Aldehydes from semicarbazones

Different solid-phase techniques for the synthesis of C-terminal peptide aldehydes have gained much attention and allowed greater accessibility to such compounds. Solid-phase techniques have been used to synthesize peptide aldehydes from semicarbazones, Weinreb amides, phenyl esters, acetals, and a, 3-unsaturated y-amino acids)47-50,60 63 The examples presented below use unique linkers to enhance the automated efficiency of C-terminal peptide aldehyde synthesis)47 For instance, the reduction of phenyl esters led to the aldehyde as the major product, but also a small amount of alcohol)50 The cleavage of u,p-unsaturated y-amino acids via ozonolysis yielded enantiomeric pure C-terminal peptides)49,61 The semicarbazone from reduction of peptide esters technique laid the initial foundation for solid-phase synthesis. Overall, Weinreb reduction is an ideal choice due to its high yields, optical purity, and its adaptability to a solid-phase platform)47 ... 

Regeneration of carbonyl compounds from certain derivatives.1 Ketones can be recovered in satisfactory yield from the phenylhydrazones, p-nitrophenyl-hydrazones, tosylhydrazones, oximes, and semicarbazones by reaction with 1 equivalent of (C6H5SeO)20. 2,4-Dinitrophenylhydrazones and N,N-dimethyl-hydrazones are inert under even rather vigorous conditions. The reagent can also be used to regenerate aldehydes from oximes or tosylhydrazones. 

Hydrazones (166) react with chloromethyleneiminium salt (1) giving, after hydrolysis, aldehydes (167 Scheme 12). In this transformation the hydrazones (166) are clearly behaving as aza-enamines.1-61 Hydrazones (168) and (169) react with chloromethyleneiminium salt (1) at both the methyl group and at nitrogen to yield the corresponding iminium salts (170) and (171), which cyclize with loss of dimethylamine to provide iminium salts (172) and (173), respectively. Hydrolysis of these salts (172) and (173) affords pyrazole-4-carbaldehyde derivatives (174) and (175 72-96% Scheme 13).1 Product (174) can also be prepared from semicarbazone (176). 

Aldehydes and ketones may frequently be identified by their semicarbazones, obtained by direct condensation with semicarbazide (or amino-urea), NH,NHCONH a compound which is a monacidic base and usually available as its monohydrochloride, NHjCONHNH, HCl. Semicarbazones are particularly useful for identification of con jounds (such as acetophenone) of which the oxime is too soluble to be readily isolated and the phenylhydrazone is unstable moreover, the high nitrogen content of semicarbazones enables very small quantities to be accurately analysed and so identified. The general conditions for the formation of semicarbazones are very similar to those for oximes and phenylhydrazones (pp. 93, 229) the free base must of course be liberated from its salts by the addition of sodium acetate. 

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. 

Semicarbazones. Dissolve 1 g. of semicarbazide hydrochloride and 1 5g. of crystallised sodium acetate in 8-10 ml. of water add 0 - 5-1 g. of the aldehyde or ketone and shake. If the mixture is turbid, add alcohol (acetone-free) or water until a clear solution is obtained shake the mixture for a few minutes and allow to stand. Usually the semicarbazone crystallises from the cold solution on standing, the time varying from a few minutes to several hours. The reaction may be accelerated,... 

Oximes, hydrazones and semicarbazones are readily prepared from the aldehydes (37, 106). 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

Ketones are more stable to oxidation than aldehydes and can be purified from oxidisable impurities by refluxing with potassium permanganate until the colour persists, followed by shaking with sodium carbonate (to remove acidic impurities) and distilling. Traces of water can be removed with type 4A Linde molecular sieves. Ketones which are solids can be purified by crystallisation from alcohol, toluene, or petroleum ether, and are usually sufficiently volatile for sublimation in vacuum. Ketones can be further purified via their bisulfite, semicarbazone or oxime derivatives (vide supra). The bisulfite addition compounds are formed only by aldehydes and methyl ketones but they are readily hydrolysed in dilute acid or alkali. 

