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ChemInform Abstract: N-tert-Butyl Triazolylidenes: Catalysts for the Enantioselective [3 + 2] Annulation of α,β-Unsaturated Acyl Azoliums.
Angewandte Chemie International Edition
Abstract
But(yl) not futile: A range of N-tert-butyl-substituted triazolylidene N-heterocyclic carbenes have been prepared. Of these, the morpholinone-derived catalyst (1) proved best suited to the enantioselective synthesis of cyclopentanes from donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The performance of this catalyst has been correlated to the electronic nature of the catalyst by (13) C NMR analysis. M.S.=molecular sieves, TMS=trimethylsilyl.
... This transformation is proposed to occur through the initial reaction of an α,β-unsaturated acyl fluoride with the NHC catalyst to form acyl imidazolium chiral triazolium catalyst (NHC-1) (Scheme 18). [35] This method enables the synthesis of multi-substituted fused cyclopentanes in moderate to good yields and enantioselectivity. ...
Acyl fluorides, carbamoyl fluorides and fluoroformates have been employed as efficient reagents in a number of organic syntheses. Their application in catalytic transformations, however, began to be explored in the early 2000s. Recently, these reagents have increasingly gained attention owing to their unique reactivity in diverse catalytic systems. This review aims to overview the advancements in the development of catalytic processes, including transition‐metal catalysis, organocatalysis, and cooperative NHC/photoredox catalysis, where these organofluorine compounds are employed as acyl, carbamoyl, and ester group donors.
... In 2018, Lupton and co-workers [78] described the application of the alkene a 1 -d 1 umpolung activation strategy to the asymmetric DKR process of the racemic di-vinyl compound 157 (Scheme 31). The terminal alkene of the racemic di-vinyl compound 157 is activated by the NHC pre-catalyst 158 [79] as a nucleophile to react with the internal alkene moiety through an asymmetric conjugate addition process. The stereogenic center at the γ-position of the internal α,β-unsaturated ester moiety isomerizes to the Scheme 28 NHC-catalyzed DKR of β-stereogenic α-keto ester. ...
N-heterocyclic carbene-catalyzed enantioselective kinetic resolutions, dynamic kinetic resolutions, and desymmetrization reactions are systematically reviewed. The content is organized according to the activation modes involved in these transformations. Future advances within this highly active research field are discussed from our perspectives on the topic.
... Lupton et al. [155] demonstrated the use of unsaturated acyl fluorides 146 as α,β-unsaturated acylazolium precursors. A highly enantioselective Ireland-Coates-Claisen rearrangement of unsaturated acyl fluorides 146 with strained silylated cyclopropanes 147 was achieved, giving the functionalized bicyclic β-lactones 149 in moderate to good yields (Scheme 35). ...
Enzymes are the core for biological transformations in nature. Their structures and functions have drawn enormous attention from biologists as well as chemists since last century. The large demand of bioactive molecules and the pursuit of efficiency and greenness of synthesis have spurred the rapid development of biomimetic chemistry in the past several decades. Biomimetic asymmetric catalysis, mimicking the structures and functions of enzymes, has been recognized as one of the most promising synthetic strategies for the synthesis of valuable chiral compounds. This review summarizes the evolution of asymmetric catalysis inspired by aldolases, vitamin B1/B6-dependent enzymes, NAD(P)H, flavin, hydrogenases, heme oxygenases, non-heme oxygenases, and dinuclear/multinuclear metalloenzymes in aspects of biomimetic design, catalyst development and related catalytic transformations. Those well-established synthetic approaches originating from biological reactions have demonstrated the unique prowess of biomimetic asymmetric catalysis in bridging the gap between bio-catalysis and chemical synthesis.
Cyclopropanols have attracted significant attention in organic synthesis as versatile three-carbon synthons, as this readily available class of donor-activated cyclopropanes undergoes miscellaneous transformations, either via ring-opening or with retention of the cyclopropane ring. This review summarizes stereoselective and stereoretentive transformations suitable for asymmetric synthesis. The utility of cyclopropanols is discussed for two main strategies: (i) substrate-controlled transformations using enantiomerically enriched cyclopropanol intermediates through a traditional approach, and (ii) the use of nonchiral or racemic cyclopropanols, where asymmetric induction is achieved through a chiral catalyst, representing a direction that has recently emerged.
As a significant variant of the Michael reaction, the 1,6‐addition reaction has undergone considerable development over the past decade. This effective strategy enables the synthesis of a variety of novel and potentially bioactive functional molecules. In this review, we summarize the recent progress in NHC‐catalyzed 1,6‐addition reactions, highlighting their efficiency in the rapid synthesis of complex functional molecules. We also provide our perspectives on the future development of this dynamic and highly active research area.
Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.
Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.
The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S‐, P‐, Si‐ and B‐stereocenters over the past decades, the catalyst‐controlled strategies to govern the formation of N ‐stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen‐stereogenic compounds through a desymmetrization approach. Intriguingly, the pro‐chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene‐bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N‐oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N‐oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.
Organoseleniums exhibit a diverse set of biological activities that are pivotal for drug discovery and are widely explored in synthetic chemistry and material science. While many transformations have been developed for non-enantioselective C–Se bond formations, the catalyst-controlled stereoselective preparation of chiral organoseleniums continues to be of considerable challenge. In particular, there are limited studies on the enantioselective seleno-Michael addition reactions to access chiral selenium functional molecules. Here, we disclose a carbene-catalyzed highly enantioselective nucleophilic C–Se bond construction through formal [3 + 3] annulations between selenocarboxamides and bromoenals, affording seleno-thiazinone products with good yields and excellent enantioselectivities. The choice of a weak inorganic base was pivotal to suppressing the unproductive racemization and decomposition of the selenium products. Notably, the catalytically generated chiral selenium-containing heterocyclic products feature remarkable antimicrobial activities that could serve as promising lead scaffolds for further agrochemical development.
