Unraveling the mechanism of epoxide formation from sulfur ylides and aldehydes

Sulfur ylides R(2)S(+)-C(-)HR' react with aldehydes R' '-CHO to form epoxides, predominantly as the trans isomers, in a synthetically useful reaction which is increasingly used in its asymmetric variant with chiral sulfides. The mechanisms of the "model" reaction (R = Me, R' = R' ' = H) and the reaction forming stilbene oxide (R = Me, R' = R' ' = Ph) have been studied in detail using density functional theory, the B3LYP density functional, and flexible basis sets. It has been shown that for this reaction involving highly polar intermediates, continuum solvation models need to be used throughout to obtain reasonable results. For the reaction of benzaldehyde with dimethylsulfonium benzylide, the key steps are shown to be quasi [2 + 2] addition of the ylide to the aldehyde to form a betaine R'-CH(S(+)Me(2))-CH(O(-))-R' ' in which the charged groups are gauche to one another, and torsional rotation around the C-C single bond of the betaine to form its rotamer with the two charged groups anti. The final step, elimination of sulfide from this second rotamer of the betaine, is found to be facile. In the case of the anti pathway, leading to trans-stilbene epoxide, the initial addition is found to be rate-determining, whereas for the diastereomeric syn pathway, leading to the cis-epoxide, it is instead the torsional rotation which is slowest. These results are in excellent agreement with experiment, unlike previous computational work. The unexpected and apparently unprecedented (for C-C bond-forming reactions) importance of the torsional rotation step, especially in the syn case, is due to the fact that all the barriers involved are low-lying. This novel picture of the mechanism provides a sound basis for the future development of chiral sulfides for enantioselective epoxide synthesis.     

Reagent controlled addition of chiral sulfur ylides to chiral aldehydes

The degree of reagent and substrate control in the reaction of chiral sulfur ylides with chiral aldehydes has been investigated. Specifically, the reactions of the two enantiomers of the chiral benzyl sulfonium salt 1 with glyceraldehyde acetonide were studied in detail. Of the two new stereogenic centers created, it was found that the C1 stereochemistry was largely controlled by the reagent, whereas control at the C2 center was dependent on the aldehyde used. In one case, the trans isomer was produced via reversible formation of the intermediate betaine, whereas in the alternative case, the C2 center was under Felkin Anh/Cornforth control through non-reversible formation of the betaine. Thus, the aldehyde stereocenter influenced the degree of reversibility in betaine formation, which impacted on the stereocontrol at the C2 position.     

Experimental investigation into the mechanism of the epoxidation of aldehydes with sulfur ylides

A mechanistic study of the epoxidation of aldehydes with sulfur ylides has been carried out. The DeltaG++ of the reaction was determined to be 22.2 kcal/mol at 298 K. A 13C kinetic isotope effect was determined to be 1.026 for the carbonyl carbon of benzaldehyde. A secondary deuterium isotope effect was determined to be 0.93 for the aldehydic hydrogen atom of benzaldehyde. Substituent effects on reaction rate were studied, and a Hammett rho of +2.50 was found.     

Water is an efficient medium for Wittig reactions employing stabilized ylides and aldehydes

Water is demonstrated to be an excellent medium for the Wittig reaction employing stabilized ylides and aldehydes. Although the solubility in water appears to be an unimportant characteristic in achieving good chemical yields and E/Z-ratios, the rate of Wittig reactions in water is unexpectedly accelerated.     

The reaction of stable phosphorus ylides with elemental sulfur. Formation of olefins; cis-trans selectivity

Metal and temperature effects on thio-Wittig reactions have been studied. Stabilized phosphorus ylides, such as carbomethoxymethylenetriphenylphosphorane, reacted with sulfur to afford dimethyl maleate and dimethyl fumarate in a 1:4 ratio. As in the case of conventional Wittig reactions with semistabilized ylides, it has been shown that the stereochemistry (E:Z ratio) of alkene formation is determined at the point that a new carbon–carbon bond has been formed to give a thiaphosphetane intermediate. The temperature dependence of this reaction is also discussed.     

Nickel-catalyzed, carbonyl-ene-type reactions: selective for alpha olefins and more efficient with electron-rich aldehydes

Described are several classes of unusual or unprecedented carbonyl-ene-type reactions, including those between alpha olefins and aromatic aldehydes. Catalyzed by nickel, these processes complement existing Lewis acid-catalyzed methods in several respects. Not only are monosubstituted alkenes, aromatic aldehydes, and tert-alkyl aldehydes effective substrates, but monosubstituted olefins also react faster than those that are more substituted, and large or electron-rich aldehydes are more effective than small or electron-poor ones. Conceptually, in the presence of a nickel-phosphine catalyst, the combination of off-the-shelf alkenes, silyl triflates, and triethylamine functions as a replacement for an allylmetal reagent.     

