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 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 synthesis of esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position from cyclobutanones with one-carbon ring-expansion

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from cyclobutanones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters, lithium enolate of carboxylic acid N,N-dimethylamides, or lithium α-carbanion of alkyl phenyl sulfones gave adducts in high yields. The adducts were treated with isopropylmagnesium chloride or ethylmagnesium chloride in dry toluene to give esters, amides, and sulfones bearing a 1-cyclopentenyl group at the α-position in moderate to good yields with one-carbon ring-expansion via magnesium carbenoid 1,2-CC insertion reaction. The magnesium carbenoid 1,2-CC insertion reaction proved to be highly stereospecific. The reaction mechanism and origin of the specificity are described.     

One-carbon ring-expansion of 2-substituted cyclohexanones via lithium- and magnesium β-oxido carbenoid rearrangement: a new synthesis of 2,7-disubstituted and 2,2,7-trisubstituted cycloheptanones

Lithium α-sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide was reacted with 2-substituted cyclohexanones to afford adducts in good yields. The adducts were treated with LDA or t-BuMgCl to give lithium or magnesium alkoxides, which were treated with t-BuLi or i-PrMgCl to afford one-carbon ring-expanded 2,7-disubstituted cycloheptanones through β-oxido carbenoids. Interestingly, 2,3-disubstituted cycloheptanones were obtained in a trace amount or were not obtained at all. The enolate intermediates of this reaction were found to be able to get trapped with electrophiles to give 2,2,7-trisubstituted cycloheptanones in moderate to good yields. This method is very useful for the synthesis of 2,7-disubstituted cycloheptanones and 2,2,7-trisubstituted cycloheptanones from 2-substituted cyclohexanones in only two steps.     

A new synthesis of β,γ-unsaturated esters from three components, aldehydes, chloromethyl p-tolyl sulfoxide, and tert-butyl acetate, via magnesium carbenoid 1,2-CH and 1,2-CC insertion as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from various aldehydes, with lithium enolate of tert-butyl acetate at −78 °C in THF gave adducts in high yields. Magnesium carbenoids were generated by treatment of these adducts with Grignard reagents via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, carbenoid 1,2-CH insertion reaction took place from the magnesium carbenoids to afford β,γ-unsaturated butyric esters having a substituent at the β-position. On the contrary, when the adducts were derived from electron-rich aromatic aldehydes, carbenoid 1,2-CC insertion reaction took place from the magnesium carbenoids to give β,γ-unsaturated butyric esters having the aromatic group at the γ-position. Highly stereospecific 1,2-CC insertion reactions were observed in the latter reactions. This procedure provides a good way for a synthesis of β,γ-unsaturated esters from aldehydes with two carbon-carbon bond-formations.     

The first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis with enantiopure cyclopropylmagnesium carbenoids

The reaction of lithium α-sulfinyl carbanion of enantiopure dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave optically active 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group with high asymmetric induction from the sulfur chiral center. Reduction of the carbonyl group followed by treatment with Grignard reagent, the 1-chlorocyclopropyl p-tolyl sulfoxides resulted in the formation of enantiopure allenic alcohols via the Doering-LaFlamme-type rearrangement of enantiopure cyclopropylmagnesium carbenoid intermediates. This is the first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis.     

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.     

Generation of magnesium carbenoids from 1-chloroalkyl phenyl sulfoxides with a Grignard reagent and applications to alkylation and olefin synthesis

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature gave magnesium carbenoids in quantitative yields. The generated magnesium carbenoids were found to be stable at lower than −60 °C for long periods of time and are reactive with Grignard reagents to give alkylated products. The reaction of the generated magnesium carbenoids with various kinds of lithium α-sulfonyl carbanions gave olefins with carbon-carbon bond-formation in good to high yields. This method offers a good way for the preparation of olefins. The scope and limitations of the above-mentioned reactions are described.     

The first example of magnesium carbenoid 1,3-CH insertion reaction: a novel method for synthesis of cyclopropanes from 1-chloroalkyl phenyl sulfoxides in high yields

Treatment of 1-chloroalkyl phenyl sulfoxides having a geminal methyl group or a geminal benzyl group at the 2-position in THF at −78 °C with isopropylmagnesium chloride gave magnesium carbenoids. Carbenoid 1,3-CH insertion reaction of the magnesium carbenoids took place instantaneously to afford cyclopropanes in high to quantitative yields.     

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.     

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.     

A method for the synthesis of cyclopropanes by regiospecific and regioselective magnesium carbenoid 1,3-CH insertion as the key reactions

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 diastereomers of the adduct, respectively. Treatment of each diastereomer with i-PrMgCl resulted in the formation of magnesium carbenoid. Highly regiospecific 1,3-CH insertion reaction was found to take place from each magnesium carbenoid to afford cyclopropanes. On the other hand, when the unsymmetrical ketones bearing an oxygen- or a nitrogen-functional group on the α-carbon were used in this procedure, the regioselective 1,3-CH insertion reaction proceeded mainly. Stereochemistry of the adducts, reaction mechanism, and essence of the specificity and the selectivity are discussed.     

