Fluorine as a Regiocontrol Element in the Ring Opening of Bicyclic Aziridiniums

The origin of the variation in the regioselectivity of the nucleophilic ring opening of a series of bicyclic aziridinium ions derived from N‐alkylprolinols was investigated by quantum‐chemical computations (M06‐2X/6‐31+G(d,p)‐SMD). These aziridiniums differ only in the degree and the configurations of F‐substitution at C(4). With the azide ion as nucleophile, the ratio of the piperidine to the pyrrolidine product was computed. An electrostatic gauche effect influences the conformation of the adjoining five‐membered ring in the fluorinated bicyclic aziridinium. This controls the regioselectivity of the aziridinium ring opening.     

Access to Optically Active 3‐Substituted Piperidines by Ring Expansion of Prolinols and Derivatives

The ring expansion of prolinols via an aziridinium intermediate gives C3‐substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.     

Synthesis of a series of vicinal diamines with potential biological activity

A broad range of vicinal diamines based on styrene oxide are synthesisedvia mixtures of regioisomeric amino alcohols. The ring opening of the intermediate aziridinium ions by primary amines proceeds with high regioselectivity, leading to the target diamines as single regioisomers for all reaction series. The compounds are of potential biological interest as ligands for cisplatin analogues. Anticancer activity tests of both groups of compounds are in progress.     

Amino Phosphate Monoesters: A Convenient Source of 2-Alkylamino-3-methoxy-3-phenylpropionates via Aziridinium Ions

The synthesis of a series of amino ethers was carried out in a two-step method involving phosphorylation of the corresponding amino alcohols and subsequent double displacement via an aziridinium intermediate. The new products were obtained in good yields with excellent regioselectivity.     

NMR evidence of the kinetic and thermodynamic products in the NIS promoted cyclization of 1-phenyl-4-pentenylamines. Synthesis and reactivity of trans-2-phenyl-5-iodopiperidines

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.     

Synthetic Applications of Aziridinium Ions

Nonactivated aziridine with an electron-donating group at the ring nitrogen should be activated to an aziridinium ion prior to being converted to cyclic and acyclic nitrogen-containing molecules. This review describes ways to generate aziridinium ions and their utilization for synthetic purposes. Specifically, the intra- and intermolecular formation of aziridinium ions with proper electrophiles are classified, and their regio- and stereoselective transformations with nucleophiles are described on the basis of recent developments.     

1,1-Dihalo-2-benzycyclopropanes in reaction with nitrous acid

Interaction of 1,1-dichoro and 1,1-dibromo-2-benzylcyclopropanes with nitrous acid generated in situ was studied. It was shown that both nitration of the aromatic ring and heterocyclization of 1,1-dihalo-2-benzylcyclopropanes take place. Heterocyclization is initiated by opening of the cyclopropane ring in the reaction with nitrosyl cation. The nature of halogen atom in the cyclopropane ring affects the regioselectivity of the reactions.     

Asymmetric synthesis via aziridinium ions: exploring the stereospecificity of the ring opening of aziridinium ions and a formal synthesis of (−)-swainsonine

The use of aziridinium ions in two different projects is described. First, the stereospecificity of the ring opening of aziridinium ions with MeNH₂ as a route to chiral diamines has been explored. When the aziridinium ion contained a phenyl or para-methoxyphenyl substituent, stereospecific ring opening occurred. In contrast, switching the para-methoxy group to a para-N,N-dimethylamino group gave a racemic diamine product. Second, starting from N-Boc pyrrolidine, asymmetric lithiation-trapping-ring expansion (via an aziridinium ion) was used to synthesise a piperidine alcohol. In this way, a formal synthesis of (?)-swainsonine was completed.     

Regioselective aziridine ring expansions

1-Phenylmethyl-2-hydroxymethylaziridine ( 1 ) undergoes regioselective reactions with carbon disulfide to form thiazolidinethiones. Deuterium labeling experiments suggest that the reaction proceeds exclusively via aziridinium ring expansion. The regiospecificity appears to be electronically controlled.     

Applications of aziridinium ions. Selective syntheses of alpha, beta-diamino esters, alpha-sulfanyl-beta-amino esters, beta-lactams, and 1,5-benzodiazepin-2-one

A variety of nucleophiles, including amines, thiolates, and alkoxides, were employed to open the aziridinium ions Az. The latter are opened stereospecifically and regioselectively at the C-3 position by a wide range of amines, and thiolate nucleophiles attack predominately at the C-2 position. Poor regioselectivities (ca. 1:1) were observed using nucleophiles derived from phenols, carboxylic acids, and imides. Base-mediated ring closure of the aziridinium opening products, from primary amines, gave beta-lactams and a 1, 5-benzodiazepin-2-one in high yields.     

