Aliphatic Carboxylic Acids Research Articles

Decarboxylative Nucleophilic Fluorination of Aliphatic Carboxylic Acids.

Herein, we present a decarboxylative nucleophilic fluorination of carboxylic acids with a silver catalyst. This strategy enables the synthesis of a myriad of diverse and valuable fluorinated motifs under mild conditions, demonstrating good functional-group tolerance and utility in late-stage functionalization. In contrast to traditional electrophilic fluorination, this nucleophilic method utilizes a more readily available nucleophilic fluorinating reagent, providing substantial advantages in terms of cost efficiency, broad substrate scope, and functional-group compatibility.

A General Iron-Catalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids.

We report an iron-catalyzed decarboxylative C(sp3)-O bond-forming reaction under mild, base-free conditions with visible light irradiation. The transformation uses readily available and structurally diverse carboxylic acids, iron photocatalyst, and 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) derivatives as oxygenation reagents. The process exhibits a broad scope in acids possessing a wide range of stereoelectronic properties and functional groups. The developed reaction was applied to late-stage oxygenation of a series of bio-active molecules. The reaction leverages the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids by photoinduced carboxylate-to-iron charge transfer. Kinetic, electrochemical, EPR, UV-Vis, HRMS and DFT studies revealed that TEMPO has a triple role in the reaction: as an oxygenation reagent, an oxidant to turn over the Fe-catalyst, and an internal base for the carboxylic acid deprotonation. The obtained TEMPO adducts represent versatile synthetic intermediates that were further engaged in C-C and C-heteroatom bond-forming reactions using commercial organo-photocatalysts and nucleophilic reagents.

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions.

Diaryliodonium(III) salts are versatile reagents that exhibit a range of reactions, both in the presence and absence of metal catalysts. In this study, we developed efficient synthetic methods for the preparation of aryl(TMP)iodonium(III) carboxylates, by reaction of (diacetoxyiodo)arenes or iodosoarenes with 1,3,5-trimethoxybenzene in the presence of a diverse range of organocarboxylic acids. These reactions were conducted under mild conditions using the trimethoxyphenyl (TMP) group as an auxiliary, without the need for additives, excess reagents, or counterion exchange in further steps. These protocols are compatible with a wide range of substituents on (hetero)aryl iodine(III) compounds, including electron-rich, electron-poor, sterically congested, and acid-labile groups, as well as a broad range of aliphatic and aromatic carboxylic acids for the synthesis of diverse aryl(TMP)iodonium(III) carboxylates in high yields. This method allows for the hybridization of complex bioactive and fluorescent-labeled carboxylic acids with diaryliodonium(III) salts.

Aminonaphthalene and aminoquinoline photocages: meta-effect and photo-release of carboxylic acids and alcohols

Three series of compounds were tested as photocleavable protective groups (photocages), which are derivatives of 1,2-substituted aminonaphthalene 4, 1,3-substituted aminonaphthalene 5, or 5,6-substituted aminoquinolines 6. Their photophysical properties and photochemical reactivity in releasing alcohols and carboxylic acids were investigated. Moreover, mechanism of photochemical reaction was studied computationally and by transient absorption spectroscopy with time-resolution from femtoseconds to milliseconds. Photocages 4 and 5 are generally fluorescent molecules with high ΦF, whereas quinoline 6 is weekly fluorescent due to photoinduced charge transfer. Derivatives 4 release alcohol with low quantum yield (release of methanol from 4d is ΦR = 0.00010 ± 0.00005), but upon prolonged irradiation can be applied in organic synthesis to deprotect both aliphatic and aromatic alcohols. On the contrary, photocages 5 undergo relatively efficient release of carboxylic acids, (release of acetic acid from 5b is ΦR = 0.22 ± 0.01), in accord with the meta-effect in photochemistry, which is our main discovery that is based on the rational design of the chromophore. The photochemical reaction mechanism involves homolytic cleavage on the singlet excited state surface and formation of radicals which were detected by transient spectroscopy. The meta-effect did not promote the heterolytic cleavage as it was the case with aniline chromophores. The subsequent electron transfer delivers naphthalenmethyl carbocation and released carboxylates. The applicability of photocages 5 in organic synthesis was demonstrated on aliphatic and aromatic carboxylic acids. The potential use in biology was suggested due to their very weak photoinduced antiproliferative effect, which was essayed on three human cancer cell lines (MCF-7 breast carcinoma, HCT 116 colon carcinoma, and H460 lung carcinoma).

