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ChemInform Abstract: Chemoselective N-Heterocyclic Carbene-Catalyzed Cross-Benzoin Reactions: Importance of the Fused Ring in Triazolium Salts.
Abstract
Morpholinone and piperidinone-derived triazolium salts are shown to catalyze highly chemoselective cross-benzoin reactions between aliphatic and aromatic aldehydes. The reaction scope includes ortho, meta, and para substituted benzaldehyde derivatives with a range of electron donating and withdrawing groups, as well as branched and unbranched aliphatic aldehydes. Catalytic loadings as low as 5 mol % give excellent yields in these reactions (up to 99%).
... [19,20] Furthermore, the stereoselective control of the reaction is still unsatisfactory because the products facile undergo enolization and retrobenzoin under basic environments. [21,22] Thus, the development of new methods for accessing enantioenriched α-oxygenated alkyl ketones is desirable. ...
... A wide variety of functional groups could be compatible in this catalytic system, such as ethers (7 and 11), thioethers (8), esters (9), silyl ethers (10), alkyl halides (12 and 13), terminal alkenes (14), internal alkenes (15), alkynes (17), and phthalamides (18). Moreover, RAEs bearing aromatic ring moieties, such as phenyl and naphthyl groups, were also suitable substrates (20)(21)(22). Notably, this protocol enables the synthesis of α-benzoxy aliphatic ketones featuring two subtly differentiated alkyl substituents with high enantioselectivity (19 and 37-38). Under the same conditions, the protecting group on the hydroxy group could be also varied with no significant reduction in both yield and enantiopurity (23)(24)(25)(26)(27). Next, we evaluated the use of various alkyl carboxylic acids as acyl donors for the coupling reaction. ...
Light‐driven decarboxylative cross‐coupling has emerged as a pivotal platform for constructing C(sp³)–C(sp²) bonds in organic synthesis and medicinal chemistry. However, using two structurally dissimilar carboxylic acids as a feedstock to form chiral α‐oxygenated ketones remains a considerable challenge due to side reactions such as decarboxylative reduction and homocoupling. Herein, we report for the first time a photoredox/nickel dual‐catalyzed enantioselective decarboxylative acylation of α‐hydroxy acid derivatives and aliphatic carboxylic acids, enabling efficient access to enantioenriched α‐oxygenated ketones. This method exhibits a broad substrate scope, good functional group tolerance, high chemoselectivity, and excellent enantioselectivity (up to 99% e.e.). The advantage of this reaction is that it eliminates the need for metal reductants and the use of precious metal photocatalysts and utilizes renewable feedstocks. The use of a coiled‐tube continuous‐flow photoreactor can shorten the illumination time by half and obtain results comparable to those of a batch reaction. Furthermore, preliminary mechanistic experiments support a pathway in which photocatalytic decarboxylation generates α‐oxy alkyl radical species, and the Ni(I)–alkyl intermediate activates the in situ–formed mixed anhydride followed by reductive elimination to give the product in enantiomerically pure form.
... 图式 35 氮杂环卡宾催化[4＋3]环加成合成七元杂环化合物 Scheme 35 Synthesis of seven-membered heterocyclic compounds by NHC-catalyzed [4＋3] cycloaddition5 羰基 ε-碳的极性反转(a 6 -d 6 )氮杂环卡宾不仅能够催化羰基 α-位、β-位、γ-位碳 的反应极性发生反转, 也能够催化羰基 ε-位碳的反应极 性发生反转. 反应中, 醛类底物和氮杂环卡宾结合转化 可以形成 azolium trienolate 中间体, 此中间体使得羰基 ε-碳 具 有 亲 核 性 ( 即 a 6 -d6 ), 同 时 羰 基 碳 具 有 亲 电 性 (Scheme 36). Azolium trienolate 中间体可以和酮、 亚胺发 生加成反应. ...
... One is the chemoselective coupling of aliphatic and aromatic aldehydes in the presence of thiazolderived NHC catalyst studied by Stetter, [8] and the other is the first highly chemoselective cross-benzoin reaction between aromatic and aromatic aldehydes utilizing morpholinone and piperidinone-derived triazolium precatalysts by Gravel. [9] Subsequently, additional cross-benzoin reactions have continued to emerge in this field. ...
N‐Heterocyclic carbenes (NHCs) catalysts have been employed as effective tools in the development of various reactions, which have made notable contributions in developing diverse reaction modes and generating significant functionalized molecules. This review provides an overview of the recent advancements in the chemo‐ and regioselective activation of different aldehydes using NHCs, categorized into five parts based on the different activation modes. A brief conclusion and outlook is provided to stimulate the development of novel activation modes for accessing functional molecules.
... Since then, numerous research groups have reported variations of the pyrrolidine-based triazolium salt and their significant synthetic applications (Figure 1). [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] The benzoin coupling reaction has been widely investigated in the field of NHC-mediated organocatalysis. Using cyanide (NaCN, KCN) as a readily available, inexpensive catalyst, Wöhler and Liebig first identified this reaction in 1832. ...
A library of functionalized pyrrolidine‐based triazolium salts containing a BF4 counterions have been prepared from readily accessible 2‐pyrolidinone via one‐pot reaction protocol. By separating imine‐ether intermediates, a detailed mechanistic pathway has been investigated. Studied mechanistic investigation improved the synthetic process, resulting in higher yields for pyrrolidine‐based triazolium NHC structures and the large‐scale synthesis of chiral NHCs pre‐catalyst with free OH‐group. The presence of a hydroxyl functional group on the NHCs has the potential for further functionalization and for non‐covalent control over catalytic reactions in which the NHCs can serve as organocatalysts or donor ligands for organometallic catalysis. This benzoin catalytic system was investigated by testing different solvents and aldehydes, NHC‐catalysts loading and time variation effects to prepare a broad range of functionalized benzoin compounds with high yields. The highly reactive pyrrolidine‐based triazolium salts (TACF5) showed significant potential application of organocatalysts in benzoin condensation‐oxidation. EDG and EWG substituted α‐hydroxy ketone derivatives were directly converted to corresponding benzil scaffolds from an aldehyde through one‐pot reaction condition with MnO2 acting as an oxidating reagent in open‐air atmosphere. Selective heterocycles, quinoxaline, imidazole and pyrazine precursor were achieved from simple benzil under green conditions.
