Nitrones tautomers

An alternative and elegant approach to bicyclo[3.3.0]isoxazolidines from alkenyl oximes was developed by Grigg (205) and applied in asymmetric reactions by Hassner et al. (206-209) and others (210). The optically active L-serine derived oxime 130 was proposed to be in a thermal tautomeric equilibrium with the nitrone tautomer 131, which underwent an intramolecular 1,3-dipolar cycloaddition to form the product 132 in 80% yield as a single stereoisomer (Scheme 12.44) (209). 

Nitroalkanes are acidic compounds the dissociation of a proton from a nitroalkane produces the nitroalkane anion, or nitronate, whose chemical and physical properties differ from those of the parent nitroalkane. The nitronate form of 2-nitropropane is more mutagenic in S. typhimurium TAIOO and TA 102 than is the neutral parent compound (Fiala et al., 1987b Dayal et al., 1989 Kohl et al., 1994), suggesting that propane 2-nitronate may act as an intennediate in the mechanism by w hich 2-nitropropane exerts its genotoxic and carcinogenic effects. This hypothesis is supported by studies indicating that both bacterial mutagenicity and induction of unscheduled DNA synthesis in rat hepatocytes are decreased by conditions (low pH or deuteration of the secondary carbon atom) that limit formation of the nitronate tautomer, and that the tautomerization of 2-nitropropane can be influenced by hepatic enzymes (Kohl et al., 1994). 

It has been proposed that 8-aminodcoxyguanosinc is formed from the nitronate tautomer of 2-nitropropane either by base nitrosation followed by reduction, or via an enzyme-mediated conversion of the nitronate anion to hydroxyiam ine-O-sulfonate or acetate, which yields the highly reactive nitrenium ion NHj (Sodum et al., 1993). Sodum et al. (1994) have provided evidence for the activation of 2-nitropropane to an aminating species by rat liver aryl sulfotransferase in vitro and in vivo. Pretreatment of rats with the aryl sulfotransferase inhibitors pentachlorophenol or 2,6-dichloro-4-nitrophenol significantly decreased the levels of nucleic acid modifications produced in the liver by 2-nitropropane treatment. Partially purified rat liver aryl sulfotransferase activated 2-nitropropane and its nitronate at neutral pH to a reactive species that aminated guanosine at the position. This activation was dependent on the presence of the enzyme, its specific cofactor adenosine 3 -phosphate 5 -phosphosulfate, and mercaptoethanol. It was inhibited... 

Hydroxyindole can be prepared in solution, but attempted purihcation leads to dimerisation via its nitrone tautomer however, 0-alkyl-derivatives can be formed easily and are stable. ... 

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

Continuing his studies on the metallation of tetrahydro-2-benzazepine formamidines, Meyers has now shown that the previously unsuccessful deprotonation of 1-alkyl derivatives can be achieved with sec-butyllithium at -40 °C <96H(42)475>. In this way 1,1-dialkylated derivatives are now accessible. The preparation of 3//-benzazepines by chemical oxidation of 2,5- and 2,3-dihydro-l/f-l-benzazepines has been reported <96T4423>. 3Af-Diazepines are also formed by rearrangement of the 5//-tautomers which had been previously reported to be the products of electrochemical oxidation of 2,5-dihydro-lAf-l-benzazepine <95T9611>. The synthesis and radical trapping activities of a number of benzazepine derived nitrones have been reported <96T6519, 96JBC3097>. 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Relative contribution of each of these structures differs significantly and is determined by internal structural characteristics of the nitrones and by the influence of external factors, such as changes in polarity of solvent, formation of a hydrogen bond, and complexation and protonation. Changes in the electronic stmcture of nitrones, effected by any of these factors, which are manifested in the changes of physicochemical properties and spectral characteristics, can be explained, qualitatively, by analyzing the relative contribution of A-G structures. On the basis of a vector analysis of dipole moments of two series of nitrones (355), a quantum-chemical computation of ab initio molecular orbitals of the model nitrone CH2=N(H)0 and its tautomers, and methyl derivatives (356), it has been established that the bond in nitrones between C and N atoms is almost... 

Silyl Nitronates The characteristic features of the behavior of SENAs in [3+ 2]-addition reactions (75, 133, 175-177, 185, 186, 189, 201a, 203, 205, 206, 216, 355-362c) are virtually identical to those of acyclic alkyl nitronates considered in the previous section. As mentioned above, minor but more reactive Z-tautomers of SENAs derived from primary AN can be detected by cycloaddition reactions (see Section 3.3.4.1 and Scheme 3.128). 

Formaldonitrone, CH2=N(H)—O (3), the elusive simplest organic nitrone, has been prepared transiently in the gas phase by femtosecond collisional neutralization of its cation radical, CH2—N(H)—0+". The latter was generated by dissociative ionization of 1,2-oxazolidine. Nitrone 3 showed negligible dissociation upon collisional neutralization and was distinguished from its tautomers formaldoxime 2 and nitrosomethane 1 that gave different NR mass spectra. The enthalpy of formation was calculated from enthalpies of atomization and two isodesmic reactions as Af//29s(3) = 58 1 kJmol . The calculated, large activation barriers for isomerization of 3 (179 and 212 kJmoH for 3 anti-2 and 3 1, respectivelyindicate that once 3 is formed and diluted in the gas phase it should not isomerize unimolecularly to either 1 or (syn/anti) 2. 

