Hydrazone, acid-sensitive

A rapid oxidative deoximination reaction using DMP (2) proceeds selectively in the presence of alcohols, O-methyl oximes, tosyl hydrazones, acid sensitive groups, and with electron rich and poor moieties in high yields. The reaction is conducted at room temperature, is rapid (within 20 min), with no over-oxidation observed due to the high chemoselectivity of DMP (2).J7... 

It has been reported that the cleavage of SAMP hydrazones can proceed smoothly with a saturated aqueous oxalic acid, and this allows the efficient recovery of the expensive and acid-sensitive chiral auxiliaries SAMP and RAMP. No racemization of the chiral ketones occurs during the weak acid oxalic acid treatment, so this method is essential for compounds sensitive to oxidative cleavage.393... 

In the case of 489, the product 490 cyclizes to the isoquinolone 491, and the amide substituent is a required part of the target molecule" . However, it frequently occurs that the amide substituent is not required in the final product, and the acid-sensitive alkenyl substituent of 492 has been used as a solution to the problem of cleaving a C—N bond in the product (Scheme 193) ° °. Weinreb-type amides 493 can also be laterally lithiated, and the methoxy group removed from 494 by TiCU" . Hydrazones similarly can be laterally lithiated and oxidatively deprotected. ... 

The mild deprotection of acetal 15 with CUSO4 in acetone was accomplished in high yield [12]. The mildness of copper Lewis acids for the hydrolysis of hydra-zones [13] is advantageous for acid-sensitive substrates (Sch. 5). The /3,a-unsaturated hydrazone 17 was effectively hydrolyzed without conjugation of the double bond to afford 18 in good yield (Sch. 5) [14]. SAMP-Hydrazones can be hydrolyzed without racemization [15]. The two-step alkylation and hydrolysis of 19 provided 20 in 84 % overall yield and 94 % ee. 

An acid-labile linker of c/ -aconityl or hydrazone between DOX and HPMA was synthesized to release the drug in the endosomes and lysosomes after endocy-totic uptake of the conjugate. Hydrolysis of the linkage occurs at weak acidic pH therefore, the release of DOX at plasma pH is insignificant. The in vivo activity of the acid-sensitive conjugate was significantly enhanced in comparison with free DOX and PKl. ... 

Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L (2004) A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci 23 393-397... 

It is usually unnecessary to isolate such hydrazones during the working up the mixture is partitioned between water and a water-insoluble solvent such as ether. The hydrazones then remain in the aqueous phase, and the other organic substances are removed in the organic phase. The carbonyl components are finally regenerated from the aqueous hydrazone phase by acid hydrolysis. Considerable fractionation of mixed carbonyl compounds can be achieved by varying the reaction conditions, notably the temperature or pH, of either the condensation or the hydrolysis. Acid-sensitive carbonyl compounds, e.g., citral, may be isolated by exchange from the hydrazone by an excess of formaldehyde.932... 

Nitromethane are particularly sensitive to base, and the reaction with base is different from that of other nitroalkanes, hydrazone acid can be formed through condensation reaction at low temperature (40-50 °C). 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

Hydrazino-l,2,4-thiadiazoles (124), which can be prepared by reduction of the corresponding nitrosamine (123) (Scheme 29) with LAH, are stable in acid and base and readily form hydrazone derivatives on reaction with suitable carbonyl compounds <65AHC(5)ll9>. In contrast, 3-hydrazino-1,2,4-thiadiazoles (125), which are synthesized by ring closure methods, are very sensitive to acid... 

The hydrazones derived from (133) and oxocarboxylic acids are thermally very sensitive and decompose immediately at 30 °C to give sulfur, nitrogen, and polymeric material. Decomposition also occurs on treatment with catalytic amounts of both acid and base. 

Hydrazones with functional groups which are sensitive to ozone can be cleaved by the "salt method 3. In this method the product hydrazones are converted quantitatively by excess iodomethane at 60 C to their methoiodides, which are hydrolyzed more easily than the corresponding hydrazones. The crude methoiodides are hydrolyzed in a two-phase system (1 -6 N hydrochloric acid/pentane) within 15 to 60 minutes, and the corresponding aldehydes or ketones are obtained in excellent yields without racemization. Under these conditions, solutions of optically active ketones can be stirred for 1 hour without change in optical rotation, whereas traces of base can cause spontaneous racemization of the carbonyl compounds. For this reason distillation of chlorotrimethylsilane in the apparatus prior to the distillation of the optically active carbonyl compound is helpful to avoid racemization caused by basic glassware6. 

A further method for estimation of sialic acid using periodic acid has been reported by Massamiri and coworkers.121 Fonnaldehyde produced by mild, oxidative cleavage of the D-en/f/iro-glycerol-l-yl side-chain of Neu can be detected by 3-methyl-2-benzothiazolinone hydrazone, which yields a green-blue color (absorbance maximum 625 nm). This test, which is slightly more sensitive than the thiobarbi-... 

Oximes, hydrazones and semicarbazones. The hydrolysis products of these compounds, i.e. aldehydes and ketones, may be sensitive to alkali (this is particularly so for aldehydes) it is best, therefore, to conduct the hydrolysis with strong mineral acid. After hydrolysis the aldehyde or ketone may be isolated by distillation with steam, extraction with ether or, if a solid, by filtration, and then identified. The acid solution may be examined for hydroxylamine or hydrazine or semicarbazide substituted hydrazines of the aromatic series are precipitated as oils or solids upon the addition of alkali. 

NA-Dimethylhydrazone 68, furnished from keto-acid 33 upon treatment with WV-dimethylhydrazine, was found to be extremely water sensitive. Attempts to form the hydrazone were thwarted by low yields under a number of conditions in which solvents were present. Azeotropic removal of water, with or without molecular sieves, was also unsatisfactory. Eventually, it was found most convenient to simply dissolve the keto-acid in neat dimethylhydrazine without desiccant. After heating for a number of hours, followed by cooling and removal of excess dimethylhydrazine, formation of the desired hydrazone was apparent by NMR due to loss of the methyl ketone resonance at 5 2.14. This initially formed hydrazone existed as a dimethylhydrazonium carboxylate, but it was found that reversion to free carboxylic acid 68 occurred in vacuo, as evidenced by the proton NMR run in dry CDClj. 

Aldehydes and ketones on complete reduction give alkanes by three different methods that are complementary to each other. The Woff-Kishner reduction is done under basic conditions and is suitable for compounds that might be sensitive to acid (Following fig.). The reaction involves the nucleophilic addition by hydrazine followed by elimination of water to form a hydrazone. The mechanism is the... 

By contrast, 3-hydrazino-l,2,4-thiadiazoles (163), which are prepared by ring closure methods, are very sensitive to acids and undergo elimination of sulfur with formation of 5-arylamino-l,2,4-triazoles (164) as indicated in Scheme 61 (63JCS4566). The mechanism of this conversion is not known but presumably involves the attack of a hard nucleophile at the 5-position followed by ring opening, loss of sulfur and recyclization as has been observed with the quaternary salts (77JCS(P1)1791) (see Schemes 22, 23, and 24). Hydrazine (163) reacts with aldehydes to produce hydrazones (165) and with dimethyl malonate to yield pyrazoles (166). Diazonium salts of type (153) have been prepared by the methods... 

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