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The State of Art in Sydnones Chemistry and Applications ACADEMIA ROMÂNĂ Rev. Roum. Chim., Revue Roumaine de Chimie 2017, 62(10), 711-734 http://web.icf.ro/rrch/ REVIEW THE STATE OF ART IN SYDNONES CHEMISTRY AND APPLICATIONS Florin ALBOTAa and Michaela Dina STANESCU b, * a ”C.D. Nenitzescu” Centre of Organic Chemistry of Roumanian Academy, 202B Spl. Independentei, Bucharest, Roumania b ”C.D. Nenitzescu” Department of Organic Chemistry, University POLITEHNICA, Polizu 1, Bucharest, Roumania Received November 16, 2016 Sydnones are mesoionic stable compounds firstly synthesized more than 80 years ago. Their aromatic behavior as well as their property to give 1,3-cycloaddition reactions make these compounds a valuable tool for the synthesis of new heterocycles having complex structures. The bioactivity of numerous sydnones, or the heterocycles resulted from them, explains easily the interest for these compounds reflected also by numerous publications in this area. The present review analyzes the recent syntheses, reactions and applications of sydnones, since 2010. The subject was of interest for a number of researchers from the Centre of Organic Chemistry for a long time and it is still included in their research area. INTRODUCTION* SYDNONE STRUCTURE The sydnones are mesoionic compounds, firstly Sydnones belong to the class of mesoionic described by Earl and Mackney in 1935.1 The heterocycles, being dipolar compounds with the interest for this class of compounds was generated positive and the negative charges delocalized. by their value as synthons in building heterocyclic According IUPAC definition mesoionic complex molecules2, as well as their pharmaceutical compounds consist usually in five member ring 3, 4 applications. heterocycles which cannot be correctly represented 12 Researchers from the Romanian Academy Centre by a covalent or only one polar structure , of Organic Chemistry have published a first paper on consequently described by multiple canonical 5 structures. Sydnones are planar conjugated entities, this subject in 1965 and since then numerous studies 13 have been performed in the field of sydnone considered aromatic. The sydnone aromaticity is 6-11 supported by: their planar structure, the delocalized synthesis or their reactions. It explains our 14 contemporary interest to evaluate the state of art in charges and the considerable resonance energy. sydnone synthesis, properties and applications. This The planarity of the sydnone ring has been review will present the new researches concerning proven by the X-ray analysis of numerous representatives. The crystal X-ray analysis of a sydnones depicted into papers published after the 15, 16 review of Browne and Harrity.2 diversity of sydnones (compounds 1-6 ) evidenced mostly a planar structure for the * Corresponding author: [email protected] 712 Florin Albota and Michaela Dina Stanescu heterocyclic ring. The carbonyl substituent in shielding of N-3 seems to be in agreement with a compounds 2, 4-6 has a small deviation (less than solvent (D-H)-sydnone interaction (the donor part D 0.1 Å) but shows conjugation with the sydnone ring. with N-3 atom and H with the O of conjugated The UV-Vis spectra 17 bring more pertinent carbonyl) leading to an electron charge migration as information concerning the conjugation of sydnone represented in Figure 2. ring with external double bonds revealing the The ab initio calculations confirm the importance of steric factors. distribution of charge in the sydnone molecule. Beside the planarity, the cyclic structure of The most probable resonance structure (see Fig. 2) sydnones enclosing six delocalized π electrons has the highest negative charge at the external sustains the aromatic structure proposal. 18 Also 1H- oxygen atom, the nitrogen N-2 having a very small NMR studies confirm the conjugated cyclic structure negative charge. 24 The mesoionic structure of ruling out any open tautomeric form. 19 Moreover sydnones is also sustained by the high values of spectral data (IR, 1H- and 13C-NMR) of substituted their dipole moments. 25 sydnones 20 correlate well with the Hammet The resonance structure A is mentioned as the constants, endorsing the aromatic properties. most accurate for describing the sydnones, but Meanwhile the reactivity of sydnones does not another representation in agreement with sydnones agree entirely with an aromatic structure. In addition spectral data seems to be B. The resonance to the electrophilic substitution reactions 21 proper to structure B is in accord with the values of the aromatic compounds, the sydnones give Huisgen 3+2 carbonyl IR stretching bands of a number of cyclo-additions 22 with alkenes or alkynes, arynes, substituted sydnones. 