P-tolyl Sulfoxide Research Articles

Chiral sulfoxide controlled asymmetric additions to CN double bond. An efficient approach to stereochemically defined α-fluoroalkyl amino compounds

This paper presents a full account of studies into the asymmetric addition reactions between α-lithium derivatives of enantiomerically pure methyl and benzyl p-tolyl sulfoxides and the N-( p-methoxyphenyl)aldimines, bearing trifluoromethyl, pentafluoroethyl and ω-hydrotetrafluoroethyl groups, to afford the corresponding α-fluoroalkyl β-sulfinylamines, synthetically versatile precursors of a series of enantiomerically pure biomedicinally important α-fluoroalkylalkylamines and α-fluoroalkyl-β-hydroxyalkylamines. The addition reactions were found to proceed under mild conditions allowing for convenient preparation of the corresponding α-fluoroalkyl β-sulfinylamines in excellent yields and good enantiomeric purity. The stereochemical outcomes of these reactions were shown to be subject to kinetic control, that is in sharp contrast to the corresponding reactions of fluorine-free imines. The absolute configurations of the addition products suggest that the fluoroalkyl group on starting imines plays a role of enantiodirecting, sterically larger substituent causing realization of an unusual for this type of reactions transition states.

Synthesis and reactivity of enantiomerically pure 2-fluoromethyl-2-(1′- p-tolylsulfinyl)alkyl oxiranes

This paper presents an efficient procedure for preparing enantio- and diastereomerically pure 2-fluoromethyl-2-(1′- p-tolylsulfinyl)alkyl oxiranes, designed as versatile chirons to be transformed to a series of synthetically useful and biologically relevant compounds. In particular, (2 S)-2-fluoromethyl-2-(1′- p-tolylsulfinyl)alkyl oxiranes, prepared by the reaction between ( R S)-α-alkyl-β-keto-γ-fluoro sulfoxides and diazomethane, can be efficiently obtained in diastereomerically pure state via formation, purification and re-cyclization of the corresponding bromohydrins. Synthetic value of these oxiranes was demonstrated by their transformation to various sulfur-free synthetically and biologically interesting compounds via the reductive desulfurization, Pummerer, ring-opening and syn-elimination reactions. The presence of the methyl in α-position to the sulfoxide group in the starting compounds was found to interfere with a normal course of the Pummerer rearrangement giving rise to the corresponding vinyl sulfides in low chemical yield. By contrast the thermal syn-elimination reaction of the p-tolyl sulfoxide group provided an efficient entry to the sulfur-free vinyl derivatives.

Two Practical and Efficient Approaches to Fluorinated and Nonfluorinated Chiral beta-Imino Sulfoxides.

Reaction of fluorinated and nonfluorinated N-substituted imidoyl chlorides 1 with lithium derivatives of enantiopure methyl p-tolyl sulfoxide 2a (or racemic methyl phenyl sulfoxide 2b) gave a wide variety of chiral N-substituted beta-imino sulfoxides 4 in good to excellent yields. The title compounds (R)-4 were also prepared by aza-Wittig reaction of gamma-fluoro-beta-keto sulfoxides (R)-5 and N-aryl iminophosphoranes 6. The imino-enamino equilibrium was studied, showing, in all instances, the imino form as the predominant tautomer independent of the nature of the N-substituent. The configuration of the C=N double bond was found to be Z for both N-alkyl and N-aryl derivatives on the basis of (1)H NMR NOE difference experiments performed over several compounds. Ab initio calculations (HF/6-31G) carried out on several representative examples of 1 and 4 are, in general, consistent with the experimental results.

Diastereoselective asymmetric cyclopropanation of (S)-(+)-α-(diethoxyphosphoryl)vinyl p-tolyl sulfoxide

The title sulfoxide 1 reacts with fully deuterated dimethylsulfoxonium methylide, diphenylsulfonium isopropylide and diphenyldiazomethane to form the corresponding cyclopropanes 4 as single diastereoisomers; the chirality of the cyclopropane (+)-4c obtained from 1 and diphenyldiazomethane is (SS,SC) as determined by X-ray diffraction analysis; based on experimental data, the steric course of the asymmetric cyclopropanation is proposed.

