Asymmetric Vinylogous Mannich‐Type Addition of α,α‐Dicyanoalkenes to α‐Fluoroalkyl Sulfinyl Imines

Abstract

The asymmetric vinylogous Mannich reaction (AVMR) of α,α‐dicyanoalkenes with α‐fluoroalkyl sulfinyl imines has been successfully accomplished. This transformation is unprecedented with fluorinated imines and, at the same time, the use of dicyanoalkenes in AVMR has been scarcely reported. Several fluorinated sulfinyl imines are compatible with the process, which gives access to a family of chiral fluorinated amines with an excellent level of stereocontrol. Interestingly, the selectivity found in our protocol is the opposite of that encountered in analogous, previously reported AVMRs. Additionally, the synthetic applicability of the addition products has been exemplified with several transformations showing the particular reactivity of the dicyanoalkene moiety of these α‐fluorinated amines.magnified image

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…The last example of an asymmetric VMnR with α,α-dicyanoolefins as vinylogous nucleophiles was reported by Fustero, Pozo, et al in 2018. 656 Linear and cyclic pronucleophiles 997 reacted with chiral enantiopure fluorinated sulfinyl imines 998 under basic conditions to furnish compounds 999 as single diastereomers in low to good yields ( Scheme 256 ). To account for the observed relative configuration of the products, the authors assumed that the reaction proceeds through a chelated transition state, where the potassium counterion in the enolate would form a chelate with the imine nitrogen atom in a chairlike modality, thus facilitating the attack of the nucleophile to the Re face of the imine.…”

“…The last example of an asymmetric VMnR with α,α-dicyanoolefins as vinylogous nucleophiles was reported by Fustero, Pozo, et al in 2018 . Linear and cyclic pronucleophiles 997 reacted with chiral enantiopure fluorinated sulfinyl imines 998 under basic conditions to furnish compounds 999 as single diastereomers in low to good yields (Scheme ).…”

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

“…Drawing from our previous studies on the chemistry of trifluoromethylated sulfinylimine 1 [ 41 – 54 ], the initial reaction conditions focused on the use of 1.3 equiv of 1-ethynyl-4-methoxybenzene ( 2a ) in the presence of n -BuLi with CH 2 Cl 2 as a solvent at −78 °C. The desired product 3a was obtained after 2.5 hours in 46% yield as a mixture of two diastereomers (55:45 dr, Table 1 , entry 1).…”

“…It should be mentioned that the Qing group also reported a method for the synthesis of α-trifluoromethylated α-propargylamines via a Ti-promoted addition reaction between acetylide and chiral CF 3 -ketimines ( Scheme 1 ) [ 35 ]. Based on our experience in the preparation of trifluoromethylated amino compounds [ 36 – 40 ] and the chemistry of N - tert -butylsulfinyl-3,3,3-trifluoroacetaldimine ( 1) [ 41 – 54 ], we noticed that the reactions of chiral imine 1 with yne nucleophiles have never been reported thus far. Accordingly, intrigued by this methodological deficiency, we decided to dedicate a special research project to this objective; herein, we report Mannich reactions between yne nucleophiles and aldimine 1 ( Scheme 1 ).…”

Fluorinated Imines in Tandem and Cycloaddition Reactions

“…[57] In this regard, our group reported in 2018 one of the first asymmetric vinylogous Mannich reactions (AVMR) by reacting α,α-dicyanoalkenes with α-fluoroalkyl sulfinyl imines under basic conditions, which gives access to a family of chiral α-fluoroalkyl amines with an excellent level of stereocontrol. [58] Moreover, α,α-dicyanoalkenes, readily prepared through the condensation of carbonyl compounds and malononitrile, have emerged in the last decade as versatile vinylogous donors acting as nucleophiles through the γ-position, [59] although the combination of dicyanoalkenes and fluorinated imines had until then been unprecedented. In fact, only two examples, reported by Qing's group, involving an AVMR with fluorinated aldimines had been described.…”