Dialkyl malonate

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

Diisopropyl Malonate. This dialkyl malonate has gained industrial importance for the synthesis of the fungicide dialkyl malonate... 

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

On heating with aqueous hydrochloric acid, the alkylated (or dialkylated) malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of C02) to yield a substituted monoacid. 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

The carbanions are involved in a number of substitutaion reactions. The example are the formation of mono and dialkyl malonic esters. 

In the previous section, aminomethylenemalonates were obtained in the reactions of amines and alkoxymethylenemalonates. The latter were prepared in a separate step from dialkyl malonates and alkyl orthoformate. Aminomethylenemalonates can also be synthetized in a one-pot procedure, starting directly from the amine, dialkyl malonate, and alkyl orthoformate or its equivalent. 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

The reactions of anilines, alkyl orthoformate, and dialkyl malonates in the presence of FeCI3 catalysts at I00-I40°C for 6 hr gave dialkyl arylaminomethylenemalonates (256) in very good yields (87M1P3 880PP93). 

Pyridylaminomethylenemalonates (262) were prepared in over 90% yields in the reactions of 2-aminopyridines, ethyl orthoformate, and dialkyl malonates at 130°C for 3-6 hr (73GEP2227651 87SC549). 

In the uncatalyzed condensations of 2-aminopyridines, alkyl orthoformate, and dialkyl malonate at 110°C, 2-pyridylaminomethylenemalona-mates (263, R = H, Me R1 = Me, Et) were obtained in 20-25% yields. When isoamyl orthoformate was applied, a 5.2 4.8 mixture of ethyl and isoamyl N-(6-methyl-2-pyridyl)aminomethylenemalonamates (263, = Me, R1 = Et and isoamyl) was isolated in 90% yield (87SC549). 

The reactions of urea, dialkyl malonates, and alkyl orthoformates at reflux temperature for 10 hr gave dialkyl ureidomethylenemalonates (268, R = H) in 40% yield (53JA671), while in the reaction at I30°C for 4 hr the yield was 66-69% [77JAP(K)131529 81CPB3181]. 

Arylaminomethylenemalonates (303) were obtained in 82-95% yields in the reactions of dialkyl malonates and N-arylformimidates in the presence of a catalytic amount of base (piperidine, sodium methylate, or potassium acetate) at 95-105°C for 24-30 hr (53USP2638480). 

Sodium methylate, potassium acetate, and piperidine were also applied as catalysts in the reactions of amidines and dialkyl malonates (53USP2638480). 

The reactions of ethyl cyanoformate and dialkyl malonates in the presence of zinc chloride and triethylamine, or in the presence of TiCl4 or SnCl4 in methylene chloride at reflux temperature for 3 hr, or at room temperature overnight, gave amino(alkoxycarbonyl)methylenemalonates (314, R1 = Et) in good yields [79TL2525 81JAP(K)71050],... 

The reactions of malononitrile and dialkyl malonates in the presence of Ni(acac)2 as catalyst in boiling chloroform under nitrogen afforded (2-cyano-l-aminoethylidene)malonates in about 22% yields (86MII1) (Scheme 28). 

Dialkyl malonates were reacted with trichloroacetonitrile in methylene chloride in the presence of Ni(acac)2 catalyst under nitrogen at room temperature for 3 hr to give dialkyl (2,2,2-trichloro-l-aminoethylidene) malonates in 65% and 80% yields (86M15) (Scheme 29). 

The SnCl4-promoted reactions of dialkyl malonates with nitriles in boiling benzene or toluene for 2-4 hr, or at ambient temperature for... 

Thioiminium salts (335) were reacted with dialkyl malonates in the presence of sodium hydride in 1,2-dimethoxyethane (DME) to give dialkyl aminomethylenemalonates (336) in 21-43% yields (88TL2299). 

The sodium salts of dialkyl malonates were reacted with isothiocyanates (346) in diethyl ether or in THF at -10°C-0°C. The products were then alkylated with alkyl halides to give mixtures of tautomeric (alkylthio)ami-... 

