Ketones reaction with hydrazides

Allylation of acyloyl-imidazoles and pyrazoles61 with allyl halide mediated by indium in aqueous media provides a facile regioselective synthesis of P, y-unsaturated ketones (Scheme 11.1), which has been applied to the synthesis of the monoterpene artemesia ketone. The same product can be obtained by indium-mediated allylation of acyl cyanide (Eq. 11.35).62 Samarium, gallium, and bismuth can be used as a mediator for the allylation of nitrones and hydrazones to give homoallylic hydroxylamine and hydrazides in aqueous media in the presence of Bu4NBr (Scheme 11.2).63 The reaction with gallium and bismuth can be increased dramatically under microwave activation. 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

Derivatives of hydrazine, especially the hydrazide compounds formed from carboxylate groups, can react specifically with aldehyde or ketone functional groups in target molecules. Reaction with either group creates a hydrazone linkage (Reaction 44)—a type of Schiff base. This bond is relatively stable if it is formed with a ketone, but somewhat labile if the reaction is with an aldehyde group. However, the reaction rate of hydrazine derivatives with aldehydes typically is faster than the rate with ketones. Hydrazone formation with aldehydes, however, results in much more stable bonds than the easily reversible Schiff base interaction of an amine with an aldehyde. To further stabilize the bond between a hydrazide and an aldehyde, the hydrazone may be reacted with sodium cyanoborohydride to reduce the double bond and form a secure covalent linkage. 

Bis-hydrazide-containing molecules also can be used to activate soluble polymeric sub-stances-containing aldehyde groups. For instance, dextran may be periodate oxidized to create numerous formyl functionalities on each molecule. Subsequent reaction with a homobifunctional hydrazide in large excess results in a hydrazide-activated polymer having multivalent-binding capability toward aldehydes or ketones (Chapter 25, Section 2.2). Insoluble support matrices suitable for affinity chromatography have been activated in a similar fashion to create the hydrazide derivative (O Shannessy and Wilchek, 1990). 

Hydrazide derivatives also may be prepared from a periodate-oxidized dextran polymer or from a carboxyl-containing dextran derivative by reaction with te-hydrazidc compounds (Chapter 4, Section 8). A hydrazide terminal spacer provides reactivity toward aldehyde- or ketone-containing molecules. Thus, the hydrazide-dextran polymer can be used to conjugate specifically glycoproteins or other polysaccharide-containing molecules after they have been oxidized with periodate to form aldehydes (Chapter 1, Section 4.4). 

Precursors for this task were obtained by addition of /-butylmagnesium bromide to the central bond of [1.1.1 ]propellane 40a followed by conversion of the 3-f-butylbicyclo[ 1.1.1 Jpentyl-1 -y 1-magnesium bromide (88) into the ketones 89 by standard methods.27 Reaction of ketones 89 with tosyl hydrazide afforded the hydrazones 90, which gave the corresponding lithium salts 91 by reaction with MeLi in ether. These salts were dried under high vacuum and then pyrolized at 4 x 10 5 torr in the temperature range of 100-130°C and the volatile products condensed in a liquid nitrogen-cooled trap. 

The conditions influence the direction of the reactions between the nucleophile and unsaturated carbonyl compounds as well. For example, the reaction of hydrazides of some organic acids with chalcone in the presence of acetic acid involves the carbonyl group of the unsaturated ketone, while basic catalysis (piperidine) promotes /3-addition [45]. An analogous influence of the acidity on the direction is observed in reactions with binucleophiles [46]. Numerous similar examples are given in the appropriate chapters of this book. 

The amino group of hydrazides react with aldehydes and ketones. For example, 2-hydrazinocarbonylpyrazine refluxed with acetone-ethanol gave 2-isopropylidene-hydrazinocarbonylpyrazine (51) [which was reduced in methanol over palladium-charcoal to 2-(2 -isopropylhydrazinocarbonyI)pyrazine] (1366,1428,1429). Other references to similar reactions include the following reactions 2-hydrazinocarbonylpyrazine with p-acetamidobenzaldehyde (138) 4-hydroxy-, 4-hydroxy-3-methoxy-and 2-carboxy-3,4-dimethoxybenzaldehydes (1319) furfural (1201) and pyruvic acid (1201) 2-amino-3-hydrazinocarbonylpyrazine with acetone and benzaldehyde (1214) and 2-hydrazinocarbonyl-5,6-dimethyl-3-methylaminopyrazine with acetone (428). 

