Formation of Enantiomerically Pure 1-Fluorovinyl and 1-Fluoromethyl Sulfoxides

Fluorinated Phosphonates: Synthesis and Biomedical Application

“…The lithiated carbanions 76 and 77 behave as typical organometallic reagents and can participate in various substitution reactions (Scheme ). ,, Methylation of the anion 76 with dimethyl sulfate gives the phosphonate 78 and alkylation of 77 with 1,3-dibromopropane provides the bisphosphonate 79 . Reaction between 76 and ( S )-(−)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding ( S s )-fluoro-( p -tolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers . Acylation of 76 using benzoyl chloride occurred smoothly to give α-fluoro-β-oxoalkylphosphonate 81 , which exists exclusively as an E / Z mixture of enol form.…”

“…Metalation of α-fluorophosphonate esters of the type (RO) 2 P(O)CH(EWG)F bearing an electron-withdrawing functional group (EWG) on the α-carbon atom (e.g., CN, CO 2 R, S(O)Ar, SO 2 Ph, PO 3 R 2 , or SiMe 3 ) smoothly proceeds in polar solvents (THF, DME, or DMF) with bases such as n BuLi, LDA, or LiHMDS (Table ). ,,,,,− Reactivity of these highly stabilized carbanions has been the focus of many studies. , The main points of interest here are (i) the elaboration of the phosphonate skeleton using alkylation reactions and (ii) the use of fluorinated phosphonate carbanions as Horner−Wadsworth−Emmons (HWE) or Peterson olefination reagents.…”

“…α-Fluoro-α-cyanomethylphosphonate anions, [(RO) 2 P(O)CF(CN)] - , are anomalous compared to their carbalkoxy counterparts in that they produce mixtures of Z and E isomers in the range of 4:1 to 1:2. , The HWE reaction between deprotonated diethyl ( S s )-fluoro-(4-tolylsulfinyl)methylphosphonate, (EtO) 2 P(O)CHF[S*(O)Tol-4], and aldehydes was found to occur with complete conversion, showing only moderate but consistent E -selectivity for butyraldehyde ( E / Z = 70:30), crotonaldehyde ( E / Z = 70:30), and benzaldehyde ( E / Z = 83:17) . Addition of fluorinated phenylsulfonylmethylphosphonate and methylenebisphosphonate anions to aldehydes typically results in E -fluoroalkenes, although a number of significant nuances have arisen. ,, The reaction in Scheme constitutes a procedure from Organic Syntheses that illustrates the application of the lithiated carbanion 110 for stereoselective synthesis of 2,2-disubstituted 1-fluoroalkenes.…”

“…Reaction between 76 and (S)-(-)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding (S s )-fluoro-(ptolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers. 144 Acylation of 76 using benzoyl chloride occurred smoothly to give R-fluoro-β-oxoalkylphosphonate 81, which exists exclusively as an E/Z mixture of enol form. The reaction of 76 with 3-chlorobutan-2-one provides the β,γepoxy-R-fluoroalkylphosphonate 82 by a Darzens-type reaction.…”

Fluorinated Phosphonates: Synthesis and Biomedical Application

“…The lithiated carbanions 76 and 77 behave as typical organometallic reagents and can participate in various substitution reactions (Scheme ). ,, Methylation of the anion 76 with dimethyl sulfate gives the phosphonate 78 and alkylation of 77 with 1,3-dibromopropane provides the bisphosphonate 79 . Reaction between 76 and ( S )-(−)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding ( S s )-fluoro-( p -tolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers . Acylation of 76 using benzoyl chloride occurred smoothly to give α-fluoro-β-oxoalkylphosphonate 81 , which exists exclusively as an E / Z mixture of enol form.…”

“…Metalation of α-fluorophosphonate esters of the type (RO) 2 P(O)CH(EWG)F bearing an electron-withdrawing functional group (EWG) on the α-carbon atom (e.g., CN, CO 2 R, S(O)Ar, SO 2 Ph, PO 3 R 2 , or SiMe 3 ) smoothly proceeds in polar solvents (THF, DME, or DMF) with bases such as n BuLi, LDA, or LiHMDS (Table ). ,,,,,− Reactivity of these highly stabilized carbanions has been the focus of many studies. , The main points of interest here are (i) the elaboration of the phosphonate skeleton using alkylation reactions and (ii) the use of fluorinated phosphonate carbanions as Horner−Wadsworth−Emmons (HWE) or Peterson olefination reagents.…”

