Scope and Limitations in the Use of α-Silyl and α-Stannyl Sulfones as Latent α-Sulfonyl Anions

Three methods for the regeneration of α-sulfonyl anions from α-silyl sulfones and α-stannyl sulfones are investigated. These methods include: (1) treatment of α-silyl sulfones with electrophiles (aldehydes and acid halides) in the presence of fluoride ion; (2) reaction of α-silyl sulfones with n-butyllithium which produces an α-silyl anion via a migration of the -SiMe₃ group from the α-position to the ortho-position of the phenyl sulfones; and (3) direct transmetalation of α-stannyl sulfone by treatment with n-butyllithium. The addition of cerium [III] chloride is shown to substantially decrease enolization problems associated with addition of α-sulfonyl anions to carbonyl compounds bearing enolizable protons.     

Enantioselective Reduction of Electrophilic CC Bonds with sodium tetrahydroborate and ‘semicorrin’ cobalt catalysts

‘Semicorrin’ cobalt complexes, prepared in situ from cobalt(II) chloride and the corresponding ligands, are efficient catalysts for the enantioselective reduction of electrophilic C?C bonds with NaBH₄. The best selectivities (> 90% ee) are achieved with α,β-unsaturated carboxamides and carboxylates. Analogous α,β-unsaturated nitriles, sulfones, and phosphonates afford enantiomeric excesses of 50–70%. Interestingly, in the reduction of α,β-unsaturated sulfones, the highest enantioselectivities were obtained with unsymmetrical ‘semicorrins’, whereas in all other cases C₂-symmetric ‘semicorrins’ proved to be superior.     

SYNTHESIS AND CONFIGURATIONAL STUDIES OF ARYL CYCLOPROPYL SULFONES

Abstract

The cycloaddition of arylthiocarbenes to styrene gave stereospecifically cis?1-(arylthio)-2-phenylcyclopropanes, which were subsequently oxidized to the corresponding sulfones. The cyclopropanation of α,β-unsaturated sulfones with dimethylsulfonium methylide yielded stereoselectively trans?1-(arylsulfonyl)-2-arylcyclopropanes. The configurational assignments of these compounds have been arrived at on the basis of IR and PMR spectral data. Chemical shifts for ring protons and other substituents reveal that all the substituents tend to cause protons cis to them to appear at higher fields than those trans to them. This has been used as a criterion to distinguish between cis and trans aryl cyclopropyl sulfones.     

Synthetic Applications of π-Electron-Deficient Sulfones

Abstract

The use of π-electron-deficient aryl sulfones, especially 3,5-bis(trifluoromethyl) phenyl alkyl sulfones (BTFP-sulfones) as soft nucleophiles, as caboxylic acid protecting group and in Julia–Kocienski olefination reactions is described. In the case of α-(arylsulfonyl)acetates dialkylation, reactions are performed under phase-transfer analysis (PTC) conditions using K ₂ CO ₃ as base. Esters derived from 2-(arylsulfonyl)ethanol can be deprotected using aqueous NaHCO ₃ . Alkyl BTFP sulfones are coupled with carbonyl compounds using KOH or P4-t-Bu as bases to give the corresponding alkenes after Smiles rearrangement.     

KINETIC STUDY OF THE REACTIONS OF TRIARYLPHOSPHINES WITH α-HALO SULFONES

Abstract

Reaction of a series of triarylphosphines with α-halo-m-cyanobenzyl phenyl sulfones gives the following Hammett ρ values: (CI) ρ = ?1.84; (Br) ρ = ?3.03; (I) ρ = ?3.36.     

Chemoselective mono halogenation of β-keto-sulfones using potassium halide and hydrogen peroxide; synthesis of halomethyl sulfones and dihalomethyl sulfones

The synthesis of α-halo β-keto-sulfones using potassium halide and hydrogen peroxide as a chemoselective mono halogenation reagent and the synthesis of α,α-symmetrical and asymmetrical dihalo β-keto-sulfones and α-halo, α-alkyl and β-keto-sulfones is described. Base induced cleavage of α-halo β-keto-sulfones, α,α-dihalo β-keto-sulfones, and α-halo, α-alkyl β-keto-sulfones afforded the corresponding halomethyl sulfones, dihalomethyl sulfones and haloalkyl sulfones.     

2-(N-Hydroxylamino) sulfone synthesis by indium-iodine-triggered aza-Michael type addition of nitroarenes to vinyl sulfones

One-pot reduction-triggered 1,4-addition reaction of various nitroarenes to the α,β-unsaturated sulfones was investigated. In the presence of indium/iodine in MeOH at room temperature, nitroarenes reduced in situ reacted with vinyl sulfones and produced β-(N-hydroxylamino) sulfones in good yields.     