... Much attention have been placed to modulate the steric interactions between the catalysts and substrates to achieve selective controls (Fig. 1a) [6][7][8][9] . N-heterocyclic carbene (NHC) catalysts [10][11][12][13][14] provide unique activation and reaction modes for a diverse set of reactions, and impressive reactions with selectivity modulated mostly by steric interactions have been widely studied [15][16][17][18][19] . Furthermore, it is well explored that the Breslow intermediates can be oxidated by various oxidants [20][21][22][23][24][25][26][27][28][29][30][31] . ...
A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in excellent selectivity. A main challenge in this reaction is chemoselective reaction of the two aldehyde moieties in the enedial substrates. Mechanistic studies via experiments suggest that our chemoselectivity controls are mostly achieved on the reducing properties of different sited Breslow intermediates. Several side reactions processes and the corresponding side adducts are also studied by high resolution mass spectroscopy analysis. Our method allows for efficient assembly of the furo[2,3-b]pyrrole structural moieties and their analogues widely found in natural products and pharmaceuticals.
... Using morpholinone-and piperidinone-derived triazolium precatalysts, cross-benzoin condensation of aliphatic and aromatic aldehydes can occur chemoselectively and efficiently. In 2014, Michel Gravel and colleagues [69] reported that using a load of just 54 at 5 mol.% for crossbenzoin condensation smooth reactions and selective benzoin reactions were observed with a wide range of linear and branched aliphatic aldehydes as well as aromatic aldehydes, as depicted in Scheme 8-10. Specifically, aliphatic aldehydes served as acyl anion equivalents, resulting in the formation of -hydroxycarbonyls (acyloins) products. ...
N-heterocyclic carbenes (NHCs) catalyze benzoin condensation, which is a unique carbon-carbon bond-forming reaction. It entails a coupling reaction between two aldehydes catalyzed by NHCs that produce a-hydroxycarbonyl compounds (acyloins). NHCs have emerged as a potent class of organocatalysts, catalyzing numerous benzoin and benzoin-type reactions. This review provides an overview of the historical development of NHCs and their application in benzoin reactions. Additionally, recent advancements in NHC catalysis, including the use of chiral NHCs, are discussed. This review aims to provide a comprehensive understanding of the current state of NHC catalysis for benzoin reactions and its potential for future developments in synthetic chemistry.
... We also tested the QMT contribution with larger, wellknown carbenes: Gravel's piperidinone-derived triazolium, 43 and Arduengo's 44 and Leeper's 45 thiazolium catalyst, all of them with benzaldehyde as a substrate (the last two were slightly simplified−see Scheme 3−and the SCT step size was enlarged to reduce the computational time of these extremely demanding jobs). The resulting values are shown in Table 2. ...
The Breslow intermediate is key to several NHC-organocatalyzed reactions. However, accessing the Breslow intermediate via a direct intramolecular hydrogen atom transfer (HAT) is unlikely and can only occur if it is aided, for instance, by a water molecule. Herein we show computationally that for a model thiazolium-based NHC catalyst quantum mechanical tunneling (QMT) significantly accelerates the water-bridged HAT in the Breslow intermediate formation. Although the reaction can proceed through a semiclassical mechanism, the contribution of thermally activated tunneling is dominant (3–82 times faster on the studied systems). Considering that traces of water are known to catalyze intramolecular HAT in many reactions, these results may allude to a general role of QMT in these processes.
... Moreover, the use of triazolylidene as catalysts by Connon, Zeitler, and co-workers enabled the reduction of steric hindrance [63]. Furthermore, Gravel discovered that carrying out the reaction with piperidine-fused triazolylidene as catalyst allowed great chemoselectivity even in the case of condensation between simple benzaldehyde and acetic aldehyde [64,65]. It is also possible to control chemoselectivity using different catalysts under the same conditions. ...
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.
A novel N‐heterocyclic carbene (NHC) catalyzed reaction between sulfonate and isatin derivatives has been successfully developed, enabling the efficient synthesis of a series of 2‐oxindole derivatives. This catalytic system demonstrated remarkable efficiency, affording the desired products in excellent yields of up to 96%. Notably, the reaction exhibited significant stereoselectivity, with the ratio of cis‐trans configurations reaching Z:E = 1:10. Mechanistically, this methodology represents a significant advancement in NHC mediated activation of sulfonyl compounds, providing a new strategic approach for the construction of biologically important 2‐oxindole scaffolds. The developed protocol features mild reaction conditions, broad substrate scope, and high functional group tolerance, making it a valuable addition to the NHC catalyzed synthetic toolbox.
Light‐driven decarboxylative cross‐coupling has emerged as a pivotal platform for constructing C(sp3)‐C(sp2) bonds in organic synthesis and medicinal chemistry. However, using two structurally dissimilar carboxylic acids as a feedstock to form chiral α‐oxygenated ketones remains a considerable challenge due to side reactions such as decarboxylative reduction and homo‐coupling. Herein, we report for the first time a photoredox/nickel dual‐catalyzed enantioselective decarboxylative acylation of α‐hydroxy acid derivatives and aliphatic carboxylic acids, enabling efficient access to enantioenriched α‐oxygenated ketones. This method exhibits a broad substrate scope, good functional group tolerance, high chemoselectivity, and excellent enantioselectivity (up to 99% e.e.). The advantage of this reaction is that it eliminates the need for metal reductants and the use of precious metal photocatalysts and utilizes renewable feedstocks. The use of a coiled‐tube continuous‐flow photoreactor can shorten the illumination time by half and obtain results comparable to those of a batch reaction. Furthermore, preliminary mechanistic experiments support a pathway in which photocatalytic decarboxylation generates α‐oxy alkyl radical species, and the Ni(I)‐alkyl intermediate activates the in situ‐formed mixed anhydride followed by reductive elimination to give the product in enantiomerically pure form.
NHC‐Catalyzed enantioselective conversion of ynals remains challenging through nucleophilic NHC‐allenolate intermediates. Herein, we present an NHC‐catalyzed highly asymmetric intramolecular [3+2] annulation of cyclohexadienone‐tethered ynals. This reaction enables a rapid and efficient construction of 6,5,5‐tricyclic frameworks bearing three contiguous stereocenters in excellent enantioselectivities. Additionally, the synthetic utility is elaborated through a gram‐scale experiment and several downstream transformations.
Phenanthrenequinones (PQs) are extensively studied in synthetic chemistry and materials science, exhibiting noteworthy biological activities essential for drug discovery. The development of efficient synthetic methods for PQ preparation has thus...
