No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
ChemInform Abstract: N-Heterocyclic Carbene-Catalyzed [4 + 2] Cycloaddition/Decarboxylation of Silyl Dienol Ethers with α,β-Unsaturated Acid Fluorides.
Abstract
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.
... [19] Therefore, the addition of HOBT in our reaction system was believed to help release the chrial NHC catalyst in the lactam formation step, which led to the promotion on the yield of the (R p ,S)-5 a and the enhancement of the reaction stereoselectivity. Other potential precursors of the α-styrenyl acylazolium intermediate we tested, such as the α-bromocinnamaldehyde (2 b), [20] the β-phenylacetylenic carbaldehyde (2 c) [21] and the cinnamic acid fluoride (2 d), [22] were not effective for this KR process. ...
An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N‐heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio‐ and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.
... undergoes a reaction with acyl azolium 154 to give Michael adduct 157. Successive aldol reaction followed by β-lactonization yields 158, which is finally decarboxylated to cyclohexadiene 159 [74] (Scheme 38). A similar reaction of silyl enol ether 160 affords β-lactone 161, which can be converted to the corresponding diol 162 by LiAlH 4 reduction [75]. ...
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.
... In 2011, Lupton and co-workers [26] reported an NHC-catalyzed all-carbon [4 + 2] cycloaddition (Figure 24a). The reaction proceeds with a range of α,β-unsaturated fluorides 109 and silyl dienol ethers 110, providing 1,3-cyclohexadienes 111 in good yields with excellent diastereoselectivity. ...
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.
... In 2011, Lupton's group reported the first NHC-catalyzed [4 + 2] cycloaddition reaction using α,β-unsaturated acid fluorides 1 and silyl dienol ethers 2 to generate 1,3-cyclohexadienes with complete diastereocontrol 7 (Scheme 2). [17] Despite being a non-benzannulation reaction, this report is a seminal achievement in the field of NHC-catalyzed annulation reactions due to an intriguing mechanistic pathway involved in the method. In the proposed mechanism, a lactone intermediate 6 forms during the catalytic turnover step, which after decarboxylation generates the desired diene product 7. ...
Aromatic compounds are ubiquitous in pharmaceutical agents and other functional materials. Therefore, synthetic methods to construct highly functionalized aromatic frameworks have attracted considerable attention, especially when utilizing acyclic precursors instead of pre‐existing benzenoid cores. A plethora of methods exist in the literature for the construction of substituted aromatic products by using transition metal catalysis and base‐promoted benzannulation reactions starting from acyclic precursors. In recent years, organocatalytic approaches such as N‐heterocyclic carbene catalysis have emerged as effective tools for the efficient and regioselective construction of highly functionalized aryl rings under metal‐free and mild reaction conditions. The fundamental objective of this minireview is to highlight the synthetic potential of NHC‐catalyzed benzannulations for the generation of aromatic rings with complex substitution patterns and to discuss these reactions from the perspective of their mechanistic design.
... lenes. [14] In 2014, Chi et al. developed the NHC-catalyzed benzene formation via [3+3] annulation of b-methyl enals with enones. [15] Subsequently, they disclosed NHC-catalyzed [4+2] annulation of dienals and 1,3-diketones for the synthesis of benzene ring. ...
Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N‐heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra‐ortho‐substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC‐catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzyl‐benzothiophene/benzofuran‐3‐carbaldehydes through a [2+4] annulation, decarboxylation, and oxidative aromatization cascade with central‐to‐axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran‐fused biaryls in high enantioselectivities and works well for the synthesis of tetra‐ortho‐substituted biaryls.
... This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 40983-41003 | 40995 cyclohexadienes with complete diastereocontrol. 57 In the next nine years, various useful NHC-catalyzed [4 + 2] strategies have been developed for constructing highly functionalized arene molecules. ...
Polysubstituted arenes serve as ubiquitous structural cores of aromatic compounds with significant applications in chemistry, biological science, and materials science. Among all the synthetic approaches toward these highly functionalized arenes, organocatalytic benzannulation represents one of the most efficient and versatile transformations in the assembly of structurally diverse arene architectures under mild conditions with exceptional chemo-, regio- or stereoselectivities. Thus, the development of new benzannulation reactions through organocatalysis has attracted much attention in the past ten years. This review systemically presents recent advances in the organocatalytic benzannulation strategies, categorized as follows: (1) Brønsted acid-catalysis, (2) secondary amine catalysis, (3) primary amine catalysis, (4) tertiary amine catalysis, (5) tertiary phosphine catalysis, and (6) N-heterocyclic carbene catalysis. Each part is further classified into several types according to the number of carbon atoms contributed by different synthons participating in the cyclization reaction. The reaction mechanisms involved in different benzannulation strategies were highlighted.
