Iron-catalyzed Oxidative Reactions Research Articles

The role of histidine buffer in the iron-catalyzed formation of oxidizing species in pharmaceutical formulations: Mechanistic studies.

Iron-catalyzed oxidation reactions are common degradation pathways in pharmaceutical formulations. Buffers can influence oxidation reactions promoted by iron (Fe) and hydrogen peroxide (H₂O₂). However, mechanistically, the specific role of buffers in such reactions is not well understood. Here, we investigate the formation of radical intermediates using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a probe. Interestingly, over the time course of our experiments histidine (His) is the only buffer that promotes significant radical production during Fe(III)-catalyzed decomposition of H₂O₂, in contrast to other common pharmaceutical buffers such as citrate, succinate, adipate, and 2-(N-morpholino)ethanesulfonic acid (MES). The critical role of His in these degradation reactions is attributed to its unique, higher affinity for Fe(II) as compared to Fe(III), facilitating the reduction of Fe(III) to Fe(II) and subsequent Fenton and/or Fenton-like reactions with H₂O₂.

Liposome-encapsulated glycyrrhizin alleviates hyperglycemia and glycation-induced iron-catalyzed oxidative reactions in streptozotocin-induced diabetic rats

Glycyrrhizin, a bioactive constituent of Glycyrrhiza glabra has been reported to ameliorate diabetes. Here, the effects of liposome-encapsulated glycyrrhizin on STZ-induced diabetes and associated oxidative stress were investigated. Wistar rats were grouped as control (NC, received placebo), diabetic (DC, STZ-induced), diabetic treated with free glycyrrhizin (DTG, 3 i.v. doses, 1.6 mg/0.5 ml), empty liposomes (DTl, 3 i.v. doses), and liposome-encapsulated glycyrrhizin (DTbd, 3 i.v. doses, 1.6 mg/0.5 ml). Serum glucose, insulin, intraperitoneal glucose tolerance test and glycohemoglobin were estimated. Free iron and iron-mediated oxidative stress were examined. Histological examinations of the kidney and liver were performed. Liposomal-glycyrrhizin treatment caused significant improvement of hyperglycemia (DC vs. DTbd p < .05), glucose intolerance (DC vs. DTG p < .01 and DC vs. DTbd p < .05), insulin (DC vs. DTG p < .1, DTbd vs. DC p < .05 and DTbd vs. DTG p < .1) and glycohemoglobin (DC vs. DTG p < .1 and DC vs. DTbd p < .05) levels in the DTbd group. Alleviation of free iron release (DC vs. DTbd p < .05), lipid peroxidation (DC + H2O2 vs. DTbd + H2O2 p < .05), deoxyribose (DC + H2O2 vs. DTbd + H2O2, p < .05), and DNA degradation occurred in the DTbd group. The abnormalities of the kidney and liver were abolished in the DTbd group. The inhibitory effects were more pronounced compared to free glycyrrhizin. Liposome-encapsulated glycyrrhizin treatment caused inhibition of diabetic complications through its antioxidant effects and can be exploited for effective treatment of diabetes.

Iron-Catalyzed Oxidative Cross-Coupling of Phenols and Tyrosine Derivatives with 3-Alkyloxindoles.

In this study, a novel iron-catalyzed oxidative cross-coupling reaction between phenols and 3-alkyloxindole derivatives is reported. The efficient method, which is based on the FeCl3 catalyst and the t-BuOOt-Bu oxidant in 1,2-dichloroethane at 70 °C, affords 3-alkyl-3-(hydroxyaryl)oxindole compounds with a high degree of selectivity. The generality of the conditions was proven by reacting various substituted phenols, naphthols, and tyrosine derivatives with 3-alkyloxindoles. To apply the chemistry for the conjugation of tyrosine-containing short peptides with oxindolylalanine (Oia) derivatives, the reaction conditions were modified [Fe(O2CCF3)3 catalyst, t-BuOOt-Bu, HFIP, 70 °C], and amino acids with acid-stable N-protecting groups were used.

Total Synthesis of (-)-Calycanthine via Iron-Catalyzed Stereoselective Oxidative Dimerization.

