Aziridination Of Imines Research Articles

Hexamethylphosphanetriamine‐mediated aziridination of imines with alpha‐ketoesters: A molecular electron density theory study

AbstractThe highly trans‐stereoselective reaction of oxyphosphonium enolate (OPE) with N‐benzylidene‐4‐methoxybenzenesulfonamide (N‐BMS) in toluene, at room temperature leading to trans‐aziridine‐2‐carboxylate (trans‐Az 3), was theoretically studied using molecular electron density theory (MEDT) at the B3LYP/6‐31G(d) computational level to shed light on the energy transformation, selectivities, and mechanistic aspects. This domino process is initialized by adding of N,N,N′,N′,N″,N″‐hexamethylphosphanetriamine (HMPT) to methyl benzoylformate to generate OPE. Subsequently, nucleophilic addition of OPE to the C–N double bond in N‐BMS leads to the intermediate IN‐Ta. Finally, trans‐Az 3 is formed through a 3‐exo‐tet ring closure step as a result of the nucleophilic attack of the negatively charged nitrogen atom on the carbon atom bearing –OP (NMe2)3 in IN‐Ta. Analysis of the relative Gibbs free energies shows that the ring closure step is the rate‐determining step. By an investigation of the conceptual density functional theory reactivity indices, OPE and N‐BMS are classified as a strong nucleophilic and as a strong electrophilic species, respectively, which indicates that the additional step of OPE to N‐BMS should display a high‐polar character. An analysis of the calculated electrophilic and nucleophilic Parr functions at the reactive sites of reagents clarifies the regioselectivity observed experimentally along the C1–C2 bond formation process.

Synthesis of Isothiocineole and Application in Multigram-Scale Sulfur Ylide Mediated Asymmetric Epoxidation and Aziridination

The synthesis of the chiral sulfide isothiocineole from limonene and elemental sulfur on multi-gram scale and its alkylation to make >50 g of the corresponding benzylsulfonium salt are described. The application of this salt to the sulfur ylide-mediated asymmetric epoxidation of aldehydes and the asymmetric aziridination of imines on a >5 g scale is demonstrated.

P(NMe2)3-Mediated Aziridination of Imines with α-Ketoesters for Synthesis of Aziridine-2-carboxylates.

Aziridination of N-sulfonyl imines with α-ketoesters in the presence of P(NMe2)3 is reported. Adducts derived from trivalent phosphorus reagents and α-ketoesters are effectively intercepted by imines, affording a range of aziridine-2-carboxylates. The diastereoselectivity of the reaction depends on steric hindrance from substituents on the substrates.

Chiral bidiaziridines by a two-step domino aziridination of meso-α-diimines

Chiral racemic α-diimines, tested in aziridination reactions with NsONHCO2Et, for the first time led to the synthesis of (±)-bidiaziridines, stereoselectively derived from the corresponding meso (E-s-trans-E)-α-diimines. Moreover, a minor bidiaziridine isomer, probably a meso form that was lost under classical work-up conditions, can be obtained by adding water to the crude mixtures at the end of amination reactions. The results definitively prove that the imine aziridination by carbamates is a two-step domino process. The structures of the compounds were determined using 2D NMR on purified bidiaziridines.

Highly Enantioselective Ruthenium/PNNP-Catalyzed Imine Aziridination: Evidence of Carbene Transfer from a Diazoester Complex

The ruthenium/PNNP complexes [RuCl(Et2O)(PNNP)]Y (Y = PF6, 4PF6; BF4, 4BF4; or SbF6, 4SbF6) (10 mol %) catalyze the enantioselective aziridination of imines with ethyl diazoacetate (EDA) as carbene...

Practical and Highly Selective Sulfur Ylide-Mediated Asymmetric Epoxidations and Aziridinations Using a Cheap and Readily Available Chiral Sulfide: Extensive Studies To Map Out Scope, Limitations, and Rationalization of Diastereo- and Enantioselectivities

The chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described. Excellent enantioselectivities and diastereoselectivities have been obtained over a wide range of aromatic, aliphatic, and α,β-unsaturated aldehydes using simple protocols. In aziridinations, excellent enantioselectivities and good diastereoselectivities were obtained for a wide range of imines. Mechanistic models have been put forward to rationalize the high selectivities observed, which should enable the sulfide to be used with confidence in synthesis. In epoxidations, the degree of reversibility in betaine formation dominates both the diastereoselectivity and the enantioselectivity. Appropriate tuning of reaction conditions based on understanding the reaction mechanism enables high selectivities to be obtained in most cases. In aziridinations, betaine formation is nonreversible with semistabilized ylides and diastereoselectivities are determined in the betaine forming step and are more variable as a result.