... In this context, normal order cycloadditions (cycloaddition that involves <6π-electron components) have been investigated in NHC catalysis in terms of in situ generated active enolate 13,14 or dienolate intermediates 15 (Fig. 1a). These pioneer works include [2 + 2] [16][17][18][19][20] , [2 + 3] [21][22][23] , [2 + 4] [24][25][26][27][28][29] , [4 + 2] [30][31][32][33][34][35] , etc. 36,37 . In 2008, Zhang et al. 18 and Duguet et al. 16 simultaneously realized an NHC-catalyzed [2 + 2] cycloaddition of enolates with imines, yielding versatile chiral βlactams. ...
Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.
... In 2011, Lupton and colleagues reported the first all-carbon NHC-catalyzed [4 + 2] cycloaddition between silyl dienol ethers of type 401 and α,β-unsaturated acid fluorides 402 to produce racemic 1,3cyclodienes 403 (Scheme 110, eq 1), in moderate to excellent yields and with complete diastereocontrol. 289 The NHC catalyst B32 furnished acyl azolium intermediates 402′, by nucleophilic substitution of the acyl fluorides, that reacted as Michael acceptors 290 with the dienolates 401′. The Michael addition followed by an intramolecular aldol reaction furnishes the [4 + 2] cycloadducts 401′′, that release the NHC catalyst following lactonization reaction. ...
The principle of vinylogy states that the electronic effects of a functional group in a molecule are possibly transmitted to a distal position through interposed conjugated multiple bonds. As an emblematic case, the nucleophilic character of a π-extended enolate-type chain system may be relayed from the legitimate α-site to the vinylogous γ, ε, ..., ω remote carbon sites along the chain, provided that suitable HOMO-raising strategies are adopted to transform the unsaturated pronucleophilic precursors into the reactive polyenolate species. On the other hand, when "unnatural" carbonyl ipso-sites are activated as nucleophiles (umpolung), vinylogation extends the nucleophilic character to "unnatural" β, δ, ... remote sites. Merging the principle of vinylogy with activation modalities and concepts such as iminium ion/enamine organocatalysis, NHC-organocatalysis, cooperative organo/metal catalysis, bifunctional organocatalysis, dicyanoalkylidene activation, and organocascade reactions represents an impressive step forward for all vinylogous transformations. This review article celebrates this evolutionary progress, by collecting, comparing, and critically describing the achievements made over the nine year period 2010-2018, in the generation of vinylogous enolate-type donor substrates and their use in chemical synthesis.
A variety of structurally diverse spirocyclohexane oxindoles featuring a quaternary carbon centre have been successfully constructed through an N‐heterocyclic carbene‐catalyzed [4+2] annulation of isatin‐derived enals with α‐cyano‐β‐methylenones. This domino process exhibits a wide substrate tolerance, operates under mild conditions, and yields products with high enantioselectivities.
The mechanism, chemoselectivity and stereoselectivity in the NHC-catalyzed reaction between enals and pyrroles for the synthesis of 5,6-dihydroindolizine were studied using DFT calculations. The cycle for catalytic generation of 5,6-dihydroindolizine proceeds via seven steps: (1) addition of the NHC to enal, (2) formation of a Breslow intermediate through [1,2]-proton transfer, (3) oxidation, (4) Michael addition, (5) [2+2] cycloaddition, (6) liberation of NHCs and (7) decarboxylation. Our results show that the presence of DMAP·H+ lowers the barrier for [1,2]-proton transfer. In addition, NHC·H+ plays a key role in decarboxylation. Michael addition which involves the formation of a new C-C bond was identified to be the chemo- and stereoselectivity-determining step, leading to the experimentally observed 5S,6R-dihydroindolizine. Analysis of the noncovalent interactions revealed that the observed stereoselectivity is attributed to the differential weak interactions (CH⋯π, LP⋯π and CH⋯CH) involved in the transition states during the Michael addition step. The computational results not only rationalize experimental observations but also provide some useful information for the future design of new catalytic processes.
An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N‐heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio‐ and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.