Dimeric cyclotryptamine alkaloids typically feature vicinal all-carbon quaternary stereocenters and four nitrogen atoms. In comparison with the actual biosynthetic tryptophan derivatives, we designed the 2N-featured monomer 7, aiming to construct vicinal all-carbon quaternary stereocenters via a one-step dimerization process to access the 4N-featured isomeric members of this family. In this work, we disclose the first synthetic route to access the skeleton of (-)-isocalycanthine, featuring an iron-catalyzed oxidative dimerization reaction in a catalytic single-step operation with an overwhelming control of the absolute and relative stereochemistry. This strategy has been successfully applied to the total synthesis of (-)-calycanthine and 16 isocalycanthine derivatives, which demonstrates a new synthetic pathway for dimeric cyclotryptamine alkaloids.

A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

Mixed tetradentate NHC/1,2,3-triazole iron complexes bearing cis labile coordination sites as highly active catalysts in Lewis and Brønsted acid mediated olefin epoxidation

Two bio-inspired non-heme iron complexes bearing mixed tetradentate N-heterocyclic carbene/1,2,3-triazole ligands with cis labile coordination sites are reported. The compounds are studied in olefin epoxidation catalysis using H2O2 as oxidant. Sc(OTf)3, HClO4 and HOAc are applied as additives resulting in significant improvement of catalytic performance. Under optimized conditions the most active catalyst exhibits activities of 76,000 turnovers per hour, which is the highest reported value for an iron(II) catalyst. The complexes reveal comparably high stability and enable the challenging epoxidation of functionalized olefins. These results prove 1,2,3-triazoles to be promising and tunable ligands for iron catalyzed oxidation reactions.

Recent Advances in Iron Catalyzed Oxidation Reactions of Organic Compounds

AbstractIron‐catalyzed oxidation reactions have been increasingly investigated in the past two decades and have seen a major increase in research activity. This review article demonstrates the vigorous research activities in the field based on examples from the most recent literature. Catalyst systems are discussed that are active in the oxygenation of alkanes and alkenes to obtain alcohols, ketones or epoxides. Iron‐catalyzed oxidation of alcohols to the corresponding carbonyl units are also included. Enantioselective and heterogeneous catalyst systems are presented as well, and a brief overview of mechanistic pictures is given.

Spectroscopic investigation and direct comparison of the reactivities of iron pyridyl oxidation catalysts

The growing interest in green chemistry has fueled attention to the development and characterization of effective iron complex oxidation catalysts. A number of iron complexes are known to catalyze the oxidation of organic substrates utilizing peroxides as the oxidant. Their development is complicated by a lack of direct comparison of the reactivities of the iron complexes. To begin to correlate reactivity with structural elements, we compare the reactivities of a series of iron pyridyl complexes toward a single dye substrate, malachite green (MG), for which colorless oxidation products are established. Complexes with tetradentate, nitrogen-based ligands with cis open coordination sites were found to be the most reactive. While some complexes reflect sensitivity to different peroxides, others are similarly reactive with either H2O2 or tBuOOH, which suggests some mechanistic distinctions. [Fe(S,S-PDP)(CH3CN)2](SbF6)2 and [Fe(OTf)2(tpa)] transition under the oxidative reaction conditions to a single intermediate at a rate that exceeds dye degradation (PDP=bis(pyridin-2-ylmethyl) bipyrrolidine; tpa=tris(2-pyridylmethyl)amine). For the less reactive [Fe(OTf)2(dpa)] (dpa=dipicolylamine), this reaction occurs on a timescale similar to that of MG oxidation. Thus, the spectroscopic method presented herein provides information about the efficiency and mechanism of iron catalyzed oxidation reactions as well as about potential oxidative catalyst decomposition and chemical changes of the catalyst before or during the oxidation reaction.

Iron-Catalyzed Oxidative Coupling Reaction of N-Acyl Glycine Esters and Malonates

An iron-catalyzed direct C–C double-bond formation process is described in this paper. Using DTBP as the oxidant and FeCl3·6H2O (20 mol%) as the catalyst, N-2-pyridinecarbonyl glycine esters were coupled with malonates to provide amido acrylates in moderate to good yields. A possible reaction pathway for the formation of the products is also discussed in this paper.

