Aldol reaction alternative

A two-step sequence of nitrile oxide-olehn cycloaddition and reduction of the resulting A -isoxazolines offers a unique and attractive alternative to the classical aldol reaction and its many variants (2J). The procedure bypasses traditional problems, including enolate equilibrium and cross condensation (20). 

Figure 23.4 Intramolecular aldol reaction of 2,5-hexanedione yields 3-methyl-2-cyclopentenone rather than the alternative cyclopropene.

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

Enantioselective nitro-aldol reaction (see Section 3.3) or Michael reaction (see Section 4.4) followed by radical denitration is useful as an alternative indirect method of enantioselective 1,2- or 1,4-addition of alkyl anions (see Eq. 7.7087 and Eq. 7.7188). 

Alternatively deprotonation of C4 makes it nucleophilic, and an aldol reaction and dehydration by Elcb... 

An alternative approach to mixed aldol reactions, and the one usually preferred, is to carry out a two-stage process, forming the enolate anion first using a strong base like EDA (see Section 10.2). The first step is essentially irreversible, and the electrophile is then added in the second step. An aldol reaction between butan-2-one and acetaldehyde exemplifies this approach. Note also that the large base EDA selectively removes a proton from the least-hindered position, again restricting possible combinations (see Section 10.2). 

A similar aldol reaction is encountered in the Krebs cycle in the reaction of acetyl-CoA and oxaloacetic acid (see Section 15.3). This yields citric acid, and is catalysed by the enzyme citrate synthase. This intermediate provides the alternative terminology for the Krebs cycle, namely the citric acid cycle. The aldol reaction is easily rationalized, with acetyl-CoA providing an enolate anion nucleophile that adds to the carbonyl of oxaloacetic acid. We shall see later that esters and thioesters can also be converted into enolate anions (see Section 10.7). 

Alternatively, and much more satisfactory from a synthetic point of view, it is possible to carry out a two-stage process, forming the enolate anion first. We also saw this approach with a mixed aldol reaction (see Section 10.3). Thus, ethyl acetate could be converted into its enolate anion by reaction with the strong base EDA in a reaction that is essentially irreversible (see Section 10.2). 

Since 2000, remarkable advances in the ntility of the enamine-catalyzed aldol reaction have been made [83]. A massive effort has been devoted to the development of more effective variants of prohne [13, 26, 64, 68, 84-174]. In addition, alternative amino acids and peptides bearing primary amino groups [175-184] as... 

Silylacetals of difluoroketene have an important synthetic potential and constitute an alternative to the Reformatsky reagent generated from ethyl bromodifluoroace-tate." They are prepared by reduction by a bromo-, iodo-di-, or trifluoroacetate in the presence of a trialky Isilylchloride. Despite the fact that they are difficult to prepare, they behave similar to their nonfluorinated analogues (aldolization reactions, conjugated addition, etc.) (Figure 2.27)." ... 

Superheated and supercritical water are used in several applications. Supercritical water is most often used in the destruction of organic wastes, including some chemical warfare agents, as an alternative to incineration (Katritzky et al., 1996 Sherman et al., 1998). Recent reports describe the use of both forms as a solvent and as a reactant in synthetic chemistry (Katritzky et al., 1996 An et al., 1997). Some of the reactions investigated include metal-mediated alkyne cyclizations, Pd-catalyzed al-kene arylations, aldol reactions, the Fischer indole synthesis, and hydrolysis reactions. Waterborne coatings and the destruction of wastes in supercritical water are fully... 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

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