The first example of direct cyclopropylation of arylamines at the 2-position with magnesium cyclopropylidenes

Treatment of magnesium cyclopropylidenes, which were generated from 1-chlorocyclopropyl phenyl sulfoxides with isopropylmagnesium chloride in THF at −78 °C, with N-lithio arylamines gave arylamines cyclopropylated at the 2-position in moderate to good yields. Use of the magnesium cyclopropylidenes having at least one substituent was found to be essential to this cyclopropylation. This procedure offers a novel synthesis of arylamines having a cyclopropane ring at the 2-position directly from arylamines.     

Direct alkenylation of arylamines at the ortho-position

Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at −78 °C in toluene, with N-lithio arylamines gave ortho-alkenylated arylamines in moderate to good yields. The reaction was found to proceed in a highly stereospecific manner at the carbenoid carbon. This reaction offers a quite novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.     

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 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.     

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.     

Insertion of cyclopropanes between a carbonyl carbon and an α-carbon of carbonyl compounds with cyclopropylmagnesium carbenoids

The reaction of the lithium enolates of α-aryl carbonyl compounds with cyclopropylmagnesium carbenoids, derived from 1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl at low temperature, resulted in the formation of β-aryl carbonyl compounds bearing a cyclopropane ring at the α-position with one-carbon homologation in variable yields. The reaction was found to be highly stereospecific with respect to the stereochemistry of the cyclopropylmagnesium carbenoids. Mechanism and origin of the stereospecificity of the reaction are also discussed. This is the first example for the insertion of cyclopropanes in between a carbonyl carbon and an α-carbon of carbonyl compounds.     

A short synthesis of 3-oxa- and 3-azabicyclo[3.1.0]hexanes from α,β-unsaturated esters based on the 1,5-CH insertion reaction of cyclopropylmagnesium carbenoids

1-Chlorocyclopropyl p-tolyl sulfoxides bearing an alkoxymethyl group at the 2-position were easily prepared from α,β-unsaturated esters with dichloromethyl p-tolyl sulfoxide and alkylhalides in three steps in good overall yields. Treatment of the 1-chlorocyclopropyl p-tolyl sulfoxides with i-PrMgCl resulted in the formation of 3-oxabicyclo[3.1.0]hexanes in up to 89% yield as a single diastereomer via the 1,5-CH insertion reaction of the generated cyclopropylmagnesium carbenoid intermediates. This procedure provides a good way for the synthesis of 3-oxabicyclo[3.1.0]hexanes from α,β-unsaturated esters in only four steps. 3-Aza- and 3-thiabicyclo[3.1.0]hexanes were also obtained from the corresponding precursors via the 1,5-CH insertion reaction of the cyclopropylmagnesium carbenoid intermediates, though the yields were low to moderate.     

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,including asymmetric synthesis,of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon–hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.     

A novel synthetic method for alkylidenecyclopropanes based on the reaction of magnesium cyclopropylidenes with lithium α-sulfonyl carbanions

Treatment of 1-chlorocyclopropyl phenyl sulfoxides with isopropylmagnesium chloride at low temperature gave magnesium cyclopropylidenes. The reaction of the generated carbenoids with lithium α-sulfonyl carbanions was found to afford alkylidenecyclopropanes in moderate to good yields. This reaction offers a novel, unprecedented, and versatile method for a synthesis of several alkylidenecyclopropanes from olefins in relatively short steps.     

Synthesis of cyclopropane-fused α-chlorolactones utilizing the nucleophilicity of cyclopropylmagnesium carbenoids

A novel method for the synthesis of cyclopropane-fused α-chloro-γ-lactones was developed utilizing the nucleophilicity of cyclopropylmagnesium carbenoids. Cyclopropylmagnesium carbenoids were generated from i-PrMgCl and 1-chlorocyclopropyl p-tolyl sulfoxides with a [(phenoxycarbonyl)oxy]methyl group at the 2-position of the cyclopropane ring. The resulting cyclopropylmagnesium carbenoids reacted with an intramolecular carbonate unit to give 1-chloro-3-oxabicyclo[3.1.0]hexan-2-ones in moderate to good yields. The asymmetric synthesis of 1-chloro-3-oxabicyclo[3.1.0]hexan-2-one was achieved using optically active dichloromethyl p-tolyl sulfoxide as a starting material.     

A new synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine as the key reaction

A new synthesis of pipecolic acid and homopipecolic acid derivative was accomplished from 1-chloroalkyl p-tolyl sulfoxides having a 2-aminophenyl group at the ω-position by treatment with i-PrMgCl via the intramolecular reaction of magnesium carbenoid with N-magnesio arylamine. In a similar way, proline and pipecolic acid derivatives were synthesized from 1-chloroalkyl p-tolyl sulfoxides having an arylamino group at the ω-position.     

A short synthesis of α-allenic alcohols from α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide

The reaction of the α-sulfinyl carbanion of dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group in good to high yields. The carbonyl groups in the products were reduced or treated with alkylmetals to give alcohols. Finally, the alcohols were treated with Grignard reagent to give α-allenic alcohols via the rearrangement of the cyclopropylmagnesium carbenoid intermediates, which were generated by the sulfoxide-magnesium exchange reaction, in good to high yields. This procedure provides a new method for a short synthesis of various α-allenic alcohols in two or three steps from relatively easily available α,β-unsaturated carbonyl compounds.     

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 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.     

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.     

Reaction of magnesium cyclopropylidene with N-lithio arylamines: a method for generation of α-amino-substituted cyclopropylmagnesiums and a study for their reactivity with electrophiles

Magnesium cyclopropylidene was generated from 1-chlorocyclopropyl phenyl sulfoxide with i-PrMgCl in THF at −78 °C in high yield by a sulfoxide-magnesium exchange reaction. The generated magnesium cyclopropylidene was found to be reactive with N-lithio arylamines to give α-amino-substituted cyclopropylmagnesiums. The reaction of the α-amino-substituted cyclopropylmagnesiums with several electrophiles was examined and a new method for a synthesis of cyclopropane amino acid derivatives was realized.     

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.     

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.     

Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide

A variety of 2-azabicyclo[2.1.0]pentanes were synthesized by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide. The 1-chlorocyclopropyl p-tolyl sulfoxides possessing an N-aryl-substituted aminomethyl group were prepared from dichloromethyl p-tolyl sulfoxide, α,β-unsaturated carboxylic acid esters, and anilines in four steps. The deprotonation of the amine with t-BuMgCl followed by sulfoxide/magnesium exchange of the sulfoxides with i-PrMgCl led to the generation of the cyclopropylmagnesium carbenoids possessing a magnesium anilide moiety. Subsequent intramolecular nucleophilic substitution of the cyclopropylmagnesium carbenoids occurred in a 4-exo-tet manner to give the 2-azabicyclo[2.1.0]pentanes. The optically active 2-azabicyclo[2.1.0]pentane was synthesized using a p-tolylsulfinyl group as a chiral auxiliary.