VICARIOUS NUCLEOPHILIC SUBSTITUTION WITH SULFUR CONTAINING CARBANIONS

Abstract

Carbanions stabilized with sulfur containing substituents are versatile intermedi-ates in organic synthesis. The great value and importance of such carbanions is connected with specific properties of the sulfur atom which is capable to exist in a variety of valent states and to form many functional groups. These various sulfur-containing groups exert different carbanion stabilizing effects and can also serve as leaving groups in nucleophilic substitution or elimination reactions. Taking into account numerous types of sulfur containing functional groups and a variety of reactions they can promote, it is well understandable that reactions of sulfur-containing carbanions have been thoroughly studied and widely exploited in organic synthesis. The reactions of such carbanions with aliphatic electrophilic partners: alkylating agents, carbonyl compounds and Michael acceptors consist a major section of this field and were subject of numerous studies as well as many monographs.¹ Contrary to that, not very much was known about reactions of such carbanions with electrophilic aromatic compounds. Actually, there are only few reports on nitroarylation of sulfur-containing carbanions via replacement of halogen orfho- or para- to the nitro group in halonitrocornpounds.² There are also some reports on the alkylation of nitroarenes and heterocyclic compounds in the reaction with sulfonium3 and sulfoxonium4 ylides, dimethylsulfoxide carbanion,⁵ and dialkyl or alkyl aryl sulfones carbanions.⁶     

Base-Catalysed H-D Exchange in 1 -Methylthiolanium Iodide

The kinetics of the base-catalysed H/D exchange of the 1-methylthiolanium cation in heavy water has been studied. Of the four α-methylene protons, two exchange much faster than the other two, a result which requires that reprotonation of the carbanion intermediate occurs with retention of configuration. NMR. spectral analysis indicates that the protons undergoing faster exchange bear a trans relation to the lone-pair on sulfur. This conclusion appears to conform to Wolfe's theory on the stability of carbanions [3].     

Nuclear magnetic resonance spectra of carbanions—VI. Cumyl-, α-methylbenzyl- and benzyl carbanions

The proton magnetic resonance spectra of the three title carbanions have been observed in THF with potassium as a counter ion. The ortho-protons in the α-methylbenzyl carbanion are nonequivalent at room temperature. This shows that the α-carbon in this carbanion is in the near-sp² configuration. The aromatic proton chemical shifts of the benzylpotassium obtained here are at higher shielding than those of benzyllithium reported previously by Sandel and Freedman. This seems to arise from the different ionic nature of the bonds between carbon and metal in the carbanions.     

Preparation of thiochromans via thermal cyclization

Formation of the thiochroman ring system is achieved by a two step synthesis that involves heating 3‐thiophenyl‐1‐propanols or 4‐thiophenyl‐2‐butanols in toluene with catalytic amounts of p‐toluenesulfonic acid. The propanols are made by the addition of sulfur stabilized carbanions to styrene oxide, ethylene oxide, propylene oxide, and isobutylene oxide. The carbanions are generated by treatment of either benzyl phenyl sulfide or thioanisole with butyllithium. The effect of substitution at the 1 and 3 positions of the propanols on the reaction yields is discussed. The mechanism of the reaction apparently involves intramolecular electrophilic aromatic substitution rather than a Claisen or thio‐Claisen rearrangement.     

CNDO/2-CALCULATIONS ON THE STABILIZATION OF CARBOCATIONS BY [sgrave]-BIVALENT SULFUR

Abstract

From the appearance potential measurements, groups with σ-bivalent sulfur are known to exert an unusual carbocation stabilization effect. In contrast to corresponding considerations on carbanions the 3d orbitals of sulfur can be invoked to rationalize this effect.     

Structures,stabilities, and energies of isomerization of α-cyano and α-isocyano carbanions

Ab initio STO -3G calculations show that α-cyano- and α-isocyano-substitution on carbanions produce a significant approximately equal stabilization of these charged species. Evidence is presented which suggests that the mechanism of such stabilization is qualitatively different for the cyano and isocyano substituents. The former appears to act through an electron delocalization process while the latter may operate by an inductive effect.     

Rate of spontaneous deactivation of styryl and α-methylstyryl carbanions

The deactivation of α-methylstyryl and styryl carbanions followed by spectral change and titration was studied kinetically. First-order rate constants were obtained for the deactivation of oligo-α-methylstyryl lithium, disodium, and dipotassium in tetrahydrofuran and of polystyryl potassium in varying degrees of polymerization in benzene that contained a small amount of tetrahydrofuran and n-hexane. It was observed that the addition of cryptate [222] exerts a significant effect on the system of oligo-α-methylstyryl disodium in tetrahydrofuran. The effect of dilution, degree of polymerization of the polymer, and counterions on the rate of deactivation of carbanions was discussed.     

