Nitronates stability

OTHER COMMENTS used as a chemical reagent for sugars, ketones, and aldehydes used in the manufacture of dyestuffs and pharmaceuticals useful in the manufacture of antipy-rine and nitron (stabilizers for explosives). 

From N-oxides of aromatic bases oxaziridines were obtained only at very low temperatures, but oxaziridines were often postulated as intermediates in the photoconversion of such N-oxides (Section 5.08.3.1.2). Isolation of the more stable photoisomers of nitrones also causes some problems due to their thermal and photochemical instability leading to acid amides, e.g. (69TL2281), or, by fragmentation, to carbonyl compounds and products of stabilization of nitrenes, e.g. from (260) (69ZN(B)477). 

Nitroalkanes show a related relationship between kinetic acidity and thermodynamic acidity. Additional alkyl substituents on nitromethane retard the rate of proton removal although the equilibrium is more favorable for the more highly substituted derivatives. The alkyl groups have a strong stabilizing effect on the nitronate ion, but unfavorable steric effects are dominant at the transition state for proton removal. As a result, kinetic and thermodynamic acidity show opposite responses to alkyl substitution. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

The parent five-membered nitronate having no substituent at the 3-position was too unstable to be isolated. However, 3-substituted derivatives were highly stabilized. Especially, the 3-ethyl derivatives having a terminal electron-withdrawing substituent are readily available by the dehydrochlorination of 3-chloro-l-nitropropane in the presence of electron-deficient alkenes. It was our delight that the reaction of 3-al-kyl-substituted five-membered nitronates was also successfully catalyzed by R,R-DBFOX/Ph-Ni(SbFg)2 complex to at room temperature. This reaction was highly endo-selective (cisjtrans= 91 9) and enantioselective for the endo cycloadduct (92% ee). 

Florio and coworkers have also reported the use of oxazolinyl groups as anion-stabilizing substituents. Lithiation/electrophile trapping of oxazolinylepoxide 202 provided access to acyloxiranes 205 [72], while deprotonation/electrophile trapping of oxazolinylepoxide 206 with nitrones gave access to enantiopure a-epoxy- 3-amino acids 208 (Scheme 5.48) [73],... 

Cycloadditions of nitrones, nitrile oxides or diazo compounds to thiete dioxides do not show the high stereoselectivity observed with acyclic vinyl sulfones, and mixtures of the two possible adducts are formed . The charge-transfer stabilization energy calculated according to the Klopman-Salem perturbational approach is able to account for the experimental trends of the isomer ratio in terms of the major stereochemical structural differences between the acyclic vinyl sulfones and the four-membered ring sulfones (see Section IV.B.3). 

The presence of /3-hydrogen in the nitroxide radical may lead to disproportionation reactions. In spin-trapping experiments, N-t-butyl-a-phenyl nitrone yields rather unstable spin adducts. This type of radical can be stabilized by coordination to Nin. The Ni11 complex with N-oxy-A-r-butyl-(2-pyridyl)phenylmethanamine (923) reveals a distorted octahedral geometry with antiferromagnetic interactions between the unpaired electrons of the metal ion and the radical spins.00... 

The pyrroline-iV-oxide 411 lost enantiomeric purity in the deprotection step. The THP protecting group could be deprotected under very mild conditions using Amberlyst 15 in methanol. However, the mixture was obtained in low yield accompanied by partial or total racemization as indicated by variation of specific rotation. Racemization also occurred during purification by silica gel chromatography or recrystallization. The lack of configurational stability of the nitrone 411 may be explained with the occurrence of a fast (not detectable by NMR), nitrone-hydroxyenamine tautomerism (Scheme 91). 

For the first time, the primary nitrone (formaldonitrone) generation and the comparative quantum chemical analysis of its relative stability by comparison with isomers (formaldoxime, nitrosomethane and oxaziridine) has been described (357). Both, experimental and theoretical data clearly show that the formal-donitrones, formed in the course of collision by electronic transfer, can hardly be molecularly isomerized into other [C,H3,N,0] molecules. Methods of quantum chemistry and molecular dynamics have made it possible to study the reactions of nitrone rearrangement into amides through the formation of oxaziridines (358). 

The study of the stabilizing effect of the nitrone group in cumyl radical (205) (Scheme 2.72) (362) and cumyl cation (206) (Scheme 2.73) (363) has shown that the nitrone group appears to be a super radical stabilizer and, at the same time, a weak cation stabilizer. ... 

Analysis of the conformational and structural stability of N-vinylnitrone CH2=CH—N(0)=CH2 and /V-(2,2-dichlorovinyl)nitrone CCl2=CH-N(0) = CH2 with DFT-B3LYP and MP2 methods revealed that they have a planar structure resulting from the apparent conjugation between C=C and N=C bonds. 

