Chiral Primary Amine Catalyzed α‐Arylation of Simple Ketones via Asymmetric Retro‐Claisen Cleavage

Abstract

Highly enantioselective α‐arylation of simple ketones has been achieved by chiral primary amine catalyzed asymmetric retro‐Claisen cleavage of β‐diketones. This mild organocatalytic strategy enables the construction of α‐aryl tertiary carbon stereocenters in good yields and excellent enantioselectivities (up to 98 % ee) with the para‐quinone monoimines as aryl sources. Furthermore, oxidative catalytic asymmetric α‐arylation has also been realized with free p‐aminophenols.

Recent Advances on Catalytic Enantioselective Protonation for Construction of α-Tertiary Carbonyl Compounds

“…2019 年, 罗三中等 [36] [37] 或对苯醌单亚胺 [38] 的不 对称逆 Claisen 反应/质子化, 高效高选择性地合成了一 系列含 α-叔碳手性中心的酮类化合物. 72% yield, 94% ee 59% yield, 77% ee 90% yield, 91% ee 29% yield, 88% ee 68% yield, 87% ee 52% yield, 94% ee…”

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline–Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones

“…Accordingly, much effort has been focused on the preparation of α,α-disubstituted β-diketones from α-monosubstituted β-diketones to be used in asymmetric retro-Claisen reaction. Much to our surprise, a literature survey revealed that 7 which could finally undergo C−C bond cleavage to form the corresponding chiral α-arylated ketones (Scheme 1b, right). However, this method suffers from at least two drawbacks: (1) only pquinone monoimines, rather than 1,4-benzoquinones, were used as aryl sources, possibly restricted by chiral primary amine catalyst, and (2) the reported catalytic method was not efficient enough for diketone substrates bearing benzylic group (R 1 ); indeed, there only one case has been reported in the literature.…”

“…The preparation of 3g could be carried out at 1 mmol scale, and similar good results were obtained. To our delight, by using electron-deficient olefin 6 as the starting material, a one-pot, The absolute configuration of 3zb was determined by comparing HPLC analysis and optical rotation with previously reported literature, 7 and the configurations of all other products 3 were assigned by analogy assuming a uniform reaction pathway. The relative configuration of 7 was established by comparison with a known compound (see the Supporting Information for details).…”

“…It should be noted that all the aforementioned reported asymmetric retro-Claisen reactions were initiated by the alkylation of the α-monosubstituted β-diketones to give chiral α-alkylated ketones. Very recently, by using the p -quinone monoimines as aryl sources, Luo and co-workers reported the first and only example of asymmetric retro-Claisen reaction involving α-arylation of α-monosubstituted β-diketones by enantioselective enamine catalysis, which could finally undergo C–C bond cleavage to form the corresponding chiral α-arylated ketones (Scheme b, right). However, this method suffers from at least two drawbacks: (1) only p -quinone monoimines, rather than 1,4-benzoquinones, were used as aryl sources, possibly restricted by chiral primary amine catalyst, and (2) the reported catalytic method was not efficient enough for diketone substrates bearing benzylic group (R 1 ); indeed, there only one case has been reported in the literature.…”

“…The absolute configuration of 3zb was determined by comparing HPLC analysis and optical rotation with previously reported literature, and the configurations of all other products 3 were assigned by analogy assuming a uniform reaction pathway. The relative configuration of 7 was established by comparison with a known compound (see the Supporting Information for details) …”