The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S‐, P‐, Si‐ and B‐stereocenters over the past decades, the catalyst‐controlled strategies to govern the formation of N‐stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen‐stereogenic compounds through a desymmetrization approach. Intriguingly, the pro‐chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene‐bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N‐oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N‐oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.
Напряженная структура циклопропанов служит своеобразным "спусковым крючком" для проведения самых разнообразных химических превращений. Особый интерес представляют процессы, протекающие с участием сопряженных непредельных соединений. Системы кратных связей характеризуются возможностью гибкого варьирования реакционной способности, вплоть до их полного вовлечения в трансформацию. В данном обзоре впервые рассмотрены варианты реализации идеи сочетания в рамках единой концепции энергии напряжения циклопропанов и синтетического потенциала сопряженных непредельных соединений. Представлен детальный анализ процессов с участием активированных циклопропанов и различных ненасыщенных карбо- и гетеросистем.
Библиография — 289 ссылок.
The reactivity of N‐Heterocyclic carbene (NHC)‐bound alkynyl acyl azoliums is underexplored in chemistry. We herein reported an NHC‐catalyzed [3+3] annulation of alkynyl acyl azoliums with β‐keto esters. The strategy features mild reaction conditions and exhibits broad substrates scope, delivering a wide range of tri‐substituted α‐pyrones in moderate to excellent yields (up to 95%). This approach extends the reactivity of alkynyl acyl azoliums to β‐keto esters binucleophiles.
Deuterium incorporation at selective sites of organic compounds has long attracted the interest of pharmaceutical industry. Here, we present a distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring-opening of cyclopropylbenzaldehydes...
ConspectusConjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut-Currier (RC) and Morita-Baylis-Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the β-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position.Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted β-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.
β-Lactones are common substructures in bioactive molecules. Herein, we developed an enantioselective N‑heterocyclic carbene (NHC)-catalyzed rearrangement of enol ε-lactones for the construction of bicyclic β-lactones. The reaction works well for...
In recent years, organocatalysis has seen a rapid rise in popularity and this has led to a subsequent increase in the research output of the area, with organocatalysis by N-heterocyclic carbenes (NHCs) playing a significant role. Beginning with the benzoin condensation, through the work of Breslow and others to modern, asymmetric protocols, NHC organocatalysis has a rich history, which has been covered in many reviews. The focus of this chapter is on recent advances within the area of NHC organocatalysis, offering a brief historical perspective and highlighting what the authors believe to be some of the key advances made within recent times, both in terms of novel processes and significant advancements on previously documented reactions.
Acyl fluorides show unique reactivity and stability, and the catalytic conversions using acyl fluorides as a divergent building block have recently attracted much attention and have been rapidly researched. Thus, a development of a new synthetic method of acyl fluorides is constantly demanded. Herein, we describe a phosphine‐catalyzed acyl‐group exchange reaction between carboxylic acids and an aroyl fluoride. A variety of acyl fluorides are directly obtained from carboxylic acids through a catalytic system composed of tricyclohexylphosphine (PCy3) and 2,6‐difluorobenzoyl fluoride. This report is the first example of utilizing an acyl fluoride as a deoxyfluorination reagent.
N-Heterocyclic carbenes (NHCs) containing triazolium motifs have emerged as a powerful tool in organocatalysis. Recently, various NHC-catalyst-mediated organic transformations have been developed. This review aims to compile the current state of knowledge on enantioselective NHC-triazolium-catalyzed named reactions as well as introduce newly developed catalytic methods. Furthermore, this review article framework provides an excellent opportunity to highlight some of the unique applications of these catalytic procedures in the synthesis of natural products and biologically active compounds, notably the extensive processes for the preparation of substituted chiral alcohols and their derivatives. This review also provides an overview of the synthesis of chiral NHC-triazolium-catalyst libraries and their applications in catalytic enantioselective reactions.
1 Introduction
2 Synthesis of N‑Heterocyclic Carbenes Containing Triazolium Motifs
2.1 Pyrrolidine-Based Triazoliums NHCs: Px
2.2 Morpholine-Based Triazoliums NHCs: Mx
2.3 Aminoindane-Based Triazoliums NHCs: AMx
2.4 Oxazolidine-Based Heteroazoliums NHCs: Ox
2.5. Acyclic Triazoliums NHCs: Ax
3 Enantioselective Organocatalytic Reactions
3.1 Enantioselective Benzoin Reactions
3.1.1 Aldehyde–Aldehyde Homo-Benzoin Reactions
3.1.2 Aldehyde–Aldehyde Cross-Benzoin Reactions
3.1.3 Aldehyde–Ketone Cross-Benzoin Reactions
3.1.4 Aldehyde–Imine Cross-Benzoin Reactions
3.1.5 Aza-Benzoin Reactions
3.2 Enantioselective Stetter Reactions
3.2.1 Intramolecular Stetter Reactions
3.2.2 Intermolecular Stetter Reactions
3.3 Enantioselective Diels–Alder Reactions
3.4 Enantioselective Michael Additions
3.5 Enantioselective Rauhut–Currier Reactions
3.6 Enantioselective Cycloadditions
3.7 Enantioselective Michael–Stetter Cascade Reactions
3.8 Enantioselective Annulation Reactions
3.9 Synthesis of Spiro Compounds
3.10 Heterocycle Synthesis
3.11 Carbocycle Synthesis
3.12 Asymmetric Steglich Rearrangement Reactions
3.13 NHC-Mediated Asymmetric Acylation/Hydroacylation Reactions
3.14 Enantioselective α-Fluorination of Aliphatic Aldehydes
3.15 Functionalization of Carboxylic Anhydrides by NHC Catalysis
3.16 Asymmetric β-Boration of Acyclic Enones
3.17 Synthesis of Tropane Derivatives via Organocatalysis
3.18 Dynamic Kinetic Resolution of Pyranones via NHC Catalysis
3.19 Enantioselective Umpolung Reactions
3.20 Enantioselective Esterification of Ketenes
3.21 Asymmetric Synthesis of trans-γ-Lactams
3.22 Oxy-Cope Rearrangements
3.23 Claisen Rearrangements
3.24 Enantioselective Synthesis of Complex Heterocycles
3.25 Atroposelective Synthesis of N-Aryl Succinimides
3.26 Asymmetric α-Fluorination via Cascade Reactions
4 Conclusion
Fused and spirooxetanes, oxetenes and β-lactones are important classes of compounds that have found numerous applications in various areas of chemistry including medicinal chemistry and total synthesis of natural products. In this chapter, the main achievements from the theoretical and synthetic point of views since its last edition are discussed.
