Evolution of a Multicomponent System: Computational and Mechanistic Studies on the Chemo‐ and Stereoselectivity of a Divergent Process

Abstract

The evolution of a ternary molecular system (imine, diene and nitrile) is analyzed to disclose the pathways leading to a divergent synthetic outcome. The Lewis acid catalyzed reaction between cyclohexadiene, 2-phenyl-indol-3-one and acetonitrile yields the imino-Diels-Alder adduct as the major product together with minor amounts of the Mannich-Ritter-amidine product. The experimental and computational data show that the relative orientation of the initial reactants dictates the synthetic outcome. The exo approach between imine and diene leads to the Diels-Alder adduct in a concerted process, whereas the endo mode leads to a polarized intermediate, which is trapped by acetonitrile to yield the multicomponent adduct.

Development of Heterocyclic Multicomponent Reactions through Guided Exploration: Direct, Reasonable and Unpredictable Processes

“…We observed the formation of the imino-Diels–Alder adduct together with minor amounts of the Mannich–Ritter compound, showing complementary stereochemical patterns (Scheme 15 ). 35 Intrigued by the mechanism of this divergent process, we looked for advice from our computational expert, Prof. F. J. Luque (U. Barcelona), who determined that the topology of the interaction dictated its synthetic outcome. An endo approach led to a polarized transition state which evolved to the cationic intermediate A .…”

Diamination/Oxidative Cross-Coupling/Bicyclization of Anilines and Methyl Ketones: Direct I2-Promoted Synthesis of 1,2-Fused Oxindoles

“…It is noteworthy that 1,2-fused oxindoles are widespread in natural alkaloids and biologically active molecules, highlighting the potential application of this new method . In contrast to previous reports pertaining to the synthesis of 1,2-fused oxindoles from preexisting indolin-3-ones or indoles, this new method allows for the concise synthesis of 1,2-fused oxindoles from readily available methyl ketones and anilines in one pot.…”

Predicting Solvent-Dependent Nucleophilicity Parameter with a Causal Structure Property Relationship

“…The majority of reactions in synthetic processes are under kinetic control, and their selectivity can be predicted through assessment of competitive reaction rates. While rationalizing and predicting stereoselectivity have been consistently demonstrated using molecular modeling of transition states in asymmetric catalysis, − prediction of chemoselectivity between dissimilar reactions of different kinetic orders remains difficult . This is further hindered by the complexity of reaction conditions and solvent dependence of reaction outcomes. − On the other hand, selecting the correct solvent and reaction conditions can be a powerful tool in manipulating and controlling reaction selectivity, as recently demonstrated by Vigo and co-workers in a synthesis of Raltegravir (see Figure ).…”