Lithium diisopropylamide reaction with ketones

There have been only a limited number of developments in this area, the majority of which involve the use of lithium diisopropylamide (LDA) with chiral l,3-dioxolan-4-ones to deprotonate the C-5 position and allow reaction with a suitable electrophile (Equation 21). Electrophiles used to alkylate the enolate include iodomethane <1996HCA1696>, ethyl crotonate <1998SL102>, a,/ -unsaturated ketones <2006T9174>, various substituted nitrostyrenes <2004T165>, substituted nitroaryl fluorides <2003SL2325> and acylsilanes <2002TA1825>. 

However, this sequence can be reversed. - Thus, the activated cyclopropane can be de-protonated by lithium diisopropylamide, reacted with an appropriate ketone and opened by various methods such as treatment with acid or desilylation with fluoride. Using this reaction sequence, y-lactones 52 with various substituents can be obtained by the intramolecular attack of the ketone oxygen on the siloxy-substituted carbon followed by oxidation with pyridinium chlorochromate. The cyclic hemiacetal intermediates 53 can be converted to the tetrahyd-rofuran derivatives 55 by deoxygenation with triethylsilane/boron trifluoride. 

Lithium bis(trimethylsilyl)amide or (more frequently) lithium diisopropylamide, upon reaction with ketones, produces an enolate that reacts with anhydrous cerium(III) chloride at — 78°C to afford a cerium enolate (Imamoto et al., 1983). 

Stereoselection in Reactions of Lithium Enolates. The (Z)-lithium enolate (2), obtained from the reaction of 2-methyl-2-tri-methylsilyloxypentan-3-one (1) with lithium diisopropylamide, reacts with aldehydes to afford syn-p-hydroxy ketones (3) exclusively (eq 1). The synthetic utility of (3) is demonstrated by conversion to /3-hydroxy acids (4), /S-hydroxy aldehydes (5), and other /3-hydroxy ketones by straightforward procedures (eqs 2-3 and eq 4). Table 1 illustrates examples of condensations of (2) with simple aldehydes and subsequent conversions to (4), (5), and (6). 

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Metalation ofa-sulfinyl dimethylhydrazones with terf-butylmagnesium bromide, butyllithium or lithium diisopropylamide, and reaction of the generated azaenolates with aldehydes, provides aldol adducts (e.g., 6) as mixtures of diastereomers. Reductive desulfurization leads to fi-hydroxy dimethylhydrazones (e.g., 7) which are cleaved to the desired /(-hydroxy ketones in 25% overall yield10 u. The enantiomeric excesses are about 50%, except for (- )-3-hydroxy-4-methyl-1-phenyl-1-pentanone (8) which was obtained in 88% ee. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Treatment of a-dichloromethyl phenyl sulfoxide with lithium diisopropylamide in THF gave monolithiated derivative 122, which upon further treatment with aldehyde afforded the )S-hydroxy-a-dichlorosulfoxide 123. Thermolysis of 123 gave dichloroketone 124, by extruding benzenesulfenic acid as shown below . Similarly, in the reaction of lithio-a-fluoromethyl phenyl sulfoxide and aldehyde, fluoromethyl ketone 126 was obtained, after thermolysis of the hydroxy intermediate 125. Diethylphosphorylmethyl methyl sulfoxide was shown by Miko/ajczyk and coworkers to be lithiated with n-BuLi to intermediate 127, which upon treatment with carbonyl compounds afforded the corresponding a, -unsaturated sulfoxides 128 in good yields. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

If this precaution is not followed, partial or complete equilibration of the enolates will occur because of proton transfers between the enolates and the excess un-ionized ketone. In an experiment where a slight excess of ketone was added, the distilled, monoalkylated product (40% yield) contained 77% of the undesired 2,2-isomer and only 23% of the desired 2,6-isomer. However, it is also important in this preparation not to allow a large excess of lithium diisopropylamide to remain in the reaction mixture this base reacts with benzyl bromide to form iraws-stilbene which is difficult to separate from the reaction product. 

Enolate ions can be formed from aldehydes and ketones containing protons on an a-carbon (Following fig.). Enolate ions can also be formed from esters if they have protons on an a-carbon. Such protons are slightly acidic and can be removed on treatment with a powerful base like lithium diisopropylamide (LDA). LDA acts as a base rather than as a nucleophile since it is a bulky molecule and this prevents it attacking the carbonyl group in a nucleophilic substitution reaction. 

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