Acyloins, a-hydroxyketones

The formation of acyloins (a-hydroxyketones of the general formula RCH(OH)COR, where R is an aliphatic residue) proceeds best by reaction between finely-divided sodium (2 atoms) and esters of aliphatic acids (1 mol) in anhydrous ether or in anhydrous benzene with exclusion of oxygen salts of enediols are produced, which are converted by hydrolysis into acyloins. The yield of acetoin from ethyl acetate is low (ca. 23 per cent, in ether) owing to the accompanying acetoacetic ester condensation the latter reaction is favoured when the ester is used as the solvent. Ethyl propionate and ethyl ji-butyrate give yields of 52 per cent, of propionoin and 72 per cent, of butyroin respectively in ether. 

Preparation of Acyloins. When aUphatic esters are allowed to react with metallic sodium, potassium, or sodium—potassium alloy in inert solvents, acyloins (a-hydroxyketones) are formed (45) ... 

If a molecule contains both aldehydic and ketonic functions, reaction with a secondary amine occurs at the former115-117. Acyloins (a-hydroxyketones) condense with secondary amines to give a-aminoketones rather than enamines118. 

Ene-carbamates 499 can be prepared via a Curtius rearrangement of a hydrolyzed MBH adduct 498 followed by the reaction of intermediate vinyl isocyanates with an alcohol (methanol or f-butanol). In addition, different acyloin (a-hydroxyketones) 500 have been obtained in good overall yields based on a Curtius rearrangement in the presence of water. These methodologies have been demonstrated in the synthesis of some bioactive compounds (501and 502) (Scheme 3.219). 

In a related process, acyloins (a-hydroxyketones and a-hydroxyaldehydes) are transformed into isomeric acyloins with dilute alcoholic sulfuric acid (H2SO4) as shown in Scheme 9.94. 

The formation of acyloins (a-hydroxyketones), versatile intermediates for natural products syntheses, is catalyzed in nature by thiamine diphosphate-dependent (ThDP-dependent) enzymes. These enzymes belong to different families, transferases as transketolase cf 5.2.), lyases as benzaldehyde lyase (cf 5.1.), and different decarboxylases. They are generally highly enantioselective... 

Another important reductive coupling is the conversion of esters to a-hydroxyketones (acyloin condensation).267 This reaction is usually carried out with sodium metal in an inert solvent. Good results have also been obtained for sodium metal dispersed on solid supports.268 Diesters undergo intramolecular reactions and this is also an important method for the preparation of medium and large carbocyclic rings. 

Another important reductive coupling is the conversion of esters to a-hydroxyketones (acyloins).185 This reaction is usually carried out with sodium metal in an inert solvent. 

The bimolecular reductive coupling of carboxylic esters by reaction with metallic sodium in an inert solvent under reflux gives an a-hydroxyketone, which is known as an acyloin. This reaction is favoured when R is an alkyl. With longer alkyl chains, higher boiling solvents can be used. The intramolecular version of this reaction has been used extensively to close rings of different sizes, e.g. paracyclophanes or catenanes. 

By contrast, the a-hydroxyketone 61 is an acyloin derived from a diester 62 that has no a-Hs, cannot enolise, and will not need the silicon treatment. Simple C-S disconnection reveals a chloroester 63. 

The so-called acyloin condensation consists of the reduction of esters—and the reduction of diesters in particular—with sodium in xylene. The reaction mechanism of this condensation is shown in rows 2-4 of Figure 14.51. Only the first of these intermediates, radical anion C, occurs as an intermediate in the Bouveault-Blanc reduction as well. In xylene, of course, the radical anion C cannot be protonated. As a consequence, it persists until the second ester also has taken up an electron while forming the bis(radical anion) F. The two radical centers of F combine in the next step to give the sodium glycolate G. Compound G, the dianion of a bis(hemiacetal), is converted into the 1,2-diketone J by elimination of two equivalents of sodium alkoxide. This diketone is converted by two successive electron transfer reactions into the enediolate I, which is stable in xylene until it is converted into the enediol H during acidic aqueous workup. This enediol tautomerizes subsequently to furnish the a-hydroxyketone—or... 

A historically significant route to dithiolenes starts from a-hydroxyketones (also called acyloins) (157). This methodology is well suited for the large-scale... 

