Hydroxylamines intermediate

Nitro functions are easily reductively alkylated and a number of alkylated anilines are made industrially starting with the appropriate nitroaromatic in the ketone as solvent. The addition reaction can occur at the hydroxylamine intermediate as well as the aniline. A process step is saved by beginning with the nitro compound. 

FIGURE 5.7 Reduction of nitro groups to amines via nitroso and hydroxylamine intermediates. 

The photoreduction of aromatic nitro compounds to the amino compounds can be carried out on the surface of semiconductor particles such as titanium oxide1 with H-atom donors (equation 1). At a shorter duration of the photoinduced reduction of p-nitroacetophenone, the hydroxylamine intermediate can be obtained in about 30% yield. The reaction mechanism proposed is based on the photoexcitation of TiC>2 to generate an electron and a positive hole (equations 2 and 3). Aliphatic nitro compounds such as 12-nitrododecanoic acid can be reduced to 12-amino dodecanoic acid in 90% yield by this method. 

Electrosyntheses of heterocycles from nitroso derivatives prepared in a batch cell according to Scheme 34 need two conditions. The first one is a good stability of the hydroxylamine intermediate and the second one is a very fast cyclization of the nitroso compound to avoid the formation of an azoxy compound by condensation of the generated nitroso and the hydroxylamine. Electroanalytical studies using cyclic voltammetry can give information on the rate of cyclization. 

However, an improved electrochemical redox methodology using a flow cell fitted with two consecutive porous electrodes of opposite polarities (cathode then anode), allows a rapid and total oxidation at the anode of the hydroxylamine intermediate produced at the cathode. Various nitroso compounds may be obtained in high yields without... 

Hydroxylamine intermediates wilt react with an adjacent nitrile function [100, 101]. Interaction with the isothiocyanate group can be achieved in acid solution... 

Catalytic hydrogenation of iV-(o-nitrophenyl)aminoacetonitriles 192 with palladium(ll) oxide hydrate gives high yields of quinoxaline A -oxides 193 through condensing the reduced hydroxylamine intermediate with nitrile (Equation 31) <2001EJ0987>. 

Gonzales and co-workers extended their work on simple nitrenium ions, examining the reactions of several small, monosubstituted nitrenium ions (XNH+, where X = H, F, Cl, CN, and Me) with water. These computational studies (QCISD(T)/6-311-1—1- G ) treated only the singlet states of the nitrenium ion. According to these calculations, each singlet nitrenium ion adds to water to form an O-protonated hydroxylamine intermediate (R2N—OHj). No activation barrier was detected for... 

The enteric bacterium Enterobacter cloacae produces a nitroreductase that reduces nitrofurans, nitroimidazoles, nitrobenzene derivatives, and quinones (Bryant DeLuca, 1991). This oxygen-insensitive enzyme has been purified and is known to require FMN to transfer reducing equivalents from NAD(P)H to the nitroaromatic compounds, TNT being the preferred substrate. Aerobically, this enzyme reduces nitrofurazone through the hydroxylamine intermediate, which then tautomerizes to yield an oxime end-product. Anaerobically, however, the reduction proceeds to the fully reduced amine adduct. When E. cloacae was grown in the presence of TNT, the nitroreductase activity increased five- to tenfold. 

Four-membered rings are not obtained during reduction of a-nitro-/ -keto alkenes the oxygen of the hydroxylamine intermediate attacks the electrophilic center1,71 with formation of isoxazole derivatives. 

Reduction of aromatic nitro groups occurs in three steps, via nitroso and hydroxylamine intermediates, to the amine. The amine can go on to form polymeric residues by a mechanism analogous to that for oxidative coupling of phenols, as in Equation 2. Abiotic nitro reduction is well documented for pesticides that contain aromatic nitro groups, such as the phosphorothioate esters methyl and ethyl parathion (22, 30-33). 

Stannous chloride-mediated reductive cyclisation-rearrangement of the nitro-ketone 269 (obtained from the nitro-acid, 268) gave the dibenzothiazepine derivative 270 in good overall yield mechanistically it was proposed that a hydroxylamine intermediate leads to the rearrangement after intramolecular nucleophilic addition to the ketone [02JOC8662]. 

Since hydroxylamines, as well as their precursor oxime derivatives, are reduced by diborane to amines, the reaction has been extended by reducing the initially formed hydroxylamine intermediates (57) to amines (58). Thus excess borane reduces nitroalkenes (56) to amines (58) in the presence of a catalytic amount of sodium borohydride (equation 32). 

The reduction can also be achieved by utilizing in situ generated BHj THF (from sodium borohydride and boron trifluoride etherate). The scope of this reaction includes the synthesis of novel 3-chroman-amine derivatives (60 equation 33). This stereoselective reaction proceeds via the hydroxylamine intermediate only c/s-2-aryl-3-amino derivatives are obtained. 

The types of nitrogen-containing compounds that are most frequently involved in reductive biotransformation are those containing nitro, azo, and N-oxide functional groups. Similar enzymes are involved that are generally located in the endoplasmic reticulum or cytosol of the liver or in the intestinal microflora. Complete reduction of a nitro compound to the primary amine involves a six-electron transfer and proceeds through nitroso and hydroxylamine intermediates [Eq. (16)]. 

Since the condensation of the hydroxylamine intermediate with its precursor nitrosobenzene is a key step in generating coupled intermediates the presence of DMSO in the reaction mixture increased hydrazo compound formation but did so at the expense of a significant decrease in reaction rate. 2> 3... 

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

The reaction we propose to study is the hydrogenation of 2-methyl-2-nitropropane into /-butylamine through the nitroso and the hydroxylamine intermediates (scheme 1). This sequence is called "the main reaction". A preliminary study, encompassing temperature, catalyst mass, hydrogen pressure, initial reactant concentration, metal and support effects has already been carried out [5], For this nitroaliphatic compound, palladium appears to be more active than platinum, and less active than rhodium. On the other hand, carbon seems to be more appropriate as support than alumina or calcium carbonate. 

Medicinal chemists have tended to avoid the aromatic nitro group as a structural component of potential drugs because of the well-known ability of compounds such as trinitrotoluene (TNT), used in munitions, to cause a high incidence of methemoglobinemia following skin absorption. The mechanism involved is presumably in vivo reduction to nitroso and phenyl-hydroxylamine intermediates. However, many nonbenzenoid nitro compounds have been utilized in clinical practice since the introduction of the nitrofuran drugs in 1944. 

The 1952 example of this rare heterocyclic system, produced by the action of hydroxylamine on the isoxazolidone (223 Ar = 4-MeC6H4) remains unsubstantiated <52JCS3428>. No evidence for the 5-methyl-2-/ -tolyl-3,4-dihydro-2/f-l,2,6-oxadiazine structure (225) is presented other than an elemental analysis, and a comparison with a similar, but equally unsubstantiated, reaction involving the action of hydroxylamine on the lactone (226), which is deemed to give the 3,4-dihydro-2/7-l, 2,6-oxadiazine (228) <01M813>. If these structures are correct, then they represent the earliest examples of the 1,2,6-oxadiazine system and their production must involve formation of an N—O bond presumably by cyclization of oxime-hydroxylamine intermediates of the type (224) and (227) as indicated in Schemes 28 and 29. 

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