A synthesis of bicyclo[n.1.0]alkanes having tert-butyl carboxylate or acetamide moiety via the intramolecular 1,3-CH insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from various cyclic ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters or N,N-dimethylacetamide gave adducts in high yields. The adducts were treated with ether solution of isopropylmagnesium chloride in dry toluene to give bicyclo[n.1.0]alkane derivatives having tert-butyl carboxylate or acetamide moiety on the bridgehead carbon in high to quantitative yields via magnesium carbenoid 1,3-CH insertion reaction. The 1,3-CH insertion reaction proved to be regioselective and stereospecific. The reaction mechanism and origin of the selectivity and specificity are discussed.     

A new method for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation through β-oxido carbenoid rearrangement as the key reaction

The addition reaction of carbonyl compounds with lithium α-sulfinyl carbanions of 1-chloroalkyl p-tolyl sulfoxides gave adducts, α-chloro β-hydroxy sulfoxides, in high to quantitative yields. The adducts were first treated with a base to give alkoxides, which were treated with i-PrMgCl or t-BuLi to give β-oxido carbenoids via a sulfoxide-metal exchange reaction. The β-oxido carbenoid rearrangement then took place to afford the enolates with one-carbon elongation. The enolate intermediates were found to be able to be trapped with electrophiles such as aldehydes, ethyl chloroformate, benzoyl chloride, haloalkanes to give α,α-disubstituted carbonyl compounds in moderate to good yields. This method provides a new and efficient way for synthesis of α,α-disubstituted carbonyl compounds from carbonyl compounds with one-carbon homologation in only two synthetic operations.     

A new method for generation of non-stabilized α-amino-substituted carbanions by the reaction of magnesium carbenoids with N-lithio arylamines: their reactivity and a new synthesis of α-amino acid derivatives

Magnesium carbenoids were generated from aryl 1-chloroalkyl sulfoxides with i-PrMgCl in THF at low temperature in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines to afford an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. On the other hand, reaction of the magnesium carbenoids with N-substituted N-lithio arylamines gave non-stabilized α-amino-substituted carbanions in good yields. Reactivity of the α-amino-substituted carbanions with some electrophiles was investigated and it was found that ethyl chloroformate reacted to give α-amino acid derivatives in good yields. As a whole, a new method for one-pot, three-component combined synthesis of α-amino acid derivatives from aryl 1-chloroalkyl sulfoxides was realized.     

Reaction of magnesium carbenoids with N-lithio arylamines: a novel method for generation of non-stabilized α-amino-substituted carbanions and a new synthesis of α-amino acid derivatives

Treatment of 1-chloroalkyl phenyl sulfoxides with a Grignard reagent at low temperature afforded magnesium carbenoids in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines and N-lithio arylamines. The reaction with N-lithio alkylamines afforded an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. The reaction with N-lithio arylamines gave the adducts, α-amino-substituted carbanions, in good yields. From these intermediates, a novel synthesis of α-amino acid derivatives and N,N-dialkyl arylamines having a deuterium at the α-position was realized.     

Synthesis of enantiopure 1-substituted, 1,2-disubstituted, and 1,4,5-trisubstituted imidazoles from 1,2-amino alcohols

A highly versatile method for the preparation of enantiopure 1-substituted, 1,2-disubstituted, and 1,4,5-trisubstituted imidazoles was developed by using the cyclocondensation reaction of a 1,2-dicarbonyl compound, an aldehyde, a 1,2-amino alcohol, and ammonium acetate.     

A novel synthesis of spiro[2.6]nonadienones by the reaction of magnesium cyclopropylidenes with naphtholates and phenolates

The sulfoxide-magnesium exchange reaction of aryl 1-chlorocyclopropyl sulfoxides with i-PrMgCl in THF at low temperature gave magnesium cyclopropylidenes. Treatment of the magnesium cyclopropylidenes with lithium naphtholates or phenolates resulted in the formation of spiro[2.6]nonadienones in up to 82% yield. The structure of the spiro[2.6]nonadienones was found to be dependent on the structure of the naphtholates and phenolates.     

A method for synthesis of bicyclo[3.3.0]oct-1-en-3-ones from cyclobutanones with one-carbon ring expansion and its application to a formal synthesis of racemic 1-desoxyhypnophilin

A method for synthesis of 2-cyanobicyclo[3.3.0]oct-1-en-3-ones and 2-substituted bicyclo[3.3.0]oct-1-en-3-ones was developed by assembly of three components, cyclobutanones, chloromethyl p-tolyl sulfoxide, and nitriles, with one-carbon ring expansion of the cyclobutane ring. As an application of this method, a formal synthesis of 1-desoxyhypnophilin in racemic form was performed starting from 3,3-di(phenylthiomethyl)cyclobutanone.