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N-Heterocyclic Carbene Catalyzed Synthesis of δ-Sultones via α,β-Unsaturated Sulfonyl Azolium Intermediates
Abstract
A limited array of reactive intermediates have enabled a wealth of discoveries in N-heterocyclic carbene organocatalysis. In this study, the viability of α,β-unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3-dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ-sultones (18 examples) in good yields (40–88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,β-unsaturated sulfonyl azolium species.
... 42 In stark contrast to these advancements relying on carbon-atom-based NHC-bound intermediates, limited attention has been given to generating heteroatom-centered analogues (e.g., sulfur, phosphorus, etc.) of NHC-bound intermediates, which, once realized, would stimulate significant opportunities for the design of numerous chemical transformations for (enantioselective) C-heteroatom bond formations. To the best of our knowledge, there is only one example, investigated by Lupton et al., 43 which involves a novel sulfonyl analogue of α, β-unsaturated acyl azoliums, namely, α,β-unsaturated sulfonyl azoliums, resulting in the preparation of δ-sultones through reaction with enolates via NHC organocatalysis ( Figure 1B). In addition, the pioneering work by Lupton has demonstrated proof of concept on the enantioselective control with one example demonstrated in modest enantioselectivity for the synthesis of δ-sultone product using a chiral NHC catalyst. ...
... Further exploration of new activation modes of heteroatom-centered carbene-bound intermediates, particularly in a high enantioselective manner, is of immense interest. 43,44 On the other hand, S(IV)-chiral scaffolds are ubiquitous in various natural products and bioactive compounds 45,46 and of great importance in the design of chiral catalysts/ligands for stereoselective synthesis ( Figure 1C). 47−54 The catalytic construction of S-stereogenic compounds has thereby attracted extensive attention from chemists. ...
... [10] Mayr and co-workers described unsubstituted ESF as an excellent Michael acceptor; [11] however, the application of its βsubstituted variants in catalysis remains challenging. According to independent studies performed by Lupton and co-workers [12] and Qin and co-workers, [13] Michael additions that were performed to introduce enolates in the presence of potassium bis(trimethylsilyl)amide with N-heterocyclic carbene or 1,8diazabicyclo(5.4.0)undec-7-ene (DBU) with external inorganic base salts as promoters, inevitably led to the elimination of sulfonyl fluorides. Therefore, a new and efficient catalytic addition reaction using ESF derivatives with functional group tolerance is needed. ...
... All aliphatic thiols (2 a-2 h) resulted in the desired addition products (3)(4)(5)(6)(7)(8)(9)(10) in quantitative yields (up to > 99 %). Aryl thiols (2 i-2 l) were also readily converted into the corresponding products (11)(12)(13)(14) in 76-99 % yields. Notably, thioacetic acid (2 m) and thiobenzoic acid (2 n), which are protected sulfur atom donor equivalents, produced the desired products in 89-95 % yields (15 and 16). ...
Sulfido sulfonyl fluoride and its derivatives have been gaining attention recently in the fields of medicinal chemistry and material science. The conventional method for the synthesis of functionalized alkyl sulfonyl fluorides requires several chemical transformations. Therefore, a direct establishment of such chemical structures remains challenging, and an efficient catalytic approach is highly desired. Herein a significant “on‐water” hydrophobic amplification was achieved, enabling a high‐turnover catalytic thia‐Michael addition to produce unprecedented β‐arylated‐β‐sulfido sulfonyl fluorides. Amounts as low as 100 ppm (0.01 mol %) of the phosphazene superbase were sufficient to successfully catalyze the reaction with excellent chemo‐/site‐selectivity and with optimal functional group tolerance. Several β‐arylated ethene sulfonyl fluorides were converted into thia‐Michael adducts up to >99 % yields. The mild conditions, high turnover, neutral pH, and scalability of the sustainable catalytic process benefit the preparation of potential pharmaceuticals (e. g., polyisoprenylated methylated protein methyl esterase inhibitors) and organic materials (e. g., electrolyte additives).
... For instance, sulfonyl fluoride headed molecules have gained a renewed interest for both organic and medicinal chemists as privileged warheads in chemical biology and drug discovery ( Figure 1) (Tschan et al., 2013;Brouwer et al., 2012;Dubiella et al., 2014;Dalton et al., 2018;Akçay et al., 2016). Moreover, the synthesis of 2-substituted ethenesulfonyl fluorides has recently attracted significant attention because of their unique properties as both "perfect" Michael acceptors and electrophiles for SuFEx manipulation (Qin et al., 2016;Zha et al., 2017aZha et al., , 2017bChinthakindi et al., 2017;Wang et al, 2018aWang et al, , 2018bNcube and Huestis, 2019;Chen et al, 2019;Allgäuer et al., 2017;Chen et al., 2017Chen et al., , 2018Ungureanu et al., 2015), since the pioneering work by Truce andHoerger in 1954 (Truce andHoerger, 1954). However, β-arylethenesulfonyl fluorides have rarely been explored as latent precursors for the constructions of chiral sulfonyl fluoride molecules (Barrow et al., 2019). ...
