Synthesis of tryptophans by Lewis acid promoted ring-opening of aziridine-2-carboxylates: optimization of protecting group and Lewis acid

The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The ratio of tryptophan to oxazolidinone products can be optimized through a judicious choice of Lewis acid and N-protecting group.     

Substitution and addition reactions of aziridine with perfluorinated hydrocarbons. Nuclear magnetic resonance spectra of N-perfluoroalkyl aziridines

The reaction of aziridine with chlorotrifluoroethylene, perfluorobenzene, cyclic perfluoroole-fins and tetracyanoethylene was investigated. The degree of substitution was affected by the ring size of the perfluoroolefin. The temperature dependence of the nuclear magnetic resonance spectra, particularly with respect to the temperature of coalescence of the aziridinyl protons, was investigated.     

A method for the parallel synthesis of multiply substituted oxazolidinones

There are many examples of both naturally occurring and synthetic molecules containing a 2-oxazolidinone ring that have significant biological activity. The oxazolidinone ring potentially has three sites for attachment of diversity elements. A synthesis that can provide for inclusion of diversity elements at all three positions should be a powerful method for the preparation of oxazolidinone libraries. In this paper we present the preparation of a 3 x 3 x 3 array yielding 27 different products with minimal workup, high yields, and, most importantly, high purity. Using an intramolecular acylnitrene-mediated aziridination reaction, we have prepared (triphenylmethoxymethyl)-3-oxa-1-azabicyclo[3.1.0]hexan-2-one as a starting material for library generation. The first substitution involves opening the aziridine ring of the azabicyclo[3.1.0]hexane ring system using a Grignard reagent. The nitrogen of the oxazolidinone is now ready for substitution via alkylation or arylation. Removing the trityl protecting group via esterification under mildly acidic conditions accomplishes the final substitution.     

High level ab initio exploration on the conversion of carbon dioxide into oxazolidinones: the mechanism and regioselectivity

Density functional theory (DFT) and second order M?ller-Plesset perturbation (MP2) calculations, employing the 6-311++G(d,p) basis set, were carried out on alkyl-substituted aziridines to explore the reaction mechanisms and regioselectivity associated with their ring-opening conversions to oxazolidinones, in the presence of carbon dioxide. Computational results, employing the self-consistent reaction field polarizable continuum model (SCRF(PCM/Bader)), indicated that the conversions proceed with thermodynamic ease in THF solvent at room temperature. It is proposed that the N-alkylaziridine promotes ring opening through a SN2 attack of the iodide ion, of catalytic lithium iodide, on the preformed complex. The oxazolidinone regioisomer ratio is highly sensitive to aziridine ring-carbon substitution. Therein, monophenyl substitutions show preference to opening more highly substituted carbon-nitrogen bonds, providing rationale as to why experimental works result in an exclusive oxazolidinone regioisomer product.     

A convenient and inexpensive conversion of an aziridine to an oxazolidinone

The conversion of an aziridine to the corresponding oxazolidinone using only carbon dioxide and a catalytic amount of lithium iodide is discussed. In all cases, either no reaction occurred or a high yield of product was obtained. HMPA has been added to the reaction mixture, as needed, to drastically improve the regioselectivity. Net retention of stereochemistry between the starting aziridine and the product oxazolidinone was observed.     

Electrochemistry of potential bioreductive alkylating quinones : Part 2. Electrochemical properties of 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone and some model compounds

The reduction mechanism of 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone (Diaziquone, AZQ) and several model compounds of the mono- and bis(1-aziridinyl)quinone type at the dropping mercury electrode in aqueous solutions was studied. In addition, the influence of methyl substitution of the aziridinyl moiety at the 2-position on the protonation of the aziridine nitrogen was investigated. Substituent effects on quinone reduction and aziridine protonation prior to and following quinone reduction were studied qualitatively.     

First synthesis of an aziridinyl fused pyrrolo[1,2-a]benzimidazole and toxicity evaluation towards normal and breast cancer cell lines

Anionic aromatic ipso-substitution has allowed an aziridine ring to be fused onto pyrrolo[1,2-a]benzimidazole. This diazole analogue of aziridinomitosene, and N-[(aziridinyl)methyl]-1H-benzimidazole are shown to be significantly more cytotoxic towards the human breast cancer cell lines MCF-7 and HCC1937 than towards a human normal fibroblast cell line (GM00637). The aziridinyl fused pyrrolo[1,2-a]benzimidazole is less cytotoxic than the non-ring fused aziridinyl analogue towards all three cell lines. The BRCA1-deficient HCC1937 cells are more sensitive to mitomycin C (MMC) compared to GM00637 and MCF-7 cells. The evidence provided indicates that different pathways may mediate cellular response to benzimidazole-containing aziridine compounds compared to MMC.     