Coordinatively Unsaturated Cp*Ru Alkoxo Complexes. 16.1Addition Products Cp*Ru(acac)L and Solution Equilibria1

With [Cp*Ru(OMe)]2 (1) as starting material, a number of 2,4-pentanedionato complexes Cp*Ru(2,4-pentanedionate) were prepared. The solid-state structure of Cp*Ru(1-phenyl-2,4-pentanedionate) (3) was elucidated by X-ray crystallography, and the complex was found to be a dimer in the solid state, as previously established for Cp*Ru(2,4-pentanedionate) (2). The molecular weight of 3 in benzene indicates a dimer (3-3) in solution as well. Low-temperature 1H NMR spectroscopy reveals a process involving dissociation of the dimer into monomers associated with an inversion of the pentanedionate ligand at Ru. The activation energy (Ea = 43.5 ± 0.7 kJ/mol, toluene-d8) reflects the enthalpy of dissociation of the dimer. All dimers are easily cleaved with two-electron ligands L, resulting in the mononuclear complexes Cp*Ru(2,4-pentanedionate)L. Besides isolable complexes with L = phosphine, phosphite, and CO, labile adducts of the same composition with σ-S and N donor ligands (L = methyl p-tolyl sulfoxide, ethyl meth...

A new and general synthesis of N-substituted fluorinated β-iminosulfoxides

Reaction of fluorinated imidoyl chlorides 1 with lithium enolates of chiral non-racemic methyl p-tolyl sulfoxide or racemic methyl phenyl sulfoxide 2 gave N-substituted γ-fluorinated β-iminosulfoxides 3 in excellent yields as the major tautomer with Z geometry.

α-Phosphoryl sulfoxides. XI. Sulfenylation of α-phosphoryl sulfoxides and a general synthesis of optically active ketene dithioacetal mono-S-oxides

Sulfenylation and selenenylation of α-phosphoryl sulfoxides 1 with S-methyl methanethiosulfonate and phenylselenenyl bromide, respectively, affording α-methylsulfenyl- and α-phenylselenenyl-α-phosphoryl sulfoxides 8 and 9 are described. Sulfenylation of (+)-(S)-dimethoxyphosphorylmethyl p-tolyl sulfoxide 2 gave a mixture of optically active diastereoisomers of the sulfoxide 8a which is a key substrate in the Horner-Wittig synthesis of enantiomeric ketene dithioacetal mono-S-oxides 10. The E Z ratio of geometrical isomers of 10 was determined and briefly discussed. The crystal and molecular structure of E-1-p-tolylsulfinyl-1-methylsulfenyl-2-phenyl-ethene 10a is reported.

α-phosphoryl sulfoxides. X. A general synthesis of optically active α-chlorovinyl sulfoxides

A general and efficient synthesis of enantiomeric α-chlorovinyl p-tolyl sulfoxides 1 using (+)-(S) C(S) S-α-chloro-α-dimethoxyphosphorylmethyl p-tolyl sulfoxide as a key substrate for the Horner-Wittig reaction with carbonyl compounds is described. The E Z ratio of geometrical isomers of 1 was determined and briefly investigated. The X-ray diffraction structures of ( Z)-1-chloro-1-p-tolylsulfinyl-2-phenyl-ethene and (Z)-1-chloro-1-p-tolylsulfinyl-2-(2-thienyl)-ethene are reported.

Total Synthesis of (−)-Maytansinol

A total synthesis of maytansinol (1) was achieved, in a convergent way, using (3S,6S,7S)-aldehyde 4 and (S)-p-tolyl sulfoxide 3 as fragments. When the anion of 3 was condensed with aldehyde 4, some induction at C(10) was observed (60% de), giving the C(1)-N(19)-open-chain compound 7, after thermal elimination of sulfinate. Pure E/E stereochemistry of the 11,13-diene was obtained. Selective modifications of the functionalities permitted macrocyclization and further elaboration to maytansinol.

Cyclobutyl phenyl sulfoxide and (SR)-cyclobutyl p-tolyl sulfoxide: new reagents for the spiroannelation of cyclopentanone

Cyclobutyl phenyl sulfide 2, cyclobutyl phenyl sulfoxide 3 and (SR)-cyclobutyl p-tolyl sulfoxide (SR)-8 have been synthesized and used for the spiroannelation of cyclopentanone. In the most effective sequence, lithiated 3 is added to ketones with formation of β-hydroxy sulfoxides 4a-g, which are ring enlarged and hydrolyzed to cyclopentanones 6a-e and sulfanylcyclopentene 6f, respectively, after reduction to β-hydroxy sulfides 5a-f. In an asymmetric version using (SR)-8, partial racemization during ring enlargement was observed.