The phase-transfer technique has been employed in the mono- and AW -di-phosphorylation of hydrazine. Full papers dealing with the preparation of acyclic and cyclic (perhydro-l,2,4,5-tetra-aza-3-phosphorine) hydrazides, a preliminary report of some of which was given in Organophosphorus Chemistry Vol. 7 (p. 114) have been published of particular interest is the formation of cage compounds (13) and (14) from monocyclic compounds by further reaction with aldehydes or ketones. 

Historically, ketosugars, including derivatives of ManNAc, Sia, and GlcNAc, were the first unnatural monosaccharide endowed with chemical reporters to be metabolically incorporated into cells (23, 26). Hydrazides and aminooxy compounds react specifically and essentially irreversibly with ketones in aqueous solution. However, this reaction is optimal in slightly acidic conditions ( pH 5.5) that are detrimental to cell viability. Furthermore, ketones. 

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

Much more widely used carbene precursors are tosylhydrazones, which are readily prepared from aldehydes or ketones by reaction with 4-toluenesulfonyl hydrazide. Tosylhydrazones produce transient diazo compounds by base-catalyzed elimination of toluenesulfinate. The diazo compound is not normally isolated, and decomposes to the carbene on heating. The whole process is known as the Bamford-Stevens reaction. The leaving group is not the famihar tosylate (toluene-p-sulfonate, p.CH3-C, H4S03 , TsO ), but the less famihar toluene-p-sulfinate (Ts , P.CH3-C5H4S02 ) (Scheme 5.7). 

Direct attempts to demonstrate the ketonic nature of the reactive lipids have been made by Seligman and co-workers (Seligman and Ashbel, 1951, 1952 Ashbel et al., 1951). They reported that a positive hydrazide reaction still occurred in droplets in the adrenal cortex and the testis following the differential blocking of aldehydes by sulfanilic acid or aniline (Oster and Mulinos, 1944). This is particularly significant since Boscott and Mandl (1949) found that aniline effectively blocked all staining with phenylhydrazine. 

Moreover, the reaction with the hydrazide was reversed rapidly by treatment with an excess of the sodium salt of orthosulfobenzaldehyde, which is capable of reversing the reaction of aldehydes only slowly but of ketones quite rapidly, because of competition of the active aldehyde group of the strongly water-soluble sulfobenzaldehyde for the hydrazide. 

It is important to re-emphasize that the hydrazide reaction is not only nonspecific for ketosteroids but is not even specific for ketones. Aldehydes have more active carbonyl groups and react even more readily with the reagent. With every tissue it is important to demonstrate by other tests that the reactive material is lipid and that it is ketonic from chemical or from biological analyses it must be known that ketosteroids are present in such tissue. 

The use of tosylmethyl isocyanide and base to convert a ketone into the homologous nitrile has been reported in detail aldehydes give oxazole derivatives under the reaction conditions. " Ketones and aldehydes may be converted into the homologous nitrile by heating the hydrazone derivatives formed from 2,4,6-tri-iso-propylbenzenesulphonyl hydrazide with excess cyanide ion (Scheme 41). ... 

The above reaction requires a 10 1 ratio of hydrazine to the ester groups. In the laboratory it can be carried out on a steam bath over a period of 2-3 hours. Approximately 60-80% of the ester groups convert. The hydrazides can form various hydrazones through reactions with aldehydes and ketones ... 

A highly enantioselective aza-Michael reaction of Af-protected benzyloxy-amines with a,p-unsaturated ketones, catalysed by 9-amino-9-deoxy-epz-quinine, was described by Deng et al. The reaction is effective for a broad range of alkyl vinyl ketones with both aryl and alkyl p-substituents, affording products in up to 90% yield and 96% ee (Scheme 15.21). Protected hydrazides were also used as nucleophiles in an aza-Michael reaction with aliphatic a,p-enones. ... 

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