The asymmetric synthesis of terminal aziridines by methylene transfer from sulfonium ylides to imines

A new ylide-based protocol for the asymmetric aziridination of imines via methylene transfer has been developed involving the use of a simple chiral sulfonium salt and an organic strong base. A systematic study identified triisopropylphenyl sulfonylimines as optimal substrates for the process. Unexpectedly, hindered C2-symmetric sulfonyl salts incorporating bulky ethers at C-2 and C-5--which had previously been useful in the corresponding epoxidation chemistry--decomposed in these aziridination reactions via competing elimination pathways. Under optimised conditions it was found that a simple salt derived from (2R,5R)-2,5-diisopropyl thiolane could mediate asymmetric methylene transfer to a range of imines with uniformly excellent yields with 19-30% ee. Since this is a similar level of enantiomeric excess to that obtained using these same salts in epoxidation chemistry, it was concluded that if more bulky sulfonium salts could be devised which were resistant to decomposition under the reaction conditions, that highly enantioselective aziridine formation by methylene transfer would be possible.

Double Stereodifferentiation in the Catalytic Asymmetric Aziridination of Imines Prepared from α‐Chiral Amines

The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α-methylbenzyl amine for cis-aziridines from α-diazo esters and for trans-aziridines from α-diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis-aziridines involved the (R)-amine with the (S)-ligand, but curiously, for trans-aziridines the matched case involved the (R)-amine with the (R)-ligand for imines derived from benzaldehyde and n-butanal, and the (R)-amine with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.

Practical Gram Scale Asymmetric Catalysis with Boroxinate Brønsted Acids Derived from the VAPOL and VANOL Ligands

Our laboratories have been engaged in utilizing catalysts derived from the VAPOL and VANOL ligands towards the development of efficient asymmetric processes over the last several years. Subsequent to their development, practical scale-up of these methodologies to gram scale has always been deemed necessary to demonstrate. This article will report on such successful gram scale asymmetric catalysis that has been realized in our laboratories using the boroxinate Bronsted acid catalysts derived from the VAPOL and VANOL ligands. The processes reviewed will be the catalytic asymmetric aziridination of imines and the direct catalytic asymmetric aminoallylation of aldehydes.

ChemInform Abstract: Monofluorinated Aziridines in Asymmetric Synthesis of Chiral Fluorinated Prop‐2‐yn‐1‐amines.

AbstractEnantioenriched fluorinated aziridines (III), obtained by aziridination of imines (I) with fluorocarbene, undergo aziridine ring opening in the presence of potassium alkynyltrifluoroborates (V) to give optically active fluorinated ynamines (VI)/(VII).

ChemInform Abstract: Ruthenium Complexes with Chiral Tetradentate PNNP Ligands: Asymmetric Catalysis from the Viewpoint of Inorganic Chemistry

AbstractReview: 166 refs.

Ruthenium complexes with chiral tetradentate PNNP ligands: Asymmetric catalysis from the viewpoint of inorganic chemistry

This is a personal account of the application of ruthenium complexes containing chiral tetradentate ligands with a P(2)N(2) ligand set (PNNP) as catalyst precursors for enantioselective "atom transfer" reactions. Therewith are meant reactions that involve bond formation between a metal-coordinated molecule and a free reagent. The reactive fragment (e.g. carbene) is transferred either from the metal to the non-coordinated substrate (e.g. olefin) or from the free reagent (e.g. F(+)) to the metal-bound substrate (e.g.beta-ketoester), depending on the class of catalyst (monocationic, Class A; or dicationic, Class B). The monocationic five-coordinate species [RuCl(PNNP)](+) and the six-coordinate complexes [RuCl(L)(PNNP)](+) (L = Et(2)O, H(2)O) of Class A catalyse asymmetric epoxidation, cyclopropanation (carbene transfer from the metal to the free olefin), and imine aziridination. Alternatively, the dicationic complexes [Ru(L-L)(PNNP)](2+) (Class B), which contain substrates that act as neutral bidentate ligands L-L (e.g., beta-ketoesters), catalyse Michael addition, electrophilic fluorination, and hydroxylation reactions. Additionally, unsaturated beta-ketoesters form dicationic complexes of Class B that catalyse Diels-Alder reactions with acyclic dienes to produce tetrahydro-1-indanones and estrone derivatives. Excellent enantioselectivity has been achieved in several of the catalytic reactions mentioned above. The study of key reaction intermediates (both in the solid state and in solution) has revealed significant mechanistic aspects of the catalytic reactions.

Organocatalytic Stereoselective Aziridination of Imines via Ammonium Ylides

Tertiary amine catalyzed reaction of imines with phen­acyl bromide derivatives expeditiously affords functionalized aziridines in high yields and stereoselectivities in a one-pot process. Advantageously, the protocol precludes the preparation and isolation of ylides and their precursors in a separate step as they are formed in situ.

