Iminium Ether Research Articles

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol.

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN3 is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods.

ChemInform Abstract: Oxidative Rearrangement of Cyclobutanone Derived N,O‐Ketals Leading to Pyrrolidone Derivatives.

AbstractThe halogen‐induced rearrangement proceeds via an iminium ether intermediate.

Oxidative rearrangement of cyclobutanone derived N,O-ketals leading to pyrrolidone derivatives.

A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained.

ChemInform Abstract: Dual Nucleophilic/Electrophilic Capture of in situ Generated Iminium Ethers: Towards the Synthesis of Functionalized Amide Building Blocks.

AbstractThe reaction proceeds via a cyclization followed by a Claisen rearrangement to yield iminium ether intermediates, which react with various nucleophiles.

Dual Nucleophilic/Electrophilic Capture of In Situ Generated Iminium Ethers: Towards the Synthesis of Functionalized Amide Building Blocks

Rearranging its feathers: The transformation of simple linear amides into a diverse range of branched, functionalized products by conversion to iminium esters is followed by sequential treatment with nucleophiles and electrophiles (see scheme). The method takes advantage of a novel Claisen rearrangement and the use of aromatic substrates greatly facilitates the formation of the intermediate iminium ether.

Synthesis and Reactivity of Bicyclo[3.2.1]octanoid-Derived Cyclopropanes

Photochemical oxa-di-π-methane rearrangement of bicyclo[3.2.1]octanoid scaffolds affords multifunctional, donor-acceptor cyclopropanes. A related photochemical reaction of an iminium ether substrate uncovered an unprecedented aza-di-π-methane rearrangement of a β,γ-unsaturated iminium. Donor-acceptor cyclopropanes have been evaluated as substrates for reactions generating several new chemotypes.

ChemInform Abstract: Development of Synthetic Organic Reaction Through the Formation of Halocyclization Intermediate as an Activating Method

We report here the results of synthetic organic reactions which proceed under mild conditions through the formation of cationic halocyclization intermediates. In the presence of I2 and collidine or lutidine, α-iodination reactions of unsaturated carboxamides and N-allylic carboxamides proceed in good yields through the activation of α-hydrogens by the formation of cyclic iminium ethers (iodolactonization intermediates). The iodine-mediated method can be also applied to the activation of enamide derivatives ; that is, in the presence of I2, the Diels-Alder reactions of N-allylic enamides which are unreactive dienophiles, proceed in good yield through the formation of the cyclic iminium ether. These activation processes are successfully extended to asymmetric α-iodination of unsaturated carboxamides having homochiral 2, 5-disubstituted pyrrolidine and asymmetric Diels-Alder reaction using novel axially chiral N-acryl anilide. Furthermore, the reactions of p-methoxybenzyl pentenyl ether with NIS and O-pentenyl oxime with NBS resulted in the activation of C-O bond and N-O bond through the formation of cationic haloetherification intermediates, and the following reaction with alcohols and migration of anti-substituent gavep-methoxybenzylation and Beckmann rearrangement products in good yields, respectively.

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

Polycyclic iminium ethers are ambident electrophilic intermediates that react with a range of nucleophiles in a highly condition-dependent manner to afford densely functionalized lactams. In an effort to expand the scope of reactivity and assist in the generation of new chemotypes from these intermediates, several iminium ethers were subjected to reaction screening using an automated microfluidics reaction platform. Application of this approach led to the discovery of several interesting reaction pathways involving the iminium ether intermediates that will be described.

Asymmetric Synthesis of Tetracyclic Benzo[a]quinolizidine Targets

We report a novel, facile, and asymmetric approach for the synthesis of polycyclic benzo[ a]quinolizidine targets. In the formation of more functionalized derivatives, we have observed the generation of an iminium ether salt intermediate, formed during an unprecedented retro-Diels-Alder/ N-acyliminium cyclization cascade. The iminium ether intermediate was isolated in good yield, characterized by X-ray crystallography, and subsequently applied as a synthetic building block.

