Amines malonates

Fig. 9.1 Yields and ee values for ring-opened products prepared using [Rh(PPF-P Bu2)l] catalyst in the presence of activated amines, malonates, or ammonium carboxylates.

Keywords aromatic aldehyde, primary amine, malonic acid monoethyl ester, Rodionov reaction, microwave irradiation, / -aryl-/ -amino acid ester, ethyl cinna-mate... 

Amines, malonates, and methanol are useful nucleophiles in the formation of pyrones 216 (75CPB2390 84CPB3384). 

Hydrogen bromide Hydrogen chloride Hydrogen cyanide Hydrogen fluoride Hydrogen sulfide Isobutyric acid Isopropyl amine Malonic acid Methacrylic acid Methane Methanol... 

Acyclic malonic esters react with most aldehydes under fairly mild conditions (secondary amines with warming), but ketones and less reactive aldehydes require conditions such as the Lehnert conditions (TiCU/amine). Malonic esters have a propensity to provide the bis-adducts via Michael addition. Cyclic malonic esters (such as Meldrum s acid) are more reactive than the corresponding acyclic versions, with reactions with simple aldehydes proceeding without catalyst in DMF or DMSO. Formation of the bis-adduct is also more common with cyclic esters, especially in the coupling with unbranched aliphatic aldehydes. ... 

It is now applied more widely to include malonic acid derivatives, such as diethyl monoethyl-malonate, ethyl cyanacetate, etc. Various amines may be used as catalysts, and usually the most effective is piperidine (hexahydro-pyridine) a mixture of piperidine and pyridine, or pyridine alone, is also often used. 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Nu = malonate anion, amines, thiolate anion, enamines, cuprates (usually requires double activation of cyclopropane)... 

The carbopalladation is extended to homoallylic amines and sulfides[466. Treatment of 4-dimethylamino-l-butene (518) with diethyl malonate and Li2PdCl4 in THF at room temperature leads to the oily carbopalladated complex 519, hydrogenation of which affords diethyl 4-(dimethylamino) butylmalonate (520) in an overall yield of 91%. Similarly, isopropyl 3-butenyl sulfide (521) is carbopalladated with methyl cyclopentanonecarboxylate and Li2PdCl4. Reduction of the complex affords the alkylated keto ester 522 in 96% yield. Thus functionalization of alkenes is possible by this method. 

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

Allylation under basic conditions. Allylation can be carried out under basic conditions with allylic acetates and phosphates, and under neutral conditions with carbonates and vinyloxiranes. The allylations under neutral conditions are treated separately in Section 2.2.2.1 from those under basic conditions. However, in some cases, allylations of the same substrates are carried out under both basic and neutral conditions to give similar results. These reactions are treated together in this section for convenience. Allylic acetates are widely used for Pd-catalyzed allylation in the presence of bases tertiary amines or NaH are commonly used[6,7,4l]. As a base, basic alumina or ICF on alumina is conveniently used, because it is easy to remove by filtration after the reaction[42]. Allyl phosphates are more reactive than acetates. The allylation with 40 proceeds stepwise. At first allylic phosphate reacts with malonate and then allylic acetate reacts with amine to give 41(43]. 

Like butadiene, allene undergoes dimerization and addition of nucleophiles to give 1-substituted 3-methyl-2-methylene-3-butenyl compounds. Dimerization-hydration of allene is catalyzed by Pd(0) in the presence of CO2 to give 3-methyl-2-methylene-3-buten-l-ol (1). An addition reaction with. MleOH proceeds without CO2 to give 2-methyl-4-methoxy-3-inethylene-1-butene (2)[1]. Similarly, piperidine reacts with allene to give the dimeric amine 3, and the reaction of malonate affords 4 in good yields. Pd(0) coordinated by maleic anhydride (MA) IS used as a catalyst[2]. 

Z-Furan. 3-(5-Nitro-2-furanyl)-2-propenamide, is prepared by condensation of 5-nitro-2-furancarboxaldehyde diacetate with malonic ester followed by PCl chlorination and amination (29). The product was marketed in Japan as a food preservative. 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

Diphenylcinnoline can be prepared from benzil monophenylhydrazone in the presence of about 80% sulfuric acid (49MI21200). Synthetically more important, however, is the cyclization of mesoxalyl chloride phenylhydrazones under Frledel-Crafts -conditions (61JCS2828). As outlined in Scheme 67, the starting mesoxalate phenylhydrazones are obtained by coupling dlazotized aromatic amines with diethyl malonate. After conversion... 

Halogenopyrimidines react with active methylene groups, such as those in diethyl malonate, ethyl cyanoacetate, ketene diethylacetal, etc. For example, 4-chloro-6-methyl-5-nitropyrimidin-2-amine (454) and dimethyl sodiomalonate give dimethyl 2-amino-6-methyl-5-nitropyrimidin-4-ylmalonate (455) (63ZOB3132) 2-chloro-4,6-... 

Tlie bifunctional sulfenyl chloride 213 was obtained by chlorination of 144 in good yield, although excessive chlorination led to the saturated compound 214 (94CB533). A series of compounds 215-220 were obtained from 213 by reactions with secondary amines ferf-butyl methyl ketone hexane-2,4-dione 2,6-dimethylcyclohexanone diethyl malonate and acetylacetone, respectively. 

Comprehensive work in this field has been done by Slovak authors (98MI1, 95M1359, 96CCC269, 96CCC371, 97CCC99). They prepared 2-substituted (H, Me, Ph) 4-, 5-, 6-, and 7-nitrobenzoxazoles, which were then reduced to amines (not isolated) and subjected to subsequent nucleophilic substitution with activated enol ethers such as alkoxymethylene derivatives of malonic acid esters and nitrile, 3-oxobutanoic acid esters, pentanedione, or cyanoacetic acid esters to yield aminoethylenes 8. 

Following the action of extraordinary stimulants (hypoxic hypoxia, hypoxia + hyperoxia, hypodynamia + hyperthermia), animals demonstrate an accumulation of malonic dialdehyde with a simultaneous fall of antiradical activity of the liver tissue. A preliminary introduction to rats of acetylene amine 3,4,5-tris(morpho-linopropynyl)-l-methylpyrazole 103 and also of tocopherol antioxidant and gutumine antihypoxant averts activation of the lipid peroxidation processes. The inhibition of peroxidation with this agent is mediated by stabilization of ly-zosomal and mitochondrial membranes. Unsaturated amines prevent destruction of the organelle membranes provoked by UV irradiation and incubation at 37°C (pH4.7)(78MIl). 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

An electrochemical method for amination has been reported by Shono et al. Derivatives of malonic esters containing an N-tosyl group were cyclized in high... 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

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