Preparation of semicarbazones

Semicarbazide and its hydrochloride may have carcinogenic, teratogenic, and mutagenic effects. Should either of these substances contact your skin, immediately flood the affected area with water. 

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Dissolve 0.5 g of semicarbazide hydrochloride and 0.8 g of sodium acetate in 5 ml of water in a test tube and then add about 0.5 ml of the carbonyl compound. Stopper and shake the tube vigorously, remove the stopper, and place the test tube in a beaker of boiling water. Discontinue heating the water, and allow the test tube to cool to room temperature in the beaker of water. Transfer the test tube to an ice-water bath, and if crystals have not formed, scratch the side of the tube with a glass rod at the interface between the liquid and air to induce crystallization. Recrystallize the semicarbazone from water or aqueous ethanol. 

If the carbonyl compound is insoluble in water, dissolve it in 5 ml of ethanol. Add water until the solution becomes turbid, then add a little ethanol until the turbidity disappears. Add the semicarbazide hydrochloride and sodium acetate, and continue as above from this point. 

Flush excess reagent and filtrates down the drain. 

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The experimental procedure to be followed depends upon the products of hydrolysis. If the alcohol and aldehyde are both soluble in water, the reaction product is divided into two parts. One portion is used for the characterisation of the aldehyde by the preparation of a suitable derivative e.g., the 2 4-dinitrophenylhydrazone, semicarbazone or di-medone compound—see Sections 111,70 and 111,74). The other portion is employed for the preparation of a 3 5-dinitrobenzoate, etc. (see Section 111,27) it is advisable first to concentrate the alcohol by dis tillation or to attempt to salt out the alcohol by the addition of solid potassium carbonate. If one of the hydrolysis products is insoluble in the reaction mixture, it is separated and characterised. If both the aldehyde and the alcohol are insoluble, they are removed from the aqueous layer separation is generally most simply effected with sodium bisulphite solution (compare Section Ill,74),but fractional distillation may sometimes be employed. 

When semicarbazide Ls heated in the absence of a carbonyl compound for long periods, condensation to blurea, NHjCONHNHCONHj, m.p. 247-250 (decomp.), may result occasionally this substance may be produced in the normal preparation of a semicarbazone that forms slowly. Biurea is sparingly soluble in alcohol and soluble in hot water, whereas semicarbazones with melting points in the same range are insoluble in water this enables it to be readily distinguished from a semicarbazone. 

The preparation of crystaUine derivatives, including 2 4-dinitro-phenyl hydrazones, semicarbazones, oximes, phenylhydrazones and p-nitrophenylhydrazones can be carried out as described under Aromatic Aldehydes, Section IV, 135. 

Reactions with Amines and Amides. Hydroxybenzaldehydes undergo the normal reactions with aUphatic and aromatic primary amines to form imines and Schiff bases reaction with hydroxylamine gives an oxime, reaction with hydrazines gives hydrazones, and reactions with semicarbazide give semicarbazones. The reaction of 4-hydroxybenzaldehyde with hydroxylamine hydrochloride is a convenient method for the preparation of 4-cyanophenol (52,53). 

Yields are in the order of 50%. A more convenient sequence, but involving two extra steps, requires prior preparation of the 2,4-dinitrophenyl-hydrazone or semicarbazone followed by an acidic dehydration, and finally removal of the protecting group. 

For unsubstitUted or lower alkylated dioxotriazines, it is advantageous to cyclize semicarbazones by sodium ethylate in ethylene glycol as described by Chang and XJlbricht. In this reaction 6-aza-uracil is obtained in 66% yield. The procedure was used for the preparation of labeled 6-azauracil ° and later for the synthesis of a number of 6-alkyl derivatives including 6-azathymine. °... 

The last of the procedures of preparation of A -alkyl derivatives of dioxotriazines is the cyclization of A-alkylated semicarbazones of a-keto acids. It was employed only in a few cases and it appears that its yields are very low. Despite the fact that even here a fundamental effect of substitution on the yield of cyclization can be expected, as the case is with analogous thiosemicarbazones (e.g., Section II,B,4,b), the method is of no particular preparative value. 

The preparation of the selenazolyl-pyrazolones was then effected by a second method, in which first the pyrazolone ring and afterward the selenazole ring was formed. For this purpose -ketoester seleno-semicarbazones were first converted to the corresponding 1-seleno-carbamoyl-3-aIkylpyrazol-5-one. These, by condensation with a-halo-genocarbonyl compounds according to the Hantzsch synthesis, formed the selenazole ring as a second step (17). 

Different 5-alkyl-2-formyl- and 5-alkyl-2-acetylselenophenes have been synthesized as well as semicarbazones derived from them.92 The acetyl derivatives have in the following reaction sequence (Eq. 27) been used for preparation of epoxyselenophenes.93... 

