Hydrazones reduction intermediates

The procedure involves the transformation of carbonyl compounds to the corresponding SAMP or RAMP hydra-zones, metalation, trapping of the intermediate azaenolates with various electrophiles, and either hydrazone cleavage (carbonyl compounds) or hydrazone reduction/N-N bond cleavage (amines). 

When a carbonyl group must be removed from a molecule, the acidic conditions of the Clemmensen reduction are not always compatible with other functional groups. An alternative method of reduction was developed in basic media that relied on the reaction of carbonyls with hydrazine to form a hydrazone. In the presence of base, a hydrazone anion intermediate (sec. 9.4.F) can be formed that removes a proton from the acidic solvent, leading to reduction. This process has been termed the Wolff-Kishner reduction. A variety of modifications have been introduced for this procedure, including isolation of the hydrazone and using an... 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

Carbonyl deductions. The classical Wolff-Kishner reduction of ketones (qv) and aldehydes (qv) involves the intermediate formation of a hydrazone, which is then decomposed at high temperatures under basic conditions to give the methylene group, although sometimes alcohols may form (40). 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

The classical procedure for the Wolff-Kishner reduction—i.e. the decomposition of the hydrazone in an autoclave at 200 °C—has been replaced almost completely by the modified procedure after Huang-Minlon The isolation of the intermediate is not necessary with this variant instead the aldehyde or ketone is heated with excess hydrazine hydrate in diethyleneglycol as solvent and in the presence of alkali hydroxide for several hours under reflux. A further improvement of the reaction conditions is the use of potassium tcrt-butoxide as base and dimethyl sulfoxide (DMSO) as solvent the reaction can then proceed already at room temperature. ... 

This silyl hydrazone formation-oxidation sequence was originally developed as a practical alternative to the synthesis and oxidation of unsubstituted hydrazones by Myers and Furrow [31]. The formation of hydrazones directly from hydrazine and ketones is invariably complicated by azine formation. In contrast, silyl hydrazones can be formed cleanly from /V,/V -bis(7< rt-butyldimethylsilyl)hydrazine and aldehydes and ketones with nearly complete exclusion of azine formation. The resulting silylhydrazones undergo many of the reactions of conventional hydrazones (Wolff-Kishner reduction, oxidation to diazo intermediate, formation of geminal and vinyl iodides) with equal or greater efficiency. It is also noteworthy that application of hydrazine in this setting may also have led to cleavage of the acetate substituents. 

The selective reduction of the D-ring olefin in 106 using a partially poisoned catalyst (Pd/C, 0.25 % pyridine) provided intermediate 107 (83 %), which was epimerized at -78 °C with sodium methoxide (HOAc quench at -78 °C, 89 %) (Scheme 10.9). Deoxygenation by means of tosyl hydrazone 108 and subsequent treatment with catechol borane and tetrabutylammonium acetate gave pentacyclic... 

Reduction of unsaturated aromatic aldehydes to unsaturated hydrocarbons poses a serious problem, especially if the double bond is conjugated with the benzene ring or the carbonyl or both. In Clemmensen reduction the a,)8-unsaturated double bond is usually reduced [160], and in Wolff-Kizhner reduction a cyclopropane derivative may be formed as a result of decomposition of pyrazolines formed by intramolecular addition of the intermediate hydrazones across the double bonds [280]. The only way of converting unsaturated aromatic aldehydes to unsaturated hydrocarbons is the reaction of... 

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 are important intermediates in a Wolff-Kishner reduction, a procedure for reducing a carbonyl group. An example of a Wolff-Kishner reduction appears in Figure 10-27, and the mechanism is in Figure 10-28. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

In the same study, a one-pot variant avoiding the isolation of the intermediate hydrazone was attempted. However, reduction of the crude hydrazone leads to the formation of by-products for example, in the reaction of benzophenone, a mixture of diphenylmethane and benzophenone azine was found (Scheme 4.38)64. 

The first report on a successful microwave-assisted one-step reduction of ketones to their respective hydrocarbons via the hydrazones appeared in 20 0 265. This so called Huang-Minlon variant of the Wolff-Kishner reduction was successfully applied to some aromatic and aliphatic aldehydes and ketones, including intermediates in the synthesis of the alkaloid flavopereirine. The reactions were performed by mixing the carbonyl compound with 2 equiv of hydrazine hydrate and an excess of powdered KOH in a commercial microwave oven. The mixtures were irradiated at 150 W for a few minutes before 250-350 W irradiations were applied (Scheme 4.39). The reaction was shown... 

The C=N bonds of imines, oximes and hydrazones can be hydrogenated to form the corresponding amines even under ambient conditions on Pt, Pd, Rh and Raney Ni catalysts in acidic, neutral or basic media (equation 42). The imines, furthermore, are intermediates in the hydrogenation of nitro compounds, nitriles and oximes, and likewise play a key role as intermediates in the reductive amination of carbonyl compounds. 

The mechanism for formation of the hydrazone is the same as the mechanism for imine formation (Key Mechanism 18-5 in Section 18-15). The actual reduction step involves two tautomeric proton transfers from nitrogen to carbon (Mechanism 18-7). In this strongly basic solution, we expect a proton transfer from N to C to occur by loss of a proton from nitrogen, followed by reprotonation on carbon. A second deprotonation sets up the intermediate for loss of nitrogen to form a carbanion. This carbanion is quickly reprotonated to give the product. 

Oximes, hydrazones, semicarbazones, diazines and carbodiimides all undergo reactions involving addition to a carbon-nitrogen double bond (A, D], but these reactions are of limited value, with the exception of the reaction with ketoximes. This last reaction, with an excess of Grignard at elevated temperatures, is a useful route to aziridines, (4), although yields are rarely high. In some cases, reduction of the intermediate azirine (2) leads to an alternative aziridine (5). 

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