Ketones, Henry reaction aldehydes with

In the presence of a catalytic amount of tetrabutylammonium fluoride, either freshly dried over molecular sieves22 or as the trihydrate16, silylnitronates 2 derived from primary nitroalkanes react readily at — 78 C or below, via their in situ generated nitronates. with aromatic and aliphatic aldehydes to give the silyl-protected (/J, S )-nitroaldol adducts 3 in excellent yield4,22-24-26,27. Silylnitronates, derived from secondary nitroalkanes. afford the adducts in 30 40% overall yield24. In contrast to the classical Henry reaction (vide supra), the addition of silylnitronates to aldehydes is irreversible. Ketones are unreaetive under such conditions. 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

Unlike the Dakin-West and Henry nitro-aldol methods previously mentioned, the reaction of aldehydes with organometallics has only been used for the synthesis of peptidyl trifluoromethyl ketones. This method, along with the Henry nitro-aldol synthesis, eliminates the use of the toxic reagents required for the Dakin-West synthesis and starts with readily... 

Nitroalkanes having an a-hydrogen atom undergo aldol-type condensation with aldehydes and ketones in the presence of a base to give p-hydroxy nitro compounds or nitroethylene compounds. The reaction is known as the Henry reaction " or nitroaldol reaction. 

When aliphatic nitro compounds are used instead of aldehydes or ketones, no reduction occurs, and the reaction has been referred to as a Tollens reaction (see 16-43). However, the classical condensation of an aliphatic nitro compound with an aldehyde or ketone is usually called the Henry reaction or the Kamlet reaction, and is essentially a nitro aldol reaction. A variety of conditions have been reported, including the use of a silica catalyst, Mg—A1 hydrotalcite, a tetraalkylam-monium hydroxide,proazaphosphatranes, " or an ionic liquid.A solvent free Henry reaction was reported in which a nitroalkane and an aldehyde were reacted on KOH powder. Potassium phosphate has been used with nitromethane and aryl aldehydes. The Henry reaction has been done using ZnEt2 and 20%... 

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkyinitro compound reacts with an aldehyde or ketone to form a p-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asyimnetric 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. 

More recently, the use of high pressure with tetra-n-butylammonium fluoride as catalyst allowed these reactions to be accomplished with cyclic ketones. Thus, the Henry reaction of nitroalkanes with 3- and 4-methylcyclohexanones in THF at 30 C and 9 kbar (1 bar = 100 kPa) afforded fair to high yields (60-90% after 4 d) of the corresponding nitro alcohols, while with 2-methyIcyclohexanones it was possible to obtain addition products, although in moderate yields. These facts explain the modest utility of the Henry reaction as a chain-lengthening reaction when the carbonyl component is a ketone, but also show the difference in reactivity of aldehyde and ketone C==0 groups with respect to nitromethane, primary and secondary nitroalkanes in the presence of a base as catalyst. Such a difference in reactivity can be considered as the most evident chemoselectivity of this reaction. 

Scheme 6.3 Henry reactions of nitroalkanes with aldehydes or ketones...

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Aryl glyoxals, ArCOCHO, or their hydrates, ARCOCH(OH)2, as well as their aliphatic analogues, typically react with nucleophiles at the aldehyde carbon, but a chiral copper(II)-iminopyridine catalyst switches the reactivity, allowing Henry reaction at the ketone, and with high ee, giving a quaternary stereocentre in the product, without any specific protection of the aldehyde. ... 

In the forward direction, diene 5 was prepared by alkylation of metallated 1,3-dithiane 9 with allylic bromide 8. In this reaction, 9 plays the role of an acyl anion equivalent . We will talk about equivalencies in more detail in Chapter 6, but at this point it is worth noticing that the dithiane will eventually emerge as the C15 protected ketone. Dienophile 4 was prepared by an aldol-dehydration reaction between nitromethane and aldehyde 10, a reaction known as the Henry reaction. The Diels-Alder reaction between 4 and... 

The Henry reaction, or nitroaldo reaction, is one of the classic carbon-chain formation methods utilized in organic synthesis. It involves the condensation of nitroalkanes with aldehydes or ketones in the presence of bases (often catalytic amount) to afford the mixtures of diastereomeric 2-nitroalcohols, which in turn can be converted into other useful synthetic intermediates, such as 2-aminoalcohols, a-hydroxyketones, homologous ketones, and perhaps most importantly, nitroalkenes through various functional transformations. 

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). 

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. 

The enantioselective Henry reaction with ketones is challenging, owing to the attenuated reactivity of the ketone carbonyl group compared to the aldehyde carbonyl moiety and the high tendency of tertiary nitro-aldol adducts to undergo a retro-addition reaction under basic conditions [15], Stereoselective construction of... 

Phosphonium ionic liquids exchanged with bicarbonate and methylcarbonate anions have been found to catalyse efficiently the Henry addition of nitroalkanes to different aldehydes and ketones under solventless conditions. These ionic liquids not only allow the selective formation of nitroaldols but also unlock a novel high-yielding access to dinitromethyl derivatives of ketones. The reaction mechanism plausibly involves the transformation of the initial catalytic species [MeP(Octyl)3+ ROCOO R= Me, H] through reversible loss and uptake of carbon dioxide. 

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