2-Aryl-substituted pyrazole 1-oxides

The 2-alkyl- or aryl-substituted pyrazole 1-oxides are usually stable, crystalline, semipolar, and slightly hygroscopic compounds. 2-Substituted pyrazole 1-oxides are weak bases, being subject to protonation at the negatively charged oxygen atom. 2-Hyd roxypyrazole 1-oxides 74 (R = OH) are acids, no pf(a values seem to have been reported. 

Alkyl- or aryl-substituted pyrazole 1-oxides 94 can be obtained in acceptable yields by oxidative cyclization of O-silylated 3-oximimines like 1 -tert-hutyldimethyIsilyloxy-4-methylamino-1 -azab nta-1,3-diene 93 using copper(II) sulfate as the oxidant and pyridine and acetonitrile as the solvent. The oximimines are prepared from 1,3-dicarbonyl compounds 92 in a one-pot process. The method also gives access to 2-alkyl and aryl-pyrazole 1-oxides R=H devoid of substituents at the ring carbon atoms (94 Ri = R2=H) (1995JCS(P1)2773) (Scheme 27). 

Aryl-substituted 6-methyl-4//-pyrazolo[3,4-c]-l,2,5-oxadiazoles 275 are easily obtained in 88-97% yields by the oxidation of 2-aryl-5-methyl-4-nitroso-2//-pyrazol-3-amines 274 with Pb(OAc)4 (Equation 52) <2000S72>. 

The aromatic 2-substituted pyrazole 1-oxides 74 are derived from pyrazoles 89 by appending an oxygen atom to the pyridine type ring nitrogen atom of the pyrazole nucleus. The second nitrogen atom of the pyrazole ring can be attached to an alkyl, aryl, hydroxy, or amino group. 

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

Similar reactions have been carried out with variously substituted pyrroline 1-oxides, imidazole 1-oxides, isoxazoline N-oxides (nitronic esters) and 3,4-diazacyclopentadienone AT-oxides in combination with a large variety of alkenic and alkynic dipolarophiles, aryl isocyanates, aryl isothiocyanates and N- sulfinylamines, leading to pyrrolidinoisoxazoles, pyrrolo[l,2-6][l,2,4]oxadiazoles, pyrrolo[2,l-d][l,2,3,5]oxathiadiazoles, isoxazolo[2,3-b ]isoxazoles and isoxazolo[l, 2-6 ]pyrazoles. 

Sequential functionalization of pyrazole-l-oxides via regioselective metallation led to the synthesis of 3,4,5-trisub-stituted-l-hydroxypyrazoles <2002JOC3904>. 3-Acylated-2-(4-methoxybenzyl)-2//-pyrazole 1-oxides were formed by the reaction between a 3-magnesium 2//-pyrazole-l-oxide and acid chlorides <2002J(P1)428>. 3-Arylated-l-hydroxypyrazoles were synthesized from 3-metallated-pyrazole 1-oxides <2001JOC8654>. The reaction between hexafluorobenzene and the anion of 1-hydroxypyrazole affords a mixture of the products of bis-, tetrakis-, and hexakis-substitution <2004ARK100>. In the case of hexakis(bromomethyl)benzene, its reaction with 1-hydroxy-pyrazole leads to the hexakis-substituted product. 

The use of aryl tosylates as electrophiles is attractive, because they can be prepared from readily available phenols with less-expensive reagents than those required for synthesis of the corresponding triflates. Importantly, tosylates are more stable towards hydrolysis than triflates, yet significantly less reactive as electrophiles. As a result, protocols for traditional cross-coupHng reactions were only recently developed (see Chapter 2). In contrast, catalytic direct arylations with aryl tosylates were not reported until recently. Interestingly, a rathenium complex derived from heteroatom-substituted secondary phosphine oxide (HASPO) preligand 78 [40] allowed for direct arylations with both electron-deficient, as well as electron-rich aryl tosylates [41]. As pronucleophiles, pyridine, oxazoline and pyrazole derivatives could be efficiently functionalized. Selective mono- or diarylation reactions could be accomplished through the judicious choice of the... 

Interestingly, the chemoselectivity of this catalytic system changed dramatically when using aryl oxazolines along with substituted allyl acetate 104. Thus, oxidative homocoupling reactions occurred under these reaction conditions (Scheme 9.37) [50]. Imidazole, pyrazole or thiazole derivatives could also be efEciently homocoupled. 

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