Acylhydrazone

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

A -Acylated 3-hydroxypyrroles prefer the oxo form (87TL4395 90LA 397). Compounds of type 116 [5-(2-acylhydrazino)-4-ethoxycarbonyl)-2-oxo-2//-pyrrole-3-acetate] are in a tautomeric equilibrium with the corresponding acylhydrazones 117 (95H1479). 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Chinon-acylhydrazone lassen sich in milder Reduktion durch Erwarmen mit Ascorbinsaure in waBriger Losung zu Aryl-hydrazinen reduzieren (s.ds. Handb. Bd. X/2, S. 233). Die Herstellung des sehr empfindlichen 2-Hydroxylamino-l-nitro-benzols ist aus 1,2-Dinitro-benzol mit Ascorbinsaure moglich (s. Bd. X/l, S. 1149). Aryl-diazoniumsalze werden liber Oxalsaure-monoarylhydrazide zu Aryl-hydrazinen reduziert (s.Bd. X/2, S. 219). 

The 1,3,4-oxadiazole 113 is formed from the azo compound 112 by the action of triphenylphosphine <96SL652>. A general synthesis of 1,3.4-oxadiazolines consists in boiling an acylhydrazone with an acid anhydride (e.g., Scheme 18) <95JHC1647>. 2-Alkoxy-2-amino-l,3,4-oxadiazolines are sources of alkoxy(amino)carbenes the spiro compound 114, for instance, decomposes in boiling benzene to nitrogen, acetone and the carbene 115, which was trapped as the phenyl ether 116 in the presence of phenol <96JA4214>. 

Moreover, Kobayashi et al. introduced chiral sulfoxides into the reactions of A -acylhydrazones with allyltrichlorosilanes as highly elBcient neutral coordi-nating-organocatalysts (Scheme 10.23)." The corresponding chiral homoallylic... 

Scheme 10.23 Allylsilylations of A-acylhydrazones with sulfoxide ligands.

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Cyclization of racemic acylimidrazone 192, prepared from the corresponding acylhydrazone of phenylalanine, gave the protected amino acid 193 in an overall yield of 57% (Equation 60) <1999JME4331>. 

For convenience, the syntheses discussed in this section are divided into groups, depending on the structures of the starting materials, despite the fact that all of them contain C-N-N-C-O fragments. Therefore, 1,2-diacylhydrazines 109 are described as O-C-N-N-C-O components, acylhydrazones 110 as C-C-N-N-C-O components, while, for example, dithioates and similar compounds 111 are treated as S-C-N-N-C-O components. 

The second most popular method of oxadiazole preparation starts from acylhydrazones 110, which undergo cyclization usually under the action of oxidizing agents (Br2, PhN02, HgO, iodobenzene diacetate). Also, the use of acetic anhydride can lead to cyclization of compound 110. The cyclization can be supported by microwave irradiation. In particular cases, heating is sufficient to accomplish the reaction. 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

Table 2 Representative examples of the synthesis of oxadiazole derivatives 122 from acylhydrazones 110a...

The literature presents a large number of examples concerning the use of known oxazolidinones as chiral auxiliaries in many kinds of reactions. Rare is the use of A-amino derivatives of oxazolidinones, which were used to synthesise new A-acylhydrazones 207. Radical addition reactions occurred with high diastereoselectivity <00JA8329>. The use of glycolate oxazolidinones 210 proved to be efficient for the enantioselective preparation of a-alkoxy carboxylic acid derivatives . Photochemical reaction of vinyl... 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Selection-coupled analysis/phase segregation. One strategy for simplifying the analytical challenge is to use phase segregation. Three subclasses are possible. In the first of these, a phase transition is part of the selection process. This includes not only the familiar crystallization-induced enantiomeric enrichment discussed above but also the experiments (primarily employed in experiments directed toward the production of novel materials) such as those described by Lehn and coworkers in 2005. In this study, an acylhydrazone library was created from guanosine hydrazide and a mixture of aldehydes (Fig. 1.22) in the presence of metal ions, formation of G-quartet structures led to the production of a gel. 

Liquid-liquid phase segregation has been accomplished using two immiscible solvents (i.e., phase transfer DCC) by several laboratories. For example, the Morrow group has reported on imine [73] and acylhydrazone [74] DCLs targeting extraction of metal ions from aqueous to halogenated solutions. As discussed above in the context of Pd-mediated transesterification, the Miller group has also contributed to this area. 

Choudhary, S. Morrow, J. R. Dynamic acylhydrazone metal ion complex libraries A mixed-ligand approach to increased selectivity in extraction. Angew. Chem. Int. Ed. 2002, 41, 4096-4098. 

Distinction was made between the addition of Con A from the beginning of DCL equilibration, and afterwards (the pre-equilibrated approach previously applied by Lehn to acylhydrazone DCLs) [8]. In the first approach, a... 

Figure 3.21 The design of dynamic nncleic acid analogs 8 and 9, or DyNAs, for dynamic acylhydrazone formation with A-C to develop polycationic polymers.

C=N bonds in acylhydrazone groups, which are formed by the condensation of hydrazides with carbonyl groups, exhibit reversibility under mild conditions. Like polyimines, polymers with acylhydrazone functionalities exhibit dynamic aspects through the reversibihty of the azomethine bond. Skene and Lehn have reported the synthesis of polyacylhydrazones and their dynamic features (Scheme 8.3) [23]. High molecular weight polyacylhydrazone 13 was prepared by the condensation of the corresponding dihydrazide and dialdehyde in the presence of an acid catalyst. When 13 was treated with aryl dialdehyde 14 or aryl dihydrazide 15 in... 

Lehn s group has also reported a series of research related to the improvement of polymer properties using the dynamic feature of polyacylhydrazone (Figs. 8.4—8.7) [24,25], Polymers containing acylhydrazone bonds in linear main chains, 25 and 26, were prepared from the corresponding bifimctional acylhydrazides 18 and 19 and dialdehydes 21 and 22. 

Table 8.1 Mechanical properties of the exchangeable acylhydrazone polymer films...

A -Acylhydrazones of 1,3-dicarbonyl compounds can exist in three tautomeric forms enhydrazine 75A, hydrazone 75A, and 5-hydroxypyrazoline... 

Bis acylhydrazones or bis aroylhydrazones of a-diketones also give derivatives of 1-aminotriazoles on mild oxidation (Scheme 21).i n The product was originally assigned a dihydrotetrazine structure, and other possibilities were considered,but Curtin and Alexandrou proposed the isoimide structure (8) which was, for the product obtained from biacetyl bis(benzoylhydrazone), confirmed by X-ray crystallography. The mechanism given in Scheme 21 has been put forward for its formation ... 

A complex of 1102 with L-P-(3,4-dihydroxyphenyl)alanine (dopa), [UO2-(dopa)] , has been reported,and a series of acylhydrazone adducts (L) [U02L2(N03)2] (L = acetyl, benzoyl, salicoyl, diacetyl, or diformylhydra-zone) and [U02L3(N03)2] (L = acetylhydrazone) have been described. The X-ray photoelectron spectral information obtained from uranyl complexes of 8-hydroxyquinoline is given in Table 3. The U 4/, 2 levels in the two... 

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