Aldehyde acid catalysed enolization

A study of acid-catalysed enolization and carbon-acid ionization of isobutyrophenone has combined the solvent isotope effect k /kv = 0.56 and substrate isotope effect kH/kD = 6.2 determined for the enolization in H2O and D2O with literature information in order to estimate the solvent isotope effect on the enolization equilibrium, A e(H20)/A e(D20) = 0.92, and on the CH ionization of butyrophenone, kf (R20)/kK(D20) = 5.4.130 This is the first report of an isotope effect on AY forketo-enol equilibrium of a simple aldehyde or ketone. 

Enolization is, in fact, quite a slow process in neutral solution, even in D2O, and we would catalyse it with acid or base if we really wanted it to happen. In the acid-catalysed reaction, the molecule is first protonated on oxygen and then loses the C-H proton in a second step. We shall use a different example here to show that aldehydes form enols too. acid-catalysed enolization of an aldehyde... 

Trimethylsilylation of enolizable carbonyl compounds and alcohols has also been accomplished by the fluoride ion promoted reaction with hexamethyldisilane and ethyl trimethylsilylacetate [48, 49], with high stereospecificity giving Z-enol ethers from ketones [50]. l-Trimethylsilyl-(l-trimethylsilyloxy)alkanes, produced from the reaction of aldehydes with hexamethyldisilane, undergo acid-catalysed hydrolysis during work up to yield the trimethylsilylcarbinols [51]. In the case of aryl aldehydes, the initially formed trimethylsiloxy carbanion produces the pinacol (Scheme 3.1). 

Concerted acid-base catalysed enolizations of a range of simple aldehydes and ketones have been measured in water at 25 °C, using a range of substituted acetic acid-acetate buffers.The buffer plots yield rate constants for acid (A a) and base ( b) catalytic terms in the normal way at low buffer concentrations. Extension up to higher concentrations (as far as [total buffer] = 2 m, typically) yields the third-order term ( ab) via upward curvature of the plots. While ab does not have a simple correlation with either k or b, it does correlate with their product, i.e. 

Protonation of glycerol 6.4 catalyses dehydration via secondary carbonium ion 6.5 to give enol 6.6. Acid catalysed elimination of a second water molecule affords acrolein 6.7. Thus glycerol acts essentially as a protected form of acrolein, slowly releasing this unstable a,p unsaturated aldehyde into the reaction medium. Better yields are realised with this approach than if acrolein itself is present from the start. The reaction proceeds with a Michael addition of aniline 6.3 to acrolein, producing saturated aldehyde 6.8 which cyclises via an aromatic substitution reaction to alcohol 6.9. Acid-catalysed dehydration to 6.10 then oxidation yields quinoline 6.1. Nitrobenzene can be used as a mild oxidant, as can iodine and ferric salts. 

If the enol component is an aldehyde, none of these methods will do and enamines or silyl enol ethers are the best choice. Enamines are excellent nucleophilic components and the iminium ion that is formed in die conjugate addition can provide the electrophilic component in a cydization reaction. Acid-catalysed hydrolysis of the f) amino-ketone liberates the amine that was used to form... 

The starting material for these aliphatic Claisen rearrangements consists of ethers with one allyl and one vinyl group. We need now to consider how such useful molecules might be made. There is no problem about the allyl half—allylic alcohols are stable easily made compounds. But what about the vinyl half Vinyl alcohols are just the enols of aldehydes (MeCHO). The solution is to use an acetal of the aldehyde in an acid-catalysed exchange process with the allylic alcohol. 

The demand for environmentally friendly chemistry and its widespread applicability have made water an increasingly popnlar solvent for organic transformations. Mixtures of water and other solvents snch as tetrahydrofnran are now commonly anployed for a number of organic transformations. For instance, the Lewis acid catalysed aldol reaction of silyl enol ethers, commonly known as the Mnkaiyama aldol reaction, which was firstly reported in the early seventies, can be carried ont in snch media. With titanium tetrachloride as the catalyst this reaction proceeds regioselectively in high yields, but the reaction has to be carried ont strictly nnder non-aqneons conditions in order to prevent decomposition of the catalyst and hydrolysis of the sUyl enol ethCTS. In the absence of the catalyst it was observed that water had a beneficial influence on this process (Table 4, entry D) . Nevertheless, the yields in the nncatalysed version WCTe still unsatisfactory. Improved results were obtained with water-tolerant Lewis acids. The first reported example for Lewis acid catalysis in aqueous media is the hydroxymethylation of silyl enol ethers with commercial formaldehyde solution using lanthanide trillates. In the meantime, the influence of several lanthanide triflates in cross-aldol reactions of various aldehydes was examined " " ". The reactions were most effectively carried out in 1 9 mixtures of water and tetrahydrofnran with 5-10% Yb(OTf)3, which can be reused after completion of the reaction (Table 19, entry A). Although the realization of this reaction is quite simple, the choice of the solvent is crucial (Table 20). 

Finally, acid catalysed reaction gives the expected thermodynamic product 40. All three products involve the aldehyde the enamines select for d2 behaviour of the aldehyde while acid catalysis brings it in as an electrophile (a1). You cannot expect to achieve such control in all examples, but it is clear that enamines have something special to offer as aldehyde specific enol equivalents. 

Me3SiCl gives a stable silyl enol ether 132. Silyl enol ethers are of course alkenes too and can be oxidised by ozone. Reductive work-up is necessary not only to prevent the H202 by-product from oxidising the aldehyde but also to reduce it to the alcohol in situ. Acid-catalysed lactonisation of 122 finally gives iridomyrmecin 121. 

Titanium complexes are often encountered in Lewis acid-catalysed reactions. This is certainly true for catalysed aldol reactions. Mikami and Matsukawa demonstrated that titanium/BINOL complexes e.g. complex (7.20) afforded high yield and enantioselectivity in the aldol reactions of thioester ketene silylacetals with a variety of aldehydes. In contrast to some of the aldol reactions described above, the stereochemistry of the adducts is dependant on the geometry of the enol ether. Thus, reaction of the (B)-enol ether (7.21) with aldehyde (7.22) yields the sy -aldol adduct (7.23) predominantly while the (Z)-e.no ether (7.24) results in isolation of the anti-adduct (7.25) as the major product. The authors invoke a closed silatropic ene transition state (structure (7.26) for syn-transition state), substantiated by suitable crossover experiments, to explain the diastereoselectivities... 

The first industrial synthesis of ) -carotene by Hoffmann-La Roche followed the Ci9 + C2 + Ci9 principle. With the Ci4-aldehyde from the Vitamin A synthesis as the starting point, the sequence of acetal formation, Lewis acid-catalysed insertion of an enol ether, hydrolysis and elimination of ethanol, produces initially a Cjg-aldehyde. Repetition of this sequence with ethyl 1-propenyl ether gives the Cjg-aldehyde. 

Acetic acid catalyses die formation of a cyclic acetal by reaction of die remaining aldehyde with the enol and the hemiacetal hydroxy groups. 

Lewis acids catalyse the cyclocondensation of acid chlorides and aldehydes to give lactones (83) and (84). Aluminium chloride catalysis favours the 1 1 product (84), via a ketene pathway, while the large ring is the predominant product using e.g. TiCl2(OPr )2, where aryl halide enolates are implicated as intermediates. 

A mild acidic equivalent of the condensation of acetate enolates with aldehydes to give /S-hydroxy-esters has been developed. This consists of a zinc chloride-catalysed cycloaddition reaction between the aldehyde and a keten acetal followed by acid-catalysed hydrolysis (Scheme 30).The method works... 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

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