Malonic acid derivatives, additions

Michael addition has been shown to lead to useful building blocks. According to a publication by Johnson and coworkers, highly functionalized unsymmetrical malonic acid derivatives are accessible in this way [268]. Moreover, as described by Takeda and coworkers, substituted four- to six-membered carbocycles 2-507 can be prepared starting from 2-504 by reaction with PhLi via the intermediates 2-505 and 2-506 (Scheme 2.115) [269]. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

When methyl 2-(trimethylsiloxy)-2-vinylcyclopropanecarboxylates 8 and 10 were reacted with C —H acidic agents such as malonic acid derivatives or nitroalkanes, in the presence of the catalyst Triton B, ring opening and formation of Michael addition products occurred. The methoxide is thought to initiate the ring opening by desilylation and generation of the C-nucleophile. 

The major part of the reactions of a-arylation which have been reported were performed on substrates containing active methylene groups, such as p-diketones, p-ketoesters, P-ketonitriles and malonic acid derivatives. Less activated compounds, such as P-ketosulfides have also been efficiently arylated on the a-carbon. (Table 5.3) The yield of the arylated product can be increased by addition of 1,1-diphenylethylene, acting as a free radical trap. For example, in the reaction of phenylation of ethyl cyclohexanonecarboxylate, addition of 1,1-diphenylethylene reduced the radical chain decomposition in such a way that an 80% yield was obtained instead of 55% in absence of 1,1-diphenylethylene. ... 

The catalytic performance of the lithium salt of (5)- or (f )-3,3 -bis[bis-(phenyl) hydroxymethyl]-2,2 -dihydroxy-dinaphthalene-l,l (4, BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Using nitrostyrene and cyclohex-2-enone as Michael acceptors efficient asymmetric C-C and C-N bond formations with up to 95% ee at room temperature were observed. A transition-state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular stmcture of the acetone solvate of BIMBOL. 

A new addition to the variety of reagents already available for the reduction of imines to the corresponding secondary amines is trichlorosilane, and trimers of simple alicyclic imines have been shown to react with malonic acid derivatives to provide the corresponding amines with formation of a C—C bond at the a-position. ... 

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

One of the most recent developments in the field of Ni-catalyzed reactions of alkyl halides with organozinc derivatives is a study of Terao et al.411 They reported the use of three additives in the couplings 1,3-butadiene, N,N-bis(penta-2,4-dienyl)benzylamine 308a, and 2,2-bis(penta-2,4-dienyl)malonic acid dimethyl ester 308b. Addition of tetraene 308b to the reaction mixtures significantly increased the product yields (Scheme 157). The remarkable effect of these additives was explained by the formation of the bis-7r-allylic complex 309 as the key intermediate (Scheme 158). 

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 most recent advances on enzymatic inhibition are related to endonucleases and polymerases. A tris-malonic acid fullerene derivative can interfere with DNA restrictive enzymatic reactions, demonstrating a dose-dependent inhibition of these enzymes, with an IC50 in the micromolar range. The addition of ROS scavenger does not revert the enzymatic activity, indicating that the fullerene action should be exerted in a direct way (Yang et al., 2007d). 

On their side, Yin and Linker [216] made use of a 2-C-branched hexopyranoside, the synthesis of which was achieved by addition of dimethyl malonate to tri-O-benzyl-D-glucal (TUPAC name 3,4,6-tri-0-benzyl-l,5-anhydro-2-deoxy-D-araZtino-hex-l-enitol, Scheme 45) [217], Thus, saponification of the 2-C-[bis(meth-oxycarbonyl)]methyl derivative 184 to the corresponding malonic acid 185 was followed by heating in refluxing toluene. This led to decarboxylation and lactoniza-tion giving 186. The method was optimized and applied to the synthesis of pentoses and disaccharides. 

The substituent R at position 2 proved to determine the type of the product formed in the malonic acid additions of 5,6-dihydro-277-l,3-oxazines 124. For compounds bearing bulky substituents R (Pr , Bn ), /ra j-substituted 1,3-oxazine / -amino acids 125 were formed in diastereoselective additions (Equation 9), while the analogs with less bulky substituents (R = Me, Et) gave C3-symmetrical, nitrogen-bridged, tricyclic 1,3-oxazine derivatives, instead of the corresponding / -amino acids, under the same conditions <1995T139>. 

Verdini and co-workers 71,81 107 were able to silylate the amine with Af,0-bis(trimethylsilyl)-acetamide 108 (BTMSA) and to ring-open Meldrum s acid in a one-pot procedure without isolating the labile Af-silyl derivative. Additional, less frequently employed methods for the synthesis of C2-substituted malonic acids are summarized in a review. 73 ... 

The benzylic free radical produced by the addition of the carbamoyl radical to the ethyl cinnamate molecule is more stable than the alternative radical alpha to the ester group. With such an orientation of addition to the a,p-unsaturated ester, this reaction should lead to derivatives of malonic acid. However, it has been found that the intermediate radical, being a stable benzylic free radical, fails to perform the subsequent abstraction of a hydrogen atom from formamide, and thus no chain-transfer step takes place. Instead of performing this step it favours the combination with a semi-pinacol radical, which is present in solution, to yield the hydroxy ester which subsequently lactonizes to give the major product of the reaction (67). 

The oxide C3O2 is well known (it is actually a derivative of the organic compound, malonic acid, HOOC—CH2—COOH) and an additional suboxide, C5O2, has been reported. The structure of the first suboxide is known to be I and that of the second is presumably II. 

Further C6o derivatives of menthol include a menthyl malonate adduct119 and a carbamate derived from l,2-epimino[60]fullerene.429 Resin acid derivatives have been prepared by Diels-Alder reaction of C6o with methyl levopi-marate, whose parent acid can be isolated from rosin.430 Finally, a derivative of a-pinene was synthesized in the context of a study on the photochemically induced addition of allyl stannanes to Cr,o, a reaction presumably proceeding via SET from the stannane to the triplet excited fullerene.431... 

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