... We envision that through using Rh(I) catalyst and appropriate chiral ligand, the reaction of 2-arylethenesulfonyl fluorides with arylboronic acids would furnish a class of novel chiral molecules bearing both chiral gem-diarylmethane moiety and sulfonyl fluoride functionality (Scheme 1). However, to the best of our knowledge, the asymmetric addition of organometallic reagents to α,βunsaturated sulfonyl fluorides for producing chiral β,β-diarylethanesulfonyl fluorides has not been divulged because there are two major challenges: first, the sulfonyl fluoride moiety (R-SO2F) is fragile in the presence of bases such as Et3N, NaHCO3, DBU to undergo nucleophilic reactions Chen et al., 2017Chen et al., , 2018Ungureanu et al., 2015), while for the Rh(I)-catalyzed 1,4-addition system, strong bases such as NaOH, KOH, CsOH, K2CO3 are typically required to drive the desired transformation to occur (Sidera and Fletcher, 2015;Tian et al., 2012;Edwards et al, 2010;Hayashi and Yamasaki, 2003;Fagnou and Lautens, 2003;Müller and Alexakis, 2012), which could partially or even completely destroy the S(VI)-F functionality; second, the -SO2F motif is much more electron-withdrawing comparing with other sulfonyl groups, carbonyl groups, phosphonates and nitro counterparties which makes the olefins conjugated with -SO2F a lot more (more than 100 times) reactive than alkenes conjugated with other electronwithdrawing groups, therefore, ethenesulfonyl fluoride performs as "perfect" Michael acceptor to proceed the addition in very short time Allgäuer et al., 2017) , which further makes the control of enantioselectivity a lot more challenging. ...
A Rh-catalyzed, highly enantioselective (up to 99.8% ee) synthesis of aliphatic sulfonyl fluorides was accomplished. This protocol provides a portal to a class of novel 2-aryl substituted chiral sulfonyl fluorides, which are otherwise extremely difficult to access. This asymmetric synthesis has the feature of mild conditions, excellent functional group compatibility, and wide substrate scope (51 examples) generating a wide array of structurally unique chiral β-arylated sulfonyl fluorides for sulfur(VI) fluoride exchange (SuFEx) click reaction and drug discovery.
... [3] Subsequently,L upton and co-workers used ESF and its derivatives as substrates for N-heterocyclic carbene catalyzed syntheses of d-sultones. [4] We herein report on the quantification of the electrophilicity of this unique compound. Ther esult was used for defining the synthetic potential of ESF.U nprecedented reactions of ESF with electron-rich pyrroles confirmed our predictions. ...
... We were therefore surprised that the anion of dimedone 10 (N = 16.27 in DMSO) [6] was reported not to react with 7 under various conditions,including the treatment of 10 with Et 3 NinTHF at 66 8 8C. [4] In line with the expectations based on Eq. (1), we obtained sultone 11 in almost quantitative yield when amixture of 7 and dimedone (10)inDMSO was treated with triethylamine at ambient temperature for one hour (Scheme 4). Attempts to replace NEt 3 by ac hiral base in order to generate 11 enantioselectively are presently under way. ...
Die Kinetik der Reaktionen von Ethensulfonylfluorid (ESF) mit Sulfonium- und Pyridiniumyliden wurde photometrisch gemessen, um den Elektrophilie-Parameter von ESF gemäß der Korrelation lg k20 °C=sN(N + E) zu bestimmen. Mit E=−12.09 gehört ESF zu den stärksten Michael-Akzeptoren in unserer Substanzklassen-übergreifenden Elektrophilie-Skala, was seine herausragende Eignung als Reaktionspartner für viele Nucleophile erklärt. Die vorhergesagte Befähigung, elektrophile aromatische Substitutionen mit elektronenreichen Arenen einzugehen, wurde durch unkatalysierte Reaktionen mit alkylsubstituierten Pyrrolen verifiziert.
... 1,2-Thiazines under the inventions are highly stable and permit further reactions [8][9][10], such as a reaction with iodine with mercuric oxide as a catalyst that leads to the formation of 6-iodo and 4,6-diiodo-1,2-thiazines (3) and (4) (Scheme 3) [11]. ...
Iodinated heterocyclic molecules are crucial structural components of many natural products, including hormones, vitamins, and medicines. The pharmaceutical survey is very interested in the investigation of the kinetics of the iodination of N-(p-chlorophenyl)-3,5-dimethyl-1,1-dioxo-1,2-thiazine. The rate of iodination is directly dependent on the concentration of both 1,2-thiazine and iodine under different molar ratios (1:10), (10:1) adopted on the isolation method, the observed rate of iodination, the pseudo-first-order and the second order using (1:1) molar ratio in the overall reaction using spectrophotometric techniques. Thermodynamic activation parameters activation energy Ea, enthalpy change ΔH#, entropy change ΔS#, and Gibbs free energy ΔG# of activation were calculated from the rate constant at temperatures 273, 283, 293, 303, and 318 K. KEY WORDS: Production rate, 1,2-Thiazine, Iodine (I2), Kinetic Bull. Chem. Soc. Ethiop. 2023, 37(5), 1253-1262. DOI: https://dx.doi.org/10.4314/bcse.v37i5.16
... Vorbrüggen and Gembus found that organosuperbases were able to promote nucleophilic substitution of sulfonyl fluorides by heteroatoms 25,26 . This strategy has been widely used and further developed by several groups [27][28][29][30][31][32] . Hydrogen bonding was another potential driving force for S VI −F activation 33 , especially during covalent capture of biomolecules under physiological conditions 19,[34][35][36][37][38] . ...
Sulfonyl and sulfonimidoyl fluorides are versatile substrates in organic synthesis and medicinal chemistry. However, they have been exclusively used as S(VI) ⁺ electrophiles for defluorinative ligations. Converting sulfonyl and sulfonimidoyl fluorides to S(VI) radicals is challenging and underexplored due to the strong bond dissociation energy of S VI −F and high reduction potentials, but once achieved would enable dramatically expanded synthetic utility and downstream applications. In this report, we disclose a general platform to address this issue through cooperative organosuperbase activation and photoredox catalysis. Vinyl sulfones and sulfoximines are obtained with excellent E selectivity under mild conditions by coupling reactions with alkenes. The synthetic utility of this method in the preparation of functional polymers and dyes is also demonstrated.