Imidazo[1,5-a]pyrid-3-ilydene(IPC)-catalyzed oxidative esterification of aldehydes was investigated. The series of IPC showed good catalytic activity, in particular, sterically hindered one. Substituents on the 3-position of imidazo[1,5-a]pyridine ring significantly influenced its catalytic activity, and electron-withdrawing substituent accelerated the reaction.
α-Alkylated aryl ketones play a prominent role in pharmaceutically active compounds. Thus, developing a straightforward and atom/step-economy strategy for modular accessing these privileged structural motifs is of central importance. Herein,...
Comprehensive Summary
The alkali tert‐butoxide (tBuOK or tBuONa) mediated generation of aryl free radical from aryl iodide remarks a milestone discovery in the free radical chemistry. However, the equivalent “alkyl halide to alkyl free radical” transformation has not yet been realized in applicable synthesis by similar catalytic tactic. In this paper, the first practical “alkyl halide to alkyl free radical” transformation mediated by tBuOK or TMSOK in the direct α‐C—H alkylation of benzoins is presented. As the parallelly significant issue as aryl free radical generation, the current work, while bringing a rather facile and useful new approach for the synthesis of diverse benzoins, represents also an important step in the alkyl free radical‐based synthesis by displaying the higher generality of simple alkali base mediated radical formation.
Herein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.
Encompassing an integrated approach to the various aspects of catalysis, covering heterogeneous, homogeneous, organo-, bio-, and computational catalysis, as well as reaction and reactor engineering on an advanced level, this textbook is ideal for graduate students with diverse backgrounds, including catalysis, engineering, and organic synthesis. The basic principles of the various fields of catalysis are introduced in a concise way, preparing the reader for the more advanced chapters. Organometallic chemistry, surface science, biochemistry, nanoscience, transport phenomena and kinetics, reactor and reaction engineering are presented, spanning from the underlying science to industrial applications. Several important case studies on industrial applications are given. It includes catalyst preparation and characterisation and explores recent developments in the understanding of catalytic mechanisms, exploring advanced techniques such as operando spectroscopy.
A general mechanistic map involving multiple intermediates and pathways has been proposed and systmatically studied for NHC-catalyzed transformation reactions of saturated carboxylic anhydrides. Based on the map, the origin of...
In this study, a novel and efficient one‐pot tandem synthesis of 2,4,5‐tri‐ and 1,2,4,5‐tetra‐substituted imidazoles is described. In the first step of the sequence, benzil is formed via benzoin condensation catalyzed by N‐heterocyclic carbene, followed by in situ aerobic oxidation. Next, it is reacted with another aldehyde and ammonium acetate (or amine) to produce the polysubstituted imidazole. The reaction proceeds smoothly in high yield and short reaction time in ethanol as a green solvent. The current strategy shows high functional group tolerance with respect to aldehydes and avoids the need for ligands and reducing agents. This method allows the synthesis of complex molecules in a one‐pot procedure without isolating intermediates.
Using density functional theory (DFT) calculations, we demonstrate that the organocatalytic properties of NHCs, such as their nucleophilicity, electrophilicity and singlet triplet gaps, are predictably influenced by electric fields. These electric fields can be delivered in practical systems using charged functional groups to provide designed local electric fields, and their effects are strong enough to be synthetically relevant even in relatively polar solvents. We also show that these electrostatically enhanced NHCs elicit dramatic changes in the energetics of key transition states of a model benzoin condensation in various solvents, which can be tuned by the sign of the applied charge and the solvent polarity. Based on these findings, we suggest that NHCs are plausible candidates for electrostatic catalysts, and that electric field effects should be considered when designing NHC frameworks.
This chapter provides an overview of the applications of computational methodologies in developing models to explain the observed reactivity and selectivity of organocatalytic reactions. While computational chemistry has been applied to all areas of organocatalysis, this chapter focuses on the role it has played in the areas of aminocatalysis, N‐heterocyclic carbene catalysis, and Lewis acid/hydrogen bond catalysis. Selected examples highlight the power of computational studies, specifical density functional theory (DFT), in providing transition state models capable of rationalizing observed reactivity and selectivity trends and the power of these models in the design of new reactions. While most of the work presented in this chapter employs DFT calculations, other methods, including molecular dynamics and the newly developed approaches for predictive modeling, are also highlighted.
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.
A route for the synthesis of 1,2,4-triazolium salts via oxidation of a thione precursor is demonstrated. N-Pentafluorophenyl-substituted salts are produced in 20-63% overall yields. Isolation and purification of the azolium salts are simplified compared to the traditional synthetic route. Late-stage selection of the counterion allows the synthesis of a variety of salts from a parent thione. The salts have been compared in Stetter and cross-benzoin reactions with an appreciable counterion effect in both reactions.
We present a DFT study of the mechanisms, chemo- and stereoselectivities in the reaction of 2-bromoenal with aryl 1,2-diamine enabled by a chiral NHC. The catalytic reaction starts with NHC addition to 2-bromoenal, subsequent [1,2]-proton transfer results in the Breslow intermediate, which then undergoes sequential CBr bond breaking and [1,3]-proton transfer. The resulting acylazolium can transform to the [3 + 4] cycloadduct through subsequent CN bond formation, [1,3]-proton transfer and cyclization. Finally, elimination of catalyst provides 1,5-benzodiazepin-2-one. DFT results reveal that OAc⁻ and HOAc play important roles respectively in the [1,2]- and [1,3]-proton transfer process. The CN bond formation step controls the enantioselectivity of the reaction, and preferably provides access to (R)-1,5-benzodiazepin-2-one. The computed enantioselectivity (97.5% ee) agrees well with experimental report (97% ee). Non-covalent NH···π, CH···N and CH···π interactions are the key factors for controlling the stereoselectivity. The NHC is demonstrated to play a role in CBr bond activation through reduce the electron density between the C and Br atoms, thus increases 2-bromoenal's electrophilicity and facilitates its subsequent reaction with diamines.
An approach to diverse cross-benzoin and α-siloxy ketone products which leverages a simple yet underutilized C-C bond disconnection strategy is reported. Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds enables access to a broad scope of aryl, heteroaryl, alkyl, alkenyl, and alkynyl derivatives. Enantiopure benzoins can be accessed via a chiral pool approach, and the utility of accessible cross-benzoins and α-siloxy ketones is highlighted in a suite of downstream synthetic applications.
The first carbene‐catalyzed asymmetric chemoselective cross silyl benzoin (Brook–Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon–silicon bond of an acylsilane by a chiral N‐heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo‐ and enantioselective manner to afford α‐silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook–Benzoin reaction was investigated through both experimental and computational methods. The chiral α‐hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.
