Pyrazoles and Isoxazoles

Resin deprotection Rink amide resin [4-(2 ,4 -dimethoxyphenyl-Fmoc-amino-methyl) phenoxy resin] with a loading of approximately 450pmolg was subjected to repeated washes with 20% piperidine/DMA until no UV absorption due to cleaved dibenzofulvene derivatives was detected in the el-uate. 

Unless otherwise specified, the resin was thoroughly washed by sequential treatments with DMA, DMSO, and iPrOH after each reaction. Previous to each reaction, traces of isopropanol were washed away with the corresponding dry solvent. 

Coupling procedure The NH2 linker group was acylated with a 0.3 m solution of the carboxylic acid reactant 39 in DMA (3 equiv.) at rt (pre-activation for 40 min -with 3.3 equiv. of DIG and 3.3 equiv. of HOBt) until the Kaiser test [81] was negative. 

Claisen condensation Resin 40 (1000 mg, 460 pmol) was suspended in a solution of the requisite carboxylic ester (13.8 mmol, 30 equiv.) in DMA (13.5 mb). Under an inert atmosphere, a 60% dispersion of NaH (180 mg, 4.6 mmol, 10 equiv.) was added and the mixture was well shaken under argon at 80 °C for 1 h. The resulting mixture was filtered, and the resin was washed with 30% (v/v) acetic acid/H20, DMA, DMSO, and iPrOH, and dried in vacuo. A 95 % conversion to the diketone resin 41 was typical. 

Alkylation (optional low-yield step) A 1 m solution of TBAF inTHF (4.5 mb, 4.5 mmol, 10 equiv.) was added to the resin-bound diketone 41 (1.08 g, 0.45 mmol) at rt and the mixture was shaken for 1 h and then treated with allyl bromide (779 pb, 9 mmol, 2 equiv.). The resulting mixture was shaken for a further 2 h, then filtered, and the resin was washed vtith CH2CI2, DMA, DMSO, and iPrOH, and then air-dried to yield the resin-bound 42. Only approximately 40 % conversion was observed at this stage. 

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A number of general reviews related to the topics covered in this chapter have appeared (Table 1) and others will be discussed in the section dealing with synthetic aspects (Section 4.04.3.1). The Sokolov review is particularly noteworthy since it is quite recent and complete, containing 304 references to pyrazoles and isoxazoles. 

The above reactions provide convenient methods for the preparation of poorly understood acetylene derivatives of pyrazole and isoxazole. 

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 effect of the nature of the substituent at the acetylene bond is not so noticeable. Substitution reduces the C-3 activity due to polarization effects and steric factors. As aresult, in the cyclization with hydrazines and hydroxylamines an increase in the content of 5-substituted pyrazoles and isoxazoles is observed (81UK1252). As mentioned above, nonsymmetiic nitrogen-containing binucleophiles H2N—YH (Y = O, NMe, NPh) react with l-heteroalk-l-en-3-ynes in two alternative pathways by functions H2N and YH. 

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...

Fig. 16 Microwave-promoted route to pyrazoles and isoxazoles via resin-bound propenones. Reagents and conditions a DMF, MW 150 °C, 10 min, closed vessel b Ph-NH-NH2, AcOH, MW 180 °C, 10min, closed vessel c HO-NH2, AcOH, MW 180 °C, 10min, closed vessel...

The resin-bound reagents thus obtained were reacted with a variety of nucleophiles to give different heterocycles (Scheme 13). So, reaction with hydrazine or hydroxylamine gave respectively pyrazoles and isoxazoles in excellent yields (94-99%, 34 examples) and excellent purities (> 95%). Reaction with guanidines afforded 2-aminopyrimidines. 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

JME696>. Construction of the five-membered ring is also the key step in the synthesis of the pyrazole- and isoxazole-fused pyridopyrimidines 470 (Equation 198) <2004HC089>. 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

The 1,2,4-oxadiazole dioxolanes 144 react with hydroxylamine and hydrazines to form the 5-pyrazole- and isoxazole-substituted 1,2,4-oxadiazoles 146 via the dioxolane ring-opened intermediates 145 (Scheme 17). Reaction of compounds 144 with amidine or guanidine salts allows access to pyrimidine substituted analogues 147, via intermediate 145 (X = C(NH)R1), albeit in lower yield <1996JHC1943, 1998JHC161>. 

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

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

Rj, R2 = atKyt or u-aacyi (see pyrazole and isoxazole synthesis. Chapter 4, and pyrimidine synthesis, Chapter 10)... 

Condensation of 1,3-diketones with hydrazines or hydroxyamines was conducted in a microflow system to give pyrazoles and isoxazoles in good yields [22]. High-throughput synthesis of pyrrole by the Paal-Knorr condensation of ethanolamine and acetonylacetone was achieved using the CPC CYTOS Lab System [23], The running of the system for 165 min resulted in 714 g of the pyrrole (Scheme 4.14). 

Marzinzik AL, Felder ER, Solid support synthesis of highly functionalized pyrazoles and isoxazoles scaffolds for molecular diversity, Tetrahedron Lett., 37 1003-1006, 1996. 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

Pellegrino G, Leonetti F et al (2010) Solid phase synthesis of a molecular library of pyrimidines, pyrazoles, and isoxazoles with biological potential. Tetrahedron Lett 51 1702-1705... 

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