Pyrimidines, Pyrazoles, and Isoxazoles

RECENT ADVANCES IN MICROWAVE-ASSISTED SOLID-PHASE SYNTHESIS 

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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... 

Scheme 8.25. Synthesis of biologically potent pyrimidines, pyrazoles, and isoxazoles.

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>. 

Dicyanoketene ethylene acetal reacts with tertiary amines to give quaternary ammonium inner salts.3 Similarly, it reacts with sulfides to give sulfonium inner salts.3 These products are generally solids that can be used to characterize tertiary amines, and sulfides. Dicyanoketene acetals can be converted to pyrimidines, pyrazoles, or isoxazoles in one step.4... 

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

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

Construction of Isoxazole, Pyrazole and Pyrimidine Rings from Aminopropenones... 

This section is divided into eight subsections, covering imidazoles, pyrazoles, isoxazoles, oxazoles, triazoles, tetrazoles, pyridines, and pyrimidines, purines, and nucleic acid bases respectively. 

It is assumed that the heterocyclic core structure is responsible for the appropriate orientation of the aromatic rings in space and finally for binding to the enzyme. A wide variety of heterocycles can serve as templates, i.e. pyrrole, thiazole, oxazole furane, furanone, imidazole, isoxazole, pyrimidine and thiophene, but at the moment pyrazole and cylopentenone seem to be the most appropriate for achieving COX-2 specificity. For optimal activity, one aromatic ring must be substituted with a methylsulfonyl or a sulfonamide substituent in the para position. Substitution at position 4 of one of the aromatic systems with a sulfonamide or a methylsulfonyl group is essential for COX inhibition. Replacement of the methylsulfonyl group by a sulfonamide group reduces COX-2 selectivity but improves oral bioavailability. 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

Diketones of the selenophene series are used to synthesize various heterocyclic systems isoxazole, pyrazole, and pyrimidine, as well as a-substituted bis-/3-diketones. Thus, /3-diketones with hydrazine hydrates yielded the corresponding disubstituted pyrazoles.130,131 The presence of the selenienyl radical as a substitutent substantially reduced the basicity of a pyrazole ring (see Section V,C) the electron-accepting ability of the selenien-2-yl radical is especially great.121 The reaction of selenophene /3-diketones with ureas gives substituted pyrimidines.125... 

For oxazole and isoxazole, one electron pair on the O is part of the pi system. The other electron pair on the O and the pair on the N is perpendicular to the pi system. Both compounds have six electron in their pi systems and are aromatic. For pyrazole, the pair of electrons on the N that is doubly bonded to the C is not part of the pi system. The pair of electrons on the N that is bonded to the H is part of the pi system. There are six electrons in the pi system, so pyrazole is aromatic. Like pyridine, the electrons on the N s of pyrimidine are not part of the pi system. There are six pi electrons, so pyrimidine is aromatic. 

An extremely simple one-pot synthesis of pyrazoles, pyrimidines, and isoxazoles has been realized by reacting enamino ketones, formed in situ with the appropriate bidentate nucleophile, under the action of microwaves [38]. Another approach to pyrazole from 4-alkoxy-l,l,l-trichloro-3-alken-2-ones and hydrazines, with toluene as solvent, is also possible under microwave conditions [39]. The Ullman coupling of (S)-[l-(3-bromophenyl)ethyl]ethylamine with N-H-containing heteroarenes such as pyrazole in N-methylpyrrolidone afforded the N-arylated compounds in high yields under microwave heating conditions at 198 °C [40]. 

Utilized Pd(OAc)2 and SPhos 24 as the catalyst system to effectively catalyze Suzuki-Miyaura cross-couplings with only 1.1 equiv. of trifluoroborates [84e]. More recently, Molander and coworkers have developed a general cross-coupling system to many classes of heteroaromatic trifluoroborates employing Pd(OAc)2 and RuPhos 23 [84j]. Furan 135, thiophene 132, pyrrole 126, pyrazole 130, isoxazole 131, pyridine 127, pyrimidine 133, indole 129, benzothiophene 136, benzofuran 135, quinoline 128, and isoquinoUne could all be cross-coupled with only 1.04 equiv. of trifluoroborate salts, affording the corresponding cross-coupled products in good yield (Scheme 2.25). 

The sulfonamide 184 is an intermediate in the synthesis of herbicidal N-(pyrimidine aminocarbonyl) thiazolesulfonamides. In addition, several sulfonyl derivatives of isoxazole, pyrazole and thiazole have shown antifungal activity. Benzothiazole 185 is reported to react with chlorosulfonic acid to only give a salt later repetition" of the reaetion with chlorosulfonic acid at both RT and 100 °C confirmed this result. On the other hand, when benzothiazole 185 was heated with excess chlorosulfonic acid (six equivalents) at 150 °C (4i hours), followed by boiling with thionyl chloride (2 hours), the reaction gave the sulfonyl chloride as a gum. Subsequent treatment with amines afforded a mixture of the 4-and 7-sulfonamides 186 and 187 respectively (Equation 49)." ... 

First we consider diacetylene transformations leading to fundamental heterocycles (pyrroles, thiophene, selenophene, tellurophenes, pyrazoles, isoxazoles, pyridines, pyrimidines). Then cyclization reactions involving 1-heterobut-l-en-3-ynes, 4-heterobut-3-en-2-ones, and 4-heterobut-3-yn-2-ones (91UK103 92KGS867 00UK642) as diacetylene equivalents are discussed. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Prior to the discovery of niacin receptors, medicinal chemistry efforts were mainly directed toward small heterocyclic carboxylic acids that are structurally similar to niacin. Systematic study of nitrogen-containing five- and six-membered heterocyclic carboxylic acids revealed that activity at GPR109A was significantly reduced for any of the variants of niacin shown in general structures (A and B) [45,46]. These heterocycles include pyrazole, isoxazole, thiazole, pyrazine, and pyrimidine. 

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