Methyl Meldrum’s acid

Phenylene bis(lead triacetate) reagents, generated in situ from the corresponding bis(boronic acid) derivatives and lead tetraacetate, react with the a-methyl Meldrum s acid derivative to afford the meta-or para-phenylene bis(Meldrum s acid) derivatives in ca 45% yield. 1 Similarly to malonic acid compounds, the unsubstituted Meldrum s acid was very slow to react and the only observed product was the a,a-diarylated product in 7-17%. 

Solvation and nucleophilic reactivity in MeCN-MeOH mixtures has been studied for the conjugate-base anions of 5-methyl Meldrum s acid and 3,3-dimethylbarbituric acid. Their nucleophilic reactivities are comparable, to each other and to those of the anions of 3,5-dinitrobenzoic acid and phthalimide. The pXa values in water vary much more. Thermodynamic data are presented and discussed. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Acylketenes, derived from Meldrum s acid, add to esters of (R)-4,5-dihydrothiazolin-4-catboxylic acid to give 81 <00OL2065>. A solid-phase synthesis of 2P-methyl substituted penam derivatives utilises a tether through an ester group <99TA3893>. 

In the reaction of A-methylaniline, ethyl orthoformate, and Meldrum s acid (421) in the presence of p-toluenesulfonic acid monohydrate at 100°C for 2 hr, then for 3 days at ambient temperature, (jV-methyl-TV-phenylamino)methylenemalonate (443) was obtained in 41% yield (69BRP1147759). 

Amino-3-benzyloxypyridine (X = CH)and4-amino-5-benzyloxypyri-midine (X = N) were reacted with Meldrum s acid (421) and methyl orthoformate in the presence of zinc chloride to give (hetarylamino)methylene-malonates (447) (89TL1529). 

Isopropylidene (7,8-difluoro-3-methyl-1,4-benzoxazin-4-yl)methylene-malonate (448, R = Me, R1 = R2 = F) was prepared in 81% yield in the reaction of 7,8-difluoro-3-methyl-l,4-benzoxazine, ethyl orthoformate, and Meldrum s acid (421) at 110-120°C [84JAP(K)122493, 84JAP(K)-216890]. 

Isopropylidene A/./V-dimethylaminomethylenemalonate (423, R = R1 = Me) was prepared in 77% yield when a solution of Meldrum s acid (421) in THF was added dropwise to a solution of DMF dimethyl acetal in THF over a period of 1 hr at 0-5°C in the presence of sodium methylate. The reaction mixture was then stirred for 17 hr (80SC661). 

The five- and six-membered isopropylidene 2-azacycloalkylidenemalo-nates (468, n = 0 and 1, R2 = R4 = H) were prepared in 94% and 76% yields, respectively, in the reactions of Meldrum s acid (421) and the appropriate cyclic lactim ether (465, n = 0 and 1, R2 = H, R5 = OMe) in the presence of triethylamine in boiling benzene overnight (79JOC3089). Under these conditions, caprolactim methyl ether did not react, but if the latter reaction was carried out in the presence of acetic acid and piperidine in boiling benzene overnight, a seven-membered cyclic compound (468, n = 2, R2 = R4 = H) was obtained in 58% yield (79JOC3089). 

Methylbenzofuran-3-carbaldehydes undergo ready condensation with Meldrum s acid (isopropylidene malonate) to afford arylmethylene derivatives 83. These on flash vacuum pyrolysis at 500-600 C give 3-dibenzofuranols 84 (Scheme 21). The arylmethylene derivative, e.g., 85, presumably undergoes conversion to a methylene ketene (86, Scheme 22) on pyrolysis, which undergoes a [1,5-H] shift and subsequent cyclization and tautomerization, yielding the dibenzofuranol 87. The derived methyl ether 88 has been converted by mild acetylation with acetyl chloride and aluminum chloride and subsequent boron trichloride-induced demethylation to the natural product ruscodibenzofuran (8). A limitation is imposed on this method because 3-acetyl-2-methyldibenzofurans fail to condense with Meldrum s acid so that l-methyl-3-dibenzofuranols are not available by this method. ... 

