Sydnones, mesoionic

Enamines and enolate anions react with benzofuroxan to give quinoxaline di-A -oxides (Scheme 38) (69AHC(10)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275) (76AHC(19)l), and from (276) the intermediate adduct (277) can be isolated (73JA8452). This is one of the few instances in which such primary cycloadducts have been isolated in the oxazole series of mesoionic compounds. 

Substitution of the nitrogen atom in (289) and subsequent ring closure of (293) under acid cyclodehydration conditions gave the mesoionic system anhydro-5-hydroxythiazoIium hydroxide (294). These reactions are analogous to the cyclodehydration of the A-nitrosogly-cines (295) with acetic anhydride to give the sydnones (296) (see Chapter 4.21). 

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 term mesoionic was suggested originally to describe compounds of the sydnone (129) or sydnone imine (130) type (49JCS307, 50JCS1542). Since then this term has been applied somewhat indiscriminately to a variety of heterocyclic molecules which can be represented formally as zwitterions. The original, rather restrictive definition put forward by Baker and Ollis (55CI(L)910) was later made even more so by Ollis and Ramsden (76AHC(19)1), and it is this most recent definition which now appears to be the most useful. 

Finally, a mesoionic sydnone, molsidomine (88), is active as an anti anginal agent. Its synthesis starts by reacting 1-aminomorpholine with formaldehyde and hydrogen cyanide to give 86. Nitrosation gives the N-nitroso analogue (86) which... 

Synthesis of the first mesoionic nematic and smectic A liquid crystals derived from sydnones has been described and their self-organization into liquid crystal phases has been studied by optical, calorimetric, and powder X-ray diffraction methods <2005CC1552>. 

The mesoionic compounds are represented by structures that cannot be properly described by Lewis forms not involving charge separation. Typical examples are the sydnones 80 the first example was obtained at the University of Sydney by the action of acetic anhydride on N-nitrosophenylglycine [75]. They were consequently named after the Australian town [76]. These structures are best approximated as resonance hybrids. They can be represented by any contributing mesomeric structure a, b, c or by the general structure d. 

Some mesoionic heterocycles, structurally correlated to the sydnones and represented by a general 5-membered ring molecule that contains the NO-moiety, behave as NO-donors. They include sydnonimines 81 and mesoionic 1,2,3,4-oxatriazolium derivatives 82 and 83. The latter will be named 3-R-l,2,3,4-oxatriazolium-5-olates (82) and S-R-l S -oxatriazolium-S-Rj-amenates (83) [77]. 

Phenylsydnone is the prototype of that class of mesoionic compounds called sydnones. On acidic hydrolysis it produces phenylhydrazine, whereas basic hydrolysis regenerates N-nitroso-N-phenylglycine. This sydnone undergoes a variety of electrophilic substitutions, including mercuration and... 

The chemistry of the 1,2,3-oxadiazole ring system is confined almost entirely to the mesoionic sydnones and related compounds. Sydnones are sensitive to hydrolysis, especially in basic media where they are rapidly cleaved. Nevertheless a range of useful reactions of sydnones, involving both ring cleavage and substitution with retention of the ring system, is known. Many of the publications that have appeared in the period 1982-1995 represent modifications or extensions to known reactions of sydnones. The subjects covered include the following. 

Electric dipole moment studies have provided excellent support for the formulation of certain heterocycles as mesoionic compounds. Hanley et al. <78JCS(P1)600> have measured dipole moments for mesoionic l,2,3,4-thiatriazol-5-imines (20), 5-ones (21) and 5-ylidenemalononitriles (22) using a vector analysis similar to that previously employed for sydnones and other mesoionic compounds assuming that mesoionic rings are regular pentagons. The dipole moment of 3-phenyl-1,2,3,4-thiatriazolium-5-anilide (20) was found to be 3.71 D and five derivatives of compounds (21) were measured and the ring moment calculated to be 3.8 D. In both cases the dipole moments are rather small but clearly consistent with the mesoionic formulation. 3-Phenyl-l,2,3,4-thiatriazolium-5-dicyanomethanide (22) was found to have a dipole moment of 8.84 D. 

The classical synthesis of mesoionic 1,2,3-oxadiazohum-5-olates (3), the so-called sydnones , by Earl and Mackney (42), involving the cyclodehydration of an N-nitrosoglycine derivative, continues to be the only viable method for their preparation. However, Turnbull and co-worker (43) reported that the use of neutral nitrosation conditions avoids the formation of C-nitrosation and allows for the synthesis of previously inaccessible 3-arylsydnones, such as 3-(2-acetylphenyl) sydnone. The method is illustrated below. 

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 much older reaction of N-nitroso a-aminoacids is their cycli-zation to the mesoionic sydnones (39 0a l 2) more recently, N-nitroso a-aminonitriles have been cyclized to the corresponding sydnone imines (U0, l, 2,43) ... 

Mesoionic compounds have been known for many years and have been extensively utilized as substrates in 1,3-dipolar cycloadditions.158-160 Of the known mesoionic heterocycles, munchnones and sydnones have generated the most interest in recent years. These heterocyclic dipoles contain a mesoionic aromatic system i.e. 206) which can only be depicted with polar resonance structures.158 Although sydnones were extensively investigated after their initial discoveiy in 1935,160 their 1,3-dipolar character was not recognized until the azomethine imine system was spotted in the middle structure of (206). C-Methyl-N-phenylsydnone (206) combines with ethyl phenylpropiolate to give the tetrasub-... 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

The mesoionic compounds known as sydnones serve as cyclic azomethine imines. Thus, sydnone (167), isolable after preparation from die corresponding nitrosamine, underwent cyclization as an azomethine imine at 20-35 C (Scheme 52).86 Photolysis of sydnones also results in cyclization but through nitrile imine intermediates vide infra). 

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