Diketones reaction with hydrazines

Poly(arylene ether phthalazine)s were prepared by two different routes [47], As shown in Eq. (13), one route involved the preparation of precursor poly(arylene ether diketone)s and subsequent reaction with hydrazine while the other route concerned the reaction of difluorophthalazine monomers with various bisphen-ols. The poly(arylene ether phthalazine)s prepared by the two routes exhibited very similar Tgs. The synthetic route to the difluorophthalazine monomers is also shown in Eq. (13). A comparison of the properties of a representative series of poly (ary lene ether diketone)s and the corresponding poly(arylene ether... 

The reaction between 1,3-dicarbonyl compounds 1 and hydrazines is the most general method for preparing l//-pyrazoles 2 (Scheme 2).2-4,5 If a 2,2-disubstituted 1,3-diketone is employed (1 R3, R4 H), reaction with hydrazine hydrate gives instead a 4//-pyrazole 3, as was first reported by Knorr.Sa Generally, the reactants are heated under reflux in a solvent such as methanol, ethanol, benzene, or carbon tetrachloride yields range from 50% to quantitative. 

A modified procedure for the preparation of pyrazoles includes the solventless condensation of diketones and hydrazines in the presence of a catalytic amount of sulfuric acid at ambient temperature <2004GC90>. 1,3-Diketones can be synthesized directly from ketones and acid chlorides and then converted in situ into pyrazoles by the addition of hydrazine <2006OL2675>. The possible modifications to the 1,3-dioxo component in the reaction with hydrazines include the use of -ketoesters, -ketonitriles, -halocarbonyl compounds, -hydroxyketones, -sulfonylketones, and 1,3-dihaloalkanes . 

Pyridazine syntheses from unsaturated 1,4-diketones have been applied in several new ways. ° The reaction with hydrazines is usually performed in the presence of mineral acid otherwise JV-aminopyrroles may be formed. Some saturated 1,4-diketones are claimed to react with hydrazines to give pyridazines. Instead of 1,4-dicarbonyl compounds,... 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The reaction of diketone 75 with hydrazine afforded the monohydrazone 76, which was further oxidized with copper(I) chloride, O2 and p5n idine or activated manganese dioxide to give the a-diazo ketone 77. Thermal decomposition of 77 in methanol gave 2-azuloin methyl ether 79,... 

Reaction of 3,4-difluoropyrrole 391 with oxalyl chloride 460 led to the corresponding 1,2-diketone 461, which was transformed into quinoxaline 463 in high yield by the reaction with 1,2-phenylenediamine 462 [150], Using reaction of 1,3-diketone 464 with hydrazine, fluorinated dipyrrolylpyrazole 465 was prepared in good yield [151]. 

The selective functionalization of indoles in position 2 and 3 can also be achieved using an I/Cu-exchange reaction. Thus, the reaction of the 2,3-diiodoin-dole derivative 25 vith (Neophyl)2CuLi provides after benzoylation the iodoindolyl ketone 26 in 84% yield. Treatment of 26 with a second equivalent of (Neophyl)2-CuLi leads, after further acylation, to the diketone 27 in 65% yield [20], Interestingly, the reaction of the diketone 27 with hydrazine furnishes the heterocycle 28 in 88% yield (Scheme 9.8) [20]. 

The compatibility with a keto functionality can also be realized by using a magnesium cuprate such as 33. In this case, the resulting copper species 34 com-plexed with MgXj undergoes a facile trapping with an acyl chloride, leading to the diketone 35 in 85% yield. Reaction with hydrazine provides the heterocyde 36 in 91% yield (Scheme 9.10) [22]. 

In these types of 1,3-dipolar cycloaddition only one of two possible isomers is obtained and the pyrazole functions have different orientations by the two methods. Another classical synthesis of pyrazoles (Section 4.04.3.2.l(ii)), the reaction between hydrazines and )3-diketones, has been used with success to prepare high molecular weight polypyrazoles (Scheme 65) (81MI40400). A-Arylation (Section 4.04.2.1.3(ix)) of 4,4 -dipyrazolyl with 1,4-diiodobenzene also yields polymeric pyrazoles (69RRC1263). 

