Aminotriazole oxidation

Indicine IV-oxide (169) (Scheme 36) is a clinically important pyrrolizidine alkaloid being used in the treatment of neoplasms. The compound is an attractive drug candidate because it does not have the acute toxicity observed in other pyrrolizidine alkaloids. Indicine IV-oxide apparently demonstrates increased biological activity and toxicity after reduction to the tertiary amine. Duffel and Gillespie (90) demonstrated that horseradish peroxidase catalyzes the reduction of indicine IV-oxide to indicine in an anaerobic reaction requiring a reduced pyridine nucleotide (either NADH or NADPH) and a flavin coenzyme (FMN or FAD). Rat liver microsomes and the 100,000 x g supernatant fraction also catalyze the reduction of the IV-oxide, and cofactor requirements and inhibition characteristics with these enzyme systems are similar to those exhibited by horseradish peroxidase. Sodium azide inhibited the TV-oxide reduction reaction, while aminotriazole did not. With rat liver microsomes, IV-octylamine decreased... 

Aminotriazoles and their derivatives can be prepared from bis hydrazones and from substituted bis hydrazones of a-diketones. The bis hydrazones may in some cases be prepared more conveniently from -bromoketones than from a-diketones. Oxidation with mercuric oxide or with manganese dioxide gives the 1-aminotriazoles directly (Scheme m-ns Although two isomeric triazoles would be ex-... 

Bis acylhydrazones or bis aroylhydrazones of a-diketones also give derivatives of 1-aminotriazoles on mild oxidation (Scheme 21).i n The product was originally assigned a dihydrotetrazine structure, and other possibilities were considered,but Curtin and Alexandrou proposed the isoimide structure (8) which was, for the product obtained from biacetyl bis(benzoylhydrazone), confirmed by X-ray crystallography. The mechanism given in Scheme 21 has been put forward for its formation ... 

Another aziridine synthesis based on intermediary nitrenes derived from the oxidation of aminotriazole 22 with IBD in the presence of alkenes is outlined in Scheme 11 (74TL2945). 

For a review of V-amino-l,2,3-triazoles, see Kuzmenko and Pozharskii <92AHC(53)85>. For the oxidation of iV-aminotriazoles and benzotriazoles, also see Section 4.01.4.11. 

Azides (24) thermally decompose to tetrazines (Equation (8)) <66TL5369> and 4-aminotriazoles (25) are cleaved by lead tetraacetate oxidation (Equation (9)) <70TL385l>, both presumably via the nitrene as intermediate. 

N-Substituted benzotriazole intermediate (77) is an excellant synthon for the synthesis of 2-ethoxy-2-vinylcyclopropanecarboxylate esters (78) [95JOC6], 1-Propargylbenzotriazole was reacted with bromoacetophenone to provide the novel 2-(benzotriazolomethyl)furan (80) in 60% yield [95JOC638]. Annelated N-aminotriazoles, on oxidation, are a good source of cyclic alkynes as illustrated for the reaction of aminotriazolotropone (80) with 4-phenyloxazole to generate the furyl[3,4-cf]tropone (82) from a Diels-Alder intermediate with facile loss of benzonitrile [94TL8421 ]. 

It is also possible to prove the occurrence of cycloheptyne (IS) and cyclohexyne (20) in solution. Here, as in the isolation of very reactive cycloalkynes, it is essential to generate the intermediate in a fast reaction at low temperatures in the absence of a reactive reagent which could add to the cycloalkyne. Again, an oxidative decomposition with lead tetraacetate, here of the corresponding 1-aminotriazoles (22) resp (27), is used for the generation of (16) and (20)14). 

There are striking similarities in the physical [Fig. 2 (126) and Fig. 3 (126b)] and chemical properties of the cyanylated enzyme (Table V) and the aminotriazole-catalase derivative. Both retain the structural integrity and ferric oxidation state of the native enzyme. In addition, as gauged by their optical spectra [Fig. 2, but see also Figs. 6A and 6B of Margoliash and Novogrodsky (111)], the modification of the apopro-... 

Diphenylhydrazine is oxidized to diphenylnitrosamine (50%) by potassium superoxide. The same reagent also oxidizes 1-methyl-1-phenylhydrazine, but here the nitrosamine is a minor product the major reaction is deamination. A better meAod of oxidative deamination of some 1,1-disubstituted hydrazines and hydrazinium salts is reaction with nitrous acid. Thus, several hydrazinium salts MezRN NHi X were deaminated to the tertiary amine by treatment with nitrous acid. The method has also been used to deaminate IV-aminoheterocyclic compounds for example, some 1,2,3-triazoles are conveniently prepared by deamination of the corresponding 1-aminotriazoles with nitrous acid. °... 

