Hydrazines 1,4-ketoesters

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. 

The reaction is generally performed between 0 and 100 °C with the majority of the reactions being mn at reflux. Polar protic solvents such as methanol, ethanol, isopropanol, and water are commonly used as solvents. Addition of acid or use of acetic acid as solvent generally helps push sluggish reactions. The use of P-ketoesters as the dicarbonyl partner occasionally requires added base for cyclization to occur to form the pyrazolone. When using alkyl hydrazine salts, base may be required to deprotonate the hydrazine for the reaction to take place. 

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. ... 

As a further typical reaction of the hydrazine group of the 2-hydrazinoselenazoles (cf. Section I,C,2), pyrazolone formation was investigated. By condensation of the hydrazines with -ketoesters in acetic acid, it was possible to synthesize a series of l-(selenazol-2-yl)-3-alkylpyrazol-5-ones (16). ... 

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. 

In Scheme 4 it can be seen that cyclisation of the ketoester with hydrazine-hydrate was part of a reaction sequence given to the kilo lab and is described in literature with a yield of approximately 60% (Schenker and Salzmann 1979). Under conventional conditions (refluxing in ethanol for 4 h), we obtained the product in 53% yield. Performing the same reaction in the Synthos 3000 microwave reactor at 140°C for 20 min, we improved the yield to 64% on a 20-g scale. Further scale-up to a batch size of 130 g of product was performed under the same conditions (140°C/20 min) with no significant problems. 

The scope of electrophiles was explored with malonates and p-ketoesters, providing chiral amine adducts in high yield and enantioselectivities (Scheme 57) [109]. Addition of cyclic P-ketoesters was also explored with hydrazines, providing cyclic and bicyclic chiral amines with quaternary centers in high enantiomeric ratios (Scheme 58). 

Recently, a completely new four-component heterocyclization of pyranopyrazoles 193 has been designed (09RCB2362,09JCO914) (Scheme 73). It consists in the simultaneous mixing of aldehydes 28, MN 27b, ketoesters 36, and hydrazine hydrate. Domino-type heterocyclization proceeds very regioselectively, probably, via formation of a pyrazolone 194 and UN 30in situ. The method is very facile and facilitates preparation of a broad variety of pyranopyrazoles 193. 

Pyrazoles were obtained from corresponding 2-hydroxy(or aIkoxy-)imino-1,3-diketones or related ketoesters and hydrazine . Thus, reaction of oximes 112 with hydrazine in ethanol afforded aminopyrazoles 113 in 48-95% yields (equation 48) . Interaction of... 

The cyanoenamino ketoester 4 reacts with hydrazines to form the pyridone derivative 5 <99H(50)791>. A -Arylsulfonylamino-2-pyridones have been prepared via the reaction of acetohydrazides with arylidenecyanoacetate derivatives <99JCR(S)6>. 

Selective 0-benzylation of pyridone 273 using Ag2C03 as a base in toluene followed by cyclization of the ketoester functional groups with hydrazine hydrate afforded the fused pyridopyridazine derivative 274 (Equation 19)... 

The synthesis of this ring system may be achieved by building the triazole onto a preformed pyrimidine ring. Cyclocondensation of ketoesters 330 with O-methylisourea (331) gave the pyrimidine 332, whose acylation gave the /V-acyl derivative 333, which can be cyclized with hydrazines to give 334 (89GEP3839711) (Scheme 64). 

Aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-l,4-dihydropyridine (amlodipine) was prepared from 2-(phthalimidoaminoethoxy)acetoacetate, 2-chlorobenzaldehyde and methyl-3-aminocrotonate under refluxing in ethanol for 24 hours. The ketoester was prepared by the method of Troostwijk and Kellog (JCS Chem. Comm., 1977, p.932). Methyl-3-aminocrotonate can be prepared by known method. Phthalimido-amino-protecting group was removed using hydrazine hydrate in ethanol at the reflux temperature. 

A modified procedure for the preparation of pyrazoles includes the solventless condensation of diketones and hydrazines in the presence of a catalytic amount of sulfuric acid at ambient temperature <2004GC90>. 1,3-Diketones can be synthesized directly from ketones and acid chlorides and then converted in situ into pyrazoles by the addition of hydrazine <2006OL2675>. The possible modifications to the 1,3-dioxo component in the reaction with hydrazines include the use of -ketoesters, -ketonitriles, -halocarbonyl compounds, -hydroxyketones, -sulfonylketones, and 1,3-dihaloalkanes . 

Several reactions are occurring in this step that have been elucidated by others (1). First, an a-ketoester is the initial condensation product of an N-acyl-aminoacid and an alkyl oxalyl chloride via a Dakin-West reaction. Second, at reflux temperatures isomeric enol esters are formed that directly condense with hydrazine to form a triazinone intermediate followed by the second ring closure. Other purines have been prepared in an analogous reaction pathway (2). 

