A-Aminomalonates

Scheme 11 Reaction control in the SCR of aldehydes diethyl a-aminomalonate and nitroalkenes...

On the other hand, Chen et al. have reported an asymmetric three-component reaction of aldehydes, diethyl a-aminomalonate and nitroalkenes. The Michael adducts were obtained in excellent yields and enantioselectivities of up to 98% ee by using a chiral bifunctional urea-tertiary amine as the organo-catalyst (Scheme 1.64). 

Amere, M. Lasne, M. C. Rouden, J. Highly Enantioselective Decarboxylative Protonation of a-Aminomalonates Mediated by Thiourea Cinchona Alkaloid Derivatives Access to Both Enantiomers of Cyclic and Acyclic a-Aminoacids. Org. Lett. 2007, 9, 2621. 

Proper electron delocalization is thus important. Furthermore, the presence of a hydroxyl group for chelation with metal ions appears essential. Surprisingly, with a-phenyl-a-aminomalonic acid in the presence of Cu(II) and appropriate model compounds (see below), an oxidation reaction takes place which has no biological precedent (303). 

A one-pot, three component 1,3-dipolar cycloaddition reaction of aldehydes (289), a-aminomalonate (290), and nitroalkenes (291) has been developed through 3,3 anthiyl substituted hinaphthol derived chiral phosphoric acids (292) (Scheme 78). ... 

MichaeU-Henry Reaction Liu et al. and Xie et al. independently found that tertiary amine-thioureas could stereoselectively promote the addition of diethyl a-aminomalonate-derived azomethine ylides to nitroolefms, affording Michael adducts other than dipolar cycloaddition adducts as the major products. Using monofunctional chiral thioureas 140d instead of tertiary amine-thiourea catalysts, Liu et al. successfully developed a three-component [3-1-2] dipolar cycloaddition of benzaldehydes 3, diethyl a-aminomalonates 45a, and nitrostyrenes 165, resulting directly in the enantioenriched pyrrolidines 208 as the only products (Scheme 2.56) [81a] while Xie et al. efficiently converted the Michael adducts 210 to pyrrolidines 208 in high yield and maintained ee by the use of 30 equiv of 2,2,2-trifluoroethanol as the additive (Scheme 2.56) [81b]. 

Amere M, Lasne MC, Rouden J. Highly enantioselective decarboxylative protonation of a-aminomalonates mediated by thiourea cinchona alkaloid derivatives access to both enantiomers of cyclic and acyclic a-aminoacids. Org. Lett. 2007 9 2621-2624. 

The a-aminomalonate anion reacts with ra 5-[Co(en)2Cl2] in the presence of triethylamine to give a-diamine and carbinolamine complexes/ " Reaction in aqueous solution gives the carbinolamine complex in the presence of air, but under N2 the a-diamine is preferentially formed. The complexes (11) and (12) have been characterized by visible spectra, and CNMR, and the crystal structure of the complex (11) determined. 

A further important advance was also achieved by Rouden et al. [17] who developed the use of thiourea cinchona alkaloids 33-34 in the enantioselective decarboxylative protonation of a-aminomalonates (Scheme 3.12). The basic idea in using these bifunctional catalysts was to take advantage of the good hydrogen-bond donor properties of the thiourea moiety to promote further interactions between the chiral proton source and the prochiral enolate intermediate. Bifunctional catalyst 33 in quinidine series turned out to be especially efficient with a large range of substrates... 

JCS2689) and 5-bromomethylpyrimidine (458) and diethyl benzyloxycarbonyl-aminomalonate (459) give initially, diethyl a-benzyloxycarbonylamino-a-(pyrimidin-5-ylmethyOmalonate (460) which can be degraded to 2-amino-3-(pyrimidin-5 -yl)propionic acid (461) (65JHCl>. 

Diethyl acetamidomalonate was first reported by Cherchez in 1931, when in an attempt to carry out a carbon alkylation of diethyl aminomalonate with acetyl chloride he obtained a quantitative yield of diethyl acetamidomalonate. This method of preparation, however, is not practical since diethyl aminomalonate is unstable and is made in relatively poor yields. 

