Revisiting the Reaction of Sulfur Ylides with Acetylenic Esters: Synthesis of Trisubstituted 1,3-Dienes, α-Carbonyl Vinyl Sulfoxides and α-Carbonyl Vinyl Sulfoxonium Ylides.

We report herein a reexamination of the reactions between sulfoxonium ylides and acetylenic esters. Continuing our previous study of conjugate additions using α-carbonyl sulfoxonium ylides, we came across an interesting transformation when dimethyl acetylenedicarboxylate (DMAD) was employed as a Michael acceptor. Trisubstituted electron-deficient 1,3-dienes and α-carbonyl vinyl sulfoxides were obtained for the first time from these sulfur ylides, in a stereoselective manner (exclusively forming the E-isomer), achieving yields of up to 70 % and 83 %, respectively. Selected dienes were subsequently utilized in the synthesis of novel nitrogen heterocycles. Interestingly, when di-tert-butyl acetylenedicarboxylate (DtBAD) or alkyl propiolates were evaluated, the isolated product arose from the classical Michael addition, yielding α-carbonyl vinyl sulfoxonium ylides in yields of up to 89 %.

Increasing the Donor Strength of Alkenylphosphines by Twisting the C=C Double Bond.

Electron-rich phosphines play a crucial role in transition metal-based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N-heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N-heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold-catalyzed hydroamination and cyclo-isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

Repurposing myoglobin into a carbene transferase for a [2,3]-sigmatropic Sommelet-Hauser rearrangement.

New-to-Nature biocatalysis has emerged as a promising tool in organic synthesis thanks to progress in protein engineering. Notably, hemeproteins have been evolved into robust catalysts for carbene and nitrene transfers and related sigmatropic rearrangements. In this work, we report the first example of a [2,3]-sigmatropic Sommelet-Hauser rearrangement initiated by a carbene transfer of the sperm whale myoglobin mutant L29S,H64V,V68F that was previously reported to catalyze the mechanistically similar [2,3]-sigmatropic Doyle-Kirmse rearrangement. This repurposed heme enzyme catalyzes the Sommelet-Hauser rearrangement between ethyl diazoacetate and benzyl thioethers bearing strong electron-withdrawing substituents with good yields and enantiomeric excess. Optimized catalytic conditions in the absence of any reductant led to an increased asymmetric induction with up to 59% enantiomeric excess. This myoglobin mutant is therefore one of the few catalysts for the asymmetric Sommelet-Hauser rearrangement. This work broadens the scope of abiological reactions catalyzed by iron-carbene transferases with a new example of asymmetric sigmatropic rearrangement.

Transition-Metal-Catalyzed Directed C-H Bond Functionalization with Iodonium Ylides: A Review of the Last 5 Years.

Transition-metal-catalyzed directed C-H functionalization with various carbene precursors has been widely employed for constructing a wide range of complex and diverse active molecules through metal carbene migratory insertion processes. Among various carbene precursors, iodonium ylides serve as a novel and emerging carbene precursor with features including easy accessibility, thermal stability and high activity, which have attracted great attention from organic chemists and have achieved tremendous success in organic transformation. In this review, recent progress on the application of iodonium ylides with multifunctional coupling characteristics in C-H bond activation reactions is summarized, and the potential of iodonium ylides is discussed.

Polycyclic Pyrazolidines by Tandem Diazomalonate Dipolar Cycloadditions and CpRu-Catalyzed Carbene Additions.

Thanks to the ability of diazo derivatives to react either as 1,3-dipoles and as carbenes after dinitrogen extrusion, combinations of oxa or aza benzonorbornadienes and diazomalonates afford polycyclic pyrazolidines via a three-step sequence of (i) a highly diastereoselective [3+2]-cycloaddition, (ii) a CpRu-catalyzed carbene addition, and (iii) a second dipolar cycloaddition. Of importance, step (II) represents a unique access to novel bench-stable N,N-cyclic azomethine imines, which behave as effective 1,3-dipoles in combination with electron-poor dipolarophiles. Each step proceeds efficiently and the 3-step process can be performed in one-pot to yield a polycyclic pyrazolidine in excellent overall yield (90 %).

Boron-Catalyzed C1 Copolymerization of Arsonium and Sulfoxonium Ylides toward Unrepresented Structures and Fluorescence Properties.

