Synthesis of Pyrazoles

The most important method for the synthesis of 3i/-pyrazoles is by 1,3-dipoIar cycloaddition between a diazo compound and an alkyne, although alkenes bearing suitable leaving groups have also been used. Other methods include the cyclization of vinyldiazo compounds, and the oxidation of pyrazolines. 

Polymer-bound enones were also used in a hetero Diels-Alder reaction for the synthesis of dihydropyranes [38,39]. 

In summary, we have shown that squaric acid, 3-hydroxy-2-methylidene propionic acids, 5-(2-bromoacetyl)pyrroles and enones are useful polymer-bound key intermediates for the synthesis of a large number of different core structures. Squaric acid was used as a fluid template, because cores structures with different ring sizes could be synthesized. All other examples started from linear templates and afforded linear core structures as well as cyclic core structures. The examples shown here demonstrate the advantages of polymer-bound templates for this type of synthesis. This strategy also reduces the optimization time needed for developing the synthetic route for a specific structure because the synthesis of the polymer-bound educt has to be evaluated only once for the variety of core structures derived from this educt. 

Several other promising templates suitable for the synthesis of multiple core structure libraries have been reported, but their synthetic potential has not yet been fully investigated. 

Further examples are epoxides, from which oxazolidinones [40] and y- and 8-lactones [41] have been synthesized, 1,3-diketones which were used in the syntheses of pyrazoles and isoxazoles [42], 1,2-aminothiols from which thiazolidines [43] were formed. 

This chapter aims to present an overview on the main peptide bond modifications which have been proposed in the recent years. The solution- and solid-phase synthesis of the new synthetic oligomers, the methods for their characterization, and their biological and folding properties will be discussed. Particular emphasis will be given to those modifications which are suitable for combinatorial chemistry applications and developments. 

For completeness, readers may be interested to compare the synthesis of pyrazoles in an FOF based system where Wiles et al. have reacted a series of 

3-diketones with hydrazines, to prepare pyrazoles in 98% conversion using only stoichiometric equivalents of the reagents [17], although a detailed study to compare the difference in reaction efficiency has not been conducted. 

Clearly, this advanced type of system is suitable for drug discovery applications and could be applied to a range of other reactions performed within microreactors 

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Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

The synthesis of pyrazoles, indazoles and their derivatives generally follows classical methods, the two most important methods for practical purposes being the reaction between hydrazines and /3-difunctional compounds, and 1,3-dipolar cycloadditions (Section 4.04.3.1.2). Both procedures are well documented (64HC(20)l, 66AHC(6)327, 67HC(22)l) and thus the length of the sections in this part of the chapter reflects not only the number of publications dealing with a particular method but also its interest and novelty. 

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). 

The important synthesis of pyrazoles and pyrazolines from aldazines and ketazines belongs to this subsection. Formic acid has often been used to carry out the cyclization (66AHQ6)347) and N-formyl-A -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588 R = H) which subsequently partially isomerizes to the more stable trans isomer (589 R = H) (Section 4.04.2.2.2(vi)). Both isomers are formylated in the final step (R = CHO). 

Figure 31 Synthesis of pyrazoles and indazoles by ring transformation...

In these types of 1,3-dipolar cycloaddition only one of two possible isomers is obtained and the pyrazole functions have different orientations by the two methods. Another classical synthesis of pyrazoles (Section 4.04.3.2.l(ii)), the reaction between hydrazines and )3-diketones, has been used with success to prepare high molecular weight polypyrazoles (Scheme 65) (81MI40400). A-Arylation (Section 4.04.2.1.3(ix)) of 4,4 -dipyrazolyl with 1,4-diiodobenzene also yields polymeric pyrazoles (69RRC1263). 

The use of diphenyl hydrazone 33 has been used in the synthesis of pyrazoles under modified conditions where the hydrazine is released in situ. Some reversal of regiochemistry is seen in the reaction with unsymmetrical dicarbonyls. With aryl hydrazine and diphenyl hydrazone, the ratio of 41 to 42 is 22 1 and 5 1, respectively. 

A solventless synthesis of pyrazoles, a green chemistry approach, has been described where an equimolar amount of the diketone and the hydrazine are mixed in a mortar with a drop of sulfuric acid and ground up. After an appropriate length of time ( 1 h) the product is purified to provide clean products. Even acyl pyrazoles 42 were obtained under the solvent-less reaction conditions in good yields. 