A recent paper by Singh et al. summarized the mechanism of the pyrazole formation via the Knorr reaction between diketones and monosubstituted hydrazines. The diketone is in equilibrium with its enolate forms 28a and 28b and NMR studies have shown the carbonyl group to react faster than its enolate forms.Computational studies were done to show that the product distribution ratio depended on the rates of dehydration of the 3,5-dihydroxy pyrazolidine intermediates of the two isomeric pathways for an unsymmetrical diketone 28. The affect of the hydrazine substituent R on the dehydration of the dihydroxy intermediates 19 and 22 was studied using semi-empirical calculations. ... 

A solventless synthesis of pyrazoles, a green chemistry approach, has been described where an equimolar amount of the diketone and the hydrazine are mixed in a mortar with a drop of sulfuric acid and ground up. After an appropriate length of time ( 1 h) the product is purified to provide clean products. Even acyl pyrazoles 42 were obtained under the solvent-less reaction conditions in good yields. 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

Different approaches towards pyrazoles have been described using microwave-accelerated cyclizations. A classical approach to pyrazoles is the cyclization of a j6-diketone with hydrazines. A series of 5-trichloromethyl-pyrazoles 58 and pyrazolium chlorides 59 were synthesized by reaction of a 4-methoxy-trihalo-3-alken-one 57 with differently substituted hydrazines (Scheme 19). The use of microwave and conventional heating for making pyrazoles gave... 

The reaction of 5,6-diphenyl-3-cyano-l,2,4-triazine with hydrazine gives the amidrazone which, with 1,2-diketones, yields 3,3 -bistriazinyls 74 <95MI03 96CA(124)86945>. 

A different example of this general type involves the ds-dihydrazone complex (64). This complex is prepared by condensation of the corresponding dialdehyde with hydrazine in the presence of nickel or copper ion (Curtis, Einstein Willis, 1984). The two uncoordinated -NH2 groups react with a ketone or a diketone such that cyclization occurs in each case [2.8], In these systems, the pendant -NH2 groups are expected to be reactive since their non-coordination results in the respective nitrogen lone pairs being readily available for nucleophilic reaction. 

Pyrazoles were obtained from corresponding 2-hydroxy(or aIkoxy-)imino-1,3-diketones or related ketoesters and hydrazine . Thus, reaction of oximes 112 with hydrazine in ethanol afforded aminopyrazoles 113 in 48-95% yields (equation 48) . Interaction of... 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Diketones are synthetically quite versatile, but they have found only modest use in the syntheses of heterophanes. When 1,3-cyclohexadecanedione (53) is treated with hydrazine hydrate or phenylhydrazine, pyrazolophane (54) or (55), respectively, is obtained (78TL2821). Reaction of dione (56) with hydroxylamine, followed by acid-catalyzed cyclization of the intermediate monoxime, gives the [3,5]isoxazolophane (57) (79TL1875). 

Halo-aldehydes and -ketones react with a wide range of substituted hydrazines to give 4,5,6,7-tetrahydro-l,2-diazepines (121) (76H(4)1509). The reaction of 1,5-diketones with hydrazine has been much used as a source of 5,6-dihydro-4W-1,2-diazepines (122) (67AHC(8)2l). 

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

Pyrazoles are very common parts of commercially available pharmaceuticals, agrochemicals and dyestuffs. The reaction of fi-diketones with hydrazines is the most widely used method to synthesize pyrazoles. The reaction proceeds via the formation of hydrazone 13 which on subsequent cyclization and dehydration produces the corresponding pyrazole 2. This method usually has the disadvantage that with unsymmetrical diketones generally a mixture of isomeric pyrazoles is formed. Here the authors report no other isomer probably because of the great electronic differences of the two ketones being substituted with an ester vs. an alkyl group. 

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