The 1,2,4-triazole ring survives oxidative destruction of aromatic substituents and rings fused to it but destabilization by a nitrene intermediate (45) permits the oxidative cleavage of 4-aminotriazoles (46 Scheme 13) (70TL3S51). Another instance of destabilization of the ring by a nitrene substituent (Scheme 14) is the thermal decomposition of azides (47) to... 

The triazole (346) can be used to stabilize plastics (73JAP7308667). The reaction of tributyl lead hydroxide and aminotriazole affords (347) which has been recommended as an antiwear component of lubricating oils (68FRP1525268). Diazonium compounds detonate, although they are safer to handle than comparable derivatives of tetrazole. Polyfluorotriazolines (67USP3326889) are oxidants their suitability as bleaching agents, for rocket fuels and constituents of pyrotechnic compositions has been claimed. 

Table 1. Yields of cycloalkyne adducts. I Grignard reaction II oxidation of bishydrazone III base elimination of bromomethylene derivative IV oxidation of aminotriazole V photolysis of tosylaminotriazole anion...

Nucleophilic additions to the acetylenic bond in various short-life cyclic acetylenes including optically active derivatives have been extensively studied . The formation of 1,2-di-bromocycloheptcne was also observed in the bromine oxidation of the aminotriazole derivative 21 n = 7). ... 

I, was oxidized with lead tetraacetate (LTA), the characteristic Diels-Alder adduct with tetracyclone (TC) could be obtained even when the diene was added following completion of N2 evolution, indicating that the polymer-bound intermediate had survived for tens of seconds. Secondly, while LTA oxidation of the monomeric aminotriazole I-a, affords the corresponding biphenylenes in high yield, the only products formed by I-b, in the absence of TC, were the aryl acetates II and III (combined yield of 80%). Monomeric o-benzyne is known to dimerize at the diffusion limited rate in the gas phase, therefore, formation of the Diels-Alder product following delayed addition of diene requires a substantially slower encounter process for the polymer-bound analog. 

A related approach makes use of an N-aminotriazole such as 5789 or 90) which on oxidation with lead tetraacetate liberates two equivalents of nitrogen along with a hetaryne. An advantage of this method is that a range of temperatures may be used to generate an intermediate. 

This method was substantially modified latter by Alexandrou and Adamopoulos, who oxidized bissemicarbazones of a-dicarbonyl compounds with lead tetraacetate [Eq. (32)] (76S482). Supposedly, the oxidant is necessary for conversion of bissemicarbazone to bisazo-compound (114), which is transformed to 1-ureidotriazole via triazole betaine (115). If substituents R and R differ, a mixture of two isomeric 1-aminotriazoles is formed, and the isomer with a bulky substituent in position 4 predominates. 

Japanese chemists, on oxidation of l-amino-5-phenyl-l,2,3-triazolo[4,5-first example of the ring enlargement on oxidation of N-aminotriazoles. Probably, the reason for this involves the known instability of fivemembered hetarynes, which lower the activation energy for the )V-nitrene rearrangement relative to that for the fragmentation. 

Addition of hydrazine to the nitrile function leads to amidrazones, which cyclocondense by dimerization yielding 1,4-dihydro-1,2,4,5-tetrazines 17 their dehydrogenation produces 20. In an alternative preparation, thiohydrazides 18 or -alkyl isothiohydrazides 19 are oxidatively dimerized, also via 1,4-dihydro-1,2,4,5-tetrazines 17, to afford 1,2,4,5-tetrazines, with 1-aminotriazoles 21 as byproducts. 

Two pathways have been described for formate metabolism a peroxidatic pathway via catalase and a folate dependent one carbon pathway. Treatment of rats with amino-triazole, an irreversible inhibitor of catalase, severely depressed a-oxidation activity but only slightly decreased the production of CO2 from exogenously added formate. " Whether the effect of aminotriazole is (solely) linked to the inhibition of catalase is unclear (see further). In addition to these above mentioned pathways our data point to a cytosolic NAD -dependent dehydrogenase activity that acts on the formate produced during a-oxidation. In peimeabilized cells or broken systems, suppUed with the qi-propriate cofactors (see further), almost no CO2 is formed, during a-oxidation unless NAD is added. ... 

Casteels, M., Croes, K., Van Veldhoven, PP. Maimaerts, G.P. (1994) Biochem. Pharmacol 48, 1973-1975. Aminotriazole is a potent inhibitor of a-oxidation of 3-methyl-substituted fatty acids in rat liver. 

Catalase activity was completely inhibited 300 minutes after the addition of aminotriazole (Rgure 1a). This was accompanied by a decrease in the CO2 assimilation rate (Figure 1b). However, contrary to expectations the H2O2 concentration remained unaffected (Figure la). This decrease appears not to be due to increased H2O2 levels resulting in oxidation of the PCR cycle enzymes as previously suggested (9,10). 

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