High on cycloaddi(c)tions: The impact of the Woodward-Hoffmann [4n+2] rule for thermally allowed cycloaddition reactions and the challenges associated with moving from six to ten electrons are discussed in this Essay.

An operationally simple, one-pot multicomponent reaction has been developed for the assembly of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepines adorned with three diversification points via an atom-economical transformation incorporating α-diketones, o-azidobenzaldehydes, propargylic amines, and ammonium acetate. This process involves tandem InCl3-catalyzed cyclocondensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions; optimization data, substrate scope, and mechanistic insights are discussed.

Reductive heterocycle-heterocycle (heterocycle → heterocycle; H–H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis-(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.

The [8+2] cycloaddition of indene-2-carbaldehydes and nitro olefins is described to provide benzonorbornene scaffolds in a highly peri-, diastereo-, and enantioselective fashion in the presence of a C -symmetric aminocatalyst. This reaction, which proceeds through a transient semi-aromatic amino isobenzofulvene, represents the first example of catalytic formation and transformation of these species. Quantum chemical calculations suggest a kinetically controlled stepwise mechanism where the stereochemistry is determined in the first bond-forming event. Beyond the useful [8+2] cycloadducts, [10+4] cycloadducts have been identified in silico as potential off-pathway intermediates.

A series of computational laboratory experiments aimed at teaching students principles of rational drug design are described and evaluated. These experiments range from an introduction to viewing protein–ligand complexes to optimizing geometries of potential drugs with quantum chemistry and automated docking. Student feedback indicates that such a course increased their appreciation for the roles of chemists in the drug discovery–development process.