Evidence for a Boroxinate Based Brønsted Acid Derivative of VAPOL as the Active Catalyst in the Catalytic Asymmetric Aziridination Reaction

Studies are described that were designed to determine the structure of the active catalyst in the asymmetric catalytic aziridination of imines with ethyl diazoacetate (AZ reaction). Evidence suggests that the active catalyst contains a boroxine ring in which one of the three boron atoms is spiro-fused with the two phenol groups of the VAPOL ligand. (11)B and (1)H NMR evidence supports the boroxinate structure B in which the counterion to the boroxinate is the protonated form of the imine. The boroxinate structure is also supported by two solid state structures of a VAPOL boroxinate in which the gegen cation is tetramethyl ammonium and 4-dimethylaminopyridinium.

Ru/PNNP-Catalyzed Asymmetric Imine Aziridination by Diazo Ester Activation

Ruthenium complexes containing chiral tetradentate PNNP ligands catalyze the carbene transfer from ethyl diazoacetate (EDA) to imines to give the corresponding cis-aziridines with up to 84% ee. Studies of the reactions with 13C- or 15N-labeled EDA show that EDA binds to ruthenium under catalysis conditions and support an unprecedented mechanism involving carbene transfer from coordinated EDA to the imine.

Mapping the Active Site in a Chemzyme: Diversity in the N-Substituent in the Catalytic Asymmetric Aziridination of Imines

The active site of the aziridination catalyst derived from either the VANOL or VAPOL ligand and B(OPh)(3) is larger than expected and can accommodate not only significant substitution on the diarylmethyl unit of the imine but also that alkyl (but not perfluorylalkyl) substituents on the aryl groups lead to enhanced rates and enantioselection. The screen of diarylmethyl N-substituents on the imine revealed that the 3,5-di-tert-butyldianisylmethyl group (BUDAM) gave exceptionally high asymmetric inductions for imines of aryl aldehydes.

Catalytic Asymmetric Aziridination with Borate Catalysts Derived from VANOL and VAPOL Ligands: Scope and Mechanistic Studies

An extended study of the scope and mechanism of the catalytic asymmetric aziridination of imines with ethyl diazoacetate mediated by catalysts prepared from the VANOL and VAPOL ligands and triphenylborate is described. Nonlinear studies with scalemic VANOL and VAPOL reveal an essentially linear relationship between the optical purity of the ligand and the product suggesting that the catalyst incorporates a single molecule of the ligand. Two species are present in the catalyst prepared from B(OPh)(3) and either VANOL or VAPOL as revealed by (1)H NMR studies. Mass spectral analysis of the catalyst mixture suggests that one of the species involves one ligand molecule and one boron atom (B1) and the other involves one ligand and two boron atoms (B2). The latter can be formulated as either a linear or cyclic pyroborate and the (11)B NMR spectrum is most consistent with the linear pyroborate structure. Several new protocols for catalyst preparation are developed which allow for the generation of mixtures of the B1 and B2 catalysts in ratios that range from 10:1 to 1:20. Studies with catalysts enriched in the B1 and B2 species reveal that the B2 catalyst is the active catalyst in the VAPOL catalyzed asymmetric aziridination reaction giving significantly higher asymmetric inductions and rates than the B1 catalyst. The difference is not as pronounced in the VANOL series. A series of 12 different imines were surveyed with the optimal catalyst preparation procedure with the finding that the asymmetric inductions are in the low to mid 90s for aromatic imines and in the mid 80s to low 90s for aliphatic imines for both VANOL and VAPOL catalysts. Nonetheless, the crystallinity of the N-benzhydryl aziridines is such that nearly all of the 12 aziridine products screened can be brought to >99 % ee with a single recrystallization.

Highly Stereoselective Aziridination of Imines with (S)‐Dimethylsulfonium‐(p‐tolylsulfinyl)methylide.

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Highly stereoselective aziridination of imines with ( S)-dimethylsulfonium-( p-tolylsulfinyl)methylide

Addition of ( S)-dimethylsulfonium-( p-tolylsulfinyl)methylide to N-tosyl imines afforded the corresponding sulfinyl aziridines with full enantio- and diastereoselectivity. The chiral sulfinyl substituent was removed without ring opening leading to enantiopure 2-substituted aziridines.

Ruthenium(II) Porphyrin Catalyzed Imine Aziridination and Crystal Structures of (meso‐Tetrakis(pentafluorophenyl)porphyrinato)ruthenium(II) Complexes Containing PhN=CH(p‐ClPh), CPh2, and Pyridine Ligands.

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