Quantification of the Electrophilicities of Diazoalkanes: Kinetics and Mechanism of Azo Couplings with Enamines and Sulfonium Ylides

Kinetics and mechanism of the reactions of methyl diazoacetate, dimethyl diazomalonate, 4-nitrophenyldiazomethane, and diphenyldiazomethane with sulfonium ylides and enamines were investigated by UV-Vis and NMR spectroscopy. Ordinary alkenes undergo 1,3-dipolar cycloadditions with these diazo compounds. In contrast, sulfonium ylides and enamines attack at the terminal nitrogen of the diazo alkanes to give zwitterions, which undergo various subsequent reactions. As only one new bond is formed in the rate-determining step of these reactions, the correlation lg k₂(20 °C)=s_N(N+E) could be used to determine the one-bond electrophilicities E of the diazo compounds from the measured second-order rate constants and the known reactivity indices N and s_N of the sulfonium ylides and enamines. The resulting electrophilicity parameters (−21<E<−18), which are 11–14 orders of magnitude smaller than that of the benzenediazonium ion, are used to define the scope of one-bond nucleophiles which may react with these diazoalkanes.     

Quantum chemical study of the effect of N,N-acyl group nature on the structure and Gibbs free energy of the sulfur ketoylides and products of their transformations

With the purpose to study the effect of the nature of the imido-group of N,N-acyl-protected β-methyl-substituted keto-stabilized sulfonium ylides on the formation of methylthiopyrrolisinediones by cyclization, the structure features of these ylides are investigated by ab initio methods. The imido-group nature is shown to insignificantly affect in most cases the structure and the relative free energy of conformers of the ketoylides in question and the products of a cyclization reaction with their participation. The energy difference between the anti-peri-planar and syn-clinal orientation of nitrogen atoms in the imido-group and ylide carbon atom is negligible. The latter orientation is necessary for the reaction of intramolecular cyclization to proceed because in this case carbon atoms between which the bond forms are drawn together. The structure of cyclic pentanomial N,N-acyl group slightly affects the calculated values of Gibbs free energy of sulfur ketoylide reactions, and a temperature increase promotes the intramolecualr cyclization reactions. Wittig and Corey-Chaykovsky reactions typical of ylides are the least thermodynamically favorable for the sulfonium ketoylides under study.     

Sulfonium ylides

The intramolecular cyclization of keto-stabilized sulfonium ylides obtained from β-alanine and containing various imide fragments was studied. On heating in toluene in the presence of PhCO₂H, ylides containing a phthalimide moiety are converted into indolizidine-2,6-dione derivatives, whereas those incorporating a 4-methyl-1,2,3,6-tetrahydrophthalimide or pyrrolidine-2,5-dione moieties do not undergo cyclization. For Part 6, see Ref. 1 Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2008–2012, November, 1997.     

Discriminating non-ylidic carbon-sulfur bond cleavages of sulfonium ylides for alkylation and arylation reactions

A sulfonium ylide participated alkylation and arylation under transition-metal free conditions is described. The disparate reaction pattern allowed the separate activation of non-ylidic S-alkyl and S-aryl bond. Under acidic conditions, sulfonium ylides serve as alkyl cation precursors which facilitate the alkylations. While under alkaline conditions, cleavage of non-ylidic S-aryl bond produces O-arylated compounds efficiently. The robustness of the protocols were established by the excellent com...     

Charge-Assisted Chalcogen Bonds: CSD and DFT Analyses and Biological Implication in Glucosidase Inhibitors

This study reports a combined Cambridge Structural Database and theoretical DFT study of charge assisted chalcogen bonds involving sulfonium, selenonium, and telluronium cations. The chalcogen bond has been recently defined by IUPAC as the net attractive interaction between an electrophilic region associated with a chalcogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. Divalent chalcogen atoms typically have up to two σ-holes and forms up to two ChBs; the same holds for tetravalent chalcogens which adopt a seesaw arrangement. In sulfonium, selenonium, and telluronium salts chalcogen atoms form three covalent bonds, three σ-holes are located opposite to these bonds, and up to three charge assisted ChBs can be formed between these holes and the counterions. The covalent bond arrangement around these chalcogen atoms is similar to trivalent pnictogen atoms and translates into a similar pattern of noncovalent interactions. We have found and studied this type of charge-assisted chalcogen bonds in various sulfonium ion-containing inhibitors of glucosidase, for example, salacinol and kotalanol.     

