N-Heterocyclic Carbene Catalyzed Research Articles

Two-Step Synthesis of α,β-Unsaturated γ-Amino Acid Esters via N-Heterocyclic Carbene Catalyzed [4+2] Cycloaddition of Enals and Nitroso Compounds

An efficient strategy for the synthesis of various of α,β-unsaturated γ-amino acid esters has been established employing N-heterocyclic carbene catalyzed [4+2] cycloadditions of β-methyl enals and aromatic nitroso compounds to afford 1,2-oxazin-6-ones in good yields. A subsequent acid-catalyzed esterification under ring opening yields the γ-amino enoates in good yields.

N-Heterocyclic Carbene Catalyzed [3+2] Cycloaddition of Enals with Masked Cinnamates for the Asymmetric One-Pot Synthesis of Adipic Acid Derivatives.

A novel short entry to 3,4-disubstituted adipic acids has been developed by employing an asymmetric NHC-catalyzed [3+2] cycloaddition of enals with masked cinnammates in moderate to good yields and high stereoselectivities. The synthetic utility of the protocol was demonstrated by the basic conversion of the masked cyclopentanone intermediates to 3S,4S-disubstituted adipic acid precursors of pharmaceutically important gababutins.

Kinetic Resolutions Enabled by N-Heterocyclic Carbene Catalysis

Kinetic Resolutions Enabled by N-Heterocyclic Carbene Catalysis

N-Heterocyclic Carbene Catalyzed Disulfide Metathesis and Phosphorylation

N-Heterocyclic Carbene Catalyzed Disulfide Metathesis and Phosphorylation

N-Heterocyclic Carbene Catalyzed Truce–Smiles Rearrangement

N-Heterocyclic Carbene Catalyzed Truce–Smiles Rearrangement

Organocatalytic Coupling of Bromo-Lactide with Cyclic Ethers and Carbonates to Chiral Bromo-Diesters: NHC or Anion Catalysis?

In the presence of a N-heterocyclic carbene (NHC) in THF, Br-substituted l-lactide (Br-LA) unexpectedly undergoes exclusive coupling with THF to form a chiral ω-bromo-α-keto-diester. This coupling reaction is completely selective (in a precise 1:1 fashion), readily scalable (>20 g scale), and extremely efficient (with only 50 ppm of NHC loading). Other cyclic ethers and carbonates can also undergo similar coupling with Br-LA, thus offering a class of Br-functionalized chiral diesters with various functions and chain lengths. Combined experimental and computational studies led to a coupling mechanism that proceeds through an anion (bromide)-mediated catalytic cycle, rather than an apparent NHC-catalyzed cycle.

Enantioselective Synthesis of 1,2-Dihydronaphthalenes via Oxidative N-Heterocyclic Carbene Catalysis

1,2-Dihydronaphthalenes are important molecules in both medicinal and synthetic chemistry, but methods for the catalytic asymmetric construction of this class of molecules are limited. The diastereo- and enantioselective N-heterocyclic carbene-catalyzed cascade annulation reactions using benzodiketones and enals under oxidative conditions, which afford a variety of 1,2-dihydronaphthalenes with two adjacent stereocenters in up to 99% yield, with >20:1 dr, and up to 99% ee, are reported. Furthermore, the product can be easily transformed to a series of useful compounds such as alcohol, amide, and epoxide.

Oxidative N-Heterocyclic Carbene Catalyzed Dearomatization of Indoles to Spirocyclic Indolenines with a Quaternary Carbon Stereocenter.

An efficient method for the asymmetric intramolecular dearomatization of indoles by using oxidative N-heterocyclic carbene catalysis is demonstrated. Valuable optically active spirocyclic indolenines bearing an all-carbon quaternary stereocenter are obtained in excellent yields and with excellent enantioselectivity. The starting indoles are readily prepared and the reactions proceed through an intramolecular indole 3-acylation with an in situ generated acyl azolium intermediate to form a spirocyclic ketone moiety.

