Isopropylidene malonate

Pyrazolotriazine 253 was prepared (88JOC887) by coupling 3-diazopyrazole 250 with isopropylidene malonate 251 via 252. Methylation of253 with methyl iodide in the presence of methanolic potassium hydroxide gave pyrazolotriazines 255 and 256, whereas mono N-methyl derivative 254 was prepared (88JOC887) by the action of dimethyl sulfate on 253 (Scheme 55). 

Isopropylidene malonate (421) was reacted with imidate hydrochlorides in the presence of triethylamine in chloroform or benzene under reflux... 

When (3-substituted phenyl)aminomethylenemaIonate (1163, 3-R = H) was applied, a mixture of 5-substituted and 7-substituted 4-hydroxyquino-lines (1164, 5-R + H and 7-R + H) was obtained. For example, the thermal cyclization of (3-nitrophenyl)aminomethylenemalonate in dibenzyl ether at 250°C afforded a 3 1 mixture of 7-nitro- and 5-nitro-4-hydroxy-quinolines (1164, R = 7-N02 and 5-NO ). 4-Hydroxyquinolines (1164) could also be prepared when a mixture of anilines, triethyl orthoformate, and isopropylidene malonate was slowly heated to 100°C in Dowtherm A, stirred over a period of 30 minutes, and then raised to a temperature of... 

Isopropylidene malonate derivatives (501) were boiled in a mixture of... 

Dialkyl and isopropylidene malonates were reacted with 2-chloro-l,3-thiazinium chlorides (1686) in methylene chloride in the presence of triethylamine to give (1,3-thiazin-2-ylidene)malonates (1687) in 5-13% yields (89AP593, 89GEP3803783). 

The synthetically important isopropylidene malonates (Meldmm acids) can be prepared in a one-pot procedure employing this method. ... 

Monosubstituted isopropylidene malonates (typical procedure To a solution of NaHTe (10 mmol) prepared as above is added a solution of isopropylidene malonate (0.72 g, 5 mmol), benzaldehyde (0.83 g, 7.5 mmol), AcOH (1.5 mL) and piperidine (four drops) at -30°C under Nj. After 10 min the mixture is warmed to room temperature, stirred for 20 min, filtered and evaporated under vacuum. Aqueous K COj (5 mL) is added to the residue. After extraction with ether (3x3 mL), the solution of K2CO3 is acidified with 6 N HCl (5 mL) and then filtered, giving the pure product (0.99 g (81%) m.p. 80-81°C). 

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. ... 

Bei der Reaktion von 3,5 mol 2,4,6-Trimethyl-benzonitriloxid mit 1 mol Isopropyliden-malon-saure-dinitril in Chloroform (140 h Sieden) werden alle drei moglichen Additionsprodukte erhalten347. Die Produktverteilung ist allerdings von den Reaktionsbedingungen abhangig. 

Hence, Stobbe-like condensation with dimethyl-isopropylidene malonate and saponification of malonic acid, half-esters afforded the corresponding 14-carboxyretinoic acids, as a mixture of all E and 9Z isomers (80/20). The all E diacid was easily removed by crystallization from MeCN or ether, Fig. (36). A stereospecific decarboxylation in 2,6-dimethylpyridine led to isotretinoin. 

Phenylation and arylation have also been performed in bifunctional compounds such as malonates, /1-diketones and /1-ketoesters (Table 8.4). Diethyl malonate was arylated at room temperature affording mixtures of mono- and bis-arylated products, whereas isopropylidene malonate (Meldrum s acid) underwent bis arylation directly. Dimedone, the all carbon analogue of Meldrum s acid, was also mono-and bis-phenylated, with some concomitant O-phenylation [33], Generally, / -diketones show often ambident reactivity but the O-arylated product is normally the minor one an exception was noted in the triketone (PhCO)2CHCOPh which underwent mainly O-phenylation (68%) [33], Several dianions from /1-diketones have been arylated in high yields at the a-position, in a procedure superior to other methods [35]. 

The required malonic acid monoesters are readily prepared by heating the strongly acidic isopropylidene malonate (Meldrum s acid, 7.3) in an alcohol. Acetone is liberated in the process. 

Corey found the reagent useful for the synthesis of half-esters of a,/3-unsaturated malonic esters. Isopropylidene malonate condenses readily with carbonyl compounds, even with the highly hindered mesitaldehyde (1). Thus the condensation of (I) and (2) was conducted in pyridine solution, and the product (3) on being refluxed with absolute ethanol and a trace of hydrogen chloride afforded ethyl hydrogen mesitylidene malonate (4). 

The checkers found that this preparation was eipially successful when a solution of 0.50 mok of diethyl isopropylidene-malonate in 100 ml. of diethyl eth(>r was added over 25 minutes... 

Methylthiophene-2-carboxaldehyde condenses with isopropylidene malonate and the product 113 undergoes flash pyrolysis (500°C at low pressure), to give 5-hydroxybenzo[b]thiophene (96%).478 6-Hydroxy-2-methylbenzo[hjthiophene is formed similarly (98%). 

The reaction is equally successful when isopropylidene malonate is used in place of malonic acid or diethyl malonate.913 The isopropylidene ester contains an unusually acidic methylene group as well as an ester group that can be... 

The first milder method for this transformation, developed by Buchwald and Hennessy in 2002 [66], employed CuI/2-phenylphenol as a catalytic system to perform the arylation of diethyl malonates. The reaction worked well at 70 °C, but for some substrates such as isopropylidene malonate, l,3desired products were observed. In addition, only aryl iodides were compatible with these reaction conditions. 

Vinylogous carboxylic acid halides s. 17, 806 Condensations with l,3-dioxan-4,6-diones Isopropylidene malonate s. 17, 807 Modified azlactone synthesis s. 18, 804... 

Carboxylic acids add to olefinic linkages under acid catalysis to form esters and the method has been employed to prepare tetrahydropyranyl (reagent dihydropyran) [52] and t-butyl (reagent wo-butene) [53, 54, 55] esters. The little used isopropylidene malonate (15) is similarly produced from iso-propenyl acetate and malonic acid in the presence of sulphuric acid [56, 57]. 

Microwaves also provide an easy access to 2-alkyl and 2-aryl-4-quinolones by the addition-elimination reaction of 5-methylthioalkylidene isopropylidene malonates with arylamine, followed by cyclization (Huang et al., 2000). A condensation, addition, cyclization and elimination reactions of aromatic aldehydes, 5,5-dimethyl-l,3-cyclohexandione and isopropylidene malonate afforded a series of 4-aryl-7,7-dimethyl-2, 5-dioxo-l,2,3,4,5,6,7,8-octahydroquinoline and 4-aiyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydroconmarin under microwaves only in 3-5 min (Tu et al., 2002). Basic silica gel (NaOH/SiO ) in solvent-free conditions and microwave exposure acts as a very efficient medium for the p-elimination (dehydrosulfe-nylation) of sulfoxides (Moghaddam and Jamshidi, 2001). 

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