Addition nucleophile des anions d'esters α-cyanoacetiques sur les cations succinimidosulfonium: Fragmentation ionique ou radicalaire des′ σ-sulfuranes intermediaires

Reactions of substituted cyanoacetate anions 4 with S,S-dialayklsuccinimidosulfonium salts resulted generally in the formation of N-alkylthiomethylketenimines and α-alkylthiomethylesters. Coupling products were also obtained with anion 4d and only observed in the case of methyl phenylcyanoacetate anion 4b. The results were interpreted by the formation of instable σ-sulfurane intermediates. Homolytic cleavage of these intermediates gave radical pairs, then the coupling products. Heterocyclic clevage gave new sulfonium salts which rearranged via sulfonium ylides.     

Rhodium(II)-catalyzed addition of 2-diazo(fluoroalkyl)acetoacetates to sulfides: a simple synthesis of stable sulfonium ylides

2-Diazo(fluoroalkyl)acetoacetates 1 reacted readily with many sulfides under mild reaction conditions in the presence of catalytic Rh₂(OAc)₄ affording to the corresponding sulfonium ylides. While thianthrene gave trans-thianthrenium 5,10-di(fluoroalkylacetoethoxycarbonyl)methylides (7a and 7b) under the same reaction condition, the structure of 7btrans-thianthrenium 5,10-di(bromodifluoroacetoethoxy-carbonyl)methylides was fully confirmed by spectral methods and X-ray single crystal diffraction analysis. All the ylide products obtained are fairly stable due to the strong electron-withdrawing properties of the fluorine atom.     

An efficient synthesis of 2-isoxazolines from α-haloketone oximes and dimethyl sulfonium salts

2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity.     

Etude de la reactivite d'ylures de sulfonium et de pyridinium stabilises par un groupement cyanoformyle

The sulfonium and pyridinium ylides stabilized by a cyanoformyl group, in an acidic medium, lead to sulfonium and pyridinium salts which are equivalents of pyridinium or sulfonium ketene salts. This originality has been used to prepare new stabilized ylides, or derivatives of substituted arylacetic acids or 4-hydroxy thiazoles.     

Controlling the fluoridophilicity of sulfonium boranes via chelation,Coulombic and hydrophobic effects

We describe the synthesis and properties of a series of sulfonium boranes featuring a dimesitylboryl unit and a dimethylsulfonium or methylphenyl sulfonium moiety connected by an ortho- or para-phenylene linker. Acid-base and fluoride anion tritration experiments carried out in aqueous media indicate that [o-(Mes₂B)C₆H₄(SMePh)]⁺ is the most Lewis acidic derivative. Structural and computational analysis indicate that the favorable properties of this cationic borane derive from the proximity of the sulfonium and boryl units which enhances the Coulombic stabilization of the ensuing zwitterions o-(Mes₂XB)C₆H₄(SMePh) with X?=?OH or F. Another important factor is the overall hydrophobicity of the sulfonium borane which, we propose, promotes anion desolvation, a factor also favoring B-X bond formation. Finally, the crystal structure of o-(Mes₂FB)C₆H₄(SMePh) shows that the zwitterion is further stabilized by formation of a BF→S chelate motif.     

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 k_{20 °C}=s_N(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.     

