Lithium hydrazones

Some advantages of this reaction are high yield if the tosylate is in a sterically accessible position excellent isotopic purity of the product (usually higher than-95%) and perhaps most important, access to stereospecifically labeled methylene derivatives. For example, deuteride displacement of 3j -tosylates (183) yields the corresponding Sa-d derivative (185) in 96-98% isotopic purity. Application of this method to the labeled sulfonate (184), obtained. by lithium aluminum deuteride reduction of a 3-ketone precursor (see section HI-A) followed by tosylation, provides an excellent synthesis of 3,3-d2 labeled steroids (186) without isotopic scrambling at the adjacent positions. The only other method which provides products of comparable isotopic purity at this position is the reduction of the tosyl-hydrazone derivative of 3-keto steroids (section IV-B). 

In certain cases this reduction (with lithium aluminum hydride) takes a different course, and olefins are formed. The effect is dependent on both the reagent concentration and the steric environment of the hydrazone. Dilute reagent and hindered hydrazone favor olefins borohydride gives the saturated hydrocarbon. The hydrogen picked up in olefin formation comes from solvent, and in full reduction one comes from hydride and the other from solvent. This was shown by deuteriation experiments with the hydrazone (150) ... 

In an altogether different type of approach, the hydrazone is formed in situ as a lithium salt. Wilson et al. (80JHC389) described this approach in the one-pot synthesis of 5-aryl-2-phenylpyrazol-3-ones 72a-f from the corresponding hydrazones 65a-f (Scheme 20). The latter were obtained by condensing ketones 64a-f with phenylhydrazine. Treatment of hydrazones 65a-f with n-butyllithium in dry THF, followed by the addition of half a molar equivalent of diethyl carbonate 67 and then quenching the reaction mixture with hydrochloric acid, produced pyrazol-3-ones 72a-f, along with products 71. The yields of the products 72 are in the range 22-97%. Four intermediates—66a-f, 68a-f, 69a-f, and 70a-f— were proposed for this reaction. 

The same type of reaction occurs in the work of Hauptman (76T1293), who, studying the chemistry of diethynylcarbenes, found that the pyrolysis of the lithium salts of diethynylketone tosylhydrazones 5 (140-150°C) in the presence of olefins leads to cyclopropanes. This process results in the formation of the corresponding 3-ethynylpyrazoles. The formation of l-p-tolylsulfonyl-3-alkynylpyrazoles from hydrazone runs in milder conditions (50°C, 14 h) (Scheme 24). 

Having retraced the remarkably efficient sequences of reactions which led to syntheses of key intermediates 14 and 15, we are now in a position to address their union and the completion of the synthesis of the spiroketal subunit (Scheme 6b). Regiocontrolled deprotonation of hydrazone 14 with lithium diisopropylamide (LDA), prepared from diisopropylamine and halide-free methyl-lithium in ether, furnishes a metalloenamine which undergoes smooth acylation when treated with A-methoxy-A-methylcarboxa-mide 15 to give the desired vinylogous amide 13 in 90% yield. It is instructive to take note of the spatial relationship between the... 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Table 3. Addition of Mcthyllithium or Butyl-lithium to A.TV-Diinethyl Hydrazone Acetals 4 Derived from F.nantioinerically Pure Diols 3 Providing Hydrazines 54-5...

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

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. 

The addition of the lithium azaenolate of the SAMP hydrazone of propanal to methyl (E)-2-butenoate to furnish the (S,S,S)-adduct in 58% yield with > 96% ee and de is illustrative for the efficiency of this asymmetric Michael addition10°. Only the anti-isomer (an / adduct) is found. This methodology was used in the synthesis of pheromones of the small forest and red wood ant200. 

Hydrazones can also be deprotonated to give lithium salts that are reactive toward alkylation at the (3-carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.119 The A N-dimcthyl hydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent... 

The anion of cyclohexanone /V,/V-dimclhyl hydrazone shows a strong preference for axial alkylation.122 2-Methylcyclohexanone N,N-dimethylhydrazonc is alkylated by methyl iodide to give d.v-2,6-dimclhylcyclohcxanone. The 2-methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently occurs anti to the lithium cation, which is on the face opposite the 2-methyl substituent. 

Fig. 1.7. Crystal structure of lithium salt of SAMP hydrazone of 2-acetylnaphthalene. Two molecules of THF are present. Reproduced from Angew. Chem. Int. Ed. Engl., 27, 1522 (1988), by permission of Wiley-VCH.

This regiospecificity has been shown to depend on the stereochemistry of the C=N bond in the starting hydrazone. There is evidently a strong preference for abstracting the proton syn to the arenesulfonyl group, probably because this permits chelation with the lithium ion. 

