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N -Heterocyclic Carbene-Catalyzed Generation of α,β-Unsaturated Acyl Imidazoliums: Synthesis of Dihydropyranones by their Reaction with Enolates
Abstract
(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.
... 1,2addition followed by cyclization [4,5,60]. α,β-unsaturated acylazoliums can be generated from α,β-unsaturated aldehyde with external oxidants [61][62][63][64][65][66], ynals, 2-bromo enals [67][68][69], α,β-unsaturated esters [70] or acyl fluorides [71,72], etc. (Figure 19). ...
... Lupton reported the Claisen type reaction of α,β-unsaturated enol esters to the corresponding acylazolium/enolate pair followed by rearranged to 2,3-dihydropyrozones ( Figure 21) [71,72]. The generated electrophilic acylazolium intermediates involved in various annulation and cycloaddition reaction with bis-nucleophiles. ...
Arduengo et al., isolated the first ‘bottleable’ carbene, the first N-heterocyclic carbene (NHC) 1,3-di(adamantyl)imidazol-2-ylidene resulted to an explosion of experimental and theoretical studies of novel NHCs being synthesized and analyzed have huge practical significance. These compounds emerged as successful ligands for coordinating transition metals, the complexes with NHC show diverse applications in the field of catalysis and organic transformation, NHC as ligand to main group elements and their properties and applications. Here this chapter provides the concise overview of N-heterocycle carbene as an organocatalyst that provides different organic transformation on to a carbonyl group. The majority of the NHC catalyzed reactions are employed in the phenomenon of reversing the electrophilic character of carbonyl carbon to nucleophilic carbon (umpolung activity) on coordination suggests benzoin, Stetter and hydroacylation reactions. Also, non-umpolung activity of bis-electrophile α,β-unsaturated acylazoliums reaction with suitable bis-nucleophiles in the organic synthesis have been studied.
... However, the differences between the Claisen reaction reported firstly in 1912 [80][81][82] As mentioned, one of the mechanistic fundamentals of the Claisen-type reactions is the generation of α,β-unsaturated acylazolium (Scheme 7). Formation of this intermediate is usually carried out via the reaction of NHCs with α,β-unsaturated enol esters or ethers [84][85][86], ynals [87][88][89][90], 2-bromoenals [91][92][93][94], or acyl fluorides [95,96]. Moreover, formation α,β-unsaturated acylazolium is possible via two-electron oxidation of Breslow intermediate [97][98][99][100][101][102][103]. ...
... As mentioned, one of the mechanistic fundamentals of the Claisen-type reactions is the generation of α,β-unsaturated acylazolium (Scheme 7). Formation of this intermediate is usually carried out via the reaction of NHCs with α,β-unsaturated enol esters or ethers [84][85][86], ynals [87][88][89][90], 2-bromoenals [91][92][93][94], or acyl fluorides [95,96]. Moreover, formation α,β-unsaturated acylazolium is possible via two-electron oxidation of Breslow intermediate [97][98][99][100][101][102][103]. ...
Giving reactions the names of their discoverers is an extraordinary tradition of organic chemistry. Nowadays, this phenomenon is much rarer, although already named historical reactions are still often developed. This is also true in the case of a broad branch of N-heterocyclic carbenes catalysis. NHCs allow many unique synthetic paths, including commonly known name reactions. This article aims to gather this extensive knowledge and compare historical reactions with current developed processes. Furthermore, this review is a great opportunity to highlight some of the unique applications of these procedures in the total synthesis of biologically active compounds. Hence, this concise article may also be a source of knowledge for scientists just starting their adventure with N-heterocyclic carbene chemistry.
... In 2009, the Lupton group disclosed an NHC-catalyzed coupling of α,β-unsaturated acyl fluorides with silyl enol ethers (Scheme 17). [34] In the presence of an achiral imidazolium catalyst, the reaction between acyl fluorides and trimethylsilyl enol ethers occurs, affording the desired dihydropyranones in moderate to good yields. 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). ...
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.
... [29] Carboxylate II nucleophilically attacks a carbonyl carbon of acyl fluoride III to furnish unsymmetrical carboxylic acid anhydride IV with the release of a fluoride ion (Scheme 7B, path a). As another path for generation of acid anhydride IV, acyl fluoride III reacts with PCy 3 to provide acyl phosphonium salt V [22a, [30][31][32] and subsequent nucleophilic substitution between V and II proceeds leading to acid anhydride IV (Scheme 7B, path b). Acid anhydride IV is then attacked from the fluoride ion, producing the desired acyl fluoride VI and carboxylate VII (Scheme 7C, path c). ...
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.
... To date, such species have only been prepared through multistep manipulations (Scheme 1 b) involving elimination reactions to form the vinyl ether moiety, [19] or transiently generated from stable enols or their esters under NHC catalysis (Scheme 1 c,d). [20][21][22][23][24][25] Clearly, an approach which employs simple starting materials and forges the coveted allylic vinyl acetal moiety with complete regio-and stereocontrol would greatly broaden the scope of the Coates-Claisen rearrangement. Seeking to address this problem, our interest in the strategic application of alkene isomerization [26][27][28][29] pointed us to identify allyl acetals of a,b-unsaturated aldehydes [30] as convenient precursors to the regioisomeric vinyl acetals (Scheme 1 e). ...
