Acyloin condensation of esters

Biradicals have also been encountered as intermediates in the Mg reduction of ketones to pinacols (p. 218) and, as radical anions, in the acyloin condensation of esters (p. 218). The thermolysis of cyclopropane (131) to propene (132) at 500° is also believed to involve... 

Alkyl alkanoates are reduced only at very negative potentials so that preparative scale experiments at mercury or lead cathodes are not successful. Phenyl alkanoates afford 30-36% yields of the alkan-l-ol under acid conditions [148]. Preparative scale reduction of methyl alkanoates is best achieved at a magnesium cathode in tetrahydrofuran containing tm-butanol as proton donor. The reaction is carried out in an undivided cell with a sacrificial magnesium anode and affords the alkan-l-ol in good yields [151]. In the absence of a proton donor and in the presence of chlorotrimethylsilane, acyloin derivatives 30 arc formed in a process related to the acyloin condensation of esters using sodium in xylene [152], Radical-anions formed initially can be trapped by intramolecular addition to an alkene function in substrates such as 31 to give aiicyclic products [151]. 

Acyloin condensations of esters conducted with TMS-Cl and sodium in toluene give 1,2-bis(trimethyl-silyloxy)alkenes. In general, the silylacyloin reaction provides higher yields than the conventional acyloin reaction and is particularly useful for the preparation of cyclic enol silyl ethers. " The synthesis of compound (47) serves as an illustration. 

Acetylides generated from trimethylsilyl acetylenes using catalytic amounts of tetrabulylammonium fluoride react with carbonyl compounds to give silyl ethers and thence alcohols (Scheme 67). ° A new route to acetylenes utilizes the acyloin condensation of esters as illustrated in Scheme 68. Yields are generally poor (30%), and are less than the procedure involving conversion of the acyloin to the bis-hydrazone followed by oxidation with metal salts. 

The thermal ring opening of l,2-bis(trimethylsiIoxy) cyclobutenes (from acyloin condensation of 1,2-dicarboxylic esters) was used in ring expansion prodecures (see p. 53f.). 

Acyloins were converted to mixtures of stereoisomeric vicinal diols by catalytic hydrogenation over copper chromite [972]. More frequently they were reduced to ketones by zinc (yield 77%) [913, 914], by zinc amalgam (yields 50-60%) [975], by tin (yields 86-92%) [173], or by hydriodic acid by refluxing with 47% hydriodic acid in glacial acetic acid (yields 70-90%) [916], or by treatment with red phosphorus and iodine in carbon disulfide at room temperature (yields 80-90%) [917] Procedure 41, p. 215). Since acyloins are readily accessible by reductive condensation of esters (p. 152) the above reductions provide a very good route to ketones and the best route to macro-cyclic ketones [973]. 

Fig. 17.59. Reduction of a carboxylic ester with dissolving sodium. Branching of the reduction paths in the presence (Bouveault-Blanc reduction) and absence (acyloin condensation) of protons.

As a matter of fact, 42 is readily accessible, starting with the acyloin condensation of succinic esters in the presence of trimethylsilylchloride to provide 1,2-disiloxycyclo-butene 161 in high yields 93). Bromination of 161 in pentane at low temperature, led to the 1,2-cyclobutanedione 162, which underwent acid or base induced ring contraction to 1-hydroxycyclopropanecarboxylic acid 4294). More conveniently, 42 was prepared in a one-pot reaction by first adding bromine in CH2C12 at —10 °C and then ice-water to 161 the hydroxyacid 42 was obtained by continuous extraction in 94 % yield, Eq. (52) 95-96). 

The biogenesis of solerone 1 and related compounds was successfully rationalized by biomimetic model reactions. As key step we established the pyruvate decarboxylase catalyzed acyloin condensation of pyruvic acid with ethyl 4-oxobutanoate 4 or ethyl 2-oxoglutarate 3 with acetaldehyde. The importance of the ethyl ester function in 3 and 4 serving as substrates for the enzymatic formation of a-hydroxy ketones 5 and 6 was demonstrated. The identification of six yet unknown sherry compounds including acyloins 5 and 6, which have been synthesized for the first time, confirmed the relevance of the biosynthetic pathway. Application of MDGC-MS allowed the enantiodifferentiation of a-ketols and related lactones in complex sherry samples and disclosed details of their biogenetic relationship. 

Thorpe-Ziegler cyclhation. Doombos and Strating used this reagent for effecting thccyclizationof(l) to (2), Acyloin condensation of analogous esters failed in this case. 

Dihydroxykaurenolide, previously isolated as a microbiological transformation product of steviol, has been found as a metabolite of a strain of Fusarium monoliforme. The acyloin condensation of the keto-ester (76) under carefully-controlled conditions affords a means of reconstructing the tetracyclic kauranoid skeleton (77). The diol (77) was converted into steviol, which was accompanied by only small amounts of the isomeric beyerane diol. 

Two sets of conditions have commonly been employed in order to effect the acyloin coupling of esters. In each case it is important that both the condensation and the work-up should be performed in the absence of moisture and of oxygen. 

