Aldehydes nitroalkanes

In general, base-catalyzed reactions of aromatic aldehydes with nitroalkanes give nitroalkenes directly (Knoevenagel reaction).54 The reaction is very simple heating a mixture of aromatic aldehydes, nitroalkanes, and amines in benzene or toluene for several hours using a Dean-Stark water separator gives the desired nitroalkenes in good yield, as shown in Eqs. 3.31-3.34.54-58... 

Entry Aldehyde Nitroalkane Catalyst Time (h) Temp (°C) Nitro- aldols Yield (%) syn/anti ee of syn %)... 

After having optimized the reaction conditions, aldehydes, nitroalkanes and benzyl bromides were varied systematically. In total, 40 isoxazolines were synthesized in parallel, with purities ranging from 52% to 90%. Only one regioisomer was formed as a mixture of diastereomers during the reaction this was shown by 2D-NMR. Scheme 6.7 shows some representative structures, with the corresponding HPLC-purities (A, = 214 nm). 

The above are examples of the Claisen - Schmidt reaction. The formation of p-nitrostyrenes by reaction of nitroalkanes with aromatic aldehydes in the presence of aqueous alkali may be included under the Claisen- hmidt condensation ... 

Higher nitroalkanes are prepared from lower primary nitroalkanes by a one-pot synthesis (69). Successive condensations with aldehydes and acylating agents are followed by reduction with sodium borohydride. Overall conversions in the 75—80% range are reported. 

Titanium alkyls, known as tamed Grignard reagents, do not add to esters, nitriles, epoxides, or nitroalkanes at low temperatures. Rather, they add exclusively ia a 1,2 fashion to unsaturated aldehydes (208—210). 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

Method A ct,ct-Donbly deprotonated nitroalkanes react with aldehydes to give intermediate nitronate alkoxides, which afford iyti-nitroalcohols as major products d8 7-47 3 by kmedc protonadon at -100 C in THF-HMPA. The carcinogenic hexamethylphosphorons triamide fHMPAi can be replaced by the ntea derivadve (T)MPU. ... 

Method G Highruiri-selecdvity is also observed in the fluoride-catalyzed reacdonof silyl nitronates v/ith aldehydes. Trialkyl silyl nitronates are prepared in good yield from primary nitroalkanes by consecndve treatment v/ith iithiiim dusopropylamide and trialkylsilyl chloride at -78 C in THF. 

To a stirred mixture of 0.2 mol of the nitroalkane, 7.8 mL of EtOH and 0.39 mL of 10 N aq sodium hydroxide is added 0.2 mol of the freshly distilled aldehyde, with the temperature being maintained at 30 35 C. After approximately two thirds of the aldehyde has been added, an additional 0.39 mL of 10 N aq sodium hydroxide and 1.5 mL of water are added, then the aldehyde addition is continued. The mixture is stirred at 38 C for 65 h and is then treated with ca. 4 mL of 2 N aq hydrochloric acid to pH 7. It is extracted with hexane and the combined extract is washed with three 50-mL portions of water and sat. aq NaCl, dried over MgSOj and evaporated to give the crude nitroaldol which is purified by bulb-to-bulb distillation. 

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 practice, the condensation of nitroalkane (60) and aldehyde (59) gives nitro lactone (57) directly. Synthesis ... 

Light and permanent gases, low molecular weight acids, alcohols, glycols, ketones, hydrocarbons, esters, nitriles and nitroalkanes. Amines, amides, alcohols, aldehydes, hydrazines and ketones. 

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. 

The 3-nitro alcohols are generally obtained in good yield by the reaction of aldehydes with nitroalkanes in the presence of a catalytic amount of base. When aryl aldehydes are used, the (3-nitro alcohols formed may undergo elimination of water to give aryl nitroalkenes. Such side reactions are not always disadvantageous, for nitroalkenes are sometimes the ultimate target for the Henry reaction. The choice of reaction conditions is important to stop the reaction at the stage of 3-nitro alcohols in aromatic cases. 

Dendritic molecules with a single triethylene amine core surrounded by hyperbranched polyether sectors catalyze the nitro-aldol reaction between aromatic aldehydes and nitroalkanes (Eq. 3.5).15 The activity of the catalysts decreases when the generation number increases. No significant changes in stereo-control are observed on passing from lower- to higher-generation dendrimers. 

The nitro-aldol reaction can also be carried out in water using NaOH in the presence of cetyltrimethylammonium chloride (CTAC1) as a cationic surfactant. CTAC1 (5 mmol) is added to a mixture of nitroalkane (50 mmol) and aldehyde (50 mmol) in NaOH 0.025 M (150 mL) at room temperature. The mixture is stirred for 2-3 h and worked up to give the product in 70-90% yield. Compared with the classical methods, this procedure has economical and environmental advantages (Eq. 3.16).27... 

A1203 can be used both as a base for the Henry reaction and as a dehydrating agent. Thus, nitroalkenes are simply prepared by mixing of aldehydes and nitroalkanes with A1203 and subsequent warming at 40 °C (Eq. 3.30).53... 

Nitromethylation of aldehydes has been carried out in a one pot procedure consisting of the Henry reaction, acetylation, and reduction with sodium borohydride, which provides a good method for the preparation of l-nitroalkanes.16b 79 It has been improved by several modifications. The initial condensation reaction is accelerated by use of KF and 18-crown-6 in isopropanol. Acetylation is effected with acetic anhydride at 25 °C and 4-dimethylaminopyridine (DMAP) as a catalyst. These mild conditions are compatible with various functional groups which are often... 

An experimentally simple procedure for stereoselectively preparing P-nitro alcohols has been developed. The alkyl nitronates, formed by the action of n-butyllithium on nitroalkanes in THF solution, react with aldehydes in the presence of isopropoxytitanium trichloride at room temperature to give the P-nitro alcohols enriched in the anri-diastereoisomers (Eq. 3.71).112... 

The addition of alkoxides to 2-nitro-l-phenylthio-l-alkenes affords P-nitro-aldehyde acetals.276 The reaction of the same nitroalkenes with amines gives nitroenamines.270 They are important intermediates for organic synthesis and are generally prepared by the reaction of nitroalkanes with triethylorthoformate in the presence of alcohols or secondary amines.2"1 0 The methods of Eqs. 4.20 and 4.21 have some merits over the conventional methods, for variously substituted (3-nitro-aldehydes acetals or nitroenamines are readily prepared by these methods. 

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). 

The Nef reaction of primary nitro compounds gives aldehydes or carboxylic acids, depending on the reaction conditions. Each transformation provides an important tool in organic synthesis. Primary nitro compounds are converted into carboxylic acids with concentrated mineral acids.22 Because such harsh conditions also lead to side reactions, a milder method is required in organic synthesis. Basic phosphate-buffered KMn04 rapidly converts primary nitroalkanes into carboxylic acids in 90-99% yield (Eq. 6.13).23... 

Recently, ///)H.YL has been found to catalyze the stereoselective addition of nitroalkanes to aldehydes in an. S -selective fashion, which is in agreement with the known stereopreference of this enzyme. This is the first example for a substitution of HCN by another carbon nucleophile, expanding the synthetic scope of this biocatalytic transformation. The addition of nitromethane to different aldehydes with moderate to good yields and enantioselectivity has been demonstrated (Figure 5.9) [58]. However, large amounts of enzyme are required to... 

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