Oxidation of one molar proportion with sodium pieriodate produces two equivalents of formic acid, in accordance with the existence of hydroxyl groups attached to four contiguous carbon atoms. This oxidation (and also that carried out with lead tetraacetate) gives an aldehyde, whose semicar-bazone has an analysis corresponding to that of the semicarbazone of an ethyl formyl-methyl-furoate (XII). By oxidation of aldehyde XII with silver oxide in alkaline solution, 2-methyl-3,4-furandicarboxylic acid (XIV) was obtained this was identical with the compound described by Alder and Rickert.20 The identity was confirmed by preparation of the respective dianilides. The acid XIV has also been prepared by the reaction between the sodium salt of ethyl acetoacetate and ethyl bromopyruvate.9... 

Experiments.—Being a primary hydrazide (of carbamic acid), semicarbazide reduces ammoniacal silver solutions and Fehling s solution. It reacts readily with aldehydes and ketones with the elimination of water and formation of semicarbazones, which, since they are more easily hydrolysed than are phenylhydrazones and oximes, are to be preferred to the latter for purposes of separation and purification of carbonyl compounds. Shake an aqueous solution of the hydrochloride (prepared as described above) with a few drops of benzaldehyde, isolate the semicarbazone and purify it by recrystallisation from alcohol. Melting point 214° decomp. Benzaldehyde semicarbazone is decomposed into its constituents by gentle warming with concentrated hydrochloric acid. 

The ketones and aldehydes, the preparation of which is described later, should be characterised in the same way by their semicarbazones. 

Aminoacetone is a versatile starting material for many syntheses, particularly for the preparation of heterocycles. The present procedure describes a convenient method for its preparation in a form suitable for storage. The aminoacetone can be generated from aminoacetone semicarbazone hydrochloride in situ as needed. 

The synthesis and preliminary biological activity of substituted 7-alkylseleno-l,4-dihydro[l,6]naphthyridines have been reported <2000DOC218> along with their further synthetic ttansformations <2001RCB122>. There have also been reports of the preparation of selenium-containing fused heterocycles. The C=0 function in benzothiophen-3-ones, 3,4-dihydrothiopyrano[3,2-. ]benzothiophen-4(2//)-ones, and 3,4-dihydro-2//,5//-thiopyrano[2, 3 4,5]thiopyrano[3,2-/ ]ben-zothiophen-4-ones reacts with selenium dioxide and thionyl chloride to give fused 1,2,3-selena and thiadiazoles via their semicarbazones <1999IJB308>. 

Preparation of hydrazone and semicarbazones Imines obtained from hydrazines are known as hydrazones, and imines obtained from semicarba-zides are called semicarbazones. 

Ethylenimines or aziridines [lb] can be considered cyclic imines and are only briefly covered in Section 5. The preparation of heterocyclic imine systems, semicarbazones, hydrazones, azines, and oximes, is omitted from this chapter. The synthesis of carbodiimides is presented in Chapter 9. 

Adrenochrome methyl and ethyl ethers (8 and 9 respectively), first isolated by Hukki and Seppalainen as their semicarbazones,66 have now been obtained in crystalline form by oxidation of the corresponding catecholamine ethers with silver oxide in dry acetonitrile.65 A-Ethylnoradrenochrome (6) has also been prepared in crystalline form by the oxidation of N-ethylnoradrenaline in 90% methanol with the calculated quantity of iodic acid65 (cf. the preparation of adrenochrome by Macciotta67). Adrenochrome 08-acetate (3-acetoxy-epinochrome) (10) was obtained by the oxidation of acetyladrena-line [j3-acetoxy-j8-(3,4-dihydroxyphenyl)ethylmethylamine].68... 

Addition products have been obtained from aminochrome derivatives such as the semicarbazone, with sodium bisulfite. Recently Correia Alves reported the preparation of a compound described as adrenochrome semicarbazone sodium sulfonate (m.p. >300°) by treating a solution of adrenochrome monosemicarbazone (90) in sodium carbonate solution with sulfur dioxide at 40° for several days192 this compound was apparently different from the substance (m.p. 227-228°) obtained in a somewhat similar manner by Iwao193-194 and may be comparable to the compound (83) (m.p. > 300°) previously described in a Belgian patent179 (see Section IV,F). Iwao established the structure of his compound as the sodium salt of epinochrome-3-sulfonic acid monosemicarbazone (93).193... 

The optical purity of A -Boc amino aldehydes has been successfully determined by way of their semicarbazone derivatives.[181 The semicarbazone derivatives were shown to have unique Boc ]H NMR and signals depending on the absolute configuration of the R1 group. In the case of derivatized Boc-D-Arg(N02)-H and Boc-Arg(N02)-H semicarbazones, distinct Boc peaks were found at 6 1.45 and 1.46. This behavior was confirmed by preparation of racemic Boc-Gly(Al)-H semicarbazone, which shows a methyl doublet and Boc signals at 5 1.42 and 1.46 with the expected 1 1 integration. 

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