Mono-substituted hydrazines

AK(30)26l). 2-Acetoxyfuran-3(2i/)-ones react with hydrazine to give 3,6-disubstituted-4-ethoxycarbonylpyridazin-4(li/)-ones (184) as the main product, but with mono-substituted hydrazines in addition to these pyridazines anhydro-5-hydroxypyridazinium hydroxide (185) derivatives and some pyrazole derivatives are also formed (Scheme 102) (79JOC3053). The... 

The reaction conditions (neutral, acidic or basic) do have an affect on the regioselectivity of the reaction. Acidic reaction conditions have also been shown to preferentially provide one regioisomer over basic conditions for reactions of aryl hydrazines. Extensive studies with 2-perfluoroacylcycloalkanones and mono-substituted hydrazines were studied to determine the selectivity of various alkyl-, aryl-, and heteroaryl-substituted hydrazines. Reactions of the aryl hydrazine 21 with the trifluoromethyl-substituted cycloalkanone 22 under neutral conditions (methanol, reflux) gave a mixture of isomers 23 and 24, whereas the reaction of the pyridyl hydrazine 25 was shown to give exclusively 26. 

Until recently it was thought that mono-substituted hydrazines invariably reacted with 5-methylisothiouronium salts to give compounds of type (XVII) [129, 192, 193] however, examples have now come to light in which the alternative isomer (XVI) has been isolated from this reaction [21, 131, 194, 195). This formulation is based on (a) the failure of the products to react with benzaldehyde, [21, 129, 131, 194], (b) the unambiguous synthesis of the two possible alternative structures [21, 129, 194], and (c) an examination of the nuclear magnetic resonance spectra of the mono- and di-protonated forms of some... 

Reaction of 1,2-disubstituted hydrazines with l,2-bis(halomethyl)benzenes 291 under microwave irradiation has shown to yield 2,3-disubstitued 1,2,3,4-tetrahydrophthalazines 292 via double nucleophilic substitution. When a mono-substituted hydrazine is used 2-substituted 1,2-dihydrophthalazine was obtained (Equation 71) <2005TL6011, 2006JOC135>. 

Hydrazines may be nucleophiles such as when they interact with aldehyde and keto groups to form hydrazones. This is the basis for the inhibition of enzymes such as transaminases, which rely on pyridoxal phosphate as a coenzyme. Mono-substituted hydrazines can be formed as metabolites when azo groups are reduced, dialkylated hydrazines are dealkylated or hydrazides are hydrolysed. 

Dialkyl acetone-1 -dicarboxylates 1 were transformed with DMFDMA by heating in ethanol into dialkyl l,5- is(dimethylamino)-3-oxo-penta-l,4-diene-2,4-dicarboxylates 52 in good yields. They were treated with ammonia, hydrazine, primary aliphatic, aromatic or heterocyclic amines to form dialkyl 1-substituted 4-oxo-l,4-dihydrop5u--idine-3,5-dicarboxylates 53 and 54.1,4-Diaminobenzene reacts with 52 in a 1 2 molar ratio to produce l,4-bis[3,5-fcis(alcoxycarbonyl)-4-oxo-l, 4-dihydropyridin-l-yl]benzene 55 in 57% yield. Hydrazine and mono-substituted hydrazines afforded 1-amino-1,4-dihydro-4-oxop5uidines 54 (00H2033) (Scheme 20). 

The second approach to aza-peptides involves the reaction of a mono-substituted hydrazine with an ester. Both isomers (1 and 2, Scheme 2)... 

Halland et al. showed that the same o-alkynylhaloarene substrates used successfully by others to access indoles (Scheme 24.1, disconnection D-3) could be used to access 2//-indazole products (Scheme 24.19) [90]. The reaction proceeded via an initial regioselective intermolecular palladium-catalyzed amination using a mono-substituted hydrazine to generate an N,N -disubstituted hydrazine. Intramolecular hydroamination then forms a dihydroindazole intermediate such as 42. Isomerization to the aromatic 2//-indazole products occurred spontaneously under the reaction conditions. A variety of examples were reported, and good functional group tolerance was observed. 

The synthesis of pyrazolcs starting from a hydrazine and a 1,3-dicarbonyl compound is a well established reaction in organic synthesis. If a mono-suhstituted hydrazine is reacted with an unsymmctrically substituted 1,3-dicarbonyl compound, two different pyrazole products which arc regioisomers could he formed (sec figure 10.3-2). 

Figure 10.3-2. The reaction ofa mono-substiluted hydrazine v/ilh an unsymmetrically substituted 1,3-dicarboiiyl compound can lead to two regioisomeric pyrazole products.