To disclose the reaction mechanism and selectivity in the NHC-catalyzed reaction of 2-bromoenal and 6-methyluracil-5-carbaldehyde, a systematic computational study has been performed. According to DFT computations, the catalytic cycle is divided into eight elementary steps: nucleophilic attack of the NHC on 2-bromoenal, 1,2-proton transfer, C-Br bond dissociation, 1,3-proton transfer, addition to 6-methyluracil-5-carbaldehyde, [2 + 2] cycloaddition, NHC dissociation, and decarboxylation. The Bronsted acid DABCO·H+ plays a crucial role in proton transfer and decarboxylation steps. The addition to 6-methyluracil-5-carbaldehyde determines both chemoselectivity and stereoselectivity, leading to R-configured carbocycle-fused uracil, in agreement with experimental results. NCI analysis indicates that the CH···N, CH···π, and LP···π interactions should be the key factor for determining the stereoselectivity. ELF analysis shows the main role of the NHC in promoting C-Br bond dissociation. The mechanistic insights obtained in the present work may guide the rational design of potential NHC catalysts.
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...
Over the recent decades, due to the special electronic characteristics and diverse reactivities, N-heterocyclic carbene (NHC) has received significant interest in organocatalyzed reactions. The formation of Breslow intermediates by NHC can convert into acyl anion equivalent, enolates, homoenolate, acyl azolium, and vinyl enolate etc., and the cycloaddition reactions of these species has attracted lots of attention. In this review, we focus on the summry of the development of NHC-activation of carbonyl carbon (or imine carbon) in situ, α-, β-, γ-, and beyond, and the cycloaddition reaction of these species.
Herein, a general strategy for chemo‐ and regioselective 1,2‐reduction of chromium‐bound arenes was developed, thus providing rapid access to 1,3‐cyclohexadienes. Selective arene activation via π‐complexation along with the use of mild hydride Ph3SiH can overcome the inherently low reactivity of arene π‐bonds while tolerating various reduction‐sensitive functional groups. Its versatility further enables a regiodivergent deuteration. Using different sequences of (non)deuterated hydride and acid reagents, the deuterated positions as well as the degrees of deuterium incorporation can be controlled precisely, which leads to a large and previously inaccessible chemical space for 1,3‐cyclohexadiene isotopologues. A reasonable mechanism was proposed based on intermediate capture and control experiments. The synthetic value of this selective 1,2‐reduction was demonstrated in the formal total synthesis of (±)‐galanthamine and (±)‐lycoramine.
Herein, a general strategy for chemo‐ and regioselective 1,2‐reduction of chromium‐bound arenes was developed, thus providing rapid access to 1,3‐cyclohexadienes. Selective arene activation via π‐complexation along with the use of mild hydride Ph3SiH can overcome the inherently low reactivity of arene π‐bonds while tolerating various reduction‐sensitive functional groups. Its versatility further enables a regiodivergent deuteration. Using different sequences of (non)deuterated hydride and acid reagents, the deuterated positions as well as the degrees of deuterium incorporation can be controlled precisely, which leads to a large and previously inaccessible chemical space for 1,3‐cyclohexadiene isotopologues. A reasonable mechanism was proposed based on intermediate capture and control experiments. The synthetic value of this selective 1,2‐reduction was demonstrated in the formal total synthesis of (±)‐galanthamine and (±)‐lycoramine.
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.
An unprecedented organocatalytic asymmetric construction of novel six-membered carbocycle fused uracils has been demonstrated by the reaction of the remotely enolizable 6-methyluracil-5-carbaldehydes with 2-bromoenals. The reaction involves an N-heterocyclic carbene-catalyzed formal [4 + 2] annulation of o-quinodimethane (oQDM) dienolates with α,β-unsaturated acylazoliums, followed by a cascade lactone formation/decarboxylation process. This protocol unlocks a new platform to access enantioenriched carbocycle-fused uracils.
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....
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.
The possible mechanism and origin of stereoselectivity of the NHC-catalyzed [3+4] annulation reaction between an enal and 5-alkenyl thiazolone leading to ε-lactone have been investigated using the density functional theory...
The N‐heterocyclic carbene catalyzed enantioselective de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzylbenzothiophene/benzofuran‐3‐carbaldehydes has been developed. This cascade process comprises a [2+4] annulation, decarboxylation, and oxidative aromatization with central‐to‐axial chirality conversion, allowing rapid access to atropoisomeric tri‐ and tetra‐ortho‐substituted biaryls with high enantioselectivities.
