Asymmetric Conjugate Additions of Carbonyl Compounds to Nitroalkenes under Solvent-Free Conditions Using Fluorous Diaminomethylenemalononitrile Organocatalyst

Abstract

The novel fluorous organocatalyst bearing a diaminomethylenemalononitrile motif is prepared. The fluorous organocatalyst efficiently promotes asymmetric conjugate additions of ketones to nitroalkenes and results in high yields of these addition products with excellent enantioselectivities under solvent-free conditions.Key words organocatalyst; fluorous; conjugate addition; solvent-free Chiral γ-nitro carbonyl compounds are significant synthons in organic and medicinal chemistry owing to their easy access to biologically active molecules.1-9) Among several synthetic methods to obtain enantiomer-enriched, γ-nitro carbonyl compounds, asymmetric conjugate addition of carbonyl compounds to nitroalkenes using organocatalysts is one of the most convenient and environmentally benign methodologies. [10][11][12][13][14][15][16][17] Organocatalysis between carbonyl compounds and nitro alkenes has been reported by several research groups; however, due to obstacles faced by most previously reported organocatalysis, such as high catalyst loading or long reaction times, the development of organocatalysts for highly efficient asymmetric conjugate additions of carbonyl compounds to nitroalkenes still remains an area of research interest. Thiourea organocatalysts, which are represented by Takemoto catalysts, are excellent catalysts and are applied to remarkably important asymmetric reactions.18-26) Good organocatalytic activity is seen when a thiourea motif functions as a double hydrogen-bond donor for a nucleophilic substrate. In addition, a squaramide motif as a further double hydrogen-bond donor was reported by Rawal and colleagues, and the squaramide organocatalyst effectively promotes the asymmetric conjugate additions of 1,3-diketones to nitroalkenes. 27) Since the Rawal's report, it has been reported that various organocatalysts with squaramide motifs are useful for several important asymmetric reactions. [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] We recently reported the diaminomethylenemalononitrile (DMM) motif as another type of double hydrogen-bond donor, and the DMM-type organocatalysts exhibited excellent asymmetric catalytic activity for several significant asymmetric reactions. [44][45][46][47][48][49][50] Organocatalyst 1 bearing a DMM motif and a cyclic secondary amine unit is a good catalyst for both asymmetric conjugate additions of cyclic ketones to nitroalkenes and direct aldol reactions of aromatic aldehydes with cyclic ketones under solvent-free conditions 45,48) (Fig. 1). On the contrary, asymmetric reactions using organocatalysts with fluorous tags have been reported by several research groups. Almost all of these reports utilize the benefits of fluorous molecules; the recycling of fluorous organocatalysts was achieved via the fluorous solid-phase extraction (FSPE) technique using fluorous silica gel. [73][74][75] We have also reported some fluorous organocatalysts and demonstrated their recyclability. [76][77][78][79][80] It was found that modifying original organocatalysts via add...

Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

“…γ-Nitroketones were obtained with good performance, although five equivalents of ketone, and 10 mol% of organocatalyst and acid additive were required. Afterwards, the same authors developed the fluorous analogue diaminomethylenemalononitrile organocatalyst 80b, with a slight improvement in the reaction performance [128].…”

“…Molecules 2023, 28, 2234 42 of 67 diaminomethylenemalononitrile organocatalyst 80b, with a slight improvement in the reaction performance [128]. In 2014, Liu's group designed a novel fluorine containing pyrrolidine organocatalyst, which was based on the remarkable impact on the pyrrolidine conformation exerted by different substituents and, in particular, by the fluorine-ammonium ion gauche effect [129].…”

Recent Advances in Solvent‐Free Asymmetric Catalysis

“…In 2017, Miura′s group accomplished the solvent‐free asymmetric conjugate additions of ketones to nitroalkenes by new fluorous organocatalyst bearing a diaminomethylenemalononitrile moiety (Scheme ) . Using 10 mol % of 41 , the reaction of cyclohexanone and nitroalkenes without sensitivity to the electronic effect of nitroalkenes for both electron‐donating and electron‐withdrawing groups, afforded the corresponding product with high yields and stereoselectivities (Scheme ).…”

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

“…However, this work focused exclusively on unsaturated ester Michael acceptors and many potential synthetic challenges remained in expanding this transformation to challenging β,β′ -disubstituted nitroolefins, while maintaining the high enantio- and diastereoselectivity previously observed. Furthermore, while enantioselective intermolecular Michael addition reactions with nitroolefins have been well-established, intramolecular desymmetrising variants that concurrently establish a quaternary carbon center are unreported. − …”