Hydrazone exchange reaction

Simple N-unsubstituted hydrazones can be obtained by an exchange reaction. 

Imine metathesis has continued to be a popular exchange reaction for DCLs. Various groups have found novel systems in which the reaction can be applied, as well as interesting ways to halt the equilibration. For example, Wessjohann and coworkers have demonstrated that Ugi reactions can efficiently halt equilibration of an imine DCL, combining an irreversible diversification process with areversible library selection [24]. Xu and Giusep-pone have integrated reversible imine formation with a self-duplication process [25], and Ziach and Jurczak have examined the ability of ions to template the synthesis of complex azamacrocycles [26]. The mechanistically related reactions of hydrazone [27] and oxime [28] exchange have also been explored as suitable foundations for DCL experiments. 

One can in principle combine different exchange reactions in the same system in order to further increase the structural diversity accessed by the library. However, as this compounds the problem of selectivity (i.e., one now has two or more reactions that must exclusively involve one pair of functional groups), there are very few examples thus far of the practical implementation of this concept. An early, highly intriguing example was described by Lehn and coworkers in 2001 [68]. In this system, imine exchange (acyl hydrazone formation) and reversible metal coordination were employed in library generation. 

In this ESI-FTMS screening proof-of-concept experiment, a DCL was generated using the hydrazone exchange reaction from two hydrazide fragments (1 and 2) and five aldehyde fragments (A-E) (Scheme 7.2). 

Simple N-unsubstituted hydrazones can be obtained by an exchange reaction. The N,N-dimethylhydrazone is prepared first and then treated with hydrazine 206... 

As already described in Sect. 2.2, the use of scandium(III) ions is also an efficient way to catalyze transimination reactions. The most effective catalysis was observed with the exchange reaction between an oxime of cyclohexanone and benzylhydroxylamine. Interestingly, crossover experiments mixing hydrazones and oximes also proved successful [24]. 

From alkylmercaptomethyleneiminium salts various types of amidinium salts have been synthesized. Ammonia, primary and secondary amines, hydrazines and IV-unsubstituted and N-monosubstituted hydrazones were the reaction partners. Side reactions can include the dealkylation of the iminium salt by the amine. If A, A(-unsubstituted salts (141 equation 85) are treated with amines, the desired exchange reaction can be accompanied by nitrile formation. 

For the preparation of hydrazones, Schonberg " recommends that equivalent amounts of the ketone and hydrazine be refluxed in -butanol (b.p. 117.7°) for 2 hrs. Use of ethanol requires a longer reflux period and use of ethylene or propylene glycol may lead to side reactions. Thus on applying the glycol procedure for conversion of fluorenone to the hydrazone, Baltzly et al. observed formation of considerable fluorene (interference by an unusually facile Wolff-Kishner reaction). On refluxing the reactants in n-butanol for 4 hrs., the hydrazone was obtained in 67% yield. However, a superior method for the preparation of hydrazones involves reaction of the ketone with N,N-dimethylhydrazine which see) followed by an exchange reaction with hydrazine. 

The arylation of imines can be applied to indole synthesis. The Fischer indole synthesis was carried out by Pd-catalyzed arylation of benzophenone hydrazone (69) to give A-arylbenzophenone hydrazone 70. The subsequent exchange reaction... 

Hydrazones. Reaction of hydrazine with aldehydes and ketones is not generally useful due to competing azine formation or competing Wolff-Kishner reduction. Exceptions have been documented. Recommended conditions for hydrazone preparation are to reflux equimolar amounts of the carbonyl component and hydrazine in n-butanol. - A more useful method for simple hydrazone synthesis involves reaction of the carbonyl compound with dimethylhydrazine followed by an exchange reaction with hydrazine. For substrates where an azine is formed, the hydrazone can be prepared by refluxing the azine with anhydrous hydrazine. gem-Dibromo compounds have been converted to hydrazones by reaction with hydrazine (eq 6). ... 

Nevertheless, derivatives of the 11-ketone have been prepared in special cases. Thus the ethylene ketal of 3a,20) -dihydroxypregnan-l l-one is obtained in 50% yield by prolonged reaction according to the direct procedure. Ketals of A/B aromatic-11-ketones are formed by exchange dioxolanation. 11 -Semicarbazones have not been prepared, but hydrazones... 

The hydrazinium nicotinate group on these reagents commonly is protected against reaction with the active ester by the addition of acetone to form the acetone hydrazone derivative. This hydrazone protective group is readily reversible at neutral or mildly acidic pH and will immediately exchange with a benzaldehyde on the corresponding chemoselective partner to form a stable hydrazone linkage. 

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