The first synthesis of well-defined poly(methylene-co-1,1-diphenylpropenenylene) (C1-co-C1'), equivalent to poly(ethylene-co-diphenylbutadiene) copolymers was accomplished by C1 copolymerization of novel diphenylpropenyl triphenyl arsonium ylides (Ph2AY) and dimethylsulfoxonium methylide (Me2SY) using B-thexylborepane as initiator. All polymerization conditions, including feed ratio, temperature, and reaction time, were optimized. A series of photoluminescent poly(ethylene-co-diphenylbutadiene)s were synthesized at different feed ratios, opening a new synthetic horizon for poly(ethylene-co-disubstitutedbutadiene) copolymers. Notably, a new C1 segment, arising from a double bond rearrangement, was confirmed by NMR, resulting in an unprecedented two-monomer three-structure random terpolymer. An unexpected red-shift phenomenon in the fluorescence spectra was observed with increasing the ratio of Ph2AY in the copolymer. This shift is attributed to the aggregation of diphenylbutadiene segment, similar to through-space conjugation (TSC), likely induced by a decrease in the crystallinity of copolymers. Furthermore, another disubstituted allylic triphenyl arsonium ylides, (E)-2-phenylbutenyl triphenyl arsonium ylide (MePhAY) was also synthesized and investigated. These additional compounds expand the knowledge and the potential applications of such copolymerization techniques in advanced materials.

Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

The Cyanoketenyl Anion [NC3O].

Cumulenes and heterocumulenes with three or more cumulative multiple bonds are usually reactive species that serve as valuable building blocks for more complex molecules but tend to isomerize or cyclize and therefore are difficult to isolate. Using a mild ligand exchange reaction at the carbon in α-metalated ylides, we have now succeeded in the synthesis and gram-scale isolation of the elusive cyanoketenyl anion [NC3O]-. Despite its assumed cumulene-like structure and the delocalization of the negative charge across the whole 5-atom molecule, it features a bent geometry with a nucleophilic central carbon atom. Computational studies reveal an ambiguous bonding situation in the anion, which can be illustrated only by a combination of different resonance structures. Nonetheless, the anion features remarkable stability, thus allowing the storage of its potassium-crown ether salt and its application as a highly functional synthetic building block. The cyanoketenyl anion readily reacts with a series of small molecules to form more complex organic compounds, including industrially valuable compounds such as cyanoacetate. This work demonstrated that reactive species can be generated by novel synthesis methods and open up atom-economic pathways to complex compounds from small abundant molecules.

Synthesis of gem-Difluorinated Keto-Sulfoxides from Sulfoxonium Ylides.

Organic molecules containing fluorine and sulfur atoms represent a large percentage of approved pharmaceuticals. Those with combination of both S and F atoms in their structure such as Xtandi, approved in 2012 for prostate cancer, indicates the importance of synthetic methods that accommodates both atoms in an organic moiety. In this study, a novel aspect of sulfoxonium ylide reactivity was explored, unveiling a streamlined and mild synthesis method for gem-difluorinated keto-sulfoxides. Our protocol offers a direct and practical approach to prepare these compounds in 14-80 % chemical yields, that were represented by 21 examples. NMR studies and Hammett correlations gave strong evidence about the mechanism of this transformation.

Impact of the Methylene Bridge Substitution in Chelating NHC-Phosphine Mn(I) Catalyst for Ketone Hydrogenation.

Systematic modification of the chelating NHC-phosphine ligand (NHC = N-heterocyclic carbene) in highly efficient ketone hydrogenation Mn(I) catalyst fac-[(Ph2PCH2NHC)Mn(CO)3Br] has been performed and the catalytic activity of the resulting complexes was evaluated using acetophenone as a benchmark substrate. While the variation of phosphine and NHC moieties led to inferior results than for a parent system, the incorporation of a phenyl substituent into the ligand methylene bridge improved catalytic performance by ca. 3 times providing maximal TON values in the range of 15000-20000. Mechanistic investigation combining experimental and computational studies allowed to rationalize this beneficial effect as an enhanced stabilization of reaction intermediates including anionic hydride species fac-[(Ph2PC(Ph)NHC)Mn(CO)3H]- playing a crucial role in the hydrogenation process. These results highlight the interest of such carbon bridge substitution strategy being rarely employed in the design of chemically non-innocent ligands.

Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity.

We have recently discovered that ester-stabilized phosphorus ylides, resulting from deprotonation of a phosphonium salt such as [Ph3PCH2COOR], can transfer protons across artificial and biological membranes. To create more effective cationic protonophores, we synthesized similar phosphonium salts with one ((heptyloxycarbonylmethyl)(p-tolyl)bromide) or two ((butyloxycarbonylmethyl)(3,5-xylyl)osphonium bromide) methyl substituents in the phenyl groups. The methylation enormously augmented both protonophoric activity of the ylides on planar bilayer lipid membrane (BLM) and uncoupling of mammalian mitochondria, which correlated with strongly accelerated flip-flop of their cationic precursors across the BLM.

Density Functional Theory Calculations: A Useful Tool to Investigate Mechanisms of 1,3-Dipolar Cycloaddition Reactions.

The present review contains a representative sampling of mechanistic studies, which have appeared in the literature in the last 5 years, on 1,3-dipolar cycloaddition reactions, using DFT calculations. Attention is focused on the mechanistic insights into 1,3-dipoles of propargyl/allenyl type and allyl type such as aza-ylides, nitrile oxides and azomethyne ylides and nitrones, respectively. The important role played by various metal-chiral-ligand complexes and the use of chiral eductors in promoting the site-, regio-, diastereo- and enatioselectivity of the reaction are also outlined.