Abstract
Axially chiral biaryl scaffolds are prevalent in natural products, chiral ligands, and organocatalysts. However, N‐heterocyclic carbene (NHC) catalyzed de novo construction of an aromatic ring with concomitant axial chirality induction for the synthesis of biaryl atropisomers is far less developed, and the efficient synthesis of axially chiral tetra‐ortho‐substituted biaryls remains an unsolved problem under NHC catalysis. Reported here is an NHC‐catalyzed de novo synthesis of axially chiral benzothiophene/benzofuran‐fused biaryls from enals and 2‐benzyl‐benzothiophene/benzofuran‐3‐carbaldehydes through a [2+4] annulation, decarboxylation, and oxidative aromatization cascade with central‐to‐axial chirality conversion. The developed method provides efficient and general access to novel axially chiral benzothiophene/benzofuran‐fused biaryls in high enantioselectivities and works well for the synthesis of tetra‐ortho‐substituted biaryls.
N-Heterocyclic carbene-catalyzed asymmetric construction of cyclopentenones using enals and α-diketones is achieved, furnishing a series of highly functionalized cyclopentenones in a highly diastereo- and enantioselective manner. The protocol tolerates substrates with both aromatic and aliphatic groups, and further transformations of the products delivered a range of value-added molecules.
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.
Density functional theory (DFT) calculations (M062X) have been employed to disclose the mechanisms, regio- and stereo-selectivities of the N-heterocyclic carbene (NHC)-catalyzed reaction of 2-benzothiazolimines and α-chloroaldehydes. The preferred mechanism is initiated by nucleophilic attack of the NHC on α-chloroaldehyde (first step), followed by 1,2-proton transfer assisted by the Brønsted acid DABCO·H+ generates the Breslow intermediate (second step). The cleavage of C-Cl bond (third step) and deprotonation (fourth step) forms the enolate intermediate. It further reacts with 2-benzothiazolimine which leads to a new C-C bond (fifth step). Subsequent cyclization takes place via forming a new C-N bond (sixth step). The catalyst regeneration completes the whole catalytic cycle and affords the final product (seventh step). DFT results indicate that the fifth step determines the stereochemistry of the reaction and leads to benzothiazolopyrimidinone with the configuration SS, which agrees well with experimental observations. The regioselectivity-determining step is found to be the intramolecular cyclization, for which the [4 + 2] annulation pathway is more preferred than that via [2 + 2] annulation, again agrees well with experimental observations. Based on the mechanism proposed, the origins of regio- and stereoselectivities have also been investigated by performing distortion/interaction, natural bond orbital (NBO) and non-covalent interaction (NCI) analyses. The mechanistic insights gained in this work should be helpful in rational design of potential catalysts for analogous reactions.
A practical approach is introduced for the rapid determination of 13C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of tert-butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional intermolecular 13C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental 13C KIEs are determined using an intramolecular KIE approach. This rapid methodology for KIE determination requires substantially less material and time compared to traditional approaches. Details of the Buchwald-Hartwig amination mechanism are investigated under varying synthetic conditions, namely a variety of halides and bases. The enantioselectivity-determining step of the l-proline catalyzed aldol reaction is also evaluated using this approach. We expect this mechanistic methodology to gain traction among synthetic chemists as a practical technique to rapidly obtain high-resolution information regarding the transition structure of synthetically relevant reactions under catalytic conditions.
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
The higher-order cycloadditions are powerful strategies for construction of polycycles in one step, however an efficient and concise version for asymmetric induce is limited. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and will be an ideal choice for enantioselective higher-order cycloadditions. Here we report an enantioselective [10+2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory (DFT) calculations provided an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.
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.
The first computational study on the mechanisms and stereoselectivities of the reaction between benzaldehyde and butadienoate generating E-4-oxo-2-butenoate catalyzed by N-heterocyclic carbene (NHC) has been carried out using density functional theory (DFT) calculations. We have located and compared several possible pathways, which allows us to determine the most preferred mechanism. We found that the most preferred mechanism consists six key steps, i.e. the addition of catalyst to the benzaldehyde (Step I), intramolecular 1,2- proton transfer affording the Breslow intermediate (Step II), carbon−carbon bond formation in which the Breslow intermediate adds to the butadienoate (Step III), the protonation of the γ-carbon (Step IV), the deprotonation of the hydroxyl group (Step V) and elimination of the catalyst (Step VI). The solvent chloroform (CHCl3) plays a vital role in the 1,2-proton transfer, protonation and deprotonation. The carbon−carbon bond formation step determines the stereoselectivity of the reaction, and the E-isomer is the predominant product, which agrees well with the experimental results. In addition, we performed non-covalent interaction analysis, and found that the transition state that responsible for generating the major product E-4-oxo-2-butenoate was stabilized by a number of weak interactions such as CH···π, OH···π and π···π interactions. The mechanistic picture presented here would be useful in designing new NHC-catalyzed reactions 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
A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers.