... S ince Sharpless and co-workers introduced sulfur (VI) fluoride exchange (SuFEx) reactions as a new generation of click chemistry 1 , the popularity of sulfonyl fluorides has grown dramatically over the recent past [1][2][3][4] , with applications in a wide range of fields, including organic synthesis [5][6][7][8][9][10] , polymer preparation [11][12][13][14] , materials science [15][16][17] , chemical biology etc [18][19][20] . Particularly, unique and appealing properties were often observed, which has attracted a fast-growing research interest on sulfonyl fluoride being a privileged warhead in chemical biology and drug discovery 1,4,18 , and successful examples keep emerging in the past years [18][19][20][21][22][23][24][25][26][27] . ...
Sulfonyl fluorides have attracted considerable and growing research interests from various disciplines, which raises a high demand for novel and effective methods to access this class of compounds. Radical flurosulfonylation is recently emerging as a promising approach for the synthesis of sulfonyl fluorides. However, the scope of applicable substrate and reaction types are severely restricted by limited known radical reagents. Here, we introduce a solid state, redox-active type of fluorosulfonyl radical reagents, 1-fluorosulfonyl 2-aryl benzoimidazolium triflate (FABI) salts, which enable the radical fluorosulfonylation of olefins under photoredox conditions. In comparison with the known radical precursor, gaseous FSO2Cl, FABI salts are bench-stable, easy to handle, affording high yields in the radical fluorosulfonylation of olefins with before challenging substrates. The advantage of FABIs is further demonstrated in the development of an alkoxyl-fluorosulfonyl difunctionalization reaction of olefins, which forges a facile access to useful β-alkoxyl sulfonyl fluorides and related compounds, and would thus benefit the related study in the context of chemical biology and drug discovery in the future.
... TMS enol ethers derived from unsymmetric diketones gave the expected δ-sultones in good yields and modest regioselectivity. In contrast, TMS enol ethers derived from β-ketoesters gave the methyl-and isopropyl-substituted δ-sultones in good yields (Ungureanu et al., 2015). ...
Sulfonyl drugs are widely used to treat various types of diseases, in which sultones have several desirable properties that have led to their increased use, including improving its simple and effective synthetic methods and/or potentially enhancing potency of drugs. This review focuses on the recent progress in typical synthesis of sultones and the latest developments in various therapeutic applications, including carbonic anhydrase inhibitory activity, HIV-I and HIV-II inhibitory activity, human cytomegalovirus inhibitory activity, and cholinesterase inhibitory activity and their structure-activity relationship. We hope that this review will encourage medicinal chemists to consider the potential benefits to incorporating sultone scaffold into future drug discovery.
... With this aim in mind, we found carboxylic acids are known to readily undergo decarboxylation to release SO alkyl radicals after activated in the form of N-hydroxyphthalimide (NHPI) esters 28-30 via photocatalysis [31][32][33][34][35][36][37][38][39][40][41][42][43] or low-valent transition metal catalysis [44][45][46][47][48] . While vinyl sulfonyl fluoride (VSF), a readily available SO 2 F-containing reagent [49][50][51][52][53][54] , could potentially be employed as the radical acceptor, though its utilization and compatibility in the radical reactions is unknown. Herein, we report our effort on this approach and the invention of a facile and general radical method for the synthesis of aliphatic sulfonyl fluorides based on naturally abundant carboxylic acid feed stock. ...
The past few years have witnessed a fast-growing research interest on the study of sulfonyl fluorides as reactive probes in chemical biology and molecular pharmacology, which raises an urgent need for the development of effective synthetic methods to expand the toolkit. Herein, we present the invention of a facile and general approach for the synthesis of aliphatic sulfonyl fluorides via visible-light-mediated decarboxylative fluorosulfonylethylation. The method is based on abundant carboxylic acid feed stock, applicable to various alkyl carboxylic acids including primary, secondary, and tertiary acids, and is also suitable for the modification of natural products like amino acids, peptides, as well as drugs, forging a rapid, metal-free approach to build sulfonyl fluoride compound libraries of considerable structural diversity. Further diversification of the SO2F-containing products is also demonstrated, which allows for access to a range of pharmaceutically important motifs such as sultam, sulfonate, and sulfonamide.
... Notably, vinyl ethers are electron rich and less reactive and thus less pronounced as cross-coupling partner. [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66] Additionally, the possibility of linear and branched isomer formation along with an additional hydrolysis step to release the carbonyl unit is noteworthy. 67 However, in stark contrast, vinyl ether worked satisfactorily under the current condition in a one-pot process. ...
In nature, enzymatic pathways generate Caryl-C(O) bonds in a site-selective fashion. Synthetically, Caryl-C(O) bonds are synthesised in organometallic reactions using prefunctionalized substrate materials. Electrophilic routes are largely limited to electron-rich systems, non-polar medium, and multiple product formations with a limited scope of general application. Herein we disclose a directed para-selective ketonisation technique of arenes, overriding electronic bias and structural congestion, in the presence of a polar protic solvent. The concept of hard-soft interaction along with in situ activation techniques is utilised to suppress the competitive routes. Mechanistic pathways are investigated both experimentally and computationally to establish the hypothesis. Synthetic utility of the protocol is highlighted in formal synthesis of drugs, drug cores, and bioactive molecules.
Herein, a water‐accelerated, N‐heterocyclic carbene (NHC)‐catalyzed aza‐Michael addition reaction was reported to access β‐aminosulfonyl fluorides, which are key hubs of the sulfur(VI) fluoride exchange (SuFEx) reaction. As a crucial reaction medium, water considerably enhanced the reaction rate with excellent chemo‐ and site‐selectivity (up to >99 : 1) compared to conventional solvents. In addition, the late‐stage ligation of bioactive molecules with the aliphatic β‐amino SuFEx hub was demonstrated. Mechanistic studies on experimental, analytical, and computational approaches support noncovalent activation over NHC catalysis “on‐water”.
