Nitroaldol mechanism

Molecular modeling studies revealed a similar binding mode for (5)-2-nitro-1 -phenylethanol in the catalytic center of ///)HNL as was determined experimentally for (5)-mandelonitrile, preserving all mechanistically important polar interactions with active-site residues. This implies that the mechanism for the cyanohydrin reaction applies to the nitroaldol reaction as well. 

Scheme 4. Possible mechanism of catalytic asymmetric nitroaldol reaction.

Shibasaki et al. have reported an asymmetric nitroaldol reaction catalyzed by chiral lanthanum alkoxide 18 to produce an optically active 2-hydroxy-1-nitroalkane with moderate-to-high enantiomeric excesses (Scheme 8B1.10) [27]. Apparently this novel catalyst acts as Lewis base. The proposed reaction mechanism is shown in Scheme 8B1.11, where the first step of the reaction is the ligand exchange between binaphthol and nitromethane. This reaction is probably the first successful example of the catalytic asymmetric reaction promoted by a Lew i s base metal catalyst. Future application of this methodology is quite promising. 

The compound 3 can be easily prepared, in one pot, through a solvent-free procedure by nitroaldol reaction of nitroalkane 1 (2.2 mmol) and aldehyde 2 (2.2 mmol, freshly distilled), on activated neutral alumina (0.6 g, the alumina was added to a mechanically stirred solution of 1 and 2, at 0°C, then at room temperature for 20 h). Then, in situ addition (0°C) of wet-alumina supported chro-mium(VI) oxide (0.88 g (8.8 mmol) of C1O3 and 2.64 g of wet alumina). After standing for additional 20 h, the product was extracted with diethyl ether and passed through a bed of alumina. Evaporation of the organic solvent and flash chromatographic purification afforded the pure a-nitro ketone 3 in good yields (68-86%). 

The LLB catalysts described above served an important role in demonstrating the proof of principle for catalysis with lanthanide-BINOL complexes. In addition, they were the first catalysts for the enantioselective nitroaldol reaction and gave respectable selectivities in synthetically useful yields. However, the reactions required at least 3.3 mol % of the catalysts for efficient conversion, and at that loading the reactions are rather slow. Clearly, the need for more effective catalysts is indicated. Consideration of the mechanism for the catalytic asymmetric... 

Figure 24. A possible mechanism for catalytic asymmetric nitroaldol reactions.

Figure 25. Proposed mechanism for the catalytic asymmetric nitroaldol reaction promoted by LLB, LLB-II, or LLB-Li-nitionate.

Catalytic asymmetric nitroaldol reactions promoted by LLB or its derivatives require at least 3.3 mol % asymmetric catalyst for efficient conversion, and even then the reactions are rather slow. To enhance the activity of the catalyst, consideration of the possible mechanism of catalytic asymmetric nitroaldol reactions is clearly a necessary prerequisite to formulation of an effective strategy. One possible mechanism of catalytic asymmetric nitroaldol reactions is shown at the top of Sch. 10. We strove to detect the postulated intermediate I by use of a variety of methods, but were unsuccessful, probably owing to the low concentrations of the intermediate, which we thought might be ascribed to the presence of an acidic OH group in close proximity. 

The proposed mechanism for the asymmetric nitroaldol reaction catalyzed by heterobimetallic lanthanoid complexes is shown in Scheme 2 [9]. In the initial step, the nitroalkane component is deprotonated and the resulting lithium nitr-onate coordinates to the lanthanoid complex under formation of the intermediate I [ 10]. Subsequent addition of the aldehyde by coordination of the C=0 double bond to the lanthanoid(III) ionic center leads to intermediate II, in which the carbonyl function should be attacked by the nitronate via a six-membered transition state (in an asymmetric environment). A proton exchange reaction step will then generate the desired optically active nitroalkanol adduct with regeneration of the free rare earth complex LnLB. 

The proposed mechanism for the asymmetric nitroaldol reaction catalyzed by heterobimetallic lanthanoid complexes is shown in Scheme 2 [5]. In the initial step, the nitroalkane component is deprotonated and the resulting lithium nitronate coordinates to the lanthanoid complex under formation of the inter-... 

Catalytic enantio- and diastereoselective nitroaldol reactions were explored by using designed guanidine-thiourea brfunctional organocatalysts like 15 (Figure 4.4) under mUd and operationally simple biphasic conditions. These catalytic asymmetric reactions have a broad substrate generality with respect to the variety of aldehydes and nitroalkanes [43]. On the basis of studies of structure and catalytic activity relationships, a plausible guanidine-thiourea cooperative mechanism and a transition state of the catalytic reactions are proposed. 

The standard aldol reaction involves the addition of an enolate to a ketone or an aldehyde. However, there are related processes and this chapter includes subsections on the isocyanide aldol, nitroaldol and Morita-Baylis-Hillmami reaction. In addition there are reactions involving additions of enolates to the C=N group and a large subsection is devoted to a discussion of the catalytic asynmietric Mamiich reaction. As well as these mechanistically related processes, the carbonyl-ene reaction is also discussed here. Whilst the mechanism of the carbonyl-ene reaction is different from the aldol reaction, the synthetic result is rather similar, and perhaps fits most comfortably into this chapter. 

For example, using LnM3(binapthoxide)3 (M = Li, Na) as catalysts, the yields for the nitroaldol reaction are veiy similar, but the ee value is 94% for Li compound, and only 2% for Na compound. The proposed mechanism for the catalytic asymmetric nitroaldol reaction is shown in Scheme 7. 

Although heterobimetallic complexes afforded nitroaldol adducts in good stereoselectivity, most reactions required a long reaction time even with relatively high catalyst loadings (3-10 mol%). To achieve a more efficient catalysis, a strategy to accelerate the reaction was investigated. A plausible mechanism of catalytic asymmetric nitroaldol reaction is shown in Scheme 13.42. The concentration of intermediate (A) was considered to be rather low in the reaction mixture because of an... 

Phosphonium ionic liquids exchanged with bicarbonate and methylcarbonate anions have been found to catalyse efficiently the Henry addition of nitroalkanes to different aldehydes and ketones under solventless conditions. These ionic liquids not only allow the selective formation of nitroaldols but also unlock a novel high-yielding access to dinitromethyl derivatives of ketones. The reaction mechanism plausibly involves the transformation of the initial catalytic species [MeP(Octyl)3+ ROCOO R= Me, H] through reversible loss and uptake of carbon dioxide. 

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