Oxidative N-Heterocyclic Carbene Catalysis Research Articles

Redox Active N-Heterocyclic Carbenes in Oxidative NHC Catalysis.

An N-heterocyclic carbene (NHC) covalently linked to a quinone introduces a novel avenue for internal oxidations within oxidative NHC catalysis. The deployment of this hybrid NHC class promotes intramolecular electronic flow in the oxidation of the Breslow intermediate to acyl azolium. The use of the redox active NHC as a catalyst is facilitated by employing aerobic regeneration, yielding carboxylic esters with efficiencies of ≤99%, while generating water as the sole byproduct.

Oxidative NHC Catalysis: An Unconventional Tool for Macrocyclic Oligoesters Synthesis.

The application of N-heterocyclic carbene (NHC) catalysis under highly diluted oxidative condition to the polycondensation of dialdehydes and diols is herein presented as an alternative, atomeconomical synthetic route to macrocyclic oligoesters (MCOs). The disclosed protocol paves the way to the straightforward access to MCOs, starting from commercial dialdehydes, avoiding the use of toxic diacyl chlorides, commonly employed in traditional MCOs synthetic processes. The method is totally metal-free, takes place in the green Me-THF solvent and requires the use of a fully recyclable quinone oxidant. The protocol versatility is confirmed by the employment of fossil-based and bio-based monomers such as 2,5diformylfuran (DFF), 2,5-bis(hydroxymethyl)furan (BHMF), and isomannide, synthesizing a series of novel and known synthetically relevant macrocyclic oligoesters, fully characterized by NMR and MALDI-TOF MS analysis, with product yields (51-86%) comparable to those obtained by traditional synthetic routes. Finally, to emphasize the synthetic relevance of the target macrocycles, an entropicallydriven ring opening polymerization (ED-ROP) key study has been performed, optimizing the organocatalyzed synthesis of poly(2,5furan-dimethylene 2,5 furandicarboxylate) (PBHMF) with numberaverage molecular weight up to 8200 g mol-1 and 66% isolated yield.

Aerobic oxidative N-heterocyclic carbene catalysis.

The ease with which simple starting materials can be transformed into highly functionalized products has made oxidative N-heterocyclic carbene (NHC) catalysis an area of significant interest. However, the use of stoichiometric amounts of high molecular weight oxidants in most reactions generates an undesired equivalent amount of waste. To address this issue, the use of oxygen as the terminal oxidant in NHC catalysis has been developed. Oxygen is attractive due to its low cost, low molecular weight, and ability to generate water as the sole by-product. However, molecular oxygen is challenging to use as a reagent in organic synthesis due to its unreactive ground state, which often requires reactions to be run at high temperatures and results in the formation of kinetic side-products. This review covers the development of aerobic oxidative carbene catalysis, including NHC-catalyzed reactions with oxygen, strategies for oxygen activation, and selectivity issues under aerobic conditions.

Frontispiece: Oxidative N‐Heterocyclic Carbene Catalysis

Oxidative N-heterocyclic carbene (NHC) catalysis offers the chance to perform oxidative and oxygenative transformations which give rise to various NHC-bound intermediates, paving the way to non-umpolung processes through activation of carbon atoms and heteroatoms. The aim of this review is to discuss the developments of the literature in the field of oxidative NHC-catalysis since 2014, with particular focus to pivotal intermediates and their mechanistic involvement. More information can be found in the Review article by C. De Risi and co-workers. (DOI: 10.1002/chem.202202467)

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer

AbstractOxidative N‐heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC‐catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single‐electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C−H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value‐added products in a straightforward and cost‐effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer.

Oxidative N-heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC-catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single-electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C-H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value-added products in a straightforward and cost-effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Oxidative N-Heterocyclic Carbene-Catalyzed Intramolecular Friedel-Crafts Alkylation of Indoles for the Synthesis of Spirocyclic Indolenines.

The stereoselective intramolecular dearomatizing spirocyclization of indoles via oxidative N-heterocyclic carbene (NHC) catalysis to afford indolenines bearing an all-carbon quaternary center at the 3-position is reported. The reaction proceeds via the intramolecular nucleophilic addition of the indole to an in situ generated α,β-unsaturated acyl azolium. The cyclized indolenine bearing an acyl azolium functionality is trapped by a suitable external nucleophile that does not efficiently react with the α,β-unsaturated acyl azolium via direct acylation.

Dearomatizing Cyclization of 2-Iodoindoles by Oxidative NHC Catalysis to Access Spirocyclic Indolenines and Oxindoles Bearing an All Carbon Quaternary Stereocenter.

An intramolecular dearomatizing spirocyclization of indoles by oxidative N-heterocyclic carbene catalysis is reported. C2-iodinated indoles are used as substrates in combination with aroyl azolium ions as acceptors, which provides C2-iodinated indolenines containing an all carbon quaternary stereocenter. The products are readily further C2-functionalized and give access to valuable oxindoles by simple hydrolysis in very good overall yields and excellent enantioselectivities.

Oxidative N-heterocyclic carbene (NHC) catalysis for the rapid access to functionalized pyrrolo-oxazinones

The N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of N-substituted pyrrole 2-carboxaldehydes under oxidative conditions allowing the facile synthesis of pyrrolo-oxazinone derivatives is reported. The keys to the success of this strategy are the generation of acylazoliums using NHC and the base-mediated formation of the enolate. Subsequent intramolecular acylation of the enolate with the acylazoliums afforded the desired product. Mild reaction conditions, good functional group compatibility and high yields of products are the advantages of the present annulation.