Synthesis of Benzimidazoles via Iron-Catalyzed Aerobic Oxidation Reaction of Imine Derivatives with o-Phenylenediamine

A simple and efficient protocol for preparing benzimidazoles via Fe(NO3)3 · 9H2O-catalyzed aerobic oxidation reaction of imine derivatives with o-phenylenediamine. This process uses air as an economical and green oxidant, tolerates a wide range of substrates, and affords the targeted benzimidazoles in moderate to excellent yields.

Stopped-in-loop flow analysis system for successive determination of trace vanadium and iron in drinking water using their catalytic reactions☆

An automated stopped-in-loop flow analysis (SILFA) system is proposed for the successive catalytic determination of vanadium and iron. The determination of vanadium was based on the p-anisidine oxidation by potassium bromate in the presence of Tiron as an activator to form a reddish dye, which has an absorption maximum at 510nm. The selectivity of the vanadium determination was greatly improved by adding diphosphate as a masking agent of iron. For the iron determination, an iron-catalyzed oxidative reaction of p-anisidine by hydrogen peroxide with 1,10-phenanthroline as an activator to produce a reddish dye (510nm) was employed. The SILFA system consisted of two peristaltic pumps, two six-port injection valves, a four-port selection valve, a heater device, a spectrophotometric detector and a data acquisition device. One six-port injection valve was used for the isolation of a mixed solution of standard/sample and reagent to promote each catalytic reaction, and another six-port injection valve was used for switching the reagent for vanadium or iron to achieve selective determination of each analyte. The above mentioned four-port selection valve was used to select standard solutions or sample. These three valves and the two peristaltic pumps were controlled by a built-in programmable logic controller in a touchscreen controller. The obtained results showed that the proposed SILFA monitoring system constituted an effective approach for the selective determination of vanadium and iron. The limits of detection, 0.052 and 0.55µgL−1, were obtained for vanadium and iron, respectively. The proposed system was successfully applied to drinking water samples without any preconcentration procedures.

Advanced Stopped-in-Loop Flow Analysis with a Reagents-Merging Zones Technique for a Catalytic Successive Determination of Vanadium and Iron.

An advanced stopped-in-loop flow analysis (SILFA) is proposed for the catalytic determinations of vanadium and iron. The chemistry relies on a vanadium- or iron-catalyzed oxidative reaction of p-anisidine by bromate or hydrogen peroxide in the presence of an activator (Tiron or 1,10-phenanthlorine) to form a red dye (510 nm). Reagents for the vanadium- or iron-catalyzed reaction are well mixed by a reagents-merging zones technique. A sample solution is loaded together with well-mixed reagents into a loop in the SILFA configuration, followed by spectrophotometric detection. The advanced SILFA system provides a selective method for the trace determination of vanadium and iron.

Iron-catalyzed cross-dehydrogenative coupling esterification of unactive C(sp3)-H bonds with carboxylic acids for the synthesis of α-acyloxy ethers.

An iron-catalyzed oxidative esterification reaction between unactivated C(sp(3))-H bonds from symmetric and asymmetric ethers and carboxylic acids using di-tert-butyl peroxide (DTBP) as the oxidant via a cross dehydrogenative coupling (CDC) reaction was established, which tolerates a wide range of cyclic ether substrates to react with aromatic acids and phenylacetic acid, providing an efficient method for the preparation of α-acyloxy ethers with good to excellent yields. Intermolecular competing kinetic isotope effect (KIE) experiments were also carried out, which indicate that C(sp(3))-H bond cleavage may be the rate-determining step of this CDC reaction.

ChemInform Abstract: Iron‐Catalyzed Oxidative Cross‐Coupling of Phenols and Alkenes.

A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method enables the direct coupling of phenols with styrene, α-alkyl- and α-arylstyrenes, β-alkyl styrenes, and stilbenes, thereby providing a new strategy for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of conditions an oxidative/addition dearomatization reaction of 1,1′-bi-2-naphthol (BINOL) with styrene can take place.

Iron-Catalyzed Oxidative Cross-Coupling of Phenols and Alkenes

A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method enables the direct coupling of phenols with styrene, α-alkyl- and α-arylstyrenes, β-alkyl styrenes, and stilbenes, thereby providing a new strategy for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of conditions an oxidative/addition dearomatization reaction of 1,1'-bi-2-naphthol (BINOL) with styrene can take place.

