Nitronic acids Henry reaction

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). 

Polynitroaliphatic alcohols are invaluable intermediates for the synthesis of energetic materials (see Section 1.11). The most important route to /i-nitroalcohols is via the Henry reaction where a mixture of the aldehyde and nitroalkane is treated with a catalytic amount of base, or the nitronate salt of the nitroalkane is used directly, in which case, on reaction completion, the reaction mixture is acidified with a weak acid. Reactions are reversible and in the presence of base the salt of the nitroalkane and the free aldehyde are reformed. This reverse reaction is known as demethylolation if formaldehyde is formed. 

The Sowden homologation [21], based on the nitroaldol condensation (Henry reaction) [22] between the aldehydo sugar and nitromethane in basic medium, followed by the Nef decomposition [23] of the resultant nitronate in strongly acidic conditions, has been employed in a more limited number of cases than the cyanohydrin synthesis. A recent example in this area is shown by the stepwise homologation of (V-acetyl-D-mannosamine (11) into /V-acetylneuraminic acid (12) [24] (Scheme 4). Also, this procedure has found... 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

Asymmetric Aza-Henry Reactions of Nitronates with Imines. Although the Henry reaction and its aza-analogs are powerful C-C bond-forming reactions, there are few reports of catalytic asymmetric versions of these reactions. The cir-DiPh-Box copper complexes are excellent catalysts for highly diastereo and enantioselective aza-Henry reactions of a variety of trimethyl-silylnitronates with Af-(p-methoxyphenyl)-a-imino-esters (eq 3). The use of an A-(/ -methoxyphenyl) group for protection prevents undesirable side reactions and can be easily removed. The aza-Henry reaction products can be further derivatized to the corresponding a,3-diamino acids whose syntheses have rarely been reported. 

Knudsen, K. R., Risgaard, T., Nishiwaki, N., Gotheif, K. V., Jorgensen, K. A. The First Cataiytic Asymmetric Aza-Henry Reaction of Nitronates with imines A Novei Approach to Opticaiiy Active 3-Nitro-a-Amino Acid- and a, 3-Diamino Acid Derivatives. J. Am. Chem. Soc. 2001, 123, 5843-5844. 

It is reported that catalytic amount of Lewis acid promotes nitroaldo condensation of imine 49 with nitronates 50 to form 2-nitroamines 51, which can be reduced to diamines 52 with 15 1 syn/anti ratio after removal of the protection group. This seminal work just sets up the stage for the development of catalytic asymmetric aza-Henry reaction. For instance, copper based chiral Lewis acid with C2-symmetry 53 is used to promote addition of nitropropane to imine 54 to form intermediate 2-nitroamine 55 with high diastereo- and enantio-selectivities, which can be further elaborated to afford chiral diamine 56. ... 

A purely ionic hydrogen bond activation mechanism might be involved in the aza-Henry reaction between a-iminoesters, a very reactive subclass of imines, and various nitroalkanes catalyzed by the BINOL phosphoric acid 44 [54]. The corresponding P-nitro-a-amino acid esters were produced in good yields, diastereo- and enantioselectivities (Scheme 29.23). The authors postulated a dual role of catalyst 44 through activation of the a-iminoester by protonation and control over the nitroaUcane/nitronate equilibrium (Scheme 29.24). 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

The nitroaldol condensation with nitromethane (Henry s reaction), followed by Nef decomposition of the resultant nitronate under strongly acidic conditions, has been used to elongate aldehydes. For instance, A-acetyl-D-mannosamine has been converted into A-acetylneuraminic acid applying this method iteratively [69]. Chikashita and coworkers [70] have reported good levels of anti diastereoselectivity better than 99% in an iterative homologation sequence using 2-lithio-l,3-dithiane [71] with 2,3-O-cyclohexylidene-D-glyceraldehyde R)-62. In the case of the BOM-protected tetrose derivative, the addition of 2-lithio-l,3-dithiane was syn selective (synlanti 82 18) (Scheme 13.30). 

The nitroaldol condensation with nitromethane (Henry s reaction), followed by Nef decomposition of the resultant nitronate under strongly acidic conditions has been used to elongate aldehydes. For instance, A-acetyl-D-mannosamine has been converted into A-acetylneu-... 

The a-hydrogens of nitroalkanes are appreciably acidic due to resonance stabilization of the anion [CH3NO2, 10.2 CH3CH2NO2, 8.5]. The anions derived from nitroalkanes give typical nucleophilic addition reactions with aldehydes (the Henry-Nef tandem reaction). Note that the nitro group can be changed directly to a carbonyl group via the Nef reaction (acidic conditions). Under basic conditions, salts of secondary nitro compounds are converted into ketones by the pyridine-HMPA complex of molybdenum (VI) peroxide. Nitronates from primary nitro compounds yield carboxylic acids since the initially formed aldehyde is rapidly oxidized under the reaction conditions. 

A re-examination of proline-catalysed enantioselective Michael addition of aldehydes (R CH2CH0) with fran -nitroalkenes (R CH=CHN02) has identified a cyclobutane intermediate (109) derived from the reactants and catalyst. In situ NMR was used to discover the presence of (109) and to And that it represents a parasitic or resting state, arising from the iminium nitronate zwitterionic intermediate, siphoning it out of the productive catalytic cycle. Detailed kinetic studies also shed light on the role of acid catalysts and stability of the cyclobutanes (109) towards water and 0 aldehyde. For a similar possibly parasitic intermediate (72), see section titled The 0 Henry (Nitroaldol) Reaction . 

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