Reductive Desulfonylation Research Articles

Lithiated γ-Tosyl-Substituted Benzylmethallylamine: New γ-Amino Methallyl Sulfone Anions in Organic Synthesis

The mono- and dilithiation of benzyl[2-(tosylmethyl)-2-propenyl]amine (9) with n-butyllithium at −78 °C leads to the new allyl sulfone monoanion 10a and dianion 10b, respectively. The intermediate 10a reacts regioselectively at the α-position with respect to the sulfone group with different electrophilic reagents (deuterium oxide, alkyl halides, propanal, phenyl isocyanate, and electrophilic olefins) to give the corresponding derivatives 11. In the case of ethyl propiolate, double Michael addition took place, and the trans-substituted methylenepyrrolidine 13 was stereoselectively obtained. Dianion 10b also reacts at the nitrogen atom when alkyl halides and ethyl propiolate are used as electrophiles. These intermediates 10 are appropriate dinucleophiles in annelation reactions with dielectrophiles to afford six-, seven-, and eight-membered ring nitrogen heterocycles 20. When 1,3-dichloroacetone, (Z)-1,4-dichloro-2-butene, and epibromohydrin were used as electrophiles the cyclization process was stereoselective. Studies on the configuration and conformation of prepared heterocycles 20 have been carried out by means of 1H NMR experiments and X-ray analysis, which have been confirmed by Molecular Mechanics calculations. Base-induced dehydrosulfinylation, reductive desulfonylation, and methylenation reactions have been studied with representative derivatives.

Exclusively endo-selective lewis acid-vatalyzed hetero diels-alder reactions of ( E)-1-phenylsuifonyl-3-alken-2-ones with vinyl ethers

( E)-1-Phenylsulfonyl-3-alken-2-ones as new hetero 1,3-dienes undergo smooth hereto Diels-Alder reactions with vinyl ethers in the presence of a catalytic amount of Lewis acid such as ZnI 2, Eu(fod) 3, and TiCl 2( i-PrO) 2. The reactions are absolutely endo-selective producing 2,4- cis-3,4-dihydro-2 H- pyrans in excellent yields, the configuration at 3-position depending upon the stereochemistry of the starting vinyl ethers. Reductive ring opening reactions of the 3,4-dihydro-2 H-pyran cycloadducts with Et 3SiH/TiCl 4 lead to 6-alkoxy-l-phenylsulfonyl-2-hexanones, and the sulfonyl-stabilized carbanions derived from the 3,4-dthydro-2 H-pyran cycloadducts are alkylated followed by reductive desulfonylation to give 2,4,6-trisubstituted 3,4-dihydro-2 H-pyran derivatives.

ChemInform Abstract: Arene‐Catalyzed Reductive Desulfonylation and Desulfinylation Reactions: New Routes for Alkyllithiums.

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Stereoselective Synthesis of 2,4,6‐Trimethylcyclohex‐4‐ene‐1,3‐diol Derivatives and of polypropionate fragments with four contiguous stereogenic centers

AbstractThe Diels‐Alder adduct (±)‐3 of 2,4‐dimethylfuran and 1‐cyanovinyl acetate was converted stereoselectively into benzyl 6‐(4‐chlorophenylsulfonyl)‐1,3‐exo,5‐trimethyl‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐exo‐yl (26) and ‐2‐endo‐yl ether (36). Addition of LiAlH4 to the latter led to the 3‐O‐benzyl derivatives 28 and 37 of (1RS,2SR,3SR,6SR)‐ and (1RS,2SR,3RS,6SR)‐5‐(4‐chlorophenylsulfonyl)‐2,4,6‐trimethylcyclohex‐4‐ene‐1,3‐diol, respectively. Methylenation of 6‐exo‐(4‐chlorophenylthio)‐1‐methyl‐5‐methylidene‐7‐oxabicyclo[2.2.1]heptan‐2‐one (16), obtained by reaction of (±)‐3 with 4‐Cl‐C6H4SCl and saponification gave, 6‐exo‐(4‐chlorophenylthio)‐1‐methyl‐3,5‐dimethylidene‐7‐oxabicyclo [2.2.1]heptan‐2‐one (43), the reduction of which with K‐Selectride afforded 6‐exo‐(4‐chlorophenylthio)‐1,3‐endo‐dimethyl‐5‐methylidene‐7‐oxabicyclo[2.2.1]heptan‐2‐endo‐ol (44). The 3‐O‐benzyl derivative 48 of (1RS,2RS,3RS,6SR)‐5‐(4‐chlorophenylsulfonyl)‐ 2,4,6‐trimethylcyclohex‐4‐ene‐1,3‐diol was derived from 44 via based‐induced oxa‐ring opening of benzyl 6‐endo‐(4‐chlorophenylsulfonyl)‐1,3‐endo‐5‐endo‐trimethyl‐7‐oxabicyclo[2.2.1]hept‐2‐endo‐yl ether (49). Benzylation of 28, followed by reductive desulfonylation and oxidative cleavage of the cyclohexene moiety afforded (2RS,3SR,4RS,5RS)‐3,5‐bis(benzyloxy)‐2,4‐dimethyl‐6‐oxoheptanal (32).

