A novel synthesis, including asymmetric synthesis, of 2,4,4-trisubstituted 2-cyclopentenones based on the reaction of 1-chlorovinyl p-tolyl sulfoxides with acetonitrile and its homologues

Reaction of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from chloromethyl p-tolyl sulfoxide and ketones in high overall yields, with cyanomethyllithium (lithium α-carbanion of acetonitrile) gave adducts in high to quantitative yields. The adducts were treated with LDA followed by lithium α-carbanion of the homologues of acetonitrile to give 3,5,5-trisubstituted enaminonitriles in good to high yields. Hydrolysis of the enaminonitriles under acidic conditions gave 2,4,4-trisubstituted 2-cyclopentenones in good yields. By using the optically active chloromethyl p-tolyl sulfoxide and unsymmetrical ketones, this procedure gave the optically pure 2,4,4-trisubstituted 2-cyclopentenones. The scope and limitations of this method and the mechanism of the reactions are also discussed. These procedures offer a new and effective method for the synthesis of 2,4,4-trisubstituted 2-cyclopentenones from four components, ketones, chloromethyl p-tolyl sulfoxide, acetonitrile, and its homologues.     

Reaction of magnesium alkylidene carbenoids with lithium alpha-sulfonyl carbanions: a novel synthesis of tri- and tetra-substituted allenes from 1-chlorovinyl p-tolyl sulfoxides and sulfones

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from ketones and chloromethyl p-tolyl sulfoxide, with ethylmagnesium chloride or isopropylmagnesium chloride at below -78 degrees C gave magnesium alkylidene carbenoids in about 90% yields. The reaction of the generated carbenoids with lithium alpha-sulfonyl carbanions was found to afford tri- and tetra-substituted allenes. Both cyclic ketones and acyclic ketones were useful in this procedure. However, the 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes gave only rearranged products, acetylenes, under the reaction conditions. The magnesium alkylidene carbenoid derived from an optically active 1-chlorovinyl p-tolyl sulfoxide was treated with lithium alpha-carbanion of 1-naphthyl phenyl sulfone; however, the obtained allene was found to be racemic. The mechanism of this reaction is also discussed.     

A novel synthesis of 2,4,4-trisubstituted 2-cyclopentenones by consecutive reaction of 1-chlorovinyl p-tolyl sulfoxides with acetonitrile and its homologues

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of ketones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium (lithium α-carbanion of acetonitrile) at low temperature gave the adducts in almost quantitative yields. The adducts were then treated with LDA followed by excess lithium α-carbanion of the homologues of acetonitrile to afford 3,5,5-trisubstituted cyclopentadienyl enaminonitriles, which were hydrolyzed and heated under acidic conditions to give 2,4,4-trisubstituted 2-cyclopentenones in good overall yields.     

Asymmetric synthesis of 4,4-disubstituted 2-cyclopentenones from optically active 1-chlorovinyl p-tolyl sulfoxides and cyanomethyllithium with formation of a quaternary chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which were synthesized from unsymmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with cyanomethyllithium gave optically active 2-amino-1-cyano-5,5-disubstituted-1,3-cyclopentadienes with very high asymmetric induction from the sulfoxide chiral center. The products were converted to the enantiomerically pure 4,4-disubstituted 2-cyclopentenones by heating with phosphoric acid in acetic acid.     

A new synthesis, including asymmetric synthesis, of spiro[4.n]alkenones from three components: cyclic ketones, chloromethyl p-tolyl sulfoxide, and acetonitrile; and a formal total synthesis of racemic acorone

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of cyclic ketones and chloromethyl p-tolyl sulfoxide in good yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium at −78°C to room temperature gave spirocyclic enaminonitriles in high yields. Acidic treatment of the enaminonitriles afforded spiro[4.n]alkenones in good yields. By using an unsymmetrical cyclic ketone, α-tetralone, and optically active chloromethyl p-tolyl sulfoxide, this procedure afforded enantiomerically pure spiro[4.5]decenone in good yield with excellent asymmetric induction from the sulfoxide chiral center. By using this method a formal total synthesis of a racemic spirocyclic sesquiterpene, acorone, was realized.     

A new synthesis, including asymmetric synthesis, of alkylidenecyclopropanes by 1,2-CC insertion of cyclobutylmagnesium carbenoides as the key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters gave adducts in high yields. The adducts were converted to 1-chlorocyclobutyl p-tolyl sulfoxides in four steps in high overall yields. Treatment of the 1-chlorocyclobutyl p-tolyl sulfoxides with cyclopentylmagnesium chloride in THF at −40 °C resulted in the formation of cyclobutylmagnesium carbenoids. The magnesium carbenoid 1,2-CC insertion reaction took place smoothly from the cyclobutylmagnesium carbenoids to afford alkylidenecyclopropanes in good to high yields. An asymmetric synthesis of optically active alkylidenecyclopropane was successfully achieved starting from optically active 1-chlorovinyl p-tolyl sulfoxide.     

