Hydroxylamines nitrones

Reactions of Halogenation and Nitrosation Nitrones with protons in the a-alkyl group can occur in tautomeric nitrone-hydroxylamine equilibrium (Scheme 2.117) similar to keto-enol and imine-enamine tautomerisms. 

DieReduktion der Nitrone, Hydroxylamine, N-Nitroso-amine usw. istz.Tl. praparativ ohne Bedeutung und bereits an anderen Stellen ds. Handb. abgehandelt. 

Transformations of nitro compounds, nitrones, nitrates, hydroxylamines, and amino-A-oxides into heterocycles 98SL939. 

Treatment of 2- 5//-dibenz[i>,/]azepin-5-yl acetaldehyde (16), prepared in 68% yield by /V-alkylation of 5/7-dibenz[A,/]azepine with bromoacetaldehyde diethyl acetal followed by acid hydrolysis, with methyl hydroxylamine yields the isolable nitrone 17, which in refluxing toluene undergoes intramolecular 1,3-dipolar cycloaddition at the CIO —Cl 1 alkene bond to give 2,3,3a, 12b-tetrahydro-2-methyl-3,8-methano-8//-dibenz[i>,/]isoxazolo[4,5-r/]azepine (18).235... 

Deacetylanisomycin (4) is synthesized using L-tartaric acid (1) as a precursor in 12% overall yield16. The key step is the diastereoselective addition of (4-methoxybenzyl)magnesium chloride to the C — N double bond of nitrone 2 at 0°C in the presence of 1 equivalent of ethylmagncsium-bromide diethyl ether complex in dichloromethane. This procedure affords a chromatograph-ically separable mixture of the hydroxylamines 3 a and 3 b in a diastereomeric ratio [(2R,35,4R)/ (25,35,47 )] 70 30 and 60% yield from 2. 

The ( + )-(/ )-methyl 4-tolyl sulfoxide anion from 1 reacts with nitrones 2 to afford optically active hydroxylamines with very high fi stereoselectivity5. The diastereomeric ratio of the products 3 a, b varies from d.r. 75 25-100 0, the highest being for R = t-Bu. The configuration of the diastereomers 3 a, b has not been determined. 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

Methyl-2-quinoxalinecarbaldehyde 1,4-dioxide (235) and A-(2-chloroethyl)-hydroxylamine hydrochloride (236) gave the nitrone, 2-(2-chloroethylimino-methyl)-3-methylquinoxahne l,4,A(-trioxide (237) (NaHCOa, 95% EtOH, warm then 20°C, 1 h 70% after separation from a byproduct). ... 

The structure-reactivity relationship between a 19-Me- and 19-nor-5,10-seco-steroid has been investigated using lOOC and intramolecular nitrone cycloaddition taking into account various stereochemical aspects (Schemes 27 and 28) [67]. The E-19-nor-5,10-seco-ketone 255 a, on treatment with hydroxylamine hydrochloride (R = H), undergoes lOOC via 256a to a single isoxazolidine 257... 

R = H, Scheme 27). On the other hand, reaction of 255a with N-methylhydrox-ylamine hydrochloride produces a mixture of two regioisomers 257 and 258 (R = Me). When the E-l(10)-unsaturated 5-oxo-5,10-secosteroid 255b was treated with hydroxylamine hydrochloride (R = H) or AT-methylhydroxylamine hydrochloride (R = Me), isoxazolidine 259 was formed regio- and stereoselec-tively in high yield via intramolecular 1,3-dipolar cycloaddition of the nitrone intermediate 256 (R = H or Me). 

A somewhat unusual sequence to generate azepanones 80 involved the intramolecular addition of hydroxylamines to alkynes 76 to form cyclic nitrones 77. A vinyl magnesium bromide addition at low temperatures and a reduction with TiCls followed by N-Boc protection led to the azepane 78. Double bond bromination and subsequent RUO4 oxidation gave the lactam 79. Several further steps allowed the generation of the lactam structure 80 proposed for d,/-aca-cialactam, but the spectral data of the synthetic material differed from that of the natural product (Scheme 16)] [23 a, b]. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Although these reactions are formulated as ionic reactions via 947 and 949, because of the apparent partial formation of polymers and inhibition of the fluoride-catalyzed reaction of pyridine N-oxide 860 with aUyl 82 or benzyltrimethylsilane 83 by sulfur or galvinoxyl yet not by Tempo, a radical mechanism caimot be excluded [61, 62]. The closely related additions of allyltrimethylsilane 82 (cf. Section 7.3) to nitrones 976 are catalyzed by TMSOTf 20 to give, via 977, either o-unsatu-rated hydroxylamines 978 or isoxazoHdines 979 (cf also the additions of 965 to 962a and 969 in schemes 7.20 and 7.21). 

Allylation of acyloyl-imidazoles and pyrazoles61 with allyl halide mediated by indium in aqueous media provides a facile regioselective synthesis of P, y-unsaturated ketones (Scheme 11.1), which has been applied to the synthesis of the monoterpene artemesia ketone. The same product can be obtained by indium-mediated allylation of acyl cyanide (Eq. 11.35).62 Samarium, gallium, and bismuth can be used as a mediator for the allylation of nitrones and hydrazones to give homoallylic hydroxylamine and hydrazides in aqueous media in the presence of Bu4NBr (Scheme 11.2).63 The reaction with gallium and bismuth can be increased dramatically under microwave activation. 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fused-chlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the jV-methylnitrone, generated in situ from JV-methyl hydroxylamine and paraformaldehyde, with porphyrin Id . It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

Oxidation of primary amines with DMD or other oxidants leads to the formation of a complex mixture of nitroso, oximes, and nitro compounds (76). Utilization of DMD in acetone affords dimethyl nitrone (22). This is likely to be a result of the initial oxidation of primary amine (19) to hydroxylamine (20) with the subsequent condensation of acetone and oxidation of imine (21) (Scheme 2.9) (77). 

Oxidations of a range of p-cyanoethyl tertiary amines (44) with m-CPBA in CH2CI2 give the corresponding A-oxides (45), which can be isolated or undergo Cope elimination affording hydroxylamines (46) in high yields (Scheme 2.16) (Table 2.1) (96). Hydroxylamines (46) can be easily oxidated into nitrones (see Section 2.2.1.3). 

In electrochemical oxidation of l-hydroxy-3-imidazoline-3-oxides containing one to four H atoms at a-C, one observes in ESR-spectra not only triplet splitting of the nucleus 14N of the nitroxyl group (a v 15-16 G) but also splitting of the neighboring protons (a// 18-20 G), with multiplets corresponding to their number (from doublet to quintet) (101). Unlike spatially hindered hydroxylamines which show reversibility in electrochemical oxidation, hydroxylamines with H at a-C are oxidized irreversibly. Oxidation of hydroxylamines with nitroxyl radical proceeds easily and with quantitative yields (102). In the oxidation of asymmetric polylluorinated hydroxylamines with Mn02, isomeric polyfluorinated nitrones have been obtained (103). 

---