N-Hydroxyamines

The syntheses of N-hydroxy-N-nitrosamines are usually carried out by the nitrosation of the corresponding N-hydroxyamines (Scheme 3.8) [123, 124]. N-Hydroxyamines are readily obtained by the reduction of the corresponding nitro-compounds. The most efficient methods are neutral or basic reactions. Recent applications of this method have resulted in the preparation of a variety of cupferron derivatives (Scheme 3.8) via nitrosation of phenylhydroxylamine with amyl nitrite/ammonia [125] or methyl nitrite/ammonia [126]. Behrend and Konig have shown that the organic... 

Fig. 4.8. Formation of mutagenic N-hydroxyamines from arylamides. Pathway a via deacetylation and subsequent IV-hydroxylation. Pathway b via IV-hydroxylation and subsequent deacetylation. Pathway c via N-acetoxy arylamine produced by IV,0-acyltransferases. [99]. Activation of hydroxylamines and hydroxylamides by O-sulfation is not shown. In all cases, the ultimate electrophile may be a nitrenium ion.

Pandey and coworkers have studied the DCN-sensitized oxidation of N-hydroxyamines without prior removal of dissolved oxygen, to nitrone intermediates. Trapping the nitrones by dimethylfumarate (282) gave the corresponding cycloadducts in good yields (Scheme 66) [317]. 

Figure 14.37 Enantioselective oxidation of racemic O methyl N hydroxyamines.

Free N-hydroxyamino acids (1) or (2) have never been isolated from living organisms, probably because of their instability. As already mentioned, N-hydroxyamino acid residues occur only as fragments of many natural products containing the N-hydroxyamide bond. The isolation of free N -hydroxy-L-arginine from the fermentation medium of Bacillus cereus (6, 7) may be considered as an exception however, this compound contains an N-hydroxyguanidine rather than an N-hydroxyamine group. 

N-Hydroxyamino acids, just like N-hydroxyamines, are strong reducing agents. At room temperature they reduce solutions of salts of such metals as silver, copper, mercury and lead (1). They also reduce Fehling s reagent (1) and decolorize iodine solutions in neutral or alkaline but not acidic media (36). As the result of the above reactions compounds of type (1) are oxidized to the oximes of a-keto acids (31). Esters of N-hydroxyamino acids (90), like N-alkylhydroxylamines, undergo oxidation to dimers of cw-nitroso compounds with a characteristic absorbance at 264 nm, this being analytically important (91). 

Palacz, Z. N-Benzylideneamino Acid N-Oxides and Their Use in the Synthesis of N-Benzylidenepeptide N-Oxide Esters and in the Synthesis of Optically Active N-Hydroxyamines. Ph. D. Thesis, University of Gdansk 1978. 

N-Tosylated P-hydroxy alkylamines (which can be easily hydrolyzed to P-hydroxyamines" ) can be prepared " by treatment of alkenes with the trihydrate of Chloramine-T and a catalytic amount of OSO4. In some cases yields can be improved by the use of phase-transfer catalysis." The reaction has been carried out enantioselectively." In another procedure, certain P-hydroxy secondary alkylamines can be prepared by treatment of alkenes with the osmium compounds... 

Method B (catalysed by polymer-supported chiral fl-hydroxyamines) The aldehyde (1 mmol) is added to the polymer-supported catalyst (0.298 g) in n-C6Hu (2 ml) at 0°C and the mixture is stirred for 15 min. The dialkylzinc (1M in rt-C6H 4, 2.2 ml) is added and the mixture is stirred for 1-8 days at 0°C. The reaction is quenched with aqueous HCI (1M, 5 ml) and the mixture is filtered and extracted with CH2C12 (3x10 ml). The dried (Na2S04) extracts are evaporated to yield the chiral secondary alcohol. 

Nucleophiles react with /V-H and Al-acyl oxaziridines with transfer of NH and /V-acyl, respectively. Much of this chemistry (91S327) has been carried out with cyclohexanespiro-3 -oxaziridine (26) attack at the NH group gives intermediate (27) which gives cyclohexanone and animation of the nucleophile. Transfers of NH to N-, 0-, S-, and C-nucleophiles, enable the syntheses of hydrazines, /V-amino-peptides, hydroxyamines, sulfenamides, thiooximes, sulfonamides, aziridines, and a-amino acids. 

