Hydrogenolysis of N-O Bonds

The nitrogen-oxygen bond is usually cleaved readily by catalytic hydrogenolysis and the reaction has wide synthetic utility. 

Nitro Compounds. Under mild conditions, aromatic nitro compounds are hydrogenated easily to amines.518 The reaction may give partially reduced products, according to the circumstances. Palladium, platinum, and nickel are used frequently for this reaction. For example, nitro and benzyl ester functions are reduced on Pd(OH)2/C on THF and on Pd/C in EtOH.519 Aliphatic nitro groups are reduced more slowly. 

Amine Oxides Catalytic hydrogenolyses of aromatic N-oxides occurs easily except if the N-O bond is hindered. Rh/C is the most active catalyst compared with Ru/C, Pt/C, and Pd/C, but this catalyst is unselective and reduces aromatic rings as well. N-Oxides can also be reduced in EtOH with a catalytic amount of Ra-Ni under hydrogen at 40°C for 1.5 hours.533 

The N-O bond in an isoxazolidine ring was hydrogenolyzed on 5% Pd/C in MeOH for 12 hours in a hydrogen atmosphere at room temperature.544 

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SCHEME 16.47 Stepwise hydrogenolysis of N—O bonds in a nitroso acetal. 

It is widely accepted that a benzyl-nitrogen bond is not as readily cleaved as a benzyl-oxygen bond. The presence of nitrogen can, however, influence the hydrogenolysis of C-O bonds. It has been reported that butylamine completely prevented the hydrogenolysis of the benzylic C-O bond [62]. The same effect was observed for molecules containing both benzylic C-O and C-N bonds [62,63]. In a mixture of A-benzylcyclohexylamine and benzyl cyclohexyl ether only the C-N bond was hydrogenolyzed on Pd/C, whereas in the presence of HCl the... 

CyrA,HuotP,BelotG, Lessard J (1990) The efficient electrochemical reduction of nitrobenzene and azoxybenzene to aniline in neutral and basic aqueous methanolic solutions at Devarda copper and Raney nickel electrodes electrocatalytic hydrogenolysis of N-O and N-N bonds. Electrochim Acta 35 147-152... 

Catalytic Hydrogenolysis of Carbon-Huonne Bonds it-Bond Participation Mechamsm Hudlicky, M J Fluorine Chem 44, 345-359 58 n o C) S ... 

Under the conditions used for the reductive cleavage of the O—N bond in isoxazoles, a similar reaction readily occurs with isoxa-zolines, e.g. on treatment with organomagnesium compounds and on catalytic hydrogenation.- Hydrogenolysis of the O—N bond (180 181 182 183) was used to elucidate the structure of isoxa-zolones from -ketoesters. -... 

Treatment of the 0,0-dibenzyl derivative of norneoenactin with 10% Pd/C in MeOH under hydrogen atmosphere resulted in the rapid deprotection (within 1 h) of the starting material. However, reduction of the benzyl ether functionality, without the concomitant hydrogenolysis of the N-O bond, required fine tuning of the conditions. When the hydrogenolysis was carried out using 20-25 mol % of 10% Pd/C at 20 or 30 mM concentrations for 22-31 hours, a... 

Catalytic hydrogenolysis of the bisbenzylated Boc-neonactin A (21 in Scheme 4.97) using 10% Pd/C provided an inseparable mixture of the deben-zylated product and the N4-deshydroxy compound (22).343 Various manipulations of the reaction conditions including changing the solvent, the mol equivalents of Pd, and the reaction time proved unsuccessful. But with the use of an extended period of reaction time, the N-O bond can be completely removed. The bisbenzylated Boc-neonactin A and 10% Pd/C in EtOH were stirred under a hydrogen atmosphere for 7 days, providing the N4-deshydroxy compound in 70% yield (Scheme 4.97). 

Hydrogenolysis of the N-O bond was also observed on Pd/C catalyst in MeOH (Scheme 4.99).344... 

Hydrogenolysis of hydroxybenzamidines to benzamidines has always been of interest to the hydrogenation chemists. The hydrogenolysis of the N—O bond in these compounds was performed on 4% Pd/C in AcOH at 60°C and 60 psi hydrogen pressure (Scheme 4.138).531,532... 

Nitroso Acetals Hydrogenation of a nitroso acetal on Ra-Ni at 1 atm H2 for 1 hour afforded a ketone via the hydrogenolysis of the N-O bonds and the cyclohexyl C—O bond (Scheme 4.147).546... 

V-( 1,1 -dimcthylbut-3-cnyl)-hydroxylamine followed by intramolecular 1,3-dipolar cycloaddition, was easily converted into the polyhydroxylated quinolizidine 192 by removal of the isopropylidene group and hydrogenolysis of the N-O bond in the presence of Raney-nickel accompanied by intramolecular reductive amination (Scheme 35) <2001CC915>. 

Generally, hydrogenolysis involves cleavage of the endocyclic N—O bond as the first step. For example, four-membered cyclic nitronates can be reduced successively to a-hydroxy-oximes (167) (Scheme 3.116, Eq. 1). Unfortunately, the yield of the target product was not reported. 

An interesting route to indolizidine 157 is based on N-O bond cleavage in perhydro[l,2-A isoxazole 156 by hydrogenolysis of the mesylated intermediate (Equation 24) <2000TL1583>. 

Oxazines are prone to hydrogenolysis since the relatively weak N-O bond is easily cleaved. This reaction has often been employed for the transformation of this cycle (generally obtained from nitrones) into amino alcohols in a stereocontrolled manner. For example, reaction of 57 with hydrogen and palladium on charcoal as catalyst (Equation 1) furnished the expected substituted pyrrolidine 58 in moderate yields <2003EJ01153>. 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

The lactone 88 having an exo-cyclic double bond was applied in a 1,3-dipolar cycloaddition with nitrile oxides in recent work by Gallos et al. (Scheme 12.29) (133). The ip/ro-isoxazoline (89) was obtained as the sole diastereomer from the addition of the stable nitrile oxide 87. The resulting adduct 89 was further subjected to N—O bond cleavage by hydrogenolysis, followed by a spontaneous cyclization to give the carbocyclic product 90 in 64% yield. 

Removal of the benzyl group in heterocyclic sulfonamide 82 can be achieved by exposure to formic acid followed by ethanolic KOH (Equation 17). This method is effective where the classical method of debenzylation, namely hydrogenolysis, would result in N-O bond cleavage as outlined above <2005TA761>. 

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