Sydnone Imines Research Articles

Plant growth‐regulating activity of α‐([sydnon‐ and sydnone imin]‐4‐yl‐thio)acetylferrocenes

The convenient method for the synthesis of α‐([sydnon‐ and sydnone imin]‐4‐yl‐thio)acetylferrocenes was elaborated. A growth‐regulating activity of these ferrocene derivatives as well as their antidote activity against Metsulfuron‐Methyl (Zinger WP) herbicide was investigated in vegetation experiments on corn seedlings. The high dose‐dependent growth regulating activity of a number of the ferrocenes bearing a mesoionic heterocyclic substituent (sydnone or sydnone imine) was discovered.

Sydnone Imines as a New Class of Promising Plant Growth and Stress Tolerance Modulators—A First Experimental Structure–Activity Overview

Due to the oncoming climate changes, various environmental stresses (drought, salinity, heavy-metals, low or high temperatures, etc.) might dramatically affect crop yields and the quality of produced foods. Therefore, to meet the growing food demand of the human population, improvement of stress tolerance of the currently cultured crops is required. The knowledge of the molecular underlying mechanisms provides a versatile instrument to correct plant metabolism via chemical tools and to thereby increase their adaptive potential. This will preserve crop productivity and quality under abiotic stress conditions. Endogenously produced nitric oxide (NO) is one of the key signaling factors activating stress tolerance mechanisms in plants. Thus, the application of synthetic NO donors as stress-protective phytoeffectors might support maintaining plant growth and productivity under stressful conditions. Sydnone imines (sydnonimines) are a class of clinically established mesoionic heterocyclic NO donors which represent a promising candidate group for such phytoeffectors. Therefore, here, we provide an overview of the current progress in the application of sydnone imines as exogenous NO donors in plants, with a special emphasis on their potential as herbicides as well as herbicide antidotes, growth stimulants and stress protectors triggering plant tolerance mechanisms. We specifically address the structure–activity relationships in the context of the growth modulating activity of sydnone imines. Growth stimulating or antidote effects are typical for 4-α-hydroxybenzyl derivatives of sydnone imines containing an alkyl substituent in position N-3. The nature of the substituent of the N-6 atom has a significant influence on the activity profile and the intensity of the effect. Nevertheless, further investigations are necessary to establish reliable structure–activity relationships (SAR). Consequently, sydnone imines might be considered promising phytoeffector candidates, which are expected to exert either protective effects on plants growing under unfavorable conditions, or herbicidal ones, depending on the exact structure.

N6-ferrocenylcarbonyl derivatives of sydnone imines: synthesis, modification, growth-regulating and antidote against herbicide “Zinger” activities

The first N6-ferrocenylcarbonyl derivatives of sydnone imines were synthesized by the reaction of sydnone imine hydrochlorides with ferrocenoyl chloride. The possibility of deprotonation of C(4)-H of the oxadiazole ring in N6-ferrocenylcarbonyl derivatives of sydnone imines under the action of n-butyllithium was demonstrated. The reactivity of 4-lithio derivatives was studied and methods of their functionalization were developed. In vegetation experiments on corn seedlings, the growth-regulating properties and antidote activity against Metsulfuron-Methyl (Zinger WP) herbicide of the synthesized ferrocenyl containing sydnone imine derivatives were studied.

Sydnone Imines: A Novel Class of Plant Growth Regulators

An increase in the yield of the main cereal crops in the context of global climate changes requires additional impacts on plants. Natural and synthetic plant growth regulators (PGRs) are used to increase plant productivity and reduce the injury level caused by abiotic stressors. There is a growing need for novel highly effective plant growth stimulants to exhibit their effects at low doses and to not pose an environmental threat or injury to the crop quality. The derivatives of sydnone imine (SI), a mesoionic heterocycle possessing a 1,2,3-oxadiazole core, have been used as medicines until now but have not been used for agricultural applications. Some SI derivatives have recently been found to exhibit PGR properties. Herein, we report on the study of the PGR potential of nine SI derivatives bearing variable substituents at N(3), C(4), and N6 positions of the heterocycle designed to disclose the “molecular structure-PGR activity” relationship in this family. The SI derivatives were used in a wide concentration range (10−9–10−4 mol/L) for a pre-sowing treatment of winter wheat (Triticum aestivum L., two cultivars) and maize (Zea mays L., two hybrids) seeds in germinating experiments. All compounds were found to affect the growth of the axial organs of germinants, with the growth-stimulating or -inhibitory effect as well as its rate being considerably different for wheat and maize and, in many cases, also for roots and shoots. In addition, a pronounced concentration dependence of the effect was disclosed for many cases. The features of the molecular structure of SIs affecting their growth-regulating properties were elucidated. Compounds 4, 6, 7, and 8, which had exhibited a growth-promoting effect in germinating experiments, were used at appropriate concentrations for pot experiments on the same crops. For all compounds, the experiments showed a stimulating effect on the growth of roots (up to 80%), shoots (up to 112%), leaf area (up to 113%), fresh weights of roots (up to 83%), and aerial parts of the plants (up to 87%) or only on some of these parameters. The obtained results show a healthy outlook for the use of SI derivatives as promoting agents for improving the growth of cereal crop plants.