The bifunctional nature and the presence of a stereocenter make a-hydroxyketones (acyloins) amenable to further synthetic transformations. There are two classical chemical syntheses for these a-hydroxyketones the acyloin condensation and the benzoin condensation. In the acyloin condensation a new carbon-carbon bond is formed by a reduction, for instance with sodium. In the benzoin condensation the new carbon-carbon bond is formed with the help of an umpolung, induced by the formation of a cyanohydrin. A number of enzymes catalyze this type of reaction, and as might be expected, the reaction conditions are considerably milder [2-4, 26, 27]. In addition the enzymes such as benzaldehyde lyase (BAL) catalyze the formation of a new carbon-carbon bond enantioselectively. Transketolases (TK)... 

Formamidine reacts with a-hydroxyketones95 and a-haloketones62 to yield oxazoles and imidazoles. Normally the formamidine is liberated from its hydrochloride by the addition of sodium butoxide in n-butanol. It is interesting to note that in the reaction with a-hydroxyketones, the aliphatic acyloins yielded mainly imidazoles (35-68% yield), whereas the benzoins gave mainly oxazoles (67-80%).95 Unlike formamidine, acetamidine and benzamidine react with both aliphatic acyloins and with benzoins to yield imidazoles exclusively.65 Bredereck65 explains the reactions as follows ... 

A skeletal rearrangement of a-hydroxyketones (103), similar to the known acid-catalysed acyloin transformation (Favorski, 1926), has been observed by Frearson and Brown (1968), who made efforts to distinguish between the possibilities of rearrangements taking place before and after ionization. These workers were of the opinion that an ion-rearrangement had been observed but the interpretation is open to question. 

This method has been used for oxidation of methyl epoxystearate to the corresponding acyloin.393 In more recent work, Tsuji391> reports that the conversion of epoxides into a-hydroxyketones proceeds in better yield by passing air into a solution of the epoxide in DMSO (no BF3). In this way styrene oxide gives phenacyl alcohol in 92% yield. No oxidation occurs in the absence of oxygen, but oxygen is... 

Polymer 149, prepared by ring-opening polymerization (ROMP) of the corresponding functionalized norbornene, provides a clear illustration of the potential of this kind of materials. This resin catalyzes (12% molar) the reaction of linear aliphatic aldehydes with unsaturated ketones to provide 1,4-dicarbonyl compounds (153, Scheme 10.23) and was used for four consecutive cycles without any detectable decrease in performance [358]. A similar dimethylthiazolium structure supported on 2% cross-linked PS-DVB (150) was studied as catalyst for the acyloin condensation of a large variety of aldehydes [364], Catalyst 150 is used in 10 mol.% and the reaction takes place in ethanol at room temperature, with triethylamine as the base, to afford the corresponding a-hydroxyketones in excellent yields. Remarkably, the catalyst can be reused 20 times without losing its activity. 

The acyloin condensation converts two esters to an a-hydroxyketone (an acy-loin), often in an intramolecular fashion. The reaction proceeds by a mechanism very similar to the pinacol coupling, except that after the radical-radical combination step there are two elimination steps and two more electron transfer steps. The intramolecular reaction works well for a wide variety of ring sizes. 

A variation of the pinacol reaction has been applied to esters for the preparation of hydroxyketones (acyloins). A simple example is the reaction of 257 with sodium metal (Na°) in refluxing xylene, which gave a good yield of 2-hydroxy cycloheptanone (258) after hydrolysis.203 The condensation of an a,(o-diester to an... 

An oxidative cleavage of cycloalkanones to unsaturated aldehyde-esters has been developed. Thus, for example, cyclononanone was converted into 2,2-dithio-trimethylenecyclononanone, which was cleaved using lead(iv) acetate (66 %), and the product so obtained treated with methanol and sodium periodate to give (208 in = 5). Cyclododecanone was similarly converted into (208 n = 8). 1,2-Bis(trimethyl-silyloxy)cycloalkenes, prepared by acyloin condensations, have been converted into 2-alkyl-2-hydroxycycloalkanones by treatment with methyl-lithium and an alkyl halide, and the oximes of these a-hydroxyketones cleaved to give open-chain co-cyanoketones using mesyl chloride-pyridine. ... 

In the enzymatic aldol reaction, the role of the donor and acceptor is strictly determined by the specificity of the enzyme and only raie coupling product can be obtained. In contrast, the possible product range is more complex in acyloin and benzoin reactions If only a single aldehyde species is used as substrate, only one product can be obtained via homocoupling however, a pair of regioisomeric a-hydroxyketones can be obtained via heterocoupling, when two different aldehydes are used, the ratio of which is determined by the choice of substrates (e.g., benzoyl formate vs. benzaldehyde, pyruvate vs. acetaldehyde), and the specificites of enzymes, respectively (Scheme 2.198). 

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