Pyrazole hydrazine

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.

From Hydrazines and P-Bifunctional Compounds. One of the oldest examples in this class is the reaction of a p-diketone with a substituted hydrazine to give a pyrazole (eq. 1). 

If 7 Rg, a mixture of the two isomeric pyrazoles is obtained. An excellent method to prepare pyrazole [288-13-1] consists in treating 1,1,3,3-tetramethoxypropane (masked malondialdehyde) with hydrazine (eq. 2). 

Reaction of an acid chloride with trimethylsilylacetylene produces an a,P-ethynyl ketone, which on treatment with substituted hydrazines yields a mixture of 1,5- and 1,3-substituted pyrazoles (34). The ratio is dependent on the reaction conditions (eq. 3). 

Reaction of 4-amino-l-azabutadienes (45) with various hydrazine salts at 60°C leads to the expected pyrazoles (46) without isolation of the hydrazone intermediate (eq. 8) (39). 

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... 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Uracil reacts with hydrazine to give pyrazol-3(2if)-one (944) and urea N-methyl- and dimethyl-hydrazine behave similarly to give the 2-methyl- and 1,2-dimethyl derivatives. The reactions of hydrazines with uridine and related nucleosides and nucleotides is well studied (67JCS(C)1528). The tautomerism and predominant form of uracil are discussed in Section 2.13.1.8.4. 

Oxygen-containing rings can be opened by amines frequently this is followed by reclosure of the intermediate to form a new heterocycle. Thus isoxazoles containing electron-with-drawing substituents give pyrazoles with hydrazine, e.g. (183 Z = O) (183 Z = NH), and... 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

The imonium salt (199), obtained from ynamines and phosgeneimonium chloVide, underwent ready reaction with monosubstituted hydrazines to give the 3,5-bis(dimethyl-amino)pyrazole (200) (68T4217, 69T3453). Similarly, the adduct (201), resulting from the addition of phosgene to ynamines, likewise reacted with sym-disubstituted hydrazines to give pyrazoles (202). With hydroxylamine derivatives the isoxazolinone (203) was obtained. 

Phenyl-l,2-dithiolylium salt (483) with hydrazine, methylhydrazine or phenylhydrazine yielded the corresponding pyrazole (485) via the intermediates (484a-c). The ring-fused system (486) is a convenient source of the ring-fused pyrazole (487) when treated with hydrazine (see Chapter 4.31). 

The isoxazoles (585) were formed regioselectively from the (dioxoalkyl)phosphonium salts (584) with hydroxylamine hydrochloride, the direction of cyclization being different from that of the nonphosphorus-containing 1,3-dioxo compound (see Chapter 4.16). Aqueous sodium hydroxide converted (585) into the isoxazole (586) and triphenylphosphine oxide. Treatment of (585) with n-butyllithium and an aldehyde gave the alkene (587). With hydrazine or phenylhydrazine analogous pyrazoles were formed (80CB2852). 

The pyrazole ring is particularly difficult to cleave and, amongst the azoles, pyrazoles together with the 1,2,4-triazoles are the most stable and easiest to work with. This qualitative description of pyrazole stability covers the neutral, anionic and cationic aromatic species. On the other hand, the saturated or partially saturated derivatives can be considered as hydrazine derivatives their ring opening reactions usually involve cleavage of the N—C bond and seldom cleavage of the N—N bond. It should be noted, however, that upon irradiation or electron impact the N—N bond of pyrazoles can be broken. 

The decomposition of (536) with hydrogen sulfide yields pyrazole (76T1909). The 1-phosphorylpyrazoles (537) are suitable reagents for the phosphorylation of alcohols, amines, hydrazines and azides (76AG(E)378). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

The synthesis of pyrazoles, indazoles and their derivatives generally follows classical methods, the two most important methods for practical purposes being the reaction between hydrazines and /3-difunctional compounds, and 1,3-dipolar cycloadditions (Section 4.04.3.1.2). Both procedures are well documented (64HC(20)l, 66AHC(6)327, 67HC(22)l) and thus the length of the sections in this part of the chapter reflects not only the number of publications dealing with a particular method but also its interest and novelty. 

This ring closure is the final step of the reaction of hydrazines with 1,3-difunctional compounds (Section 4.04.3.1.2(ii)), and numerous examples in the literature of pyrazoles have been described. In some cases the N—C ring closure occurs by a concerted mechanism, classified by Huisgen (80AG(E)947) as 1,5-electrocyclizations. 

In this section formation of pyrazoles from the reaction of heterocycles with compounds other than hydrazines will be discussed. 

Most of these compounds, for instance pyrazole itself, are today commercially available, so there is only a minor interest in detailing the experimental procedures used. The best way to prepare pyrazole is the Protopopova method (Section 4.04.3.3.2) and a modification using hydrazine hydrate instead of a hydrazine salt has recently been patented (80GEP2922591). 

Anthra[l,9]pyrazol-6(2//)-one (735) dyes have also been described in the literature (B-70MI40403). TTiesc compounds result by acid ring closure of 1-anthraquinonyl hydrazine or its V-sulfonic acid. 

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). 

Isothiazolium salts (59) react with phenylhydrazine to give pyrazoles (60) (72AHC(14)l) (see Section 4.02.1.6). When treated with hydrazine hydrate, 3-chloro-l,2-benzisothiazole gives di-(o-cyanophenyl) disulfide (73SST(2)556), but 2,1-benzisothiazole gives o-aminobenz-aldehyde azine (72AHC( 14)43). 2-Substituted saccharins give the expected o-sulfamoyl-benzohydrazides. 

K N O R R Pyrazole Synthesis Pyrazole synthesis from a -dicarbonyl compourxi arxi a hydrazine. 

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

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