Aqueous reactions hydroxamic acids

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Other zinc reductions have been used extensively. Zinc dust in aqueous ammonium chloride is a standard reagent for the reductive cyclization of nitro esters to hydroxamic acids. These reactions are usually carried out at low temperatures (0°-10°) to avoid further reduction. Despite the fact that good yields can often be obtained, these reductions are highly capricious, depending on the quality of the zinc (impurities seem to improve the reaction) and other unknown factors. 

A mixture of 3-hydroxy-4-phenylfurazan and 1,2,4-oxadiazole 243 was prepared from a-phenyl-a-hydroximino hydroxamic acid by acylation and subsequent treatment with 15% aqueous NaOH (Scheme 164) (25G201). The reaction of tetraacetate 244 with sodium acetate hydrate in glacial acetic acid at 70°C gives 3,4-dihydroxyfurazan (9%) (92URP1752734). a-Hydroximino ester 245 reacts with hydroxylamine to form furazan 246 in 25% yield (Scheme 164) (79JHC689). 

In the Lossen reaction a hydroxamic acid derivative (usually an 0-acyl derivative) is deprotonated by base, and rearranges via migration of the group R to give an isocyanate 2. Under the usual reaction conditions—i.e. aqueous alkaline solution—the isocyanate reacts further to yield the amine 3. The Lossen reaction is closely related to the Hofmann rearrangement and the Curtins reaction. 

The intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

An intramolecular hetero-Diels-Alder reaction of enantiomerically pure iV-acyl nitroso derivatives 78, prepared from hydroxamic acids 77 by oxidation on treatment with Pr4NI04 in an aqueous medium, afforded a mixture of diastereomeric pyrido[l,2-A][l,2]oxazin-8-ones 79 and 80 (Scheme 5) <1996J(P1)1113, 20000L2955,... 

Bromolactamization (11, 76). This reaction can be used for stereoselective preparation of 3,4-disubstituted 3-lactams.1 Thus the P,-y-unsaturated hydroxamic acid 1, prepared in several steps from tiglic acid, on reaction with bromine and K2C03 in aqueous CH,CN cyclizes mainly to a rrans-p-lactam (2). In contrast, the protected a-amino-p,y-unsaturated hydroxamic acid 3, prepared in several steps from L-methionine, cyclizes on reaction with bromine mainly to a ris-p-lactam (4). 

Ho and coworkers" have observed that the addition of small amounts of solid KCN (0.2 equivalents) can effectively accelerate the formation of hydroxamic acids 112 from methyl esters 111 (Scheme 58). The authors suggested that this reaction proceeds through an acylcyanide intermediate followed by nucleophilic substitution by 50% aqueous hydroxylamine at room temperature. The use and advantage of this methodology have been demonstrated for both solution-phase and solid-phase applications. 

The structures of the N-substitution products are reminiscent of the C-8 adduct that is the major product of the reaction of 2-fluorenyl-, 4-biphe-nylyl- and other N-arylhydroxylamine and hydroxamic acid esters with 2 -deoxyguanosine, (d-G) 2 deoxyguanosine-5 -phosphate (d-GMP), guano-sine, (G) or DNA in an aqueous environment." The mechanism of this reaction was not seriously investigated for many years because of the mistaken impression that the reaction was inefficient and could not compete with... 

Hydroxamic acids have been the subject of six papers 43 90 94 Earlier the operation of the a-effect in the reaction of p-nitrophcnyl acetate with benzohydroxamates in aqueous MeCN was discussed.43 The conformational behaviour of series of mono- (105) and di-hydroxamic acids (106) in MeOH, DMSO, and chloroform and in the solid state has been examined witii IR and NMR spectroscopy.90 X-ray crystal structure determinations of (105 X = Me, R = Me) and die monohydrate of glutarodihydroxamic acid (106 n = 3, R = H) together widi ab initio MO calculations for several hydrated and non-hydrated acids have been performed. The cis-Z conformation of the hydroxamate groups is preferentially stabilized by H-bonding witii water. 

Butler, R.J., Sinkov, S., Renshaw, J.C. et al. 2000. Reactions of plutonium with aceto-hydroxamic acid in aqueous solution First results. ATALANTE 2000, Avignon, France, October 24-26, P2-09. 

Aliphatic nitroso compounds can be prepared from IV-alkylhydioxylamines oxidation widi bromine, chlorine or sodium hypochlorite in weakly acidic solution, reaction with potassium dichromate in acetic or sulfuric acid, and by oxidation widi yellow mercury(II) oxide in suspension in an organic solvent. Silver carbonate on Celite has also been used to prepare aliphatic nitroso compounds, such as ni-trosocyclohexane, in high yield from the corresponding hydroxylamines." Aqueous sodium periodate and tetraalkylanunonium periodates, which are soluble in organic solvents, are the reagents most commonly used for the oxidation of hydroxamic acids and IV-acylhydroxylamines to acylnitroso compounds... 

