Nitronates, Henry reaction

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. 

In general, the Henry reaction proceeds in a non-selective way to give a mixture of anti (erythro) and syn (threo) isomers. Ab initio calculations on the Henry reaction suggest that free nitronate anions (not influenced by cations) react with aldehydes via transition states in which the nitro and carbonyl dipoles are antiperiplanar to each other. This kind of reaction yields anti-nitro alcohols. The Henry reaction between lithium nitronates and aldehydes is predicted to occur via cyclic transition states yielding syn-nitro alcohols as major products (Eq. 3.64).108... 

Bicyclic trimethylsilyl nitronates undergo stereoselective Henry reactions with benzalde-hyde in the presence of fluoride ion to give cyclic hemiacetals in good yield with high diastereo-selectivity (95% ds) (Eq. 3.68).110... 

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). 

Silyl Nitronates in Henry Reactions Topologically, condensations of SENAs with carbonyl and nitroso groups, as well as with an imino fragment, belongs to Henry reactions. 

Few of these studies (460, 462) dealt with the Michael reaction one study (461) with the Henry reaction. The efficiency, stereoselectivity, and enantiose-lectivity of this process are rather high. The mechanism of the transformations is poorly known. Presumably, the chiral cation should shield the Si surface of nitronate, thus providing the Re approach of the substrate. In addition, the approach of the reagents, resulting in generation of syn isomers, is considered less favorable than the approach yielding anti isomers. 

The classical Henry reaction conditions (base catalyzed addition) have some drawbacks sometimes the nitro alcohols are obtained in low yields and diastereoselectivities are not always high. To improve these results, a number of modifications were introduced. One of them is the Seebach s silyl nitronate method,25 that involves a reaction between an aldehyde with a silyl nitronate prepared by metalation of the corresponding nitro alkane with LDA, followed by reaction of the resulting nitronate with tert-butyldimethylsilyl chloride.26... 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

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. 

Ooi has recently reported application of chiral P-spiro tetraaminophosphonium salt 37 as a catalyst for the highly enantio- and diasterioselective direct Henry reaction of a variety of aliphatic and aromatic aldehydes with nitroalkanes (Scheme 5.51) [92]. Addihon of the strong base KO Bu generates in situ the corresponding catalyhcally active triaminoiminophosphorane base A. Ensuing formation of a doubly hydrogen-bonded ion pair B positions the nitronate for stereoselective addition to the aldehyde. This catalyst system bears many similarities to guanidine base catalysis. 

The authors interpreted the outcome of these Henry reactions with an activation of the aldehyde component through double hydrogen-bonding interactions with the thiourea moiety facilitating the product-forming nucleophilic attack of the in situ generated nitronate (Scheme 6.162) [319]. 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

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. 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

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. 

Significant improvements to the Henry reaction have been achieved by using silyl nitronates and catalytic amounts of fluoride ion or, alternatively, a,a doubly deprotonated primary nitroalkanes. Both of these procedures, discovered by the Seebach group, have proved to be useful for the stereoselective preparation of vicinal amino alcohols. 

A stereoselective Henry reaction has also been observed between bicyclic trimethylsilyl nitronates and benzaldehyde with fluoride ion as the catalyst. The reaction results in the formation in high yield of a cyclic hemiacetal (equation 20) and is highly diastereoselective (95% ds)P-... 

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