N-Heterocyclic Carbene Catalyzed Synthesis of 3,4-Dihydrocoumarins

Key words coumarins - quinone methides - N-heterocyclic carbenes - cyclization

N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl Azolium

First reported less than a decade ago, the α,β-unsaturated acyl azolium has emerged as a central reactive intermediate for reaction discovery using N-heterocyclic carbene catalysis. In this Perspective, an introduction to the four main reactivity patterns accessible from this intermediate is provided. The Perspective is handled in a largely chronological fashion, with an emphasis on alternate approaches to the key intermediate and first-in-class reaction cascades. Finally, a brief discussion of emerging trends in this field of catalysis is presented. Although not exhaustive, the Perspective provides an overview of this active area of research and serves as a guide for future investigations.

Polyhalides as Efficient and Mild Oxidants for Oxidative Carbene Organocatalysis by Radical Processes.

Simple and inexpensive polyhalides (CCl4 and C2 Cl6 ) have been found to be effective and versatile oxidants in removing electrons from Breslow intermediates under N-heterocyclic carbene (NHC) catalysis. This oxidative reaction involves multiple single-electron-transfer (SET) processes and several radical intermediates. The α, β, and γ-carbon atoms of aldehydes and enals could be readily functionalized. Given the low cost of the oxidants and the broad applicability of the reactions, this study is expected to greatly enhance the feasibility of oxidative NHC catalysis for large-scale applications. Also this new SET radical process with polyhalides as single-electron oxidants will open a new avenue in the development of NHC-catalyzed radical reactions.

Polyhalides as Efficient and Mild Oxidants for Oxidative Carbene Organocatalysis by Radical Processes

AbstractSimple and inexpensive polyhalides (CCl4 and C2Cl6) have been found to be effective and versatile oxidants in removing electrons from Breslow intermediates under N‐heterocyclic carbene (NHC) catalysis. This oxidative reaction involves multiple single‐electron‐transfer (SET) processes and several radical intermediates. The α, β, and γ‐carbon atoms of aldehydes and enals could be readily functionalized. Given the low cost of the oxidants and the broad applicability of the reactions, this study is expected to greatly enhance the feasibility of oxidative NHC catalysis for large‐scale applications. Also this new SET radical process with polyhalides as single‐electron oxidants will open a new avenue in the development of NHC‐catalyzed radical reactions.

N-Heterocyclic-Carbene-Catalyzed Umpolung of Imines.

N-Heterocyclic carbene (NHC) catalysis has been widely used for the umpolung of aldehydes, and recently for the umpolung of Michael acceptors. Described herein is the umpolung of aldimines catalyzed by NHCs, and the reaction likely proceeds via aza-Breslow intermediates. The NHC-catalyzed intramolecular cyclization of aldimines bearing a Michael acceptor resulted in the formation of biologically important 2-(hetero)aryl indole 3-acetic-acid derivatives in moderate to good yields. The carbene generated from the bicyclic triazolium salt was found to be efficient for this transformation.

NHC-Organocatalyzed CAr -O Bond Cleavage: Mild Access to 2-Hydroxybenzophenones.

A Truce-Smiles rearrangement of acyl-anion equivalents generated by N-heterocyclic carbene (NHC) catalysis has been achieved. The developed method includes CAr -O, CAr -S, or CAr -N bond cleavage for the formation of a CAr -C bond and enables access to 2-hydroxybenzophenones, an important structural motif that is present in several bioactive natural products. By utilizing this procedure, the alkaloid taxilamine was synthesized in three steps. DFT calculations and control experiments support a classical SN Ar mechanism with a catalyst-bound Meisenheimer-type intermediate. The method features mild reaction conditions, excellent functional-group tolerance, and a broad substrate scope, including various classes of (hetero)arenes.

