Henry reaction 3-amino alcohols

The synthedc ndlity of the Henry reaction is shovm in Scheme 3.1, where fi-nitro alcohols are converted into fi-amino alcohols, amino sugars, ketones and other important compounds. 

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

Scheme 10.32 Cu-catalysed Henry reactions with thiolated amino alcohol ligands.

Nitro alcohols prepared by the Henry reaction are important precursors for (3-amino alcohols. The reduction of the nitro group to the amino function is commonly carried out by hydrogenation in the presence of Raney Ni in EtOH or Pd/C in THF and MeOH (see Section 4.2). The conversion into 3-amino alcohols is also described in the Sections 3.2.5 and 3.3. 

P-Nitro alcohols can be hydrogenated to the corresponding amino alcohols with retention of configuration the stereoselective Henry reaction is a useful tool in the elaboration of pharmacologically important P-amino alcohol derivatives including chloramphenicol, ephedrine, norephedrine, and others. Some important P-amino alcohols are listed in Scheme 3.11.107... 

They react with a wide range of aliphatic and aromatic aldehydes in the presence of catalytic amounts of tetrabutylammonium fluoride (TBAF) to give the trialkylsilyl ethers of P-nitro alcohols with high anti-selectivity (98%). The diastereoselective Henry reaction is summarized in Table 3.2. The products are reduced to P-amino alcohols using Raney Ni-H2 with retention of the configuration of P-nitro alcohols (Scheme 3.12). 

The nucleophilic addition of nitroalkane to carbonyl groups is known as the Henry reaction. The products of the Henry reaction are 2-nitroalkanols,115 which are useful intermediates for nitroalkenes, 2-amino alcohols, and 2-nitro-ketones. However, this does not always give high yields because of the possible O-alkylation in preference to C-alkylation during the Henry reaction. 

The nitroaldol (Henry) reaction constitutes a powerful C-C bond-forming process in organic chemistry, providing efficient access to valuable functionalized organic compounds such as 1,2-amino-alcohols, a-hydroxy-carboxylic acids and 3-hydroxy-nitroalkanes [215, 216]. 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,14 15 cf. the overview given in the Organic Syntheses preparation of nitroacetaldehyde diethyl acetal.16 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.14 18 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),19 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.20 21... 

The Henry nitro-aldol condensation involves the use of P-amino alcohols as the building blocks of fluoromethyl ketones. Although this method has been used extensively in the synthesis of monofluoropeptides (Table 2),19-121 it is more widely utilized as a method for synthesizing trifluoromethyl ketones and the details of the reaction will be discussed in Section 15.1.4.3.2. 

The asymmetric catalytic nitroaldol reaction, also known as the asymmetric Henry reaction, is another example of an aldol-related synthesis of high general interest. In this reaction nitromethane (or a related nitroalkane) reacts in the presence of a chiral catalyst with an aldehyde, forming optically active / -nitro alcohols [122], The / -nitro alcohols are valuable intermediates in the synthesis of a broad variety of chiral building blocks, e.g. / -amino alcohols. A highly efficient asymmetric catalytic nitroaldol reaction has been developed by the Shibasaki group, who used multifunctional lanthanoid-based complexes as chiral catalysts [122-125],... 

Nitroalkanols are intermediate compounds of /1-amino alcohols that are used extensively in many important syntheses. They are obtained by Henry s reaction through the condensation of nitroalkanes with aldehydes. Different nitro compounds have been reacted with carbonyl compounds in reactions catalysed by alkaline earth metal oxides and hydroxides/621 Among the catalysts examined, MgO, CaO, Ba(OH)2, and Sr(OH)2, exhibited high activity for the reaction of nitromethane with propionaldehyde. The yields were between 60 % (for MgO) and 26 % [for Sr(OH)2] at 313 K after 1 h in a batch reactor. The study of the influence of the pretreatment temperature of the solid showed that for MgO and CaO a... 

The nitroaldol (Henry) reaction, first described in 1859, is a carbon-carbon bondforming reaction between an aldehyde or ketone and a nitroalkane, leading to a nitroalcohol adduct [29]. The nitroalcohol compounds, synthetically versatile functionalized structural motifs, can be transformed to many important functional groups, such as 1,2-amino alcohols and a-hydroxy carboxylic acids, common in chemical and biological structures [18, 20, 30, 31]. Because of their important structural transformations, new synthetic routes using transition metal catalysis and enzyme-catalyzed reactions have been developed to prepare enantiomerically pure nitroaldol adducts [32-34]. 

Aliphatic nitro compounds are highly versatile building blocks in organic synthesis7 8 (see Scheme 1). For example, the nitroaldol addition (Henry reaction)9 leads to the formation of 1,2-nitro alcohols, 2, which are easily transformed into 1,2-amino alcohols, 3, by reduction, and into a-hydroxycarbonyl compounds, 4, by hydrolysis10 (Nef reaction). The former process, mostly using nitromethane, has been widely employed in carbohydrate chemistry.11... 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

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. 

Regarding the hydroxylation of nitroolefins, the reaction is performed under hydrogen-bonding catalysis using quinine-derived thiourea 170 (5 mol%), ethyl glyoxylate oxime as nucleophile in toluene at -24°C [374], This process, which constitutes a valid alternative to the Henry reaction, yields the corresponding hydroxylated nitrocompounds in good yields (63-83%) and enantioselectivities (48-93% ee) from ahphatic electrophiles (styrene derivatives are prone to retio-Michael addition) and has been successfully employed in the synthesis of optically active P-amino alcohols (Scheme 2.132) [375]. 

Chiral cyclopropane amino alcohols complexed to zinc catalyse enantioselective Henry reactions. ... 

Copper(II) and BINAP-derived amino alcohols catalyse Henry reactions in high yield, de, and ee ... 

A fascinating variant of the enzymatic cyanohydrin formation consists in the use of nitroalkanes (as nonnatural nucleophiles) instead of cyanide (Scheme 2.209) [1568,1569]. Overall, this constitutes a biocatalytic equivalent to the Henry-reaction producing vicinal nitro-alcohols, which are valuable precursors for amino alcohols. Using (5)-HNL, the asymmetric addition of nitromethane to benzaldehyde gave the nitroalcohol in 92% e.e., while for p-nitrobenzaldehyde the stereoselectivity dropped sharply. With nitroethane, two stereocenters are created Whereas the stereoselectivity for the alcoholic center was high (e.e. 95%), the recognition for the adjacent center bearing the nitro moiety was modest and other (dia)stereomers were formed in up to 8%. 

From aliphatic 2-nitroalkanols, readily accessible via the Henry reaction,i3i the reduction by aluminum amalgam also gives hydroxylamines as intermediates, further reduced to amino alcohols.i mildly basic conditions permit the acylation of the amino group, and the amino alcohols can be conveniently isolated as the N-acetyl or benzoyl derivatives. 

A syn- and enantio-selective Henry reaction employs copper(II) acetate and a chiral -amino alcohol catalyst. 

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