Manganese Oxide / Silica catalysed Decarboxylative Ketonization of Aliphatic Carboxylic Acids in a Continuous Flow Reactor.

The sustainable synthesis of long carbon chain molecules from carbon dioxide, water and electricity relies on the development of waste-free, highly selective C-C bond forming reactions. An example for such a power-to-chemicals process is the industrial-scale fermentation for the production of hexanoic acid. Herein, we describe how this product is transformed into 6-undecanone via decarboxylative ketonization using a heterogeneous manganese oxide / silica catalyst. The reaction reaches full conversion with near-complete selectivity when carried out in a continuous flow reactor, requires no solvent or carrier gas, and releases carbon dioxide and water as the only by-products. The reactor was operated for several weeks with no loss of reactivity, producing 7 kg of 6-undecanone from 10 g of catalyst and achieving a productivity of 1.135 kg per litre of reactor volume per hour. 6-Undecanone and other long-chain ketones accessible this way can be hydrogenated to industrially meaningful alkanes, or converted into valuable fatty acids via a hydrogenation / elimination / isomerizing hydrocarboxylation sequence.

Three 3D Supramolecular Organic Salts Assembled from Melamine and Aliphatic Carboxylic Acids: Preparation, Crystallographic Characterization, and Hirshfeld Surface Analysis

Three 3D Supramolecular Organic Salts Assembled from Melamine and Aliphatic Carboxylic Acids: Preparation, Crystallographic Characterization, and Hirshfeld Surface Analysis

SO2F2‐Mediated Thioesterification of Carboxylic Acids with Thiols

The generation of thioesters through thioesterification of carboxylic acid has significant synthetic value given the easy availability of various carboxylic acids and the extensive application of thioesters. An economical and rapid thioester synthesis approach is still needed. Herein, we achieved thioesterification of carboxylic acids with valuable glycosyl thiol, aromatic and aliphatic thiols mediated by sulfonyl fluoride (SO2F2). The compatibility of numerous carboxylic acid substrates was tested, including (hetero)aromatic and aliphatic carboxylic acids and the reaction proceeded smoothly under mild conditions at good yields. Late‐stage modification of drug molecules rac‐Naproxen and Loxoprofen proved feasible. Besides, the gram‐scale reaction demonstrated the utility of this protocol.

Use of Aliphatic Carboxylic Acid Derivatives for NHC/Photoredox-Catalyzed meta-Selective Acylation of Electron-Rich Arenes

AbstractWe describe the use of acyl imidazoles derived from aliphatic carboxylic acids for the N-heterocyclic carbene/organic photoredox co-catalyzed meta-selective functionalization of electron-rich arenes. Compared to our previous work, a change of the wavelength of the applied LED light from 440 nm to 390 nm promotes this reaction efficiently.

Insight into structure features of coals with different metamorphic degrees via step-wise oxidation

A step-wise oxidation method, combining H2O2 oxidation and alkali-oxygen oxidation (AOO), was applied to study the structure features of coals with different metamorphic degrees. The results show that the conversion of Baiyinhua coal, Hongshaquan coal, Pingshuo coal and Hongliulin coal in 30 % H2O2 solution for 10 h at 60 °C are 89.8 wt%, 79.0 wt%, 29.5 wt%, and 14.8 wt%, respectively. The oxygen containing species retrieved from water-soluble product by ethyl acetate extraction are mainly concentrated in O4-O8 class species, including aliphatic carboxylic acids with a carboxylic range of 1–5 and carbon numbers from 3 to 11, and phenols or aromatic carboxylic acids of 1–3 ring. The residues from H2O2 oxidation of four coals can be completely depolymerized through AOO. The maximum benzene carboxylic acid (BCA) yield of RBYH is 7.66 wt%, while that of RHSQ, RPS, and RHLL are 18.24 wt%, 19.52 wt%, and 19.91 wt%, respectively. The AOO products of four residues show the similar BCA distributions, and mellitic acid, benzenepentacarboxylic acid, pyromellitic acid, trimellitic acid, hemimelitic acid, and phthalic acid are the main BCAs. Therefore, step-wise oxidation can be used as an effective method to understand the structural features of coal, including the small molecule structures obtained after breaking weak bonds and the aromatic substitution information in the residue.

