3,5-Disubstituted pyrazoles

Acylaminopyrazoles (306), prepared by acylation of 1,3-disubstituted pyrazole-5-amines, react with phosphorus pentachloride to yield the chlorimidoyl chlorides (307) (Scheme 26). The latter condense with nitriles in the presence of stannic chloride to yield the pyrazolo[3,4-treatment with chloromethanimines <75S645>. 

An important publication by Kost et al. (63JGU525) on thin-layer chromatography (TLC) of pyrazoles contains a large collection of Rf values for 1 1 mixtures of petroleum ether-chloroform or benzene-chloroform as eluents and alumina as stationary phase. 1,3- and 1,5-disubstituted pyrazoles can be separated and identified by TLC (Rf l,3>i y 1,5). For another publication by the same authors on the chromatographic separation of the aminopyrazoles, see (63JGU2519). A-Unsubstituted pyrazoles move with difficulty and it is necessary to add acetone or methanol to the eluent mixture. Other convenient conditions for AH pyrazoles utilize silica gel and ethyl acetate saturated with water (a pentacyanoamine ferroate ammonium disodium salt solution can be used to visualize the pyrazoles). 

A 6-oxo bicycle (43) was also produced from base-induced cyclization of the N,N-disubstituted pyrazole 42. The isomer 45 was formed from the cro-tonate 44 in liquid paraffin at 250°C.46 Analogous reactions have been reported in the aminopyrazole series (Section II,7,a). 

Long range H—13C coupling constants in pyrazoles and /(13C—,3C) (C3, C4 = 51.5 Hz, C4, C5 = 64.6 Hz) coupling constants in 1-methylpyrazole have been used for confident assignment of isomeric 1,3- and 1,5-disubstituted pyrazoles (87T4663,94MRC62). 

Treatment of l-benzylamino-5-methylhexan-3-one oxime 97 with copper(II) sulfate in pyridine acetonitrile yields 2,5-disubstituted pyrazole 1-oxides 98 (1994JHC281) (Scheme 28). 

N-Unsubstituted pyrazole is readily converted into 3(5)-substituted derivatives in a one-pot sequence, using formaldehyde both for N-protection and to mediate the lithiation at the 5-position the transient N-(hy droxymethy 1) unit is readily removed during work-up. Direct lithiation of 1-substituted pyrazoles provides an efficient entry to 1,5-disubstituted pyrazoles. 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

This pyrazole synthesis, which undoubtedly profits from the thermodynamic stability of the end products, gives excellent yields (Table VI). Its range of application is limited, however, by the fact that the reaction of 3-substituted unsymmetrical dithiolium salts with substituted hydrazones leads to mixtures of isomers which can be separated only with difficulty. On the other hand, it does permit the preparation of a single 4,5-disubstituted pyrazole from a 3,4-disub-stituted salt and a substituted hydrazine. 

The basicities of 3,5-disubstituted pyrazoles carrying a heterocyclic substituent (a-furyl, a-thienyl, a-selenienyl) (4) were all less than that of the unsubstituted pyrazole and fall into the order indicated hence all the above heterocyclic groups are electron-acceptors with respect to hydrogen for the pyrazole ring.97 Pyrazole, when substituted as... 

Diketones of the selenophene series are used to synthesize various heterocyclic systems isoxazole, pyrazole, and pyrimidine, as well as a-substituted bis-/3-diketones. Thus, /3-diketones with hydrazine hydrates yielded the corresponding disubstituted pyrazoles.130,131 The presence of the selenienyl radical as a substitutent substantially reduced the basicity of a pyrazole ring (see Section V,C) the electron-accepting ability of the selenien-2-yl radical is especially great.121 The reaction of selenophene /3-diketones with ureas gives substituted pyrimidines.125... 

After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, hydrazines 29, and acetic acid are added and reacted in the same reaction vessel. Best results for the formation of pyrazoles 30 are obtained by dielectric heating in the micro-wave oven at 150°C for 10 min in the presence of methanol. Pyrazoles 30 are obtained in good to excellent yields, predominantly as colorless crystalline solids (Scheme 21) [113]. This concept has also been applied to the nonregioselective synthesis of 3,5-disubstituted pyrazoles 30 (R = H) upon conductive heating in the cyclocondensation step [114]. 

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3(5)-phenyl- or 3,5-disubstituted pyrazoles 725 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-pyridylacetylene with diazo compounds 724 generated in situ from aldehydes 723 has been reported (Scheme 91) <2003JOC5381>. Cyclization of ort o-(arylethynyl)benzene diazonium salts 727, prepared from alkynyl aniline 726, having substituents at the /> ra-position of the aryl ring furnished indazoles 728 (Scheme 92) <2003TL5453>. 

Substituted 2-diazopentane-l,3,5-triones have been transformed into 3,5-disubstituted-4-hydroxypyrazoles <2003RJ01644>. Disubstituted pyrazoles were obtained by the reaction of 4-aryl-2,4-oxobutanoic acid aryl amides with diazomethane or diazoethane <2002RJ0840>. The reaction of 2-methylene-l,3-dicarbonyl compounds with ethyl diazoacetate gave 4,5-dihydro-l//-pyrazole derivatives in good yields, which were stable for several months at room temperature <2001CPB1638>. 

In addition, thallium adducts featuring 3,4- and 3,5-disubstituted pyrazole-containing ligand systems are known. They include [HB(l,4-dihydroindeno[l,2-c]Pz)3]Tl, " [HB(3-(i-Pr),... 

Table 5 Tpx ligands derived from 3,4-disubstituted pyrazole rings and references to their synthesis.

With 3,5-disubstituted pyrazole the melt method is preferred, since tetrasubstitution does not take place, and high temperatures can be employed. It would be better to use a large excess of Hpzx (Hpzx MBH4 in 6 1 molar ratio) to prevent the precipitation of the less soluble potassium or sodium salt and decomposition. After completion of the reaction, the excess of Hpzx is sublimed out and the residue is converted to the Tl1 salt in the usual way. 

A variety of 4-amino-5-alkoxy- and acyloxy-l,3-disubstituted-pyrazoles have been treated with alkylating agents such as alkyl halides to give 4-dialkylamino-3-pyrazolin-5-ones.525 There is a simultaneous alkylation of ring nitrogen and extranuclear nitrogen. 

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