Alkylations lithiated hydrazones

Alkylations of hydrazone anions derived from aldehydes and ketones are closely related to imine anion alkylations. Lithiated hydrazones are particularly powerful nucleophiles for alkylation reactions. The alkylated hydrazones may be cleaved with periodate, as shown below.The choice of solvent and base is critical to the success of hydrazone alkylations hexane-free medium is essential for complete metalation. °... 

Regiospecific and enantioselective aldol reactions 168) were also performed with SAMP (137). Lithiated hydrazones obtained from ketones (154) as described above were alkylated with carbonyl compounds and the adducts then treated with chloro-trimethylsilane. The resulting trimethylsilylethers (155) were finally oxidatively hydrolyzed to yield the chiral (3-hydroxyketones (156) (e.e. = 31-62%)168),... 

As is depicted in Scheme 1.2.29, the epoxide 128 was synthesized starting from 2,2-dimethyl-l,3-dioxan-5-one RAMP hydrazone (R)-96, which was double-alkylated with methyl iodide at a- and a -positions leading to the trons-dimethylated hydrazone 131 in 79% yield over two steps and excellent stereoselectivity (de, ee > 96%) [68]. The quaternary stereocenter bearing the desired tertiary alcohol function was generated using benzyloxymethyl chloride (BOMCl) as the electrophile to trap the lithiated hydrazone 131, providing the a-quaternary hydrazone 132 in very good yield (92%), excellent diastereomeric and enantiomeric excesses (de, ee > 96%) and with the required cis relationship of the methyl substituents. 

In this latter structure, roughly depicted as (154), there are two different lithium atoms as well as two different anion residues. In one of the residues a lithium is -coordinated and in the other residue the lithium is T) -coordinated. Hie possible origins of the selectivity of the alkylations of the metallated hydiazones are discussed relative to this structure. Hie lithiated hydrazone enolate (155) prepared from (S)-(-)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of 2-acetylnaphthalene (156) yields the monomeric bis-THF-solvated species (157) as ruby red crystals. Hiis is one of the few examples of the crystallization of a resolved enolate substrate. ... 

Fortunately, the use of lithiated hydrazones derived from (S)- or ( )-l-amino-2-methoxymethylpyiro-lidine (SAMP or RAMP) as nucleophiles for asymmetric alkylations have provided a solution to the problems described above with metallated acyclic ketimines and aldimines. Lithiated SAMP or RAMP hydrazones of cyclic ketones are also alkylated in high yields. A major advantage of these chiral hydrazones is that their derivatives of aldehydes, acyclic and cyclic ketones all yield mainly ( )cc-. (Z)cN-Iithiated species on deprotonation with LDA in ethereal solvents under kinetic control. The ( )cc-configuration obtains as a result of the minimization of steric interactions in the usual closed transition... 

Alkylation of lithiated hydrazones forms the basis of an efficient method for the asymmetric alkylation of aldehydes and ketones, using the optically active hydrazines (5)-l-amino-2-(methoxymethyl)pyrroUdine (SAMP) 59 and its enantiomer (RAMP) as chiral auxiliaries. Deprotonation of the optically active hydra-zones, alkylation and removal of the chiral auxiliary under mild conditions (ozonol-ysis or acid hydrolysis of the A-methyl salt) gives the alkylated aldehyde or ketone with, generally, greater than 95% optical purity. This procedure has been exploited in the asymmetric synthesis of several natural products. Thus, (S)-4-methyl-3-heptanone, the principal alarm pheromone of the leaf-cutting ant Am texana, was prepared from 3-pentanone in very high optical purity as shown in Scheme 1.74. 

The stereoselectivity of deprotonation is dependent on the solvent. Thus, the lithiated SAMP-hydrazone of propanal, which is generated in tetrahydrofuran, shows Ecc-Zcs configuration in >98% stereoselectivity. On the other hand, deprotonation in tetrahydrofuran/hex-amethylphosphoric triamide leads to a species with the opposite Zee cN configuration in >95% stereoselectivity. Alkylation of these azaenolates provides products of opposite absolute configuration23. 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

A practical and efficient asymmetric synthesis of 2-substituted oxetane-3-ones 46 has been developed by Shipman and co-workers by lithiation of SAMP/RAMP hydrazones of oxetane-3-one 45, followed by interception of the putative azaenolate lithiated intermediate with a range of electrophiles that include alkyl, aUyl and benzyl halides, and an aldehyde (Scheme 13) (2013JOC12243). As for the bases, w-BuLi and <-BuLi were found to be the most suitable for the metalation step providing adducts 46 in good yields and enantioselectivities (up to 84% ee), whereas LDA was less effective. Conversion of hydrazones 46 to the enantiomerically enriched 2-substituted oxetane-3-ones 47 can be achieved without detectable racemization using aqueous oxaHc acid at room temperature. 

Triazoles and Benzotriazoles.—1,2,3-Triazoles. The X-ray structure of the amino-triazole ester (603) has been reported. " A new general synthesis of 1-alkyl-u/c-triazoles is exemplified by the reaction of the lithiated nitrosoamine LiCH2NMeNO with benzonitrile to yield (604). The bis-toluene-p-sulphonyl-hydrazone of benzil cyclises to the triazole (605) in in the presence of mercury(ii)... 

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