Mesoionic compounds, and

In connection with these results, and as an extension of their studies toward the reactivity of new bicyclic mesoionic compounds and their usefulness in the synthesis of condensed heterocycles, they further reported the stereoselective synthesis of spiro-(3-lactams 153, 154 (Scheme 36) by reactions of imines with mesoionic compounds or ketenes generated from A-acyl-thiozolidine-2-carboxylic acids 152 [110]. 

This review has attempted to highlight the bio active mesoionic compounds and stimulate further development in this field. Mesoionic compounds are still considered as exotic structures even within the field of heterocyclic chemistry. Much attention has been directed toward the syd-nones (2), sydnonimines (3), l,2,3,4-oxatriazolium-5-aminates (9), and 1,3,4-thiadiazolium-2-aminates (7). In particular, their properties as NO-releasing compounds have been of interest. 

Cycloaddition reactions of the C(3)=N bond of azirines are common (Scheme 45) <71AHC(13)45, B-83MI 101-03,84CHEC-I(7)47>. Azirines can participate in [4 + 2] cycloadditions with dienes including cyclopentadienones, isobenzofurans, triazines, and tetrazines. They also participate in 1,3-dipolar cycloadditions with azomethine ylides, nitrile oxides, mesoionic compounds, and diazomethane. Cycloadditions with heterocumulenes, benzyne, and carbenes are known. Azirines also participate in other pericyclic reactions, such as ene reactions. 

B. Mesoionic Compounds and Heterocycles without a Formal Diene System.. 210... 

One-bond carbon-nitrogen couplings, Dcn of ca. 3 Hz have been measured by Kelemen et aU for a series of labelled alkoxyamines, the model compounds for nitroxide-trapping studies in free radical copolymerization. Absolute Dcn values have been obtained for some mesoionic compounds and related structures by Jazwinski and Staszewska-Krajewska. " ... 

Until very recently, it has not been recognized that the tautomerism of suitable mesomeric betaines is a source of NHCs. l,2,4-Triazolium-3-aminide 48 is a mesoionic compound and it has been used as analytical reagent for the detection of nitrate anions for a period of almost 100 years ( nitron, Busch s reagent) (1905CB861), before it was realized that nitron is in equilibrium with its NHC (Scheme 13). Numerous trapping reactions of the latter have been carried out (2012CC227). Rhodium complexes 49 were prepared, as well as thione formations and trapping reactions with carbon disulfide. 

Desmotropy of some five-, six-, and seven-membered heterocyclic rings and of some important pharmaceutical compounds and tautomeric equilibria of heterocyclic carbenes with mesoionic compounds and ylides are described. 

The thiazolyl-2-thioglycollic acid (119) undergoes intramolecular ring closure to give mesoionic compound 120 under treatment with acetic anhydride and triethylamine (Scheme 60) (192). The parent acid (119) can be recovered from 120 by hydration with hot 50% aqueous sulfuric add. Compound 120 affords monohydrate of bis(-cyclopentenothiazolyi-2-thio)acetone (121) (192). 

The 4-Hydroxy-thiazoles are characterized by infrared absorption near 1610 cm (KBr) (3) or 1620 to 16.S0cm (CCI4) (8), indicating a strongly polarized carbonyl group. H-5 resonates near 5.6 ppm in the NMR spectrum like similar protons in other mesoionic compounds (3). Two fragmentations of the molecular ion are observed in the mass spectra. The first involves rupture of the 1,2 and 3,4 bonds with loss of C2R 0S . In the second, the 1,5 and 3,4 bonds are cleaved with elimination of C2R 0. ... 

Mesoionic compounds undergo a variety of photochemical fragmentations. Examples are shown in which CO2 or PhNCO is extruded (Schemes 3 and 4, respectively) (76AHC(i9)l). 

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. 

The mesoionic compounds are derived from pyrazolium salts (22) when R is replaced by a negatively charged heteroatom, like the anhydro-4-hydroxypyrazolium hydroxide (28). According to Ollis and Ramsden (76AHC(l9)l) they belong to the mesoionic class B type. 