Synthesis and diels-alder reactions of ( R)-4-hydroxy-4- p-tolylsulfinylmethyl-2,5-cyclohexadienone

Enantiomerically pure ( R)-4-hydroxy-4- p-tolylsulfinylmethyl-2,5-cyclohexadienone 1 was synthesized in two steps and 80% overall yield from 4,4-dimethoxy-2,5-cyclohexadienone and ( R)-methyl- p-tolyl sulfoxide. The Diels-Alder reaction of cyclopentadiene with 1 ocurred exclusively from the C-4 hydroxyl face in either thermal or catalytic conditions. From the reaction carried out in the presence of BF 3·OEt 2 at −78°C adduct 6 was isolated in a 75 % yield.

Cyclobutyl phenyl sulfoxide and ( SR)-cyclobutyl p-tolyl sulfoxide: New reagents for the spiroannelation of cyclopentanone

Cyclobutyl phenyl sulfide 2, cyclobutyl phenyl sulfoxide 3 and ( SR)-cyclobutyl p-tolyl sulfoxide (SR)- 8 have been synthesized and used for the spiroannelation of cyclopentanone. In the most effective sequence, lithiated 3 is added to ketones with formation of β-hydroxy sulfoxides 4a-g, which are ring enlarged and hydrolyzed to cyclopentanones 6a-e and sulfanylcyclopentene 6f, respectively, after reduction to β-hydroxy sulfides 5a-f. In an asymmetric version using (SR)- 8 , partial racemization during ring enlargement was observed.

Improved Large Scale Preparation on Both Enantiomers of Methyl p-Tolyl Sulfoxide from Diacetone-D-glucose

Improved Large Scale Preparation on Both Enantiomers of Methyl p-Tolyl Sulfoxide from Diacetone-D-glucose

Prochiral sulfides as in vitro probes for multiple forms of the flavin-containing monooxygenase

A homologous series of alkyl-substituted p-tolyl sulfides have been synthesized and evaluated as in vitro, isozyme-selective substrate probes for the microsomal flavin containing monooxygenases. Straight-chain and branched-chain alkyl homologs were metabolized to the corresponding ( R)- and ( S)-sulfoxides which were analyzed by chiral phase high-performance liquid chromatography. Initial studies demonstrated that the stereochemical composition of alkyl p-tolyl sulfoxides generated by FMO2, purified from rabbit lung, was a function of the degree of steric crowding about the prochiral center. In contrast, purified rabbit liver FMO1 formed the ( R)-sulfoxide from the n-alkyl series of substrates in a highly stereoselective manner (> 90%). Similar results were obtained with these two rabbit cDNAs expressed in E. coli. In contrast to rabbit FMO1 and FMO2, a characteristic feature of catalysis by cDNA-expressed rabbit FMO3 was the lack of stereoselectivity observed for formation of methyl p-tolyl sulfoxide. Collectively, these data demonstrate that the stereochemical composition of sulfoxides generated from the n-alkyl series of sulfides is isozyme-dependent. Metabolism of methyl p-tolyl sulfide by detergent-solubilized hepatic microsomes from a wide variety of experimental animals yielded predominantly ( R)- methyl p-tolyl sulfoxide, which, at least in rabbit liver, is indicative of catalysis dominated by FMO1. However, solubilized human and macaque liver preparations catalyzed this reaction in a relatively non-stereoselective manner. Macaque liver FMO was purified and the metabolite profile generated from the n-alkyl p-tolyl sulfides was found to be most similar to rabbit FMO3. Moreover, antibodies directed against macaque liver FMO selectively reacted with rabbit FMO3 and a microsomal protein expressed in adult human, but not fetal human liver, adult human kidney or adult human lung. Therefore, an FMO isoform expressed selectively in adult primate liver has catalytic and immunochemical properties consistent with its classification in the FMO3 family.

Synthesis and use of (E)-1-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1-enes

Condensation of the lithium salt of (R)-methyl p-tolyl sulfoxide 1 with fluorinated α,β-unsaturated ketones 2 leads to (3R/S,RS)-(E)-1-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1-enes 3, whose absolute stereochemistry was determined by X-ray diffraction and NMR analyses. Reductive removal of the sulfinyl chiral auxiliary allows the preparation of both enantiomers of fluorinated tertiary alcohols of type 8 and 9

(Z)-(–)-(R)-β-Styryl p-tolyl sulfoxide

The crystal structure determination of Z-(-)-(R)-beta-styryl p-tolyl sulfoxide, C15H14OS, confirms its absolute configuration and establishes that the slightly twisted olefinic bond is not antiperiplanar to the S-O bond. It also provides a molecular basis for the theoretical study of cycloadditions between nitrones and vinylic sulfoxides.