Sydnone Methides: Intermediates between Mesoionic Compounds and Mesoionic N‐Heterocyclic Olefins

AbstractSydnone methides represent an almost unknown class of mesoionic compounds which possess exocyclic carbon substituents instead of oxygen (sydnones) or nitrogen (sydnone imines) in the 5‐position of a 1,2,3‐oxadiazolium ring. Unsubstituted 4‐positions give rise to the generation of anionic N‐heterocyclic carbenes by deprotonation. Preparations of new sydnone methides are described here. They can be represented by mesomeric structures with either exocyclic carbanionic groups like −C(CN)2−, −C(CN)(COOMe)−, −C(CN)(CONH2)−, and −C(CN)(SO2Me)−, or with the corresponding exocyclic C=C double bonds as a common feature with mesoionic N‐heterocyclic olefins. An X‐ray single structure analysis revealed a length of 140.7(3) pm of the exocyclic bond in the solid state. From the coalescence temperature (55 °C) determined by a series of 13C NMR experiments (150 MHz) at various temperatures, an energy of rotation of 18.5 Kcal/mol was calculated for this bond. The 13C NMR signals of the anionic N‐heterocyclic carbenes, from which the 2‐mesityl‐substituted anionic NHC proved to be stable up to 10 °C, are highly shifted upfield (δcarbene=157.9 ppm−160.5 ppm). The carbenes can be reacted in situ with elemental selenium and chlorophosphanes to yield sydnone methide selenoethers after methylation and 4‐phosphanylsydnone methides in good to excellent yields, respectively.

NOBF4-Mediated Assembly of the Sydnone Imine Scaffold in the Synthesis of Double Nitric Oxide Donors

AbstractA direct approach toward the construction of furoxan-sydnone imine double NO-donors involving the NOBF4-mediated nitrosation–cyclization sequence of α-amino nitriles as a key synthetic step was developed. The described protocol excludes the isolation of carcinogenic N-nitrosamines, operates broad substrate scope, and enables the preparation of fully substituted sydnone imines linked to the furoxan ring via different linkers or directly through C–C bond. Synthesized library of furoxan-sydnone imine hybrids demonstrated a promising ability to release NO in a wide range of concentrations which is useful for various biomedical insights.

Ferrocenyl alkylation of 4‐mercapto derivatives of sydnones and sydnone imines. New antidotes for sulfonylurea herbicides

The first representatives of ferrocenes containing mesoionic heterocyclic substituents were obtained by the ferrocenyl alkylation of 4‐mercapto derivatives of sydnones and sydnone imines. Several synthesized derivatives showed high antidote activity against metsulfuron‐methyl (Zinger WP) herbicide.

A Comparative Study of Growth-Stimulating Effects of Sydnone Imine Derivatives on Corn, Sunflower, and Winter Wheat Plants

A Comparative Study of Growth-Stimulating Effects of Sydnone Imine Derivatives on Corn, Sunflower, and Winter Wheat Plants

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors.

Nitric oxide (NO) is a key signaling molecule that acts in various physiological processes such as cellular metabolism, vasodilation and transmission of nerve impulses. A wide number of vascular diseases as well as various immune and neurodegenerative disorders were found to be directly associated with a disruption of NO production in living organisms. These issues justify a constant search of novel NO-donors with improved pharmacokinetic profiles and prolonged action. In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones). The synthetic potential of each heterocyclic system along with biochemical mechanisms of action are emphasized.

4-lithiosydnone imines: Generation and stability. Plant growth regulating activity of 4-hydroxymethyl derivatives of sydnone imines

The C(4)-deprotonation of N6-substituted sydnone imines with lithium hexamethyldisilazide (LHDMS), lithium diisopropylamide (LDA), lithium diethylamide (LDEA), and n-BuLi was studied. A thermal stability of 4-lithiosydnone imines was investigated and an efficiency of subsequent reactions of the generated C(4)-lithio derivatives with electrophiles was shown to depend on the exploited deprotonating reagent. It was found that 4-(α-arylhydroxymethyl)sydnone imines, when used for pre-sowing treatment of corn seeds at very low doses (0.25-5 g t−1), promoted a plant growth up to 60%.

Methyl sydnone imine and its energetic salts

First investigation of this new energetic cation, which may greatly expand the range of possible energetic salts available.

Sonogashira-Hagihara and Buchwald-Hartwig cross-coupling reactions with sydnone and sydnone imine derived catalysts

Sonogashira-Hagihara and Buchwald-Hartwig cross-coupling reactions with sydnone and sydnone imine derived catalysts

Cycloadditions of anionic N-heterocyclic carbenes of sydnone imines

Sydnone imines were deprotonated with lithium bis(trimethylsilyl)amide at the C4 position to give the corresponding sydnone imine anions as lithium adducts. These can be represented as lithium stabilized anionic N-heterocyclic carbenes. Treatment with diisopropyl azodicarboxylate (DIAD) gave the corresponding C4 adducts, i.e. 4-hydrazinyl-sydnone imines, which form tautomers in solution. Reductive 1,3-dipolar cycloadditions of the sydnone imine anions with tetracyanoethylene (TCNE) resulted in the formation of pyrazoles, the mechanism of formation of which differs from known reactions. Reaction of the anion derived from the 2-methoxyphenyl sydnone imine with N,N-diisopropylcarbodiimide gave a ring-cleaved bisiminonitrile. Structure elucidations were accomplished by NMR spectroscopy and by four single crystal X-ray analyses.

