Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

Abstract

An ew catalytic asymmetric tandem a-alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N'dioxide/Zn II complexes.T he proton shift preferentially proceeded instead of as ilyl shift after a-alkenyl addition of silyl enol ether to the ketimine.Awide range of b-amino silyl enol ethers were synthesized in high yields with good to excellent ee values.C ontrol experiments suggest that the Mukaiyama-Mannich reaction and tandem a-alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained b-amino silyl enol ethers were easily transformed into b-fluoroamines containing two vicinal tetrasubstituted carbon centers.

Recent Advances in Catalytic Enantioselective Synthesis of Pyrazolones with a Tetrasubstituted Stereogenic Center at the 4-Position

“…In 2019, Feng and co-workers reported the first asymmetric Zn(II)-catalyzed alkenylation reaction of pyrazole-4,5-dione ketimines using silyl enol ethers; they had expected the Mukaiyama-Mannich reaction, which is a competitive process under these conditions (Scheme 20). 51 4-Boc-amino-substituted pyrazolones were obtained in low to excellent yields (21-98%) and good to excellent enantioselectivities (up to 99% ee) using chiral N,N′-dioxide metal complexes that they had previously developed. 52 This methodology achieves excellent enantiomeric excess regardless of whether the pyrazole-4,5-dione substituent at C-3 (R 1 ) is a methyl or phenyl group (92% ee and 93% ee, respectively).…”

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

“…Other isatin-derived ketimines with different protecting groups,s uch as -Cbz and -CO 2 Et, on the nitrogen atom, gave al ittle decrease in yield and enantioselectivity,w hich was likely attributed to the decreased steric bulk compared with that of the Boc group.In addition, the low reactivities of aryl and -SO 2 t Bu protected ketimines could not give the target products (see Table S3). [11] Ag ram-scale reaction between 1a (6 mmol) and 2a (4 mmol) provided 3a in 86 % yield with 95 % ee. [11] Ag ram-scale reaction between 1a (6 mmol) and 2a (4 mmol) provided 3a in 86 % yield with 95 % ee.…”

“…[12] Subsequently,w et urned our attention to broadening the substrate scope with respect to the silyl enol ethers (Scheme 3). [11] We next explored the tandem a-alkenyl addition/proton shift reaction between pyrazolinone-derived ketimines (5) [13] and silyl enol ethers (Scheme 4). 1-Indanone-derived substrates were smoothly transformed into the corresponding products 3j-m in good yields (68-90 %) with excellent ee values (90-93 %).…”

“…1-Indanone-derived substrates were smoothly transformed into the corresponding products 3j-m in good yields (68-90 %) with excellent ee values (90-93 %). [11] Thecyclohexanone-derived cyclic silyl enol ether was also explored in the current catalytic system, and provided the corresponding product 6c in 98 % yield with 84 % ee. Thes ilyl enol ethers bearing a'-methyl, benzyl, and chloro-alkyl underwent the reaction smoothly,delivering 3np in 61-77 %yields,8:1-> 19:1 d.r.,and 94-97 % ee.…”

“…The b-fluoroamine motif [14] is an important skeleton and is found in numerous drug candidates. [11] To gain insight into the mechanism of the tandem a-alkenyl addition/proton shift in the current catalytic system, control experiments were studied. [11] To gain insight into the mechanism of the tandem a-alkenyl addition/proton shift in the current catalytic system, control experiments were studied.…”