Lucifer Yellow CH is soluble in aqueous solution, and it should be stable for awhile if protected from light. The reagent is available as three different salts of the sulfonate groups. The ammonium salt of the fluorophore is soluble to a level of 9 percent in water, while the lithium and potassium salts have a solubility of 5 and 1 percent, respectively. A concentrated stock solution of the fluorophore may be prepared in water and an aliquot added to a buffered reaction medium to facilitate the transfer of small quantities. For aqueous reactions, a pH range of 5-9 will result in efficient hydrazone formation with aldehyde or ketone residues. 

Ketone p-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

Precursors for this task were obtained by addition of /-butylmagnesium bromide to the central bond of [1.1.1 ]propellane 40a followed by conversion of the 3-f-butylbicyclo[ 1.1.1 Jpentyl-1 -y 1-magnesium bromide (88) into the ketones 89 by standard methods.27 Reaction of ketones 89 with tosyl hydrazide afforded the hydrazones 90, which gave the corresponding lithium salts 91 by reaction with MeLi in ether. These salts were dried under high vacuum and then pyrolized at 4 x 10 5 torr in the temperature range of 100-130°C and the volatile products condensed in a liquid nitrogen-cooled trap. 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

Lead tetraacetate, oxidation of a hydrazone to a diazo compound, 50, 7 Lithio ethyl acetate, 53, 67 Lithium, reductions in amine solvents, 50, 89 Lithium aluminum hydride, reduction of exo-3,4-dichloro-bicyclo-[3.2.l]oct-2-ene to 3-chlorobicyclo[3.2.l]oct-2-ene, 51, 61... 

Cyclododecene may be prepared from 1,5,9-cyclododecatriene by the catalytic reduction with Raney nickel and hydrogen diluted with nitrogen, with nickel sulfide on alumina, with cobalt, iron, or nickel in the presence of thiophene, with palladium on charcoal, with palladimn chloride in the presence of water, with palladium on barium sulfate, with cobalt acetate in the presence of cobalt carbonyl, and with cobalt carbonyl and tri- -butyl phosphine. It may also be obtained from the triene by reduction with lithium and ethylamine, by disproportionation, - by epoxidation followed by isomerization to a ketone and WoliT-Kishner reduction, and from cyclododecanone by the reaction of its hydrazone with sodium hydride. ... 

Like any aldehydes aromatic aldehydes undergo Clemmensen reduction [758, 778] and Wolff-Kizhner reduction [759, 774] and give the corresponding methyl compounds, generally in good yields. The same effect is accomplished by conversion of the aldehydes to p-toluenesulfonyl hydrazones followed by reduction with lithium aluminum hydride (p. 106). 

Aldoximes yielded primary amines by catalytic hydrogenation benzaldehyde gave benzylamine in 77% yield over nickel at 100° and 100 atm [803, with lithium aluminum hydride (yields 47-79%) [809, with sodium in refluxing ethanol (yields 60-73%) [810] and with other reagents. Hydrazones of aldehydes are intermediates in the Wolff-Kizhner reduction of the aldehyde group to a methyl group (p. 97) but are hardly ever reduced to amines. 

Hydrazones treated with alkalis decompose to nitrogen and hydrocarbons [845, 923] Woljf-Kizhner reduction) (p. 34), and p-toluenesulfonylhydra-zones are reduced to hydrocarbons by lithium aluminum hydride [812], sodium borohydride [785] or sodium cyanoborohydride [813]. Titanium trichloride hy-drogenolyzes the nitrogen-nitrogen bond in phenylhydrazones and forms amines and ketimines which are hydrolyzed to the parent ketones. Thus 2,4-dinitrophenylhydrazone of cycloheptanone afforded cycloheptanone in 90% yield [202]. 

Chiral hydrazones have also been developed for enantioselective alkylation of ketones. The hydrazones can be converted to the lithium salt, alkylated, and then hydrolyzed to give alkylated ketone in good chemical yield and with high enantioselec-tivity83 (see entry 4 in Table 1.3). 

Other papers of interest in this section report transamination of camphor-3-carbothioamides with secondary cyclic amines, reaction of camphorquinone with dimethyl /S-ketoglutarate, the use of fenchone (212 X=0) in alkene formation from Grignard reagents, bromination of 2-e/itfo-6-endo-dibromobornane to yield 2,3,6-endo-tribromoborn-2-ene, and camphor-enol trimethylsilyl ether formation by quenching the reaction mixture of butyl-lithium and camphor tosyl-hydrazone with trimethylsilyl chloride. ... 

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