The [3,3]‐sigmatropic rearrangement of allylic vinyl acetals, first investigated by Coates nearly four decades ago, is set apart from other variants of the Claisen rearrangement owing to the versatile monoprotected 1,5‐dicarbonyl motif featured in the products. Unfortunately, the synthetically elusive nature of the substrates has thus far precluded the widespread application of this attractive transformation. Herein, we show that the key allylic vinyl acetals can be efficiently generated through alkene isomerization of their readily available regioisomeric counterparts (derived from allylic alcohols and α,β‐unsaturated aldehydes), thus enabling the first systematic study of the substrate scope of this rearrangement, as well as the discovery of exceptionally mild conditions for its mediation by Lewis and Brønsted acids.
... To date, such species have only been prepared through multistep manipulations (Scheme 1 b) involving elimination reactions to form the vinyl ether moiety, [19] or transiently generated from stable enols or their esters under NHC catalysis (Scheme 1 c,d). [20][21][22][23][24][25] Clearly, an approach which employs simple starting materials and forges the coveted allylic vinyl acetal moiety with complete regio-and stereocontrol would greatly broaden the scope of the Coates-Claisen rearrangement. Seeking to address this problem, our interest in the strategic application of alkene isomerization [26][27][28][29] pointed us to identify allyl acetals of a,b-unsaturated aldehydes [30] as convenient precursors to the regioisomeric vinyl acetals (Scheme 1 e). ...
The strategic use of alkene isomerization has enabled the first systematic study of the [3,3]-sigmatropic rearrangement of allylic vinyl acetals, first discovered by Coates nearly forty years ago and rarely applied since. We explore the mediation of this rearrangement by Lewis and Brønsted acids and demonstrate the synthetic utility of the products through a concise synthesis of the iridoid natural product isoneomatatabiol.
Abstract
The [3,3]-sigmatropic rearrangement of allylic vinyl acetals, first investigated by Coates nearly four decades ago, is set apart from other variants of the Claisen rearrangement owing to the versatile monoprotected 1,5-dicarbonyl motif featured in the products. Unfortunately, the synthetically elusive nature of the substrates has thus far precluded the widespread application of this attractive transformation. Herein, we show that the key allylic vinyl acetals can be efficiently generated through alkene isomerization of their readily available regioisomeric counterparts (derived from allylic alcohols and α,β-unsaturated aldehydes), thus enabling the first systematic study of the substrate scope of this rearrangement, as well as the discovery of exceptionally mild conditions for its mediation by Lewis and Brønsted acids.
We summarize in this review the recent key progresses in the NHC-catalyzed electrophilic activation of carbonyl compounds for the regioselective functionalization of saccharides, enantioselective construction of heterocycles, and asymmetric synthesis...
N-Heterocyclic carbenes (NHCs) have been used as organocatalysts for a multitude of C-C and C-heteroatom bond-forming reactions. They enable diverse modalities of activating a wide range of structurally distinct substrate classes and allow access to electronically distinct intermediates. The easy tunability of the NHC scaffold contributes to its versatility. Recent years have witnessed a surge of interest in various organocatalytic reactions of NHCs, leading to the forays of NHC catalysis into the relatively newer domains such as reactions involving radical intermediates, atroposelective synthesis, umpolung of electrophiles other than aldehydes, and the use of NHCs as non-covalent templates for enantioinduction. This tutorial review provides an overview of various important structural features and reactivity modes of NHCs and delves deep into some frontiers of NHC-organocatalysis.
The enantioselective synthesis of tricyclic oxoquinolines via NHC-catalyzed cascade reaction of enals with malonates bearing 2-aminophenyl group is reported. The chiral α,β-unsaturated acylazoliums underwent a smooth Michael-aldol-lactamization-dehydration quadruple cascade with...
A new and unprecedented stereoselective synthetic approach to δ-oxoesters derivatives from readily available starting materials has been developed. This method, catalyzed by N-heterocyclic carbene, involves an annulation–deoxalation reaction of alkynyl aldehydes with 2,4-diketoesters and proceeds via the chiral α,β-unsaturated acylazolium intermediates. The annulation includes the in situ formation of dihydropyranones, which undergo ring-opening methanolysis with Lewis acid activation, followed by deoxalation to afford chiral 1,5-ketoesters in moderate to good yields.
Both furan and 1,4‐dihydropyridine (1,4‐DHP) are key structural motifs in pharmaceuticals. Herein, we report the synthesis of 4‐(furan‐2‐ylmethyl)‐1,4‐dihydropyridines from pyridiniums and furfural derivatives under NHC catalysis. This reaction involves the generation of NHC‐bounded trienolates from furfural derivatives and following addition to the C‐4 position of N‐aryl pyridinium salts. This protocol features good yields (41–99%), and high levels of regioselectivity (>20:1 for all cases).
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.
An N-heterocyclic carbene (NHC)-catalyzed chemoselective activation reaction of 1-cyclopropylcarbaldehydes and α-alkynyl enals is reported. NHC selectively catalyzes 1-cyclopropylaldehydes, followed by a [2 + 4] cycloaddition reaction with α-alkynyl enals. The target dihydropyranone derivatives bearing different substituents and substitution patterns can be obtained in good to excellent yields with excellent enantio- and diastereoselectivities under mild conditions.
The NHC-catalyzed benzannulation of enals and β-trifluoromethylenones is developed for the synthesis of benzotrifluorides. This process involves NHC-catalyzed [4+2] annulation/lactonization/decarboxylation/oxidative aromatization cascade. The reaction features mild reaction conditions, excellent functional...
