Malonic ester system

The sodiocompound may be written [CHtCOOCjHjij] Na, and it must always be home in mind that the anion is mesomeric. The system reacts smoothly with an alkyl halide to give a C-substituted malonic ester, evidently through the carbanion (I) ... 

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Blocked isocyanates are particularly helpful in dual cure mechanisms. In one instance, UV light first polymerizes an acrylate polymer containing hydroxyl groups. The system also contains a malonate ester-blocked isocyanate. The one-component system is heated, which starts the polymerization of the acrylate. Higher temperatures unblock the isocyanate, permitting the cure of the urethane to proceed [15]. 

Tabushi and Fujiyoshi have prepared alkylated cyclam derivatives for the purpose of suspending these systems from a polymer backbone. They have utilized a malonic ester alkylation reaction followed by cyclization and reduction to accomplish this end. ... 

An other procedure for constructing this ring system started with 2-methylbenzimidazole 583 whose reaction with malonic ester 584 gave 585... 

These model reactions were of great value in the extension of the C-glycosylation reaction with malonic esters to five-membered ring-systems. Treatment of 2,3 5,6-di-O-isopropylidene-a-D-manno-furanosyl bromide122,123 (150) with diethyl sodiomalonate led to an anomeric mixture of C-glycosyl compounds that could be separated by column chromatography, with the a (151) and /B (152) anomers in... 

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]. 

Esters are hydrolysed under basic conditions in the presence of quaternary ammonium salts [e.g. 1-7], Microwave activation of basic soliddiquid systems without an added solvent enhances the rate of saponification and the reaction is not affected by steric factors [3], Microwave irradiation has also been used in the hydrolysis and decarboxylation of malonic esters [8] and p-keto esters [9] (>90%). Lactones... 

When a new carbon-carbon bond is produced by nucleophilic addition to conjugated systems, the process is called Michael addition. The generalised process involves an a, b-unsaturated compound and a compound containing an active hydrogen attached to a carbon atom (e.g., malonic ester, acetoacetic ester, nitrocompounds, aldehydes, ketones etc.) These are condensed in the presence of a base. The overall reaction and its mechanism can be represented as follows ... 

Carrie and co-workers studied the cycloaddition of oxime esters derived from methyl cyanoacetate and malonate esters 82 (Scheme 8.20) with diazomethane and some monosubstituted derivatives. Thermally labile 1,2,3-triazolines 83 were obtained when tosyloxy- and benzoyloxyimines were used (141), while methyl acetoxyimino-cyanoacetate (82, X = CN, Y = C02Me, = Ac) gave products derived from both a 1,2,3- and a 1,2,4-triazoline, depending on the stmcture of the diazo compound (142). Not unexpectedly, diazomethane reacted with the corresponding imino-malononitrile (82, X = Y = CN) system at the nitrile function rather than at the C=N bond (143). 

The straightforward step used to form the ring system means that the chemistry involved in the preparation of the scores of barbiturates that have been used clinically in fact devolves on the syntheses of the various malonic esters. It should be noted that little success has been achieved in changing the side effect spectrum of these dmgs. The main differences between the various agents involve their pharmacokinetic properties these in turn are manifested as variations in bioavailablity by parenteral and oral routes as well as in time to the onset and duration of action. 

Stabilized carbon nucleophiles (e.g. from 3-diketones, 3-keto esters, malonate esters, etc.) can be aryl-ated by substitution for chloride on the arene in (Fe(arene)Cp] cation complexes.72-78 81 A base is necessary and two heterogeneous systems are favored potassium carbonate in DMF or potassium fluoride prepared on Celite-545. As usual in the [FeCp]+ system, detachment of the substituted arene requires somewhat extreme conditions, usually pyrolytic sublimation at 200 C.46 An example is given in equation (27). 

A palladium-cataly/ed C-C coupling reaction—the Heck reaction — is used in the construction of bicyclic system 13. Cyclization leads to a q3-alIyl-Pd complex, which undergoes nucleophilic attack by malonic ester anion 12. This in turn leads to formation of the C4 side chain The mechanism of this reaction therefore differs from that of a normal Heck reaction. 

A general convenient alkyl methyl ketone synthesis, which utilises the /7-keto ester system as an intermediate, involves the acylation of a malonate ester by way of the ethoxymagnesium derivative. Hydrolysis and decarboxylation to the ketone is accomplished by heating in acid solution the synthesis of cyclohexyl methyl ketone is the illustrative example (Expt 5.96). 

Unlike the reversed shift of the emission band compared to the dihydrogen addend type, the singlet lifetime in the bis- and tris(bis-(ethoxycarbonyl)-methylene) derivatives is increased comparable to the former multiple adducts. The values range from 1.7 to 3.1 ns (tris-adduct), depending on the distorted T7-electron system of the fullerene core [67,108], In comparison to C6o, the fluorescence quantum yield for the malonic ester hexaadduct is increased by the factor 10 (30 X 10 4) [67,111], In the case of both pyrrolidino hexa-adducts (Th 14 and D3 15, Fig. 13), the effect is remarkably higher. The fluorescence quantum yields are increased about 100-fold (-0.02) compared to C6o. On the other hand, the singlet lifetime is only partly increased with -3.5 ns [111,112],... 

