A-Acyl hydrazine

The hydrolysis of l-alkyl-2-acyldiaziridines to A -alkyl-A -acyl-hydrazines possesses preparative interest. For example, A -cyclohexyl-A" -toluenesulfonylhydrazine [Eq. (51), yield 67% ] and 1-cyclohexyl-4-phenylsemicarbazide [Eq, (52) yield 73%] can be prepared by hydrolysis of the substituted diaziridines 46 and 62. ... 

A wide range of groups are tolerated in this position including esters, amides, thioesters, ureas, acyl hydrazines and carbamates exhibiting a wide range of potencies and microsomal stabilities (Table 6.2) [24, 33-36]. 

Disubstituted tetrazoles are conveniently prepared from acyl hydrazines (98) and diazonium salts.166 The reaction proceeds through the intermediate tetrazenes (99) followed by cyclization to the tetrazole (100) (Scheme 13). The intermediate can be isolated under mildly basic conditions. Symmetrically 1,2-diacylated hydrazines yield 1-substituted tetrazoles through the elimination of one of the acyl groups.166 - 168 Diformyl-hydrazine is a very convenient starting material for 1-substituted tetrazoles.166, Unsymmetrically 1,2-diacylated hydrazine usually results in mixtures.169... 

Spectral evidence" indicates an equilibrium between tetrahedral and octahedral Co" in iViV-dimethylacetamide and the equilibrium constant for [Co (tet)]/[Co (oct)] is reported at various temperatures. The complexes of acetylhydrazine (A), [CoA3]X2 (X = Cl or Br) and [Co(NCS)2A2]H20 and the tri-N-deuterio-analogue[Co(NCS)2(Ad3)2]D20 have been isolated and examined by i.r. Cationic complexes of JV-acyl hydrazines have been isolated with ligands in their keto-form, RCO-NH-NH2 however, the ligands also react in their enol form, RC(OH) = NNH2, forming neutral complexes (R = Me, Pr", Pr , or Ph). ... 

N-Acetyl derivatives of 3-phenyloxaziridine can also transfer their nitrogen function to nucleophiles. 2-(4 -Nitrobenzoyl)-3-phenyloxaziridine (69) converts piperidine to the acyl-hydrazine (101) in 92% yield within some minutes at room temperature (67JPR(36)86). Since (69) is stable in the absence of a nucleophile a nitrene is not involved in the reaction, which is assumed to occur by nucleophilic attack of the amine on the oxaziridine nitrogen. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Most 1-aminopyrroles have been synthesised from y-diketones and a substituted hydrazine. If the parent N- aminopyrrole is desired, a hydrolyzable hydrazine derivative is used, for example semicarbazide or an acyl- or sulfonyl-hydrazide (equation 182) (B-77MI30607). 

Amino-l,2,4-triazin-5-ones (674) have been prepared by the reaction of a-acyl-hydrazonocarboxylates (672) or the chloro derivatives (673) with hydrazine. The chloroazines (673) with hydroxylamine afford 4-hydroxy-1,2,4-triazin-5-ones (675 Scheme 26) <78HC(33)189, p. 563). 

A related series of 5-substituted-2-amino-oxadiazole compounds have also been prepared in a one-pot procedure using a microwave-assisted cyclisation procedure (Scheme 6.26)164. Rapid preparation of the pre-requisite ureas from the mono acyl hydrazines and various isocyanates (or the isothiocyanate) was easily achieved by simple mixing. The resulting products were then cyclo dehydrated by one of the two procedures either by the addition of polymer-supported DMAP and tosyl chloride or alternatively with an immobilised carbodiimide and catalytic sulphonic acid. Purity in most cases was excellent after only filtration through a small plug of silica but an SCX-2 cartridge (sulphonic acid functionalised - catch and release) could be used in the cases where reactions required additional purification. 

The small-molecule-based machine conceived by von Delius, Geertsema, and Leigh [45] is a linear (for reviews, see [46], [100]) motor based on dynamic covalent chemistry [19-24] (forming, breaking, and reforming of dynamic covalent bonds with relatively fast equilibration in response to stimuli), namely on acyl-hydrazone and disulfide exchanges. The motor consists of a track that has four functional groups disposed alternately aldehyde-thiol-aldehyde-thiol which are the positions 1,2, 3, and 4 of the track, a walker NH2-NH-CO-(CH2)5-SH which has the feet A (hydrazide or acyl-hydrazine) and B (thiol), and a placeholder with a foot C of type thiol (Fig. 10). 

The one-pot, three-component synthesis of 1,2,4-triazoles from primary amines, acyl hydrazines and dimethoxy-A(-A(-dimethylmethanamine [84] was utilized for the preparation of compounds 235 (Scheme 41), which were evaluated for their anticonvulsant and neurotoxic properties [85]. The anticonvulsant activity was measured in mice by the maximal electroshock test (MES) and the neurotoxicity in mice by the rotarod neurotoxicity test (Tox). The majority of the compounds... 

In general the synthesis of suitably protected amino acid and peptide hydrazides from the corresponding alkyl or aryl esters by reaction with hydrazine hydrate is carried out in alcohols or DMF at ambient temperature.P However, with C-terminal branched amino acids such as valine or isoleucine, or larger peptides, more vigorous conditions are required, i.e. higher temperature (25-80°C) and longer reaction times. To avoid formation of symmetrical bis(A-acyl-aminoacyl)hydrazides an excess of hydrazine hydrate or hydrazine is recommended, which also enhances the reaction rates. In this context, the solvent is known to play an important role, with alcohols being more appropriate than DMFP 0 or solvent mixtures such as dioxane/methanol.f l The use of hydrazine hydrate without any solvent has also been reported. ... 

Under certain conditions, amides can add directly to alkenes to form V-alkylated amides. Sulfonamides react in a similar manner. 3-Pentenamide was cyclized to 5-methyl-2-pyrrolidinone by treatment with trifluorosulfonic acid. Acyl hydrazine derivatives also cyclized in the presence of hypervalent iodine reagents to... 

A less used route to the substrate is the treatment of an acyl hydrazine RCONHNH2 (formed from an ester and hydrazine) with nitrous acid. Detailed compilations and reviews list the many hundreds of examples of the rearrangement recorded up to 1961. The... 

A-nitrosamides behave in acid solution like A-nitrosamines they are reduced to acylated hydrazines. In this way alkylhydrazines may be prepared from primary amines by the following reactions [216]. 

Pellizzari reaction. Formation of substituted 1,2,4-triazoles by the condensation of amides and acyl hydrazines. When the acyl groups of the amide and acylhydrazine are different, interchange of acyl groups may occur, with formation of a mixture of tri azoles. 

Acyl-2-pyrazoIin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-ones and conversion of other heterocycles. As might be expected the reaction of /J-ketoesters with hydrazines has been utilized.124,1124,1532,1533 In this case the /J-ketoester has an a-acyl substituent (eq. 216). Both Borsche and Lewinsohn124 and Vila1533... 

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