Lithium diisopropylamide, reaction with acetals

A reported procedure based on lithium diisopropylamide induced double elimination of ethanol from bromoacetaldehyde diethyl acetal also was not very effective for the large scale preparation of phenylthioacetylene.8 Another more recent synthesis of the title compound relies on the reaction of dimethyl(chloroethynyl)carbinol with an alkali metal phenylthiolate, followed by... 

This transformation was first explored by treatment of l-bromo-4-(cyanomethyl)pentacyclo-[4.3.0.02 5.03-8.04-7]nonan-9-one ethylene acetal (61) with lithium diisopropylamide in tetrahy-drofuran at 0 °C, which resulted in almost quantitative yield of an inseparable mixture of two alkenes to which the structures l-bromo-4-cyanomethyltricyclo[4.2.1.02,5]nona-3,7-dien-9-one ethylene acetal (66) and l-bromo-4-(cyanomethylene)tricyclo[4.2.1.02,5]non-7-en-9-one ethylene acetal (67) were assigned.170,171 As illustrated below, the overall cage-degradation reaction can be mechanistically represented by the stepwise C —C bond fission reactions, whose driving force can be attributed to the apparently substantial reduction in cage constraint. 

Preparative Methods conveniently prepared - by reaction of the magnesium enolate of r-butyl acetate (readily made with Bromomagnesium Diisopropylamide) with (-)-(lR,2S,5R)-Menthyl (S)-p-Toluenesulfinate (eq 1). It was also made in 91% yield by reacting a solution of Lithium Diisopropylamide with (R)-(+)-methyl p-tolyl sulfoxide and 7-butyl carbonate (eq 2). It should be noted that asymmetric oxidation of 7-butyl 2- p-tolylsulfinyl)acetate with a modified Sharpless reagent gave a... 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

The reaction of a-phosphoryl sulfoxide with the dimethyl acetal of pyruvic aldehyde allowed the preparation of the corresponding vinylic sulfoxide as a 1 1 mixture of (E) and (2) isomers which could be isomerized with Lithium Diisopropylamide to the lithiated (E) isomer, used for the asymmetric synthesis of a-tocopherol (eq 9). ... 

The a proton of a substituted cyclopropane is also rendered acidic if the substituent is attached to the ring by C-P bonds. A few reports have appeared on a-substitution in such compounds.(Cyclopropyl)triphenylphosphonium bromide was converted to a (1-ethoxy-carbonylcyclopropyl)triphenylphosphonium salt 18 in 80% yield by sequential treatment with lithium diisopropylamide and ethyl chloroformate. Furthermore, some diethyl cyclopropyl-phosphonates were converted, in some cases in excellent yield, to diethyl (1-hydroxymethyl-cyclopropyl)phosphonates by treatment with lithium diisopropylamide followed by addition of an aldehyde." Thus, typically, diethyl 2-hexylcyclopropylphosphonate gave diethyl 2-hexyl-l-[hydroxy(phenyl)methyl] cyclopropylphosphonate (19b) in 90% yield on reaction with benzaldehyde. ° Other electrophiles such as acetone, acetyl chloride, acetic anhydride, and ethyl acetate, were not sufficiently reactive to undergo addition to the anion. 

The aldehyde was then used in an aldol reaction with the anion from 3-isopropylbut-2-enolide. [The lactone was prepared in the following way bromination of 3-methyl-2-butanone under kinetic conditions (-15 °C) afforded the 1-bromo derivative. The bromine was displaced by acetate on refluxing a solution in acetone with anhydrous KOAc. Reaction of the resulting keto-acetate with the anion from triethylphosphonoacetate afforded the desired butenolide in 55% yield.] The anion was generated in tetrahydrofuran from the butenolide and lithium diisopropylamide and was cooled to -78 °C before addition of the aldehyde. The temperature was maintained below -70 °C for 5h and the reaction was quenched with ammonium chloride at this temperature. Under these conditions (kinetic) the 22R23R intermediate (3) was obtained in 65% yield (26). 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

The acetimidamide side chain originating from the reaction of the amino group in 3-aminopy-ridazine-4-carbonitrile with A.A-dimethylacetamide dimethyl acetal (vide infra) has been used for pyridine ring closure. Thus, treatment of 3- [(l-dimethylamino)ethylidene]amino pyrid-azine-4-carbonitrilc with lithium diisopropylamide at — 70°C gives 7V, (V7-dimethylpyrido-[2,3-c]pyridazine-5,7-diamine (10).21... 

