A variety of 3-azabicylo[3.1.0]hexanes were synthesized via 1,5-C–H insertion of cyclopropylmagnesium carbenoids as a key step. 1-Chlorocyclopropyl p-tolyl sulfoxides with an N,N-disubstituted aminomethyl group on the cyclopropane ring were prepared from dichloromethyl p-tolyl sulfoxide, α,β-unsaturated carboxylic acid esters, primary amines, and alkyl halides. Treatment of the sulfoxides with i-PrMgCl generated cyclopropylmagnesium carbenoids, which were inserted into an intramolecular C–H bond adjacent to a nitrogen atom to give 3-azabicyclo[3.1.0]hexanes in yields of up to 94%. The reactivity of the C–H bond toward the insertion increased in the order of NCH3, NCH2CH3, NCH2Ph, and NCH(CH3)2. Optically active 3-azabicyclo[3.1.0]hexane was successfully synthesized using an S-chiral p-tolylsulfinyl group as a chiral auxiliary.

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.

The reaction of magnesium carbenoids with lithium enolate of ketones resulted in the formation of cyclopropanols in moderate to good yields. These reactive species (i.e., magnesium carbenoids and lithium enolate of ketones) were generated from 1-chloroalkyl p-tolyl sulfoxides with i-PrMgCl and ketones with LDA in the reaction medium at −78 °C in a one-pot reaction.

The reaction of (E)-2-aryl-1-chlorovinyl p-tolyl sulfoxides with lithium acetylides gave a variety of (Z)-3-arylhex-3-ene-1,5-diynes in yields of up to 80% with high stereoselectivity. The structure of the (Z)-enediyne was confirmed by X-ray molecular structure analysis. The result of the reaction with deuterium- and 13C-labeled sulfoxide suggested that the reaction proceeds through cleavage of the C–H bond at the β-position of the 2-aryl-1-chlorovinyl unit in sulfoxide.

1-Chloro-3-cyanoalkyl p-tolyl sulfoxides were easily prepared from 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from carbonyl compounds and chloromethyl p-tolyl sulfoxide, with lithium α-cyano carbanion of acetonitrile derivatives in good yields. Treatment of these sulfoxides with i-PrMgCl resulted in the formation of multi-substituted α-chlorocyclobutanones in good to high yields via the 4-Exo-Dig nucleophilic ring closure of the generated magnesium carbenoid intermediates to the nitrile group. This procedure provides a new and good way for the synthesis of multi-substituted α-chlorocyclobutanones from carbonyl compounds and substituted acetonitriles with formation of three carbon–carbon bonds in relatively short steps.

1-Alkoxy-1-[2-chloro-2-(p-tolylsulfinyl)ethyl]cycloalkanes were prepared from various cyclic ketones in good overall yields. Treatment of these cycloalkanes bearing a sulfinyl group with i-PrMgCl resulted in the formation of 1-oxaspiro[4.n]alkanes in high to quantitative yields via the 1,5-CH insertion reaction of generated magnesium carbenoid intermediates. When this procedure was commenced with acyclic ketones, multi-substituted tetrahydrofurans were obtained in up to a 96% yield. This procedure provides a new and good way for the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans with the formation of a carbon–carbon bond between a carbenoid carbon and a non-activated carbon in high yields. The oxygen atom in the magnesium carbenoid intermediates was proved to act very important roles in the 1,5-CH insertion reaction.

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.

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.

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.

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.

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.

The treatment of enantiopure aryl dichloromethyl sulfoxides in THF with strong bases such as LDA, LiHMDS, NaHMDS, and KHMDS resulted in racemization of the sulfur stereogenic center of the sulfoxides even at −78 °C. The rate of the racemization was found to be dependent on the alkali metal of the bases used. This is the first example of the racemization of the sulfur stereogenic center of α-sulfinyl carbanions at low temperatures.