An enantioselective functionalization of the indole NH group is developed. The reaction stereo-selectivity is controlled by an N-heterocyclic carbene catalyst that adds to an aldehyde moiety at the C7-carbon of indole. The NH group participated in the carbene-catalyzed reaction is part of the heteroaromatic rings of the indole substrate. Our reactions afford multi-cyclic products bearing pyrroloquinazoline or oxazinoindole scaffolds widely presented in bioactive molecules. Our study shall encourage further exploration of carbene-catalyzed reactions of aromatic molecules and asymmetric transformation of heteroatoms in various functional molecules.
Disclosed herein is a new catalytic approach for an efficient access to cyclic β‐amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ‐carbon atoms of α,β‐unsaturated imines to enals by iminium organic catalysis. This highly chemo‐ and stereo‐selective reaction affords cyclic β‐amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.
Disclosed here is a new catalytic approach for a most efficient access to cyclic β‐amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ‐carbon atoms of α,β‐unsaturated imines to enals via iminium organic catalysis. This highly chemo‐ and stereo‐selective reaction affords cyclic β‐amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.
A chiral N-heterocyclic carbene (NHC)-catalyzed [4 + 2] annulation of γ-chloroenals and α-arylidene pyrazolinones was developed in the absence of expensive oxidants. The reaction proceeds smoothly via a vinyl enolate intermediate to afford spirocyclohexane pyrazolones in moderate to good yield (up to 86%) with high diastereoselectivities (up to 15:1 dr) and excellent enantioselectivities (up to >99% ee).
Organocatalyzed asymmetric Friedel–Craft reactions have enabled the rapid construction of chiral molecules with highly enantioselectivity enriching the toolbox of chemists for producing complex substances. Here, we report N-heterocyclic carbene-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation with α,β-unsaturated acyl azolium as the key intermediate, affording a large variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The reaction mechanism is also investigated, and the reaction products can be easily converted to highly functionalized indole frameworks with different core structures.
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).
Zwei C-C-Bindungen bilden sich zwischen drei konjugierten Akzeptoren durch NHC-katalysierte Polaritätsinversion α,β-ungesättigter Ketone und Ester. Inter- und intramolekulare (5+1)-Anellierungen sind möglich, wobei eine ungewöhnliche Vinyldianionsynthon-Strategie genutzt wird. Die Reaktion erlaubt den Zugang zu mono- und bicyclischen Cyclohexanonen. Mechanistische Studien und Derivatisierungen werden ebenfalls berichtet. EWG=elektronenziehende Gruppe, NHC=N-heterocyclisches Carben.
Abstract
Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which β-unsubstituted conjugate acceptors undergo homoenolate formation and C−C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, β-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.
Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N‐heterocyclic carbene (NHC) catalyzed reactions, in which β‐unsubstituted conjugate acceptors undergo homoenolate formation and C−C bond formation twice, have been developed. Specifically, the all‐carbon (5+1) annulations give a range of mono‐ and bicyclic cyclohexanones (31 examples). In the first family of annulations, β‐unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.
The Diels-Alder reaction, which forms a six-membered ring from an alkene (dienophile) and a 1,3-diene, is synthetically very useful for construction of cyclic products with high regio- and stereoselectivity under mild conditions. It has been applied to the synthesis of complex pharmaceutical and biologically active compounds. Although evidence on natural Diels-Alderases has been accumulated in the biosynthesis of secondary metabolites, there has been no report on the structural details of the natural Diels-Alderases. The function and catalytic mechanism of the natural Diels-Alderase are of great interest owing to the diversity of molecular skeletons in natural Diels-Alder adducts. Here we present the 1.70 A resolution crystal structure of the natural Diels-Alderase, fungal macrophomate synthase (MPS), in complex with pyruvate. The active site of the enzyme is large and hydrophobic, contributing amino acid residues that can hydrogen-bond to the substrate 2-pyrone. These data provide information on the catalytic mechanism of MPS, and suggest that the reaction proceeds via a large-scale structural reorganization of the product.