The first carbene‐catalyzed asymmetric chemoselective cross silyl benzoin (Brook‐Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon‐silicon bond of an acylsilane by a chiral N‐heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo‐ and enantioselective manner to afford α‐silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook‐Benzoin reaction was investigated through both experimental and computational methods. The chiral α‐hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.
N-Heterocyclic carbenes (NHCs) containing triazolium motifs have emerged as a powerful tool in organocatalysis. Recently, various NHC-catalyst-mediated organic transformations have been developed. This review aims to compile the current state of knowledge on enantioselective NHC-triazolium-catalyzed named reactions as well as introduce newly developed catalytic methods. Furthermore, this review article framework provides an excellent opportunity to highlight some of the unique applications of these catalytic procedures in the synthesis of natural products and biologically active compounds, notably the extensive processes for the preparation of substituted chiral alcohols and their derivatives. This review also provides an overview of the synthesis of chiral NHC-triazolium-catalyst libraries and their applications in catalytic enantioselective reactions.
1 Introduction
2 Synthesis of N‑Heterocyclic Carbenes Containing Triazolium Motifs
2.1 Pyrrolidine-Based Triazoliums NHCs: Px
2.2 Morpholine-Based Triazoliums NHCs: Mx
2.3 Aminoindane-Based Triazoliums NHCs: AMx
2.4 Oxazolidine-Based Heteroazoliums NHCs: Ox
2.5. Acyclic Triazoliums NHCs: Ax
3 Enantioselective Organocatalytic Reactions
3.1 Enantioselective Benzoin Reactions
3.1.1 Aldehyde–Aldehyde Homo-Benzoin Reactions
3.1.2 Aldehyde–Aldehyde Cross-Benzoin Reactions
3.1.3 Aldehyde–Ketone Cross-Benzoin Reactions
3.1.4 Aldehyde–Imine Cross-Benzoin Reactions
3.1.5 Aza-Benzoin Reactions
3.2 Enantioselective Stetter Reactions
3.2.1 Intramolecular Stetter Reactions
3.2.2 Intermolecular Stetter Reactions
3.3 Enantioselective Diels–Alder Reactions
3.4 Enantioselective Michael Additions
3.5 Enantioselective Rauhut–Currier Reactions
3.6 Enantioselective Cycloadditions
3.7 Enantioselective Michael–Stetter Cascade Reactions
3.8 Enantioselective Annulation Reactions
3.9 Synthesis of Spiro Compounds
3.10 Heterocycle Synthesis
3.11 Carbocycle Synthesis
3.12 Asymmetric Steglich Rearrangement Reactions
3.13 NHC-Mediated Asymmetric Acylation/Hydroacylation Reactions
3.14 Enantioselective α-Fluorination of Aliphatic Aldehydes
3.15 Functionalization of Carboxylic Anhydrides by NHC Catalysis
3.16 Asymmetric β-Boration of Acyclic Enones
3.17 Synthesis of Tropane Derivatives via Organocatalysis
3.18 Dynamic Kinetic Resolution of Pyranones via NHC Catalysis
3.19 Enantioselective Umpolung Reactions
3.20 Enantioselective Esterification of Ketenes
3.21 Asymmetric Synthesis of trans-γ-Lactams
3.22 Oxy-Cope Rearrangements
3.23 Claisen Rearrangements
3.24 Enantioselective Synthesis of Complex Heterocycles
3.25 Atroposelective Synthesis of N-Aryl Succinimides
3.26 Asymmetric α-Fluorination via Cascade Reactions
4 Conclusion
In the realm of NHeterocyclic carbene (NHC) catalysis, γ-carbon functionalization of carboxylic esters has rapidly developed in recent years, however, the mechanisms and stereoselectivity of β-carbon functionalization of carboxylic esters remain poorly understood. Herein, we investigated the mechanism and key factors controlling the regio- and stereoselectivity of the [3 + 3] cycloaddition between an ester and a benzofuran mediated by chiral NHC catalyst using density functional theory (DFT) computations. Our proposed mechanism includes binding of the NHC to ester, C − O bond dissociation, carbon-carbon bond formation, HOAr-assisted protonation, HCO3⁻-mediated deprotonation, intramolecular cycloaddition and elimination of the NHC. The carbon-carbon bond formation determines the stereoselectivity and preferably generates the S-configurational δ-lactam, in consistent with experimental observations. Non-covalent interaction (NCI) results indicate that weak C–H···O, C–H···N and π···π interactions play key roles to control the stereoselectivity. The global reactivity indexes (GRIs) and electron localization function (ELF) analyses show that the role of the NHC is to promote the dissociation of C–O bond of the ester, thus making it more electrophilic to react with the nucleophilic benzofuran.
Bicyclic triazolium scaffolds are widely employed in N-heterocyclic carbene (NHC) organocatalysis. While the incorporation of a fused ring was initially for synthetic utility in accessing chiral, modular triazolyl scaffolds, recent results highlight the potential for impact upon reaction outcome with the underpinning origins unclear. The common first step to all triazolium-catalyzed transformations is C(3)-H deprotonation to form the triazolylidene NHC. Herein, we report an analysis of the impact of size of the fused (5-, 6-, and 7-membered, n = 1, 2, and 3, respectively) ring on the C(3) proton transfer reactions of a series of bicyclic triazolium salts. Rate constants for the deuteroxide-catalyzed C(3)-H/D-exchange of triazolium salts, kDO, were significantly influenced by the size of the adjacent fused ring, with the kinetic acidity trend, or protofugalities, following the order kDO (n = 1) > kDO (n = 2) ≈ kDO (n = 3). Detailed analyses of X-ray diffraction (XRD) data for 20 triazolium salts (including 16 new structures) and of computational data for the corresponding triazolylidene NHCs provide insight on structural effects of alteration of fused ring size. In particular, changes in internal triazolyl NCN angle and positioning of the most proximal CH2 with variation in fused ring size are proposed to influence the experimental protofugality order.
A theoretical study of the mechanism of the N-heterocyclic carbene (NHC)-catalyzed C-S bond cleavage and reconstruction reaction of unsaturated thioesters was conducted using density functional theory (DFT). The origin of stereoselectivity and the role of the NHC were also explored based on the established mechanism. The computational results showed that C-S bond cleavage was the rate-determining step, giving an α,β-unsaturated acyl azolium intermediate and sulfur anion species. Stereoselectivity can be generated by the sequential Michael addition process, preferentially generating an S-configured product. Topological analysis of the stereocontrolling transition states revealed that stronger weak interactions, such as π⋯π, C-H⋯O, LP⋯π and C-H⋯π interactions, were key for controlling the stereoselectivity. The key role of the NHC was also determined by electron localization function (ELF) analysis.