Snyder and Smith prepared diethyl acetamidomalonate in 40% yield by reduction of diethyl isonitrosomalonate in ethanol over palladium on charcoal followed by direct acetylation of diethyl aminomalonate in the filtrate with acetic anhydride. Ghosh and Dutta used zinc dust instead of palladium. A modification using Raney nickel is described by Akabori et al. Shaw and Nolan reported a 98% yield by conversion of diethyl oximino-malonate-sodium acetate complex. 

B. Diethyl aminomalonate hydrochloride. The crude diethyl aminomalonate is diluted with 80 ml. of dry ether and filtered to remove a small amount of white solid. The filtrate is collected in a 250-ml. Erlenmeyer flask and cooled in an ice bath. Dry hydrogen chloride is passed just over the solution while it is being stirred mechanically (Note 6). The fine white crystals which precipitate are collected by suction filtration and washed three times with a total of 60 ml. of dry ether (Note 7). The filtrate and washings are treated again with hydrogen chloride, and a second crop of diethyl aminomalonate hydrochloride is collected and washed as before. This process is repeated until no further precipitation results from passing hydrogen chloride into the solution. A total of 16.5-17.4 g. (78-82% yield based on diethyl malonate) of diethyl aminomalonate hydrochloride, m.p. 162-163°, is obtained. Recrystallization from alcohol-ether affords a purer product, 164-165°. 

Diethyl aminomalonate is a useful intermediate, lending itself to N-acylation the N-acyl derivatives may be alkylated by procedures as established for syntheses via malonic ester. 

Intermediate carbenes are also involved in the alkylation by haloforms of carbanions derived from Schiff bases of a-ammo esters [126] or aminomalonates... 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

The formic acid Is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This Is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. 

B) Preparation of 7-Chloro-3-Methoxycarbony/-5-Phenyl-2-0xo-2,3-Dihydro-iH-Benzo [fl-1,4-Diazepine (4347 CB) A solution of 9.2 g (0.04 mol) of compound 4356 CB in 20 ml of methanol is added dropwise, in the course of one hour and 30 minutes, to a boiling solution of 9.2 g (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml of methanol. When this is completed, heating under reflux is continued for 30 minutes and the product then concentrated to dryness under reduced pressure. The residue is taken up in water and ether, the ethereal layer separated, the product washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue, which consists of the methyl ester, could not be obtained in the crystalline state. It is dissolved in 25 ml of acetic acid, heated under reflux for 15 minutes, the product evaporated to dryness and the residual oil taken up in ether. A colorless solid separates which... 

IB) 1-(2-Amino-5-chlorophenyl)-1-(2-fluorophenyl)-3,3-bis-(ethoxycarbonyl)-2-a2a-prop-1-ene A mixture of 88 g of the product obtained above, 300 g of ethyl aminomalonate hydrochloride and 60 ml of acetic acid in 2.3 liters of absolute ethanol is heated to the reflux temperature for 6 hours. The alcohol and the acetic acid are evaporated in vacuo and the residue is taken up in ether. The solution is washed with a dilute sodium bicarbonate solution and... 

A. G. Ogston in 1948 explained the dilemma of how an enzyme can enan-tiospecifically produce a chiral product from a prochiral molecule such as citric acid or 2-aminomalonic acid. He pointed out two requirements three-point contact at three active sites (a, b, and c ) and catalytic dissimilarity between the two active sites (a and b ) associated with the pro-R and pro-5 groups (a and b) of the prochiral molecule as shown in Fig. 3.2. 

Reagent and conditions i, diethyl chloromalonate, DMF ii, DBN, MeOH iii, AcOH, H2O iv, AcONa, diethyl aminomalonate HCI, MeOH/H20 v, MeONa, MeOH vi, 2,5-dimethoxyTHF, 4-chloropyridine hydrochloride, dioxane vii, pyrrolidine viii, (a)POCI3, (b) 10%NaOH... 