Regiodivergent Isosorbide Acylation by Oxidative N-Heterocyclic Carbene Catalysis in Batch and Continuous Flow

A new N-heterocyclic carbene (NHC)-catalyzed strategy for the regioselective monoesterification of isosorbide (IS) at either the endo (5-OH) or exo (2-OH) position is described. Site-selective acylation proceeds under oxidative conditions in the presence of a quinone oxidant using aldehydes as mild acylating agents. Experimental evidences suggest a role of the stereoelectronic features of the acyl azolium salt intermediate in determining the selectivity of the acylation process. The solvent effect was also investigated, considering conventional and sustainable solvents. Aromatic aldehydes, including bio-based furfural and 5-hydroxymethyl furfural, together with α,β-unsaturated aldehydes proved to be effective reaction partners affording monoacyl-isosorbides with satisfactory levels of regioselectivity (exo/endo: 5.3–3.5; endo/exo: 5.3–3.3). Additionally, the exo-selective triazolium salt promoter was successfully transferred into the heterogeneous phase and applied to continuous-flow catalysis. In particular, the polystyrene-supported version of the selected NHC showed a catalytic activity comparable to that of the homogeneous counterpart in terms of both conversion efficiency (turnover number = 108) and regioselectivity (exo/endo up to 5.3). Also, the corresponding packed-bed mesoreactor was operated with long-term stability (ca. 110 h on stream) to produce 2-benzoyl-IS (1.32 mmol h–1 mmolcat–1), which is the key intermediate in the synthesis of a commercial active pharmaceutical ingredient, namely, the vasodilator isosorbide-5-mononitrate.

Enantioselective N‐Acylation of Biginelli Dihydropyrimidines by Oxidative NHC Catalysis

The oxidative N‐acylation reaction of 3,4‐dihydropyrimidin‐2‐(1H)‐ones (DHPMs) with enals and N‐heterocyclic carbene (NHC) catalysts is described. The reaction proceeds in the presence of quinone oxidant without additional acyl transfer agents and in the asymmetric variant produces pharmaceutically relevant N3‐acylated products with good‐to‐moderate enantioselectivity.

Dearomative [4 + 2] annulations between 3-nitroindoles and enals through oxidative N-heterocyclic carbene catalysis

A novel intermolecular dearomative [4 + 2] annulation of 3-nitroindoles and enals under oxidative N-heterocyclic carbene catalysis has been developed. This protocol was also suitable for the oxidative cyclisation of 2-nitrobenzothiophenes with enals.

Highly Enantioselective Synthesis of Functionalized Glutarimide Using Oxidative N-Heterocyclic Carbene Catalysis: A Formal Synthesis of (−)-Paroxetine

A simple yet highly effective approach toward enantioselective synthesis of trans-3,4-disubstituted glutarimides from readily available starting materials is developed using oxidative N-heterocyclic carbene catalysis. The catalytic reaction involves a formal [3 + 3] annulation between enals and substituted malonamides enabling the production of glutarimide derivatives in a single chemical operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a broad range of functionalized glutarimides with excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal synthesis of (-)-paroxetine and other bioactive molecules.

Oxidative NHC catalysis: direct activation of β sp3 carbons of saturated acid chlorides.

The first activation of saturated acid chlorides by oxidative N-heterocyclic carbene catalysis has been successfully utilized to synthesize enantio-enriched spirooxindole lactones and δ-lactones. The reaction involves the transformation of the β sp3 carbon of saturated acid chlorides into an electrophilic carbon as a key step. The product was obtained in excellent yield and stereoselectivity.

Oxidative NHC Catalysis for the Generation of Imidoyl Azoliums: Synthesis of Benzoxazoles.

N-Heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of aldimines generated from 2-amino phenols and aromatic aldehydes leading to the synthesis of 2-arylbenzoxazoles under mild conditions is presented. The reaction proceeds via the generation of the aza-Breslow intermediates from imines and NHC, which under oxidative conditions form the key imidoyl azoliums and a subsequent intramolecular cyclization furnishes the product. The reaction tolerates a broad range of functional groups, and the products are formed in generally good yields.

Enantioselective N-Heterocyclic Carbene-Catalyzed Cascade Reaction for the Synthesis of Pyrroloquinolines via N-H Functionalization of Indoles.

Functionalization of the indole N-H bond for enantioselective synthesis of biologically important pyrroloquinoline derivatives has been reported under oxidative N-heterocyclic carbene catalysis conditions. The interception of catalytically generated chiral α,β-unsaturated acylazoliums with the indole derivatives proceeds in an aza-Michael/Michael/lactonization sequence to deliver the pyrroloquinoline derivatives in good yields, diastereoselectivities, and enantioselectivities. The simultaneous enhancement of reactivity and selectivity observed in polar aprotic solvents is noteworthy.

Oxidative Asymmetric [2 + 3] Annulation of Aldehydes with Azomethine Imines Enabled by N-Heterocyclic Carbene Catalysis.

An efficient asymmetric [2 + 3] annulation of simple aldehydes with N,N'-cyclic azomethine imines via oxidative N-heterocyclic carbene (NHC) catalysis is disclosed, affording bicyclic pyrazolidinones bearing two vicinal tertiary stereogenic centers with moderate to good yields (56-84% for 19 examples), good to excellent diastereoselectivities (>20:1 for 17 examples), and good to excellent enantioselectivities (66-98% for 19 examples). This direct α-carbon functionalization reaction of aldehyde can be readily performed on gram scale under mild conditions, and a five-membered transition state is proposed to rationalize the stereochemical outcome.

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.

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.