“…α-Fluoro-α-cyanomethylphosphonate anions, [(RO) 2 P(O)CF(CN)] - , are anomalous compared to their carbalkoxy counterparts in that they produce mixtures of Z and E isomers in the range of 4:1 to 1:2. , The HWE reaction between deprotonated diethyl ( S s )-fluoro-(4-tolylsulfinyl)methylphosphonate, (EtO) 2 P(O)CHF[S*(O)Tol-4], and aldehydes was found to occur with complete conversion, showing only moderate but consistent E -selectivity for butyraldehyde ( E / Z = 70:30), crotonaldehyde ( E / Z = 70:30), and benzaldehyde ( E / Z = 83:17) . Addition of fluorinated phenylsulfonylmethylphosphonate and methylenebisphosphonate anions to aldehydes typically results in E -fluoroalkenes, although a number of significant nuances have arisen. ,, The reaction in Scheme constitutes a procedure from Organic Syntheses that illustrates the application of the lithiated carbanion 110 for stereoselective synthesis of 2,2-disubstituted 1-fluoroalkenes.…”

“…Reaction between 76 and (S)-(-)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding (S s )-fluoro-(ptolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers. 144 Acylation of 76 using benzoyl chloride occurred smoothly to give R-fluoro-β-oxoalkylphosphonate 81, which exists exclusively as an E/Z mixture of enol form. The reaction of 76 with 3-chlorobutan-2-one provides the β,γepoxy-R-fluoroalkylphosphonate 82 by a Darzens-type reaction.…”

α-Fluoroacrylonitriles: Horner–Wittig synthesis and conversion into 2-fluoroallylamines and C-(1-fluorovinyl)nitrones

“…With the remaining substrates, little or no stereoselectivity was found. The generally low and unpredictable stereoselectivities found for a-fluoroacrylonitriles 2 contrast the high, consistent selectivities found for a-fluorinated acrylates [18], and vinyl sulfoxides [15]. Notably, the non-fluorinated diethyl phosphonate analogue, which was expected to be a good indicator for the stereochemistry of 1 [18], did not show much (E)/(Z)-selectivity either [16].…”

Fluorinated Phosphonates: Synthesis and Biomedical Application

“…The lithiated carbanions 76 and 77 behave as typical organometallic reagents and can participate in various substitution reactions (Scheme ). ,, Methylation of the anion 76 with dimethyl sulfate gives the phosphonate 78 and alkylation of 77 with 1,3-dibromopropane provides the bisphosphonate 79 . Reaction between 76 and ( S )-(−)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding ( S s )-fluoro-( p -tolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers . Acylation of 76 using benzoyl chloride occurred smoothly to give α-fluoro-β-oxoalkylphosphonate 81 , which exists exclusively as an E / Z mixture of enol form.…”

“…Metalation of α-fluorophosphonate esters of the type (RO) 2 P(O)CH(EWG)F bearing an electron-withdrawing functional group (EWG) on the α-carbon atom (e.g., CN, CO 2 R, S(O)Ar, SO 2 Ph, PO 3 R 2 , or SiMe 3 ) smoothly proceeds in polar solvents (THF, DME, or DMF) with bases such as n BuLi, LDA, or LiHMDS (Table ). ,,,,,− Reactivity of these highly stabilized carbanions has been the focus of many studies. , The main points of interest here are (i) the elaboration of the phosphonate skeleton using alkylation reactions and (ii) the use of fluorinated phosphonate carbanions as Horner−Wadsworth−Emmons (HWE) or Peterson olefination reagents.…”

“…α-Fluoro-α-cyanomethylphosphonate anions, [(RO) 2 P(O)CF(CN)] - , are anomalous compared to their carbalkoxy counterparts in that they produce mixtures of Z and E isomers in the range of 4:1 to 1:2. , The HWE reaction between deprotonated diethyl ( S s )-fluoro-(4-tolylsulfinyl)methylphosphonate, (EtO) 2 P(O)CHF[S*(O)Tol-4], and aldehydes was found to occur with complete conversion, showing only moderate but consistent E -selectivity for butyraldehyde ( E / Z = 70:30), crotonaldehyde ( E / Z = 70:30), and benzaldehyde ( E / Z = 83:17) . Addition of fluorinated phenylsulfonylmethylphosphonate and methylenebisphosphonate anions to aldehydes typically results in E -fluoroalkenes, although a number of significant nuances have arisen. ,, The reaction in Scheme constitutes a procedure from Organic Syntheses that illustrates the application of the lithiated carbanion 110 for stereoselective synthesis of 2,2-disubstituted 1-fluoroalkenes.…”

