Malonate esters, addition with

Aminothiazole, with acetaldehyde, 42 to 2-mercaptothiazoie, 370 4-Aminothiazole-2,5-diphenyl, to 2,5 di-phenyl-A-2-thiazoline-4-one, 421 Ammothiazoie-A -oxide, 118 2-Aminothiazoles. 12 acidity of, 90 and acrylophenone, 42 acylations of, with acetic acid. 53 with acetic anhydride, 52 with acyl halides, 48 with chloracetyl chloride, 49 with-y-chlorobutyrylchloride, 50 with 0-chloropropionylchloride, 50 with esters, 53 with ethy acrylate, 54 with indoiyl derivatives, 48 with malonic esters, 55 with malonyl chloride, 49 with oxalyl chloride, 50 with sodium acetate, 52 with unsaturated acyl chloride, 49 additions to double bonds, 40 with aldehydes, 98 alkylations, with alcohols, 38 with benzyhydryl chloride, 34 with benzyl chloride, 80 with chloracetic acid, 33 with chloracetic esters, 33 with 2-chloropropionic acid, 32 with dialkylaminoalkyl halides, 33 with dimethylaminoethylchloride, 35 with ethylene oxide, 34, 38... 

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. 

Hydroxymethylation is achieved by crossed aldol addition reaction (Section 18-6) of the malonic ester enolate with formaldehyde. 

Acyclic malonic esters react with most aldehydes under fairly mild conditions (secondary amines with warming), but ketones and less reactive aldehydes require conditions such as the Lehnert conditions (TiCU/amine). Malonic esters have a propensity to provide the bis-adducts via Michael addition. Cyclic malonic esters (such as Meldrum s acid) are more reactive than the corresponding acyclic versions, with reactions with simple aldehydes proceeding without catalyst in DMF or DMSO. Formation of the bis-adduct is also more common with cyclic esters, especially in the coupling with unbranched aliphatic aldehydes. ... 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

The reaction mixture is filtered with suction and the cake is washed thoroughly with two 200-ml. portions of glacial acetic acid (Note 4). The combined filtrate and washings are evaporated under reduced pressure on the steam bath until a thick oil, which generally partially crystallizes, remains. To purify the crude product, 100 ml. of water is added, and the flask is warmed on a steam bath until the solid melts. The mixture of water and oil is stirred rapidly in an ice bath, and diethyl acetamidomalonate crystallizes as a fine white product. After cooling in an ice bath for an additional hour, the product is collected by filtration, washed once with cold water, and dried in air at 50°. A second crop is obtained by concentrating the mother liquor under reduced pressure. The yield of diethyl acetamidomalonate, m.p. 95-97° (Note 5), is 52-53 g. (77-78%) based on malonic ester. 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

Mildly basic liquiddiquid conditions with a stoichiometric amount of catalyst prevent hydrolysis during alkylation [101] and, more recently, it has been established that solid-liquid or microwave promoted reactions of dry materials are more effective for monoalkylation [102-106] of the esters and also permits dialkylation without hydrolysis. Soliddiquid phase-transfer catalytic conditions using potassium f-butoxide have been used successfully for the C-alkylation of diethyl acetamido-malonate and provides a convenient route to a-amino acids [105, 107] use of potassium hydroxide results in the trans-esterification of the malonate, resulting from hydrolysis followed by O-alkylation. The rate of C-alkylation of malonic esters under soliddiquid phase-transfer catalytic conditions may be enhanced by the addition of 18-crown-6 to the system. The overall rate is greater than the sum of the individual rates observed for the ammonium salt or the crown ether [108]. 

Good yields of 1,4-addition products have also been obtained with alkylidene malonate esters which generally react with organomanganese reagents in the absence of copper salts9 (see Table IV). 

The Gould-Jacobs sequence (Scheme 4.1) commences with an addition-elimination reaction between aniline 30 and substituted ethylenemalonate derivative 31 to yield malonic ester 32. Subsequent intramolecular cychzation delivers the 4-hydroxy-3-carboalkoxy-quinolone 33. In the presence of an alkylating agent, 33 is converted to 34. Saponfication of the ester affords quinolone core 35. 

The Grohe-Heitzer sequence (Scheme 4.2) begins with acylation of malonate derivative 37 with benzoyl chloride 36 to give malonate 38 (Mitscher, 2005). Condensation of the malonate with an ortho-ester in the presence of a dehydrating agent such as acetic anhydride affords enol ether 39. The enol ether then undergoes an addition-elimination... 