The advent of sulfur(vi)-fluoride exchange (SuFEx) processes as transformations with click-like reactivity has invigorated research into electrophilic species featuring a sulfur–fluorine bond. Among these, sulfonyl fluorides have emerged as the workhorse functional group, with diverse applications being reported. Sulfonyl fluorides are used as electrophilic warheads by both medicinal chemists and chemical biologists. The balance of reactivity and stability that is so attractive for these applications, particularly the resistance of sulfonyl fluorides to hydrolysis under physiological conditions, has provided opportunities for synthetic chemists. New synthetic approaches that start with sulfur-containing substrates include the activation of sulfonamides using pyrilium salts, the deoxygenation of sulfonic acids, and the electrochemical oxidation of thiols. Employing non-sulfur-containing substrates has led to the development of transition-metal-catalysed processes based on palladium, copper and nickel, as well as the use of SO2F2 gas as an electrophilic hub. Selectively manipulating molecules that already contain a sulfonyl fluoride group has also proved to be a popular tactic, with metal-catalysed processes again at the fore. Finally, coaxing sulfonyl fluorides to engage with nucleophiles, when required, and under suitable reaction conditions, has led to new activation methods. This Review provides an overview of the challenges in the efficient synthesis and manipulation of these intriguing functional groups. Sulfonyl fluorides are highly electrophilic and yet they exhibit stability towards hydrolysis under physiological conditions. This unique combination makes them highly attractive in chemical biology. This Review looks at the emerging synthetic approaches and applications for this intriguing functional group.
Sulfur(VI) fluoride exchange (SuFEx) click chemistry provides a powerful tool for rapid construction of modular connections. Here, we report a novel catalytic silicon-free SuFEx reaction with sulfonyl fluorides. Under the catalysis of 10 mol% N-heterocyclic carbene (NHC), a range of phenols and alcohols react with different sulfonyl fluorides to afford sulfonate esters in 49-99% yields. In addition, Under the relay catalysis of 10 mol% N-heterocyclic carbene and 10 mol% 1-hydroxybenzotriazole (HOBt), a variety of primary and secondary amines react with different sulfonyl fluorides to produce sulfonamides in 58%-99% yields. More than 140 sulfonylated products, including 17 natural product derivatives have been prepared through this method. Mechanism study showed that NHCs might act as a carbon-centered Brønsted base to catalyse the SuFEx click reactions via the formation of hydrogen bonding with phenols or alcohols.
Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well‐overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp³‐enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non‐classical sp³‐enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gem‐difluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.
[3+2] Cycloaddition reactions of vinyl sulfonyl fluorides with an in‐situ generated nonstabilized azomethine ylide is described for the first time. The resulting pyrrolidine‐3‐sulfonyl fluorides were obtained in 50–83 % yield on a scale of up to 25 g. Their utility as reagents for sulfur(VI)–fluoride exchange (SuFEx) and some other transformations was also demonstrated. [3+2] Cycloaddition reactions of various vinyl sulfonyl fluorides with an unsubstituted azomethine ylide result in the formation of pyrrolidine‐3‐sulfonyl fluorides. The method is scalable, and the products are suitable building blocks for sulfur(VI)–fluoride exchange (SuFEx), which has been referred to as another click reaction.
This microreview summarizes recent advances in sultone synthesis, focusing on the transition metal-catalyzed reactions reported from 2012 to 2017.
Enantioselective organocatalysis by N-heterocyclic carbenes (NHCs) has emerged as a powerful strategy to construct complex chiral molecules. Recent enantioselective NHC-catalyzed reactions have remarkable advances, involving dis-tinct activation intermediates. Which mainly include Breslow intermediate, homoenolate intermediate, α,β-unsaturated acyla-zolium, azolium enolate, and azolium dienolate, generated by the nucleophilic addition of NHC to aldehydes. Meanwhile, NHC-catalyzed reactions through non-covalent bonding interactions have also been developed. Principally, this review focuses on recent advances in enantioselective NHC catalysis.
E )‐2‐(hetero)arylethenesulfonyl fluorides and ( E,E )‐1,3‐dienylsulfonyl fluorides are bis‐electrophiles and rare members of the sulfonyl fluoride family with limited information being known of their reactivity and synthetic utility. The direct annulation reaction of these 2‐substituted ethenesulfonyl fluorides with medicinally important enolizable pyrazolones and 1,3‐dicarbonyl compounds utilizing catalytic DBU in DCM under mild conditions leads to over 50 structurally diverse δ‐sultone fused heterocycles with a pyrazolone ring or a cyclic enone, respectively, in good to excellent yield. The double bond at the 1‐position adjacent to the sulfonyl fluoride group in 1,3‐dienylsulfonyl fluoride is the chemoselective site of reactivity but is less reactive than the double bond of arylethenesulfonyl fluoride. High turnover and robustness of construction for these fused heterocycles, including the novel fused pyrazolone δ‐sultone heterocycle series, may make compounds like these attractive to drug discovery, development and material science.
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A practical oxidative Heck reaction between organoboronic acids and ethenesulfonyl fluoride (ESF) is developed. Aryl‐ and heteroaryl‐boronic acids react efficiently and stereoselectively with ESF in the presence of a catalytic amount of Pd(OAc) 2 and 2,3‐dichloro‐5,6‐dicyano‐ p ‐benzoquinone (DDQ) or AgNO 3 in AcOH to afford the corresponding E ‐isomer of β‐arylethenesulfonyl fluoride products. The utility of this reaction is exemplified by an expanded scope of 47 examples including N‐, O‐, and S‐containing heteroaromatics, demonstrating chemoselectivity over aryliodides, and gram‐scale operation without the requirement for strict anhydrous or oxygen‐free conditions. Furthermore, this procedure discriminates against the formation of arylboronic acids homo‐coupling byproducts. In addition, the preparation of the first aryl vinylsulfonate polymer, a material with functionalizable Michael acceptor sites, from a starting arylboronic acid is described.
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Herein we report the enantioselective (4+2) annulation of donor–acceptor cyclobutanes and unsaturated acyl fluorides using N-heterocyclic carbene catalysis. The reaction allows a 3-step synthesis of cyclohexyl β-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.
Herein we report the enantioselective (4+2) annulation of donor–acceptor cyclobutanes and unsaturated acyl fluorides using N-heterocyclic carbene catalysis. The reaction allows a 3-step synthesis of cyclohexyl β-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.
A strategy for the NHC-catalyzed asymmetric synthesis of spirobenzazepinones, spiro-1,2-diazepinones, and spiro-1,2-oxazepinones has been developed via [3+4]-cycloaddition reactions of isatin-derived enals (3C component) with in-situ-generated aza-o-quinone methides, azoalkenes, and nitrosoalkenes (4atom components). The [3+4] annulation strategy leads to the seven-membered target spiro heterocycles bearing an oxindole moiety in high yields and excellent enantioselectivities with a wide variety of substrates. Notably, the benzazepinone synthesis is atroposelective and an all-carbon spiro stereocenter is generated.
A strategy for the NHC-catalyzed asymmetric synthesis of spirobenzazepinones, spiro-1,2-diazepinones, and spiro-1,2-oxazepinones has been developed via [3+4]-cycloaddition reactions of isatin-derived enals (3C component) with in-situ-generated aza-o-quinone methides, azoalkenes, and nitrosoalkenes (4atom components). The [3+4] annulation strategy leads to the seven-membered target spiro heterocycles bearing an oxindole moiety in high yields and excellent enantioselectivities with a wide variety of substrates. Notably, the benzazepinone synthesis is atroposelective and an all-carbon spiro stereocenter is generated.
The kinetics of the reactions of ethenesulfonyl fluoride (ESF) with sulfonium and pyridinium ylides were measured photometrically to determine the electrophilicity parameter of ESF according to the correlation lg k20 °C =sN (N+E). With E=-12.09, ESF is among the strongest Michael acceptors in our comprehensive electrophilicity scale, which explains its excellent performance in reactions with many nucleophiles. Its predicted usability as a reagent in electrophilic aromatic substitutions with electron-rich arenes was confirmed by uncatalyzed reactions with alkyl-substituted pyrroles.
The controlled metal-free preparation of fused δ-sultone derivatives has been developed starting from hydroxyallenynes. The use of 2-(3,3-diethyltriaz-1-enyl)-4-methylbenzene-1-sulfonyl chloride in a sulfonylation/rearrangement sequence gives access to 1,3-dien-2-yl arenesulfonates. These functionalized enynes suffered a direct cyclization/desaturation radical cascade, allowing the synthesis of a variety of enynyl [1,2]oxathiine 1,1-dioxides. Stereoselective cyclization of the readily formed core through intramolecular Diels-Alder reaction has also been demonstrated, affording β-lactam- and glucofuranoside-fused δ-sultone polycycles. These selective reactions have been studied experimentally and additionally, their reaction mechanisms have been investigated computationally by means of density functional theory calculations.
Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used SVI electrophiles, and the parent sulfuryl chloride, O2SVICl2, has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the SVICl bond is exceedingly sensitive to reductive collapse yielding SIV species and Cl−. Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2-F and SO2F2) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt’s unnoticed 1979 full paper exposition on CH2CH-SO2-F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.
Arylsulfonylchloride (z. B. Ts-Cl) sind die am häufigsten eingesetzten SVI-Elektrophile in der organischen Synthesechemie, und auch die Stammverbindung, das Sulfurylchlorid (O2SVICl2), wurde zur Synthese von Sulfaten und Sulfamiden genutzt. Allerdings wird die gewünschte Halogenidsubstitution oftmals durch die Zersetzung des Schwefelelektrophils in SIV-Spezies und Cl− verhindert, denn die SVI-Cl-Bindung ist äußerst reduktionsanfällig. Mit Schwefel(VI)-fluoriden (z. B. R-SO2-F und SO2F2) verläuft die Umsetzung hingegen ausschließlich über den Substitutionsweg. Wie es bei der Click-Chemie zumeist der Fall ist, wurden viele entscheidende Aspekte der Reaktivität von Schwefel(VI)-fluoriden vor langer Zeit in Deutschland entdeckt.6a Überraschenderweise gerieten diese außerordentlichen Arbeiten in der Mitte des 20. Jahrhunderts ziemlich abrupt aus dem Blickfeld. In diesem Aufsatz versuchen wir, dieser Chemie neues Leben einzuhauchen. Insbesondere stützen wir uns dabei auch auf John Hyatts unbeachtet gebliebene Veröffentlichung über CH2CH-SO2-F aus dem Jahr 1979.98 Wir tragen mehrere neue Beobachtungen bei, einschließlich dem Befund, dass das ansonsten sehr stabile Gas SO2F2 eine exzellente Reaktivität unter den richtigen Umständen aufweist. Wir zeigen auch, dass Protonen oder Siliciumzentren den Austausch von S-F-Bindungen gegen S-O-Bindungen aktivieren können und dass der Sulfat-Konnektor überraschend hydrolysestabil ist. Anwendungen dieser kontrollierbaren Ligationschemie auf kleine Moleküle, Polymere und Biomoleküle werden diskutiert.