A new synthesis of cyanocyclopropanes by the intramolecular alkylation of magnesium carbenoids as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with cyanomethyllithium gave adducts in quantitative yields. Treatment of the adducts with i-PrMgCl in THF resulted in the formation of cyanocyclopropanes via the intramolecular alkylation of the generated magnesium carbenoids. The intermediate of this reaction was proved to be a cyclopropylmagnesium chloride, and it was found to be reactive with electrophiles to give multi-substituted cyanocyclopropanes. The key reaction, intramolecular alkylation of magnesium carbenoid, is the first example for the reaction of the magnesium carbenoids with nitrile-stabilized carbanions.     

Alkenylation of thiophenes and furans at the 2-position and a synthesis of allenes conjugated with α,β-unsaturated ester with magnesium alkylidene carbenoids

The reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with i-PrMgCl at −78 °C gave magnesium alkylidene carbenoids. Treatment of the magnesium carbenoids with 2-lithiothiophenes and 2-lithiofurans resulted in the formation of 2-alkenylated thiophenes and furans, respectively, in good to high yields. The intermediates of these reactions were found to be alkenylmagnesium, which could be trapped with several electrophiles to afford thiophenes and furans bearing a fully substituted alkene at the 2-position. Treatment of the magnesium alkylidene carbenoids with 2-lithio-5-methoxyfuran afforded allenes conjugated with α,β-unsaturated methyl ester in moderate yields. These procedures offer a new and versatile one-pot synthesis of 2-alkenylthiophenes, 2-alkenylfurans, and allenes conjugated with α,β-unsaturated methyl ester from 1-chlorovinyl p-tolyl sulfoxides.     

A novel synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones through [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with ring expansion

Treatment of [chloro(p-tolylsulfinyl)methylidene]cyclobutanes, which were synthesized from cyclobutanones and chloromethyl p-tolyl sulfoxide in three steps in high overall yields, with excess cyanomethyllithium gave enaminonitriles in high yields. Heating of these enaminonitriles with H₃PO₄ in acetic acid gave 2-cyanobicyclo[3.3.0]oct-1-en-3-ones in good yield. On the other hand, treatment of the [chloro(p-tolylsulfinyl)methylidene]cyclobutanes with cyanomethyllithium followed by lithium carbanion of the homologues of acetonitrile afforded enaminonitriles having a substituent at the 3-position. Heating of the enaminonitriles with H₃PO₄ in acetic acid gave 2-substituted bicyclo[3.3.0]oct-1-en-3-ones in good to high yields. This method offers a novel and versatile procedure for synthesis of 2-substituted bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones in good overall yields.     

Synthesis of conjugated enynes by assembly of three components, ketones, chloromethyl p-tolyl sulfoxide, and acetylenes, with the magnesium carbenoid 1,2-CC insertion as the key reaction

The reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of the adducts with Grignard reagents resulted in the formation of magnesium carbenoids by the sulfoxide-magnesium exchange reaction. 1,2-Carbon-carbon insertion (1,2-CC insertion) reaction of the generated magnesium carbenoids took place to afford conjugated enynes in good to high yields. This procedure provides a good method for the synthesis of multi-substituted conjugated enynes.     

A versatile synthesis, including asymmetric synthesis, of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium carbenoid 1,3-CH insertion as a key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quantitative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane was realized.     

The first example of regiospecific magnesium carbenoid 1,3-CH insertion: its mechanism and stereochemistry

Addition reaction of two geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides, derived from unsymmetrical ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl acetate gave single isomers of the adduct, respectively. Treatment of each diastereomer with i-PrMgCl resulted in the formation of magnesium carbenoids. Highly regiospecific 1,3-CH insertion reaction was found to take place from the magnesium carbenoids to afford cyclopropanes in high yields. Stereochemistry of the adducts, reaction mechanism, and origin of the regiospecificity are discussed.     

A new synthesis of β,γ-unsaturated esters and allenic esters with construction of a carbon-carbon bond between α- and β-positions by the reaction of magnesium alkylidene carbenoids with lithium ester enolates

Treatment of lithium ester enolates with magnesium alkylidene carbenoids, generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride via the sulfoxide-magnesium exchange reaction, gave β,γ-unsaturated esters in moderate to good yields. When this reaction was conducted with the lithium ester enolates of α-chlorocarboxylic acid esters, allenic esters were obtained. This procedure provides an unprecedented way for the synthesis of β,γ-unsaturated esters and allenic esters from ketones with the construction of a carbon-carbon bond between α- and β-positions.     