The high yield and regioselective conversion of an unactivated aziridine to an oxazolidinone using carbon dioxide with ammonium iodide as the catalyst

The conversion of an unactivated 2-alkylaziridine to the corresponding oxazolidinone generally requires a very high pressure of carbon dioxide, a high temperature, an expensive catalyst, and/or a long reaction time. Here, a new, high yield (over 95%), and highly regioselective (over 95%) conversion of an unactivated aziridine to an oxazolidinone is reported. This reaction is easy to perform because it requires a low pressure of carbon dioxide, low temperature, no co-solvent, and the catalyst is the salt ammonium iodide.     

Oxazolium-derived azomethine ylides. External oxazole activation and internal dipole trapping in the synthesis of an aziridinomitosene

Intermolecular alkylation of the aziridinyl oxazole 20 using PhSO(2)CH(2)CH(2)OTf is possible despite the presence of potentially nucleophilic aziridine nitrogen. The resulting oxazolium salt 22 reacts with BnNMe(3)(+)CN(-) to produce the azomethine ylide 24b via electrocyclic ring opening of an oxazoline 23b. Internal cycloaddition affords 26 in 66% yield. After saponification and base-induced cleavage of the N-phenylsulfonylethyl group, conventional cyclization provides access to 33. Deprotection and DDQ oxidation completes the synthesis of the aziridinomitosene derivative 9b. The starting cis-disubstituted aziridine ester 16 can be prepared by the aza-Darzens reaction of 15 with tert-butyl chloroacetate.     

(Salen)chromium(III)/DMAP: an efficient catalyst system for the selective synthesis of 5-substituted oxazolidinones from carbon dioxide and aziridines

[reaction: see text] (Salen)chromium(III)/DMAP was found to be an active catalyst system for the coupling of CO(2) and aziridines. The oxazolidinone products were produced in high yield and selectivity from the opening of the aziridine at the most substituted N-C bond. This catalyst system worked well for a wide variety of monosubstituted N-aryl and N-alkyl aziridines as well as a 2,3-disubstituted N-alkyl aziridine.     

The reaction of aziridine with perhalogenated nitriles

Reaction of one or two molecules of aziridine with the cyano groups of trichloroacetonitrile and trifluoroacetonitrile was observed. The resulting aziridinyl amino derivatives represent novel functional groups. Intramolecular cyclization of a bis-aziridinyl structure involving one aziridinyl group was observed. New synthetic routes to imidazolines and imidazolidines are a result of these rearrangments.     

1-(Phenylethynyl)aziridine in reactions with amines

The reaction of 1-(phenylethynyl)aziridine with a primary or secondary amine gave 2-benzylimidazoline-2 or N-aminoethyl substituted phenylacetamidine via nucleophilic attack on the aziridine ring. The mechanism of aziridine ring opening by an amine was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 600–603, May, 1989.     

Synthesis of well‐defined polymers end‐functionalized with crosslinkable aziridine groups by living anionic polymerization

Well‐defined end‐functionalized polystyrene, poly(α‐methylstyrene), and polyisoprene with polymerizable aziridine groups were synthesized by the termination reactions of the anionic living polymers of styrene, α‐methylstyrene, and isoprene with 1‐[2‐(4‐chlorobutoxy)ethyl]aziridine in tetrahydrofuran at ?78 °C. The resulting polymers possessed the predicted molecular weights and narrow molecular weight distributions (weight‐average molecular weight/number‐average molecular weight < 1.1) as well as aziridine terminal moieties. The cationic ring‐opening polymerization of the ω‐monofunctionalized polystyrene having an aziridinyl group with Et₃OBF₄ gave the polymacromonomer, whereas the α,ω‐difunctional polystyrene underwent crosslinking reactions to afford an insoluble gel. Crosslinking products were similarly obtained by the reaction of the α,ω‐diaziridinyl polystyrene with poly(acrylic acid)‐co‐poly(butyl acrylate). © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4126–4135, 2005     

Front Cover: Facile Multicomponent Synthesis of Oxazolidinones from Primary Amines and Cesium (Hydrogen)Carbonate (Eur. J. Org. Chem. 27/2023)

A facile multicomponent, catalyst-free oxazolidinone synthesis from primary aliphatic or aromatic amines, dibromoethane (DBE), and the usage of either cesium carbonate or cesium hydrogencarbonate as the simultaneous base and C1 source is reported. The applicability of this technically simple reaction was demonstrated by a broad scope with generally high yields, enabling concise late-stage functionalization of amino groups into N-substituted oxazolidinones. The proposed operating reaction mechanism consists of a first-step nucleophilic substitution reaction between DBE and the primary amine, followed by the formation of a carbamate or carbonate intermediate and subsequent cyclization. Additional versatility of the herein-developed protocol has been showcased in a medicinal chemistry approach by the generation of an oxazolidinone-modified dipeptidyl peptidase 8 (DPP8) inhibitor.     