A second and related consequence in aliphatic nitro compounds is the acidification of the directly bonded CH unit through the attendant stabilization of the derived conjugate bases (5,6). As with all delocalized anions, reprotonation gives rise to tautomers, the original C-nitro compound (I) and the oci-nitro or isonitro form (II), Eq. 2.1. The aci-nitro tautomers are typically present in very minor concentrations, with equilibrium constants (A eq) between 10 and 10 (7). Alkylation of the delocalized anion leads to both a-substituted nitro compounds and the regioisomeric nitronic esters (nitronates). Nitronates were described as early as 1894 (8), however, the first isolated nitronic ester was obtained several years later upon the addition of diazomethane to phenylazonitromethane (1), Eq. 2.2 (9). 

Nitropropane exists in equilibrium with its tautomer propane-2-nitronic acid, present in physiological media as the anion propane-2-nitronate. Dayal et al. (1991) have investigated the metabolism of both 2-nitropropane and propane-2-nitronate in mouse microsomes and found that the oxidative denitrification of propane-2-nitronate was 5-10 times more extensive than that of 2-nitropropane. Acetone formed by this reaction affords the source of 002 detected when 2-nitro -C prop iiic was administered in vivo. However, neither 2-nitropropane nor propane-2-nitronate was cytotoxic to mouse hepatocytes. 

Reduced derivatives of benzofurano[3,2-c]pyrrole (334) and (335) were obtained by the thermal elimination of water from the phenolic nitrones (332) and (333 Schemes 114 and 115). The reaction is postulated to occur via an M- hydroxyindolenine tautomer, i.e. (336 Scheme 116) (73JOC3012). 

Several examples of ring-chain tautomerism are known where the cyclic tautomer is formed as a result of an intramolecular hydroxy group addition to the C = N bond of nitrones, yielding hydroxylamine derivatives. 

No cyclic tautomers of C-aryl- (83LA1937) and C-cyclohexyl-A-(3-hydroxypropyl)nitrone 39 (R = Ar, QHn) (84CZ283) were observed in solution on H-NMR spectroscopy. However, acylation of these nitrones gave 0-acyl derivatives with the cyclic structure. A mixture of two isomers ([B]/[A] = 0.43, H-NMR) was detected (84CZ283) in a CDC13 solution of the nitrone 39 (R = Me). 

Nitronic acids are stabilized by inter- and intramolecular hydrogen bonding. Kang et al. [6b] showed that nitro compound 4 is slowly, but spontaneously converted to nitronic acid tautomer 4t due to the stabilization that results from... 

Evidently the a-H is likely to be involved in the early stages of the decomposition process [16], perhaps moving to an adjoining nitro group to form a nitronic acid tautomer, 4 [35,45,46]. These are known to be reactive and unstable [47], The transfer or loss of a proton to yield a nitronic acid or a nitronate (aci) anion has also been invoked as the initial step in the decompositions of other energetic molecules, e.g. picric acid [35,48] and amine-sensitized nitromethane [49-51]. 

Nitronic ester The result of O-alkylation of the carbanion of the aci tautomer of a nitro compound and having the general formula R2C=N+(0-)0R. 

Tautomers of hydroxylamines may also be oxidized easily. Amidin-N2-oxides as the nitrone form of N -hydroxyamidines have been oxidized with different agents24 ... 

On the other hand oxidation above the nitrone stage 171 is possible in aminyl-oxides like 173. In these cases the intermediate nitrones 174 being potential tautomers of corresponding hydroxylamines (p. 69) are further dehydrogenated giving aminyloxides 175. Thus aminyloxides 176 and 178 containing amino groups in the... 

For such compounds several possible isomeric and tautomeric forms can be considered. These include the ( ) and (Z) geometfical isomers (a and b), as well as the tautomers nitrone (c), 5-hydroxy-isoxazolidine (d), and oxazirid-ine (e). Examination of the and NMR spectra of the... 

It is known that 4-benzal-l-phenyl-A -pyrazolin-5-one reacts both like an heterodiene and an alkene in a Diels-Alder reaction towards 2,3-dimethylbutadiene <88T5229>. The 1,3-dipolar cycloaddition of nitrones to the N//-tautomer of l-phenyl-3-methyl-3-pyrazolin-5-one yields a nonisolated cycloadduct which rearranges to a 4-substituted derivative of the starting material (4-substituent = CH(Ar)— N(Ph)—OH) <94JCR(S)154>. 

Nitroenamines with a primary or secondary amino group can exist also in two tautomeric forms the imino-nitro form (511) and the imino-nitronic acid form (512). Although the enamine form represents the thermodynamically more stable tautomer, the imino-nitro form has been observed when severe steric hindrance prevents planarity of the conjugated system Compounds 513, derived from 2-nitrocycloalkanones, have been reportedto exist exclusively as the imino-nitronic acid tautomer, although the spectroscopic evidence presented is also consistent with the enamine form,... 

Carbanions derived from carbonyl compounds are often referred to as enolates, a name derived from the enol tautomer of carbonyl compounds. The resonance-stabilized enolate anion is the conjugate base of both the keto and enol forms of carbonyl compounds. The anions of nitro compounds are called nitronates and are also resonance stabilized. The stabilization of anions of sulfones is believed to be derived primarily from polar and polarization effects. 

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