N-Heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C–C and C–H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives (such as acids, bases, other species, or even a solvent) was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation, in situ detection, isolation, and characterization of the Breslow intermediate are scattered over a series of reports spanning well over a decade, and we intend to consolidate them in this review and provide a critical assessment of these developments. Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same.
Umpolung reactions of imines, especially the asymmetric reactions, have been extensively studied as they provide access to important chiral amines in an efficient manner. The reactions studied range from simple Michael reactions to several kinds of other reactions such as the aza-benzoin reaction, aza-Stetter reaction, addition with MBH carbonate, and Ir-catalysed allylation. Herein, we report the first umpolung alkylation reaction of α-iminoesters with alkyl halides mediated by iminophosphorane as an organic superbase. The desired products were obtained in up to 82% yield with almost perfect regioselectivities. The key to the regioselectivity of this reaction was the use of 4-trifluoromethyl benzyl imines as a substrate. The products were successfully derivatised into the more functionalised molecules in good yields.
A reductive cross‐coupling reaction between aromatic aldehydes and arylnitriles using a copper catalyst and a silylboronate as a reductant is reported. This protocol represents an unprecedented approach to the chemoselective synthesis of α‐hydroxy ketones by electrophile–electrophile cross‐coupling.
An N-heterocyclic carbene-catalyzed synthesis of dibenzofulvenes and fluorenyl alcohols was developed. In the presence of 10 mol% NHC (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and 4 Å molecular sieves, 9-(trimethylsilyl)fluorene undergoes an olefination reaction with aldehydes to produce dibenzofulvenes in 43-99% yields. However, on reducing the NHC loading to 1 mol% and with the addition of water, 9-(trimethylsilyl)fluorene selectively undergoes nucleophilic addition with aldehydes to afford fluorenyl alcohols in 40-95% yields.
In this work, a visible‐light enabled coupling of acylsilanes with aldehydes to give a range of cross‐benzoin type products α‐hydroxyketones is described. The reaction could proceed at ambient temperature, with the irradiation of low energy visible light, and without addition of photosensitizer or any other additives.
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The condensation reaction can occur in acidic, basic conditions or in the presence of other catalysts. This type of reactions is an essential part of our life as it is an important to form peptide bonds in between amino acids in protein and the biosynthesis of fatty acids. This chapter provides valuable information on reaction details, step‐by‐step mechanism, experimental procedures, applications, and (patent) references of some named condensation reactions. The reactions covered are Aldol condensation reaction, Mukaiyama Aldol reaction, Evans Aldol reaction, Henry reaction, Benzoin condensation, Claisen condensation, Darzens Glycidic ester condensation, Dieckmann condensation, Knoevenagel condensation, Pechmann condensation, Perkin condensation, and Stobbe condensation.
The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl substituent. It was found that increasing both the steric requirement and the electron-withdrawing characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry, however both quenching the reaction at different times and deuterium incorporation experiments involving the product revealed that this is complicated by product racemisation in situ (except in the case of benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-good yields with moderate to excellent enantioselectivity.
Catalysis using N-heterocyclic carbenes (NHCs) has been widely employed for the umpolung of aldehydes, and these reactions proceed via the generation of nucleophilic Breslow intermediates. These acyl anion equivalents can be added to aldehydes, ketones, imines, Michael acceptors, and even unactivated carbon–carbon multiple bonds. In a majority of the cases, aromatic aldehydes are used in NHC catalysis. However, the use of aliphatic aldehydes is relatively less explored because of the low electrophilicity of the aliphatic aldehydes compared to aromatic aldehydes for the nucleophilic addition of carbenes, and the presence of α-acidic protons leading to side reactions under basic conditions. There are several NHC-catalyzed reactions that engage aliphatic aldehydes, and this Highlight summarizes the advances in NHC catalysis using aliphatic aldehydes as substrates.
Density functional theory (DFT) and multiconfigurational self-consistent field theory (MCSCF) methods are employed to investigate variation of the electronic properties of various N-heterocyclic carbenes. Alterations to the backbone by increased or decreased conjugation, heteroatom substitution in the NHC ring, and electron-donating or -withdrawing backbone substituents are modeled. The MCSCF calculations show extensive delocalization of both the highest occupied and lowest unoccupied molecular orbitals for NHCs with polymerizable backbone substituents. The free energies of the intermediates and transition structures for benzoin condensation are also shown to be sensitive to substitution of the NHC backbone. Taken together, these results imply great sensitivity of the reactivity of poly(NHC) catalysts to backbone modification at this moiety. Implications with respect to enhancement of poly(NHC)s employed in umpolung catalysis are discussed.
N‐Heterocyclic carbene (NHC) organocatalysis has been developed as an important approach in modern organic synthesis. Versatile activation modes within NHC organocatalysis have been established with countless transformations being realized in both efficient and selective fashion. We would like to provide an overview on the key progresses achieved within this field in the past two decades. Since numerous excellent reviews have been documented within this area, we will mainly focus on the scientific development of this research field based on the basic reaction modes and typical reaction intermediates.
Attempts were made to minimize the amounts of catalyst and solvent in the NHC-catalyzed benzoin reactions of solid aldehydes. In some case, solid-to-solid conversions proceeded in the solvent-free NHC-catalyzed benzoin reactions. Even if a mixture of the substrate, N-heterocyclic carbene (NHC) precursor, and inorganic base was initially a powdery solid, the reaction did proceed at reaction temperature lower than the melting points of each compound. The solid mixture partially melted or became a slurry or suspension in the meantime. We call this solid/liquid mixture a semisolid state. The reaction giving an optically active product was faster than that giving a racemic mixture of the same product. Melting-point depression was observed for a series of mixtures of the substrate and product in different substrate/product ratios. Solvent-free solid-to-solid conversions were accelerated by the formation of a semisolid state resulting from the melting-point depression of the solid substrate accompanied by the product formation. In the case of solid substrates with high melting points, melting-point depression was useless, and the addition of a small amount of solvent was needed. The first total synthesis of isodarparvinol B was achieved via the NHC-catalyzed intramolecular benzoin reaction using a small amount of solvent as an additive.
