First catalytic asymmetric synthesis of β-amino-β-polyfluoroalkyl ketones via proline-catalysed direct asymmetric carbon–carbon bond formation reaction of polyfluoroalkylated aldimines

Abstract

Proline-catalysed direct asymmetric carbon-carbon bond formation reaction of polyfluoroalkylated aldimines with acetone afforded the corresponding beta-(p-methoxyphenyl)amino-beta-polyfluoroalkyl ketones in high enantioselectivities (up to 98% ee).

Facile Synthesis of Chiral α‐Difluoromethyl Amines from N‐(tert‐Butylsulfinyl)aldimines

“…Despite its importance for applications related to life sciences, the synthesis of α‐difluoromethyl amines has not been well explored. The few known methods are mainly based on the use of difluoromethyl carbonyl compounds or their imine derivatives as precursors 8–12. Pey and Schirlin reported the multistep synthesis of α‐difluoromethyl amines from substituted malonate esters with CHF 2 Cl followed by a Curtius rearrangement 13.…”

“…Pey and Schirlin reported the multistep synthesis of α‐difluoromethyl amines from substituted malonate esters with CHF 2 Cl followed by a Curtius rearrangement 13. However, the general and efficient asymmetric synthesis of α‐difluoromethyl amines still remains a challenge although it has drawn many synthetic endeavors 9–12. 14 The asymmetric hydrogenation of fluorinated imines are usually difficult, and recently Uneyama and co‐workers reported that the palladium‐catalyzed asymmetric hydrogenation of difluoromethyl imino esters proceeded with poor enantioselectivity (30 % ee ) 9.…”

Catalytic Asymmetric Construction of Stereogenic Carbon Centers that Feature a gem‐Difluoroalkyl Group

“…Funabiki et al. reported a highly enantioselective proline‐catalyzed asymmetric Mannich reaction of 69 a and acetone for the synthesis of β‐amino‐β‐CF 2 H ketone 70 a 27a. Under the same conditions, aldimine 69 a proved to be more reactive than the corresponding α‐CF 3 and α‐C 2 F 5 aldimines 69 b and 69 c (Scheme ).…”

Trifluoromethyl aldimines: an overview in the last ten years

“…The first L-proline-catalyzed enantioselective Mannich-type reaction on a fluorinated aldimine, namely trifluoromethyl N-(p-methoxyphenyl)aldimine (11), was reported by Funabiki and coworkers, 34 using acetone both as reagent and as solvent (Scheme 5). The reaction led to the corresponding β-amino β-trifluoromethyl ketone (S)-13 in good yields but very low enantioselectivity.…”