Treatment of 2-methoxyimidazoline (585a) with hydrazine produced the cyclic aminoguanidine (586), which reacted with a-ketoesters (587) to give imidazo[2,l-c]-[l,2,4]triazin-4(8//)-ones such as (588) (72LA(764)112)... 

By far the most widely used synthesis for 2-pyrazolin-5-ones is the condensation of a /3-ketoester with a hydrazine (eq. l).6 11-6 269-303-805... 

In summarizing this method of synthesis it can be said that it is so extremely general that almost any non-substituted or monosubstituted /3-ketoester will react with almost any monosubstituted hydrazine to form a 2-pyrazolin-5-one. 

A number of syntheses of compounds having nitrogen on a carbon attached to 2-pyrazolin-5-one rings have already been mentioned, but several others are known. The most important of these is the reaction of 4-formyl- or 4-acyl-2-pyrazolin-5-ones with hydroxylamine, hydrazines, semicarbazide and similar chemicals.559 1841 These compounds can also be obtained by direct synthesis from an appropriate /3-ketoester or derivative and a hydrazine (eq. 50).138 512-1100 An interesting syn-... 

The l,l -bis(2-pyrazolin-5-ones) (Table IX) have been prepared by three methods. Two of these are variants on the familiar / -ketoester condensation with hydrazines but in these cases compounds having two hydrazine moieties are used.116,212,255,459,1037 These two methods are illustrated in eq. 85. The R in the hydrazines used in the direct con-... 

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with jS-ketoesters forms 2-aryl-3-pyrazolin-5-ones.679,849,984,988,1001 The aeyl group is lost in the cyclization and these products have no N-l substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3-pyrazoIin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus penta-chloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a j8-ketoester to give l,2-disubstituted-3-pyrazolin-5-ones.54,370 The sub-... 

Synthesis of 4-amino-2-pyrazolin-5-ones is usually achieved by treatment of an a-amido-/3-aldehydo- or /9-ketoester with hydrazines according to the classical method for preparation of 2-pyrazolin-5-ones. Variants on this procedure consist of using an a-amidoester which has /9-substituents whose reaction is equivalent to that of a /9-carbonyl substituent. Such compounds are D-benzylpenicilloic acid a-methyl ester,1027 ethyl phenylpenaldate243 and the acetal of an a-amido-/9-formyl ester.59,243 Cornforth has isomerized 2-phenyl-4-hydrazino-methylidyneoxazolidone to 4-benzamido-2-pyrazolin-5-one. The same compound was obtained by treatment of 1-ethoxyvinyl-2-phenyl-oxazolidone with phenylhydrazine.319... 

A method frequently used and capable of a large number of variations is the cyclization of a-substituted-jS-ketoesters, apiides or hydra-zides with hydrazines to 4-arylazo-2-pyrazolin-5-ones. One variant of this is the treatment of an a,/J-diketoester with hydrazine (eq. 182).627,1573,1574,1576 Instead of the ester, hydrazides of a j8-diketoacids... 

Huebner and Link870 have prepared 4-arylazo-2-pyrazolin-5-ones by the reaction of hydrazines with 4-hydroxycoumarin, 3,3 -methylene-bis(4-hydroxycoumarin) and with 2,3,4-triketochroman derivatives. In the case of the 4-hydroxycoumarins oxidation by phenylhydrazine occurs to give the bisphenylhydrazone of an a,/ -ketoester. The reaction then proceeds as previously discussed for such compounds. 

The standard /3-ketoester-hydrazine reaction for preparation of 2-pyrazolin-5-ones has been used for direct synthesis of the 4-oximino derivatives by starting with an a-oximino-jS-ketoester.269,1125,1534,1536 In a modification of this by Biilow and Bozenhardt258 a hydrazone of the a-oximino-j8-ketoester was used. Ponzio and Ruggeri1125 have used a-oximino-j8-hydrazonohydroxamic acids and hydrazines, and other oximino compounds, as illustrated in eq. 209. 

Acyl-2-pyrazoIin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-ones and conversion of other heterocycles. As might be expected the reaction of /J-ketoesters with hydrazines has been utilized.124,1124,1532,1533 In this case the /J-ketoester has an a-acyl substituent (eq. 216). Both Borsche and Lewinsohn124 and Vila1533... 

Functional group substituents on N-l of 2-pyrazolin-5-ones (Table XXXVII) are acyl, sulfonyl and various carboxyl derivatives, such as carbalkoxy, amides, thioamides, hydrazides, thiohydrazides and amidines. The usual synthesis of these compounds is by the classical 2-pyrazolin-5-one synthesis, reaction of a /J-ketoester with a hydrazine. In these cases the hydrazines are special types such as hydrazide,... 

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