Reaction of stable arsenic ylides with aldehydes

Summary Stable arsenic ylides can be successfully used for the synthesis of olefins according to the Wittig reaction.Translated from Izvestiya Akadeemii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1474–1476, August, 1965 Original article submitted November 23, 1964     

Scope and limitations of cyclopropanations with sulfur ylides

The rates of the reactions of the stabilized and semistabilized sulfur ylides 1a-g with benzhydrylium ions (2a-e) and Michael acceptors (2f-v) have been determined by UV-vis spectroscopy in DMSO at 20 °C. The second-order rate constants (log k(2)) of these reactions correlate linearly with the electrophilicity parameters E of the electrophiles 2 as required by the correlation log k(2) = s(N + E), which allowed us to calculate the nucleophile-specific parameters N and s for the sulfur ylides 1a-g. The rate constants for the cyclopropanation reactions of sulfur ylides with Michael acceptors lie on the same correlation line as the rate constants for the reactions of sulfur ylides with carbocations. This observation is in line with a stepwise mechanism for the cyclopropanation reactions in which the first step, nucleophilic attack of the sulfur ylides at the Michael acceptors, is rate determining. As the few known pK(aH) values for sulfur ylides correlate poorly with their nucleophilic reactivities, the data reported in this work provide the first quantitative approach to sulfur ylide reactivity.     

Polyimido sulfur anions and ylides

Isovalent electronic replacement of the oxygen atoms in the classic SO(n)(m-) molecules and ions by NR imido groups yields the polyimido sulfur species S(NR)(n)(m-), n = 2, 3, 4 and m = 0, 2. The crucial cornerstone to the richness of SN chemistry is the access to sulfur diimides S(NR)(2) and triimides S(NR)(3). While the syntheses of the first are well established the preparations of the second were hazardous and of poor yields. A new facile, safe and elaborated route to give quantitative yields is presented. It involves the synthesis of triimido sulfites S(NR)(3)(2-), which are versatile ligands in their own right. With a trigonal pyramidal shape, containing three basal negatively charged nitrogen atoms, they are rare examples of dianionic tripodal ligands. Various (mixed) metal complexes are presented. Lithium coordination at the N-S-N bisections converts the dianion into the inverse tripod ligand Li(3)(NR)(3)S(+), capable of anion solvation. Among others, this motif stabilizes unprecedented monomeric methyllithium and lithium enolate. In the reaction of sulfur diimides S(NR)(2) and triimides S(NR)(3) with organometallics the diimidosulfinates RS(NR)(2)(-) and triimidosulfonates RS(NR)(3)(-) are synthesised. Both display a rich coordination chemistry to various metals, which is discussed in the review. Furthermore, the S-organo substituent can be modified in various ways. It can be a linker between two SN moieties or can be shaped to a R(2)N- or R(2)P-donating side arm of any form or length to give hemilabile scorpionates. Their ample application in metal coordination and anion solvation is presented. These monoanions can be converted to the related ylides by deprotonation of the S-alkyl group. The diimidosulfur(iv) ylides (R(2)C)S(NR)(2)(2-) and triimidosulfur(vi) ylides (R(2)C)S(NR)(3)(2-) contain the CR(2) methylene group, isoelectronic to the NR imido group. Their coordination behaviour and reactivity are discussed. In addition to the rich SN chemistry the S-N and S-C bonding is elucidated by means of theoretical and experimental charge density investigations and topological analyses on the basis of multipole refinement. As the most important result hypervalency at sulfur and S[double bond, length as m-dash]N(C) double bonding are ruled out as superfluous concepts.     

Formation of 1,3-oxathioles and 1,3-oxaselencles by reactions of carbonyl-stabilized sulfonium ylides with elemental sulfur and selenium

Carbonyl-stabilized sulfonium ylides readily react with elemental sulfur and selenium to afford 1,3-oxathiole and 1,3-oxaselenole derivatives, respectively, in good yields, thus providing a simple method for constructing these ring systems which uses easily accessible compounds as starting materials.     