N-Terminal-Specific Dual Modification of Peptides through Copper-Catalyzed [3+2] Cycloaddition.

Site-specific introduction of multiple components into peptides is greatly needed for the preparation of densely functionalized and structurally uniform peptides. In this regard, N-terminal-specific peptide modification is attractive, but it can be difficult due to the presence of highly nucleophilic lysine ϵ-amine. In this work, we developed a method for the N-terminal-specific dual modification of peptides through a three-component [3+2] cycloaddition with aldehydes and maleimides under mild copper catalysis. This approach enables exclusive functionalization at the glycine N-terminus of iminopeptides, regardless of the presence of lysine ϵ-amine, thus affording the cycloadducts in excellent yields. Tolerating a broad range of functional groups and molecules, the present method provides the opportunity to rapidly construct doubly functionalized peptides using readily accessible aldehyde and maleimide modules.

A facile synthesis of chromeno[3,4-c]spiropyrrolidine indenoquinoxalines via 1,3-dipolar cycloadditions.

A one-pot, four-component reaction for the synthesis of novel chromeno[3,4-c]spiropyrrolidine-indenoquinoxalines is described via a 1,3-dipolar cycloaddition of 3-acetyl-coumarins with the azomethine ylides followed by deacetylation and protonation (deuteration). The products were obtained in moderate to high yields, and their structures were confirmed by 1H NMR, 13C NMR, FT-IR, and MS spectroscopy.

Chiral 4-MeO-Pyridine (MOPY) Catalyst for Enantioselective Cyclopropanation: Attenuation of Lewis Basicity Leads to Improved Catalytic Efficiency.

The design of pyridine-derived organocatalysts aims at the increase of their Lewis basicity, however such an approach is not always efficient. For example, strongly Lewis basic DMAP is completely inefficient as catalyst in the cyclopropanation reaction. Herein we disclose an alternative approach that relies on attenuation of DMAP Lewis basicity. Specifically, the replacement of 4-dimethylamino substituent in DMAP for 4-MeO group delivered a highly efficient catalyst for cyclopropanation of electron-deficient olefins with α-bromoketones. Kinetic studies provide compelling evidence that the superior catalytic efficiency of 4-MeO pyridine (MOPY) is to be attributed to the favorable balance between Lewis basicity and leaving group ability. The use of chiral, enantiomerically pure MOPY catalyst has helped to achieve high enantioselectivities (up to 91 : 9 er) in the previously unreported pyridine-catalyzed cyclopropanation reaction.

Quo Vadis CO2 Activation: Catalytic Reduction of CO2 to Methanol Using Aluminum and Gallium/Carbon-based Ambiphiles.

We report on so-called "hidden FLPs" (FLP: frustrated Lewis pair) consisting of a phosphorus ylide featuring a group 13 fragment in the ortho position of a phenyl ring scaffold to form five-membered ring structures. Although the formation of the Lewis acid/base adducts was observed in the solid state, most of the title compounds readily react with carbon dioxide to provide stable insertion products. Strikingly, 0.3-3.0 mol% of the reported aluminum and gallium/carbon-based ambiphiles catalyze the reduction of CO2 to methanol with satisfactory high selectivity and yields using pinacol borane as stoichiometric reduction equivalent. Comprehensive computational studies provided valuable mechanistic insights and shed more light on activity differences.

Phosphonium-substituted Diphosphaindenylide (PPI): Exploration of Biradical Character and Ligand Properties.

Starting from C6 H4 (PCl2 )2 and the TMS-substituted ylide (TMS)2 C=PR3 (TMS=trimethylsilyl, R=p-tolyl), the phosphonium-substituted diphosphaindenylide PPI was prepared in two steps. CASSCF calculations as well as the reactivity toward diphenyl acetylene suggest a notable biradical character in PPI. Reaction with [Cr(CO)3 (MeCN)3 ] affords the complex [Cr(CO)3 (η5 -PPI)] (5). This complex was employed to explore the ligand properties of PPI, which demonstrates considerable potential through the combination of strong metal-ligand interactions and the possibility of a pronounced indenyl effect.

Pyridinium-Derived Mesoionic N-Heterocyclic Olefins (py-mNHOs).

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

Rhodium-Catalyzed [3+2]-Cycloaddition of in-situ Generated Nitrile Ylides with Nitrosoarenes.

Herein we report the rhodium-catalyzed one-pot three-component reaction of diazo compounds, nitriles, and nitrosoarenes to construct 2,5-dihydro-1,2,4-oxadiazole derivatives. Mechanistic studies indicate that the transformation may proceed through the formation of nitrile ylides intermediates, which then undergo [3+2]-cycloaddition with nitrosoarenes. The strategy exhibits several synthetic advantages, including operational simplicity, good functional group tolerance, and scalability.

Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium.

Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4' atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component.