Sulfonium Ylides Research Articles

Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane Assembly.

An asymmetric total synthesis of (+)-6-hydroxythiobinupharidine (1b) and (-)-6-hydroxythionuphlutine (2b), a set of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies of the Nuphar genus, is described. The central bis-spirocyclic tetrahydrothiophene ring was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ from the coupling of a copper-carbene with a spirocyclic thietane. This strategy diverges both from the proposed biosynthesis1 and previous syntheses of this family of alkaloids,2,3 all of which employ dimerization of symmetric monomers to form the aforementioned thiaspirane. The coupling of unsymmetrical monomers allowed access to the unsymmetrically oxidized product 2b for the first time.

Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors.

In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H2C═CH-Acc, 1) and styrenes (PhCH═CH-Acc, 2) with pyridinium ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloromethyl anion 5. Substitution of the 57 measured second-order rate constants (log k) and the previously reported nucleophile-specific parameters N and sN for 3-5 into the correlation log k = sN(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters sN, N, and E for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of 3-5 at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4 and 5), respectively. The electrophilicity parameters E thus determined can be used to calculate the rates of the reactions of Michael acceptors 1 and 2 with any nucleophile of known N and sN. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with the LUMO energies and with Parr's electrophilicity index ω, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities.

Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived dehydroalanines

A three-step synthesis of cyclopropyl peptides is reported. The protocol involves a consecutive Ugi-4CR/elimination reaction to prepare dehydroalanines followed by a Corey-Chaykovsky cyclopropanation reaction. Peptide-like molecules that resemble some pharmacologically active compounds with a variety of substituents in the cyclopropane ring were prepared. When (2-ethoxy-2-oxoethyl) dimethyl sulfonium ylide was used the reaction exclusively gives the cis-diastereoisomer cyclopropanes in good yields from readily prepared starting materials. A collection of 26 highly substituted cyclopropyl peptides were obtained.

Monofluoromethyl-Substituted Sulfonium Ylides: Electrophilic Monofluoromethylating Reagents with Broad Substrate Scopes.

Two electrophilic monofluoromethylating reagents, monofluoromethyl(phenyl)sulfonium bis(carbomethoxy)methylide (3 a) and monofluoromethyl(4-nitrophenyl)sulfonium bis(carbomethoxy)methylide (3 b), and their reactions under mild conditions with a variety of nucleophiles, such as alcohols and malonate derivatives, sulfonic and carboxylic acids, phenols, amides, and N heteroarenes, are described. Mechanistic studies with deuterated reagents [D2 ]3 a/[D2 ]3 b suggest that these monofluoromethylation reactions proceed through an electrophilic substitution pathway.

Monofluoromethyl‐Substituted Sulfonium Ylides: Electrophilic Monofluoromethylating Reagents with Broad Substrate Scopes

AbstractTwo electrophilic monofluoromethylating reagents, monofluoromethyl(phenyl)sulfonium bis(carbomethoxy)methylide (3 a) and monofluoromethyl(4‐nitrophenyl)sulfonium bis(carbomethoxy)methylide (3 b), and their reactions under mild conditions with a variety of nucleophiles, such as alcohols and malonate derivatives, sulfonic and carboxylic acids, phenols, amides, and N heteroarenes, are described. Mechanistic studies with deuterated reagents [D2]3 a/[D2]3 b suggest that these monofluoromethylation reactions proceed through an electrophilic substitution pathway.

Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides.

The trifluoromethylthio (SCF3) functional group has been of increasing importance in drug design and development as a consequence of its unique electronic properties and high stability coupled with its high lipophilicity. As a result, methods to introduce this highly electronegative functional group have attracted considerable attention in recent years. Although significant progress has been made in the introduction of SCF3 functionality into a variety of molecules, there remain significant challenges regarding the enantioselective synthesis of SCF3-containing compounds. Here, an asymmetric trifluoromethylthiolation that proceeds through the enantioselective [2,3]-sigmatropic rearrangement of a sulfonium ylide generated from a metal carbene and sulfide (Doyle-Kirmse reaction) has been developed using chiral Rh(II) and Cu(I) catalysts. This transformation features mild reaction conditions and excellent enantioselectivities (up to 98% yield and 98% e.e.), thus providing a unique, highly efficient and enantioselective method for the construction of C(sp3)-SCF3 bonds bearing chiral centres.

