Aldol and Nitroaldol Henry Reactions

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. 

I 28 Aldol and Mannich-Type Reactions Table 28.8 Brensted base catalyzed nitroaldol (Henry) reactions. 

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. 

The basic character of lanthanide alkoxides such as Lu3(Of-Bu)9 seem to effect aldol, cyanosilylation, aldol, and Michael reactions [111]. Complexes 2 and 22, abbreviated as LnMB (Ln = lanthanide, M = alkali metal, B = BR IOL) [112] were thoroughly studied in the catalytic, asymmetric nitroaldol reaction (Henry reaction eq. (10)) [113]. 

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. 

Related to the aldolization reaction is the Mannich reaction, which proceeds readily in water [193]. Allylsilanes [194] and allylstannanes [131] were also shown to add to iminium salts under Mannich-like conditions. As for the Mukaiyama reaction, the reaction between a vinyl ether with iminium salts was catalyzed by ytterbium triflate in a water/THF mixture. The Henry reaction which can be performed in an aqueous medium has been made more efficient in the presence of surfactants. The nitroaldol products were obtained in 65 -95 % yields [195]. 

The Henry reaction is an aldol-type reaction between a nitroalkane and an aldehyde in the presence of a base. Since basic reagents are also catalysts for the aldol condensation, the nitroaldol reactions must be strictly controlled. An interesting alternative lies in the use of surfactants to perform the reaction in an aqueous medium [63], The Reformatsky reaction, which involves a-haloketones and aldehydes, can be mediated by zinc, tin or indium in water in the latter case the proportion of undesirable reduction products could be strongly reduced [64]. 

Nitroaldol Reaction (The Henry Reaction). The nitroaldol reactions (or Henry reaction) is an aldol type reaction between a nitro compound and a carbonyl compound. The primary aldol products may be dehydrated to the corresponding alkenes. 

To start with the first option of such a chemoenzymatic process sequence, namely initial biotransformation and subsequent chemocatalytic or classical chemical reaction(s), an early example from the Gijsen and Wong [40] already in 1995 demonstrated a one-pot process for the synthesis of a cyclitol, which is based on an initial enzymatic aldol reaction of aldehyde 37 with 0-monophosphorylated dihy-droxyacetone, followed by a subsequent spontaneous cyclization via intramolecular Horner-Wadsworth-Emmons olefination reaction (Scheme 19.14). Furthermore, the resulting functionalized cyclopentene derivative 39 was deprotected in situ in the presence of an added phosphatase. By means of this one-pot three-step process, the desired trihydroxylated cyclopentene derivative 40 was formed, which was then further transformed via acetylation into the desired product 41 with an overall yield of 71%. A closely related process represents the combination of an enzymatic aldol reaction with a subsequent nitroaldol reaction (Henry reaction). Examples for such a type of process were developed independently by the Wong [41] and Lemaire [42] groups. 

With regard to asymmetric aldol reactions, it has been shown that prolinamine catalysts such as 22 can also work well for intramolecular aldol [126-128], Henry (nitroaldol) [129], Mannich [130, 131], and domino-Michael-aldol reactions [132] as valuable asymmetric transformations. 

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 Henry (nitroaldol) reaction was reported under very mild reaction conditions, in aqueous media using a stoichiometric amount of a nitroalkane and an aldehyde, in NaOH 0.025 M and in the presence of cetyltrimethylammonium chloride (CTAC1) as cationic surfactant (Eq. 8.94) 240 Good to excellent yields of (i-nitroalkanol are obtained. Under these conditions several functionalities are preserved, and side-reactions such as retro-aldol reaction or dehydration of 2-nitroalcohols are avoided. 

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