Iron-Catalyzed Oxidative Tandem Reactions with TEMPO Oxoammonium Salts: Synthesis of Dihydroquinazolines and Quinolines

A straightforward iron-catalyzed divergent oxidative tandem synthesis of dihydroquinazolines and quinolines from N-alkylanilines using a TEMPO oxoammonium salt as a mild and nontoxic oxidant has been developed. Fe(OTf)2 was the Lewis acid catalyst of choice for the formation of dihydroquinazolines, whereas FeCl3 led to better results for the synthesis of quinolines. This divergent approach implies that, for both syntheses, direct oxidative functionalization of a α-C(sp(3))-H bond of the N-alkylanilines occurs, leading to C-N bond formation or C-C bond formation upon homocondensation or reaction with simple olefins, respectively. Cyclization followed by a final oxidation generates these classes of interesting bioactive heterocycles in one synthetic transformation. Additionally, the one-pot multicomponent synthesis of quinolines from anilines, aldehydes, and olefins has also been successfully developed under these mild oxidative conditions.

Synthesis of substituted quinolines by iron-catalyzed oxidative coupling reactions

A simple and efficient method has been developed for the synthesis of quinoline derivatives from N-alkyl anilines and alkynes or alkenes by iron-catalyzed oxidative coupling reactions. A variety of substituted quinolines are prepared in good to excellent yields.

Iron-Catalyzed Oxidation of Tertiary Amines: Synthesis of β-1,3-Dicarbonyl Aldehydes by Three-Component C–C Couplings

β-1,3-Dicarbonyl aldehydes were synthesized by iron-catalyzed oxidative reactions between 1,3-dicarbonyl compounds and two molecules of tertiary amines in the presence of tert-butyl hydroperoxide (TBHP). α,β-Unsaturated aldehydes generated by tertiary amine oxidation in situ act as key intermediates under mild reaction conditions.

Antioxidant Treatment Attenuates Intestinal Mucosal Damage and Gut Barrier Dysfunction After Major Hepatectomy. Study in a Porcine Model

BackgroundThis study aims to evaluate whether injury of gut mucosa in a porcine model of post-hepatectomy liver dysfunction can be prevented using antioxidant treatment with desferrioxamine. MethodsPost-hepatectomy liver failure was induced in pigs combining major (70%) liver resection and ischemia/reperfusion injury. An ischemic period of 150 minutes, was followed by reperfusion for 24 h. Animals were randomly divided into a control group (n = 6) and a desferrioxamine group (DFX, n = 6). DFX animals were treated with continuous IV infusion of desferrioxamine 100 mg/kg. Intestinal mucosal injury (IMI), bacterial and endotoxin translocation (BT) were evaluated in all animals. Intestinal mucosa was also evaluated for oxidative markers. ResultsDFX animals had significantly lower IMI score (3.3±1.2 vs. 1.8 ± 0.9, p < 0.05), decreased BT in the portal circulation at 0 and 12 h of reperfusion (p = 0.007 and p = 0.008, respectively), decreased portal endotoxin levels at 6 (p = 0.006) and 24 h (p = 0.004), decreased systemic endotoxin levels (p = 0.01) at 24 h compared to controls. Also, 24 h post-reperfusion mucosal malondialdehyde and protein carbonyls were decreased in DFX animals compared to controls (4.1±1.2 vs. 2.5 ± 1.2, p = 0.05 and 0.5±0.1 vs. 0.4 ± 0.1, p = 0.04 respectively). ConclusionDesferrioxamine seems to attenuate mucosal injury from post-hepatectomy liver dysfunction possibly through blockage of iron-catalyzed oxidative reactions.

Iron-Catalyzed N-Alkylation of Azoles via Oxidation of C−H Bond Adjacent to an Oxygen Atom

Azole derivatives were synthesized by iron-catalyzed oxidative reactions of azoles and ethers in good to excellent yields. A wide variety of azoles and ethers were selectively transformed into the corresponding oxidative coupling products under neutral reaction conditions.