. While the palladium-catalyzed isocyanide insertions often require high reaction temperatures and have the tendency to undergo multiple consecutive insertions, [5] the use of isocyanides as somophiles for insertion reactions holds promise for practical synthetic applications under mild reaction conditions.…”

Palladium(0)-Catalyzed Benzylic C(<i>sp</i>³)–H Functionalization for the Concise Synthesis of Heterocycles and Its Applications

“…We initially focused on a cascade reaction involving a combination of benzylic C(sp 3 )-H functionalization with Pd-catalyzed isocyanide insertion [81][82][83][84][85][86] for the synthesis of indole derivatives, which are an important class of nitrogen-containing heterocycles in the pharmaceutical sciences. Several other groups had previously reported concise methods for the synthesis of carbo-and heterocyclic systems through isocyanide insertion and C(sp 2 )-H activation steps.…”