Enolate, Magnesium

A useful modification of the 1,4-addition reaction to A -20-ketones is provided by direct acetylation of the magnesium enolate present in the... 

Synthesis, structure, and transformations of a-pyrone derivatives, viz., xanthy-rones, glaucyrones, and chelated magnesium enolates 98T8243. 

Another side-reaction can be observed with sterically hindered ketones that contain an a-hydrogen—e.g. 18. By transfer of that hydrogen onto the group R of RMgX 2, the ketone 18 is converted into the corresponding magnesium enolate 19, and the hydrocarbon RH 14 is liberated ... 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

On the other hand, the predominant formation of the diastereomeric aldols 3 b results from the titanium enolate 1 b of (S )-5,5-dimethyl-4-tert-butyldimethylsilyloxy-3-hexanone. For this purpose, the ketone is first deprotonated with A-(bromomagnesio)-2,2,6,6-tetramethylpiperidine and the magnesium enolate, presumably (E) configurated, formed is thereby treated with hexamethylphosphoric triamide and triisopropyloxytitanium chloride. After sonification, the aldehyde is added to give predominantly aldol adducts 3b the diastereomeric ratio of 3b/2b surpasses 95 5 and the chemical yields range from 85 to 88%53b. 

Among the preformed enol derivatives used in this way have been enolates of magnesium, lithium, titanium, zirconium, and tin, ° silyl enol ethers, enol borinates,and enol borates, R CH=CR"—OB(OR)2. The nucleophilicity of silyl enol ethers has been examined. In general, metallic Z enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. The ( ) isomers generally react nonstereoselectively. However, anti (or threo) stereoselectivity has been achieved in a number of cases, with titanium enolates, with magnesium enolates, with certain enol bor-inates, and with lithium enolates at — 78°C. ... 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

Similar chelation effects are present in a-alkoxymethyl derivatives. Magnesium enolates give predominantly the Z-enolate as a result of this chelation. The corresponding trimethylsilyl ketene acetals give E,Z mixtures.248... 

Continuing to age the reaction after the ester 33 had been consumed or adding more i-BuMgCI did not convert the ketone 3 to alcohol 61. We believed that the ketone was protected as the magnesium enolate 63, as shown in Figure 3.10. If this were true, then there must be a competition between deprotonation to give the enolate and addition to give the tertiary alcohol [18],... 

Reactions of imidazolides with the magnesium enolates of malonates (Mg2+/malo-nate, ratio 1 1) are used for the elongation of carboxylic acids by two carbon atoms to give jS-ketoesters (Tables 14—3 and 14-4). 

The magnesium enolates are prepared by treatment of malonic acid half ester either with magnesium ethylate[24],[32] or with isopropylmagnesium bromide[24] or chloride.t26] Ref. [23] describes the synthesis of a 13C-labelled ethyl acetoacetate. Concerning the synthesis of porphyrin / -ketoesters,[3 1 it was noticed that the method via imidazolides is more efficient than the other approach via acid chlorides and sodiomalonic esters. 

It is advantageous to utilize neutral magnesium salts in the cases cited in Table 14—5 instead of basic magnesium enolates, because with the latter reagents the yields are much... 

The well-defined single-site magnesium enolate initiator (187) initiates the living polymerization of MMA at -30 °C.452 Mw/Mn values are typically 1.07-1.11, and Mn increases linearly both with... 

A magnesium enolate of 99 is susceptible to aldol condensation with 4-pentenal, and the crude product can be directly protected to give its ethyl carbonate 100. a-Hydroxylation of the carbonyl group yields the hydroxyl carbonate 101. Reduction of the carbonyl group generates a triol, and this compound can be simultaneously converted to carbonate 102. Swern oxidation of 102 gives ketone 103, which can be rearranged25 to produce lactone product 104 (Scheme 7-32). 

Aldol reactions of 1 and 2 can be used to obtain any one of the four possible stereoisomers of a,3-dihydroxy esters.3 Thus 1 reacts with aldehydes to provide (2S)-aldols, and 2 reacts to provide (2R)-aldols. The syn/anti ratio of the aldols can be controlled by the choice of the enolate counterion. Thus lithium or magnesium enolates provide mainly an/i-aldols, whereas 5yn-aldols predominate with zirconium enolates. Ethanolysis of the purified adducts yields the optically pure a,p-dihydroxy esters without epimerization with recovery of 8-phenylmenthol. 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

An additional important observation that (Z)-enolates exhibit erythro diastereoselection was made by Dubois and Fellmann (5b). Their investigation demonstrated that the magnesium enolate 24a (20°C, Et2 0) condensed with benzaldehyde under kinetic conditions to give exclusively the erythro diastereomer 25E (R3 = Ph, E T>95 5), and upon prolonged equilibration afforded the isomeric threo adduct (T E > 95 5) (eq. [ 15]). Heathcock has reported... 

This aldol bond construction, carried out under kinetic conditions with the magnesium enolate, has been reported to give the expected C7-diastereomer C with selectivities (C AC) ranging from 3 1 for X = SiMej (97b) to >8 1 for X = benzyl (97a). 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

The chapter is organized under the headings Preparation and Reactivity of magnesium enolates. 

II. PREPARATION OF MAGNESIUM ENOLATES A. Reductive Metal Insertion into Carbon-Halogen Bonds... 

Similarly, the bromo magnesium enolate 4 of 2,2-diphenylcyclohexanone has been prepared by the action of magnesium on 6-bromo-2,2-diphenylcyclohexanone 3 (equation 2). A small amount of iodine is added to initiate the reaction. The enolate 4 is obtained in 79% yield after 15 min at reflux. ... 

Colonge and Grenet have reported that this type of reaction may be utilized in the preparation of magnesium enolates from simple aliphatic a-bromo ketones. ... 

Side-reactions can sometimes be avoided by preparing the magnesium enolate in the presence of the electrophile. 

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