An efficient N-heterocyclic carbene (NHC)-catalyzed enantioselective [3 + 3] annulation of 2-bromoenals with 2-amino-1H-indoles has been developed. A series of functionalized 2-aryl-2,3-dihydropyrimido[1,2-a]indol-4(1H)-ones were synthesized using NHCs as the catalyst in...
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.
A direct photoredox catalyzed radical-triggered tandem cyclization of 1,7-enynes with alkyloxalyl chlorides is developed. With this approach, a variety of dihydropyranones containing all-carbon quaternary centers are prepared through alkoxycarbonylation/6-exo-dig cyclization/6-endo-trig...
After a long history of medical and biochemical investigations of vitamin B1, N-heterocyclic carbenes (NHCs) have recently been used as organocatalysts for a variety of synthetic reactions. This review article highlights the application of NHC-catalyzed reactions including enantioselective reactions to the heterocyclic synthesis. NHC-catalyzed benzoin condensation and Stetter reaction of ether- and amine-linked aldehydes give four- to six-membered oxygen and nitrogen heterocycles. NHC-catalyzed conjugate additions of enals to ketones and imines afford γ-lactones and γ-lactams. When the NHC-catalyzed reaction intermediates of enals are protonated, the reaction of the resulting enols with enones and ene-imines furnish formal hetero-Diels-Alder products. Acyl fluoride and esters can be activated by NHCs, and subsequent aldol and Michael reactions give β-lactones. Oxidation of intermediates derived from enals or the intermediates from ynals provide unsaturated acyl azolium which are transformed into cyclic products via subsequent nucleophilic reactions. NHCs also catalyze [2+2] cycloadditions of ketenes and other heterocumulenes and ring expansion of cyclic aldehydes.
The enantioselective synthesis of functionalized pyrazoloquinolin-3-ones via N-heterocyclic carbene-catalyzed cascade reaction of α-bromoenals with 2-aminoaryl N-tosyl hydrazones is reported. The in situ-generated α,β-unsaturated acylazoliums underwent an aza-Michael-Mannich-lactamization sequence to afford the tricyclic products bearing three contiguous stereocenters, including a sterically demanding quaternary stereocenter with high enantioselectivity. The unprotected amine-triggered aza-Michael pathway over the competing amidation pathway is noteworthy.
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...
The facile syntheses of multicyclic molecules through multi‐step cascade reactions with N‐Heterocyclic carbene (NHC)‐catalyzed LUMO activation strategies are summarized. The reaction mechanisms involved in these cascade catalytic transformations are also provided and discussed. The review article is arranged according to the reaction starting materials that are used for the NHC‐catalytic activation processes.
The N-heterocyclic carbene (NHC)-organocatalyzed [3 + 3] annulation of 2-bromoenals with β-oxodithioesters resulting in the enantioselective synthesis of dihydrothiopyranones is presented. The chiral α,β-unsaturated acylazoliums generated from 2-bromoenals and carbenes underwent smooth interception with the sulfur nucleophiles to furnish the sulfur heterocycles in satisfactory yields/selectivity. The regioselective formation of dihydrothiopyranones over the competing dihydropyranones is noteworthy.
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.
An N-heterocyclic carbene (NHC) organocatalyzed benzyne chlorination reaction was reported. Chlorinated solvents, usually shown to be inert, were widely used in either carbene chemistry or benzyne chemistry. However, the combination...
This chapter summarizes the new advancements of N ‐heterocyclic carbene (NHC) organocatalysis in the recent decade (roughly between 2010 and 2020). Particular focus is drawn to the basic activation and reaction modes enabled by NHC as a key catalyst. Examples of these key development include NHC‐catalyzed reactions beyond simple aldehydes to unsaturated aldehydes and functionalized aldehydes as substrates, activation of carboxylic esters for asymmetric reactions, single‐electro‐transfer radical reactions, cooperative catalysis involve NHC and other catalysts such as transition metals, and applications of NHC‐catalyzed reactions in the synthesis of sophisticated molecules.
Numerous studies on the activation of carbon–fluorine bonds have been reported in recent years. For example, acyl fluorides have been utilized as versatile reagents for acylation, arylation, and even fluorination. In this review, we focus on acyl fluorides as compounds with carbon–fluorine bonds, and highlight recent advances in strategies for the activation of their C–F bonds via transition-metal catalysis, N-heterocyclic carbene (NHCs) catalysis, organophosphine catalysis, and classical nucleophilic substitution reactions.
1 Introduction
2 Transition-Metal-Mediated C–F Bond Activation
2.1 Acylation (Carbonyl-Retentive) Coupling Reactions
2.2 Decarbonylative Reactions
2.3 C–F Bond Activation by Other Transition Metals
3 C–F Bond Activation by N-Heterocyclic Carbenes (NHCs)
3.1 NHC-Catalyzed Cycloaddition of Acyl Fluorides
3.2 NHC-Catalyzed Radical Functionalization of Acyl Fluorides
3.3 NHC-Catalyzed Nucleophilic Fluorination of (Hetero)aromatics
4 C–F Bond Activation by Phosphines
4.1 Phosphine-Catalyzed Direct Activation of the C–F Bond of Acyl Fluorides
4.2 Phosphine-Catalyzed Indirect Activation of the C–F Bond of Acyl Fluorides
5 C–F Bond Activation by Classical Nucleophilic Substitution
6 Miscellaneous Examples
7 Summary and Perspective
Herein we report the deoxygenated fluorination of readily available carboxylic acids. A series of acyl fluorides have been synthesized using shelf-stable N-trifluoromethylthiophthalimide as a fluorinated reagent for the first time....