Reaction of 1-bromovinyl and 1-bromo-2-phenylvinyl sulfones with some CH acids

Benzyl, methyl, and phenyl α-bromovinyl sulfones reacted with malononitrile and dimethyl malonate sodium enolates in THF to give sulfonyl-substituted cyclopropanes. Reactions of the same sulfones with methyl acetoacetate sodium enolate afforded the corresponding sulfonyl-substituted cyclopropanes as mixtures of cis and trans isomers with a small impurity of 5-sulfonyl-4,5-dihydrofuran derivative. Phenyl and p-tolyl 1-bromo-2-phenylvinyl sulfones reacted with methyl acetoacetate sodium salt to produce a mixture of trans-isomeric 5-sulfonyl-4,5-dihydrofuran and Michael adduct of the CH acid with activated acetylene generated by concurrent 1,2-dehydrobromination of the initial α-bromovinyl sulfone.     

New synthesis of allylidenecyclobutanes by the reaction of cyclobutylmagnesium carbenoids with vinyl sulfones

The reaction of cyclobutylmagnesium carbenoids, which were generated from 1-chlorocyclobutyl p-tolyl sulfoxides with EtMgCl via the sulfoxide-magnesium exchange reaction at low temperature, with carbanions derived from vinyl sulfones with n-BuLi or LDA resulted in the formation of allylidenecyclobutanes in moderate to good yields. The actual reactive species of the sulfones in this reaction were proved to be the lithium α-sulfonyl carbanion of allyl sulfones derived from the vinyl sulfones by double bond migration with the bases used. Mono- and di-substituted allylidenecyclobutanes can be obtained by using a variety of vinyl sulfones.     

Inorganic base-catalyzed formation of antivirally active N-substituted benzamides from α-amido sulfones and N-nucleophile

Background

Heteronucleophiles as well as carbanionic reagents can be used to react with α-amido sulfones, thus giving the opportunity to prepare a large array of amino derivatives. Since, novel 1,3,4-oxadiazole-2-thiol derivatives can serve as potent nucleophiles, we employed 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the nucleophilic source of nitrogen in the reaction with α-amido sulfones.

Results

A series of N-substituted benzamides bearing 1,3,4-oxadiazol unit were prepared for the first time by the reaction of in situ generated protected imine from α-amido sulfones with 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophile. Some of the synthesized products displayed favourable antiviral activity against cucumber mosaic virus (CMV) in preliminary antiviral activity tests. The title compounds 5c, 5o and 5r revealed curative activity of 42.2%, 48.7% and 40.5%, respectively against CMV (inhibitory rate) compared to the commercial standard Ningnanmycin (53.4%) at 500 μg/mL.

Conclusion

A practical synthetic route to N-benzoyl-α-amido sulfones by the reaction of 5-subsititued phenyl-1,3,4-oxadiazole-2-thiols as the source of nitrogen nucleophiles with in situ generated protected imine from N-benzoyl-α-amido sulfones is presented. The reaction catalyzed by an inorganic base has considerable significance to exploit the potential of α-amido sulfones in organic synthesis.     

Convenient synthesis of α,β-unsaturated sulfones via a Mizoroki-Heck reaction of arylboronic acids with phenyl vinyl sulfones

Palladium acetate catalyzed Mizoroki-Heck reaction of arylboronic acids with phenyl vinyl sulfones afford α,β-unsaturated sulfones in good yields.     

Cross-metathesis reaction of vinyl sulfones and sulfoxides

Cross-metathesis reactions of α,β-unsaturated sulfones and sulfoxides in the presence of molybdenum and ruthenium pre-catalysts were tested. A selective metahesis reaction was achieved between functionalized terminal olefins and vinyl sulfones by using the ‘second generation’ ruthenium catalysts 1c-h while the highly active Schrock catalyst 1b was found to be functional group incompatible with vinyl sulfones. The cross-metathesis products were isolated in good yields with an excellent (E)-selectivity. Both the molybdenum and ruthenium-based complexes were, however, incompatible with α,β- and β,γ-unsaturated sulfoxides.     