Synthesis of α‐phosphonylated phosphonium and sulfonium ylides: Study of their thermal behavior

The additions of two equivalents of trialkylphosphites onto phosphonodithioformates produce stabilized α‐sulfanyl‐α‐phosphonyl phosphonium ylides. Their subsequent reaction with alkyl or benzyl halides gives stabilized sulfonium ylides. Thermal treatment of these phosphonium and sulfonium ylides leads to α‐sulfanyl methylene bis‐phosphonates through protonation–dealkylation intramolecular reactions. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:164–171, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20530     

二价钌催化的金属卡宾经由的硫叶立德[2,3]-σ重排反应研究

报道烯(炔)基硫醚与α-重氮羰基化合物, 在[RuCl₂(p-cymene)]₂催化下, 经由金属卡宾发生硫叶立德[2,3]-σ重排反应(Doyle-Kirmse反应). 在Ru(II)作用下, α-重氮羰基化合物与烯丙基硫醚的反应以较好收率生成相应的[2,3]-σ重排产物高烯丙基硫醚. 同样条件下与炔丙基硫醚的反应则生成[2,3]-σ重排产物联烯和呋喃衍生物, 后者是联烯进一步在Ru(II)作用下重排的产物.     

Reactions of silyl-stabilised sulfur ylides with organoboranes: enantioselectivity, mechanism, and understanding

The reaction of trimethylsilyl-substituted sulfonium ylides with organoboranes (Ph(3)B, Et(3)B) has been studied and although homologated products were obtained in good yield (after oxidation to the corresponding alcohols), the enantiomeric excesses were low with our camphor-based chiral sulfide (up to 40% ee, cf. corresponding phenyl-substituted sulfonium ylides gave >95% ee). Cross-over experiments were conducted to ascertain the nature of this difference in selectivity. Thus, aryl- and silyl-substituted sulfonium ylides (1 equiv.) were (separately) reacted with Et(3)B (1.5 equiv.) followed by Ph(3)B (1.5 equiv.) The experiments were repeated changing the order of addition of the two boranes. It was found that the aryl-substituted sulfonium ylide only trapped the first borane that was added indicating that ate complex formation was non-reversible and so was the selectivity determining step. In contrast the silyl-substituted sulfonium ylide only trapped Ph(3)B (it is more reactive than Et(3)B) indicating that ate complex formation was reversible and so 1,2-migration was now the selectivity determining step. The reactions have been studied computationally and the experimental observations have been reproduced. They have further revealed that the cause of reversibility in the case of the silyl-substituted sulfonium ylides results from ate complex formation being less exothermic and a higher barrier to 1,2-migration.     

Sulfonium ylides

The thermal transformations of phthalimido-substituted keto-stabilized sulfonium ylides, including optically active ylides, were studied. The thermolysis of sulfonium ylides obtained from α- and β-amino acids leads to methylthio-substituted pyrrolizidine- and indolizidinediones. Racemization of optically active ylides does not occur. Sulfonium ylides with longer carbon chains do not undergo intramolecular cyclization.     

The stereochemistry of sulfonium ylides derived from 9-alkylidenethioxanthenes– The relationship between ring inversion and S+?C− bond rotation

A series of sulfonium ylides has been prepared by the reaction of 9-alkylidenethioxanthenes with dimethyl diazomalonate. The e' electron pair on sulfur is more efficient than the a' in trapping the “carbenes” generated by copper(II) catalyzed decomposition of diazo compounds. Consequently, e' ylides are the kineti-cally-controlled reaction products. Varying the C2 substituent does not alter this. Sulfides and sulfonium ylides containing the isopropylidene moiety do not undergo rapid ring inversion. Rotation about the S+? C^? bond occurs in the pseudo-axial conformation but not the pseudo-equatorial. The use of the anisochronicity of portions of the malonylide fragment as a criterion for heterocyclic ring inversion is presented. It is suggested that the sulfoxides of phenothiazine, phenoxathiin, thianthrene, and related sulfoxides, undergo rapid ring inversion.     