O-Trifluoromethylation of Carboxylic Acids via the Formation and Activation of Acyloxy(phenyl)trifluoromethyl-λ3-Iodanes.

Here we report the challenging O-trifluoromethylation of carboxylic acids via the formation and activation of acyloxy(phenyl)trifluoromethyl-λ3-iodanes. The method provides an easy access to various potentially valuable and hitherto elusive trifluoromethyl carboxylic esters. A remarkably wide range of substrates with commonly encountered functional groups are compatible with this reaction, including aromatic and aliphatic carboxylic acids, as well as Food and Drug Administration (FDA) approved drugs and pharmaceutically relevant molecules. The reaction mechanism and the origins of the enhanced reactivity by zinc chloride (ZnCl2) were discussed from experimental evidence and density functional theory (DFT) calculation.

O‐Trifluoromethylation of Carboxylic Acids via the Formation and Activation of Acyloxy(phenyl)trifluoromethyl‐λ3‐Iodanes

AbstractHere we report the challenging O‐trifluoromethylation of carboxylic acids via the formation and activation of acyloxy(phenyl)trifluoromethyl‐λ3‐iodanes. The method provides an easy access to various potentially valuable and hitherto elusive trifluoromethyl carboxylic esters. A remarkably wide range of substrates with commonly encountered functional groups are compatible with this reaction, including aromatic and aliphatic carboxylic acids, as well as Food and Drug Administration (FDA) approved drugs and pharmaceutically relevant molecules. The reaction mechanism and the origins of the enhanced reactivity by zinc chloride (ZnCl2) were discussed from experimental evidence and density functional theory (DFT) calculation.

Increased oxidative stress in shoe industry workers with low-level exposure to a mixture of volatile organic compounds.

This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O2 •-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidant-antioxidant balance (PAB), oxidative stress index (OSI), superoxide dismutase (SOD) and paraoxonase-1 (PON1) enzyme activity, total SH group content (SHG), and total antioxidant status (TAS). Trace metal levels (copper, zinc, iron, magnesium, and manganese) were analysed in whole blood. All oxidative stress and antioxidative defence parameters were higher in the exposed workers than controls, except for PON1 activity. Higher Fe, Mg, and Zn, and lower Cu were observed in the exposed vs control men, while the exposed women had higher Fe and lower Mg, Zn, and Cu than their controls. Our findings confirm that combined exposure to a mixture of VOCs, even at permitted levels, may result in additive or synergistic adverse health effects and related disorders. This raises concern about current risk assessments, which mainly rely on the effects of individual chemicals, and calls for risk assessment approaches that can explain combined exposure to multiple chemicals.

Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats).

Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (ft ,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo ft ,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

Synthesis of Chiral Vicinal Amino Alcohol Derivatives via Lewis Acid‐Catalyzed Asymmetric Ring Opening of Aziridines with Alcohols and Carboxylic Acids

AbstractUnder the catalysis of a Cu(I) or Ag(I) salt with a chiral diphosphine ligand, the enantioselective nucleophilic ring opening of racemic 2‐styrenylaziridines via kinetic resolution or dynamic kinetic asymmetric transformation (DyKAT) and of meso aziridines via desymmetrization with alcohols was realized. The reaction provided a range of chiral vicinal amino ether derivatives in 47%‐98% yields and with 50%–98% ee. The reaction could be extended to aliphatic carboxylic acids as nucleophiles. The synthetic utility was demonstrated in a four‐step formal synthesis of a diastereomer of the antirythmetic agent vernakalant.

Ag-Catalyzed Practical Synthesis of N-Acyl Anthranilic Acids from Anthranils and Carboxylic Acids.

A practical synthesis of valuable N-acyl anthranilic acids has been achieved via a silver-catalyzed imino-ketene generation from readily available anthranils and carboxylic acids. A wide range of carboxylic acids including sterically demanding aliphatic carboxylic acids, aromatic carboxylic acids, acrylic acids, and amino acids are compatible in this reaction. Moreover, this method can be used to modify drug molecules and natural products, such as ibuprofen, probenecid, and acetylglycine.

