Acylation dimethyl malonate

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

Scheme 6.123 Spectrum of adducts of the 122-catalyzed asymmetric Mannich addition of dimethyl malonate to acylated aldimines.

Alkylation of vinyl epoxides. Although Pd(0) catalyzes the rearrangement of vinyl epoxides (9,452-453), alkylation of cyclic or acylic vinyl epoxides with dimethyl malonate under neutral conditions is possible with the same catalyst or with bis[l,2-bis(diphenylphosphino)ethane]palladium. The rearrangement and alkylation proceed with different regio- and stereoselectivity.19... 

Gutman,50 in his process route, which did not report any yields, hydrogenated the pyridine ring first to access the piperidine moiety and constructed the indanone ring system via an intramolecular Friedel-Crafts acylation (Scheme 5). Hydrogenation of diester 31, obtained from condensation of 4-pyridine carboxaldehyde and dimethyl malonate, followed by benzylation of the piperidine intermediate afforded A-benzylated piperidine 32. Alkylation of 32 with 3,4-dimethoxybenzyl chloride (33) and subsequent hydrolysis gave dicarboxylic acid 34. Subjection of 34 to strong acid resulted in intramolecular Friedel-Crafts acylation and in situ decarboxylation to provide 3. 

As a mechanistically interesting example the reaction of an unsaturated dimethyl malonate derivative with Mn(OAc)3 resulted in the formation of substituted cyclopentanes. The primary radical can either be trapped by CO or cyclize to an unstable radical intermediate, which in turn reacts with CO. Because the trapping of the first-generated radical is reversible, the cyclized acyl intermediate gives the desired product after oxidation [52]. 

Cyclic vinyl epoxides are versatile building blocks (Table 11) which have been used in palladium-assisted routes to carbocyclic nucleosides. A formal synthesis of ( )-aris-teromycin101, the carbocyclic analog of adenosine, has been accomplished employing ni-tromethane as the nucleophile which serves as an acyl anion equivalent (Table 11. entry 2). The aldehyde is released by subsequent basic potassium permanganate oxidation. If nitromethane is used diluted in tetrahydrofuran, then a mixture of mono- and bis-alkylated product is formed. Whereas the alkylation of cyclohexenoxide with dimethyl malonate proceeds in a 1,4-crs fashion under palladium(O) catalysis, the 1.2-/ra/i.v-product is formed under basic conditions in the absence of the palladium(O) catalyst. 

Allyl A,A-ditosyhmides and allyl A-acyl-A-tosylimides can be used as substrates for the Pd-catalyzed reaction with nucleophiles. The Pd-catalyzed aUylation of dimethyl sodiomalonate gives mono- and diallylated dimethyl malonate (Scheme... 

Complexation of alkenes to iron carbonyl fragments increases the electrophilicity of the alkene, owing to the electron-withdrawing ability of the carbonyl ligands. The anion of dimethyl malonate will attack the iron tetracarbonyl complex of methyl acrylate 6.295 (Scheme 6.113). " The resulting anion 6.296 is obviously related to the intermediates involved in the reactions of Collman s reagent (Section 4.5.1). Thus, carbonylation and addition of an alkyl halide results in acylation. 

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). 

Shaprio described a nonoxidative method for preparing 2-substituted 4-ox-azolecarboxylic acid esters 591 (Scheme 1.161). He prepared the key intermediate, dimethyl amino[(phenylthio)methyl]malonate 588, in three straightforward steps from diethyl aminomalonate hydrochloride. Acylation of 588 gave the A-acyl derivative 589 in excellent yield, which was sequentially chlorinated and cyclized in one pot to afford the 2,4,4,5-tetrasubstituted oxazoline 590. The author noted that anhydrous conditions were required to minimize sulfoxide formation. This was the only product isolated if the chlorination cyclization sequence was carried out in a hydroxylic solvent. 

Treatment of [ C]malonic acid with oxalyl chloride in the presence of catalytic amounts of DMF affords [ C]malonyl chloride in nearly quantitative yield. The structure of the reagent was confirmed by acylation of 2-methoxypropene, which provided a 3 1 mixture of phloroglucinol monomethyl ether (428) and 4-hydroxy-6-methyl-2//-[2,4- " C]pyran-2-one (427). Etherification of the latter with dimethyl sulfate followed by ring opening upon treatment with sodium methoxide and recychzation afforded 429, which was combined with the original portion of 428 and etherified to give 1,3,5-trimethoxy-[1,3,5- C]benzene, which was used as a key intermediate in the synthesis of several carbon-14 labeled cholesterol acyltransferase inhibitors . ... 

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