Sulfur, mercury, and boron adducts of sydnone imine derived anionic N-heterocyclic carbenes.

The sydnone imines (5-benzoylimino)-3-(2-methoxyphenyl)-sydnone imine and molsidomine were deprotonated at C4 to give sydnone imine anions which can be represented as anionic N-heterocyclic carbenes, respectively. Trapping reactions with sulfur gave unstable sydnone imine sulfides which were stabilized by the formation of methyl thioethers, methyl sulfoxides, gold complexes [(PPh3)Au–S-sydnone imine] and a bis(ligand) mercury(ii) complex. The latter possesses a tetrahedral coordination of the mercury central atom to the sulfur atoms with the N6 nitrogen atoms coordinating as neutral ligands. Water converted the molsidomine anion into ethyl(2-morpholino-2-thioxoacetyl)carbamate. Mercury(ii)chloride and triphenylborane were employed to trap the sydnone imine carbenes as mercury complexes as well as BPh3 adducts.

Heterocycle Syntheses with Anionic N‐Heterocyclic Carbenes: Ring Transformations of Sydnone Imine Anions

Sydnone imines were deprotonated at the C4 position to give lithium‐stabilized anions, which proved to be stable for several months in solution. These anions are elements of the intersection of the substance classes of N‐heterocyclic carbenes and mesomeric betaines. They can be formulated as anionic N‐heterocyclic carbenes. The negative charge translates into high‐field shifts of the 13C NMR resonance frequencies of C4 in comparison to other NHCs. Similar to the chemistry of N‐heterocyclic carbenes, reactions with isocyanates and isothiocyanates gave 4‐(N‐carbamoyl)‐benzoylsydnone imines in trapping reactions. As a result of ring transformations involving the characteristic π‐architecture of the mesoionic framework, imidazolidine‐2,4‐dithiones, imidazolin‐2,4‐diones and 1,2,4‐triazol‐5‐ones were formed depending on the substitution pattern of the starting materials and the reaction conditions.

Synthesis of N6-phosphorylated sydnone imines and their functionalization via 4-Li derivatives. Novel bicyclic sydnone imines

The highly efficient gram-scale method for preparation of up to date hardly available N6-phosphorylated sydnone imines based on the reaction of sydnone imine hydrochlorides with substituted phosphinate or phosphonate acids chlorides in the presence of a base was elaborated. A possibility of straight deprotonation of sydnone imines with n-BuLi followed by the reaction 4-Li-derivatives thus obtained with electrophiles was demonstrated. Novel representatives of bicyclic sydnone imines fused via 4,5-edge of the oxadiazolium ring were obtained. Also sydnone imines containing both phosphorus and sulfur functionalities were obtained with high yields.

N6-tert-Butoxycarbonyl derivatives of sydnone imines: Preparation and synthetic use

A highly efficient gram-scale method for the C(4)-functionalization of sydnone imine hydrochloride derivatives was developed. This new approach was realized through consecutive reactions including the preparation of a C(3)-substituted N6-tert-butoxycarbonyl sydnone imine derivative, deprotonation with n-BuLi and reaction of the lithiated-intermediate with an electrophilic agent, and removal of the Boc protecting group.

Anionic N-heterocyclic carbenes derived from sydnone imines such as molsidomine. Trapping reactions with selenium, palladium, and gold

The sydnone imines Molsidomine and 5-(benzoylimino)-3-(2-methoxyphenyl)-1,2,3-oxadiazolium-2-ide gave anionic N-heterocyclic carbenes on deprotonation at C4 which were trapped as methylated selenium adducts, gold complexes (X-ray analysis) as well as palladium complexes (X-ray analysis). The 13C NMR resonance frequencies of the carbene carbon atom are extremely shifted upfield and appear at δ = 142.1 ppm (Molsidomine carbene) and δ = 159.8 ppm (sydnone imine carbene). The Pd complexes were applied as catalysts in Suzuki-Miyaura and Sonogashira-Hagihara cross-coupling reactions.

N6-α-haloacyl sydnone imine derivatives

A preparative method of synthesis of N6-α-haloacyl sydnone imine derivatives has been developed. These compounds are convenient intermediates for the synthesis of a large variety of N6-α-amino-substituted and N6-α-thio-substituted acyl derivatives of sydnone imines. The obtained sydnone imine derivatives may be of interest in the context of searching for new physiologically active compounds.

4,5]-Bicyclic sydnone imines

Lithiation of N6-(α-haloacyl)-3-isopropylsydnone imines at 4-position followed by treatment with sulfur affords the 4-lithiosulfanyl derivatives whose intramolecular cyclization leads to [4,5]-bicyclic sydnone imines.