NHC-catalyzed cascade reaction of enals with suitably substituted β-(hetero)aryl enones allowing the enantioselective synthesis of tetra-substituted tetralines and tetrahydro indolizines is presented. The catalytically generated chiral α,β-unsaturated acylazoliums from enals...
3,4-Dihydropyranone and 3,4-dihydropyridinone substructures are widely found in a variety of natural products and pharmacologically active molecules, so the efficient synthesis of chiral 3,4-dihydropyranones and 3,4-dihydropyridinones has received more and more attention from pharmaceutical chemists and organic chemists. In recent years, organocatalytic asymmetric reaction has become an efficient synthetic method for the construction of chiral heterocyclic compounds. In this review, the remarkable progress and advances in organocatalytic asymmetric reactions for the synthesis of 3,4-dihydro- pyranones and 3,4-dihydropyridinones from 2003 to 2020 are summarized and discussed based on the different types of organocatalysts and reaction mechanisms.
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.
An oxidative NHC‐catalyzed kinetic resolution (KR) of racemic mixtures is presented. The developed reaction furnishes tricyclic dihydropyranones with three contiguous stereocenters in excellent dia‐ and enantioselectivity, with good‐to‐moderate yields. Mechanistic studies indicate that the rate‐determining step of the reaction is the formation of the Breslow intermediate, while the selectivity determining step occurs later in the mechanism. The presented methodology enables rapid synthesis of complex structures in a single step.
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.
A dual catalytic chemo-selective cross-coupling reaction of two enals is developed. One enal (without α-substitution) is activated by an NHC catalyst to form an acylazolium enolate intermediate that undergoes Michael-type addition to another enal molecule bearing an alkynyl substituent. Mechanistic studies indicate that non-covalent interactions between the alkynyl enal and the NHC·HX catalyst play important roles in substrate activation and enantioselectivity control. Many of the possible side reactions are not observed. Our reaction provides highly chemo- and diastereo-selective access to chiral lactones containing functionalizable 1,3-enyn units with excellent enantioselectivities (95 to >99% ee).
The secondary amine‐catalyzed reactions proceeding via α,β‐unsaturated iminiums and the N‐heterocyclic carbene (NHC)‐catalyzed transformations taking place via α,β‐unsaturated acylazoliums are the two widely used electrophilic intermediates in organocatalysis. Over the last two decades, these two intermediates are extensively utilized for the enantioselective construction of valuable molecules. Both intermediates are generated by the covalent binding of catalysts to the substrates leading to LUMO activation of α,β‐unsaturated carbonyls. A variety of soft nucleophiles are known to add to the α,β‐unsaturated iminiums and acylazoliums in a conjugate fashion, and in many cases, striking similarity in reactivity has been observed. Having said this, there are few cases where these intermediates exhibit difference in reactivity. This Minireview is aimed at highlighting the resemblances in reactivity between α,β‐unsaturated iminiums and acylazoliums thereby shedding light on the unnoticed parallels of the two intermediates in organocatalysis.
Made for each other! Striking similarity in reactivity has been observed for organocatalytically generated α,β-unsaturated iminiums and acylazoliums towards various nucleophiles. Analogous [3+3] and [3+2] annulations, cascade reactions, and Michael additions of these highly electrophilic intermediates are highlighted in this Minireview.
Abstract
The secondary amine-catalyzed reactions proceeding via α,β-unsaturated iminiums and the N-heterocyclic carbene (NHC)-catalyzed transformations taking place via α,β-unsaturated acylazoliums are the two widely used electrophilic intermediates in organocatalysis. Over the last two decades, these two intermediates are extensively utilized for the enantioselective construction of valuable molecules. Both intermediates are generated by the covalent binding of catalysts to the substrates leading to LUMO activation of α,β-unsaturated carbonyls. A variety of soft nucleophiles are known to add to the α,β-unsaturated iminiums and acylazoliums in a conjugate fashion, and in many cases, striking similarity in reactivity has been observed. Having said this, there are few cases where these intermediates exhibit difference in reactivity. This Minireview is aimed at highlighting the resemblances in reactivity between α,β-unsaturated iminiums and acylazoliums thereby shedding light on the unnoticed parallels of the two intermediates in organocatalysis.