Since discovering the first stable nucleophilic carbene, the application of N-heterocyclic carbenes (NHCs) has dramatically drawn attention in organic chemistry. Recently, NHCs have become popular ligands in organometallic chemistry and many complexes incorporating NHCs have been used in organic synthesis. NHCs act as not only ligands for metal, but also as organocatalysts. The nucleophilic carbene attacks onto carbonyl groups to afford the key intermediate, so called the Breslow intermediate, which attacks to the other carbonyl compounds to afford the products. In addition, catalytic asymmetric reactions using chiral NHCs have been reported with good to excellent stereoselectivities. Here, amino acid-derived chiral triazolium and imidazolium salts, each bearing a pyridine ring, were developed as N-heterocyclic carbene organocatalysts and chiral ligands toward catalytic asymmetric reactions.
This Account chronicles our efforts in the development of the catalytic asymmetric Stetter reaction using chiral triazolium salts as small molecule organic catalysts. Advances in the mechanistically related azolium-catalyzed asymmetric benzoin reaction are discussed, particularly as they apply to catalyst design. A chronological treatise of reaction discovery, catalyst optimization and reactivity extension follows.
1 Introduction
2 Proposed Mechanism of the Benzoin and Stetter Reactions
3 The Benzoin Reaction
4 Synthesis of Chiral Bicyclic Triazolium Salts
4.1 Aminoindanol-Derived Bicyclic Scaffold
4.2 Phenylalanine-Derived Bicyclic Scaffold
5 The Intermolecular Stetter Reaction
6 The Asymmetric Intramolecular Stetter Reaction
6.1 Recent Contributions to the Asymmetric Intramolecular Stetter Reaction
6.2 Comparison of the Asymmetric Intramolecular Stetter Reaction with Two Different Triazolium Carbene Scaffolds
6.3 Scope of the Intramolecular Stetter Reaction with Different Tethers
6.4 Electronic Effects of the Aromatic Backbone of the Aldehyde on the Intramolecular Stetter Reaction
6.5 Effects of the Michael Acceptor on the Asymmetric Intra-molecular Stetter Reaction
6.6 The Asymmetric Intramolecular Stetter Reaction of Aliphatic Aldehydes
7 Effects of Pre-existing Stereocenters on the Intramolecular Stetter Reaction
8 Synthesis of Quaternary Stereocenters via the Asymmetric Intramolecular Stetter Reaction
9 Synthesis of Contiguous Stereocenters via the Asymmetric Intramolecular Stetter Reaction
10 Asymmetric Synthesis of Hydrobenzofuranones via the Intramolecular Stetter Reaction
11 Applications to Total Synthesis
12 Summary and Outlook
Based on our recent finding that 2,6-dimethoxyphenyl-substituted NHCs show superior reactivity in the hydroacylation reactions of electron-neutral olefins compared with known NHCs, we now report the syntheses and crystal structures of four highly electron-rich 2,6-dimethoxyphenyl-substituted NHCs and show the increase in efficiency caused by the electron-rich aryl substituent in hydroacylation reactions. The synthesis and crystal structures of four highly electron-rich 2,6-dimethoxyphenyl-substituted NHCs are reported. These NHCs should have interesting applications as ligands or in NHC organocatalysis.
We found that chemoselectivity of the crossed acyloin product is controlled by the adjustment of the aromatic aldehyde/aliphatic aldehyde ratio. Moreover, we observed the persistent catalytic activity of the homogeneous NHC catalyst in a solution due to NHC catalyst robustness.
Catalytic reactions promoted by N-heterocyclic carbenes (NHCs) have exploded in popularity since 2004 when several reports described new fundamental reactions that extended beyond the long-studied generation of acyl anion equivalents. These new NHC-catalyzed reactions allow chemists to generate unique reactive species from otherwise inert starting materials, all under simple, mild reaction conditions and with exceptional selectivities. In analogy to transition metal catalysis, the use of NHCs has introduced a new set of elementary steps that operate via discrete reactive species, including acyl anion, homoenolate, and enolate equivalents, usually generated by oxidation state reorganization (“redox neutral” reactions). Nearly all NHC-catalyzed reactions offer operationally simple reactions, proceed at room temperature without the need for stringent exclusion of air, and do not generate reaction byproducts. Variation of the catalyst or reaction conditions can profoundly influence reaction outcomes, and researchers can tune the desired selectivities through careful choice of NHC precursor and base.
Pentafluorophenyl triazolium carbenes, widely used in NHC-catalysis, can decompose by several mechanisms. Under high concentration conditions, the azolium may undergo a pentafluorophenyl exchange by a proposed SNAr mechanism to give an inactive salt. In the presence of appropriate substrates, cyclization on the ortho-position of the arene can occur, also by SNAr. These adducts provide a potential pathway for catalyst decomposition and serve as a caveat to the development of new reactions and catalysts.
Chiral triazolium salts bearing a pyridine ring were developed as N-heterocyclic carbene precursors. In the presence of the chiral triazolium salt and a base, the catalytic asymmetric benzoin condensation proceeded to afford the product in high level of chemical yield and enantioselectivity. A wide range of aromatic aldehydes were applicable to this reaction.
The in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to a range of substituted benzaldehydes is probed. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen–deuterium exchange (kex) at C(α) of these intermediates for a range of N-aryl triazolinylidenes is reported. These combined studies give insight into the preference of N-pentafluorophenyl NHCs to participate in benzoin and Stetter reaction processes.
It has been shown for the first time that relatively electron deficient triazolium pre-catalysts promote (at low loadings in the presence of base) highly chemoselective crossed acyloin condensation reactions between aldehydes and α-ketoesters to afford densely functionalized products incorporating a quaternary stereocentre of considerable synthetic potential. Hydroacylation pathways which have hitherto been dominant in these reactions can be completely avoided. The scope of the process is extraordinarily broad with respect to both coupling partners, and a preliminary study has established the principle that a high degree of stereochemical control over the reaction can also be exercised via the use of a chiral NHC precursor. It has also been shown for the first time that coupling of benzyl α-ketoesters with aldehydes followed by acylation and simple hydrogenolysis furnishes a product formally derived from the chemoselective 1:1 coupling of two different aliphatic aldehydes in high yield with absolute control over which coupling partner behaves as the acyl-anion equivalent.
The enantioselective synthesis of 3-hydroxy-4-chromanones bearing a quaternary stereocenter via an N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction is described.
