3,6-dimethyl-l,4-dioxane-2,5-dione

One synthetic approach involves cyclization of a substituted six-membered heterocycle which becomes the central ring of the product (6 6 6). For example, the reaction of 2,6-diaminopyridine with 2,2-dimethyl-l,3-dioxane-4,6-dione and trimethoxymethane gives the bis-adduct 118 which is a precursor to the angular tricyclic product 119 (Scheme 14) <2005AXCol>. 

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). 

Pyrido[2,3-, pyridazine derivatives 48 have been synthesized by refluxing equimolar amounts of an appropriate 5-benzylidene-2,2-dimethyl-l,3-dioxane-4,6-dione 47 with 5-amino-6-phenylpyridazin-3(2/7)-one 46 in methanol or a methanol acetic acid mixture. The electron-poor carbon atom of the polarized carbon-carbon double bond of 47 is the electrophile attacking C-4 of the 5-aminopyridazinone 46. Imino-enamine tautomerization of the intermediate is followed by ring closure and subsequent loss of acetone and carbon dioxide affording the reaction products 48 as stable crystalline solids in 70-90% yield (Scheme 9) <2000T2473>. 

Oxazolone At-oxides 91 have been obtained by heating a solution of 5-isonitroso-2,2-dimethyl-l,3-dioxane-4,6-dione 90 with the corresponding ketone in toluene. It has been postulated that the reaction occurs through an intermediate nitrosoketene that is generated from 90 via loss of CO2 and acetone, respectively. 

The pathway via Meldrum s acid is not feasible (Section I,B,2) since it requires a more favorable synthesis for 5-alkoxycarbonyl-2,2-dimethyl-l,3-dioxan-4,6-dione. Attempts to synthesize this compound from Meldrum s acid, chloroformate and pyridine give rise to yet another, pyridine-containing product (92LA813). 

In the second method (Scheme 26) a 3-oxo ester is synthesized from an acid chloride and 2,2-dimethyl-l,3-dioxane-4,6-dione. Then, reductive amination of the 3-oxo ester with a-methyl(phenyl)methylamine provides a 3-amino- 3-alkyl propionic acid ester. This compound is then converted into the corresponding aldehyde, which is condensed with an eno-late to afford the final product. A representative synthetic procedure of this method is given in detail. 

Cyclic nitrones, which are commonly formed by cycloaddition of ketones to nitrosoketene, can also be obtained by pyrolysis of 5-isonitroso-2,2-dimethyl-l,3-dioxane-4,6-dione (73) (isonitroso Mcldrum s acid) in the presence of various ketones. Two possible reaction pathways (Scheme 8) have been proposed previously to account for formation of cyclic nitrones from (73), but the proposed nitrosoketene intermediate could not be observed. Spectroscopic evidence for generation of the nitrosoketene in the gas phase at > 80 °C has now been found and ab initio calculations in support of the vibrational frequencies observed have been reported.35... 

Pyrolysis of Meldrum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione) 362 proceeds by loss of acetone and CO2 to give ketene. Because of the ready availability of the starting material and the ease with which it can be functionalized at the acidic 5-position, pyrolysis of Meldrum s acid derivatives has been widely studied. Pyrolysis of the 5-formyl and 5-acyl derivatives 363 gives formyl or acylketenes 364, which can be trapped in a number of ways170-171. in many cases, loss of acetone and CO2 is accompanied by loss of CO to give a carbene, and this is illustrated by FVP of 365 at 560 °C which affords the Q -diketone 368 by way of ketene 366 and carbene 367172. 

Dimethyl-l,3-dioxane-4,6-dione 0.58 g, 4.0 mmol (Meldrum s acid)... 

A new, simple, synthesis of 2,4-diaryl-l, 3,5-triazines is shown in Scheme 1. It arose from an attempt to obtain the pyrano[4,3-rf]pyrimidine system by reacting aryl amidines with the 3-methoxymethylenedihydropyran-2,4-dione (1 X= CH2). As well as the desired products, diaryl-I,2,3-triazines were obtained in 30-40% yield. The use of 5-methoxymethylene-2,2-dimethyl-l,3-dioxan-4,6-dione (1 X= 0)(derived from Meldrum s acid) gives the triazines in better yield (> 50%). It was also observed that 3-methoxymethylenefuran-2,4-dione reacted with 5-methylisothiouronium bromide to yield 2,4-bismethylthio-l,3,5-triazine [95M99]. 

McNab and coworkers95 have made and 13C DNMR and X-ray crystallographic studies of a series of mono-, di- and trienamines based on dimethyl malonate (43a-43c) and on 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum s acid 44a-44c). As expected, the C—N barriers (Table 8) were found to decrease with increasing conjugation (except for 43a), and they were also found to be higher for the cyclic compounds than for the corresponding acyclic diesters, also in agreement with previously discussed results. In these compounds, there are several possibilities for C=C rotations, but it seems as if... 

