(3+2) Annulation Reactions of Azaoxyallyl Cations: Synthesis of Pyrroloindolines and Imidazolone

1. Utilization of Azaoxyallyl Cation Intermediates in Synthesis: A Review.;In recent years, azaoxyallyl cation intermediates have been applied to a wide assortment of (4+3), (3+3), and (3+2) annulation reactions for the facile synthesis of azacycles. Azaoxyallyl cations, as 1,3-dipole synthons, may be accessed in situ from alpha-haloamides. Annulation reactions of azaoxyallyl cations are amenable with a broad range of substrates including indoles, aldehydes, ketones, esters, amides, sulfur ylides, alkynes, alkenes, nitriles, and more. An overview of these annulation reactions of azaoxyallyl cations with various partners is covered within this review.;2. (3+2) Annulation Reactions of Azaoxyallyl Cations and 3-Substituted Indoles: Synthesis of Pyrroloindolines.;(3+2) annulation reactions of azaoxyallyl cations and 3-substituted indoles for the synthesis of pyrroloindolines were demonstrated. Density Functional Theory (DFT) calculations (B3LYP-D3/6-311G**++) of the annulation mechanism of azaoxyallyl cations and 3-substituted indoles suggest a stepwise process with an initial C--C bond formation and subsequent cyclization. The DFT calculations also suggest the regioselectivity of the pyrroloindoline to be under kinetic control. Hydrogen bonding solvents, like HFIP, stabilize azaoxyallyl cation intermediates and lower the transition state energy to the C(3) alkylated intermediate. Efforts toward diastereoselective (3+2) annulation reactions with azaoxyallyl cations were then discussed. Finally, a small library of pyrroloindolines was screened as potential TRPA1 agonists and GLP-1 secretagogues.;3. Further Exploration of (3+2) Annulation Reactions with Azaoxyallyl Cations: Synthesis of Imidazolones and 2-Aminoimidazolones.;Continued investigation of the reactivity of azaoxyallyl cations in annulation reactions was discussed. (3+2) annulation reactions between azaoxyallyl cations and nitriles for the synthesis of 2-aminoimidazolones and imidazolones were demonstrated. This imidazolone synthetic methodology was then applied to the formal synthesis of irbesartan, an antihypertension drug co-marketed by Sanofi and Bristol Myers Squibb. In addition, (3+2) annulation reactions between azaoxyallyl cations and epoxides for the synthesis of morpholin-3-ones were shown. Finally, efforts toward (3+2) annulation reactions of imidazoles and benzimidazoles with azaoxyallyl cations were examined.