Hydrazine hydrazinolysis reactions

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. 

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... 

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... 

Other nitrogen nucleophiles such as hydrazines, hydrazides, and Schiff bases have affected ring opening of oxazolones. Most often, hydrazine or substituted hydrazines are used. For example, hydrazinolysis of 525 affords the corresponding hydrazides 526 that, depending upon the substituents and the reaction conditions, can cyclize in the reaction medium to the aminoimidazolone 527 (Scheme 7.167 ... 

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... 

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). 

In the microwave-assisted methodology, the linear polypeptide and hydrazine solution, contained in a loosely covered conical flask, was exposed to a few minutes of irradiation using an unmodified domestic microwave oven. To monitor the hydrazinolysis progress, dimethyl sulfoxide was added to dilute the reaction mixture that allowed aliquots of the reaction mixture to be drawn every few minutes over a period of about an hour. Then, the aliquots were analyzed by mass spectrometry. As an illustration. Figure 19-17 displayed fast-atom bombardment (FAB) mass spectra of microwave-assisted Akabori... 

Although hydrazinolysis of uracil derivatives into pyrazoles is well known (see Scheme 133), reaction of 5-formyluracils with hydrazines in the presence of acetic acid causes another type of ring contraction... 

An extensive study of the reaction of hydrazine with collagen under different conditions has been carried out recently by de la Burde et al. (1963). They used steer corium collagen before and after a short liming and carried out hydrazinolysis at room temperature for 30 hr in up to 70 % aqueous hydrazine. The treated fibers examined under the electron microscope still showed the characteristic cross-striations and periodicity of native collagen provided the hydrazine concentration did not exceed 55 %. 

In general the /er/-butyl esters, as used in the Z/tBu strategy in solution, are stable towards hydrazinolysis. Therefore, peptide intermediates containing Glu(OtBu) residues are readily converted into the corresponding hydrazides, although in the case of Asp(OtBu) residues controversial results were reported depending upon the reaction conditions and apparently even upon the peptide sequence.t In the case of the base-sensitive Asp-Gly and Asp-Ser sequences the tert-butyl ester protection does not prevent aspartimide formation similarly, in cases of Asn-Gly sequences a P transpeptidation on treatment with hydrazine was found to occur although to a lower extent. 

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. 

In the case of the protected peptide alkyl ester containing Arg(N02), Asp(OtBu), Asp(OBzl), or Glu(OBzl), treatment with hydrazine hydrate results in side reactions, such as hydrazinolysis of side-chain functional groups. In order to avoid such side reactions, it is preferable to synthesize the protected peptide hydrazide from the corresponding substituted hydrazide. The representative substituted hydrazides for R C(0)NH-CHR -C(0)-NHNH-X are X = Z,b°3] c(0)OTrt,[i° l Boc,[i l Troc,[i l C(0)0CH2-4-pyridyl,b°d and C(0)OCMc2-CCl3.[ l... 

There are many instances in which the introduction of amines with specific substitution patterns is desired. With the abundance of structurally diverse commercially available amines from which to choose, the use of these compounds as nucleophiles is extremely valuable. While the example illustrated in Scheme 6.29 focuses on the hydrazine displacement of a secondary tosylate from a furanose sugar derivative [56], this type of reaction is easily achieved with most primary and secondary amines. Where the introduction of direct NH2 groups is desired, the best methods rely on the reduction of azides or nitro groups, or the hydrolysis (hydrazinolysis) of imides [32]. 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

The other angular pyrazoloquinoline derivative 327 was obtained by hydrazinolysis of 2-imino-7,7-dimethy-4-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-2H-benzopyran-3-carbonitrile (326). The reaction can be proceeded by substitution of the methylsulfanyl group by hydrazine followed by cyclization to give 327 (97JCR(S)256) (Scheme 61). 

The 4-acetyl-3,5-dioxo-l-methylcyclohexane carboxylic acid (ADCC) linker 2n [128] was developed to provide a support for anchoring primary amines via a preformed handle method. The anchor is stable toward acids and bases including piperidine and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and is thus compatible with Fmoc chemistry. The amine can be released by rapid hydrazinolysis on treatment with 2% hydrazine in DMF. A formamidine linker 2o has been obtained from Merrifield resin by reaction with the appropriate phenol. Secondary amines can be anchored to the support by an amidine exchange reaction and after further transformations cleaved by treatment with hydrazine [129]. 

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