In addition to the application of malonic esters, four-membered ring compounds can also be realized by using methyl methylsulfanylmethyl sulfoxide (14) as the active methylene component.25 27 As demonstrated in the following scheme, when the potassium salt of methyl methylsulfanylmethyl sulfoxide is allowed to react with 1,3-dibromopropane, cyclobutanone dimethyl dithioacetal 5-oxide (16) is isolated in 97% yield.8,10 Of particular interest is that the... 

For such hex-3-enopyranosid-2-uloses as 127 or 129, reaction with lithium dimethylcuprate,261 or with anions of malonic ester-type, methylene components in the presence of bis(2,4-pentanedionate)-Ni(II) catalyst,263 affords, in each case, the 1,4-addition products (128 and 130, respectively), in which the branching group is in the axial orientation. The methyl-branched pyranosides 126 and 128, readily accessible in this way, have been of use as chiral precursors for the synthesis of multistria-tins.264-285... 

T) Diethyl sec.-Butylmalonate.—To 700 cc. of absolute alcohol in a 2-1. three-necked, round-bottomed flask equipped with a long, wide-bore reflux condenservs added 35 g. (1.52 gram atoms) of sodium cut in pieces of suitable size. When all the sodium has reacted, the flask is placed on a steam cone and fitted with a mercury-sealed stirrer, a dropping funnel, and a reflux condenser bearing a calcium chloride tube (Note 1). The flask is heated, and 250 g. (1.56 moles) of diethyl malonate is added in a steady stream with stirring. After the ester addition, 210 g. (1.53 moles) of see.-butyl bromide is added at such... 

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). 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Less basic malonic ester anions may be employed for the twofold alkylation of dibromides. Cyclic 1,1-dicarboxylic esters are formed, if the reaction is executed in an appropriate manner. In the synthesis of cyclobutane diester A the undesired open-chain tetraester B was always a side product (J.A. Cason, 1949), the malonic ester and its monoalkylation product were always only partially ionized. Alkylation was therefore slow and intermolecular reactions of mono-alkyl intermediates with excess malonic ester prevailed. If the malonic ester was dissolved in ethanol containing sodium ethoxide, and 1,3-dibromopropane as well as more sodium ethoxide were added slowly to the solution, 63% of A and only 7% of B were isolated. The latter operations kept the malonic ester and its monoalkylated product in the ionic form, and the dibromide concentration low, so that the intramolecular reaction was favored against intermolecular reactions. The continuous addition of base during the reaction kept the ethoxide concentration low, which helped to prevent decomposition of the bromide by this nucleophile. 

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. 

Upon further addition of addends of the malonic ester type (Fig. 12), e.g., 2, 3, or 6 addends, the emission spectra are partly effected. However, the direction of change in the spectral features seems to correlate with the symmetry of the adducts. Addition of 2 or 3 malonic ester units lead to a small red-shift of the main emission band, while the emission band in the spectra of the hexakis adducts is barely blue-shifted compared to the corresponding monoadduct [108], Changing the solvent from methylcyclohexane to the more polar benzene or toluene the main emission... 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

Diesters of -a I k an cd i car boxy I i c acids can be monosaponified by addition of one equivalent of hydroxide. Best results are obtained if conditions can be found under which the desired product precipitates from the reaction mixture. This is, for instance, observed for all the examples shown in Scheme 10.1. The products of monosaponification of malonic esters are significantly less electrophilic than the diesters, which leads to a highly selective reaction. This is, however, not so for the undecanoic diacid diester. With this compound precipitation of the monoester salt from the reaction mixture is presumably the main reason for the high yield obtained. 

The benzylic free radical produced by the addition of the carbamoyl radical to the ethyl cinnamate molecule is more stable than the alternative radical alpha to the ester group. With such an orientation of addition to the a,p-unsaturated ester, this reaction should lead to derivatives of malonic acid. However, it has been found that the intermediate radical, being a stable benzylic free radical, fails to perform the subsequent abstraction of a hydrogen atom from formamide, and thus no chain-transfer step takes place. Instead of performing this step it favours the combination with a semi-pinacol radical, which is present in solution, to yield the hydroxy ester which subsequently lactonizes to give the major product of the reaction (67). 

As shown in Table 11, the slow addition of a P-keto ester and the use of CH2C12 as the solvent are generally quite effective methods for suppressing the reduction in enantiomeric excess for the various Michael adducts. On the other hand, malonates give adducts with high enantiomeric excesses regardless of the solvent used.25 These results can be explained by comparing the pKa of a P-keto ester with... 

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