The NHC‐catalysed intermolecular Stetter reaction provides direct access to 1,4‐diketones, however current NHC catalysts for this specific transformation remain underdeveloped, significantly limiting the use of this reaction in target‐oriented synthesis. Here we report a novel N‐mesityl thiazolium NHC as a high‐performing catalyst for this reaction, enabling high yields and short reaction times for a range of sterically non‐trivial aliphatic aldehydes reacting with enone substrates. Quantification of the properties of novel and known NHC organocatalysts revealed that both steric and electronic properties play an important role in the success of the new N‐mesityl thiazolium NHC for this reaction. These developments will facilitate wider application of the Stetter reaction as a key carbon‐carbon bond forming reaction for coupling of complex fragments under mild conditions.
N-heterocyclic carbene-catalyzed intramolecular aza-Michael addition of alkyl amines to α,β-unsaturated carboxylic acid has been realized. The corresponding pyrrolidine and piperidine derivatives can be obtained in good to excellent yields. Reaction using chiral NHC catalyst showed promising enantioselectivities up to 55% ee. Further chemical transformations of the products provided carboxylic acids, alcohols, and unprotected amines.
Identifying the special role of N-heterocyclic carbene (NHC) remains to be one of the most important challenges in organocatalysis field. Herein, we proposed a theoretical model for NHC-catalyzed decarboxylation reactions,...
Although breakthroughs in the N-heterocyclic carbene (NHC)catalyzed inert C−C bond activation strategy have been achieved, understanding the role of the catalyst as well as the origin of its chemo- and stereoselectivities is still one of the most challenging questions in the field of organocatalysis. Herein, we propose an NHC and NHC·H⁺ cooperative catalytic model for these kinds of reactions and perform density functional theory calculations in the case of an NHC-catalyzed [4 + 2] annulation reaction of conjugated dienal and α-aryl ketone. The calculated results indicate that the organocatalyst either works as a Lewis base to prevent the bad frontier molecular orbital overlap mode, promoting [2 + 2] cycloaddition, or as a noncovalent organocatalyst to provide a hydrogen bonding network to facilitate the release of CO2. The latter is remarkably different from its well-known role as a Lewis base. In addition, we devised an atomic electrophilicity index to correctly predict the site of the stereoselective C−C bond formation involved in [4 + 2] cycloaddition. Further analysis results show that hydrogen bonds significantly contribute to the favorable stereoselective pathway, which was associated with axial chirality of the main final product in an experiment. The obtained insights should be valuable for the prediction and rational design of organocatalytic inert C−C activations with special chemoselectivity and high stereoselectivity.
Organocatalysis represents a powerful and reliable tool in modern organic chemistry. Cyclopropanes are a versatile compound class whose reactivity exceeds that of other cyclic hydrocarbons. The organocatalytic synthesis of cyclopropanes has become an established and well-studied transformation. However, the implementation of the cyclopropyl motif into the scaffolds of organocatalysts and the activation of cyclopropanes offers potential to further combine these two areas. Here, we discuss organocatalytic cyclopropanations together with organocatalytic reactions where the cyclopropane motif is implemented either in the catalyst or the substrate to demonstrate how organocatalysis can benefit from the unique reactivity of cyclopropanes.
An approach to the α,β-unsaturated acyl azolium has been developed that exploits N-heterocyclic carbenes (NHCs) and acyl fluorides, without additional oxidants, bases, or preactivated coupling partners. These conditions have been applied in 4-classes of NHC catalyzed reaction. In all cases the expected products were produced with high yield and enantioselectivity, using two sets of closely related reaction conditions, without additional optimization
In recent years, acyl fluorides have received a great deal of attention in organic chemistry. Among carboxylic acid derivatives, acyl fluorides display a good balance between stability and reactivity due to their moderate electrophilicity. They are easily prepared from the corresponding carboxylic acids and can be used without any special precautions against moisture. In this review, we describe the recent progress of transformation with acyl fluorides: Lewis base-assisted reactions and transition-metal-catalyzed reactions. The reactions with Lewis base proceeded well to provide a variety of acyl compounds such as lactones, and ketones, etc. In addition, transition-metal-catalyzed transformation gave the corresponding acyl compounds or decarbonylative compounds such as ketones and biaryls, etc.
This review describes the development of enantioselective methods for the ring opening of cyclopropanes. Both approaches based on the reaction of nonchiral cyclopropanes and (dynamic) kinetic resolutions and asymmetric transformations of chiral substrates are presented. The review is organized according to substrate classes, starting by the more mature field of donor-acceptor cyclopropanes. Emerging methods for enantioselective ring opening of acceptor- or donor-only cyclopropanes are then presented. The last part of the review describes the ring opening of more reactive three-membered rings substituted with unsaturations with a particular focus on vinylcyclopropanes, alkylidenecyclopropanes, and vinylidenecyclopropanes. In the last two decades, the field has grown from a proof of concept stage to a broad range of methods for accessing enantioenriched building blocks, and further extensive developments can be expected in the future.