Deactivation (weak) from the adjoining ring does not prevent facile disubstitution of 4-methyl- and 4-phenyl-2,7-dichloro-1,8-naphthyridines wdth alkoxides (65°, 30 min), p-phenetidine (ca. 200°, 2 hr), hydrazine hydrate (100°, 8 hr), or diethylaminoethylmer-captide (in xylene, 145°, 24 hr) mono-substitution has not been reported. Nor does stronger deactivation prevent easy 2-oxonation of 5,7-dimethoxy-l-methylnaphthyridinium iodide wdth alkaline ferricyanide via hydroxide ion attack adjacent to the positive charge and loss of hydride ion by oxidation. 

Only a few displacements involving mono-substituted compounds are known. 4-Chloropyrido[2,3-d]pyrimidine reacts readily (96°, 30 min) with aqueous aniline, hydrazine, or ammonia and with diethylamine (0°, 16 hr). In contrast to the 1,3,6-isomers, the 4-oxo and 2,4-dioxo derivatives are readily converted into chloro and thioxo derivatives by phosphorus oxychloride and pentasul-... 

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 Raschig process can also be used to react amines with chloramine to make mono-substituted or unsymmetrical disubstituted hydrazines. 

A process for preparing mono- and diacyl-substituted hydrazine derivatives using carboxylic acids is described (3). 

Aldosuloses react with substituted hydrazines to give mono- and bis-hydrazones. It is possible to remove one hydrazone residue from the latter to obtain aldosulose monohydrazones having the hydrazone residues attached to C-l.The position of substitution was established when d-arabino-hexosulose mono-(/V-mcthyl-/V-phenyl)hydrazone (31) was converted into D-mannose A-methyl-Ar-phenylhydrazone (32) on catalytic hydrogenation (Scheme 8),143... 

Carbohydrazides can be obtained from amides and hydrazine hydrate or substituted hydrazines. The products are mono- or di-acyl derivatives of hydrazine according to the reaction conditions, the proportions of the reactants, and the nature of any substituents already present on the hydrazine. 

Z = F Y = F, Z = Me). Decafluoro-l,4-dihydronaphtha] ie also reacts with piperidine, sodium methoxide, hydrazine, ammonia, and pentafluorophenyl lithium at the 6-position, and the 1,2-dihydronaphthaIene gives the 6- and 7-mono-substituted products wdth the first two of these reagents. ... 

The regioselectivity of palladium-catalyzed aUylic substitutions with heteroatom nucleophiles is often much different from that of reactions with carbon nucleophiles. In general, reactions of oxygen and nitrogen nucleophiles form more branched product than do reactions of carbon nucleophiles, at least as the kinetic product of substitution. For example, reactions of aryloxide nucleophiles with mono-substituted aUylic carbonates catalyzed by palladium complexes of Trost s ligand form more branched than linear product (Equation 20.32). Reactions of geminaUy disubstituted aUylic acetates with aziridines, hydroxylamine and hydrazine derivatives catalyzed by palladium complexes of bisphosphines form the branched prenyl product as the major isomer (Equations 2033a and 20.33b). " ... 

A similar transamination reaction occurs with hydrazine, but in this case only mono-substitution is achieved. Reaction with excess hydrazine only serves to form the hydrazinium salt of the conjugate base of the mono-substituted product (Scheme 10). 

The cross-coupling reactions of hydrazines with aryl halides to give substituted hydrazines is very important from the point of view of nitrogen heterocyde synthesis (for example, indoles, indazoles, pyrazoles, and aryltriazoles, and before this report by Straddiotto s group [28a], there was no literature method for the Pd-catalyzed cross-coupling of hydrazine to aryl electrophiles. Hydrazines are difficult substrates because of their reducing power and the reactivity of the mono-arylated hydrazine product to further arylation. 

The adrenochrome-sodium bisulphite addition product [28, 29] has been isolated in the solid state as a pale yellow crystalline solid [194, 195]. This substance reacts with substituted hydrazine-type ketone reagents (such as semicarbazide) to give mono-condensation products, which can be easily converted to the corresponding adrenochrome monohydrazone derivative by the action of either heat or alkali [194]. This, together with other evidence [28, 29], suggested that the bisulphite residue was not attached to the C-5-carbonyl group directly [194]. 

The stable crystalline complexes of various mono- and di-substituted hydrazines with 18-crown-6 have recently been described for the first time, and used for the formation of substituted hydrazones from carbonyl compounds in lipophilic solvents.An alternative procedure uses the carbonyl compound and the hydrazine with 0.1—1 equivalents of crown, and both variants give a fast reaction in a homogeneous non-aqueous phase. 

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