Regiochemical Studies of the Ring Expansion Reactions of Hydroxy Azides with Cyclic Ketones

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified

Base-Promoted Reactions of Bridged Ketones and 1,3- and 1,4-Haloalkyl Azides: Competitive Alkylation vs Azidation Reactions of Ketone Enolates

The reactions of 1,3- and 1,4-haloalkyl azides with enolates of 2-norbornanone (and a ring-expanded analog) afford polycyclic 1,2,3-triazolines in good yields. The reaction occurs by the initial azidation of the ketone enolate, followed in order by triazoline formation and O-alkylation. An interesting element of this process is the preferential reaction of the alkyl azide with an enolate anion as opposed to the more familiar reaction of the alkyl halide (including Cl and I derivatives). Reactions of acyclic or monocyclic enolates generally lead to 1,2,3-triazoles but none of the alternative C-alkylation product

Base-Promoted Reactions of Bridged Ketones and 1,3- and 1,4-Haloalkyl Azides: Competitive Alkylation vs Azidation Reactions of Ketone Enolates

The reactions of 1,3- and 1,4-haloalkyl azides with enolates of 2-norbornanone (and a ring-expanded analog) afford polycyclic 1,2,3-triazolines in good yields. The reaction occurs by the initial azidation of the ketone enolate, followed in order by triazoline formation and O-alkylation. An interesting element of this process is the preferential reaction of the alkyl azide with an enolate anion as opposed to the more familiar reaction of the alkyl halide (including Cl and I derivatives). Reactions of acyclic or monocyclic enolates generally lead to 1,2,3-triazoles but none of the alternative C-alkylation product

First Asymmetric Total Synthesis of (+)-Sparteine

The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement

Regiochemical Studies of the Ring Expansion Reactions of Hydroxy Azides with Cyclic Ketones

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified

Regiochemical Studies of the Ring Expansion Reactions of Hydroxy Azides with Cyclic Ketones

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified

Rearrangements of Bicyclic Nitrones to Lactams: Comparison of Photochemical and Modified Barton Conditions

The rearrangement of nitrones to lactams can be carried out by photochemical activation or by treatment with Tf2O followed by KOH-promoted rearrangement (a modification of conditions originally introduced by Barton). Substrates in which the nitrone is part of a fused bicyclic ring system have traditionally proven problematic for this kind of reaction. In this study, a series of mono-, bi-, and tricyclic ring-fused nitrones were prepared to investigate the dependence of products on nitrone ring size and tether length. Results indicated that photochemical rearrangement of nitrones in benzene afforded reasonably good yields (30−68%) of lactams, while the two-step nonphotochemical process provided slightly better average yields (30−95%) of the same targets

Nucleophilic Addition to Iminium Ethers in the Preparation of Functionalized <i>N</i>-Alkyl Heterocycles

Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using 18O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed

Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones

An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed

Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones

An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed