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The azomethine ylides are generally used in 1,3-dipolar cycloadditions with various dipolarophiles. In this work, a new and diverse route has been developed for the azomethine ylides, for synthesis of novel pyrrole derivatives. The azomethine ylide, produced via C–H activation of unreactive C(sp3)–H bond of 2-methylquinoline, by molecular iodine, in the presence of pyridine. Herein, we represent novel pyrrole derivatives, synthesized from the reaction of pyridinium ylide with olefins, which formed via a reaction of isatin, dialkyl acetylenedicarboxylate derivatives and pyridine as a base in moderate to excellent yields. Various features of this cyclization, discussed.

Primary acyl-phosphines are scarce in the literature. Here we show that the reaction of Ph3 GePCO with the ylide Ph3 PCH2 proceeds to give the species Ph3 PCHC(O)PH(GePh3 ) 1. Deprotonation of 1 with Na[N(SiMe3 )2 ] generates the salt [Na(THF)2 ][Ph3 PCHC(O)P(GePh3 )] 2 which provides subsequent access to the bis-germanylated acylphosphine, Ph3 PCHC(O)P(GePh3 )2 3. Alternatively, treatment of 1 with HCl in dioxane affords the primary acylphosphine Ph3 PCHC(O)PH2 4. Compound 4 is a rare example of an air stable primary acyl-phosphines and the first devoid of a stabilizing heteroatom adjacent to the carbonyl fragment.

Metal carbene plays a vital role in modern organic synthesis. The neutral divalent carbon of metal carbene renders it an active intermediate throughout a range of reactions. In experiments, diverse metal carbene-related transformation reactions have been established, including transition-metal-catalyzed cross-coupling reactions using N-heterocyclic carbenes as ligands, metal carbene insertion into σ bonds, cyclopropanations, ylide formation, and so forth. The remarkable progress achieved in synthetic chemistry, in turn, has increased the demand for mechanistic studies of carbene chemistry. A thorough understanding of reaction mechanisms can extend the application scope of metal carbene compounds and inspire the rational design of new carbene transformation reactions.Density functional theory (DFT) calculations have been performed in our group to gain more mechanistic insights into metal carbene-related reactions. This account focuses on computational studies of transition-metal-catalyzed carbene transformation reactions with nucleophiles. The generation of metal carbene or metal-ligated free carbene and subsequent carbene transformation pathways is discussed. According to our mechanistic studies of carbene transformation with nucleophiles, three generalized reaction models are summarized, including the intramolecular migratory insertion of metal carbene, intermolecular nucleophilic addition toward metal carbene, and outer-sphere nucleophilic addition to the metal-ligated free carbene.In general, the intermolecular nucleophilic addition mechanism is commonly proposed since metal carbene has an electrophilic carbene carbon. From a mechanistic point of view, the intramolecular migratory insertion mechanism is also widely used because metal carbene insertion into σ bonds formally occurs through this mechanism. An outer-sphere nucleophilic addition mechanism is proposed for reactions that form a metal-ligated free carbene complex instead of the commonly proposed metal carbene. The metal-ligated free carbene complex contains a naked carbene carbon that is not coordinated with the metal center. In this case, a transition-metal catalyst is used only as a Lewis acid, and nucleophilic addition occurs directly at the free carbene carbon. Our computational results suggested that outer-sphere nucleophilic addition is a facile step because metal ligation could stabilize the transition state as well as the generated intermediate. The intramolecular migratory insertion mechanism also has a low energy barrier due to the lack of an entropy penalty. Carbene formation from carbene precursors is usually the rate-determining step, except in intermolecular nucleophilic addition, and the reactivity of nucleophiles has a significant influence on the overall reaction rate. We can also envision that the weak nucleophilicity of nucleophiles would suppress outer-sphere nucleophilic addition. These computational studies showcase the characteristics of three carbene transformation models, and we hope that it will spur the development of mechanistic studies of carbene chemistry.

The first C5 polymerization is reported, where the main‐chain is growing by five carbon atoms of the monomer at a time. Three dienyltriphenylarsonium ylide monomers were synthesized and polymerized with triethylborane as an initiator, leading to random terpolymers (C1, C3, C5) with mainly C5 repeating units (up to 84.1 %). It has been found that the methyl group (electron‐donating substituent) on the conjugated double bond of the ylides facilitates the formation of C5 segments. A mechanism was proposed based on NMR characterization and DFT calculations. The high C5 content ensures that things are on the right track for pure C5 homopolymerization., Reported for the first time is an unusual borane‐initiated polymerization of arsonium ylide monomers, where the main‐chain grows by five carbon atoms, from the monomer, at a time and leads to unique structures.

Endohedral clusterfullerenes exhibit unique chemical properties due to intramolecular electron transfer of the encaged metal cluster to the outer fullerene cages. Herein, we report the synthesis of two Sc 3 N@ D 3 h -C 78 monoadducts 2a and 2b through the 1, 3-dipolar reaction of Sc 3 N@ D 3 h -C 78 with carbonyl ylide bearing anomalous cis-conformation regioselectivity. The molecular structures of these monoadducts are unambiguously confirmed by single-crystal X-ray crystallography, revealing that both of 2a and 2b have cis-conformations within furan moiety grafted via [6,6]-closed addition patterns. Under the same conditions, the control reaction of C 60 with carbonyl ylide affords two monoadducts 3a and 3b , which however exhibit respectively the cis - and trans -conformations with [6,6]-closed addition patterns. According to theoretical calculations, the exclusive formation of the cis -only Sc 3 N@ D 3 h -C 78 monoadducts is interpreted by the conjunct effects of thermodynamic stability of adducts, the reactivity of the addition site, and the cis-dipole intermediate from trans 1 .

The Mes2 P-C≡C-SiMe3 alkyne reacts with the borane H2 B-Fmes by means of a rare 1,1-hydroboration reaction to give an unsaturated C2 -bridged frustrated P/B-H Lewis pair. Most of its reactions are determined by the presence of the B-H functionality at the FLP function and the activated connecting carbon-carbon double bond. It reduces carbon monoxide to the formyl stage. With nitriles it reacts in an extraordinary way: it undergoes a reaction sequence that eventually results in the formation of a P-substituted dihydro-1,2-azaborole derivative. Several similar examples were found. In one case a P-ylide was isolated that was related to an intermediate of the reaction sequence. It subsequently opened in an alternative way to give an alkenyl borane product.

The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.

We report a new class of stable mesoionic N‐heterocyclic olefins, featuring a highly polarized (strongly ylidic) double bond. The ground‐state structure cannot be described through an uncharged mesomeric Lewis‐structure, thereby structurally distinguishing them from traditional N‐heterocyclic olefins (NHOs). mNHOs can easily be obtained through deprotonation of the corresponding methylated N,N′‐diaryl‐1,2,3‐triazolium and N,N′‐diaryl‐imidazolium salts, respectively. In their reactivity, they represent strong σ‐donor ligands as shown by their coordination complexes of rhodium and boron. Their calculated proton affinities, their experimentally derived basicities (competition experiments), as well as donor abilities (Tolman electronic parameter; TEP) exceed the so far reported class of NHOs., Highly charged: A new class of mesoionic N‐heterocyclic olefins is described featuring a highly ylidic double bond. The compounds can be utilized as ligands in main‐group and transition metal chemistry. Their donor properties exceed previously reported traditional N‐heterocyclic olefins.

The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfur ylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.

Catalytic enantioselective [2,3] Stevens and Sommelet-Hauser rearrangements of α-diazo pyrazoleamides with sulfides were achieved by utilizing chiral N,N'-dioxide/nickel(II ) complex catalysts. These rearrangements proceeded well under mild reaction conditions, providing rapid and facile access to a series of functionalized 1,6-dicarbonyls or sulfane-substituted phenylacetates with high to excellent enantioselectivities. The catalytic system shows excellent stereocontrol, discriminating between the heterotopic lone pairs of sulfur and controlling both the 1,3-proton transfer and the [2,3]-σ rearrangement.

A Rh(I)/Sc(III) co-catalyzed synthesis of highly valuable functionalized 1,4-diketone derivatives in good yields and with an excellent diastereoselectivity. The established method provides a rapid approach to structurally diverse 1,4-diketone scaffold in a very mild and rapid fashion from simple starting materials. Moreover, the protocol could be easily scaled up to gram-scale synthesis. An attempt to develop an asymmetric version of the Rh(I)/guanidine system was also explored, resulting in a moderate enantioselectivity (71% ee).

Methods to synthesize alkylated pyridines are valuable because these structures are prevalent in pharmaceuticals and agrochemicals. We have developed a distinct approach to construct 4-alkylpyridines using dearomatized pyridylphosphonium ylide intermediates in a Wittig olefination-rearomatization sequence. Pyridine N-activation is key to this strategy, and N-triazinylpyridinium salts enable coupling between a wide variety of substituted pyridines and aldehydes. The alkylation protocol is viable for late-stage functionalization, including methylation of pyridine-containing drugs. This approach represents an alternative to metal-catalyzed sp2 -sp3 cross-coupling reactions and Minisci-type processes.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of cortisone to cortisol and controls a key pathway in the regulation of stress. Studies have implicated 11β-HSD1 in metabolic diseases including type 2 diabetes and obesity, as well as stress-related disorders and neurodegenerative diseases, such as depression and Alzheimer's disease (AD). We have previously developed [11C]AS2471907 as a PET radiotracer to image 11β-HSD1 in the brain of nonhuman primates and humans. However, the radiosynthesis of [11C]AS2471907 was unreliable and low-yielding. Here, we report the development of the 18F-labeled version [18F]AS2471907, including the synthesis of two iodonium ylide precursors and the optimization of 18F-radiosynthesis. Preliminary PET experiments, composed of a baseline scan of [18F]AS2471907 and a blocking scan with the reversible 11β-HSD1 inhibitor ASP3662 (0.3 mg/kg), was also conducted in a rhesus monkey to verify the pharmacokinetics of [18F]AS2471907 and its specific binding in the brain. The iodonium ylide precursors were prepared in a seven-step synthetic route with an optimized overall yield of ∼2%. [18F]AS2471907 was synthesized in good radiochemical purity, with the ortho regioisomer of iodonium ylide providing greater radiochemical yield as compared with the para regioisomer. In monkey brain, [18F]AS2471907 displayed high uptake and heterogeneous distribution, while administration of the 11β-HSD1 inhibitor ASP3662 significantly reduced radiotracer uptake, thus demonstrating the binding specificity of [18F]AS2471907. Given the longer half-life of F-18 and feasibility for central production and distribution, [18F]AS2471907 holds great promise to be a valuable PET radiotracer to image 11β-HSD1 in the brain.

A novel rhodium-catalyzed dearomatization of O-substituted pyridines to access N-substituted 2-pyridones has been developed. A computational study suggests a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4-acyl migratory rearrangement from O to C. Furthermore, the chiral dirhodium complexes serve as the catalyst for the asymmetric transformation with excellent enantioselective control. DFT calculations indicate the chirality is transferred from axial chirality to the central stereogenic centre. The stronger π-π interaction and CH-π interaction account for the high enantioselectivity.

Cycloadditions are powerful processes to synthesize complex polycyclic scaffolds. Herein, we disclose a [4+3]-cycloaddition between an in situ generated ortho-quinone methide and an isomunchnone to yield oxa-bridged oxazocine cores, generating N2 and H2 O as the sole by-products. Using only catalytic amounts of camphorsulfonic acid, it is possible to generate both reactive intermediates in one step, eliminating the need for rhodium catalysts generally employed for isomunchnone formation. Spectroscopic data and X-ray crystallography indicate the formation of the syn diastereomer, with the main side-product arising from a hydrate participating in a competing [4+2]-cycloaddition pathway.

A convenient method for synthesizing elongated aliphatic esters from alkenes is reported. An (alkoxycarbonyl)methyl radical species is generated upon visible-light irradiation of an ester-stabilized phosphorus ylide in the presence of a photoredox catalyst. This radical species adds onto the carbon-carbon double bond of an alkene to produce an elongated aliphatic ester.

The assigned structure of the dinoflagellate-derived toxin belizentrin was prepared by total synthesis in form of the corresponding methyl ester for stability reasons. The successful route features an unusual solution for the preparation of a recalcitrant ylide on a C-glycosidic segment; moreover, it involves an asymmetric hetero-Diels-Alder reaction en route to the tertiary hemiacetal substructure, a Negishi cross-coupling of two elaborate building blocks, and a macrocyclization based on an intramolecular aminolysis of a spirolactone. A modified Kocienski olefination ultimately allowed the polyol side chain to be attached to the macrocycle although this transformation faced the exceptional base sensitivity of this polyunsaturated target compound.

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the β-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

Phosphines are important ligands in homogenous catalysis and have been crucial for many advances, such as in cross‐coupling, hydrofunctionalization, or hydrogenation reactions. Herein we report the synthesis and application of a novel class of phosphines bearing ylide substituents. These phosphines are easily accessible via different synthetic routes from commercially available starting materials. Owing to the extra donation from the ylide group to the phosphorus center the ligands are unusually electron‐rich and can thus function as strong electron donors. The donor capacity surpasses that of commonly used phosphines and carbenes and can easily be tuned by changing the substitution pattern at the ylidic carbon atom. The huge potential of ylide‐functionalized phosphines in catalysis is demonstrated by their use in gold catalysis. Excellent performance at low catalyst loadings under mild reaction conditions is thus seen in different types of transformations.

Described herein is a direct cyclization of simple tertiary aryl amines with iodonium ylides leading to a broad range of N-heterocycles. Completely different from the known reactivity of iodonium ylides, the finding reported herein is that an iodonium ylide is capable of cleaving a C(sp3 )-H bond and accepting two hydrogen atoms of a tertiary aryl amine, thus inducing a novel cyclization process. This transformation can proceed without the assistance of a transition-metal catalyst and eliminates the need for the premodification of the amine or the use of an additional initiator/oxidant.

Silanone substituted by bulky amino- and phosphonium bora-ylide substituents has been isolated in crystalline form. Thanks to the exceptionally strong electron-donating phosphonium bora-ylide substituent, the life-time at room temperature of silanone 2 is dramatically extended (t1/2 = 4 days) compared to the related (amino)(phosphonium-ylide)silanone (t1/2 = 5 hours), allowing easier manipulation and its use as precursor of new valuable silicon compounds. The interaction of silanone with a weak Lewis acid such as MgBr2 increases further its stability (no degradation after 3 weeks at room temperature).

The reaction of (C5Me5)2Th(CH3)2 with the phosphonium salts [CH3PPh3]X (X=Cl, Br, I) was investigated. When X=Br and I, two equivalents of methane are liberated to afford (C5Me5)2Th[CHPPh3]X, rare terminal phosphorano-stabilized carbenes with thorium. These complexes feature the shortest thorium–carbon bonds (≈2.30 A) reported to date, and electronic structure calculations show some degree of multiple bonding. However, when X=Cl, only one equivalent of methane is lost with concomitant formation of benzene from an unstable phosphorus(V) intermediate, yielding (C5Me5)2Th[κ2-(C,C′)-(CH2)(CH2)PPh2]Cl. Density functional theory (DFT) investigations of the reaction energy profiles for [CH3PPh3]X, X=Cl and I showed that in the case of iodide, thermodynamics prevents the production of benzene and favors formation of the carbene.

Highly selective divergent cycloaddition reactions of enoldiazo compounds and α-diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2-a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]-cycloaddition of a carbonyl ylide. Use of Rh2 (pfb)4 or Rh2 (esp)2 directs the reactants to regioselective [3+2]-cycloaddition generating cyclopenta[2,3]pyrrolo[2,1-b]oxazoles with good yields and excellent diastereoselectivities.

Two electrophilic monofluoromethylating reagents S-monofluoromethyl-S-phenyl-bis(carbomethoxy) methylide sulfonium ylide 3a and S-monofluoromethyl-S-(4-nitrophenyl)-bis(carbo -methoxy) methylide sulfonium ylide 3b and their reactions with a variety of nucleophiles such as alcohols and malonate derivatives, sulfonic and carboxylic acids, phenols, amides, and nitrogen of heteroarenes under mild conditions were described. Mechanistic studies by employing deuterated reagents 3a-D2/3b-D2 suggest that these monofluoromethylating reactions proceed via an electrophilic substitution pathway.

Electropositive boron-based substituent (phosphonium bora-ylide) with an exceptionally strong π- and σ-electron donating character dramatically increases the stability of a new type of N-heterocyclic silylene 2 featuring amino- and bora-ylide-substituents. Moreover, the related silylium ion 4 and transition-metal–silylene complexes, with trigonal-planar geometries around the silicon center, are also well stabilized. Therefore, the N,B-heterocyclic silylene 2 can be used as a strongly electron-donating innocent ligand in coordination chemistry similarly to N-heterocyclic carbenes.

The first highly enantioselective, diastereoselective, and regioselective [2,3]-rearrangement of iodonium ylides has been developed as a general solution to catalytic onium ylide rearrangements. In the presence of a chiral copper catalyst, substituted allylic iodides couple with α-diazoesters to generate metal-coordinated iodonium ylides, which undergo [2,3]-rearrangements with high selectivities (up to >95:5 r.r., up to >95:5 d.r., and up to 97 % ee). The enantioenriched iodoester products can be converted stereospecifically into a variety of onium ylide rearrangement products, as well as compounds that are not accessible by classical onium ylide rearrangements.

The umpolung alkylation of silyl enol ethers with an iodonium(III) ylide proceeds under mild conditions to afford various 1, 4‐dicarbonyl compounds in high yields in the presence of a halogen‐bonding catalyst. Unlike typical transition‐metal activation processes of such ylide precursors, which tend to proceed via carbenoid intermediates, experimental and computational studies indicate that halogen bonding (XB) between the XB donor catalyst and the iodonium ylide plays a crucial role in promoting the reaction. The identification of a compatible Bronsted base catalyst enabled the extension of this method to enols generated in situ to give the corresponding adducts in good yields.

A borylidene-phosphorane, the lightest phosphoranylidene, which is stabilized by an N-heterocyclic carbene ligand, was synthesized and fully characterized. Experimental electron density analysis and DFT calculations indicate an enhanced ylene character (rather than an ylide character) with an exceptionally strong B→P π-back bonding related to the less electronegative boron compared to phosphorus.

Treatment of [Ph3 EMe][I] with [Na{N(SiMe3 )2 }] affords the ylides [Ph3 E=CH2 ] (E=As, 1As; P, 1P). For 1As this overcomes prior difficulties in the synthesis of this classical arsonium-ylide that have historically impeded its wider study. The structure of 1As has now been determined, 45 years after it was first convincingly isolated, and compared to 1P, confirming the long-proposed hypothesis of increasing pyramidalisation of the ylide-carbon, highlighting the increasing dominance of E+ -C- dipolar resonance form (sp3 -C) over the E=C ene π-bonded form (sp2 -C), as group 15 is descended. The uranium(IV)-cyclometallate complex [U{N(CH2 CH2 NSiPri3 )2 (CH2 CH2 SiPri2 CH(Me)CH2 )}] reacts with 1As and 1P by α-proton abstraction to give [U(TrenTIPS )(CHEPh3 )] (TrenTIPS =N(CH2 CH2 NSiPri3 )3 ; E=As, 2As; P, 2P), where 2As is an unprecedented structurally characterised arsonium-carbene complex. The short U-C distances and obtuse U-C-E angles suggest significant U=C double bond character. A shorter U-C distance is found for 2As than 2P, consistent with increased uranium- and reduced pnictonium-stabilisation of the carbene as group 15 is descended, which is supported by quantum chemical calculations.

The application of aziridines as nonvulnerable mechanophores is reported. Upon exposure to a mechanical force, stereochemically pure nonactivated aziridines incorporated into the backbone of a macromolecule do not undergo cis-trans isomerization, thus suggesting retention of the ring structure under force. Nonetheless, aziridines react with a dipolarophile and seem not to obey conventional reaction pathways that involve C-C or C-N bond cleavage prior to the cycloaddition. Our work demonstrates that a nonvulnerable chemical structure can be a mechanophore.

We have developed a method for the highly diastereo- and enantioselective construction of 2,3-dihydrobenzofurans bearing tetrasubstituted carbon stereocenters by means of annulation reactions between carbenes and 2-iminyl- or 2-acyl-substituted phenols through catalysis by readily accessible copper(I)/bisoxazoline catalysts under mild conditions. These reactions feature a unique mechanism in which the copper catalyst serves a dual function: first it reacts with the diazo compound to generate a metal carbene, and second, upon formation of an oxonium ylide, it acts as a Lewis acid to activate the imine or ketone for diastereo- and enantioselective cyclization.

The metalated ylide YNa [Y=(Ph3PCSO2Tol)−] was employed as X,L‐donor ligand for the preparation of a series of boron cations. Treatment of the bis‐ylide functionalized borane Y2BH with different trityl salts or B(C6F5)3 for hydride abstraction readily results in the formation of the bis‐ylide functionalized boron cation [Y−B−Y]+ (2). The high donor capacity of the ylide ligands allowed the isolation of the cationic species and its characterization in solution as well as in solid state. DFT calculations demonstrate that the cation is efficiently stabilized through electrostatic effects as well as π‐donation from the ylide ligands, which results in its high stability. Despite the high stability of 2 [Y−B−Y]+ serves as viable source for the preparation of further borenium cations of type Y2B+←LB by addition of Lewis bases such as amines and amides. Primary and secondary amines react to tris(amino)boranes via N−H activation across the B−C bond.

A novel cascade reaction has been developed for the synthesis of 2,6-methanopyrrolo[1,2-b]isoxazoles based on the gold-catalyzed generation of an N-allyloxyazomethine ylide. This reaction involves sequential [3+2]/retro-[3+2]/[3+2] cycloaddition reactions, thus providing facile access to fused and bridged heterocycles which would be otherwise difficult to prepare using existing synthetic methods. Notably, this reaction allows the efficient construction of three C-C bonds, one C-O bond, one C-N bond and one C-H bond, as well as the cleavage of one C-C bond, one C-O bond and one C-H bond in a single operation. The intermolecular cycloaddition of an N-allyloxyazomethine ylide and the subsequent application of the product to the synthesis of tropenol is also described.

An isolable heterocyclic silylene (4) with two different π-donating substituents, namely a classical amino group and a more electropositive and stronger carbon-based π-donating phosphonium ylide, was synthesized and fully characterized. The combination of these two different π-donating substituents confers high thermal stability and an unusual nucleophilic character on silylene 4. Therefore, silylene 4 behaves as a strong donor ligand toward transition metals with a donating character comparable to N-heterocyclic carbenes, in contrast to classical N-heterocyclic silylenes, which generally present a weak donating character.

The first example of a biocatalytic [2,3]-sigmatropic rearrangement reaction involving allylic sulfides and diazo reagents (Doyle-Kirmse reaction) is reported. Engineered variants of sperm whale myoglobin catalyze this synthetically valuable C–C bond forming transformation with high efficiency and product conversions across a variety of sulfide substrates (i.e., aryl-, benzyl-, and alkyl-substituted allylic sulfides) and α-diazo esters. Moreover, the scope of this myoglobin-mediated transformation could be extended to the conversion of propargylic sulfides to give substituted allenes. Active site mutations proved effective toward enhancing the catalytic efficiency of the hemoprotein in these reactions as well as modulating its enantioselectivity, resulting in the identification of a myoglobin variant, Mb(L29S, H64V, V68F), capable of mediating asymmetric Doyle-Kirmse reactions with an enantiomeric excess up to 71%. This work extends the toolbox of currently available biocatalytic strategies for realizing the asymmetric formation of carbon–carbon bonds.

A general method for the formation of alkyl difluoromethylethers under mild reaction conditions and with good functional-group tolerance was developed. The development of the method was based on the invention of a stable, electrophilic, difluoromethylating reagent, difluoromethyl-(4-nitrophenyl)-bis(carbomethoxy) methylide sulfonium ylide, which was synthesized by reaction of the easily available 4-nitrophenyl (difluoromethyl)thioether and dimethyl diazomalonate in the presence of a rhodium catalyst.

We have developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylides and cyclic imines with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings-azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participate in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into the core skeletons of bioactive natural products. DFT calculations revealed that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition.

This is the peer reviewed version of the following article: Vaitla, J., Bayer, A. & Hopmann, K.H. (2018). Iron‐Catalyzed Carbenoid Transfer Reactions of Vinyl Sulfoxonium Ylides: An Experimental and Computational Study. Angewandte Chemie International Edition, 57(49), 16180-16184, which has been published in final form at https://doi.org/10.1002/anie.201810451. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. A method for the generation of unprecedented vinyl carbenoids from sulfoxonium ylides has been developed and applied in the synthesis of a diverse array of heterocycles such as indolizines, pyrroles, 3‐pyrrolin‐2‐ones, and furans. The reactions proceed by FeBr2 catalysis under mild reaction conditions with a broad substrate scope. A reaction pathway involving iron carbenoids is proposed based on a series of control experiments and DFT calculations.

The first example of iron-catalyzed decarboxylative (4+1) cycloaddition reactions is described in this publication. By using this method, a wide range of functionalized indoline products were prepared from easily available vinyl benzoxazinanones and sulfur ylides in high yields and selectivities. A possible reaction pathway involving an allylic iron intermediate is discussed based on a series of control experiments and density-functional theory calculations.

We report herein a powerful and highly stereoselective protocol for the domino-type reaction of diazoesters with ortho-quinone methides generated in situ to furnish densely functionalized chromans with three contiguous stereogenic centers. A transition-metal and a Bronsted acid catalyst were shown to act synergistically to produce a transient oxonium ylide and ortho-quinone methide, respectively, in two distinct cycles. These intermediates underwent subsequent coupling in a conjugate-addition-hemiacetalization event in generally good yield with excellent diastereo- and enantioselectivity.

Using dimethylsulfoxonium methylide as the methylene transfer reagent, 2a,8b-dihydrobenzo[b]cyclobute[d]pyran-3-ones were converted into 2,2'-biphenol derivatives as major products and dihydrodibenzofurans as minor products. The reaction mechanism was extrapolated from a deuteration experiment with CD2=S(O)(CD3)2.

Nickel wurde als Katalysator fur die Cyclopropanierung von unaktivierten Olefinen durch in situ hergestelltes Lithiomethyltrimethylammoniumtriflat als Methylendonor identifiziert. Eine mechanistische Hypothese wird vorgeschlagen, welche die Entstehung eines reaktiven Nickelcarben beinhaltet, um einige interessante Beobachtungen zu erklaren. Zudem beleuchten unsere Resultate einen Bericht von Franzen und Wittig aus dem Jahre 1960, der spater wegen Irreproduzierbarkeit zuruckgezogen wurde, und liefern eine rationale Basis fur eine systematische Entwicklung der Reaktion fur praparative Zwecke als Alternative zu Diazomethan oder Simmons-Smith-Bedingungen.

A Bu3P-mediated cyclization reaction of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2-c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl-substituted furo[3,2-c]coumarins by the treatment with carbonyl electrophiles under basic conditions.

Benzopyrylium ylides generated in situ from 1-acetoxyisochroman-4-ones reacted with α,β-unsaturated aldehydes in the presence of a bifunctional secondary-amine/squaramide catalyst to furnish [5+2] cycloaddition products in good yield with high diastereo- and enantioselectivity. The reaction proceeds by dienamine activation and involves β,γ-functionalization of the enal. The dienamine intermediates showed exclusive β,γ-reactivity and provided direct access to compounds with the 8-oxabicyclo[3.2.1]octane framework. The ability of the bifunctional secondary-amine/squaramide catalyst to engage in hydrogen-bonding interactions with the ylide made it particularly effective in terms of both the yield and the stereoselectivity of the transformation.

The functionalization of carbon-hydrogen bonds in non-nucleophilic substrates using α-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross-coupling reactions of sulfoxonium ylides with C(sp2 )-H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C-H activation, migratory insertion of the ylide into the carbon-metal bond, and protodemetalation, the last step being turnover-limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium-catalyzed dehydrative cyclization.

The chiral Rh(I)-diene-catalyzed asymmetric three-component reaction of aryldiazoacetates, aromatic amines, and β-nitroacrylates was achieved to obtain γ-nitro-α-amino-succinates in good yields and with high diastereo- and enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of Rh(I)-associated ammonium ylides by nitroacrylates. This new transformation represents the first example of Rh(I)-carbene-induced ylide transformation.

In our continued quest for novel stable carbenes, silylenes, and germylenes, here we compare and contrast multiplicities and relative stabilities of carbenes affected with four different α-ylides. The latter include carbon, immonium, phosphorus, and sulfur ylides substituted at the alpha positions of carbenes with acyclic, cyclic and cyclicunsaturated structural frameworks. Related thermodynamic data are calculated at B3LYP/6-311++G**//B3LYP/6-31+G* and B3LYP/AUG-cc-pVTZ//B3LYP/6-31+G* levels. Investigations reveal the enlargement of the singlet-triplet energy gaps (ΔE s-t ) in the order of immonium > phosphorus > sulfur > carbon. The observed trend, which is taken as an indication of stability, is thoroughly analyzed by applying appropriate isodesmic reactions which differentiate the substituent effects on each of our singlet or triplet carbene. The effect of unsaturation is also probed in each series of the ylide carbenes. The reactivity of the species is discussed in terms of nucleophilicity and electrophilicity.

Heterocyclic compounds are widely distributed in nature,[1] and their core structures are present in a vast array of pharmaceuticals.[2] Although extensive efforts have been concentrated on their syntheses,[3] including asymmetric catalytic processes,[4] the demand for greater structural diversity continues to be of intense interest.[5] In particular, there are increasing efforts for asymmetric syntheses of dihydropyridine, dihydroquinoline, dihydroisoquinoline and related heterocycles that are core structures in natural products and other bioactive molecules.[4a–4f] However, asymmetric syntheses of heterocyclic structures with more than one nitrogen-atom are rare. [6–8] The use of N-iminoquinolinium ylides for the asymmetric construction of dihydroquinoline derivatives by a [3+3]-cycloaddition with 1,1-cyclopropane diesters, originally reported by Charette for the non-asymmetric version, [7e] has recently been communicated. [4a] Good yields and high enantiocontrol were achieved in this kinetic resolution, but high catalyst loadings of nickel(II) perchlorate and the chiral In-Box ligand were required. We have been investigating the dirhodium-catalyzed 1,3-dipolar [3+3]-cycloaddition with enol-diazoacetates 1[9,10] whose metal enolcarbene intermediates, generated by dinitrogen extrusion, have electrophilic character at both the carbene and vinylogous positions with preferential reaction occurring at the vinylogous position (Scheme 1). Could these dipolar intermediates be effective for the asymmetric construction of dihydroquinoline derivatives with N-iminoquinolinium ylides? Prior efforts have shown that enolcarbene intermediates underwent [3+3]-cycloaddition reactions with nitrones to form 3,6-dihydro-1,2-oxazines (3) [9a] and with hydrazones to form tetrahydropyridazine derivatives (4), [9c] each by a stepwise process initiated by nucleophilic reaction at the vinylogous position that occurs with high enantiocontrol. Unlike cycloaddition reactions with nitrones and hydrazones, however, reactions with N-iminoquinolinium ylides afford a barrier to cycloaddition with the required dearomatization, and for this reason it is perhaps not surprising that cycloaddition reactions with N-iminopyridinium ylides have not yet been reported. We wish to report that N-iminopyridinium ylides undergo efficient and highly enantioselective [3+3]-cycloaddition reactions in chiral dirhodium-catalyzed reactions with enol diazoacetates. Scheme 1 Vinylogous dirhodium-enolcarbene formal [3+3]-cycloaddition reactions. Pyridine-N-aminidines 5a (N-acyliminopyridinium ylides) [4a,11] are stable but reactive dipolar species. Treatment of 5a with enoldiazoacetate 1a in the presence of a catalytic amount of rhodium(II) acetate in dichloromethane (DCM) at room temperature produced the dearomatized bicyclic tetrahydropyridazine derivative 6a (92% isolated yield) in one step (Eq 1). This transformation is a more direct and convenient way to the tetrahydropyridazine derivatives compared to previous two-step one-pot methodology from N-arylhydrazones and 1a, [9c] and the bicyclic tetrahydropyridazine products that are obtained (6) offer more functional diversity compared to 4. (1) Based on our previous studies, [9a,9c] Hashimoto’s dirhodium carboxylate catalysts were considered to have the reactivity and selectivity suitable for high enantioselectivity in the [3+3]-cycloaddition reaction; [12] however, although 100% conversion was obtained when the reaction was catalyzed by Rh2(S-PTA)4 in DCM, only 5% enantiomeric excess (ee) was detected (Table 1, entry 1). [13] Enantiomeric excess was increased to 45% by switching the solvent from DCM to methyl tert-butyl ether (TBME) or toluene with 71% and 100% conversion respectively (entries 2 and 3). Catalyst screening showed that increasing steric demand of the ligands on rhodium provided higher enantioselectivity (entries 3–8), which was opposite to previous results with reactions of enoldiazoacetates and nitrones[9a] or hydrazones[9c] (Scheme 1) in which the less sterically encumbered catalyst gave higher reactivity and selectivity. Further optimization with solvents (entries 9–12) gave 6a in up to 93% ee in chloroform but there was only 26% conversion (entry 12). The outcome having the highest conversion/yield and %ee was obtained when the reaction was catalyzed by Rh2(S-PTTL)4[14] in fluorobenzene at 0 °C with 85% isolated yield and 90% ee (entry 9). Similar results were obtained with Rh2(S-PTAD)4[15] in fluorobenzene or toluene, which was also used for exploration (entries 13 and 14). Table 1 Optimization of conditions for the enantioselective formal [3+3]-cycloadditon of enlodiazoacetate 1a with 5a.[a] A variety of enoldiazoacetates 1 were examined under the optimized reaction conditions. As shown in Table 2, except for benzyl enoldiazoacetate 1e (entry 5, 85% yield 77% ee), all of the TBS or TIPS protected enoldiazoacetates gave the corresponding bicyclic tetrahydropyridazines 6 in high yield with high to excellent enantioselectivity (entries 1–4 and 6–7, >75% yield, 90–95% ee). It is worth mentioning that enantioselectivity increased with increasing steric demand of the enoldiazoacetates 1 without affecting product yields. In our previously reported reactions of enoldiazoacetates with steric bulky hydrazones, the yields of the corresponding tetrahydropyridazine derivatives dropped dramatically with increasing steric demand. [9c] For the TIPS protected tert-butyl diazoacetate 1g, conditions A, C or D gave similar enantioselectivities (entries 7–9), while condition A offered higher yield. Table 2 Enantioselective formal [3+3]-cycloadditon of enlodiazoacetates 1 with 5a.[a] The reaction scope was extended to substituted N-acyliminopyridinium ylides, and these results are summarized in Table 3. The steric and electronic properties of the substituents on the phenyl group had slight influences on reactivity or selectivity (Table 3, entries 1–5), and the reaction could be carried out on a 1.0 mmol scale with 96% ee (entry 4). Notably, quinoline and isoquinoline derivatives were both well tolerated in this [3+3]-cycloaddition reaction and gave tricyclic tetrahydropyridazine derivatives in high yield with 97% ee and 96% ee respectively (entries 6 and 7). In addition, with a 3-methyl group introduced to the pyridinium ring, high regioselectivity (>19:1) was found (Scheme 2, 6o and 6o’),[16] and 95% ee was obtained for the major isomer, while up to 32% ee was determined for the minor one. These results indicated that during the ring closing step the dirhodium catalyst is still associated with the substrate, and this association determines the outcome between the two possible positions. [17] Scheme 2 Highly regioselective and enantioselective formal [3+3]-cycloadditon of enlodiazoacetate 1g with 5i. Table 3 Enantioselective formal [3+3]-cycloadditon of enlodiazoacetates 1g with 5.[a] The (S)-configuration of the generated chiral center in bicyclic tetrahydropyridazine derivatives was confirmed by single-crystal X-ray diffraction analysis of 6i, [18] and the configurations of other compounds were tentatively assigned by analogy (Figure 1), As is evident from this determination, the (S)-configured catalyst yields the (S)-configyred cycloaddition product. The generated bicyclic tetrahydropyridazine derivatives have multi-functional groups, including ester, ether, acyl, and diene generated by dearomatization of N-acyliminopyridinium ylide. A one-pot reaction with N-phenylmaleimide to give the polycyclic product 7 in 77% yield with 2:1 endo:exo selectivity, and enantiomeric excesses for both of the diastereoisomers were the same as that of 6g (Scheme 3). Figure 1 (S)-Configuration of 6i is produced with catalysis by Rh2(S-PTAD)4. Scheme 3 Sequential one-pot [3+3]-/[4+2]-cycloaddition reactions. In summary, we have developed a direct formal [3+3]-cycloaddtion that is a effective access to the bicyclic and tricyclic 1,2,3,6-tetrahydropyridazine derivatives starting from enoldiazoacetates and N-acyliminopyridinium ylide in good to high overall yields, high regioselectivities and excellent enantioselectivities that are controlled by catalysts and conditions. The sequence of reactions is triggered by Rh(II)-catalyzed dinitrogen extrusion followed by vinylogous addition with N-acyliminopyridinium ylide. Intramolecular asymmetric pyridinium ylide addition to the catalyst-activated vinyl ether functional group of 8 forms the [3+3]-cycloaddition product 6 (Scheme 4). And the generated 1,2,3,6-tetrahydropyridazine product can be transformed to polycyclic skeletons via [4+2]-cycloaddition without sacrifice the enantiomeric excess. Further expansion of the cycloaddition with electrophilic enolcarbene intermediates applied broadly is being pursued. Scheme 4 Proposed reaction pathway for the [3+3]-cycloaddition.