Thieme Chemistry Journals Awardees – Where Are They Now? Carbene Organocatalysis for Stetter, Benzoin, Domino, and Ring-Expansion Reactions

N-Heterocyclic carbene catalysis allows the rapid formation of functionalized carbon–carbon bonds. Our group has spent the previous decade focusing on broadening practical applications of this type of catalysis. The design and discovery of novel reactivities and catalysts in our group can best be divided into work focusing on the Stetter, ring-expansion, and cross-benzoin reactions. Along with our expansion of the reaction scope, our introduction of novel bis(amino)cyclopropenylidene catalysts for the Stetter reaction successfully suppresses formation of side products, increasing synthetic utility. Concurrent work on ring-expansion reactions allows access to functionalized lactones and lactams. In addition to expanding the scope of the cross-benzoin reaction through use of α-ketoesters and α-amino aldehydes, the introduction of a new triazolylidene catalyst has allowed access to general chemoselective cross-benzoin reactions between aliphatic and aromatic aldehydes. 1 <b/>Introduction 2 Stetter Reactions 2.1 Domino Stetter Reactions 3 Ring-Expansion Reactions 4 Cross-Benzoin Reactions 5 Summary and Outlook

Enantioselective synthesis of cyclopenta[b]benzofurans via an organocatalytic intramolecular double cyclization.

An enantioselective organocatalytic strategy, combining Brønsted base and N-heterocyclic carbene catalysis in a unique manner, is demonstrated for a concise construction of the privileged cyclopenta[b]benzofuran scaffold, present in many bioactive compounds having both academic and commercial interests. The reaction concept relies on an intramolecular one-pot double cyclization involving a cycle-specific enantioselective Michael addition followed by a benzoin condensation of ortho-substituted cinnamaldehydes. Cyclopenta[b]benzofurans were achieved in moderate to good yields, with excellent stereoselectivities. A proof of principle for a diastereodivergent variation is demonstrated through the synthesis of cyclopenta[b]benzofurans containing two contiguous aromatic substituents in a substitution pattern present in commercial and natural compounds. Furthermore, several transformations have been performed, demonstrating the synthetic utility of the products. Finally, insights into the activation mode and stereoindution models are presented for this new synthetic strategy.

Enantioselective [2+2] annulation of simple aldehydes with isatin-derived ketimines via oxidative N-heterocyclic carbene catalysis.

An asymmetric [2+2] annulation reaction through direct α-carbon functionalization of simple aldehydes via oxidative N-heterocyclic carbene catalysis is disclosed. These in situ generated triazolium enolate intermediates undergo a highly stereoselective Mannich reaction with isatin-derived ketimines followed by intramolecular lactamization to afford enantioenriched spirooxindole β-lactams bearing two vicinal stereogenic centers.

ChemInform Abstract: Cooperative Catalysis and Activation with N‐Heterocyclic Carbenes

AbstractReview: [79 refs.

ChemInform Abstract: N‐Heterocyclic Carbene Catalyzed [4 + 2] Annulation Reactions with in situ Generated Heterocyclic ortho‐Quinodimethanes.

An efficient strategy for the in situ generation of heterocyclic ortho-quinodimethanes (oQDMs) from 2-methyl-heteroarene-3-carboxylic esters by N-heterocyclic carbene (NHC) catalysis is disclosed. These heterocyclic oQDMs undergo highly enantioselective [4 + 2] annulation reactions with isatin-derived ketimines to afford optically pure heteroarene-fused δ-lactams bearing a quaternary stereogenic center. The main features of this reaction include challenging direct C(sp3)–H bond functionalizations, excellent enantioselectivities, readily available starting materials, mild reaction conditions, high efficiency, and operational simplicity.

Enantioselective Cascade Reactions under N-Heterocyclic Carbene Catalysis

The use of chiral N-heterocyclic carbenes (NHCs) as catalysts in asymmetric synthesis has opened a wide range of applications due to their unique ability to generate reaction intermediates with unusual reactivity patterns that very often involve the reversal of the typical polarity associated with the functional groups present in the starting materials. In this sense, the direct activation of aldehydes or surrogates by these reactive species provides different chemical structures (conjugated Breslow intermediates, azolium enolates and dienolates, or unsaturated acyl azolium cations) which constitute excellent platforms for initiating cascade or domino reactions in the presence of a polyfunctional reagent. 1 Introduction 2 Cascade Reactions Initiated by the Participation of Homoenolate Equivalents 3 Cascade Reactions Initiated by the Participation of Azolium Enolates 4 Cascade Reactions Initiated by the Participation of Dienolate Equivalents 5 Cascade Reactions Initiated by the Participation of α,β-Unsaturated Acyl Azolium Intermediates 6 Summary and Outlook