Semicarbazone formation from aldehyde 50 with hydrazine... 

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. 

Carboxanilides, such as 359, are obtained from 335-type precursors (91MI1, 92MI1). Amidation of protected chiral educt 360 proceeds via coupling to protected aspartyl aldehyde synthon 361 followed by successive removal of the ferf-butyl ester and semicarbazone protecting groups to yield inhibitor 362 (98BML2757). 

On reduction, nitroguanidine is converted first into nitrosoguanidine and then into aminoguanidine i.e. guanylhydrazine. The latter is used for the manufacture of tetrazene (p. 206), and in organic chemistry to form crystalline derivatives from aldehydes and ketones, just as semicarbazide forms semicarbazones. 

Semicarbazones are prepared by dissolving semicarbazide hydrochloride (ca Ig) and sodium acetate (ca 1.5g) in water (8-lOml) and adding the aldehyde or ketone (0.5-lg) and stirring. The semicarbazone crystallises out and is recrystallised from ethanol or aqueous ethanol. These are hydrolysed by steam distillation in the presence of oxalic acid or better by exchange with pyruvic acid (Hershberg dOC 13 542 1948). 

Oxidation of p-toluenesulfonylhydrazones.1 Carbonyl compounds can be regenerated in good yield from the tosylhydrazones by treatment with 1 equivalent of Tl(OAc), in HOAc. Room temperature suffices in the case of aldehydes, whereas reflux temperatures are used for ketones. The other product is T1(0S02C6H4CH3). This method is less useful for oxidative cleavage of semicarbazones long reflux periods are necessary, and acetoxylation is a side reaction. 

Enantiomerically pure tripeptide aldehydes are typically synthesized by azide or mixed anhydride coupling of dipeptides to a-amino aldehydes or their semicarbazone derivatives. For example, Ac-Leu-Leu-Phe-H was synthesized by the azide coupling of Ac-Leu-Leu-OH with Phe-H semicarbazone, prepared by catalytic hydrogenation of Z-Phe-H semicarbazone. The tripeptide semicarbazone was deprotected with 37% HCHO/HC1 solution (Table 2)J5 C-terminal argininal, ornithinal, and lysinal peptides such as Z-Leu-Leu-Orn(Boc)-H and Z-Leu-Leu-Lys(Boc)-H were prepared by mixed anhydride coupling of Z-Leu-Leu-OH with Orn(Boc)-H semicarbazone or Lys(Boc)-H semicarbazone. 3 Z-Leu-Leu-Arg(N02)-H was prepared by mixed anhydride coupling of Z-Leu-Leu-OH with Arg(N02)-H semicarbazone trifluoroacetate, prepared from the reaction of TFA and Boc-Arg(N02)-H semicarbazone (Table 2) J31... 

The reduction of a-amino mixed anhydrides with lithium tri-/ert-butoxyaluminum hydride in THF at —70 °C is a very efficient method for synthesis of amino aldehydes (Table 9). 551 Three approaches were taken for the reduction of a-amino mixed anhydrides. 55 The first approach reduced Boc-Ala-OC02Et with lithium tri-terf-butoxyaluminum hydride was unsuccessful due to intramolecular rearrangements that gave Boc-Ala-OEt in addition to the Boc-Ala-H. The second approach involved reduction of diphenylacetic anhydride derivatives, which were prepared from Boc amino acids and diphenyl ketene, gave a diphenylacetic acid byproduct that was very difficult to remove unless the aldehyde was converted into its semicarbazone and separated chromatographically yields were 51-69%. The last and... 

Aluminium alkoxides very often promote aldol condensations between the aldehyde or ketone, resulting from the oxidation, and the carbonyl compound used as the oxidant. That is why, Oppenauer oxidations are seldom employed for the obtention of aldehydes, as these compounds have a greater tendency than ketones to be involved in aldol condensations. Likewise, although Oppenauer oxidation can be made in the presence of ketones,49 it may be advisable to protect them, for example as semicarbazones.50... 

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