Synthesis of Pyrazolones

To demonstrate the possibilities of Michael additions, we chose the synthesis of pyrazolones [27] as an example (Fig. 6.11). The addition of p-ketoesters in the presence of BEMP as base provided resin-bound P-ketoesters, which were transformed into the cor- 

For systematic variation of the aldehydes, ethyl acetoacetate and phenylhydrazine were used as constant building blocks (Table 6.3). 4-Trifluoromethylbenzaldehyde and phenylhydrazine were used in the variation of the P-ketoester (Table 6.4), while 4-tri-fluoromethylbenzaldehyde and ethyl acetoacetate were applied in the arylhydrazine variation (Table 6.5). All compounds were analyzed by ES-MS and HPLC (1 = 214 nm). 

An efficient and general method to prepare diverse P-ketoesters linked to a solid support was developed by Tietze et al. using readily available acid chlorides 259 and haloalkanes as building blocks. The obtained polymer-bound 1,3-dicarbonyl compounds served as substrates toward the preparation of a library of substituted pyrazolones, which are well known for their widespread biological activity as analgesics, antipyretics, antiphlogistics, antirheumatics, antiarthritics and 

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The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

A number of other five-membered ring nitrogen heterocycles have been prepared by cyclative cleavage. The illustrative examples (Fig. 4) depict the synthesis of pyrazolones,12 succinimides and phthalimides,13 pyrrolo[3,4-h] pyridines,14 2-aminoimidazolones,15 imidazo[4,5-fr]pyridin-2-ones,16 and l,2,4-triazoline-3,5-diones.17... 

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]. 

The sonosynthesis technique was employed to promote the synthesis of pyrazolones (56) via the reaction of P-keto esters (54) with hydrazine derivatives (55) in ethanol (Al-Mutairi et al. 2010). The reactions were completed in short times (2-25 min) and afforded the products in poor to excellent yields (Scheme 8.18). 

Scheme 3.3 Synthesis of pyrazolone-pyrimidine derivatives by using nanoparticles of NaX Zeolite catalysts...

SCHEME 22 Synthesis of pyrazolones 88 in aqueous medium at room temperature. 

A. Ziarati, J. Safaei-Ghomi, S. Rohani, Sonochemically synthesis of pyrazolones using reusable catalyst Cul nanoparticles that was prepared by sonication, Ultrason. Sonochem. 20 (2013) 1069-1075. 

Other base-modifications. Hassan and co-workers reported a novel synthesis of pyrazolone nucleosides and their antimicrobial activities. Mata and his group reported the stereoselective AAglycosylation of 2-deo3ythioribosides. This facile synthesis (shown in Scheme 3) involves N-2-deo3yribosylation of a modified nucleobase with 2-deoiythioriboside in the presence of bis-(trimethylsilyl)acetamide, AT-iodosuccinimide and trimethylsilyl trifluoromethanesulfonate to afford stereoselective nucleosides (19) in excellent yields. 

AminothiaZoles. In contrast to the pyrazolones, pyridones, and indoles just described, aminotliiazoles are used as diazo components. As such they provide dyes that ate more bathochromic than their benzene analogues. Thus aminothiazoles are used chiefly to provide dyes in the red-blue shade areas. The most convenient synthesis of 2-aminothiazoles is by the condensation of thiourea with an a-chlorocarbonyl compound for example, 2-aminothiazole [96-50A-] (94) is prepared by condensing thiourea [62-56-6J with a-chloroacetaldehyde [107-20-0J both readily available intermediates. 

Sucrow, studying the chemistry of the enehydrazines (83CB1520), has found several methods for the synthesis of pyrazoles. For example, he has described (79CB1712) the cyclization of monomethylhydrazones of dialkyl oxalacetates to 5-pyrazolones via an enehydrazine (Scheme 47). 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Carpino et al. recently disclosed the synthesis of the fused pyrazolinone-piperidine dipeptide 56 with potent growth hormone secretagogue activity. The synthesis of the intermediate pyrazolone was accomplished by reacting the ketoester 54 with methyl hydrazine in refluxing ethanol. ... 

One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound -keto esters starting from acid chlorides and Meldrum s acid. One such resin-bound y3-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-ffee N-2-unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-37/-pyrazol-3-ones was reported. 

The l-arylpyrazol-5-ones (4.9), prepared by the two-step condensation of an arylhydrazine with ethyl acetoacetate, are the most commonly used coupling components for the synthesis of greenish yellow azo dyes. Coupling occurs at the 4-position of the pyrazolone ring which, as in the case of the acetoacetarylamides discussed above, is activated towards electrophilic attack by the two flanking unsaturated carbon atoms (Scheme 4.14). 

Fig. 3.12. Synthesis of the compounds by the methods (a) and (b). A = -NHC6H4S03H (dye la) A = -NHCH2CH=CH (dye lb) A = -OCH2CH=CH2 (dye lc). SP = N-(4 -sulpho)phenyl-3-methy 1-5-pyrazolone m-PDA = l,3-phenylendiamine-4-sulphonic acid. Reprinted with permission from T. Konstantinova et al. [90],...

Knorr, L. Ber Dtsch. Chem. Ges. 1883, 16, 2597. Ludwig Knorr (1859—1921) was bom near Munich, Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

The most widely used method for the synthesis of 4//-pyrazoles employs 2,2-disubstituted 1,3-diketones and hydrazine. Other useful methods include the reaction between l//-pyrazoIes and electrophiles, the transformation of pyrazolone derivatives, and thermal rearrangements of 3//-pyrazoles. 

Important works were devoted to the synthesis of calixarenes bearing different groups (malonamide, glycolamide, pyrazolone, thiopyrazolone, terpyridine, TTFA). Unfortunately, none of these compounds displayed a sufficient extracting ability. 

In the stepwise synthesis of the unsymmetrical complex dye 13 [ 70236-60-1] [10], the azo dye made from diazotized l-amino-2-hydroxy-5-nitrobenzene and 1-phenyl-3-methyl-5-pyrazolone and the 1 1 chromium complex obtained from 6-nitro-l-diazo-2-hydroxynaphthalene-4-sulfonic acid and 2-naphthol are heated together at 80 °C for 5 h. The adduct is salted out with NaCl. A black powder is obtained that dyes wool and leather in dark brown shades. The resulting colors are fast, particularly on shrink-resistant wool. 

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