Facial selectivity in the Diels-Alder reactions of 1,3-cyclopentadienes substituted at C-5 by a variety of simple alkyl groups has been assessed with a number of dienophiles. The results are consistent with an explanation based on steric hindrance. Syn addition is more favored with sterically less demanding dienophiles. Diene 6, which is substituted at C-5 with methoxymethyl, shows a remarkable preference for syn addition with less encumbered dienophiles. This may indicate a conformational difference in its syn transition state relative to the transition states for addition syn to methyl, ethyl, or n-butyl substituants (dienes 1, 4, and 5). Dienophiles are more reluctant to add syn to the larger C-5 group with 1,2,3,4,5-pentamethyl-1,3-cyclopentadiene (2) and derivatives (3, and 7) and conformational effects become very important when C-5 bears two alkyl groups, as in dienes 3 and 7.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
A graphical abstract is available for this content
Facial selectivity in the Diels-Alder reactions of 1,3-cyclopentadienes substituted at C-5 by a variety of simple alkyl groups has been assessed with a number of dienophiles. The results are consistent with an explanation based on steric hindrance. Syn addition is more favored with sterically less demanding dienophiles. Diene 6, which is substituted at C-5 with methoxymethyl, shows a remarkable preference for syn addition with less encumbered dienophiles. This may indicate a conformational difference in its syn transition state relative to the transition states for addition syn to methyl, ethyl, or n-butyl substituents (dienes 1, 4, and 5). Dienophiles are more reluctant to add syn to the larger C-5 group with 1,2,3,4,5-pentamethyl-1,3-cyclopentadiene (2) and derivatives (3, and 7) and conformational effects become very important when C-5 bears two alkyl groups, as in dienes 3 and 7.
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.
The viability of the 1,6-electrocyclic route to 1,3-cyclohexadienes has been significantly increased by using a phenylsulfonyl substituent in a multi-purpose (≥3) role.
A variety of dienophiles was used to assess the facial selectivity of Diels−Alder reactions in a series of 1,3-cyclopentadiene derivatives (1−3, 6−10) in which chlorine, bromine, and iodine were plane-nonsymmetric atoms pitted against hydrogen or methyl at C-5. The results were rationalized in terms of the major factor controlling the facial selectivity being related to steric hindrance between the diene and the dienophile. Selectivity did not correlate with reactivity. Facial selectivity in the reactions with 4-phenyl-1,2,4-triazoline-3,5-dione as the dienophile was also influenced by a second significant factor, postulated to be filled-orbital repulsion with the halogen substituent.
Kinetic isotope effects were determined for the chlorotrimethylsilane-mediated reactions of cyclohexenone with lithium dibutylcuprate in tetrahydrofuran and with lithium butyl(tert-butylethynyl)cuprate in ether. For the reaction in tetrahydrofuran, the observation of a significant carbonyl oxygen isotope effect (16k/17k = 1.018−1.019) and small olefinic carbon isotope effects (12k/13k = 1.003−1.008) is consistent with rate-limiting silylation of an intermediate π-complex. Theoretically predicted isotope effects for model reactions support this conclusion. Rate-limiting silylation is also supported by relative reactivity studies of chlorotrimethylsilane versus chlorodimethylphenylsilane. The absence of a significant butyl-group carbon isotope effect on product formation indicates that the cuprate butyl groups are nonequivalent in the intermediate leading to the product-determining step. In diethyl ether the isotope effects revert to values similar to those found previously in reactions of cyclohexenone with lithium dibutylcuprate in the absence of chlorotrimethylsilane, consistent with no change in the overall mechanism in this solvent. A mechanistic hypothesis for the differing effects of TMSCl with changes in solvent and substrate is presented.
