Sydnone synthesis

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. 

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 standard synthesis of sydnones (Section 5.03.9.2) has benefited from the use of A,./V,iV, iV -tetrabromobenzene-1,3-disulfonamide (TBBDS) as an efficient promoter of the one-pot conversion of various iV-arylglycines to sydnone products <2006H(68)2343>. Conversion of A-arylglycines to sydnones was achieved in 85 to 95% yield using a combination of NaN02 and AczO in CH2C12 promoted by TBBDS, under mild and neutral conditions. 

An interesting variation of this quinoxaline synthesis is outlined by the synthesis of sydnoquinoxalines shown in Scheme 103. The starting material is phenylsydnone 288 with an iminophosphorane group in an o-position. With isocyanate or isothiocyanate carbodiimide intermediates 289 are formed by an electrophilic aromatic substitution at the sydnone ring (4 position), the 4-(arylamino)sydno[3,4-a]quinoxalines (290) are obtained (91S745). 

The addition to alkenes normally leads to unstable adducts that lose carbon dioxide under the reaction conditions. The intramolecular cycloaddition of the sydnone (30) takes place at room temperature, however (Equation (5)) and the cycloadduct (31) has been characterized <86HCA927>. The unstable species formed by the loss of carbon dioxide are also azomethine ylides. It is therefore possible for a second 1,3-dipolar addition to take place, as illustrated in Scheme 6 for the reaction of 3-phenylsydnone with Al-phenylmaleimide <86TL317,92JA8414>. This 2 1 addition has been used as the basis of a synthesis of polyimides. Imides of the type (32) were used as the dipolarophiles and their reaction with 3-phenylsydnone gave linear polymers <87MM726>. 

The use of sydnones for the synthesis of polyimides is referred to in Section 4.03.5.2.6. 3-Methylsydnone has been used as a polar, water-miscible solvent for electrolytes <84CL1477>. 

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. 

The standard route to sydnones is the cyclodehydration of iV-nitroso-P-amino acids. 2-Chloro-4,5-dihydro-13-dimethylimidazolium chloride 97 has been shown to be an excellent reagent for this conversion, as, for example, in the synthesis of 3-phenylsydnone 98 <99JOC6989>. Functional group manipulations of fused sydnones have led to the isolation of several new compounds including 99 and 100 <99H(51)1433>. 4-Acetylsydnones react with hydrazine at room temperature to give 2,4-dihydropyrazol-3-ones 101 <99H(51)95>. ... 

Dipolar cycloaddition of sydnones with 1-aryl-3,3,3-trifluoropropynes is a general synthesis of 4-trifluoromethylpyrazoles (93JHC365). 

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... 

This type of preparation of 1,2-diazepines has been reported earlier involving the dipolar cycloaddition of sydnones with benzocyclobutene <1996CHEC-II(9)113>. This method could be further exploited by the use of the correct hydrazone derivative (1,3-electrophile, nucleophile) with a,/3-unsaturated ketone (1,4-electrophile, nucleophile) for the synthesis of 1,2-diazepines. 

Dihydrodiazepines can also be obtained in the reactions with unsaturated ketones if one of the amino groups of the diamine in the heterocycle is endocyclic (e.g., amine 37, Scheme 4.11) [48]. This reaction is achieved under rather severe conditions (long-duration heating in dimethylformamide). An interesting case using sydnones 40 in the synthesis of 1,5-dihydrodiazepines 41 was described by Kavali and Badami [49] (Scheme 4.12). 

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