Hydrazone reduction with sodium

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. 

Another route to the formation of a hydrazide on a surface is to use an aldehyde-containing particle (such as HEMA/acrolein copolymers) and subsequently modify the aldehydes to form hydrazone linkages with bis-hydrazide compounds, which then can be stabilized by reduction with sodium cyanoborohydride (Chapter 2, Section 5). The resulting derivative contains terminal hydrazides for immobilization of carbonyl ligands (see Figure 14.18). 

The 1-isopropoxymethyl derivative of pyrrolo-benzothiazepine 376 can be obtained from aldehyde 375 through the tosyl hydrazone followed by reduction with sodium borohydride in 2-propanol. 1-Methyl substituted 378 is available from aldehyde 375 and hydrazine monohydrate followed by potassium tert-butoxide (Scheme 76, Section 5.1.1 (2004JMC143)). 

A final method of alkene formation from a-derivatized ketones entails formation of unsaturated tosyl-hydrazones from a,P-unsaturated ketones followed by conjugate reduction with sodium cyanoborohy-diide in acid media. This transformation, which proceeds with regioselective migration of the original double bond, has been applied to the synthesis of quassinoids by Ganem et al. (Scheme 22). A similar... 

From Oximes and Hydrazones.—The oximes and hydrazones obtained from ketone acids yield amino acids on reduction with sodium amalgam and glacial acetic acid. 

Constitution. The alkaloid yields a crystalline semicarbazone, m.p. 169°, a liquid hydrazone, b.p. 154-5°/29 mm., and a liquid oxime, b.p. 160°/12 mm., from which a crystalline picrate, m.p. 106°, can be prepared. The methiodide crystallises in cubes, m.p. 156°. On oxidation with chromic acid in sulphuric acid solution the base yields N-methylpiperdine-2-carboxylic acid, and the hydrazone on reduction with sodium in alcohol at 150-70° forms N-methylconiine (p. 17). 

Estevez et al. (28J) isolated from cell-free extracts of Evernia prmastri the enzyme DL-usnic acid dehydrogenase which catalyzed the reduction of (-1-)- and (-)-usnic acid formula 495 was presumed to be that of the reduction product. Some time later Vicente and co-workers (708, 709) purified a second dehydrogenase which converted only the dextrorotatory enantiomer of usnic acid to 1-dihydrousnic acid (496) (see Scheme 154). The structure proposals for both dihydro derivatives were primarily based on the IR spectra and need to be confirmed by NMR, MS and/or X-ray analysis. Phenyl and isonicot-inoyl hydrazones of (—)-usnic acid (497, 498) have been reported, while reduction with sodium borohydride gave a mixture of 13a- and 13p-dihydrousnic acid (499) (555). 

Similar intermediates are probably involved in the thionyl-chloride-promoted cyclization of 6-(benzylidene-l-methylhydrazino)-l,3-dimethyl-uracils (246 R = Me R = H) to pyrazolo[3,4-ff]pyrimidinediones (247). Less easily explained is the cyclization of hydrazones (246 R = Me R = H) to the oxazolo [5,4-f/]pyrimidines (245 X = 0) by sodium nitrite in boiling acetic acid. Undoubtedly, nitrosation at the 5-position is the initial step in these reactions, but thereafter events remain unclear. Interestingly, the ketone hydrazones (246 R = H, R = Me), on similar treatment, followed by reduction with sodium dithionite, furnish 6-aryl-l,3-dimethyl-lumazines (248) in low yields (10—15%). ... 

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80°C (191), with acetic acid anhydride in pyridine at 100°C (192), with acetyl chloride and pyridine in toluene at 60°C (193), or by the action of ketene in alcohoHc suspension. 4-Hydroxyacetanihde also may be synthesized directiy from 4-nitrophenol The available reduction—acetylation systems include tin with acetic acid, hydrogenation over Pd—C in acetic anhydride, and hydrogenation over platinum in acetic acid (194,195). Other routes include rearrangement of 4-hydroxyacetophenone hydrazone with sodium nitrite in sulfuric acid and the electrolytic hydroxylation of acetanilide [103-84-4] (196). 

Thus, the reduction of tosylhydrazones with sodium borodeuteride in dioxane provides only monodeuterated analogs. For the insertion of two deuteriums it is necessary to first exchange the hydrazone proton and to carry out the reduction in aprotic or deuterated solvents. Under these conditions the reduction of the tosylhydrazone derivatives of 7- and 20-keto... 

Wolff - Kishner reduction of aldehydes and ketones. Upon heating the hydrazone or semicarbazone of an aldehyde or ketone with potassium hydroxide or with sodium ethoxide solution (sealed tube), the corresponding hydrocarbon is obtained ... 

The deoxygenation of aldehydes and ketones to the corresponding hydrocarbons via the hydrazones is known as the Wolff-Kishner reduction.28 Various modifications of the original protocols have been suggested. One of the most useful is the Huang-Minlon modification, which substituted hydrazine hydrate as a safer and less expensive replacement of anhydrous hydrazine. In addition, diethylene glycol together with sodium hydroxide was used to increase the reaction... 

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... 

If a small molecule is involved, however, reduction of the hydrazone with sodium cyanoboro-hydride is recommended to produce a leak-resistant bond. 

Another spectrophotometric method measuring both simple and combined sugars was described in papers by Johnson and Sieburth [158] and Burney and Sieburth [159]. The basic method comprised reduction of sugars to alditols with sodium borohydride, and oxidation of the alditols to form free formaldehyde. The formaldehyde was then determined spectrophotometrically with 3-methyl-2-benzothiazolinone hydrazone hydrochloride. 

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. ... 

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. 

Reduction of the carhonyl group to methylene is carried out hy Clemmensen reduction [160, 758], hy Wolff-Kizhner reduction [280, 282], or hy its modifications decomposition of hydrazones with potassium /er/-butoxide in dimethyl sulfoxide at room temperature in yields of 60-90% [845], or hy reduction ofp-toluenesulfonylhydrazones with sodium borohydride (yields 65-80%) [811] (p. 134). 

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]. 

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]. 

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