Cyclopentanones lithium enolates

Seebach, Dunitz and cowoikers fust described the THF-solvated tetrameric aggregates obtained from THF solutions of 3,3-dimethyl-2-butanone (pinacolone) and cyclopentanone lithium enolates. These are represented as (137). The pinacolone enolate also crystallizes as the unsolvated hexamer (138) from hydrocarbon solution, but this hexamer rearranges instantaneously to the tetramer (137) in the presence of THF. Williard and Carpenter completed the characterization of both the Na+ and the K+ pinacolone enolates.Quite unexpectedly the Na pinacolone enolate is obtained from hydrocarbon/THF solutions as the tetramer (139) with solvation of the Na atoms by unenolized ketone instead of by THF. Hie potassium pinacolone enolate is a hexameric THF solvate depicted as (140) and described as a hexagonal prism. A molecular model of (140) reveals slight chair-like distortions of the hexagonal faces in (140) so that the solvating THF molecules nicely fit into the holes between the pinacolone residues. 

The lithium enolates of cyclopentanone and cyclohexanone undergo addition-elimination to the 2,2-dimethylpropanoic acid ester of ( )-2-nitro-2-hepten-l-ol to give 2-(l-butyl-2-nitro-2-propenyl)cycloalkanones with modest diastereoselection. An analogous reaction of the enolate ion of cyclohexanone with the 2,2-dimethylpropanoic acid ester of (Z)-2-nitro-3-phenyl-2-propenol to give 2-(2-nitro-l-phenyl-2-propenyl)cyclohexanones was also reported. The relative configuration of these products was not however determined6. 

In a related study the adduct of the lithium enolate of methyl bis(trimethylsilyl)acetale and ( —)-(/J)-2-(4-methylphenylsulfinyl)-2-cyclopentanone was transformed to ( — )-methyl jasmonate in > 99% ee. In contrast to the previous study described in this section, addition of the enolate proceeded apparently through a chelated form of the enone15. 

Phenol annelation.1 This modified methyl vinyl ketone can be used for synthesis of 5,6,7,8-tetrahydro-2-naphthol or 5-indanol by reaction with the lithium enolate of cyclohexanone or cyclopentanone, respectively. The former reaction is formulated in equation (I). 

Seebach, Dunitz and coworkers reported, in 1981226, the first crystal structures of lithium enolates of simple ketones, obtained in THF from pinacolone (3,3-dimethyl-2-butanone) and cyclopentanone. Both were arranged as tetrasolvated cubic tetramers, one THF molecule capping each lithium cation (Scheme 58A). Note that pinacolone enolate can also be crystallized, from heptane at — 20 °C, as a prismatic unsolvated hexamer exhibiting an approximate S6 symmetry and six slight it-cation interactions227,228 (Scheme 58B) or as a dimer in the presence of 2 molecules of TriMEDA29. Similarly,... 

On the other hand, lithium enolates derived from substituted endocyclic ketones have largely been exploited in the synthesis of steroids since the regioselectivity of their deprotonation can be controlled and high levels of 1,2- and 1,3-stereoselection occur9,418. The control is steric rather than electronic, with the attack directed to the less substituted ji-face of the enolate for conformationally rigid cyclopentanones, whereas stereoelectronic control becomes significant for the more flexible cyclohexanones. Finally, an asymmetric variant of the formation of a-branched ketones by hydration of camphor-derived alkynes followed by sequential alkylation with reactive alkyl halides of the resulting ketones was recently reported (Scheme 87)419. 

High diastereoselecivities are normally observed in the alkylation of five-membered ring enolates (eqnations 7 and 8), implying that the alkylation is mainly controlled by steric factors. Thus, with 3-substituted cyclopentanones formation of only the frawi-product (23 and 25, respectively) is preferred. Representative examples are the alkylations of lithium enolates derived from ketones 22 and 24 . Before the electrophiles were added, the enolate solutions were stirred at higher temperature for a longer time to secure the... 

In this chapter the focus is primarily on the recent structural work concerning carbanions of alkali and alkaline earth cations that are widely utilized in synthetic organic chemistry. In this context the year 1981 is significant because the first detailed X-ray ffhu tion analyses of two lithium enolates of simple ketones, i.e. 3.3-dimethyl-2-butanone and cyclopentanone, were published. Since 1981 a number of detailed X-ray diffinction analyses of synthetically useful enolate anions of alkali and alkaline earth cations... 

Exactly 10 years after the previous statement appeared, the first lithium enolate crystal structures were published as (5) and (6). Thus, structural information derived from X-ray diffraction analysis proved the tetrameric, cubic geometry for the THF-solvated, lithium enolates derived from r-butyl methyl ketone (pinacolone) and from cyclopentanone. Hence, the tetrameric aggregate characterized previously by NMR as (7) was now defined unambiguously. Moreover, the general tetrameric aggregate (7) now became embellished in (5) and (6) by the inclusion of coordinating solvent molecules, i.e. THE. A representative quotation from this 1981 crystal structure analysis is given below. 