Secondary Metabolite Profiling of the Endophytic Fungus Trichoderma longibrachiatum L2D2 Isolated from Anaphalis contorta

In the last few decades, research on endophytic fungi has been increasing due to its applications in agriculture, medicine, and the pharmaceutical industry. Many studies indicate that fungal endophytes produce various types of bioactive compounds. In this study, the endophytic fungus Trichoderma longibrachiatum L2D2 was isolated from the leaf of the medicinal plant Anaphalis contorta and secondary metabolites were collected. The crude extract was analyzed for the presence of seven phytochemicals, and it was observed that alkaloids, flavonoids, phenolics, steroids, tannins, and terpenoids were produced. It was also found that the endophyte extract had a total flavonoid content of 126.07 (µg of quercetin equivalent/mg) and a total phenolic content of 43.97 (µg of gallic acid equivalent/mg). The Gas Chromatography–Mass Spectrometry (GC-MS) analysis reveals the presence of the major compound Dithiooxamide, which has a retention time (RT) of 50.030%, and the Liquid Chromatography–Mass Spectrometry (LC-MS) study shows the most abundant compounds as Hexanal (RT of 3.687 min) in positive ionization and Rosamultin (RT of 24.387 min) in negative ionization. Fourier-Transform Infrared (FTIR) Spectroscopy analysis also shows the presence of alcohol, aldehyde, aliphatic ether, aliphatic primary amine, alkene, alkyl halide, amine, aromatic amine, aromatic compound, carboxylic acid, ketone, phenol, and sulfoxide as functional groups. Further studies, like the purification of bioactive compounds and their biological activities, will reveal the applicability of T. longibrachiatum L2D2 in industries.

Electrocatalytic Asymmetric Nozaki-Hiyama-Kishi Decarboxylative Coupling: Scope, Applications, and Mechanism.

The first general enantioselective alkyl-Nozaki-Hiyama-Kishi (NHK) coupling reactions are disclosed herein by employing a Cr-electrocatalytic decarboxylative approach. Using easily accessible aliphatic carboxylic acids (via redox-active esters) as alkyl nucleophile synthons, in combination with aldehydes and enabling additives, chiral secondary alcohols are produced in a good yield with high enantioselectivity under mild reductive electrolysis. This reaction, which cannot be mimicked using stoichiometric metal or organic reductants, tolerates a broad range of functional groups and is successfully applied to dramatically simplify the synthesis of multiple medicinally relevant structures and natural products. Mechanistic studies revealed that this asymmetric alkyl e-NHK reaction was enabled by using catalytic tetrakis(dimethylamino)ethylene, which acts as a key reductive mediator to mediate the electroreduction of the CrIII/chiral ligand complex.

Visible‐Light‐Mediated Synthesis of Aryl Ketones and Aldehydes from N‐(acyloxy)phthalimides Esters

AbstractA visible‐light‐mediated decarboxylative oxidation of benzylic redox active esters is described. A diverse array of aromatic ketones or aldehydes could be achieved (15 examples) from secondary or primary aliphatic carboxylic acids. A mechanism involving resonance transformation in the presence of Cs2CO3 is proposed.

Photoinduced Decarboxylative Radical Phosphinylation.

Reported herein is an unprecedented protocol for C(sp3 )-phosphinylation. With 1 mol % 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene) as the catalyst, the visible light induced reaction of redox-active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional-group compatibility, enabling the late-stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical-polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.

Photoinduced Decarboxylative Radical Phosphinylation

AbstractReported herein is an unprecedented protocol for C(sp3)‐phosphinylation. With 1 mol % 4CzIPN (1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene) as the catalyst, the visible light induced reaction of redox‐active esters of aliphatic carboxylic acids with dimethyl arylphosphonites or diethyl alkylphosphonites at room temperature provides the corresponding decarboxylative phosphinylation products in satisfactory yields. The protocol exhibits broad substrate scope and wide functional‐group compatibility, enabling the late‐stage modification of complex molecules and rapid synthesis of bioactive phosphinic acids such as glutamine synthetase phosphinothricin and a kynureninase inhibitor. A radical‐polar crossover mechanism involving the formation and subsequent oxidation of phosphoranyl radicals followed by nucleophilic demethylation (or deethylation) is proposed.