Consecutive catalytic electrophilic fluorination/amination of β-keto esters: toward α-fluoro-α-amino acids?

Monofluorination of β-keto esters with Selectfluor® (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate)) using CpTiCl3 as a catalyst, followed by amination with diazodicarboxylates using a Cu/Ph-Box catalyst leads to α-fluoro-α-hydrazino-β-keto esters in good yields and good selectivities (ee up to 94%).

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2-Fluoro-N′,N-bis(benzyloxycarbonyl)-2-hydrazino-3-oxo-butyric acid ethyl esterC22H23FN2O7Ee = 67%[α]D = +10.9 (c 2.0, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(benzyloxycarbonyl)-2-hydrazino-3-oxo-butyric acid methyl esterC21H21FN2O7Ee = 90%[α]D = +13.1 (c 2.6, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(ethoxycarbonyl)-2-hydrazino-2,2-dimethyl-3-oxo-pentanoic acid ethyl esterC15H25FN2O7Ee = 28%[α]D = +28 (c 0.94, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(ethoxycarbonyl)-2-hydrazino-3-oxo-3-phenyl-butyric acid ethyl esterC17H21FN2O7Ee = 87%[α]D = −2.6 (c 1.06, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(benzyloxycarbonyl)-2-hydrazino-3-oxo-3-phenyl-butyric acid ethyl esterC27H25FN2O7Ee = 60%[α]D = −4.8 (c 0.84, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(benzyloxycarbonyl)-2-hydrazino-2,2-dimethyl-3-oxo-pentanoic acid ethyl esterC25H29FN2O7Ee = 88%[α]D = +44 (c 1.0, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N′,N-bis(benzyloxycarbonyl)-2-hydrazino-3-oxo-butyric acid menthyl esterC30H37FN2O7Ee = 87.5:12.5 dr[α]D = +44.6 (c 1.2, CH2Cl2)Source of chirality: asymmetric catalysis

2-Fluoro-N,N′-bis(benzyloxycarbonyl)-2-hydrazino-3-oxobutyric acid-diphenylamideC32H28FN3O6Ee = 69%[α]D = +23.8 (c 1.0, CH2Cl2)Source of chirality: asymmetric catalysis