Arene-catalysed reductive desulfonylation and desulfinylation reactions: New routes for alkyllithiums

The reaction of alkyl phenyl sulfones ( 1) with an excess of lithium powder and a catalytic amount of naphthalene (8 mol %) in the presence of a carbonyl compound or chlorotrimethylsilane (Barbier-type conditions) in THF at temperatures ranging between −78 and 20°C leads, after hydrolysis, to the expected products ( 2) arising from the corresponding alkyllithium generated in situ. When the same methodology is applied to sulfolene ( 3) or different alkyl phenyl sulfoxides ( 6), cyclic sulfinates 5 or products 2 are, respectively, obtained, the yields being, in general modest.

Tandem Radical Cyclizations: a One-Step Synthesis of Stereoisomeric Tricyclo[6.3.0.02,6]undecanes From Acyclic Precursors

Radical cyclization of (1E,5Z)-1-iodoundeca-1,5,10-triene with triphenyltin hydride provides one acyclic, one monocyclic, two bicyclic and four tricyclic products. At low concentration (0.002 M), the title tricycloundecane products resulting from triple cyclization predominate, but the stereoselectivity is low. Cyclization of (1E,5Z)-1-iodo-8,8-bis( phenylsulfonyl )undeca-1,5,10-triene followed by reductive desulfonylation provides a similar ratio of products to the parent. The results show that this class of triple cyclization occurs well, but the level of stereoselectivity must be raised for it to become synthetically useful.

Naphthalene-catalysed reductive desulfonylation with lithium: Alkyllithiums from alkyl phenyl sulfones

The reaction of alkyl aryl sulfones 1 with an excess of lithium powder and a catalytic amount of naphthalene (8 mol %) in the presence of a carbonyl compound [Pr iCHO, PhCHO, Et 2CO, ( CH 2) 5CO] or trimethylchlorosilane (Barbier-type conditions) in THF at temperatures ranging between −78 and 20°C leads, after hydrolysis with water, to the expected coupling products, arising from the corresponding alkyllithium in situ generated, in 30–61% yields.

Development of a strategy for the synthesis of the spherical hydrocarbon p-[4 2.5 8]decahedrane

A directed synthesis of triketone 20, an immediate precursor to a “capped” [4]peristylane, has been accomplished in 10 laboratory operations. Starting from the previously described cyclobutanone 11, a fulvene is formed and transformed into 13 by means of a Diels-Alder cycloaddition. The C s symmetry of this early intermediate is preserved throughout the remainder of the scheme. Once a cyclopentadiene ring is annealed as in 14, the cyclobutane base is elaborated by [4+2]π addition of ( Z)-1,2-bis(phenylsulfonyl)ethylene from below-plane, reductive desulfonylation, and [2+2] photocyclization. Following cleavage of the oxirane ring with periodic acid, arrival at 20 required debenzylation and oxidation. Unfortunately, the efficiency of this pathway is low (0.05% overall) and requires optimization before subsequent transformations that could produce 2 can be implemented.

