A convenient approach to difluoromethylated all-carbon quaternary centers via Ni(ii)-catalyzed enantioselective Michael addition

Abstract

A Ni(II)-catalyzed enantioselective Michael addition of 2-acetyl azarenes with b-difluoromethyl substituted nitroalkenes was successfully realized, which afforded chiral CF 2 H-containing compounds in good enantioselectivities (up to 93% ee). This protocol provides a new convenient approach to all-carbon quaternary stereogenic centers featuring a CF 2 H group.

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

“…In 2008, the Ricci group reported a new organocatalytic route to β-nitronitriles with all-carbon quaternary stereocenter, based on the conjugate addition of acetone cyanohydrin 17 to β,β-disubstituted nitroalkenes 16 (Scheme 5). [12] The reaction was conducted in the presence of a Cinchona alkaloid-derived phasetransfer catalyst (Cat-1, 10 mol%), and afforded the desired products (18) in moderate yields and enantioselectivities (up to 75% yield and 72% ee). However, owing to the relatively high acidity of their γ-protons, the nitroalkenes 16 could undergo isomerization to form vinylogous nitronates under basic catalytic conditions.…”

“…In 2018, Yu et al. reported the nickel‐catalyzed asymmetric Michael addition of 2‐acetyl azaarenes ( 43 ) to β‐CF 2 H‐β,β‐disubstituted nitroalkenes ( 42 ) [18] . In the presence of a Ni(II)‐bisoxazoline ( L4 ) complex as the catalyst, this reaction yielded the desired adducts ( 44 ) with difluoromethylated all‐carbon quaternary stereocenter in good enantioselectivities (up to 92% yield and 93% ee , Scheme 11).…”

“…[5] The β‐nitro compounds with quaternary stereocenters formed via conjugate addition to β,β‐disubstituted nitroalkenes can be easily transformed into several important species such as β 2,2 ‐amino acids and γ‐aminobutyric acids (GABAs) [6,7,8] . Therefore, the past few decades have witnessed the extensive development of catalytic asymmetric conjugate additions to β,β‐disubstituted nitroalkenes and the emergence of the corresponding elegant strategies [9–60] …”

Recent developments in enantioselective nickel(ii)-catalyzed conjugate additions

“…In 2018, these authors also investigated the asymmetric Michael addition of 2-acetyl azaarenes to β-difluoromethyl-β-disubstituted nitroalkenes in the presence of the same catalyst system (Scheme 12). 30 The process was also performed in isopropanol as solvent albeit at a lower temperature (−20 °C), leading to chiral difluoromethylated products bearing an all-carbon quaternary stereocenter with both moderate to high yields (38–86%) and enantioselectivities (67–93% ee). A variety of azaarenes containing a five-membered N-heterocycle reacted with moderate to high enantioselectivities (67–93% ee) with 2-acetyl N -methyl 2-imidazole furnishing the best result (93% ee).…”

Catalytic Asymmetric Construction of Tertiary Carbon Centers Featuring an α-Difluoromethyl Group with CF2H-CH2-NH2 as the “Building Block”

“…In those reports, aromatic groups attached to the N-end of the imine were not easily removed, hindering the further application of such blocks. When aldehydes, − ketones, − and alkenes, − carrying a difluoromethyl group, acted as CF 2 H-containing building blocks, metal catalytic conditions were normally used.…”