Malonate enolates

Mechanistically, the nucleophilic addition can occur either by internal ligand transfer or by external attack. Generally, softer more stable nucleophiles (e.g., malonate enolates) are believed to react by the external mechanism and give anti addition, whereas harder nucleophiles (e.g., hydroxide) are delivered by internal ligand transfer with syn stereochemistry.120... 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

Michael, j. On the Course of Addition of Malonic Enolates to a,)3-Unsatu-... 

The previously described lanthanide triflate promoted ring opening of indoles 115 with 1,1-cyclopropanediesters 116 has been extended to provide an annulation reaction of indoles, wherein nucleophilic ring opening by the indole C-3 followed by attack of the intermediate malonic enolate 117 on the iminium moiety to afford the annulated products 118 <99TL5671>. 

Selective fluorination of a wide variety of carbanions has been carried out very effectively with iV-fluoro-Y-alkyl sulfonamides by Barnette63. Treatment of carbanions of malonates, enolates of ketones, acids and amides, and alkyl and aryl organometallics results in the transfer of fluorine from nitrogen to carbon (equation 43). Yields are fair to... 

Double alkylation of the malonate enolate to give a four-membered ring is followed by es hydrolysis and decarboxylation. 

An alternative route to 79b involved nucleophilic displacement from an enantiomerically pure hydroxy acid 82 with a malonate enolate. The OH group was activated as a triflate 83. This method depends on the availability of optically pure hydroxyacid.12 Notice that the wrong enantiomer of 82 must be used as inversion occurs during the SN2 reaction leading to 79b. 

Now the second alkene comes into play as 234 is really an allyl o-complex that prefers to exist as an allyl p3 cation complex 235. If a suitable nucleophile, such as a malonate enolate, is present this will attack the allyl cation complex. It must attack from the opposite face to the palladium and prefers to attack next to the H atom rather than the Me group giving 236. 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and... 

Scheme 6.39. Asymmetric cyclopropanation of malonate enolates for steroid synthesis [143,144].

The Knoevenagel Condensation. Another classical reaction called the Knoevenagel condensation involves malonate enolates in a condensation reaction with aldehydes, usually a non-enolizable aldehyde. An aldehyde or ketone can be condensed with an active methylene compounds such as a malonic... 

This racemic synthesis of actinophyllic acid (3) was accomplished in eight steps with an overall 15% yield from the readily available indole di-ferf-butyl malonate 9. The intramolecular oxidative coupling of ketone and malonate enolates and an aza-Cope-Mannich rearrangement for the construction of the unprecedented actinophyllic acid ring skeleton are the key transformations. 

Double alkylation of the malonate enolate gives the four-membered ring and hydrolysis and decarboxylation gives the carboxylic add product. 

Chiral A -phosphonyl imines (66) have been found to react smoothly with lithium dialkyl malonate enolates to give chiral jS-phosphorylamino mal-onates (67) in excellent diastereoselectivity and good chemical yields (47-90%) (Scheme 12). ... 

D.ii.a. Termination by Soft Carbon Nucleophiles. Termination by stabilized enolates as carbon nucleophiles has mostly been achieved using dialkyl malonate enolates, which in general cause no problans in connection with palladium catalysts and have a high enough nucleophihcity. 

F.i.a. Soft Nucleophiles. As mentioned before, dialkyl malonate enolates are useful terminators for cascade carbopalladations, leading eventually to rr-allylpalladium intermediates. This has been demonstrated by Ma and Negishi in their studies regarding allenes as relays for medium- to large-ring synthesis (Scheme... 

The reaction of malonate enolates with cyclohexane epoxides leads to mixtures of the two possible lactones (87) and (88)," convertible into the corresponding a-methylene-lactones by now relatively standard procedures. In a similar vein, the bis-spirolactone (90) can be obtained from epoxide (89). Spirolactones can also be prepared from cyclic ketones by condensation with ethyl a-bromomethylacrylate in the presence of zinc, and cyclization of the adduct in cold, dilute acid." ... 

A further example of the synthetic potential of ir-allylpalladium complexes in the formation of carbon—carbon bonds (c/. refs. 152, 189) is the coupling of malonate enolates to complexes (135) to give the unsaturated triesters (136) in virtually quantitative yield.Treatment of diketene with the Grignard reagent... 

In contrast, especially to these diphenyl-substituted allylic substrates, the results obtained with cyclic substrates such as 55 were disappointing in the beginning. For example, when cyclohexenylacetate was treated with dimethyl malonate enolate in the presence of a PHOX ligand, no enantioselectivity was observed at all. However, by switching to other ligands, such as Trost s ligand, high enantiomeric excess values could be obtained also with cyclic allylic substrates (Scheme 12.28) [49]. 

Recently, Maulide el al. have presented another deracemization process in which the product has more than one stereogenic element and therefore allows the existence of different diastereomers. Each and every one of the four different stereoisomeric products (for diethyl(butyl)malonate enolate as the nucleophile) could be prepared from the racemic ds-cyclobutene lactone 61 with high selectivity by employing the Hgands LI, en Ll, 12, and mt-L2 (Scheme 12.30). The observed overall inversion in the presence of ligand L2 (and mt-L2) is thought to be a result of stereoretentive it-allyl generation caused by internal coordination of the carboxylate, followed by classical nucleophilic attack on the opposite side of palladium [51]. 

The reaction of diethyl malonate (90) with sodium hydride generates enolate anion 91 as the conjugate base, and hydrogen gas is the conjugate acid. It has the three resonance contributors shown in the illustration, although 91A has the highest concentration of electron density, and 91 will react as a carbanion nucleophile. There is one extra resonance form in the malonate enolate anion relative to a simple ester due to the second carbonyl unit, and it means that 91 is more stable than the enolate derived from a monoester. In part, this accounts for the enhanced acidity and easier formation of the enolate anion using a weaker base. Once formed, 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. 

The instructions for this problem point to a disconnection at the nucleophilic alpha carbon, thereby creating a four-carbon electrophile (RX) and a three-carbon nucleophile (enolate). However, the resulting enolate is not stable. Addition of an ester electron-withdrawing group leads to a starting material that can be further simplified. A second disconnection at the alpha carbon results in the familiar diethyl malonate enolate. Recognizing the TM as a derivative of acetic add can help you recognize the double disconnection that is possible. 

Rather than pyridine or ammonia, bases such as sodium hydride or sodium ethoxide can be used to generate a malonate enolate anion. Such enolates are easier to control, from a synthetic viewpoint, and allow a wider range of reactions. For this reason, they are collected into this section. An example is the reaction of the sodium enolate of diethyl 2-methylmalonate with the bromine moiety in phthalimide derivative 4.42. This displacement reaction was followed by removal of the phthalimidoyl group, hydrolysis of the esters and decarboxylation to give 2-methyl-6-aminohexanoic acid (4.4J),23 Phthalimide 4.42 was prepared by reaction of 1,4-dibromobutane with potassium phthalimide.23 The length of the carbon chain in the... 

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