Michael with malonic acid ester

Michael additions. In this sense, the preferred formation of the (S)-diastereomers of the Michael adducts 17 generated from the enolate 15 of the diacetone-glucose dithiane-2-carboxylic acid ester with arylidene malonic acid esters 16 can be explained by assuming that the electrophile attacks from the lithium site in a way, which minimizes the steric repulsion between the dithiane ring and the aryl group ( formula A) ... 

The application of 3-aminopropyl phosphine (3) [41,46] as a building block for incorporation into -COOH functionalized frameworks provides an excellent example of the utility of preformed primary phosphine frameworks (Scheme 8) [46]. The reactions involved Michael addition of ferf-butyl acrylate to malonic acid dimethyl ester to produce the intermediate adduct, 2-methoxycarbonyl-pentanedioc acid 5-ferf-butyl ester 1-methyl ester, which upon treatment with trifluro-acetic acid (TFA) produced the corresponding diester acid,2-methoxy-carbonyl-pentanedioic acid 1-methyl ester, in near quantitative yield. It is remarkable to note that the reaction of NH2(CH2)3PH2 (3) with the diester acid is highly selective as the -COOH group remained unattacked whereas the reaction occurred smoothly and selectively at the -COOMe groups to pro-... 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

Different cyclic products are formed in the double Michael addition of malonic acid ethyl methyl ester to ( vE)-l,5-diphenylpenta-l,4-dien-3-one under basic conditions. Label the stereogenic units in the reaction products with the appropriate stereodescriptors. 

Problem 26.5 In an example of the Michael condensation, malonic ester reacts. with ethyl 2-butenoate in the presence of sodium ethoxide to yield A, of formula C13H22O6. The sequence of hydrolysis, acidification, and heating converts A into 3-methylpentanedioic acid. What is A, and how is it formed Hint See Sec. 8.20. Check your answer in Sec. 27.7.)... 

The second procedure worth presenting involves the Michael addition of tryptophan ester (22) to pro-pynoate ester (33 R = H) to give (34 R = H), and subsequent acid-induced cyclization via the iminium salt (35 R = H Scheme 19), to afford tetrahydro-P-carboline (36 R = H), which could not be prepared by the simple Pictet-Spengler reaction with malonic hemialdehyde. Again, asymmetric induction can be achieved through the amino acid derived ester function. Extension of this procedure to... 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

A very useful reaction in organic synthesis is the so-called Michael addition of an organic compound RH to an a,/ -unsaturated system C=C—X, in which X may represent an electron-withdrawing group such as C=0, COOR, C=N, N02, S(=0)R. The addition, in which R attaches to the / -carbon atom to give R—C—CH—X, occurs in a protic medium with sufficiently acidic compounds, e.g., nitroalkanes, alcohols, thiols, malonic esters and requires a basic catalyst. 

The catalytic performance of the lithium salt of (5)- or (f )-3,3 -bis[bis-(phenyl) hydroxymethyl]-2,2 -dihydroxy-dinaphthalene-l,l (4, BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Using nitrostyrene and cyclohex-2-enone as Michael acceptors efficient asymmetric C-C and C-N bond formations with up to 95% ee at room temperature were observed. A transition-state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular stmcture of the acetone solvate of BIMBOL. 

Base-catalyzed cyclocondensation (a) of alkynones with malonic esters and (b) of 1,3-diketones with acetylenic acids yields esters 27 of 2H-pyran-2-one-3-carboxylic acid or 5-acyl-2H-pyran-2-ones 29, respectively. In both cases, Michael additions are the primary steps, which afford 5-oxopentenoic esters 26 or 28 providing the 2H-pyran-2-one system by enolization and enollactone formation [12] ... 

Using these optimized conditions, the conjugate addition of 45 to the malonates 49 in the presence of the solid base provided access to the Michael adducts in good yields and high diastereoselectivities. The removal of the chiral TADDOL auxiliary could be accomplished without epimerization or racemization in this case, too. After esterification of the very polar acid intermediates with diazomethane the corresponding dimethyl esters 52 were obtained with yields of 72-94% and enantiomeric excesses ee of 84-94% (Scheme 1.1.13). 

As is to be expected, an alkynic ketone undergoes a Michael addition with a carbanion, leading eventually to a pyranone (50JA1022). Using malonic esters, a 3-alkoxycarbonyl derivative results, which is hydrolyzed to the 2-oxopyran-3-carboxylic acid under alkaline conditions, but to the pyranone by sulfuric acid. Rapid ester exchange is observed with the initial products, the alcohol used as solvent determining the nature of the alkyl group in the 3-carboxylic esters (Scheme 90). 

The resulting tetraethyl ester on hydrolysis and decarboxylation yields propane-1, 2,3-tricarboxylic acid.155 In this example the malonate anion is generated by using one molar proportion of sodium ethoxide this is Michael s original method. However, these conditions sometimes lead to competing side reactions and the formation of abnormal reaction products. Better yields of the required product are often obtained with small amounts of sodium ethoxide (the so-called catalytic method) or in the presence of a secondary amine (e.g. diethyl-amine, see below). 

C-Alkylation of the sodio derivative is accomplished by a technique similar to the alkylation of malonic ester. Primary halogen compounds, quaternary ammonium salts,and an alkene oxide have been used as alkylating agents. Alkylation by secondary halides has been less successful. Hydrolysis of the substituted esters to acetylated amino acids is described for leucine (64%) and phenylalanine (83%). Hydrolysis with deacylation has been used to prepare histidine (45%) and phenylalanine (67%). Glutamic acid (75%) is obtained from substituted acylaminomalonates prepared by the Michael condensation of methyl acrylate and the acylated amino esters. ... 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

Tsuji has completed three syntheses of zearalenone (119), all by quite similar routes. The first, shown in Scheme 1.28, began with acetate 59b, the minor product from the telomerization of butadiene in acetic acid. Cleavage to the alcohol and gas-phase dehydrogenation led to enone 141. Chain extension to 142 was accomplished in 70% yield by way of Michael addition of diethyl malonate to enone 141. Decarboalkoxylation and protection of the ketone then gave 143 (63%). Conversion of the ester to the primary tosylate 144 was achieved by conventional methods in 62% yield. A Wacker oxidation of the terminal olefin followed by reduction and exchange of the tosylate for an iodide then provided the aliphatic segment 145 in 64% yield. 

The known bicyclo[3.1. Ojhexene 167 was hydroborated and oxidized to afford anti alcohol 168 in up to 80% yield. Chromic acid oxidation of 168 was followed by p elimination of malonate anion with EtaN to produce enone 169 (86%). Initial deprotonation of 169 followed by the addition of cuprate 166 afforded an 82% yield of 170. As expected, Michael addition to the enone occurred anti to the malonate unit. Reduction of ketone 170 with LiBH4 gave a 4 1 mixture of Cy alcohols, the major product being the desired a-hydroxy isomer. Chromatographic separation of the alcohols, followed by protection and ester cleavage, then gave the diacid 171. 

The title compound can be prepared by condensing an alkyl a-bromocaprylate with a trialkyl propane-1,1,3-tricarboxylate to give a substituted cyclopentanone. Hydrolysis, decarboxylation, and esterification of the resulting monocarboxylic acid with methanol yields the desired ester [139]. Trialkyl propane-1,1,3-tricarbox-ylates can be prepared by Michael addition of dialkyl malonates to alkyl acrylates. 

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