The synthesis of pyrazoles and isoxazoles from l-heterobut-l-en-3-ynes is performed, as a rule, in an aqueous acid medium, i.e., under conditions favoring the hydrolysis and hydration of the initial enyne. This circumstance impedes rationalization of the experimental results. Therefore, it is reasonable to consider in brief the protonation and behavior of l-heterobut-l-en-3-ynes under the conditions of acid-catalyzed hydrolysis. 

The concept of the use of dilithio reagents for the preparation of heterocyclic systems has been extended to the synthesis of 2-isoxazolin--5-ones10 by carboxylation of a dilithio oxime, followed by eyolin-zation, and the synthesis of pyrazoles from dilithiophenylhydrazones and trilithiothiohydrazones.11 12... 

Fig. 14 Microwave-assisted synthesis of pyrazoles and isoxazoles on cellulose. Reagents and conditions a Camphorsulfonic acid, DMF, MW 80 °C, 15 min, open vessel b NH2XH, MW 82 °C, 15 min, open vessel. X = N,0 Y = NH, NEt, O R = Me, i-Pr, BUCH2, PhCH2, Et(Ph)CH, R = alkyl, aUyl, and aryl groups...

R = Aliphatic, aromatic, X = -OR, -NR2 R = Aromatic Scheme 20 Two step synthesis of pyrazoles from /3-ketoesters... 

Hence the investigations made so far were aimed more at showing the capability of an automated micro-reactor system, using the Knorr synthesis as a model reaction however, to a certain extent, information on this synthesis itself was also gained (see Section 4.9.6.5) [20]. The Knorr synthesis of pyrazoles chosen is of industrial interest since by this route compounds with a wide range of biological activity can be produced. 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring opening of 3-aryl-2-benzoyl-l,l-cyclopropanedicarbonitriles 14 with hydrazine provided a new process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. 

Steric effects and FMO control have been combined in an elegant way to achieve regiospecific synthesis of pyrazole inhibitors of dihydroorotate dehydrogenase <2006SL901>. When the size of the propargylic acid ester 86 is increased from ethyl to diphenylmethyl, pyrazole 87 is formed from compound 85 regiospecifically (Scheme 3 Table 4) <2006H(68)1007>. 

Szczepaikiewicz et al. [85] reported the synthesis of pyrazoles (e.g., 167) from the diketone 168 with hydrazine hydrate, shown in Scheme 43. Nigram et al. executed a similar synthetic sequence [86]. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

III. Synthesis of Pyrazoles Condensed to Five-Membered Rings. 251... 

Since the early review on sydnones by Stewart (192) and the subsequent coverage by Potts (1), several new applications of these remarkably stable mesoionic heterocycles have been described. In particular, the synthesis of pyrazoles from sydnones has been pursued by several groups. Badachikar et al. (193) prepared several new potential antibacterials (297) from the appropriate sydnones 296, which were synthesized in the standard fashion by the cyclodehydration of the corresponding A-nitroso-A-arylglycine. 

A review on the synthesis of pyrazoles and condensed pyrazoles covering the period of 1989-1998 was written <99JHC321>. 

The above described methodology was found to be very useful in a solid-supported synthesis of pyrazoles and pyrimidines via propenones developed by Westman and co-workers35 (Scheme 5.19). Merrifield resin was reacted with methylamine in water at 150°C for 10 min to form the solid-supported benzylmethylamine (3) in high yield (86% yield, 1.08 mmol/g based on elemental analysis). After washing, the resin was treated with 5 equiv. DMFDEA and 5 equiv of 4-phenoxyacetophenone at 180°C for 10 min in DMF to form the solid supported benzyl methyl aminopropenones (4). 

Quiroga et al. have described the synthesis of pyrazole 26c g and pyrimidine 27a,b TB derivatives and suggested the mechanism of their formation from isolated intermediates (02TL5617, 02JCS(P1)1588). In this case, C-alkylation served to initiate... 

Scheme 21 Microwave-promoted multicomponent synthesis of pyrazoles and isoxazoles...

C. Synthesis of Pyrazoles from Aliphatic Diazo Compounds 381... 

Enol ethers of 1,3-diketones react in weakly acidic media as the diketones themselves.236 The synthesis of pyrazoles with various heterocyclic substituents has been liberally covered in the literature.237-259... 

Acetals of /9-keto aldehydes are hydrolyzed in acid media and hence under these conditions they give pyrazoles just as the ketoaldehydes themselves.297-300 Recently the bis-acetal of malondialdehyde has been used extensively for the synthesis of pyrazoles unsubstituted on the ring carbon atoms the reaction yields single products since the bis-acetal is symmetrical.217,271,273,301-307 Cyclization takes place in... 

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