Azaallyllithium reagents

Silylation of azaallyllithium reagents derived from hydrazones unlike silylation of enolates seems to occur mainly on cartwn. While chiral (S)-l-amino-2-methoxymethylpyrrolidine (SAMP) aldehyde hydrazones (c/. equation 4) alkylate to a greater extent on nitrogen to form an azaallylsilyl reagent, ketones give predominant C-silylation. In the case of chiral ketone hydrazones derived from (5)-(4), a-silylated ketone hydrazones are produced in these reactions with consistently high ee ( 6%) ... 

Side reactions can occur in formation of hydrazone anions and limit the thermal stability of these anions. Most commonly these side reactions involve addition at the carbonyl carbon or elimination of a dialkylamide anion and nitrile formation. Normant has described both problems and has suggested that nitrile formation also occurs slowly in cases where HMPA has been added to azaallyllithium reagents derived from /V,N-dimethylhydrazones. These problems are exacerbated in the case of aldehyde hydrazones when there is branching at the carbon a or p to the carbonyl carbon. 

More recently, Enders group has described the X-ray crystal structure of the chiral hydrazone anion (19). This internally chelated chiral hydrazone crystallizes as the bis(tetrahydrofuran) monomeric adduct. The lithium in this structure is 17° out of the C—C— N plane and is predominantly associated with the anionic nitrogen (and the chelating methoxy group). Interactions with the =CH2 carbon are minimal. Earlier studies by Bauer and Seebach had examined the association behavior of (19). They found that in THF this azaallyllithium reagent was monomeric. While there is no or ri -interaction with the azaallyl anion, the lithium in this structure is tetracoordinate and prochiral. Preferential coordination of lithium to an electrophile such as a carbonyl oxygen with selective replacement of one THF moiety could be involved in some of the asymmetric aldol reactions discussed below. 

Corey, Enders and Bock were among the first to describe the utility of lithium dimethylhydrazone anions for crossed aldol reactions. In the reaction shown in equation (14), an azaallyllithium reagent derived from an aldehyde dimethylhydrazone was first silylated with trimethylsilyl chloride to yield a silyl aldehyde dimethylhydrazone. Subsequent lithiation using lithium diethylamide at -20 C for 1 h generated the silylated azaallyllithium reagent (29). Subsequent addition of one equivalent of an aldehyde or ketone at -78 C and warming to -20 C then yielded the product a,p-unsaturated aldehyde dimethylhydrazone in yields of 85-95%. Hydrolysis produced the unsaturated aldehyde in 75% overall yield. 

The 1,2-addition of simple azaallyllithium reagents derived from ketone and aldehyde dimethylhydra-zones to aldehydes and ketones was also first described by Corey and Enders.Regioselective deprotonation of 2-pentanone dimethylhydrazone with Bu"Li followed by addition of an aldehyde or... 

Conjugated ketene thioacetals have been successfully prepared starting with aldehyde dimethylhydra-zones. In these reactions, the first-formed azaallyllithium reagent was allowed to react with carbon disulfide to form an intermediate lithium 3-dimethylhydrazonoalkanedithiolate. A second deprotonation of this dithiolate with a second equivalent of LDA then generated a dianion that was successfully alkylated with two equivalents of methyl iodide to yield the ketene thioacetal (e.g. 55 equation 25). This two step sequence avoided competing formation of a methyl dithiocarbamate by addition of LDA to carbon disulfide. 

Regiospecific alkylation of dimethylhydrazone anions with the masked acrolein equivalent, 3-bromo-propionaldehyde dimethyl acetal, has brcn used as an alternative to a conventional Michael reaction in Corey s total synthesis of picrotoxinin (c/. equation 13). Azaallyllithium reagents derived from aldehyde and ketone hydrazones, unlike enolates, yield monoalkylation products with control of both regio-chemistry and stereochemistry. In appropriate cases, alkylation followed by deprotection to form a dicarbonyl product can be a very effective synthetic strategy. 

An earlier application of 1,4-conjugate additions employing azaallyllithium reagents formed from ketone dimethylhydrazones is Kelly s hydrazone version of the classical Knoevenagel route to substituted pyridine derivatives.71 In this chemistry, a mixed cuprate derived from a dimethylhydrazone lithio anion and copper thiophenoxide was first allowed to react with an a,p-unsaturated ketone. The product enolate can then be acylated or protonated to yield either a diketo hydrazone or a keto hydrazone. Addition of... 

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