Pyrazoles, mesoionic

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 chemical behaviour of the mesoionic pyrazole (459) has been studied by Boyd et al (74JCS(P1)1028). Protonation and alkylation take place on the exocyclic nitrogen atom and a thermal rearrangement of a methyl group is observed when (459) is boiled in benzonitrile for several hours giving (460). 

Diazoalkanes add to the carbon-carbon double bonds of 2,3-diphenylthiirene 1-oxide and 1,1-dioxide. The adducts lose SO or SO2 to give pyrazoles and related compounds (Scheme 103) (80CB1632). Mesoionic oxazolones (75CLH53), 4-methyl-5-phenyl-l,2-dithiolene-3-thione (80JOU395) and pyrylium betaines (72JOC3838) react similarly via intermediate adducts (Scheme 104). Enamines (Scheme 96) and ynamines add to the double bond of 2,3-diarylthiirene 1,1-dioxides to give acyclic and cyclic sulfones by a thermal. 

Methyl 3-acyl-l-diphenylmethyleneamino-4,5-dioxo-4,5-dihydro-l//-pyrrole-2-carboxylates 489 are formed from 488 and oxalyl chloride in good yields. Preparative thermolysis of these compounds at 130-140°C gives mixtures of dipyrazolo[l,2- l,2- [l,2,4,5]tetrazines 491 as major products and pyrazoles 492 as minor hydrolytic by-products. The intermediacy of mesoionic compound 490 is expected (Scheme 83) <2004T5319>. 

Reaction of PTAD with a-angelica lactone gives the pyrazolotriazole 97 via an acyl ene reaction,152 and reaction with 4,4-diethyl-3,5-dimethyl-4//-pyrazole 2-oxide gives 98 after heating.153 A mesoionic bicyclic system 99 is proposed as a product from the reaction of DEAZD with triethylborane.154... 

The mesoionic compound prepared from L-Pro (83TL1067) reacts with acetylenic compounds to give pyrrolo[l,2-a]pyrazoles after extrusion of carbon dioxide ( Scheme 47). With phenylpropiolic acid, the natural product withasomnine (a) was formed in low yield (7%) together with its regioisomer (b, 5%) (85TL5739). 

A convienient route to pyrazolo[l,5-t/]-l,2,4-triazines utilizing pyrazol-5-carbohydrazide (128) has been reported (55JA1148). Thus, 128 R = H, afforded pyrazolo[l,5-cTl-l,2,4-triazine (131) on treatment with orthoesters, probably via acyclic intermediate 130. Treatment of 128 with orthoesters afforded mesoionic 129 (Scheme 17) (80JHC1291). Treatment of 4-ribosylpyrazol-5-aldehyde ethoxycarbonylhydrazone with cesium carbonate afforded C-ribosylpyrazolo[l,5-cf -l,2,4-triazin-4-one (83MI1). 

Another nonclassical heterocycle, thienol3,4-cJpyrazole, was synthesized, utilizing the ability of mesoionic ring systems to act as 1,3 dipoles in cycloadditions. Condensation of IV-phenylsydnone (162) with dibenzoylacetylene formed 3,4-dibenzoyl-1-phenylpyrazole (163) (85%) with phosphorus pentasulfide in refluxing pyridine, this gave 85% of 2,4,6-triphenyIthieno[3,4-c]pyrazole (164) [Eq. (44)]. The synthesis of 5-methyl-l,3,4,6-tetraphenylthieno[3,4-c]pyrrole is also described. ... 

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. 

Two closely related mesoionic systems, 59 and 60, were obtained by reductive cyclization of 61 with TEP,62 and by oxidation of 62 with lead tetraacetate,63 respectively. The pyrazolo[4,3-c]pyrazole 64 was obtained from the azo compound 63 by reduction with dithionite, followed by diazotization of the resultant amine and cyclization with... 

Thermal dimerization of several arylazoethynylarenes in cyclohexane gave mesoionic pyrazolo[4,3-c]pyrazoles (116) in fair yield. The structure of one product 116 (Ar1 = Ph Ar2 = p-ClC6H4) was supported by thermal degradation (500°) to cr-(p-chlorophenylimino)-phenylacetonitrile and hydrogenation to give two iV-arylpyrazoles.115... 

The mesoionic pyrazoles 116 and 117123 on heating with DMAD yield the pyrazolium fumaric esters 118 and 119 with concomitant loss of a methyl group.124... 

Huisgen, Gotthardt, and Grashey518 have shown that 4,5-diphenyl-isosydnone (99) reacts with EPP in p-cymene at 150° giving the corresponding pyrazole ester (103) in 53% yield. Ohtaand Kato have stated 519 that these mesoionic-l,3,4-oxadiazoles do not react with dialkyl acetylenedicarboxylates either thermally or photochemically. McCarthy,... 

Substituted derivatives. The 4-substituted analogues can in principle exist as two uncharged tautomeric forms 270 and 271 and as the type B mesoionic tautomer 272. All the evidence shows that these compounds exist predominantly as the NH2, OH, or SH tautomers 270. The equilibrium between the pyrazole 273 and the mesoionic tautomer 274 has been shown to favor the hydroxypyrazole 273 strongly (AG 6.15 kcal mol-1) <1972T463>. 

From a qualitative viewpoint there is no doubt that the compounds classified as aromatic in Section 4.04.1.1 (pyrazoles, indazoles, isoindazoles, pyrazolones, indazolones, mesoionic derivatives) indeed have aromatic properties to a greater or lesser extent. Dihy-drobenz[cd]indazole (115) is also formally an aromatic compound since it has an odd number of electron pairs (n =7). However, due to the presence of two adjacent nitrogen atoms the aromatic tautomer (115a) is not stable, and the compound exists as the 1,5- or 1,3-dihydro tautomers (115b) or (115c) <72JCS(P2)68). The antiaromatic benz[cd]indazole (116), although unstable, has been fully characterized by N, H and NMR spectroscopy... 

Dithiolium salts react with hydrazines similarly to amines, but further cyclization gives pyrazoles (46) or pyrazolium salts (47). When there are replaceable substituents, hydrazones and azines are formed. A mesoionic l,2-dithiole-3-olate (20 R = Ph) reacts similarly at C(3) with aniline, but with eventual formation of the products (48) and (49) <87CJC2830,92T8127). The reaction... 

---