Oxidative transformation of ciprofloxacin by alkaline permanganate – A kinetic and mechanistic study

This spectroscopic study presents the kinetics and degradation pathways of oxidation of ciprofloxacin by permanganate in alkaline medium at constant ionic strength of 0.04 mol⁻³. Orders with respect to substrate, oxidant and alkali concentrations were determined. Effect of ionic strength and solvent polarity of the medium on the rate of the reaction was studied. The oxidation products were identified by LC-ESI-MS technique. Product characterization of ciprofloxacin reaction mixtures indicates the formation of three major products corresponding to m/z 263, 306, and 348 (corresponding to full or partial dealkylation of the piperazine ring). The piperazine moiety of ciprofloxacin is the predominant oxidative site to KMnO₄. Product analyses showed that oxidation by permanganate results in dealkylation at the piperazine moiety of ciprofloxacin, with the quinolone ring essentially intact. The reaction kinetics and product characterization point to a reaction mechanism that likely begins with formation of a complex between ciprofloxacin and the KMnO₄, followed by oxidation at the aromatic N1 atom of piperazine moiety to generate an anilinyl radical intermediate. The radical intermediates subsequently undergo N-dealkylation. Investigations of the reaction at different temperatures allowed the determination of the activation parameters with respect to the slow step of proposed mechanism. The proposed mechanism and the derived rate laws are consistent with the observed kinetics.     

Studies on a General Method for the Demethylation of Quaternized Nitrogen Heterocycles

Probably the best general method so far developed for the dealkylation of quaternized nitrogen heterocycles is the reaction of the iodide salts in an aprotic solvent in the presence of triphenylphosphine.^1,2 It has since been established³ that the iodide counterion is the active dealkylating agent, with the triphenylphosphine acting as a “methyl sponge”, preventing the reverse reaction from occurring. It follows, therefore, that any heterocycle (1) ought to be able to fulfil the same role as the triphenylphosphine with respect to the dealkylation of the quaternary salt of a less nucleophilic heterocycle (2). Since the reactivity to methylation of a large number of heterocycles with a reactivity range of ca 10⁶ is known⁴, the choice of a convenient heterocycle (1) to go with any heterocycle (2) is, in principle, a wide one.     

Heterocyclic diazo compounds. 5. Reaction of benzimidazole-2-diazonium salts with naphthols and their ethers

The principal pathways for the reaction of benzimidazole-2-diazonium ion salts with naphthols and their methyl ethers in a mixture of phosphoric acid annd acetic acid have been elucidated. In concentrated acidic media, in addition to substitution at the 4-position in naphthol and its ether, azo coupling at the 8-positin is also possible. It has been found that a 2-methoxy group in naphtylazobenzimidazole exhibits anomalously high reactivity with respect to hydrolytic cleavage, which explains the observed ease of dealkylation of the azo compound during the course of the azo coupling sequence.For Communication No. 4, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67–72, January, 1992.     

Regeneration of the Oxidation Catalysts Based on the Aqueous Solutions of Non‐Keggin Mo‐V‐P Heteropoly Acids by Molecular Oxygen

Kinetic peculiarities of regeneration of the aqueous solutions of non‐Keggin‐type Mo‐V‐P heteropoly acids H_aP_zMo_yV_x′O_b (HPA‐x′) and their acidic salts by O₂ are studied. The HPA‐x′ solutions have heightened thermal stability that permits to consider them as highly efficient catalysts for different oxidation processes. In the HPA‐x′ and their salts solutions, these peculiarities prove to be similar. The studied reaction is of the first order with respect to O₂ and V(IV), if [V(IV)] is higher than 0.8 M. As [V(IV)] decreases during the reaction, its order with respect to V(IV) increases to the third. The apparent activation energy of the reaction at temperatures 150–170°С is 37.5 kJ mol^?1. The obtained kinetic equation was used to calculate a new effective air reactor for the regeneration of the homogeneous HPA‐x′ catalyst in a pilot process of methylethylketone synthesis.     

