Nitroalkanes aldol condensations

The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. 

Kinetic template effects have been postulated in more typical organic aldol condensations, where metals such as lithium and zinc are likely to coordinate both the enolate or enamine nucleophile and the aldehyde in the transition state. The examples shown in Schemes 58184 and 59185 are illustrative of these reactions and the degree of selectivity obtained. The carboxylation of ketones and nitroalkanes by methyl magnesium carbonate to produce P-keto acids and a-nitro acids respectively provides early examples of similar reactions (Scheme 60).186 187 See also Section 61.1.4.4. 

The enolate A or the nitronate A, respectively, initially adds to the C=0 double bond of the aldehyde or the ketone. The primary product in both cases is an atkoxide, D, which contains a fairly strong C,H acid, namely, of an active-methylene compound or of a nitroalkane, respectively. Hence, intermediate D is protonated at the atkoxide oxygen and the C-fi atom is deprotonated to about the same extent as in the case of the respective starting materials. An OH-substituted enolate C is formed (Figures 13.52 and 13.53), which then undergoes an Elcb elimination, leading to the condensation product B. The Knoevenagel condensation and the aldol condensation have in common that both reactions consist of a sequence of an enolate hydroxy alkylation and an Elcb elimination. 

The acidifying effect of the nitro group is so profound that very mild bases can be used to catalyse the reaction. This enables selective removal of the proton next to the nitro group and helps to avoid side-reactions involving aldol condensations of the carbonyl component, Common examples include amines, quaternary ammonium hydroxides, and fluorides, Even basic alumina is sufficient to catalyse virtually quantitative addition of this benzylic nitroalkane to cyclohexenone at room temperature ... 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

Sitro-aldol reaction fl-amino alcohols. Primary nitro compounds form silyl nitronates (1) when treated in sequence with LDA (THF, -78°) and then a silylating reagent. These silyl nitronates undergo aldol condensation with aldehydes in the presence of tetra-n -butylammonium fluoride (there is no reaction in the absence of the catalyst). The products 2 are reduced to /3-amino alcohols (3) in good yield by lithium aluminum hydride (equation 1). Secondary nitroalkanes undergo the same reaction sequence, but the silyl nitronates are less stable and are obtained in only... 

Henry reaction Aldol condensation between nitroalkanes and carbonyl compounds to form 3-nitro alcohols. 202... 

Condensations. The aldol condensation of an aldehyde with a nitroalkane can be effected with the strongly basic IRA-400. ... 

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]. 

Synthesis of 3-nitro and derived 3-amino sugars by aldol condensation of sugar-derived dialdehydes with nitroalkanes (see 1st edition). 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

HENRY Nttro Condensation Aldol condensation of nitroalkanes with aldehydes. 

Silyl nitronates undergo aldol condensation with aldehydes in the presence of a catalytic amount of anhydrous TBAF to form highly diastereoselective erythro products, which can be elaborated to give synthetically useful 1,2-amino alcohols (eq 22). A one-pot procedure has been developed for direct aldol condensation of nitroalkanes with aldehydes by using TBAF trihydrate with Triethylamine and tert-ButyldimethylchlorosilaneP It appears that silyl nitronates are not reactive intermediates in this case, and the reactions proceed by a different mechanism... 

Jorgensen used p-ketoesters with a,p-unsaturated aldehydes for the construction of optically active 5-(triallq7lsilyl)cyclohex-2-enones. These compounds served as suitable starting material for other syntheses. Enders developed a domino nitroalkane-Michael addition/aldol condensation. This process provided an efficient asymmetric synthesis of trisubstituted... 

Enders et al. [54] developed an asymmetric organocatalytic domino reaction of y-nitroketones 83 and enals. The reaction, catalyzed by compound VII, renders the final cyclohexene 84 via a Michael-Aldol cascade reaction followed by dehydration, with moderate yields and diastereoselectivities and good enantioselectivities (Scheme 10.23). Two years later, the same research group reported a related reaction starting from 2-(nitromethyl)benzaldehyde [55]. The reaction proceeds via a domino nitroalkane-Michael-aldol condensation reaction that leads to the final 3,4-dihydronaphthalenes in excellent yields and enantioselectivities. 

Since aliphatic nitroalkanes are active methylene compounds, these may be used as starting materials for the preparation of more complex products by typical reactions of methylene compounds such as alkylations, aldol condensations, Michael condensations, and Mannich reactions. 

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... 

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