Convincing evidence was found that the majority of acyclic aldo-nitrones exist in the Z-form, by investigating the ASIS-effect (aromatic solvent induced shift effect) (399). However, in some cases, specified by structural factors and solvent, the presence of both isomers has been revealed. Thus, in C -acyl-nitrones the existence of Z -and -isomers was detected. Their ratio appears to be heavily dependant on the solvent polar solvents stabilize Z-isomers and nonpolar, E-isomers (399). A similar situation was observed in a- methoxy-A-tert-butylnitrones. In acetone, the more polar Z-isomer was observed, whereas in chloroform, the less polar E-isomer prevailed. The isomer assignments were made on the basis of the Nuclear Overhauser Effect (NOE) (398). /Z-Isomerization of acylnitrones can occur upon treatment with Lewis acids, such as, MgBr2 (397). Another reason for isomerization is free rotation with respect to the C-N bond in adduct (218) resulting from the reversible addition of MeOH to the C=N bond (Scheme 2.74). The increase of the electron acceptor character of the substituent contributes to the process (135). 

Oxaziridines, the products of photochemical isomerization of polymeric nitrones, are characterized by high stability. The formation of an intramolecular hydrogen bond stabilizes the nitrone group with respect to UV-irradiation... 

Conventional alkylating agents (alkyl halides, sulfates, etc.) are rather rarely used in the synthesis of alkyl nitronates. This is associated with relatively low reactivity of these compounds which, combined with low thermal stability of nitronates (for more details, see Section 3.3.1.1), does not allow one to isolate target products in the individual state. 

Both C-alkylation products and the corresponding O-alkyl nitronates were detected in the reaction mixture prepared by the reactions of above mentioned salt with primary alkyl halides (Scheme 3.9, Eq. 1). However, isoxazolidines (1) are the main identified products of the reactions with secondary or tertiary alkyl halides. The possible pathway of their formation is shown in Scheme 3.9. Here, the key event is generation of the corresponding olefins from alkyl halides. These olefins can be trapped with O-nitronates that are simultaneously formed in [3 + 2]-cycloaddition reactions. Presumably, these olefins are generated through deprotonation of stabilized cationic intermediates (see Scheme 3.9). 

Therefore, all prerequisites are present for the development of a general strategy for the synthesis of nitronates (24) from a-functionalized primary AN through stabilized carbenium intermediates and nitrocyclopropanes (23). This approach allows the stereoselective synthesis of nitronates (24) from simple molecules (Scheme 3.29). 

Since inactivated alkenes do not contain the substituent X stabilizing the positive charge in intermediate B (see Scheme 3.40), the latter can undergo a hydride shift to form a more stabilized cationic center (intermediate B in Scheme 3.42), which finally gives rise to an impurity of five-membered cyclic nitronate (24). 

Scheme 3.45, Eq. 2) through the most stabilized zwitterion to give only one stereoisomer of target 5-methylene-substituted nitronate (35 h). 

Potassium nitroacetate 53a reacts with Me3SiCl in aprotic solvents to give SENA (51a) in moderate yield. At the same time, the introduction of yet another electron-withdrawing group (N02 or CC>2Me) stabilizes the anion of salt (53) to an extent that it does not react with Me SiCl by the Sm mechanism without electrophilic assistance. Hence, K or Na salts 53b, C are inert with respect to halosilanes, and silver or mercury salts are required for the preparation of the corresponding nitronates. The latter salts are much safer to use as diox-anate complexes. These complexes react with halosilanes in inert aprotic solvents... 

Generally, anionic intermediates A smoothly react with trialkylchlorosilanes as the temperature is raised to room temperature. To improve the solubility of intermediate magnesium nitronates (A in scheme 3.56), it is advantageous to add HMPA to the reaction mixture. The addition of Et3N stabilizes SENAs as intermediate. 

There is also evidence that conjugation of the nitronate fragment with jt systems can stabilize acyl nitronates. For example, Perekalin and coworkers (224) isolated a very stable nitronate (63a), which was prepared by acetylation of l,4-dinitrobut-2-ene salts (65) in a mixture with the corresponding C-acylation product (66) (Scheme 3.66), by column chromatography. 

However, taking into account the unusually high stability of the resulting acyl nitronates shown in Schemes 3.66 and 3.67, additional data are required to confirm their structures. 

As can be seen from Scheme 3.69, the resulting nitronates have different structures (71a-e are dimers, whereas 71f-h and 71ij are chelates). Low yields of some target substrates are attributed to their low thermal and hydrolytic stability. 

Since different types of nitronates decompose through different pathways, their stability will be considered separately. 

Stability of Acyclic Alkyl and Acyl Nitronates A weak point of acyclic alkyl nitronates is their thermal instability because these compounds can be involved in two electrocyclic reactions presented in Scheme 3.72. 

Table 3.5 gives the most typical examples of acyclic nitronic esters, which have unusually high thermal stability. These data contradict the known data on fast thermal decomposition of alkyl nitronates derived from the simplest nitroalkanes (237) and relatively low thermal stability of nitronate (73a). On the basis of the available data, the following empirical mle can be derived an extension of the conjugation chain of the nitronate fragment increases stability of nitronates. 

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