A novel route to fully substituted cyanoallenes from three components, ketones, chloromethyl p-tolyl sulfoxide, and nitriles, via α-bromocyclopropyl p-tolyl sulfoxides

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide in high yields, with lithium α-carbanion of nitriles gave the adducts in quantitative yields. The adducts were converted to α-bromocyclopropyl p-tolyl sulfoxides in two steps in good yields. Finally, the sulfoxides were treated with excess lithium carbanion of isobutyronitrile to afford fully substituted cyanoallenes in high to quantitative yields via sulfoxide-lithium exchange reaction. This procedure offers a novel synthetic method for fully substituted cyanoallenes with coupling of three components (ketones, chloromethyl p-tolyl sulfoxide, and nitriles) in good overall yields.     

A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts were converted to optically active esters and carboxylic acids having a chiral center at the α-position. When this addition reaction was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was realized.     

Conjugate addition of lithium ester enolates to 1-chlorovinyl p-tolyl sulfoxides: a novel synthesis of functionalized esters and lactones having a tertiary or a quaternary carbon at the β-position

Addition of the lithium ester enolates to 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from chloromethyl p-tolyl sulfoxide and ketones or aldehydes, gave esters having a tertiary or a quaternary carbon at the 3-position, and chlorine and sulfinyl groups at the 4-position in high to quantitative yields. The adducts were converted to various esters having methyl, formyl, and hydroxycarbonyl groups at the 3-position. A novel method for the synthesis of γ-lactones, including spiro-type γ-lactones and α-methylene γ-lactones, was realized from the adducts in good overall yields. The scope and limitations of this method and the mechanism of the reactions are also discussed.     

Synthesis of conjugated enynes from ketones and aldehydes by 1,2-CC insertion and 1,2-CH insertion of carbenoids as the key reactions

The addition reactions of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of the adducts with Grignard reagents resulted in the formation of conjugated enynes in good to high yields via the 1,2-carbon-carbon insertion (1,2-CC insertion) reaction of the generated magnesium carbenoid intermediates. On the other hand, the addition reactions of 1-chlorovinyl p-tolyl sulfoxides derived from aldehydes with lithium acetylides directly gave conjugated enynes bearing a p-tolyl sulfinyl group at the 1-position through the 1,2-carbon-hydrogen insertion (1,2-CH insertion) reaction of the generated lithium carbenoid intermediates. These procedures provide a good way for the synthesis of multi-substituted conjugated enynes from ketones and aldehydes.     

A novel synthesis of cyclic α-amino aldehydes, amino alcohols, and α-amino acid methyl esters from cyclic ketones through sulfinylaziridines

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps in good yields, with N-lithio arylamines gave sulfinylaziridines in high yields. On treatment with N-lithio aniline or N-lithio p-chloroaniline, the sulfinylaziridines gave α-amino aldehydes in high yields. The α-amino aldehydes were converted to amino alcohols and α-amino acid methyl esters in moderate to good yields. This procedure offers an efficient method for synthesis of cyclic α-quaternary α-amino aldehydes, amino alcohols, and α-amino acid derivatives from cyclic ketones.     

Direct alkenylation of arylamines at the ortho-position with magnesium alkylidene carbenoids and some theoretical studies of the reactions

1-Chlorovinyl p-tolyl sulfoxides were synthesized from ketones and chloromethyl p-tolyl sulfoxide in high yields. Treatment of the sulfoxides with isopropylmagnesium chloride at −78 °C in toluene gave magnesium alkylidene carbenoids (α-chloro alkenylmagnesium chlorides), which were treated with N-lithio arylamines to afford ortho-alkenylated arylamines in moderate yields. The reaction, in some cases, proceeded in a highly stereospecific manner at the carbon bearing the chlorine and the sulfinyl group. The structures of the α-chloro alkenylmagnesium chlorides and the reactivity of the N-lithio meta-substituted anilines were studied at the B3LYP and MP2 levels of theory with the 6-31(+)G* basis set. This reaction offers a quite novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.     

Reaction of magnesium alkylidene carbenoids with lithium acetylides and lithium thiolates: a novel synthesis of conjugated enynes and vinyl sulfides

Magnesium alkylidene carbenoids were generated from 1-chlorovinyl p-tolyl sulfoxides with i-PrMgCl at −78 °C in THF or toluene via the sulfoxide-magnesium exchange reaction. Reaction of the generated magnesium alkylidene carbenoids with lithium acetylides or lithium thiolates gave conjugated enynes or vinyl sulfides, respectively, in moderate to good yields. The intermediate of this reaction was found to be the alkenyl anion and it could be trapped with some electrophiles to give tetra-substituted conjugated enynes and vinyl sulfides.