Synthesis and some applications of a novel [(18)F]-fluorinated prosthetic group based on the promising sultone radiochemistry and suitable for the labelling of amine-containing (bio)chemical compounds are described. The combined sequential use of two easy and efficient conjugation reactions namely the fluoride ring-opening of a 1,3-propanesultone moiety and the aminolysis of an N-hydroxysuccinimidyl ester is the key component of this original radiolabelling strategy. The mild reaction conditions and the release of a free sulfonic acid moiety as a result of the [(18)F]-induced sultone ring-opening reaction, both make this [(18)F]-conjugation method suitable for the radiofluorination of fragile and hydrophobic biomolecules and fluorophores, particularly by making the separation of the targeted [(18)F]-tagged sulfonated compound from its starting precursor easier and thus faster. The ability of this unusual prosthetic group to readily introduce the radioisotope within complex (bio)molecular architectures has been demonstrated by (1) the preparation of the first [(18)F]-labelled cyanine 5.5 (Cy 5.5) dye, a suitable precursor for the construction of hybrid positron emission tomography/near-infrared fluorescence (PET/NIRF) imaging probes and (2) the radiolabelling of a biologically relevant peptide bearing a single lysine residue.
NHC-Katalysator: Eine Reihe von N-tert-Butyl-substituierten N-heterocyclischen Triazolylidencarbenen wurde hergestellt. Darunter erwies sich der von Morpholinon abgeleitete Katalysator 1 als am besten geeignet für enantioselektive Synthesen von Cyclopropanen ausgehend von Donor-Akzeptor-Cyclopropanen und α,β-ungesättigten Acylfluoriden. Die Aktivität dieses Katalysators wurde durch eine 13C-NMR-Analyse mit den elektronischen Eigenschaften korreliert. M.S.=Molekülsieb, TMS=Trimethylsilyl.
Katalytische Umwandlungen mit N-heterocyclischen Carbenen (NHCs) haben sich als effiziente Ansätze zum Aufbau komplexer Moleküle erwiesen. Seit der Veröffentlichung von Stetter 1975 zur Totalsynthese von cis-Jasmon und Dihydrojasmon durch Carbenkatalyse hat sich die Anwendung von NHCs in der Totalsynthese, insbesondere in den letzten zehn Jahren, schnell verbreitet. Dieser Aufschwung ist zweifellos die Folge neuerer Entwicklungen bei NHC-katalysierten Reaktionen, einschließlich der neuen Benzoin-, Stetter-, Homoenolat- und Aroylierungsprozesse. Die Umwandlungen ermöglichen ebenso typische wie auf Umpolung beruhende Bindungsbildungen und sind bereits als Schlüsselschritte in mehreren neuen Totalsynthesen aufgetreten. Dieser Kurzaufsatz beschreibt diese neuen Arbeiten und zeigt die verstärkten Einsatzmöglichkeiten der Carbenkatalyse in der Totalsynthese auf.
High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
Während sich die organokatalytischen Dominoreaktionen (auch Organokaskadenkatalysen genannt) im letzten Jahrzehnt zu einem wichtigen Hilfsmittel in der Synthesechemie entwickelt haben, fand die Anwendung von N-heterocyclischen Carbenen (NHCs) als Katalysatoren in Dominoreaktionen erst in den letzten drei Jahren zunehmend Beachtung. Unter Berücksichtigung der besonderen Aktivierungsmodi der Substrate durch die NHC-Katalysatoren ist eine Unterscheidung zwischen einer einzelnen chemischen Transformation und einer sequenziellen Eintopfreaktion schwierig. Das Ziel dieses Kurzaufsatzes besteht darin, die Domino-, Kaskaden- und Tandemkatalyse in Gegenwart von NHC-Katalysatoren kritisch zu betrachten und jüngste Publikationen auf diesem Gebiet vorzustellen.
leahciM! Die von einem N-heterocyclischen Carben (NHC) katalysierte Umpolung von Michael-Akzeptoren gelingt unter Bildung von Desoxy-Breslow-Intermediaten (siehe Schema; EWG=elektronenziehende Gruppe). Diese nukleophile Spezies kann intermolekular mit einem weiteren Michael-Akzeptormolekül reagieren, wobei homo- oder heterodimere Olefine entstehen können. Diese „Michael-Umpolung“ kann nützlich für die Synthese dicht funktionalisierter Olefine sein.
The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.
1,4 aber nicht 1,2! Die Reaktivität von 1 gegenüber verschiedenen Nukleophilen (deprotonierte β‐Diketone, Enamine und Malonodinitril) wurde durch NMR‐Spektroskopie und kinetische Experimente untersucht. Die Ergebnisse belegen, dass die C‐C‐Bindungsknüpfung über eine Michael‐1,4‐Addition erfolgt und nicht über eine 1,2‐Addition mit nachfolgender [3,3]‐sigmatroper Umlagerung. Außerdem wird die erste Kristallstruktur eines α,β‐ungesättigten Acylazoliumions 1 vorgestellt.
Ester – was sonst! Eine neue Strategie in der NHC‐Organokatalyse (NHC=N‐heterocyclisches Carben) ermöglicht die α‐, β‐ und γ‐Aktivierung gesättigter und ungesättigter Ester (siehe Schema). Die entstehenden Acylazolium‐Intermediate gehen effizient Dominoreaktionen mit geeigneten Substraten ein, wodurch Carbo‐ und Heterocyclen mit sehr guten Diastereo‐ und Enantioselektivitäten gebildet werden.
In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC50 values of 0.12-1.0μM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC50=0.12μM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC50=1.3μM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents.
Esters-what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.
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.
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.
Alkylimidazole-2-carboxylates may be alkylated with methyl triflate to give the corresponding N-methylimidazolium salts. These salts react with benzyl alcohol in the presence of 1,4-diazabicyclo[2.2.2]octane, with 1-(pyrrolidin-1-yl)cyclohexene and with diethylamine to give benzyl alkyl carbonates, an enamino ester and a urethane respectively; in one case a tetrahedral intermediate is observed. The corresponding phenyl ester was consumed without attack by benzyl alcohol at the carbonyl group. A 2-cyanoimidazolium salt underwent similar ill-defined consumption whereas a 2-dimethylaminocarbonyl derivative remained unchanged. 2-Methylsulfonylimidazolium salts suffered attack by benzyl alcohol at the ring C-2.
