Solvent- and temperature-dependent functionalisation of enantioenriched aziridines

A highly stereo‐ and regioselective functionalisation of chiral non‐racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio‐ and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N‐alkyl trans‐2,3‐diphenylaziridines (S,S)‐ 1 a , b , two differently configured chiral aziridinyllithiums could be generated (trans‐ 1 a , b‐Li in toluene and cis‐ 1 a , b‐Li in THF), thus disclosing a solvent‐dependent reactivity that is useful for the synthesis of chiral tri‐substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)‐ 1 c showed a temperature‐dependent reactivity to give chiral ortho‐lithiated aziridine 1 c‐ ortho ‐Li at ?78 °C and α‐lithiated aziridine 1 c‐α‐Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho‐ and α‐functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X‐ray and NMR spectroscopic analysis. The usefulness of chiral non‐racemic functionalised aziridines has been demonstrated by reductive ring‐opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2‐, 1,3‐ and 1,5‐aminoalcohols. It is remarkable that the solvent‐dependent reactivity observed with (S,S)‐ 1 a , b permits the preparation of both the enantiomers of amines ( 11 and ent‐ 11 ) and 1,2‐aminoalcohols ( 13 and ent‐ 13 ) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α‐lithiated aziridine ( 1 c‐α‐Li ) has been generated at 0 °C. In addition, ortho‐hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.     

BH3-promoted stereoselective β-lithiation of N-alkyl-2-phenylaziridines

BH(3) complexes of N-alkyl-2-phenylaziridines have been synthesized and their structure and stereochemistry proved with DFT calculations and NMR experiments. It has been demonstrated that the Lewis acid complexation is able to promote a regioselective β-lithiation in 2-phenylaziridino-borane complexes. The lithiated intermediates were configurationally stable, allowing an enantioselective preparation of cis-2,3-disubstituted aziridines.     

Dynamic Phenomena and Complexation Effects in the α-Lithiation and Asymmetric Functionalization of Azetidines

In this work it is demonstrated that enantiomerically enriched N-alkyl 2-oxazolinylazetidines undergo exclusive α-lithiation, and that the resulting lithiated intermediate is chemically stable but configurationally labile under the given experimental conditions that afford enantioenriched N-alkyl-2,2-disubstituted azetidines. Although this study reveals the configurational instability of the diastereomeric lithiated azetidines, it points out an interesting stereoconvergence of such lithiated intermediates towards the thermodynamically stable species, making the overall process highly stereoselective (er > 95:5, dr > 85:15) after trapping with electrophiles. This peculiar behavior has been rationalized by considering the dynamics at the azetidine nitrogen atom, the inversion at the C-Li center supported by in situ FT-IR experiments, and DFT calculations that suggested the presence of η³-coordinated species for diastereomeric lithiated azetidines. The described situation contrasted with the demonstrated stability of the smaller lithiated aziridine analogue. The capability of oxazolinylazetidines to undergo different reaction patterns with organolithium bases supports the model termed “dynamic control of reactivity” of relevance in organolithium chemistry. It has been demonstrated that only 2,2-substituted oxazolinylazetidines with suitable stereochemical requirements could undergo C=N addition of organolithiums in non-coordinating solvents, leading to useful precursors of chiral (er > 95:5) ketoazetidines.     

Reactivity of activated versus nonactivated 2-(bromomethyl)aziridines with respect to sodium methoxide: a combined computational and experimental study

The difference in reactivity between the activated 2-bromomethyl-1-tosylaziridine and the nonactivated 1-benzyl-2-(bromomethyl)aziridine with respect to sodium methoxide was analyzed by means of DFT calculations within the supermolecule approach, taking into account explicit solvent molecules. In addition, the reactivity of epibromohydrin with regard to sodium methoxide was assessed as well. The barriers for direct displacement of bromide by methoxide in methanol are comparable for all three heterocyclic species under study. However, ring opening was found to be only feasible for the epoxide and the activated aziridine, and not for the nonactivated aziridine. According to these computational analyses, the synthesis of chiral 2-substituted 1-tosylaziridines can take place with inversion (through ring opening/ring closure) or retention (through direct bromide displacement) of configuration upon treatment of the corresponding 2-(bromomethyl)aziridines with 1 equiv of a nucleophile, whereas chiral 2-substituted 1-benzylaziridines are selectively obtained with retention of configuration (via direct bromide displacement). Furthermore, the computational results showed that explicit accounting for solvent molecules is required to describe the free energy profile correctly. To verify the computational findings experimentally, chiral 1-benzyl-2-(bromomethyl)aziridines and 2-bromomethyl-1-tosylaziridines were treated with sodium methoxide in methanol. The presented work concerning the reactivity of 2-bromomethyl-1-tosylaziridine stands in contrast to the behavior of the corresponding 1-tosyl-2-(tosyloxymethyl)aziridine with respect to nucleophiles, which undergoes a clean ring-opening/ring-closure process with inversion of configuration at the asymmetric aziridine carbon atom.     