Treatment of enantiomerically pure 1-chlorovinyl p-tolyl sulfoxides, derived from cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, with the lithium enolate of tert-butyl carboxylates gave adducts in quantitative yields as single diastereomers. The adducts were treated with i-PrMgCl in toluene to afford optically active bicyclo[n.1.0]alkanes bearing a tert-butyl carboxylate moiety in up to 99% enantiomeric excess through the enantioselective 1,3-CH insertion reaction of the generated chiral magnesium carbenoids. This is the first example of the enantioselective 1,3-CH insertion reaction of magnesium carbenoid.(1′S,5′R)-Bicyclo[3.1.0]hex-1-ylacetic acid tert-butyl esterC12H20O2Ee = 96%[α]D29=-4.9 (c 0.39, acetone)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (1′S,5′R)(1′S,6′R)-Bicyclo[4.1.0]hept-1-ylacetic acid tert-butyl esterC13H22O2Ee = 92%[α]D30=+1.7 (c 0.69, acetone)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (1′S,6′R)(1′S,7′R)-Bicyclo[5.1.0]oct-1-ylacetic acid tert-butyl esterC14H24O2Ee = 99%[α]D30=-56.6 (c 0.52, acetone)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (1′S,7′R)(1′S,8′R)-Bicyclo[6.1.0]non-1-ylacetic acid tert-butyl esterC15H26O2Ee = 99%[α]D31=-86.8 (c 0.45, acetone)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (1′S,8′R)(2R,1′R,6′R)-2-Bicyclo[4.1.0]hept-1-yl-4-phenylbutyric acid tert-butyl esterC21H30O2Ee = 98%[α]D28=-41.5 (c 0.22, EtOH)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (2R,1′R,6′R)(2R,1′R,7′R)-2-Bicyclo[5.1.0]oct-1-yl-4-phenylbutyric acid tert-butyl esterC22H32O2Ee = 99%[α]D30=-26.2 (c 0.27, EtOH)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (2R,1′R,7′R)(2R,1′R,8′R)-2-Bicyclo[6.1.0]non-1-yl-4-phenylbutyric acid tert-butyl esterC23H34O2Ee = 99%[α]D22=-18.7 (c 0.98, EtOH)Source of chirality: (−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (2R,1′R,8′R)

The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from ω-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substitution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction. Proline and pipecolic acid derivatives were also synthesized from ω-(arylamino)-1-chloroalkyl p-tolyl sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,RS)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained. The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these reactions is also discussed.(S,RS)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-methylamineC17H20ClNOS[α]D29=-158 (c 1.35, CHCl3)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (S,RS)(R,RS)-N-{2-[3-Chloro-3-(toluene-4-sulfinyl)propyl]phenyl}-N-methylamineC17H20ClNOS[α]D25=-80.8 (c 0.45, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R,RS)(R)-1-Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl esterC13H17NO2[α]D26=-32.1 (c 0.5, EtOH)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)

The addition reaction of the sodium α-sulfinyl carbanion of a racemic aryl dichloromethyl sulfoxide to (−)-menthone in the presence of boron trifluoride diethyl etherate gave an adduct as a mixture of two easily separable diastereomers. After separation of the diastereomers, they were each treated with sodium hydride to afford enantiomerically pure aryl dichloromethyl sulfoxides and (−)-menthone both in high yields. This procedure provides a simple and efficient method for the resolution of racemic aryl dichloromethyl sulfoxides.(S)-Dichloromethyl p-tolyl sulfoxideC8H8Cl2OSEe = 99%[α]D28=+172.3 (c 0.36, acetone)Source of chirality: (−)-menthoneAbsolute configuration: (S)(S)-Dichloromethyl phenyl sulfoxideC7H6Cl2OSEe = 97%[α]D29=+152.3 (c 0.50, acetone)Source of chirality : (−)-menthoneAbsolute configuration: (S)(S)-Dichloromethyl 2-naphthyl sulfoxideC11H8Cl2OSEe = 99%[α]D29=+182.8 (c 0.30, acetone)Source of chirality: (−)-menthoneAbsolute configuration: (S)(S)-Dichloromethyl 4-methoxyphenyl sulfoxideC8H8Cl2O2SEe = 98%[α]D29=+152.8 (c 0.30, acetone)Source of chirality: (−)-menthoneAbsolute configuration: (S)(S)-Dichloromethyl 4-chlorophenyl sulfoxideC7H5Cl3OSEe = 99%[α]D27=+160.6 (c 0.25, acetone)Source of chirality: (−)-menthoneAbsolute configuration: (S)(S)-Dichloromethyl 4-nitrophenyl sulfoxideC7H5Cl2NO3SEe = 99%[α]D28=+153.6 (c 0.30, acetone)Source of chirality: (−)-menthoneAbsolute configuration: (S)