ConspectusThe identification of reliable, general, and high yielding methods for the formation of C(sp2)-fluorine bonds remains a major challenge for synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions of aryl chlorides or nitroarenes. Despite being known for more than a century, traditional SNAr fluorination reactions suffer from significant limitations, particularly on a process scale. These include the high cost of common reagents [e.g., cesium fluoride (CsF)], a requirement for elevated temperatures and long reaction times, poor functional group tolerance, and the need for rigorous exclusion of water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many of these challenges. This collaboration has provided a platform for fundamental scientific advances involving the development of new methods, reagents, and substrates for mild and high yielding nucleophilic fluorination reactions.Our early studies established that the combination of potassium fluoride (KF) and superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as a cost-effective alternative to CsF for the SNAr fluorination of chloropicolinate substrates. However, these reactions still require elevated temperatures (>130 °C) and afford moderate yields due to competing decomposition of the substrate and product. The need for high temperature is largely due to slow reaction rates resulting from the low concentration of the active fluorinating reagent [anhydrous tetrabutylammonium fluoride (Bu4NF)] under these conditions. To address this issue, we developed several strategies for generating high concentration solutions of anhydrous tetraalkylammonium fluoride in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) with tetraalkylammonium nucleophiles (R4NCN or R4NOR). These systems enable SNAr fluorination under unusually mild conditions, affording nearly quantitative yield with chloropicolinate substrates at room temperature. However, the high cost of the electrophiles and the generation of large quantities of byproducts in the R4NF-forming step render this approach unsuitable for process scale applications. As an alternative, we next explored anhydrous tetramethylammonium fluoride (Me4NF) for these transformations. This highly reactive fluoride source can be synthesized directly from inexpensive KF and Me4NCl and then dried by heating under vacuum. Unlike Bu4NF, it is not susceptible to Hofmann elimination. As such, anhydrous Me4NF is stable and isolable, as well as highly effective for the room temperature SNAr fluorination of chloropicolinates and other electron deficient substrates.The studies with anhydrous R4NF drew our attention to another challenge associated with traditional SNAr fluorination reactions: their limitation to substrates bearing resonance electron-withdrawing groups. We hypothesized that this challenge could be addressed by circumventing the Meisenheimer intermediate, a canonical mechanistic feature of SNAr fluorination. By designing reactions that involve an alternative concerted delivery of the fluoride to the ipso C(sp2) center, we developed a deoxyfluorination of arylfluorosulfonates using anhydrous Me4NF. This reaction exhibits a broad scope with respect to the aryl electrophile, with substrates bearing both electron-withdrawing (CN, ester, CF3, Cl) and moderately electron donating (phenyl, alkyl) substituents participating in deoxyfluorination. These deoxyfluorination conditions were also expanded to nonaromatic substrates, including aldehydes and benzylic/aliphatic alcohols.This Account concludes by delineating several ongoing challenges and opportunities in this fast-moving field. For instance, one important future direction will be to address the high moisture sensitivity of these transformations. In addition, the application of these new reagents and methods in the synthesis of pharmaceuticals, agrochemicals, and PET imaging agents will continue to test the versatility and functional group compatibility of these methods.
The unprecedented enantioselective NHC-catalyzed [3 + 3] annulation of α-bromoenals with amidines via a dual C-N bond formation is described. The protocol allows a rapid preparation of 5,6-dihydropyrimidinones in acceptable yields with good enantioselectivities.
Newly reported synthetic procedures to access pyrans and their benzo derivatives from 2007 to 2018 are summarized. The sub-chapters are organized by the structural similarity starting from pyrans, reduced, oxidized, and benzene-fused structures. Mechanistic considerations and relevant substrate scope are discussed for each transformation to help readers to access necessary information.
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.
N-heterocyclic carbene (NHC) catalyzed regiospecific β-additions of nitrogen-containing nucleophiles including nitrogenous heterocycles and trifluoromethylated acylhydrazone to alleneoates were accomplished under mild reaction conditions, harnessing NHC as a Lewis base to furnish branched N-alkyl compounds in moderate to good yields with high E/Z selectivity and broad substrate scope. DFT calculations on the possible reaction mechanisms show that β-addition pathway is more energetically favourable than γ-addition pathway, which is in agreement with the experimental observations.
A survey of catalysts able to mediate the transesterification/acylation reaction is presented. Metal and organic catalysts are capable of facilitating this important transformation.
• 1 Introduction
• 2 Transesterification Reactions Catalyzed by Lewis Acids
• 2.1 Lanthanide (Sm) Catalysis
• 2.2 Tin Catalysis
• 2.3 Indium Catalysis
• 2.4 Yttrium Catalysis
• 3 Transesterification Reactions Catalyzed by Nucleophilic Catalysts
• 3.1 Superbase-Catalyzed Transesterification of Esters with Alcohols
• 3.2 Nucleophilic N-Heterocyclic Carbene (NHC) Catalysis
• 4 Conclusions
N-Heterocyclic carbene catalyzed ring expansion of readily accessible 2-acyl-1-formylcyclopropanes was developed. With 5 mol % of triazolium salt 5 and 30 mol % of DBU, ring expansion of various 2-acyl-1-formylcyclopropanes led to 3,4-dihydro-alpha-pyrones in good to excellent yields.
A new selective synthetic method of enol esters (O-acylated products) from silyl enol ether and acid chloride in the presence of CuCl is described. This reaction proceeds smoothly in DMI (1,3-dimethyl-2-imidazolidinone) but not in a less polar solvent. The silicon-copper exchange reaction pathway is proposed for this transformation as in the cases of hydrosilane and alkynylsilane which were previously reported.
Alpha-chloroaldehyde bisulfite adducts were successfully employed in chiral NHC-catalyzed hetero-Diels-Alder reactions with various oxodienes under biphasic reaction conditions with high levels of enantioselectivity. This new protocol makes possible enantioselective additions from commercially available chloroacetaldehyde sodium bisulfite and demonstrates that this unique class of catalysts readily tolerates aqueous conditions.
N-Heterocyclic carbenes have been demonstrated to react through divergent pathways under the same conditions. Experimental and computational evidence demonstrates that the ability to favor generation of homoenolate equivalents from alpha,beta-unsaturated aldehydes versus the oxidation of aldehydes to esters is highly dependent upon the choice of solvent. The solvation environment plays an important role due to the mechanistic differences in these processes, with polar protic solvent favoring the oxidation process due to solvation of intermediates with greater charge separation.