Figure 6.8 Proposed mechanism for lactone ring formation. Cardenolides an intermediate malonate ester is involved, and ring formation probably occurs via an aldol addition process giving the cardenolide digitoxigenin, the carboxyl carbon of the malonate ester being lost by decarboxylation. Bufadienolides three carbons from oxaloacetate can be incorporated by a similar esterification/aldol reaction sequence to yield the cumaline ring system. (From Dewick, 2002.)...

Cyanide (method 388), sulfone, " or nitro compound," " The vinyl group in the alpha or gamma positions on the pyridine nucleus also "ndergoes this type of addition. " The activity of the labilizing group is trans- mitted to the terminal double bond of a vinylogous system. Thus, methyl vinylacrylate reacts with malonic ester as follows ... 

The 1,4-naphthoquinone system is not only a good acceptor for stabilized carbanions, as exploited by Kraus and Wu [31, 32] (see Scheme 6), but also for radicals. The angular skeleton of the benzo[fl]anthraquinone system is constructed in an elegant one-step transformation by a manganese (Ill)-induced radical addition of a malonic ester derivative 161 to 1,4-naphthoquinone 40 followed by addition of the newly generated radical to the benzene ring to form 162 (Scheme 41) [111], However, the principle has not yet been used in advanced syntheses of angucyclinones. 

In this sequence, malonic ester was used as a synthetic equivalent of the enolate anion derived from acetic acid. The presence of an additional carboxyl substituent served as an auxiliary tool to stabilize the enolate species. This approach was extended to the alkylation of enolates of more complicated structure, but here it was mandatory to create first the required )8-dicarbonyl system by supplementing the initial structure with an additional carbonyl substituent. This auxiliary operation, while being generally viable, noticeably... 

In the biosynthesis of fats (Sec. 37.6). long-chain carboxylic acids arc made via a series of what are basically malonic ester syntheses. Although in this case reactions are catalyzed by enzymes, the system still finds it worthwhile to consume carbon dioxide to make a malonyl compound, then form a new carbon-carbon bond, and finally eject the carbon dioxide. 

The function of the base is to abstract (step 1) a hydrogen ion from malonic ester and thus generate a carbanion which, acting as a nucleophilic reagent, then attacks (step 2) the conjugated system in the usual manner. 

When adding malonic ester anion to an allenic sulfoxide, rearrangement of the derived addition product leads to an allylic alcohol which cyclizes to (18) and isomerizes to the isolated product (19). If one alkylates the intermediate carbanion one gets an entry to a -methylenelactone system (18 Scheme 23). ... 

C. Wiese and co-workers have synthesized 5-fluoro-D/L-dopa and the corresponding [ F]5-Fluoro-L-dopa starting from 5-nitrovanillin via malonic ester synthesis, the Balz-Schiemann reaction, and the separation of the racemic mixture [ F]5-fluoro-D/L-dopa utilizing a chiral FIPLC system. The inactive 5-fluoro-D/L-dopa was obtained in an eight-step synthesis with an overall yield of 10%. 

Russell, R. R., VanderWerf, C. A. Malonic ester synthesis with styrene oxide and with butadiene oxide. J. Am. Chem. Soc. 1947, 69,11-13. Mizuno, Y., Adachi, K., Ikeda, K. Condensed systems of aromatic nitrogenous series. XIII. Extension of malonic ester synthesis to the heterocyclic series. Pharmaceutical Bulletin 1954, 2, 225-234. 

Silyl enol ethers can be modified prior to Heck reaction by treatment with BuSC F, Either a 5 5-fused or 5 6-fused ring system can be created from an acyclic bromoalkadiene with is terminated at one end with a malonate ester residue. The phosphine ligand and additives control the reaction pathways. ... 

Another type of reaction which has been realized with the allyl system is the so-called Sn2 displacement. Here the attacking reagent strikes an atom different from the one to which the halogen atom is attached. An allylic shift occurs, and the halogen atom is displaced. Thus, when 3-chloro-l-pentene (XVI) is allowed to react with sodiomalonic ester, 2-pentenyl malonic ester is obtained (XVII).19 Second-order kinetics... 

Similarly, by treatment with malonic ester, 2-amino-1,4,5,6-tetrahy-dropyridine-3-carboxylate (13) is smoothly and exclusively converted to the pyrido[l,2-a]pyrimidine system 193.116 Basic catalysts convert asymmetrical 1,3-dicarbonyl compounds, such as acetoacetates 194 and cycloalkanone-2-carboxylates, to pyrido[l,2-a]pyrimidines 195 and 197a isomers such as 198 were not found.116 Structures 195 and 197a are supported by their UV spectra.117,118 H-NMR spectroscopy of 195 reveals a tautomeric equilibrium (1951 195II)116 (Scheme 46). 

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