When reacted with trialkyl phosphite in benzene for 1 hr, dialkyl magnates (364, X = F) gave a mixture of amino(trifluoromethyl)methylene-malonates (365) (20% yields), dialkyl trifluoromethyl(substituted amino)-methylenemalonates (366) (40-45% yields), and dialkyl chlorophosphate (-20%) (86ZOB805). The reactions of dialkyl malonates (364, X = F, Cl) and triphenylphosphine in the presence of triethylamine in diethyl ether for 1 hr gave trihalomethyl(substituted amino)methylenemalonates (367) in 87-95% yields. The treatment of a solution of dialkyl trifluoromethyl-(substituted amino)methylenemalonates (366, R1 = Et) in benzene with aqueous hydrochloric acid gave amino(trifluoromethyl)methylene-malonates (368) in 82-84% yields (86ZOB805) (Scheme 32). 

Because of the higher CH acidity (by 7-8 pKa units) of alkylidene malonates (441), as compared with that of dialkyl malonates (87JA809), one-pot syntheses of alkylidene aminomethylenemalonates (442) could be carried out readily with a wide variety of primary and secondary aliphatic and cycloaliphatic amines, anilines, naphthylamines and heterocyclic amines, trialkyl orthoformate, and alkylidene malonates (83MI1 86MI9). It was proposed that the higher CH acidity of alkylidene malonates was a consequence of the electrostatic (dipole-dipole) repulsion effects... 

Dimethyl and diethyl (l-methylpyrrolidin-2-ylidene)malonates (e.g., Scheme 38,467, n = 0, R = R1 = Me, Et R2 = H R4 = Me) and diethyl (l-methyl-l,2-dihydroquinolin-2-ylidene)malonate were obtained in 30-52% yields when l-methylpyrrolidin-2-one and 1-methyl-1,2-dihydroquinolin-2-one were first reacted with phosgene and then with dialkyl malonates in the presence of triethylamine in benzene at 60°C (61CB2278 69JA6683). 

In the reactions of /rans-2-iodocyclohexyl isothiocyanate and dialkyl malonates in the presence of sodium hydride in diethyl ether, or in the presence of butyllithium in THF at room temperature for 10-20 hr, 2-(c/s-octahydrobenzothiazol-2-ylidene)malonates (530) were obtained in 69-87% yields (85AJC745). 

Ketene can also be oxidatively carbonylated, using PdC as the catalyst and alkyl nitrites as the oxidant, to give dialkyl malonates (Eq. 26) [125]. Ke-todiesters have been obtained from diketene (Eq. 27) [126]. 

Overall, the process requires the consumption of two electrons and two protons. The structure and acidity of effective proton donors vary from mineral to carbon acids often, a simple dialkyl malonate is effective. It is easy to monitor current consumption using a simple, commercially available coulometer [3,4]. 

Scheme 6.56 Typical products of the asymmetric Michael addition of dialkyl malonates to frans-P-nitrostyrenes in the presence of 12.

The presented protocol tolerated a spectrum of enolizable species including dialkyl malonates, 1,3-diketone, ketoester, 1,3-dinitriles, and nitroesters to be added to the model trons-chalcone 1,3-diphenyl-propenone producing the desired Michael adducts in good to excellent yields (67-99%) and with attractive ee values (88-93%). Figure 6.41 shows some selected results of the nucleophile evaluation. 

Scheme 6.126 Mannich adducts obtained from the 121- and 124-catalyzed asymmetric addition of dialkyl malonates to N-Boc aldimines. The product configurations were not determined.

Reactions of magnesium dialkyl malonate or magnesium hydrogen alkyl... 

Diketones react more rapidly with fluorine than the corresponding keto-esters, and dialkyl malonates do not react at all under these conditions. However, if dialkyl malonates are first converted into their sodium salts, reaction with fluorine gives the corresponding fluoro-compound (Fig. 50) [128]. 

Olefins react with manganese(III) acetate to give 7-lactones.824 The mechanism is probably free-radical, involving addition of CH2COOH to the double bond. Lactone formation has also been accomplished by treatment of olefins with lead tetraacetate,825 with a-bromo carboxylic acids in the presence of benzoyl peroxide as catalyst,826 and with dialkyl malonates and iron(III) perchlorate Fe(C104)3-9H20.827 Olefins can also be converted to 7-lactones by indirect routes.828 OS VII, 400. 

---