A facile synthesis of 5-substituted 3-aminopyrrole-2-carboxylates has been developed wherein condensation of diethyl aminomalonate with a-cyano ketones 46 was facilitated by prior formation of the p-toluenesulfonyl enol ether 47 <00JOC2603>. Addition of the amine component is followed by cyclization and decarboxylation to afford the pyrroles 48. 

The low percentage of obtaining products belonging to the a-kainic acid series (at best 50%) was attributed to unfavorable transition states with repulsion between one of the aminomalonate ester groups and the isoprenyl chain. These difficulties were circumvented by using a simple a-amino ester (131) in lieu of the aminomalonate group this has led to a simple synthesis of a-kainic acid (Scheme 33) (178). 

This sequence was obviously not amenable to a synthesis of optically active a-allokainic acid given the fact that an aminomalonate group was necessary. After unfruitful assays with menthyl esters, the Swiss group was rewarded by the discovery that the phenylmenthyl group (180) brings sufficient asymmetry to the reaction intermediate to afford products with a high percentage of favorable diastereoisomer (Scheme 35) (181). 

The joint action of primary or secondary amines (aniline, allylamine, benzylamine, butylmethylamine, iV-mcthylglycine methyl ester etc.) and copper bis(acetylacetonate) on the thiophen ylide 258 leads to dimethyl aminomalonates 259 by a carbene insertion reaction294. 

The stereoselective Michael addition of the anion derived from diethyl acetyl-aminomalonate with chalcone has been found to be most effective under soliddiquid two-phase conditions in the absence of an added solvent [62]. For optimum overall conversion and enantiomeric excess (56% with 60% ee), A-benzyl-V-methyl-... 

Palekar, A. G., Tate, S. S., Meister, A. Rat liver aminomalonate decarboxylase. Identity with cytoplasmic serine hydroxymethylase and allothreonine aldolase. J. Biol. Chem. 248, 1158-1167 (1973). 

Diethyl aminomalonate reacts with 1,3-diketones in boiling acetic acid to the corresponding pyrrolecarboxylates 11 (87JOC3986). From N-ac t-amidomalonate and acroleins, pyrrolidines were prepared and they were further transformed into functionalized pyrroles, which are a part of the antibiotic lyncomycin and an antimalarial agent (67JA2459 72JMC1255). 

A new synthetic method for 4-hydroxyproline was devised from N-acylated diethyl aminomalonate. In the first step this reacts with acrolein in the presence of a base to give 12 (90JHC507). 

The reaction of -protected aminomalonate with the Mitsunobu reagent (TPP and DIAD) gave a mixture of a triazoline as the main product and 53 (31%). This compound was formed by the attack of the azodicarboxylate oxygen rather than nitrogen during the cyclization step (88TL4661). 

In 2008, Gong and coworkers introduced a new chiral bisphosphoric acid 19 (Fig. 4) that consists of two BINOL phosphates linked by an oxygen atom for a three-component 1,3-dipolar cycloaddition (Scheme 42) [66]. Aldehydes 40 reacted with a-amino esters 105 and maleates 106 in the presence of Brpnsted acid 19 (10 mol%) to afford pyrrolidines 107 as endo-diastereomers in high yields (67-97%) and enantioselectivities (76-99% ee). This protocol tolerated aromatic, a,P-unsaturated, and aliphatic aldehydes. Aminomalonates as well as phenylglycine esters could be employed as dipolarophiles. 

This enzyme [EC 4.1.1.12], also known as desulfinase, catalyzes the conversion of aspartate to alanine and carbon dioxide. Pyridoxal phosphate is a required cofactor. The enzyme will also catalyze the decarboxylation of aminomalonate as well as the desulfination of 3-sulfino-alanine to sulfite and alanine. 

Mesoionic oxazolium-5-oxides 49 react with aminomalonic ester to give pyrrolidinones 50 as the major or exclusive products <99H(50)71> and the oxazolamine 51 is converted by sodium acetate in acetic acid into the hydantoin 52 <99JHC283>. The intramolecular Diels-Alder cycloaddition of the oxazole 53 and related compounds has been used as a route to substituted isoquinolines <99JOC3595>. ... 

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