Reactions of N-(4-methoxybenzylidene)-N,N-dialkyliminium and 2-(4-methoxyphenyl)pyridinium salts with aliphatic amines

The reaction of 4-methoxybenzylideneiminium salts with methylamine and dimethylamine on heating results in replacement of the MeO group by an alkylamino-group, whereas the reaction with piperidine affords 3,5-bis-(4-methoxybenzyl)pyridine. N-Methyl-2-(4-methoxyphenyl)pyridinium iodide on treatment with methylamine undergoes dealkylation to the arylpyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1226–1229, September, 1990.     

Catalyst activity in alkylthiophene dealkylation

The transformations of 2-alkylthiophenes on various catalysts were studied. In the presence of oxide and sulfide catalysts, 2-methylthiophenes and 2-isopropylthiophenes underwent dealkylation to thiophene. The reaction was complicated by isomerization to 3-alkylthiophene and cracking. The dealkylation of 2-ethylthiophene occurred only in the presence of oxide catalysts. Side-chain dehydrogenation resulting in the formation of 2-vinylthiophene primarily occurred under the action of sulfide and some oxide catalysts. Acid catalysts (amorphous aluminosilicate and zeolites in the form of hydrogen) were the most active and selective in the dealkylation of 2-alkylthiophenes. It is believed that the dealkylation reaction of 2-alkylthiophenes on these catalysts occurs by means of a protolytic mechanism.Translated from Kinetika i Kataliz, Vol. 46, No. 1, 2005, pp. 97–103.Original Russian Text Copyright © 2005 by Mashkina, Chernov.     

Determination of hydrogen peroxide by photoinduced fluorogenic reactions

4-Hydroxyproline, 8-hydroxyquinoline, 4-hydroxyquinoline-2-carboxylic acid and 4-hydroxyphenylacetic acid (HPA) react with H₂O₂ when irradiated with UV light to yield fluorescent products. Sub-micromolar detection limits of H₂O₂ are possible with HPA. The fluorescent product is the same as that formed in the peroxidase enzyme-mediated H₂O₂ oxidation of HPA. Several compounds that participate in the photomediated reaction do not react in the enzyme-mediated system. A mechanism for the photomediated reaction involving an aryloxy radical derived from the substrate is suggested. Although the limits of detection for H₂O₂ do not equal the best achievable with the enzyme-mediated systems, the simplicity of a single-step reaction and an ability to “photodevelop” the product offer a range of novel analytical possibilities.     

One-pot synthesis of hydrogen phosphonate derivatives of d4T and AZT

A simple and one-pot route for the synthesis of d4T or AZT hydrogen phosphonate derivatives via reaction of d4T or AZT with phosphorus trichloride, then alcoholysis and dealkylation in the presence of the corresponding alcohol is described.     

Intramolecular monodealkylation during the attempted synthesis of diethylphosphonoacetohydroxamic acid

The reaction of diethyl methyl phosphonoacetate ( 1 ) with hydroxylamine in NaOH solution resulted in the loss of one of the phosphorus ethyl groups, and yielded monoethylphosphonoacetohydroxamic acid ( 2 ) as the major product (79%) and diethylphosphonoacetic acid ( 3 ) as the minor product (21%). A series of control experiments were carried out to elucidate the sequence of the reactions leading to 2 . When the reaction of 1 with NH₂OH was carried out in NaHCO₃ solution, a transient product 4 was also observed, which slowly transformed to 2 . Compound 4 was assigned the structure diethylphosphonoacetohydroxamic acid. There was no dealkylation observed at the phosphorus when 1 was reacted with methoxylamine or when O‐methyl diethylphosphonoacetohydroxamate ( 7 ) was placed in alkaline solution. The dealkylation at phosphorus was interpreted in terms of intramolecular nucleophilic catalysis by the hydroxamic OH group attacking the phosphorus in 4 , involving cyclic 1,2,5‐oxazaphospholidine intermediates. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:67–71, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10082     

Synthesis of 2-substituted indoles via a palladium-catalyzed domino Heck reaction and dealkylation

A palladium-catalyzed domino Heck reaction and dealkylation for the preparation of 2-substituted indoles is described. This novel transformation is based on an intramolecular Heck reaction followed by dealkylation.     