An exceedingly sterically demanding, rigid, and chiral NHC ligand, IBiox[(-)-menthyl] (1), was prepared and structurally characterized. With a buried volume of approximately 50%, this ligand arguably represents one of the most sterically demanding monodentate ligands. The ability to use aryl chloride substrates in intramolecular palladium-catalyzed alpha-arylations reveals its unique reactivity. Moreover, C(2)-symmetric 1 allows the highly enantioselective formation of oxindoles with up to 99% ee.
The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).
Newly synthesized cinchona alkaloid-derived pyrimidines function as effective asymmetric catalysts for the Michael reaction between cyclic diketones and beta,gamma-unsaturated alpha-ketoesters. The reactions of electrophiles with either aryl or alkyl gamma-substituents give 64-99% yields and 94-99% ee.
Chiral triazolium- and imidazolium-derived N-heterocyclic carbene catalysts promote the direct annulation of alpha,beta-unsaturated aldehydes and achiral alpha-hydroxy enones to afford cyclopentane-fused lactones with high enantioselectivity. Remarkably, otherwise structurally identical imidazolium and triazolium precatalysts afford different major products. These studies provide both an efficient entry to valuable chiral structures and a dramatic demonstration of stereodivergency of chiral imidazolium versus triazolium-derived N-heterocyclic carbene catalysts.
Much of what we know about the neurosciences is the direct result of studying psychoactive natural products. Unfortunately, there are many gaps in our understanding of the basic biological processes that contribute to the etiology of many CNS disorders. The investigation of psychoactive natural products offers an excellent approach to identify novel agents to treat CNS disorders and to find new chemical tools to better elucidate their biological mechanisms. This review will detail recent progress in a program directed toward investigating psychoactive natural products with the goal of treating drug abuse by targeting kappa opioid receptors.
N-heterocyclic carbenes (NHCs) catalyze a domino Michael addition/acylation reaction to form 3,4-dihydrocoumarins. The reaction proceeds through addition of the NHC to an aryloxyaldehyde followed by elimination of a phenoxide leaving group, generating an enol intermediate. This transient nucleophile generated in situ performs a 1,4-addition onto a conjugate acceptor, and the carbene catalyst is regenerated upon acylation of the phenoxide anion resulting in formation of 3,4-dihydrocoumarins.
Homoenolate, a species containing anionic carbon beta to a carbonyl group or a moiety that can be transformed into a carbonyl group, is a potential three carbon synthon. Recent introduction of a protocol for the generation of homoenolate directly from enals by NHC (nucleophilic heterocyclic carbene) catalysis has made it possible to explore the synthetic utility of this unique reactive intermediate. The versatility of NHC-bound homoenolate is illustrated by its annulation with various carbonyl compounds leading to gamma-butyrolactones, spiro-gamma-butyrolactones, and delta-lactones. Interception of homoenolate with imines afforded gamma-lactams and bicyclic beta-lactams. Formation of cyclopentenes and spirocyclopentanones respectively by reaction with enones and dienones is also noteworthy. This tutorial review focuses on these and other types of reactions which attest to the synthetic potential of NHC-bound homoenolates in organic synthesis.
For Abstract see ChemInform Abstract in Full Text.
N-Heterocyclic carbenes, prepared in situ from diarylimidazolium salts, serve as highly effective catalysts for the generation of reactive homoenolates from alpha,beta-unsaturated aldehydes. The catalyst-bound homoenolate reacts with electrophilic aldehydes leading, via the key intermediacy of an activated carboxylate, to gamma-butyrolactones in good yields and stereoselectivities. Importantly, this process demonstrates an unprecedented reaction mode for the generation of nucleophilic carbanions with a multifunctional organocatalyst under exceptionally mild and convenient reaction conditions.
Chiral N-heterocyclic carbenes, which are derived from C2-symmetric 1,3-bis(1-arylethyl)imidazolium salts, catalyze enantioselective acylation of racemic secondary alcohols.
A metal-free, organocatalytic approach to living polymerization using N-heterocyclic carbenes as nucleophilic catalysts generated and used in situ in a single-pot process is detailed. The N-heterocyclic carbene catalyst platform is extremely versatile, as the nature of the substituents has a pronounced effect of catalyst stability and activity toward different substrates. The generation of imidazolium- and thiazaolium-based carbenes was accomplished from the reaction of the corresponding salts with the appropriate bases. This allowed the rapid screening of libraries of catalysts that provided a basic understanding of catalyst structure (sterics, electronics, etc.) with the polymerization rate, control, substrate, and range of molecular weights. The imidazole-based catalysts were significantly more active toward ROP than the thiazolium-based analogues. No appreciable differences between imidazol-2-ylidene and imidazolin-2-ylidene catalysts were observed. Less sterically demanding carbenes were found to be more active toward ring-opening polymerization (ROP) than their sterically encumbered analogues for lactone polymerization. These data prompted the investigation of ionic liquid as a precatalyst reservoir in a phase-transfer polymerization with an immiscible THF solution of monomer and initiator. In situ activation of the ionic liquid generates carbene that migrates to the organic phase effecting living ROP. Precatalyst (ionic liquid) regeneration terminates polymerization. This simple reaction/recycle protocol readily allows repetitive ROPs from the ionic liquid using commercially available materials.