The rates and enantioselectivities of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate co-catalyst. The degree of the enhancement is correlated with the basicity of the utilized carboxylate. Using a co-catalyst and newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols are achieved with extremely high selectivity (up to s 218 and 99% ee, respectively) with low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference toward alcohols over amines, which are not converted into amides under the reac-tion conditions.
But(yl) not futile: A range of N-tert-butyl-substituted triazolylidene N-heterocyclic carbenes have been prepared. Of these, the morpholinone-derived catalyst (1) proved best suited to the enantioselective synthesis of cyclopentanes from donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The performance of this catalyst has been correlated to the electronic nature of the catalyst by (13) C NMR analysis. M.S.=molecular sieves, TMS=trimethylsilyl.
Chiral bicyclic 1,2,4-triazolium salts having a defined face of the heterocyclic ring hindered have been synthesised and they catalyse the benzoin condensation in good yield; the enantiomeric excesses obtained (up to 80%) are much better than with closely related thiazolium salts and the opposite enantiomer of benzoin predominates.
Three different chiral bicyclic thiazolium salts, 10, 16 and 19, have been synthesised in enantiomerically pure form. These salts all catalysed the formation of benzoin and butyroin from benzaldehyde and butyraldehyde respectively and the product had the R-configuration in each case with e.e.'s in the range 10–33%. Possible reasons for these results are discussed.
The development of a family of chiral bicyclic triazolium salts is described. Treatment of these salts with base provides a nucleophilic carbene which may be used as an organic catalyst for asymmetric acyl anion chemistry including the benzoin and Stetter reactions, and some recently developed redox chemistry. Throughout the development of these reactions, the nature of the N-aryl substituent on the triazole ring has proven to have a profound effect on both reactivity and selectivity. These observations have also paralleled those made by others using our family of catalysts.
The majority of N-heterocyclic carbene catalyzed reactions of α-functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design.
An electron-deficient, valine-derived triazolium salt is shown to catalyze a highly chemo- and enantioselective cross-benzoin reaction between aliphatic aldehydes and α-ketoesters. This methodology represents the first high yielding and highly enantioselective intermolecular cross-benzoin reaction using an organocatalyst (up to 94% ee). Further diastereoselective reduction of the products gives access to densely oxygenated compounds with high chemo- and diastereoselectivity.
Enzymes create chiral microenvironments that may simultaneously generate several stereogenic centers in the same catalytic cycle, broadening the possibilities of biocatalysis. Benzaldehyde lyase (BAL) affords highly diastereoselective α-hydroxy-ketones by simultaneously performing ligation and kinetic resolution of a racemic aldehyde. Thus, to the well-known enantioselective BAL-carboligation of aldehydes (C-C bond formation), another property, namely diastereoselectivity, is added in this paper for the first time.
Second order rate constants have been determined for deuteroxide ion-catalyzed exchange of the C(3)-proton for deuterium, kDO (M-1s-1), of a series of twenty triazolium salts in aqueous solution at 25 °C and ionic strength I = 1.0 (KCl). Evidence is presented that the rate constant for the reverse protonation of the triazol-3-ylidenes by solvent water is close to that for dielectric relaxation of solvent (1011 s-1). This data enabled the calculation of carbon acid pKa values in the range 16.5-18.5 for the twenty triazolium salts. pD-rate profiles for deuterium exchange of the triazolium salts reveal that protonation at nitrogen to give dicationic triazolium species occurs under acidic conditions, with estimates of pKaN1 = -0.2-0.5.
N-Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter's report in 1975 of the total synthesis of cis-jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC-catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.
The condensation of formaldehyde with another aldehyde catalyzed by 3-ethylbenzothiazolium bromide in the presence of triethylamine gives selectively 1-hydroxy 2-ones. This selective cross-acyloin condensation indicates an inverse selectivity in the reactions of the conjugate base of thiazolium salt 17 and of the carbanion bound to thiazolium ring 19 toward aldehyde.
A rather stable thiazolium zwitterion has been detected by deuterium exchange studies, and a mechanism of thiamine action is suggested which involves such a zwitterion. It is shown that the mechanism accommodates the data which have been obtained by study of model systems for biochemical reactions catalyzed by thiamine.
A family of thiazolium salt derived N-heterocyclic carbenes (NHCs) bearing sterically demanding aryl substituents on the nitrogen and with varying backbone substitution patterns have been synthesized. Investigation of the catalytic activity of these NHCs in a number of benzoin-type coupling reactions revealed markedly different levels of reactivity and selectivity. To elucidate the underlying factors leading to differences in reactivity, a study of the electronic and steric properties of these NHC catalysts was conducted. By using the best catalyst in this study, the intermolecular cross-benzoin condensation reaction was explored in more detail.
A solution to the long-standing challenge of developing a highly effective method for the enantioselective intermolecular benzoin condensation of aromatic aldehydes is described. The chiral bis-bicyclic triazolium salt – 1,3-bis{(S)-5-benzyl-6,8-dihydro-5H-[1,4]oxazino[2,1-c][1,2,4]triazol-2-ium-2-yl}benzene dichloride [(S)-5a-1] is currently the most efficient precatalyst for the asymmetric variant of the benzoin condensation.
A direct intermolecular cross‐benzoin‐type condensation catalyzed by an N‐heterocyclic carbene has been developed. The cross‐coupling of commercially available aromatic aldehydes and trifluoromethyl ketones results in α‐hydroxy‐α‐trifluoromethyl ketones bearing a quaternary stereocenter with excellent chemoselectivity and good to excellent yields.
Two new conformationally-restricted chiral bicyclic thiazolium salts have been synthesized by a concise, high-yielding route. These salts are effective catalysts for the benzoin condensation, affording benzoin in 20–30% yield, with a similar range of enantiomeric excesses.
Kinetic studies show that the benzoin condensation catalyzed by 3,4,5-trimethylthiazolium iodide and triethylamine in DMSO has a transition state with two benzaldehyde and one thiazolium components, while the conversion of nitrobenzaldehyde to the thiazolium adduct is kinetically first order in thaizolium salt and aldehyde. These findings exclude proposals that thiazolium dimers are the true catalytic species.Kinetic studies show that the benzoin condensation catalyzed by 3,4,5-trimethylthiazolium iodide and triethylamine in DMSO does not involve thiazolium dimers as the catalytic species, as has been proposed.
A family of enantiopure 1,2,4-triazolium salts were prepared starting from the inexpensive (S)-pyroglutamic acid. After treatment with base, the corresponding N-heterocyclic carbenes were tested as organocatalysts in the asymmetric benzoin condensation and gave good yields and up to 95% ee.