Noncovalent organocatalytic synthesis of enantioenriched terminal aziridines with a quaternary stereogenic center

A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via an aza-Michael initiated ring-closure (aza-MIRC) reaction of α-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino thiourea. The feasibility of the aziridine regioselective ring-opening to valuable α,α-disubstituted α-amino acid esters has been demonstrated.     

Synthesis of allenylzinc reagents by 1,2-rearrangement of alkynyl(disilyl)zincates derived from acetylenic epoxides and acetylenic aziridines

Lithium alkynyl(disilyl)zincates obtained from metalated ethynyloxiranes, as well as from N-tert-butanesulfinyl(ethynyl)aziridines or N-tert-butanesulfonyl(ethynyl)aziridines, undergo 1,2-migration of the organosilyl group with ring opening of the oxirane or aziridine ring by S_Ni displacement. A developed protocol that involves nBuLi for the metalation step offers a straightforward approach to the corresponding δ-oxy- and δ-amino α-silyl allenylzinc intermediates. The reagents derived from the epoxides are amenable to subsequent in situ condensation with aldehydes or ketones to provide 1,3-diols but not those derived from aziridines that only react sluggishly in similar condensations.     

Reaction of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines with boron trifluoride etherate in methanol

The reaction of boron trifluoride etherate in methanol with trans-1-methyl(ethyl)-or cis-1-cyclohexyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines leads to the formation of the corresponding boron fluoride complexes on the nitrogen atom of the aziridine ring. Reaction with trans-1-cyclohexyl-2-phenyl-3-(2-methyl-2,3-epoxypropionyl)aziridines occurs with stereospecific opening of the aziridine ring to give diastereomeric 2-methyl-5-methoxy-5-phenyl-4-cyclohexylamino-1,2-epoxypen-tan-3-ones, as well as products from the opening of the epoxide and aziridine rings — tetrahydrofuranones and tetrahydropyranones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 596–600, May, 1986.     

A synthesis of 6-azabicyclo[3.2.1]octanes. The role of N-substitution

The intramolecular cyclization reactions of aziridines with pi-nucleophiles can be a useful route to a number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this cyclization reaction for the synthesis of 6-azabicyclo[3.2.1]octanes. We report here the development of a new synthesis of the aziridine necessary for the aziridine--pi-nucleophile cyclization. We also report on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction, do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads efficiently to the bicyclic ring system and can be readily deprotected.     

Regio- and diastereoselective synthesis of bifunctionalized limonenes

High regio- and diastereoselective ring opening of limonene aziridines with a variety of nucleophiles is described. The resulting novel chiral derivatives are readily accessible from limonene aziridine in either enantiomeric form in 35-94% yield.     

Selective ring-opening of nonactivated amino aziridines by thiols and unusual nucleophilic substitution of a dibenzylamino group

[Reaction: see text]. The reaction of chiral 2-(1-aminoalkyl)aziridines 1 with different thiols, in the presence of BF3*Et2O, is reported. The obtained products were dependent on the structure of the starting amino aziridines 1. Thus, enantiopure (2S,3S)-2-(alkylthio)alkane-1,3-diamines 2 were obtained from aziridines with C-2 substituents with lower steric congestion and partially racemized (2S,3S)-2,3-bis(alkylthio)alkan-1-amines 3 (ee = 56-66%) from aziridines with larger C-2 subtituents. In both cases, the opening of the nonactivated aziridine ring at C-2 took place with retention of configuration and proceeded with regio- and stereoselectivity at C-2. In the synthesis of 3, 2 equiv of thiol reacts with 1 and the opening of aziridine ring at C-2 was followed by an unusual displacement of the dibenzylamino group by a second equivalent of thiol. The regiochemistry and relative configuration of compounds 3 was established by single-crystal X-ray analysis. A mechanism is proposed to explain the results obtained.     

Aziridines N-Non substituées. Détermination des Paramètres Thermodynamiques ΔG°, ΔH°, ΔS° Liés à l'Equilibre Conformationnel à partir de Mesures RMN 1H à Haut Champ

Although nitrogen inversion in unsubstituted aziridines has been shown by ¹H NMR, it was only possible to study quantitatively the distribution of both invertomers and determine the thermodynamic parameters by a systematic high field NMR study (CAMECA 250 MHz). Thermodynamic parameters have been determined for 32 compounds. In C-aryl aziridines, the steric hindrance of the aromatic group and its variation with other aziridine ring substituents can be studied. These observations are in agreement with a conjugation phenomenon between the aromatic system and the aziridine ring.     

Regio- and stereoselective lithiation of 2,3-diphenylaziridines: a multinuclear NMR investigation

The alpha-lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines (s-BuLi or s-BuLi/TMEDA), taking place with a stereochemistry which dramatically depends on the solvent coordinating ability (inversion of configuration in THF and retention in toluene), has been carefully investigated. 1H,13C, and 7Li multinuclear NMR investigations at low temperature suggest that two differently configured lithiated aziridines (monomeric cis-1-Li in THF and dimeric trans-1-Li in toluene) are involved.     