Formate ester synthesis via reaction of 2-bromoethylamines with dimethylformamide

2-Bromoethylamines are converted to the corresponding formate esters in the presence of DMF. Both primary and secondary bromides are smoothly transformed to the esters in satisfactory yields. The reaction mechanism involves the formation of an aziridinium ion, which upon reaction with DMF forms a Vilsmeier-type intermediate that is further hydrolyzed to the corresponding formates. Participation of the β-amino group appears to control not only the regioselectivity but also the stereoselectivity of the reaction. Application of the reaction conditions to chiral substrates indicated that non-rearranged products are formed with retention of configuration at the reacting center.     

Ring Contraction of 3‐Hydroxy‐3‐(trifluoromethyl)piperidines: Synthesis of 2‐Substituted 2‐(Trifluoromethyl)pyrrolidines

A ring contraction of 3‐hydroxy‐3‐(trifluoromethyl)piperidines was achieved via an aziridinium intermediate. This contraction facilitates the synthesis of a series of 2‐substituted 2‐(trifluoromethyl)pyrrolidines incorporating a quaternary center at the C2 position.     

Reaction of esters of 2-arylcyclo-propanecarboxylic acids with nitrous acid. Synthesis of aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles and 3-ethoxycarbonylisoxazoles

Esters of 2-arylcyclopropanecarboxylic acids react with nitrous acid generated in situ with regioselective insertion of the nitrosyl cation into the cyclopropane ring. Depending on the substrate/nitrosylating agent ratio, the reaction proceeds with the formation of either aryl-substituted 3-ethoxycarbonyl-4,5-dihydroisoxazoles or the corresponding isoxazoles. The nature and position of the substituents in the aromatic ring of the starting 2-arylcyclopropanecarboxylic acid esters affect the reaction rate but have no effect on the regioselectivity of the attack by the nitrosyl cation on the three-membered ring. A dependence of the reactivity of isomeric substrates on their stereochemistry and position of the nitro group in the aromatic ring is noted for 2- and 4-nitrophenyl derivatives of esters of cis- and trans-2-arylcyclopropanecarboxylic acids.     

Assessing the rates of ring-opening of aziridinium and azetidinium ions: a dramatic ring size effect

Rates for the ring-opening of aziridinium and azetidinium ions by DMAP were measured. The four-membered ring appears to be ca. 17,000 times less reactive compared to the three-membered ring but is still highly relevant from a synthetic viewpoint. The electrophilicity of these strained ammonium ions is measured for the first time.     

Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: synthesis and ring opening with selected O- and N-nucleophiles

We report herein the synthesis of enantiomerically pure 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and on the nitrogen protecting group.     

Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl)aziridinium salts by bromide

Enantiomerically pure 2-(aryloxymethyl)aziridines are efficiently transformed into chiral N-(2-bromo-3-aryloxypropyl)amines via a regio- and stereospecific ring opening of the intermediate aziridinium salts, and the experimental results are rationalized on the basis of some high level ab initio calculations.     

Nucleophile‐Dependent Regio‐ and Stereoselective Ring Opening of 1‐Azoniabicyclo[3.1.0]hexane Tosylate

1‐[(1R)‐(1‐Phenylethyl)]‐1‐azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2‐(3‐hydroxypropyl)aziridine upon reaction with p‐toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH₃CN to afford either piperidines or pyrrolidines through regio‐ and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring‐opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.     

Regioselectivity of Birch reductive alkylation of biaryls

[reaction: see text] The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, providing that the acidic proton has been removed prior to the Li/NH3 reduction.     

Alkylative Aziridine Ring-Opening Reactions

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-containing molecules with concomitant introduction of an external nucleophile at either its α- or β-position.     

Reaction de paiticipation d'amines tertiaires : applictions a la synthese d'aminoglycopyramosides

Methyl glycopyranosides with diallylamino and mesylate groups in $\text{trans}$ relationship undergo an intramolecular reaction in which the amino group assists the replacement of the mesylate group by a nucleophile. Such a reaction may result in a 1,2-shift of the nitrogen atom depending on which carbon atom of the intermediate aziridinium ion is attacked by the nucleophile. A further N,N-dideallylation using palladium on charcoal leads, for example, to chloro- or fluoroaminoglycopyranosides with a good regioselectivity.