Preparation of 2,2-dimethyl-l,3-dioxane-4,6-dione-5-(3-methoxybenzyl) ketone... 

A solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (65 mmol) and pyridine (100 mmol) dissolved in CH2C12 at 0°C was treated with the dropwise addition of 3-methoxyphenylacetyl chloride (10.0 g) over 2 hours, then stirred an additional 2 hours at ambient temperature. The mixture was partitioned between 2 M HC1 and CH2C12, the organic layer isolated, dried, and concentrated. The residue was isolated as an oil and used without further purification. 

Dimethyl-l,3-dioxane-4,6-dione (50g) (Meldrum s acid) was dissolved in a solution of 100 ml pyridine and 400 ml CH2CI2, cooled to 5°C, and the product from Step 1 (10.00 g) added over 1 hour. The mixture was acidified using 400 ml 2M HCl, the layers separated, and extracted with CH2CI2. The extracts were washed twice with 120 ml 2M HCl, water, and concentrated. The residue was dissolved in 200 ml ethyl alcohol, refluxed 1 hour, and the reaction extent monitored by TLC on silica gel using EtOAc/petroleum ether, 40 60, where an Rf = 0.7, 0.1 for the product and stating material, respectively, was observed. The solution was concentrated, the residue extracted 3 times with toluene, washed twice with 100 ml water, 100 ml NaHC03, dried, and concentrated. H-NMR data supplied. 

A solution of benzoyl chloride (60 mmol) dissolved in 50 ml CCI3H was added dropwise over 1 hour to a cold solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum s acid) (50 mmol) dissolved in 150 ml CCI3H containing 4-dimethylamino-pyridine (100 mmol). The cold mixture reacted one hour while stirring and then stood at ambient temperature for one hour. The mixture was washed three times with 30 ml 10% HCl, the organic... 

Dimethyl-l,3-dioxane-4,6-dione (Meldmm s acid) (O.lOmol) and pyridine (0.25 mol) were dissolved in 200 ml CH2CI2 and the mixture cooled with ice. Octadecyl-1,18-dicarboxylic acid dichloride (0.05 mol) dissolved in 50 ml CH2CI2 added over 15 minutes, and the reaction mixture stirred 30 minutes while being kept cool with ice. The mixture was then treated with 100 ml apiece 10% HCl and CH2CI2 and solvent removed under reduced pressure at ambient temperature. Thereafter, precipitated crystals were isolated by filtration, re-crystallized using CH2Cl2/diethyl ether, 1 5, and the product isolated, MP = 96-98 °C. H- and i C-NMR data supplied. 

Tosyloxyimino)-2,2-dimethyl-l,3-dioxane-4,6-dione l,3-Dioxane-4,5,6-trione, 2,2-dimethyl-, 5-0-[(4-methylphenyl)sulfonyl]oxime (9) (215436-24-1)... 

Meldrum s acid, (2,2-dimethyl-l,3-dioxane-4,6-dione), is available from the Janssen Chimica Society (France) or can be prepared from malonic acid and acetone. The checkers purchased Meldrum s acid from the Aldrich Chemical Company, Inc. 

Derivatives of 2,2-dimethyl-l,3-dioxan-4,6-dione (Meldrum s acid) and the sodium salts of substituted malonic esters undergo electrophilic C-arylation in high yield with aryllead triacetates this provides a useful route to a-arylalkanoic acids, compounds of interest in the pharmaceutical industry and as synthetic intermediates (Scheme 13.8) [36]. 

In a typical experiment 200 mg of Zr(03POK)2 were added to a solution of piperonal 1 (75 mg, 5 mmol) and Meldrum s acid 2a (72 mg, 5 mmol) in dichloro-methane (2 mL) placed in a 100-mL round-bottomed flask. The solvent was removed under reduced pressure. The round-bottomed flask was placed in a micro-wave oven (Whirlpool, M430, Jet 900) and irradiated (450 W) for a total of 14 min and in 2-min intervals. After cooling, the crude product was purified by sublimation (10 mTorr, isomantle at a temperature between 180 and 220 °C) to give 5-(3,4-methylenedioxyphenyl)methylene-2,2-dimethyl[l,3]dioxane-4,6-dione 3a (0.14 g, 100%), mp 179°C. 

To stirred Dowtherm (600 mL) preheated to 245-250°C was added 5-( [2-(4-pyiidyl)pyriniidin-4-yl]-amino]methylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (15.6 g, 48 mmol). The mixture was kept at this temperature for 4 min, and then cooled to rt. The tan solid that crystallized was collected, washed with CHClj and dried yield 6.19 g (57%) mp > 300°C. 

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