Ring Opening Of Aziridines Research Articles

Nucleophilic ring opening reactions of aziridines.

Aziridine ring opening reactions have gained tremendous importance in the synthesis of nitrogen containing biologically active molecules. During recent years, a great effort has been put forward by scientists toward unique bond construction methodologies via ring opening of aziridines. In this regard, a wide range of chiral metal- and organo-catalyzed desymmetrization reactions of aziridines have been reported with carbon, sulfur, oxygen, nitrogen, halogen, and other nucleophiles. In this review, an outline of methodologies adopted by a number of scientists during 2013-2017 for aziridine ring opening reactions as well as their synthetic applications is described.

Stereodivergent Catalysis.

This review covers diastereo- and enantiodivergent catalyzed reactions in acyclic and cyclic systems using metal complexes or organocatalysts. Among them, nucleophilic addition to carbon-carbon and carbon-nitrogen double bonds, α-functionalization of carbonyl compounds, allylic substitutions, and ring opening of oxiranes and aziridines are considered. The diastereodivergent synthesis of alkenes from alkynes is also included. Finally, stereodivergent intramolecular and intermolecular cycloadditions and other cyclizations are also reported.

Preparation of Chiral Contiguous Epoxyaziridines and Their Regioselective Ring-Opening for Drug Syntheses.

Synthetically valuable chiral (aziridin-2-yl)oxirane-3-carbaldehydes bearing three consecutive functional groups including aziridine, epoxide, and aldehyde were prepared from the stereoselective epoxidation of (aziridin-2-yl)acrylaldehydes with H2 O2 using organocatalyst (2R)- or (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as organocatalyst. The regioselective ring opening of aziridines and epoxides enabled us to achieve the highly efficient asymmetric synthesis of the antibiotic edeine D fragment 3-hydroxy-4,5-diaminopenatanoic acid, an intermediate for the formal synthesis of non-proteinogenic amino acid (-)-galantinic acid, and for potent antifungal agent (+)-preussin, and the medicinally important framework 3-hydroxy-2-hydroxymethylpyrrolidine.

Ab initio and DFT investigations on the ring opening of aziridines using singlet unsaturated carbenes

cis-2,3-dimethylaziridine undergoes ring cleavage with unsaturated carbenes to yield corresponding olefins. Ab initio and density functional investigations of this ring opening reaction show that this reaction takes place in a single step. Initially the reactants form a pre-reactive complex, followed by a transition state which gives alkene with the same stereochemistry. Computations suggest that the asynchronous concerted cleavage of CN bonds leads to retention of stereochemistry. Intrinsic reaction coordinate analysis and Wiberg bond order analysis reveal the asynchronous nature of the transition state very well and fix the reaction mechanism. Substitution of groups at R3 and R4 of carbene carbon predict the same trend. The higher exothermicity observed in the reaction indicates the release of ring strain.

Diastereoselective synthesis ofcis-1,3-disubstituted isoindolinesviaa highly site-selective tandem cyclization reaction

A highly site-selective tandem reaction involving regioselective ring opening of aziridines and Michael addition of electron-deficient alkenes has been described.

Atom-Economical and Metal-Free Synthesis of Multisubstituted Furans from Intramolecular Aziridine Ring Opening.

Multisubstituted furans were prepared from dialkyl 2-(aziridin-2-ylmethylene)malonate and/or 1,3-dione through aziridine ring opening by the internal carbonyl oxygen with the assistance of BF3·OEt2, followed by aromatization. This synthetic method is free from any metal and is atom-economical with all of the atoms in the starting material retained in the final product.

Synthesis of the four enantiomers of diethyl 1,2-di(N-Boc-amino)propylphosphonates

A simple and efficient synthetic strategy to all four enantiomerically pure diethyl 1,2-di(N-Boc-amino)propylphosphonates has been elaborated starting from the corresponding N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes, employing a one-pot three-components Kabachnik-Fields reaction followed by the hydrogenolytic removal of the chiral auxiliary and aziridine ring opening with simultaneous protection of the amino groups as the N-Boc derivatives.

