Hydrazide oximes

The reaction of hydroxamoyl chlorides with hydrazine has also been investigated and hydrazide-oximes XXIX (. 69 obtained. However, the hydrazine derivative XXX yields N-substituted 2-amino-5-methyl-mercapto-l,3,4-thiadiazoles XXXI upon reaction with hydroxamoyl chlorides ( ). 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Related (diisopropoxyphosphoryl)- and (diisobutoxyphosphoryl)formonitrile oxides (114), generated in basic media from the corresponding oximes react in situ with alcohols, phenols, alkanethiols, thiophenols, aliphatic and aromatic primary amines, hydrazines and hydrazides as well as 4-aminoantipyryne to give hydroxymates, thiohydroxymates, and amidoximes, respectively. It is important to note that the addition is stereoselective and gives E-adducts with the exception of (i-Pr0)2P(0)C( N0H)0Me, which is formed as a 1 1 mixture of E and Z isomers. 

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. 

Reaction of isatin 3-monooxime sulfonate 159 with hydrazides leads to 1-aryltriazoli-nones 160 with 41-46% yields (equation 70) . Interaction of oxime PhC(=NHPh)CCl=... 

As illustrated in Scheme 1, hydrazide and aminooxy groups readily form stable hydrazone and oxime bonds, respectively, with aldehydes at pH values between 3 and 5.5. The Cys 1-amino-2-thiol moiety forms a stable thiazolidine ring with the aldehyde between pH 4 and 5, whereas at these pH values an amino group, if it reacts at all, gives a readily reversible Schiff base. 

Curtius rearrangement of a-oximino acid azides is reported as a new method of synthesis for 3-substituted 5-hydroxyoxadiazoles. In this method, the oxime of an a-ketoester is converted to the acid hydrazide, which in turn is converted to the azide by reaction with nitrous acid 115a). 

In this section we consider peptide analogues containing the amide surrogates 1 to 11 (Scheme 1). These can be isosteric with the amide group in the sense that consecutive a-carbons are separated by three bonds, as in link 1, the (nitrono) peptides, and link 2, the [methyleneamino(hydroxy)] or (TV-hydroxy reduced amide) peptides. They also can be an N-modified amide, as in link 3, the (TV-hydroxy amide) peptides, and link 4, the (V-aminoamide) peptides. Elongation of the peptide unit by one covalent bond has been realized by the introduction of a heteroatom or a methylene into the backbone, as in link 5, the (hydrazide) peptides, link 6, the (amidoxy) peptides, link 7, the (oxomethyleneamino) peptides, link 8, the [(hydroxy)ethyleneamino] peptides, link 9, the (ethyleneamino) peptides, and link 10 the (oxime) peptides. Finally, insertion of an ethylenic bond (two covalent bonds) between the a-carbon and the carbonyl gives rise to link 11, the (but-2-enamide) or (vinylogous amide) peptides. 

Peptides can also be cyclized through their side-chain functionalities (e.g. using lysine, cysteine, glutamic acid, or aspartic acid [68-71]), or with the aid of synthetic spacers ([72] see also Table 8.5). Examples have been reported of the preparation of cyclic peptides using safety-catch linkers (e.g. (4-alkylmercapto)phenol [62], sulfonamide [73], or hydrazide [74]), 2-nitrophenyl ester attachment [61], or oxime ester... 

Seifier, S., P. M. Gallup, S. Michaels and E. Meilman Analysis of hydroxamic acids and hydrazides preparation and properties of dinitrophenyl derivatives of hydroxamic acids, oximes, hydrazides and hydrazones. J. Biol. Chem. 235, 2613 (1960). 

The commercially available oxime linker 1.15 (72) has been used in peptide synthesis and for the SPS of small organic molecules such as indoles. Cleavage is carried out with either hydrazine (0.5 M hydrazine in CHCb-MeOH 2/1 for 10 min at rt) or with aliphatic amines or amino esters (DCM at rt for 12 h) to produce hydrazides and amides, respectively. 

Protected peptides are cleaved from the resin with N-hydroxypiperidine (HOPip), followed by treatment with zinc in AcOH to afford the free acidJ Resin-bound peptides can be cleaved from the oxime resin using the tetrabutylammonium salts of side-chain protected amino acids to directly provide the a-amino-protected (Boc), side-chain-protected pep-tide.[ 3o- 32] Peptide esters can be obtained from peptidyl oxime resin by treating with amino acid estersJ Peptide hydrazides are derived from peptidyl oxime resins on treatment with anhydrous hydrazine.b Protected peptide amides can be also derived from peptidyl oxime resins on treatment with ammoniaJ l Cyclic peptide acids as carboxy components were successfully prepared by this procedure through the Pac ester. 

---