The mesoionic compound 3-phenylsydnone (10) (see Houben-Weyl, Vol. E8c, p 398ff) reacts with benzocyclobutadiene (9), generated by the action of zinc on /ra x-l, 2-dibrotno-l, 2-dihy-drobenzocyclobutadiene(8), to give 3-phenyl-3//-2,3-benzodiazepine(13). The process involves sequential 1,3-dipolar cycloaddition to give 11, decarboxylation to 12 and, finally, valence... 

The reaction of N-amino heterocycles 759 and 760 with diaryl carbodii-mide gave triazolotriazine 761 in good yield. In some cases the intermediate guanidines are isolated which by thermal or basic treatment cyclized (86H3363 89H1607) to neutral or mesoionic compounds. 

Non-enolizable imines such as 9-fluorene imines react with alkynylcarbene complexes to afford mixtures of mesoionic pyrrolium carbonyltungstates and dihydropyrrole derivatives [68] (Scheme 23). Although both compounds can be considered as [3C+2S] cycloadducts, formation of each of them follows a very different pathway. However, the first intermediate of the reaction is common for both compounds and supposes the conjugated addition of the imine to the alkynylcarbene complex to form a zwitterionic intermediate. A cyclisation... 

Tetrazolium ylides are quite reactive and are easily alkylated.168 The mesoionic tetrazolium thiolate 117 readily adds bromine to yield 174 which can then react with a number of active methylene compounds to give mesoionic compounds, e.g., 175.293,294 They also undergo 1,3-dipolar cycloaddition with olefins and acetylenes to yield bicyclic tetrazolo-thiazolines... 

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>. 

The mesoionic compound 78 adds to both PTAD and DEAZD as a 1,3-dipole to give 79 and 80, respectively, in high yield. The DEAZD adduct can be converted into 2,5-diphenyl-1,3,4-thiadiazole (Scheme 8).129... 

The mesoionic tetrazole dehydrodithizone is transformed by iron penta-carbonyl into 4-phenyl-2-phenylazo-A2-l,3,4-thiadiazolin-5-one, presumably by a mechanism of ring opening, complexation, carbonyl insertion and subsequent ring closure (Scheme 128).193 Unfortunately, analogous processes do not occur on other mesoionic compounds in the 1,2,3-oxadiazole, s-triazole or tetrazole series, and the scope of this unusual carbonylation is probably limited. 

Methyl- and 3-ethylsydnone have been used as aprotic solvents for electrolytes <2000MI20, 2002MI334>, whereas 3-phenylsydnone has been employed as a filter for recording the absorption spectra and refractive indexes of polymer films containing other mesoionic compounds <2002MI2290>. 

Benzothiadiazoles 3 have been extensively studied. Fully aromatic mesoionic compounds such as 4 continue to be synthesized. A number of examples of 4,5-dihydro-l,2,3-thiadiazole derivatives such as compound 5 <1993JOC82> and more recently the phenyl derivative 6 <2003RJ01501> have been reported. The corresponding 2,3-dihydro-l,2,3-thiadiazoles have also been reported and Hurd and Mori reported the N-Z phenylsulfonyl derivative 7. The electron spin... 

There are several examples of alkyl halides reacting with 1,2,3-thiadiazoles at nitrogen to yield either salts or mesoionic compounds <1996CHEC-II(4)289>. Similarly, with Meerwein s reagent, several substituted thiadiazoles yielded various 2- and 3-methylated 1,2,3-thiadiazoles (Scheme 4 Table 8) <1993JHC301>. The isomer ratios were determined by integrating the methyl singlets in the H NMR spectra and the compounds were further studied by 1SN NMR spectroscopy (Section 5.07.3.4). 

Mesoionic compounds (Section 5.07.1.3) are fully aromatic and usually have an exocyclic heteroatom bearing a charge attached to the ring. A new one-step method for converting the exocyclic oxygen of 3-phenyl-l,2,3-thiadiazolium-5-olate 52 into the exocyclic sulfur of 3-phenyl-l,2,3-thiadiazolium-5-thiolate 53 makes use of Lawesson s reagent (Equation 14) <1988BCJ2977>. 