To avoid any possible a — 7 conversion promoted by the anhydrous conditions during esterification Franzblau (1962) and Franzblau el al. (1963) developed a method by which the hydroxamic acids could be formed directly from the unmodified proteins in an aqueous system. This was achieved using a water-soluble carbodiimide, 1-cyclohexyl-3[2-morpholinyl-(4)-ethyl]-carbodiimide metho-p-toluene sulfonate (Fig. 5). The reaction conditions (pH 4, 25°C, in aqueous medium) eliminated any possibility of a —> 8 conversion. These conditions also precduded the possibility of hydroxyaminolysis of the natural ester linkages of collagen which will be discussed in Section V. This method, in common with all the others used to study 7-glutamyl links, was not quantitative. After subsecpient dini-... 

Three papers from Ghosh s group deal with the hydrolysis of benzohydroxamic acids in acidic and alkaline conditions. A pre-equihbrium protonation followed by a slow A-2 type nucleophilic attack by water is seen as the mechanism of the acid-catalysed hydrolysis of j -chlorophenylbenzohydroxamic acid (107 R = / -ClCgEU) by mineral acids (HCl, HCIO4) in 20% aqueous dioxane. An A-2 mechanism was also supported for the reaction of (107 R = Me) imder comparable conditions. The alkaline hydrolysis imder micellar conditions of (107 R = Ph) and a series of para-substituted derivatives has been investigated in the presence of cationic and anionic micelles in 5% dioxane-water medium at 55 °C. Cationic surfactants exerted a catalytic effect and anionic surfactants were inhibitory. The rate-surfactant profiles were analysed in terms of the pseudophase and Piszkiewicz models. The detection of N2O in the products of the oxidation of hydroxamic acids suggests the intermediacy of nitroxyl, HNO, in the process. Scheme 9 may represent the pathway followed. 

Electrophilic N-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and C>-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35)." This reaction has been extended to synthesis of N-arylhyd ines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of N-aryl-O-acetylhy oxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions." ... 

The original procedure for the Nef reaction involved the aqueous sulfuric acid hydrolysis of the salts (170) obtained by the treatment of primary and secondary nitroalkanes with sodium hydroxide (equation 30). In contrast, if a neutral primary nitro derivative is treated in hot concentrated mineral acid, the corresponding carboxylic acid (172) is formed via the hydroxamic acid (171 equation 31). This reaction is known as the Meyer reaction and was first described in 1873. Protonation of salts of nitroalkanes occurs preferentially at the oxygen atom to give the aci form (173 equation 32). 

Lossen Rearrangement,78 The thermal decomposition of hydroxamic acid derivatives leads to isocyanates or, in aqueous solution, to amines. This reaction is usually called the Lossen rearrangement. Its mechanism... 

Other methods, among which thermolysis or photolysis of tetrazene [59], photolysis of nitrosoamines in acidic solution [60], photolysis of nitrosoamides in neutral medium [61], anodic oxidation of lithium amides [62], tributylstannane-mediated homolysis of O-benzoyl hydroxamic derivatives [63, 64], and spontaneous homolysis of a transient hydroxamic acid sulfinate ester [65] could have specific advantages. The redox reaction of hydroxylamine with titanium trichloride in aqueous acidic solution results in the formation of the simplest protonated aminyl radical [66] similarly, oxaziridines react with various metals, notably iron and copper, to generate a nitrogen-centered radical/oxygen-centered anion pair [67, 68]. The development of thiocarbazone derivatives by Zard [5, 69] has provided complementary useful method able to sustain, under favorable conditions, a chain reaction where stannyl radicals act simply as initiators and allow transfer of a sulfur-containing... 

DFP is stable and in the absence of moisture can be stored for considerable periods without decomposition. Hydrolysis in neutral aqueous solution occurs slowly. The reaction is catalyzed by both acid and base. At pH>7, hydrolysis is proportional to the hydroxide ion concentration and at high pH is extremely rapid. The product is always diisopropyl phosphoric acid (equation 38), except under more forcing conditions which eventually produce phosphate (and propan-2-ol). The hydrolysis is strongly catalyzed by the addition of a-effect nucleophiles such as hypochlorite, peroxide, hydroxylamine, hydroxamic acid and their substituted derivatives . Under basic conditions, such nucleophiles (HOX) are present as the anion and are responsible for the rapid initial displacement of fluoride ion from DFP to give intermediate 36 shown in equation 39. Displacement of OX by hydroxide ion regenerates the catalytic OX anion. The reaction with hydrogen... 

---