Structural Study‐Guided Development of Versatile Phase‐Transfer Catalysts for Asymmetric Conjugate Additions of Cyanide

Abstract

Significant advances have been made in the development of catalytic 1,2-asymmetric cyanations using both chiral metal and organic catalysts. [1] In contrast, only a few highly enantioselective catalytic conjugate additions of cyanide ions have been realized despite the potential of such transformations in providing efficient enantioselective access to synthetically valuable chiral building blocks. [2] The first breakthroughs were reported by Jacobsen and co-workers, who described chiral Al-Salen [3] and bimetallic cooperative catalyst systems [4] for the enantioselective conjugate additions of trimethylsilyl cyanide (TMSCN) to a,bunsaturated imides. Shibasaki, Kanai, and co-workers reported two chiral bifunctional catalysts derived from gadolinium, strontium, and different asymmetrically prepared or carbohydrate-based chiral ligands for a highly enantioselective 1,4-addition of cyanide with HCN/trialkylsilyl cyanides to a,b-unsaturated N-acyl pyrroles [5] and enones, [6] respectively. Feng [7] and co-workers have reported a modular titanium catalyst for the cyanation of alkylidine malonates. Very recently, Ohkuma [8] and co-workers disclosed a chiral Ru complex for the conjugate addition of TMSCN to enones. These existing reactions, while representing remarkable success in establishing general substrate scope and high catalyst efficiency, require the use of various trialkylmetal cyanides in super-stoichiometric amounts. Thus, we became interested in the development of highly enantioselective catalytic 1,4-additions of cyanide with readily accessible and easy to handle cyanation reagents.Chiral phase-transfer catalysis has been developed as an effective strategy for the activation of practical cyanation reagents, such as KCN [9] and acetone cyanohydrin, [10] for asymmetric 1,2-additions of cyanides. On the other hand, this strategy has so far been attempted only with 1,4-additions of cyanide to nitroalkenes. [11] These attempts have so far been met with limited success. Our recent development of cupreinium salts 1, as highly enantioselective phase-transfer catalysts for an asymmetric Darzens reaction, [12] prompted us to explore them for the asymmetric conjugate addition of cyanide. Similar to other known bifunctional phase-transfer catalysts that bear a hydrogen-bond-donor moiety, [13][14][15] cupreidinium salts CPD-1, could in principle mediate phasetransfer catalysis by their association with an anionic cyanation species, presumably a cyanide or cyanoalkoxide ion, by simultaneous ion-pair and hydrogen-bonding interactions (I, Scheme 1). Alternatively, CPD-1 could promote the conjugate addition by simultaneous interactions with both the cyanation species and the enone (II, Scheme 1).We first investigated the asymmetric conjugate addition of acetone cyanohydrin to enone 5 a. As the equilibrium between cyanohydrin and the enone is known to favor the latter under basic conditions, [16] we reasoned that chiral phase-transfer catalysis might provide an attractive strategy to address the 1,2-vs. 1,4-chemoselectivity ...

Efficient Access to Trifluoromethyl Diarylpyrrolines and their N‐Oxides through Enantioselective Conjugate Addition of Nitromethane to β,β‐Disubstituted Enones

“…[11] Therefore, we focused on the cupreidine-based phase-transfer catalyst, since they have a different mode of hydrogen bonding to substrates. [12] Gratifyingly, an improved ee value of 57 % was observed in the presence of 4 c (entry 3). When the reaction was carried out using the methylether cupreidinium salt 4 d, the desired 5 a was obtained in 49 % with 85 % ee (entry 4).…”

“…Rb 2 CO 3 , Cs 2 CO 3 , and K 3 PO 4 showed higher reactivities, but enantioselectivities were lower than those obtained with K 2 CO 3 (entries [8][9][10][11]. A subsequent solvent survey (entries [12][13][14][15][16][17][18][19][20] revealed that benzene was the solvent of choice with regard to enantioselectivity (entry 15). Further improvement of selectivity was observed in the presence of 4 M.S.…”

“…A series of trifluoromethylated enone derivatives (2 a-g, 2 i-o) with a variety of substituents, such as methyl, methoxy, fluoro, chloro, bromo, and nitro groups, on their aromatic rings were converted into the corresponding 5 a-g, i-o in high to excellent yields with ee values in the range of 90-93 % (entries [1][2][3][4][5][6][7][9][10][11][12][13][14][15]. The sterically demanding naphthyl-substituted enones 2 h and 2 p also reacted, thus affording 5 h and 5 p, respectively, in excellent yields with 90 % ee (entries 8 and 16).…”

Organocatalyzed Formal [4+2] Cycloaddition of in situ Generated Azoalkenes with Arylacetic Acids: An Efficient Approach to the Synthesis of 4,5‐Dihydropyridazin‐3(2H)‐ones

“…To the best of our knowledge, the reported synthetic strategies for the synthesiso fd ihydropyridazinones are normally limited to the condensation of costly substrate goxo acids andh ydrazine. [3] Therefore,t he development of an ew strategyt hat allowsr apid access to dihydropyridazinones from readily accessible starting materials using ap ractical method is still highly desirable and an enduring goal of organic chemistry.…”

Magnesium Complexes as Highly Effective Catalysts for Conjugate Cyanation of α,β‐Unsaturated Amides and Ketones

“…The reaction proceeded at 10 8C and resulted in a higher enantioselectivity without an obvious sacrifice of reaction rate (Table 1, entries 1-4). Further screening of the solvents revealed that CH 2 Cl 2 appeared to be the most suitable reaction media (entries [5][6][7][8]. When the catalyst load-ing decreased to 10 mol % or no molecular sieves were added, low selectivity and yield were observed (entries 9-10).…”