Enantiospecific Synthesis of β-Substituted Tryptamines

Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis where isomer formation can be controlled. 3,5-Dinitrobenzoyl (DNB)-protected aziridines undergo regioselective, enantiospecific ring opening to produce β-substituted tryptamines for a series of indoles. Attack at the more substituted aziridine carbon occurs in an SN2-like fashion to generate DNB-tryptamine products as synthetic precursors.

N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile

The preparation of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), a key fragment of fluoroquinolone antibiotic PF-00951966 and others was achieved by N-methylative aziridine ring opening, addition of methyl group at the ring nitrogen, and ring-opening via a cyanide nucleophile in a single operation starting from bicyclic (R)-2-[(R)-pyrrolidine-3-yl]aziridine. The starting compound was elaborated from stereoselective conjugate addition of nitromethane to (R)-aziridine-2-yl acrylate followed by selective reduction without breaking the aziridine ring.

Diastereoselective and Enantiospecific Synthesis of 1,3-Diamines via 2-Azaallyl Anion Benzylic Ring-Opening of Aziridines.

The 1,3-diamine motif appears in numerous complex molecules, yet there are few methods for the stereoselective construction of this moiety. Herein, we demonstrate a stereocontrolled synthesis of 1,3-diamines, which bear up to three contiguous stereogenic centers, through benzylic ring-opening of aziridines with 2-azaallyl anion nucleophiles. Reactions proceed efficiently (yield up to 95%), diastereoselectively (dr up to >20:1), site selectively, and enantiospecifically to deliver products with differentiated amino groups.

Syntheses of Tetrahydrobenzoazepinoindoles and Dihydrobenzodiazepinoindoles via Ring-Opening Cyclization of Activated Aziridines with 2-(2-Bromophenyl)-1H-indoles.

Two efficient, modular, step- and pot-economic strategies to access various 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indoles and 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[1,7-a]indoles are disclosed that advance via SN2-type regioselective ring opening of enantiopure aziridines with 2-(2-bromophenyl)-1H-indoles at their C3 and indolyl N centers, respectively, followed by Cu-mediated C-N cyclization which furnishes the products in excellent yields with outstanding enantiomeric excesses (up to >99%).

LiAlH4‐Induced Thia‐Aza‐Payne Rearrangement of Functionalized 2‐(Thiocyanatomethyl)aziridines into 2‐(Aminomethyl)thiiranes as an Entry to 5‐(Chloromethyl)thiazolidin‐2‐ones

Nonactivated 2‐(thiocyanatomethyl)aziridines with diverse substitution patterns were deployed as substrates to effect a LiAlH4‐promoted thia‐aza‐Payne rearrangement to provide access to functionalized 2‐(aminomethyl)thiiranes in good to excellent yields (78–94 %). The developed strategy involved hydride reduction of the thiocyanato moiety followed by intramolecular aziridine ring opening. Subsequent exposure of the obtained 2‐(aminomethyl)episulfide intermediates to triphosgene resulted in the formation of 5‐(chloromethyl)thiazolidin‐2‐ones.

Enantioselective Oxidative Ring Opening of Aziridines

Enantioselective Oxidative Ring Opening of Aziridines

Stereoselective Copper-Catalyzed Cross-Coupling of Aziridines with Benzimidazoles via Nucleophilic Ring Opening and C(sp2)-H Functionalization.

A copper-catalyzed cross-coupling of 2-alkyl-/2-arylaziridines with benzimidazoles is reported. The reactions involve a regiospecific ring opening of aziridines with benzimidazoles to give benzoimidazolylethylamine derivatives that lead to dehydrogenative cross-coupling between C(sp2)-H and N-H bonds to produce dihydroimidazobenzimidazoles. Optically active 2-arylaziridines can be stereoinvertivebly cross-coupled with high enantiomeric purities (77-97% ee). These aerobic catalytic systems comprise an inexpensive Cu(II) salt and PCy3 ligand at moderate temperature.

