Hydroxylamines cycloaddition reactions

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

Both [4 + 2] and [3 + 2] cycloadditions are a direct and versatile method for preparation of cyclic hydroxylamines. These reactions have been extensively studied, used and reviewed so reactivity and chemoselectivity in these reactions can be reliably... 

Aliphatic and aromatic nitroso compounds are powerful dienophiles and react with a variety of acyclic, cychc and heterocyclic 1,3-dienes producing cyclic hydroxylamines. The reaction proceeds with a high regioselectivity at room temperature (equation 99 291-293 Asymmetric variation of the reaction with chiral copper-BINAP catalyst has been reported ". The cycloaddition is reversible and some amounts of diene and nitroso components may be observed in reaction products. 

B. Hydroxylamines through [3 + 2] Cycloaddition Reactions of Nitrones and Oximes to Alkenes... 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

The in situ formation of nitrones from oximes by 1,3-APT or 1,2-prototropy is clearly a powerful synthetic strategy but conventional nitrone generation, in particular hydroxylamine-carbonyl condensation, has been applied to numerous syntheses, in intra- and intermolecular mode (258). Accordingly, the ring systems similar to those synthesized using 1,3-APT/intramolecular nitrone-alkene cycloaddition (INAC) methodology by Heaney (313-315) (see Section 1.11.2) or Padwa and Norman (340) have been made using conventionally prepared nitrones (Scheme 1.67). As with the previous examples, once formed, the nitrones are suitably placed for a spontaneous intramolecular cycloaddition reaction with the... 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

Sneider et al. (27,28) applied a familiar nitrone for the synthesis the immunosuppressant (—)-FR901483 (14) in a recent study (Scheme 12.7). The nitrone 12 is generated in situ from ketone 10 and the optically pure hydroxylamine 11 at 25 °C. The resultant nitrone 12 underwent a 1,3-dipolar cycloaddition reaction with ethyl acrylate in refluxing toluene to give the diastereomer 13 with 71 % diastereomeric excess (de). In 22 synthetic steps including the 1,3-dipolar cycloaddition, the target molecule 14 was obtained. 

Aminofuro[3,2- ]pyridinium tosylates can be prepared from furopyridines by treatment with 0-(4-methylbenzene-sulfonyl)hydroxylamine. Treatment of the tosylate salt with base, such as potassium carbonate, leads to a pyridinium A -imide, 50. Compound 50 readily undergoes 1,3-dipolar cycloaddition reactions <1999CCC539>. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Addition of anionic nucleophiles to alkenes and to heteronuclear double bond systems (C=0, C=S) also lies within the scope of this Section. Chloride and cyanide ions are effieient initiators of the polymerization and copolymerization of acrylonitrile in dipolar non-HBD solvents, as reported by Parker [6], Even some 1,3-dipolar cycloaddition reactions leading to heterocyclic compounds are often better carried out in dipolar non-HBD solvents in order to increase rates and yields [311], The rate of alkaline hydrolysis of ethyl and 4-nitrophenyl acetate in dimethyl sulfoxide/water mixtures increases with increasing dimethyl sulfoxide concentration due to the increased activity of the hydroxide ion. This is presumably caused by its reduced solvation in the dipolar non-HBD solvent [312, 313]. Dimethyl sulfoxide greatly accelerates the formation of oximes from carbonyl compounds and hydroxylamine, as shown for substituted 9-oxofluorenes [314]. Nucleophilic attack on carbon disulfide by cyanide ion is possible only in A,A-dimethylformamide [315]. The fluoride ion, dissolved as tetraalkylammo-nium fluoride in dipolar difluoromethane, even reacts with carbon dioxide to yield the fluorocarbonate ion, F-C02 [840]. 

Dipolar cycloaddition reactions of nitrones, prepared by the oxidation of suitable hydroxylamines, have been used in a number of alkaloid syntheses. The preparation of tetrahydropyridine /V-oxides by means of the oxidative cleavage of suitable bicyclic isoxazolidines has been studied in connection with projected syntheses of... 

The Grigg group also studied the tautomerization of oximes to N-H nitrones followed by a dipolar cycloaddition reaction. The well-known H-bonding dimeric association of oximes, in both solution and the solid state, allows for a concerted proton transfer to occur and provides nitrone 56 (Scheme 11) (91TL4007). Another possible pathway involves tautomerization of the oxime to an ene-hydroxylamine (i.e. 57) followed by a 1,4-hydride shift to give nitrone 58. To probe the ene-hydro-xylamine mechanism, deuterated oxime 59 was prepared and heated at 140 °C in xylene. The physical characteristics of the isolated product, however, were consistent with compound 60, suggesting that the 1,2-prototropic reactions does not proceed... 

Nr" f RUO4 (PSP) From Amberlyst IR 27 by treatment with aq. KRuO,2< -2io Oxidation of primary and secondary alcohols.- " In situ oxidation of hydroxylamines to nitrones and subsequent [3+21 cycloaddition reactions. ... 

The fused cyclobutane derivatives produced via the above cycloaddition reactions have been utilized as synthetic precursors for the preparation of indole-2-acetonitriles (Scheme 6) [23]. First, the acetyl-substituted cyclobutanes 28 were converted to the cyclobutanone derivatives 29, which were in turn treated with hydroxylamine to provide the corresponding oximes. Beckmann fission of oximes 30 in the presence of thionyl chloride then produced the l-benzoylindole-2-aceto-nitrile derivatives 31 in good yield. 

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