Reactions involving C–F, Si–F, and S–F bond cleavage with N-heterocyclic carbenes and isoelectronic species are reviewed. Most examples involve activation of aromatic C–F bond via an SNAr pathway and nucleophilic substitution of fluorine in electron-deficient olefins. The mechanism of the C–F bond activation depends on the reaction partners and the reaction can proceed via addition–elimination, oxidative addition (concerted or stepwise) or metathesis. The adducts formed upon substitution find applications in organic synthesis, as ligands and as stable radical precursors, but in most cases, their full potential remains unexplored.
1 Introduction
1.1 The C–F Bond
1.2 C–F Bond Activation: A Short Summary
1.3 C–F Bond Activation: A Special Case of SNAr
1.4 N-Heterocyclic Carbenes (NHCs)
1.5 The Purpose of this Article
2 C–F bond Activation in Acyl Fluorides
3 Activation of Vinylic C–F Bonds
4 Activation of Aromatic C–F Bonds
5 X–F Bond Activation (X = S or Si)
6 C–F Bond Activation by Main Group Compounds Isoelectronic with NHCs
7 Conclusions and Outlook
N-Heterocyclic carbene (NHC)-catalyzed [3 + 3] annulation of thioamides with modified enals allowing the enantioselective synthesis of functionalized 1,3-thiazin-4-ones is reported. The NHC generated from the chiral triazolium salt was optimal and the reaction is initiated by the thia-Michael addition to catalytically generated α,β-unsaturated acylazolium intermediates derived from 2-bromoenals, followed by intramolecular cyclization. This operationally simple procedure offers a straightforward and rapid access to target compounds in moderate to good yields and enantiomeric ratio values.
Bisenoate sind, vermutlich wegen ihrer geringen Elektrophilie, nur schlecht für enantioselektive Rauhut-Currier-Reaktionen geeignet. Die Verwendung nucleophiler N-heterocyclischer Carbene ermöglicht jetzt die ersten enantioselektiven Rauhut-Currier-Reaktionen dieser Verbindungen. Enantiomerenangereicherte Hydrocumarine wurden in drei Stufen aus kommerziellen Materialien zu erhalten.
Abstract
While the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high-nucleophilicity N-heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).
While the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high‐nucleophilicity N‐heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).
A simple yet highly effective approach towards enantioselective synthesis of trans-3,4-disubstituted glutarimides from readily available starting materials is developed using oxidative NHC-catalysis. The catalytic reaction involves a formal [3+3] annulation between enals and substituted malonamides enabling production of glutarimide derivatives in single chemical operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a board range of functionalized glutarimides in excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal synthesis of (-)-paroxetine and other bioactive molecules.
Enantioselective [3+4] annulation of 3-formylindol-2-methyl-malonates with 2-bromoenals catalyzed by NHCs is described to afford functionalized azepino[1,2-a]indoles in high yields with excellent enantioselectivities. This method, in which the 3-formyl group in...
The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.
The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine. Die Umpolung von Iminen ist ein wenig erforschter Bereich der enantioselektiven Katalyse. N‐heterocyclische Carbene (NHCs) wurden zur Katalyse einer enantioselektiven Aza‐Stetter‐Reaktion verwendet. Im Gegensatz zu Acyl‐Umpolung mit NHCs erfordert diese Reaktion stark nukleophile Katalysatoren. Die Reaktion ist enantioselektiv (≥96:4 er) und kann mit verschiedenartigen Iminen und 3‐Methylenchroman‐2‐onen durchgeführt werden.
Over the past decade, the α,β‐unsaturated acyl azolium(1) has been extensively examined in modern N‐heterocyclic carbene (NHC) organocatalysis. There are five general methods currently known to access the α,β‐unsaturated acyl azolium intermediates. In four of these methods, a redox approach is exploited that involves initial formation of an acyl anion intermediates. The simplest reactions of the α,β‐unsaturated acyl azolium involve bond formation at the acyl carbon to provide ester products. The α,β‐unsaturated acyl azolium could be derived from either enal or enal equivalent and was reacted with a variety of enamines to give dihydropyridinones containing various functional groups including the ester, nitro, and nitrile. Annulation of the α,β‐unsaturated acyl azoliums can also produce cyclopropanes via (2+1) annulation. In 2012, Studer and coworkers reported the NHC‐catalyzed synthesis of cyclopropyl carboxylic acid esters from enals, sulfur ylides, and alcohols.
An asymmetric assembly of naphthopyran was realized via the N-Heterocyclic Carbene (NHC)-catalyzed formal [3+3] annulation of bromoenal and β-tetralone. The key advantages of this protocol include readily availability of starting...
Asymmetric hydrogenation of sterically hindered substrates still constitutes a long-standing challenge in the area of asymmetric catalysis. Herein, an efficient palladium acetate (an inexpensive Pd salt with low toxicity) catalyzed asymmetric hydrogenation of sterically hindered N-tosylimines is realized with high catalytic activities (S/C up to 5000) and excellent enantioselectivities (ee up to 99.9%). Quantum chemical calculations suggest that uniformly high enantioselectivities are observed due to the structurally different S- and R-reaction pathways.
The first activation of saturated acid chlorides by oxidative N-heterocyclic carbene catalysis has been utilized to synthesize enantioenriched spirooxindole lactones and δ-lactones. The reaction involves the transformation of β sp3...
This Focus Review is aimed at highlighting the recent developments in the organocatalytic enantioselective methods for the synthesis of beta‐lactone derivatives. Owing to the importance of the beta‐lactones as a key heterocyclic motif present in various natural products and biologically active molecules, there are several catalytic methods for the synthesis of these compounds in enantiomerically pure form. Moreover, the inherent strain in the four‐membered ring in beta‐lactones has been utilized in a number of selective synthetic transformations, thus making beta‐lactones a versatile intermediate in organic synthesis. The organocatalytic methods employing N‐heterocyclic carbenes, cinchona alkaloids, isothioureas, DMAP derivatives, phosphines etc. allow the highly enantioselective synthesis of beta‐lactones from cheap and readily available starting materials. A concise account on the developments that occurred in this field has been presented in this Review.