26 etc. Such reactions are an important asset for the synthesis of new interesting heterocyclic compounds with plentiful applications. SYNTHESIS OF NEW SYDNONES The quantum-calculations18 promote the sydnone aromaticity, the aromatic stabilization energy (ASE) Most of the lately synthesized sydnones has an of the heterocyclic ring having a positive value. The aromatic substituent at N-3, which enhances the application of Ramsden atom connectivity-matrix stability of the compound. Their preparation 27, 28 analysis 23 sustains also an aromatic conjugated followed mostly the well known multi-steps structure for sydnones. method generally used for sydnone synthesis. It New hints concerning the resonance structures of may start by preparing the aromatic amine 29-32 sydnones have been given by the study of solvent followed by the corresponding substituted polarity effect on the nitrogen shielding in the glycocol. The resulted intermediate is transformed spectrum of 3-methylsydnone.24 The small influence by nitrosation and cyclization, usually using acetic of the solvent polarity and its hydrogen donor anhydride, into the N-substituted sydnone. An capacity for the N-2 shielding, exclude a resonance example is the synthesis of coumarinyl derivative structure with a negative charge at this atom. The 7, described by Patel and Patel 29 (Scheme I). Br Br X O Br Br Br + N Ph O NO Ph O P N O O + O Ph + N O N O + + N Br + N H N N HN N N N N O O O Cl S O N Br N O 3 4 a,b (X = H, OCH ) 5 N 6 1 O 2 O O 3 Fig. 1 – Different sydnones analyzed by X-ray spectroscopy. Fig. 2 – The electron charge migration and the charge Fig. 3 – The resonance structures frequently accepted distribution in 3-methyl-sydnone (R=CH3). for sydnones. Sydnones chemistry 713 Scheme I O OH O COOC8H9 COONa O O N N HN HN N NH2 + N O O OH O O OH O O OH O O OH O O OH Me Me Me Me Me 7 33 Starting from the corresponding diamines, a number of bis-sydnones 8 have been synthesized: O O C + + C H N R NH N R N 2 2 O O N N 8 R = CH2, O, SO2 In some cases the N-3 substituent may be build The recent interest concerning fluorinated after the sydnone ring synthesis. An example is the aromatic and heteroaromatic compounds generates work of Patel and coworkers 34 for preparing a new approach in the synthesis of sydnones compounds 9 (Scheme II). containing fluorine. The preparation may start with Another example is the synthesis of some stilbene the corresponding fluorinated pyruvic ester by a derivatives 35 such as compounds 10 (Scheme III). stepwise procedure 37 as presented in Scheme V. Or the more complex structures 11 and 12,36 shown in Scheme IV. Scheme II ClCH COOH 2 H NaNO N O Cl 2 NH2 Cl N OH Cl N OH 10% NaOH Nitrosation O O N Morpholine + N (CH3CO)2O + O O O N N Cl N o Cyclization 60 C O O 9 Scheme III NaBH CH OH CHO COOCH3 4 2 t-BuOH, MeOH MnO2, CH2Cl2 R R R + + + N N N O O O N N N O O O R' + R = H R' R' = CH R = CH 3 3 R' = Cl R = Ph NaOEt R' = Br R' = OCH R EtOH 3 + N O CH2P+Ph3Br- N O 10 714 Florin Albota and Michaela Dina Stanescu Ar CN Scheme IV CN O CN COOEt N ArCHO H COOEt CH3COONH4 CH3COONH4 O + O N Ar N 11 O O ArCHO N + Ar CN N + N CN O O N O O CN NH2 ArCHO N CN CH3COONH4 CN CH3COONH4 N + N O O 12 Scheme V O H N CO Me PPh F3C CO2Me 2 zinc N CO2Me 3 Ar Ar Ar N3 Ar N PPh3 ether toluene CF AcOH 3 CF3 i) isoamylnitrite H O Lil N CO H DME Ar 2 O EtOAc ii) TFAA, DCM reflux CF3 o N 0 C F3C + N Ar Ar = 4-methoxyphenyl 13 Ar = phenyl A polycyclic compound 14 was synthesized starting from a cyclic compound as raw material, as was described by Mani and coworkers: 38 O O O OH NaNO2/HCl OH TFAA O NH N O N N + N 14 Thus, the sydnone synthesis depends on the Both types of reactions have been lately studied, available raw materials as well as the structure generating a variety of products with numerous design for the final product. practical applications due to their bioactivity. 1. Reactions conserving the sydnone moiety SYDNONE REACTIONS The reactions performed starting from sydnones 1.1. Reactions at C-4 may be classified into two groups: The works considered in this chapter consist in 1. Reactions conserving the sydnone moiety; substitution reactions performed at the C-4. These 2. Reactions leading to the loss of sydnone reactions are either electrophilic substitutions at moiety. the carbon atom of the sydnone ring bearing the Sydnones chemistry 715 less positive charge (C-4), or oxidative coupling active compounds 40 like 15-18, as represented in reactions. Scheme VI. There are other substitution reactions of Electrophilic substitution sydnones.
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