Reversibility unsymmetrical ketones

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

It has long been known that unsymmetrical ketones can be prepared by the reaction of aldehydes with alkenes under free-radical reaction conditions. Recently the revision of this chemistry has been reported by the Roberts group [42], They introduced thiols as a polarity reversal catalyst for the addition of aldehydes to alkenes. Thiyl radicals are electrophilic, and therefore a polar Sh2 type transition state for the hydrogen transfer step from an aldehyde would be ideal in this situation. Indeed, the addition of aldehydes to a variety of alkenes can be effected by... 

A similar trend may be seen in a study of the reaction of chloral with unsymmetrical ketones (equation S3 Table 3). Reactions were carried out in glacial acetic acid with or without added sodium acetate as catalyst. Several control experiments showed that the isomer ratios obtained were kinetic. The lack of reversibility in this reaction implies that AG is much more negative than for the simple aldol reactions discussed previously. This is presumably because of the inductive effect of the chlorines, which is known to favor hydration and other nucleophilic additions to chloral. 

The stereochemistry of the Peterson reaction has been investigated. When unsymmet-rically substituted a-silylcarbanions react with aldehydes or unsymmetric ketones, E or Z olefins are produced. In many cases the E Z ratio is 1 1, however, some workers have reported a predominance of cis olefins when aldehydes are employed. Typical results are given in Table 15. Unlike the Wittig reaction the stereochemical outcome of the Peterson reaction is insensitive to counterion, solvent, added salts and temperature255. Stereochemical control of the Wittig reaction usually depends upon the reversibility of the first step. However, as discussed earlier, the first step of the Peterson reaction is irreversible. Thus the stereochemical outcome is determined solely by the relative rates of formation of threo and erythro 0-silyl alkoxides (/ct and k in Scheme 5). 

The idea of kinetic versus thermodynamic control can be illustrated by a brief discussion of the formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and is discussed more fully in Chapter 6 and in Section 1.1.2 in Part B. Most ketones can give rise to more than one enolate. Many studies have shown that the ratio among the possible enolates that are formed depends on the reaction conditions. " This can be illustrated for the case of 2-hexanone. If the base chosen is a strong, sterically hindered one, such as lithium diisopropylamide, and the solvent is aprotic, the major enolate formed is 3 in the diagram below. If a protic solvent or a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Under these latter conditions, equilibration can occur by reversible formation of the enol. Enolate 3 is the kinetic enolate, but 2 is thermodynamically favored. 

With unsymmetrical ketones, a mixture of regioisomeric enolates may be formed, resulting in a mixture of Michael adducts. Deprotonation in a protic solvent is reversible and leads predominantly to the thermodynamically favoured, more-substituted enolate. Reaction with a Michael acceptor then gives the product from reaction at the more-substituted side of the ketone carbonyl group. The 1,5-dicarbonyl compound 24 is the major product from conjugate addition of 2-methylcyclohexanone to methyl acrylate using potassium tert-butoxide in the protic solvent tert-butanol (1.39). In contrast, the major product from Michael addition... 

Allenic esters readily react with dialkylzinc reagents in the presence of DIFLUORPHOS-complexed copper (from Cu(OAc)2) in THF at -20 While this initial adduct bears no new central chirality, the intermediate nonracemic copper/zinc enolate can then add in a stereocontrolled 1,2-fashion to unsymmetrical ketones. Ring closure to the resulting S-lactone completes the sequence. Both 4 A molecular sieves and 20 mol% Lewis basic Ph2S=0 (or DMSO, hexamethylphosphoramide [HMPA]) are required to direct attack at the y-position rather than the otherwise reversible aldol event at the a-site, thereby facilitating conversion to cyclic products. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

Ketones can present a problem in specificity. Under basic conditions, they may react with two or more molecules of the electrophile to give a mixture of products. Furthermore, unsymmetric ketones may present a choice of two enolate sites so that control is necessary to direct to the desired one. Many alternatives have been developed for this problem. One solution is to incorporate a temporary group on one enolate site to render that site more acidic so that the electrophile will react there. The familiar p-ketoester reactions (acetoacetic ester synthesis) are widely used. For another alternative, the ketone is first converted to an imine (Section 6.2.3) or a dimethyl hydrazone, and the enolate of that derivative is used with electrophiles [28]. Stereospecificity of the addition is obtained by forming a derivative with (5)-l-amino-2-methoxymethyl-pyrrolidine (SAMP) as shown in Equation 7.15 [29]. Without derivati-zation, alkylation of unsymmetric ketones will occur mostly at the more substituted enolate site under reversible deprotonating conditions. Using a base such as EDA will give alkylation primarily at the least substituted enolate. 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

The original ketone here is unsymmetrical, so two enamines are possible. However, the formation of solely the less substituted enamine is typical. The outcome may be explained as the result of thermodynamic control enamine formation is reversible so the less hindered enamine predominates. 

Noyori was subsequently able to show that triethylamine salts of formic acid (TEAF) could be used to reduce ketones to alcohols and imines to amines with high enantioselectivities [4]. The byproduct of this reaction is carbon dioxide gas and this prevents the possibility of the reverse reaction. Strangely, aminoalcohol ligands are poor in this reaction, whilst unsymmetrical 1,2-diamines have proven very effective. A particularly effective ligand is mono-N-tosyl-l,2-diphenylethylene-diamine. 

In a regiochemical investigation of the reaction of iminium salt (32) with a series of unsymmetrical methyl ketones, Jasor et al. have observed that the site of aminomethylation is solvent dependent (equation 7, Table S). It is found that in MeCN, reaction occurs exclusively at the least-substimted position, while in TFA it occurs mainly at the most-substituted position. Yields are good (70-90%) in TFA but are somewhat reduced in MeCN due to dialkylation, which can be overcome if the more bulky NA -diisopro-pyliminium salt is used. How the solvent influences the two possible rate-determining steps, enolization versus aminomethylation, and the extent of reversibility of the reaction need further investigation in order to determine the basis for the observed dichotomy in regiochemistry. 

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