The first example of racemization of the sulfur stereogenic center of α-sulfinyl carbanions at low temperatures

The treatment of enantiopure aryl dichloromethyl sulfoxides in THF with strong bases such as LDA, LiHMDS, NaHMDS, and KHMDS resulted in racemization of the sulfur stereogenic center of the sulfoxides even at ?78 °C. The rate of the racemization was found to be dependent on the alkali metal of the bases used. This is the first example of the racemization of the sulfur stereogenic center of α-sulfinyl carbanions at low temperatures.     

Photochemical naphthylation at(α-carbon atom of carbonyl and its equivalences

The photostimulated reaction of halonaphthalene with a series of carbanions derived from,propionic acid derivatives in liquid ammonia led to the naphthylation at a-carbon of the carbanions inan isolated yield ranging from 25％ to 86％.In all cases,the dehalonaphthalenes were found to,be by-products and the reaction was inhibited by p-dinitrobenzere.An electron transfer from thecarbanion to the halonaphthalene followed by ejection of halogen led to naphtbyl radical,as predictedby comparing the LUMOs of the carbanions and the halonaphthalenes,was involved in the process.Absence of the alkylnaphthalene and 1,2-dinaphthylalkane in the products indicates the smoothelectron transfer between(Naph-Nu)~+ and Naph-X.C-vs.O-naphthylation is fully addressed interms of MNDO calculations and acid-base principle.     

Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

The reaction of α-haloketones with N-alkyl benzothiazolium salts

Phenacyl chloride ( 1a ) reacts with the 3-methylbenzothiazolium quaternary salt ( 2 ) to give 4-methyl-2-benzoyl-4H-1,4-benzothiazine ( 4a ). A mechanism is discussed. Secondary α-haloketones give benzothiazolines. Merocyanine dyes are formed by the reaction of 2 with carbanions. It is shown that 2 functions as a hydride ion abstractor in the formation of merocyanine dyes.     

SN2’ versus SN2 Reactivity: Control of Regioselectivity in Conversions of Baylis–Hillman Adducts

TiCl₄‐induced Baylis–Hillman reactions of α,β‐unsaturated carbonyl compounds with aldehydes yield the (Z)‐2‐(chloromethyl)vinyl carbonyl compounds 5 , which react with 1,4‐diazabicyclo[2.2.2]octane (DABCO), quinuclidine, and pyridines to give the allylammonium ions 6 . Their combination with less than one equivalent of the potassium salts of stabilized carbanions (e.g. malonate) yields methylene derivatives 8 under kinetically controlled conditions (S_N2’ reactions). When more than one equivalent of the carbanions is used, a second S_N2’ reaction converts 8 into their thermodynamically more stable allyl isomers 9 . The second‐order rate constants for the reactions of 6 with carbanions have been determined photometrically in DMSO. With these rate constants and the previously reported nucleophile‐specific parameters N and s for the stabilized carbanions, the correlation log k (20 °C)=s(N + E) allowed us to calculate the electrophilicity parameters E for the allylammonium ions 6 (?19<E <?18). The kinetic data indicate the S_N2’ reactions to proceed via an addition–elimination mechanism with a rate‐determining addition step.     

The carbanions of S-alkanoate-O,O-dialkyl phosphates: new synthons for reaching α, β-ethylenic esters

The stabilization of phosphorothiolate carbanions has been achieved. Condensation of these carbanions with carbonyl derivatives lead to the corresponding α,β-unsaturated esters; a mechanism, via a β-hydroxyphosphorothiolate-β-mercaptophosphate rearrangement, is described. These new synthons are compared with the phosphonate analogs (Wittig-Horner's reagent).     

2-aryl-1,3-dithianes and -dithiolanes: A nearly ideal series for relating the energies for bond breaking to electron transfer

By virtue of the stabilizing effect of the 1,3-sulfur atoms on the carbocations, radicals, and carbanions generated from the title compounds, it has been possible to measure a variety of bond-making and bond-breaking processes in the two very similar solvents, DMSO and sulfolane, and relate them to electron-transfer energies obtained by electrochemical techniques. Important properties reported from this and previously published work are as follows: heats of hydride transfer to the cations from cyanoborohydride ion, pK in aqueous acid, heats of deprotonation by K⁺ DMSYL/DMSO, pK_HA, redox potentials for the cations, and carbanions, which relate their energies to their conjugate radicals and to each other. The results support our previous assertion that the electron-transfer energy between the three trivalent oxidation states of carbon and the Parr-Pearson absolute hardness, ϵ, derived from it are the fundamental properties that determine energies for making and breaking two-electron bonds and thus determine most of organic chemistry. Excellent correlations are found for the substituent effects on energy changes associated with the various processes for making and breaking bonds to the cations, radicals, and carbanions and the electron-transfer energies for interconverting them. Many comparisons can be made with the corresponding 2-aryl-1,3-dioxo systems. Careful “bookkeeping” of these energies through appropriate thermochemical cycles shows excellent consistency despite a small solvent effect for transferring the ions from sulfolane to DMSO. Direct reaction of the carbocation with the carbanion of 2-phenyl-1,3-dithiane produced a clean formation of the dimer from which the heat of heterolysis (40.6 kcal/mol) and homolysis (19.1 kcal/mol) could be calculated. AM1 structures and heats of formation of two neutral species and two cations, a radical and an anion, have been computed and are generally consistent with stabilizing interactions of the gem sulfurs with the reactive center. The present study is the first, to our knowledge, to provide a coordinated view of the energies for generating the carbocations, radicals, and carbanions from a series of heterocycles. These energies are related to each other and to the electron-transfer energies for interconverting these reactive trivalent forms of carbon. © 1996 John Wiley & Sons, Inc.     

