Pyrazolones, reaction with aldehyde

The tautomeric character of the pyrazolones is also illustrated by the mixture of products isolated after certain reactions. Thus alkylation normally takes place at C, but on occasion it is accompanied by alkylation on O and N. Similar problems can arise during acylation and carbamoylation reactions, which also favor C. Pyrazolones react with aldehydes and ketones at to form a carbon—carbon double bond, eg (41). Coupling takes place when pyrazolones react with diazonium salts to produce azo compounds, eg (42). 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

Pyrazolones show a great variety of reactions with carbonyl compounds (B-76MI40402). For instance, antipyrine is 4-hydroxymethylated by formaldehyde and it also undergoes the Mannich reaction. Tautomerizable 2-pyrazolin-5-ones react with aldehydes to yield compound (324) and with acetone to form 4-isopropylidene derivatives or dimers (Scheme 8 Section 4.02.1.4.10). 

Another variation of the Biginelh condensation involved the reaction of aldehyde 42, guanidine hydrochloride with various pyrazolones 41 to provide pyrazo-lopyrimidines 43 (Scheme 10) [30]. All the products obtained were tested against the M. tuberculosis H37 Rv strain and found to be active. In particular, compounds 44-46 had comparable activity (MIC =1.2 pg/mL) to first-Une drugs such as rifampicin (RIP) (MIC = 1 pg/mL). 

Pyrazolones also condense with aldehydes in aldol-type processes, or react with other electrophiles, such as carbon disulfide, in each case reaction presumably proceeding via the enol tautomer, or its anion. In basic solution isoxazol-3-ones alkylate either on oxygen or nitrogen, and the choice of base can influence the ratio. ... 

The catalysed alkylation of l//,4//-pyrazol-5-ones is solvent dependent. In benzene, bis-alkylation occurs at the 4-position whereas, in a carbon disulphide benzene mixture, O-alkylation is observed, although the major product (4, Scheme 5.22) results from nucleophilic attack by the pyrazolone on the carbon disulphide, followed by alkylation of the dithiolate dianion [92]. The catalysed reaction of 2-thiono-3-aryl-thiazolidin-4-ones with alkylating agents under soliddiquid two-phase conditions results in alkylation at the 5-position (60-80%) [93]. The aldol condensation of the thiazolidinones with aryl aldehydes is also catalysed by quaternary ammonium salts. 

Michael-type condensation of cyanoacetohydrazide (NCCH2CONHNH2, CAH) with 1,3-dicarbonyl compounds gave pyrazolo[3,4-b]pyridines under certain conditions. With l,l,l-trifluoropentane-2,4-dione in the presence of piperidine a 1 3 mixture of pyrazolone 92a and the expected aminopyridone 91a was obtained.15 The bicycle was also obtained from hydrazone (90) or by thermal reaction between its two precursors.32 Reaction of CAH and / -keto aldehydes gave good yields of only bicyclic products 92b,20 whereas ethyl benzoylacetate in the presence of piperidine gave bicycle 92c (Ar = Ph)... 

Three-component reactions of aromatic aldehydes with a series of cyclic CH-acids, for example, with 230, and 5-amino-3-pyrazolones 228 have a high regioselectivity involving the carbon atom at position 4 and yield compounds like 231 [195] (Scheme 3.64). 

Reaction of phenylhydrazine with the /J-keto ester (64) gives the pyrazolone (65).55 The hydantoin (66) has been obtained by the action of potassium cyanide and ammonium carbonate on ferrocenecarbox-aldehyde.67-69 The potentiometric titration64 of hydantoin (67) has been reported. 

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>. 

The derivatization of aldehydes in reducing carbohydrates can also be performed by a condensation reaction between the active hydrogens of l-phenyl-3-methyl-5-pyrazolone (PMP) and the aldehyde functionality under slightly basic condition. The formed bis-PMP derivatives can be separated by CZE and detected by UV absorbance. Oligosaccharides can also be separated as complexes with a variety of compounds, including acetate, molybdate, germanate, stannate, arsenite, wolfra-mate, vanadate, and tellurate of various alkali and alkaline... 

Pyrazolones (154) and isoxazolones (155) can also be used in the Knoevenagel reaction. Thus condensations with aliphatic aldehydes, aromatic aldehydes and ketones in the presence of ethylenediammon-ium diacetate or other typical catalysts provide the corresponding alkylidene and benzylidene compounds in good yields (for stereochemistry see Section 1.1A new method involves the use of dicyclohexylcarbodiimide at 20 C without an additional catalyst. ... 

Condensation of 403 with aromatic aldehydes in the presence of ZnCl2 produced the corresponding 4-arylidenepyrazole derivatives 404 in 50-75% yield after 5-8 h heating at 140-150 °C. However, when the reaction was done under MWI for 5-7 min, the products were identified as l/f-pyrazolo[3,4-Z)]quinolines 405 and not 404 albeit in lower yields (40-71%) (Scheme 81) (00MI4). Reaction of 407 with pyrazolones 406 gave 408 (99SC4403). 

In the presence of a catalytic amount of Sc(OTf)3, benzoylhy-drazones react with ketene silyl acetals to afford the corresponding adducts, 8-lV-benzoylhydrazino esters, in high yield (eq 10). Several benzoylhydrazones including those derived from aromatic, aliphatic, a,/3-unsaturated aldehydes, and glyoxylate work well. The reactions of polymer-supported hydrazones with silyl enolates are also catalyzed by Sc(OTf)3 to produce pyrazolone derivatives after base treatment. ... 

This reaction was first reported by Knorr in 1883. It is the preparation of pyrazole derivatives from 1,3-dicarbonyl compounds and hydrazines. Similarly, pyrazole derivatives can also be prepared from hydrazines and equivalent molecules of 1,3-dicarbonyl compounds, such as a-ethoxymethylene a-phenylacetone. In a special case, -carbonyl aldehyde reacts with a simple hydrazine to afford tautomers of 3- and 5-substituted pyra-zoles, of which the proton oscillates rapidly back and forth between two nitrogen atoms. These two tautomers are distinguishable only at sufficiently low temperatures." It should be pointed out that the reaction of hydrazine with j8-carbonyl ester leads to the formation of pyrazolone. ... 

Ziarati et al. [69] developed the synthesis of compounds with pharmaceutical and biological properties. Thus, 2-aryl-5-methyl-2,3-dihydro-lH-3-pyrazolones (72) were synthesized via a four-component reaction of ethyl acetoac-etate (66), hydrazine (67), aldehyde (69), and p-naphthol (70) in water under ultrasound irradiation with a multiwave ultrasonic generator in the presence of nanoparticles of copper iodide as catalyst, using a simple preparation protocol (Scheme 17). It should be mentioned that the catalyst could be recycled and reused for five times without evidently... 

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