Contrasting with the reported formation of fused [l,3,4]thiadiazole rings in the course of the reaction of 3-substituted-4-amino-5-thio-47/-[l,2,4]triazoles 83 with various isothiocyanates (cf. Section 11.07.8.3, Table 3), the reactions with methyl isothiocyanate and with phenylisocyanate afford 3,7-disubstituted-6,7-dihydro-57/-[l,2,4]triazolo[4,3-f] [l,2,4]triazole-6-thiones 110 and -triazole-6-ones 111, respectively (Equation 29) <1986MI607, 1992IJB167>.The same reaction of 4-amino-l-methyl-3,5-bis(methylthio)[l,2,4]triazolium iodide 112 with aryl isothiocyanates yields the mesoionic compounds 113 (Equation 30) <1984TL5427, 1986T2121>. 

The mesoionic compound 41 was further used in a reaction with dimethyl acetylene dicarboxylate (DMAD) to produce a nine-membered cycloadduct 44 which is formed by a reaction cascade of double addition of the alkyne and transannular ring opening of the intermediate 43 (Scheme 7) <20030BC978>. 

The nucleophilic addition of the mesoionic compound 41 was further investigated upon addition to arynes <20030BC978> (Scheme 8). In this case the process stops at a single addition of the anion to the aryne to form 45 and workup under aqueous conditions led to the formation of the tetrazolium-5-olate 46. 

In the course of investigation of reactivity of the mesoionic compound 44 (Scheme 2) the question arose if this bicyclic system participates in Diels-Alder reactions as an electron-rich or an electron-poor component <1999T13703>. The energy level of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were calculated by PM3 method. Comparison of these values with those of two different dienophiles (dimethyl acetylenedicarboxylate (DMAD) and 1,1-diethylamino-l-propyne) suggested that a faster cycloaddition can be expected with the electron-rich ynamine, that is, the Diels-Alder reaction of inverse electron demand is preferred. The experimental results seemed to support this assumption. 

Huckel s 4n+2 //-electron rule is a necessary but not a sufficient condition for aromaticity. Coplanarity and electronegativity restrictions of constituent atoms represent the most important restrictions. Phos-phole is a marginally aromatic five-membered heterocycle76 (see further examples and discussion). Mesoionic compounds, mesomeric betaines, and 2H-and 4i+-pyrone have all been considered to be weakly aromatic or non-aromatic, though their conjugated acids are aromatic. Spectroscopic data evidenced the aromaticity of dioxolium and oxathiolium cations 59 (Scheme 28) and mesoionic oxathioles not in the classical sense but by their ring currents and chemical stability.77... 

The reaction of tetrahydro-l,3-thiazine-2-thione and diethyl 2-chloro-malonate in the presence of triethylamine in boiling methylene chloride for 1.5 hr gave tetrahydro-1,3-thiazin-2-ylidenemalonate (508) in 33% yield via 507 through Eschenmoser sulfur elimination, together with traces of the mesoionic derivative (509) [77JCS(P 1) 1107]. In a similar reaction, diethyl 2-bromomalonate afforded the mesoionic compound (509) in 80% yield. Tetrahydro-l,3-thiazin-2-ylidenemalonate (508) was also obtained in 42% yield from 509 by irradiation in the presence of tributylphosphine in ethanol for 15 hr under argon [77JCS(P1)1107]. 

A mesoionic compound PR-G-138-C1 (XXXIX) from Pharma Research in Canada is reported to lower blood pressure in man at low doses by a vasodilator type mechanism (43). This structure is related to SIN-10 (XL) which was reported earlier by Japanese scientists as active in dogs (44). Compounds related to structure XXXIX were compared in spontaneous hypertensive rats and those with the oxadiazole ring hydrogen replaced by chlorine or bromine were as active as the parent compound, although replacement by methyl caused a loss of activity (45). 

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