A mild and efficient interconversion from silyl ethers to sulfonates esters is reported with good yields. This silyl-sulfonyl exchange proceeds readily in acetonitrile at room temperature in the presence of p-toluenesulfonyl fluoride and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7ene (DBU). This method can be used with trimethysilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl (TBDMS) ethers.
This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed. Cascading down: Reaction of an aldehyde with an NHC provides the corresponding Breslow intermediate A, which can be readily oxidized with various organic and inorganic oxidants to give the acylazolium ion B (see scheme). Intermediate B can react with various nucleophiles either at the 2 or 4-position. With enals as starting aldehydes, elegant cascade processes have been developed using oxidative carbene catalysis.
Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.
The NHC-catalyzed Claisen rearrangement of hybrid Ireland Coates structures has been achieved allowing (3 + 2) annulation between donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The reaction proceeds with high diastereoselectivity (>20:1) affording a diverse range of β-lactone fused cyclopentanes. Mechanistic studies are detailed.
N-Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter's report in 1975 of the total synthesis of cis-jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC-catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.
Ethenesulfonyl fluoride (ESF), a stable compound that is readily available from commercial isethionic acid (2-hydroxyethanesulfonic acid) or 2-chloroethanesulfonyl chloride, was shown to be a highly reactive yet selective and versatile intermediate in the synthesis of a wide variety of organosulfur compounds. ESF reacted with active methylene compounds, amines, sulfinates, and thiols to afford 2-fluorosulfonylethyl derivatives in generally excellent yields. The fluorosulfonyl group was stable to most reaction conditions but could be converted by simple, one-step procedures to sulfonamides, sulfonylimidazolides, and sulfonates and to sulfonic acids. ESF reacted with 2-aminoheterocyclic compounds such as 2-aminopyridine to produce fused 1,2,4-thiadiazine 1,1-dioxides, and it reacted with simple enamines to give 2-aminocyclobutanesulfonyl fluorides. Excellent yields resulted from alkylation of 3-amino-2-butenoates with ESF. Both classes of enamine products could be hydrolyzed to give fluorosulfonylated aliphatic and alicyclic ketones and aldehydes. ESF underwent cycloaddition to 2-methoxyfuran to yield 1-methoxy-6-(fluorosulfonyl)-7-oxabicyclo[2.2.1]hept-2-ene, which was hydrolyzed to 2-(fluorosulfonyl)phenol in water. The general utility of ESF in synthesis was demonstrated by its application in the preparation of over 100 otherwise difficultly accessible new compounds.
Lewis base catalysed 1,3-dipolar cycloaddition between α,β-unsaturated acyl fluorides and N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition experiments and (19)F-NMR studies indicate that the cycloaddition occurs preferentially between the α,β-unsaturated acyl fluoride and the unstabilised azomethine ylide. In addition, an enantioselective variant, using chiral isothiourea catalysts, has been achieved with 14% ee.
N-heterocyclische Carbene können durch konjugierte Umpolung von α,β-ungesättigten Aldehyden unter milden Bedingungen Homoenolatäquivalente erzeugen. Diese organokatalysierte Reaktion ermöglicht eine effiziente einstufige Synthese substituierter γ-Butyrolactone (1; siehe Schema, Mes=Mesityl).
Die asymmetrische Organokatalyse hat sich zu einer effektiven Methode für die Herstellung optisch aktiver Verbindungen entwickelt. Während sich erste Untersuchungen im Wesentlichen auf die Verwendung einfacher Reagentien als Nachweis der Realisierbarkeit konzentrierten, befassen sich neuere Studien der asymmetrischen Organokatalyse nun damit, das Konzept auf ziel- und diversitätsorientierte Synthesen zu erweitern. Dank ihrer zahlreichen Transformationsmöglichkeiten und ihrer Fähigkeit zur Generierung nucleophiler wie auch elektrophiler Reaktionspartner spielen dabei Sulfone als Substrate eine besondere Rolle in der Organokatalyse.
A study was conducted to demonstrate the latest developments in the synthesis and application of sultones. It was demonstrated that several researchers were investigating sultone chemistry, as sultones were synthetically useful heterocycles in organic synthesis. Many powerful methodologies were developed for the synthesis of the sultones, such as intramolecular Diels-Alder reactions, ring-closing metathesis, Pd-catalyzed intramolecular coupling reactions, Rh-catalyzed C-H insertion, and Rh-catalyzed carbene cyclization cycloaddition cascade reactions. The syntheses of sultones have been divided into two categories for better understanding, such as asymmetric synthesis and nonasymmetric synthesis. Asymmetric syntheses of sultones became an attractive goal for the researchers, as chiral sultones offered novel possibilities for stereoselective transformations.
1,4 but not 1,2! The reactivity of 1 towards different nucleophiles (deprotonated β-diketones, enamines, and malonodinitrile) was investigated by NMR and kinetic experiments. These investigations proved that CC bond formation occurs by a Michael-type 1,4-addition and not by a 1,2-addition and subsequent [3,3]-sigmatropic rearrangement. The first X-ray structure of an α,β-unsaturated acyl azolium salt (1) is also presented.
N-heterocyclic carbenes catalyze the rearrangement of 1,1-bis(arylsulfonyl)ethylene to the corresponding trans-1,2-bis(phenylsulfonyl) under mild conditions. Tandem rearrangement/cycloadditions have been developed to capitalize on this new process and generate highly substituted isoxazolines and additional heterocyclic compounds. Preliminary mechanistic studies support a new conjugate addition/Umpolung process involving the ejection and subsequent unusual re-addition of a sulfinate ion.