Dilithiated 2-(Chloromethyl)-3-tosylpropene: A New γ-Chlorinated Allyl Sulfone Dianion in Organic Synthesis

Dilithiation of 2-(chloromethyl)-3-tosylpropene ( 1) with n-butyllithium at −90°C in the presence of DMPU affords the allylic dianion 2 which reacts with deuterium oxide or very reactive alkylating agents to give α,α-disubstituted products 3 or 4, respectively. Monoalkylation at the α-position followed by cyclopropanation reaction takes place with n-alkyl bromides to provide tosylated methylenecyclopropanes 5. The reaction of dianion 2 with aldehydes or electrophilic olefins occurs at the α-position followed by the corresponding annulation process obtaining tosylated 2,5-dihydrofurans 6 or cyclopentenes 8, respectively. When ketones are used as electrophiles, dianion 2 reacts at the γ-position yielding 3-(tosylmethylene)tetrahydrofurans 7. Reductive desulfonylation of compounds 5-8 with sodium amalgam or samarium(II) iodide to afford the corresponding desulfonylated derivatives 22-26 has been also studied.

A new, stereoselective approach to C(7)-alkylated estra-1,3,5(10)-triene derivatives

17β-Acetyloxy-3-methoxy-6-(phenylsulfonyl)estra- 1,3,5(10),6-tetraene ( 4) was prepared as a substrate for conjugate addition of organolithium reagents by a three-step sequence starting from 17β-acetyloxy-3-methoxyestra- 1,3,5(10)-trien-6-one ( 2). While methyllithium showed only poor face selectivity, higher alkyllithium species (n-BuLi, t-BuLi) preferred to add to the β-face of 4. 7α-Substituted derivatives, on the other hand, were generated stereoselectively by utilizing alkynyllithium reagents in the addition step. Removal of the phenylsulfonyl group at C(6) from alkylated products was achieved by conventional reductive desulfonylation methods. A short synthesis of the estrogen receptor antagonist 1 exploiting these observations is presented.

Oxidative radical cyclization to pyrroles under reducing conditions. Reductive desulfonylation of α-sulfonylpyrroles with tri-n-butyltin hydride

1-(2-Bromobenzyl)-2-alkanesulfonylpyrroles (1c, 1d) and 1-(4-bromobutyl)-2-methylsulfonfylpyrrols (8) undergo oxidative radical cyclization with partial or complete reductive desulfonylation to the pyrrolizidine derivatives 5 and 9 by an AIBN initiated reaction with tri-n-butyltin hydride. These cyclizations are suggested to proceed via a pseudo SRN1 process involving radical addition to the α position of the pyrrole nucleus not bearing the sulfonyl group. Reductive removal of the alkylsulfonyl moiety is proposed to occur in a second process after completion of the oxidative radical cyclization. The site of the radical addition is supported by deuterium labelling studies. Consistent with the timing of the loss of the sulonyl group is that 2-alkysulfonylpyrroles 11 are reductively desulfonylated under the same conditions that effect the oxidative radical cyclizations.

(E)-2-Oxo-1-sulfonyl-3-alkenes as Reactive Hetero 1,3-Dienes. Absolutely endo-Selective Hetero Diels-Alder Reactions with Vinyl Ethers in the Presence of a Lewis Acid Catalyst

Abstract (E)-2-Oxo-1-sulfonyl-3-alkenes as new hetero 1,3-dienes undergo smooth hetero Diels-Alder reactions with vinyl ethers in the presence of Eu(fod)3 or TiCl2(i-PrO)2. The reactions are absolutely endo-selective producing 2,4-cis-3,4-dihydro-2H-pyrans in excellent yields, sufficient catalytic cycles being attained. The sulfonyl-stabilized carbanions derived from the cycloadducts are alkylated followed by reductive desulfonylation.

