Hydrazine hydrazinolysis with

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

Peptide hydrazides are readily obtained by hydrazinolysis of suitably protected peptides linked to the resin via a benzyl ester.Alternative to the hydroxymethyl ester linkage of the Merrifield resins, l-methyl-2-oxo-phenylethyl ester,2-nitrobenzyl ester O or 4-meth-oxybenzyl ester type linkages are also utilized.b - Recently, fuUy protected hydrazides were obtained in good yields on 2-methoxy-4-alkoxybenzyl alcohol resin (Sasrin ) by hydrazinolysis with 20% anhydrous hydrazine in DMF using DMA as solvent the reaction was significantly slower, but with less side products. 

The levulinyl function (CH3C(CH2)2CO—) is even more sensitive to hydrazine than the benzoyl analogue. This has been attributed to a loss of conjugation between the phenyl and carbonyl functions in the transition state for hydrazine addition. With the methyl function, no such conjugation was present prior to the hydrazinolysis. 

The corresponding sulfonylamino acid methyl esters 518 were prepared by treatment of the sulfonylamino acids 517 with absolute methanol-pure thionyl chloride at low temperature (—5 °C to —10 °C). The esters 518, by hydrazinolysis with hydrazine hydrate, afforded the hydrazides 519. The sulfonylamino acids 517 were coupled with the appropriate amino acid methyl ester hydrochloride in THF-water-triethylamine mixture using DCC as the coupling reagent to yield the corresponding sulfonylamino dipeptide methyl esters 520 (Scheme 16). The synthetic sequence depicted in Scheme 16 has been successfully applied to a number of different aromatic sulfonyl chlorides as illustrated by the following examples. 

Sulfobenzyl esters were prepared (cesium salt or dicyclohexylammonium salt, Na03SC6H4CH2Br, DMF, 37-95% yield) from A -protected amino acids. They are cleaved by hydrogenolysis (H2/Pd), or hydrolysis (NaOH, dioxane/water). Treatment with ammonia-or hydrazine results in formation of the amide or hydrazide. The ester is stable to 2 M HBr/AcOH and to CF3SO3H in CF3CO2H. The relative rates of hydrolysis and hydrazinolysis for different esters are as follows ... 

This reaction forms the basis of one method of terminal residue analysis. A peptide is treated with excess hydrazine in order to cleave all the peptide linkages. One of the terminal amino acids is cleaved as the free amino acid and identified all the other amino acid residues are converted to acylhydrazides. Which amino acid is identified by hydrazinolysis, the N terminus or the C terminus ... 

The lead tetraacetate reaction between jV-aminophthalimide and (E) stilbene was first described by Rees,5 and the hydrazinolysis of the addition product by Carpino.6 The procedures described here incorporate their methods, with improvements. The dimesylate-hydrazine reaction was first described by Paulsen7 in the carbohydrate series. 

Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring opening of 3-aryl-2-benzoyl-l,l-cyclopropanedicarbonitriles 14 with hydrazine provided a new process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. 

Pentono- and hexono-1,4-lactones yielded substituted arylhydrazides on treatment with m- and />-tolyl-, m- and p-methoxyphenyl, p-bromophenyl, and p-ethoxycarbonylphenyl-hydrazines (131). It was found that the rate of hydrazinolysis depends on the configuration of the aldonolactone, as well as on the aryl substituent on the hydrazine. 

Aminolysis of activated forms by methylamine provides a convenient derivative for characterizing activated forms. Boc-valine methylamide (Figure 7.37) was the derivative made to confirm the structure of the 2-tert-butoxy-4-isopropyl-5(4//)-oxazolone that had been prepared for the first time (see Section 1.18). However, for activated forms that might undergo enantiomerization or epimerization during aminolysis, hydrazinolysis is the reagent of choice for their derivatization and for establishing the isomeric nature of a substance. Reaction with hydrazine produces... 

Identification of carboxy-terminal amino acids was also attempted. Studies by Bergmann and his associates in the 1930s (see below) had characterized various peptidases with differing specificities. One of these was carboxypeptidase which required a free carboxy terminus adjacent to the peptide bond to be hydrolyzed. The specificity of the enzyme was limited but Lens in 1949 reported alanine to be at one end of insulin. Fromageot and his colleagues (1950) and Chibnall and Rees (1951) reduced the carboxy termini to B-aminoalcohols and showed glycine as well as alanine to be carboxy-terminal. Hydrazinolysis was also attempted the dry protein was treated with hydrazine at 100 °C for 6 h so that the carboxy-terminal amino acid was released as the free... 