NHC‐bound azolium enolate and azolium dienolate intermediates have proven to be competent reaction partners in a range of [4+2], [2+2], [2+3], and [2+2+2] cycloadditions. By choosing suitable chiral NHC as catalyst, asymmetric cycloaddition reactions could be also achieved with excellent stereoselectivities. NHC‐catalyzed cycloaddition reactions have attracted a great deal of attention because they have been becoming an important synthetic strategy for the preparation of natural products and drug‐like cyclic scaffolds. This chapter summarizes some key progress with regard to N‐heterocyclic carbene (NHC)‐catalyzed cyclization to give structurally diversified cycloadducts. Wang, Lin, and co‐workers reported the oxidative NHC‐catalyzed [4+2] cycloaddition of aldehydes and 5‐alkenyl thiazolones, giving the enantiomericallyenriched thiazolo pyrones in good yields with excellent enantioselectivities as well as diastereoselectivities. Lupton and co‐workers reported the NHC‐catalyzed [4+2] cycloaddition of silyl dienol ethers and α,β‐unsaturated acid fluorides, giving 1,3‐cyclohexadienes in good yields with excellent diastereoselectivities.
Organocatalytic domino processes have become a rapidly growing area of research. N-heterocyclic carbenes (NHCs) have emerged as powerful organocatalysts for various transformations and continue to have widespread application. In the last decade, domino reactions catalyzed by NHCs have seen significant progress since the different activation modes could be successfully combined in one process. The most attractive features of these domino sequences include the readily available catalysts and substrates, the simple operational procedures, and the rapid assembly of complex molecular scaffolds with excellent levels of stereocontrol under mild reaction conditions. This review covers the advances in NHC-catalyzed domino reactions by focusing on the reaction scope, limitations, and mechanism with a close attention to the features of the reaction substrates.
The highly stereoselective intermolecular all-carbon [4+2] annulation between in situ generated acyclic dienolates and α,β-unsaturated acyl azoliums is disclosed. The identification of 2-acyloxy-3-butenones as suitable diene precursors is key to the success of this transformation. The corresponding highly functionalized cyclohexene products, which are inaccessible from Diels-Alder reactions, were delivered with high levels of diastereo- and enantioselectivities. A series of further transformations based on the product showed the potential of this reaction.
Enantioselective organocatalysis by N-heterocyclic carbenes (NHCs) has emerged as a powerful strategy to construct complex chiral molecules. Recent enantioselective NHC-catalyzed reactions have remarkable advances, involving dis-tinct activation intermediates. Which mainly include Breslow intermediate, homoenolate intermediate, α,β-unsaturated acyla-zolium, azolium enolate, and azolium dienolate, generated by the nucleophilic addition of NHC to aldehydes. Meanwhile, NHC-catalyzed reactions through non-covalent bonding interactions have also been developed. Principally, this review focuses on recent advances in enantioselective NHC catalysis.
An efficient N-heterocyclic carbene (NHC)-catalyzed asymmetric [3 + 4] annulation reaction of N-Ts hydrazones with 2-bromoenals has been developed. A series of functionalized tetrahydro-1H-1,2-diazepines with two consecutive stereocenters was obtained using NHCs as the catalyst in good yields with excellent diastereo- and enantioselectivities.
The origin of stereoselectivity of NHC-catalyzed annulation reactions of ynals and stable enols was studied with Density Functional Theory. The data suggest that the C-C bond formation is the stereo-determining step. Only the deprotonated pathway (containing an oxy anion and overall neutral species) was found to give rise to discrimination of the competing stereoisomers. This is due predominantly to electrostatic repulsion of the β-stabilizing enolate functionality with the π-cloud of the aryl group in the NHC-catalyst.
4,4a,9,9a‐Tetrahydro‐1‐oxa‐4‐azafluoren‐3‐one
(1 R , 2 S )‐(+)‐ cis ‐!‐Amino‐indol
2‐Pentafluorophenyl‐6,10b‐dihydro‐4 H ,5a H ‐5‐oxa‐3,10c‐diaza‐2azoniacyclopenta[ c ]fluorene;tetraborate
Trimethyloxonium tetrafluoroborate
Pentafluorophenyhydrazine
Höher, schneller, weiter! Eine neu entwickelte Familie von elektronenreichen 2,6-Dimethoxyphenyl-substituierten NHCs katalysiert die diastereo- und enantioselektive Titelreaktion, die strukturell wertvolle Acylcyclopropanen liefert. Erste kinetische Untersuchungen zeigen die Überlegenheit der neuen Katalysatoren über bisher bekannte NHCs in dieser anspruchsvollen Reaktion.
Katalytische Umwandlungen mit N-heterocyclischen Carbenen (NHCs) haben sich als effiziente Ansätze zum Aufbau komplexer Moleküle erwiesen. Seit der Veröffentlichung von Stetter 1975 zur Totalsynthese von cis-Jasmon und Dihydrojasmon durch Carbenkatalyse hat sich die Anwendung von NHCs in der Totalsynthese, insbesondere in den letzten zehn Jahren, schnell verbreitet. Dieser Aufschwung ist zweifellos die Folge neuerer Entwicklungen bei NHC-katalysierten Reaktionen, einschließlich der neuen Benzoin-, Stetter-, Homoenolat- und Aroylierungsprozesse. Die Umwandlungen ermöglichen ebenso typische wie auf Umpolung beruhende Bindungsbildungen und sind bereits als Schlüsselschritte in mehreren neuen Totalsynthesen aufgetreten. Dieser Kurzaufsatz beschreibt diese neuen Arbeiten und zeigt die verstärkten Einsatzmöglichkeiten der Carbenkatalyse in der Totalsynthese auf.
