Hydrazone exchange

Thus, the reduction of tosylhydrazones with sodium borodeuteride in dioxane provides only monodeuterated analogs. For the insertion of two deuteriums it is necessary to first exchange the hydrazone proton and to carry out the reduction in aprotic or deuterated solvents. Under these conditions the reduction of the tosylhydrazone derivatives of 7- and 20-keto... 

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... 

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

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. 

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. 

Ingerman, L. A. Waters, M. L. Photoswitchable dynamic combinatorial libraries Coupling azobenzene photoisomerization with hydrazone exchange. J. Org. Chem. 2009, 74, 111-117. 

Figure 3.25 Racemic dynamic combinatorial library targeting (-)-adenosine. Left Racemic porline containing dipeptide library building block. Middle Various enantiomeric oligomers formed through reversible hydrazone exchange. Right The SS enantiomer selected upon equilibration with (-)-adenosine.

Carbonic anhydrase [17] Acyl hydrazone exchange <300 ESI-FTICR-MS... 

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). 

Scheme 7.2 Dynamic combinatorial chemistry targeting carbonic anhydrase. (a) Fragments for hydrazone exchange, (b) Dynamic combinatorial library generation.

Hydrazide 1 was designed as the CA anchor fragment and hence necessitated dual functionality an Ar-SO NH moiety for reliable CA affinity and a hydrazide moiety to take part in hydrazone exchange. Hydrazide 2 lacked the sulfonamide moiety of 1, but was still able to participate in hydrazone exchange and thus functioned as a control compound. Fragments A-E, the exchange partners for 1 and 2, were selected to introduce an array of tails onto 1 to enable exploration of periphery recognition interactions with CA. 

Acid halides react with vinylphosphoranes (56) to afford isolable N-acylaminophosphonium salts (57), which are hydrolyzed by alkali to N-vinylamides (58). By treatment with triethylamine and phenol the halogen in 57 can be nucleophilically exchanged for phenolate. Thiophenol, secondary amines, and hydrazones can be employed instead of phenol this leads to diverse 1-hetero-substituted 2-aza-1,3-dienes 59 (Scheme 31) (90TL3497). 

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

Compound 203 (R1 = R2 = H, X = Br) underwent hydrazone exchange with hydrazine hydrate to give 2-amino-5-bromobenzophenone hydra-zone. The same benzotriazocine was ring-opened with lithium aluminum hydride to afford 2-benzyl-4-bromoaniline, while hydrolysis of the compound yielded 2-amino-5-bromobenzophenone (83CHE337). 

Figure 7.12 Fragments equipped with a hydrazide (1 and 2) or aldehyde (A-E) functional groups for DCC utilizing hydrazone exchange and targeting carbonic anhydrase.

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