Selective dealkylations of aryl alkyl ethers and thioethers by sodium in HMPA

The reaction of sodium with bis- and tris(alkoxy)benzenes in HMPA gives selectively the products of monodealkylation. The reaction proceeds through a dianion which fragments into an alkyl and an aryloxy anion. The positional selectivity of this fragmentation is governed by the structure of both the alkyl and aryloxy groups. With bis- and tris(alkoxy)benzenes which for symmetry reasons can afford aryloxy anions having the same basicity, the dealkylation involves exclusively the less substituted alkyl group. On the contrary, in the asymmetric terms, the positional selectivity of the dealkylation process is governed by the basicity of the aryloxy anion. On the basis of these concepts several efficient and synthetically useful reactions have been developed. In most cases the selectivity obtained in the present reactions is different from that observed with other previously developed methods which use sodium methoxide or sodium alkanethiolates in HMPA. It is shown that the appropriate chioce of the reagent allows selective dealkylation of the desired alkoxy group of a poly(alkoxy)benzene.

The reaction of sodium with bis(alkylthio)benzenes in HMPA gives the bis(mercapto)benzenes. If the reduction is caried out with a solution of sodium in HMPA, the reaction gives instead the products of monodealkylation. This however is not selective. It is suggested that in the case of thioethers the dealkylation products originate from the fragmentation of the radical anions.     

Superelectrophilic amidine dications: dealkylation by triflate anion

Superelectrophiles: Formamides were designed that when treated with triflic anhydride would be transformed into superelectrophilic amidine dications. These dications were so electrophilic that they underwent in?situ dealkylation by the triflate anion (see scheme; Tf=trifluoromethanesulfonyl). DFT calculations were used to determine the mechanistic details of the dealkylation reaction.     

Novel cleavage reaction of the C16-N17 bond in naltrexone derivatives

A dealkylation reaction of tertiary amines using chloroformate was a useful method for synthesizing morphinan derivatives without 17-substituents; however, the reaction has been applied to only the 14-hydromorphinans. In the course of the investigation of the 17-dealkylation reaction in 14-hydroxymorphinan, the novel cleavage reaction of the C16-N17 bond in the naltrexone derivative was found. A plausible reaction mechanism based on the stereoelectronic effect is presented. The examinations of dealkylation reactions in general tertiary amines ranked the tendency of cleavage as follows: benzyl > cyclopropylmethyl (CPM) ≈ allyl > methyl, ethyl. The preferable cleavage of the CPM group may be explained by the polarization of CPM-N17 bond due to a postulation of extreme stability of the cyclopropylcarbinyl cation.     

Microwave activation of catalytic transformation of t-butylphenols

Kinetics of catalytic transformation of 2- and 4-t-butylphenol (2TBP and 4TBP) in the liquid phase on a heterogeneous KSF catalyst has been studied in detail under conventional and microwave conditions. The process includes dealkylation, isomerization and transalkylation reactions. Its kinetics has been described using the method of initial reaction rates. It was found that microwaves affect both the reaction rate and the selectivity. The results were explained in terms of “microwave-induced polarisation” assuming an interaction of microwaves with a highly polarised reagent molecule in adsorbed state on the acidic active site. Temperature and solvent effects were also examined. The reaction mechanism of t-butylphenol transformation is discussed on the basis of electrophilic aromatic substitution via bimolecular reactions.     

