Nucleophilic Addition to Iminium Ethers in the Preparation of Functionalized N-Alkyl Heterocycles

Abstract

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.

Reaction Discovery Using Microfluidic-Based Multidimensional Screening of Polycyclic Iminium Ethers

“…The preference for product formation via one path over another is dependent upon several factors, including nucleophile size and the nature of the anion-stabilizing group 15. Since all of the reaction partners used in this study were larger than those previously shown to result in path a products, it is not surprising that we observed a preference for addition to the less hindered site (path b in Table 3).…”

Schmidt Rearrangement Reactions with Alkyl Azides

“…Labeling experiments suggest that pathway (2) is the more likely. 28 Alternatively, the transient formation of a tetrahedral intermediate is required for the formation of lactone 18 (control experiments ruled out direct conversion of 17 to 18 under these strongly basic conditions). N -Protonation of the aminal (pK a ca.…”

“…28,29 Through the addition of nucleophiles in a solution of DMF at ambient temperature, a range of lactams bearing terminal functional groups including ethers, halides, azides, and sulfi des were readily prepared (Table 7.4 ). It was also found that mild reduction (NaBH 4 ) of iminium ethers to the tertiary amine was possible, whereas reduction of the corresponding lactams typically required LiAlH 4 or borane.…”

Oxidative Rearrangement of Cyclobutanone Derived <i>N</i>,<i>O</i>-Ketals Leading to Pyrrolidone Derivatives

“…The reaction represents an alternative to Schmidt reaction using hydroxyalkyl azides. [22][23][24][25][26][27][28] Studies of halogen-induced oxidative rearrangements of N,O-ketals were performed using 1a as a test substrate. Compound 1a was readily prepared by the condensation of cyclobutanone with a commercially available amino alcohol, 2-amino-3-phenylpropan-1-ol.…”

“…The iminium ether intermediate ii has ambident electrophilicity, and the C2 and C4 positions of the oxazoline ring can react with nucleophiles. [22][23][24][25][26][27][28][30][31][32][33] Methyl ether 3a′ is not produced, and therefore nucleophilic attack by MeOH on intermediate ii selectively occurs at the C2 position rather than the C4 position of the oxazoline ring, to give a possible intermediate iii, which affords alcohol 3a on aqueous work-up.…”