Hydrazones dianions

In another example, a sequence of methylation-elimination-hydroxymethylation was used to install the functionality pattern found in the A-ring of taxol. The hydrazone dianion was generated and methylated at low temperature. The hydrazone was then deprotonated again using excess n-butyllithium and allowed to warm to room temperature, at which point formation of the vinyllithium occurred. Reaction with paraformaldehyde generated the desired product.290... 

The classical Bamford-Stevens reaction6 is a two-step elimination process involving a hydrazone dianion intermediate. The latter sequentially... 

Hydrazones are useful intermediates in the preparation of pyrazoles. 3-Oxo-3-(pyrrol-2-yl)-propanenitrile 9 was coupled with aromatic diazonium salts to yield the corresponding 2-arylhydrazones 10, which then reacted with chloroacetonitrile and ethyl chloroacetate to yield 4-aminopyrazole derivatives 11 <07SC3579>. The cyclization of hydrazone dianions of 12 with diethyl oxalate 13 afforded pyrazole-5-carboxylates 14 <07TL3591>. 

The Shapiro reaction of tosylhydrazones with base has now been extended as a route to a wider variety of functionalized olefins. Thus, treatment of tosylhydrazones, which contain only a tertiary a-hydrogen, with lithium iso-propylamide, can now yield trisubstituted olefins. The yields are only moderate, but the procedure is convenient. Regiospecifically generated tosyl-hydrazone dianions may be trapped with aldehydes and ketones to give, on neutralization, /3-hydroxytosylhydrazones further treatment with alkyl-lithium reagents yields allylic and homoallylic alcohols. These procedures are exemplified in Scheme 21. 

The synthesis of pyrazolines and pyrazoles of the [CCNN + C] type with the creation of two bonds, N(2)-C(3) + C(3)-C(4) (or N(l)-C(5) + C(5)-C(4)), has been studied by several groups. Beam and coworkers have published a series of papers on the synthetic utility of lithiated hydrazones. Thus, the methylhydrazone of acetophenone (598) is converted by butyllithium into the dianion (599), which in turn reacts with methyl benzoate to afford the pyrazole (600) (76SC5). In earlier publications Beam et al. have used aldehydes and acyl chlorides to obtain pyrazolines and pyrazoles by the same method. 

Ethynyl derivatives of 2-aryl-4,5,6,7-tetrahydroindazole were prepared from the p-chlorophenyl hydrazone of cyclohexanone. The hydrazone was treated with two equivalents of -butyllithium at —78°C to generate the dianion, which was then quenched with the appropriate substituted ethyl ester (94MT29). 

These results are consistent with a syn deprotonation of the hydrazone monoanion conformer, in which the a-alkyl group R is anti to the hydrazone moiety (a lower steric interaction in 107 than in 108) during the formation of the dianion (equation 31. ... 

Ketone dilithio-c /S-dianions (30, formed by treatment of /3 -stannylketones, RCOCH2-CH2SnBuCl2, with 4 equiv. of BuLi) react with imines and hydrazone selectively at the /3-anion portion to give dilithium enolate amides (31).82 Subsequent reaction with electrophiles gives y-amino ketones and related heterocycles. 

The reactions of ketone dilithio ,/i-dianions with imines and hydrazones have been investigated.77 The nucleophilic addition reaction to C—N double bonds took place selectively at the -position of dianions to form lithium (Z)-enolates containing a lithium amide portion, which is then transformed into y-amino ketones and related compounds by the subsequent reaction with electrophiles. 

Alkylation of a-nitro keto imines. The key step in a conversion of cyclic a-nitro ketones to cyclic 3-substituted 1-nitroalkenes (4) involves alkylation of the dianion of an a-nitro imine (2) or hydrazone. The dianions are easily generated,... 

The decomposition of the dianions of arenesulfonylhydrazones, known as the Shapiro reaction,4 is one of the most reliable ways of making vinyllithium reagents. In the earliest, and still widely used, version of the reaction,1 a ketone is condensed with p-toluenesulfonylhydrazine 1 to yield a crystalline hydrazone such as 2. Deprotonation of 2 with base (usually BuLi) gives a monoanion 3, which, if heated, decomposes to a carbene 4 in... 