This group of nucleosides could also be named glycerolyl heterocycles. A modified procedure for the synthesis of the pyrazole nucleoside 1026 was carried out by the hydrazinolysis of the epimeric hydrazine 1025, obtained from 1024, by hydrolysis with HCl. The use of 1025 is more efficient than using 1027 obtained from the hydrazinolysis of 1023, which in turn was obtained from 1022 [75JHC75 85JCS(P1)1425]. 

Ethyl 4-oxopyridazine-5-carboxylates (35) afford pyrazolo[3,4-treatment with hydrazine. Similarly, treatment of 4-cyanopyridazinone with POCI3 followed by hydrazinolysis gave py-razolo[3,4- ( pyridazines (84CB3349). 

Hydrazinolysis products obtained from oxazolones 528 are versatile synthetic intermediates and can be further elaborated to a variety of different heterocycles depending on the substituents and on the experimental conditions. For example, N-aminoimidazolones 529, isolated from reaction of 528 and hydrazine, have been acylated ° or condensed with carbonyl compounds to produce 530 and 531, respectively. On the other hand, ring-opening 528 with hydrazine affords a dehydroamino acid hydrazide 532. Condensation of 532 with aldehydes yields a hydrazone 533 that can be cyclized to an A -iminoimidazolone 534 (Scheme 7.168). ... 

R = Ar,R2 = H), which were deoxygenated in one instance.19 Other N-oxides (133 R1 = Ar,R2 = H and R1 = R2 = Ph) were obtained directly by hydrazinolysis of the 4-chloropyridine 131b.126 Reaction of hydrazine with the pyridinium salt 134 caused replacement of the methoxy group with formation of 135 29 and, more unexpectedly, 3-carbethoxy-4-pyrrolylpyridine (136) and hydrazine afforded an almost quantitative yield of 137 by expulsion of the pyrrole nucleus.130... 

Hydrazinolysis of the imidate and carboxylic ester functions of 1-aryl-oxycarbonyl-l,6-dihydro-2-methoxypyrimidines (61) with 1 molar equivalent of hydrazine hydrate culminated in the formation of the 1,2,4-tria-zolo[4,3-a]pyrimidine-3-ones 63 [89GEP(0)3839711] (Scheme 25). 

Phthalimide protection is stable towards acids and bases, but can be cleaved with strong nucleophiles, such as hydrazines or sulfides, or by reduction with sodium boro-hydride [230]. More sensitive towards nucleophilic attack than unsubstituted phthalimide is tetrachlorophthalimide [33]. This group has been successfully used as N(a) protection of amino acids in the solid-phase synthesis of peptides (deprotection N2H4/DMF (15 85), 40 °C, 1 h coupling DIC/HOAt/amino acid (1 1 1), 3 equiv. of each, DMF, 25 °C, 4 h [294]). Typical conditions for the removal of phthaloyl protection on cross-linked polystyrene include treatment of the resin with hydrazine hydrate [295,296], with methyl hydrazine [297], or with primary aliphatic amines [298] in DMF, EtOH, or solvent mixtures for several hours at room temperature or above [296,299,300]. Illustrative examples are sketched in Figure 10.15. It has been claimed that the hydrazinolysis of polystyrene-bound phthalimides proceeds more readily in DCM or DCE than in DMF [301]. 

Reaction of C-acetyl-7V-(2-benzimidazolyl)methanehydrazonoyl chloride 21b with phenylhydrazine yielded a product that was assigned structure 271. No spectral data were given to substantiate such an assignment, however (83MI1). Also, hydrazinolysis of 10b with hydrazine hydrate gave the hydrazidine 272 (80JHC209). 

Tetraza-3,6-diphenyldiborine was obtained by hydrazinolysis of phenyl-bis(butylmercapto)borane 199>. However, the best laboratory method again appears to be a transamination of aminoboranes 197-200> 2°i) with hydrazine. 

Incomplete cleavage of hydrazinolysis products with piperidine. Hydrazine has reacted with C s or T s giving products with an altered charge and/or mass which have resisted subsequent cleavage with piperidine... 

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