A Mild and Efficient Method for the Syntheses and Regioselective Ring-Opening of Aziridines

We have developed a new synthetic method for the synthesis of aziridines using Chloramine-T as an effective reagent in the presence of NH2OH·HCl and NaIO4. We found that the same combination of NH2OH·HCl and NaIO4 is also very effective for nucleophilic ring opening of aziridines.

Supercritical CO2 for the synthesis of nanometric ZIF-8 and loading with hyperbranched aminopolymers. Applications in CO2 capture

ZIF-8 nanometric particles are prepared via an environmentally friendly supercritical method aimed to minimize the environmental impact of current developed technologies for the synthesis of metal organic frameworks. In this synthetic process, CO2 and ZIF-8 precursors are exclusively employed, avoiding the use of organic liquids, difficult to recover additives or large amounts of expensive ligand excess. The straight and high yield precipitation of empty-pore ZIF-8 nanopowder with tunable morphology was achieved. The powder was fully characerized in regard to the composition, structure, stability, morphology and textural properties. This work also focuses in the development of an eco-efficient method for the in situ polymerization of ethyleneimine inside the synthetized ZIF-8 pores, by using supercritical CO2 as a solvent, reaction medium and catalyst for the aziridine ring-opening. The use of the prepared materials in CO2 capture is assessed by analyzing CO2 adsorption isotherms.

Concise Synthesis of 3-(Aminomethyl)pyrrolizidines via an In(OTf)3-Mediated Ring Rearrangement of 2-[2-(1-Pyrrolin-2-yl)-alkyl]aziridines

In this study, an efficient ring rearrangement of 2-[2-(1-pyrrolin-2-yl)alkyl]aziridines, prepared from 2-(bromomethyl)aziridines, toward novel trans- and cis-3-aminomethyl-substituted pyrrolizidines was developed. To that end, addition of In(OTf)3 as an appropriate Lewis acid catalyst resulted in the formation of intermediate pyrrolizidinium salts via regioselective aziridine ring opening, which were then trapped by a hydride or cyanide nucleophile. Column chromatographic purification allowed the isolation of the major trans-isomers, exclusively.

Activation of Alkynylzinc Reagents by a Hemiaminal‐Driven Catalytic Microenvironment

1,2‐Aziridinyl propargylic amines have been obtained through a zinc‐catalyzed multicomponent reaction. This process relies on the dimeric amino aldehyde assembly orchestrating the intramolecular 1,2‐alkyne addition to an iminium ion. The resulting products can be readily elaborated through regioselective aziridine ring opening. A catalytic cycle and stereochemical rationale for the highly anti‐selective alkyne addition is proposed.

Nucleophilic ring opening of aziridines with amines under catalyst- and solvent-free conditions

Aza-addition of aziridines under catalyst- and solvent-free conditions was performed to provide access to a wide array of vicinal diamines in up to 95% yields, thus facilitating the scale-up synthesis of the 4-amino-1,2,3,4-tetrahydroisoquinoline derivative.

AgOTf-catalyzed sequential synthesis of 4-isoquinolones via oxidative ring opening of aziridines and aza-Michael addition.

An efficient AgOTf-catalyzed sequential reaction involving the oxidative ring-opening of aziridines by DMSO and aza-Michael addition has been developed. A series of 2,3-dihydro-4(1H)-isoquinolones were afforded in moderate to good yields by the formation of one new C[double bond, length as m-dash]O bond and one new C-N bond. The features of this sequential reaction include high bonding efficiency, use of a catalytic amount of catalysts, a broad substrate scope and mild conditions. This methodology provides a good choice for constructing the libraries of 2,3-dihydro-4(1H)-isoquinolones.