Various materials have been examined for use as deep UV resists poly(methyl methacrylate) (PMMA) (1), poly(methyl isopropenyl ketone) (PMIPK) fS.7L and the novolak-Meldrum s acid solution inhibition system (S). Each however has a problem related to sensitivity and/or resolution. While PMMA is insensitive to light of X > 230 nm because of its weak absorption, its high resolution properties make it an attractive starting point for the design of a resist that will perform well in the 230-280 region. The photochemical properties of PMMA could be modified by the incorporation of a small percentage of photolabile groups so as to have both the desired sensitivity and base polymer properties. 

Since ketones are stronger acids than carboxylic esters (Table 8.1), we are not surprised that 8 is a stronger acid than 10. But cyclization of 8 to 9 increases the acidity by only 2.1 p/C units while cyclization of 10 to 11 increases it by 8.6 units. Indeed, it has long been known that 11 (called Meldrum s acid) is an unusually strong acid for a 1,3-diester. In order to account for this very large cyclization effect, molecular orbital calculations were carried out two conformations of methyl acetate and of its enolate ion by two groups.136 Both found... 

Methyl ketones Methyl ketones are available by acylation of Meldrum s acid (I) followed by hydrolysis with aqueous acetic acid (equation I). The method fails when R = C6H5 because of hydrolysis to benzoic acid. 

METHYL KETONES AUyltrimethyl-silane, Bis(acetonitrilo)chloronitro-palladium (11). Dicarb ony lbis( triphenyl-phosphine)nickel. Dichloro-dicyano-benzoquinone. Hydrogen peroxide-Palladium acetate. Meldrum s acid. Palladium r-butyl peroxide trilluoro-acctate. Palladium tl) chloride. 

B. and C. 2-Methyl-4H-pyran-4-one. A 1000-mL, round-bottomed flask equipped with a stir bar and a reflux condenser is charged with the crude acylated Meldrum s acid, 80 mL of butyl vinyl ether and 287 mL of toluene (or benzene) (Note 6). The reaction mixture is heated to 80°C for 7 hr (Note 7). The volatile components are removed under reduced pressure to yield 31.81 g of product (Note 8). To the residue are added 765 mL of tetrahydofuran, 191 mL of water and 2.7 g of p-toluenesulfonic acid. The mixture is heated to reflux for 18 hr, then the reaction is quenched with 10 g of solid sodium bicarbonate and allowed to stir for 15 min at 25°C (Note 9). The mixture is filtered to remove the sodium bicarbonate and the volatile components are removed under reduced pressure. The residue is dissolved in 500 mL of methylene chloride, placed in a separatory funnel and washed with 200 mL of water and 200 mL of brine solution. The aqueous layers are collected and extracted with methylene chloride (2 x 200 mL). The organic layers are combined, dried over 20 g of sodium sulfate for 1 hr, filtered into a 1000-mL, round-bottomed flask, and concentrated under reduced pressure. The resulting red oil is purified by chromatography using a 6-cm diameter glass column packed with 400 g of silica gel... 

Ethyl a-(Hexahydroazepinylidene-2) Acetate from 0-Methyl-caprolactim and Meldrum s Acid... 

The solid acyl Meldrum s acid, without purification, is refluxed 1n 250 mL of anhydrous methanol for 2.5 hr. The solvent is removed with a rotary evaporator, and the residual oil 1s distilled under reduced pressure to give 25.2 g (82 ) of methyl phenylacetylacetate as a colorless liquid, bp 126-128°C/(0.6 mm). 

Methanolysis or ethanolysls of an acyl Meldrum s acid is performed simply by refluxing in methanol or ethanol solution. The products are methyl or ethyl g-keto esters, and they can usually be purified by distillation. When a higher ester (such as benzyl, t-butyl, or trichloroethyl) is required, it is... 

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