The concise, total syntheses of the indole alkaloids (±)-reserpine (1) and (±)-α-yohimbine (4) have been completed by the application of a general strategy that features an intramolecular Diels-Alder reaction for the facile construction of the functionalized hydroisoquinoline ring system that comprises the essential D/E ring subunit of the target natural products. Thus, thermolysis of the trienic amide 23, which was readily assembled in six steps from propargyl alcohol, delivered the cycloadduct 24. Subsequent elaboration of 24 into the key intermediate 32, which bears all five of the contiguous stereogenic centers present in the E ring of reserpine required only four additional steps. Refunctionalization of the D/E ring subunit 32 provided the secondary amine 48, which was converted into (±)-reserpine (1) by sequential alkylation with 6-methoxytryptophyl bromide followed by mercuric ion induced, oxidative cyclization. The unsaturated lactam 30, which was an intermediate in the total synthesis of reserpine (1), also served as a precursor to the related indole alkaloid (±)-α-yohimbine (4). In the event, 30 was converted by a straightforward sequence of reactions into the bicyclic amine 60, which was subjected to catalytic hydrogenation and hydrogenolysis to afford the secondary amine 61. Coupling of 61 with tryptophyl bromide and subsequent oxidative cyclization under standard conditions afforded (±)-α-yohimbine (4). Efforts to employ the amine 60 as an intermediate in a synthesis of the novel alkaloid (±)-19,20-dehydro-α-yohimbine (5) were unsuccessful.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The N-heterocyclic carbene-catalyzed reaction of alkynyl aldehydes with 1,3-keto esters or 1,3-diketones has been studied. This protocol offers an entirely new, mild and atom-economical access to highly functionalized 3,4-dihydropyranones.
Suitable dienes, covalently connected to a Lewis acid, such as 1-dimethylaluminum dienolates, undergo very rapid and selective Diels-Alder cycloadditions with various dienophiles. For these processes, a cooperativity between enthalpic (dienophile activation) and entropic (reactants preassociation) factors is thought to be responsible for the high reactivities and regio/stereo-selectivities observed.
A conceptionally novel 1,3-asymmetric induction has been established. It controls the relative and absolute configuration of up to 5 stereocenters. They emerge from the anionic Diels-Alder reactions ("Deslongchamps annulations") between oxocyclohexenecarboxylates 25, 29 and dienolates 26, 30. The latter contain a gamma-lactone. A Ph3Si-CH2 substituent therein controls the asymmetry of C-C bond formation with ds approximate to 10:1. Strangely, the preferred sense of attack of the dienophile is contrasteric. Cycloadduct 31 was processed by an unprecedented fluoride-induced ambient-temperature tandem fragmentation. It turned the lactone moiety into an allyl group and the beta-oxo (trimethylsilyl) ethyl ester into a ketone. (C) Wiley-VCH Verlag GmbH & Co.
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.
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 diastereoselective 6π-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote asymmetric induction is described. This new asymmetric manifold for pericyclic ring closure further underscores the significance of the allenamide chemistry.
A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.
Cycloaddition of 3-carbomethoxy-2H-pyran-2-one to a vinylated sugar followed by the loss of bridging CO(2) from the cycloadduct affords a cyclohexadiene which can be manipulated to a carbasugar-sugar pseudodisaccharide.
The catalytic generation of chiral ester enolate equivalents from α,β-unsaturated aldehydes with chiral N-hetereocyclic carbene catalysts makes possible highly enantioselective hetero-Diels-Alder reactions. The reactions proceed under simple, mild conditions with both aliphatic and aromatic substituted enals as substrates. Previous attempts to employ these starting materials as enolate precursors gave structurally different products via catalytically generated homoenolate equivalents. Critical to the success of the enolate generation was the strength of the catalytic base used to generate the active N-heterocyclic carbene catalyst. To complement these studies, we have investigated the enolate structure using computational methods and find that it prefers conformations perpendicular to the triazolium core.
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.
The diastereoselective N-heterocyclic carbene (NHC) catalyzed rearrangement of α,β-unsaturated enol ester (S)-2b has been used to assemble dihydropyranone (S)-3b, a material embodying the bicyclic core of the iridoid family of natural products. Elaboration of this intermediate, by chemoselective reduction followed by stereoselective β-glycosylation, has allowed the total synthesis of (-)-7-deoxyloganin (1) to be achieved in four subsequent steps.
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.
Intermolecular [2+2+2] cycloaddition of tert-butylacetylene with alpha,omega-dienes was successfully achieved by NbCl(3)(DME) catalyst to afford 5-omega-alkenyl-1,4-disubstituted-1,3-cyclohexadienes in excellent yields with high chemo- and regioselectivity.
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.
A general strategy for the catalytic asymmetric syntheses of the bakkenolides is reported. The key bond-forming step involves an N-heterocyclic carbene catalyzed desymmetrization of a 1,3-diketone to form three new bonds in one step with excellent enantio- and diastereoselectivity. This intramolecular reaction allows direct access to the hydrindane core of the bakkenolide family and enables a facile synthesis of these natural products.