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl formate 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 (alkyl, alkoxy, or dibenzylamino group) at the α-position with high 1,4-chiral induction from the sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and α-amino acid derivatives having a chiral center at the α-position. When this addition reaction was carried out with an 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 enolate, 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 achieved.(R)-1-Chloro-2-methyl-1-(p-tolylsulfinyl)-1-propeneC11H13ClOSEe = 99%[α]D24=+156.2 (c 1.0, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-[Chloro-(p-tolylsulfiny)methylidene]cyclohexaneC14H17ClOSEe = 99%[α]D25=+213.0 (c 1.0, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-[Chloro-(p-tolylsulfinyl)methylidene]cyclopentadecaneC22H35ClOSEe = 99%[α]D24=+120.7 (c 1.3, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-1-Chloroethenyl p-tolyl sulfoxideC9H9ClOSEe = 99%[α]D25=+151.4 (c 0.8, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2,3,3-trimethyl-4-(p-tolylsulfonyl)butanoateC18H28O4SEe = 96%[α]D30=-14.3 (c 1.2, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclohexy}propionateC21H32O4SEe = 97%[α]D26=-5.3 (c 1.8, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclopentadecyl}propionateC30H50O4SEe = 97%[α]D24=-4.3 (c 0.9, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-ethyl-3,3-dimethyl-4-(p-tolylsulfonyl)butanoateC19H30O4SEe = 93%[α]D26=-3.0 (c 1.7, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclohexyl}butanoateC22H34O4SEe = 99%[α]D26=-4.9 (c 1.8, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclopentadecyl}butanoateC31H52O4SEe = 97%[α]D26=-1.7 (c 0.9, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-[1,1-dimethyl-2-(p-tolylsulfonyl)ethyl]hexanoateC21H34O4SEe = 96%[α]D28=-0.5 (c 2.8, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2R)-(−)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclopentadecyl}hexanoateC33H56O4SEe = 97%[α]D27=-1.9 (c 0.9, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(−)-2,3,3-Trimethylbutyric acidC7H14O2Ee = 96%[α]D28=-20.8 (c 0.7, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(+)-3-Benzyloxy-4,4-dimethyldihydrofuran-2-oneC13H16O3Ee = 99%[α]D28=+112.5 (c 0.22, CHCl3)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(+)-4-Benzyloxy-2-oxaspiro[4.5]decan-3-oneC16H20O3Ee = 97%[α]D27=+101.2 (c 0.91, CHCl3)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(+)-3-Dibenzylaminodihydrofuran-2-oneC18H19NO2Ee = 87%[α]D28=+26.5 (c 0.22, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(+)-3-Dibenzylamino-4,4-dimethyldihydrofuran-2-oneC20H23NO2Ee = 99%[α]D29=+137 (c 0.47, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(+)-4-Dibenzylamino-2-oxaspiro[4.5]decan-3-oneC23H27NO2Ee = 99%[α]D27=+91.5 (c 1.0, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(R)-(−)-(4,4-Dimethyl-2-oxotetrahydrofuran-3-yl)carbamic acid methyl esterC8H13NO4Ee = 99%[α]D28=-8.2 (c 1.0, CHCl3)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (R)(2S)-(+)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclopentadecyl}propionateC30H50O4SEe = 99%[α]D23=+5.05 (c 1.34, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (S)(2S)-(+)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]cyclopentadecyl}butanoateC31H52O4SEe = 99%[α]D25=+1.75 (c 0.45, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (S)(2S)-(+)-tert-Butyl 2,3,3-trimethyl-4-(p-tolysulfonyl)butanoateC18H28O4SEe = 80%[α]D28=+9.8 (c 0.84, ethanol)Source of chirality: (R)-(−)-chloromethyl p-tolyl sulfoxideAbsolute configuration: (S)