Enantioselective cascade reactions of stable sulfur ylides and nitroolefins through an axial-to-central chirality transfer strategy

An enantioselective [4 + 1] annulation/rearrangement cascade of stable sulfur ylides and nitroolefins has been developed through an efficient axial-to-central chirality transfer with the use of a chiral BINOL-derived sulfide as a reliable stereocontroller. It can provide pharmaceutically and synthetically important oxazolidinones in high stereoselectivities (up to 96:4 e.r. and >95:5 d.r.). Moreover, this strategy was also successfully applied to the asymmetric [4 + 1]/[3 + 2] cycloaddition cascade of sulfur ylides with alkene-tethered nitroolefins, and the corresponding enantioenriched fused heterocycles (up to 87:13 e.r. and >95:5 d.r.) were obtained in good to excellent yields (54-95% yields).     

Sulfur ylides 13. Synthesis and intramolecular cyclization of keto-stabilized sulfur ylides

Keto-stabilized sulfur mono-and bisylides were obtained from N-phthalylglutamic acid and their intramolecular cyclization was studied. The intramolecular cyclization of the ylide obtained at the α-carboxy group gave a product of the pyrrolizidinedione structure; bisylide yielded a cycloheptene derivative as the result of intramolecular recombination of intermediate dicarbene. The ylide obtained at the γ-carboxy group underwent no cyclization, giving methylthio ketone and oxo benzoate. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2771–2776, December, 2005.     

Arsirane synthesis by reaction of sulfur ylides with diazaarsoles

N-unsubstituted diazaarsoles 4 undergo an N alkylation by reaction with sulfur ylides. N-substituted diazaarsoles 5 and 9 react with dimethylsulfoxonium ylide to give stable bicyclic arsiranes 11 and 12.     

Improved density functionals for water

The accuracy of existing density functional methods for describing the noncovalent interaction energies in small water clusters is investigated by testing 25 density functionals against a data set of 28 water dimers and 8 water trimers whose structures are taken from the literature and from simulations. The most accurate functionals are found to be PW6B95 with a mean unsigned error of 0.13 kcal/mol and MPWB1K and B98 with mean unsigned errors of 0.15 kcal/mol; the best functional with no Hartree-Fock exchange is mPWLYP, which is a GGA with a mean unsigned error of 0.28 kcal/mol. In comparison, the most popular GGA functionals, PBE and BLYP, have mean unsigned errors of 0.52 and 1.03 kcal/mol, respectively. Since GGAs are very cost efficient for both condensed-phase simulations and electronic structure calculations on large systems, we optimized four new GGAs for water. The best of these, PBE1W and MPWLYP1W, have mean unsigned errors of 0.12 and 0.17 kcal/mol, respectively. These new functionals are well suited for use in condensed-phase simulations of water and ice.     

Reactions of cyclic sulfur ylides with some carbonyl compounds

The reaction of a six‐membered sulfonium ylide 5 with aldehydes or ketones afforded the oxirane derivatives 6a–d as a mixture of cis and trans isomers in excellent yields. In addition, the same reactions, using five‐ or six‐membered cyclic oxosulfonium ylides 7 and 11 , gave the corresponding oxirane derivatives in good yields. Moreover, the reaction of 11 with two equimolar amounts of base and 4‐hexen‐3‐one afforded the cyclooctene oxide derivative 16 with high stereoselectivity in 59% yield via a sequential Michael–Michael‐type addition of the ylide and the resulting enolate ion followed by an intramolecular Corey–Chaykovsky reaction. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:216–222, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10022     

An ab initio and density functional theory study of the structure and bonding of sulfur ylides

Sulfur ylides are useful synthetic intermediates that are formed from the interaction between singlet carbenes and sulfur-containing molecules. Partial double-bond character frequently has been proposed as a key contributor to the stability of sulfur ylides. Calculations at the B3LYP, MP2, and CCSD(T) levels of theory employing various basis sets have been performed on the sulfur ylides H(2)S-CH(2) and (CH(3))(2)S-CH(2) in order to investigate the structure and bonding of these systems. The following general properties of sulfur ylides were observed from the computational studies: C-S bond distances that are close in length to that of a typical C-S double bond, high charge transfer from the sulfide to the carbene, and large torsional rotation barriers. Analysis of the sulfur ylide charge distribution indicates that the unusually short C-S bond distance can be attributed in part to the electrostatic attraction between highly oppositely charged carbon and sulfur atoms. Furthermore, n --> sigma* stabilization arising from donation of electron density from the carbon lone pair orbital into S-H or S-C antibonding orbitals leads to larger than expected torsional barriers. Finally, natural resonance theory analysis indicates that the bond order of the sulfur ylides H(2)S-CH(2) and (CH(3))(2)S-CH(2) is 1.4-1.5, intermediate between a single and double bond.