Usable vinyllithiums are obtained if (a) ortholithiation-resistant hydrazones derived from triisopropylphenylsulfonylhydrazine 15 are used,9 and (b) if the Shapiro reaction is carried out in a TMEDA-hexane mixture, which avoids protonation of the vinyllithium.10 For example, 16 forms stereoselectively from 15, with steric hindrance directing formation of the E hydrazone. The dianion of 16 decomposes at 0 °C to yield the vinyllithium 17 which reacts with electrophiles to yield products such as 18.11... 

Oxygenation of the dianion of a ketoxime - by MoOPH (c/. Section 2.3.2.1.2) provides a-l droxy ketones after hydrolysis, albeit in relatively low yield. The equivalent process for hydrazcmes was unsuc-essful, although it appears that this was a problem associated with manipulation of the products rather than an intrinsic failure of reaction. Indeed subsequent work with hydrazone anions has shown that the process is viable. 

Organometallic addition to the /V-methoxy-A -methylamide (15) also affords an exceptionally stable tetrahedral intermediate (16) and carbonyl-protecting group, first used in the synthesis of X-206. Deprotonation of the hydrazone in intermediate (16) was subsequently carried out with lithium diisopropylamide. The resulting dianion initiated a novel attack upon epoxide (17) and in the ensuing transformation was followed by tetrahydrofuran ring formation as depicted, in 71% yield, all in one pot (Scheme 4). 

Alkenylithium reagents derived from symmetrical acyclic ketone hydrazones possess the /ran -configuration, which is consistent with a jyn-deprotonation of the hydrazone anion in a conformation that places the alkyl group R anti to the hydrazone moiety during dianion formation. The presence of an a-branch such as an isopropyl group, however, diminishes the stereoselectivity. 

Many of the same features of imine and imine anion structure previously discussed (Section 4.1.3.2) are apparent with hydrazones and their anions and with oxime ether anions. A number of investigations of the structure of A A -dialkylhydrazone and oxime ether anions as well as oxime dianions have been carried out. Most notable are the experimental studies of Collum and Clardy, " and the theoretical treatment by Glaser and Streitwieser. As might be expected, and as was observed for lithiated imine anions iyida supra), lithiated hydrazones exist in the solid as aggregates, with two lithiums coordinated to the aza anion system (Figure 3). ... 

The synthon of the a-acrylate anion is available from a secondary a-keto carboxamide by the Shapiro reaction. The secondary a-ketoamide trisylhydrazones ate ptepar in a one-pot synthesis by reaction of the isocyanides with acid chloride, water and trisylhydrazine in sequence. In DME solvent, the hydra-zone (103) is smoothly metallated with BuLi to give Ae trianion (KH). Allylation of the trianion (104) gives the hydrazone (105). Alternatively, warming (104) up to room temperature yields the dianion (106) which can be intercepted with several electrophiles (Scheme 23). The adduct (107) is readily transformed into the rran -iodo lactone (108) stereospecifically (equation 56). This chemistry also has been applied to a new synthesis of -lactams (Scheme 24). ... 

The group of Tietze has described syntheses of variously substituted pyrazolones 20 starting from solid-phase-bound p-keto esters. Single or iterative alkylation of the dianion of immobilized acetoacetate with allyl-, benzyl- or alkyl halides produced a set of y-substituted ketoesters 18 that could be transformed to the phenyl-hydrazones 19. Treatment of these intermediates in toluene at 100 °C produced 1-phenylpyrazolone derivatives 20 in 40-75% yield (Scheme 6) [14]. 

Potassium salts of hydrazones are also available by other procedures. Potassium amide has been used to generate potassium salts of monoaryl ketone hydrazones. The reactive intermediate generated in these cases is a dianion. Highly dispersed forms of potassium have also been reported to generate potassium salts from N.N-dimethylhydrazones at -60 C. The use of K/AI2O3 in metalation of aldehyde hydrazone anions produces modest yields of alkylated products in THF suspension. In hexane suspension, side reactions believed to include nitrile formation lead to lower synthetic yields of hydrazone pr ucts. 

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