“…Reaction between 76 and (S)-(-)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding (S s )-fluoro-(ptolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers. 144 Acylation of 76 using benzoyl chloride occurred smoothly to give R-fluoro-β-oxoalkylphosphonate 81, which exists exclusively as an E/Z mixture of enol form. The reaction of 76 with 3-chlorobutan-2-one provides the β,γepoxy-R-fluoroalkylphosphonate 82 by a Darzens-type reaction.…”

α-Fluoroacrylonitriles: Horner–Wittig synthesis and conversion into 2-fluoroallylamines and C-(1-fluorovinyl)nitrones

“…With the remaining substrates, little or no stereoselectivity was found. The generally low and unpredictable stereoselectivities found for a-fluoroacrylonitriles 2 contrast the high, consistent selectivities found for a-fluorinated acrylates [18], and vinyl sulfoxides [15]. Notably, the non-fluorinated diethyl phosphonate analogue, which was expected to be a good indicator for the stereochemistry of 1 [18], did not show much (E)/(Z)-selectivity either [16].…”

Fluorinated Phosphonates: Synthesis and Biomedical Application

“…The lithiated carbanions 76 and 77 behave as typical organometallic reagents and can participate in various substitution reactions (Scheme ). ,, Methylation of the anion 76 with dimethyl sulfate gives the phosphonate 78 and alkylation of 77 with 1,3-dibromopropane provides the bisphosphonate 79 . Reaction between 76 and ( S )-(−)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding ( S s )-fluoro-( p -tolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers . Acylation of 76 using benzoyl chloride occurred smoothly to give α-fluoro-β-oxoalkylphosphonate 81 , which exists exclusively as an E / Z mixture of enol form.…”

“…Metalation of α-fluorophosphonate esters of the type (RO) 2 P(O)CH(EWG)F bearing an electron-withdrawing functional group (EWG) on the α-carbon atom (e.g., CN, CO 2 R, S(O)Ar, SO 2 Ph, PO 3 R 2 , or SiMe 3 ) smoothly proceeds in polar solvents (THF, DME, or DMF) with bases such as n BuLi, LDA, or LiHMDS (Table ). ,,,,,− Reactivity of these highly stabilized carbanions has been the focus of many studies. , The main points of interest here are (i) the elaboration of the phosphonate skeleton using alkylation reactions and (ii) the use of fluorinated phosphonate carbanions as Horner−Wadsworth−Emmons (HWE) or Peterson olefination reagents.…”

“…α-Fluoro-α-cyanomethylphosphonate anions, [(RO) 2 P(O)CF(CN)] - , are anomalous compared to their carbalkoxy counterparts in that they produce mixtures of Z and E isomers in the range of 4:1 to 1:2. , The HWE reaction between deprotonated diethyl ( S s )-fluoro-(4-tolylsulfinyl)methylphosphonate, (EtO) 2 P(O)CHF[S*(O)Tol-4], and aldehydes was found to occur with complete conversion, showing only moderate but consistent E -selectivity for butyraldehyde ( E / Z = 70:30), crotonaldehyde ( E / Z = 70:30), and benzaldehyde ( E / Z = 83:17) . Addition of fluorinated phenylsulfonylmethylphosphonate and methylenebisphosphonate anions to aldehydes typically results in E -fluoroalkenes, although a number of significant nuances have arisen. ,, The reaction in Scheme constitutes a procedure from Organic Syntheses that illustrates the application of the lithiated carbanion 110 for stereoselective synthesis of 2,2-disubstituted 1-fluoroalkenes.…”

“…Reaction between 76 and (S)-(-)menthyl toluenesulfinate occurred with complete inversion of configuration to give the corresponding (S s )-fluoro-(ptolylsulfinyl)methylphosphonate 80 as a mixture of diastereomers. 144 Acylation of 76 using benzoyl chloride occurred smoothly to give R-fluoro-β-oxoalkylphosphonate 81, which exists exclusively as an E/Z mixture of enol form. The reaction of 76 with 3-chlorobutan-2-one provides the β,γepoxy-R-fluoroalkylphosphonate 82 by a Darzens-type reaction.…”

α-Fluoroacrylonitriles: Horner–Wittig synthesis and conversion into 2-fluoroallylamines and C-(1-fluorovinyl)nitrones

“…With the remaining substrates, little or no stereoselectivity was found. The generally low and unpredictable stereoselectivities found for a-fluoroacrylonitriles 2 contrast the high, consistent selectivities found for a-fluorinated acrylates [18], and vinyl sulfoxides [15]. Notably, the non-fluorinated diethyl phosphonate analogue, which was expected to be a good indicator for the stereochemistry of 1 [18], did not show much (E)/(Z)-selectivity either [16].…”