N-Heterocyclic carbenes derived from benzimidazolium salts are effective catalysts for generating homoenolate species from alpha,beta-unsaturated aldehydes. These nucleophilic intermediates can be protonated, and the resulting activated carbonyl unit is trapped with an alcohol nucleophile, thereby promoting a highly efficient conversion of an alpha,beta-unsaturated aldehyde into a saturated ester. A kinetic resolution of secondary alcohols can be achieved using chiral imidazoylidene catalysts. [reaction: see text]
[reaction: see text] The reaction of dimedone with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles in THF, catalyzed by catalytic amounts of both DBFOX/Ph-nickel(II) perchlorate trihydrate and 2,2,6,6-tetramethylpiperidine, in the presence of acetic anhydride in THF produces the corresponding enol lactones in high enantioselectivities through enantioselective Michael additions followed by cyclization with removal of the pyrazole auxiliary. Other related nucleophile precursors can be successfully applied in the enantioselective enol lactone synthesis under the double catalytic conditions.
[reaction: see text] The synthetic utility of chiral N-heterocyclic carbenes, which have been used mainly in transition metal-catalyzed reactions as a ligand, was demonstrated by the enantioselective acylation of secondary alcohols.
The enantioselective addition of beta-ketoesters to unsaturated N-acylthiazolidinethiones catalyzed by Ni(II) Tol-BINAP Lewis acid complexes is reported. Notable features of this reaction are its operation simplicity, the obviated need for the addition of an external base, and the ease with which the adducts are converted into a range of potentially useful derivatives. In particular, the dihydropyrone adducts are versatile scaffolds for further stereoselective elaboration.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF.
Treatment of alpha,alpha-dichloroaldehydes with various phenols in the presence of chiral triazolium salt catalysts and excess base results in the synthesis of alpha-chloro aryl esters in good yield and enantioselectivity. The reaction is tolerant of various functionality on the aldehyde as well as several electronically diverse phenols. The product chloroesters were further transformed into chloroacid, chlorohydrin, and azidoesters with nearly complete retention of enantioselectivity.
[reaction: see text]. Nucleophilic heterocyclic carbene (NHC) catalyzed annulation of enals and cyclic 1,2-dicarbonyl compounds, opening a route to gamma-spirolactones, has been observed for the first time. The strategy works well with isatins, leading to spiroannulated oxindole derivatives. It is conceivable that the spiroannulation protocol reported herein will be applicable to the synthesis of important natural products that are endowed with a spiro gamma-butyrolactone motif, especially oxindoles and norsesquiterpenoids.
N-Heterocyclic carbenes can catalyze beta-alkylations of a range of alpha,beta-unsaturated esters, amides, and nitriles that bear pendant leaving groups to form a variety of ring sizes. In this process, the nucleophilic catalyst transiently transforms the normally electrophilic beta carbon into a nucleophilic site through an unanticipated addition-tautomerization sequence.
A planar-chiral DMAP derivative catalyzes an intriguing [3 + 2] annulation reaction of silylated indenes to produce diquinanes that bear three contiguous stereocenters (one quaternary and two tertiary).
Highly enantioselective, N-heterocyclic carbene (NHC)-catalyzed aza-Diels-Alder reactions are described. A novel chiral triazolium salt based on the cis-1,2-aminoindanol platform serves as an efficient precatalyst for the NHC-catalyzed redox generation of enolate dienophiles that undergo LUMOdiene-controlled Diels-Alder reactions with N-sulfonyl-alpha,beta-unsaturated imines in good yields and with exceptional diastereo- and enantioselectivities (>99% ee). In contrast to uncatalyzed variants, this organocatalytic process proceeds at room temperature without stoichiometric reagents, producing synthetically valuable, enantiomerically pure cis-3,4-disubstituted dihydropyridinone products.
Nucleophilic heterocyclic carbene-catalyzed cyclopentannulation of enals and chalcones via homoenolate has been observed for the first time. Serendipitously, the reaction lead to a very efficient synthesis of 3,4-trans-disubstituted-1-aryl cyclopentenes instead of the expected cyclopentanones. The strategy works well with thienylidene tetralone also, leading to the tricyclic cyclopentene derivative.
Chiral N-heterocyclic carbene (NHC) catalyzed redox reactions of racemic alpha-chloroaldehydes lead to the generation of chiral enolates suitable for highly enantioselective inverse-electron-demand 1-oxodiene Diels-Alder reactions. Significantly, these reactions proceed under mild, operationally friendly reaction conditions (EtOAc, room temperature, 2-8 h) using less than 1 mol % of a chiral N-mesityl triazolium salt as the precatalyst. A broad array of densely functionalized dihydropyran-2-ones bearing either aliphatic or aromatic substiutents are formed in excellent yields and exceptional enantioselectivities from readily available reactants. Stereochemical mismatching between the racemic starting materials and the chiral catalyst is avoided by rapid epimerization of the chloroaldehydes under the reaction conditions.
N-heterocyclic carbenes catalyze the oxidation of allylic, propargylic, and benzylic alcohols to esters with manganese(IV) oxide in excellent yields. A variety of ester derivatives can be synthesized, including protected carboxylates. This one-pot tandem oxidation represents the first organocatalytic oxidation of alcohols to esters. Saturated esters can also be accessed from aldehydes using this method. Through the utilization of a chiral catalyst, the acyl-heteroazolium intermediate becomes a chiral acylating agent, which can desymmetrize meso-1,2-diols. [reaction: see text].
