Ketones asymmetric Henry reaction

The Henry reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones. It is similar to the aldol addition, and is also referred to as the nitroaldol reaction. Since its discovery in 1895 [1] the Henry reaction has become one of the most useful reactions for the formation of C-C bonds, and most particularly for the synthesis of P-nitroalcohol derivatives [2]. The general features of this reaction are (i) the potential offered by the nitro and hydroxyl groups on the products for transformation into other compound families such as P-amino alcohols, P-amino acids, or nitroalkenes (ii) only a catalytic amount of base is required (iii) up to two contiguous stereogenic centers may be created in a single step concomitantly to the C-C bond formation. Several recent reviews with a focus on the asymmetric Henry reaction and its applications have appeared [3j. 

Table 29.2 Asymmetric Henry reaction of ketones catalyzed by cinchona-derived catalysts.

Jenner investigated the kinetic pressure effect on some specific Michael and Henry reactions and found that the observed activation volumes of the Michael reaction between nitromethane and methyl vinyl ketone are largely dependent on the magnitude of the electrostriction effect, which is highest in the lanthanide-catalyzed reaction and lowest in the base-catalyzed version. In the latter case, the reverse reaction is insensitive to pressure.52 Recently, Kobayashi and co-workers reported a highly efficient Lewis-acid-catalyzed asymmetric Michael addition in water.53 A variety of unsaturated carbonyl derivatives gave selective Michael additions with a-nitrocycloalkanones in water, at room temperature without any added catalyst or in a very dilute aqueous solution of potassium carbonate (Eq. 10.24).54... 

Quite recently, Bandini, Umani-Ronchi and coworkers also reported the highly enantioselective Henry reaction of the various trifluoromethyl ketones 54 with nitromethane catalyzed by the C6 -hydroxy quinine derivatives S3 (5 mol%) [24]. Various aliphatic and aromatic ketones were smoothly converted to the desired tertiary carbinols SS in high yields and ee values (up to 99%) without any significant electronic or steric demands (Scheme 8.17). The difluoroketones 56 proved just as useful as substrates (Scheme 8.18). Of note, the parent alkaloid, quinine, as a catalyst did not give rise to any asymmetric induction. 

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkylnitro compound reacts with an aldehyde or ketone to form a 3-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asymmetric catalysis has allowed this venerable reaction to contribute to a plethora of stereoselective aldol condensations. Reviews (a) Ballini, R. Bosica, G. Fiorini, D. Palmieri, A. Front. Nat.Prod. Chem. 2005, 1, 37-41. (b) Ono, N. In The Nitro Group in Organic Synthesis Wiley-VCH Weinheim, 2001 Chapter 3 The Nitro-Aldol (Henry) Reaction, pp. 30-69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. 

The nitroaldol (Henry) reaction involves the addition of nitronates to aldehydes and ketones to give a P-nitroalcohol. These products are usefrd synthetic building blocks as the nitro group can be transformed into a range of other functional groups, and this has stimulated some recent research into the development of a catalytic asymmetric variant. Some of the catalyst systems used in the asymmetric aldol rection have been successfully employed in the catalytic asymmetric nitroaldol process. 

One of the more reactive and selective catalysts of this type involves a bifunctional catalyst containing an alkali metal cation and an anionic lanthanide complex resulting from addition of excess binolate with lanthanide halides. Such catalysts have been used in asymmetric nitroaidol (Henry) reactions of ketones. Heterobimetallic Li-La alkoxo complexes (Figure 4.15) catalyzed these reactions with particularly high enantioselectivity. ... 

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

The asymmetric reaction of nitromethane with aldehydes as well as activated ketones (e.g., trifluoroacetophenone and a-ketoesters) is possible with various chiral metallic complexes or organocatalysts under atmospheric pressure with good yield and enantioselectivity. However, the Henry reaction of aryl alkyl ketones still remains problematic and challenging. Matsumoto s group also tested the very difficult reaction of acetophenone and nitromethane with quinidine. No product was observed under Ibar and only traces at 7 kbar, but application of 10 kbar resulted in a significant improvement in yield (31%) -unfortunately, no enantioselectivity was detected (Scheme 21.3). 

Fluorinated amino acids and amino alcohols have shown extensive biological activity [18]. In 2008, the Bandini and Umani-Ronchi group developed an efficient Henry reaction between nitromethane and fluoromethyl ketones catalyzed by cinchona alkaloids [19]. They showed that benzoylcupreines bearing electron-withdrawing substituents at the C9 position of the catalyst structure are essential for good results (Table 29.2,14 versus 15). Remarkably, comparable levels of asymmetric induction could be obtained with both aromatic and aliphatic ketones. 

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