Regioselective synthesis of quinolone-annulated sulfur heterocycles by aryl radical cyclization

The tin hydride-mediated cyclizations of a number of sulfides and sulfones under mild, neutral conditions, have been investigated accompanied by some amount of β-scission product for sulfides. The sulfides were derived from 4-mercaptoquinolone and 2-bromobenzyl bromides by phase transfer catalyzed reaction and the corresponding sulfones were prepared by treatment of the sulfides with m-CPBA at room temperature. The sulfides and the corresponding sulfones were then reacted with ⁿBu₃SnH-AIBN to give regioselective quinolone-annulated sulfur heterocycles.     

Preliminary investigations on novel camphor-derived chiral sulfones: completely stereoselective formation of tricyclic β-hydroxy sulfones from 8- and 10-functionalized camphor derivatives

Some camphor-derived chiral allylic and benzylic sulfones in which the sulfonyl group is located at the C-10, C-9 or C-8 methyl groups of (+)-camphor were synthesized. The C-9 and C-8 substituted sulfones were obtained via Wagner-Meerwein rearrangements of the bicyclic camphor framework. On treatment with LDA, the C-10 and C-8 substituted sulfones cyclized with complete stereoselectivity, affording tricyclic β-hydroxy sulfones whose relative configurations were determined by X-ray crystallography. Tricyclic sulfones 23 and 24 underwent both β-elimination and retro-aldol reactions on further exposure to base. Reduction of the carbonyl group of the C-10 substituted sulfones afforded exo-configured isobornyl sulfones with high stereoselectivity. Reaction of the lithiated isobornyl benzyl sulfone 32 with benzaldehyde generated all four of the possible product diastereomers, of which three were isolated pure by chromatography. Attempted desulfonylation of these diastereomers failed to generate the desired optically active homobenzylic alcohols but the same sulfonyl carbanion trapping/desulfonylation sequence was successful in a model achiral series of compounds.     

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.     

Aerobic copper-catalyzed synthesis of (E)-alkenyl sulfones and (E)-β-halo-alkenyl sulfones via addition of sodium sulfinates to alkynes

Copper-catalyzed sulfonylation of alkynes using sodium sulfinates in air produced regio- and stereoselectively (E)-alkenyl sulfones. When a CuCl catalyst was employed, the hydrosulfonylation proceeded syn-selectively, and (E)-alkenyl sulfones were synthesized in excellent yields. In contrast, the reaction using CuI catalyst produced (E)-β-haloalkenyl sulfones anti-selectively in the presence of potassium halides. Furthermore, the (E)-β-bromoalkenyl sulfones are possible to convert into various alkenyl sulfones by Suzuki–Miyaura coupling.     

A facile stereoselective synthesis of (Z)-α-arylsulfonyl-α,β-unsaturated ketones

Palladium-catalyzed hydrostannylation of acetylenic sulfones 1 in benzene at room temperature gives highly regio- and stereoselectively (E)-α-stannylvinyl sulfones 2 in high yields. (E)-α-Stannylvinyl sulfones 2 are new difunctional group reagents which undergo Stille coupling reactions with acyl chlorides 3 to afford stereoselectively (Z)-α-arylsulfonyl-α,β-unsaturated ketones 4 in good yields. A one-pot stereoselective synthesis of (Z)-α-arylsulfonyl-α,β-unsaturated ketones 4 has also been achieved by tandem hydrostannylation-Stille coupling reaction of acetylenic sulfones 1 under mild conditions.     

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.     

Synthesis and RNase A inhibition study of C2-symmetric bis-isochromenyl sulfones

A new class of C₂-symmetric bis-isochromene derivatives with 3,3′-linkage has been synthesized from bis-propargyl sulfones. The method involves treatment of the sulfones with triethylamine to form the isochromene derivatives presumably via the intramolecular Michael addition to the intermediate bis-allenic sulfones. Interestingly, the product expected from the Garratt-Braverman pathway was not obtained. The bis-isochromene 7d displayed RNase A inhibition activity, much stronger than the isochromene 8 and bis-isocoumarin 9.     

Metal-free,one-pot highly selective synthesis of (E)-vinyl sulfones and sulfoxides via addition–oxidation of thiols with alkynes

We have developed a highly selective one-pot method for the synthesis of (E)-vinyl sulfones and sulfoxides from thiols with terminal alkynes. The sulfones and sulfoxides could be obtained with excellent selectivity in good isolated yields. It is simple, efficient and environmentally benign, and metal-free. The mechanism for the formation of the (E)-vinyl sulfones was also proposed.     

TiCl4-promoted addition of nucleophiles to open chain α-amidoalkylphenyl sulfones

Linear α-amidoalkylphenyl sulfones are converted into the corresponding N-acyliminium ions by treatment with TiCl₄ at low temperature and then made to react with different nucleophiles such as allyltrimethylsilane, silyl ketene acetal, anisole and thiophene.     

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.     

Enantioselective bioreduction of β-keto sulfones with the fungus Curvularia lunata

β-Keto sulfones bearing bulky groups are reduced with high enantioselectivities to the corresponding optically active β-hydroxy sulfones by the fungus Curvularia lunata CECT 2130; the cells can be re-used without loss of their catalytic activity.     

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.     

