Mesoionic heterocycles

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]. 

For NO-release from these compounds it is essential that they decompose easily, either spontaneously or after enzymatic cleavage of stabilizing substituents at the imino group, to nitrosohydrazine intermediates that represent the real NO-precursors. 

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Lakner et al. carried out studies on new mesoionic heterocyclic structures <2005TL5325> (Scheme 6). These authors found that although the salt 68 is stable at 100-120 °C (in dimethyl sulfoxide (DMSO)) in the presence of various amines, it easily undergoes ring opening upon microwave irradiation under the same reaction conditions to yield amides 69. 

Since the nomenclature and classihcation of mesoionic heterocyclic ring systems has been adequately presented by Potts (1), and has been discussed further by Ollis et al. (2), these topics will not be repeated here. 

While this section ostensibly deals only with the new syntheses of mesoionic heterocycles, it is appropriate in some cases to include the accompanying 1,3-dipolar cycloaddition reactions reported by the authors. 

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

The original synthesis of thiomiinchnones (4) (l,3-oxathiohum-5-olates) (53-55), which involves the cyclodehydration of an (5)-acylthioglycolic acid, was used by (jribble and co-workers (56) to generate 2,4-diphenylthiomiinchnone (94) and trap it with 1,5-cyclooctadiene in a tandem 1,3-dipolar cycloaddition sequence to afford sulfide 95 (Scheme 10.16). Apart from this one report, this mesoionic heterocycle has received no attention since the review by Potts (1). 

Somewhat earlier, Souizi and Roberts (63) reported mesoionic heterocycle interconversions leading to l,3-thiazolLum-4-thiolates, l,3-thiazolium-4-olates, and l,3-dithiolium-4-thiolates from l,3-dithiolium-4-olates. This elegant chemistry, which involves cycloaddition reactions, is presented in Section 10.3.8. 

The first synthesis of 1,3-dioxolium-4-olates (here defined as oxamiinchnones) was reported in 1980 by Berk et al. (64) but it was work of Hamaguchi and Nagai (65,66) that demonstrated the accessibility and utility of these new mesoionic heterocycles in cycloaddition reactions. Thus, reaction of diazoacetic benzoic anhydrides 108 with a 7t-allyl palladium complex affords oxamiinchnones 109. 

Subsequent trapping with DMAD affords the expected furan 110 in excellent yield (65) (Scheme 10.20). Additional chemistry of this novel mesoionic heterocycle is presented in Section 10.2.7. 

The statement made in 1986 by Gingrich and Baum (10), with regard to miinchnones, that the most important reactions (of mtinchnones) from a synthetic point of view are 1,3-dipolar cycloaddition reactions, certainly applies to all mesoionic heterocycles and is more true today than it was in 1986. Although the factors governing the regioselectivity of unsymmetrical mesoionic cycloadditions are not always completely understood, the synthetic utility of this chemistry is enormous and indisputable. 

As we have seen in previous discussions, DMAD is a powerful and reliable dipolarophile that is routinely used to trap mesoionic heterocycles. If DMAD is unable to ambush a suspected mesoionic heterocycle, then the latter most probably has not been generated ... 

Kato et al. (119) explored reactions of fulvenes with a variety of mesoionic heterocycles. Unfortunately, reactions of miinchnone 38 with several fulvenes afforded complex mixtures in each case, and no identifiable products were reported, although Friedrichsen and co-workers (120-122) previously reported the reaction between mtinchnones and fulvenes to give cycloadducts. Kato et al. (123) also studied the cycloaddition reactions of tropone with several mesoionic heterocycles. Despite heroic efforts, the reaction of tropone with miinchnone 38 was complex and could not be unraveled. However, as described later, the reaction of tropone with isomtlnchnones was successful. Wu et al. (124) effected the cycloaddition between a miinchnone and fullerene-60 (Ceo) to give the corresponding dihydropyrrole in excellent yield. 

Kato et al. (123) also found that isomtinchnone 51a reacts with tropone (251) to afford 252, which is apparently the hrst example of a [47i+6ti] cycloadduct involving both a mesoionic heterocycle and a carbonyl ylide (Scheme 10.34). The one-pot reaction of 253 gave 252 in somewhat higher yield. Whereas heating the latter in bromobenzene affords o-benzoylmandelanilide (69%), heating 252 in refluxing toluene in the presence of DMAD leads to furan 254. 

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. 

Cavalleri et al. (219) studied the cycloaddition of thioisomiinchnones with 5-amino-4-methylene-l,2,3-triazolines. The resulting cycloadducts afford 2-pyridones with Raney Ni or 8-thia-6-azabicyclo[3.2.1]octanes with acid. Kato has continued his extensive exploration of cycloaddition studies of mesoionic heterocycles with atypical dipolarophiles. Thus, whereas thioisomiinchnone (320) gave a complex mixture with 6,6-dimethylfulvene (119), it reacted with 2-tert-butyl-6,6-dimethylfulvene to afford 321 in 17% yield (151,152). The cycloaddition of 320 with benzocyclobutadiene was much cleaner to give 322 in 70% yield (114). 

Regitz and co-workers (140,142) continued their exploration of the chemistry of mesoionic heterocycles with phosphaalkynes. Thus, 339 (R = R =Ph) reacts with tert-butyl- and mesitylphosphaacetylene to give 1,3-thiaphospholes (346). This same 2,5-diphenyl-l,3-dithiolium-4-olate reacts with 2,3,4-tri-tert-butylazete to give 347 in low yield (143). This reaction is believed to proceed via diphenylthiir-ene by loss of carbonyl sulfide from 339. 

Robert and co-workers (239,240) discovered novel conversions of 2-amino-1,3-dithiolium-4-olates (348) into other mesoionic heterocycles. For example, reaction of 348 with carbon disulfide, phenyl isocyanate, or phenyl isothiocyanate affords l,3-dithiolium-4-thiolates (349), l,3-thiazolium-4-olates (350), and 1,3-thiazolium-4-thiolates (351), respectively. Some of these reactions proceed via the ring-opened ketene tautomer of 348 (240). 

The 1,3-dipolar cycloaddition reactions of several other mesoionic heterocycles have been investigated since Potts review (1). Kato et al. (113,114,123) found that the l,3-thiazohum-5-olate (358) ring system affords low yields or complex reaction mixtures with benzocyclopropene (113), benzocyclobutadiene (114), and tropone (123). Likewise, Vedejs and Wilde (209) isolated in low yields a cycloadduct of 358d with thiopivaldehyde, along with a ring-opened thiamide. Also, 1,3-thiazo-lium-5-olate 359 reacts with thiopivaldehyde to give 360 (209). 

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-... 

The mesoionic heterocycles called munchnones function as cyclic azomethine ylides in cycloaddition reactions.63 The alkenyl moiety can be attached at carbon or at nitrogen. 

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