Alkyl- and arylsubstituted ketenedithioacetal tetroxides: Diels-alder reactivity and reductive desulfonylation of the adducts

The Diels-Alder reactivity of the representative alkyl and aryl-substituted ketenedithioacetal tetroxides of general formula 1is reported. These dienophiles reacted under thermal conditions (refluxing toluene) with cyclopentadiene to afford predominantly the endo adduct. In the case of 1C and 1D the endo and exo adducts were formed with total stereoselectivity with respect to the biphenyl or binaphthyl residue as determined on the basis of n.O.e. experiments. Dienophiles 1A-D failed to react with other dienes under similar reaction conditions but reacted efficiently in ether containing 5 M lithium perchlorate under sonication. Under these reaction conditions, the cycloaddition to quadricyclane, 1-methoxy-, 1- and 2-trimethylsilyloxy-1,3-butadiene and to the Danishefsky diene were investigated. In the cycloaddition to 1-trimethylsilyloxy-1,3-butadiene and to the Danishefsky diene the open chain adducts ( Z)- 14 and 17 were obtained in high yield as primary adducts. Eventually, the former undergoes isomerization to ( E)- 14, while the latter is further hydrolyzed to 18. The open-chain compound 19 was also obtained via base treatment of 12Ac. The generation of a highly stabilized bis(phenylsulfonyl)-substituted carbanion is probably the driving force of these transformations. Reductive desulfonylation of 8Ac unexpectedly afforded the norbormadiene 20, possibly via a carbene intermediate. At variance, adduct exo- 8Dc and 10Ac upon reduction gave the hydrocarbon exo- 21 and 22. Finally, reduction of 12Ac occurred with concomitant reduction of the carbonyl group to give alcohol 23.

Synthesis of 5-Alkyl Substituted Uracil Derivatives from Barbituric Acid

A new two step synthesis of 5-alkyluracil derivatives from barbituric acids is described. Regioselective mono O-mesylation of barbituric acids, followed by desulfonylation under reductive conditions, afforded uracils in high overall yield. The reductive desulfonylation step is also discussed

Viologen-mediated reductive desulfonylation of α-nitro sulfones by sodium dithionite

Reductive desulfonylation of α-nitro sulfones to give the corresponding nitro compounds was carried out conveniently with sodium dithionite, by using octylviologen as an electron-transfer catalyst in organic solvent–water two-phase systems. Sulfones which do not have an α-nitro group are not desulfonylated. A reaction scheme involving a nitroalkyl radical has been proposed.

Reductive desulfonylation of phenyl sulfones by samarium(II) iodide-hexamethylphosphoric triamide

Samarium(II) iodide in tetrahydrofuran reductively desulfonylates phenyl sulfones in the presence of hexamethylphosphoric triamide. This transformation is illustrated here for ten substrates, which include secondary alicyclic, β-hydroxy, vicinal bis-, and α,β-unsaturated sulfones.

A novel regioselective synthesis of allylsilanes.

The anions derived from allyl sulfones were silated in the α-position. Reductive desulfonylation gave the desired allylsilanes regioselectively.

Regiocontrolled cyclohexenone annulation via acylation of a ketone carbonyl

1-(1-Ethoxyvinyl)cycloalkenes, readily available by palladium-catalyzed condensation of enol triflates with ethyl vinyl ether or its α-trimethylstannyl derivative, enter into Diels-Alder reaction with (Z)-1,2-bis(phenylsulfonyl)ethylene. These adducts undergo smooth reductive desulfonylation to provide cyclohexenones after enol ether hydrolysis. Migration of the double bond into the thermodynamically more stable internal conjugated position completes the annulation scheme

Electron‐rich 2‐Pyridones, III: Stereochemistry and Reactivity of Phenylsulfonyl‐ substituted 2‐Azabicyclo[2.2.2]octan‐6‐ones

Abstract[4+2]cycloaddition of electron‐rich 5‐benzyloxy‐2‐pyridone (1) with phenylvinyl sulfone furnished, after functional group transformation, 2 in a syn/anti ratio of 3/7. Deprotonation with LDA provided the thermodynamic stable 2a. The α‐sulfonyl carbanion can be alkylated to 4. During reductive desulfonylation complete epimerisation to 5 occured. Synthesis of 5b was also accomplished by conjugate addition of ethylphenylsulfonyl carbanion to 11.

ChemInform Abstract: Syntheses of Cholesta‐5,7‐diene‐3β,25‐diol and Cholesta‐5,7‐diene‐1α,3β,25‐triol.

AbstractThe intermediate (IX) can alternatively be prepared from 1α‐hydroxyergosterol.