Stereoselective Cyclopropanation of (–)-Levoglucosenone Derivatives Using Sulfonium and Sulfoxonium Ylides

The synthesis of tri- and tetrasubstituted cyclopropanes from 3-aryl-substituted levoglucosenones (LGO) has been developed. In contrast to the unstabilised ylide dimethylsulfonium methylide which gives epoxides from LGO via 1,2-addition, we have found that the soft nucleophile dimethylsulfoxonium methylide affords cyclopropanes in moderate yields from LGO and in excellent yields and stereoselectivity with 3-aryl LGO derivatives. The use of 1,1,3,3-tetramethylguanidine as base in DMSO to generate the ylide provided the best yields and shortest reaction times. Ester stabilised sulfonium ylides could also be used to generate tetrasubstituted cyclopropane derivatives. One of the products was converted into a cyclopropyl lactone via Baeyer–Villiger oxidation to demonstrate the utility of applying cyclopropanation chemistry to LGO.

Microwave‐Mediated Sulfonium Ylide Cyclopropanation. Stereoselective Synthesis of Cyclopropa[c]pentalenes

AbstractStereoselective sulfonium ylide cyclopropanation is a useful transformation due to the presence of this moiety in numerous bioactive compounds. The procedures described to date involve long reaction times and variable stereoselectivity outcomes. We show here that performing these reactions under MW mediation gives good yields and selectivity after short reaction periods. The methodology is applied to different substrates including sterically hindered cyclopentenones, open chain unsaturated esters and pentalenones (Pauson‐Khand products). From these latter substrates, highly connected cyclopropa[c]pentalenes were synthesized in good yields, including a precursor of natural product pentalenene.

Medium-Sized Cyclic Ethers via Stevens [1,2]-Shift of Mixed Monothioacetal-Derived Sulfonium Ylides: Application to Formal Synthesis of (+)-Laurencin.

A novel approach to medium-sized cyclic ethers was devised using a Stevens [1,2]-shift of a sulfonium ylide derived from a readily accessible six-membered mixed-monothioacetal precursor. The concise and efficient transformation offers a surprising degree of chirality transfer with observed retention of stereochemical configuration on the anomeric migrating carbon and has been applied as the key step in an enantioselective formal synthesis of (+)-laurencin.

Hemin-catalyzed sulfonium ylide formation and subsequently reactant-controlled chemoselective rearrangements

Hemin-catalyzed competing routes of [1,2]-Stevens and Sommelet-Hauser rearrangements of benzyl sulfonium ylides through an iron porphyrin carbenoid were established. These rearrangements can be controlled by the electronic property of the substituents on the benzyl group together with solvent effects. Electron-donating or weak electron-withdrawing groups lead to the [1,2]-Stevens rearrangement, whereas strong electron-withdrawing groups at the para-position favor the latter pathway under aqueous conditions.

Enantioselective Synthesis of α-Mercapto-β-amino Esters via Rh(II)/Chiral Phosphoric Acid-Cocatalyzed Three-Component Reaction of Diazo Compounds, Thiols, and Imines.

An enantioselective method for the synthesis of α-mercapto-β-amino esters has been developed via a rhodium(II)/chiral phosphoric acid-cocatalyzed three-component reaction of diazo compounds, thiols, and imines. This transformation is proposed to proceed through enantioselective trapping of the sulfonium ylide intermediate generated in situ from the diazo compound and thiol by the phosphoric acid-activated imine. With this method, a series of α-mercapto-β-amino esters were obtained in good yields with moderate to good stereoselectivities.

ChemInform Abstract: Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide.

AbstractA broad range of primary aliphatic and benzylic, secondary and even tertiary alcohols which may contain diverse functional groups is transformed according to the title reaction.

Sulfonium Ylides by (3+2) Cycloaddition of Arynes with Vinyl Sulfides: Stereoselective Synthesis of Highly Substituted Alkenes.

