1.3.5- Trisubstituted pyrazoles

Dichlorination was also observed when two molar equivalents of NCS or /-butyl hypochlorite reacted with 1-hydroxypyrazoles and their 2-oxides. One equivalent of NCS gave only the 4-monochloro derivative in high yield (80JOC76). When there was already a 4-substituent present, as with 3,4,5-trisubstituted pyrazole 2-oxides or 1-hydroxy-3,4,5-trisubsti-tuted pyrazole 2-oxides, the reaction products were 4-chloro-4// derivatives (77JOC3721). With 2 mol of /-butyl hypochlorite, 3,5-diphenylpyra-zole gave the unstable 1,4-dichloro derivative, which rearranged to form... 

Synthesis of l-iodo-3,4,5-trisubstituted pyrazoles 25 (R=Me, X=C1, Br, I, Me) may be carried out by the reaction of the corresponding silver salts of pyrazole with iodine (70CB1949). 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

The reaction direction remains the same for methyldiacetylene and diphenyl-diacetylene (120°C, 20 h, yield 85.8%) (71AKZ743), the cyclization products being 1,3,5-trisubstituted pyrazoles 20 and 21. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

Novel applications of benzotriazole methodology in organic synthesis include regiospecific preparation of 1,4,5-trisubstituted pyrazoles <2007ARK(i)9>, efficient synthesis of 1,5-disubstituted tetrazoles <2007SL1204>,... 

The 4-proton chemical shifts in the NMR spectra of 1,3,5-trisubstituted pyrazoles correlate with Lo, indicating that such effects are electronic rather than anisotropic,360 while correlations for the PMR spectra of antiparasitic 2-(substituted styry 1)-5-nitro-N-substituted imidazoles have also received attention.361... 

Diazo compounds have also been used as precursors in the preparation of pyrazoles and indazoles. The copper-promoted cycloaddition reaction of lithium acetylides 18 with diazocarbonyl compounds 19 provided a direct and efficient approach to the synthesis of pyrazoles 20 <07AG(I)3242>. A facile, efficient, and general method for the synthesis of 1-arylated indazoles 22 and A-unsubstituted indazoles 23 by the 1,3-dipolar cycloaddition of benzynes, generated from 21, with diazomethane derivatives has been reported <07AG(I)3323>. Reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate <07S3371>. 

Willy B, Muller TJJ (2008) Regioselective three-component synthesis of highly fluorescent 1,3,5-trisubstituted pyrazoles. Eur J Org Chem 4157 168... 

Recently, Muller and co-workers [145] have reported a series of 3,5-disubstituted and 1,3,5-trisubstituted pyrazoles 104 and 105 by reacting an acyl chloride, a terminal alkyne and a hydrazine via a consecutive one-pot three-component Sonogashira coupling/Michael addition/cyclocondensation sequence under microwave irradiation. The desired products were obtained in good to excellent yields. These obtained pyrazoles are highly fluorescent, both in solution and in the solid state (Scheme 81). 

The orientation of the substituent gtoups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonittile oxides with an unsymmetrically substituted hydrazine, has been determined by C NMR assignments <1998JHC161>. The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from / -amino enones and hydrazine derivatives were investigated by C chemical-shift prediction mles for 1,3,5-trisubstituted pyrazoles <2001H(55)331>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Aminopyrazoles were prepared from the reaction of hydrazines with a resin-supported /3-ketonitrile <1997TL9065>. Cyanoacetophenone has been employed as a synthon for the assembly of 1,4,5-trisubstituted pyrazoles <1998M1207>. 2-Tosylethylhydrazine 559 could be condensed with either / -ketonitriles 557 or /3-aminoacrylonitriles 558 to give 5-aminopyrazoles 560, which were deprotected with sodium ethoxide to give 3(5)-aminopyrazoles 561 (Scheme 69)... 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Table 8 Tpx ligands derived from trisubstituted pyrazole rings and references to their synthesis.

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