Mapping the Electronic Structure and the Reactivity Trends for Stabilized α-Boryl Carbanions

The chemistry of stabilized α-boryl carbanions shows remarkable diversity, and can enable many different synthetic routes towards efficient C−C bond formation. The electron-deficient, trivalent boron center stabilizes the carbanion facilitating its generation and tuning its reactivity. Here, the electronic structure and the reactivity trends of a large dataset of α-boryl carbanions are described. DFT-derived parameters were used to capture their electronic and steric properties, computational reactivity towards model substrates, and crystallographic analysis within the Cambridge Structural Dataset. This study maps the reactivity space by systematically varying the nature of the boryl moiety, the substituents of the carbanionic center, the number of α-boryl motifs, and the metal counterion. In general, the free carbanionic intermediates are described as borata-alkene species with C−B π interactions polarized towards the carbon. Furthermore, it was possible to classify the α-boryl alkylidene metal precursors into three classes directly related to their reactivity: 1) nucleophilic borata-alkene salts with alkali and alkaline earth metals, 2) nucleophilic η²-(C−B) borata-alkene complexes with early transition metals, Cu and Ag, and 3) α-boryl alkyl complexes with late transition metals. This trend map aids selection of the appropriate reactive synthon depending on the reactivity sought.     

Regioselectivity of the Base-Induced Ring Cleavage of 1-Oxygenated Derivatives of Cyclobutabenzene

Oxy anions 3 generated from 1,2-dihydrocyclobutabenzen-1-ones 1 through addition of a charged nucleophile or from 1-hydroxy-1,2-dihydrocyclobutabenzenes 2 by deprotonation with base lead to stable products through distal and/or proximal cleavage of the strained four-membered ring via benzyl carbanion 4 and/or aryl carbanion 5. A systematic study of this process reveals the relative stability of the two isomeric carbanions 4 and 5 as a key factor in determining the course of the ring-cleavage reaction. While benzyl carbanions 4 can be trapped with carbon electrophiles, attempts at trapping aryl carbanions 5 with electrophiles other than H⁺ failed. In protic solvents, the magnesium salt of the tertiary alcohol 2 shows an increased rate of proximal cleavage as compared to its alkali salts. From this, we conclude that, in contrast to benzyl carbanions 4 , free aryl carbanions 5 are of transient existence only. Proximal C,C-bond cleavage seems to occur either through protonation of 5 from a fast, reversible equilibrium 3 ? 5 in which 3 strongly predominates, or in protic solvents possibly even through a rate-limiting protonation of 3 at the aromatic C-atom, bypassing free anion 5 altogether. Thus, additional factors other than just the relative stability of isomeric carbanions 4 and 5 are of importance in determining the regiochemistry of the base-induced C,C-bond cleavage in ketones 1 and in alcohols 2 .     

Quantification of the electrophilic reactivities of aldehydes, imines, and enones

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.     

Synthesis of optically pure α-halo-α′-sulphinyl-ketones

When optically pure sulphinyl carbanions are reacted at ?75°C with α-chloro or α-bromo carboxylic acid esters addition on the carboxyl group occurs and corresponding α-halo-α′-sulphinyl-ketones are obtained in optically pure form.     

S-BLOCK COMPLEXES OF α, α′-STABILIZED CARBANIONS: RINGS,CHAINS, AND 2D NETWORKS

A series of lithiated and sodiated α, α′-stabilized carbanions, [RSO ₂ CHCN]^? and [(RO) ₂ P(O)CHCN]^? have been characterized in the solid-state and found to adopt related structures. A common structural theme is the “head-to-tail” bonding of the ligands to form ring dimers, polymeric chains, or two-dimensional networks.     

SULFAMOYLATION OF ESTER ENOLATE ANIONS

Abstract

Stabilized carbanions such as the α-carbanions of carboxylic acid esters react with sulfamoyl chlorides by nucleophilic displacement at chlorine which results in chlorination of the carbanion. Thus direct sulfamoylation of these carbanions with sulfamoyl chlorides fails. Conversion of sulfamoyl chlorides to N-sulfonylamines followed by addition of carbanions at -78°C results in sulfamoylation of the carbanion. The method has not been successful with carbanions from diethyl acetamidomalonate and ethyl diphenylacetate.