Oxidative Enamine Catalysis Research Articles

Bond Energies of Enamines.

Energetics of reactive intermediates underlies their reactivity. The availability of these data provides a rational basis for understanding and predicting a chemical reaction. We reported here a comprehensive computational study on the energetics of enamine intermediates that are fundamental in carbonyl chemistry. Accurate density functional theory (DFT) calculations were performed to determine the bond energies of enamines and their derived radical intermediates. These efforts led to the compilation of a database of enamine energetics including a thermodynamic index such as free-energy stability, bond dissociation energy (BDE), and acid dissociation constant (pKa) as well as a kinetic index such as nucleophilicity and electrophilicity. These data were validated by relating to experimentally determined parameters and their relevance and utility were discussed in the context of modern enamine catalysis. It was found that pKa values of enamine radical cations correlated well with redox potentials of their parent enamines, the former could be used to rationalize the proton-transfer behavior of enamine radical cations. An analysis of the BDE of enamine radical cations indicated that these species underwent facile β-C–H hydrogen transfer, in line with the known oxidative enamine catalysis. The enamine energetics offers the possibility of a systematic evaluation of the reactivities of enamines and related radicals, which would provide useful guidance in exploring new enamine transformations.

Redox Property of Enamines.

Enamines are electron-rich compounds bearing intriguing redox properties. Herein, a series of secondary enamines condensed from primary amine and β-ketocarbonyls were synthesized and their electrochemical oxidation properties were systematically studied by cyclic voltammetry. Furthermore, theoretical calculation of oxidation potentials of enamines, particularly those catalytic intermediates, was also conducted to further broaden the scope investigated. Possible structural factors on oxidation and the nature of the resulted radical cation intermediates were revealed and discussed. Correlation of redox potentials with molecular properties such as highest occupied molecular orbital energies and natural population analysis charge were explored, and there appears no simple linear correlation. On the other hand, a good correlation with Mayr's nucleophilicity parameter N was noted among a range of catalytically relevant enamines. Spin population analysis disclosed that enamine radical cations mainly exhibit the carbon-center free radical feature. Taking experimental and computation data together, a comprehensive picture about the redox property of enamines is presented, which would provide guidance in the development of oxidative enamine catalysis and transformations.

Catalytic Asymmetric Oxidative Enamine Transformations

Enamine catalysis is a prevalent strategy for the functionalization of aldehydes/ketones with electrophiles. Recently, the advent and development of oxidative enamine catalysis have allowed for the coupling of enamines with readily available nucleophiles under oxidative conditions, significantly expanding the domain of typical enamine catalysis. In this perspective, we summarize the recent advances in asymmetric oxidative enamine catalysis. On the basis of the oxidative strategy, these could be classified as (1) oxidation of nucleophile, (2) oxidation of enamine via single-electron transfer (SOMO catalysis), and (3) oxidation of enamine to α,β-unsaturated iminium ion, i.e. oxidative iminium catalysis. These strategies have enabled efficient oxidative functionalizations of aldehydes/ketones with various O-, N-, and C-centered nucleophiles in a highly stereocontrolled manner.

Achieving elusive transformations with organocatalysis: direct $\beta $-carbon activation of saturated carbonyl compounds

Direct $\beta $-carbon activation of saturated carbonyl compounds for carrying out fast forward $\beta$-functionalization has been one of the most difficult to achieve tasks in catalysis. In the past few years, this challenging issue has attracted considerable attention among the chemical community that has led to fruitful developments to accomplish this elusive transformation. In this short review, we highlight recent developments for direct $\beta $-carbon functionalization of saturated carbonyl compounds based on conceptually new methods including oxidative enamine catalysis, $N$-heterocyclic carbene (NHC)-assisted catalysis, and photoredox catalysis.

Stereoselective organocatalytic oxidation of alcohols to enals: a homologation method to prepare polyenes.

A novel method for organocatalytic oxidation through oxidative enamine catalysis was developed with excellent compatibility for the direct syntheses of enals from simple saturated alcohols. By using this amine-catalyzed IBX-oxidation, a wide range of aromatic and aliphatic substituted enals were successfully generated in high yields and exclusively stereoselective E-geometry. Moreover, varying the solvents and/or the loading amounts of IBX allowed for the selective oxidation of alcohols and aldehydes. Importantly, the homologous application of this method provided a selective and efficient way of preparing various highly sensitive conjugated polyene frameworks, which are enriched in natural products.

ChemInform Abstract: Enantioselective Organocatalytic Oxidative Enamine Catalysis—1,5‐Hydride Transfer—Cyclization Sequences: Asymmetric Synthesis of Tetrahydroquinolines.

The first organocatalytic enantioselective intramolecular oxidative enamine catalysis and 1,5-hydride transfer–ring closure reaction cascade is described. This neutral reaction cascade allows for the efficient formation of ring-fused tetrahydroquinolines with high enantioselectivities.