Oxidative Carbenkatalyse kehrt über zwei aufeinanderfolgende Umpolungsreaktionen die Reaktivität der β-Position in α,β-ungesättigten Aldehyden um: von der typischen elektrophilen zur nukleophilen und wieder zur elektrophilen. Die redoxaktivierten Michael-Akzeptoren sind in β-Position reaktiver als die Aldehyde. Mit β-Dicarbonylverbindungen entstehen unter milden Bedingungen Dihydropyranone in guten bis exzellenten Ausbeuten.
Während sich die organokatalytischen Dominoreaktionen (auch Organokaskadenkatalysen genannt) im letzten Jahrzehnt zu einem wichtigen Hilfsmittel in der Synthesechemie entwickelt haben, fand die Anwendung von N-heterocyclischen Carbenen (NHCs) als Katalysatoren in Dominoreaktionen erst in den letzten drei Jahren zunehmend Beachtung. Unter Berücksichtigung der besonderen Aktivierungsmodi der Substrate durch die NHC-Katalysatoren ist eine Unterscheidung zwischen einer einzelnen chemischen Transformation und einer sequenziellen Eintopfreaktion schwierig. Das Ziel dieses Kurzaufsatzes besteht darin, die Domino-, Kaskaden- und Tandemkatalyse in Gegenwart von NHC-Katalysatoren kritisch zu betrachten und jüngste Publikationen auf diesem Gebiet vorzustellen.
1,4 aber nicht 1,2! Die Reaktivität von 1 gegenüber verschiedenen Nukleophilen (deprotonierte β‐Diketone, Enamine und Malonodinitril) wurde durch NMR‐Spektroskopie und kinetische Experimente untersucht. Die Ergebnisse belegen, dass die C‐C‐Bindungsknüpfung über eine Michael‐1,4‐Addition erfolgt und nicht über eine 1,2‐Addition mit nachfolgender [3,3]‐sigmatroper Umlagerung. Außerdem wird die erste Kristallstruktur eines α,β‐ungesättigten Acylazoliumions 1 vorgestellt.
Neue Hydroacylierungs‐Katalysatoren: Die Verwendung von elektronenreichen N‐heterocyclischen Carbenen ermöglicht die intermolekulare Hydroacylierung von ungespannten Olefinen. Diese bisher beispiellose organokatalytische Kupplung verknüpft einfache und universelle Aldehyde und Styrole, um so wertvolle Keton‐Produkte zu erhalten. EWG=elektronenziehende Gruppe, EDG=elektronenschiebende Gruppe.
The in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to a range of substituted benzaldehydes is probed. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen–deuterium exchange (kex) at C(α) of these intermediates for a range of N-aryl triazolinylidenes is reported. These combined studies give insight into the preference of N-pentafluorophenyl NHCs to participate in benzoin and Stetter reaction processes.
The first example of Brønsted/Lewis base cascade catalysis using an N-heterocyclic carbene has been realised through the rearrangement of cyclopropylesters to dihydropyranones. The scope and mechanism of this transformation has been examined implicating a novel NHC-mediated electrocyclic cyclopropanerearrangement followed by an anionic oxy Claisen-rearrangement.
Chiral bicyclic 1,2,4-triazolium salts having a defined face of the heterocyclic ring hindered have been synthesised and they catalyse the benzoin condensation in good yield; the enantiomeric excesses obtained (up to 80%) are much better than with closely related thiazolium salts and the opposite enantiomer of benzoin predominates.
Using the chiral triazolium salt 1 as catalyst, a novel asymmetric variant of the benzoin reaction is reported. For the first time, the scope of the method is extended to a broader range of aromatic aldehydes 2, affording the acyloins 3a–h in yields of 22–72% and enantiomeric excesses up to 86%.
Stable to 150 °C, the heterocyclic carbene 1 is characterized by the typical reactivity of a nucleophilic carbene. Dihydrotriazole 1 can be prepared by simple thermal decomposition of its methanol adduct. X-ray crystal structure analysis, ab initio calculations, and reactivity studies confirm the nucleophilic carbene character of 1.
Die in großer Vielfalt zur Verfügung stehenden 2-(Trialkylsiloxy)cyclopropancarbonsäuremethylester C1–C31 werden unter sehr milden Bedingungen und in hohen Ausbeuten in die 4-Oxoalkansäure-methylester D1–D31 übergeführt, die als Synthesebausteine von Bedeutung sind. Es können auch empfindliche Ester mit Formyl-, Vinylketon- oder Trimethylsiloxyfunktion dargestellt werden. Der regioselektiven Synthese von C entsprechend kann man gezielt isomere 4-Oxoalkansäureester D aufbauen. Die alkylierende Ringöffnung in Gegenwart eines Elektrophils führt zu 2-substituierten 4-Oxoalkansäureestern, deren Alkylierungsgrad allerdings 60% nicht übersteigt. Weitere Spaltungsvarianten, die im Eintopfverfahren andere 4-Oxoalkansäurederivate liefern, werden mitgeteilt.Ring Opening Reactions of Methyl 2-Siloxycyclopropanecarboxylates to 4-Oxoalkanoic Acid DerivativesA great variety of methyl 2-(trialkylsiloxy)cyclopropanecarboxylates C1–C31 are cleaved under very mild condition and with excellent yields providing 4-oxoalkanoic esters D1–D31 Which are important synthetic building blocks. Even sensible esters with formyl, vinyl ketone, or trimethylsiloxy functions can be prepared. Corresponding to the regioselective synthesis of C isomeric pairs of D Can deliberately be constructed. In the presence of an electrophile alkylating ring opening delivers 4-oxoalkanoates substituted in position 2, however, the degree of alkylation does not exceed 60%. Several other cleavage variations allow syntheses of other 4-oxoalkanoic acid derivatives in effective one-pot procedures.
