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Electrochemistry provides a powerful tool for the late-stage functionalization of complex lactams. A two-stage protocol for converting lactams, many of which can be prepared through the intramolecular Schmidt reaction of keto azides, is presented. In the first step, anodic oxidation in MeOH using a repurposed power source provides a convenient route to lactams bearing a methoxy group adjacent to nitrogen. Treatment of these intermediates with a Lewis acid in dichloromethane permits the regeneration of a reactive acyliminium ion that is then reacted with a range of nucleophilic species.

The Lewis acid-promoted reactions of alkyl azides with ketones can afford several products. Chief among these result from a Schmidt-like insertion of the azide into the carbon−carbon bond adjacent to the carbonyl group. Alternatively, an acid-promoted rearrangement of the azide to an iminium species can occur, mostly with benzylic azides; the iminium species can then be trapped by the enol of the carbonyl compound in a variation of the Mannich reaction. The scope of each of these reactions, the dependence of the observed products upon azide and ketone structure, and the nature of acid promotion are discussed. In broad strokes, cyclohexanones and other cyclic ketones react in the presence of TiCl4 to afford insertion products, whereas the Mannich route predominates when benzyl azide and triflic acid are used. The features that lead to each reaction type and possible mechanistic implications are discussed.

Although alkyl azides can react with ketones to form ring-expanded lactams, the reaction suffers from poor generality and the need to use powerful Lewis acid promotion. The reactions of 1,2- and 1,3-hydroxyalkyl azides with ketones yield N -hydroxyalkyl lactams in high yields under the action of protic or Lewis acids such as BF 3 ·OEt 2 . The reaction appears to succeed due to the initial formation of a hemiketal, which then renders the attack of azide on an oxonium ion intramolecular. The scope of this reaction vis a vis ketone and hydroxyalkyl azide structure is discussed.

The reaction of cyclic ketones with alkyl azides to afford N-alkyl lactams can be effected by TiCl 4

A synthesis of enantiomerically pure indolizidine alkaloid 209B, beginning from naturally occurring pulegone, is described. The key step is the formation of a bicyclic lactam via the intramolecular Schmidt reaction of an alkyl azide with a cyclic ketone. The 11-pot synthesis was accomplished in an overall yield of 21.9%

Although alkyl azides can react with ketones to form ring-expanded lactams, the reaction suffers from poor generality and the need to use powerful Lewis acid promotion. The reactions of 1,2- and 1,3-hydroxyalkyl azides with ketones yield N -hydroxyalkyl lactams in high yields under the action of protic or Lewis acids such as BF 3 ·OEt 2 . The reaction appears to succeed due to the initial formation of a hemiketal, which then renders the attack of azide on an oxonium ion intramolecular. The scope of this reaction vis a vis ketone and hydroxyalkyl azide structure is discussed.

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 (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.

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 (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.

The reaction of cyclic ketones with alkyl azides to afford N-alkyl lactams can be effected by TiCl 4

A synthesis of enantiomerically pure indolizidine alkaloid 209B, beginning from naturally occurring pulegone, is described. The key step is the formation of a bicyclic lactam via the intramolecular Schmidt reaction of an alkyl azide with a cyclic ketone. The 11-pot synthesis was accomplished in an overall yield of 21.9%