1,4,5-Trisubstituted pyrazol-3-ones

From 2-aryl-N-phenylacetohydrazides. An expedient route to 1,4,5-trisubstituted pyrazol-3-ones 73 consists of condensing poly-lithiated 2-aryl-N-phenylacetohydrazides 221a-e with aromatic esters 222a-e and excess LDA. The reaction most probably proceeds via polylithiated C-acyl intermediates 223 that cyclize to pyrrolidinones 224, after addition of hydrochloric acid, which on heating dehydrate to pyrazol-3-ones 225a-e (01JHC695) (Scheme 50). 

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... 

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). 

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>. 

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>. 

The 1,3-dipolar cycloaddition reaction of pyridinium ylides (40) with 3-alkenyl oxindoles (41) yielded spiro-cycloadducts (42) related to oxindole alkaloids, such as strychnofoline (Scheme 12). The one-pot 1,3-dipolar cycloaddition of 3-arylsydnones with a,/ -unsaturated ketones formed 1,3,4-trisubstituted pyrazoles in refluxing dry dimethylbenzene. ... 

Palladium-catalyzed cross-coupling reactions of aryl chlorides 5 with hydrazine afforded intermediate arylhydrazines 6 at ambient temperatures, which reacted further with P-diketones to give 1,3,5-trisubstituted pyrazoles 7 in one-pot (13AG(E)3434). Palladium-catalyzed Heck car-boxylative cross-coupling reactions of aryl iodides with acetone afforded the in situ 1-aryl-1,3-butadiones, which reacted with an aqueous solution of hydrazine in ethanol to give 3-methyl-5-arylpyrazoles in moderate yields (13CEJ12624). 

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