ChemInform Abstract: Organocatalytic Oxidative Enamine Catalysis and 1,5‐Hydride Transfer/Cyclization: Synthesis of Tetrahydroquinoline Derivatives.

AbstractSynthetically useful fused tetrahydroquinoline derivatives are obtained in good yield and diastereoselectivity via a hitherto not reported organocatalytic oxidative enamine catalysis and hydride transfer/ring closure reaction cascade.

Enantioselective organocatalytic oxidative enamine catalysis–1,5-hydride transfer–cyclization sequences: asymmetric synthesis of tetrahydroquinolines

The first organocatalytic enantioselective intramolecular oxidative enamine catalysis and 1,5-hydride transfer-ring closure reaction cascade is described. This neutral reaction cascade allows for the efficient formation of ring-fused tetrahydroquinolines with high enantioselectivities.

Organocatalytic Oxidative Enamine Catalysis and 1,5-Hydride Transfer/Cyclization: Synthesis of Tetrahydroquinoline Derivatives

E-mail: dyoung@sch.ac.krReceived August 5, 2013, Accepted September 20, 2013Key Words : Asymmetric synthesis, Oxidative enamine catalysis, 1,5-Hydride transfer, Tetrahydroquinolines,Organocatalysis The development of C-C bond formation via C-H bondsactivation has become an area of intense interest in syntheticorganic chemistry. Because such reactions offer efficientmethods for the construction of structurally complex andbiologically active compounds.

ChemInform Abstract: Recent Developments in Amine‐Catalyzed Non‐Asymmetric Transformations

Amine catalysis has emerged as a powerful and elegant method to construct diverse chiral scaffolds in asymmetric synthesis. However, amine-based non-asymmetric organocatalysis is still in its infancy. This Focus Review examines recent developments in amine-catalyzed non-asymmetric transformations based on enamine, iminium, di- or trienamine, and oxidative enamine catalysis.

Recent Developments in Amine‐catalyzed Non‐asymmetric Transformations

AbstractAmine catalysis has emerged as a powerful and elegant method to construct diverse chiral scaffolds in asymmetric synthesis. However, amine‐based non‐asymmetric organocatalysis is still in its infancy. This Focus Review examines recent developments in amine‐catalyzed non‐asymmetric transformations based on enamine, iminium, di‐ or trienamine, and oxidative enamine catalysis.

Oxidative Enamine Catalysis: Direct Catalytic Enantioselective β‐Functionalization of Aldehydes

Jekyll and aldeHyde: The oxidation of enamines to iminium species by 2-iodoxybenzoic acid (IBX) or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) catalyzed by a chiral secondary amine catalyst enabled the unprecedented enantioselective β-functionalization of aldehydes with various nucleophiles in high stereoselectivity.

Efficient preparation of trans-α,β-unsaturated aldehydes from saturated aldehydes by oxidative enamine catalysis

A mild and highly efficient amine-catalyzed, IBX-mediated oxidation of aldehydes to (E) selective α,β-unsaturated aldehydes has been achieved in good yields. The process features a new oxidation of enamines to iminium ions in a catalytic fashion.

Enantioselective β-Functionalization of Aldehydes via Oxidative Enamine Catalysis

The authors expand enamine-­iminium catalysis for the β-functionalization of aldehydes via enamine oxidation. By using a stoichiometric amount of an oxidant (e.g., IBX), in situ generated enamines are oxidized to the corresponding α,β-unsaturated iminium ions, which ­undergo Michael reactions with moderate yields and good to excellent enantioselectivities. The synthetic potential of this methodology is also demonstrated by conducting various cascade ­reactions, which give rise to complex chiral building blocks from simple aldehydes. In the absence of a nucleophile, the authors could observe the corresponding α,β-unsaturated enal, which is formed via hydrolysis of the iminium intermediate.

Organocatalytic enantioselective β-functionalization of aldehydes by oxidation of enamines and their application in cascade reactions

Iminium catalysis, involving the transformation of iminium ions to enamines, has been extensively studied in the context of a number of organic processes. However, the reverse of this process involving conversion of enamines to iminium species has not been realized. Here, we describe a new transformation-'oxidative enamine catalysis'-in which direct oxidation of an enamine occurs to generate an iminium species. We show that the use of o-iodoxybenzoic acid as an oxidant in the presence of a secondary amine catalyst serves as effective system for promoting rapid conversion of enamines to iminium ions. The preparative power of this process has been demonstrated in the context of direct asymmetric β-functionalization of simple aldehydes. Moreover, a variety of enantioselective cascade transformations, including triple and quadruple cascades, have been developed for the 'one-pot' synthesis of versatile chiral building blocks and structural frameworks starting with simple aldehydes.