Enantioselective fluoride ring opening of aziridines enabled by cooperative Lewis acid catalysis

The enantioselective ring opening of aziridines using a latent source of HF is described. A combination of two Lewis acids, (salen)Co and an achiral Ti(IV) cocatalyst, provided optimal reactivity and enantioselectivity for the trans β-fluoroamine product. The use of a chelating aziridine protecting group was crucial. Acyclic and cyclic meso N-picolinamide aziridines underwent fluoride ring opening in up to 84% ee, and the kinetic resolution of a piperidine-derived aziridine was performed with k_rel=6.6. The picolinamide group may be readily removed without epimerization of the fluoroamine. Preliminary studies revealed a bimetallic mechanism wherein the chiral (salen)Co catalyst delivers the nucleophile and the Ti(IV) cocatalyst activates the aziridine.     

Stereospecific ring expansion of chiral vinyl aziridines

In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis- or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.     

Alpha- vs ortho-lithiation of N-alkylarylaziridines: probing the role of the nitrogen inversion process

The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the alpha-position. Evidence is reported that ruled out the possibility that the alpha-lithiation, observed for the diphenylaziridines, is the result of an ortho- to alpha-translocation phenomenon, thus substantiating a direct alpha-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity alpha- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.     

Two-step syntheses of 2,4,6-triisopropylbenzenesulfonyl aziridines

In a continuing study on the α-lithiation of N-tosyl aziridines, it is reported that ortho-lithiation of the N-tosyl group is occurring under typical α-lithiation conditions (s-BuLi/PMDETA). Thus, a simple, two-step synthesis of N-2,4,6-triisopropylbenzenesulfonyl aziridines was optimised. The route involves epoxide ring opening using a sulfonamide, mesylation and base-mediated ring closure. The scope and limitations of this route were assessed and five new N-2,4,6-triisopropylbenzenesulfonyl aziridines were prepared in good yields. Since this method was unsuitable for the preparation of cyclooctene aziridine, an alternative two-step method was developed. This method involved aminobromination of cyclooctene using NBS/2,4,6-triisopropylbenzenesulfonamide.     

Addition reactions of iodomethyllithium to imines. A direct and efficient synthesis of aziridines and enantiopure amino aziridines

An efficient and general synthesis of aziridines by the reaction of imines derived from p-toluenesulfonamides with in situ generated iodomethyllithium, with a simple and rapid experimental protocol, is reported for the first time. The reaction with the chiral aldimine derived from phenylalaninal allowed access to (2R,1'S)-2-(1'-aminoalkyl)aziridine with very high diastereoselectivity, in enantiopure form. A mechanism to explain this novel reaction is proposed.     

On the α-lithiation-rearrangement of N-toluensulfonyl aziridines: mechanistic and synthetic aspects

A detailed study of the rearrangement of five cycloalkene N-toluenesulfonyl (tosyl) aziridines using sec-butyllithium (with and without added ligands such as (−)-sparteine and TMEDA) has been carried out. Allylic sulfonamides were the main products from the cyclopentene and cyclohexene aziridines whereas bicyclic sulfonamides were obtained from the cycloheptene and cyclooctene aziridines. In most cases, p-toluenesulfonamide (TsNH₂) was produced as a by-product and a mechanistic explanation for its formation is forwarded. These reactions are believed to involve α-lithiation to a lithiated aziridine which can then partition through two pathways: (i) rearrangement to allylic or bicyclic sulfonamides via C-H insertion reactions or (ii) reductive alkylation to alkenes via attack by sec-butyllithium and subsequent elimination of TsNH₂. In the (−)-sparteine reactions, the products were generated with 38-66% ee and the sense of asymmetric induction involved lithiation of the S-aziridine stereocentre. This is opposite to that observed with epoxides.     

Synthesis and stereochemistry of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl) aziridines

Two diastereoisomeric 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl) aziridines with an E configuration of the aziridine ring were obtained by the reaction of 2-methyl-2-cinnamoyoxiranes with iodine-methylamine and iodine-ethylamine complexes. The relative configuration of the chiral centers of the synthesized compounds was established by means of spectral data. The predominant formation of diastereomers with the RRR (SSS) relative configuration is explained by the effect of steric factors in the diastereomeric chelated amino enols that precede the formation of the epoxy keto aziridines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 880–883, July, 1980.     

Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents

The conversion of a prochiral methylene group into a stereogenic center by means of a lithiation/substitution sequence has emerged as a powerful synthetic transformation over the past 15 years. This reaction proceeds via a chiral organolithium intermediate, and the stereochemical fidelity of the overall reaction sequence is intimately dependent on the stereochemical behavior of the chiral organolithium as well as on the rate and stereochemical sense of the electrophilic substitution step. Chiral organolithium reagents were first reported by Letsinger, Curtin, and Applequist half a century ago. The lithiated intermediates in these early studies were not highly configurationally stable, and applications in stereoselective synthesis were not immediately forthcoming. The two decades that followed the 1980 report by Still and Sreekumar of a configurationally stable alpha-oxyorganolithium were marked by an increased interest in these reagents. As the synthetic applications of chiral organolithium reagents have grown, so have accompanying mechanistic studies of these intermediates which serve as the basis for this review.