Isoprene functionalisation : Chlorination of C10-isoprenoid sulfones with hexachloro-ethane

Lithiation of the sulfones 1–3 in THF at ?78° with lithium diisopropyl amide (LDA) is regioselective, since deuteration of the α-lithiosulfone 4 results in formation of the α-monodeuteriated sulfone 7. Higher temperature causes an intramolecular 1,4-addition of the lithiated sulfone 4 to the lithiated cyclic sulfone 19 and an intermolecular 1,4-addition of the lithiated sulfones 5 and 6. The cyclisation of Z-sulfone 1 has been used for the isolation of the isomeric E-sulfone 2 from mixtures of 1 and 2. The lithiated sulfones 4–6 are chlorinated with hexachloroethane (HCE). Due to acid/base reactions the α,α-dichlorinated cyclic sulfone 23 and α,α'-dichlorinated butadienyl sulfones 13–15 are formed in small amounts.     

Practical synthesis of N-Boc- and N-Cbz-α-amido stannanes from α-amido sulfones using TMSSnBu3 and CsF

In the presence of TMSSnBu(3) and CsF, stannylation of N-Boc- and N-Cbz-α-amido sulfones proceeded very well to afford the corresponding α-amido stannanes in moderate-to-high yields. This reaction tolerated α-aryl-, alkenyl-, and alkyl-substituted α-amido sulfones as well as substrates containing either an ester or cyano moiety, which might be reactive with lithium or magnesium stannides employed in conventional stannylation.     

Catalytic enantioselective conjugate additions with α,β-unsaturated sulfones

We describe the development of a highly efficient catalytic asymmetric conjugate addition to α,β-unsaturated sulfones. Utilizing practical bifunctional organic catalysts and involving air- and moisture-tolerant conditions, conjugate additions of a wide range of Michael donors to α,β-unsaturated sulfones proceeded in excellent enantioselectivity/diastereoselectivity and high yield. This efficient and operationally simple new catalytic asymmetric reaction should provide a versatile approach for the asymmetric synthesis of chiral sulfones bearing all-carbon quaternary stereocenters.     

Formyl Radical Generation from α-Chloro N-Methoxyphthalimides Enables Selective Aldehyde Synthesis

The aldehydes installation by radical formylation constitutes an attractive synthetic strategy. However, the generation of formyl radicals for organic synthesis applications remains unknown. Herein we report the first formyl radical generation from α-chloro N-methoxyphthalimides, which selectively synthesize aldehydes by alkene hydroformylation under mild photoredox conditions. The aldehydes can be installed on acrylates, acrylamides, vinyl sulfones, vinyl ketones, and complex steroids by radical hydroformylation in excellent chemoselectivity and regioselectivity. The concerted hydrochloride elimination for the formyl radical generation from α-chloro methoxy radicals is established by experimental and computational approaches.     

Configurational inversion and hexachloroethane chlorination of α-sulfonylcarbanions

The cis fused bicyclic sulfones 1a, 1c and 3a are lithiated in benzene with n-butyllithium under concomitant cis/trans isomerization of the ring fusion, involving intramolecular proton transfer. H/D exchange of the three α-hydrogens in protic solvents proceeds with retention of configuration. The lithiated sulfones are chlorinated with hexachloroethane (HCE) and show a strong preference for introduction of halogen at an equatorial α-position.     

Conformational Analysis of Acyclic α-Fluoro Sulfur Motifs

Bioactive small molecules containing α-fluoro sulfur motifs [RS(O)_nCH₂F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors. Prominent examples include the anti-asthma drug Flovent^® and the phenylpyrazole insecticide pyrafluprole. Given the popularity of these structural units in bioactive small molecule design, together with the varying oxidation states of sulfur, a conformational analysis of α-fluoro sulfides, sulfoxides, and sulfones, would be instructive in order to delineate the non-covalent interactions that manifest themselves in structure. A combined crystallographic and computational analysis demonstrates the importance of hyperconjugative donor-acceptor interactions in achieving acyclic conformational control. The conformational disparity in the syn- and anti-diastereoisomers of α-fluorosulfoxides is particularly noteworthy.     

Rhodium‐Catalyzed Regioselective C7‐Functionalization of N‐Pivaloylindoles

An efficient rhodium‐catalyzed method for direct C? H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,β‐unsaturated ketones. Both the N‐pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.     

Silver‐Catalyzed Decarboxylative Allylation of Difluoroarylacetic Acids with Allyl Sulfones in Water

A practical silver‐catalyzed decarboxylative allylation of α,α‐difluoroarylacetic acids with allyl sulfones is described, which provides a variety of β,β‐difluorinated alkenes in good yields. Notably, the reaction proceeds smoothly in water with good functional group tolerance. The practicality and synthetic value of this process was demonstrated by scaled‐up experiment and elaboration of the products via reduction or Heck reaction. Primary mechanism investigations suggest that a radical process might be involved.