Scheme 2 shows the results of two studies on the methylation of the lithium enolate of cyclopentanone (10), which was prepared by deprotonation of the ketone with trityllithium in DME or by cleavage of the 1-trimethylsiloxycyclopentene with methyllithium in THF. A signiEcant quantity of over-alkylation occurred when the enolate was treated with methyl iodide, particularly when DME was employed as the solvent at room temperature. Also, as indicated in Scheme 2, Noyori and coworkers showed that by adding 3 equiv. of HMPA to the enolate (10) and reducing the temperature at which the reaction was conducted, the yield of 2-methylcyclopentanone was greatly improved.

Lithiumlithium triethylaluminum, sodium triethylboron, sodium triethanolamine borate,- potassium triethylboron and tri-n-butyltin cyclohexanone enolates have been successfully monoalkyl-ated. In Scheme 6 the behavior of the lithium enolate of cyclohexanone (11) and the lithium triethylaluminum enolate upon reaction with methyl iodide is compared. The latter enolate gives better results since no dimethylation products were detected, but clearly the cyclohexanone enolate (11) is much less prone to dialkylation than the cyclopentanone enolate (10). Scheme 6 also provides a comparison of the results of alkylation of the potassium enolate of cyclohexanone, where almost equal amounts of mono- and di-alkylation occurred, with the alkylation of the potassium tiiethylboron enolate where no polyalkylation occurred. The employment of more covalently bonded enolates offers an advantage in cyclohexanone monoalkylations but not nearly as much as in the cyclopentanone case. 

Only in modern times has aldol stereochemistry seemed a subject worth studying, or indeed even accessible to chemists. Formerly it was left to look after itself. Then Dubois carried out some simple experiments on the condensations between cyclic ketones and aldehydes in base.3 Though largely neglected at the time, these results showed that if LiOH (not NaOH) was used as the base, the anti aldol predominated. Indeed, with cyclopentanone and /-PrCHO, >95% anti-5 was formed, and syn-5 could not be detected. Later Heathcock4 showed that the lithium enolate of the open chain ketone 6 condensed with PhCHO to give >98 2 syn ami aldol 7. 

Zirconocene dichloride. 14. 12 Aldol reaction. Zirconiu amides derived from (- >-ps< corresponding lithium enolates ( Cyclopentanones.- C ck) valuable method for the prep application is found in a symhei... 

Lithium enolates of ketones exist as aggregates in solution.29-3l,34d,35 Mixed aggregates between the enolate anion and the amide base are also possible. In 1981, Seebach and co-workers confirmed by X-ray crystallography that the lithium enolates of pinacolone and cyclopentanone form a tetrameric aggregate in the solid state, and it was assumed that a similar species exited in solution. A THF solvated tetramer of lithium pinacolonate is shown (see 33), as it was reported by Seebach. Williard et al. reported the X-ray structure of... 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCl4 or SnCl4. Most fortunately, this is just the type of compound that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. Below is an example the alkylation of cyclopentanone with 2-chloro-2-methylbutane. The ketone was converted to the trimethylsilyl enol ether with triethylamine and trimethylsilylchloride we discussed this step on p. 466 (Chapter 20). Titanium tetrachloride in dry dichloromethane promotes the alkylation step. 

Fig. 7.2. Crystal structures of some lithium enolates to ketones of ketones. (A) Unsolvated hexameric enolate of methyl t-butyl ketone. (B) Tetrahydrofuran solvate of tetramer of enolate of methyl t-butyl ketone. (C) Tetrahydrofuran solvate of tetramer of enolate of cyclopentanone. (D) Dimeric enolate of 3,3-dimethyl-4-(t-butyldimethylsiloxy)-2-pentanone. Structural diagrams are reproduced from Refs.

We mentioned that by mixing vinyl epoxides and zerovalent palladium, the alcoholate formed was usually sufficiently basic to deprotonate the pronucleophile entity. In some cases, especially with ketones, low reactivity and yields were reported (Table To overcome the problem of the weak basicity of the alcoholate, silyl enol ethers, keto adds, or preformed lithium enolates have successfully been employed.f f" f f /3-Keto acids are masked enolates via the decarboxylation of the intermediary Tr-allylpalladium ]3-ketocarboxylate complexes. The main limitation of the use of keto adds as pronucleophiles seems to be their low reactivity toward the hindered cyclic vinyl epoxides. In these cases, the cationic n-allylpalladium complex undergoes ]S-elimination. Indeed, the reaction between benzoyl acetic acid and cyclobutadiene monoxide in the presence of Pd(PPh3>4 gives only the corresponding cyclopentanone and acetophenone as the... 

The trimethylammonium iodide of 2-(dimethylaminomethyl)-3-(trimethylsilyhnethyl)-1,3-butadiene is a useful reagent for the introduction of both electrophile and nucleophile. Treatment with lithium enolate in the presence of Pd(PPh3)4 catalyst gives the allylated cyclopentanone, and subsequent intramolecular allylation of carbonyl group in the presence of B114NF gives vicinal exocyclic alcohol (Scheme 5). ... 

The lithium enolate of diethyl ethylmalonate adds stereospecifically to the vinyl bromide (89) to give the diester (90) similarly the ethynyl bromide (91) is converted into (92).These potentially useful intermediates afford the corresponding vinyl and ethynyl bromides on treatment with N-bromosuccinimide. The reactions are also successful with the lithium enolate of 2-ethoxycarbonyl-cyclopentanone. 

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