Catalytic Properties of Heteropolyacid-Modified ZrO2 in the Partial Oxidation of Lower Alkanes by Nitric Oxide

The partial oxidation of C₃ and C₄ hydrocarbons by nitric oxide, in particular, their oxidation to alcohols, occurs on zirconium dioxide modified by various heteropolyacids (HPA). The catalyst activity depends on the amount of deposited HPA, while the reaction selectivity relative to the partial oxidation products correlates with the acid properties of the surface, in particular, with the concentration of weak acid sites.     

Synthesis of the antimalarial drug FR900098 utilizing the nitroso-ene reaction

The antimalarial drug FR900098 was prepared from diethyl allylphosphonate involving the nitroso-ene reaction with nitrosocarbonyl methane as the key step followed by hydrogenation and dealkylation. The utilization of dibenzyl allylphosphonate as the starting compound allows one-step hydrogenation with dealkylation, which simplifies the preparative scheme further.     

Enantioselective Oxidative Aerobic Dealkylation of N‐Ethyl Benzylisoquinolines by Employing the Berberine Bridge Enzyme

N‐Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N‐dealkylation has not been yet reported. In this study, exclusively the (S)‐enantiomers of racemic N‐ethyl tertiary amines (1‐benzyl‐N‐ethyl‐1,2,3,4‐tetrahydroisoquinolines) were dealkylated to give the corresponding secondary (S)‐amines in an enantioselective fashion at the expense of molecular oxygen. The reaction is catalyzed by the berberine bridge enzyme, which is known for C? C bond formation. The dealkylation was demonstrated on a 100 mg scale and gave optically pure dealkylated products (ee>99 %).     

Reactions of 1-methyl-derivatives of 2-oxo-1,2,3,4-tetrahydropyrimidine with phosphorus pentachloride and phosphorus oxychloride

In the reaction of 4-phenyl- and 4,6-diphenyl-1-methyl-2-oxo-5-ethoxycarbonyl-1,2,3,4-tetrahydropyrimidines with phosphorus pentachloride, oxidation and dealkylation takes place in addition to chlorination and as a result one obtained 4-phenyl- and 4,6-diphenyl-1-methyl-5-ethoxycarbonyl-2-pyrimidones and also 4-phenyl-, (4,6-diphenyl)-5-ethoxycarbonyl-2-chloropyrimidines. 1,6-Dimethyl-2-oxo-4-phenyl-5-ethoxycarbonyl-1,2,3,4-tetrahydropyrimidine in the same reaction gives 1-methyl-2-oxo-4-phenyl-5-ethoxycarbonyl 6-dichloromethyl-1,2,3,4-tetrahydropyrimidine, together with 6-chloromethylene- and 6-dichloromethylene-1-methyl-2-oxo-4-phenyl-5-chloro-5-ethoxycarbonylhexahydropyrimidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 668–671, May, 1987.     

An efficient FeCl3‐promoted O‐alkyl cleavage of esters to carboxylic acids

A reliable and practical procedure for FeCl₃‐promoted ester cleavage has been developed. Lewis acids including TiCl₄, ZnO and FeCl₃ etc. were investigated as promoters for O‐alkyl cleavage of carboxylic acid ester. Under optimal reaction conditions, FeCl₃ (1.5 equiv.) was found to possess the highest activity and efficiently enhanced dealkylation of aryl esters, alkyl esters and aromatic heterocyclic esters to give their corresponding carboxylic acids in 54–98% yield, the method provides a complementary access to dealkylation of ester under neutral condition. Copyright © 2011 John Wiley & Sons, Ltd.     

Cleavage by halogens of carboncobalt bonds in organometallic complexes of cobalt(III) : II. Organobis(dimethylglyoximato)cobalt(III) complexes

The reaction between organocobaloximes and ICl in chloroform has been studied. In absence of an excess of added chloride ion the reaction is electrophilic in character; in presence of an excess of chloride ion both oxidative dealkylation and radical attack can occur.