Sulfides,sulfones, and sulfoxides of the furan-2(5H)-one series. synthesis and structure

A number of 4- and 5-R-sulfanylfuran-2(5H)-one derivatives were synthesized, and their oxidation with various reagents was studied. The corresponding sulfones were obtained using hydrogen peroxide in acetic acid. 4-R-sulfanyl derivatives were selectively oxidized to sulfoxides with m-chloroperoxybenzoic acid. The molecular and crystal structures of some new sulfones and sulfoxides were determined by X-ray analysis.     

β-Ferrocenyl-α,β-unsaturated phosphonates and sulfones

Ferrocene reacts with β-ketophosphonates and β-ketosulfones (or acetals of formylphosphonates and sulfones) in the presence of a strong acid (triflic or methanesulfonic) to afford β-ferrocenyl-α,β-unsaturated phosphonates and β-ferrocenyl-α,β-unsaturated sulfones in good yield. The (E)-stereochemistry of these compounds was confirmed by spectral and analytical data, as well as by X-ray diffraction.     

A facile stereoselective synthesis of 1,3-dienyl sulfones via Stille coupling reactions of (E)-α-stannylvinyl sulfones with alkenyl iodides

Palladium-catalyzed hydrostannylation of acetylenic sulfones 1 in benzene at room temperature gives stereoselectively (E)-α-stannylvinyl sulfones 2 in good yields. (E)-α-Stannylvinyl sulfones 2 are new difunctional group reagents which undergo Stille coupling reactions with alkenyl iodides 3 to afford stereoselectively 1,3-dienyl sulfones 4 in high yields.     

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.     

A two-step synthesis of allylic syn 1,3-diols via an intramolecular oxa-Michael reaction followed by a modified Julia olefination

A two-step process for the synthesis of allylic syn 1,3-diols is developed. An intramolecular oxa-Michael reaction onto vinyl heteroaromatic sulfones allows the diastereoselective formation of 1-sulfonyl 2,4-diols protected as benzylidene acetals. These sulfones are then engaged in a modified Julia olefination to furnish the olefins contiguous to the benzylidene acetal ring with good E/Z selectivity.     

Hydrogenation of β-Keto Sulfones to β-Hydroxy Sulfones with Alkyl Aluminum Compounds: Structure of Intermediate Hydroalumination Products

β-Hydroxy sulfones are important in organic synthesis. The simplest method of β-hydroxy sulfones synthesis is the hydrogenation of β-keto sulfones. Herein, we report the reducing properties of alkyl aluminum compounds R₃Al (R = Et, i-Bu, n-Bu, t-Bu and n-Hex); i-Bu₂AlH; Et₂AlCl and EtAlCl₂ in the hydrogenation of β-keto sulfones. The compounds i-Bu₂AlH, i-Bu₃Al and Et₃Al are the at best reducing agents of β-keto sulfones to β-hydroxy sulfones. In reactions of β-keto sulfones with aluminum trialkyls, hydroalumination products with β-hydroxy sulfone ligands [R₂AlOC(C₆H₅)CH₂S(O)₂(p-R¹C₆H₄]_n [where n = 1,2; 2aa: R = i-Bu, R¹ = CH₃; 2ab: R = i-Bu, R¹ = Cl; 2ba: R = Et, R¹ = CH₃; 2bb: R = Et, R¹ = Cl] and {[Et₂AlOC(C₆H₅)CH₂S(O)₂(p-ClC₆H₄]∙Et₃Al}_n 3bb were obtained. These complexes in the solid state have a dimeric structure, while in solutions, they appear as equilibrium monomer–dimer mixtures. The hydrolysis of both the isolated 2aa, 2ab, 2ba, 2bb and 3bb and the postreaction mixtures quantitatively leads to pure racemic β-hydroxy sulfones. Hydroalumination reaction of β-keto sulfones with alkyl aluminum compounds and subsequent hydrolysis of the complexes is a simple and very efficient method of β-hydroxy sulfones synthesis.     

Fragmentation of carbohydrate anomeric alkoxyl radicals. Synthesis of highly functionalized chiral vinyl sulfones

The reaction of derivatives of 3-acetyl-d-glucal, 3-acetyl-l-rhamnal, 3-acetyl-d-galactal, and 3-acetyl-d-lactal with sodium benzenesulfinate in acid medium catalyzed by HgSO₄ afforded diastereoisomeric mixtures of the corresponding 2,3-dideoxy-3-(phenylsulfonyl)-hexopyranoses through a Ferrier rearrangement. The anomeric alkoxyl radical fragmentation of these γ-hydroxy sulfones using the system (diacetoxyiodo)benzene and iodine gave vinyl sulfones with structures of 1,2-dideoxy-4-O-formyl-2-(phenylsulfonyl)-pent-1-enitol and configurations d-erythro, l-erythro, and d-threo at the two stereogenic centers.     

Synthesis and fungicidal activity of bis(2-arylcarbonylamino-1<Emphasis Type="Italic">H</Emphasis>-benzimidazol-5-yl) sulfones

A procedure has been developed for the synthesis of bis(2-arylcarbonylamino-1H-benzimidazol-5-yl) sulfones by reaction of the corresponding substituted benzoyl chloride with sodium cyanamide and subsequent treatment of the N-cyanobenzamide thus formed with 3,3′,4,4′-tetraaminodiphenyl sulfone in acid medium. The products were tested for fungicidal activity.