Synthesis of Phenylcyclopropane-Based Secondary Amine Catalysts and Their Applications in Enamine Catalysis

Abstract

A novel chiral motif based on a phenylcyclopropane scaffold has been designed, and a facile synthetic route to the key intermediate for the synthesis of phenylcyclopropane-based chiral secondary amines has been developed. Newly synthesized chiral amines function as effective catalysts for several asymmetric reactions through enamine intermediates.

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

“…However, the reaction site of the s- trans -enamine is too far from the Z -ketimine activated by the triflimide group, and only the s- cis -enamine can react with the distant Z -ketimine to give predominantly syn -isomer (2 R ,3 R )- 2 ( TS3 ). 17,18 A computational study of the Mannich reaction of a ketimine using proline and a similar catalyst by Fu is consistent with the proposed transition state models TS2 and TS3 . 20…”

“…We have previously developed the axially chiral amino sulfonamide catalyst ( S )- 6 17 and the chiral phenylcyclopropane-based amine catalyst ( S , R )- 7 . 18 In the Mannich reaction with aldimines, ( S )- 6 and ( S , R )- 7 show a diastereoselectivity opposite to proline and related catalysts. Fortunately, the binaphthyl-based amine catalyst ( S )- 6 promoted the reaction of 3-phenylpropanal with 1a to preferentially afford syn - 2a , albeit with low syn -selectivity (entry 7).…”

Design of Bifunctional Amino Tf‐Amide Organocatalysts and Application in Various Asymmetric Transformations

“…The new catalyst XIII was indeed practically synthesized from 2-bromo-6-iodobenzaldehyde (58) as shown in Scheme 30. [34] Thus, treatment of 58 with ethylene glycol in the presence of p-toluenesulfonic acid monohydrate produced On the other hand, XIII showed better results in several specific asymmetric transformations. The asymmetric Mannich reaction of ketimine 59 with 3-phenylpropanal in the presence of 10 mol% of XIII in acetonitrile at room temperature afforded desired adduct syn-59 in slightly improved yield with syn-selectivity (Scheme 32a).…”

“…The new catalyst XIII was indeed practically synthesized from 2‐bromo‐6‐iodobenzaldehyde ( 58 ) as shown in Scheme 30 [34] . Thus, treatment of 58 with ethylene glycol in the presence of p ‐toluenesulfonic acid monohydrate produced acetal VIIIa .…”

The Design and Synthesis of Phenylcyclopropane-Based Secondary Amine Catalysts and Their Applications in Asymmetric Reactions

“…This motivated us to develop ( S , R )- 4 , a novel chiral motif possessing a phenylcyclopropane scaffold that can be prepared using a scalable processes by employing readily available and inexpensive reagents (Figure 2 ). 11 The unique stereoselectivity in the reactions using binaphthyl-modified catalyst ( S )- 1a is mainly caused by the spatial relationship between two nitrogen atoms, the secondary amine moiety and the acidic functional group. To achieve this arrangement, the seven-membered ring of the catalyst needs to be fixed in the correct conformation by the binaphthyl skeleton.…”