The reaction of in situ generated arynes with vinyl sulfides provides benzannulated sulfonium ylides in a (3+2) cycloaddition. Trapping of the intermediate ylides with electrophiles (proton transfer or a second aryne addition) and subsequent β-elimination give rise to di-, tri-, or tetrasubstituted alkenes with high stereoselectivity. Experimental studies and DFT calculations provide insight into the mechanisms of these cascade reactions.

Mixed arsonium–iodonium and sulfonium–iodonium ylides: synthesis and characteristics

The preparation and properties of novel mixed arsonium–iodonium and sulfonium–iodonium ylides are reported. A series of substituted arsonium and sulfonium ylides was obtained by the nucleophilic substitution of iodonium groups in mixed ylides. A one-pot process, which included the nucleophilic substitution and silylation of arsonium–iodonium ylides with subsequent elimination of the silyl group and a Wittig olefination reaction, provided route to access Z-α,β-unsaturated haloketones.

ChemInform Abstract: Activation of Trifluoromethylthio Moiety by Appending Iodonium Ylide under Copper Catalysis for Electrophilic Trifluoromethylation Reaction.

A novel iodonium-ylide compound 2 that appends atrifluoromethylthio (SCF3) group is disclosed as a new, shelf-stable electrophilic trifluoromethylation reagent. Unlike known shelf-stable electrophilic trifluoromethylation reagents, 2 has a stable SCF3 group which is activated by appending iodonium ylide under copper catalysis via sulfonium ylide to generate a cationic trifluoromethyl (CF3) species. Reagent 2 was found to be an efficient electrophilic trifluoromethylation reagent for a wide range of silyl enol ethers 3 under copper catalysis. Cyclic and acyclic α-trifluoromethyl ketones 4 were obtained by reagent 2 in moderate to good yields. On the other hand, a difluoromethylthio analogue 5 did not affect intermolecular transfer difluoromethylation to substrates. Instead, intramolecular 1,4-migration proceeded similar to the Stevens rearrangement to provide 6 in 21% yield, independent of the presence of nucleophiles 3.

Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide.

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.

Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide

AbstractA 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.

Ethenesulfonyl Fluoride: The Most Perfect Michael Acceptor Ever Found?

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.

Demonstration of 11–21‐Membered Intramolecular Sulfonium Ylides: Regio‐ and Diastereoselective Synthesis of Spiro‐Oxindole‐Incorporated Macrocycles

AbstractAn expeditious and convenient method for the generation of 11–21‐membered intramolecular macrocyclic sulfonium ylides using catalytic Rh2(OAc)4 is presented. Using this approach, a wide variety of sulfur‐macrocycles incorporating the oxindole unit were produced in good yields and with high diastereoselectivity. Interestingly, tetracyclic macrocycles were also attained in good yields and with good regioselectivity using the disclosed sulfonium ylides. Ring‐opening reactions of tetracyclic macrocycles were also demonstrated.

Activation of Trifluoromethylthio Moiety by Appending Iodonium Ylide under Copper Catalysis for Electrophilic Trifluoromethylation Reaction

AbstractA novel iodonium‐ylide compound 2 that appends atrifluoromethylthio (SCF3) group is disclosed as a new, shelf‐stable electrophilic trifluoromethylation reagent. Unlike known shelf‐stable electrophilic trifluoromethylation reagents, 2 has a stable SCF3 group which is activated by appending iodonium ylide under copper catalysis via sulfonium ylide to generate a cationic trifluoromethyl (CF3) species. Reagent 2 was found to be an efficient electrophilic trifluoromethylation reagent for a wide range of silyl enol ethers 3 under copper catalysis. Cyclic and acyclic α‐trifluoromethyl ketones 4 were obtained by reagent 2 in moderate to good yields. On the other hand, a difluoromethylthio analogue 5 did not affect intermolecular transfer difluoromethylation to substrates. Instead, intramolecular 1,4‐migration proceeded similar to the Stevens rearrangement to provide 6 in 21% yield, independent of the presence of nucleophiles 3.