Pachybasin, 2-methyl-4-hydroxyanthra-9,10-quinone has been obtained in 73% yield by Diels-Alder addition from 2-bromonaphthoquinone and the vinylketene mixed acetal, 1-trimethylsiloxy-1-methoxy-3-methylbuta-1,3-diene, by reaction in dichloromethane containing potassium carbonate, heating with sodium acetate and finally aromatisation of the crude product by refluxing in ethanol The diene was accessible from methyl senecioate (methyl 3-methylbut-2-enoate) by treatment with lithium diisopropylamide and trimethylchlorosilane (ref.25). 

Ibrning to structurally more complex applications of 100, it has been shown that it can function as a Michael acceptor. For example, when the enolate of 2,4-dimethyl-cyclo-hexen-3-one (152) is treated with 100 in the presence of lithium hexamethyldisilazane (LiHMDS), dichlorovinylation takes place and 153 is formed. On the other hand, with lithium diisopropylamide (LDA) as base, the 1-chloroacetylene derivative 151 is produced [98-100] (Scheme 2-15). The reaction, which also takes place with other 1-chloroacetylenes, most likely involves the Michael intermediate 154 which — depending on reaction conditions — is either protonated or loses a chloride ion. On treatment with copper powder in tetrahydro-furan/acetic acid, 151 is dechlorinated the resulting terminal acetylene has been used for further transformations. 

The enol acetate mixture can be analyzed by gas chromatography or by nmr analysis. Table 1.2 shows the data obtained for several ketones. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate, as is true in each of the cases shown in Table 1.2. The principal reason for this result is probably that removal of the less hindered hydrogen is more rapid, for steric reasons, than removal of more hindered protons, and this more rapid reaction leads to the less substituted enolate. Similar results were obtained when an amine anion, lithium diisopropylamide, was used instead of triphenylmethyllithium. On the other hand, at equilibrium it is the more substituted enolate that is usually the dominant species. The stability of carbon-carbon double bonds increases with increasing substitution, and it is this substituent effect that leads to the greater stability of the more substituted enolate. 

Cleavage of enol trimethylsilyl ethers or enol acetates by methyllithium (entries 1 and 2, Scheme 1.3) as a route to specific enolate formation is limited by the availability of these materials. Preparation of the enol trimethylsilyl ethers and enol acetates from the corresponding ketones usually affords a mixture of the two possible derivatives, which must be then separated. It is sometimes possible to find conditions that favor the formation of one isomer for example, reaction of 2-methyl-cyclohexanone with lithium diisopropylamide and trimethylchlorosilane affords the less highly substituted enol ether preferentially by 99 1 over the more highly substituted one (kinetically controlled conditions). ... 

AUylation of the /3-ketoester 136 was achieved with good enantioselectivity using the Trost ligand 20. AUylation of the ketone 138 could also be achieved, and although trimethyltin chloride was usually added, it was not an essential feature for obtaining reaction, once the ketone had been deprotonated with lithium diisopropylamide. Alkylation of cinnamyl acetate 140 using the /3-ketophosphonate 141 has been carried out using a palladium/BINAP 17 catalyst (Scheme 30). ... 

Similar results were obtained with methyl acetate (70% yield of 1.183). Another acid surrogate was used with 1.185 to produce an amino acid. Meyers developed an oxazolidine derivative (7.754)110 that was readily converted to the carbanion by reaction with lithium diisopropylamide. In the presence of Ti (IV), this carbanion was used in a reaction with 7.755 to give the methyl carbamate of methyl... 

A typical reaction that uses an amino acid derivative involves initial conversion to an enolate anion. This nucleophilic species is then reacted with an alkyl halide or a carbonyl derivative. An example that produces a new amino acid is the reaction of the ethyl ester of n-benzyl glycine with lithium diisopropylamide to give the enolate. Subsequent reaction with the mixed anhydride shown below proceeded with displacement of acetate to give /.22J.13 Acid hydrolysis generated a P-keto amino acid, which decarboxylated under the reaction conditions to give 4-oxo-5-aminopen-tanoic acid 1.156, also known as 5-aminolevulinic acid). 

Preparative Method obtained by reaction of methyl acetate with lithium diisopropylamide in THF/HMPA and subsequent trapping with f-butyldimethylchlorosilane (72% yield). ... 

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