Hydrazones conjugate bases

Aldehydes, ketones, carboxylic esters, carboxylic amides, imines and N,A-disubstiluted hydrazones react as electrophiles at their s/ 2-hybridized carbon atoms. These compounds also become nucleophiles, if they contain an H atom in the a-position relative to their C=0 or C=N bonds. This is because they can undergo tautomerization to the corresponding enol as seen in Chapter 12. They are also C,H-acidic at this position, i.e., the H atom in the a-position can be removed with a base (Figure 13.1). The deprotonation forms the conjugate bases of these substrates, which are called enolates. The conjugate bases of imines and hydrazones are called aza enolates. The reactions discussed in this chapter all proceed via enolates. 

The conjugate base that is formed is stabilized by resonance. It can protonate on the nitrogen to regenerate the hydrazone or on the carbon. This product is a tautomer of the hydrazone. 

Assorted anions. These are generated by deprotonation of allylic halides," chloromethylphosphonic esters, conjugated hydrazones, chiral carbamates,unsaturated a-aminonitriles, phosphonamides," and sulfonamides. The dianions derived from tu-haloalkanecarboxylic acids cyclize, and this reaction forms the basis of a synthesis of V-Boc cyclic imino acids. The conjugate bases of 2-(arylmethoxy)-methyl-2-oxazolines are unstable as [2,3]sigmatropic rearrangement takes place even at — 75°C. 

Stereospecific formation of ( )-stilbenes (120) on reaction of benzaldehyde tosyl-hydrazones with benzotriazole derivatives, in the presence of strong base, is believed to proceed via dianion (118) formed by an addition reaction between the respective conjugate bases (116) and (117). ... 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Olefinic azo compounds, in which the double bond is conjugated with the azo group, have been prepared from a-halocarbonyl compounds by reaction with a substituted hydrazine to form a hydrazone which, on treatment with a base, is dehydrohalogenated and isomerized to an olefinic azo compound. The reaction may be represented by Eqs. (19) and (20). 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

A simple synthesis of pyrazolo[4, 5 ][60]fullerenes from pyrazolyl hydrazones with [60]fullerene was achieved with microwave irradiation evidence of intramolecular charge-transfer interaction was shown <1999TL1587>. Novel C6o-fused isoxazolines have been synthesized from 1,3-dipolar cycloadditions of pyrazole nitrile oxides to Ceo under thermal or microwave irradiation <1999T4889>. A new triad based on pyrazolino[60]fullerene and a conjugated... 

Synthesis of Aromatic Aidehyde-Derived Hydrazone-Based mPEG-HZ-PE Conjugates... 

A set of different synthetic methods were designed based on the use of various aldehydes that can produce the hydrazone linkage between PEG and PE (54). Synthesis of aliphatic aldehyde-derived hydrazone containing PEG-PE conjugate was pursued in two steps. First, phospholipid was activated with four... 

Half-lives of different hydrazone-based mPEG-HZ-PE conjugates incubated in phosphate buffered saline, pH 7.4 and pH 5.0 at 37°C over a period of time, h... 

This would support the fact that PEG-HZ-PE conjugates containing hydrazone bond derived from the aliphatic aldehyde are more prone to hydrolytic degradation. Aromatic aldehyde-derived hydrazone bond is too stable for the purpose of pH-triggered drug release. Careful selection of an aldehyde and an acyl hydrazide would be necessary for the application of the hydrazone-based chemistry for the development of pH-sensitive pharmaceutical nanocarriers. 

The Oppolzer sultam 35-1 (Scheme 35, reaction (101) [84] reacts with even higher stereoselectivies and is easier to remove. The main domains of the Oppolzer sultam are conjugate 1,4-additions or simple double bond additions [Scheme 35, reactions (102) and (103)] [85], which show diastereoselectivities of >95% in most cases. Scheme 36 presents examples of persistent, restorable and selfimmolative auxiliaries which are all based on amino acids or amino alcohols, finders RAMP-SAMP [86] is attached to ketones or aldehydes in form of a hydrazone 36-1 which is used for highly stereoselective electrophilic a-alkyla-tions. After the reaction the auxihary is removed via ozonolysis which generates the nitrosamine 36-2 first. In an ensuing step this is reduced to the original auxiliary. In Schollkopf s bislactim ether alkylations [Scheme 36, reaction (105)]... 

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