Determination of Peroxyacetic Acid Using High-Performance Liquid Chromatography with External Calibration

A new method for the determination of peroxyacetic acid (PAA) in aqueous solutions is described. Methyl p-tolyl sulfide (MTS) is oxidized by PAA, forming the corresponding methyl p-tolyl sulfoxide (MTSO), which can be separated easily by high-performance liquid chromatography on a reversed-phase column and detected by ultraviolet spectroscopy at a wavelength of 230 nm. MTSO is a commercially available solid substance which can be used as an external standard for calibration. Therefore, calibration with the unstable PAA can be avoided

Prochiral Sulfoxidation as a Probe for Multiple Forms of the Microsomal Flavin-Containing Monooxygenase: Studies with Rabbit FMO1, FMO2, FMO3, and FMO5 Expressed in Escherichia coli

Multiple forms of the microsomal flavin-containing monooxygenase (FMO) exist in rabbit tissues. In order to better understand the catalytic properties of these isoforms, we have expressed rabbit FMO1, FMO2, FMO3, and FMO5 in Escherichia coli and examined their kinetic parameters and prochiral selectivities for the sulfoxidation of methyl-, ethyl-, n-propyl-, and n-butyl-substituted p-tolyl sulfides. FMO1 and FMO2 exhibited high affinities for these substrates (Km<10 μM), in contrast to the low-affinity FMO3 form for which Km values ranged between 100 and 280 μM. FMO5 did not form quantifiable levels of sulfoxide metabolites at the concentrations used. The individual stereochemical metabolite profiles generated by FMO1, FMO2, and FMO3 were unique and served to distinguish among these three cDNA-expressed isoforms. To investigate the relationship between the kinetic parameters for the cDNA-expressed enzymes and the native microsomal enzymes, we examined the kinetics and stereoselectivity of metabolism of methyl p-tolyl sulfide by detergent-solubilized rabbit liver microsomes. We analyzed these data with respect to FMO1 and FMO3, the two predominant hepatic isoforms. Sulfoxidation of methyl p-tolyl sulfide by FMO1 and FMO3 solubilized from E. coli microsomes proceeded with apparent Kms of 18 and 270 μM, respectively. FMO1 was essentially stereospecific for formation of (R)-methyl p-tolyl sulfoxide, whereas FMO3 generated this metabolite with little prochiral selectivity. Sulfoxidation of methyl p-tolyl sulfide by detergent-solubilized rabbit liver microsomes was best described by a two-enzyme model, with apparent Km values of 11 and 340 μM. The enantiomeric purity of the (R)-methyl p-tolyl sulfoxide metabolite, generated by detergent-solubilized rabbit liver microsomes, decreased progressively with increasing substrate concentration, from a high of 96% enantiomeric excess at a substrate concentration of 5 μM to a low of 63% enantiomeric excess at a substrate concentration of 2 mM. The kinetic and stereochemical properties of the high-affinity and low-affinity components of detergent-solubilized rabbit liver microsomes were similar to those exhibited by cDNA-expressed FMO1 and FMO3, respectively. Therefore, methyl p-tolyl sulfide, used at the appropriate substrate concentrations, is useful for discriminating between FMO1- and FMO3-mediated catalysis in rabbit liver microsomal preparations.

Synthesis of Enantiopure 2-Malonylvinyl Sulfoxides via Addition-Elimination Reactions of 2-Halo- and 2-(Mesyloxy)vinyl Sulfoxides

Enantiomerically pure (E)-2-bromo- and (E)-2-iodovinyl sulfoxides 3a and 3b have been prepared in multigram quantities from (E)-1,2-bis(tri-n-butylstannyl)ethene; enantiomerically pure (E)-2-(mesyloxy)vinyl sulfoxide 3c has been synthesized by reaction of the enolate derived from condensation of 1-lithiomethyl p-tolyl sulfoxide and DMF with methanesulfonyl chloride. These compounds react with anions derived from diethyl alkylmalonates to produce enantiopure 2-malonylvinyl sulfoxides in good to excellent yields and with a high degree of stereoselectivity. The transformations proceed through an «addition-rotation-elimination» sequence, and the stereochemical results reinforce the conceptthat nucleophilic additions to vinyl sulfoxides are sterically controlled and occur predominately syn to the sulfinyl electron lone pair

Ligand Exchange Reaction of Sulfoxides in Organic Synthesis. A Novel Method for Synthesizing Acetylenes from Carbonyl Compounds through β-Trifluoromethanesulfonyloxy Vinyl Sulfoxides

Abstract α-Sulfinyl ketones were prepared by the reaction of alkyl phenyl sulfoxide or chloromethyl p-tolyl sulfoxide with aldehydes or methyl esters in high yields, and were converted to acetylenes through β-trifluoromethanesulfonyloxy vinyl sulfoxides by the ligand exchange reaction of the sulfinyl group.