Synthesis of Polycyclic Isoindolines via α-C-H/N-H Annulation of Alicyclic Amines.

Relatively unstable cyclic imines, generated in situ from their corresponding alicyclic amines via oxidation of their lithium amides with simple ketone oxidants, engage aryllithium compounds containing a leaving group on an -methylene functionality to provide polycyclic isoindolines in a single operation. The scope of this transformation includes pyrrolidine, piperidine, azepane, azocane, and piperazines.

α,α'-C-H Bond Difunctionalization of Unprotected Alicyclic Amines.

A simple one-pot procedure enables the sequential, regioselective, and diastereoselective introduction of the same or two different substituents to the α- and α'-positions of unprotected azacycles. Aryl, alkyl, and alkenyl substituents are introduced via their corresponding organolithium compounds. The scope of this transformation includes pyrrolidines, piperidines, azepanes, and piperazines.

α-C-H Bond Functionalization of Unprotected Alicyclic Amines: Lewis-Acid-Promoted Addition of Enolates to Transient Imines.

Enolizable cyclic imines, obtained in situ from their corresponding lithium amides by oxidation with simple ketone oxidants, are readily alkylated with a range of enolates to provide mono- and polycyclic β-aminoketones in a single operation, including the natural product (±)-myrtine. Nitrile anions also serve as competent nucleophiles in these transformations, which are promoted by BF etherate. β-Aminoesters derived from ester enolates can be converted to the corresponding β-lactams.

Diversification of Unprotected Alicyclic Amines by C-H Bond Functionalization: Decarboxylative Alkylation of Transient Imines.

Despite extensive efforts by many practitioners in the field, methods for the direct α-C-H bond functionalization of unprotected alicyclic amines remain rare. A new advance in this area utilizes N-lithiated alicyclic amines. These readily accessible intermediates are converted to transient imines through the action of a simple ketone oxidant, followed by alkylation with a β-ketoacid under mild conditions to provide valuable β-amino ketones with unprecedented ease.

Rapid functionalization of multiple C-H bonds in unprotected alicyclic amines.

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C-H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C-H bond functionalization methodology that enables the introduction of up to three substituents in a single operation.

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters.

β-Amino esters are obtained with high levels of enantioselectivity via the conjugate addition of cyclic amines to unactivated α,β-unsaturated esters. A related strategy enables the kinetic resolution of racemic cyclic 2-arylamines, using benzyl acrylate as the resolving agent. Reactions are facilitated by an unprecedented selenourea-thiourea organocatalyst.

Redox-Annulations of Cyclic Amines with -Cyanomethylbenzaldehydes.

Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with -cyanomethylbenzaldehydes. These amine α-C-H bond functionalization reactions are promoted by acetic acid. The resulting β-aminonitriles can be converted to the corresponding β-aminoalcohols in diastereoselective fashion.

Traceless Redox-Annulations of Alicyclic Amines.

Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with -(nitromethyl)benzaldehyde. Benzoic acid acts as a promoter in these reactions, which involve concurrent amine α-C-H bond and N-H bond functionalization. Subsequent removal of the nitro group provides access to tetrahydroprotoberberines not accessible via typical redox-annulations.

α-Functionalization of Cyclic Secondary Amines: Lewis Acid Promoted Addition of Organometallics to Transient Imines.

Cyclic imines, generated in situ from their corresponding N-lithiated amines and a ketone hydride acceptor, undergo reactions with a range of organometallic nucleophiles to generate α-functionalized amines in a single operation. Activation of the transient imines by Lewis acids that are compatible with the presence of lithium alkoxides was found to be crucial to accommodate a broad range of nucleophiles including lithium acetylides, Grignard reagents, and aryllithiums with attenuated reactivities.

Redox-Annulations of Cyclic Amines with Electron-Deficient o-Tolualdehydes.

Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with 2-methyl-3,5-dinitrobenzaldehyde and closely related substrates. Acetic acid serves as the solvent and sole promoter of these transformations which involve dual C-H functionalization.

Direct α-C-H bond functionalization of unprotected cyclic amines.

Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds.

Decarboxylative Annulation of α-Amino Acids with β-Ketoaldehydes.

Indolizidine and quinolizidine derivatives are readily assembled from l-proline or (±)-pipecolic acid and β-ketoaldehydes via a decarboxylative annulation process. These reactions are promoted by acetic acid and involve azomethine ylides as reactive intermediates.

Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α- and β-C-H Functionalization.

Cyclic amines such as pyrrolidine and piperidine are known to undergo condensations with aldehydes to furnish pyrrole and pyridine derivatives, respectively. A combined experimental and computational study provides detailed insights into the mechanism of pyrrole formation. A number of reactive intermediates (e.