Sydnones pyrazoles

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. 

A-Substituted polypyrazoles can also be obtained by using A-alkylhydrazines, and it should be noted that these polymers consist of a random mixture of head-to-head and head-to-tail structures. Other syntheses of polypyrazoles have been described in the literature. Thus polyphenylene pyrazoles (742) and (743) occurred when m- or p-diethynyl-benzene (DEB) reacted with 1,3-dipoles such as sydnones or bis(nitrilimines) (Scheme 64). 

Tetrazoles (744), as bis(nitrilimine) (745) generators (Section 4.04.3.1.2(ii)), afford polypyrazoles when reacted with diynes. Benzoquinone has also been condensed with bis-sydnones to incorporate a fused pyrazole nucleus (746). 

Photolysis of the triazepine products produces 2,2-dimethylpropanenitrile and the corresponding pyrazole in quantitative yield <1997BSF927>. Reaction of sydnone 89 with fulvene 91 proceeds by [ji4s + jt6s]-cycloaddition followed by spontaneous loss of carbon dioxide and a molecule of dimethylamine or acetic acid from the pseudo-azulene , cyclopentaMpyridazine 92 (Equation 9) <1996CC1011, 1997T9921>. 

Dimethylfulvene 93 also reacts with sydnone 89, albeit sluggishly, to form the dihydrocyclopenta[c]pyrazole 94 after elimination of carbon dioxide and hydrogen (Equation 10). Molecular orbital energies and coefficients of 3-phenylsydnone 89 and fulvenes 91 and 93 have been calculated (PM3-MNDO), but when orbital symmetries... 

The ortfe-directed lithiation protocol allows selective functionalization of 3-arylsydnones in the aryl ring, the C4 position of the sydnone ring, or both simultaneously. The method allows access to fused ring structures (Sections 5.03.5.2.4 and 5.03.7.1.1). Reliable routes to otherwise unknown oxadiazolidines have been established (Section 5.03.9.4). Regiospecificity can now be achieved by judicious choice of substituents when propargylic esters react with sydnones to form pyrazoles (Section 5.03.5.2.6). 

The final products derived from 1 1 addition of sydnones to alkenes are usually pyrazoles or dihydropyrazoles. The pyrazoles are formed by oxidation of intermediate dihydropyrazoles. An unusual example of aromatization by elimination of an alkane (toluene) in prefence to hydrogen is illustrated in Scheme 7 <89TL4625>. 

Isosydnones (146) react with alkynes to give pyrazoles (150). For example, 4,5-diphenylisosydnone (146, R = R = Ph) and ethyl phenyl propiolate gives 4-ethoxycarbonyl-l,3,5-triphenylpyrazole (150, R = R = R = Ph, R = CO Et) identical with the product from 4,5-diphenylsydnone (1, R = R = Ph). The rate of 1,3-cycloaddition for isosydnones (146) is relatively slow in comparison with sydnones (1).2o, 04 number of other cycloaddition reactions of isosydnones with alkenes, alkynes, and carbonyl compounds have been reported. ... 

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. 

Dumitrascu and co-workers (52) transformed 4-halosydnones into 5-halopyr-azoles by cycloaddition with DMAD and methyl propiolate followed by retro-Diels-Alder loss of CO2. Turnbull and co-workers (194) reported that the cycloadditions of 3-phenylsydnone with DMAD and diethyl acetylenedicarboxylate to form pyrazoles can be achieved in supercritical carbon dioxide. Nan ya et al. (195) studied this sydnone in its reaction with 2-methylbenzoquinone to afford the expected isomeric indazole-4,7-diones. Interestingly, Sasaki et al. (196) found that 3-phenylsydnone effects the conversion of l,4-dihydronaphthalene-l,4-imines to isoindoles, presumably by consecutive loss of carbon dioxide and A-phenylpyrazole from the primary cycloadduct. Ranganathan et al. (197-199) studied dipolar cycloadditions with the sydnone 298 derived from A-nitrosoproline (Scheme 10.43). Both acetylenic and olefinic dipolarophiles react with 298. In... 

Destro et al. (201) examined the reactions of several sydnones with triazoles to give pyrazoles, and the stable bicyclic sydnone 302 has been prepared by Storr and co-workers (202). Reaction with DM AD affords the pyrazolothiazole 303. 

Meier and Heimgartner (208) achieved an intramolecular sydnone-alkene cycloaddition to give adduct 306 in 50% yield. Other tether lengths did not so react, but photolysis of these other sydnones led to novel fused pyrazoles via decarboxylation and subsequent cycloadditions from the subsequent nitrile-imines. 

Magnetic criteria have received wide application mainly as a qualitative test for aromaticity and antiaromaticity. The values of the exaltation of diamagnetic susceptibility (in 10-6A cm-3 mol-1), and therefore aromaticity, decrease in the sequence thiazole (17.0) > pyrazole (15.5) > sydnone (14.1). The relative aromaticity of heterocycles with a similar type of heteroatom can be judged from values of the chemical shifts of ring protons. The latter reveals paramagnetic shifts when Tr-electron delocalization is weakened. For example, in the series of isomeric naphthoimidazoles aromaticity decreases in the sequence naphthof 1,2-djimidazole (8 = 7.7-8.7 ppm) > naphtho[2,3- perimidine (8 = 6.1-7.2 ppm). This sequence agrees with other estimates, in particular with energetic criteria. 

Sydnones behave as 1,3-dipolar systems and undergo addition reactions with various dipolarophiles. Huisgen, Grashey, Gotthardt, and Schmidt503,504 were the first to react acetylenic esters with sydnones and obtained pyrazoles e.g., 71 with DMAD (1 hour, 120°, in xylene) gave 99% of the pyrazole 73. These reactions have also been carried out with propiolic and phenylpropiolic esters, and their kinetics have been studied.505... 

Potts806 showed that heating the sydnone precursor 74 with DMAD and acetic anhydride gave the pyrazole 75. 

The reactions of sydnones with acetylenic esters are generally thermally induced concerted processes which are allowed on orbital symmetry considerations.8 On the basis of Huisgen s mechanistic study,805 the conversion of 71 into 73 proceeds through the formation of 72 in a slow rate-determining step, followed by rapid loss of carbon dioxide, giving the pyrazole 73. 

Ollis, and Ramsden520 treated 99, 100 and 101 with neat EPP and obtained the pyrazole 103 and the phenylpropiolic ester dimer 104, but no 105. A comparative study was carried out with phenylacetylene. When 100 was heated with DM AD in dioxane, 25% of the pyrazole 106 was obtained. These authors have concluded that the cycloaddition of alkynes to isosydnones is analogous to that of sydnones but the reactions are slower and the cycloadducts are obtained in lower yields. 

Nitrile imine cycloadditions provide access to pyrazolines and pyrazoles. Intramolecular cyclizations to alkynes were first reported in 1974.88 Perhaps the most useful method for generation of nitrile imines involves 1,3-elimination of hydrogen chloride from an a-chlorohydrazone. Tetrazoles and sydnones are also precursors to nitrile imines. 

The reactions between sydnones (e.g. 26) and unsaturated compounds frequently yield pyrazoles. Pyrazolines are produced by 1,3-dipolar addition to alkenes, and pyrazoles from alkynes.372-374 The cyanopyrazolines formed from a,/3-unsaturated nitriles are immediately converted to pyrazoles.373... 

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