ChemInform Abstract: Nucleophilic Addition to Iminium Ethers in the Preparation of Functionalized N‐Alkyl Heterocycles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Nucleophilic Addition to Iminium Ethers in the Preparation of Functionalized N-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 (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.

Modular Synthesis of Cyclic Peptidomimetics Inspired by γ‐Turns.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Modular Synthesis of Cyclic Peptidomimetics Inspired by γ-Turns

[reaction: see text] A series of peptidomimetics based on a gamma-turn motif were synthesized using a modular approach, in which N-protected piperidones were reacted with a selection of 2-hydroxyalkyl azides derived from common l-amino acids. Hydrolysis of the initially formed iminium ethers afforded the targeted series of substituted 1,4-diazepin-5-ones.

Unusual Tethering Effects in the Schmidt Reaction of Hydroxyalkyl Azides with Ketones: Cation—π and Steric Stabilization of a Pseudoaxial Phenyl Group.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Unusual Tethering Effects in the Schmidt Reaction of Hydroxyalkyl Azides with Ketones: Cation−π and Steric Stabilization of a Pseudoaxial Phenyl Group

The Lewis acid-promoted reactions of chiral 2-aryl-3-azido-1-propanols with 4-substituted cyclohexanones lead to iminium ethers and ultimately caprolactams (following a hydrolysis step). In this study, it is shown that these reactions afford variable ratios of products, depending on the electronic nature of the phenyl group. These results are interpreted in the context of a cation-pi stabilizing effect in the product-determining reaction intermediate. Remarkably, the best selectivity was obtained when an azidopropanol reagent containing a quaternary center was used; a control experiment showed that the high selectivity observed in this result depended upon the free rotation of the pseudoaxial aromatic group in the intermediate that affords the major product.

Asymmetric Schmidt Reaction of Hydroxyalkyl Azides with Ketones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

ChemInform Abstract: Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides: Synthesis of Macrocyclic Lactams and Lactones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides: Synthesis of Macrocyclic Lactams and Lactones

The hydrolysis of iminium ether intermediates formed by a nitrogen insertion sequence involving azido alcohols 1 or 2 and ketones was investigated. Ketones containing 6−12-membered rings were surveyed and shown to provide lactams and lactones in good to excellent overall yield. Reactions employing acetone or 5-nonanone gave similar results, generating analogous amides and esters. The relative amounts of lactone vs lactam produced in a given reaction were found to depend on the structures of the reactants and the pH of the basic media used to hydrolyze the iminium ethers. A mechanism accounting for the formation of each product is discussed in terms of ring strain and the protonation state of ortho ester aminal intermediates.

ハロ環化中間体形成を活性化手法として用いる有機合成反応の開発

We report here the results of synthetic organic reactions which proceed under mild conditions through the formation of cationic halocyclization intermediates. In the presence of I2 and collidine or lutidine, α-iodination reactions of unsaturated carboxamides and N-allylic carboxamides proceed in good yields through the activation of α-hydrogens by the formation of cyclic iminium ethers (iodolactonization intermediates). The iodine-mediated method can be also applied to the activation of enamide derivatives ; that is, in the presence of I2, the Diels-Alder reactions of N-allylic enamides which are unreactive dienophiles, proceed in good yield through the formation of the cyclic iminium ether. These activation processes are successfully extended to asymmetric α-iodination of unsaturated carboxamides having homochiral 2, 5-disubstituted pyrrolidine and asymmetric Diels-Alder reaction using novel axially chiral N-acryl anilide. Furthermore, the reactions of p-methoxybenzyl pentenyl ether with NIS and O-pentenyl oxime with NBS resulted in the activation of C-O bond and N-O bond through the formation of cationic haloetherification intermediates, and the following reaction with alcohols and migration of anti-substituent gavep-methoxybenzylation and Beckmann rearrangement products in good yields, respectively.