The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
The N-heterocyclic carbene catalyzed (4 + 2) cycloaddition between α,β-unsaturated acid fluorides and TMS dienol ethers provides cyclohexene fused β-lactone intermediates stable below -20 °C. These can be intercepted reductively or with organolithium reagents to produce diastereomerically pure cyclohexenes (>20:1 dr) with up to four contiguous stereocenters. The mechanism has been investigated using theoretical calculations and by examining secondary kinetic isotope effects. Together these studies implicate the formation of a diastereomerically pure β-lactone intermediate by a stepwise (4 + 2) cycloaddition involving Michael addition, aldol cyclization, and lactonization.
While organocatalyzed domino reactions or "organocascade catalysis" developed into an important tool in synthetic chemistry during the past decade, the utility of N-heterocyclic carbenes (NHCs) as catalysts in domino reactions has only received growing attention in the past three years. Taking into account the unique activation modes of the substrates by NHC catalysts, it is often difficult to distinguish between a single chemical transformation and a sequential one-pot transformation. Therefore, herein we present a critical consideration of domino, cascade, and tandem catalysis in the case of NHC catalysts and highlight recent publications in this area.
Sultones were subject to ring opening by nucleophilic attack with [(18)F]fluoride to afford easily purified (18)F-labelled hydrophilic sulfonated products in high yields. A two-step sequence including radiofluorination and coupling to lysine was then developed from a bis-sultone precursor as a model approach for the labelling of biopolymers.
leahciM! The N-heterocyclic carbene catalyzed umpolung of Michael acceptors proceeds through the formation of a deoxy-Breslow intermediate (see scheme; EWG=electron-withdrawing group). This nucleophilic species can react with other Michael acceptors in an intermolecular fashion, thereby resulting in the formation of homo- or heterodimeric olefins. This "Michael umpolung" should become a valuable method for the formation of densely functionalized olefins.
Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon β to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,β-unsaturated aldehydes via N-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.
Highly selective tail-to-tail dimerization of methyl methacrylate has been realized by an N-heterocyclic carbene catalyst, giving dimethyl 2,5-dimethyl-2-hexenedioate with an E/Z ratio of 95:5 in 86% isolated yield. The umpolung mechanism is proposed on the basis of interception of the intermediates using ESI-MS analyses and deuterium-labeling experiments.
We have designed and synthesized novel irreversible serine protease inhibitors containing aliphatic sulfonyl fluorides as an electrophilic trap. These substituted taurine sulfonyl fluorides derived from taurine or protected amino acids were conveniently synthesized from β-aminoethanesulfonyl chlorides using KF/18-crown-6 or from β-aminoethanesulfonates using DAST. Their potency of irreversible inhibition of serine proteases is described in different enzyme assays using chymotrypsin leading to binding affinities up to 22 μM.
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.
The development of new asymmetric methodologies that afford different structures in an enantioselective fashion is one of the most exciting goals for chemists nowadays. In this subject, lately, the use of sulfones has become a fast growing field. From the works of Tan and Shibata until the last works of Palomo, sulfones have demonstrated their versatility and power in organocatalytic asymmetric reactions. Moreover, the easy removal of sulfones with Mg or Hg/Na makes this group a perfect choice to afford easily naked alkyls. Remarkably, bissulfones can be used as nucleophiles or electrophiles, being vinyl sulfones excellent electrophiles, while bismethylensulfones derivatives such as fluoro are excellent nucleophiles. This double possibility has been studied by several research groups, leading to new methodologies that allow obtaining formally simple alkylation in an enantioselective fashion, by using organocatalysis. The aim of this tutorial review is to summarize the last trends in the use of sulfones in organocatalytic processes, giving a complete scenario of these new reagents.
cis-1,2-Cyclohexanediol (L3) has been shown to be an efficient and versatile bidentate O-donor ligand that provides a highly active Cu-catalytic system. It was more effective than diols such as trans-1,2-cyclohexanediol or ethylene glycol. This commercially available cis-1,2-cyclohexanediol ligand facilitated the Cu-catalyzed cross-coupling reactions of alkyl, aryl, or heterocyclic thiols with either alkyl, aryl, heterocyclic, or substituted vinyl halides. This new catalytic system promoted the mild and efficient stereo- and regiospecific synthesis of biologically important vinyl sulfides. The yields obtained using electron-rich substituted vinyl sulfides with this catalyst system are generally 75-98%. Most importantly, this singular catalyst system is extremely versatile and provides entry into a wide range of sulfides. This method is particularly noteworthy given its mild reaction conditions, simplicity, generality, and exceptional level of functional group tolerance.
Asymmetric organocatalysis has become a powerful tool for the synthesis of optically active compounds. Whereas early research mainly focused on combining simple reagents as a proof-of-concept for asymmetric organocatalysis, recent investigations are directed towards extending the concept to more target- and diversity-oriented synthesis. As a result of the many transformation possibilities and their ability to generate both nucleophilic and electrophilic reaction partners, sulfones have become especially important substrates in the field of organocatalysis.
(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 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.
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]
N-Heterocyclic carbenes can catalyze beta-alkylations of a range of alpha,beta-unsaturated esters, amides, and nitriles that bear pendant leaving groups to form a variety of ring sizes. In this process, the nucleophilic catalyst transiently transforms the normally electrophilic beta carbon into a nucleophilic site through an unanticipated addition-tautomerization sequence.
The extensive applications and reaction pathways of thiazol- (A), triazol- (B), imidazol- (C), and imidazolin-2-ylidenes (D) as versatile synthetic methods were discussed. The organocatalytic process have made synthetic strategies in addition to its facile reaction, selectivity and its being environmental friendly. The topics being described include the enzymes as archetypes, the benzoin condensation, the stetter reaction, the a3 to d3 umpolung, the transesterification reactions, the polymerization reactions, the ring-opening reactions, and finally the 1,2-additions.
- De Castro
Mayr unpublished results
- D Allgauer