The majority of N-heterocyclic carbene catalyzed reactions of α-functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design.
α-Amino ketones, which are versatile building blocks for organic synthesis, were obtained with the title reaction. A free hydroxy group on the NHC catalyst was found to be crucial for the reaction, and the possible competing reaction through a homoenolate or enolate was not observed with this catalyst.
N-heterocyclic carbenes are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions - those utilizing α-reducible aldehydes to access previously unexplored catalytic intermediates - has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.
Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.
New hydroacylation catalysts: Highly electron-rich N-heterocyclic carbenes (NHCs) facilitate the intermolecular hydroacylation of unstrained olefins. This unprecedented organocatalytic coupling joins simple and abundant aldehydes and styrenes to yield valuable ketone products. EWG=electron-withdrawing group, EDG=electron-donating group.
The NHC-catalyzed Claisen rearrangement of hybrid Ireland Coates structures has been achieved allowing (3 + 2) annulation between donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The reaction proceeds with high diastereoselectivity (>20:1) affording a diverse range of β-lactone fused cyclopentanes. Mechanistic studies are detailed.
N-Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter's report in 1975 of the total synthesis of cis-jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC-catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.
Die Quantifizierung und Variation der charakteristischen Eigenschaften von Ligandenklassen ist ein spannendes und lohnenswertes Forschungsgebiet. N-heterocyclische Carbene (NHCs) sind dabei wegen ihres Elektronenreichtums und ihrer Struktur von besonderem Interesse. Deshalb haben NHCs weite Verbreitung als Liganden in der Übergangsmetallkatalyse und der Organometallchemie sowie auch direkt in der Organokatalyse gefunden. Hier wird ein Überblick über die physikochemischen Daten (Elektronik, Sterik, Bindung) von NHCs gegeben, die für das Design, die Anwendung und das mechanistische Verständnis dieser Verbindungen in der Katalyse nützlich sind.
A family of enantiopure 1,2,4-triazolium salts were prepared starting from the inexpensive (S)-pyroglutamic acid. After treatment with base, the corresponding N-heterocyclic carbenes were tested as organocatalysts in the asymmetric benzoin condensation and gave good yields and up to 95% ee.
The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered ambiguous both the origins of selectivity and the reaction pathway. Here, we show that a concerted, but highly asynchronous, Diels-Alder reaction occurs rather than the stepwise Michael-type or Claisen-type pathways. In addition, two crucial interactions are identified that enable high selectivity: an oxyanion-steering mechanism and a CH-π interaction. The calculations accurately predict the enantioselectivity of a number of N-heterocyclic carbene catalysts in the hetero-Diels-Alder reaction.
A series of chiral N-heterocyclic carbenes (NHCs), derived from L-pyrogutamic acid, were found to be efficient catalysts for the asymmetric dimerization of alkylarylketenes to give the corresponding α-quaternary β-alkylidenyl-β-lactones in good yields with up to 97% ee. A chiral NHC with a proximal hydroxy group is superior in comparison with the corresponding NHC with its hydroxy group protected.
Cross-coupling reactions are among the most widely utilized methods for C-C bond formation; however, the requirement of preactivated starting materials still presents a major limitation. Methods that take direct advantage of the inherent reactivity of the C-H bond offer an efficient alternative to these methods, negating the requirement for substrate preactivation. In this process, two chemically distinct activation events culminate in the formation of the desired C-C bond with loss of H(2) as the only byproduct. Herein we report the catalytic asymmetric α-acylation of tertiary amines with aldehydes facilitated by the combination of chiral N-heterocyclic carbene catalysis and photoredox catalysis.
1,4 but not 1,2! The reactivity of 1 towards different nucleophiles (deprotonated β-diketones, enamines, and malonodinitrile) was investigated by NMR and kinetic experiments. These investigations proved that CC bond formation occurs by a Michael-type 1,4-addition and not by a 1,2-addition and subsequent [3,3]-sigmatropic rearrangement. The first X-ray structure of an α,β-unsaturated acyl azolium salt (1) is also presented.
A combination of a chiral N-heterocyclic carbene catalyst and α,β-unsaturated aldehyde leads to a catalytically generated α,β-unsaturated acyl azolium, which participates in a highly enantioselective annulation to give dihydropyranone products. This full account of our investigations into the scope and mechanism of this reaction reveals the critical role of both the type and substitution pattern of the chiral triazolium precatalyst in inducing and controlling the stereochemistry. In an effort to explain why stable enols such as naphthol, kojic acid, and dicarbonyl are uniquely efficient, we have postulated that this annulation occurs via a Coates-Claisen rearrangement that invokes the formation of a hemiacetal prior to a sigmatropic rearrangement. Detailed kinetic investigations of the catalytic annulation are consistent with this mechanistic postulate.
The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
The N-heterocyclic carbene catalyzed (4 + 2) cycloaddition between α,β-unsaturated acid fluorides and TMS dienol ethers provides cyclohexene fused β-lactone intermediates stable below -20 °C. These can be intercepted reductively or with organolithium reagents to produce diastereomerically pure cyclohexenes (>20:1 dr) with up to four contiguous stereocenters. The mechanism has been investigated using theoretical calculations and by examining secondary kinetic isotope effects. Together these studies implicate the formation of a diastereomerically pure β-lactone intermediate by a stepwise (4 + 2) cycloaddition involving Michael addition, aldol cyclization, and lactonization.
