Diesters, reaction with ketones

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). 

Among the methods described in Section 10.6.5, the syntheses reported by Umezawa et alJ78 and Garcfa-Lopez et al.179,80 have been most widely used. As summarized in Scheme 33, the synthesis is initiated with the preparation of a diazo ketone through the reaction between a N-protected a-amino acid and isobutyl chloroformate followed by treatment with diazomethane. The chloromethyl ketone is prepared by adding 2.5 M hydrochloric acid to the diazo ketone. Transhalogenation is exploited to obtain the iodomethyl ketone. Through in situ reaction with the sodium derivative of dimethyl malonate, the 4-oxo diester is obtained. 

In the carbonylation of unconjugated dienes the nature of the products is influenced by reaction conditions. With Pd halides in ethanol at 100°C and 97 atm CO, 1,5-cyclooctadiene is successively carbonylated to the unsaturated monoester and then to the saturated diester (II). With (Ph3P)2PdCl2 in ethanol-HCl and 300-700 atm CO, the monoester is produced selectively at 60°C and the diester at 100°C (8). Finally, with (Bu3P)2PdI2 in THF at 150°C and 1000 atm CO, 1,5-cyclooctadiene undergoes transannular addition of CO to give a cyclic ketone in 40-45% yield (14, 15). The mechanism proposed involves a a-7r-cyclooctenyl... 

In his synthesis of the [4.4.4] propellane 19, Paquette made the diester 16 easily but wanted the mono methyl ketone 18. Rather than add MeLi directly, he first hydrolysed one ester to the free acid 17 and then made the acid chloride with oxalyl chloride. Reaction with Me2CuLi gave the ketone in excellent yield.5... 

The Claisen ester condensation gives the right product just by treatment with base The reasons for this are discussed in Chapter 28. We had then planned to react the keto-diester with methyl-hydrazine but there is a doubt about the regioselectivity of this reaction—the ketones are more electrophilic than the ester all right, but which ketone will be attacked by which nitrogen atom ... 

Cyclopentanones. The reaction of the sodium enolate of the keto diester 2 with 1 in THF at 20° leads to the cyclopentene 3 in 90% yield. The product is readily converted to the ketone 4 by treatment with TFA. 

For example, reaction of an ester enolate with diethyl carbonate yields a p-diester (Reaction [1]), whereas reaction of a ketone enolate with ethyl chloroformate forms a p-keto ester (Reaction [2]). 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

Pyridine derivatives will undergo aza-annulation at elevated temperatures. For example, reaction of ketone 416 with the diester 47 at 150-190 °C led to formation of quinolizone 417 (eq. 85).101 The ketone substituent R played an important role on the outcome of the reaction, in which substrates with an alkyl substituent gave much greater yields than those with a phenyl substituent. 

The use of oxirane together with Na2HP03 to prepare (2-hydroxyethyl)phosphonic acid as its disodium salt is of historical interest. Other poorly exploited, yet interesting and potentially valuable, reactions include the combination of a trialkyl phosphite and dialkyl chlorophosphate with an oxirane to yield O-phosphorylated derivatives of (2-hydrox-yalkyl)phosphonic diesters (reaction 10)" and, following the initial reaction of an a,j8-unsaturated ketone with a phosphorus(III) triester to give the cyclic phosphorane 272, the subsequent further reaction of the latter with an aldehyde followed by hydrolysis (reaction 11)" Dialkyl acetyl phosphites are reported to react with oxirane through anionic intermediate species with the formation, albeit in low yields, of dialkyl (2-acetyloxyethyl)phos-phonates hydrolysable with concentrated HCl, to give (2-hydroxyethyl)phosphonic acid ... 

Indeed, one of the main uses of j -phosphorylated ketones is the synthesis of C-phos-phorylated heterocyclic systems, and in this respect the reactions very often complement those of isomeric acylphosphonates. In the first of the examples chosen, the ketone 304 cannot be converted into 305 in a direct reaction with the appropriate amine instead, the carbonyl group must be protected as in 307, when a reaction with the amine then gives 308 hydrolysis of 308 with 3 M HCl yields 305. When treated with ZnCl2 under toluene, 305 yields the indolylphosphonic diester 310" In the same way, a direct reaction between 304 and ArONa fails to give 306, which must therefore be prepared via 307 and 309 with acid hydrolysis to 306 when the latter is treated with hot polyphosphoric acid, cyclization occurs to give the benzofuranylphosphonic diester In order to obtain the isomeric... 

The treatment of diethyl (trichloromethyl)phosphonate with BuLi in thf affords diethyl [lithio(dichloromethyl)]-phosphonate the latter undergoes reactions with aldehydes or ketones to give, not only dichloroalkenes, C12C=CR R but also, from RCHO, the saturated esters RCH=CAB (A, B = Cl or P03Et2) The products from the interaction of the (l-haloalkyl)phosphonic diesters, (EtO)2P(0)CHXR (X = Cl, Br or I R = H or Me) and alk-1-enes, H2C=CHR (R = pentyl, OEt, OBu, OAc, CN or Ac) under free radical conditions, are mixtures containing moderate amounts of the esters 658 and 659, as well as diethyl methylphosphonate, in relative amounts which depend on reaction conditions " ... 

B.I. The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

The intramolecular Michael addition reaction of ketone enolate to p-alkoxyacrylate proceeded selectively (in a ratio of 5.9 1) with Barton s base (5) to give tetrahydrofuran 36 [8]. In a model smdy, LDA was much less effective than Barton s base (28 5% versus 96% yield). The diester 36 was converted into 38, which corresponds to the A-D ring system for lactonamycin (39) (Scheme 7.6). 

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. 

Hydroxyethyl esters can be prepared from the free acid by reaction with ethylene carbonate. During an attempt to protect the ketone group of a keto-acid by 1,3-dioxolane formation, it has been found that mixed carboxylate sulphonate esters [e.g. (121) from ethylene glycol and tosic acid] can easily be formed extensions of this reaction show it to have a general applicability. In the presence of fluoride ions, carboxylic acids become sufficiently nucleophilic to attack alkyl halides. Thus, reaction between an acid and 1,3-dibromopropane leads to diesters (122). Molecular sieves have been recommended as suitable absorbants... 

Aqueous acid workup of 92 gives the alcohol, 93. With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating because the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. Although it is possible to isolate 83, it is more usually difficult. The enolate anion of malonate esters also reacts with ketones and may be condensed with other esters in acyl substitution reactions. When 90 is treated with NaOEt in ethanol and then with ethyl butanoate, the final product after mild hydrolysis is a keto-diester, 95. 

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