Indeed, O-benzylation increases N-coupling yields of the hydroxyamine terminus and has three other advantages (i) it prevents undesirable O-acylation in further coupling steps, (ii) it decreases the polarity of the (A-hydroxy) peptide formed, hence facilitating its purification, and (iii) it is easily cleaved by catalytic hydrogenolysis or treatment with B(TFA)3. 44 ... 

Propanal has been enantioselectively hydroxyaminated with nitrosobenzene (Ph-N=... 

Substituted imidazole 1-oxides 228 can be prepared by N-oxidation of imidazoles 248, by N-alkylation of 1-hydroxyimidazoles 249, or by cycliza-tion using suitable starting materials derived from a 1,2-dicarbonyl compound, an aldehyde, an amine, and hydroxyamine. The substituents at the three first starting materials are transferred to the product and make control over the substituents in the imidazole 1-oxide 228 possible depending on the protocol used by the synthesis. The synthesis of 3-hydroxyimidazole 1-oxides is presented in Section 3.1.6. 

This book is intended to provide an overview of several areas of research in which amination plays a key role, and to introduce the reader to new concepts that have been developed quite recently for generating new C - N bonds. As the pharmaceutical and chemical industries move rapidly away from the development of racemic compounds, the access to synthetic routes that lead efficiently to enantiomerically pure materials is becoming increasingly important. For this reason, most of the contributions in this book refer to asymmetric synthesis. However, no attempt has been made to present a comprehensive work, and important areas such as asymmetric hydroxyamination [1] have not been dealt with. Furthermore, it may be worth mentioning that viable, useful and comprehensive sources of information about the methodological approaches to electrophilic amination developed since 1985 have already been reported [2], and that a chapter in Houben-Weyl reviewing several aspects of the asymmetric electrophilic amination [3] compiles important contributions up to 1995. 

Recent work has shown that the carbamate reaction shows no legioselectivity in the rather demanding case of 1,2,3,6-tetrahydropyiidines 1,2-dihydropyiidines react at the 5,6 double bond, but with no selectivity in the N,0 orientation. The regioselectivities of the Sharpless oxyaminations have been rationalize, and the react on has recently been studied from the point of view of the inoiganic chemist These procedures and ther cis hydroxyaminations below produce stereochemistry complementaiy to that provided by ring Of ming of the epoxidized alkene. ... 

Hydroxyamin N-(2-Chlor-5-trifluormethyl-phenyl)- E16a, 58/62 (Niro-Red.), 261 (O-Umarylier.)... 

Zard has developed the use of N-amidyl radicals. The precursors of the radical intermediates are 0-benzoyl hydroxyamines such as 37. Addition of a tributylstannyl radical to the carbonyl group of the benzoate moiety is followed by the cleavage of the weak N - O bond. A subsequent 5-exol6-endo tandem cyclization takes place to yield the skeleton of the natural product deoxyserratine (Scheme 12) [49]. Later, the same group disclosed a tin-free source of amidyl radicals that relies on the use of M-(0-ethyl thiocarbonyl-sulfanyl) amides and lauryl peroxide as initiator. Examples of polycyclization were also given [50]. On the occasion of a model study toward the synthesis of kirkine, the use of thiosemicarbazide precursors gave access to the tetracyclic structure of the natural product [51]. 

An efficient and straightforward synthesis of isomers of DMDP 36 (2,5-dihy-droxymethyl-3,4-dihydroxypyrrolidine), a known naturally occurring glycosidase inhibitor, has been recently reported. o-Xylose is converted into nitrone 37 in a few steps. Vinylation of 37 gives hydroxyamine 38 which is reduced into the corresponding pyrrolidine with zinc. N-Protection, alkene ozonolysis, and reduction with NaBH4 lead to compound 39. Final deprotection gives 2,5-dideoxy-2,5-imino-L-mannitol (e f-36) (Scheme 14) [92]. 

Pinidine (188) was recently synthesized from methyl 6-ketoheptanoate. An asymmetric electrophilic hydroxyamination of a chiral N-acylsultam was used to form the piperidine ring, and hydrogenation of the nitrone gave the required cis-2,6 substitution [466]. 

Polycyclic borazines (55) X = 0, NH, or NMe, n = 2 or 3) result from the reaction of a trisalkylthioborane with hydroxyamines or amines. Their i.r. and mass spectra, with possible mechanisms of formation, were reported. Photochemical reactions of borazine in the presence of (photochemically generated) radicals derived from hexafluoroacetone have led to the formation of B-(2H-hexafluoro-2-propoxy- and B-(perfluoro-butoxy)-borazine. ... 

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