Synthesis of Functionalized Novel α‐Amino‐β‐alkoxyphosphonates through Regioselective Ring Opening of Aziridine‐2‐phosphonates

Aziridines are highly useful compounds as building blocks for the synthesis of important organic compounds. Amino acid synthesis by aziridine ring opening reaction is a good example to the use of aziridines. Although this reaction is studied by many groups, the synthesis of amino phosphonic acids is less explored. In this study, we have carried out the ring opening reaction of aziridinyl phosphonates with a variety of alcohols including the more functional propargylic and allylic alcohols. These reactions provided functionalized α‐amino‐β‐alkoxyphosphonates in 40–91 % yield.     

Readily available unprotected amino aldehydes

We report a new class of bench-stable compounds that contain seemingly incompatible functional groups: an aldehyde and an unprotected secondary amine. The thermodynamic driving force to undergo condensation between these two functionalities is offset by a high barrier imposed on this process by the aziridine ring strain. The resulting amino aldehydes exist as dimers and in the solid state. They are stable to epimerization and contain two orthogonal reaction centers, namely, an amine/aziridine and an aldehyde. Their ability to act as linchpins has been evaluated in complex heterocycle synthesis. For instance, pentacyclic frameworks can be made in one simple operation using N-benzyltryptamine as the reaction partner. Construction of other molecular skeletons with minimal use of protecting group manipulations should be feasible.     

The conversion of an aziridine plus a phenyl-substituted amine oxide or aminoether to a benzodiazepine derivative

The conversion of an aziridine to a tetrahydrobenzodiazepine derivative using LiI, an iron carbonyl complex, and an amine oxide, or using LiI and a gem-aminoether is studied. The reaction of an aziridine with LiI and a phenyl-substituted iminium salt generates mainly a 1,2-diamine. The addition of t-butoxide to the iminium reaction changes the product ratio leading to a diamine as the minor product and a benzodiazepine as the major product. The structure proof of the tetrahydrobenzodiazepine derivative and the mechanism of these transformations are discussed.     

Ring Expansion and Skeletal Rearrangement of Propargyl Alcohol Substituted Aziridines Induced by Ruthenium Complexes

The ring expansion and skeletal rearrangement of two types of propargyl alcohol substituted aziridines with or without cycloalkane moieties was induced by a ruthenium cyclopentadienyl phosphine complex. In the simple aziridine system with no cycloalkane, the unique cycloisomerization process altered the absolute connectivity of the two‐carbon unit in the three‐membered ring to give organometallic products with substituted pyridine or dihydropyridine ligands. For the aziridine on a cyclohexyl ring, the cycloisomerization process was controlled by an interchange process between vinylidene and allenylidene species, thus creating a better relative configuration of the aziridinyl and the alkynyl units. This determines the stereochemistry of the metal carbene products of the octahydroindole derivatives. The structures of five products were determined by X‐ray diffraction analysis.     

Solution-phase synthesis of 2-cyano and 2-amido aziridinyl peptides

Starting from a library of 2-l-α-amino acyl (E)-acrylonitriles, different short 2-cyano and 2-amido aziridinyl peptides, potential protease inhibitors, were obtained under parallel solution-phase conditions. The transformations include careful selection of conditions for aziridine deprotection and cyano group partial hydrolysis.     

Selection rules for helicate ligand component self-assembly: steric, pH, charge, and solvent effects

The reaction between 1,10-phenanthroline-2,9-dicarboxaldehyde, copper(I), and certain primary amines was found to give quantitatively a dicopper double-helicate product (two of which were crystallographically characterized) by imine self-assembly around Cu(I) templates. The parameters of this reaction were investigated, and important roles were found to be played by (i) the steric bulk of the amine, (ii) the charge of the amine, (iii) the solvent used, and (iv) the pH of the solution. Water was found to allow the broadest range of structures to form, and ligand-component exchange reactions (involving the substitution of an aromatic for an aliphatic amine) were demonstrated to proceed readily in this solvent.