While organocatalyzed domino reactions or "organocascade catalysis" developed into an important tool in synthetic chemistry during the past decade, the utility of N-heterocyclic carbenes (NHCs) as catalysts in domino reactions has only received growing attention in the past three years. Taking into account the unique activation modes of the substrates by NHC catalysts, it is often difficult to distinguish between a single chemical transformation and a sequential one-pot transformation. Therefore, herein we present a critical consideration of domino, cascade, and tandem catalysis in the case of NHC catalysts and highlight recent publications in this area.
Faster, higher, stronger! The N-heterocyclic carbene (NHC) catalyzed diastereo- and enantioselective hydroacylation of cyclopropenes affords structurally valuable acylcyclopropanes. A new family of electron-rich, 2,6-dimethoxyphenyl-substituted NHCs induces excellent reactivity and enantioselectivity. Preliminary kinetic studies unambiguously demonstrated the superiority of this family of catalysts over known NHCs in this challenging transformation.
NHC catalysed rearrangement of α,β-unsaturated enol esters derived from formyl acetates and cyclopentyl annulated α,β-unsaturated acids provides the cyclopentapyranone core of (-)-7-deoxyloganin (1) with diastereo- and chemoselectivity in 6 steps starting from (-)-citronellal. The elaboration to the natural product has been investigated using two new approaches. The most successful intercepts our previous work on (-)-7-deoxyloganin (1) allowing completion of a formal total synthesis in 10-steps.
The use of β,γ-unsaturated-α-ketoesters in the intermolecular Stetter reaction furnishes 1,2,5-tricarbonyl compounds in high yield and excellent enantioselectivity. The α,δ-diketoesters generated using this methodology serve as useful synthetic building blocks via chemo- and diastereoselective transformations.
Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon β to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,β-unsaturated aldehydes via N-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.
Herein we report the first all-carbon N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition. The reaction proceeds with α,β-unsaturated acid fluorides and silyl dienol ethers and produces 1,3-cyclohexadienes with complete diastereocontrol (dr >20:1) while demonstrating a new type of reaction cascade exploiting α,β-unsaturated acyl azoliums.
Caught in the act: Acyl azoliums have long been thought to be key reactive intermediates in N-heterocyclic carbene catalysis, but they have never been observed under catalytic conditions. Now, this has been successfully achieved by the characterization of α,β-unsaturated acyl azoliums (see scheme) using different spectroscopic techniques. Kinetic studies revealed the origin of their unexpected chemoselectivity in acylation and annulation reactions.
A library of chiral triazolium salts has been prepared by late-state diversification of a triazolium amine salt. By utilizing a primary amine as a functional handle, a single triazolium salt can be transformed into a variety of chiral N-heterocyclic carbene precatalysts. This approach makes the preparation of chiral N-heterocyclic carbenes possible by a single-step modification of a triazolium salt, rather than the usual need for multistep organic synthesis and challenging heterocycle formation for each member of a catalyst library. We have screened these catalysts for control of diastereo- and enantioselectivity in a γ-lactam-forming reaction between α,β-unsaturated aldehydes and cyclic ketimines.
Enals react with various 1,3-dicarbonyl compounds as redox-activated Michael acceptors in the presence of TAZ as NHC precursor and a bisphenol derived quinone TBQ as the organic oxidant to produce dihydropyranones.
Choose the right cat.: A highly enantioselective synthesis of oxazolin-4-ones by the formal [3+2]-cycloaddition of ketenes and a racemic oxaziridines has been developed (see scheme; cat.=N-heterocyclic carbenes for disubstituted ketenes or cinchona alkaloids for monosubstituted ketenes, Ts=4-toluenesulfonyl).
Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [4+2] cycloaddition reaction of alkyl(aryl)ketenes and 3-alkylenyloxindoles to give the corresponding 3,4-dihydropyrano[2,3-b]indol-2-ones in excellent yields with good diastereo- and enantioselectivities.
Quantification and variation of characteristic properties of different ligand classes is an exciting and rewarding research field. N-Heterocyclic carbenes (NHCs) are of special interest since their electron richness and structure provide a unique class of ligands and organocatalysts. Consequently, they have found widespread application as ligands in transition-metal catalysis and organometallic chemistry, and as organocatalysts in their own right. Herein we provide an overview on physicochemical data (electronics, sterics, bond strength) of NHCs that are essential for the design, application, and mechanistic understanding of NHCs in catalysis.
In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step. This catalytic system was applied to the synthesis of enantioenriched kojic acid derivatives, a reaction of demonstrated synthetic utility for which other methods for catalytic enantioselective Claisen rearrangements have not provided a satisfactory solution.
(Chemical Equation Presented) Catalytic generation of α,β- unsaturated acyl imidazolium cations and enolates has been achieved, and their involvement in a Michael addition acylation sequence exploited, to provide a range of dihydropyranones. α,β-Unsaturated enol esters, or α,β-unsaturated acid fluorides in association with TMS enol ethers, serve as appropriate substrates for this reaction. The transformation can also be achieved enantioselectively using catalysts derived from chiral triazolium salts.
The special issue of Chemical Reviews highlighted the use of 13C NMR spectroscopy as an analytical tool for investigating and characterizing Arduengo-type carbenes and their derivatives. The 13C NMR for the most commonly used symmetric substituted diaminocarbenes and their corresponding azolium salts were used to demonstrate the efficiency of 13C NMR spectroscopy as an analytical tool. It was demonstrated that the chemical shift of a given 13C depended on the orientation of the electronic distribution relative to the applied magnetic field in the solid-state. It was also demonstrated that the molecules were rapidly tumbling on the NMR time scale leading to all potential molecular orientations in the magnetic field in solution.
An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used. The products may be further elaborated to provide synthetically useful intermediates.
The asymmetric intermolecular Stetter reaction is catalyzed by a novel triazolium salt derived N-heterocyclic carbene leading to 1,4-diketones in moderate to excellent yields (49-98%) and moderate to good enantioselectivities (56-78% ee), which could be enhanced by one recrystallization to excellent levels (90-99% ee).