Ketone enolates metal enolate formation

The intermolecular dimerization of ketone enolates to give 1,4-diketones has been accomplished earlier with cupric6.7 and ferric salts.6 These transition metal salts have also been used to achieve intramolecular carbon-carbon bond formation.7.6.16 However, step C represents the only reported example11 of cyclopropane construction via technology of this type. 

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76],... 

On the other hand, with heterosubstituted chiral aldehydes, the product distribution for the reaction with methyl ketone enolates is strongly influenced by the nature of the metal, the nature of the heteroatom and its position within the molecule. A chair-like transition state explained the formation of the Felkin adduct, while a boat-like transition state was invoked for the formation of the anti-Felkin adduct. However, this assumption was recently challenged by Roush and coworkers using deuterated pinacolone lithium enolate565. Performing a set of aldolizations with chiral and non chiral aldehydes led these authors to show that the isomeric purity of the enolate correlates almost perfectly with the ratio and pattern of deuterium labeling in the 2,3-an/t-aldol formed consistent with a highly favoured chair-like transition state (Scheme 115). 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Crotti and co-workers extensively studied the ring-opening functionalization of oxi-ranes using a variety of alkali-metal salts. Several oxiranes were reacted with ammonium halides [119], KCN [120], NaNa [121], lithium acetyhde [122], amines [123], and ketone enolates [124] in the presence of alkali-metal salts to afford the formation of the corresponding 8-functionalized alcohols and some of the results are listed in Table 1. 

A number of experimental details have contributed to an understanding of the mechanism of reductions carried out under these conditions. Among the more important observations are the facts that ketones react with one and only one equivalent of alkali metal in NH3 enolizable ketones afford equal amounts of enolate and alcohol, while nonenolizable ketones give metal ketyls which are stable at low temperatuie. Also, pinacol formation is a major reaction path with Li, but K affords little or no pina-col. - Finally, a-deuterio ketones afford product alcohols in which deuterium has been transferred to the carbinol carbon of the product alcohol or alcohols. - ... 

The regioselectivity of enolate formation is governed by the usual factors so that methyl benzyl ketone forms the more stable enolate with sodium metal. This undergoes smooth and rapid conjugate addition to acrylonitrile, which is unsubstituted at the P position and so very reactive. 

Treatment of enolates with (R0)2P(0)C1 also results in 0-trapping to yield the corresponding enol phosphates. Dissolving metal reduction of enol phosphates is a useful procedure for the deoxygenation of ketones with concomitant, regiospecific formation of the alkene. ... 

There are numerous base-solvent combinations that are capable of quantitatively converting even weakly acidic simple ketones into their enolate anions. However, in order to avoid aldol condensation and unwanted equilibration of enolates of unsymmetrical ketones during enolate formation, it is best to choose conditions under which the ketone, the base and the metal enolate are soluble. Likewise, solutions should be produced when indirect methods of enolate formation are employed. While certain metal cations such as Hg form a-metallated ketones, most of the metal cations in Groups 1, II and III exist as 0-metallated tautomers. - For organotin derivatives both the 0-metallated and C-metallated forms probably exist in equilibrium. ... 

Any discussion of enolate geometry must include the structure of the enolate. It is well known that metal enolates exist as dimers a or other aggregates in ether solvents S (see Section 9.2.C. for a discussion of aggregate formation with LDA).28d Jackman and Szeverenyi suggested that the lithium enolate of isobutyro-phenone exists as a tetramer (31) in THF solution but exists as a dimer (32) in DME. o Such aggregates were proposed by House et ah,3 who found that ketone enolates of groups 1 (lA), 2 (llA), and 3 (lllA) metals... 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

Combination of achiral enolates vith achiral aldehydes mediated by chiral ligands at the enolate counter-ion opens another route to non-racemic aldol adducts. Again, this concept has been extremely fruitful for boron, tin, titanium, zirconium and other metal enolates. It has, ho vever not been applied very frequently to alkaline and earth alkaline metals. The main, inherent, dra vback in the use of these metals is that the reaction of the corresponding enolate, vhich is not complexed by the chiral ligand, competes vith that of the complexed enolate. Because the former reaction path vay inevitably leads to formation of the racemic product, the chiral ligand must be applied in at least stoichiometric amounts. Thus, any catalytic variant is excluded per se. Among the few approaches based on lithium enolates, early vork revealed that the aldol addition of a variety of lithium enolates in the presence of (S,S)-l,4-(bisdimethylamino)-2,3-dimethoxy butane or (S,S)-1,2,3,4-tetramethoxybutane provides only moderate induced stereoselectivity, typical ee values being 20% [177]. Chelation of the ketone enolate 104 by the chiral lithium amide 103 is more efficient - the j5-hydroxyl ketone syn-105 is obtained in 68% ee and no anti adduct is formed (Eq. (47)) [178]. 

Among alkali metal enolates, those derived from ketones are the most robust one they are stable in etheric solutions at 0 C. The formation of aldehyde enolates by deprotonation is difficult because of the very fast occurring aldol addition. Whereas LDA has been reported to be definitely unsuitable for the generation preformed aldehyde enolates [15], potassium amide in Hquid ammonia, potassium hydride in THE, and super active lithium hydride seem to be appropriate bases forthe metallation of aldehydes [16]. In general, preformed alkali metal enolates of aldehydes did not find wide application in stereoselective synthesis. Ester enolates are very frequently used, although they are more capricious than ketone enolates. They have to be formed fast and quantitatively, because otherwise a Claisen condensation readily occurs between enolate and ester. A complication with ester enolates originates from their inherent tendency to form ketene under elimination... 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

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