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 use of N-heterocyclic carbenes (NHCs) to promote organocatalytic transformations has rapidly expanded in recent years, building upon
the classic use of these compounds to generate acyl anion equivalents from aldehydes. This chapter gives an overview of the
recent progress made in this area, describing the use of NHCs to generate synthetic intermediates from a range of readily
accessible starting materials and recent developments in their reactivity. The reaction of an NHC can result in the formation
of a range of d1, d2 and d3 synthons (acyl anion, azolium enol or enolate, and azolium homoenolate intermediates) or an electrophilic a1 acylazolium species, with typical processes that proceed through each of these intermediates described. The use of NHCs to
participate in stereoselective reaction processes within each of these areas is also described, with an emphasis upon a mechanistic
understanding of these processes given where appropriate.
New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic α-substituted β-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Highly substituted β-lactones are produced in good yield with good to excellent selectivities (see scheme).
Highly enantioenriched mixed benzoins are obtained selectively through a biocatalytical cross-coupling reaction of aromatic aldehydes using ThDP-dependent enzymes.
The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
While organocatalyzed domino reactions or "organocascade catalysis" developed into an important tool in synthetic chemistry during the past decade, the utility of N-heterocyclic carbenes (NHCs) as catalysts in domino reactions has only received growing attention in the past three years. Taking into account the unique activation modes of the substrates by NHC catalysts, it is often difficult to distinguish between a single chemical transformation and a sequential one-pot transformation. Therefore, herein we present a critical consideration of domino, cascade, and tandem catalysis in the case of NHC catalysts and highlight recent publications in this area.
The use of N-heterocyclic carbenes as catalysts for organic transformations has received increased attention in the past 10 years. A discussion of catalyst development and nucleophilic characteristics precedes a description of recent advancements and new reactions using N-heterocyclic carbenes in catalysis.
Cyclische Umwandlung: Die Schlüsselreaktionen der asymmetrischen Totalsynthese des marinen Naturstoffs Seragakinon A sind zwei durch ein N-heterocyclisches Carben katalysierte Benzoincyclisierungen, die zwei Ringe ergeben, und eine Pinakolumlagerung, um den Prenylsubstituenten am Brückenkopf einzuführen.
An unprecedented high level of regioselectivities (up to 96%) in the intermolecular crossed acyloin condensations of various aromatic aldehydes with acetaldehyde was realized by an appropriate choice of N-heterocyclic carbene catalysts.
The addition of acyl anion equivalents to aliphatic aldehydes (crossed-acyloin reaction) has been developed. Cesium fluoride with isopropanol as solvent promotes the addition of O-silyl thiazolium carbinols to various aliphatic aldehydes in moderate to good yields. These reactions represent a general procedure for the selective coupling of aliphatic aldehydes by an acyl anion reaction which have been problematic until now.
Chiral oxidovanadium(V) methoxides prepared from 3,5-disubstituted-N-salicylidene-l-tert-butylglycines and vanadyl sulfate in air-saturated MeOH serve as highly enantioselective catalysts for asymmetric aerobic oxidations and kinetic resolution of alkyl, aryl, and heteroaryl α-hydroxy-ketones with differed α-substituents at ambient temperature in toluene or TBME (tert-butyl methyl ether). The best scenarios involve the use of complexes which bear the tridendate templates derived from 3,5-diphenyl- or 3-o-biphenyl-5-nitro-salicyaldehyde. The kinetic resolution selectivities of the aerobic oxidation process are in the range of 12 to >1000 based on the selectivity factors (k(rel)).
The N-heterocyclic carbene-catalyzed coupling of several aldehydes with paraformaldehyde is reported, directly providing the corresponding valuable hydroxymethyl ketones. Results of first mechanistic experiments for this remarkably selective transformation are also provided.
It has been shown for the first time that triazolium precatalysts promote (in the presence of base) highly chemoselective crossed acyloin condensation reactions between aliphatic and ortho-substituted aromatic aldehydes. An o-bromine atom can serve as a temporary directing group to ensure high chemoselectivity (regardless of the nature of the other substituents on the aromatic ring) which then can be conveniently removed. The process is of broad scope and is operationally simple as it does not require the preactivation of any of the coupling partners to ensure selectivity. Preliminary data indicate that highly enantioselective variants of the reaction are feasible using chiral precatalysts.
A new triazolium salt derived N-heterocyclic carbene catalyses an asymmetric cross-benzoin-type reaction of heteroaromatic aldehydes and various trifluoromethyl ketones in good to excellent yields (69-96%) and moderate to good enantioselectivities (ee = 39-85%). Up to 99% ee can be achieved by recrystallisation.
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.
Improved catalyst design by incorporating a hydrogen bond donating substituent to improve enantiocontrol together with an acidifying pentafluorophenyl substituent to enhance catalyst efficiency results in a triazolium ion precatalyst that promotes the asymmetric archetypal benzoin condensation with excellent efficiency and unprecedented enantioselectivity.
Bicyclic tertiary alcohols 1 bearing quaternary stereocenters at the two adjacent bridgehead positions were synthesized with high stereoselectivity via the intramolecular crossed benzoin reactions catalyzed by NHC organocatalysts.
For Abstract see ChemInform Abstract in Full Text.
The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.
The asymmetric intermolecular Stetter reaction is catalyzed by a novel triazolium salt derived N-heterocyclic carbene leading to 1,4-diketones in moderate to excellent yields (49-98%) and moderate to good enantioselectivities (56-78% ee), which could be enhanced by one recrystallization to excellent levels (90-99% ee).
[reaction: see text] Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with methoxy and dimethoxy acetaldehyde and furnishes (R)-2-hydroxy-3-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-dimethoxy-1-arylpropan-1-one in high yields and enantiomeric excess via acyloin linkage. Aromatic aldehydes and benzoins are converted into enamine-carbanion-like intermediates prior to carboligation.
Stereochemically and functionally rich polycyclic compounds are obtained by the first crossed aldehyde-ketone benzoin reaction in excellent yield under mild reaction conditions (5-20 mol % thiazolium salt, 10-70 mol % DBU, tBuOH, 40 degrees C, 30 min). This novel catalytic methodology offers a convenient approach to sophisticated molecular architectures useful for the stereocontrolled construction of polycyclic compounds as well as the fully regiocontrolled synthesis of anthra- and naphthoquinones.