Two types of sodium hydride are available commercially a dry, granular material about 8 to 200 mesh in size, and a semidispersion of micronsized crystals in mineral oil. The oil-dispersed sodium hydride is the safer and easier to handle, as the high reactivity of the hydride is protected by the oil. The principal use of sodium hydride is to carry out condensation and alkylation reactions which proceed through the formation of a car-banion (base-catalyzed). The sodium hydride dispersion has been evaluated in comparison with dry sodium hydride, sodium metal, soda-mide, and sodium methylate. Yields and reaction rates in the self-condensation of esters, ester-keto condensations, and the Dieckmann condensation have been outstandingly superior. Amines can be successfully alkylated by a new technique employing polar solvents. Dehalogenations do not occur, nor does reduction unless there is no a-hydrogen present. Acyloin formation and reduction side reactions do not interfere when sodium hydride is used. 

This reaction was first reported by Bouveault and Blanc in 1903, and was further extended by Bouveault and Locquin. It is the synthesis of symmetrical a-hydroxy ketones via the reductive condensation of esters in an inert solvent in the presence of sodium. Since symmetrical a-hydroxy ketones, the aliphatic analogs of benzoins, are generally known as acyloins, the formation of a-hydroxy ketones from esters is simply referred to as acyloin condensation. In a few cases, it is also referred to as acyloin reaction." For the individual acyloin, the name is derived by adding the suffix oin to the stem name of corresponding acid, e.g., acetoin prepared from acetate. The most common method used to make acyloin is the reductive condensation of aliphatic esters with sodium in inert solvents, such as ether, xylene or even in liquid NH3 The yield of this reaction can be greatly improved when trimethylchlorosilane presents." " Intromolecular acyloin condensation from aliphatic diesters affords cyclic ketones of different ring sizes. 

Cyclization of difunctional compounds is illustrated by the acyloin condensation of diesters (Fig. 19), conventionally performed with sodium in refluxing solvents, and improved by the presence of trimethylchlorosilane. A practical improvement was made with the use of technical-grade TMSCl and ultrasonically dispersed sodium.Thus, the reaction occurs at 0°C in 0.5 to 3 h. An experimental description is given in Ch. 9, p. 331. A chiral center at the a-position of the carbonyl does not suffer racemization. With p-halo esters, cyclizations lead to cyclopropyl derivatives in high yields, except with sterically hindered substrates. A similar reaction occurs with zinc and oxazabutadienes substituted by trifluoromethyl groups, with a fluoride ion as the leaving group (Eq. 15).ii ... 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

Guareschi imides are useful synthetic intermediates. They are formed from a ketone reacting with two equivalents of the cyanoacetic esters and ammonia. This transformation is illustrated in the formation of 4,4-dimethylcyclopentenone 30.The synthesis was initiated with the Guareschi reaction of 3-pentanone 27 with 28 to generate imide 29. This product was hydrolyzed to the diacid and esterified. Cyclization of the diester via acyloin condensation followed by hydrolysis and dehydration afforded the desired target 30. 

Upon heating of a carboxylic ester 1 with sodium in an inert solvent, a condensation reaction can take place to yield a a-hydroxy ketone 2 after hydrolytic workup. " This reaction is called Acyloin condensation, named after the products thus obtained. It works well with alkanoic acid esters. For the synthesis of the corresponding products with aryl substituents (R = aryl), the Benzoin condensation of aromatic aldehydes is usually applied. 

This modification has become the standard procedure for the acyloin ester condensation. By doing so, the formation of products from the otherwise competitive Dieckmann condensation (Claisen ester condensation) can be avoided. A product formed by ring closure through a Dieckmann condensation consists of a ring that is smaller by one carbon atom than the corresponding cyclic acyloin. 

A spectacular application of the acyloin ester condensation was the preparation of catenaries like 11. These were prepared by a statistical synthesis which means that an acyloin reaction of the diester 10 has been carried out in the presence of an excess of a large ring compound such as 9, with the hope that some diester molecules would be threaded through a ring, and would then undergo ring closure to give the catena compound ... 

In this section primarily reductions of aldehydes, ketones, and esters with sodium, lithium, and potassium in the presence of TCS 14 are discussed closely related reductions with metals such as Zn, Mg, Mn, Sm, Ti, etc., in the presence of TCS 14 are described in Section 13.2. Treatment of ethyl isobutyrate with sodium in the presence of TCS 14 in toluene affords the O-silylated Riihlmann-acyloin-condensation product 1915, which can be readily desilylated to the free acyloin 1916 [119]. Further reactions of methyl or ethyl 1,2- or 1,4-dicarboxylates are discussed elsewhere [120-122]. The same reaction with trimethylsilyl isobutyrate affords the C,0-silylated alcohol 1917, in 72% yield, which is desilylated to 1918 [123] (Scheme 12.34). Likewise, reduction of the diesters 1919 affords the cyclized O-silylated acyloin products 1920 in high yields, which give on saponification the acyloins 1921 [119]. Whereas electroreduction on a Mg-electrode in the presence of MesSiCl 14 converts esters such as ethyl cyclohexane-carboxylate via 1922 and subsequent saponification into acyloins such as 1923 [124], electroreduction of esters such as ethyl cyclohexylcarboxylate using a Mg-electrode without Me3SiCl 14 yields 1,2-ketones such as 1924 [125] (Scheme 12.34). 

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. 

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