Asymmetric hydration of alpha,alpha-dichloro aldehydes and alpha-halo enals via a NHC-catalyzed redox process to yield enantioenriched alpha-chloro and alpha-fluoro carboxylic acids is described herein. The developed reaction allows for installation of an alpha-deuterium to give rise to enantioenriched alpha-deutero alpha-halo acids using D(2)O as the deuteron source.
Not just one but two carbenes of the same structure act cooperatively in oxidative acylations of alcohols with aldehydes by using a readily available cheap organic oxidant. Alcohols are selectively acylated in the presence of amines by cooperative carbene catalysis. Quantum chemical calculations support the suggested mechanism.
This tutorial review presents some recent examples of intramolecular Diels-Alder (IMDA) reactions as key complexity-generating steps in the total synthesis of structurally intricate natural products. The opportunities afforded by transannular (TADA) versions of the IMDA reaction in complex molecule assembly are also highlighted. The review is aimed at a wide audience, ranging from advanced undergraduates to seasoned practitioners of total synthesis; since this is an educational overview, only selected highlights from the period 2000-2009 are presented, along with chosen references to other, more comprehensive, reviews.
(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 Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.
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.
A new bifunctional catalyst, chiral amino-indanol 1a, containing both Brønsted base and hydrogen bonding donor moieties, has been identified. It is easily prepared in a single step from commercially available amino-indanol. It was found to be an excellent catalyst for Diels-Alder reactions of both 3-hydroxy-2-pyridone and 3-hydroxy-2-pyrone. Various dienophiles including N-substituted maleimides were investigated. The Diels-Alder adducts were obtained in excellent yields and high enantioselectivities.
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.
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.
Enantioselectivity switch: A catalytic enantioselective [4+2] cycloaddition reaction of alkylarylketenes with N‐aryl‐N′‐benzoyldiazenes or N,N′‐dibenzoyldiazenes to give 1,3,4‐oxadiazin‐6‐ones 1 was developed by employing N‐heterocyclic carbene (NHC) catalysts. The enantioselectivities could be switched for most reactions by changing the substituents on the NHC catalyst. TBS=tert‐butyldimethylsilyl, Mes=2,4,6‐trimethylphenyl.
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.
Irradiation of pyran-2-ones bearing pendent furans in aqueous MeOH followed by heating furnished fused bicyclic products containing a cyclooctatriene ring.
The chiral N-hetrocyclic carbenes (NHC)-catalyzed formal [4+2] cycloaddition of ketones with enones to give δ-lactones was reported. The results show that reaction at 0°C leads to better enantioselectivity and yield, while at -10°C result in slightly better enantioselectivity with lesser yield. It is also noted that the diasterometric ratios and enantiometric excess is improved by a single recrystallization from hexane/2-propanol 9:1. The cis-isomer of δ-lactones could be obtained with high diasteroselectivity and enantioselectivity by the in situ deprotonation-protonation after the NHC-catalyzed cycloaddition. The NHC-catalyzed [4+2] cycloaddition of ketones are possibly initiated by the nucleophilic addition of NHC to ketenes to give triazolium enolates.
The viability of the 1,6-electrocyclic route to 1,3-cyclohexadienes has been significantly increased by using a phenylsulfonyl substituent in a multi-purpose (≥3) role.
The catalytic generation of activated carboxylates from epoxyaldehydes enables the direct, stereoselective synthesis of beta-hydroxyesters under mild, convenient reaction conditions. In addition to providing a new method for the synthesis of anti-aldol adducts, this chemistry unveils a mechanistically viable solution to the catalytic, waste-free synthesis of esters.
Certain dienynes give cyclorearrangement by tandem cyclopropanation/ring-closing alkene metathesis, triggered by either a ruthenium carbene or noncarbene ruthenium(II) precatalyst. The process represents a variation of enyne metathesis where presumed cyclopropyl carbene intermediates undergo a consecutive ring-closing metathesis. A mechanistic proposal is offered, and sequential use of catalysts provided a tandem ring-closing enyne/alkene metathesis product.
Reactivity umpolung allows us to consider nontraditional bond disconnections. We report herein that treatment of an alpha-haloaldehyde with a nucleophile in the presence of catalytic amounts of nucleophilic carbenes results in an internal redox reaction giving rise to a dehalogenated acylating agent as an intermediate by a new reaction manifold. A brief illustration of the scope of this reaction is presented along with evidence supporting the direct intervention of the carbene in the acylation step.
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.
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]
In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the pi system of a carbon-carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing "extended" dienol ethers derived from gamma-enolizable alpha,beta-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.