Asymmetric Alkynylation of Imines by Cooperative Hydrogen Bonding and Metal Catalysis

Abstract

asymmetric catalysis · Brønsted acids · cooperative catalysis · organocatalysis · transition metals Chiral propargyl amines are important building blocks for the total synthesis of complex natural products, [1] pharmaceuticals, [2] and plant pesticides (herbicides and fungicides).[3]In addition to their synthetic utility, some propargylic amine derivatives display interesting biological properties.[4] The most direct access to these important synthetic blocks relies on the asymmetric alkynylation of imines. In spite of their importance, the number of available methodologies for their preparation remains scarce.[5] They are mainly based on organometallic protocols involving copper, [6] zinc, [7] zirconium, [8] or boron, [9] and Lewis bases as chiral ligands. Typically, these ligands are complex chiral molecules obtained by a multistep synthesis, and their optimization by structural/ functional modifications is often not easy as it requires timeconsuming functional group manipulations. Thus, alternative catalytic models based on the use of simple chiral ligands that can be assembled in a fast and easy manner would be highly desirable. Cooperative catalytic models based on chiral Brønsted acids and metal catalysis have emerged as such an alternative. Recent studies [10,11] have shown that high enatioselective alkynylations of imines can be performed according to the cooperative catalytic model shown in Scheme 1. The model comprises two well-differentiated and parallel catalytic cycles: the addition of metallic alkynylides to imines (cycle I) [12] and the use of chiral Brønsted acids as chiral imine activators (cycle II). [13] Whereas the organometallic cycle I has the task of supplying the achiral metallic alkynylide reactant, the organocatalytic cycle II delivers the chiral ion pair bearing the activated imine component. The reaction of both components should lead to the corresponding propargyl amine, liberating the catalysts to reinitiate the cycles. This catalytic model features two important practical properties: firstly, chiral catalyst accessibility-a large pool of chiral Brønsted acids is commercially available (amino acids, natural carboxylic acids, chiral phosphoric acids), and secondly, metal/ligand simplicity-commercial achiral ligands are much more accessible than their more elaborate chiral homologues, and therefore, the metal reactivity can be much more easily modulated. In spite of its apparent power, the number of described cooperative catalytic systems involving both Brønsted acids and metals is scarce.[14] Actually, only a few systems operating under this paradigm have been implemented. [15] Rueping et al. [10] have implemented a cooperative Brønst-ed acid/metal catalytic system for the enantioselective alkynylation of a-imino esters catalyzed by silver salts and chiral binol hydrogen phosphates (Scheme 2). The reaction of aryl-substituted alkynes and N-protected a-imino esters in the presence of catalytic amounts of a silver salt (5 mol %) and a chiral phosphoric acid (10 mol %) generates propargy...

Methylation of Ylidene‐Triazenes: Insight and Guidance for 1,3‐Dipolar Cycloaddition Reactions

“…[7] Alkyne-azide 1,3-dipolar cycloadditions are an especially practical subclass of reactions, given that molecules comprising terminal alkyne [8][9][10] and azide [11] functionalities are synthetically accessible and often commercially available. Huisgen first described alkyne-azide 1,3-dipolar cycloadditions over 40 years ago, [12] however the low yields of products obtained and the lack of regioselectivity limited the practical scope of this transformation.…”

Enantioselective Alkynylation of Trifluoromethyl Ketones Catalyzed by Cation‐Binding Salen Nickel Complexes

“…Since Carreirasp ioneering report, [4a] several catalysts have been developed for the enantioselective alkynylation of aldehydes, [4] imines, [5] and alkyl ketones. [6] In contrast, there are fewer reports on the enantioselective alkynylation of trifluoromethyl ketones, [7,8] as the high reactivity of these electron-deficient electrophiles has led to significant challenges associated with facial selectivity.A lthough there have been some reports on the enantioselective variant of this transformation, they all suffer from significant drawbacks, such as high temperatures, [7a] large excesses of expensive reagents, [7b,d] or the use of precious,s econd-row transition metals as catalysts ( Figure 1b).…”

Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base‐Free Catalytic Asymmetric C−C Bond Formation with Terminal Ynamides

“…[1] In contrast to the general advance with asymmetric alkynylations of aldehydes, [2] ketones, [3] and imines, [4] trifluoromethyl ketones have remained challenging substrates, [5] and initially required the use of stoichiometric amounts of lithium or zinc aminoalkoxides. [6] Shibasaki first demonstrated the feasibility of asymmetric catalysis, providing CF 3 -substituted propargylic alcohols in up to 52% ee.…”