Hydrazones, hindered

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) ... 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

A -Alkanoylhydrazones of benzoylacetaldehyde exist as several isomers in the solid state, depending on the structure of substituent R (83-ZOR2333). When R = H, it is 75B (R = R = H R = Ph) when R = Me, Et, and Pr, it is 75A- and when R = t-Bu, it is 75A - . In (CD3)2SO solution, up to five-component equilibrium mixtures appear, containing hydrazone 75A- (two conformers with respect to the hindered rotation around the CO —N bond), enhydrazine 75A - and Z, and pyrazoline 75B tautomers. An increase in the steric bulk of substituent R increases the amount of the enhydrazine tautomer 75A. The steric demands of the substituent R are mostly expressed for the pyrazoline tautomer 75B, which does not form at all when R = t-Bu. 

A reaction of sterically hindered hydrazone 179 with sulfur monochloride led to disubstituted tetrathiolane 180 in low yield together with 1-adamantyl-ferf-butyl thioketone 181 as the main product (1996CC2681 Scheme 91). 

A diird strategy for controlling enolate formation is to convert the carbonyl group to a jV,jV-dimediylhydrazone. The hydrazone is less reactive than die carbonyl group, and removal of an a proton by a strong base takes place at the least hindered a position. Alkylation followed by hydrolysis gives back carbonyl product that is die same as die result of kinetic control of enolate... 

Notes. (1) The hydrazones are prepared by the following general procedure.12 The carbonyl compound and a 10 per cent molar excess of toluene-p-sulphonylhydrazine in absolute ethanol (c. 2 ml per gram of carbonyl compound) are heated on a steam bath until a clear solution results (15 minutes). Cooling affords crystalline products in good to excellent yields. Recrystallisation is accomplished from ethanol or aqueous acetone. For hindered ketones periods of up to 14 hours of reflux are suggested. 

An exceptionally high influence of the C-substituent at the C=N bond on the cyclization direction has been observed (89KGS927) in a large series of derivatives 80. In the solid state and in solution in several solvents, these compounds exist solely as the isomer 80B. Independently of the mutual disposition of the oxime and hydrazone moieties—i.e., for either X = NCOR, Y = O or for X = O, Y = NCOR and for X = Y = NCOPh—the intramolecular cyclization proceeds only along the path involving nucleophilic XH or YH group addition to the more reactive and less hindered aldoxime or aldohydrazone C=N bond. However, in the gas phase, the presence of small amounts of the isomers 80A and 80B was detected. 

Beyond the scope discussed so far, Michael additions also include additions of stoichio-metrically generated enolates of ketones, SAMP or RAMP hydrazones, or esters to the C=C double bond of ,/Tun saturated ketones and a,/Tunsaturated esters. These Michael additions convert one kind of enolate into another. The driving force stems from the C—C bond formation, not from differential stabilities of the enolates. It is important that the addition of the preformed enolate to the Michael acceptor is faster than the addition of the resulting enolate to another molecule of the Michael acceptor. If that reactivity order were not true, an anionic polymerization of the Michael acceptor would occur. In many Michael additions, however, the enolate created is more hindered sterically than the enolate employed as the starting material, and in these cases Michael additions are possible without polymerization. 

Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-ary I hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140]. 

The synthetic utility of this base (1) was demonstrated in the preparation of vinyl iodides in high yields from simple ketohydrazones and iodine (Table), a process that normally gives mixtures of vinyl iodides and geminal diiodides if less hindered bases are employed.6 This base has also been used in the elimination of sulfonic acids from the corresponding sulfonates, the alkylation of compounds containing active methylene groups, the conversion of hydrazones to vinyl selenides, and the preparation of esters from sterically hindered acids.4 5... 

Vinyl iodides. The reaction of iodine in the presence of triethylamine with ketone hydrazones can result in gem-diiodides or vinyl iodides (4, 260). Hindered hydrazones are converted mainly into the latter products however, yields are generally only moderate. 

The anions of hindered hydrazones allow the introduction of electrophiles at the a-position, thus functioning as acyl anion equivalents after isomerization back to a hydrazone and hydrolysis.For example, the r-butylhydrazone of acetaldehyde gives phenylacetone following the sequence of reactions shown in equation 44. 

Since its introduction early in this century, the deoxygenation of aldehydes and ketones to methyl or methylene derivatives, respectively, via base treatment of hydrazone intermediates (equation 1) has proven to be one of the most convenient and synthetically useful processes available for this important type of transformation. The reaction is termed the Wolff-Kishner reduction in recognition of the two original independent discoverers.However, the initial recipes introduced proved tedious and unreliable with many structural, especially hindered, examples. This led to substantial efforts devoted over the years to developing more convenient and successful experimental procedures, resulting in a number of improved and more reliable modifications which are most often utilized at present. More recently, modified procedures have been provided which utilize hydride reductions of p-toluenesulfonylhydrazone (to-sylhydrazone) derivatives and subsequent decomposition to release the hydrocarbon products under much milder and less basic conditions than those normally required for Wolff-Kishner reductions (equation 2). 

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