Chiral N-heterocyclic carbene catalysts generated from triazolium salts promote the cyclopentene-forming annulation of alpha,beta-unsaturated aldehydes and 4-oxoenoates with excellent levels of enantioinduction and preference for the cis-1,3,4-trisubstituted cyclopentene diastereomer. Although the observed products could arise by conjugate additions of catalytically generated homoenolates, our mechanistic and stereochemical investigations strongly support a novel reaction manifold featuring an intermolecular crossed-benzoin reaction and an NHC-catalyzed oxy-Cope rearrangement.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Chiral quaternary ammonium phenoxides were readily prepared from commercially available cinchona alkaloids and proved to be useful new asymmetric organocatalysts. Among various chiral quaternary ammonium phenoxides, a cinchonidine-derived catalyst that bears both a sterically hindered N1-9-anthracenylmethyl group and a strongly electron withdrawing 9-O-3,5-bis(trifluoromethyl)benzyl group were found to be highly effective for the Michael addition of ketene silyl acetals (derived from phenyl carboxylates) and alpha,beta-unsaturated ketones followed by lactonization. Optically active 3,4-dihydropyran-2-one derivatives were obtained in high yields with excellent control of enantio- and diastereoselectivity. This catalyst can be handled in air and stored at room temperature in a sealed bottle without decomposition for at least one month.
N-Heterocyclic carbenes (NHCs) prove to be efficient catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction of cyclopent-2-en-1-one or cyclohex-2-en-1-one with a variety of N-tosylarylimines to give the aza-MBH adduct in high yields. Crossover experiments show NHC can add to N-tosylarylimines in a reversible manner, which allows the addition of NHC to cyclic enones and thus catalyzes the aza-Mortia-Baylis-Hillman reaction.
The extensive applications and reaction pathways of thiazol- (A), triazol- (B), imidazol- (C), and imidazolin-2-ylidenes (D) as versatile synthetic methods were discussed. The organocatalytic process have made synthetic strategies in addition to its facile reaction, selectivity and its being environmental friendly. The topics being described include the enzymes as archetypes, the benzoin condensation, the stetter reaction, the a3 to d3 umpolung, the transesterification reactions, the polymerization reactions, the ring-opening reactions, and finally the 1,2-additions.
A wide range of alpha,beta-unsaturated aldehydes induding 3-alkyl derivatives undergo N-heterocyclic carbene (NHC)-catalyzed annulations with N-sulfonyl ketimines under mild condition, to provide bicyclo[3.2.0]lactams with outstanding diastereo- and enantioselectivity. This concise route to beta-lactams established four new chiral centers in a single operation. Although this process could occur via the intermediacy of a catalytically generated homoenolate equivalent, the stereochemical outcome supports a tandem or concerted aza-Benzoin/oxy-Cope reaction as the key bond forming step.
The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.
A new synthetic approach to chiral imidazolium salts makes possible the first synthesis of an N-mesityl substituted, aminoindanol-derived N-heterocyclic carbene precursor, 1.ClO4. The successful synthesis allows the first direct comparison of otherwise identical imidazolium and triazolium precursors across a number of NHC-catalyzed processes. These studies confirm striking differences in reactivity and mechanism between the two classes.
A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze the intramolecular Stetter reaction with good reactivity and enantioselectivity. The substrate scope has been examined and found to be broad; both electron-rich and -poor aromatic aldehydes undergo cyclization in high yield and enantioselectivity. The tether can include oxygen, sulfur, nitrogen, and carbon linkers with no detrimental effects. In addition, the incorporation of various tethered Michael acceptors includes amides, esters, thioesters, ketones, aldehydes, and nitriles. The catalyst loading may be reduced to 3 mol % without significantly affecting the reactivity or selectivity of the reaction.
Screening of a range of azolium salts, bases and solvents for reactivity indicates that triazolinylidenes, generated in situ with KHMDS in THF, promote the Steglich rearrangement of oxazolyl carbonates with high catalytic efficiency (typical reaction time 5 min at <1.5 mol % NHC). This protocol shows wide substrate applicability, even allowing the efficient generation of vicinal quaternary centers. An improved experimental procedure is also described that allows a simplified one-pot reaction protocol to be employed with similarly high catalytic efficiency.
For a review on transesterification, see: (a)
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For a review on transesterification, see: (a) Grasa, G. A.;
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Thomson, R. J.; Francisco, F. J. Am. Chem. Soc. 2005, 127, 10816. For organocatalytic approaches not using NHCs: (c) Tozawa, T.; Nagao, H.;
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Interestingly the conjugate addition of NHCs to R,-unsaturated carbonyls are known ( (a)
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For an approach using an NHC catalyzed ring expansion For transition metal based approaches to pyranones: (a) Itoh
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For a hetero Diels-Alder approach to dihydropyranones using NHC-enols as the dieneophile, see: (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. (c) He, M. H.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817. For an approach using an NHC catalyzed ring expansion: (d) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623. (10) For transition metal based approaches to pyranones: (a) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979. (b) Evans, D. A.;
131, 8344, and references therein. (16) Absolute configuration inferred from studies with pyranone 4l and ref 10a. (17) For medicinal lactones, see: Prisinzano
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73, 2784. (12) Differing reactivity between imidazolium and triazolium NHCs: (a) Struble
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