Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2‐Dioxides Catalyzed by Cinchona Alkaloid‐based Primary Amines

Abstract

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2-dioxides could be successfully carried out utilizing a combination of cinchona alkaloid-derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89-97 % ee and with various aryl methyl ketones in 85-98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.

Recent Developments and Perspectives in the Asymmetric Mannich Reaction

“…Cinchona‐based primary amine catalysts 138 – 141 have been successfully developed for asymmetric Mannich reaction (Figure ) . The catalytic effects of these catalysts were examined on model substrates, such as a cyclic imine and acetophenone.…”

“…The synthetic utility of the asymmetric Mannich reaction has been extensively explored. For example, the chiral Mannich adduct that was obtained from primary alkyl substrates was the highlight of the first organocatalytic coupling‐reagent‐free synthesis of antidiabetic drug (−)( R )‐sitagliptin …”

C2-Symmetric 1,2-Diphenylethane-1,2-diamine-Derived Primary–Tertiary Diamine-Catalyzed Asymmetric Mannich Addition of Cyclic N-Sulfonyl Trifluoromethylated Ketimines

“…In this case, primary–tertiary 1,2-diamines have been extensively used as organocatalysts for the enantioselective addition to CO and CC double bonds for the Aldol and Michael-type reactions, respectively; however, relatively limited examples are reported for enantioselective additions to the CN double bond (Scheme ). For example, natural cinchona alkaloid A and l -amino acid derivatives B both bearing a primary–tertiary 1,2-diamine motif successfully catalyzed the highly enantioselective reactions (>90% ee) involving the enantioselective addition to the CN systems. , C 2 -symmetric chiral molecules have attracted great attention in the rational design of chiral catalysts, as a large number of privileged chiral catalysts possess the C 2 -symmetric axis . Simple and commercially available chiral trans -cyclohexane-1,2-diamine and trans -1,2-diphenylethane-1,2-diamine are well known C 2 -symmetric diamines .…”

“…Catalytic asymmetric Mannich reactions are powerful strategies for the formation of C–C bonds via the addition to imines to synthesize chiral β-amino carbonyl compounds . Recently, using cyclic imines with endocyclic reactive CN double bonds, especially cyclic N -sulfonyl imines, as the substrates has received growing attention for catalytic highly enantioselective Mannich reactions , and the corresponding decarboxylative Mannich reactions, which can effectively construct optically active sultams and sulfamidates . Furthermore, the asymmetric Mannich reactions of cyclic trifluoromethylated ketimines may provide the most efficient route to the trifluoromethylated N -heterocycles skeleton with a C–CF 3 stereogenic center and a carbonyl group .…”

Substrate‐Induced Dimerization Assembly of Chiral Macrocycle Catalysts toward Cooperative Asymmetric Catalysis

“…Upon sulfate-induced dimerization, the macrocycles adopt an extroversive conformation and reciprocally complement the interaction sites.A si nspired by the induced-fit regulation of enzymes,wewondered if this dynamic assembly system can be applied on cooperative catalysis.D ecarboxylative Mannich reaction of cyclic aldimines 1 with bketoacids provides an alternative means to the direct Mannich reaction [17] for accessing valuable b-amino ketones, but efficient organocatalytic asymmetric transformation is lacking. [18] We speculated that the imine substrate could be activated toward nucleophilic attack through induced dimerization assembly of the chiral macrocycle catalysts ( Figure 2).…”