Cycloadditions of `Thiocarbonyl Ylides' with Tetracyanoethylene (=Ethenetetracarbonitrile): Interception of Intermediates

Thiocarbonyl ylides (=sulfonium ylides) belong to the most nucleophilic 1,3‐dipoles (high HO energy). In their reactions with tetracyanoethylene (TCNE=ethenetetracarbonitrile; low LU energy), a borderline crossing from the concerted mechanism to a two‐step pathway via a 1,5‐zwitterion was observed. Steric hindrance at one or both termini of the 1,3‐dipole is an additional requirement. The ylides 3 and 13 , set free by N₂ elimination of dihydro‐1,3,4‐thiadiazoles, underwent electrocyclization or 1,4‐H shift. Ylides 3 and 13 are bases and afforded MeOH adducts of different regiochemistry. Whereas 3 and TCNE in abs. THF at 45° furnished the (3+2) cycloadduct 20 , a MeOH content of 0.5 – 5 vol‐% in THF gave rise to a seven‐membered lactim ether 22 and thiolane 20 in a 65: 35 ratio (Scheme 4). Water (0.5 – 1 vol‐%) in THF led to lactam 24 and adduct 20 in the same ratio. The zwitterion 26 , assumed to be the first intermediate, enters competing reactions: the irreversible ring closure to thiolane 20 and the reversible formation of a strained, cyclic seven‐membered `ketene imine' 28 , which is intercepted by MeOH or H<sub>2</sub>O. The gauche‐conformation 32 of an analogous zwitterion, produced from the tetrasubstituted `thiocarbonyl ylide' 13 with TCNE (Scheme 5), led to the thiolane derivative 35 , while the anti‐conformation 33 afforded the thioxo compound 5 and cyclopropane derivative 36 by intramolecular nucleophilic substitution.     

Cesium-Fluoride-Promoted Synthesis of Stable Organocesium Reagents and Their Ambident Reactivities with Arynes

Described are the diverse reactivities of novel, stable, ambident thio-organocesium reagents (bearing electron withdrawing groups) against benzynes. Reactions at reflux temperature predominantly led to the generation of various functionalized stable sulfonium ylides and at 40 °C the same reaction underwent direct c-arylation. Furthermore, lack of internal hydrogen on the cesium reagent helped to produce different ortho-bifunctional arynes in both the reactions. Interestingly, depending on the reactivities of substrates, the one-pot tri-component procedure generated either ylides or σ-bond insertion products.     

Asymmetric Sulfonium Ylide Mediated Cyclopropanation: Stereocontrolled Synthesis of (+)‐LY354740

The reaction of ester‐stabilized sulfonium ylides with cyclopentenone to give (+)‐ 5 ((1S,5R,6S)‐ethyl 2‐oxobicyclo[3.1.0]hexane‐6‐carboxylate), an important precursor to the pharmacologically important compound (+)‐LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)₂, ethyl diazoacetate, 60 °C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo‐ and enantioselectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base‐mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide‐mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95 % ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.     

The first example of the generation of azomethine ylides from a fluorocarbene: 1,3-cyclization and 1,3-dipolar cycloaddition

The reaction of Schiff bases with fluorocarbene, generated by reduction of dibromofluoromethane with active lead in the presence of Bu₄NBr under ultrasound irradiation, involves the formation of fluoro-substituted azomethine ylides which undergo cyclization into aziridines. 1,3-Cyclization of ylides, generated from N-arylimines of benzaldehyde, proceeds stereoselectively. When carrying out the reaction of Schiff bases with fluorocarbene in the presence of dimethyl maleate or dimethyl acetylenedicarboxylate, the products of dehydrofluorination of the primary adducts of the 1,3-dipolar cycloaddition of fluoro-substituted azomethine ylides to multiple bonds of dipolarophiles were obtained. In the case of the reaction of N-alkylimines of benzaldehyde the cycloaddition of ylides to dimethyl maleate completely suppressed the cyclization to aziridines.